Organic Chemistry-III CH-423kpk/Chap1-FGT.pdf · Mitsunobu and related reactions, introduction of...

Krishna P. Kaliappan Department of Chemistry

Indian Institute of Technology-Bombay Mumbai 400 076 INDIA

http://www.chem.iitb.ac.in/~kpk [email protected]

9/3/14

Organic Chemistry-III CH-423

Syllabus

CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 (2013)/Chem/IIT-B Dr. Kaliappan, Krishna P. Organic Chemistry III Classification of reactions: A brief introduction to substitution, elimination, addition, oxidation, reduction, rearrangement and pericyclic reactions. Functional group transformations: alcohols to alkylating agents, Mitsunobu and related reactions, introduction of functional groups by nucleophilic substitution at saturated carbon, nucleophilic cleavage of C-O bonds in ethers and esters and inter-conversion of carboxylic acid derivatives. Oxidation: Metal based oxidizing reagents: A review and detailed discussion of chromium, manganese, ruthenium, silver and other metal-based reagents. Non-metal based oxidizing reagents: DMSO, peroxide, peracid and oxygen based oxidation. Miscellaneous oxidizing reagents like IBX, DMP, CAN, DDQ, periodate etc.

Syllabus


CH-423 (2013)/Chem/IIT-B Dr. Kaliappan, Krishna P. Organic Chemistry III Reduction: Homogeneous and heterogeneous hydrogenations; Discussion on borane based racemic and chiral reagents, aluminum, tin, silicon based reducing agents. Dissolving metal reductions. Selectivity and protecting groups: Illustration of chemoselectivity, regioselectivity and stereoselectivity with examples; protecting groups for alcohols, amines, acids, ketones and aldehydes. Cycloaddition reactions: Diels-Alder reaction; general features, dienes, dienophiles, selectivity, intramolecular and intermolecular reactions, hetero-Diels Alder reaction. 1,3-dipolar cycloaddition reactions; general features, dipoles, dipolarophiles. [2+2] cycloaddition reactions; general features, selected examples. Molecular rearrangements: Illustration of electron deficient and electron rich skeletal rearrangements with examples; Sigmatropic rearrangements-Claisen and related rearrangements, Cope and oxy-Cope rearrangements; 2,3-sigmatropic rearrangements and ene reaction.

Syllabus


Suggested Books/Reviews: Jerry March, “Advanced Organic Chemistry”, Fifth Ed., Wiley, 2007. F. A. Carey and R. J. Sundburg, “Advanced Organic Chemistry, Part B”, Fifth Ed., Springer, 2007. J. Clayden, N. Greeves, S. Warren and P. Wothers, “Organic Chemistry”, First Ed., Oxford University Press, 2001. W. Carruthers, I. Coldham , “Modern Methods of Organic Synthesis”, Cambridge University Press K. Peter C. Vollhardt and Neil E. Schore “Organic Chemistry” W. H. Freeman and Company, 1999. Evaluation Pattern

Mid-Semester 30% End Semester + Assignment 50% Quiz (2) 20%

-There will be a total of 36 (1h) lectures, and 7 tutorials

Functional Groups


Only With Carbon and Hydrogen

C C C C

With Heteroatoms

With One Oxygen Atom:

1.  Alcohol:

2. Ether:

R OHPrimaryalcohol

OH

R

R

secondary alcohol

R

OH

RR

tertiary alcohol

ODiethyl ether

O

anisoleO

diphenyl ether

9/3/14 6 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Functional Groups

5. Epoxide, Cyclic Ethers:

4. Aldehyde:

3. Ketone: O

Acetone

O

Acetophenone

H

O

Acetaldehyde

H

O

Benzaldehyde

O

Epoxide

O

Oxetane

With One Oxygen Atom:

Functional Groups


With Two Oxygen Atoms: With Heteroatoms

1. Acid:

OH

O

Acetic acid

OH

O

Benzoic acid2. Ketal:

R R

OR' OR'

3. Acetal:

R H

OR' OR'

4. Ester:

OEt

O

Ethyl acetate

O

O

Ethyl benzoate

Functional Groups


With Two Oxygen Atoms:

6. Peroxides:

With Three Oxygen Atoms:

1. Anhydrides:

With heteroatoms

5. Lactones (Cyclic Esters):

O

O

γ-lactone

O

O

δ-lactone

ROOR

O

O O

Acetic anhydride

Functional Groups


With Three Oxygen Atoms:

3. Peracids:

With Heteroatoms

2. Hydroxy acids:

O

OHOH

O

OH

OH

O

OHOH

γ-hydroxy acidβ-hydroxy acidα-hydroxy acid

O

OOH

Cl

meta-chloro perbenzoic acid

Functional Groups


With Heteroatoms

1) Amines:

With One Nitrogen Atom

H3CNH2 H3C

HN

CH3 NMethyl amine

(primary amine)Dimethyl amine

(secondary amine)Triethyl amine (tertiary amine)

2) Aromatic Amines: NH2

Aniline

3) Nitriles:

H3CCN

Acetonitrile

Functional Groups


4) Aziridines:

With Heteroatoms With One Nitrogen Atom

HN

aziridine

5) Aromatic Amines:

NNH

Pyridine Pyrrole

6) Imines:

R H

NH

Primary aldimine

R H

NR

Secondary aldimine

R R

NH

Primary Ketimine

R R

NR

Secondary Ketimine

Functional Groups


With Heteroatoms With Two Nitrogen Atoms

H2C N2Diazomethane

1) Diazo:

N NR

R2) Azo:

N N

Benzenediazonium cation

3) Diazonium:

With Three Nitrogen Atoms 1) Azides:

RNNN

NN

HN

NN

HN

1,2,3-triazole 1,2,4-triazole

2) Triazole:

N NN

HN

1-triatrazole

1) Tetrazole:

With Four Nitrogen atoms

Functional Group


With Heteroatoms With One Nitrogen Atom and One Oxygen Atom

1) Amides:

2) Lactams:

R NH2

O

NH NH

OO

γ−lactamβ−lactam

R H

NOH

R R

NOH

aldoxime ketoxime

RNO

R N O

3) Oximes:

4) Nitroso:

5) Nitrile Oxides:

Functional Group


With Heteroatoms With One Nitrogen Atom and Two Oxygen Atoms

1) Nitro: 2) Nitrones:

RNO2

NO

RR

With Two Nitrogen Atom and One Oxygen Atom

1) Urea:

H2N NH2

O

Functional Group


With Heteroatoms (Sulfur)

1) Thiols:

SH SH

ThiophenolEthanethiol

2) Thio Ethers:

RSR

3) Thio carbonyl:

R R

S

S

4) Thiirane:

5) Heterocycles:

SThiophene

Functional Group


With Heteroatoms (Halogens)

1) Halides:

2) Halohydrin:

3) Dihalides:

4) Acid Chloride:

5) Halolactones:

H3CI

BrMethyl iodide Ethyl bromide

HOClR

OHR

I

ClCl

1,2-dichloroethane

Cl

O

Acetyl chloride

O

O

I

Functional Group Transformations

17 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Organic Synthesis and Music: What is Common Between Them?

Reactions Can be Classified into Seven Types

Elimina'on

Oxida'on

Pericyclic


Functional Group Transformations 1. Addition Reaction:

a. Nucleophilic Addition

R R'

O

NuR R'

O

Nu

E

R R'

OE

Nu

Reaction is categorized by first step and not by second step

b. Electrophilic Addition

Br2 Br

Br

Br

Br

X. X . Y.

Y

Xc. Radical Addition


Functional Group Transformations 2. Elimination Reactions

E1, E2, E1CB, syn, anti, pyrolytic

OAc

O

OH

AcOH

OAc

HAcOH

Syn elimination

OH NaHCS2, MeI

OHH Side reactions like Wagner-Meerwein

rearrangement can take place

Syn Elimination:

O SMe

SH

Xanthate ester

+ HS SMe

OCOS + MeSH



3. Substitution Reactions

a. Aromatic Substitution b. Aliphatic Substitution

1. Nucleophilic Substitution

SN1, SN2, SNi

1. Nucleophilic Substitution

F

NO2

OR

NO2OR

2. Addition- Elimination

CNBrNaNH2

CN

via Benzyne

2. Electrophilic

E1, E2, E1CB, syn, anti, pyrolytic


R'OHRCO2H + RCO2R'H+

R'OHRCO2H + RCO2R'Base

R

O

O

O

RR'OHBase R

O

OR'

Base must be non nucleophilic

N

HO

HO

O

Morphine (Acute pain killer)

Ac2OH+ N

AcO

AcO

O

Heroin

Functional Group Transformations Esters

Ways to make esters


R

O

OH

CH2N2R

O

OMe

R

O

OHH2C

N2 R

O

O H3C N2

If compound containing nitrogen having more nitrogen content (more than 50%), then compound may be explosive (CH2N2 is explosive)

OH

CH2N2

OMe

R OHCH2N2

R OMeProton must be acidic enough to pick by CH2N2

OH

OH

CH2N2

OH

OMe

Ways to Make Esters Functional Group Transformations


R'-IRCO2H + RCO2R'base

R'OHRCO2H + RCO2R'DCC

N C N

N,N'-Dicyclohexylcarbodiimide (DCC)

N C N

R O

OH

R'OH

HN C NO

O

RRCO2R'

NH

O

NH

Dicyclohexyl urea

+

Sometimes its difficult to separate product from DCU, in that case, use EDCI instead of DCC

Functional Group Transformations Ways to Make Esters


Baeyer-Villiger Oxidation

O

OO

mCPBA

Favorskii Rearrangement

O

Br CO2EtNaOEt/EtOH

Mitsunobu Reaction R'OH+RCO2H

DEAD, PPh3 RCO2R'

N NCO2Et

EtO2C

Ph3P

N NCO2Et

EtO2C

Ph3P

O R

OH

N NH

CO2Et

EtO2C

Ph3P

ROH

RCO2+

R O

ORCO2R'O PPh3 +

HN N

H

CO2Et

EtO2C+

R O PPh3

Functional Group Transformations Ways to Make Esters


Mitsunobu Reaction

R R1

OH

PPh3, DIADR2CO2H

R R1

O R2

O

N NCO2R

RO2CR = iPr, DIAD

Diisopropyl azodicarboxylateR = Et, DEAD

Diethyl azodicarboxylate

O

O

OBnO

?

O

O

OBnO

H+, H2O

HO

O

BnOOHO

PPh3, DEAD


R R1

OH PPh3DEAD

OHR R1

OPh

26

Functional Group Transformations Mitsunobu Reaction

Nitrogen Nucleophile:

OBnOH

PPh3, DEAD

TsNHCH3

OBnNTsH3C

N

HN

O

PPh3

DEAD

OH

N

N

O

Intramolecular Mitsunobu Reaction:

HNHO

CO2EtCO2EtPh PPh3

DEAD NCO2Et

CO2EtPh


Weak Nitrogen Nucleophile: O

BnO OBn

OHBnO

NH

R

PPh3, DEADO

BnO OBn

BnON

R

27

Functional Group Transformations Mitsunobu Reaction


Azides: ROH + PPh3 + DEAD HN3 PPh3 +RO

HN

HN CO2EtEtO2CRN3

RN3 + Ph3PO N N CO2EtEtO2CPPhO OPhO

H

O(PhO)2P N3 Can be used instead of HN3

N N CO2EtEtO2C

(PhO)2P N3

O

PPh3

N N CO2EtEtO2CPPhO OPhO

PPh3

OHR

N N CO2EtEtO2CPPhO OPhO

HR O PPh3 +

N N N

R N3 + PhP O

O(PhO)2P N3ROH + + PPh3 + DEAD


Alcohols

Reduction:

Primary alcohols

R NaOH, H2O2

BH3

R

OH

HCHORMgX

RCH2OH

RCHO NaBH4

RCO2RLiAlH4

RCO2HLiAlH4



Secondary Alcohols R R'

Oreduction

RCHORMgX

ROxymercuration

RMgXHCO2R symmetrical 2o alcohol

formate ester

Tertiary Alcohols

R R'

