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). Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD Page 2 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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. Joint initiative of IITs and IISc – Funded by MHRD Page 3 of 35 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 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 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). 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 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 + 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). Joint initiative of IITs and IISc – Funded by MHRD Page 6 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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 Joint initiative of IITs and IISc – Funded by MHRD Page 7 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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. 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 .. 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. Joint initiative of IITs and IISc – Funded by MHRD Page 9 of 35 NPTEL – Chemistry – Principles of Organic Synthesis 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.