A New Application of the Pictet-Spengler Reaction to the Preparation of 4-Substituted 1H-2,3-Benzoxazines

Xiufang Zheng; Xiaolei Wang; Junbiao Chang; Kang Zhao

doi:10.1055/s-2006-951564

LETTER

A New Application of the Pictet-Spengler Reaction to the Preparation of 4-Substituted 1H-2,3-Benzoxazines

Xiufang Zheng^a, Xiaolei Wang^a, Junbiao Chang*^a,b, Kang Zhao*^a
^a College of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27890968; e-Mail: kangzhao@tju.edu.cn;
^b School of Pharmaceuticals, Xinxiang Medical College, Xinxiang 453003, P. R. of China

Abstract

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Abstract

Intramolecular coupling reaction of benzylic O-hydroxamates and aldehydes was investigated to afford a variety of 4-substituted 1H-2,3-benzoxazine ring systems in good to excellent yields. The reaction involved an intramolecular C-C bond formation between an N-acyl- or N-sulfonyl-oxoiminium ion with the aryl ring. Under the studied conditions, electron-donating groups in the aryl ring are essential for the desired coupling reactions.

Key words

1H-2,3-benzoxazine - Pictet-Spengler reaction - oxoiminium ion - hydroxamate - aldehyde

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Referenzen

References and Notes

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General Procedure for the Synthesis of Benzoxazines 2a-h.
To a solution of hydroxamate 2 (0.6 mmol) in dry CH₂Cl₂ (4 mL) was added aldehyde (0.6 mmol) in one portion. The resulting mixture was chilled to -78 °C and BF₃·OEt₂ (1.2 mmol) was added dropwise under N₂. The reaction mixture was allowed to warm to r.t. and quenched with Et₃N. The solvent was evaporated under reduced pressure and the residue was isolated by chromatography on silica gel to afford the desired benzoxazines 2a-h.

General Procedure for the Synthesis of Benzoxazines 2i-s. To the solution of hydroxamate 2 (0.6 mmol) in dry MeCN (6 mL) was added aldehyde (0.9 mmol) in one portion followed by NaI (1.8 mmol) under N₂. Then, TMSCl (1.8 mmol) was added dropwise. The resulting mixture was stirred until all the hydroxamate was consumed. The resulting mixture was treated with 20% NaHSO₃ (6 mL) and extracted with EtOAc (3 × 10 mL). The organic phases were collected, washed (sat. NaHCO₃ and brine), dried (Na₂SO₄) and evaporated under reduced pressure. The residue was isolated by chromatography on silica gel to afford the desired benzoxazines 2i-s.

