On the scope of acylnitrilium ion initiated heteroannulations: monocyclizations terminated by unactivated alkenes

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 On the scope of acylnitrilium ion initiated heteroannulations: monocyclizations terminated by unactivated alkenes David J. Hughes and Tom Livinghouse*'t Department of Chemistry and Biochemistry, Montanu State Uniuersity, Bozemun, MT 5971 7, USA Intramolecular trapping of transient acylnitrilium ions by di- and tri-substituted alkenes has been shown to occur with reasonable efficiency to provide the corresponding 2,3,4,5-tetrahydropyridineand 3,4-dihydro- 2H-pyrrole derivatives in moderate overall yield. Annulations initiated by heteroatom-stabilized carbocations have played a prominent role in the synthesis of numerous carbocyclic and heterocyclic natural products. The vast majority of cyclizations in this category involve alkene participants that give rise to metastable carbocations which are subsequently trapped by a waiting nucleophile or rapidly transmutated via facile molecular reorganization.Efficient cyclizations that proceed under mild conditions via relatively long-lived carbocations are comparatively few in number. Our interest in the prospective use of an acylnitrilium ion 'initiated alkene-cascade cyclization for the synthesis of the A ristotelia alkaloid ( +)-makonine (1) (Scheme 1) prompted our examination of prototypical cyclizations between these cations and simple, unactivated alkenes. Herein we report the results of this study. The isocyanides employed throughout this investigation were prepared from the corresponding amines by sequential N-formylation/dehydration.Accordingly, formylation of the amine 4 (EtOCHO, reflux, 5 h) followed by dehydration (POCI,-Et,N, THF, 0 "C) furnished the isocyanide 5 in 82 yield after distillation. Cyclization studies The initial conversion of compound 5 into the corresponding a-keto imidoyl chloride 6 was achieved by treatment with trimethylacetyl chloride (TMAC) (1.05 equiv.) as described previously.7b Whereas ionization of 6 could be readily achieved by exposure to AgBF, (1.10 equiv.) in accord with literature precedent CH,Cl,-(CH,Cl),, -70 OC,' subsequent cycliz- ation of the resulting acylnitrilium ion 7 took an unexpected course. When the reaction mixture was warmed to -2OoC, cyclization of 7 proceeded by way of the tertiary carbonium ion 8 to provide 9$ and 10a (9/10a = 2) in 64 isolated yield.The formation of 9 could be completely suppressed by the use of AgO,SCF, for generation of the initial acylnitrilium cation. Accordingly, treatment of 6 with AgO,SCF, (1.10 equiv., CH,CI,, -70 "C-, -40 "C)provided the isomeric hexahydro- isoquinolines IOa and 10b 10a/10b = 1 (NMR) in 61 overall yield from the isocyanide 5. Exposure of this mixture to silica gel resulted in quantitative conversion of 10b into 10a which could be isolated in analytically pure form in 61 yield.$ As expected. the regiochemistry of the foregoing cyclizations (fused us. spiro) would appear to be governed by the relative stabilities of the respective post-cyclization carbocations.A similar outcome was observed in the acylative cyclization of f Fellou of the Alexander von Humboldt Foundation, 1993 1995. 8 The bicyclic fluoride 9 was determined to be stereochemically homogeneous by "C NMR and GC-mass spectral analysis. 5 All new compounds were fully characterized by IR, 'H and I3C NMR spectroscopy and possessed satisfactory combustion analyses or an exact mass measurement. L 1 2 a 3 Scheme 1 3-cyclohexylidenepropyl isocyanide 11.ISequential reaction of 11 with TMAC (1.05 equiv.) followed by ionitation/cyclization of the resulting a-keto imidoyl chloride AgO,SCF, (1.10 equiv.), CH,Cl,, -70 "C-, -40 "C provided the 3,4-dihydro- 2H-pyrrole 125 to the exclusion of the corresponding spiro- cycle 13 in 54 yield after chromatography. Not surprisingly, conformational restriction of the 3-cyclohex- 1-enyl substituent precluded facile isomerization of the nonconjugated alkene within 12 (vide supra).As a prelude to the intended synthesis of (+)-makonine 1, we next turned our attention to the construction of bridged bicyclic ring systems via acylnitrilium ion-alkene cyclizations. Reaction of 4-isocyanomethyl-2,4-dimethylcyclohex-1-ene 14 11 with TMAC (1.05 equiv.) followed by Ag' mediated cyclization AgO,SCF, (1.10 equiv.), CH,CI,, -70 "C+ -40 "C secured the azabicyclo3.3.lnonanes 15a and 15b 15a/15b = 1.5 (NMR) in 51 yield after chromatography.** Presumably 15a and b arise as a consequence of divergent proton elimination from a common carbocationic intermediate.In contrast to this result, acylation/cyclization of the 1,2-disubstituted alkene- containing isocyanide 16 (vide supra) furnished the bicyclic alcohol 17 as the only major product after an aqueous quench albeit in low (33) isolated yield.tt In this instance, a series The isonitrile 11 was prepared by the reaction of (2-chloro-ethy1idene)cyclohexane with isocyanomethyllithium. (1 The isocyanide 14 was prepared by the conversion of 1.4-dimethyl- cyclohex-3-ene-1 -arbaldehyde to the corresponding amine i, H,N-OTHP; ii, LiAlH, (74 overall) followed by N-formylation-dehydration.