Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines

Li Zhang; Xiu-Fang Zheng; Gregory Linn; Kang Zhao

doi:10.1055/s-2007-967948

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Synlett 2007(3): 0374-0380
DOI: 10.1055/s-2007-967948

LETTER

Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines

Li Zhang, Xiu-Fang Zheng, Gregory Linn, Kang Zhao*
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27890968; e-Mail: kangzhao@tju.edu.cn;

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Publication History

Received 17 October 2006
Publication Date:
07 February 2007 (online)

Abstract
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Abstract

The synthesis of 1,3-disubstituted N-amino-1,2,3,4-tetrahydroisoquinolines from the corresponding hydrazide intermediate via Pictet-Spengler reaction is described and the effect of the aldehyde on the stereoconfiguration of the products is discussed.

Key words

quinolines - aldehydes - heterocycles - reduction - ring closure

References and Notes

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11

All melting points were determined on a Kofler hot-plate microscope apparatus and are uncorrected. Mass spectra ESI were recorded on Q-TOF Micromass spectrometer. ¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 500 MHz instrument.
Selected data of compounds 5:
5a: mp 109-110 °C. ¹H NMR (CDCl₃): δ = 7.76 (br s, 1 H, anti), 7.85 (br s, 1 H, syn), 6.79-6.83 (m, 2 H, 2 isomers), 6.75-6.77 (m, 2 H, anti), 6.66-6.68 (m, 2 H, syn), 6.74 (s, 1 H, anti), 6.62 (br s, 1 H, syn), 3.85-3.87 (m, 9 H, 2 isomers), 3.57 (d, J = 4.0 Hz, 2 H, anti), 3.52 (br s, 2 H, syn), 1.71 (d, J = 1.0 Hz, 3 H, anti), 2.06 (d, J = 6.5 Hz, 3 H, syn). MS (ESI): m/z = 267.0 [M + H]⁺. 5b: mp 144-146 °C. ¹H NMR (CDCl₃): δ = 8.75 (br s, 1 H, anti), 8.99 (br s, 1 H, syn), 7.83 (br s, 2 H, anti), 7.60 (d, J = 16.0 Hz, 2 H, syn), 7.52-7.54 (m, 1 H, anti), 7.49-7.52 (m, 2 H + 1 H′), 7.36 (t, J = 7.5 Hz, 2 H, syn), 6.81 (s, 3 H, anti), 6.71 (s, 3 H, syn), 3.86 (s, 3 H, anti), 3.88 (s, 3 H, syn), 3.85-3.86 (m, 3 H, 2 isomers), 3.63-3.69 (m, 2 H, 2 isomers), 1.86 (s, 3 H, anti), 2.15 (s, 3 H, syn). MS (ESI): m/z = 313.0 [M + H]⁺.

12

Selected data of compounds 6:
6a: mp 114-116 °C. ¹H NMR (CDCl₃): δ = 7.60 (d, J = 7.0 Hz, 2 H), 7.49 (t, J = 2.0 Hz, 1 H), 7.40 (t, J = 2.5 Hz, 2 H), 7.30-7.32 (m, 2 H), 7.20-7.26 (m, 3 H), 4.49 (br s, 1 H), 3.40 (sext, J = 6.5 Hz, 1 H), 2.83 (q, J = 6.5 Hz, 1 H), 2.67 (q, J = 7.0 Hz, 1 H), 1.13 (d, J = 6.0 Hz, 3 H). MS (ESI): m/z = 255.2 [M + H]⁺. 6b: ¹H NMR (CDCl₃): δ = 7.16 (td, J = 8.0, 9.5 Hz, 1 H), 7.16 (dd, J = 1.5, 7.5 Hz, 1 H), 6.86 (td, J = 7.5, 8.5 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 4.01 (sext, J = 6.0 Hz, 1 H), 3.73 (s, 3 H), 2.71-2.76 (m, 2 H), 1.16 (s, 3 H). MS (ESI): m/z = 181.4 [M + H]⁺. 6f: mp 82-84 °C. ¹H NMR (CDCl₃): δ = 7.61-7.63 (m, 2 H), 7.48-7.52 (m, 1 H), 7.39-7.42 (m, 2 H), 7.68-7.87 (m, 2 H), 7.14-7.17 (m, 2 H), 3.79 (s, 3 H), 3.37 (sext, J = 6.5 Hz, 1 H), 2.78 (q, J = 7.0 Hz, 1 H), 2.64 (q, J = 6.5 Hz, 1 H), 1.14 (d, J = 6.5 Hz, 3 H). MS (ESI): m/z = 285.4 [M + H]⁺.

