Tin Triflate Catalysed Selective Synthesis of N,N′-Unsymmetrically Substituted N-(Hydroxyclovanyl)-N′-aryl Acetamidines

Abstract

The unsymmetrically substituted amidines 6a-d have been prepared in one step from caryophyllene oxide (2), aromatic amines (4a-c, 5), and tin triflate as catalyst, in refluxing MeCN.

Key words

natural products - cyclization - epoxides - Lewis acids - amidines

References

• 1 Greenhill JV. Lue P. In Amidines and Guanidines in Medicinal Chemistry. Progress in Medicinal Chemistry   Vol. 30:  Ellis GP. Luscombe DK. Elsevier; Amsterdam: 1993.  p.203 
• 2 Usui H. Watanabe Y. Kanao M. J. Heterocycl. Chem.  1993,  30:  551 
• 3a Granik VG. Russ. Chem. Rev.  1983,  52:  377 
• 3b Boyd GV. In Recent Advances in the Synthesis of Amidines, The Chemistry of Amidines and Imidates   Patai S. Rappoport Z. John Wiley and Sons; Chichester: 1991.  p.339 
• 4a From microbial broth of Pseudomonas fluorescens: Hida T. Tsubotani S. Funabashi Y. Ono H. Harada S. Bull. Chem. Soc. Jpn.  1993,  66:  863 
• 4b From Niembergia hippomanica: Buschi CA. Pomilio AB. Phytochemistry  1987,  26:  863 
• 4c From Brunfelsia grandiflora D: Lloyd HA. Fales HM. Goldman ME. Jerina DM. Plowman T. Schultes RE. Tetrahedron Lett.  1985,  26:  2623 
• 4d From Streptomyces distallicus: Arcamone F. Orezzi PG. Barbieri W. Nicolella V. Penco S. Gazz. Chim. Ital.  1967,  97:  1097 
• 4e Oxley P. Short WF. J. Chem. Soc.  1946,  147 
• 4f Streptomyces spp.: Nakamura S. Karasawa K. Yonehara H. Tanaka N. Um H. J. Antibiot. Ser. A  1961,  14:  103 
• 4g From Indigofera spicata: Hegarty MP. Pound AW. Nature (London)  1968,  217:  354 
• 4h Peck RL, Schafer HM, and Wolf FJ. inventors; US Pat.  2804463. From microbial broth of Nocardia Formica, beta-(5-imino-2-pyrrolidine-carboxamido)-propanamidine:
• 4i Peck RL, Schafer HM, and Wolf FJ. inventors; US Appl. Pat.  594267. Also see:
• 5 Grivas JC. Taurins A. Can. J. Chem., Rev. Can. Chim.  1961,  39:  761 
• 6a Pinner A. Chem. Ber.  1885,  18:  2845 
• 6b Stilz HU. Jablonka B. Just M. Knolle J. Paulus EF. Zoller G. J. Med. Chem.  1996,  39:  2118 
• 7 Schnur RC. J. Org. Chem.  1979,  44:  3726 
• 8a Alkali metal salts: Passet BV. Voropaev TI. Kalashni NA. Kulbitsk GN. Zh. Org. Khim.  1972,  8:  1246 
• 8b Aluminium amides: Garigipati RS. Tetrahedron Lett.  1990,  31:  1969 
• 8c Ammonium alkyl or aryl sulfonates: Charlton PT. Maliphant GK. Oxley P. Peak DA. J. Chem. Soc.  1951,  485 ; ref. 4e
• 8d Lewis acids (AlCl₃, ZnCl₂) at 150-200 °C: Oxley P. Partridge MW. Short WF. J. Chem. Soc.  1947,  1110 
• 8e Cu(I)Cl: Rousselet G. Capdevielle P. Maumy M. Tetrahedron Lett.  1993,  34:  6395 
• 8f FeCl₃ and alkyl halides: Fuks R. Tetrahedron  1973,  29:  2147 
• 8g Triethyloxonium tetrafluoroborate: Lambert C. Merenyi R. Caillaux B. Viehe HG. Bull. Soc. Chim. Belg.  1978,  94:  457 
• 9 Lanthanide(III) triflates: Forsberg JH. Spaziano VT. Balasubramanian TM. Liu GC. Kinsley SA. Duckworth CA. Poteruca JJ. Brown PS. Miller JL. J. Org. Chem.  1987,  52:  1017 
• 10 SmI₂: Xu F. Sun JH. Shen Q. Tetrahedron Lett.  2002,  43:  1867 
• PCl₅, POCl₃ and SOCl₂:
• 11a Partridge MW. Smith A. J. Chem. Soc., Perkin Trans. 1  1973,  5:  453 
