Chemistry of Hetero Aromatics

NHAc

R2 O

R1

SPh

C

R2

SPh

NHAcR1

∆

O

NAcR1

R2

CH2

Section 1-Chemistry of Heteroaromatics

SPh

O2,3-shift

BF3.OEt2

NEt3O

O O

HHO

OCH2Ph PhCH2O

NN

N

X

CN

Ph

Ph N

N

X

Ph

Ph

Literature of Heterocyclic Chemistry

1. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1984, Pergamon, Vol. 1-8

2. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1996, Pergamon, Vol. 1-11

3. "The Chemistry of Heterocyclic Compounds," Weissberger/Taylor, >50 volumes.

4. "Advances in Heterocyclic Chemistry," Katritzky/Boulton, (Vol. 40, p. 1 has review by Katritzky which lists heterocyclic reviews)._____________________________________________________________

Nomenclature of Heterocycles

1. "Nomenclature of Heterocycles" by McNaught/Smith in "Comprehensive Heterocyclic Chem." 1984, Vol. 1, Chap. 2.

2. "Revision of the Extended Hantzsch-Widman System of Nomenclature for Heteromonocycles," Pure Appl. Chem. 1983, 55, 409 [IUPAC].

3. McNaught, in Adv. Heterocycl. Chem. 1976, 20, 175.

4. "Nomenclature of Organic Chemistry" (IUPAC) (The "Blue Book") Pergamon, 1979. Has heterocyclic section.

5. Chemical Abstract Service, "Index Guide" 1982-1986; Appendix IV "Chemical Substance Index Names" •includes heterocycles • generally same as IUPAC, but many exceptions

6. Chemical Abstract service, "Ring Index"

Section one - Chemistry of Heteroaromatics

1

HN

N

N N

N

N

N

NN

O

HN

S

ON

N

N

N

N

N NN

N

N

O

SN

HN

O

N N N

1

3

Pyrazole Pyridine Pyrazine Pyrimidine

O

Pyridazine

O

S

Pyrrole

Furan

N

Thiophene

Isoxazole

HN

N

Quinoline

N

Quinoxaline

Quinazoline

NHN

Cinnoline

Phthalazine

HN

N

Isobenzofuran

Isothiazole

HN

NN

N

Indole

Accepted Trivial Names (partial list)

Pyran(2H-shown)

N

Chromene(2H-shown)

Xanthene

N

N N

N

Phenoxathiin

2H-Pyrrole Imidazole

N

Indolizine

NN

3H-Indole

N

1H-IndazoleIsoindole Purine

N

4H-Quinolizine

NN

N

Isoquinoline Naphthyridine (1,8-shown)

NN

4aH-carbazole CarbazolePteridine

N

N

β-Carboline

S

N

Phenanthridine Acridine Perimidine

ONN

Phenanthroline (1,7-shown)

Phenazine

O

Furazan

H

1

2

8

2

1

27 1

2

H

1

2

1

9 1 9810 11

2

12

12

1

2

1

2

H

1

2

3

1 1 1 1 1 11

22

22 2 2

3

8

4 3

7

3 3 34

7

4

56

7

8

9

1

4

9

5

8 12

3

8 1

2

8 1

2

3

8 1 8 1

4

8 8 1

2

8 1

35

8 9 1

4a

89

1

89

1

4

10

1

4

56

8 9 1

5

10

4

1 3

4

6

7

9

1

104

5

6

7

9 10 1

45

1

2

1

4

10

5

1

2

1

62

Phenothiazine

12

5


2

Eproxindine--Antiarrhythmic agent

S

Manazodil--Vasodilator

NH

N

Vibunazole--Antiviral agent

Methdilazine--Antihistamine

Clopidogrel--Antithrombotic agent

C

N

N

N

NHNH2

NHNH2

N

NN

Me

MeO

N CONHCH2CH(OH)CH2NEt2

Ph

OMe

S

N

Me

MeNHCH2

S

NH2C

Dihydralazine--Antihypertensive agent

N

H

H

NCH2CH=CHPh

Elks, J.; Ganellin, C. R. Dictionary of Drugs, Chapman and Hall, 1990, N.Y.

Cinprazole--Antiulcerogenic agent

N

NN

CH2 C

tBu

OH

CH2 ClO

Epirizole--Antiflammatory agent

Dictionary of Drugs

Me

OMe

CO2Me

Cl

NMe


3

Lednicer, D.; Mitscher, L. A.; The Organic Chemistry of Drug Synthesis Wiley-Interscience: New York; Vols 1-4, 1990

S

Cl

F

NH2 Cl

F

N

CO2EtEtO2C

Cl

F

N

OHCO2Et

Cl

F

N

OCO2Et

Et

N

F

N

OCO2H

Me2NCH2CNH2

Et

+

N

BrCH2COCO2Et

Me

Pefloxacin--antimicrobial agent with oral activity

NBr Br NBr

O

MeNBr

Me

N

NCHO

Me

N

N

Me

N

HO2C

Nizatidine--antagonist of histamine at H-2 receptors

Acrivastine--a nonsedating H-1 antihistamine

N

SMe2NCH2

CO2Et

N

SMe2NCH2

CH2S(CH2)2NH2N

SMe2NCH2

CH2S(CH2)2

MeHN

HN H

NO2


4

CH3

N

ONH

SThiophene

2. Extended Hantzsch-Widman Nomenclature

FuranPyrrole

1. Trivial Names

No structural information, often based on origin.

3-Picoline (from coal tar) Latin picatas = tarry

(systematic name = 3-methylpyridine)

Currently over 60 trivial names accepted by IUPAC for use as "parents" in systematic nomenclature. (See McNaught/Smith for full list.)

Examples:

use for less than10-membered rings

stem and prefix

N = aza-

P = phospha-

O = oxa-indicates ringsize and degreeof unsaturation. S = thia-

indicates which heteroatoms are present

B C N O

drop "a" ending whenfollowed by a vowel.

P S

F

Cl

Br

highest

lowest

Priority of heteroatomsfor numbering purposes:

Se(i.e., O > S > N > P)


5

OO H

NHN

NH

HN

N

HN

3

NH

HN

3 3

Isochroman

H

These compounds remain as trivial names but are not recommended for use in fusion.

HN

NH

PyrrolidineChroman Pyrroline

Imidazolidine

HN

Imidazoline (∆2 shown)

Pyrazolidine

NH

HN

Pyrazoline(∆3 shown)

Piperidine Piperazine Indoline

HN

Isoindoline

Quinuclidine

NH

Morpholine

O

NNH

8 1

2

4

8 1

4

51

21

2

3

2

1 1

2

12

3

12

3

1

4

71

3

7 1

8

43

216

5

7 1

4

2

2

1


6

NHN

O O

Ring Size Maximum Unsaturation

HN

(e.g.) Fully Saturated

(e.g.)

O

3 -irine(N only)

-iridine(N only)

Aziridine

N

Stems: (see McNaught/Smith for full discussion)

Azirine

-irene(O,S,...)

-irane(O,S,...)

4 -ete

Azete

Oxirene Oxirane

Azetidine

-etane(O,S,...)

Oxetane

5

NH

-ole*

Oxazole

-olidine*(N only)

N

N

N

Thiazolidine

-olane*(O,S,...)

1,3-dioxolane

O

N

-etidine(N only)

6

SHN

OO

-ine*

*Exception

HN NH

HN

1,2,3-Triazine

Does notoverrideacceptedtrivialnames

Pyrrole,not "azole"

-ane(N only)

1,2,3-Triazane

-inane(O,S,...)

-epineHN

Azepine

7O-epane

Oxepane

8 910

-ocine-onine-ecine

-ocane-onane-ecane


7

N

Indicated Hydrogen

HN

-- To locate hydrogen (or a substituent) when fullyunsaturated but a "saturated" atom present

O

•Use H prefix (pronounce the letter "H")

italicized

N

•The saturated position takes priority in numbering

e.g.

HN

2H-azirine (not 3H )

1H-azirine

4H-pyran2H-pyrrole (not 5H )

NHN S

1H-pyrrole(often leave out the 1H-)

Partial Unsaturation

•Use fully unsaturated name with dihydro, tetrahydro, etc.

•Alternative: Trivial names are sometimes still used.

N

2,3-dihydro-1,2,5-thiadiazole(Note numbering toward saturated atom)

"1-pyrroline", "∆1-pyrroline"(Better: 3,4-dihydro-2H-pyrrole)

1

23

1

2

3

4 1

2

34

5

1

34 2

5


8

N

NN

N N

N

Fused Rings ("Fusion names")•CAS Ring Index useful

•If there is an accepted trivial name for a fused compound, you should use it.

HNN

Quinoline

e.g.Otherwise, use fusion name.

•Regard common atoms as belonging to both systems:

regard

as

Pyrimidine

and

Imidazole

Step 1. Choose one component as "base component."

pyrrole

imidazole

pyrrolo-

imidazo - (not imidazolo-)

Step 3. Label "faces" of base component

see "HeterocyclicChemistry" 2nd ed.by T. L. Gilchrist forgood flowchart -pp 376-377

a. N-rings have priorityb. If no N, choose ring with highest priority atomc. Choose system with greatest # of ringsd. Start with larger ring sizee. Choose ring with most heteroatoms

HNN

In our example, pyrimidine is base component.

Step 2. Other component named as prefix by changing ending:

1 2

3

N

N

4

5Step 4. Number second component

a

fe

d

c

b

Step 5. Combine: NN

Nimidazo[1,5-a]pyrimidine

italics

Step 6. Number the new ring system (not easy)


9

As

Replacement Nomenclature

•Use carbocyclic nomenclature with hetero prefixes.•Most systematic, but not widely used except for (a) heterocycles containing unusual atoms (b) >10-membered rings, and (c) bridged- and spirocyclic systems.

arsabenzene

7-oxabicyclo[2.2.1]hepta-2,5-diene

1 2

O

3

O

5

O

4

6

7

1,6-dioxaspiro[4.5]decane1

2

34

567

8 9 10

(von Baeyer names used for bridged-bicyclics)

AROMATIC HETEROCYCLES

"π-Excessive"

X

"π-Deficient"

X

X=N, P, As, Sb, O , SX=NH, PH, AsH, SbH, O, S, etc;

General Aspects


10

N

N N H

NR H

RR

Basic lone pair in plane of ring

Perpendicular toπ-system, not involvedin aromaticity

H+

pKa = 5.2

still aromatic (about like an imine)

N N H

c.f. Me3N_H

9.8 ( sp3)

~5(sp2)

~0(sp)

R_C≡N_H

>1 heteroatom: Greatly decreased basicity due to electronegativity

N

pKa = 0.4

π-Nucleophilicity decreased vs

slower than

El

π-Electrophilicity increased vs

El

NNuc much faster than

π-Deficient Heteroaromatics

Nuc

H

Basic compounds

..


11

N

N

CH3

N

CH3

HH

N

CH3

N

CH3

H

H

H

H

N

N

OCH3

Si(iPr)3

Ph

O Cl

O

N

OCH3

Si(iPr)3

OR*O

OEE

MgBr

CH3I

N

OR*O

HO

NaBH4

H2O, 15oC pH >7

NaBH4

Si(iPr)3

No reaction

N

1-methylpyridinium

H

OH

NaBH4pH 2-5

H+

Cl

1.

2. H3O

(-)-elaeokanine C

OO

CominsJACS, 1991, 113, 6672

CH3


12

N O

N

N O

N

Li

N N

El

Electrophilic attack at N much faster than attack at carbon

El

13

Deprotonation at ring C-H generally requires activating group

nBuLi

H , Lewis acids (e.g., BF3),alkyl halides (primary iodidesand triflates), and acylating agents

N H N

H H

HH

Electrophiles:

N

H

HH

π-Excessive Heteroaromatics

Basicity

N

1 heteroatom: Poor base - no basic lone pair

HH

1 heteroatom: May be basic - has basic lone pair

N

H

lone pair used in aromaticity, not available for protonation

C-3

H

H

C-2

Nonaromaticpka ~ -5.9

N-protonation

Nonaromaticpka ~ -3.8

Nonaromaticpka ~ -10

Pyrrole is a verypoor base. Whenprotonation isforced, C-2 ispreferred.

H


:

>

..

NH

O

XX

H

El

X

HEl

X

El

X XEl

H

El

H

Calculated π-electron densities:

1.2

X

1.067

H

El

1.078

1.710

X

1.090

1.647

El

1.087

X

1.000

Regioselectivity

X

El

El

H

C-3

-H+

minor

major

X

Preferred for X=NH, NR, S

Preferred for X=O

H

El

Still aromatic

vs.

Aromaticity disrupted

-

ElC-2


14

N N O

NR

NH O

H

R

HHOO

RNH2

N NH2

H

OHH

OO

O

XX

O

OMeMeO

O

ClClN

NN

N

O

XR

Cl

O

XX

O

O

RR

O

R R

O O

Synthesis of Heteroaromatics

General

Look for these fragments in target heterocycle

R R

O


15

O

R

O

R

RHN NHR

X

enamine

enamine

R NHR

X

;

imine

;

O

•Typically, condense bis-nucleophile with bis-electrophile

RNH E X E

1,5-dicarbonylcompound

bis-nucleophiles

1,1:

1,2:

1,3:

1,1: H2O, NH3, H2S

1,2: RNH-NH2, RNH-OH

1,3:

enamine1,4-dicarbonyl

compound

;

;

;

;

;

;

;

;

;

NH3

bis-electrophiles

•Many methods rely on carbonyl chemistry

•Analogies: We know how to make:

XY

XY

XY

X Y X Y

A Classical Method to Prepare Heteroaromatic Ring Systems1Electrophile-Nucleophile Interactions

X

A

O O

A

B

Cyclization Reactions for Heterocyclic Synthesis

O

O

X

OX

XA

Y

HO

X

B

Z

sp3 X: exo-tet

Z

XH

HO O

sp2 X: exo-trig

Z

sp2 Y: endo-trig

X

HO

H

OH

H

Z

X

H H

X

Y

HH

Y

A

H H

Y

X

H H

Z

sp X: exo-dig

H H

sp Y: endo-dig

Aldol-Type Condensations

Synthesis of Five Ring Heteroaromatics Using General Routes

XH2H2

H

H

- 2 H2O

Types of nucleophile-electrophile cyclizations

or B

Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734


16

O R4

R3

R1

R2

R3R2

R1 R4

OO

R1

O

ClR2

O

OR1R2

COOR3

CH2COOR3

OR1

R2CH2Br

Br COOEt R1

O

R2

CH2COOEt

Ten Top Methods to Synthesize Furans

N

O

1. Cyclization of 1,4-Diketones and Related Compounds (Paal Knorr Reaction)

O

+

O

Base

H+

R2

Obrecht, D. Helvetica Chimica Acta 1989, 72, 447.

+ R4 R5

To a stirred solution of sodium ethoxide, prepared from sodium (2.1 g, 0.092 mol) metal in ethanol (150 mL) isadded the methylene compound (1.0 mol) at –5 °C. The solution turns yellow and, after several min, a solution ofthe chloroketone (10 g, 0.037 mol) in ethanol (15 mL) is added. Stirring is continued for 24 h at 25 °C. The mixture is neutralized by addition of 10% aqueous HCl, the solvent is removed under reduced pressure, water (50 mL) isadded to the residue, the mixture is extracted with ether, and the product is purified by column chromatographyon silica gel.

3. Ring Transformation of Oxazoles

R5 R4

Feist, F. Ber. 1902, 35, 1545. Benary, E. ibid. 1911, 44, 493.

Base

R3R1 R1R3

2. Base Catalyzed Reaction of ββββ-Ketoesters with αααα-Haloketones

To a stirred solution of 10.0 mmol of the acetylenic acetal in toluene (30 mL) was added a 2 N aqueous HClsolution (10 mL) at room temperature. The mixture was stirred at room temperature, diluted with Et2O (100 mL)and poured onto ice (50 g). The aqueous phase was extracted with Et2O (100 mL), the combined organic fractions were washed with brine (50 mL) and the solvent was removed. The residue was chromatographed on SiO2 (80g)and distilled under reduced pressure.

+

Moubarak, I.; Vessiere, R. Synthesis 1980, 52-53.

∆

Hutton, J.; Potts, B. and Southern, P.F. Synth. Commun. 1979, 9, 789-797.

A mixture of oxazole (14.5 g, 10 mmol) and bis-trimethylsilylbuta-1,3-diyne (19.4 g, 10 mmol) was heated in asealed tube at 210°C for 16 h. The crude reaction mixture was distilled and then chromatographed on silica gel using hexane as the eluent to give 22.6 g of the product in 95% yield.


17

(Feist Benary Reaction)

OR1

R4R5

CSMe2

R2R4CH2COR1

H

R3

R1

R2

R3

O

O

R1

R2

R3

O

O

CH2

R1

R2

R3

O

O

CH3

OO O

A solution of the allene (10 mmol) in ethanol (110 mL) was treated with the ketone (10 mmol) and sodium ethoxide (10 mmol) in ethanol (100 mL). The mixture was heated at reflux for 4 h and the ethanol was distilled and etherwas added to the residue. Filtration and distillation of the filtrate gave the desired product.

5. Direct and Indirect Alkylation of Furan

+NaOEtEtOH

1/ 1 eq base

2/ E1+

E1E2

Batty, J.W.; Howes, P.D. and Stirling, C.J.M. J.Chem.Soc. Perkin1 1973, 65-68.Aso, M.; Ojida, A.; Yang, G.; Cha, O.J.; Osawa, E. and Kanematsu, K. J.Org.Chem. 1993, 58, 3960-3968.

(1) base

(2) E2+

E1+, E2

+ = Aryl, Alkyl, Acyl

Wong, M., K.; Leung, C., Y. and Wong, H., N., C. Tetrahedron Lett. 1997, 53, 3497.Song, Z., Z.; Ho, M., S. and Wong, H., N., C. J.Org.Chem. 1994, 59, 3917.Wong, H.,N.,C. Pure and Appl. Chem. 1996, 68, 2, 335.

H2C CSMe2

To a stirred solution of the silyl furan (1.3 g, 6 mmol) in anhydrous THF (24 mL) was added 6.5 ml of n-BuLi (1M solution in hexane) through a syringe under nitrogen. The mixture was stirred for 30 min and then benzylbromide (1.1 g, 6 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting solution wasstirred for another 30 min and was poured into Et2O (40 mL) and washed with water. The crude productobtained after evaporation of the solvent was purified by chromatography on a silica gel column (50 g, hexane) to give the desired product as a colorless oil (1.5 g, 82%).

+

4. Reaction of Allenic Sulfonium Salts and Enolate Anions of 1,3-Dicarbonyl Compounds

H

NaOEtEtOH

p-TsOH

OE1


18


19

Davies, H.M.L., Cantrell, W.R., Romines, K.R., Baum, J.S. Org. Synth. CV 9, 422.

Me OEt

N2

O OPh H

OPh Me

COOEt

6. Diazo-Promoted Furan Cyclization

A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, an addition funnel, and a refluxcondenser is flushed with argon. The reaction vessel is charged with 44 g of phenylacetylene (0.44 mol), 0.38 g ofrhodium(II) acetate dimer, and 100 mL of dichloromethane and the mixture is heated at reflux under an argonatmosphere. The addition funnel is charged with 13.5 g of ethyl diazoacetoacetate (0.087 mol) and 200 mL ofdichloromethane, and this solution is added dropwise over 1.5 h to the reaction mixture. After the reaction mixture is heated under reflux for an additional 12 h, it is cooled and the solvent is removed under reduced pressure. Thecrude product is purified by chromatography on silica gel, followed by vacuum distillation to yield 10 g (50%) of thefuran as a pale yellow liquid.

Rh(II)

R4

CR2

R1O

OH

R1

R2H R2

O

R1

O

R1

R2

7. Pd(0) Catalyzed Formation of Polysubstituted Furans

Ma, S., Zhang, J. Chem. Commun. 2000, 117.

The reaction was carried out using 1.5 equiv of the 1,2-allenyl ketone, 1.0 equiv of R3X, 5 mol % of Pd(PPh3)4, 2.0 equiv of NEt3, and 10 mol % of Ag2CO3. The reaction was heated at reflux in toluene for 13 h.

8. Furans from Acetylenes and Allyl Alcohols

Trost, B.M. and Flygare, J.A. J. Org. Chem. 1994 59 1078.

NMO (1.00 mmol) followed by osmium tetraoxide (0.008 mmol) were added to a solution of 0.84 mmol of the ketone in 4 mL of THF, 1 mL of tBuOH, and 1 mL of water at rt. After stirring for 12 h, 2.5 mmol of p-toluenesulfonyl hydratewas added and stirring was continued for 10 additional h. The reaction was quenched with 100 mg of sodium sulfiteand ether. The ether layer was washed with saturated sodium carbonate, 10% sodium bisulfate, and brine. After drying (Na2SO4) and evacuation in vacuo, the compound was chromatographed on silica gel (hexane) to give the desired product in 88% yield.

R3X

Ag2CO3, Et3N

Pd(PPh3)4

OR1

R4

R3

+R2

OsO4

CpRu(Ph3P)2Cl

20

10. New Advances in Oxo- and Thio-substituted Furans

Section One- Chemistry of Heteroaromatics

Rubin, M., Sromek, A.W., Gevorgyan, V. Synlett 2003, 15, 2265

Greico, P.A., Pogonowski, C.S., Burke, S., J. Org. Chem. 1975, 40, 543.

X = OAc, OTs, OPO(OEt)2, SAr, SR, RCOO, RO, ArO

9. Organoselenium as a Route to Furans via Butenolide Formation

A solution of DIBAL (0.5 M in THF) was added to 1.5 equiv of butenolide (0.3 M in THF). After 3 h of stirring at -20 oC, the reaction was quenched by addition of 10 % sulfuric acid and the reaction mixture was warmed to rt. Water and brineworkup followed by drying with MgSO4 yielded the desired furan in 99% yield.

X

R2R3

R1O

OR1

R2 X

R3

O

O

R1 R2

R3

SePh O

O

R1 R2

R3

O R1

R2R3

H

Copper chloride (0.05 mmol, 5 mg) was loaded into an oven-dried 3 mL microreactor in a glovebox. Anhydrous DMA (1 mL), triethylamine (0.2 mmol, 28 mL), and acyloxy alkynyl ketone (1 mmol) were successively added. The reactor was capped with a Mininert valve and then placed in a preheated aluminum block (130oC), shielded from light, and stirred from 2 to 24 h. After the reaction was complete, the microreactor was allowed to cool and the mixture was poured into 10 mL of water and thoroughly extracted with hexane. The organic layer was dried over anhydrous Na2CO3, concentrated, and chromatographed over silica gel using hexane-ethyl acetate as the eluent.

Rashatasakhon, P. Padwa, A. Org. Lett. 2003, 5 189.

Synthesis of 2-Amido Substituted Furans

To a solution of the lactam (0.5 mmol) in 5 mL of DCM at -78 oC, was added pyridine, (2.7 mmol) and then triflicanhydride. The crude reaction mixture was allowed to warm to rt over 30 min and was stirred at 25oC for an additional 10 min. Water was added and the organic layer was separated. The aqueous layer was extracted with chloroform and theorganic phase was washed with water, brine and then dried over MgSO4. The crude mixture was purified by flashchromatography on silica gel using 20% Et2O in hexane to give the desired furan in 90% yield.

Padwa, A., Crawford, K.R., Rashatasakhon, P., Rose, M. J. Org. Chem. 2003, 68, 2609.

N

O

Me

OH

R Tf2O N

TfO

MeOH

RN

TfO

Me

O

R

O NHRMe

DIBAL

+

5% AgBF4

O

Br

ORO

CH2

OR

Me

OR OOH

PTSAnBu3SnH

AIBN

NBS

Radical cyclization for furan synthesis

45 %


Srikrishna, A.; Pullaiah, K. C. Tetrahedron Lett. 1987, 5203

OOH

R1R3 R3R1

R2

R3

R1

H

H

O

OR2

R3

H

R1C

R1

HC C

R3

O

OMe

OMe

C

O

O

OMe

OMeO

OMeH

N2

PO(OEt)2

-40 °C

70-86 %

H+

-

tBuOK

-

-

Buxton, S. R.; Holm, K. H.; Skattebol, L. Tetrahedron Lett. 1987, 2167

67 %

R2

R2R2

tBuOK

Marshall, J. A.; Dubay, W. J. J. Org. Chem. 1991, 56, 1685

Isomerization of alkynyl oxiranes

21

ClC

TBDMSO O

TBDMSC

OTBDMS

TBDMS

OO

TBDMSTBDMS

O

H

I

O O

PdI

O

PdI

O O

Et PdI Et

O

BrBr

SO2Ph

O ONa

SO2Ph

BrO

H

O

PhSO2 PhSO2

O O

H

+

+

+AlCl3.

+

Pd (0)

HPdI

2) deformylation

MeONa1) addition/elimination+

Regiocontroled [3+2] annulation reactions of allenylsilanes with acylium ions

Palladium-catalyzed coupling of aryl iodides

General method for the synthesis of 2 and 3 substituted furans

-20 °C

76 %

83 %-HPdI

85 %

New Syntheses of Substituted Furans

available from propargyl alcohol

Na-Hg

Padwa, A.; Murphree, S. S. Org. Prep. and Procedures, 1991, 23, 545. Padwa, A.; Murphree, S. S.; Yeske P. E. J. Org. Chem. 1990, 55, 4241. Padwa, A.; Austin, D. J.; Ishida, M.; Muller, C. L.; Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1992, 57, 1161. Padwa, A.; Ishida, M.; Muller, C.L.; Murphree, S. S. J. Org. Chem. 1992,57, 1170

Larock, R. C.; Stinn, D. E.Tetrahedron Lett. 1988, 4687

Danheiser, R. L.; Stoner, E.; Koyama, H.; Yamashita, D;. Klade, C. A. J. Am. Chem. Soc. 1989,111, 4407


22

NR1 R2

R3

R1 R2O O

R2 CH2X

O

R3 R4

O O R3 R4

R2

OO

N R2R4

R3

O

R1O

R2 H

O

R4

OR3

2. n-BuLi

R2

O

O

R4

R3

N

R3

R4R2

R1

+

N

R2

R3EtOOC

R1

I. Paal-Knorr Method

Ten Top Methods to Synthesize Pyrroles

R1NH2

EtO

ONO2

R3

O

R2

•••• Reaction of αααα-Haloketones with the Anion of ββββ–Dicarbonyl Compounds

A mixture consisting of a 40% solution of methylamine in 100 mL of water, 2,5-hexanedione (114 g), andbenzene (150 ml) was slowly heated to reflux in a flask fitted with a Dean-Stark trap. After the water wascollected, the reaction mixture became clear and homogeneous. On distillation, the fraction boiling at 60oC (11 mm) was collected to give 82 g (75%) of the product.

Grayson, Martin; Eckroth, David Kirk-Othmer Encycl. Chem. Technol., 3rd Ed. 1982, 19, 499-520Bean, Gerritt P. Chem. Heterocycl. Compd. 1990, 48 (Pyrroles, Pt.(1), 105-294Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33, 2057

EtOOCR3

NO2

R2 O

•••• Cyanide or Thiazolium-ion-Catalyzed Michael Addition of a Vinyl Ketone

Lyer, R. N.; Gopalachari, R. Ind. J. Chem. 1973, 11, 1260

EtOOCR3

O

R2 O

• Michael Addition of Ethyl Nitroacetate to a Vinyl Ketone

Stetter, H.; Krasselt, J. J. Heterocycl. Chem. 1977, 14, 573Jones, R. A. Tetrahedron. 1986, 42, 3753

O3

Thompson, W. J.; Buhr, C. A. J. Org. Chem. 1983, 48, 2769

R1NH2

1. NaCN

3.

