Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules

<ul style="display: flex;"><li style="flex:1">ACCOUNT </li><li style="flex:1">21 </li></ul>Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules Shunsuke Chiba* Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore Fax +6567911961; E-mail: [email protected] Received 31 May 2012 Organic azides possess diverse chemical reactivities.4 Owing to their 1,3-dipole character, they undergo [3+2] cycloaddition with unsaturated bonds, such as those in alkynes and alkenes as well as carbonitriles (Scheme 1, part a).5 Organic azides can also be regarded as nitrene equivalents (Scheme 1, part b).6 Accordingly, their reactions with nucleophilic anions, electrophilic cations, and radicals can formally provide the corresponding nitrogen anions, cations, and radicals, respectively, forming a new bond with the internal azido nitrogen and releasing molecular nitrogen. Moreover, the generation of anions, cations, and radicals at the a-position to the azido moiety can result in rapid denitrogenation to deliver the corresponding iminyl species, which can be used in further synthetic transformations (i.e., carbon–nitrogen bond formation). Abstract: In this account, recent advances made on the reactions of several types of organic azides, such as vinyl azides, cyclic 2-azido alcohols, a-azido carbonyl compounds, towards the synthesis of nitrogen-containing molecules are described. <ul style="display: flex;"><li style="flex:1">1</li><li style="flex:1">Introduction </li></ul><ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">Chemistry of Vinyl Azides </li></ul><ul style="display: flex;"><li style="flex:1">2.1 </li><li style="flex:1">Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicar- </li></ul>bonyl Compounds 2.2 2.3 2.4 Manganese(III)-Catalyzed Formal [3+2]-Annulation with 1,3-Dicarbonyl Compounds Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annulation with Cyclopropanols Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl Azides and Internal Alkynes by Rhodium–Copper Bimetallic Cooperation 33.1 Chemistry of Cyclic 2-Azido Alcohols Manganese(III)-Catalyzed Ring Expansion of 2-Azidocyclobutanols (a) 1,3-Dipoles N RNN<ul style="display: flex;"><li style="flex:1">3.2 </li><li style="flex:1">Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido </li></ul>Alcohols <ul style="display: flex;"><li style="flex:1">C</li><li style="flex:1">C</li></ul><ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">alkenes </li></ul>alkynes nitriles RRNN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul>CCCCCNRNCNtriazolines 44.1 Chemistry of a-Azido Carbonyl Compounds Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives +CNtriazoles RNCN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul>Ntetrazoles <ul style="display: flex;"><li style="flex:1">4.2 </li><li style="flex:1">Generation of Iminylcopper Species and Their Catalytic </li></ul>Carbon–Carbon Bond Cleavage under an Oxygen Atmosphere (b) Nitrene equivalents +N2 RN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li><li style="flex:1">R</li></ul>N4.3 5 Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclohexadienones Conclusion nitrenes with carbanions or other nucleophiles RN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul>X– <ul style="display: flex;"><li style="flex:1">+</li><li style="flex:1">+</li></ul>+ RRNXCN2 Key words: azides, nitrogen-containing heterocycles, radical reactions, redox reactions, oxygenations with carbocations RN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul>C+ +NN2 N2 with carbon radicals + RN<ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">N</li></ul>C<ul style="display: flex;"><li style="flex:1">+</li><li style="flex:1">R</li></ul>NC<ul style="display: flex;"><li style="flex:1">1</li><li style="flex:1">Introduction </li></ul>chemistry of α-azido anions, cations, and radicals CCCNNNNNNNNN +++CCCNNNN2 N2 N2 The chemistry of organic azides commenced with the synthesis of phenyl azide by Griess in 18641 and the discovery of the rearrangement of acyl compounds with hydrogen azide (HN3) by Curtius in 1890.2 Since 1950, various synthetic organic reactions have been developed using acyl, aryl, and alkyl azides, which have been extensively applied for the synthesis of nitrogen-containing azaheterocycles as well as peptides.3 Scheme 1 We have been interested in the intriguing chemical reactivity of organic azides, such as vinyl azides, cyclic 2-azido alcohols, and a-azido carbonyl compounds (Scheme 2). In this account, we describe recent advances made on the reactions of these organic azides towards the synthesis of nitrogen-containing molecules which