• 11b Bredereck H. Gompper R. Klemm K. Rempfer H. Chem. Ber.-Recueil  1959,  92:  837 
• 12 Tetrakis(dimethylamino)titanium: Wilson JD. Wager JS. Weingarten H. J. Org. Chem.  1971,  36:  1613 
• 13 Dunn PJ. In Amidines and N-Substituted Amidines, Comprehensive Organic Functional Groups Transformations   Vol. 5.:  Katritzky AR. Meth-Cohn O. Rees CW. Elsevier; Amsterdam: 1995.  p.751 
• 14 Newbery G. Webster W. J. Chem. Soc.  1947,  738 
• 15a Collado IG. Hanson JR. Macías-Sánchez AJ. Tetrahedron  1996,  52:  7961 
• 15b Collado IG, Hanson JR, and Macías-Sánchez A. inventors; J. Span. Pat. ES  2154185.  ; Chem. Abstr. 2001, 135, 195688
• 15c Collado I. G., Hanson J. R., Macías-Sánchez A.; Span. Pat. Appl. ES 1998-2241, 1998
• 16 Collado IG. Hernández-Galán R. Durán-Patrón R. Cantoral JM. Phytochemistry  1995,  38:  647 
• 17 Hanson JR. Pure Appl. Chem.  1981,  53:  1155 
• 18a Rebordinos L. Cantoral JM. Victoria-Prieto M. Hanson JR. Collado IG. Phytochemistry  1996,  42:  383 
• 18b Collado IG. Hernandez-Galán R. Victoria-Prieto M. Hanson JR. Rebordinos L. Phytochemistry  1996,  41:  513 
• 19 Collado IG. Hanson JR. Macías-Sánchez AJ. Mobbs D. J. Nat. Prod.  1998,  61:  1348 
• Excess of nucleophiles:
• 20a Möller F. In Methoden der Organischen Chemie (Houben- Weyl)   Vol. 11/1, 4th ed.:  Müller E. Thieme Verlag; Stuttgart: 1957.  p.311 
• 20b Mousseron M. Jullien J. Jolchine Y. Bull. Soc. Chim. Fr.  1952,  757 
• 20c Deyrup JA. Moyer CL. J. Org. Chem.  1969,  34:  175 
• 20d Crooks PA. Szyndler R. Chem. Ind. (London)  1973,  1111 
• 21 Metal amides and Lewis acids: Cossy J. Bellosta V. Hamoir C. Desmurs J.-R. Tetrahedron Lett.  2002,  43:  7083 ; and references cited therein
• Lewis acids with poorly nucleophilic counter-anions:
• 22a Ph₄SbOTf: Fujiwara M. Imada M. Baba A. Matsuda H. Tetrahedron Lett.  1989,  30:  739 
• 22b Yb(OTf)₃: Meguro M. Asao N. Yamamoto Y. J. Chem. Soc., Perkin Trans.1  1994,  2597 
• 22c Hou X.-L. Wu J. Dai L.-X. Xia L.-J. Tang M.-H. Tetrahedron: Asymmetry  1998,  9:  1747 
• 22d Ln(OTf)₃: Chini M. Crotti P. Favero L. Macchia F. Pineschi M. Tetrahedron Lett.  1994,  35:  433 
• 22e LiOTf: Auge J. Leroy F. Tetrahedron Lett.  1996,  37:  7715 
• 23 Sekar G. Singh VK. J. Org. Chem.  1999,  64:  287 
• 26 Herman H. Tezuka Y. Kikuchi T. Supriyatna S. Chem. Pharm,. Bull.  1994,  42:  138 
• 28 Gautier JA. Miocque M. Fauran C. Lecloare AY. Bull. Soc. Chim. Fr.  1971,  2:  478 
• 29 When a less hindered epoxide is prepared on the caryophyllane skeleton, normal opening products are observed: Collado IG. Hanson JR. Hitchcock PB. Macías-Sánchez AJ. J. Org. Chem.  1997,  62:  1965 

24

Typical Experimental Procedure: To a magnetically stirred solution of caryophyllene oxide (2) (450 mg, 2.045 mmol) and aniline (4a) (353 mg, 8.18 mmol) in anhyd MeCN (8 mL), Sn(OTf)₂ (351 mg, 0.51 mmol) was added and the reaction mixture was heated to 80 °C. After 24 h., once compound 2 was consumed (TLC), the solvent was evaporated under reduced pressure and the crude reaction mixture was purified by column chromatography on silica gel to yield the amidine 6a (340 mg, 47%) and the amine 7a (36 mg, 5%).

