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 H3O + RCO H OH N O NH 2 H2O H 2

Mechanism

OH2 H -H2O :NC-R H2O OH OH N N R N R 2 C R

OH O H2O proton H3O + RCO2H N R N R NH2 -H3O transfer H

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 Chlorobenzene O 91% S. J. Chang, Organic Process Research and Development 1999, 3, 232.

Me Me Me Me Me Me Me Me

SnCl4 MeCN CH2 CH2 Cl N N

T.-L. Ho, R.-J. Chein, J. Org. Chem. 2004, 69, 591. Me Me

O Ph HNCHO Ph OH Ph HN

H2SO4 Me H2SO4 N TMSCN N MeCN N Bn Bn 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 O O CO - KOH R-X 2KOH 2 N-H N-K N-R + RNH - 2 -H2O -KX CO2 O O O

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Mechanism H O O O O O CO2 R-X OH H proton :N-R O H :N:K :N-R N N transfer -KX R O R O O O O

OH

CO CO2 CO2H protic 2 proton + RNH H RNH2 + 2 N workup CO transfer CO2H 2 R Notes: 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 RX NH N K R-NH + 2 NH NH2-NH2 O O

Examples:

O

NH2-NH2 N EtOH H2N O 82% C. Serino, N. Stehle, Y. S. Park, S. Florio, P. Beak, J. Org. Chem. 1999, 64, 1160. O

N NH Me Me 2 O NH2-NH2 S S EtOH 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).

O O CO2R O O O O O OR OR Cl OR OEt N-K N N N H O O O O O O OH O

OR keto-enol OR N 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).

AgNO2 Br NO2 + ONO Ether 70% 15%

AgNO2 Br + Ether NO2 ONO 20% 30%

AgNO2 Cl NO + Ether 2 ONO trace 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).

N=N=N CO2H Pd/C, H2 CO2H CO2H Br -Br N NH2 N -alanine N

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 MeI H2N-NH2 MeNH-NH2 Me2NH-NH2 -HI -HI

Hofmann bromination of alkylurea can give manoalkylated hydrazines in good yield (Scheme 6).

H H KOBr N N NH2 R R NH2 O

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).

N

6H2C=O + 4NH N N 3 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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O OC8H17 O

HO OH

t-Bu H17C8O t-Bu

CHCl3, 3 h, 40 °C Ph Ph

H2N NH2 H2N NH2

Ph Ph

OC8H17 N N N N OC8H17

* OH HO * * OH HO * t-Bu H17C8O t-Bu t-Bu t-Bu H17C8O 25 25 [] D = + 376 (0.1 CHCl3) [] D = + 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 O R" "R N R"' + R'NH + R"'NC N R H 2 + R"CO2H H O R H

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Mechanism

H O R" O R" H R' H R" O N O H O R' N O + R'NH R' N: O R H 2 R H H C R .N. R"' O H R N-R"' N H R"' O R"

R' O "R N R"' N H O R H

Scheme 8 Examples:

O O N CHO H2N CO2H H MeOH N + + t-BuNC N OMe RT H 67% N

G. Dyker, K. Breitenstein, G. Henkel, Tetrahedron: Asymmetry 2002, 13, 1929. R' H "R N N

CO2H O R'CHO, R"NH2

NRBoc NRBoc NC

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 .. O : OH H H H OH H-OOH .. 2 -H2O R2NH .. R N R2N HR N H 2 H H 2 H H O O H -H R N H 2 HR2N CH3 R2N CH3 -CO2 Scheme 9 Examples:

Me HCHO Me NH HCO H 2 2 NMe2 66% W. E. Parham, W. T. Hunter, R. Hanson, T. Lahr, J. Am. Chem. Soc. 1952, 74, 5646.

NH NR N N 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 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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Problems: A. Complete the follwoing.

CN O H 1. + t-BuO Me

N Cu(II) 2. N3 N DMF, heat H

CH CHO, MeOH 3. NH2 3 CO2H t-BuNC

H N Fe(III) 4. + O=C C Ph

CO2H PhCH2NH2 5. CO2H heat

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B. Formulate mechanisms for the following reactions.

O O CN O Me N 1. H MeO H2SO4 MeO

O

NH2-NH2 2. N H2N EtOH O CO Me CO2Me 2

CH2O 3. NH HCO2H

MeO2C CO2Me

O O H i-PrCHO, MeOH N 4. NH2 N CO2 t-BuNC 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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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.

Me O COOH N H + MeNH + O H 2 + 2H2O + 2CO2 CO H O 2 O

Mechanism

The synthesis involves two Mannich reactions followed by spontaneous decarboxylation of the dibasic -keto acid.

COOH

O-H O O H OH H H MeNH2 -H2O CO2H NH2Me Proton NMe NMe H H Transfer H Proton CHO CHO Transfer O O

CO2H CO2H CO2H H O H O H O Proton NHMe CO2H NHMe CO2H NMe CO2H H Transfer continues H H O O HO

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Me CO2H Me N N H O-H OH O -CO2 keto-enol CO H NMe 2 O -H2O HO C tautomerism HO C H 2 2 O-H H O Me Me N Me N N -CO2 keto-enol

tautomerism O O O OH O H

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Examples:

CHO HO2C CO2H O NMe

MeNH2 CHO 70% O L. A. Paquette, J. W. Heimaster, J. Am. Chem. Soc. 1966, 88, 763.