R1NH2

-+

+ R3NH2+acid 2H2O


23

R1

NH2

O

O R2

Z

NH

Z

R2

OR1

NH

Z

R2

HOR1

NH

Z

R2

R1

R R

O O

NEWG R

R

R1

R3EtO

CHOR1NHCH2CO2R2

NCOOR2

R3

O

H

N

R3

COOEt

2. Knorr Pyrrole Synthesis

R1

Condensation of an α-Aminoketone with a Carbonyl Compound.

+

A solution of 7.2 g of sodium nitrite in 25 mL of water was slowly added to a stirred mixture of 19.2 g of benzyl acetoacetate in 30 mL of acetic acid at 5 °C. The mixture was kept at 5 °C for 15 h and was then slowlyadded to a mixture of 13 g of ethyl acetoacetate in 70 mL of glacial acetic acid. Simultaneously, a mixture of18.5 g of Zn and 18.5 g of anhydrous sodium acetate was added in small portions. When the addition wascompleted, the mixture was heated for a further 1.5 h at 75 °C. The mixture was poured over ice-water,filtered, and the residue was crystallized from methanol to give the product (21 g, 70%).

R1

Rezzano, I.; Buldain, G.; Fryman, B. J. Org. Chem. 1982, 47, 3059

3. Condensation of αααα-Aminoketone with 1,3-Dicarbonyl Compounds

NH

EWG-CH2NHR1

+R1 X

O

A mixture of dibenzoylmethane (500 mg) and ethyl glycinate hydrochloride (3.3 g) in dimethylformamide (50mL) was heated at reflux for 24 h. The solution was poured into water (200 mL) and the resultant mixture wasallowed to stand overnight. The precipitated product was isolated by filtration and recrystallized from hexane to give colorless prisms (yield, 74%).

Walizei, G. H.; Breitmaier, E. Synthesis, 1989, 337

+

R1

OR2

Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis, 1982, 157

EWG=electron-withdrawing group

+

Cohnen, E.; Dewald, R. Synthesis, 1987, 566

H2NCH2COR2


24

TMS N CN

Ph

F-H2C N

Ph

HC CCOOMeN

COOMe

Ph

NCOOMe

Ph

DDQ

N

R1

R1 R4

COOR3

R

R1

O

XR4 OR3

O ORNH2

CH2

4. Formation of Pyrroles via 1,3-Dipolar Cycloaddition Reaction

A. Padwa, Y. Y. Chen, W. Dent, and H. Nimmessgern, J. Org. Chem., 1985, 50, 4006

To a solution of the nitroolefin (200 mg) and isocyanide (169 mg) in a 1:1 mixture of THF and isopropanol (5 mL) was added the guanidine base (180 mg). The resulting solution was heated to 50 °C for 3 h,poured into water, and extracted with CH2Cl2. The organic layer was dried over sodium sulphate andfiltered through a short column of silica gel. Evaporation of the solvent gave the desired pyrrole as apale crystalline solid (272 mg, 90%).

5. αααα-Haloketone-ββββ-Ketoester-Amines Synthesis of Pyrroles

R2 +

Aqueous ammonia was added to the acyl acetate and the halo-compound (0.1 mole) and the mixturewas stirred for 2 h while the temperature rose to 60 °C. After stirring for 24 h, the product was extracted into ether and the extracts were washed with 10% NaOH, water, 5% HCl, and again with water. Theether was removed under reduced pressure and the product crystallized from the residue.

+-


25

N

HN

H

N

H

62 %CO2Me

heatCO2Me

N3

Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474Roomi, M.W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689

X=halo

6. Rhodium Mediated Masked 1,4-Dicarbonyl Compounds

Cunha, A. C.; Pereira, L. O. R.; de Souza, R. O. P.; Ferreira, V. F. Synthetic Commun. 2000, 30, 3215.Deng, G.; Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 11, 1913.

R1

O

MeN2

O

OBuOBuO Me

O

R1

N

O

R1

Me

R2

Rh2(OAc)4 R2NH2


+

7. Formation of Pyrroles via the Hantzch Reaction

Condensation of an α-haloketones or aldehydes with β-ketoesters in the presence of an amine.

Grigg, R.; Savic, V. J. Chem. Soc., Chem. Commun. 2000, 873.

DMF, rtBr

NH2

CO2Et

Ph

Br

N

H

Ph

CO2Et

N

H

CO2Et

Ph

Me

Pd(OAc)2, PPh3,+

A solution of starting materials was stirred in DMF at rt until TLC showed complettion of the reaction. The product obtained was subjected to 10 mol % Pd(OAc)2, 20 mol % PPH3, and 2 equiv K2CO3 in DMF at85oC. The product was poured into a saturated NaHCO3 solution, extracted with EtOAc, washed withbrine, dried, filtered and concentrated. The crude product was chromatographed over silica gel usingEtOAc/petroleum ether as the eluent.

To a solution of sulfone and ethyl isocyano acetate (2 equiv) in anhydrous THF was added DBU at rt.After the mixture was stirred for 3 h, aqueous 1 M HCl was added and the mixture was extracted withEtOAc. The organic phase was washed with H2O, brine, dried, filtered, and concentrated. The residue was chromatographed on silica gel with EtOAc and hexane as the eluent.

26

Uno, G.; Tanaka, M.; Inoue, T.; Ono, N. Synthesis 1999, 3, 471.Abel, Y.; Haake, E.; Schmidt, W.; Struve, D.; Walter, A., Montforts, F. Helv. Chim. Acta. 1998, 81, 1978.

R2 R1

SO2R3

N

R1R2

EtO2C

H

CNCH2CO2Et

Base, THF

8. Barton-Zard Synthesis of Pyrroles

Condensation of electron-deficient alkenes with isocyanomethylide anions.

9. Synthesis of Pyrroles from Alkenyl ββββ-Dicarbonyl Compounds

Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M.; Payret, M. E. Tetrahedron 1999, 55, 10915.

Al2O3, CH2Cl2, rt reflux

NHBn

CO2Et

NICH2

CO2Et

N

CO2Et


Bn Bn

10. Route to Pyrroles via an Intramolecular Wittig Reaction

Burley, I.; Bilic, B.; Hewson, A. T.; Newton, J. R. A. Tetrahedron Lett. 2000, 41, 8969.

OMe

NHCOPhMe

SPh

PPh3NMe

Me SO2Ph

COPh

NMe

Me

COPh

KOt-Bum-CPBA

NaH+

t-BuOH

27

Condensation of ketones and acetylenes (or synthetic equivalents) with oximes

Pyrrole Formation via the Trofimov Reaction

100-110oC

Mikhaleva, A. I.; Sigalov, M. V.; Kalabin, G. A. Tetrahedron Lett. 1982, 23, 5063.

A mixture of the oxime (88 mmol), KOH (53 mmol), water (10 mmol), and DMSO (100 mL) was autoclaved with acetylene at 100oC for 1 h (initial pressure 50 psig). Aqueous workup followed by extraction and vacuum distillation afforded the product.

NOHN

Trofimov, B. A.; Mikhaleva, A. I. Heterocycles 1994, 37, 1193.Brandsma, L.; Nedolya, N. A.; Trofimov, B. A. Eur. J. Org. Chem. 1999, 2663.

KOH, DMSONOH

HH

NH

H

KOH/DMSOHH+

To a solution of the appropriate acyclic β-enamino ester (1 mmol) in anhydrous CH2Cl2 (15 mL) were added solidNaHCO3 (1.1 mmol), Al2O3 (1 g), and I2 (1.1 mmol). After stirring at rt for 24 h, the reaction mixture was extracted with ethyl acetate, washed with NaHSO3, NaHCO3, brine, dried, filtered, and concentrated. The crude productwas either recystallized from cold ethanol (solid) or chromatographed over silica gel utilizing hexane:ethyl acetateas the eluent.

The sulfone (1.5 mmol) was dissolved in dry THF (20 mL) and 1 M potassium t-butoxide in t-butanol (1.5 mmol) was added. The solution was heated at reflux for 2 h. The THF was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. Flash chromatography with ethyl acetate/hexane as the eluent gave the pyrrole (93%).

NaHCO3, I2, DBU, toluene

R2 X

CNR1

NC CN

SKMeS O

R1

X

S-

S-CN

Y

R2R1

O

R1

R2O

O

R3HSCH2CO2H

DMSO

S

YNH2

RNHCO SMe

S

XR2

R1NH2

S

OH

R1CO2R3

S

NH2CN

MeS

R1

O

S

OHR2

R1 CO2R4

To a mixture of phenacyl bromide (2.0 g, 10 mmol) and acetic acid (4 mL), a solution of the sulfur salt (1.9 g, 10 mmol) in dimethyl sulfoxide (20 ml) was added dropwise at 60 oC. After complete addition, the mixture was stirred for 30 min and then poured into water (200 mL). After stirring for 2 h the crude product was collected by filtration andrecrystallized from ethanol (66 %).

1. Gewald Synthesis

Gewald, K. Angew. Chem., 1961, 73, 114.Rehwald, M.; Gewald, K.; Battcher, G. Heterocycles 1997, 45, 493.

Chloracetamide (5 mmol) followed by methyl iodide (5 mmol) were added to the sulfur salt (5 mmol) in dimethylformamide (5 mmL). The mixture was stirred for 5 min, diluted with water (100 mL) and heated 70 oC. Potassiumcarbonate (5 mmol) was added to induce the cyclization and the solution was left to cool. The product was filtered from the cold solution and recrystallized from 1-propanol.

2. Gomper Synthesis

3. Fiesselman Synthesis

A mixture of the 3-alkyl-alkoxyacrylonitrile (10 mmol) and the mercaptoacetic ester (10 mmol) in a suitable alcohol (10 mL) containing potassium acetate (15 mmol) is heated at reflux for 0.5-2 h. The crystals which precipitate during the reaction are collected by filtration.

Woodward, R. B.; Eastman, R. H. J. Am. Chem. Soc., 1946, 68, 2229.Fiesselman, H. Schippark, P. Chem. Ber. 1954, 87, 835.Saito, K.; Kambe, S.; Sakurai, A.; Midorikawa, H. Synthesis, 1982, 12, 1056.


+

S/Morpholino

EtOH/60 oC

+60 oC

1) ClCH2CONHR2) NaOH3) MeI

Henriksen, L.; Autrup, H. Acta Chem. Scand., 1972, 26, 3342.

Y = -CO2Et, -CN, -CONHMe, -CONH2

HSCH2CO2R3

+1) H+, R4OH

2) NaOR5

Note: Acetylenes, β-ketoesters, α,β-dihalocarboxylates, α-haloarylates, α,β-dihalonitriles, β-chloro acrylonitriles, 1,3-dicarbonyl have been used

2

Top Ten Methods to Synthesize Thiophenes

28

R1 O

XR2

S

R1

R1

NaSH

O R2

R3O

R1 O

SHR2

O R3

R4X

DDQ

S

R3R1

R4R2

S

R3R2

R1R1

S R4

R2

O

O R3

R1

S

R3R1

R4R2

S

OHOHR1 R3

R2 R4

H+

To a stirred solution of t-BuOK ( 310 mg, 2.7 mmol) in THF (5 mL) was added a solution of the diol (300 mg, 0.9 mmol)in THF (2 mL) over a period of 30 min at -18 oC under argon. After 1 h the reaction was quenched by adding ice-water (30 mL) and then pentane (50 mL). The organic layer was washed with water, dried over MgSO4, concentrated, andchromatographed on a column of silica. The column was eluted with pentane, and the pentane was evaporated slowlyunder reduced pressure (86 %).

4. Nakayama Synthesis

Nakayama, J.; Kurado, K. J. Am. Chem. Soc., 1993, 115, 4612.

5. Hinsberg Synthesis and Modifications

To a stirred solution of the diketone (2.7 g, 10 mmol) and biacetyl (1.0 g, 11.6 mmol) in 40 mL of methanol was added0.5 mL of a solution of sodium methoxide (0.5 g of sodium dissolved in 100 mL of methanol) at 40 oC. Theprecipitation of crystals occurred immediately with the evolution of heat. After stirring for 1 h, the product was collected by filtration and washed with methanol. To the filtrate, biacetyl (0.5 g) and the base solution (0.5 mL) were added togive an additional amount of product. The overall yield was 92 %.

Hinsberg, O. Ber., 1910, 43, 901.Miyahara, Y.; Inazu, T.; Yoshiro, T. Bull. Chem. Soc. Jpn., 1980, 53, 1187.


+Base

TiCl4/ZnTiCl4/Zn

+NaOEt, EtOH R1 = ester, cyano, ketone

rt 0oC

29

H2NOC CN

NMe2Me

R3R2

OR1

OR4

HS CO2Et

∆

P4S10

EtONa

O

Ar

MeSOR

O

R1 R2

SMeMeS

S

Ar

OR

O

ZnCH2

SI

R1 R2

Me

SMe

I

H2NOC CN

SMe CO2Et

S

R3R2

R1 R4

I-

R2

SMeH

H

IZnOR1

Me

S

S

R2R1

SMe

S

NH2H2NOC

Me CO2Et

To a solution of the diketone (0.5 g, 0.002 mol) in CH2Cl2 (10-15 mL), was added phosphorous pentasulfide (2.2 g, 0.05mol) with stirring. Solid sodium bicarbonate (0.84 g, 0.01 mol) was added in 5-6 portions during 5 min. After stirring the reaction mixture overnight at rt, water (50 mL) was added and the mixture was transferred to a separatory funnel and theaqueous layer was extracted with CH2Cl2 and the combined organic extracts were washed with water. Concentration ofthe dried CH2Cl2 extracts gave a crystalline product (75%).

6. Paal-Knorr Reaction

Volz,W.; Vob, J. Synthesis, 1990, 25, 670.Moriarty, R.; Prakash, O.; Duncan, M. Syn. Commun. 1985, 15, 789.

The ester (120 mmol) and K2CO3 (1 g, 7 mmol) were added to a suspension of the enamine (100 mmol) in 100 mL of anyhydrous EtOH. The reaction mixture was refluxed for 16 h, diluted with water, and cooled. The precipitate that formed was filtered off and washed with water to give the aminothiophene.

Ryndina, S. A.; Kadushkin, A. V.; Solov'eva, N. P.; Granik, V. G. Russ. Chem. Bull. 2002, 51, 854.

Et2O/THF

7. Thorpe-Ziegler Cyclization

8. Simmons-Smith Conditions

To a well stirred suspension of zinc-copper couple (4.0 g) in dry ether (25 mL) under nitrogen atmosphere, was addeda small crystal of iodine and CH2I2 (6.7 g, 25 mmol). The reaction mixture is heated at reflux for 45 min. A solution ofthe enone (2.4 g, 10 mmol) in dry THF (15 mL) is added and the reaction mixture was heated at reflux with stirring for8 h. The solvent is removed under reduced pressure and the residue is diluted in water (200 mL) followed by theaddition of CHCl3 (150 mL). The reaction mixture is filtered, the residue washed with CHCl3 and the combined oragnic layer is washed with NHCl4 solution and water, dried (Na2SO4) and evaporated to give the crude product.

Thomas, A.; Singh, G.; Ila, H. Tet. Lett., 1989, 30, 3093.


R1= aryl, hetaryl, alkylR2= H, alkyl, allyl, Ph, Bn

CH2I2/Zn-Cu

Et2O/THF

CH2I2/Zn-Cu

+

30

O

R3

R1R3

O

R1R2

R3R4 H2S

∆

S

R1R3

R3

S

R3R2

R1 R4

Benzene (10 mL) and Lawesson's reagent (6 mmol) was added to the epoxide (5 mmol) and the mixture heated to reflux. After 5 min., p-toluenesulfonic acid (10 mg) was added, and the mixture was further heated for 1 h. Thereaction was partitioned between sat. NaHCO3 and ether. The aqueous layer was extracted with ether. Thecombined organic layers were washed with water and dried over Na2SO4. Purification by chromatography onsilica gel gave the thiophene derivative.

9. From ββββ,γγγγ-Epoxy Carbonyl Compounds

Kang, K.; J. S. Syn. Commun. 1995, 25, 2647.

Commonly used industrial procedure. However, the yields of the reaction are poor and it is difficult to perform experimentally. In general, alkenes give better yields than alkanes.

For a review: Gronowitz, S. Thiophenes and Its Derivatives; Interscience Publisher: New York, vol. 44, pt. 1, pp. 4-11.

10. Thermally From Alkanes and Alkenes


+Al-Cr catalyst

Lawesson's Reagent

p-TsOH (cat.)Benzene/∆

S

O

CHO

CO2Et

O

EtO2C O

SCH2CO2SEtO2C CO2H

CHOCHOEtO2CCHSCH2CO2Et H

EtO2CS

CO2Et

O O

-H+ -H2O

H+

H

Hinsberg αααα-Diketone-thiodiacetate Thiophene Synthesis

-EtO

Wynberg, H.; Kooreman, H. J. J. Amer. Chem. Soc. 1965, 87, 1739

31

A sample of DAST (0.24 mmol) is added dropwise at -78°C to a solution of the hydroxy amide in CH2Cl2 (2 mL). After 30 min, the reaction mixture is warmed to -40°C and bromotrichloromethane (0.8 mmol) is added dropwise, followed bywarming to 0°C and addition of DBU (0.8 mmol). The reaction mixture is stirred for 8 h while warming to 20 °C, thenquenched with a saturated NaHCO3 solution. The solution is extracted with EtOAc and the organic layer was dried overMgSO4, filtered, and concentrated.

1. Cyclizations of ββββ-Hydroxy Amides

Ten Top Methods to Synthesize Oxazoles

The carboxylic acid (10 mmol) and DCC (10.5 mmol) is added to a stirred solution of the aminomalononitrilep-toluenesulfonate (10.5 mmol) in pyridine (50 mL) and the mixture is stirred overnight. After removal of the white precipitate by filtration, the filtrate is concentrated to give the oxazole, which is purified by flash chromatography.

2. 2-Substituted 5-Amino-4-cyano-1,3-oxazoles

pyridine 76%

Freeman, F.; Chen, T.; van der Linden, J.B., Synthesis 1997, 861.

+

68%

Phillips, A.J.; Uto, Y.; Wipf, P.; Reno, M.J.; Williams, D.R., Org. Lett. 2000, 2, 1165.

3. 2,5-Disubstituted Oxazoles from N-Propargyl Amides

Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F., Org. Lett. 2001, 3 , 2501.

Pd2(dba)3, P(2-furyl)3

+

75%

A sample of P(2-furyl)3 (0.06 mmol) is added to a solution of Pd2(dba)3 (0.016 mmol) in anhydrous MeCN (3.5 mL)under argon and the solution is stirred at rt for 15 min. The N-propargylamide (0.63 mmol), iodobenzene (0.75 mmol),and NaOtBu (1.2 mmol) is added and the mixture stirred at 40°C for 4 h. The reaction mixture is diluted with EtOAc,washed with 0.1 N HCl and saturated NaHCO3, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified with an axially compressed silica gel column using hexane/EtOAc as the eluent.

2. DBU, BrCCl3

H

CN

CN

NH3•OTs

O

NH

NH

CO2CH3

OH

O

OH

NH

OI

NHO

NCO2CH3

N

O

CN

NH2

N O

1. DAST

DCC

NaOtBu


32

4. Substituted Oxazoles from Ketoximes

Bhatt, M.V.; Reddy, G.S., Tet. Lett. 1980, 21, 2359.

80%

pyridine

Acetyl chloride+

Ph

N OH

O

O O N O

Ph


Benzylmethylketoxime (20 mmol) is dissolved in dry pyridine (20 mmol) and acetic anhydride (20 mmol). Themixture is cooled to 0°C and acetyl chloride (26 mmol) is added, then heated over a boiling water bath for 4 h.Dry HCl gas is passed for 3 h (at 100°C). The reaction mixture is cooled, poured into crushed ice, extracted with CH2Cl2, then dried, filtered, and concentrated. The residue is purified by column chromatography to afford theoxazole.

Trifluoromethanesulfonic acid (4.5 mmol) is added to a solution of acetonitrile (10 mL) and iodobenzene diacetate (1.2mmol) and the reaction mixture is stirred at rt for 20 min. Acetophenone (1.0 mmol) is added and the mixture is heated at reflux for 2 h, then concentrated to remove excess acetonitrile. The residue is extracted into CH2Cl2 and the organiclayer washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Theproduct is purified by elution through a short pad of silica gel.

5. 2,5-Disubstituted Oxazoles from Iodobenzene Diacetate

Varma, R.S.; Kumar, D., J. Heterocyclic Chem. 1998, 35, 1533.

94%

6. Ethyl 5-Oxazole Acetate

Dow, R.L., J. Org. Chem., 1990, 55 (1), 386.

88%

+IOAc

OAcPh

O

NH

O

O

OEt

O

Ph

N

O

H

Ph

NO

OEt

O

Ph

CF3SO3H

MeCN

POCl3

Phosphorus oxychloride (18 mmol) is added to a stirred solution of the keto ester (6 mmol) in DMF (10 mL) andthe reaction mixture is heated at 90°C for 20 min. The mixture is cooled, poured onto ice, and the resulting slurry was stirred for 30 min. The solution is added to a saturated NaHCO3 solution and extracted with EtOAc. Theorganic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reducedpressure. The resulting residue is purified by flash chromatography (silica, EtOAc/hexane).

33

To a solution of the sulfone (0.6 mmol) in dry THF (4 mL) and DMSO (0.5 mL) at 0°C is added lithiumbis(trimethylsilyl)amide (0.7 mmol) under argon. After 40 min, the mixture is diluted with ether and quenched with 1 N HCl. The organic layer is washed with saturated NaHCO3 and brine, then dried with MgSO4, filtered, and concentrated to a residue which is purified by chromatography to afford the oxazole.

7. Synthesis of Oxazoles from Sulfones

Short, K.M.; Ziegler, Jr., C.B., Tetrahedron Lett. 1993, 34, 71.

95%

To an ice-cooled solution of the substituted 2-bromoacetophenone (5 mmol) in DMF (10 mL) was added NaN3 (5.5 mmol) in one portion. After approximately 20 min, POCl3 (30 mmol) was added dropwise. The mixture is warmed to rt and heated at 90°C for 4.5 h to provide the oxazole in good yield.

8. Vilsmeier Cyclizations for the Synthesis of Oxazoles

Majo, V.J.; Paramasivan, T.P., Tetrahedron Lett. 1997, 38, 6889.

56%

9. Synthesis of Oxazoles from Ketones

Lee, J.C.; Kim, S.; Lee, Y.C., Syn. Commun. 2003, 33 , 1611.

To a solution of ethyl pyruvate (1.0 mmol) in acetonitrile (40 mL) is added [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]-benzene (HDNIB) (1.2 mmol) and the mixture is refluxed for 2 h. After cooling to rt, benzamide (3.0 mmol) is added andthe mixture is refluxed for an additional 10 h. The solvent is removed and the residue extracted with CH2Cl2, followed by washing with saturated NaHCO3 and H2O. The organic layer is dried with MgSO4 and the solvent was evaporated underreduced pressure. The resulting product is purified by flash chromatography.

71%

2. PhCONH2

-ODNs =

EtO2C

O

O

BrBr

N

SO2Ph

I

N

OPh

EtO2C

N

O SO2Ph

ON

CHOBr

O S

O

O

NO2

NO2

1. PhI(OH)ODNs

LiN(TMS)2

1. NaN3

2. POCl3


OHC

H

34

3. Gold(III) Catalyzed One Pot Synthesis of Isooxazoles from Terminal Alkyne

RC CH +N

OR

O

+

Gasparrini, F.; Giovannoli, M.; Misiti, D.; Natile, G.; Palmieri, G.; Maresca, L. J.Am.Chem.Soc, 1993, 115, 4401-4402.

In a typical experiment, the alkyne (5.0 mmol) was dissolved in nitromethane (8 mL) and treated with aqueous HNO3, (16 mL, 25.0 mmol,1.5 M) in the presence of tetrabutylammonium tetrachloroaurate (0.25 mmol) and sodium nitrite (1.0 mmol). The mixture was stirred at 50 oC until complete disappearance of the alkyne and then was extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of Na2S2O3 which removed the catalyst and was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give the isoxazole in 35-50% yield.

Ten Top Methods to Synthesize Isoxazoles

Oximation of 1,3-Dicarbonyl Compounds1.

O

O O

Me NH2OH

ON

MeHO

NaOH

H2O/MeOH

Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920.

A solution of nitroethane (2.5 g, 33 mmol) and triethylamine (15 drops) in dry benzene (15 mL) was added dropwise to a solution of 4-chlorophenyl isocyanate (8.6 g, 56 mmol) and trans-4-methoxy-3-buten-2-one (3.0 g, 30 mmol) in dry benzene (25 mL). The reaction mixture was stirred for 1 h, then refluxed for an additional hour. 4-Chlorophenyl isocyanate (6.2 g, 41 mmol), nitroethane (1 mL, 9.8 mmol), and 5 drops of triethylamine were added to the reaction mixture. The solid was filtered and the filtrate was concentrated to give a yellow oil, which was distilled to give the isoxazole (3.3 g, 88% yield).

To a solution of sodium hydroxide (5.2 g, 130 mmol) in a mixture of water (5 cm) and methanol (100 cm) was added, the oxoester (23 g, 125 mmol). To this solution at -70 °C was added a filtered solution of sodium hydroxide (10.3 g, 260 mmol) and hydroxylamine hydrochloride (17 g, 240 mmol) in a mixture of water (10 cm) and MeOH (100 cm). The reaction mixture was stirred for 2 h, and during this period the temperature was raised to 10 °C. Upon addition of acetone (9 cm, 125 mmol), the reaction mixture was poured into hydrochloric acid at 80 °C, and this mixture was stirred for 30 min. The volume was reduced to 100 mL by evaporation and left at 5 °C overnight. The product (16.9 g) was filtered, and the mother liquor was extracted with dichloromethane. The filtrate was dried (magnesium sulfate), the organic phases were evaporated and the residue was subjected to column chromatography to give 17.4 g of 5-tert-butyl-4-methylisoxazol-3-ol (91%).

2. Cycloaddition of Nitrile Oxides to Unsaturated Compounds

R N O+ - OCH3

CH3

O+O

N

R CH3

O

benzene

Brehm, L.; Johansen, J.S.; Krogsgaard-Larsen, P.; J.Chem. Soc., Perkin Trans I, 1992, 16, 2059-2063.

Me


35

+

TBA+AuCl4-HNO3

and Nitric Acid

H2O

4. Synthesis of Isoxazoles from αααα-Halo Ketone and Isocyanide

R1X

NOH

base

R2NC

Buron, C.; Kaim, L. El.; Uslu, A. Tetrahedron Lett. 1997, 38, 8027-8030

To a solution of the α-halo ketone oxime (2 mmol) in dry dichloromethane (10 mL) is added the isocyanide (8 mmol) and sodium carbonate (850 mg, 8 mmol).

