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Application of the tert-Amino Effect for the Synthesis of Annulated Heterocyclic Systems

Application of the tert-Amino Effect for the Synthesis of Annulated Heterocyclic Systems. International Symposium on Organic Chemistry December 9-12, 2006 - Sofia, Bulgaria. Ivo C. Ivanov. Department of Organic Chemistry

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Application of the tert-Amino Effect for the Synthesis of Annulated Heterocyclic Systems

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  1. Application of the tert-Amino Effect for the Synthesis ofAnnulated Heterocyclic Systems International Symposium on Organic Chemistry December 9-12, 2006 - Sofia, Bulgaria Ivo C. Ivanov

  2. Department of Organic Chemistry Faculty of Pharmacy, Medical University of Sofia,Dunav 2, BG-1000 Sofia, Bulgaria

  3. Introduction • The term tert-amino effect was firstused by Meth-Cohn and Suschitzky in 1972. This effectis operative insome ortho-substituted tertiary anilines as an unusual cyclizationreaction with a new C-C bondformationtoafford a fused-ring system. • The first transformation of this type was reported in the 19th century by J.Pinnow [Ber. dtsch. Chem. Ges., 28, 3039 (1895)].

  4. Types of ring-closure reactions involving the tert-amino effect Usually a 5- or 6-membered ring is formed in the transition state.

  5. a 1H-pyrido[1,2-a]quinoline Type 2 ring-closure leadingto six-membered rings • A special version of the type 2 reactions is the one in which both X and Y are carbon atoms forming a vinyl group. Recent review: Mátyus, P.; Éliás, O.; Tapolcsányi, P.; Polonka-Bálint, A.; Halász-Dajka, B. Synthesis2006, 2625–2639.

  6. 1,5-Hydrogen transfer • The mechanism for the formation of the six-membered heterocycles is presented in this scheme. The first, rate-limiting step consists of an intramolecular suprafacial 1,5-hydrogen migration (possibly 1,5-hydride shift) to afford a dipolar intermediate. EWG = CN, COOR The second step involves C-C bond formation by addition of the carbanion to the iminium double bond to give a new six-membered ring.

  7. Some typical examples from the literature E. V. D’yachenko, T. V. Glukhareva, L. V. Dyudya, O. V. Eltsov, Yu. Yu. Morzherin,Molecules10,1101-1108 (2005).

  8. Reagents and conditions: (i) amine, Et3N, DMF, reflux, 3 h (55–85%); (ii) malononitrile, toluene, r.t., 10 h (90–95%); (iii) DMSO,140 °C, 1–2.5 h (65–86%). * 14a was not formed. Some typical examples from the literature 4-bromo- nicotinaldehyde P. Mátyus, O. Éliás, P. Tapolcsányi, A. Polonka-Bálint, B. Halász-Dajka, Synthesis2006, 2625–2639 (review article).

  9. Some typical examples from the literature I. Devi, B. Baruah, P. J. Bhuyan, Synlett2006, 2593–2596

  10. Some typical examples from the literature N,N‘-dimethylbarbituric acid I. V. Paramonov, N. A. Belyaev, T. V. Glukhareva, A. S. Volkov, E. V. Deeva,Yu. Yu. Morzherin, Chem. Heterocyclic Comp., 42, 127 (2006).

  11. Microwave-assisted ring-closure reactions Preparation of some spiro-heterocycles Some typical examples from the literature P. Mátyus, O. Éliás, P. Tapolcsányi, A. Polonka-Bálint, B. Halász-Dajka, Synthesis2006, 2625–2639 (review article).

  12. Mannichreaction I.C. Ivanov, S.K. Karagiozov, Synthesis 633-634 (1995). • Two methods for the synthesis of 3-dimethyl-amino 4-amino-coumarins; • New type of intramolecular hydride transfer.

  13. Hydride transfer I.C. Ivanov, S.K. Karagiozov, Synthesis 633-634 (1995). A plausible explanation of this intramole-cular oxidation-reduction would be an intramole-cular 1,5 hydride shift

  14. I. C. Ivanov, T. N. Glasnov, F. Belaj –prepared for publication (2006).

  15. I. C. Ivanov, T. N. Glasnov, F. Belaj –J. Heterocyclic Chem., 45, 177 (2008).

  16. I. C. Ivanov, T. N. Glasnov, F. Belaj –prepared for publication (2006). Our trials to use malononitrile in the Knoevenagel step afforded an unexpected ammonium salt.

  17. 8a 1H-NMR of compound 5c(CDCl3) 8a-H AB-quartet: • Had = 3.54d (1H) • Hbd = 3.01d (1H) J = 16.8 Hz • 8a-H d = 2.82~t (1H) J ≈ 11.8 Hz

  18. X-Ray crystallographic analysis Compound 5a

  19. Similarity between the two reaction mechanisms

  20. Acknowledgements: Dr. Toma Glasnov Prof. Dr. F. Belaj(X-rays)- Graz Dr. S. K. Karagiosov Prof. Dr. D. Heber - Kiel Mme S. Alexandrova tert-Amino effect

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