Me N HO2C CO2H CHO O

CHO MeNH2 34% O O. L. Chapman, T. H. Koch, J. Am. Chem. Soc. 1966, 88, 763.

Me N HO2C CO2H CHO O O O CHO MeNH2

J. Bermudez, J. A. Gregory, F. D. King, S. Starr, R. OJ. Summersell, Biorg. Med. Chem. Lett. 1992, 2, 519

MeO2C O MeO2C HO C CO H Me CHO 2 2 Me NPr O Me Me CHO PrNH2, THF

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' O O AcOH N + R'NH + HCN H OH R H 2 R

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Mechanism

OH O :NH R' OH2 -H O R' H H OH 2 H proton 2 R' R' .. H CN N N R H R H R N H2 transfer H R H R

R' R' R' OH2 R' N-H proton N: H N H2O N N H N N H N H H R H R H transfer R R

H R' OH R' O R' OH R' O proton H proton N N NH N NH N N H NH2 H 2 H 3 H H H OH2 H OH H transfer H2O R transfer R R H R

R' O -NH3 HN 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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Examples:

O N NH HN N 2 Ph NH NH HN N O 2 mol% CN OMe 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 OH HCN CHO TBSO + Chiral Zr Catalyst NH 80% yield NH2 Me 91% ee Me CN 4 OTBS 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 R' R2NH R-X 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 R2N OH2 R2NH O-H R NH 2 R'-X R' H2O R' Proton R' H H H Transfer O R'

The overall process amounts to an enolate alkylation. The reaction conditions are mild and no self-condensation is observed.

Examples:

.. .. O CO2H O Ph CO H N CO2H N N 2 Ph NO2 Hydrolysis NO2 H Ph NO2 DMSO B. Kist, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423.

O N CO Me N 2 H CO2Me Me Me

TsOH, H2O 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.

O O R'NH2 Br RO RO NR' Et3N

Mechanism

O O O H-Et3N O O Br Br Br NEt RO RO -Br Br R'NH2 RO 3 -NEt3 RO .. RO NHR' NHR' NHR' NHR' H

-Et3NH Et3N

O

RO NR' Examples:

CO2Me O H2N O Me CO Me Br MeO 2 MeO N Et N, CHCl 3 3 Me S. N. Filigheddu, M. Taddei, Tetrahedron Lett. 1998, 39, 3857.

O O Br O O NH , DMSO MeN 3 MeN N N Me NH Br Me Ph Me Ph 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.

i. Base, phthalimide ii. R'CHO PR3 H2N R' iii. Hydrolysis

Mechanism

O O O O Base PR3 R'CHO NH N N N PR3 PR3 O O O O R' O H O O R' R' -R3PO Hydrolysis N N PPh3 H2N O 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 N

R R' R R' LiCNBH 3 Mechanism

HN O N LiCNBH3 N R R' R R' R R'

"H"

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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.

N O Reactivity towards reducing agent: > > R R' R R'

Examples:

H O N H2NPr

LiBH3CN MeOH 81% R. F. Borch, H. D. Durst, J. Am. Chem. Soc. 1969, 91, 3996.

CHO LiBH CN H N 3 2 MeOH 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 N Ar NH2 Me CO2H

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Mechanism

H OH O

Ar H OH proton H OH2 -H2O CO2H H .. H transfer Ar NH2 N Ar N Ar N H H H H

CO H CO H H O CO2H 2 2 HO CO H 2 HO H 2 H -H2O O H proton .. transfer Ar N Ar N N Ar N Ar H H H H CO H CO2H 2 autoxidation

N Ar N Ar H Examples:

O CO2H CHO Me CO2H + NH2 N Ph Me Me 20% G. J. Atwell, B. C. Baguley, W. A. Denny, J. Med. Chem. 1989, 32, 396. O CO2H MeO OHC Me CO2H MeO +

NH2 Me N G. A. Epling, A. A. Provatas, Chem. Commun. 2002, 1036. Me

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Problems: A. What major products would you expect from the following reactions? O O i. PhCHO, Me CO2H 1. Me CHO NH 2 ii. Cl O NH3 2. CO2NH3 LiCNBH3, MeOH

O NaCNBH Me 3 3. O H, MeOH

N OH OPh

B. How will you carry out the following conversion? Explain with mechanism.

CHO + N NH2 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.

O O R2NH R Cl R NR2 + HCl

O O O R2NH + R O 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.

O R2NH O

R OH DCC 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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O O heat O NH2 -NH3 H N O N NH O 2 H 2 O N NH N O O 2 H 3 H

 Cyclic imides can be easily prepared (practical method) by heating a mixture of acid anhydride and amine.

O H O H Ph PhCH2NH2 O N + H2O heat H H O O

 The reaction of amines with ethyl chloroformate and carbonyl chloride affords urethanes and ureas, respectively.