5. Condensation of Aromatic Aldehyde and Nitroethane or Nitropropane

Ar O EtNO2 / NaOH ON

ArMe

A mixture of nitroethane or nitropropane (9.3 mmol), the aldehyde (4.41 mmol) and ethanol (7 mL) was stirredrapidly at rt. A solution of NaOH (6.4 M, 2 mL) was added dropwise and the mixture was heated at reflux for 5 to 18 h. The cooled reaction mixture was extracted with ether and the organic layer was washed with brine anddried over MgSO4. The residue remaining after evaporation of the ether was purifed either by columnchromatography (silica) or by distillation.

6. Condensation of Carboxylic Acid Derivatives with 1,4-Dilithium Oxime Salts

NOMe

Me

NOH

+O

N

Me

n-BuLi

THF

Me

ON

ArR1

NHR2

Nitz, T.J.; Volkots, D.L.; Aldous, D.J.; Oglesby, R.C. J. Org. Chem., 1994, 59, 5828-5832

To a chilled (0 °C) solution of acetone oxime (1.1 g, 15 mmol) in THF (30 mL) was added dropwise 2.5 M n-BuLi in hexane (12 mL, 30 mmol). The initially formed white suspension gave a colorless solution after all of the n-BuLihad been added. After an additional 30 min, N-methoxy-N-methylisobutylamide (2.6 g, 18 mmol) in THF (120 mL)was added dropwise over 20 min. After 30 min, the pale yellow solution was poured into a solution of concentratedH2SO4 (2.5 mL) in THF/water and refluxed for 1 h. The chilled reaction mixture was neutralized with NaHCO3.Sufficient water was added to dissolve the salts, and the mixture was extracted with ether. The combined etherealextracts were washed with brine, dried, and concentrated in vacuo to give a yellow oil which was purified by silicagel chromatography to give 1.5 g (72%) of a colorless oil.

Best, W.M.; Ghisalberti, E. L. ; Powell, M. J. Chem. Res. (S)., 1998, 7, 388-389


36

H

7. Synthesis of Isoxazoles from ββββ,,,,γγγγ-Acetylenic Oximes

R2NOH

MeOH

ON

R1

R2

Short, K. M.; Ziegler, C. B.Jr. Tetrahedron Lett., 1993, 34, 75-78.

The alkyne(0.6g) was reacted with potassium carbonate (1.5 g) in methanol (15 mL) for 12 h, then the solution was concentrated in vacuo. The residue was treated with water and ethyl acetate. The organic phase was washed with 5% HCl, brine, filtered and the residue was chromatographed on silica gel to give the isoxazole.

8. Synthesis from Benzyl Propargyl Ether and Methyl Nitroacetate

OBnO2NCH2CO2Me

OCNC6H4NCO, Et3N

ON

R

OBn

Alkyne 1 (3.3 g, 22.7 mmol) and methyl nitroacetate (2.7 g, 22.7 mmol) were combined in THF (100 mL), and 1,4-phenylene diisocyanate (9.1 g, 56 mmol) was added in one portion. Thereaction was initiated by the addition of a catalytic amount of triethylamine. When the reaction had gone to completion, 2-3 drops of water were added to quench any excess isocyanate. The polymerized urea by-product was removed by filtration through a plug of Celite, and the filtrate was concentrated to give the isoxazole (4.2 g, 76%) as a light yellow solid.

Sammelson, R. E.;Miller, R.; Kurth, M. J. J. Org. Chem., 2000, 65, 2225-2228

9. Cyclization of N,O-Boc αααα-Keto Hydroxamic Acids Synthesized via Acyl

N

O O

Boc

Boc

The starting ketoamide (450 mg, 1.4 mmol) was dissolved in MeOH (3 mL) and this solution was added toconcentrated HCl (10 mL) at 50 °C. The mixture was stirred for 1 h, cooled to rt, and concentrated in vacuo. Theresidue was dissolved in water (10 mL) and the pH adjusted to 3-4 with 2 M aqueous NaOH followed byextraction with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the final product in high yield.

Conc. HCl ON

HO

Me

Sorensen, U. S.;Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem., 65, 2000, 1003-1007


Meldrum’s Acids

K2CO3

37

Otting, C.; Messerle, B. A.; Soler, P. L. J. Am. Chem. Soc. 1996, 118, 5096

An Interesting Variation

90%

+

+

O

Br NN

R

Ar1

O O

NN

Ar2

+

Neidlein, R.; Schroeder, G. Helv. Chim Acta 1992, 75, 825.

CO2HAr1

CO2H

A mixture of the 6-aryl-4,6-dioxohexanoic acid (20 mmol), the aryl hydrazine hydrochloride (20 mmol) andtriethylamine (20 mmol) in methanol (150 mL) was stirred at rt for 6 h. The mixture is concentrated in vacuo and the residue is taken up in ether, washed with 5% HCl, and brine (40 mL), dried (Na2SO4), filtered, andconcentrated to an oil. The residue is crystallized from ether/ acetone to afford the product in 94% yield.

Ten Top Methods to Synthesize Pyrazoles

H

1. Reaction of ββββ-Bifunctional Compounds with Hydrazines

94%

69%

Murray, W.; Wachter, M; Barton, D.; Forero-Kelly, Y. Synthesis 1991, 18.

•HCl


38

o

o

o

o

N

HN

Ethanol (35 mL ) and water (55 mL) were added to hydrazine sulfate (2.1 g, 16 mmol) and the solution was stirredand heated at 75oC for 1.5 h until the hydrazine fully dissolved. Malonaldehyde bis(dimethylacetal) (2.7 g, 16mmol) was added dropwise and the solution was stirred and heated at 75 oC for 2 h. The mixture was then stirred for 24 h at room temperature. The ethanol was removed under reduced pressure and the solution was neutralizedwith CaCO3. After addition of water the solution was filtered through celite. The eluent was extracted with etherthe ether solution was dried over K2CO3 and filtered again through celite. The volume of ether was reduced bydistillation to give the product.

NH2NH2 . H2SO4

Ar2NHNH2

RNHNH2

DMF

MeOH

K2CO3

Et3N

O NH2

NN

R1

CH3

R1N

N

R1

CH3

CNHN

NH2CN

HN

CNN

Ph

NNBn

NH2

80-95%

+

4. Synthesis of 3-Amino Pyrazoles

Me

N

O

A mixture of the β-amino enone (2.8 mmol) and the hydrazine derivative (3.4 mmol) in 5 mL of ethanol were stirred at20oC-80oC with 1 mL AcOH as the catalyst. The solution was poured into water (20 mL) and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Theresidue was purified by recrystallization or chromatography on silica gel.

Alberola, A.; Bleye, L. C.; Gonzalez-Ortega, A.; Sadaba, M. L.; Sanudo, M. C. Heterocycles, 2001, 55, 331.

NN

Me

RH2N


39

heat

2. ββββ-Substituted Enones and Alkyl Hydrazines

85% total yield

Holschbach, M.H.; Wutz, W.; Olsson, R. A. Tetrahedron Lett. 2003, 44, 41.

+ conc. HCl

Butler, D.; Alexander, S.M. J. Hetereocyclic Chem. 1982, 19, 1173.

95%

+

3. One-pot Synthesis of 3-Amino Pyrazoles

RNH2 R

R

HOAc

N2H4.H2O C6H5CHO

NaOH

RNHNH2

EtOH

NH2

OEt

NHONO2

Cl

ONHN

HN

ONO2

5. Synthesis of 3-Acylaminopyrazoles Starting from Acylated ββββ-Keto Imino Ethers

+

A 5.0 g (0.024 mol) sample ofthe imino ether was added to 4.2 mL (0.05 mol) of pyridine in 25 mL of methylenechloride and cooled in an ice bath. The suspension was stirred for 5 min and 2.9 mL (0.025 mol) of benzoyl chloride was added dropwise over 3 min. The reaction was stirred 5 min at ice bath temperatures and the bath removed andthe reaction stirred at ambient temperatures for 1 h. The reaction was poured into 100 mL of water and 100 mL ofethyl acetate added. After shaking, the aqueous layer was removed, the organic layer washed with water, driedover magnesium sulfate and concentrated to yield 7.0 g (100%) of acylated β-ketone imino ether as a clear oil.Without purification, 5.0 g (0.018 mol) of this compound was dissolved in 50 mL ethanol at room temperature and0.64 mL (0.02 mol) hydrazine added dropwise over 1 min. After 30 min the reaction was poured into water, ethylacetate added and after shaking, the organic layer was washed once with dilute hydrochloric acid and then withwater. The organic layer was dried over magnesium sulfate and concentrated to give 4.1 g (93%) of a white solid.

1. Pyridine, CH2Cl2

2. NH2NH2

U.S., 6593477, 15 Jul 2003.Robert, F.; Susan M.93%


R SiR1R2

CF2-CF2-RF

R

O

F

F

R

OSiR1R2

CF2-RF

F

NNMe

F R

RF

CH2Cl

ArN

N

6. Synthesis of Fluoro-pyrazoles from Organofluorosilicon Building Blocks

Ar

(CF2)n-1CF3

To a solution of the starting material (0.6 mmol) in ether (5 mL) was added methylhydrazine (2 equiv., 1.2mmol). The mixture was stirred at room temperature for 5 h and filtered. After solvent removal, the pyrazole was purified by silica gel chromatography.

Bouillon, J.- P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187-192.

95%

An interesting Variation

Ohkoshi, M.; Yoshida, M.; Matsuyama, H.; Iyoda., M. Tetrahedron Lett. 2001, 42, 33-36.

40

Me-NH-NH2

OH

RFMe-NH-NH2

H

Et2O, rtRF=C4F9 R=alkyl, aryl

- HF,- H2O

CF3(CF2)nI +1. (Bu3Sn)2, hv, O2, benzene

2. NH2NH2.AcOH, EtOH 69%

Cl

Ph

Cl

Ph

Padwa, A.; MacDonald, J. G. J. Heterocyclic Chem. 1987, 24 (4) 1225-1227

R2 R3

O ON

NH

NN

Ar

Ar

BrR1

R1

R2O

R3

O NO

OMe

ArHNN

Br

OEtO

NN

OMe

O

O OEt

Ar


7. Nitrile Imines as Precursors for Pyrazoles


Shawali, A.S.; Parkanyi, C. J. Hetereocyclic Chem. 1980, 17, 833.

The appropriate 1,3-dicarbonyl compound (0.01 mol) was added to an ethanolic sodium ethoxide solution.After stirring for 10 min, the hydrazonyl bromide (0.01 mol) was added and stirring was continued overnight. The product was collected by filtration or by dilution with water and filtration. Purification by recrystallizationfrom ethanol gave the product in 78-84% yield.

8. Hydrazonyl Bromides and ββββ-Dicarbonyl Anions

Shawali, A.S.; Abdelhamid, A.O. J. Hetereocyclic Chem. 1976, 13, 989.

To a stirred solution containing 1.5 mmol of diphenyl hydrazonyl chloride and 1.5 mmole of carboxymethylenetriphenyl phosphorane in 30 mL benzene at 250 oC was added 1mL of triethylamine. The solution was allowed to stir for 6 h and was filtered. The residue obtained upon removal of the solvent was subjected to silica gelchromatograhy.

41

PhNHN (Ph)3PNEt3

NaOEt

Et3N

+

90%

78-84%

+

+

72%

NN

Ph

EtO

Ph Ph

NH

N

O

CH2

CF3 Br

NH

N

CO2Et

CF3

+

O


Et2O0°C to reflux

2 hr

Ethyl diazoacetate (11 mmol) in ether (3 mL) was added dropwise to a solution of bromopropene (7.6 mmol) in ether (2 mL) at 0°C. The temperature was allowed to rise to 20°C, and was then heated at reflux for 2 h . The productwas distilled using a Kugelrohr apparatus and recrystallized from hexane to give 86% of the desired pyrazole.

H

10. Alkyl Diazo Compounds and Multiple Bonds

85%

42

Plancquaert, M.; Redon, M; Janousek, Z.; Viehe, H. Tetrahedron 1996, 52, 4383.

86%


Bowden, K.; Jones, E.R.H. J. Chem. Soc. 1946, 953.

+

NHR1

Ar

R2

R3 NH NN

R1

9. Sulfur Monoxide Extrusion from 1,2,6-Thiadiazine S-Oxides

Ar

R2 R3

NS

NPyridine

O

R1Ar

R2

R3

Thionyl chloride (0.012 mol) was added to the starting diimine (0.01 mol) in pyridine (50 mL) at 0 °C. The stirredmixture was warmed to rt and after 2 h, 4N H2SO4 was added. The intermediate thiadiazine S-oxide was extractedinto ether and purified by recrystallization from hexane. Heating this intermediate in toluene at 90 °C for 8 h, followed by concentration in vacuo and recrystallization from hexane gave the desired pyrazole in 80% yield.

toluene+

Barluenga, J.; Lopez-Ortiz, J.F.; Gotor, V. J. Chem. Soc., Chem. Commun. 1979, 891.Barluenga, J.; Lopez-Ortiz, J.F.; Tomas, M.; Gotor, V. J. Chem. Soc., Perkin. Trans. 1 1981, 1891.

90°C

CH2N2Et2O

EtO2CCHN2

SOCl2

-60 ˚C, 0.5 h

(Method B)

R2

Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Prigden, L. N. J. Org Chem. 1997, 62, 8449.

2. TOSMIC Reagent for Synthesis of 4,5-Disubstituted Imidazoles

K2CO3

CHCl3/H2O

A solution of amidine (30 mmol) and 2-bromo-3-(1-methylethoxy)-2-propenal (45 mmol) in chloroform (60 mL) andwater (7.5 mL) was treated with solid potassium carbonate (45 mmol) and stirred at ambient temperature for 18 h.After cooling, the reaction mixture was partitioned between methylene chloride and water. The organic phase waswashed with water and brine and dried (MgSO4). The product was isolated by flash chromatography on silica with 5% (v/v) acetonitrile/methylene chloride as eluent in 83% yield.

1R

N

NHR2Br X

Oi-PrH

1. Synthesis of 1,2,5-Trisubstituted Imidazoles

Method A (Preparation of 5-benzyl-4-butylimidazole). To a cold (-78 ˚C) solution ofN,N-bis(trimethylsilyl)formamide (1.6 mL, 7.5 mmol) in anhydrous THF (10 mL) was added slowly a solution ofn-butyl lithium in hexane (4.7 mL, 1.6 N, 7.5 mmol). After the mixture was stirred at -78 ˚C for 30 min, a solution of the anion of tosylbenzylmethyl isocyanate [prepared by addition of a solution of lithium bis(trimethylsilyl)amide(7.15 mL, 1 N, 7.16 mmol) to a cold (-55 ˚C) solution of tosylbenzylmethyl isocyanate (2.0 g, 7.16 mmol) inanhydrous THF (5 mL) followed by stirring for 30 min at -50 to -60˚C] was added by cannula. The resultantsolution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h) and was then stirred at room temperature for16 h. The reaction mixture was concentrated, the residue was diluted with 30 mL distilled water, and the solutionwas adjusted to pH = 10 by the addition of 1 N HCl. Sodium chloride was added to saturate the aqueous solutionand this solution was extracted with ethyl acetate/ methylene chloride (4 : 1). The combined organic extracts weredried over anhydrous sodium sulfate and potassium carbonate, concentrated, and purified by flash chromatographyon silica gel to give 5-benzyl-4-butylimidazole (1.0 g, 66%).

Method B. (General procedure). To a solution of an aldehyde (1.5 mmol) in anhydrous THF (2 mL) at -60 ˚C wasadded dropwise a solution of lithium bis(trimethylsilyl)amide (1.5 mmol). The resulting solution was warmed to -30˚C (20 min), and then a solution of the anion of tosylmethylisocyanate (1.4 mmol) was added (prepared asdescribed in Method A). The resultant solution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h), andthen stirred at room temperature for 16 h. The reaction mixture was worked up as described in Method A.

-78 ˚C, 0.5 h

(Method A)

N

N1R

X

4R-Li OCHN(SiMe3)2

4R-CHO

4R NSiMe3

Li-N(SiMe3)2HN N

Ten Top Methods to Synthesize Imidazoles

4R = CH3, n-C4H9, C6H5 5R = H, CH3, C6H5CH2

R4

Shih, N. Y. Tetrahedron Letters 1993, 34, 595.

5R


TosCR5LiNC

1R = n-C4H9, C6H5 2R = C6H5, CH2Ph-4-CO2H, CH2-1-naphthyl

X = CHO, CN

43

1R

EtON CH2CO2R2

1R

EtO N

H

H

N

N

H

OEtR1

1R

EtO CO2R2

2RO2CCH2

H

1R = CH3, C4H9, (CH3)2CHCH2, (CH3)3C, C6H11

N

NR1

R1 CONHCH2CO2R2

2RO2CCH2

N

NR1

R1 CO2R2

R2O2CCH2

- 2EtOH

H

Morel, F.; Lerestif, J. M.; Bazureau, J. P.; Hamelin, J.; Tonnard, F. Heteroatom Chemistry 1996, 7, 187.


CO2R2

1R = CH3, (CH3)2CH, C6H5CH2, C6H52R = CH3, (CH3CH2)2, CH2CCH

4. Historic Method Improved by Acidic Conditions To Furnish 1-Alkylimidazoles

Gridnev, A. A.; Mihaltseva, I. M. Synthetic Communications 1994, 24, 1547.

3. Acid Induced Synthesis of 1,2,5-Trisubstituted-4-Imidazoyl Glycinates

AcOH

70 ˚C -1RCO2Et- 2ROH

A freshly distilled imidate (40 mmol) and glacial acetic acid (13.2 mmol, 0.79 g) were heated to 70 ˚C under drynitrogen with vigorous stirring for an appropriate reaction time as monitored by tlc. After elimination of thecorresponding alcohols and ester under reduced pressure, the crude reaction mixture was titurated with dry ethylether. After standing 24 hours at 4 ˚C, the precipitated product was filtered, washed with ether, dried in a desicator over CaCl2, and recrystallized from a mixture of Et2O/CH2Cl2 to yield the purified product in 96 % yield.

A 100 mL flask equipped with a mechanical stirrer dropping funnel and reflux condenser was loaded with glyoxal (0.1mol, 11.5 mL of 40% aqueous solution), formaldehyde (0.1 mol, 15 mL of 20% aqueous solution) and thealkylammonium salt (0.1 mol), which had been obtained by acidification of the appropriate alkylamine solution in 8-15 mL of water with phosphoric acid until the pH = 2. The reaction mixture was warmed to 90-95 ˚C and a saturatedaqueous solution of 0.1 mol ammonium chloride was added to the stirred reaction mixture over a period of 60-75min. After an additional 10 min of stirring at 95 oC, the crimson reaction mixture was chilled, solid KOH was addedand the mixture was extracted with ethyl acetate. The combined extract was evaporated and distilled under vacuumto provide the product in 50% yield.

O O

[RNH3]XH H

O

H H N

N

R+

44

+ -

N

N

1R

X(CH3)n

Ph

R

N

N

1R

X(CH3)n

Ph

R

CH2

I

Zn CH2IN

R

N

H

X(CH3)n1R

Ph

N

R

N

HPh

R1

1R N CO2CH3

2RX NXR2

CO2CH3

R1

(CH3)2N

NXR2

CO2CH3

R1

RNH N

1R

R

CO2CH3

5. Simmons Smith Reagent for Imidazole Synthesis

Jayakumar, S.; Ishar, M. P. S.; Mahajan, P. Tetrahedron Letters 1998, 39, 6557.

(CH3)2N OEt

H OEt

To a well stirred solution of zinc-copper couple (0.1 mmol) in dry ether (20 mL), under a nitrogen atmosphere, asmall crystal of iodine and diiodomethane (0.25 mmol) are added, and the reaction mixture is heated to reflux with stirring for 10 min. A solution of 1,3-diazabuta-1,3-diene (0.1 mmol) in dry THF (25 mL) is added slowly and thereaction mixture is again heated to reflux for 3-4 h and monitored by tlc. The solvent is removed under reducedpressure and the residue is treated with water (100 mL) and CHCl3 (75 mL). The reaction mixture is filtered, theresidue is washed with CHCl3 (30 mL) and the combined organic extract is washed with water, dried over Na2SO4and evaporated to give the crude product which is purified by column chromatography on silica gel using hexane-ethyl acetate mixture (10:1) as eluent.


1R = CH3 , CH3S2RX = OEt, SCH3

R = N(CH3)2, NH(CO2CH3), PhCH2NH2

R = H, CH3 1R = N(CH3)2, N(CH2)5, N(CH2)4O

X = S, n = 1

X = N, n = 2

- 2RXH

CH2I2,Zn(Cu)

Et2O/THF

A solution of imidate (1.0 mmol) and N,N-dimethylformamide diethylacetal (1.1 mmol) in acetonitrile was heated to reflux for 72 h. Removal of solvent under reduced pressure was followed by addition of amine (1.1 mmol) andheating to 70 ˚C for 3 days. The crude product was purified by column chromatography to provide the imidazolecarboxylate in 70 % yield.

Acetonitrile RNH2

-(CH3)2NH

Jouneau, S.; Bazureau, J. P. Tetrahedron Letters 1999, 40, 8097.

HN

6. Aza-Annulation Provides Imidazole-4-Carboxylates

45

Acetonitrile

reflux

R = CH3, C6H5, C6H5CH2NH, C2H5O

Allylamine (5.05 mmol) is added to a solution of 3-hydroximino-2,4-pentadione (5 mmol) in anhydrous acetonitrile(5 mL). The violet solution is stirred at room temperature for 12 h and then heated at reflux for 2 h. The mixture is concentrated and purified by column chromatography on silica gel using ethyl acetate as eluent. Recrystallizationfrom ethyl ether-hexane provided the pure product in 65 % yield.

1RCH2

2R N OH

Veronese, A. C; Vecchiati, G.; Sferra, S.; Orlandini, P. Synthesis 1984, 300.

8. Imidazoles via Hetero-Cope Rearrangement

Cl Ph

NR3

N Ph

3R

2R N

NHR3Ph

O

7. Synthesis of 2-Vinylimidazole Derivatives

1R

N

N

1R

2R

Ph

R3p-TsOH

NEt3

1R = 2R = (CH2)43R = CH3

Lantos, I.; Zhang, W.; Shui, X.; Eggleston, D.S. J. Org. Chem. 1993, 58, 7092.

To a cooled solution of N-methylbenzenecarboximidoyl chloride (R3 = Me) (3.1 g, 20 mmol) in dry THF (50 mL) at-78°C was added a 3.5 molar excess of triethylamine. The mixture was stirred for 0.5 h, and a solution of cyclo-hexanone oxime (1.1 g, 10 mmol) was added. The solution was heated at reflux for 12 h. Water was added andthe mixture was extracted with CH2Cl2. The combined organic layer was washed with saturated NaCl and dried.The solvent was removed under reduced pressure and the crude product was purified by column chromatography. N-Methyl-N-[2-[[(methylamino)phenylmethylene]amino]-1-cyclohexen-1-yl]benzamide was obtained as an oil in52% yield. The amidine (1 g, 2.8 mmol) was heated with p-toluenesulfonic acid (2.5 molar equiv) in toluene atreflux in a Dean-Stark apparatus for 12 h. The solution was cooled to ambient temperature and was washed with 1N NaOH solution. The mixture was concentrated under reduced pressure and purified by chromatography. Theproduct was obtained as white crystals in 97% yield.


R CH3

O O

N

OH

H2NN

N

H

RO

46

4RBr

O

4RNHR1

O N

N

NO

NH

R5

NR2

O

H2N R5

O

ONHN

R5

O

N N

R5

O

2R

9. 1,4-Disubstituted Imidazoles

1RNH2

ether, -78°

HCONH2

∆1R = t-Bu4R = benzyl

82% yield

Under an argon atmosphere, a pressure-equalizing dropping funnel charged with the α-bromo ketone (10.0 g) indiethyl ether (20 mL) was attached to a 300-ml round-bottomed flask, containing a magnetic stir bar and asolution of the primary amine (3 equiv) in diethyl ether (70 mL). The solution was stirred while cooling in a dryice-acetone bath to -78°C. The solution of the bromide was added dropwise over 15 min, and the mixture wasstirred for an additional 1 h at -78°C . The cooling bath was removed and the mixture allowed to warm to roomtemperature and to stir for several hours, until precipitation of the HBr salts appeared complete. The contents ofthe flask were poured into a separatory funnel and shaken with a small amount of 15% aqueous NaOH until thewhite solids dissolved. The ether layer was washed with water and brine and dried over MgSO4. Filtration andconcentration of the solution afforded the crude amino ketone as a light yellow oil. This material could be isolated by vacuum distillation or flash chromatography, but typically was used immediately in its crude form.

Sorrel, T.N.; Allen, W.E. J. Org. Chem. 1994, 59, 1589

R2

R1

10. Imidazoles From 4-Aminoisoxazoles

R1

Reiter, L. J. Org. Chem. 1987, 52, 2714.

R1

A 300-mL two necked flask with an attached air-cooled condenser was charged with formamide (35 mL), whichwas heated to 180°C under argon with stirring. A pressure-equalizing dropping funnel containing the amino ketone was fitted to the reaction vessel, and the amino ketone was added dropwise over 1 h. The mixture was allowed toreact for an additional 2-3 h at 180°C. After cooling, the dark reaction mixture was treated with an equal volume ofwater and 20 mL of 15% aqueous NaOH. The mixture was extracted twice with 200-mL portions of toluene, whichwere combined, washed with water and brine, and dried over Na2SO4. The drying agent was removed by filtration,and the toluene was evaporated at reduced pressure to yield a yellow-brown oil which was purified by flashchromatography with ethyl acetate as the eluent. Short-path distillation under reduced pressure with use of aKugelrohr apparatus afforded the colorless, hygroscopic 1,4-disubstituted imidazole.

R1


4R

NO

N

R5

R2

OR1

4R 4R

4R4R

After acylation by standard procedures, 4-(acylamino)isoxazole was hydrogenated at 40 psi over 10 % palladium on carbon in ethanol (ca. 10 mL/mmol of reactant). After 1 h, the reaction was usually complete by tlc. The catalyst isremoved by filtration and washed with ethanol. The filtrate containing the intermediate β-amino-α,β-unsaturatedketone was treated with NaOH (pellets, 1.1 equiv) at reflux for 1 h. Solid NH4Cl (1.2 equiv) was then added, thereaction allowed to cool to r t, and the ethanol removed in vacuo . The residue was slurried in acetone and themixture filtered. Concentration of the filtrate gave the crude product which is purified by column chromatography orrecrystallization to give pure imidazole in 80 % yield.

R1

4R

H2, Pd/C

EtOH, RT

AcylatingReagent

NaOH

EtOH

R1 = CH3, Ph, PhCH2

R2 = H, CH3, CH2CH3, Ph, CF3, C(CH3)3

R4 = H, CH3

R5 = H, CH3

-H2O-

47

SO2CH2

Me

N C N

OPh

N

NH

Ph

NH

CO2MeMe

N

S

Ts

-

Et2OCCH2COMe

van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337

+

NH

NO2Ph

NH

CNPh

NH

CO2EtPh

Ts

Ts

van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337

MeNO2

tBuOK

S

tBuOK92 %

99 %

94 %

van Leusen, D.; Flentge, E.; van Leusen, A. M. Tetrahedron 1991, 47, 4639 van Leusen, D.; van Echten E.; van Leusen, A. M. J. Org. Chem. 1992, 57, 2245

PhCN

1) PhCHO/nBuOK

64 %

NaH

MeCH=CHCO2Me

KOH

70 %

60 %

53 % Ph

N

TsH

Ph CN CH2Ts C

Use of Tosmic Reagent for Heterocyclic Synthesis

n-BuLi (2 eq.)

