Download Lecture 10 Carbon-Nitrogen Bonds Formation I

NPTEL – Chemistry – Principles of Organic Synthesis
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
R
H, RCN
OH
O
N
H
H2O
H3O
NH2
+ RCO2H
Mechanism
H
-H2O
OH
OH2
OH
H2O
-H3O
N
R
N
O
proton
transfer
N
H
C
N
R
N
R
H3O
R
OH2
H2O
:NC-R
NH2
+ RCO2H
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:
Me
H
N
H2SO4
+
N
O
Chlorobenzene
91%
S. J. Chang, Organic Process Research and Development 1999, 3, 232.
Me Me
SnCl4
CH2
Me Me
Me Me
Me Me
MeCN
CH2
N
Cl
T.-L. Ho, R.-J. Chein, J. Org. Chem. 2004, 69, 591.
N
Me
Me
O
Ph HNCHO
Ph
H2SO4
TMSCN
N
Bn
Ph HN
OH
Me
H2SO4
N
Bn
MeCN
N
Bn
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).
O
N-H
KOH
N-K
-H2O
O
O
O
R-X
N-R
-KX
O
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2KOH
CO2+
CO2-
O
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RNH2
NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism
H
O O
O
O
R-X
:N:K
OH
:N-R
O
O
N
:N-R
-KX
transfer
R
O
O
O
H proton
CO2
H
N
R
O
O
OH
CO2H
RNH2 +
+
workup
CO2H
Notes:
CO2
protic
RNH2
CO2
CO2
H
N
proton
transfer
O OH
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.
O
O
N K
RX
NH2-NH2
NH
NH
R-NH2 +
O
O
Examples:
O
NH2-NH2
N
EtOH
H2N
82%
O
C. Serino, N. Stehle, Y. S. Park, S. Florio, P. Beak, J. Org. Chem. 1999, 64, 1160.
O
Me
N
Me
O
S
NH2
NH2-NH2
S
S
EtOH
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).
O
CO2R
O
O
O
OR
Cl
N-K
O
O
O
OR
OR
OEt
N
N
N
O
O
H
O
O
O
O
OH O
OR
N
keto-enol
OR
N
tautomerism
OH
OH
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).
Br
AgNO2
Ether
Br
AgNO2
Ether
AgNO2
Cl
Ether
70%
NO2
NO2 +
20%
NO2 +
trace
+
ONO
15%
ONO
30%
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
N=N=N
-Br
Br
CO2H
CO2H Pd/C, H2
NH2
N
N
N
-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.
MeI
H2N-NH2
-HI
MeNH-NH2
MeI
Me2NH-NH2
-HI
Hofmann bromination of alkylurea can give manoalkylated hydrazines in good yield
(Scheme 6).
R
H
N
NH2
KOBr
R
H
N
NH2
O
Scheme 6
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NPTEL – Chemistry – Principles of Organic Synthesis
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).
N
6H2C=O +
4NH3
N
N
N
Urotropine
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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OC8H17
O
O
HO
OH
t-Bu
H17C8O
t-Bu
CHCl3, 3 h, 40 °C
H2N
NH2
Ph
Ph
H2N
NH2
Ph
OC8H17
N
N
N
OH HO
*
H17C8O
t-Bu
**
[]25D = + 376 (0.1 CHCl3)
N
OC8H17
OH HO
t-Bu
t-Bu
Ph
*
t-Bu
H17C8O
[]25D = + 166 (0.1 CHCl3)
Mw = 18512, PDI =1.2
Mw = 4864, PDI = 1.4
Solubility = CHCl3, CH2Cl2, THF
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.
O
R
"R
H
+ R'NH2
+ R"CO2H + R"'NC
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R"
N
O
O R H
N
H
R"'
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NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism
H
O
R
+ R'NH2
H
R'
N
H
O
R"
O
R
H
C
N
R"'
H
O
R"
R' N
O
R"
HO
R' N :
O
H R
H
N-R"'
N R"' O
..
H
O
R"
R
R'
N
"R
O
O
R H
N
H
R"'
Scheme 8
Examples:
N
H2N
CHO
+
O
CO2H
+ t-BuNC
MeOH
RT
N
H
67%
H
N
O
OMe
N
G. Dyker, K. Breitenstein, G. Henkel, Tetrahedron: Asymmetry 2002, 13, 1929.
R'
H
"R
N
N
O
CO2H
R'CHO, R"NH
2
NRBoc
NC
NRBoc
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).
O
R2NH
..
H
O
H
HR2N
..
:OH
H
R2N
H
H-OOH
H
H
..
R2N
OH2
H
-H2O
H
O
O
H
H
R2N
-CO2
HR2N CH3
-H
R2N CH3
Scheme 9
Examples:
Me
HCHO
Me
NH2 HCO2H
NMe2
66%
