Lecture 10 Carbon-Nitrogen Bonds Formation I -...
Transcript of Lecture 10 Carbon-Nitrogen Bonds Formation I -...
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Lecture 10 Carbon-Nitrogen Bonds Formation I
4.1 Principles
The methods for the formation of bonds between nitrogen and aliphatic carbon can be
broadly divided into two categories: (i) reaction of nucleophilic nitrogen with
electrophilic carbon, and (ii) reaction of electrophilic nitrogen with nucleophilic carbon.
In this section, we will try to cover some of the important reactions.
4.2 Substitution of Nitrogen Nucleophiles at Saturated Carbon
4.2.1 Ritter Reaction
Treatment of a tertiary alcohol or the corresponding alkene with concentrated sulphuric
acid and a nitrile affords an amide that in acidic conditions undergoes hydrolysis to give
amine. First, a
OH
H, RCN
H2ONH
R
OH3O
NH2+ RCO2H
Mechanism
OH
H
OH2
-H2O :NC-R
NC
R
N R
H2O
N R
OH2
H2O
-H3ON R
OH
NH
R
OH3O
NH2+ RCO2H
proton
transfer
Scheme 1
tertiary carbocation is formed which is attacked by the nitrile to give a quaternary ion.
The latter is decomposed by water to provide an amide which, in acidic conditions, is
hydrolyzed to give an amine (Scheme 1).
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Examples:
+N
MeH2SO4
Chlorobenzene
HN
O
91%S. J. Chang, Organic Process Research and Development 1999, 3, 232.
Cl
Me Me
SnCl4 MeCNCH2
Me Me
CH2
Me Me
N
Me
N
Me Me
MeT.-L. Ho, R.-J. Chein, J. Org. Chem. 2004, 69, 591.
N
Ph OH
Bn
H2SO4
MeCN N
Ph
Bn
HN
Me
O
H2SO4
TMSCNN
Ph
Bn
HNCHO
H. G. Chen, O. P. Goel, S. Kesten, J. Knobelsdorg, Tetrahedron Lett. 1996, 37, 8129.
4.2.2 Gabriel Synthesis Gabriel method provides an effective route for the synthesis primary amine. In this
reaction, phthalimide, having an acidic N-H group, reacts with base to afford a nitrogen
containing anion that, as a nucleophile, undergoes substitution on alkyl halides. The
resulting compound on hydrolysis with alkali gives the primary amine (Scheme 2).
N-H
O
O
KOH
-H2ON-K
O
O
R-XN-R
O
O
-KX
2KOH
CO2-
CO2-
+ RNH2
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Mechanism
:N:K
O
O
R-X
-KXN-R
O
O
:OH
N-R
O
:
O O
HO
OH
OR
N
proton
transfer
OR
HN
CO2
OH
R
HN
CO2
O OH
proton
transferRNH2+
CO2
CO2protic
workupCO2H
CO2H
RNH2 +
Notes:
B. P. Mundy, M. G. Ellerd, F. G. Favalorao Jr, Name Reactions and Reagents in Organic Synthesis, Wiley Interscience, New Jersey, 2005.
Scheme 2
The use of hydrazine to release the primary amine has been subsequently accomplished.
This procedure is called Manske modification which finds more useful because it is
gentle to other functional groups.
N
O
O
KRX
NH2-NH2
R-NH2 +NH
NH
O
O
Examples:
N
O
O
NH2-NH2
EtOH H2N82%
C. Serino, N. Stehle, Y. S. Park, S. Florio, P. Beak, J. Org. Chem. 1999, 64, 1160.
N
O
O
Me
S
S
NH2-NH2
EtOH
NH2Me
S
S 62%L. G. Sevillano, C. P. Melero, E. Caballero, F. Tome, L. G. Lelievre, K. Geering, G. Grambert, R. Carron, M. Medarde, A. San Feliciano, J. Med. Chem. 2002, 45, 127.
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4.2.3 Gabriel-Colman Rearrangement
Potassium phthalimide proceeds nucleophilic substitution with -halo acetate and the
resulting product in the presence of base undergoes rearrangement to afford isoquinoline
derivatives (Scheme 3).