25

Selected physical data for compound 6a: [α]_D +16.6 (c 9.2 mg/mL, MeOH). Selected physical and spectroscopic data for compound 6b: [α]_D -3.2 (c 43.3 mg/mL, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 0.86 (s, 3 H, H₃-15′), 0.89 (s, 3 H, H₃-13′α), 1.01 (s, 3 H, H₃-14′β), 1.20 (d, J _{12 ′ a-12 ′ b} = 11.0 Hz, 1 H, H-12′a), 1.42 (d, J _{12 ′ b-12 ′ a} = 11.0 Hz, 1 H, H-12′b), 1.62 (dd, J _{3 ′ α - 2 ′ α} = 6.6 Hz, J _{3 ′ α - 3 ′ β} = 11.4 Hz, 1 H, H-3′α), 1.70 (t, J _{3 ′ β - 2 ′ α} = J _{3 ′ β - 3 ′ α} = 11.4 Hz, 1 H, H-3′β), 1.94 (m, 1 H, H-10′b), 2.04 (s, 3 H, H₃-2), 3.16 (br s, 1 H, H-9′β), 3.72 (s, 3 H, H₃-1′′′), 4.04 (dd, J _{2 ′ α -3 ′ β} = 11.40 Hz, J _{2 ′ α -3 ′ α} = 6.6 Hz, 1 H, H-2′α), 6.92 (d, J _{3 ′′ - 2 ′′} = J _{5 ′′ - 6 ′′} = 9.0 Hz, 2 H, H-3′′, H-5′′), 7.19 (d, J _{2 ′′ - 3 ′′} = J _{6 ′′ - 5 ′′} = 9.0 Hz, 2 H, H-2′′, H-6′′). ¹³C NMR (100 MHz, CD₃OD): δ = 18.60 (c, C-2), 21.56 (t, C-6′), 24.62 (c, C-13′), 26.54 (t, C-10′), 28.79 (t, C-11′), 29.01 (c, C-15′), 30.91 (c, C-14′), 33.92 (t, C-7′), 36.01 (s, C-8′), 36.62 (t, C-12′), 39.07 (s, C-4′), 45.29 (t, C-3′), 47.03 (s, C-1′), 51.91 (d, C-5′), 56.07 (c, C-1′′′), 61.97 (d, C-2′), 75.13 (d, C-9′), 115.92 (2C, d, C-3′′, C-5′′), 128.65 (s, C-1′′), 129.50 (2C, d, C-2′′, C-6′′), 161.34 (s, C-4′′), 165.71 (s, C-1). MS (EI): m/z (rel. int.) = 384 (87) [M⁺], 369 (22) [M - 15]⁺, 325 (41), 262 (33). Compound 6c: [α]_D +12.9 (c 20 mg/mL, MeOH). ¹H NMR (400 MHz, CD₃OD): δ 0.92 (s, 3 H, H₃-15′), 0.94 (s, 3 H, H₃-13′α), 1.05 (s, 3 H, H₃-14′β), 1.74 (m, 1 H, H-12′b), 1.77 (s, 3 H, H₃-2), 2.00 (m, 1 H, H-10′b), 3.22 (br s, 1 H, H-9′β), 4.29 (m, 1 H, H-2′α), 6.70 (d, J _{2 ′′ -3 ′′} = J _{6 ′′ -5 ′′} = 8.4 Hz, 2 H, H-2′′, H-6′′), 7.33 (d, J _{3 ′′ -2 ′′} = J _{5 ′′ - 6 ′′} = 8.4 Hz, 2 H, H-3′′, H-5′′). ¹³C NMR (100 MHz, CD₃OD): δ = 18.08 (c, C-2), 21.76 (t, C-6′), 25.02 (c, C-13′), 26.79 (t, C-10′), 29.04 (t, C-11′), 29.18 (c, C-15′), 31.31 (c, C-14′), 34.46 (t, C-7′), 35.93 (s, C-8′), 37.19 (t, C-12′), 38.40 (s, C-4′), 45.74 (t, C-3′), 46.68 (s, C-1′), 52.11 (d, C-5′), 59.40 (d, C-2′), 75.78 (d, C-9′), 115.64 (s, C-4′′), 126.18 (d, 2 C, C-2′′, C-6′′), 132.63 (d, C-3′′, C-5′′), 152.51 (s, C-1′′), 159.51 (s, C-1). MS (EI): m/z (rel. int.) = 434(48) [M + 2]⁺, 432 (47) (M⁺), 375 (23), 373 (22), 353 (41) [M - 79]⁺, 292 (27), 262(46). Compound 6d: [α]_D +98.4 (c = 17 mg/mL, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 0.96 (s, 3 H, H₃-15′), 1.00 (s, 3 H, H₃-13′), 1.14 (s, 3 H, H₃-14′), 1.86 (2 H, H-3′α, H-3′α), 2.08 (m, 1 H, H-10′b), 2.59 (m, 3 H, H₃-2), 3.25 (sa, 1 H, H-9′β), 4.02 (dd, J _{2 ′ α -3 ′ β} = 11.1 Hz, J _{2 ′ α -3 ′ α} = 6.3 Hz, 1 H, H-2′α), 7.40 (t, J _{4 ′′ -3 ′′} = J _{4 ′′ - 5 ′′} = 5.0 Hz, 1 H, H-4′′), 8.81 (d, J _{3 ′′ - 4 ′′} = J _{5 ′′ - 4 ′′} = 5.0 Hz, 2 H, H-3′′, H-5′′). ¹³C NMR (100 MHz, CD₃OD): δ = 17.81 (c, C-2), 21.60 (t, C-6′), 24.77 (c, C-13′), 26.64 (t, C-10′), 28.89 (c, C-15′), 29.01 (t, C-11′), 30.91 (c, C-14′), 33.83 (t, C-7′), 36.03 (s, C-8′), 36.46 (t, C-12′), 39.49 (s, C-4′), 46.34 (t, C-3′), 46.61 (s, C-1′), 51.87 (d, C-5′), 65.85 (d, C-2′), 75.14 (d, C-9′), 119.82 (d, C-4′′), 159.16 (s, C-1′′), 159.69 (d, 2 C, C-3′′, C-5′′), 165.96 (s, C-1). HMBC cross peaks (selected): C-1 → H-2′α, H₃-2. MS (EI): m/z (rel. int.) = 357 (27) [M + 1]⁺, 339 (40) [M + 1 - 18]⁺, 263(24)

