Novel Preparation of Dihydrooxazines Condensed to Ring D of the Estrane Skeleton

Abstract

The reactions of cis-16-azidomethyl,17-hydroxyestrone derivatives with a range of aldehydes under the conditions of the Schmidt reaction were examined. The 16β-azidomethyl,17β-hydroxy isomer resulted in 5,6-dihydro-4H-1,3-oxazine fused to the estrane skeleton. This method allowed preparation of the 5,6-dihydro-4H-1,3-oxazine condensed to positions 16α,17α of the estrone, the isomeric (2R)5,6-dihydro-2H-1,3-oxazine also being formed stereoselectively.

steroids - Lewis acids - ring closure - dihydrooxazines - stereoselective synthesis

References

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17

General Experimental Procedure: A solution of 1 mmol of 3-methoxy-16β-azidomethyl-1,3,5(10)-trien-estra-17β-ol (preparation [13] ) and 1.1 mmol of the corresponding aldehyde in 3 mL of CH₂Cl₂ was cooled to 0 °C, followed by the dropwise addition of 2 mmol of acidic catalyst in 2 mL of CH₂Cl₂. The addition of the catalyst was accompanied by N₂ evolution. The reaction was allowed to warm to r.t. and the solution was stirred for 60 min and monitored by TLC [tert-butyl methyl ether:light petroleum (30:70)]. After the complete conversion of the 3-methoxy-16β-azidomethyl-1,3,5(10)-trien-estra-17β-ol, sat. NaHCO₃ solution was added to the reaction mixture, which was stirred until bubbling ceased. After extraction with CH₂Cl₂, the combined organic phase was washed with brine, dried with anhydrous Na₂SO₄, and then evaporated. The crude products were chromatographed on silica gel with tert-butyl methyl ether:light petroleum (20:80).

18

The reactions with several acids gave the following results. Acid catalyst, yield of 6a: H₃[P(W₃O₁₀)₄] (2 equiv), 17%; H₂SO₄ (2 equiv), 52%; SnCl₄ (2 equiv), 60%; BF₃·OEt₂ (2 equiv), 82%.

19

Characteristic data for compound 5a: yield 91%, mp 197-199 °C, [α]_D ²⁰ +124.