N-K
O
O
Cl
CO2R
N
O
OH
O
ORN
O
O
O
OR
N
O
O
ORO
N
O O
OR
OH
keto-enol
tautomerismN
OH O
OR
OH
OEt
Scheme 3
4.2.4. Reactions of other Nitrogen Nucleophiles
4.2.4.1 Nitrite
Metal nitrites can react with alkyl halides at both nitrogen and oxygen to give nitro
compounds and nitrites, respectively, whose proportions depend on the structure of the
reactants and reaction conditions. For example, silver nitrite suspended in ether reacts
with alkyl halides to give a mixture of nitro-compounds and nitrites whose proportions
depend on the nature of alkyl halides (Scheme 4).
BrAgNO2
EtherNO2 + ONO
70% 15%
BrAgNO2
EtherNO2
+
20%
ONO
30%
ClAgNO2
EtherNO2
+
trace
ONO
60%
Scheme 4
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4.2.4.2 Azide
Azides react with halides to give alkyl azides that could be reduced to afford primary
amines (Scheme 5).
CO2H
Br
N=N=N
-Br
CO2H
N
N
N
Pd/C, H2 CO2H
NH2
-alanine
Scheme 5
4.2.4.2 Hydrazine
The reaction of hydrazine with alkyl halides generally gives dialkylated products. This is
because the introduction of the first alkyl group increases the nucleophilicity of the
alkylated nitrogen, so that further alkylation tends to takes place.
H2N-NH2
MeI
-HI
MeI
-HIMe2NH-NH2MeNH-NH2
Hofmann bromination of alkylurea can give manoalkylated hydrazines in good yield
(Scheme 6).
R
HN NH2
O
KOBrR
HN
NH2
Scheme 6
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4.3 Addition of Nitrogen Nucleophiles to Unsaturated Carbon
4.3.1 Reactions with Aldehydes and Ketones
The condensation of aldehydes with amines finds wide applications. The fate of the
adduct depends on the structure of the aldehydes, amine, and the reaction conditions. For
examples, formaldehyde reacts with ammonia to give urotropine
(hexamethylenetetramine).
+ 4NH3 NN
N
N
Urotropine
6H2C=O
Aromatic aldehydes generally provide condensation products. This strategy has been
used to construct stereoregular chiral main chain polymers from optically active diamines
and dialdehydes with excellent yield which are otherwise difficult to access by other
methods (Scheme 7).
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OH
t-Bu
HO
t-Bu
OO OC8H17
H17C8O
CHCl3, 3 h, 40 °C
OH
t-Bu
NOC8H17
H17C8O
N
HO
t-Bu
* * HO
t-Bu
N OC8H17
H17C8O
PhPh
N
OH
t-Bu
* *
H2N NH2
PhPh
H2N NH2
[]25D = + 376 (0.1 CHCl3)
Mw = 18512, PDI =1.2
Solubility = CHCl3, CH2Cl2, THF
[]25D = + 166 (0.1 CHCl3)
Mw = 4864, PDI = 1.4
Solubility = CHCl3, CH2Cl2, THF
S. Jammi, L. Rout, T. Punniyamurthy, Tetrahedron: Asymmetry 2007, 17, 2016.
Scheme 7
4.3.1.1 Ugi Reaction
The four-component condensation of isocyanide, a carboxylic acid, an aldehydes or
ketone and ammonia or amine gives bisamide (Scheme 8). The product formation
probably takes place from a reaction between carboxylic acid, the isocyanide, and the
imine formed from the aldehydes or ketone and ammonia or the primary amine. The use
of N-protected amino acids allows the reaction to be used for peptide synthesis.
R H
O
+ R'NH2 + R"CO2H + R"'NC"R
R"N
NH
O R H
O
R"'
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Mechanism
R H
O
+ R'NH2 R H
NH R' H
O R"
O
C
N
R"'
N O
R"
O
N-R"'H R
H
R' :ON
N
O
H
R"
R"'RH
R'
HO R"
O..