14

Compound 7a: ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.21 (br s, 1 H), 7.99 (s, 1 H), 7.57-7.63 (m, 4 H) 3.69 (s, 3 H). 7b: ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.87 (br s, 1 H), 8.47 (s, 1 H), 7.92 (d, J = 7.5 Hz, 2 H), 7.74 (d, J = 5.4 Hz, 2 H), 7.46-7.61 (m, 6 H).

15

3b: Crystallized in triclinic, space group P-1 with cell parameters: a = 5.2532(11) Å, b = 10.676(2) Å, c = 20.717(4) Å, α = 101.19°, β = 93.87°, γ = 102.61°, V = 1104.9(4) Å³, D _c = 1.447 g/cm³, Z = 2.

16

Synthesis of compound 3: To the mixture of compound 6a (200 mg, 0.64 mmol) and 4-bromobenzaldehyde (118 mg, 0.64 mmol) in MeCN (8 mL), anhyd NaI (334 mg, 2.23 mmol) was added under stirring at r.t., followed by TMSCl (0.28 mL, 2.23 mmol). After 40 min, the reaction was concentrated and the products were purified by column chromatography (10-30% EtOAc-PE). Unless otherwise indicated, each product was separated as an enantiomeric mixture and characterized by NMR spectroscopy.
Selected data of compounds 3:
3a: mp 227-229 °C. ¹H NMR (CDCl₃): δ = 7.43-7.47 (m, 1 H), 7.39-7.42 (m, 4 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.96 (br s, 1 H), 6.63 (d, J = 2.5 Hz, 1 H), 6.59 (dd, J = 2.5, 8.5 Hz, 1 H), 6.49 (d, J = 8.5 Hz, 1 H), 5.81 (br s, 1 H), 4.12 (br s, 1 H), 3.76 (s, 3 H), 3.00 (br s, 1 H), 2.88 (dd, J = 3.5, 16.0 Hz, 1 H), 1.29 (d, J = 6.5 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 167.65, 158.03, 142.74, 135.33, 133.78, 131.56, 131.51, 131.19, 129.34, 128.65, 126.64, 121.45, 112.37, 112.25, 66.56, 55.19, 54.11, 39.01, 19.70. MS (ESI): m/z = 451.2, 453.2 [M + H]⁺. 3b: mp 216-217 °C. ¹H NMR (CDCl₃): δ = 7.41-7.47 (m, 5 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.23 (d, J = 7.5 Hz, 2 H), 6.99 (br s, 1 H), 6.59 (s, 1 H), 6.04 (s, 1 H), 5.83 (br s, 1 H), 4.14 (br s, 1 H), 3.85 (s, 3 H), 3.59 (s, 3 H), 2.96 (br s, 1 H), 2.82 (dd, J = 2.5, 15.5 Hz, 1 H), 1.28 (d, J = 6.0 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 167.65, 147.78, 147.26, 142.61, 133.75, 131.56, 131.50, 131.21, 129.39, 128.65, 126.65, 126.41, 121.50, 111.08, 110.45, 66.38, 55.90, 55.84, 53.84, 38.38, 19.67. MS (ESI): m/z = 481.0, 483.0 [M + H]⁺. 3c: mp 171-172 °C. ¹H NMR (CDCl₃): δ = 7.40-7.56 (m, 5 H, 2 isomers), 7.15-7.18 (trans), 7.03-7.05 (m, 4 H, cis), 6.70 (br s, 1 H, 2 isomers), 6.43 (s, 1 H, trans), 6.49 (s, 1 H, cis), 5.69 (br s, 1 H, trans), 5.37 (s, 1 H, cis), 4.00 (br s, 1 H, trans), 3.24-3.26 (m, 1 H, cis), 3.86 (s, 3 H, trans), 3.87 (s, 3 H, cis), 3.73 (s, 3 H, trans), 3.79 (s, 3 H, cis), 3.14 (s, 3 H, trans), 3.46 (s, 3 H, cis), 2.95 (br s, 1 H, 2 isomers), 2.74-2.83 (m, 1 H, 2 isomers), 1.23 (d, J = 6.0 Hz, 3 H, trans), 1.17 (d, J = 6.0 Hz, 3 H, cis). ¹³C NMR (CDCl₃): δ (trans/cis) = 166.35/167.48, 152.56/153.22, 150.70/151.06, 140.57/144.76, 140.46/139.35, 133.75/134.04, 131.61/131.45, 131.17/130.87, 130.81/130.77, 128.67/129.32, 126.76/127.04, 121.61/123.79, 120.43/119.81, 106.14/106.56, 64.05/60.71, 60.50/60.38, 59.12/60.16, 55.87/55.93, 48.52/53.08, 39.53/32.95, 19.63/18.86. MS (ESI): m/z = 511.1, 513.1 [M + H]⁺. 