PhCOOEt

2) POCl3/Et3N

PhCSCH2CO2H+

Me SO2

Et2OCCH2CN

n-BuLi (2 eq.)

tBuOK

Ts =

SO2CH2

Me

N C

SO2CH2

Me

+

N C

-

+ -

SO2CH2

Me

N C+ -

+ -+ -

Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1972, 5777


van Nispen, S. P.J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 3723

van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S111. Zwanenburg, B.; Klunder, A. J. H. in Perspectives in the Organic Chemistry of Sulfur.; Elsevier Science Publishers: Amsterdam, 1987, pp 119-144 van Leusen, A. M.; Schut, H. Tetrahedron Lett. 1976, 285

48

TsCH2N C

O

MeO

t-BuOK

CN

MeO

Br

OTHP

TsCH2N CNaOH

OTHP

Ts

NC NaOH

Br

OTHP

C

OTHP Ts NC OTHP(NH4)2SO4

O

O

CHO

MeO

MeOTsCH2N C

MeO

MeO

Ts

NC

NH

OMe

OMe

MeO

MeO

Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. J. Org. Chem. 1977, 42, 3114.

49

Applications of Tosmic for Complex Molecule Synthesis

1. Reductive Cyanation

+

2. Use as a Connective Reagent

69%

+

Yadav, J. S.; Gadgil, V. R. Tetrahedron Lett. 1990, 31, 6217.

3. Knoevenagel-type Condensation

+

1) t-BuOK

2) POCl3, i-Pr2NH

64%

papaverine

Barrett, A. G.; Barton, D. H.; Falk, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1979, 652.

van Leusen, D.; van Leusen, A. M. In Organic Reactions; Overman, L. E., Eds.; Wiley & Sons: New York, 2001, 57, 417; Tandon, V. K.; Rai, S. Sulfur Reports 2003, 24, 307.

82%

75%

H


t-BuOK

t-BuOK

TsCH2N CN

NO

H

NaOMeN

NN

O

TsCN

MeO

O

MeO

MeO

ON

CH2O

Na2CO3

TsCH2N C

Van Leusen, D.; Batist, J. N.; Lei, J.; Van Echten, E.; Brouwer, A. C.; Van Leusen, A. M. J. Org. Chem. 1994, 59, 5650.

50

4. Synthesis of Oxazoles

+

5. Synthesis of Oxazoles

35%

Dopamine D4 Receptor Ligands

Haubmann, C.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 3143.

+

96%

+

O

SH

TsCH2N Cn-BuLi

H

OH

SN

Tos

6. Synthesis of Thiazoles

+79%

Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.


TsCH2N C NH

OMe

MeO

Ph

O

Ph

NaHNH

OMe

MeO

Ph

OHN

Ph

CN

NH2

CN

N

N

CO2Me

NH2

NH

N

N HN

O

SO2NH2

MeO

O

CHO

51

7. Synthesis of Pyrroles

+55%

Black, D. S.; Bowyer, M. C.; Kumar, N. Tetrahedron 1997, 53, 8565.

8. Synthesis of Imidazoles

Fevig, J. M.; Pinto, D. L.; Han, Q.; Quan, M. L.; Pruitt, I. C.; Jacobson, I. C.; Galemmo, R. A.; Wang, S.; Orwat, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Lam, P. Y.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2001, 11, 641.

1)

2) TOSMIC, K2CO3

Benzamidine Factor Xa Inhibitors

N

N

NH CHO

N

N

N

NTs

N

N

N

N

TsCH2N CDBU

Na2HPO4

9. Synthesis of Pyrimidines

Minguez, J. M.; Vaquero, J. J.; Alvarez-Builla, J.; Castano, O.; Andres, J. L. J. Org. Chem. 1999, 64, 7788.

+Na/Hg

80%55%


+TsCH2N CN CHO

N

ON

N

S

Ts

S

N

SMeS

Ts

K2CO3

82%

+N CHO

H

van Leusen, A.M.; Wildeman, J. Synthesis 1979, 501.

+ CS2BuN+Br-, 10% NaOH

Bu4N

90%

To a mixture of 2-pyridinecarboxaldehyde (0.01 mol) and tosylmethyl isocyanide (1.9 g, 0.01 mol) in 30 mL ofMeOH was added K2CO3 (1.4 g, 0.01 mol). The solution was refluxed for 2 h and the solvent was removedunder reduced pressure. The residue was poured into ice water and extracted with ether. The organic layer was washed with 2% HCl and water and dried over Na2SO4. After filtration and evaporation of the solvent, the cruderesidue was distilled (95-98°C/0.15 torr) to give an 82% yield of the desired oxazole.

To a solution of tosylmethyl isocyanide (1.9 g, 10 mmol), carbon disulfide (5 mL) and chloroform (10 mL) wasadded tetrabutylammonium bromide (3.5 g, 11 mmol) and 10% NaOH (10 mL). The mixture was stirred for 1.5 hat rt and the layers were separated. The aqueous layer was extracted with chloroform and the combined organic layers were washed with water and dried over MgSO4. After filtration and removal of the solvent, the cruderesidue was taken up in chloroform (20 mL), methyl iodide (2.8 g, 20 mmol) was added, and the mixture wasstirred for 3 h at rt. The solvent was removed and the crude solid was washed with methanol, ether, and dried.Recrystallization from chloroform/methanol gave 2.6 g (90%) of the desired thiazole.

N N

Ts

Reaction with Carbon Disulfide to Form Thiazoles

Tosmic Reagent and Its Use in Heterocyclic Synthesis

Reaction with Aldehydes to Form Oxazoles

R1

R2

R3R3R2

R1

Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A.M. Chem. Pharm. Bull. 1979, 27, 793.

Formation of Pyrrolo[1,2-c]pyrimidines

DBU, THF

61-82%

Minguez, J.M.; Vaquero, J.J.; Garcia-Navio, J.L.; Alvarez-Builla, J. Tetrahedron Lett. 1996, 37, 4263.

To a mixture of 214 mg (1.1 mmol) of tosylmethyl isocyanide and 167 mg (1.1 mmol) of DBU in 2 mL of THF was added 95 mg (1 mmol) of pyrrole-2-carboxaldehyde in 2 mL of THF. The mixture was stirred at rt for 2 h andthen neutralized with acetic acid. The solvent was removed under reduced pressure and the residue waschromatographed on silica gel and recrystallized from CH3CN to give the desired product in 82% yield.

MeITsCH2N C

TsCH2N C

52


TOSMIC

NPh

Cl

N

N

Ph

Ts

Ph

N

NC

TsH

Ph

Ph

Ph

CN

N

Ph CN

H

N CTs

CH3

A solution of tosylmethyl isocyanide (390 mg, 2.0 mmol) and N-phenylbenzimidoyl chloride (430 mg, 2.0 mmol) in 5 mL of DME was added over 15 min to a suspension of NaH (50 mg, 2.0 mmol) in 5 mL of DME at rt. The mixturewas stirred for 45 min and then slowly poured into water. The precipitate was collected and recrystallized frombenzene/hexane to give 450 mg (60%) of the desired imidazole.

CO2tBu

van Leusen, A.M.; Wildeman, J.; Oldenziel, O.H. J. Org. Chem. 1977, 42, 1153.

NaH

60%

N

CO2tBu

SO2Ph

Reaction with Imidoyl Chlorides to Form Imidazoles

+tBuOK (2 eq.)

CH3

88%

To a stirred solution of t-BuOK (1.0 g, 13 mmol) in THF (30 mL) at -30 °C was added a solution of tosylmethylisocyanide (1.2 g, 6.0 mmol) in THF (10 mL). The mixture was stirred for 4 min and a solution of cinnamonitrile (0.77 g, 6.0 mmol) in THF (10 mL) was added over 4 min. After stirring for 15 min at -10 °C, the mixture was poured onto50 g of ice. The THF was removed under reduced pressure and the precipitate was filtered, washed with water,and dried under vacuum to give 0.89 g (88%) of the desired pyrrole.

Reaction with Olefins to Form 3,4-Disubstituted Pyrroles

N

SO2Ph

van Leusen, D.; van Echten, E.; van Leusen, A.M. J. Org. Chem. 1992, 57, 2245.

CH3

NtBuO2C

SO2PhN

N

H

HO2C

OMe

OH

Ac

Sequential Tosmic Reactions in the Synthesis of PDE II

+1) NaH, HMDS

2) PhSO2Cl, NaH HMDS, Imidazole

TosMICNaH, HMDS

PDE II

H+

Ph+TsCH2N C

TsCH2N C


53

:

N

S R1

R

N

S

n-C8H17

NH2

Top Ten Methods to Synthesize Thiazoles

1. Modified Hantzsch Type Synthesis

Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-W.; J. Org. Chem., 2003; 68(20); 7887-7888.

To a stirred solution of (Z)-(2-acetoxy-1-decenyl)-iodane (25 mg, 0.05 mmol) and thiourea (5 mg, 0.06 mmol)in dry methanol (1.5 mL) was added triethylamine (6 mg, 0.06 mmol) under nitrogen at room temperature andthe mixture was stirred for 5 h. After removal of the solvent under reduced pressure, the residue was dissolved in a mixture of ether (30 mL) and water (10 mL). The organic layer was washed with water and brine, driedover Na2SO4, and concentrated. Purification by preparative TLC (hexane-ethyl acetate) gave the thiazole(91%) as colorless plates.

2. The Charette Synthesis

DeRoy, P. L.; Charette, A. B.; Org. Lett. 2003; 5, 4163-4165.


54

R

AcO IPh

BF4 MeOH

S

CNH2R1 , Et3N

n-C8H17

AcO IPh

BF4MeOH

S

CNH2 , Et3N

MeHN

O1. Tf2O, pyr, CH2Cl2

2. L-Cysteine HCl, pyr

90%

N

SO

EtO N

SO

EtO

BrCCl3, DBU

99%

H2N

To a solution of diispropylamine (5 mL, 51 mmol) in anhydrous THF (80 mL) at -20 oC was added a solution of butyllithium (1.6 M in THF), stirred for 15 min, and cooled to -78 oC. A solution of the thioester (6 g, 51 mmol)in THF (20 mL) was cannulated slowly into the yellow solution and stirred for an additional 15 min.Chlorotrimethylsilane (6.4 mL, 51 mmol) was added, and the solution was stirred for an additional 1 h at-78oC. The solution was warmed to rt over a 1 h period before being diluted with pentane (150 mL) andwashed with phosphate buffer pH 7 (100 mL). The organic layer was dried over Na2SO4, concentrated, anddistilled under vacuum to furnish the (Z) silylketene thioacetal. To a solution of thiazoline (4.8 g, 24 mmol) inCH2Cl2 (90 mL) at 0 oC was added DBU (7.2 mL, 48 mmol) and the resulting mixture was stirred for 10 min.Bromotrichloromethane (2.4 mL, 24.1 mmol) was added dropwise and the reaction was then warm up to rt.After 1 h, the reaction was quenched with a saturated aqueous solution of NaHCO3 and transferred in aseparatory funnel and the aqueous phase was discarded. The organic phase was dried over anhydrousMgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by columnchromatography on silica gel (20% EtOAc/hexane) to afford the thiazole (4.8 g, 99%) as a colorless oil.

.

Synthesis of 2,4-Disubstituted Thiazoles from (Z)-(2-Acetoxyvinyl) phenyl-iodanes

Synthesis of Thiazole from Thiazoline

R2 NH2

C

N

SH

S R1

NH

S R1

R2N

S R1

R2

H2N

NH2

C

N

N

S SHH2N

EWGCH2N C-R OEt

S+N

S

EWG

REWG

N

S

R OEt

-

+

3. Cook-Heilbron Type Synthesis

+

α-Aminobenzyl cyanide (13.5 g) was refluxed in ether (250 mL) with carbon disulphide (10 g) for 8 h. Upon cooling, large yellow crystals were deposited. The yield of yellow crystals (12.8 g) was augmented byallowing the filtrate to stand in carbon disulphide overnight. The total yield of5-amino-2-mercapto-4-phenylthiazole was 19.6 g (93%).

CS2

Et2O

Cook, A. H.; Heilbron, I.; Levy, A. L.; J. Chem. Soc. 1947, 1598.

4. Isocyanide Synthesis

Reaction of α-Metallated Isocyanides with Thiono Esters

+

+

H OEt

SN

S

EtO2C

+

base

EtOH

Hartman, G. D.; Weinstock, L. M. Synthesis, 1976, 6, 681.

NaCN

N

EWGCH2N C-

A solution of ethyl isocyanoacetate (4.5 g, 40 mmol) and O-ethyl thioformate (3.6 g, 40 mmol) in dry ethanol(15 mL) was added dropwise with vigorous stirring to a suspension of sodium cyanide (0.25 g) in ethanol (10mL). An exotherm developed during the addition and the reaction mixture was heated at 50 oC for 0.5 h.The solvent was removed under reduced pressure and the resulting dark oil was extracted several times with hot hexane to give 5.8 g (92%) of the product.

C

+


55

Reaction of α-Aminonitriles with Dithioacids and their Derivatives

-

N

SNHR

5. One-pot Synthesis of 2-Aminothiazoles using Supported Reagents

A mixture of α-bromo ketone (1 mmol), KSCN/SiO2 (5 mmol) and NH4OAc/Al2O3 (6 mmol) was stirred in benzene at 80oC for 6 h, and then the used solid reagents were removed by filtration. The filtrate wasevaporated to leave a crude product, which was purified by column chromatography over silica gel.

6. Synthesis of 2-Acylaminomethylthiazoles

Henkel, B.; Sax, M.; Domling, A. Tetrahedron Letters 2003, 44, 3679-3682.


56

Kodomari, M.; Aoyama, T.; Suzuki, Y.Tetrahedron Letters 2002, 43, 1717-1720.

R1R2

O

Br

R1R2

O

SCN

R1

R2

KSCN/SiO2 NH4OAc/Al2O3

PhBr

O

Ph

N

S

HN

Ph

Ph

KSCN/SiO2- NH3OAc/Al2O3

Deprotected Rink resin (purchased from Pepchem, Tubingen) (200 mg, 0.21 mmol) was washed with 3 mL oftrimethylorthoformate. Isobutyraldehyde (0.19 mL, 2.1 mmol) was dissolved in 3 mL of trimethylorthoformateand added to the resin which was agitated for 16 h. The resin was filtered and washed withtrimethylorthoformate, a 1:1 mixture of dichloromethane and methanol and finally with methanol. Subsequently, 0.19 g of 3-(N,N-dimethylamino)-2-isocyanoacrylate (1.3 mmol) and 0.15 ml of thiobenzoic acid (1.3 mmol)dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1) was added to the resin and the mixturewas allowed to react for 16 h. The resin was filtered and washed twice with dichloromethane and methanol andagain three times with dichloromethane. The resin was treated with 3 mL of 50% trifluoroacetic acid indichloromethane for 2 h. The cleavage mixture was filtered and the resin washed twice with dichloromethane.The combined solution was evaporated to dryness. The crude product was obtained in 71% yield and waspurified via preparative HPLC using a methanol/water gradient.

97%

NH2 CHOR1

MeOOC

O

R2 SH 16h, 20oC

N

SMeOOC R1

N R2

O

16h, 20oCN

S

MeOOC

R1

NH

O

R2 31~96%

Reaction of α-bromo ketone with KSCN/SiO2 and NH4OAc/Al2O3

Multicomponent solid-phase synthesis

N

S

Ph

7. Synthesis of 4-Substituted 2-Phenylaminothiazoles from Amidines

Romero-Ortega, M.; Aviles, A.; Cruz, R.; Fuentes, A.; Gomez, R. M.; Plata, A.; J. Org. Chem. 2000, 65, 7244.

+


57

NH

Ph NH2

HX Et N C SNaOH/H2O

THF / 0oC CN N

H

S

EtPh

NH2

Et3N

C6H5COCH2Br

Ph

O

NH

Et

A suspension of amidine salt (1 equiv) in THF (2-5 mL/mmol amidine) was added at 0 oC to aqueous sodium hydroxide (1equiv) and phenyl isothiocyanate (1 equiv), and the reaction mixture was stirred for 1-2 h at this temperature. The mixture was then diluted with ethyl acetate (20 mL), and the organic phase was washed with saturated sodium chloride solution and dried (Na2SO4 ). Evaporation of the solvent in vacuo gave the crude products as a solid. The pure material was obtained after crystallization from hexane-dichloromethane.

The R-bromo carbonyl compound (1 equiv) was added slowly at room temperature to a stirred solution of the N-phenylthiocarbamoylamidine (1 equiv) in anhydrous THF (2 mL) containing anhydrous triethylamine (1 equiv) maintained under a nitrogen atmosphere. The reaction mixture was stirred for an additional 2-3 h, diluted with ethyl acetate (20 mL), the mixture was washed with saturated NH4Cl solution (30 mL). The organic phase was separated, dried (Na2SO4),and evaporated in vacuo.

85%

CN N

S

EtPh

NH2

Ph O

CN N

S

EtPh

NH2

Ph OH

-NH3

68%

R1 O

R2 X

NH2

S R3

R1 O

R2 S R3

NH2+ N

S R3

R1

R2

CH2Br

EtO2C O

S

NH2 HN Ph

O

N

S

MeO2CHN Ph

O

8. Hantzsch Type Synthesis

X-

+

+MeOH

Li, G.; Warner, P. M.; Jebaratnam, D. J. J. Org. Chem., 1996, 61, 778.

Ethyl bromopyruvate (11.6 g, 60 mmol) was added dropwise, over a 0.5 h period, to a 50 oC solution of thethioamide (11.5 g, 59 mmol) in methanol (100 mL) after which time the reaction was refluxed for an additional 2 h. Most of the product crystallized when the solution was set aside at room temperature overnight. The filtratewas evaporated, redissolved in benzene, washed successively with a saturated aqueous sodium bicarbonateand water, dried over anhydrous sodium sulfate, and evaporated. Recystallization of this residue frommethanol provided 12 g (74%) of the product.

Reaction of amidine salt with phenyl isothiocyanate

Condensation of α-Halocarbonyl Compounds with Thioamides

NHR2

OO

R1R3

N

S OH

R1

R2

NH

HN CO2Me

OO

NH

S

N

9. Gabriel Type Synthesis

CO2Me

heat

P2S5

P2Cl5

Uchikawa, O.; Fukatsu, K.; Aono, T. J. Heterocyclic Chem. 1994, 31, 877.

pyridine

To a solution of the diamide (5.2 g) in pyridine (50 mL) was added phosphorous pentasulfide (5.4 g) and themixture was heated at 100 oC for 5 h. After being cooled to room temperature, a saturated aqueous sodiumhydrogen carbonate solution was added to the reaction mixture, and the product was extracted with chloroform.The organic layer was washed with water and dried over magnesium sulfate. The filtrate was concentrated andthe residue was purified by column chromatography. The residue was recrystallized from ethyl acetate to yield 2.8 g (54%) of the product.


R1 Br

R2 O

HS CH3

O

S

OOR2

CH3R1

N

S CH3

R2

R1

R1 Br

R2O

HS R3

O N

S R3

R2

R1

Et3N

HOAc

NH4OAc

10. Dubs Type Synthesis

+

2-Bromo-butanone (15 g, 0.1 mol) was added to a solution of thioacetic acid (7.6 g, 0.1 mol) in glacial aceticacid (84 mL), combined with ammonium acetate (27 g, 0.35 mol), and kept at reflux for 4 h. Afterneutralization with a saturated sodium hydroxide solution and extraction with pentane, the combined extractswere dried and concentrated. The residue was distilled through a Vigreux column to afford 9.1 g (72%) of the product .

Dubs, P.; Stuessi, R. Synthesis, 1976, 6, 696.

+NH4OAc

HOAc

58

Reaction of α-Acylaminoketones with Phosphorous Pentachloride

Condensation of α-Acylthioketones with Ammonia

Dry methylene chloride (25 mL) was cooled to 0-5oC with an ice/water bath under nitrogen. Thionyl chloride (5 mmol) was added dropwise and the solution was stirred for 10 min. Pyridine (5 mmol) was added and the mixture was allowed to stir for another 15 min at 0oC. The oxime in dry methylene chloride was added dropwise to the solution over a period of 15 min. The solution was stirred for 1 h at 0oC, warmed to room temp, and was then stirred for another 8-10 h. The reaction mixture was diluted with 60 mL diethyl ether, washed with 10% HCl, saturated sodium bicarbonate, distilled water, and brine. The organic phase was dried over MgSO4. Filtration, followed by removal of the solvent and silica gel column chromatography gave the isothiazole in 75-90% yield.

1. From αααα-Oxo Ketene Dithioacetals

2. Conversion of 2,5-Disubstituted Furans into Isothiazoles

A solution of ethyl carbamate (4.3 mmol), SOCl2 (4.3 mmol), and pyridine (2.0 mL) in benzene (20 mL) was stirred under nitrogen at ambient temperature for 30 min. The appropriate furan (1 mmol) was added and the mixture was heated at reflux until the starting material was consumed. The solvent was removed under reduced pressure and the the resulting residue was dissolved in CH2Cl2 (15 mL), washed with HCl, H2O and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography giving the isothiazole in 56-100% yield.

R. Karl Dieter and Hsiu Ju Chang; J. Org. Chem. 1989, 54, 1088-1092

Laaman, S.M.; Meth-Cohn, O.; Rees, C.W.; Synthesis 1999, 5, 757-759

R SCH3

SCH3N

R1

HO

NS

R R1

SCH3

SOCl2, Pyridine

O R1R SN

R1

R

O

ethyl carbamate, SOCl2, pyridine in refluxing benzene

Top Ten Methods to Synthesize Isothiazoles

3. Oxidative Cyclization of Imino Thioamides

R1

NH

NH2

S

R2

NS

R1 R2

NH2

Goerdeler, J.; Pohland, H.; Angew. Chem. , Int. Ed. Engl. 1961, 2950

A 1.9 g sample of the β-iminothioamide was taken up in 80 mL of CHCl3 in an ice bath. A mixture of 1.6 g of bromine in a small amount of CHCl3 was added dropwise. After a short period, the hydrobromide salt precipitated out of solution. The mixture was stirred for 5 min and the salt was filtered. Recrystallization from ethanol/ether gave the isothiazole in 85% yield.


oxidation

59

4. Cyclization of ββββ-Thioacrolein with Liquid Ammonia

NS

O

H SRliq. NH3

Wille, F.; Capeller, L.; Steiner, A. Angew. Chem. , Int. Ed. Engl. 1962, 335

Wille, F.; Schwab, W.; Schmitzer, J.; Jochum, C. Chem. Ber. 1997, 110, 264

A 67 g sample of the acrolein derivative was taken up in 70 mL of liquid ammonia at -78 oC. The mixture was stirred until a bright yellow solution had formed. The ammonia solution was left to evaporate at roomtemperature and the residue was steam distilled and this was followed by extraction of the distillate with etherand drying over KOH to give 17.7g of the isothiazole (60% yield).

5. Use of Diene Derivatives for Isothiazole Formation

Cl

ClCl

Cl

ClNO2

SN

Cl

Cl CCl3S8

heat

Kaberdin, R.V.; Potkin, V. I.; Oldekop, Yu. A.; Zh. Org. Khim. 1990, 26(7), 1560-166

The polychloro nitrodiene was heated with neat sulfur to give the isothiazole in 52% yield.


NH2

RX

+S

SN

ClCl

ClS

NNC

RX

6. Use of Primary Enamines for Isothiazole Formation

Clarke, D,; Emayan K.; Rees C.W.; J. Chem. Soc., Perkins Trans. 1, 1998, 77

A mixture of the enamine (3 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (3 mmol) indichloromethane (25 mL) was stirred at room temperature for 1 h. Pyridine was added to the mixturewhich was allowed to stir for an additional 30 min. The product was separated by flash chromatography on silica gel eluting with 1:3 dichloromethane/pentane to give the isothiazole in 40-78% yield.

+

-

60

7. From Nitrile Sulfide Cycloaddition Chemistry

R NH2

O SN

O ORC NR S

SOCl2 heat

-CO2

NS

NS

R R1

R2

R R1

R2

CC

R1

R2

CHCH

R1

R2

Oxathiazolone in xylene was heated (5 h) under reflux with 10 equiv of diethyl furmarate until thestarting material was consumed. After the evaporation of solvent and dipolarophile, by-products were removed by distillation and/or recrystallization (40-80% yield). The resulting isothiazolone (1.4 mmol)in dichloromethane (20 mL) was stirred vigorously with 8% aqueous NaOCl (40 mL) andbenzyltriethylammonium chloride (0.2 mmol) until no starting material remained (5 h). The organiclayer was separated, washed with water, dried over MgSO4, and concentrated under vaccum. Thecrude isothiazole was purified by recrystallization and/or distillation in 86-92% yield.

Crosby, J.; McKie, M. C.; Paton, M. R.;Ross, J. F. ARKIVOC 2000, 1(5), 720-734


8. From Allylic Derivatives using Trithiazyl Trichloride

R4 R1

R2

R3

SN

R4R3

R2

(NSCl)3

Duan, X-G.; Duan, X-L.; Rees, C.W.; J. Chem. Soc., Perkins Trans. 1, 1997, 127

Either procedure A or B was used depending on the isothiazole. In procedure A, a mixture of the allylicderivative (1 mmol) and the trithiazyl trichloride (1 mmol) in 20 mL tetrachloromethane was heated atreflux overnight. The solvent was evaporated and the residue was purified by flash chromatograhy onsilica using dicloromethane and light petroleum. Procedure B differs only in the use of 4 Ao molecularsieves (2 g) and 25 mL tetrachloromethane. The sieves were filtered and washed with dichloromethane to give the isothiazole in good yield.

9. From 1,2,4-Dithiazane Derivatives

SN

SCH3

CH3

R

SN

CH3 R

CH3

heat

Bryce, M. R. et. al, J. Chem. Soc., Perkin Trans. 1, 1992, 2295

Bryce, M. R.; Davison, G. R.; Gough, S.; J. Chem. Soc., Perkin Trans. 1, 1994, 2571

A solution of the 1,2,4-dithiazane (1 mmol) in dry toluene ( 5 mL) was heated at reflux for 18 h. The solvent was removed under reduced pressure and the mixture was chromatographed on silica gel to give the isothiazole in 55-100% yield.

+ -

oxid

Bryce, M. R. et. al., J. Chem. Soc., Chem. Comm., 1992, 478

61

NO2

CH3

NO2

NMe2

NH

O2N NH NCH3

COOC2H5

O2N

NCOOC2H5

PPA (4 eq)

Top Methods to Synthesize Indoles

1. The Leimgruber-Batcho Indole Synthesis

H

NHCl NR

R1CH3S

NH

R1

R

R.D. Clark, D. Repke, Heterocycles, 1984, 22, 195

A solution of methyl 2-methyl-3-nitrobenzoate (9.8 g, 0.05 mol) and DMFDMA (17.8 g, 0.15 mol) in 50 ml ofDMF was heated at 130 oC for 6 h. The DMF was removed under reduced pressure, and the residue wasdistilled at 120 oC (0.2 mm) to give 10.7 g (86%) of 6-carbomethoxy-β-dimethylamino-2-nitrostyrene. A mixtureof 7.0 g (28 mmol) of 6-carbomethoxy-β-dimethylamino-2-nitrostyrene in 140 ml of dry benzene containing 1.4 g of 10% Pd/C was shaken in a Parr apparatus under a hydrogen atmosphere of 50 psi for 1.5 h. The catalystwas removed by filtration and the benzene solution was washed with 5% HCl and brine, dried (MgSO4) andconcentrated. Chromatography of the residue on silica gel afforded 6.9 g (82%) of methylindole-4-carboxylate.