"R NNH
R"'
O
R'
R H
O
Scheme 8
Examples:
N CHO
+
H2N CO2H
+ t-BuNCMeOH
RTNH
HN
OMe
O
N
O
67%
G. Dyker, K. Breitenstein, G. Henkel, Tetrahedron: Asymmetry 2002, 13, 1929.
NRBoc
CO2H R'CHO, R"NH2
NCNRBoc
N
HN"R
O
R'
C. Hulme, J. Peng, S.-Y. Tang, C.J. Burns, I. Morize, R. Labaudiniere, J. Org. Chem. 1998, 63, 8021.
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4.3.1.2 Eschweiler-Clarke (Clark) Methylation
Secondary amines could be readily methylated using the combination of formaldehyde
and formic acid under heating. This process has been extensively used in total synthesis
(Scheme 9).
H H
O
..HR2N
OH
HR2N
OH
HH
..:
H-OOHR2N
OH2
HH
.. -H2O
R2N
O
H
O
H
-CO2
HR2N CH3
-HR2N CH3
R2NH
Scheme 9
Examples:
NH2
Me HCHO
HCO2H
66%NMe2
Me
W. E. Parham, W. T. Hunter, R. Hanson, T. Lahr, J. Am. Chem. Soc. 1952, 74, 5646.
N
NH
N
NR
DMSO
Microwave
HCHO, DCO2D R = CH2D
DCHO, DCO2D R = CHD2
DCDO, DCO2D R = CD3
J. R. Harding, J. R. Jones, S.-Y. Lu, R. Wood, Tetrahedron Lett. 2002, 43, 9487.
OMe
MeO
NH2
H2CO
HCO2H, heat NMe
OMe
MeO
G. Lakshmaiah, T. Kawabata, M. Shang, K. Fuji, J. Org. Chem. 1999, 64, 1699.
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Problems:
1.
CN
t-BuO Me
O
+H
2.
NH
NN3
Cu(II)
DMF, heat
3. NH2CO2H
CH3CHO, MeOH
t-BuNC
A. Complete the follwoing.
4.
HN
+ O=C CFe(III)
Ph
5.
CO2H
CO2H
PhCH2NH2
heat
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MeO
CNO Me
O
H2SO4 MeO
NH
O
1.
2. N
O
O
NH2-NH2
EtOH
H2N
3.NH
MeO2C
CO2Me
CH2O
HCO2H
CO2Me
CO2Me
4.
O
NH2CO2
i-PrCHO, MeOH
t-BuNC
O
N
HN
OO
B. Formulate mechanisms for the following reactions.
Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic
Synthesis, Wiley Interscience, New Jersey, 2005.
J. March, Advanced Organic Chemistry, 4th
ed, Wiley Interscience, Yew York, 1992.
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Lecture 11 Carbon-Nitrogen Bonds Formation II
4.3.1.3 Robinson-Schopf Reaction
Compounds that are enolic or potentially enolic react with a mixture of aldehydes and
primary or secondary amine in the presence of an acid to afford amine salt which, after
basification, gives an aminomethyl derivative. The reaction has found wide applications
in organic synthesis. For example, the synthesis of tropinone can be accomplished in 90%
yield. This reaction follows biomimetic approach to forming alkaloids.
H
H
O
O
+ MeNH2 +
COOH
CO2H
O
MeN
O
+ 2H2O + 2CO2
Mechanism
The synthesis involves two Mannich reactions followed by spontaneous decarboxylation
of the dibasic -keto acid.
H
H
O
O
MeNH2
COOH
CO2H
O-H
H
NH2Me
O
O H
Proton
TransferCHO
NMe
OH H
H
-H2O
CHO
NMe
ProtonTransfer
H
H
O
NHMe
CO2HO
CO2H
H
NHMe
CO2HO
CO2H
OH
Proton
Transfer
H
NMe
CO2HO
CO2H
HOH
continues
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MeN
O
H
NMe
CO2HO-H
CO2H
H
OH
-H2OHO2C
O
O
H
-CO2
MeN
O-HHO2C
keto-enol
tautomerism
MeN
OO
H
O
-CO2
MeN
OH
keto-enol
tautomerism
MeN
O
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Examples:
CHO
CHO
HO2C CO2H
O
MeNH2
O
NMe
70%
L. A. Paquette, J. W. Heimaster, J. Am. Chem. Soc. 1966, 88, 763.
CHO
CHO
HO2C CO2H
O
MeNH2
34%
MeN
O
O. L. Chapman, T. H. Koch, J. Am. Chem. Soc. 1966, 88, 763.
O
CHO
CHOHO2C CO2H
O
MeNH2
MeN
O
O
J. Bermudez, J. A. Gregory, F. D. King, S. Starr, R. J. Summersell, Biorg. Med. Chem. Lett. 1992, 2, 519
Me
Me CHO
CHO
MeO2C
HO2C CO2H
O
PrNH2, THF
Me
MeNPr O
MeO2C
T. Jarevang, H. Anke, T. Anke, G. Erkel, O. Sterner, Acta Chemica Scandinavia 1998, 52, 1350.
4.3.1.4 The Strecker Synthesis
The condensation of an aldehyde with amine gives imine that can undergo reaction with
cyanide ion in situ to give an -aminonitrile which on hydrolysis gives -amino acid.
This process constitutes a useful method for -amino acid synthesis. Asymmetric version
has also been explored.
R H
O
+ R'NH2+ HCN
AcOH
HN
OH
R'
R
O
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Mechanism
R H
O H
R H
OH :NH2R'
NH2
OHH
R
R'proton
transferNH
OH2H
R
R' ..-H2O
N
R'
H
H
R
CN
HN
R'
R
N: HH
N
R'
R
N-H
HN
R'
R
N
H
H2OH
N
R'
R
N
H
OH2proton
transfer
HN
R'
R
N
H
OH
H
proton
transferH
N
R'
R
NH2
O
H
H
H2O
HN
R'
R
NH2
OH
H OH2
proton
transferH
N
R'
R
NH3
O
H OH
H
-NH3 HN
R'
R
O
OH
Notes:
T. Laue, a. Plagens, Named Organic Reactions, John Wiley and Sons, Inc., New York, 1998, pp. 253-254.
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Examples:
N
OMe
HN
NH
O
O
Ph
NN
NH2
NH
HCN, MeOH
2 mol%
HN
OMeCN
97% yield99% ee
M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910.
TBSOCHO +
Me
OH
NH2
HCN
Chiral Zr Catalyst
OH
Me
NH
OTBS
CN4
80% yield
91% ee
H. Ishitani, S. Komiyama, Y. Hasegawa, S. Kobayashi, J. Am. Chem. Soc.2000, 122, 762.
4.3.1.4 Stork Enamine Synthesis
Enamines are specific enol equivalents to alkylate aldehydes and ketones. They are
formed when aldehydes or ketones react with secondary amines.
O NR2
R2NH R-X
Hydrolysis
O
R'
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Mechanism
The mechanism shows how they react with alkylating agent to form a new carbon-carbon
bond.
O NR2
R'-X
NR2
R'
O
R'
X
H2OH
R'H
R2N OH2
Proton
Transfer
R'H
R2NH O-HR2NH
The overall process amounts to an enolate alkylation. The reaction conditions are mild
and no self-condensation is observed.
Examples:
O
NH
CO2H
DMSO
N CO2H..
PhNO2
NCO2H..
NO2
PhHydrolysis
O
NO2
Ph
B. Kist, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423.
Me
O
CO2Me NH
TsOH, H2O
Me
N
CO2Me
S. Hunig, E. Lucke, W. Brenninger, Org. Synth. CV5, 808.
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4.3.1.5 Gabriel-Cromwell Reaction
Amines react with -bromoacrylates to give aziridines in the presence of base.
ROBr
OR'NH2
Et3NRO
O
NR'
Mechanism
ROBr
O
R'NH2RO
O
NHR'
ROBr
O
NHR'
H
NEt3RO
Br
O
NHR'
H-Et3N
ROBr
O
NHR'..