20 Gadre SR. Suresh CH. J. Org. Chem.  1997,  62:  2625 

21

Representative Examples: 6b: ¹H NMR (500 MHz, CDCl₃): δ = 0.85 (s, 3 H, 18-H₃), 1.30-2.39 (overlapping m, 12 H, 7-H₂, 8-H, 9-H, 11-H₂, 12-H₂, 14-H, 15-H₂, 16-H), 2.88 (m, 2 H, 6-H₂), 3.09 (dd, 1 H, J = 15.3 Hz, 10.5 Hz, 16a-H_ax), 3.78 (s, 3 H, 3-OCH₃), 3.97 (dd, 1 H, J = 15.3 Hz, 7.6 Hz, 16a-H_eq), 4.15 (d, 1 H, J = 9.8 Hz, 17α-H), 6.64 (d, 1 H, J = 2.4 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, 2.4 Hz, 2-H), 7.22 (d, 1 H, J = 8.6 Hz, 1-H), [8.11 (d, 2 H, J = 8.8 Hz) and 8.23 (d, 2 H, J = 8.8 Hz)]:[2′-H, 6′-H, 3′-H, 5′-H]. ¹³C NMR (125 MHz, CDCl₃): δ = 13.4 (C-18), [26.2, 27.5, 29.7, 31.2, 37.6]:[C-6, C-7, C-11, C-12, C-15], 31.0 (C-16), 38.1 (C-8), 44.0 (C-9), 44.6 (C-13), 48.0 (C-14), 49.2 (C-16a), 55.2 (3-OCH₃), 85.7 (C-17), 111.6 (C-2), 113.8 (C-4), 123.2 (2C, C-3′, C-5’), 126.3 (C-1), 128.0 (2C, C-2′, C-6′), 132.1 (C-10), 137.7 (C-5), 139.8 (C-1′), 149.0 (C-4′), 155.5 [C(N,O)], 157.5 (C-3). MS: m/z = 446 [M⁺]. C₂₇H₃₀N₂O₄.
6c: ¹H NMR (500 MHz, CDCl₃): δ = 0.85 (s, 3 H, 18-H₃), 1.30-2.41 (overlapping m, 12 H, 7-H₂, 8-H, 9-H, 11-H₂, 12-H₂, 14-H, 15-H₂, 16-H), 2.88 (m, 2 H, 6-H₂), 3.09 (dd, 1 H, J = 15.2 Hz, J = 10.6 Hz, 16a-H_ax), 3.78 (s, 3 H, 3-OCH₃), 3.96 (dd, 1 H, J = 15.2 Hz, J = 7.4 Hz, 16a-H_eq), 4.16 (d, 1 H, J = 9.8 Hz, 17α-H), 6.64 (d, 1 H, J = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, 2.7 Hz, 2-H), 7.22 (d, 1 H, J = 8.6 Hz, 1-H), 7.56 (t, 1 H, J = 8.0 Hz, 5′-H), [8.27 (d, 1 H, J = 8.0 Hz), 8.31 (d, 1 H, J = 8.0 Hz)]:[4′-H, 6′-H], 8.79 (s, 1 H, 2′-H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.3 (C-18), [26.2, 27.5, 29.7, 31.2, 37.6]:[C-6, C-7, C-11, C-12, C-15], 31.0 (C-16), 38.1 (C-8), 44.0 (C-9), 44.6 (C-13), 47.9 (C-14), 49.0 (C-16a), 55.2 (3-OCH₃), 85.7 (C-17), 111.6 (C-2), 113.8 (C-4), 122.2 (C-2′), 124.9 (C-4′), 126.3 (C-1), 129.0 (C-5′), 132.2 (C-10), 133.0 (C-6′), 135.9 (C-1′), 137.7 (C-5), 148.3 (C-3′), 155.2 [C(N,O)], 157.6 (C-3). MS: m/z = 446 [M⁺]. C₂₇H₃₀N₂O₄.
6d: ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (s, 3 H, 18-H₃), 1.27-2.49 (overlapping m, 12 H, 7-H₂, 8-H, 9-H, 11-H₂, 12-H₂, 14-H, 15-H₂, 16-H), 2.87 (m, 2 H, 6-H₂), 3.02 (dd, 1 H, J = 14.5 Hz, 11.2 Hz, 16a-H_ax), 3.77 (s, 3 H, 3-OCH₃), 3.92 (dd, 1 H, J = 14.5 Hz, 7.3 Hz, 16a-H_eq), 3.99 (d, 1 H, J = 8.8 Hz, 17α-H), 6.63 (d, 1 H, J = 2.6 Hz, 4-H), 6.71 (dd, 1 H, J = 8.6 Hz, 2.6 