ORMgX

ROxymercuration

RMgXRCO2R

Functional Group Transformations Alcohols


ROH Pyridine, MsclR OMs Mesylate

ROH Pyridine, TsclR OTs Tosylate

ROH Pyridine, BrclR OBs Brosylate

ROHPyridine, Nscl

R ONs Nosylate

ROH Pyridine, Tf2OR OTf Triflate

R OTs NaBrAcetone R Br Finkelstein reaction

Alcohols are important class of compounds but they are not good leaving group −OH is not a reactive alkylating agent. Reactivity can be enhanced by converting into a better leaving group like sulfonate esters or halides

Most reactive

Functional Group Transformations Activation of Hydroxyl Group

Preparation of Sulfonate Esters:


R OH

ClSO

Cl OSO

ClR

Cl


Preparation of Alkyl Halides:

R Cl + +SO2 Cl

Alkyl halides are involved in the formation of C−C bond by nucleophilic substitution

Inversion of configuration

But, if reaction is taking place in solvent like 1,4-dioxane

OSO

ClR

O

O

O O RCl

R Cl

Retention of configuration

Reaction with SOCl2

Activation of Hydroxyl Group


PCl

Cl

RO 2ROH POR

OR

RO


PCl

ClClROH

Reaction with Phosphorous Halides

- HCl

The reaction will stop at this stage if it is carried out in presence of an amine

POR

OR

RO H+

When amine is not present

POR

OR

OH

Cl

R2RCl+P

OHOH

OH

Inversion of configuration

Drawbacks: Not suitable for acid sensitive compounds Amines can not be used

OHOO

BrOO

?

R Cl PHOR

OR+O



Ph3P Br Br Br Ph3P Br+

R OH

R O PPh3

Br

- HBr

Reaction with Alkoxyphosphonium Salts

R Br O PPh3

Formation of strong phosphoryl double bond is the driving force

HO

Ph3P

Br2Br

R OH PPh3+ R BrO

Br

Br

Br

Br+

Bromide source

Functional Group Transformations Activation of Hydroxyl Group


Cl CCl

ClCl

Ph3P R O PPh3ClCCl3 +

R OH

Cl3C CO

CCl3

PPh3R Cl

PPh3/ CCl4

CCl3

R OH

Ph3P Cl

R ClHexachloroacetone can be used as chloride source

PPh3/ I2/ Imidazole N

NH

I2 R OHPPh3 R I


Ph3P I IPh3P I

RHO

-HI

ImidazoleROPPh3

I

R I




Reaction with 2-Halo-3-alkylbenzoxazolium Cation

O

NCl RHO

Addition

Elimination O

NOR

Cl

O

NO R Cl

Mitsunobu Reaction

N NCO2Et

EtO2C

Ph3P

Me I

N NCO2Et

EtO2C

Ph3P

MeI+

OHR

N NCO2Et

EtO2C Me

HIR O PPh3R I



HBr BrBrO BrBr

HBr

HBrOH

Br HO Br

HBr

H2O Br

BrBrBr


Mild Method OH MsCl

Py

OMs LiCl ClMsOLi

Some Other Methods

O

O



Functional Group Transformations Nitriles

Dehydration

RCONH2

Abnormal

BeckmannRearrangement

N

R

OHR CN

LAH

H 2/ Pd-C

RCH2NH2

H3O+ RCO2H

R'MgBrRCOR'

DIBAL-H

RCHO

RX + NaCN

Alkylation

R'

R' CN


Functional Group Transformations Preparation of Nitriles

R X NaCN R CN R

O

NH2

P2O5 R CN

aldoxime

Beckmann rearrangenment can also occur

Reaction proceed faster in polar aprotic solvents

NHO

NH2O

H+N H

NO

H2O

N OH N OH2 N

NC

H+

tertiary carbocation

-H+

R

N

H

OHp-TsCl, Py

AcCl, PyR CN


Functional Group Transformations Preparation of Nitriles

RCH2Br + KCN18-Crown-6

CH3CN83oC

RCH2CN

R CHOR

OH

CN

stable under mild acidic condition unstable under basic condition

OH-

R CHO + CN-

R CHOR

OTMS

CN

KCN

H+

TMSCN

ZnBr2


R CNR'MgBrH+/H2O

RO

R'

