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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). Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 35 R NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD 2KOH CO2+ CO2- O Page 2 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 3 of 35 R NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD Page 4 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD Page 5 of 35 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). Joint initiative of IITs and IISc – Funded by MHRD Page 6 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD R" N O O R H N H R"' Page 7 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 8 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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. Joint initiative of IITs and IISc – Funded by MHRD Page 9 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 10 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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. Joint initiative of IITs and IISc – Funded by MHRD Page 11 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD CO2H H CO2H O NMe Transfer HO CO2H continues H Page 12 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD O Page 13 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD H R' N O OH R Page 14 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 15 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD Page 16 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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. Joint initiative of IITs and IISc – Funded by MHRD Page 17 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 18 of 35 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" Joint initiative of IITs and IISc – Funded by MHRD Page 19 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD Page 20 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD N Me Page 21 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 22 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 23 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD O Cl -HCl slower R NHNH R Page 24 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD OH -H NO O N OH O O O Page 25 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD O MeO N O NO2 -OMe Ph CN Ph CN Page 26 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 27 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD 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 Joint initiative of IITs and IISc – Funded by MHRD 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. Joint initiative of IITs and IISc – Funded by MHRD 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. Joint initiative of IITs and IISc – Funded by MHRD Page 31 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD Page 32 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD H N O Me N H O Phe-Gly-Ala OH O Page 33 of 35 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 Joint initiative of IITs and IISc – Funded by MHRD NH2-R' O O N H R' O-Protected amino acid N H N H DCU Page 34 of 35 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. Joint initiative of IITs and IISc – Funded by MHRD Page 35 of 35