2. Fischer Indole Synthesis

Hughes, D. Organic Preparations and Procedures, 1993, 609Guy, A.; Guette, J-P. Synthesis, 1980, 222

Ethyl 2-(4-nitrophenylhydrozono)-propanoate (3,4-nitophenylhydrazone of ethyl pyruvate (1.5 g, 7 mmol) was added to a stirred suspension of PPA (6 g) in xylene (15 ml) at 80 oC. The mixture is heated at 110 oC for 1h, then washed with water, dried over magnesium sulfate and evaporated to dryness. The product isrecrystallized from diisopropyl ether to give the product in 83% yield.

3. The Gassman 2,3-Sigmatropic Shift Protocol

R1

To a vigorously stirred solution of 0.044 mol of aniline in 150 mL of CH2Cl2 at -65 oC was added dropwise asolution of 0.044 mol of t-butyl hypochlorite in 20 mL of CH2Cl2. After 5-10 min, 0.044 mol of the sulfidedissolved in 20 mL of CH2Cl2 was added causing an isotherm. Stirring was continued at -65 oC for 1 h. To this mixture was added 0.044 mol of triethylamine in 20 mL of CH2Cl2. After the addition was complete, the coolingbath was removed and the solution was allowed to warm to 25 oC. A 50 mL portion of water was added and theorganic layer was separated, dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using CH2Cl2 as the eluent. Recrystallization gave the pure indole. A solution of0.022 mol of the thioindole in absolute ethanol was stirred with an excess of Ra/Ni for 30 min. The organic layerwas decanted from the catalyst and the catalyst was washed thoroughly with ethanol, and the solvent wasremoved under reduced pressure to give the indole.

Gassman, P.G.; Cue, B.W. J. Am. Chem. Soc. 1974, 20, 5495 Gassman, P.G.;Gilbert, D. P. J. Chem. Soc. Chem. Commun. 1974, 201 Hamel, P.; Girard, Y. J. Org. Chem. 1994, 59, 6372 Ishikawa, H.; Uno, T. Chem. Pharm. Bull. 1990, 38, 2459 Gassman, P.G.; Gruetzmacher, G. J. Am. Chem. Soc. 1974, 96, 5512

Me2NCH(OMe)2

DMF, 130o

H2

Pd-C

97% 80%

LiAlH4CH3SCHCOR

NEt3

110 oC, 90 min83%


62

NRCON

OO

H

R OH Ts

N

R TsTs

H2SO4

n-Bu3SnH (1.1 equiv)AlBN (5%), CH3CN, 100 °C

4. Preparation of Indoles by Annelation of Pyrroles

Muratake, H.; Natsume, M. Heterocycles, 1989, 29, 783Muratake, H.; Natsume, M. Heterocycles, 1990, 31, 683

NC

R

NH

R1

R

To a solution of 3-cyclohexanoyl-1-(4-methylphenylsulfonyl)pyrrole (85 mg) in THF (3 mL) at -20 oC under Ar was added the Grignard reagent prepared from 2-(1,3-dioxan-2-yl) ethyl bromide (0.6 mL) and Mg (90mg) in THF (3.4 mL). After 15 min, the reaction was quenched with aqueous NH4Cl and extracted withCH2Cl2. After washing, the intermediate carbinol was obtained in 97 % yield. A portion of this productwas dissolved in 6% H2SO4 in isopropanol (4.5 mL). The solution was heated at reflux for 30 min. Aftercooling and dilution with water, the solution was extracted with CH2Cl2 and chromatographed to give theindole in 82% yield.

5. Tin-Mediated Indole Synthesis

Fukuyama, T.; Chen, X; J. Am. Chem. Soc, 1994, 116, 3127

A solution of 0.85 mmol ofthe isonitrile, 0.93 mmol of n-Bu3SnH, and 0.04 mol of AIBN in 5 mL of dryacetonitrile was heated to 100 oC for 1 h in a tightly capped culture under an Ar atmosphere. The reactionwas cooled to room temperature and 1.02 mol of triethylamine, 0.04 mmol of Pd(PPh3)4, and 1.02 mmol of bromobenzene was added. The mixture was heated for additional 5 h under Ar. The reaction mixture waspartioned between hexane and CH3CN. Ether was added to the combined hexane layer and the organiclayer was washed with a 1:1 mixture of 3N HCl and brine. The extracts were washed with brine, driedover sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by flash silicagel chromatography to give desired indole.

R1X, Pd(PPh3)4 (5%), NEt3 (1 equiv), 100 °C

63


NC N

R

H

R

NC

R1

N

R1

CSnBu3

N SnBu3

R1

N SnBu3

R1

N

R1

N R2

R1

H

HH

NC N

CO2Me

H

1) n-Bu3SnH (1.1 equiv) AIBN (5%), CH3CN, 100oC

NC N

H

H+

R2X, Pd(0)

Bu3SnH

CO2Me

OTHP

Synthesis of 3-Substituted Indoles via a Tin Mediated Cyclization

OTHP

2) H3O+


Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127

64

Synthesis of (+) Vinblastine via Radical Indole Cyclizations


Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137

65

NH

NOH

MeO2CN

N

HOAc

OH

CO2MeMeMeO

N

N

HOAc

OH

CO2MeMeMeO

N

MeO2C

Et

OTFA

OTs

Ns

NH CO2Me

MeO

OH

MeO NH

S

OR

NH

RO

S

OREt

OR

MeO2COR

NR

OREt

OR

MeO2C OR

RO

NH

CO2Bn

CO2Me

Plausible Mechanism

R NH

NH

RR

OR

RS

R NH

NH R

R

OR

SSnBu3R

SSnBu3

H

N RR

RO RO

RO

-HSSnBu3

SnBu3

(+) Vinblastine

+

Additional Methods to Synthesize Indoles


66

NH

SiEt3

Ma, C.; Cook, J.M.; et. al. J. Org. Chem. 2001, 66, 4525Wu, T.H.Y.; Ding, S.; Gray, N.S.; Schultz, P.S. Org. Lett. 2001, 3, 3827Roesch, K.R.; Larock, R.C. J. Org. Chem. 2001, 66, 412Larock, R.C.; Yum, E.K.; Refvik, M.D. J. Org. Chem. 1998, 63, 7652Larock, R.C.; Yum, E.K. J. Am. Chem. Soc. 1991, 113, 6689

To a three-neck flask (3 L) equipped with an overhead stir were charged 2-iodo-5-methoxyaniline (150 g, 0.6 mol) and the Schöllkopf derivative (265 g, 0.7 mol), as well as lithium chloride (2.5 g, 0.06 mol), sodiumcarbonate (160 g, 1.5 mol), palladium(II) acetate (1.7 g, 1 mol%), and dry DMF (2 L). The mixture wasdegassed with a vacuum pump at room temperature. The suspension that resulted was heated for 36 h at100˚C under an atmosphere of Ar. The reaction mixture was cooled to room temperature and the DMF wasremoved under vacuum. Methylene chloride (2L) was added to the residue, and the suspension that resultedwas filtered to remove unwanted salts. After removal of the CH2Cl2, the crude product was purified by flashchromatography to give 77% (223 g, 0.46 mol) of the desired 6-methoxy substituted indole.

I

NH2

CH2R

MeO MeO

CH2REt3Si

1% Pd(OAc)2, Na2CO3, LiClDMF, 100˚C, 77%

Titanium Catalyzed Indole Synthesis

Fürstner, A.; Hupperts, A.; Seidel, G. Org. Synth. 1999, 76, 142Fürstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron, 1996, 52, 7329

NH

OCl

OEt

O

A flask charged with N-(2-benzoyl-4-chlorophenyl)oxanilic acid ethyl ester (13 g, 40 mmol), titanium(III)chloride (TiCl3) (12.3 g, 80 mmol), zinc dust (10.4 g, 160 mmol) and DME (250 mL) was heated at reflux for 2 hrs with stirring. The mixture was allowed to cool to ambient temperature and then slowly filtered through ashort pad of silica washed with ethyl acetate (5 x 50 ml). The product was recrystallized from ethyl acetate /hexane to afford ethyl 5-chloro-3-phenylindole-2 carboxylate in 85% yield.

TiCl3, Zn, DME

NH

PhCl

O

OEt>85%

N

O

R3

R1

R2

O

Reductive Coupling of Oxo Amides to Indole Derivatives

[Ti]

N

R1

R2

R3

Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215

Palladium Based Strategy for Indole Synthesis


Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem. Int. Ed. 2003, 42, 4257 (& refs. therein)Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671 (refs. 2-8)Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc . 2000, 122, 5662 (refs. 2 & 3)

67

NH

R3Y

R2

YN

R2

R3

R1

NH

R3Y

R2

X

N

R3Y

NY

R

R2

R1X

X

R1

+

R

N

R3Y

XR1

X

YN

R2R1

R3

c

b,e a

a,e

a,d f

Synthesis of Carbazole Intermediate by Domino Palladium ReactionSaulnier, M.G.; Frennesson, M.S.; Deshpande, M.S.; Vyas, D.M. Tetrahedron Lett. 1995, 36, 7841

NH HN

COCF3 COCF3 Pd(PPh3)4,K2CO3

MeCN, 50oC, 19h, 52%

N

NH

NH

Bn

O O

+

N

Bn

O O

BrBr

f

c

de

ba

N N

CP2Zr

N

El El

R

Cp2Zr

R R

N

Br

RN

CP2Zr

R

N

I I

R

NH2

MeOOMe

NH2

Br

OMeMeO

OMeMeO

BrHN

OMeMeO

BrN N

I

IOMe

MeO

Me

N

INBn

N

N

N

N

Me

MeO

OMeH

Me

MeOOMe

MeOOMe

Me

Me

Bn

2 El+

Regiospecific Synthesis of Polysubstituted Indoles by Means of Zirconocene Stabilized Benzyne Complexes

Cp2Zr(CH3)Cl

Br

2 t-BuLi, THF-78oC to RT

I2, CH2Cl2

OoC

R=Bn; allyl65-70%

H

Bu4NBr3

MeCHCH2Cl2

65%

K2CO3 NaI

74%

Mol

K2CO3

96%

1. Cp2Zr(Me)Cl t-BuLi THF -78oC - RT

2. I2 CH2Cl2

BnNH2

THF

78%

2.5 mol%Pd2(dba)3P(o-tolyl)3

NaO tBu, tol 80oC 72%

10 mol% Pd/C HCO2NH4

MeOH, reflux

80%

Alkaloid Synthesis using the Buchwald Zirconium Benzyne Complex


Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797

Peat , A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028

68

NO2

R2R1

N

H

R2

R1

CH

NO2

NR

NN

R

NO2

XR

N

XR

N

R

R

N

HR

NN R

N

R

R

N

RH

RN

HR

R

+ 2CO

PdCl2(PPh3)2 SnCl2

+ 2CO

PdCl2(PPh3)2 SnCl2

+ 2CO2 (1)

+ 2CO2 (2)

Palladium Catalyzed Reductive N-Heterocyclization of Nitroarenes

[Pd], 2CO

-2CO2

[Pd]

X = CH

-[Pd]

-[Pd]X = N

[1,5] shift


Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375

69

N

Me

MeO

HN

Me

H OMe

O

ON

Me

H O

O

N

H

Me

Me

N

ON3

CO2Et

N

OOEt

OH

N

HOOEt

OH

N

H Me

N

N

O

H

Me

Me

ON

Me

N

H

N

N

O

H

H

ellipticinemurrayaquinone B murrayafoline A

N

O

H

NOH

O Ar

murrayaquinone A

PhBrreflux78%

toluene

reflux 87%

ellipticine

PhBr reflux 71%

Synthesis of Carbazole Alkaloids using the Diels-Alder Reaction of Pyranoindolones with Alkynes

ellipticine

N

H

N

N

OH

+

staurosporinine

BA

D

C

E F

from N3 or NO2

N

O

H

NOH

Ar

CO2R


Moody, C. J. Synlett 1994, 681

70

N

COOH

NN

NMe2NH

O

CH3

CH3

O

NH

CH3

CH3

N

N

ClI

N

ClLi

O

N

OCH3

O

May, C.; Moody, C. J. I. Chem. Soc. Perkin Trans. 1 1988, 247.

To a magnetically stirred solution of 3-chloro-4-iodopyridine (1.3 g, 5.4 mmol) in dry THF (25 mL) under N2 at -95 °C was added tert-BuLi (2.0 M in pentane, 5.5 mL, 11.0 mmol). There immediately resulted abright red color and after 20 min at -95 °C, furan (4.0 mL, 55 mmol) was added via syringe. The reactionmixture was allowed to warm to -25 °C over 2 h, maintaining at this temperature for 1 h, and then allowedto warm to rt overnight. The dark polymeric material was filtered and washed well with Et2O. The organicportions (300 mL) were washed with saturated aqueous NaHCO3 and the aqueous phase was extractedfurther with CH2Cl2. The combined organic portions were washed with brine, dried (K2CO3), andconcentrated in vacuo to afford 0.58 g of a dark oil. Distillation gave 0.26 g (33%) of the cycloadduct as alight amber liquid: bp 92 - 100 °C / 0.25 mm.

Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151.

A solution of pyranoindolone (76 mg, 0.36 mmol) and the triazene (180 mg, 0.93 mmol) in dry acetonitrile (15mL) was heated under reflux for 36 h. The solvent was evaporated and the residue chromatographed onsilica gel eluting with chloroform, slowly increasing to 5 % methanol in chloroform to give ellipticine (18 mg, 20 %), mp 312 - 314 °C and isoellipticine (18 mg, 20 %), mp 244 - 247 °C.

N

OTfTMS

Cl

NPhO2S

CH3

CH3

NO

Cl

NPhO2S

CH3

CH3

NO

Cl

NPhO2S

O

CH3

CH3

O

DÍaz, M. T.; Cobas, A.; Cuitián, E.; Castedo, L. Synlett 1998, 157.

2-Chloro-3-trifluoromethanesulfonyloxy-4-trimethylsilylpyridine (2.07 g, 6.2 mmol) was added portionwiseto a suspension of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole (200 mg, 0.62 mmol) and CsF (1 g, 6.2 mmol) in acetonitrile (8 mL). The mixture was stirred at rt until the mesylate was consumed, and thenthe solvent was removed and the residue was dissolved in CH2Cl2. The solution was washed with water,dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed to affordthe major isomer (170 mg, 63 %) (mp 81 °C) in addition to the minor isomer (70 mg, 26 %), mp 185 °C.

+

+

n-BuLi-78 °C, 2 h

Use Of Pyridynes for Heterocyclic Synthesis

heat

TBAFand

71


XH

E XH

E XH

E

Electrophilic substitution

Intermediates formed by electrophilic attack at C-2 and at C-3

++

X

+

X

Reaction of indoles with electrophile-preferred site is C-3

HE E

H

H+H+ H2O H+, H2O

NH

O Te Se S

+

Ring-opening reactions of furans - electrophilic substitution reactions

>> > > >

+

+

+

+

+

NH

NH

NH

NH

H

E

H E H E

O

H

H O O

HH

O

H

OH O O+

Chemical Behavior of Five-Membered π-Excessive Heterocycles

Order of Reactivity

.. ..

..

H H

.. ..

E+ E+


72

O CN

ON2

CO2EtO

CO2EtO

CO2Et

NH

OOH

NH O

(CH2)3Me

O

O O

HHO

OCH2Ph PhCH2OH

OO

SS

O O

H

SS O

O

H

HO

BF3.OEt2

hν

BF3.OEt2

HCO2H

-N2

Examples of ring-opening reactions

NEt3

Furan cationic cyclization reactions

72%

72%

(10 equiv)64%

∆

O O

Hoffman, R. V.; Shechter, H. J. Am. Chem. Soc. 1978, 100, 7934

100%

MeOH

NH

O

O

O O

O

O

CN

CHO CHO

MeO CN

R = H

R R R


Tanis, S. P.; Chuang, Y. H.; Head, D. B. J. Org. Chem., 1988, 53, 4929. Tanis, S. P.; Dixon, L. Tetrahedron Lett., 1987, 2495 Tanis, S. P.; Johnson, G. M.; McMills, M. C. Tetrahedron Lett., 1988, 4521

Hiraoka, H. Tetrahedron 1973, 29, 2955

73

N

SO2PhN Li

SO2Ph

NO

O

O

N

PhO2S O

N

CO2H

NH

O

N

CO2H

N

N

O

O

Li

Heteroaromatic lithiates - An alternative route for electrophilic substitution

NH

N

Me

Me

ERLiE

LDA

THF - 100 oC83 %

K2CO3

∆

NH

100 %

90 oC84 %

NLi

OO

NH

EI

1) 2 eq MeLi - 100 oC to rt

2) NaBH4 96 %

Indole lithiates for alkaloid synthesis

Indole lithiation at C-2 position

nBuLi

CO2

X EX Li X EX

MeOH-H2O

Ac2O

nBuLi

EI

H

El = D, Me, COPh, CO2H 59-86 %


Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 5935

Gribble, G. W. In Adv. in Heterocyclic Natural Product Synthesis; Pearson, W. H., Ed.; JAI Press: Greenwich: 1990 Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48, 607 Gribble, G. W., Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. J. Org. Chem. 1989, 54, 3264

74

SCO2Me

O

OS O

OO

New tactics for effecting Diels-Alder reactions

O

OMe

1) liq HCN

O

H

H

2) H3PO4

3) HCl, AcOH-H2O4) SOCl2, ∆

50 %

+

OMe

O

H

H

O

7 kbar, rt, 24 h

(10 g scale)

Ra-Ni, EtOAc∆, 3 h

51 % overall(+8 % epimer)

OH

CH2

H

H

Cantharidin

5 kbar, 72 h

80%

O

+

6 steps

Jatropholone A

Cycloadditions at high pressure

S

OO

Smith and Uchida

O O

OO

O

O


Smith, A. B.; Liverton, N. J.; Hrib, H.; Sivaramakrishnan, H.; Winzenberg, K. J. Am. Chem. Soc. 1986, 108, 3040

Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 999

Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 7126

Dauben, W. G.; Gerdes, J. M.; Smith, D. B. J. Org. Chem. 1985, 50, 2576

75

CO2Me

OBnO

CH2 CO2Me

CH2OBn

O

Me

CH2OBn

CO2Me

O

Me

CH2OBn

CN

OAcO

CH2OBn

MeAcO

CN

O

Me

CH2OBn

H+

O

MeO2C

LiOHMeOH

175,000 psi

O

MeO2C

KOH

O

MeO2C

290 oC

O

MeO2C

Vinyl furan Diels-Alder reactions

oxygenated targetsFuranoheliangolides

290 oC

100 %

97 %

High pressure furan cycloaddition

CH2Cl298 %

H2O91 % O

O

HC CCH2SMe2+ Br


Cooper, J. A.; Cornwall, P.; Dell C. P.; Knight, D. W. Tetrahedron Lett. 1988, 29, 2107

Paquette, L. A.; Brown, D. S. J. Org. Chem. 1992, 57, 4512

76

NN

NNN

NNH2

NH2

O CO2Me

CO2Me

OOO

CO2Me

CO2Me

N SiMe3

F Br

Cl

F

HN

NO

Ph NN

N

NH2

N

Ph

O

O

NMe

O

O

2 equiv.

+Pb(OAc)4

N Me

O

O

O

rt 47 %

+

1) n-BuLi2) H2O

49 %

+

Pb(OAc)4

0 oC, 0.5 h

~ 100 % -PhCN

benzene80 oC, 3 h

rt78 %

[4+2]-Cycloaddition of Five-Ring Heterocycles with Benzyne

Double cycloaddition of benzyne with furan

Cycloaddition with oxazole

Cycloaddition with pyrrole


Hart, H.; Ok, D. J. Org. Chem. 1986, 51, 979

Witney, S. E.; Rickson, B. J. Org. Chem. 1988, 53, 5595

Anderson, P. S.; Christy, M. E.; Engelhardt, E. L.; Lundell, G. F.; Ponticello, G. S. J. Hetereocyclic Chem. 1977, 14, 213

77

NR2 R1

CO2Me

C

C

CO2Me

CO2Me

NR1

CO2Me

CO2Me

NH CO2Me

R2R2

CO2Me

CO2MeR1

CO2Me

N

O

C

CO2Et

CO2Et

N

O

CO2Et

CO2Et

N

O

CO2Et

CO2Et

CO2Et

N

O

CO2Et

NH

O

CO2Et

O

Br

BrO

Br

Br

OO O

OH

O+

Fe2(CO)9

Zn-Cu

H2, Pd (C)

+AlCl3

CH2Cl2

AlCl3

OR

O

R1

R2O

R

R2 R1

O

+KH

BF3-OEt2

NBSLiCl, DMF

2 M KOH

NH2NH2H2O

Diels-Alder reactions of pyrroles

[4+3]-Cycloadditons of furans

Diels-Alder reaction of pyrrole with allene

12 kbar

25 oC

R, R1, R2 = H, Me 43-65 %

70 %

NO

CO2Et

O

High pressure intramolecular Diels-Alder reaction of furan as a diene

75 %

R1 = H; R2 = Me

75 %85 %


Keay, B. A.; Dibble, P. W. Tetrahedron Lett. 1989, 30, 1045

Bansal, R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1970, 48, 1472

Kozikowski, A. P.; Kuniak, M. P. J. Org. Chem. 1978, 43, 2083

Noyori, R.; Makino, S.; Okita, T.; Hayakawa, Y. J. Org. Chem. 1975, 40, 806

78


Lee, J. C.; Jin, S.-J.; Cha, J. k. J. Org Chem. 1998, 63, 2804Lee, J. C.; Cha, J. k. Tetrahedron 2000, 56, 10175

Synthesis of (-) -colchicine

O

MeO

MeO

N

OMe

H

OAc +

OTMS

OMe

OMe

TMSOTf

MeO

MeO

N HOAc

OMe OO

O

MeO

MeO

N

OMe

H

Boc+

OTMS

OMe

OMe

TMSOTf

MeO

MeO

NH

Boc

OMe OO

OMe

OMe

Halogen-substituted oxyallyl cations

O

CO2Me

OTBS

+Cl Cl

Cl

O1. Et3N, CF3CH2OH

2. Zn, MeOH

CO2Me

OTBS

OO

Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523

Harmata, M. Acc. Cham. Res. 2001, 34, 595

O

SPhOH

CH2TMS

Tf2O, CH2Cl2

2, 6-lutidine, -78 oC 50%

O

H SPh

79

Me Me

O

Br Br

N MeN

OMe

N

Me

CH2

SCH2Ph

N

SCH2Ph

Me

N

O

Me

N

NMe

N

N NMeMeO

NN

Me O

Me

Me

Me MeN

OHMe

Me

N

Me

Me

S

LAH

O O

89 %

+

O

O

NaH

BnCl

Pyrrole [4+3 ]-cycloaddition

Vinyl pyrroles as dienes for Diels-Alder reactions

NO

∆

Ph

- HCN

OAc

NaI, Cu

N

Ph

OAc

MeCN

THF

1)

2) DDQ

220 oC70 %

OOAc

21% overall

PhC NO

1 : 1

Intramolecular [4+2]-cycloaddition of imidazoles

+180 oC

Tandem Diels-Alder/Retro Diels-Alder reaction of oxazoles

+16 h90 %


Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1974, 13, 410

Murase, M.; Yoshida, S.; Hosaka, T.; Tobinaga, S. Chem. Pharm. Bull. 1991, 39, 489

Wuonala, M. A.; Smallheer, J. M. Tetrahedron Lett. 1992, 34, 5697

Liotta, D.; Saindane, M.; Ott, W. Tetrahedron Lett. 1983, 24, 2473

80

O

OMe

OMe

NO

O

O

O

Me

O

Me

O

Me

O

O

OMe

N

O

O

OOMe

OH

OH

N

OMe

OTBDMSOTBDMS

TMS

O

NO

N

O

O

TMS O

N

H+

> 50 %

∆

Intramolecular Cycloadditions with Oxazoles

∆

60 %

Gnididione

98 %

Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859

94 %

Paniculide-A

Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859

∆

(-) Norsecurinine

O

O

OOMe

NO

Me

OMeSO2

NO

MeSO2Me

NO

Me

OH

+130 oC

O- MeSO2H

Oxazole cycloadditions - Synthetic equivalent of 2-aza-1,3-dienes

Böll, W.; König, H. Ann. 1979, 1657. Firestone, R. A.; Harris, E. E.; Reuter, W. Tetrahedron 1967, 23, 943

75 %


Jacobi, P. A. In Advances in Heterocyclic Natural Product Synthesis, Pearson, W. H., Ed.; JAI Press: Greenwich, 1992.Jacobi, P. A.; Walker, D. G.; Odeh, I. M. A. J. Org. Chem. 1981, 46, 2065. Jacobi, P. A.; Craig, T. J. Am. Chem. Soc. 1978, 100, 7748.Jacobi, P. A.; Selnick, H. G. J. Org. Chem. 1990, 55, 202

81

O

N

O OMeN

O

OMe

O

OOMe

O

O

OH

O

N S

OEtMe

S

O

R

OEt

OMe

Me

MeS

N

PhEt

S

O MeMeMe

MeMe

reflux

- MeCN

O

Me

Me

1) NaBH4

2) pH5O

O

OH

H

Retro Diels-Alder of Oxazoles

H H H

Synthesis of furans or functionality derived from a substituted furan

R = CH2OMe

Diels-Alder of Thiazole Derivatives

Formation of fused ring thiophenes

∆ HRa-Ni

H

Paniculide A

O

R - MeCN

1 : 1

94 %

57 %

O

74 % 85 %

Jacobi, P. A.; Weiss, K.; Egbertson, M. Heterocycles 1984, 22, 281.Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.Jacobi, P. A.; Frechette, R. F. Tetrahedron Lett. 1987, 2937

Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron 1987, 43, 5475


82

N

R2

R4

R4

R1

R3

N

OH

R4

R4

R1

R3

NO

R2

R1

R3

R4

R4

N

R4

R4

R1

R3

N

OH

R4

R1

R3

N

OH

R4

R4

R1

R3

OHR2

NAc

O

N

NAc

N

O

NAc

N

+

-H2O

-R2H

-R4H

N

O

R2 = H

[O], -H2

R2

R1R4

R4R3

R2 = H

4+2 Cycloaddition of oxazole derivatives

Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 38

Intramolecular Kondrat'eva Pyridine Synthesis

∆

o-DCBDBN

∆

-H2O

OTBS OTBS OTBS

H

H

Addition of DBN is helpful to intramolecular cycloadditions.


Kondrat'eva, G. Y. Khim. Prom. (Moscow) 1957, 2, 666Kondrat'eva, G. Y. Izv. Akad. Nauk. SSSR, Ser. Khim. 1959, 484

Bubramanyam, C.; Noguchi, M.; Weinreb, S. M. J. Org. Chem. 1989, 54, 5580

83

N NH

O O O O

N N O

NH2

O

..

Monocyclic 6-membered heteroaromatics

XH2

O O

O

A

Analysis of Two Methods of Constructing Pyridines

NH3

B

+ NH3

+

Route A

+

Hantzch Synthesis

X

X

H

OHHOX

H

Route B Guareschi-Thorpe Synthesis

NH2

O

+

OO

H

XO

H

H

HO.. ....