-Br
Et3N-Et3NH
RO
O
NR'
-NEt3
Examples:
MeOBr
O
CO2Me
Me
H2N
Et3N, CHCl3
MeO
O
N
CO2Me
Me
S. N. Filigheddu, M. Taddei, Tetrahedron Lett. 1998, 39, 3857.
MeN N
O
Me
Me Ph
O
Br
Br
NH3, DMSO MeN N
O
Me Ph
O
NH
Me
G. Cardillo, L. Gentilucci, C. Tomasini, M. P. V. Castjon-Bordas, Tetrahedron Asymmetry 1998, 39, 3857.
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4.3.1.6 Schweizer Allyl Amine Synthesis
This reaction involves the combined use of Gabriel and Wittig chemistry for the synthesis
of allyl amines from phthalimide, vinyl phosphonium salt and aldehyde in the presence of
base.
PR3
i. Base, phthalimide
ii. R'CHO
iii. HydrolysisH2N R'
Mechanism
NH
O
O
BaseN
O
O
PR3
N
O
OPR3
R'CHON
O
OPR3
R'H
O
N
O
OR'
HO
PPh3
-R3PON
O
O
R'
Hydrolysis
H2N
R'
4.3.1.7 Borche Reduction
Aldehydes and ketones react with amines to give imine that could be reduced using
MCNBH3 (M= Li, Na) to amines.
R R'
OHN
LiCNBH3R R'
N
Mechanism
R R'
O HNLiCNBH3
R R'
N
"H"
R R'
N
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The success of this method rests on the much greater reactivity of imine salt compared to
carbonyl group of aldehydes and ketone to the reducing agent.
R R'
O
R R'
N
> >Reactivity towards reducing agent:
Examples:
OH2NPr
LiBH3CN
HN
MeOH 81%
CHO
S. E. Sen, G. D. Prestwich, J. Am. Chem. Soc. 1989, 111, 8761.
LiBH3CN
MeOHH2N
HN
R. F. Borch, H. D. Durst, J. Am. Chem. Soc. 1969, 91, 3996.
4.3.1.8 Doebner Reaction (Beyer Synthesis)
Aryl amine reacts with aldehydes and enolizable carbonyl compounds via condensation
followed by aromatic electrophilic substitution and autoxidation to give quinolines.
NH2
ArCHO
Me CO2H
ON
CO2H
Ar
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Mechanism
NH2
Ar H
OH
N
OH
H HAr
Hproton
transfer N
OH2
HAr
H..-H2O
N
H
Ar
H
O
CO2H
H
NH
CO2H
Ar
O H
NH
CO2H
Ar
HO
..
NH
Ar
HHO CO2H
proton
transfer NH
Ar
H2O CO2H
H -H2O
NH
CO2H
Ar
autoxidation
N
CO2H
Ar
Examples:
NH2
Me CO2H
O
N
CO2H
PhMe Me 20%
G. J. Atwell, B. C. Baguley, W. A. Denny, J. Med. Chem. 1989, 32, 396.
NH2
Me CO2H
O
N
CO2H
MeO
+
OHC
Me
MeO
MeG. A. Epling, A. A. Provatas, Chem. Commun. 2002, 1036.
+
CHO
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Problems:
Me
NH2
Oi. , Me CO2H
O
ii.
CHO1.
2. CO2NH3
ONH3
LiCNBH3, MeOH
3.Me
OPh
O
O
N
OH
NaCNBH3
H, MeOH
A. What major products would you expect from the following reactions?
Cl
PhCHO
B. How will you carry out the following conversion? Explain with mechanism.
NH2
+CHO
N
Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic
Synthesis, Wiley Interscience, New Jersey, 2005.
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Lecture 12 Carbon-Nitrogen Bonds Formation III
4.4 Substitution by Nuclophilic Nitrogen at Unsaturated Carbon
These reactions are analogous to the base-catalyzed hydrolysis of the carbonyl
compounds. The order of reactivity of the compounds having different leaving groups is:
acid halide > anhydride > ester > amide.
4.4.1 Reactions of Ammonia and Amines
Amines readily react with acylating agents such as acid chlorides and acid
anhydrides in the presence of base to give amides. These are the general practical
methods used for the acylation reactions.
R Cl
O
R NR2
O
R O
O
R NR2
O
+ RCO2HR2NH
R
O
R2NH+ HCl
The condensation of carboxylic acid with amines using DCC is also a popular
route for the amide formation which will be discussed in the section on peptide
synthesis. DCC is converted into urea which can be separated by filtration.