W. E. Parham, W. T. Hunter, R. Hanson, T. Lahr, J. Am. Chem. Soc. 1952, 74, 5646.
NH
N
NR
N
DMSO
Microwave
HCHO, DCO2D
DCHO, DCO2D
R = CH2D
R = CHD2
DCDO, DCO2D
R = CD3
J. R. Harding, J. R. Jones, S.-Y. Lu, R. Wood, Tetrahedron Lett. 2002, 43, 9487.
OMe
OMe
MeO
MeO
H2CO
HCO2H, heat
NMe
NH2
G. Lakshmaiah, T. Kawabata, M. Shang, K. Fuji, J. Org. Chem. 1999, 64, 1699.
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NPTEL – Chemistry – Principles of Organic Synthesis
Problems:
A. Complete the follwoing.
O
CN
+
1.
H
t-BuO
Cu(II)
N
2.
N3
N
H
NH2
CO2H
3.
4.
H
N
Me
DMF, heat
CH3CHO, MeOH
t-BuNC
Fe(III)
+ O=C C
Ph
CO2H
PhCH2NH2
CO2H
heat
5.
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B. Formulate mechanisms for the following reactions.
O
CN
O
O
Me
N
H
1.
H2SO4
MeO
MeO
O
NH2-NH2
N
2.
H2N
EtOH
O
CO2Me
CO2Me
CH2O
3.
NH
HCO2H
MeO2C
CO2Me
O
4.
O
NH2
CO2
i-PrCHO, MeOH
t-BuNC
H
N
N
O
O
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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NPTEL – Chemistry – Principles of Organic Synthesis
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.
O
Me
N
COOH
H
+ MeNH2 +
H
O
+ 2H2O + 2CO2
CO2H
O
O
Mechanism
The synthesis involves two Mannich reactions followed by spontaneous decarboxylation
of the dibasic -keto acid.
COOH
O-H
O
O H
MeNH2
H
H
O
NH2Me
H
OH
Proton
Transfer
H
NMe
H
CHO
-H2O
CO2H
NMe
Proton
Transfer
CHO
O
CO2H
O
H
NHMe
H
O
H
CO2H
CO2H
O
Proton
NHMe
O
H
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CO2H
H
CO2H
O
NMe
Transfer
HO
CO2H
continues
H
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NPTEL – Chemistry – Principles of Organic Synthesis
H
NMe
H
-CO2
O
OH
CO2H
-H2O
Me
N
Me
N
Me
N
CO2H
O-H
-CO2
O
H
HO2C
O
Me
N
keto-enol
HO2C
tautomerism
O-H
Me
N
keto-enol
tautomerism
O
O
H
O
OH
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O
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CHO HO2C
CO2H
NMe
O
MeNH2
70%
CHO
O
L. A. Paquette, J. W. Heimaster, J. Am. Chem. Soc. 1966, 88, 763.
CHO
HO2C
Me
N
CO2H
O
MeNH2
34%
O
O. L. Chapman, T. H. Koch, J. Am. Chem. Soc. 1966, 88, 763.
CHO
CHO
HO2C
CO2H
O
O
Me
N
O
MeNH2
CHO
J. Bermudez, J. A. Gregory, F. D. King, S. Starr, R. O
J. Summersell, Biorg. Med. Chem. Lett. 1992, 2, 519
MeO2C
O
MeO2C
CHO HO2C
Me
Me
CHO
CO2H Me
PrNH2, THF
NPr
Me
O
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.
O
R
AcOH
H
+ R'NH2 + HCN
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H
R'
N
O
OH
R
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NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism
O
R
H
H
R'
N
R
N:
H
H
-NH3
R'
N
OH
H proton
N
H2 R
N-H
H
transfer
R'
N
R
OH
R
R'
H
R
R'
N
H
H
:NH2R'
OH
H
N
H
proton
transfer
R'
HN
R'
N
H
H
R
O
NH2
R
H
H2O
R' ..
N
H
-H2O
OH
NH2
OH2
H
N
H
H
R'
N
OH2
R
R
R'
R
H2O
N
H
R'
N
H
H
OH2
H
N
H
proton
transfer
CN
R
proton
transfer
R'
N
H
H
H
R
O
NH3
OH
O
OH
R
Notes:
T. Laue, a. Plagens, Named Organic Reactions, John Wiley and Sons, Inc., New York, 1998, pp. 253-254.
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NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
O
N
HN
Ph
NH
N
HN
2 mol%
O
OMe
NH2
N
NH
CN
OMe
HCN, MeOH
97% yield
99% ee
M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910.
OH
CHO +
TBSO
NH2
OH
HCN
Chiral Zr Catalyst
NH
Me
Me
80% yield
91% ee
CN
OTBS
4
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
O
NR2
R2NH
R-X
R'