84

R2 H

O

OR3

O

R2O

NH3

NH

R2 R2

R

R3O

O

OR3

O

NR2 R2

R

R3O

O

OR3

O

RO O

RO

OR

Top Ten Methods to Synthesize Pyridines

RO O

N

1. Hantzsch Pyridine Synthesis

Watanabe, Y.; Shiota, K.; Hoshiko, T.; Ozaki, S. Synthesis 1983 761; Pfister, J. R.Synthesis 1990, 689;Singer, A; McElvain, S.M. Org. Synth., Coll. Vol. II 1943, 214-216.

A mixture of aldehyde, β-ketoester, 60 mL of ethanol, and 10 mL of concentrated aqueous ammonia was heatedfor 3 h on a steam bath. To a solution of the above compound in 15 mL of acetone is added a solution of cericammonium nitrate in 3.5 mL water. The orange color of the reagent disappears immediately on addition of eachdrop. After stirring for 10 min, the resulting solution is concentrated to a small volume under reduced pressure.To this mixture is added 20 mL of water and the mixture is extracted with methylene chloride. The organic phase is washed with brine, dried over MgSO4, and evaporated under reduced pressure.

2. Guareschi-Thorpe Condensation

NH3


N

85

HO OH

RN

+

Holder, R.W.; Daub, J.P.; Baker, W.E.; Gilbert, R.H.; Graf, N.A. J. Org. Chem. 1982, 47, 1445-1450.I. Guareschi, Mem. Reale Accad. Sci. Torino II 1898, 46, 7, 11, 25.

+or NH4OAc,AcOH

In a round-bottom flask were combined the diester (0.4 mol), the cyanoester ((0.6 mol), ammonium acetate (0.1 mol), glacial acetic acid (0.5 mol), and benzene (100 mL). The flask was equipped with a Dean-Stark tube fitted to acondenser attached to a CaCl2 drying tube. The solution was heated at reflux for 45 h. The cooled benzene solutionwas washed with with 75 mL portions of water, dried over CaCl2, and concentrated. Distillation through a 10 cm Vigreaux column afforded the product.

oxid

N R6R2

R3R4

R2

O

R3

R4

R6

OH

R1

O

BrN

R1

O

NR3 R2

O

MnO2, NH4OAcPhMe-AcOH

reflux(60-96%)

Br

4. Modified Bohlmann-Ratz Reaction

N

Bagley, M.C; Hughes, D.D.; Sabo, H.M.;Taylor, P.H.; Xong, X. Synlett 2003,10, 1443-1446.Bagley, M.C.; Lunn, R.; Xiong, X. Tetrahedron Lett. 2001, 43, 8331-8334.

R1


R3

86

R2

A solution of ester (0.3 mmol), propargylic alcohol (0.6 mmol), ammonium acetate (6 mmol), and activatedMnO2 (6.0 mmol) in toluene-glacial acetic acid was heated at reflux overnight. The mixture was allowed tocool, filtered through Celite, partitioned between a sat. aq. NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic layers were sequentiallywashed with aq. NaHCO3 solution (20 mL) and brine (20 mL), dried (Na2SO4) and evaporated in vacuo.Further purification was accomplished by flash chromatography on silica gel.

3. Krohnke Pyridine Synthesis

The pyridinium bromide 2 (6 mmol) and the α,β−unsaturated ketone 3 (6 mmol) are heated with ammonium acetate (4g) in glacial acetic acid (6 mL) at 80oC for 2 h. The mixture is treated with water (40 mL), theprecipitate is filtered off, dissolved in boiling pyridine (20 mL), and reprecipitated with water.

Krohnke, F. Synthesis 1976, 1-24.

NH4OAc, AcOH

R2 = Me, PhR3 = CO2-alkylR4 = H, EtR5 = alkyl, Ar

40-97%

R1, R2, R3 many functional groups

+ -


N

R2

R1

N N

N

CHCl3 R2 N

R1

5. Inverse Electron Demand Diels-Alder with 1,2,4-Triazine

+45 oC

A solution of enamine (0.8 mmol) in 0.5 mL CHCl3 was added to a stirred solution of 1,2,4-triazene (1.2mmol) in 0.5 mL CHCl3 under nitrogen at 25oC. The resulting dark orange solution was warmed to 45 oC for 20 h. Chromatography afforded the pure product.

Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179-2182

N

Ar

N

H2N

CN

N

CN

MeArNaH, DMF15 hr rt, 4 hr 100oC

6. Reaction with Vinylogous Iminium Salts

A 100 mL three-neck round-bottom flask was equipped with a stir bar, condenser and placed under a nitrogenatmosphere. Into the flask was placed 0.3g (7.5 mmoles) of a 60% mineral oil dispersion of sodium hydride.The sodium hydride dispersion was washed twice with dry hexane, and the hexane was removed via cannula.Part of a 40 mL portion of dry DMF was added to the sodium hydride, and 0.79 g (9.6 mmol) of3-aminocrotonitrile were subsequently added. The solution was allowed to stir for 15 min. Finally, 1.0 g (2.8mmol) of vinamidinium salt and the remaining DMF was added, and the reaction was allowed to proceed atroom temperature overnight followed by heating at 100oC for 4 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned several times between water andchloroform. The combined chloroform extracts were dried and concentrated. The crude product was passedthrough a short pack of silica gel and purified by radial chromatography using a gradient solution of hexane:ethyl acetate.

Petrich, S.A.; Hicks, F.A.; Wilkinson, D.R.; Tarrant, J.G.; Bruno, S.M.; Vargas, M.; Hosein, K.N.; Gupton, J.T.;Sikorski, J.A. Tetrahedron 1995, 51(6), 1575-1584

87

+

N

N

O

CO2Me

Ac

∆

N

N

Ac

8. Kondrat'eva Pyridine Synthesis

A solution of oxazole (0.4 mmol) and DBN (0.4 mmol) in anhydrous o-dichlorobenzene (60 mL) wasdeoxygenated with argon for 45 min. The mixture was heated at 150o C under argon for 1.5 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flashchromatography.

Subramanyam, C.; Noguchi, M.; Weinreb, S.M. J. Org. Chem. 1989, 54, 5580-5585


o-DCB, DBN

AcOH

OH

R1

OR2

R2 O

R1

R3

O

R3

R2 O

O

R1

NH4OAc

NR2 R3

7. Sequential Solventless Aldol Condensation and Michael Addition

NaOH(s)grind

grind

Aldehyde (9.7 mmol) ,ketone (9.7 mmol), and NaOH (9.7 mmol) were combined using a mortar and pestle, and the yellow medium was aggregated until a yellow powder formed (~10 min). The second ketone (9.7mmol) was added with stirring (~10 min). The powder was tranferred to a suspension of ammonium acetate(5g, excess) in glacial acetic acid (25 mL) and heated at reflux for 2 h. The crude product was precipitatedout of solution by the addition of water, collected and washed with water and ethanol.

Cave, G.W.V.; Raston, C.L. J. Chem. Soc., Perkin Trans. 1 2001, 24, 3258-3264

64-92%

88

R1

C(O)NEt2

R2

CO2Et

N

Ph

PPh3

R1CHO

Ti(O-i-Pr)2

C(O)NEt2

R2

R1

N

Ph

R3 CO2Et

Ts C N

N

C(O)NEt2R1

R2H

10. Tandem Aza-Wittig/Electrocyclization

The aldehyde or isocyanate (5 mmol) was added to a stirred solution of the phosphazene (5 mmol) in dry acetonitrile (20 mL) or toluene (20 mL) and the mixture was heated at reflux for 12-28 h. Thesolvent was evaporated and the residue was purified by column chromatography.

Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans. 1 1990, 2193-2197Molina, P.; Arques, A.; Fresneda, P.M.; Vinader, M.V.;Foces, M.C.F.; Cano, F.H. Chem. Ber. 1989, 122, 307-313

9. Metal-Mediated [2+2+2] Cycloaddition

Suzuki, D.; Tanaka, R.; Urabe, H Sato, F. J. Am. Chem. Soc. 2002, 124, 3518-3519Varela, J.A.; Saa Chem. Rev. 2003, 103, 3787-3801


To a stirred solution of N,N-diethyl-2-nonynamide (25 mg, 1.2 mmol) and Ti(O-i-Pr)4 (0.44 mL, 1.5mmol) in 10 mL of Et2O was added i-PrMgCl (1.40 M in Et2O, 2.1 mL, 3.0 mmol) at -78 °C underargon to give a yellow homogeneous solution. The solution was warmed to -50 °C over 30 min,during which period its color turned red. After stirring at -50 °C for an additional 5 h, 1-octyne (0.14mL, 0.9 mmol) was introduced to the reaction mixture at -50 °C and the solution was stirred foranother 3 h. Then, pulverized p-toluenesulfonylnitrile (260 mg,1.4 mmol) was added and the reaction mixture was stirred for 3 h at -50 °C. The reaction wasterminated by the addition of water (0.5 mL)and quickly warmed to room temperature. The resulting heterogeneous mixture was dried overanhydrous sodium sulfate and filtered through a short pad of Celite. The filtrate was concentrated invacuo to give a crude oil, which was chromatographed on a silica gel column.

+

Ti(O-i-Pr)4/2 i-prMgCl

1.25 eq.-50o C

orR2NCO

∆R3 = R1 or R2NH-

68-86%

1.

2. H+ (or I2)

¢

55-70%(or I)

89

PPA, arsenic acid

Can replace glycerol with pre-formed α,β-unsaturated compounds. However, this increases risk of carbonyl polymerization.

NC

CC

C

N

C

C

HO

HO

HO CH2 CH CHONH

C

NH

HO H

N

SkraupDoebner-von MillerCombesConrad-LimpachKnorr

MeO

NO2

NH2

FriedlanderPfitzinger

Arylamine-Glycerol Quinoline Synthesis

H2SO4

CH2 CHCHO

C6H5NH2

H2SO4

N

H2SO4

MeO

oxidation

- H2O

60 %

O

H

Quinoline Synthesis

Skraup, Z. H. Monatsh. 1880, 1, 316. Skraup, Z. H. Ber. 1880, 13, 2086Manske, R. H. F.; Kulka, M. Organic Reactions 1953, 7, 59.Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1


Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1948, 70, 254

90

NHAc N N

CH2

POCl3

CH3

Cl ClH H

N Cl

Me2N NMe2

N ClN

CHO

Cl

NMe2

To the Vilsmeier complex prepared from DMF (20 mmol) and POCl3 (60 mmol) in 1,2-dichloroethane (150 mL) at 0 °C, was added acylanilide (20 mmol) with stirring. The solution was heated to reflux for 5 h, cooled, pouredinto ice water, made alkaline (pH 9) with 40% aqueous NaOH, and stirred for 30 min. The aqueous phase wasextracted with CH2Cl2, the combined organic layer was dried (MgSO4) and evaporated. The residue waspurified by chromatography on alumina to give 2-chloro-quinoline-3-carbaldehyde.

1. Vilsmeier Approach to Quinolines

Meth-Cohn, O.; Narine, B. Tetrahedron Lett., 1978, 19, 2045.Meth-Cohn, O. Heterocycles, 1993, 35, 539.

N RN R

RXRX

N R

RXH

N

R

RX

OH

RXN RCF3SO3H

2. Synthesis of Quinolines via Intramolecular Cyclization of Oxime Derivatives

Kusama, H.; Yamashita, Y.; Narasaka, K. Chem. Lett., 1995, 5.

Top Methods to Synthesize Quinolines

To a 1,2-dichloroethane suspension (6 mL) of 4-(3,4-methylenedioxyphenyl)butan-2-one oxime (0.98 mmol),4-chloranil (0.51 mmol), and Molecular Sieves 5 Å (100 mg), was added a solution of trifluoromethanesulfonic acid (1.0 mmol) in 1,2-dichloroethane (4 mL) and the mixture was immediately heated at reflux. After 1 h, thereaction was quenched with a saturated aqueous sodium hydrogen carbonate solution and the resultinginorganic materials were filtered through Celite. The organic layer was extracted with CH2Cl2. Afterevaporation of the solvent, the crude product was purified by chromatography to afford the quinoline.

ClH2O

Bu4NReO4

DMF

X = O, N; R = Me, Et

[oxid]


91

NHCOR1

RI CH(OH)R2

NHCOR1

RCH(OH)R2

RN R2

N

N

Mahanty, J.; De, M.; Das, P.; Kundu, N. G. Tetrahedron, 1997, 53, 13397.

4. Fischer Carbene Benannulation Approach

Me

BocMe N

Me

BocMe

OMe

Cr(CO)5

R

Me

Me

A mixture of o-iodoaniline (1.0 mmol), (Ph3P)2PdCl2 (0.014 mmol) in Et3N (15 mL) was stirred under N2 at rt for 15 min. Freshly distilled propargyl alcohol (2.5 - 3.0 mmol) was added and the mixture was further stirred at rtfor 24 h. The solvent was removed under reduced pressure and the residue was purified by columnchromatography to give the substituted hydroxyalkynyl anilide. To the freshly prepared sodium ethoxide(1.3 mmol) in ethanol (3 mL) was added the above hydroxy-alkynyl anilide (0.28 mmol). The reaction mixturewas refluxed under N2 for 5 h. The mixture was cooled, poured into H2O and extracted with CHCl3. Thecombined organic layer was washed with saturated brine, H2O and dried (Na2SO4). The solvent wasremoved and the resulting residue upon chromatography gave the quinoline as a light yellow solid.

Boc

OHR

OMe

3. Palladium Catalyzed Annulation Approach

Peterson, G. A.; Wulff, W. D. Tetrahedron Lett., 1997, 38, 5587.

A THF solution of α-lithio-1,4-dihydropyridine was transferred to a slurry of chromium hexacarbonyl in THF at-45 °C. The reaction mixture was allowed to warm to rt overnight and then was methylated by the addition of 1 equiv of methyl fluorosulfonate. The reaction was quenched after 30 min with sodium bicarbonate, andpurification by silica gel chromatography gave the carbene complex as a red oil. The benzannulation wascarried out under argon in THF at 0.04 M with the carbene complex together with 1.5 equiv of alkyne at 60 °Cfor 42 h. The dihydroquinoline product was isolated as yellow oil.

NaOEt in EtOH

(Ph3)2PdCl2,Et3N, DMF, rt

R1 = CH3, CF3

1) s-BuLi,2) Cr(CO)6,

3) MeSO3F


92

NAr

NO2

O

O

NAr

NH2

O

O

N

O

O

OMe

NH

O

OO

CO2

NH2 O R1

R2

N

R2

R1

CO2

N

R2

R1

Na2S

p-CH3OC6H4COCH3, HO

Pfitzinger, W. J. Prakt. Chem. 1886, 33 (2), 100

NaOH+

N

N

NaOH

H , Cu powder+ CO2

Isoquinoline Synthesis

Bischler - NapieralskiPictet - GamsPictet - Spengler

H

Pomeranz - Fritsch

H

Difference in isoquinoline ring structure necessitates different starting materials to those used in quinoline synthesis.


Borsche, W.; Sell, F. Chem. Ber. 1950, 83, 78(164) Borsche, W.; Barthenheier, J. Annalen 1941, 548, 50

93

MeO

N

OBr

OMeOMe

MeON

Br

MeOOMe

HO2C

CO2Me

BnOOH

NH2

BnOOH

NHO

CO2Me

BnO

N

CO2Me

POCl3MeCN

POCl3

Ten Top Methods to Synthesize Isoquinolines

1. The Bischler-Napieralski Method

Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 142.Jones, G. Compr. Heterocycl. Chem. II, 1996, 179, 182.Zhou, D. -M.; Yue, B. -Z.; Cui, J. -Q.; Cai, M. -S.; Zhang, L. -H. Heterocycles 1997, 45, 439.Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30, 1581.

Pictet-Gams Modification of the Bischler-Napieralski Reaction


A solution of the amide (1.2 mmol) and phosphorus oxychloride (1.3 g, 8.5 mmol) in dry acetronitrile (20 mL) was heated at reflux for 2-5 h. The excess reagent and solvent were removed under vacuum and theresidue was poured into 5% sodium hydroxide and then extracted with CH2Cl2. The extracts were dried overmagnesium sulfate and evaporated to give a white solid in 91% yield. The solution was dissolved in CH2Cl2and HCl gas was bubbled through to give the hydrochloride salt.

A solution of 2.2 g (10 mmol) of the acid and 1.5 mL (20 mmol) of thionyl chloride in 20 mL of benzene washeated at reflux for 1.5 h. After cooling, the solution was evaporated. The residue contained 2.4 g (100%) of the corresponding acetyl chloride as an orange solid which was used in the next reaction without any furtherpurification. To a solution of 2.4 g (10 mmol) of the amino alcohol in 11 mL of 1 N (11 mmol) NaOH and 20 mLof dioxane was added a solution of 2.4 g of the acid chloride in 15 mL of ether and 3 mL of dioxane. Afterstirring for 1.5 h, the mixture was filtered, the solid was washed with water and dried to give 3.6 g (80%) of theamide as a white solid. To a stirred and boiling solution of 2.7g (6 mmol) of the amide in 50 mL of acetonitrilewas added dropwise 5.6 mL (60 mmol) of phosphorus oxychloride. After 1.5 h at reflux, the solution was cooledand aqueous 5% sodium hydrogen carbonate was added carefully until pH 8.0 was reached. The mixture wasextracted with ethyl acetate. The organic phase was dried and the solvent evaporated. The residue waspurified by silica gel chromatography to give 2.1 g (85%) of the isoquinoline as a white solid.

+

H

94

HO

NH2.HCl

O

HOBn HO

N

BnO

2. The Pictet-Spengler Method

Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 170. Jones, G. Compr. Heterocycl. Chem. II, 1996, 170.Hom, R. K.; Katzellenbogen, J. A. J. Org. Chem. 1997, 62, 6290.

MeOH, reflux

The amine salt, which was synthesized from norphenylephrine hydrochloride according to literatureprocedures, was dissolved in methanol (30 mL) and to this solution was added the (benzyloxy)- acetaldehyde (3.5 g , 1.1 equiv.) with stirring at rt. This mixture was heated at reflux for 18 h. Concentration and flashchromatography of the residue yielded 4.2 g (73%) of the product.

NH

OPh

NHPh

OPOCl2

NH

Ph OPOCl2

N

Ph

N

Ph

Bischler - Napieralski-Synthesis

P2O5, POCl3

xylene - H+

- POCl2(OH) Pd / C 160oC

- Reagents used for ring-closure include P2O5, PCl5, POCl3, and PPA.- Electron-donating substituents improve yield and rate of reaction by enhancing the electrophilic ring-closure step.- Isoquinolines unsubstituted at 1-position require N-formylamines as precursors. This results in poor yields unless the benzene ring contains e- releasing groups.


+

95

MeO

MeON

O O

O

SMe

MeO

MeON

O O

O

SMe

MeO

MeON

O O

O

SMeH

MeO

MeON

X

HSMe

OMeO

MeON

O

O

Ac2O

Modified Pictet-Spengler Initiated by Pummerer Reaction for Alkaloid Synthesis

Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 27.

N

MeMe

NOEt

OEtconc. H2SO4

3. Pomeranz-Fritsch Method

MeOH, 2 h

Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 218.Chelucci, G.; Cabras, M. A.; Saba, A.; Sechi, A. Tetrahedron: Asymmetry 1996, 7, 1027.Jones, G. Compr. Heterocycl. Chem. II, 1996, 190.

A solution of o-methylbenzylideaminoethanaldiethoxyacetal (2.0 g, 10 mmol) in MeOH (5 mL) under a nitrogen atmosphere was slowly added to concentrated H2SO4 (50 mL) and heated at 160oC. The mixture was madebasic with 50% NaOH solution and the product was removed from the resulting black solution by steamdistillation. The distillate was extracted with ether, the organic phase separated, dried over anhydrous Na2SO4and the solvent was evaporated. The residue was purified by Kougelrohr distillation to give 0.36 g (25%) of8-methylisoquinoline.


72 %

+ +

-

+

96

NCOR2

SOPh

R1

R1

NCOR2

SPh

R1

R1

NCOR2

R1

R1

Pummerer reaction

5. Intramolecular Pummerer Reaction

Suhinohara, T.; Toda, J.; Sano, T. Chem. & Pharm. Bull. 1997, 45(5), 813-819.Toda, J.; Sakagami, M; Sano, T. Chem & Pharm. Bull. 1999, 47(9). 1269-1275.Padwa, A; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175-203.

97%-98%

TFAA (5 equiv.) was added to 500 mg of the sulfoxide in 40 mL of the appropriate solvent at room temperature andthe mixture was stirred for several hours. The reaction mixture was concentrated under reduced pressure and theproduct was purified by column chromatography. NaBH4 (10 equiv.) was then added in small portions to a stirredsolution of the product with NiCl26H20 in MeOH-THF (3:1)(40 mL) under ice cooling. After the addition, stirring wascontinued at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was suspended in water, acidified with 5% HCl-H20, and extracted with CHCl3. The product was isolated by column chromatography and was purified by recrystallization.

6. One-Pot Synthesis of Ethyl Isoquinoline-3-Carboxylate by Domino Reaction

OO

H2NCO2Et

CO2EtON CO2Et

CO2Et

N

OH

CO2Et

CO2EtN

CO2EtO O

N

CO2Et

+

EtONa, dry EtOH∆, MgSO4, 4h.

-H2O

-EtOH-CO2

80%

Meziane, M.A.; Sylvain, R.; Bazureau, J.P. Tet. Lett. 2001, 42, 1017-1020.

......................................................................................................................................


97

R

R

Br

NO R1

N

R

R

R1

HN

R

R

R1

HO

2. Et2AlCl -90oC to rt 77-83%

1. PCC, NaOAc mol. sieves, CH2Cl22. KOH, MeOH/THF

7. Tetrahydroisoquinolines from Perhydrobenzoxazines

- Creates stereogenic carbon at C-1 simultaneously with ring closure.- The perhydrobenzoxazine starting material is obtained in high yield in three steps.

Pedrosa, R.; Andres, C.; Iglesias, J.M. J. Org. Chem, 2001, 66, 243-250.

A solution of the substrate in dry ether was treated with t-BuLi (2.2 equiv) at -90oC, and after 5 min, 2 equiv of Et2AlCl was added. The mixture was allowed to reach room temperature and was stirred 16 h. Isolationand purification by flash chromatography, after hydrolysis afforded the tertrahydroisoquinoline derivative.


1. t-BuLi Et2O, -90oC

8. Benzal Aminoacetal Isoquinoline Synthesis

HO

Cl

CHON

HO

Cl

N

OEtEtO

H2NCH2CH(OEt)2

Gensler, W. J. Organic Reactions, 1951, 6, 191

- Intially for aldimine which is recycled to isoquinoline- Acetal group prevents amonialdehyde self-condensation.- 3-Substituted aldehyde give 7-substituted isoquinolines- these are difficult to prepare by other methods.

98

NR1

COCF3

CHO

RO

RO

S

O:

Ar

HC

Li

(MeO)2P

Ar= C6H5, CH3C6H4, 2,4,6-(iC3H7)3C6H2

NR1

COCF3

RO

RO

STol

O

..

NR1

COCF3

RO

RO

S

O

Tol ..

9. Chiral Vinyl Sulfoxide Cyclization

N

RO

ROR1

SO

Tol

.. ..

N

RO

ROR1

SO

Tol

..

+

Pyne,S.G., J. Chem. Soc., Chem. Commun., 1986, 1688.Pyne, S. G., Chapman, S.L., J . Chem. Soc., Chem. Commum., 1986, 1688.Pyne, S.G., Bloem, P., Chapman, S.L., Dixon, C.E., Griffith, R., J.Org. Chem., 1990, 55, 1086.Pyne, S.G., Tetrahedron Lett., 1979, 28, 4737.

PhCH2NEt3OH-OH

+


O

OMeN

Me

CO2Et

O

NMe

CO2EtO

NMe

NaOEt OH-

H+

10. Dieckmann Type Condensation

Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 215.Grethe, G.; Lee. H. L.’ Uskokovic, M.; Brossi, A. J. Org. Chem. 1968, 33, 494.Klein, J. T.; Davis, L.; Effland, R. C. J. Heterocycl. Chem. 24, 1987, 725.

A 16.3 g (0.7 mol) portion of sodium metal was added to absolute ethanol (150 mL) and after the reaction wascomplete, the excess ethanol was removed by distillation. A solution of N-(2-carboxmethoxybenzyl)-sarcosineethyl ester (150 g, 0.57 mol) in benzene (200 mL) was added, and slow azeotropic distillation was carried out.The solvent was removed, the resultant yellow solid was dissolved in ethanol (200 mL) and 2N sodiumhydroxide (600 mL)was added and the mixture was heated at reflux for 2 h. The mixture was cooled slowly toroom temperature, then acidified with 6N hydrocloric acid, and refluxed for 3 h. The reaction mixture was cooled, was made basic with 6 N sodium hydroxide, and was extracted with chloroform. The chloroform extracts werewashed with water, brine, dried over MgSO4, and evaporated to give 84 g (92%) of the product.

99

NH2

N

H

NH2

MeCHO

MeCHO

N

Me

N

H

N

Me

H2SO4

H2SO4

NH

Me

H

N

H

N

Me

40 %

tetrahydro-β-carboline

86 %

tetrahydroisoquinoline

Pictet-Spengler Cyclization in Heterocyclic Synthesis


Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030 Decker, H.; Becker, P. Liebigs Ann. Chem. 1913, 395, 342 Whaley, W. M.; Govindachari, T. R. Org. React. (N. Y.) 1951, 6, 151 Ungemach, F.; Cook, J. M. Heterocycles, 1978, 9, 1089

NHCOR

MeO

MeO CAN

RN

R

SiR3

TMSCH2I

RN

R

SiR3

NCOR

MeO

MeO

-SiR3

NCOR

MeO

MeO

TMS

RN

R RN

R

CH2

Oxidative Pictet Spengler Cyclizations

R=Ph, OBn

Single Electron Transfer Mechanism:

SET+

.

SET +

Mariano, P.; Kim, H. J.; Yoon, U. C.; Jung, Y.; Park, N. S.; Cederstrom, E.; J.. Org. Chem. 1998, 63, 860.

Used for the synthesis of indolopiperidines, pyroglutamic acid derived pyrrolidinones, and phenanthreneindolizidines

CAN CH2

.

100


NSO2R5

SR6

HNSO2R5

(R6S)3CH

TMS

NSO2R5

SR6

NSO2R5

Thio-orthoEsters in Pictet Spengler Cyclizations

Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett 2003, 44, 6137.

dichloromethane, reflux

R5= Ts, R6= Ph

ZnCl2, dichloromethane

NHR

OMe

R=SiMe3

N

OMe

Regiospecific Silyl Directed Pictet Spengler Cyclization

Miller, R.; Cutter, P.; Schore, N.; Tetrahedron 2002, 58 , 1471. Miller, R.; Tsang, T.; Tet. Lett. 1988, 51, 6715.

HCHO, pH=6

98%

Used for the synthesis of tetrahydropalmatine, canadine, sinactine, corypalmine and isocorypalmine

NH

N CO2Me

NH

N CO2Me

H

Mercuric Acetate Catalysed Pictet Spengler Reaction

Hg(OAc)2 / 10% AcOH / 50% EtOH

101

HNTs

R1

R2

R3

R

O

SPh

ClN

Ts

O R

R1

R2

R3

Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett. 2001, 42, 8947.