** AzabicycloC3.3. llnonane 15a was isolated from this mixture by careful chromatography on silica gel and was fully characterized (see footnote $).tt The stereochemical disposition of the hydroxy group of 17 has not been determined. 2374 J. CHEM. SOC. PERKIN TRANS. I 1995 c1' i, EtOCHO ii. POC13. Eta v 5 6I""'"(-70 "C) 8 7 9 1Oa 10b (T= BF,-: 9/10a= 2.64) (2-=CF3SO3-: 10d10b= 1.61) +-/-EC: i, Bu'COCl cb ii, Ag03CF3 13 11 12 of DEPT and 'H--I3C HETCOR experiments was used to establish unambiguously the connectivity of the core hetero- cycle and rule out the isomeric r3.2.21 ring system. The regio- selectivity of cyclization in the case of 17 is likely a reflection of preferential 6-membered ring formation. The preceding examples clearly show that even isolated, unactivated alkenes can serve as suitable terminators for cyclizations involving acylnitrilium ions.Although cyclization efficiencies are somewhat lower than in previous examples, ' these results indicate that isolated alkenes in various settings might serve as effective cationic relay moieties for cascade type annulations. Experimental ~Cyclohex-l-enyl-5-trimethylacetyl-3,4-dihydro-2H-pyrrole 12 A 50-cm3 round bottom flask fitted with a magnetic stirrer bar, flame-dried and cooled under a stream of argon, was charged with (3-isocyanopropyl)cyclohexane(1 49 mg, I .O mmol). The system was again flushed with argon, sealed with a septum and an argon balloon was attached to it. Dichloromethane (1.5 cm3) was added via a syringe to the flask followed by trimethylacetyl chloride (127 mg, 1.05 mmol) also added via a syringe.The mixture was stirred under argon at room temperature. (A previously performed NMR tube reaction dictated how long this reaction takes.) When the acylative insertion was complete, the reaction mixture was diluted with dichloromethane (15 cm3) and the flask was cooled to ca. -70 "C in a Pr'OH-CO, bath (NB: -78 "C is too cold!). Silver trifluoromethanesulfonate (283 mg, 1.1 mmol) was added to the reaction mixture as a solid all at once after which the system was sealed and stirred in the range -60 to -70 "C under argon for 1 h (after 10 min a pale precipitate was seen in the flask). The reaction mixture was 14 15a 15b (15d15b= 1.5; 51) HO' 16 17 (33) Reagents:i, Bu'COCl; ii, AgO3m3; iii, H20 then allowed to warm slowly to -35 "C over 30 min and was maintained at that temperature overnight (16 h).Water (10 cm3) was added to the reaction mixture which was then allowed to warm to room temperature with stirring over over 10 min. The mixture was filtered through a pad of wet Celite with dichloromethane (20 cm3) and the filtrate was transferred to a separatory funnel with further dichloromethane (10 cm3). The biphasic mixture was shaken, separated and the aqueous layer was extracted with dichloromethane (2 x 10 em3). The combined organic phases were dried (MgSO,), filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ca. 10 x 1.5 cm) by gradient elution with mixtures of ether and hexane (50 cm3 each of 5, 10, 20, 50 and 100 polar solvent in non-polar as necessary) to provide the title compound 12 as a colourless oil (1 26 mg, 54); G,(CDCl,) 5.38-5.33 (m, 1 H, C=CH), 4.0H.00 (m, 2 H, CH,N), 3.71 (m, 1 H, CH), 2.13-1.99 (m, 3 H), 1.81- 1.65 (m, 2 H), 1.63-1.45 (m, 4 H) and 1.25 s, 9 H, C(CH,),; Gc(CDC13) 205.9, 174.2, 136.5, 123.3, 61.9, 56.4, 44.1, 28.7, 26.9, 26.8, 25.2, 22.8 and 22.2; v,,,,,(thin film)/cm-' 3042, 2929, 2860,2837,1684, 1617, 1481 and 1458; m/z 233 (M+),218, 177, 148 and 57 (100)Found (HRMS): M', 233.1769.Calc. for C1,H2,NO:M+, 233.17801. Acknowledgements Generous support for this research by a grant from the National Institutes of Health is gratefully acknowledged. References 1 W. S. Johnson, V.R. Fletcher, B. Chenera, W. R. Barlett, F. S. Tham and R. K. Kullnig, J. Am. Chem. Soc., 1993,115,497. 2 W. J. Klaver, H. Heimstra and W. N. Speckamp, J. Am. Chem. Soc., 1989,111,2588. 3 S. D. Knight, L. E. Overman and G. Pairaudeau, J. Am. Chem. Soc., 1993,115,9293. 4 S. R. Harring, E. D. Edstrom and T. Livinghouse, in Advances in Heterocyclic Natural Product Syntheses, vol. 2, ed. W. H. Pearson, JAl Press, Tnc., Greenwich, CT, 1992, pp. 299-376. 5 M.H. Hopkins, L. E. Overman and G. M. Rishton, J. Am. Chem. SOC.,1991, 113, 5354. 6 For example see: A. A. Schegolev, W. A. Smit, G. V. Roitburd and V. F. Kucherov, Tetrahedron Lett., 1974, 3373; R. R. Sobti and S. Dev, Tetrahedron Lett., 1967,2893. 7 (a) C. H. Lee, M. Westling, T. Livinghouse and A. C. Williams, J. Am. Chem. Soc., 1992,114,4089; (b)G. Luedtke, M. Westling and T. Livinghouse, Tetrahedron, 1992,48,2209, and references therein. 8 I. R. C. Bick and M. A. Hai, Heterocycles, 1981, 16, 1301. 9 J. E. Baldwin and M. L. Lusch, J. Org. Chem., 1979,44, 1923. Paper 5/04402B Received 6th July 1995 Accepted 8th August I995