Hydrolysis
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Mechanism
The mechanism shows how they react with alkylating agent to form a new carbon-carbon
bond.
X
O
NR2
NR2
R2NH
R'
H
R'-X
H2O
R2N OH2
R'
H
Proton
Transfer
R2NH O-H
R'
H
O
R'
The overall process amounts to an enolate alkylation. The reaction conditions are mild
and no self-condensation is observed.
Examples:
O
N
H
CO2H
..
N
..
N
CO2H
NO2
Ph
CO2H
Ph
NO2 Hydrolysis
O
Ph
NO2
DMSO
B. Kist, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423.
O
Me
CO2Me
N
H
N
Me
CO2Me
TsOH, H2O
S. Hunig, E. Lucke, W. Brenninger, Org. Synth. CV5, 808.
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NPTEL – Chemistry – Principles of Organic Synthesis
4.3.1.5 Gabriel-Cromwell Reaction
Amines react with -bromoacrylates to give aziridines in the presence of base.
O
O
R'NH2
Br
RO
RO
NR'
Et3N
Mechanism
O
O
O
R'NH2
Br
RO
RO
Br
O
H-Et3N
Br
NEt3 RO
-NEt3
NHR'
NHR'
H
RO
O
Br
..
NHR'
-Br
RO
NHR'
-Et3NH
Et3N
O
RO
NR'
Examples:
CO2Me
H2N
O
Br
MeO
O
Me
CO2Me
MeO
N
Et3N, CHCl3
Me
S. N. Filigheddu, M. Taddei, Tetrahedron Lett. 1998, 39, 3857.
O
MeN
O
N
Me
Br
Me
Ph
O
Br
NH3, DMSO
O
MeN
N
Me
Ph Me
NH
G. Cardillo, L. Gentilucci, C. Tomasini, M. P. V. Castjon-Bordas, Tetrahedron Asymmetry 1998, 39, 3857.
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NPTEL – Chemistry – Principles of Organic Synthesis
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. Hydrolysis
H2N
R'
Mechanism
O
O
O
O
PR3
Base
R'CHO
N
NH
N
N
PR3
PR3
O
O
R'
O
O
-R3PO
N
O
H2N
O
O
H
R'
Hydrolysis
N
PPh3
O
R'
O
R'
O
H
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.
HN
O
R
R'
N
LiCNBH3
R
R'
Mechanism
HN
O
R
R'
N
R
N
LiCNBH3
R'
R
R'
"H"
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NPTEL – Chemistry – Principles of Organic Synthesis
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.
N
Reactivity towards reducing agent:
R
O
R'
>>
R
R'
Examples:
H
N
O H NPr
2
LiBH3CN
MeOH
81%
R. F. Borch, H. D. Durst, J. Am. Chem. Soc. 1969, 91, 3996.
CHO
LiBH3CN
MeOH
H2N
H
N
S. E. Sen, G. D. Prestwich, J. Am. Chem. Soc. 1989, 111, 8761.
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.
CO2H
ArCHO
O
NH2
Me
N
Ar
CO2H
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NPTEL – Chemistry – Principles of Organic Synthesis
Mechanism
H
O
OH
Ar
H
NH2
CO2H
HO CO2H
H
HO
H
..
N
H
Ar
..
N
H
transfer
CO2H
O
N
H
proton
OH
H
N
Ar
H H
OH2
H
Ar
H
-H2O
H2O CO2H
H
transfer
Ar
N
H
Ar
N
H
proton
N
H
Ar
CO2H
-H2O
Ar
CO2H
CO2H
autoxidation
N
H
N
Ar
Ar
Examples:
O
CHO
+
Me
CO2H
CO2H
NH2
N
Ph
Me
Me 20%
G. J. Atwell, B. C. Baguley, W. A. Denny, J. Med. Chem. 1989, 32, 396.
O
CO2H
OHC
MeO
Me
CO2H MeO
+
NH2
Me
G. A. Epling, A. A. Provatas, Chem. Commun. 2002, 1036.
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N
Me
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NPTEL – Chemistry – Principles of Organic Synthesis
Problems:
A. What major products would you expect from the following reactions?
O
O
i. PhCHO , Me
1. Me
CO2H
CHO
NH2
ii.
Cl
O
NH3
2.
CO2NH3
LiCNBH3, MeOH
O
3.
Me
O
NaCNBH3
H, MeOH
N
OH
OPh
B. How will you carry out the following conversion? Explain with mechanism.
CHO
+
NH2
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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NPTEL – Chemistry – Principles of Organic Synthesis
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.
O
O
R
O
R