R1= H, OMe, R2= OMe, HR3= OMe, H, R= Ph, tBu

SnCl4 / ZnBr2, dichloromethane,-78oC

O-methyl velucryptine and other benzoyl isoquinoline alkaloids

α-Chloro α-Phenylthio Ketones in the Pictet Spengler Reaction

NH2

MeO

MeOR1

O

R2

N

MeO

MeO

R1 R2

CHO

CF3COOH

N

MeO

MeO

Me Ph

N

MeO

MeOR1 R2

CHO

Pictet Spengler Cyclization using Titanium Isopropoxide as an Imination Reagent

Horiguchi, Y..; Nakamura, M.; Kida, A.; Kodama, H.; Saitoh, T.; Sano, T.: Heterocycles. 2002, 59, 691.

Ti (O-iPr)4

HCOOH / Ac2O +

R1= Me, Ph, R2= Ph, Me, Et, CH2SPh

102

NN

H

CO2H

CO2Me

N

NN

N N

N

N N

H

CN

MeO2C CO2Me

H

H H

CO2Me

H

MeO2C CO2Me

H H

N

CO2Me

HO2C

N CO2Me

H

NN

HEt

MeO2C CO2Me

NN

HEt

MeO2C CO2Me

NN

HEt

MeO2C CO2Me

PhPOCl2

HCl (aq)

83 %

1) AgBF4, THF

2) MeOH, HCl

Hβ = 75 %Hα = 25 %

PhPOCl2

HCl (aq)

Hβ = 75 % Hα = 25 %

MeOH

HClHH

+

Various methods used to generate iminium ion precursors

69 % 10 %

70 %

60 %

Hβ = 80 %Hα = 20 %


Grierson, D. S. Org. React. (N. Y.) 1990, 39, 85 Grierson, D. S.; Vuilhorgne, M.; Husson, H. P. J. Org. Chem. 1982, 47, 4439 Kametani, T.; Suzuki, T.; Kamada, S.; Unno, K. Heterocycles 1982, 19, 815

103

N

MeEtO2C

Me

H

N

MeEtO2C

Me

HH

NN

MeEtO2C

Me

H N

OH

NN

MeEtO2C

Me

OHN OMe

Me

CO2Me OMe

NHCO2Me

N

CO2Me

MeO

O

N

Me

CO2Me

O

O

NO

OHMeO2C

N

NBr

OSiMe3

NN

H

H

CHO

NN

H

MeO2C

HO

CH2O CH2O

C6H11NH2

-H2O

Amidoalkylation reaction of furan ring

+

H2RSO3H

PhH, 80 oC70 %

DMF, Pri2NEt

70 oC

74 % Vincamine

Bimolecular Mannich reaction using pyrroles

Mannich type cyclization from pyridinium ion precursors

Oppolzer, W., Hauth, H., Pfaeffli, P., Wenger, R. Helv. Chim. Acta. 1977, 60, 180

+

H

75%

68%


Wenkert, E. Acct. Chem. Res. 1968, 1, 78. Wenkert, E.; Dave, K. G.; Stevens, R. V. J. Am. Chem. Soc. 1968, 90, 6177

Shono, T.; Matsumura, K.; Tsubata, K.; Takata, J. Chem. Lett. 1981, 1121

Burke, W. J.; Hammer, G. N. J. Am. Chem. Soc. 1954, 76, 1294

104

O

N N

N

N

N N

R R

R

R

R

R

EDG

N

N R

R

N

R

R

R

N

N N

N

R

R

N

N

R

R

N

N

RNO

R2

N NN

OR2

N NN

R2

R

R

R1

NO

R2

O

R1

R1

NH

CO2CH3

CO2CH3 R1

N N

N

R2

R1

N N

N

N N

N

R2

R1

N

NR2

R1

N

O R1

R2

N R1

N

R2

R = HR = CO2Et

R = CO2CH3

R = CO2CH3R = SCH3

N

R1

R2

N

N

N

R2

R1

N

Heteroaromatic azadiene Diels-Alder reactions

R = SO2CH3

+

- pyrrolidine

-N2

+ pyrrolidine

+

R = HR = CO2EtR = SCH3

R = CO2CH3R = H, Cl

R = CO2CH3R = SCH3

R = CO2CH3R = SCH3

+

Catalytic Diels-Alder Reaction

NH

1,2,4-Triazine - enamine [4 + 2] cycloaddition


Boger, D. L. Chem. Rev. 1986, 86, 781

105

N

N

N

CO2Et

CO2EtEtO2CNH2

R

NH-HClN N

CO2Et

CO2EtH2N

R

N

N

N

CO2Et

CO2EtEtO2CN

NHN NH

HN

CO2Et

CO2Et

N

N

N

CO2Et

CO2EtEtO2CN

N

CO2Et

CO2EtHN NH

HN

N

N

N

CO2Et

CO2EtEtO2C

N

N

N N

N

N

SMe

SMeMeS

NH2R

NH-HCl

NH2R

NH2-HCl

SMeR

NH-HI

R = H, 90 oC, 24 h, 85 %

+

+

SMeR

NH2-HI

R = SMe, 90 oC, 48 h, 90 %

100 oC, 24 h, 75 %

+

OMeR

NH-HCl

R = Ph, 100 oC, 24 h, 82 %

R = Me, 100 oC, 72 h, 80 %

Representative 1,3,5-triazine - amidine Diels-Alder reactions

OMeR

NH2-HCl

100 oC, 36 h, 52 %

Diene and dienophile substituent effects

Dienophile Reactivity

Diene Reactivity


106

NN N

NN

SCH3

SCH3

CH3

CH3

NN

CH3

CH3

SCH3

SCH3

N

CH3

HCH3

CH3

NN N

N

CO2CH3

CO2CH3

H COCH3

CH3O OCH3

NN

CO2CH3

CO2CH3

OCH3

COCH3

HONH

NOH

OCH3

O

NN N

N

CO2CH3

CO2CH3

cis-Trikentin A

A solution of 3,6-bis(methylthio)-1,2,4,5-tetrazine (5.6 g, 32 mmol) in benzene (25 mL) at 0 °C was treated withthe pyrrolidine enamine of 2,4-dimethylcyclopentanone (11.3 g, 2.1 equiv), and the resulting solution was allowed to warm to room temperature and stirred for 1 h. Glacial acetic acid (25 mL) was added, and the resultingreaction mixture was stirred for 10 h at room temperature before the solvent was removed in vacuo.Chromatography followed by recrystallization afforded 6.6 g (85%) of the product as a white crystalline solid.

PDE-I

N

NMe2

[4+2]-Cycloaddition of 1,2,4,5-Tetrazines

Boger, D. L., Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230

NN N

CO2CH3

CO2CH3

NMe2

A mixture of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (14.6 g, 74 mmol) and 4,4-dimethoxybut-3-en-2-one (14.4 g, 110 mmol) in 250 mL of dry dioxane was warmed with stirring at 60 °C under N2. The solvent wasremoved in vacuo, and the residue was dissolved in CH2Cl2 and filtered through a short column of silica gel.Flash chromatography afforded the product (13.9 g, 70%) as a yellow, crystalline solid.

Boger, D. L., Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717

Benson, S. C., Gross, J. L., Snyder, J. K. J. Org. Chem. 1990, 55, 3257

Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1.0 g, 5.0 mmol) and dimethylcyanamide (0.4 mL, 0.35 g, 5 mmol) were dissolved in anhydrous o-xylene (10 mL) under argon and refluxed for 12 h. After cooling to roomtemperature, the crude reaction mixture was subjected to flash chromatography on silica gel to give the pureproduct (0.71 g, 59% yield).

+

CONH2

+

+

107


N

NN

N

CH3

CH3

NN

CH3O2C

CO2CH3 Et3SiO

CO2CH3

CH3

CH3

HNR R

CH3CH3CH3O2C

NH

HN

N N

N

NN

N

OCH3

NN

CH3O2C

CO2CH3 CH3O

CO2CH3

OCH3

CH3O2C

NH

NH

CH3O N

C5H11

CH3

HN

CH3O

CH3O2C R

N

N N

N N

N

SCH3

SCH3

SO2CH3

SO2CH3

N

N

N

NR

SO2CH3

R = CO2CH3R = H

25 oC

N

N

NR

SO2CH3

87 %

+

Zn/HOAc

NCOCH3

SO2CH3

Preparation of OMP

NaOH;-CO2

NCOCH3

68 %

N

N

SO2CH3

NAc

PRODIGIOSIN

SO2CH3 SO2CH3

Key steps of the prodigiosin total synthesis

Intramolecular 1,2-diazine - allene Diels-Alder reaction

N

OMP

N

R = CO2CH3R = H

N

93 %

NH2

NH2

Zn/HOAc

Ac

77 %

Ac

+

Ac

25 oC

ii) m-CPBA97 % x 95 %

235 oC, 22 h

68 %

-N2 -CH3SO2H

120-160 oC

70 %

i)

76 %

27 h, 87 %

R = COCH3

25 oC, 63 %


108

CH3O

H2N

O

O

NN COOH

CH3H2N

OH

OCH3

OCH3

CH3O

N

NO2

NH

SCH3

N

CH3O

NO2

NN

N

CH3O2C

CO2CH3

N

NN

N

CH3O2C

CO2CH3

N

CH3O

NO2

N CO2CH3

CH3CH3O2C

OCH3

NCH3

OCH2Ph

OCH3

OCH3

OCH3

OCH2Ph

N

NN

N

NN

N

NN

NN

HN

CO2CH3

CH3O2C

CO2CH3Ar

CH3O2C

ArX

CO2CH3

CH3O2C

NH

X NN

N CO2CH3

CH3O2C

N

NN

N CO2CH3

CH3O2C

STREPTONIGRIN

C

B

80 oC

+

X

Ar NH

1,2,4,5-Tetrazine - thioimidate Diels-Alder reaction

Key steps of the streptonigrin total synthesis

25 oC, 50 %

A

N

NHN

CO2CH3

CH3O2C Ar

X

D

82 %

N

N

6.2 kbar

X = SCH3X = OEtX = NH2, NEt2

80 oC, 4 h, 70 %

-N2

-HX

+

80 oC, 20 h, 33 %25 oC, 1 h, 0 %

Diels-Alder Reactivity: NH2, NR2 > OEt = SCH3Elimination (Aromatization): SCH3 > OEt >> NH2, NR2


109

N N

N

CO2Me

NN

CO2Me

NNO2

MeO

CN

NNO2

MeO

NH

SMe

N N

NN

CO2Me

MeO2C

N

NO2

MeO

NN

N

MeO2C

CO2Me OBn

MeR2N

OMe

OMe

NN CO2Me

MeMeO2C

OBn

OMe

OMe

NO2

MeO

Hetero Diels-Alder Reactions

Cycloadditions involving heteroaromatic azadienes

+ rt

1) H2S, Et2NHdioxane

2) MeI, MeCN

dioxane80 °C, 22 h

82 %

CH2Cl2, 6.2 Kbarrt, 120 h

65 %(2.8 : 1)

+

NN CO2H

MeNH2

OH

OMe

OMe

O

MeO

NH2

O

+

-N2

49 % -pyrrolidineN

NN

NR2

CO2Me

4 eq

42 %

10 steps

Streptonigrin


Boger, D. L. Chem. Rev. 1986, 86, 781Dittmar, W.; Sauer, J.; Steigel. A. Tetrahedron Lett. 1969, 5171

Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717

110

N

N N

N

CO2Me

CO2Me

NR

N

N

CO2Me

CO2MeN

R

N

N

R1

R2

R3

R4

CH2

OMeMe2N

R1

R2

R3

R4

X

N

N

NN

NN

RH

R1

R1R

NN

Me

- H2

N

N

R

R1

R1

R

+X = NMe2, OMe

57-93 %

Inverse electron demand 4+2 reactions of pyridazines

Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 1955

Indole as a dienophile in inverse electron demand Diels-Alder reaction

-N2

-H2

+

-N2

- N2

CO2Me

CO2Me

NEt2MeO2C

CO2Me

NEt2

Me

MeO2C

MeO2C

N N

NN

MeC≡CNEt2

R1CH=CHR1R

R

Neunhoeffer, H.; Werner, G. Tetrahedron Lett. 1972, 1517Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 437

H

R = Bz

Inverse electron demand 4+2 reactions of 1,2,4,5-tetrazinesNeunhoeffer, H. Comprehensive Heterocyclic Chemistry; Pergamon: London, 1984; Vol. 3, p 550Neunhoffer, H. Chemistry of Heterocyclic Compounds, Wiley: New York, 1978, Vol. 33, pp. 1095-1097

NOTE: Dimethyl aniline derivative formed predominately.

74 %


Benson, S. C.; Palabrica, C. A.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257

Sauer, J.; Heinrichs, G. Tetrahedron Lett. 1966, 4979

111

N N

NN

CO2Me

CO2Me

NNMe2

H R

NH

EtO Ph

N

NN

N

N

MeO2C H

RNMe2

CO2Me

NN

NN

N

MeO2C Ph

OEtH

CO2Me

N

N

N

NN

N

CO2Me

Ph

CO2Me

CO2Me

NMe2

R

CO2Me

N

NN

N

CO2Me

CO2Me

N

C

NMe2N

NN

N

N

MeO2C

CO2MeNN

N

CO2Me

CO2Me

NMe2NMe2

NN

N

X

CN

Ph

Ph N

N

X

Ph

Ph

R = alkyl, Ph

27 %

-N2

+PhCl, ∆ -N2

78 %

X = O, NCOCF3

225-235 oC

Diels-Alder reactions of electron deficient heteroaromatic dienes

Route to condensed pyrazines via internal cycloadditions using nitriles as dienophiles

-N2

EtOH

56-81%

Taylor, E. C.; French, L. G. J. Org. Chem. 1989, 54, 1245Taylor, E. C.; French, L. G. J. Org. Chem. 1986, 51, 1967

71 %


Roffey, P.; Verge, J. P. J. Heterocycl. Chem. 1969, 6, 497Seitz, G.; Overheu, W. Arch. Pharm. 1979, 312, 452Müller, K.; Sauer, J. Tetrahedron Lett. 1984, 2541Balcar, J.; Chrismam, G.; Huber, F. X.; Sauer, J. Tetrahedron Lett. 1983, 1481Burg, B.; Dittmar, W.; Reim, H.; Steigel, A.; Sauer, J. Tetrahedron Lett. 1975, 2897

Seitz, G.; Overheu, W. Chem. Zeit. 1979, 103, 230

112

NN

N NCO2MeMeO2C

N

N

MeO2C

CO2Me

OMeO

MeO

OMe

O

NNNAc

MeO O

RO

NAc

OR

O

MeO

NAcHN

MeO2C

MeO OH

N

N

NN

CO2Me

MeO2C OMe

OMeO

dioxane - N2

several230 oC

R = t-BuMe2Si

N

N N

Ph

Ph

R1HN

N

N

N

N

N

N

OR1

N

K

PhPh

N

O N

N

N

N

Ph

Ph

CH3

+

BC

Diels-Alder Reaction of 1,2,4,5-tetrazine-3,6-dicarboxylate

Boger, D. L.; Wysocki, R. J. J. Org. Chem. 1989, 54, 714

70 %

87 %

reflux - MeOH

NN

NO

steps

(Im)2CO

CH3

CH2Cl2

(50%)(R1 = CH3)

Ph

Ph

Inverse Electron Demand Diels-Alder Reaction of Triazines with Indole

∆


Fan, W. -H.; Parikh, M.; Snyder, J. K. Tetrahedron Lett. 1995, 36, 6591

113

NH

EN

H

E NH

E

N N N

N N N

H

E

H

E

H

E

H EH EH E

NX

YN

X

YN

X

Y

N N N

N N N

Intermediates in the Electrophilic Substitution of Pyridine

X

Y

X

Y

X

Y

X YX YX Y

Intermediates in the Nucleophilic Displacement of X- by Y- in X-Substituted

Pyridines

+ +

+

++

+

+

+

+

--

-

-

- -

-

-

-


114

Br

NO2

O

H N

S

S

N

73 %

R'-Pd-OR"

90 %

R'-X

Pd(PPh3)4

Pd(PPh3)4

FeSO4

FeSO4

Synthesis of Thieno Fused Quinoline Derivatives

Proposed Catalytic Cycle for the Suzuki Reaction

Pd (0)

R'-Pd-XR'-Pd

R"O-Na

NaXRB

OR

ROB

RO

R'

H

O

B(OH)2

H

OH

O

O2N

S S

SS

B(OH)2Br

NO2

Oxidative Addition

transmetallation

R

R

Reductive Elimination

+

+


Gronowitz, S.; Lawitz, K. Chemica Scripta 1983, 22, 265 Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1986, 26, 383 Gronowitz, S. Chemica Scripta 1987, 27, 535 Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 383 Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 311 Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1984, 23, 120 Gronowitz, S.; Peters, D. Heterocycles 1990, 30(1), 645

Suzuki, A. Acc. Chem. Res. 1982, 15, 178 Suzuki, A.; Yanagai, T.; Miyaura, N. Synth. Commun. 1981, 11, 513 Suzuki, A.; Suginome, H.; Yamada, K.; Miyaura, N. J. Am. Chem. Soc. 1985, 107, 972 Suzuki, A.; Makoto, S.; Norio, M. Tetrahedron Lett. 1986, 27, 3754 Suzuki, A.; Satoh, M.; Miyaura, N. Tetrahedron Lett. 1984, 23, 120

115

NO2

S B(OH)2

CHO

S Br

NHBoc

S

N

S

S

NHBocBrS

N

S

S CHO

B(OH)2

N

H2N NN

S

Malm, J.; Rehn, B.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 11

67 %

90 %

+

Pd (0)NaHCO3

1. Pd (0)NaHCO3

2. HCl

2. TsONH2HClO4

81 %

60 %

1. Pd (0)NaHCO3

2. HCl

B(OH)2

CHOS Br

NHBoc N

S

Gonowitz, S. J. Heterocyclic Chem. 1992, 29, 1049

Yang, Y.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1989, 26, 865

I

Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 641

S CHO

B(OH)2

NBr

N+

N

S

55 %

ClO4-

+

1. Pd (0)NaHCO3

Suzuki Coupling of Polycondensed Thiophenes

+

+Pd (0)Na2CO3

S

S N

N

OtBu

Peters, D.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1990, 27, 2165

OtBu

Pd (0)NaHCO3

(OH)2B+

Br

55 %

N

N

OtBu

OtBu

S

S

116


B(OH)2

CON(i-Pr)2N

Br

Et2NOCON

Et2NOCO

CON(i-Pr)2

Pd (0)

NHt-BOC O

H

N

O

O

O

O

NHt-BOC

Br

Br

O

HN

NHt-BOC

B(OH)2

O

H

Br

N

B(OH)2

B(OH)2

Pd(0)

Synthesis of 6H-[2]benzopyrano[4,5-c]pyridin-6-one

Benzo(j)phenanthridine

Benzo(c)phenanthridine

Pd (0)

+

+

+

Benzo(k)phenanthridine

+

Synthesis of Benzophenanthridines

Pd (0)

Et2NOCO

N

CON(i-Pr)2O

N

O

H3O+

92 %

47%

18%

30%

80%


Snieckus, V. Chem. Rev. 1990, 90, 879 Snieckus, V. Pure Appl. Chem. 1990, 62, 671 Snieckus, V.; Siddiqui, M. A. Tetrahedron Lett. 1988, 29, 5463 Snieckus, V. Siddiqui, M. A. Tetrahedron Lett. 1990, 31, 1523 Snieckus, V.; Alo, B. I.; Kandil, A.; Patil, A.; Sharp, M.; Siddiqui, M. J. Org. Chem. 1991, 56, 3763

Sharp, M. J., Snieckus, V. Tetrahedron Lett. 1985, 26, 5997

117

R'-Pd-R

Pd(0) Cross Coupling for Heteroaromatic Synthesis

General Pd(0) Cross Coupling Catalytic Cycle

Pd (0)

R-Pd-R'

Oxidative Addition

Transmetallation

Reductive Elimination


118

R-X + R'-M R-R'Pd(0) Cat.

R = (het)aryl, alkynyl, vinyl, benzyl X = I,Br,Cl,OTf, SR"

R' = (het)aryl, alkynyl, vinyl, alkyl, benzylM = B, Sn, Zn, Si, In

General Reaction Scheme

R-Pd-X

R-X

R'-MM-X

R-R'

Cross Coupling Example

N

F

I

+OEt

Sia2B

O O OAlllyl)2Pd2Cl2NaOEt, CH3CN

N

F

OEt

O O O

99% yield

HMG-CoA Reductase InhibitorNK-104

Miyachi, N.; Yanagawa, Y.; Iwasaki, H.; Ohara, Y.; Hiyama, T. Tetrahedron Lett. 1993, 43, 8267-8270



119

Wellmar, U.; Hornfeldt, A.; Gronowitz, S. J. Heterocyclic Chem. 1995, 32, 1159

CON(iPr)2

B(OH)2

CON(iPr)2

N

Et2NOCO

BrN

Et2NOCO

To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixturewas stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in aminimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv). The mixture was refluxed for 18 h, cooled, and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated with asaturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product(81%).

81%Tol / aq. Na2CO3

N

N

OAc

AcO

B(OH)2 +OBr

Br DMENaHCO3

N

N

OAc

AcO

OBr

2.5 M HClHN

NH

O

O

OBr

86%

De, D.; Krogstad, J. Org. Lett, 2000, 7, 879-882

N

Br

Cl

+

N

BEt2

NCl

N

+

70%THF, K2CO3

Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.

The Suzuki-Miyaura Coupling

Pd(PPh3)4

Pd(DIPHOS)2

Pd(PPh3)4



120

Yang, Y.; Wong, H. N. C. J. Chem. Soc., Chem. Commun. 1992, 656.Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583.

A mixture of dichloropurine (126 mg, 0.45 mmol), stannylfuran (0.17 mL, 0.54 mmol), Pd2dba3 (13 mg, 0.013 mmol) and tri(2-furyl)phosphine (23 mg, 0.10 mmol) was added to dry DMF (3 mL) and heated under N2 at50 oC for 22 h. The reaction mixture was evaporated in vacuo and a saturated solution of KF in methanol(20 mL) was added. The resulting mixture was stirred at ambient temperature overnight and evaporated invacuo. Flash chromatography gave 123 mg of the product (88%yield).

Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Queguiner, G.; Siddiqui, M.A..; Snieckus, V. J. Org. Chem. 1995,60, 292.

O

SnBu3Bu3Sn

PdCl2(PPh3)2 THF O

COPhBu3Sn

Pd(PPh3)4 HMPA O

COPh

O2N

81%82%

N OMe

CON(i-Pr)2

B

Pd(PPh3)4/NaOH

NH2

I

N OMe

CON(i-Pr)2

NH2

N

N

OTf

OMe

+N

Bu3Sn

dioxane 79%

N

N

OMeN N

N

NMe

O

O

Amphimedine

Langli, G.; Gundersen, L.; Rise, F. Tetrahedron, 1996, 15, 5625-5638.

N

N

N

Cl

Cl

Ph

+ OSnBu3

Pd[P(2-furyl)3]2 THF N

N

N

Cl

Ph

O

88%

The Stille Coupling

THF,61%

Pd(PPh3)4/LiCl

p-NO2PhBrPhCOCl,

Pd(0) Cross Coupling for Heteroaromatic SynthesisSection one - Chemistry of Heteroaromatics

121

The Negishi Coupling

Cesnek, M.; Hocek, M.; Holy, A. Coll. Czech. Chem. Commun. 2000, 65, 1357.

tBuLi (1.9 mL, 2.8 mmol) was added to THF (8 mL) at -78o C. A solution of 2-bromo-methylpyridine (500 mg, 2.9mmol) in THF (2 mL) was added dropwise. After the mixture had been stirred at -78o C for 30-45 min, a solution ofanhydrous ZnCl2 (490 mg, 3.6 mmol) in THF (5 mL) was added slowly and the reaction mixture was stirred for 2-3 h atroom temperature. Next a solution of Pd(PtBu3)2 (19 mg, 0.038 mmol, 3% Pd) and 2-chloro-6-methoxypyridine (380 mg,2.6 mmol) in THF (5 mL) was added and the reaction heated at reflux until no further consumption was observed byTLC. After cooling to room temperature, a suspension of EDTA (3 g, 10.3 mmol) in water (60 mL) was added and stirred for 15 min then brought to pH 8 with saturated Na2CO3. The mixture was extracted several times with CH2Cl2 and thesolvent was removed in vacuo. The pure product (447 mg, 85%) was obtained after column chromatography.

Dobler, M. R. Tetrahedron Lett. 2003, 44, 7115-7117.

p38MAP kinase inhibitor

Lutzen, A,; Hapke, M,; Staats, H.; Bunzen, J. Eur. J. Org Chem. 2003, 3948-3957.

N

N N

N

I

H2N OP(O)(Oi-Pr)2

Pd(PPh3)4N

N N

N

H2N OP(O)(Oi-Pr)2

N

NClZnMe

+

NNMeNucleotideAnalogue

O

N

N

O

OO

Bn

(i) tBuLi, THF, -78o C(ii) ZnCl2, -78o C to rt(iii) Pd(OAc)2

NI O

N

N

O

OO

Bn

N82% yield

N Br

N ClMeO

(i) tBuLi, THF, -78o C(ii) ZnCl2, -78o C to rt(iii) Pd(PtBu3)2

N

NOMe

85%

83%



122

The Liebeskind-Srogl Coupling

Liebeskind, L.S.; Srogl, J. Org. Lett. 2002, 4, 979-981.Egi, M.; Liebeskind, L.S. Org. Lett. 2003, 5, 801-802.

Novak, Z.; Kotschy, A. Org. Lett. 2003, 5, 3495-3497.

SSMe

OEtO2C +

(HO)2B

CO2Me4% Pd2dba316% TFP1.3 equiv. CuTC

CO2MeS

O

EtO2C

82%

TFP = P(2-furyl)3CuTC = copper (I) thiophene-2-carboxylateCuMeSal = copper (I) 3-methylsalicylate

N

SSPh +

OBu3Sn 5% Pd(PPh3)42.2 equiv. CuMeSal

O

N

S96%

The Sonogashira Coupling

N

N N

N

NEt2

Cl

BuH+

5% Pd(PPh3)2Cl25% CuI

N N

NNEt2N Bu 65%

I

NHCOPh

BuH+

5% Pd(PPh3)2Cl210% CuI

HN

Bu 96%

Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51, 1170-1173.

2 equiv. TEADMA

TBAF,THF

NBr

Me

NCl2(Et)Si

Me

Br

CN

CNN

Me

SBr

S

Ph

O

S

Br

(i) BuLi, THF, -78o C

92%

S

Ph

5% Pd(PPh3)2Cl2

+

+ 1/3InPh3

OOHC

Br

4% Pd(PPh3)4 61%

Indium Cross Coupling

OOHC

Me



123

The Hiyama Coupling

Hiyama, T. J. Organometallic Chem. 2002, 653, 58-61.

N

In

Lee, P.H.; Lee, S.W.; Lee, K. Org. Lett. 2003, 5, 1103-1106.

MeMe

10% Pd(OAc)220% PPh32 equiv. PhSi(OCH3)3

MeMe

Mowery, M.E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.

95%4% Pd(PPh3)2Cl2

+

Jaber, N.; Schumann, H.; Blum, J. J. Heterocyclic Chem. 2003, 4, 565-567.