O O O O RNH2 2RNH2 + HCl + 2HCl Cl OEt HNR OEt Cl Cl RHN NHR

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 O O O O NH2NH2 R Cl R Cl R NHNH2 R NHNH R -HCl -HCl slower faster

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 Hydroxylamine reacts with carboxylic acid derivatives giving hydroxyamic acids.

O O OH NH2OH R OEt R NH-OH R N-OH -EtOH

 Reaction of acid chloride with sodium azide gives acid azide which is the substrate precursor for Curtius rearrangement.

O O NaN3 + NaCl R Cl R N3

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 N HNO2 H2O O H2O + NO O OH N N NO -H

O O :OH O OH O O O

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In the second, enoalte reacts with the nitrite in a manner similar to the Claisen condensation.

EtO O OH N O N OEt EtO O N OEt N OEt -OEt OEt Ph OEt OEt Ph Ph Ph Ph O O O 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.

COEt NOH NH2 CO2Et Zn/AcOH O CO2Et CO2Et EtO2C N O O 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 O MeO N O NO MeO N 2 EtO O -OMe Ph CN Ph C Ph CN Ph CN N

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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.

N(CH ) 3 2 N(CH3)2

CHO N(CH3)2 CH3 CH2 NO NO H O 2 2 :B NO2 N O N 3 +

H:B NO2 NO2 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.

N-terminal C-terminal amino acid amino acid O R' O R"' O H H H N N N 2 N N OH H n H R O R" O R""

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.

Br NH2 PBr3 NH3 R CO H 2 R CO2H R CO2H Br2 -HBr

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.

PBr Br Br-Br O 3 O R Br R H R + Br R O -HBr O O O H PBr2 OH Br R Br O Br Br OH R The halogen from PX3 is not R R + transfered to the-position O O O

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O O Br Br Br , P Br2, PCl3 OH 2 4 OMe + MeOH CO2H CO2H 67% 90% K. Estieu, J. Ollivier, J. Salauen, Tetrahedron Lett. 1996, L, A, Carpino, L. V. McAdams, III, Org. Syn. CV6, 403. 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 CO2Et O O S CO Et CO2Et Me Cl 2 N K Br N N CO Et -KBr CO2Et Base 2 O O O S O NH Me CO H 2 1. OH 2 -CO OH + 2 Me H2N HO2C S OH CO2H 2. H Methionine O S Me The amino group can also be introduced via nitrosation (4.5.1) followed by reduction and hydrolysis processes.

Cl Zn, AcOH, Ac O EtO C CO Et EtO C HNO2 EtO2C CO2Et 2 2 2 2 EtO2C CO2Et H N NHOAc Base OH CO2H EtO C 2 CO2Et Hydrolysis HO2C NHOAc EtO2C NHOAc Decarboxylation 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' O O AcOH N + R'NH + HCN H OH R H 2 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 H N OH KCN, (NH4)2CO3 HN NH H3O 2 R R' R EtOH, H2O R O R' O R' hydantoin

Mechanism

O O O NH NH2 H N O (NH4)2CO3 2 CN O C O 2 proton HN OH R R' R R' R R' R R' transfer NC NC R C R' N O O O O O C H N NH NH NH HN O H N O N NH2 2 R R R R N R O R' O R' O R' R' NH R' 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 CO H 2 H O KCN, (NH4)2CO3 N O EtOH, H2O 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 N O O O NH O KCN, (NH4)2CO3 O

O EtOH, H2O O Co2Et 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 OH R O

O H 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 H R O RCOOH + O OH

-H + H O 2 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 O RNH2 H N O NHR + HO N O Na2CO3 O O 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 NHR : O NHR + H2N + O O

H -CO2 O NHR + N: RNH2 + HN: H O

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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.

O Me O NHS H H O N O O N CO2H + H2N N O H O O O Me Fmoc-Gly DCC DCU Ala-Bu Fmoc-Gly-Ala-t-Bu OH O N O NHS = Deprotection HN Ph

Ph OH HN O Me FmocHN O Me H Fmoc N O O H2N O Deprotection N N N H H H O O NHS O DCC DCU Fmoc-Phe-Gly-Ala-t-Bu

Ph Ph O Me O Me H H N O H N OH H2N N H2N N H H O O O O Phe-Gly-Ala

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The Role of DCC and NHS in Peptide Synthesis

N-Protected amino acid OH O N O O O HN O R-COOH HN C N C N NHS N + C R O N R O HO O N DCC o-acylisourea -NHS NH2-R' good leaving group O O R' R N N N H O-Protected H H amino acid DCU

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Problems: A. Complete the following.

P, Br 1. O 2 OH

2. O Br2, P4 MeOH OH

HCN/NH3 3. EtO CHO

HCl/MeOH 4. CHO

O heat/H2O 5. CO2H N3

B. Outline synthetic routes to the following compounds.

NH2 1. CO2H

CO2H 2. NH2

CO H 3. HS 2

NH2 Ph O H 4. N H2N 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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