have been developed in our research group. SYNLETT 2012, 23, 21–44 <ul style="display: flex;"><li style="flex:1">x</li><li style="flex:1">x</li><li style="flex:1">.x </li><li style="flex:1">x</li><li style="flex:1">.2 </li><li style="flex:1">0</li><li style="flex:1">1</li><li style="flex:1">1</li></ul>Advanced online publication: 09.12.2011 DOI: 10.1055/s-0031-1290108; Art ID: A59911ST © Georg Thieme Verlag Stuttgart · New York 22 S. Chiba ACCOUNT NNNinyl species serve for the formation of carbon–nitrogen bonds. In this section, we present the synthesis of azaheterocycles from vinyl azides via several types of reaction mode based on the above chemical reactivities. NNNRNNN HO R' ROa-azido carbonyl compounds cyclic 2-azido alcohols vinyl azides <ul style="display: flex;"><li style="flex:1">2.1 </li><li style="flex:1">Thermal [3+2]-Annulation of Vinyl Azides </li></ul>with 1,3-Dicarbonyl Compounds Scheme 2 During the course of our study on the chemistry of 2H- azirine derivatives,11 it was found that the reaction of azirine 1 with acetylacetone (2) in 1,2-dichloroethane at room temperature gave tetrasubstituted pyrrole 3 in quantitative yield after 33 hours (Scheme 4). <ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">Chemistry of Vinyl Azides </li></ul>Intermolecular annulation reactions can allow for the straightforward and selective construction of complex cyclic molecular structures in a one-pot manner from relatively simple building blocks, one of the most ideal processes in organic synthesis from an atom-7 and stepeconomical8 point of view. Inspired by this perspective, we have recently been interested in the application of vinyl azides as a three-atom unit including one nitrogen for various types of annulation reactions to prepare azaheterocycles. EtO2C Cl COMe Me Cl <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li><li style="flex:1">CO2Et </li></ul>+NCl 1N<ul style="display: flex;"><li style="flex:1">Me </li><li style="flex:1">Me </li></ul>DCE r.t., 33 h HCl 2 (1.2 equiv) 3 quant Scheme 4 While the reaction of azirine 1 with acetylacetone (2) in tetrahydrofuran (THF) has been reported, the yield of pyrrole 3 was low.12 The generation of 3 in high yield in the above reaction (Scheme 4) led us to further investigate the pyrrole formation. One of the attractive chemical properties of vinyl azides is their ability to undergo thermal decomposition to give highly strained three-membered cyclic imines, 2H-azirines, via vinylnitrene intermediates following denitrogenation (Scheme 3, part a).9 Moreover, the carbon–carbon double bond of vinyl azides can be used for the formation of new carbon–carbon bonds with appropriate organometallic compounds (R′–[M]) or radical species (R¢) which results in the generation of iminyl metals or iminyl radicals, respectively (Scheme 3, parts b and c).10 These im- The reaction may proceed through the addition of acetylacetone (2) to the imino carbon of azirine 1,13 followed by nucleophilic attack of the nitrogen in the resulting aziridine to a carbonyl group with concurrent ring opening of the strained three-membered ring.14 However, the instability and poor accessibility of the 2H-azirines prevented us using this strategy as a synthetic method for pyrroles. Accordingly, we planned to use vinyl azides as precursors of 2H-azirines which can be easily synthesized15 and handled (Scheme 5). R R RΔNNN (a) N– N2 N2H-azirines vinylnitrenes RR RAs proposed in Scheme 5, simple heating of a mixture of ethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) and acetylacetone (2) in toluene at 100 °C provided pyrrole 5 in 86% yield (Table 1, entry 1).16 Various 2-azido-substituted cinnamates possessing electron-donating and -withdrawing groups on the phenyl group (entries 2–8), as well as a derivative containing a pyridyl moiety (entry 9), reacted with acetylacetone (2) to give the corresponding 2- R R' R' R'–[M] [M] NNNNNN (b) (c) N[M] – N2 R R' R' RNNNNNN R' – N2 NScheme 3 Biographical Sketch <ul style="display: flex;"><li style="flex:1">Shunsuke Chiba was born University of Tokyo (work- Nanyang </li><li style="flex:1">Technological </li></ul>in Zushi, Kanagawa, Japan, ing under Professor Koichi University, Singapore, as an in 1978. He obtained his Narasaka). He was appoint- assistant professor. His reB.Eng. from Waseda Uni- ed as a research associate at search focus is methodology versity in 2001 and received the University of Tokyo in development in the area of his Ph.D. in 2006 from the 2005. In 2007, he moved to synthetic organic chemistry. Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 23 indoles via intramolecular C–H amination.17,18 It is noteworthy that the above intermolecular reactions of 2-azidosubstituted cinnamate derivatives with acetylacetone (2) gave pyrroles exclusively without any indole formation. <ul style="display: flex;"><li style="flex:1">R2 </li><li style="flex:1">R2 </li></ul>R1 COMe Me R1 <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>Δ– N2 – H2O +N<ul style="display: flex;"><li style="flex:1">Me </li><li style="flex:1">Me </li></ul>NN2 H2– N2 – H2O As b-substituents (R1) of azidoacrylates, ethoxycarbonyl and alkyl groups could be introduced, giving the corresponding pyrroles in good yields (entries 12 and 13). Simple azidoacrylate 30 also reacted smoothly (entry 14). Using a-aryl-substituted vinyl azides, not only phenyl groups, but also naphthyl, indolyl, pyrrolyl, and benzothiophenyl moieties could be installed at the 3-position of the resulting trisubstituted pyrroles (entries 15–26). aAlkyl-substituted vinyl azide 56 reacted smoothly to give the corresponding pyrrole 57 in 82% yield (entry 27). An E,Z-mixture of 2-phenylvinyl azide (58) could also be used to prepare trisubstituted pyrrole 59 in 85% yield (entry 28). Tetrasubstituted pyrroles 61 and 63 were success- R2 Me <ul style="display: flex;"><li style="flex:1">R2 </li><li style="flex:1">R2 </li></ul>R1 COMe <ul style="display: flex;"><li style="flex:1">R1 </li><li style="flex:1">R1 </li></ul>HN <ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">Me </li></ul>NO Me OH HO H O NMe HMe B AScheme 5 arylpyrroles in good yields. Vinyl azides 22 and 24 bearing acetyl and (dimethylamino)carbonyl moieties instead of an a-ethoxycarbonyl group could be employed to give the corresponding pyrroles 23 and 25 (entries 10 and 11, respectively). It is known that the thermolysis of 2-azidosubstituted cinnamates and their derivatives delivers 1H- Table 1 Synthesis of Pyrroles from Vinyl Azides and Acetylacetone (2)a <ul style="display: flex;"><li style="flex:1">R2 </li><li style="flex:1">R2 </li></ul>R1 COMe Me R1 Δ<ul style="display: flex;"><li style="flex:1">O</li><li style="flex:1">O</li></ul>+N– N2 – H2O <ul style="display: flex;"><li style="flex:1">Me </li><li style="flex:1">Me </li></ul>NN2 H2<ul style="display: flex;"><li style="flex:1">Entry </li><li style="flex:1">Vinyl azides </li><li style="flex:1">Pyrrolesb </li></ul>Entry 24 Pyrrolesb O Vinyl azides : R = 2,6-Cl 5 86% 7 93% 9 90% 11 89% 13 96% 15 90% 17 90% 19 81% 412345678c 26: R = H 8: R = 4-Me 10: R = 2-Me 12: R = 3-NO2 14: R = 4-Br 16: R = 4-CN 18: R = 4-MeO <ul style="display: flex;"><li style="flex:1">EtO2C </li><li style="flex:1">COMe </li></ul>Me TsN <ul style="display: flex;"><li style="flex:1">51 92% </li><li style="flex:1">50 </li></ul>Me Me <ul style="display: flex;"><li style="flex:1">CO2Et </li><li style="flex:1">N</li></ul>Ts RN3 N3 NH N<ul style="display: flex;"><li style="flex:1">H</li><li style="flex:1">R</li></ul>OOEtO2C COMe Me TsN Me Me 52 54 53 92% 25 26 NTs CO2Et 9<ul style="display: flex;"><li style="flex:1">20 </li><li style="flex:1">21 94% </li></ul>NHN3 NHN3 NN SR2 COMe Me R2 <ul style="display: flex;"><li style="flex:1">22: R2 = COMe </li><li style="flex:1">23 74% </li></ul>25 quant 10d 11 Me Me N3 24: R2 = CONMe2 55 96% S NH NHN3 EtO2C R1 COMe Me 26: R1 = CO2Et 28: R1 = CH2Ph 30: R1 = H 27 82% 29 96% 31 85% <ul style="display: flex;"><li style="flex:1">12 </li><li style="flex:1">CO2Et </li></ul>N3 R1 O 13e 14 Ph Me Me Ph N56 27 57 82% HN3 32: R = H 33 75% 35 98% 37 95% 39 86% 41 92% 43 91% 45 86% <ul style="display: flex;"><li style="flex:1">N</li><li style="flex:1">15 </li></ul>16 17 18 19 20 21 R H34: R = 4-Me 36: R = 4-OMe 38: R = 2-OMe 40: R = 4-Br 42: R = 3-Br 44: R = 4-CO2Me COMe Me R COMe Me N3 N<ul style="display: flex;"><li style="flex:1">58 </li><li style="flex:1">59 85% </li></ul>61 66% 63 91% 28 29 30 N HN3 (E:Z = 1:1) HO Me Me COMe Me <ul style="display: flex;"><li style="flex:1">47 94% </li><li style="flex:1">46 </li></ul>48 22 23 60 62 NN3 N3 H NHO Me COMe Me Me Me 49 65% <ul style="display: flex;"><li style="flex:1">N3 </li><li style="flex:1">N3 </li></ul>Me N N<ul style="display: flex;"><li style="flex:1">H</li><li style="flex:1">H</li></ul>a Unless otherwise noted, the reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and acetylacetone (2) (1.2 equiv) in toluene at 100 °C for 2–24 h. b Isolated yields are shown. c The reaction was performed at 85 °C for 16 h. d The reaction was performed at 85 °C for 20 h in the presence of acetylacetone (2) (2 equiv). e The reaction was performed at reflux for 5 h. © Thieme Stuttgart · New York Synlett 2012, 23, 21–44 24 S. Chiba

Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules

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