(ii) EtSiCl3 -78o C to rt

KF, DMF

2 equiv TBAFDMF

1 atm COTHF

Benzene

CON(iPr)2

B(OH)2

CON(iPr)2

N

Et2NOCOBr

N

Et2NOCO

O

N

O

OMeMeO

MeOBr

CHOB(OH)2

CONiPr2

OMeOMe

OMeMeO

MeO

CHO

CONiPr2

OMeOMeOMe

MeO

MeOCONiPr2

OMeOMe

NH2

OMeMeO

MeO

Metallation/Cross Coupling for Polycondensed Heteroaromatics

N

OMe

OMe

Suzuki Coupling

Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.

Aryl Lithiation Followed by Suzuki Coupling

Fu, J.-M.; Zhao, B. -P; Sharp, M.J.; Snieckus, V. Can. J. Chem. 1994, 72, 227.

To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixture was stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in aminimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv), and the mixture was refluxed for 18 h,cooled, and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated witha saturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product(81%). A solution of the biaryl compound (0.30 g, 0.75 mmol) was refluxed in 2 M HCl (10 mL) for 24 h.Normal workup followed by chromatography afforded 0.14 g (92%) of the cyclized product.

A mixture of Pd(PPh3)4 (0.44 g, 0.40 mmol) and 5-bromo-2,3,4-trimethoxybenzaldehyde (2.2 g, 8.0 mmol) in DME was stirred at room temperature for 5 min. To this mixture was added dropwise a solution of2-N,N-diisopropylcarboxamido-3,4-dimethoxyphenylboronic acid (3.2 g, 10.4 mmol) dissolved in aminimum amount of EtOH and an aqueous solution of 2 M Na2CO3. The resulting mixture was heated atreflux for 12 h, cooled, and the solid was removed by filtration. The filtrate was evaporated to drynessand the residue was washed with ether. Standard workup followed by flash chromatography afforded thebiaryl product (93%). To a solution of LDA (2.2 mmol) in THF (5 mL) was added a solution of amine (0.28g, 0.6 mmol) in THF (1 mL) at 0 °C. The mixture was stirred for 10 h. Standard workup followed by flashchromatography afforded 0.076 g (36%) of the cyclized product.

81%

reflux

2N HCl

92%

Pd(PPh3)4Tol / aq. Na2CO3

+

Pd(PPh3)4/DMF2M aq Na2CO3

reflux 93%

LDATHF

36%


124

CONEt2

Br

CONEt2

NH

MacNeil, S.L.; Gray, M.; Briggs, L.E.; Li, J.J.; Snieckus, V. Synlett 1998, 419.

O

O

N

BrO

O

N

HO

O

N

NMe

O

Commercial Merrifield resin (1% cross linked, 1 mequiv Cl/g, 0.15 g) was swollen in anhydrous DMF (5 mL) and thesystem was flushed with argon (30 min). A sample of Pd(PPh3)4 (0.05 equiv) was added and the reaction mixture wasstirred (10 min). The stannane (3 equiv) was added and the mixture was stirred at 60 °C (24 h), cooled to rt, andtreated with NH4Cl solution (5 mL) and stirred (10 min). The resin was removed by filtration (fritted glass funnel) andthe filtrate was washed successively with DMF (5 mL), H2O (15 mL), EtOAc (10 mL), MeOH (15 mL), and dried invacuo (12 h). To cleave the product from the solid support, the resin was swollen in THF (2.5 mL) for 30 min.,LiOH•H2O (5 equiv) dissolved in MeOH:H2O (2:1, 1.5 mL) was added, and the mixture was refluxed for 18-42 h.After cooling to rt, a solution of 1M HCl (3 mL) was added and the whole was stirred (10 min) and subjected tofiltration (fritted glass funnel). The resin was successively washed with THF (30 mL), and Et2O (30 mL) and the filtrate was repeatedly extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4) andevaporated to dryness to give the acid (96%).

A thick-walled screw cap glass tube was charged with a mixture of N,N-diethyl 2-bromobenzamide, aniline (0.2 mL, 2.3mmol), NaOt-Bu (0.27 g, 2.8 mmol), Pd2(dba)3 (5 mg, 0.006 mmol), BINAP (10 mg, 0.017 mmol) and toluene (5 mL)under a N2 atmosphere. The tube was sealed and heated (90-100 °C) with stirring for 21 h, and cooled to rt. Additionof aqueous NH4Cl and standard workup, followed by flash column chromatography afforded N,N-diethylN-phenylanthranilamide (430 mg, 81%). A solution of N,N-diethyl N-phenylanthranilamide (0.11 g, 0.40 mmol) in THF (3 mL) was cooled to 0 °C under argon atmosphere and treated with a solution of LDA (1.4 mmol) in THF (2 mL)precooled to 0 °C for 1.5 h and warmed to rt. Addition of aqueous NH4Cl and standard workup, followed by silica gelflash column chromatography afforded N-methylacridone (0.07 g, 79%).

Stille Coupling on the Merrifield Resin

Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4175.

Application of the Buchwald-Hartwig Amination Protocol

PhSnBu3

Pd(0)

96%

1. LiOH/H2O

2. 1M HCl

AnilinePd2(dba)3, BINAPNaOtBu

90 - 100 °C

1. N-Methylation 98%

2. LDA 79%

81%


125

N3Me

N

O

Me

O

N

N

O

Me

Me

N3

ONR

CORN

ONR

PPh3

CORN

ONR

R

A Route to Quinazolinones via Intramolecular Aza-Wittig Reaction

PPh3

25 oC, 2 h

N

O

O N3

99 %

Intramolecular aza-Wittig reaction forisoxazolo[4,3-c]quinoline formation

N

O

N

Efficient route to iminolactam derivatives via intramolecular aza-Wittig reaction

(CH2)n(CH2)n

PPh3

toluene, 25 oC 94 %

1) PPh3, xylene rt, 1 h

2) reflux, 2h

b. n = 2; 92 %

R = Me

a. n = 1; 92 %


Takeuchi, H.; Eguchi, S. Tetrahedron Lett. 1989, 30, 3313Lambert, P. H.; Vautier, M.; Carrie J. Chem. Soc., Chem. Commun. 1982, 1224Lambert, P. H.; Carrie, R. J. Org. Chem. 1985, 50, 5352Molina, P.; Alajarin, M.; Ferao, A. Synthesis 1986, 843 Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1988, 3849

Purwono, B.; Smalley, R. K.; Porter, T. C. Synlett. 1992, 231.

Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun. 1989, 602

126

NAr PPh3Ar N3

C

Ph

N

Ar

NH

Ar

Ph

R1

R2

N3

O

R1

R2

N

O

PPh3

R1

R2

NPPh3

O

R1

R2

N OPPh3

Conversion of Butenyl Azides into Benz[f]indoles by Aza-Wittig reaction

R1

R2

N

reflux

Epoxidation - Staudinger Reaction of o-Allylphenyl Azides

Ph2C C O

toluene, rt

45 %

50 %

PPh3

Et2O

PPh3

N

Ar

Ph

R1 = OCH2PhR2 = OMe

Mn2O2toluene

CHCl3


Molina, P.; Leonardo, C. L. Tetrahedron Lett. 1993, 34, 2809

Molina, P.; Alajarin, M.; Lazaro, A. L. Tetrahedron Lett. 1992, 33, 2387For a review of the Staudinger reaction see: Gololobov, Y. G.; Zhmurova, I. N.; Kasushim, L. F. Tetrahedron 1981, 37, 437

127

N

O R2

RN3

O

O

R2

R

R1R1

NH

R = p-MeC6H4

R1 = HR2 = Me

N3R

R2

O

R1

O R2

R1

R

O

(EtO)3P, CyH, 90 °C, sealed tube, 24 h

93%

N

N

R2

96%

Ph3P, PhH, rt, 2 h

99%

R

Ph3P, Et2O, rt, 24 h

To a solution of 10 mmol of the azide in 20 mL of anhydrous ether was added 2.6 g (10 mmol) oftriphenylphosphine, with stirring, until all the phosphine had dissolved. Nitrogen evolution started after a few seconds. The reaction mixture was kept at room temperature for 24 h. The solvent was removed in vacuo,and the residue triturated with 40 mL of a 1:1-mixture of ether and petroleum ether. Triphenylphosphineoxide was collected by filtration, and the crystals were thoroughly washed with cold ether. After removal ofthe solvent, the product was purified by Kugelrohr distillation.

3. Imidazolinones via an Intramolecular Aza-Wittig Reaction

R =

RN3

O

R1

O

R2

1. Oxazoles via an Intramolecular Aza-Wittig Reaction

Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J. Org. Chem. 1989, 54, 431

To a stirred solution of the vinyl azide (1 mmol) in dry cyclohexane (5 mL) in a sealed tube was added triethylphosphite (10 mmol). Nitrogen gas evolution started immediately and ceased after 1 h. The mixture washeated at 90 °C for 24 h with continued stirring. The cooled mixture was chromatographed on a short silica gel column, eluting with ethyl acetate-hexane to give the oxazole.

Use of the Aza-Wittig Reaction for Heterocyclic Synthesis

nn

R = OEtR1 = R2 = H

O

2. Vinylogous Urethanes via an Intramolecular Aza-Wittig Reaction

Lambert, P.H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352

R1

OTakeuchi, T.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375

To a stirred solution of the imide (1 mmol) in benzene (10 mL) was added triphenylphosphine (1.1 mmol).The mixture was stirred for 2 h at room temperature and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column to give the imidazolinone.

R1 = MeR2 = H


128

NH2

N

O

O

N

N

O

N3

N

O

O

CO2Me

4. 2,3-Dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-one via an

1. Ph3PBr22. Et3N

60%

Al-Khathlan, H.; Zimmer, H. J. Heterocyclic Chem. 1988, 25, 1047

A solution of dibromotriphenylphosphorane prepared from 1.4 g of triphenylphosphine and 0.84 g ofbromine in CH2Cl2 was added dropwise to a solution of 1 g of the amine in 150 mL of CH2Cl2. To thismixture was added triethylamine (1.0 g, 10.5 mmol) and the solution was refluxed for 12 h. The resulting solution was extracted with water, dried over anhydrous magnesium sulfate, the solvent was distilled toafford the product.

5. Pyrrolo[2,1-b]quinazolines via an Intramolecular Aza-Wittig Reaction

Ph3P, rt, 4 h, then 80 °C, 9 h

HCl/THFN

N

O CO2Me

Okawa, T.; Sugimori, T.; Eguchi, S.; Kakehi, A. Heterocycles, 1998, 47, 375.

To a solution of the azide (0.144 g, 0.5 mmol) in dry benzene (25 mL) was added triphenylphosphine (0.14 g, 0.55 mmol) under a nitrogen atmosphere at rt. The reaction mixture was stirred for 4 h thenheated to 80 °C for 9 h. After the solvent was evaporated, flash chromatography of the residue gavethe quinazolinyl carboxylate.


129

Intramolecular Aza-Wittig Reaction

Tandem aza-Wittig / electrocyclization reaction

Bonini, C.; Funicello, M.; Scialpi, R. Spagnolo, P. Tetrahedron 2003, 59, 7515.

S

OMe

N PPh3S N

OMe CO2Me

MeCHCl3, 34 h, 45 oC

CH3COCH=CHCO2Me

Synthesis of Vasicinone Based on Intramolecular aza-Wittig Reaction with Imide

(1) PBu3, toluene, rt 1 h, reflux, 2 h, 76%

Synthesis of Benzodiazepines and Benzothiadiazepines via aza-Wittig Reaction with Ketone

Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou, C. Tetrahedron Lett. 2000, 41, 10107.

(1) PhMgBr, THF

-40 oC

X = SO2 or COR = n-Bu, Ph or polymer supportR1 = H, Me

(2) P(OMe)3, MeOH

60 oC

83% 2 steps

Dess-Martin Toluene, reflux


(2) TBAF, THF, 0 oC rt

15 h, 82%

l-Vasicinone

Synthesis of 2, 4-Disubstituted Thiazoline via aza-Wittig Reaction with Thioester

Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281.Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125, 8734.

PPh3, THF, 50 oC

67%

Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J. Org. Chem. 1996, 61, 7316.

N3

N

O O

OTBDMS

N

N

O

OH

XN

NS

O

R1

R1PR3

XNH

N

R1

PR3

R1

OH

N

NHX

R1

R1

TESO Me

Me

OTBS

N

S

CO2Me

Me

S

TESO Me

Me

O O

CO2Me

MeN3

TBS

XNH

N

R1

PR3

R1

O

130

Key step in the Synthesis of the Indole Alkaloid Hamacanthin B via an Aza-Witig Reaction with Ketone

PBu3, toluene, reflux

12 h, 82%

R = TsR = H, (Hamacanthin B)L-Selectride

Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1396.


5

10

Synthesis of Phloeodictine A1 via aza-Wittig with an Imide

Neubert, B. J.; Snider, B. B. Org. Lett. 2003, 5, 765.

PPh3, toluene, 25 oC, 30 min

reflux, 4 h

retro Diels-Alder

Phloeodictine A1

NTsBr

NH

N3

O

O

NH

Br

NRBr

N

NH

NH

Br

O

O

N

O

O

N3

N

N

O N

N

OH

NH

H2N NH2

O

N

N

O

131


Synthesis of the marine alkaloid variolin B via aza-Wittig reaction

Molina, P.; Fresneda, P. M.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2002, 43, 1005.Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2000, 41, 4777.

Variolin B

Preparation of 2-amino-1,4-disubstituted imidazoles via aza-Wittig reaction

Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999, 64, 2540.

PPh3 / Et2O, rt Ts-NCO, Et2O, rt

R-NH2, Et2O, 0 oC

PhCO2Et

N3

PhCO2Et

N PPh3

PhCO2Et

N C N Ts

PhCO2Et

N C NHTs

HN R

N

NPh

OR

NHTsN

NPh

R

NH2

N

N

OCH3

NH

CO2Et

NPPh3

N

OH

N

NNH2

N

N

NH2

N

OCH3

NH

CO2Et

NCNCH(CH3)Ph

OCH3

N

NN

CO2Et

H

PhCH(CH3)NCO

THF, rt, 100%

Ph

CH3

132

1. Pd Catalyzed Amination of Five-membered Heterocyclic Halides

Hartwig, J. F.; Utsunomiya, M.; Hooper, M. W. J. Org. Chem. 2003, 68, 2861.


133

O Br

S

NCl

O

Br

S Br

S

Br

N

NCl

Me

O

NCl

O NMePh

O

NMePh

S

NMePh

S NMePh

S

NNnBu2

N

NN

Me

O

O

NN O

S

NBr

S

NNnBu2

OHN

2% Pd(dba)2, PtBu3

PhNHMe

56%

82%

85%

93%

PtBu3, HNnBu2

71%

77%

5% Pd(O2CCF3)2, PtBu3

1.1 eq. base, tol,

74%

51%

In a dry box, aryl bromide (0.5-2.5 mmol), amine (0.5-2.5 mmol), and NaOtBu (0.55 - 2.75 mmol) were weighed directlyinto a screw capped vial. A stir bar and 0.5-2.5 mL of toluene were added. Pd(dba)2 (2 mol %, 0.01-0.05 mmol) andPtBu3 (2 mol %, 0.01-0.05 mmol) were weighed directly into a small vial and suspended in 0.5-2.5 mL of toluene. Thecatalyst suspension was then added to the reactants to give a purple mixture. The mixture was allowed to stir for 16 h atroom temperature in the drybox or at 100 °C for 16 h outside the drybox. After this time, the mixture was poured intopentane (15 mL), filtered, and concentrated in vacuo. The crude product was adsorbed onto neutral alumina and purified by flash chromatography.

In a drybox, aryl halide (1.0 mmol), NaOtBu or K3PO4 (1.10 mmol), and amine (1.0-4.0 mmol) were added to asuspension of Pd(O2CCF3)2 and PtBu3 (0.02-0.05 mmol) in 1.0-2.0 mL of toluene in a screw capped vial. A small stirbarwas added, and the vial was sealed with a cap containing a PTFE septum. The mixture was allowed to stir at roomtemperature in the drybox or at elevated temperature outside of the drybox. After the reaction, the mixture was adsorbed onto neutral alumina and purified by flash chromatography.

1.1 eq. NaOtBu, tol

1.1 eq. base, tol

5% Pd(O2CCF3)2,

2. Pd Catalyzed Amination of Chloropyridines

Buchwald, S. L.; Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J. Org. Chem. 2000, 65, 1158.

Pd(0) catalyzed amination of heteroaromatics - Section one - Chemistry of Heteroaromatics

134

N Cl

N

Cl

N

Cl

O

HN

PhP(R)2

N NO

N

NO

.HCl

H2NBnN

N(H)Bn

N

NBn

N

L Pd0 L

L Pd0

Ar-X

PdIIAr

LX

PdIIL Ar

X NHRR'

PdIILAr

NRR'

70% (27:1)

An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with palladiumacetate (0.5 mol %), 1 (1.0 mol %), and NaOt-Bu (1.4 equiv) and evacuated and backfilled with argon. The flask wascapped with a rubber septum, and toluene (2 mL/mmol halide), the aryl chloride (1.0 equiv), and the amine (1.2 equiv)were added through the septum (aryl chlorides or amines that were solids at room temperature were added as solidsfollowing the addition of NaOt-Bu). The septum was replaced with a Teflon screwcap, the flask was sealed, and themixture was heated to 80 °C with stirring until the starting aryl halide had been completely consumed as judged by GCanalysis. The mixture was cooled to room temperature, diluted with ether (30 mL), filtered through Celite, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. N-(2-Pyridyl)morpholine: conducted on a2 mmol scale using a reaction temperature of 100 °C and ligand 2. N-(3-Pyridyl)morpholine: 1 mol % Pd(OAc)2 and areaction temperature of 110 °C gave. N-Benzyl-4-aminopyridine: 1 mol % Pd(OAc)2, 2 mol % 2, 2.8 equiv of NaOt-Bu,dioxane solvent, and a reaction temperature of 100 °C, determined to contain 3.6% of bis(4-pyridyl)benzylamine by 1HNMR analysis.

Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.

General Catalytic Cycle for Buchwald-Hartwig Amination

-LLoxidative addition

NHRR'

amine coordination

NaOtBu

NaX + tBuOH

deprotonation

Ar-NRR'

reductive elimination

+

5 mol % Pd(OAc)2, tBuONa, DMF, 80oC

cat.

+

95%

70%

+ 1 - R=tBu

2 - R=Cy


135

N Cl

+

N N

Me

N

Br

O

HN

HNPh

Me

N

N

Cl

+N Br

N

N

N

Me

Me

N

NPh

Cy2P

P NNi-Bu

i-Bui-BuN

Me

O

NNcat. Pd(OAc)2,1.5 eq. NaOtBu, tol,

cat.

4. Pd Catalyzed Amination of Pyrazine and Quinoline

Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.; Dommisse, R. A. Synlett. 2003, 12, 1822.

cat. Pd(OAc)2,1.4 eq. NaOtBu, tol,

80%

A pressure vial of 10 mL was charged with (azahetero)aryl chloride (1 mmol), amine (1.2 mmol or 1.5 mmol) andt-BuONa (0.13 g, 1.4 mmol) in air. Subsequently the vial as flushed with Ar for 1 min. Then, 1 mL of a stock solution ofprecatalyst [Pd/2L: Pd(OAc)2 and DCPB [DCPB = 2-(dicyclohexylphosphanyl)biphenyl] in anhydrous toluene was added via a syringe and the resulting mixture was flushed with Ar for an additional 2 min under magnetic stirring. Next, the vialwas sealed with an Al crimp top with septum and heated at 150 °C or 200 °C in a CEM Discover microwave apparatus.The initial power supplied was 300 W. Once the temperature was reached (IR measurement), the power dropped andfluctuated to maintain the temperature at the desired value. The total heating time of all reactions was 10 min. After thereaction vials were cooled down to rt. using a propelled air flow, they were opened and filtered over Celite and rinsedwell with 100 mL CH2Cl2 or Et2O. The filtrate was subsequently evaporated under reduced pressure and the residuepurified by flash column chromatography on silica gel.

microwave, 10 min

83%

3. Pd Catalyzed Amination of Bromopyridines

Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.

93%

84%

An oven dried Schlenk flask equipped with a magnetic stirring bar was charged with Pd(OAc)2 or Pd(dba)2 and CS2CO3(1.5 mmol). Amine (1.2 mmol) and aryl bromide (1.0 mmol) were also added at this time. The flask was capped with arubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. The ligand was then added via syringe from a stock solution. Aryl bromide (if a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol), and toluene (3 mL)were then successively added by syringe. The reaction mixture was heated to 80oC until the starting material had beencompletely consumed as judged by TLC (15-20 h). The mixture was cooled to room temperature, adsorbed onto silicagel, and then purified by column chromatography using a mixture of hexane and ethyl acetate as the eluent.

A flame-dried 10 mL round bottom flask was charged with tris(dibenzylideneacetone), dipalladium(0) (4.0 mg, 0.005mmol, 2.5 mol %), Xantphos (10 mg, 0.02 mmol, 10 mol %), pyridone (0.05 g, 0.18 mmol), and Cs2CO3 (0.09 g, 0.27mmol). The solid reactants were dissolved in 5 mL of dioxane and the appropriate aniline derivative (25 uL, 0.27 mmol)was added to the flask. The flask was capped with a condensor and kept under an atmosphere of argon. The reactionwas heated at 100oC for 1-2 h or until the starting triflate had been completely consumed as judged by TLC. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through a pad of celite and concentratedunder reduced pressure. The crude material was purified by flash column chromatography on silica gel or florisil to givethe 2,3-dihydro-1H-indolizin-5-one.

5. ββββ-Carbolinone Synthesis

1.5 eq. Cs2CO3, tol.

10 mol % Pd(PPh3)2

1.2 eq. Cs2CO3, dioxane, 110oC

Padwa, A.; Harris, J. M. J. Org. Chem. 2003, 5, 4195.


136

NCO2Et

I

MeO NHMe

NCO2Et

N

MeO

Me

NH

N

HO

Me

Me

N

O O

N2

SO2Ph

N

O

TfO

CO2MeCO2Me

NH2

Br

N

O

NH

CO2Me

Br

N

O

NH

CO2Me

Pd(PPh3)4 (92 mg, 0.08 mmol) was added to a mixture of the indole (0.32 g, 0.80 mmol), NEt3 (4 mL), and K2CO3 (0.33 g, 2.4 mmol) in toluene (10 mL). The yellow mixture was heated to 200 °C for 15 h, cooled to rt, and poured into aseparatory funnel containing Et2O (15 mL) and water (15 mL). The organic layer was washed with water (10 mL) andbrine (10 mL), dried over MgSO4, and filtered, and the solvents were removed using a rotary evaporator. The productwas purified by flash chromatography (4:1 hexane/ethyl acetate) to give 0.18 g (82%) of the product as a white powder.

6. Tetrahydopyrroloquinolines - Dehydrobufotenine

10 mol %Pd(PPh3)4K2CO3, NEt3

81%

1. BBr3

2. MeI

Buchwald, S. L.; Peat, A. J. J. Am. Chem. Soc. 1996, 118, 1028.

50% - 6 steps; 17% overall yield

1. , Rh(II)

2. Tf2O

80% 65%

+

5 mol %Pd(OAc)210% Xantphos

7. Functionalized Pyrido[2,3-b]indoles

cat. Pd2(dba)3

Dodd, R. H.; Abouabdellah, A. Tetrahedron Lett. 1998, 39, 2119.For procedure see: Buchwald, S. L.; Marcoux, J.; Wagaw, S. J. Org. Chem. 1997, 62, 1568.

8. Pd Catalyzed Coupling of Glycosylamines and 6-Chloropurines

Chida, N., Suzuki; T.; Tanaka, S.; Yamada, I. Tetrahedron Lett. 1999, 40, 2573.

1. BBr3, CH2Cl2, -78oC

74%


137

N

N

N

N

Cl

SEM

N Br

O

H

Me

N Br

HO

Me

O

O

NHBoc

N Br

Me

O

O

NH2

TFA, Me2SLiHMDS SnCl4, -78oC

O

OBocHN

N

Me

N

O

O

O

NH2

OBn

BnO

BnO

OBn

O

NH

OBn

BnO

BnO

OBn

N N

NN MPM

+

O

NH

OH

HO

HO

OH

N N

NNH

5 mol % Pd2(dba)3, 10 mol %BINAP

51%90%

57%

SEM= Me3SiCH2CH2OCH2-

81%

To a mixture of mannopyranosylamine (32 mg, 60 umol) and 6-chloropurine (33 mg, 120 umol), in toluene (2.5 ml) wasbubbled a stream of Ar for 15 min. The reaction mixture was then heated at 140oC in a sealed tube for 9 hr. After cooling, the mixture was diluted with ether and washed with brine, and dried. Removal of the solvent left a syrup, which waschromatographed on a column of silica gel (4 g), with EtOAc-toluene (1:3) to give the product as an anomeric mixture.

tBuONa, DMF, 80oC

(-) BINAP, NaOtBu, tol.

2. recrystallization (H2O)

A round bottom flask was flushed with nitrogen and charged with Pd(OAc)2 (13 mg, 0.06 mmol, 2%), (±)-BINAP (37 mg, 0.06 mmol, 2%) and toluene (10ml). The mixture was stirred under nitrogen for 10 min. In another round bottom flask,dichloropyridine (0.44 g, 3 mmol), amine (3.6 mmol, 1.2 equiv.) and K2CO3 (8.3 g, 60 mmol) were weighed. Then, thePd(OAc)2/BINAP solution was added, and the flask was rinsed with an additional 17 mol toluene. The resulting mixturewas subsequently refluxed in an oil bath under N2 with vigorous stirring until the starting dichloropyridine haddisappeared as judged by TCL and DCI-MS. After cooling down, the solid material was filtered off and washed with 100ml CH2Cl2. The solvent was evaporated and the resulting crude product was purified by flash column chromatography.

10. Selective Pd Catalyzed Aminations of Dichloropyridines

2% Pd(OAc)2, 2% BINAP

83%

Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027.


138

N

N

F

Cl N

N

F

NH

HN (CH2)CH3

H2N

HN

(CH2)CH3

N

Cl

Cl N

Cl

NH

R

N

NN

O

N

N CH3

CH3

N

N

2 mol% Pd2(dba)3,

9. Multiamino Based Structures

Senanayake, C. H.; Hong, Y.; Xiang, T.; Vandenbossche, C.P.; Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998, 39, 3121.

77%

+

Anhydrous toluene was degassed with argon for 20 min. prior to use. A dry 25 mL 2-neck flask was charged withN-propylethylenediamine (0.43 mL, 3.5 mmol), tris(dibenzylideneacetone)-dipalladium(0) [Pd2(dba)3] (40 mg, 0.044mmol), 2,2'-Bis(diphenylphosphino)- 1-1 '-binaphthyl (81 mg, 0.13 mmol) [BINAP], sodium tert-butoxide (300 mg, 3.2mmol), and aryl halide (500 mg, 2.9 mmol). The resulting mixture was evacuated and purged with argon, followed by theaddition of anhydrous toluene (10 mL). The solution was degassed with argon for 5 min, at which time it was heated to85°C for 2 h. The reaction was cooled to room temperature, quenched with 0.1N NaOH and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. Silica gelcolumn chromatography was performed using EtOAc:MeOH.

60%

90%

91%

R=

H2N-Ar, 20 eq. K2CO3

BINAP, NaOtBu

Chemistry of Hetero Aromatics

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