27

Selected physical and spectroscopic data for compound 8: [α]_D +14.0 (c 2.2 mg/mL, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (s, 3 H, H₃-13′α), 0.95 (s, 3 H, H₃-15′), 1.06 (s, 3 H, H₃-14′β), 1.66 (dd, J = 10.8, 11.6 Hz, 1 H, H-3′β), 1.76 (m, 1 H, H-11′b), 1.77 (s, 3 H, H₃-2), 2.00 (m, 1 H, H-10′b), 3.24 (s, 3 H, H₃-1′′′), 3.31 (br s,1 H, H-9′β), 3.46 (dd, J = 6.0, 10.8 Hz, 1 H, H-2′α), 7.08 (d, J = 7.6 Hz, 2 H, H-2′′, H-6′′), 7.17 (t, J = 7.6 Hz, 1 H, H-4′′), 7.32 (d, J = 7.6 Hz, 2 H, H-3′′, H-5′′). ¹³C NMR (75 MHz, CDCl₃): δ = 15.06 (q, C-2), 21.02 (t, C-6′), 25.51 (q, C-13′α), 26.45 (t, C-10′), 28.12 (t, C-11′), 28.50 (q, C-15′), 31.38 (q, C-14′β), 33.45 (t, C-7′), 34.95 (s, C-8′*), 36.76 (t, C-12′), 38.62 (s, C-1′*), 39.67 (q, C-1′′′), 46.09 (s, C-4′*), 47.46 (t, C-3′), 50.75 (d, C-5′), 67.55 (d, C-2′), 75.41 (d, C-9′), 125.41 (d, C-4′′), 126.75 (d, 2 C, C-2′′, C-6′′), 129.15 (d, 2 C, C-3′′, C-5′′), 147.17 (s, C-1′′), 156.02 (s, C-1). HMBC cross peaks(selected): C-1 → H₃-1′′′, H-2′α, H₃-2; C-1′′ → H₃-1′′′, H-3′′, H-5′′. MS (EI): m/z (rel. int.) = 368 [M]⁺(10), 353 [M - 15]⁺(5), 262 (20).