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.

natural products - cyclization - epoxides - Lewis acids - amidines

References

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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)

26 Herman H. Tezuka Y. Kikuchi T. Supriyatna S. Chem. Pharm,. Bull.  1994,  42:  138 

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).

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