R OH
O
R NR2
O
DCC
R2NH
Amides are weak nucleophiles and the further acylation occurs very slowly that
leads to isolation of the monoacylated product. However, intramolecular
displacement can take place if a five or six membered ring formation is possible.
For example, heating of the acyclic diamide of succinic acid affords succinimide
in good yield.
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NH2H2N
O
O
heatNH2
O
O
NH2 NH
O
O
NH3
-NH3
NH
O O
Cyclic imides can be easily prepared (practical method) by heating a mixture of acid
anhydride and amine.
O
O
O
N
O
O
PhCH2NH2
heat
Ph
+ H2O
H
H
H
H
The reaction of amines with ethyl chloroformate and carbonyl chloride affords
urethanes and ureas, respectively.
Cl OEt
O RNH2
HNR OEt
O
+ HCl Cl Cl
O2RNH2
RHN NHR
O
+ 2HCl
4.4.1 Reactions of other Nitrogen Nucleophiles
Acid chloride, anhydrides and esters react with hydrazine to provide acid
hydrazides which are less nucleophilic and the further acylation requires a more
vigorous conditions. Thus, monoacylated product can be obtained in high yield.
R Cl
O
R NHNH2
ONH2NH2
-HCl
faster
R NHNH
O
R Cl
OO
R
slower-HCl
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Hydroxylamine reacts with carboxylic acid derivatives giving hydroxyamic acids.
R OEt
ONH2OH
-EtOHR NH-OH
O
R N-OH
OH
Reaction of acid chloride with sodium azide gives acid azide which is the
substrate precursor for Curtius rearrangement.
R Cl
ONaN3
R
O
NaClN3+
4.5 Reactions of Electrophilic Nitrogen
Four electrophilic nitrogen containing groups, nitroso (-NO), nitro (-NO2), arylazo (-
N=NAr), and arylimino (=NAr), could be bonded to aliphatic carbon via C-N bond
formation.
4.5.1 Nitrosation
The reactions of nitroso group may be done by two ways. In first, enols react with nitrous
acid or an organic nitrite by an acid-catalyzed process. The electrophile is to be the
nitrosonium ion, NO+.
HNO2
HH2O
NO H2O NO+
O O OH O:
NO
OH O
NO
-H
O O
NOH
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In the second, enoalte reacts with the nitrite in a manner similar to the Claisen
condensation.
PhOEt
O
OEt
PhOEt
O
EtON
O
PhOEt
O
NOEtO
PhOEt
O
NO
-OEtPh
OEt
O
NOH
The products have two main synthetic applications. First, several heterocyclic syntheses
are performed by reducing -keto oximes in the presence of compounds with which the
products can proceed reaction to give cyclized products such as pyrroles.
CO2Et
O
NOH CO2Et
OZn/AcOHCO2Et
O
NH2
NH
COEt
EtO2C
Second, the oxime is hydrolyzed into a carbonyl group.
O
NOH
O
OH3O
4.5.2 Nitration
Compounds generate enolate react with alkyl nitrate by base-catalyzed procedure. The
reaction pathway is similar to that of the base-catalyzed nitrosation process.
Ph CN
MeO N
O
OPh CN
N OO
MeO
-OMePh CN Ph CN
NO2EtO
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4.5.2 Imine Formation
Compounds that can generate enolates react with aromatic nitroso compounds to give
imine which on hydrolysis affords carbonyl group. For example, 2,4-nitrotoluene can be
converted into 2,4-dinitrobenzaldehyde by this process.
NO2
NO2
CH3
:B
H:B
NO2
NO2
CH2
N(CH3)2
N O
N(CH3)2
N
NO2
NO2
H3O
NO2
NO2
CHO
+
N(CH3)2
NH2
4.6 a-Amino Acids, Peptides and Proteins
Peptides and proteins are naturally occurring polymers in living systems. They are
derived from-amino acids linked together by amide bonds. The distinction between
peptides and proteins is that the polymers with molecular weights less than 10000 are
termed peptides and those with higher molecular weights are termed proteins.
