Lecture 10 Carbon-Nitrogen Bonds Formation I - NPTELnptel.ac.in/courses/104103022/download/module4.pdf · NPTEL – Chemistry – MPrinciples of Organic Synthesis Joint initiative

NPTEL – Chemistry – Principles of Organic Synthesis

Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 35

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).



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



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.



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



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



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).



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"'



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.



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.



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



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.



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



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



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



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.



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'



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.



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.



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



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



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



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:


York, 2009.

B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic

Synthesis, Wiley Interscience, New Jersey, 2005.



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.



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



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



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



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.



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



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



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.



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.



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 :



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



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'



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:


York, 2009.

J. March, Advanced Organic Chemistry, 4th

ed, Wiley Interscience, Yew York, 1992.

Documents

Lecture 10 Carbon-Nitrogen Bonds Formation I - NPTELnptel.ac.in/courses/104103022/download/module4.pdf · NPTEL – Chemistry – MPrinciples of Organic Synthesis Joint initiative