R2NH
Cl
HCl
O
O
O
NR2 +
R
R2NH
R
R
NR2 +
RCO2H
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.
R2NH
O
R

OH
DCC
O
R
NR2
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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NPTEL – Chemistry – Principles of Organic Synthesis
O
H2N
O
heat
NH2
O
O

N
H2
O
NH2
O
N
H
-NH3
NH3
O
N
H
O
Cyclic imides can be easily prepared (practical method) by heating a mixture of acid
anhydride and amine.
H O
H O
O
PhCH2NH2
heat
+ H2O
H O
H O

Ph
N
The reaction of amines with ethyl chloroformate and carbonyl chloride affords
urethanes and ureas, respectively.
O
Cl
O
RNH2
HNR
OEt
O
OEt + HCl
Cl
O
2RNH2
RHN
Cl
NHR
+ 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.
O
NH2NH2
R
O
O
O
Cl
-HCl
faster
R
R
NHNH2
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O
Cl
-HCl
slower
R
NHNH R
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NPTEL – Chemistry – Principles of Organic Synthesis

Hydroxylamine reacts with carboxylic acid derivatives giving hydroxyamic acids.
O
O
R

NH2OH
OEt
R
OH
NH-OH
R
-EtOH
N-OH
Reaction of acid chloride with sodium azide gives acid azide which is the
substrate precursor for Curtius rearrangement.
O
O
R
NaN3
N3 +
R
Cl
NaCl
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+.
H
HNO2
H2O
N
H2O + NO
O
N
O
O
: OH O
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OH
-H
NO
O
N
OH O
O
O
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NPTEL – Chemistry – Principles of Organic Synthesis
In the second, enoalte reacts with the nitrite in a manner similar to the Claisen
condensation.
EtO
OEt
OEt
Ph
EtO
OEt
Ph
N
O
O
OEt
Ph
O
O
N
N
-OEt
O
OEt
Ph
O
N
OH
OEt
Ph
O
O
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.
Zn/AcOH
CO2Et
CO2Et
O
EtO2C
O
O
COEt
CO2Et
NH2
NOH
N
H
Second, the oxime is hydrolyzed into a carbonyl group.
NOH
O
H3O
O
O
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.
O
N
MeO
O
EtO
Ph
CN
Ph
C
N
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O
MeO N O
NO2
-OMe
Ph
CN
Ph
CN
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NPTEL – Chemistry – Principles of Organic Synthesis
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.
N(CH3)2
CH3
N(CH3)2
NO2
NO2
:B
N O
NO2
H3O
N
+
NO2
H:B
NO2
N(CH3)2
CHO
CH2
NH2
NO2
NO2
NO2
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.
C-terminal
amino acid
O
R'
O
R"'
O
H
H
H2N
N
N
N
N
OH
nH
H
R
O
R"
O
R""
N-terminal
amino 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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NPTEL – Chemistry – Principles of Organic Synthesis
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 -bromoderivative which could be reacted with ammonia to give -amino acid.
NH2
Br
R
CO2H
NH3
PBr3
R
Br2
CO2H
R
-HBr
CO2H
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.
O
R
PBr3
H
O + Br
R
O
Br
O
Br
O H
Br-Br
-HBr
OH
R
R
R
O
O PBr
2
Br
Br
R
Br
O
OH
R
+
Br
R
O
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O
The halogen from PX3 is not
transfered to the-position
Page 28 of 35
NPTEL – Chemistry – Principles of Organic Synthesis
O
Br
Br2, PCl3
OH
CO2H
CO2H
O
67%
L, A, Carpino, L. V. McAdams, III, Org. Syn. CV6, 403.
Br
Br2, P4
+ MeOH
OMe
90%
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.
O
EtO2C
O
CO2Et
Br
NK
O
CO2Et
S
Me
N
CO2Et
-KBr
CO2Et
Cl
N
O
O
O
1. OH
OH +
H2N
OH
2. H
CO2Et
Base
O
S
Me
NH2
CO2H
-CO2
HO2C
CO2H
S
Me
Methionine
O
S
Me
The amino group can also be introduced via nitrosation (4.5.1) followed by reduction
and hydrolysis processes.
EtO2C
CO2Et
HNO2
H
EtO2C
EtO2C
CO2Et Zn, AcOH, Ac2O EtO2C
EtO2C
N
CO2Et EtO2C
NHOAc
OH
CO2Et
Hydrolysis
NHOAc
Decarboxylation
Base
CO2H
HO2C
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NHOAc
Glutamic acid
Page 29 of 35
Cl
NPTEL – Chemistry – Principles of Organic Synthesis
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.
O
R
AcOH
+ R'NH2 + HCN
H
H
R'
N
O
OH
R
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.
O
O
R
KCN, (NH4)2CO3 HN
R' EtOH, H O
2
R
R'
NH
H2N
H3O
R
O
R'
OH
O
hydantoin
Mechanism
O
O
R
NH2
(NH4)2CO3
R'
R
HN
R
R'
CN
H N
N
R
R'
O
NH
H2N
R
R'
O
O
R
R'
NC
O
proton
transfer
O
O
C
N
NH2
O
O H
O C O
R
R'
NC
R'
O
NH2
N
R
R'
NH2
O
HN
R
R'
OH
C N
O
NH
R
R'
NH
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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Page 30 of 35
NPTEL – Chemistry – Principles of Organic Synthesis
Examples:
CO2H
O
CO2H H
N
KCN, (NH4)2CO3
O
NH
40% O
J. Ezquerra, B. Yruretaguyena, C. Avendano, E. de la Cuesta, R. Gonzalez, L. Prieto, C. Peqregal, M. Espada, W.
Prowse, Tetrahedron 1995, 51, 3271.
H
O
N
O
O
NH
O
O
KCN, (NH4)2CO3
EtOH, H2O
O
EtOH, H2O
Co2Et
O
Co2Et
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
O