H2NNH
HN
NH
HN
R
O R'
O
O
R"
R"'
On
R""
OH
O
C-terminal amino acid
N-terminalamino acid
The acid-catalyzed hydrolysis of peptides and proteins provides the constituent -amino
acids which are, except glycine, chiral having L-configuration. The syntheses of peptides
followed to date have been based on the reverse of this process. Therefore -amino acids
are of significant importance.
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4.6.1 The Synthesis of -Amino Acids
The following are the some of the common methods used for the synthesis of -amino
acids.
4.6.1.1 From -Halo acids
The simplest method consists of the conversion of carboxylic acid into it’s -bromo-
derivative which could be reacted with ammonia to give -amino acid.
R CO2HBr2
PBr3R CO2H
BrNH3
-HBrR CO2H
NH2
Hell-Volhard-Zelinski reaction is generally employed for the preparation of -bromo
acid. It involves the treatment of the acid with bromine in the presence of a small amount
of phosphorus to give acid bromide which undergoes (electrophilic) bromination at the
-position via its enol tautomer. The resulting product exchanges with more of the acid
to afford -bromo acid together with more acid bromide for the further bromination.
RPBr3
O
OH R
O
O
PBr2
+ Br R
O
BrR
O
Br
H
Br-Br
-HBr
R
O
Br
Br R
O
OH
R
O
Br
R
O
OH
Br
+The halogen from PX3 is not transfered to the-position
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CO2H
Br2, PCl3
CO2H
Br
L, A, Carpino, L. V. McAdams, III, Org. Syn. CV6, 403.
OH
O
+ MeOHBr2, P4 OMe
OBr
90%67%K. Estieu, J. Ollivier, J. Salauen, Tetrahedron Lett. 1996,
37, 623.
The amino group may also be introduced by Gabriel procedure (4.2.2) which gives better
yield compared to that of the above described reaction with ammonia as an aminating
agent.
N
O
O
K
EtO2C CO2Et
-KBr
N
O
O
CO2Et
CO2Et
MeS
ClN
O
O
CO2Et
CO2Et
S
Me
Base
1. OH
2. H
H2N
O
O
CO2H
CO2H
S
Me
OH
OH+
-CO2HO2C S
Me
NH2
Methionine
Br
The amino group can also be introduced via nitrosation (4.5.1) followed by reduction
and hydrolysis processes.
EtO2C CO2EtHNO2
H
EtO2C CO2Et
NOH
Zn, AcOH, Ac2O EtO2C CO2Et
NHOAc
Hydrolysis
Decarboxylation
EtO2CCl
EtO2C
EtO2C CO2Et
NHOAc
Base
HO2C
CO2H
NHOAc
Glutamic acid
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4.6.1.2 The Strecker Synthesis
The condensation of aldehydes with amine gives imine that can undergo reaction with
cyanide ion in situ to give an -aminonitrile which on hydrolysis gives -amino acid. For
mechanism see 4.3.1.4.
R H
O
+ R'NH2+ HCN
AcOH
HN
OH
R'
R
O
4.6.1.3 Bucherer-Bergs Reaction
Ketones proceed reaction with ammonium carbonate in presence of cyanide ion to afford
hydantoin that could be hydrolyzed to -amino acid.
R R'
OKCN, (NH4)2CO3
EtOH, H2O
NHHN
RR' O
O
hydantoin
H3O OHH2N
RR' O
Mechanism
R R'
O (NH4)2CO3
R R'
NH2 CN
R R'
NH2
NC
O C O
R R'
H2N
NC
O
O
proton
transferR
R'
HN
C
OH
O
N
OHN
O
RR' N
HON
O
RR' NH
H N
RR' O
C
O
NH2NH2N
O
RR' O
NHNH
O
RR' O
F. L Chubb, J. T. Edward, S. C. Wong, J. Org. Chem. 1980, 45, 2315.A. Rousset, M. Lasperas, J. Taillades, A. Commeyras, Tetrahedron 1980, 36, 2649.
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Examples:
CO2H
OKCN, (NH4)2CO3
EtOH, H2O
CO2H
NH
HN
O
O
40%
J. Ezquerra, B. Yruretaguyena, C. Avendano, E. de la Cuesta, R. Gonzalez, L. Prieto, C. Peqregal, M. Espada, W. Prowse, Tetrahedron 1995, 51, 3271.