R CNLDAR'I R CN

R'

R CN

R CN

R CN

R CN

LAHor

H/Pd-C

R CH2NH2

partial hydrolysis

R

O

NH2

H3O+

RefluxR CO2H

SnCl2/HClDIBAL-H R

O

H

Stephen reaction

Utility of Nitriles



Functional Group Transformations Azides

R N3

NF

N3ROH

PPh 3, HN 3

DEAD

ROH

P(OPh)2

ON3 DBUROH

H 2/ Pd-

C

RNH2

PPh3, H2ORNH2

1,3-Dipolar

cycloaddition

N NNR

NaN3 , DMSO

R'CH2Br

R'CH2Br NaN3, PTC


R XNaN3, DMF

R N3

R N3PPh3, DEAD

HN3R OH

Preparation of Azides


RCH2BrNaN3

TBAB25oC

RCH2N3

At room temperature & phase transfer condition:

From alcohols:

Mitsunobu Reaction

N F

HO RMe

N OMe

R N OMe

RN3 +

R OH(PhO)2 P N3

O

DBUR N3 1,8-Diazabicycloundec-7-ene

N

NDBU

N3


Utility of Azides


R N3H2/Pd-C R NH2

PPh3, H2OR N3 R NH2

Staudinger Reaction

R N N N

PPh3

R N N NPPh3

-N2 R N PPh3H2O R NH2

R N N N PPh3 R N N N PPh3N

N PPh3

N

R

R N PPh3R NH2H2O

Ph3P O N2

R N PPh3

R N PPh3


Preparation of Amines With same number of carbon atom

RNO2 RNH2 RN3 RNH2

RCN RCH2NH2

R

O

NR"

R' R NR"

R'

R X+ N

O

O

RNHNH

O

O

RNH2NH2NH2 +

R NOH R NH2

R R'

NOH

R R'

NH2

Gabriel amine synthesis

Functional Group Transformations Amines

N

O

O

K


With One Carbon Atom More

R X CN+ R CN reduction R CH2NH2

R XCH3NO2Base

R CH2NO2reduction R CH2NH2

CH3NO2BaseR CHO R

NO2 RNH2reduction

With One Carbon Atom Less

R NH2

OR NH2

R N3

O

R OH

O

R NH2

R NH2

Hoffmann Rearrangement

Curtius Rearrangement

Lossen Rearrangement

Schmidt Rearrangement

R NH2

Functional Group Transformations Preparation of Amines

R NH

O

OH


Functional Group Transformations Reduction:

Can be achieved by using either one of the reagents

R NH2

RH2C NH2

R NO2H2/ Pd-C LAH Zn/ HCl

R CN

H2/ Pd-C BH3 NaBH4 LAH Li/ NH3

R N3 R NH2

H2/ Pd-C B2H6 NaBH4 PPh3, H2O

N

R'R

OHNH2

R'R

H2/ Pd-C LAH Raney Ni

O

NRR'

R"NRR'

R"

H2/ Pd-C B2H6 LAH

Preparation of Amines


How to Get Secondary and Tertiary Amine ?

R NCreduction R NH

CH3Reaction is not facile

R OR'NH2 NaBH4 R N

HR'

Secondary amine

R O

R' NaBH4R N

HR''

R'

R O R NR''N

HR''R'

R'R N

R''NaCNBH3

R'One pot


R NR'

Schiff base

R''NH2R N

R''

Schiff base

R'


Synthetic Utility of Amines

R NH2NaNO2HCl

R N2

Ar N2 Ar XX= Br, CN, I

Sandmeyer reaction

R NH2

CNR N

CN

CN

R NH2R'CHO

RNR'



Amides

R

O

NHR'

DCC

R

O

NHR'

R

O

ClHN

OMe

Me+


Reaction of an Activated Acid or Acid Derivative with Amine:

R

O

NOMe

MeWeinreb amide

Preparation of Amides

R

O

OHR' NH2+

R

O

ClR' NH2+

OP(OPh)2N3

O

OR

O

ORP(OPh)2

O

N3

O

N3R

O

NHR'R

R'NH2


Functional Group Transformations Preparation of Amides

Schimdt type Rearrangement: O

R'RHN3

O

NHR'R

1-Hydroxybenzotriazole:

Reaction with N-hydroxysuccinimide:

R

O

OHN

O

O

HO N

O

O

OO

R

R' NH2

R

O

NHR'N

O

O

HO

NN

N

OH

BocHN COOH H2N CO2Me

Ph

DCC

BocHN

NHCO2Me

Ph

O



Alkaline Hydroperoxide:

R CNO

R NH2

H2O2, NaOHO O

H

HOH O O

H

R C N

OO H

NH

R OOH

H2O2O

R NH2O2 + H2O

O

NH

O

HN3

or Beckmann

rearrangement

O

CH2N2

O

O

Bayer-Villiger Oxidation


N3

O N N NH

OHN N2

HN3 -N2 NH

O

NH

O

NaH, MeIPPh3, DEAD

ROH

N

OR

N

OMe


OH

Synthetic Utilities of Amides

Beckmann Rearrangement: N

R R'

OHPCl5

O

NHRR'

Interconversion of Carboxylic Acid Derivatives RCOOR

RCOOH RCOCl

RCONH2

53



Synthetic Utilities of Amides

R

O

NOMe

Me

R'MgBr

N OMgBr

OR

R'

MeR

O

R'

H+, H2O

HNBr

O

N

O

HNOH

O

PPh3, DEAD N

O

H2O

R

O

HR

O

NOMe

Me

DIBAL-HNO

AlO

HR

Me

Me


Ethers

R OH H+R OR R OH NaH, R'I

Ar OH CH2N2 Ar OMe Ar OHNaOHMe2SO4

Ar OMe

OH OH OPPh3, DEAD

R OHNaHBnBr R OBn

Basic condition


Preparation:

R OR'

COCH3OH

HO

COCH3OH

MeO

MeIK2CO3


Cl3C CN BnOH, DBUCl3C

NH

OBnCSA

Cl3C

NH2

OBn

Cl3C

NH2

O Bn

ROH

R OBnCl3C

O

NH2

trichloro acetamide

+

Functional Group Transformations Preparation of Ethers

R OH R OBn

NH

Cl3C OBnCSA O

SO3HCamphor sulphonic acid

Acidic Condition

56



Cleavage of C-O Bonds in Ethers & Esters

R O CH3Nu

R O H3C Nu

C O CH3

OR

NuC OO

R H3C Nu

R O R R OH R BrBBr3

B(OH)3 2 HBr

R O RTMS-I

R O RSiMe3

IR O

SiMe3

R I

C O R'O

RTMS-I I

R' IC O R'O

R

SiMe3

C OO

R SiMe3

H2O

C OHO

R

Mechanism in next slide


OMe O

Me

BBr2

Br

OMe

OHTMSITMSCl, NaI

R OR HX ROH RX+ mix of products

OMe HBr

OHCH3Br+

OMe

H

Br

Functional Group Transformations Synthetic Utility of Ethers

BBr3OMe

BBr Br

Br

OHMeBr

58



Interconversion of Carboxylic Acid Derivatives

C O CH3

OR

OHC OO

R H3C OH

C OHO

RSOCl2

C ClO

R SO2 HCl

C ClO

RR'2NH

C NR'2

OR HCl

C C ClO

ClO

C OHO

R- Cl

CCCl

OO

OR

OCl

C ClO

R

59



Iodolactonization:

Selenolactonization: Selenoetherification:

Epoxylactonization:

O

O

I

HO

OKI3

NaHCO3

O

O

SePh

HO

OPhSeCl

Base

O

SePh

HO

N

O

O

PhSe

O

O

OH

HO

O

O

Mildbase

O

OH

HOO

NaHCH2CO2H I2

NaHCO3

O

I

O

60



CO2HOH OO

OO

I

HOO

CO2Me

CO2Me

O OI

NaOMe

OMe

OMeOO

OMe

CO2MeOH

MeO

Organic Chemistry-III CH-423kpk/Chap1-FGT.pdf · Mitsunobu and related reactions, introduction of...

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