SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2017, 49, 3801–3834 review 3801 en Syn thesis A. V. Listratova, L. G. Voskressensky Review Recent Advances in the Synthesis of Hydrogenated Azocine- Containing Molecules Anna V. Listratova Leonid G. Voskressensky* 0000-0029-6765-846 RUDN University, Miklukho-Maklaya St. 6, Moscow, 117198, Russian Federation [email protected] Dedicated to the memory of Professor N. S. Prostakov (1917–2007) on the occasion of his 100th anniversary. Received: 22.01.2017 1 Introduction Accepted after revision: 05.04.2017 Published online: 01.08.2017 DOI: 10.1055/s-0036-1589500; Art ID: ss-2017-e0041-r The chemistry of annulated azocines has not been ex- License terms: plored in detail owing to the lack of efficient methods for their synthesis. The only exception is azocinoindoles, which Abstract This review covers recent advances in synthesis of azocine- have been investigated extensively due to the great number containing systems. The most approaches towards azocines are dis- of alkaloids with an azocinoindole fragment in their struc- cussed. ture. This review highlights most recent approaches to- 1 Introduction wards annulated azocine derivatives published after the 2 Ring-Expansion Reaction 1 2.1 Ring-Expansion Reaction of Cyclopentane Containing the 1,4- year 2009; the previous review was published in 2008. Diketone Moiety with Primary Amines (from 5 to 8) 2.2 Ring-Expansion Reaction of Annulated Tetrahydropyridines under the Action of Activated Alkynes (from 6 to 8) 2.3 Reductive Ring-Expansion Reaction of Cyclic Oximes 2.4 Other Ring-Expansion Reactions 3 Heck Reaction O R 4 Cycloaddition O N 5 Ring-Closing Metathesis (RCM) R-NH2 Ph 6 Cyclization COPh 6.1 Metal-Catalyzed Cyclization CO R1 Bi(NO3)2•5H2O 2 THF, 100 °C, 16 h 6.2 Radical Cyclization 1 1a R = Me 1 6.3 Friedel–Crafts Cyclization CO2R b R1 = Et 2a–c 6.4 Other Examples of Cyclizations 1 7 Microwave- and Photo-Assisted Reactions R-NH2 2a R = R = Me; 28% 8 Other Methods THF, 100 °C, 16 h b R = Me, R1 = Et; 40% 8.1 Cascade and Tandem Reactions c R = Bn, R1 = Et; 8% 8.2 Aldol Condensation O R N 8.3 Thermolysis Ph 2d R = Me; 38% 8.4 Ring Opening e R = Bn; 21% 8.5 Other Methods f R = CH2CH2OEt; 15% 9 Conclusion 2d–f CO2Et Key words azocine, ring-closing metathesis, cycloaddition, ring ex- Scheme 1 Synthesis of benzo[c]azocines pansion, Heck reaction, domino reaction Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3801–3834 3802 Syn thesis A. V. Listratova, L. G. Voskressensky Review N CO H N CO Me N CO Me 2 (a) 2 (b) 2 CN (a) CO 2 Et (b) O CO 2 Et (c) N N N 92% 68% Br Br CO2tBu 83% 74% 47% Me Me Me O N CO Me (c) 2 (d) N CO2Et (d) CO2Et N N (e) CO2tBu 92% 50% Cl 54% CH(CO2Et)2 50% CO2tBu 3 O O O Me O (f) (g) N N N N N COPh (e) (f) Ph CO2tBu COPh 59% 36% CO2tBu 31% CO2tBu 64% 6 7 4 5 CO2tBu (a) 1. H2SO4/H2O, 130 °C, 17 h; O Me 2. EtOH, 80 °C, 4 h; (a) SOCl2, MeOH, 0–85 °C, 24 h; (b) CH2=CHCO2tBu, Pd(OAc)2, PPh3, N (b) m-CPBA, CHCl3, 0-23 °C, 19 h; Et3N, DMF, 110 °C, 18 h; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 22 h; Ph N (c) TsCl, 1,4-dioxane, 100 °C, 1.5 h; (d) NaH, THF, 0–50 °C, 1 h; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 2 h; (f) MeNH , THF, 100 °C, 16 h. (d) Na in EtOH, CH2(CO2Et)2, THF, 0-23 °C, 2 h; 2 (e) Na, in EtOH, 65 °C, 2 h; Scheme 2 Synthesis of a pyrido[2,3-c]azocine (f) PhCOCH2Br, K2CO3, acetone, 40 °C, 3 h; CO tBu (g) MeNH , THF, 100 °C, 17 h. 8 2 2 Scheme 3 Synthesis of a pyrido[3,4-c]azocine 2 Ring-Expansion Reactions ethyl 1-oxo-indane-2-carboxylate 1, containing a 1,4-dike- 2.1 Ring-Expansion Reaction of Cyclopentane Con- tone motif, and primary amines under the bismuth-cata- taining the 1,4-Diketone Moiety with Primary lyzed ring-expansion reaction conditions gave benzo[c]azo- Amines (from 5 to 8) cine derivatives 2 in moderate yields (Scheme 1).3 It was also shown that, in some cases, the presence of bismuth ni- In 2006 the Cristoffers group2 discovered a novel bis- trate was not essential.3 muth-catalyzed ring-expansion reaction of 1,4-diketones A bismuth-free strategy of ring enlargement was also with primary amines that furnished an eight-membered successful in the case of regioisomeric