Compound 2a: white solid, mp 98-100 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.96 (t, J = 7.2 Hz, 3 H), 1.52 (br, 2 H), 1.78 (br, 1 H), 2.10 (br, 1 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 3.85 (s, 3 H), 4.66, 4.76 (AB, J = 13.2 Hz, 2 H), 5.53 (br, 1 H), 6.40 (s, 1 H), 6.64 (s, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.77 (br, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.17, 19.86, 38.27, 52.80, 55.46, 56.11, 56.20, 71.45, 107.22, 109.81, 113.36, 122.61, 125.78, 127.24, 131.12, 148.27, 148.44, 161.93, 168.98.
Compound 2b: white solid, mp 109-111 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.01 (br, 3 H), 1.58 (br, 2 H), 1.84 (br, 1 H), 2.04-2.12 (m, 1 H), 3.81 (s, 3 H), 3.89 (s, 3 H), 4.67 (br, 1 H), 4.77 (br, 1 H), 5.57 (br, 1 H), 6.43 (s, 1 H), 6.67 (s, 1 H), 7.40-7.49 (m, 3 H), 7.75 (br, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.22, 19.91, 38.33, 52.75, 56.19, 56.29, 71.70, 107.20, 109.81, 122.56, 127.17, 128.17, 128.75, 130.98, 134.07, 148.37, 148.52, 169.49.
Compound 2c: yellow solid, mp 61-63 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.04 (t, J = 7.5 Hz, 3 H), 1.49-1.65 (m, 2 H), 1.85-1.91 (m, 1 H), 2.05-2.13 (m, 1 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.70, 4.76 (AB, J = 13.5 Hz, 2 H), 5.57 (dd, J = 10.0, 3.5 Hz, 1 H), 6.44 (s, 1 H), 6.69 (s, 1 H), 7.91 (d, J = 8.5 Hz, 2 H), 8.29 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.18, 19.89, 38.27, 53.03, 56.21, 56.31, 72.20, 107.11, 109.70, 121.89, 123.41, 126.53, 129.80, 140.04, 148.53, 148.75, 149.15, 167.08.
Compound 2d: white solid, mp 72-75 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (t, J = 7.2 Hz, 3 H), 1.19 (t, J = 7.6 Hz, 3 H), 1.37-1.53 (m, 2 H), 1.70-1.79 (m, 1 H), 1.87-1.97 (m, 1 H), 2.39-2.48 (m, 1 H), 2.59-2.67 (m, 1 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 4.84, 5.01 (AB, J = 13.6 Hz, 2 H), 5.38 (dd, J = 9.6, 4.0 Hz, 1 H), 6.48 (s, 1 H), 6.63 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 9.16, 14.18, 19.73, 25.66, 38.38, 52.22, 56.14, 56.22, 71.64, 107.10, 109.76, 122.70, 127.33, 148.19, 148.43, 172.80.
Compound 2e: white solid, mp 115-117 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.94 (t, J = 7.0 Hz, 3 H), 1.34-1.52 (m, 2 H), 1.73-1.80 (m, 1 H), 1.88-1.96 (m, 1 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 4.27, 4.33 (AB, J = 13.0 Hz, 2 H), 4.89 (d, J = 13.5 Hz, 1 H), 5.14 (d, J = 13.5 Hz, 1 H), 5.33 (dd, J = 9.5, 4.0 Hz, 1 H), 6.48 (s, 1 H), 6.61 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.17, 19.61, 38.42, 40.92, 53.20, 56.22, 56.30, 72.42, 107.05, 109.63, 122.16, 126.35, 148.46, 148.64, 165.01.
Compound 2f: white solid, mp 121-123 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.97 (t, J = 7.0 Hz, 3 H), 1.48-1.56 (m, 2 H), 1.75-1.82 (m, 1 H), 1.92-1.99 (m, 1 H), 3.12 (s, 3 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.83 (dd, J = 9.0, 5.0 Hz, 1 H), 4.84, 5.43 (AB, J = 14.0 Hz, 2 H), 6.49 (s, 1 H), 6.60 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.07, 19.85, 38.27, 39.30, 54.82, 56.15, 56.26, 69.37, 107.01, 109.63, 122.25, 125.63, 148.21, 148.61.
Compound 2g: white solid, mp 60-61 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (t, J = 7.5 Hz, 3 H), 1.39-1.46 (m, 2 H), 1.60-1.67 (m, 1 H), 1.86-1.93 (m, 1 H), 3.71 (s, 3 H), 3.76 (s, 3 H), 3.80 (s, 3 H), 4.67, 4.88 (AB, J = 14.0 Hz, 2 H), 5.06 (d, J = 14.0 Hz, 1 H), 6.42 (s, 1 H), 6.54 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.02, 19.82, 38.06, 53.29, 55.83, 56.14, 56.22, 69.96, 107.28, 109.52, 123.18, 127.07, 148.23, 148.29, 155.95.
Compound 2h: white solid, mp 113-114 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.04 (d, J = 9.0 Hz, 3 H), 1.16 (d, J = 6.0 Hz, 3 H), 2.28-2.35 (m, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.65, 4.71 (AB, J = 13.0 Hz, 2 H), 5.43 (br, 1 H), 6.42 (s, 1 H), 6.72 (s, 1 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.83 (br d, J = 6.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 19.15, 20.34, 34.53, 55.55, 56.14, 56.24, 57.31, 71.31, 107.05, 110.46, 113.34, 123.24, 125.75, 125.96, 131.26, 148.15, 148.34, 161.86, 169.44.
Compound 2i: white solid, mp 115-117 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.78 (s, 3 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 4.84, 5.01 (AB, J = 13.6 Hz, 2 H), 6.54 (s, 1 H), 6.59 (s, 1 H), 6.66 (s, 1 H), 6.90 (dd, J = 9.2, 2.4 Hz, 2 H), 7.29-7.75 (m, 5 H), 7.77 (dd, J = 9.2, 2.4 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 55.58, 56.21, 56.24, 56.53, 71.58, 106.91, 110.86, 113.40, 123.49, 124.78, 125.71, 128.15, 128.66, 129.16, 131.22, 140.99, 148.70, 148.73, 162.05, 168.46.