Hz, 2-H), 7.19 (d, 1 H, J = 8.6 Hz, 1-H), 7.53 (t, 1 H, J = 7.6 Hz, 4′-H), 7.60 (t, 1 H, J = 7.6 Hz, 5′-H), [7.78 (d, 1 H, J = 7.6 Hz), 7.81 (d, 1 H, J = 7.6 Hz)]:[3′-H, 6′-H]. ¹³C NMR (125 MHz, CDCl₃): δ = 13.4 (C-18), [26.1, 27.5, 29.7, 30.7, 37.3]:[C-6, C-7, C-11, C-12, C-15], 30.7 (C-16), 38.1 (C-8), 44.0 (C-9), 44.4 (C-13), 47.8 (C-14), 48.9 (C-16a), 55.2 (3-OCH₃), 87.3 (C-17), 111.5 (C-2), 113.8 (C-4), 123.7 (C-3′), 126.3 (C-1), 129.9 (C-1′), 130.3 (C-6′), 131.0 (C-4′), 132.2 (C-10), 132.3 (C-5′), 137.7 (2C, C-5, C-2′), 157.0 [C(N,O)], 157.5 (C-3). MS: m/z = 446 [M⁺]. C₂₇H₃₀N₂O₄.
8c: ¹H NMR (500 MHz, CDCl₃): δ = 0.90 (s, 3 H, 18-H₃), 1.26-2.86 (overlapping m, 14 H, 6-H₂, 7-H₂, 8-H, 9-H, 11-H₂, 12-H₂, 14-H, 15-H₂, 16-H), 2.76 (m, 2 H,), 3.67 (m, 2 H, 16a-H₂), 3.77 (s, 3 H, 3-OCH₃), 4.30 (d, 1 H, J = 5.5 Hz, 17β-H), 6.59 (d, 1 H, J = 2.7 Hz, 4-H), 6.70 (dd, 1 H, J = 8.6 Hz, 2.7 Hz, 2-H), 7.18 (d, 1 H, J = 8.6 Hz, 1-H), 8.14 (d, 2 H, J = 8.9 Hz, 2′-H, 6′-H), 8.23 (d, 2 H, J = 8.9 Hz, 3′-H, 5′-H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.1 (C-18), [26.0, 27.9, 29.8, 31.0, 31.2]:[C-6, C-7, C-11, C-12, C-15], [32.7, 39.0, 43.6]:[C-8, C-9, C-16], 45.9 (C-16a), 47.5 (C-13), 49.0 (C-14), 55.2 (3-OCH₃), 85.6 (C-17), 111.5 (C-2), 113.8 (C-4), 123.3 (2C, C-3′, C-5′), 126.2 (C-1), 127.9 (2C, C-2′, C-6′), 132.2 (C-10), 137.8 (C-5), 139.8 (C-1′), 149.1 (C-4′), 155.5 [C(N,O)], 157.5 (C-3). MS: m/z = 446 [M⁺]. C₂₇H₃₀N₂O₄.
9c: ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (s, 3 H, 18-H₃), 1.33-2.41 (overlapping m, 11 H, 7-H₂, 8-H, 9-H, 11-H₂, 12-H₂, 14-H, 15-H₂), 2.68 (m, 1 H, 16-H), 2.84 (m, 2 H, 6-H₂), 3.76 (s, 3 H, 3-OCH₃), 3.95 (d, 1 H, J = 5.1 Hz, 17β-H), 5.57 [t, 1 H, J = 2.9 Hz, CH(N,O)], 6.62 (d, 1 H, J = 2.6 Hz, 4-H), 6.71 (dd, 1 H, J = 8.6 Hz, 2.7 Hz, 2-H), 7.20 (d, 1 H, J = 8.6 Hz, 1-H), 7.79 (d, 2 H, J = 8.5 Hz, 2′-H, 6′-H), 8.03 (t, 1 H, J = 2.7 Hz, 16a-H), 8.23 (d, 2 H, J = 8.5 Hz, 3′-H, 5′-H).
¹³C NMR (125 MHz, CDCl₃): δ = 16.4 (C-18), [26.0, 28.0, 28.9, 29.8, 30.7]:[C-6, C-7, C-11, C-12, C-15], [38.1, 38.8, 43.4, 47.1]:[C-8, C-9, C-14, C-16], 46.6 (C-13), 55.2 (3-OCH₃), [82.5, 85.2]:[CH(N,O), C-17], 111.6 (C-2), 113.8 (C-4), 123.4 (2C, C-3′, C-5′), 126.3 (C-1), 127.6 (2C, C-2′, C-6′), 132.4 (C-10), 137.8 (C-5), 147.5 (C-4′), 147.9 (C-1′), 157.5 (C-3), 165.1 (C-16a). MS: m/z = 446 [M⁺]. C₂₇H₃₀N₂O₄.
The compounds gave correct elemental analyses.