O
O
O
Co2Et
KCN, (NH4)2CO3
EtOH, H2O O
O
Co2Et
NH
HN O
O
C. Dominguez, J. Ezquerra, S. R. Baker, S. Burrelly, L. Preto, M. Espada, C. Pedregal, Tetrahedron Lett. 1998, 39, 9305.
4.6.2 The Synthesis of Peptides
In the synthesis of peptides one amino acid is protected at its amino end with group Y
and the second is protected at its carboxyl end with a group Z. The condensation of these
protected amino acid derivatives is then carried out using dehydrating agent such as DCC
to generate peptide bond. As per the requirement, one of the protecting groups is now
removed and a third protected amino acid is introduced to the second peptide bond.
Repetition of the procedure affords the desired peptide.
Protection and Deprotection of Carboxyl Group
The carboxyl group is normally protected by converting it into its t-butyl ester
using isobutylene in the presence of sulfuric acid.
R OH
O H
R O
O
The protecting group could also be easily removed using mild acid hydrolysis via
the formation of a t-butyl carbocation.
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R O
O
H R O
OH
RCOOH +
+ H2OOH
-H
Protection and Deprotection of Amino Group
(9-Fluorenyl)methyoxycarbonyl group (Fmoc) is commonly used as protecting
group for the protection of the amino group of amino acid which can be facilitated
using Na2CO3 in a mixture of DME and water.
O ON
H
OO
ORNH2
Na2CO3
O NHRH
O
+ NHO
O
O
The important characteristic of this protecting group is that it can be easily
removed by treatment with amine base, such as piperidine.
O NHRH
O
HN :
+ H2N :O NHR
O
+
N:O NHR
O
+H
H
-CO2 RNH2 + HN :
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Synthesis of Tripeptide
Let us try the synthesis a tripeptide having Phe-Gly-Ala sequence. Coupling of Fmoc-
glycine to the free amino group of t-butyl protected alanine could be effected by the
reagent 1,3-dicyclohexylcarbodiimide (DCC) in the presence of N-hyroxysuccinimide
(NHS). DCC is converted into DCU. The resulting protected dipipetide could be
deproteced using piperdine and coupled with Fmoc-phenylalanine to give the protected
tripeptide Fmoc-Phe-Gly-Ala-tBu. The protecting groups could be deprotected using
weak base (Fmoc) and mild acid (tBu) to afford the target peptide, Phe-Gly-Ala.
OHN CO2H
O
+ H2NO
Me
O
N OO
OH
DCC DCU
OHN
O
O
NH
O
Me
O
Fmoc-Gly-Ala-t-Bu
HNDeprotection
H2N
O
NH
O
Me
O
FmocHNOH
Ph
Fmoc-GlyAla-Bu
O
DCC DCU
NHS
NHS
NHS =
HN
O
NH
O
Me
O
NH
Fmoc
O
Ph
Fmoc-Phe-Gly-Ala-t-Bu
HN
Deprotection
HN
O
NH
O
Me
O
H2N
O
Ph
H HN
O
NH
OH
Me
O
H2N
O
Ph
Phe-Gly-Ala
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The Role of DCC and NHS in Peptide Synthesis
R-COOHN C N
DCC
C
HN
NOR
O
o-acylisourea
good leaving group
N
OH
OO
NHS
N-Protected amino acid
OR
O
N
O
O
+
NH
NH
O
C
HN
NHO
DCU
NH2-R'
R
O
O-Protected amino acid
-NHS
NH
R'
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Problems:
O
OH
P, Br21.
2. O
OH
Br2, P4
MeOH
B. Outline synthetic routes to the following compounds.
CO2H
NH2
1.
2.
CO2H
NH2
3. HSCO2H
NH2
4. H2N
HN
Ph
O
O
CO2H
A. Complete the following.
3. EtO CHOHCN/NH3
4. CHOHCl/MeOH
5.N3
CO2H
Oheat/H2O
Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
J. March, Advanced Organic Chemistry, 4th
ed, Wiley Interscience, Yew York, 1992.