pyrido[c]azocines.4 ring. In 2011, they extended their relatively simple method Synthesized from commercially available materials, three to the synthesis of annulated azocines. Thus, starting from cyclopentapyridine derivatives 3, 6, and 9, containing β-oxo Biographical Sketches Prof. Leonid G. Voskressensky 2001 he joined the group of Since 2013 he has been the was born in 1968 in Moscow, Prof. Cosimo Altomare (Universita Dean of the Science Faculty at Russia. He obtained his B.Sc. in degli Studi di Bari, Italy) as a PFUR. His group’s scientific in- chemistry from the Peoples’ postdoctoral fellow in medicinal terests focus mainly on domino Friendship University of Russia chemistry. In 2001, he became reaction methodology, new (PFUR) in 1992, and his M.Sc. in assistant professor, in 2006 multicomponent reactions, and 1994. He obtained his Ph.D. in associate professor, and in 2011 medicinal chemistry. organic chemistry from the full professor in the organic same university in 1999. In chemistry department at PFUR. Dr. Anna Listratova was born in Russia (PFUR) in 2003, followed university in 2008 under guid- Moscow, Russia. She obtained by an M.Sc. degree in 2005. She ance of Prof. L. G. Voskressensky her B.Sc. in chemistry from the obtained the Ph.D. degree in or- and remains a member of his People’s Friendship University of ganic chemistry from the same group. Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3801–3834 3803 Syn thesis A. V. Listratova, L. G. Voskressensky Review ester moieties, were alkylated with phenacyl bromide to CO2H CO2iPr CO2iPr give 1,4-diketones 4, 7, and 10. The latter were subjected to (a) (b) (c) ring-expansion reactions with methylamine giving pyri- Br CO2tBu S 94% S Br 85% S 99% do[2,3-c]azocine 5 (Scheme 2), pyrido[3,4-c]azocine 8 O (Scheme 3), and pyrido[3,2-c]azocine 11 (Scheme 4) in 36– CO2iPr 64% yield. (d) (e) CO2tBu CO2tBu S 54% S 94% O (a) CO 2 Et (b) CO2Et 12 CO2Et O O Me Me Cl 34% 90% COPh N N Me N (f) Ph O CO2tBu 39% (c) CO2Et (d) (e) S S CO2tBu 13 14 CO2tBu 67% CH(CO2Et)2 74% 71% N N (a) 1. SOCl2, reflux, 3.5 h, 2. DMAP (cat.), iPrOH, 90 °C, 20 h; 9 (b) CH2=CHCO2tBu, Pd(PhCN)2Cl2, Me2NCH2CO2H, NaOAc, NMP, O Me 130 °C, 20 h; (c) Pd/C (cat.), H (1 atm), iPrOH, 23 °C, 1 d; (d) tBuOK, O 2 N THF, 0 °C, 45 min; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 23 h; (f) Ph (f) MeNH , Bi(NO ) •5H O, THF, 120 °C, 4 d. COPh 2 3 2 2 CO tBu 48% Scheme 5 Synthesis of a tetrahydrothieno[3,2-c]azocine N 2 N 10 11 CO2tBu (a) 1. NH4OAc, toluene, 110 °C, 2 h; 2. CH2=CHCHO, 110 °C, 2.5 h; CO2H CO2iPr CO2iPr (b) DMF, trichloroisocyanuric acid, CH2Cl2, 23 °C, 16 h; (a) (b) S S S (c) Na, in EtOH, CH2(CO2Et)2, THF, 0–23 °C, 4 h; (d) NaH, THF, 65 °C, 1 h; (e) PhCOCH2Br, K2CO3, acetone, 56 °C, 3 h; 96% 91% Br Br CO2tBu (f) MeNH2, THF, 100 °C, 15 h. O Scheme 4 Synthesis of a pyrido[3,2-c]azocine (c) CO 2 i Pr (d) CO tBu S S 2 86% 51% 15 In 2015, a six-step sequence for the synthesis of regio- CO2tBu O Me isomeric thieno[c]azocines started from commercially O N available bromothiophenecarboxylic acids was worked Ph (e) COPh (f) out.5 Isopropyl esters of the bromothiophenecarboxylic ac- S S ids were subjected to Heck reaction followed by catalytic 82% CO 2 t Bu 37% hydrogenation and Dieckmann condensation giving the cy- 16 17 CO2t-Bu clic β-oxo esters 12, 15, and 18, alkylation of which with (a) 1. SOCl2, reflux, 3 h, 2. DMAP (cat.), iPrOH, 90 °C, 15 h; phenacyl bromide led to 1,4-diketones 13, 16, and 19. The (b) CH2=CHCO2tBu, Pd(OAc)2, Ph3P, Et3N, DMA, 130 °C, 21 h; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 4 d; following step, a bismuth-catalyzed ring expansion of cy- (d) tBuOK, THF, 0 °C, 45 min; clopentathiophene derivatives 13, 16, and 19 with methyl- (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 19 h; (f) MeNH2, Bi(NO3)2•5H2O, THF, 120 °C, 4 d amine, produced the target tetrahydrothieno[3,2-c]azocine 14 (Scheme 5), tetrahydrothieno[3,4-c]azocine 17 (Scheme Scheme 6 Synthesis of a tetrahydrothieno[3,4-c]azocine 6), and tetrahydrothieno[2,3-c]azocine 20 (Scheme 7). Overall yields for the final products were 25%, 16%, and 12%, ple bond of the activated alkyne, followed by a nucleophilic respectively.