Compound 2j: white solid, mp 125-127 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.77 (s, 3 H), 3.86 (s, 3 H), 4.86, 5.00 (AB, J = 14.0 Hz, 2 H), 6.54 (s, 1 H), 6.58 (s, 1 H), 6.65 (s, 1 H), 7.26-7.69 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 55.97, 55.9, 56.36, 71.51, 106.70, 110.58, 123.20, 124.38, 127.91, 127.99, 128.45, 128.51, 128.88, 130.88, 133.58, 140.59, 148.51, 148.54, 168.64.
Compound 2k: white solid, mp 191-197 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.78 (s, 3 H), 3.88 (s, 3 H), 4.85, 4.95 (AB, J = 14.0 Hz, 2 H), 6.55 (s, 1 H), 6.58 (s, 1 H), 6.66 (s, 1 H), 7.34-7.43 (m, 5 H), 7.83 (dd, J = 7.0, 2.0 Hz, 2 H), 8.25 (dd, J = 7.0, 2.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 56.02, 56.04, 56.26, 71.99, 106.62, 110.49, 122.59, 123.17, 123.81, 128.33, 128.62, 128.90, 129.55, 139.55, 140.12, 148.71, 148.80, 148.98, 166.20.
Compound 2l: white solid, mp 170-171 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.16 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.98, 5.14 (AB, J = 13.6 Hz, 2 H), 6.51 (s, 1 H), 6.53 (s, 1 H), 6.59 (s, 1 H), 7.28-7.35 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 20.52, 55.34, 56.22, 71.84, 106.88, 110.78, 123.62, 124.74, 128.21, 128.63, 129.10, 140.93, 148.66, 148.78, 169.08.
Compound 2m: white solid, mp 134-136 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H), 3.73 (s, 3 H), 3.89 (s, 3 H), 5.06, 5.40 (AB, J = 13.5 Hz, 2 H), 5.78 (s, 1 H), 6.43 (s, 1 H), 6.62 (s, 1 H), 7.34-7.41 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 35.79, 56.20, 56.21, 61.92, 72.71, 106.74, 110.69, 123.99, 125.81, 128.77, 129.10, 130.38, 137.78, 148.72, 148.74.
Compound 2n: white solid, mp 113-115 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.75 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 4.92, 5.22 (AB, J = 14.0 Hz, 2 H), 6.09 (s, 1 H), 6.52 (s, 1 H), 6.60 (s, 1 H), 7.27-7.37 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.45, 56.20, 59.08, 70.94, 107.02, 110.61, 124.16, 124.79, 128.24, 128.62, 129.05, 140.64, 148.55, 148.66, 155.40.
Compound 2o: white solid, mp 186-188 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.77 (s, 3 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 4.91, 5.23 (AB, J = 14.0 Hz, 2 H), 6.59 (s, 1 H), 6.60 (s, 1 H), 6.64 (s, 1 H), 7.15-7.43 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.62, 55.34, 5.18, 56.19, 70.16, 107.14, 110.00, 123.72, 124.63, 127.38, 129.37, 129.71, 130.83, 133.55, 138.95, 148.78, 155.50.
Compound 2p: white solid, mp 127-129 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.77 (s, 3 H), 3.81 (s, 3 H), 3.89 (s, 3 H), 4.92, 5.21 (AB, J = 14.0 Hz, 2 H), 6.04 (s, 1 H), 6.49 (s, 1 H), 6.60 (s, 1 H), 7.25-7.33 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.56, 56.22, 56.25, 58.53, 70.92, 107.15, 110.50, 124.04, 124.18, 127.29, 128.50, 129.18, 129.87, 134.51, 142.53, 148.69, 148.90, 155.29.
Compound 2q: white solid, mp 57-59 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.76 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 4.91, 5.21 (AB, J = 13.8 Hz, 2 H), 6.05 (s, 1 H), 6.48 (s, 1 H), 6.60 (s, 1 H), 7.26-7.31 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.51, 56.20, 58.41, 70.98, 107.09, 110.46, 124.18, 124.32, 128.78, 130.47, 134.18, 139.11, 148.66, 148.81, 155.34.
Compound 2r: white solid, mp 150-151 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.79 (s, 6 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 3.89 (s, 3 H), 4.92-5.20 (AB, J = 13.8 Hz, 2 H), 6.02 (s, 1 H), 6.56 (s, 1 H), 6.58 (s, 2 H), 6.60 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.50, 56.18, 56.26, 56.34, 56.44, 59.10, 60.99, 70.91, 106.23, 107.00, 110.63, 124.09, 124.53, 136.34, 138.02, 148.52, 148.70, 153.27, 155.36.
Compound 2s: white solid, mp 98-99 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.79 (s, 3 H), 3.80 (s, 3 H), 4.96, 5.25 (AB, J = 14.0 Hz, 2 H), 6.11 (s, 1 H), 6.64 (d, J = 2.5 Hz, 1 H), 6.79 (dd, J = 8.5, 2.5 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H), 7.26-7.36 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 53.47, 55.58, 59.14, 71.42, 109.18, 113.94, 125.13, 128.16, 128.59, 128.95, 129.38, 133.30, 140.95, 155.41, 158.77.
Compound 2t: white solid, mp 180-182 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.76 (s, 3 H), 3.90 (s, 3 H), 4.12, 4.34 (AB, J = 13.2 Hz, 2 H), 5.02, 5.28 (AB, J = 13.6 Hz, 2 H), 6.44 (s, 1 H), 6.52 (s, 1 H), 6.60 (s, 1 H), 7.30-7.37 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 41.30, 56.24, 56.48, 72.53, 106.80, 110.67, 123.21, 124.00, 128.52, 128.73, 129.18, 140.25, 148.83, 148.92, 164.87.