R
OH
H
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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NPTEL – Chemistry – Principles of Organic Synthesis
R
H
O
R
O
O
RCOOH +
OH
+
-H
H2O
OH
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
H
O
O
N
O
RNH2
H
O
Na2CO3
O
O
O

NHR + HO N
O
The important characteristic of this protecting group is that it can be easily
removed by treatment with amine base, such as piperidine.
HN :
H
O
+ H2N :
NHR
NHR
+
O
NHR
O
O
O
+
H
N:
-CO2
RNH2
+ HN :
H
O
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NPTEL – Chemistry – Principles of Organic Synthesis
Synthesis of Tripeptide
Let us try the synthesis a tripeptide having Phe-Gly-Ala sequence. Coupling of Fmocglycine 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.
H
N
O
O
CO2H
+ H2N
O
Fmoc-Gly
NHS
O
DCU
DCC
Ala-Bu
Me
O
N
H
O
Me
O
NHS =
O
H
N
O
O
Fmoc-Gly-Ala-t-Bu
OH
N
O
Deprotection HN
Ph
Ph
HN
Fmoc
Deprotection
N
H
H
N
O
O
N
H
OH
FmocHN
Me
NHS
O
O
H2N
O
O
Me
N
H
O
O
DCU
DCC
Fmoc-Phe-Gly-Ala-t-Bu
Ph
H
N
H2N
O
O
Ph
Me
N
H
O
H
H2N
O
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H
N
O
Me
N
H
O
Phe-Gly-Ala
OH
O
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NPTEL – Chemistry – Principles of Organic Synthesis
The Role of DCC and NHS in Peptide Synthesis
N-Protected amino acid
O
O
R-COOH
N C N
DCC
R
O
HN
C
OH
N
O
O
N
NHS
R
O
O
N
+
O
HN
C
HO
N
o-acylisourea
-NHS
good leaving group
R
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NH2-R'
O
O
N
H
R'
O-Protected
amino acid
N
H
N
H
DCU
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NPTEL – Chemistry – Principles of Organic Synthesis
Problems:
A. Complete the following.
P, Br2
O
1.
OH
2.
Br2, P4
O
MeOH
OH
3. EtO
HCN/NH3
CHO
4.
CHO
HCl/MeOH
O
5.
CO2H
N3
heat/H2O
B. Outline synthetic routes to the following compounds.
NH2
1.
CO2H
CO2H
2.
NH2
CO2H
3. HS
NH2
Ph
H
N
4. H N
2
O
CO2H
O
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.
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