3d: mp 215-218 °C. ¹H NMR (CDCl₃): δ = 7.42 (t, J = 7.5 Hz, 1 H), 7.34-7.36 (m, 4 H), 7.27-7.33 (m, 5 H), 6.95 (br s, 1 H), 6.59 (s, 1 H), 6.09 (s, 1 H), 5.79 (br s, 1 H), 4.13 (br s, 1 H), 3.85 (s, 3 H), 3.56 (s, 3 H), 2.97 (br s, 1 H), 2.83 (dd, J = 3.5, 15.5 Hz, 1 H), 1.30 (d, J = 6.0 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 167.75, 147.63, 147.14, 143.33, 134.07, 131.36, 130.08, 129.52, 128.53, 128.38, 127.65, 126.68, 126.38, 113.31, 110.38, 68.07, 55.83, 54.06, 38.46, 19.73. MS (ESI): m/z = 403.3 [M + H]⁺. 3e (trans): mp 210-211 °C. ¹H NMR (CDCl₃): δ = 7.42-7.45 (m, 3 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 6.91 (br s, 1 H), 6.82 (d, J = 8.5 Hz, 2 H), 6.58 (s, 1 H), 6.10 (s, 1 H), 5.73 (br s, 1 H), 4.10 (br s, 1 H), 3.85 (s, 3 H), 3.78 (s, 3 H), 3.58 (s, 3 H), 2.96 (br s, 1 H), 2.82 (dd, J = 3.5, 15.5 Hz, 1 H), 1.29 (d, J = 6.0 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 167.79, 158.98, 147.60, 147.12, 135.37, 134.12, 131.36, 130.59, 130.29, 128.55, 126.70, 126.37, 113.69, 111.34, 110.33, 55.86, 55.21, 38.39, 19.78. MS (ESI): 433.1 [M + H]⁺. 3e (cis): mp 210-211 °C. ¹H NMR (CDCl₃): δ = 7.66 (d, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 6.75 (s, 1 H), 6.66 (s, 1 H), 6.39 (s, 1 H), 5.18 (s, 1 H), 3.90 (s, 3 H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.36 (sept, J = 6.0 Hz, 1 H), 2.90 (dd, J = 5.0, 17.0 Hz, 1 H), 2.82 (dd, J = 10.0, 17.0 Hz, 1 H), 1.17 (d, J = 6.5 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 166.18, 159.10, 148.23, 147.70, 134.18, 132.46, 131.50, 131.21, 128.60, 127.02, 126.20, 125.72, 113.54, 111.46, 110.84, 67.83, 55.87, 55.27, 49.04, 33.05, 18.26. MS (ESI): m/z = 433.1 [M + H]⁺. 3f (p, cis): mp 202-204 °C. MS (ESI): m/z = 437.1, 439.1 [M + H]⁺. 3f (m, trans): mp 182-183 °C. MS (ESI): m/z = 437.1, 439.1 [M + H]⁺. 3f (o): mp 99-101 °C. MS (ESI): m/z = 437.1, 439.1 [M + H]⁺. 3g: mp 203-206 °C. ¹H NMR (DMSO-d ₆): δ = 9.43 (br s, 1 H), 8.12 (d, J = 8.5 Hz, 2 H), 7.63 (br s, 2 H) 7.49 (d, J = 7.5 Hz, 2 H) 7.45 (t, J = 7.5 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 2 H), 6.74 (s, 1 H), 6.02 (s, 1 H), 5.24 (br s, 1 H), 3.71 (s, 3 H), 3.42 (s, 3 H), 3.23 (br s, 1 H), 2.91 (br s, 1 H), 2.83 (dd, J = 3.0, 16.0 Hz, 1 H), 1.17 (d, J = 6.0 Hz, 3 H). ¹³C NMR (125 Hz, CDCl₃): δ = 167.40, 151.23, 148.08, 147.46, 147.41, 133.33, 131.70, 130.25, 128.63, 126.56, 126.49, 123.53, 110.83, 110.73, 67.78, 55.88, 55.83, 54.47, 38.29, 19.48. MS (ESI): m/z = 448.2 [M + H]⁺. 3h: mp 158-160 °C. ¹H NMR (CDCl₃): δ = 7.72 (d, J = 7.0 Hz, 2 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.08 (br s, 1 H), 6.60 (s, 1 H), 6.52 (s, 1 H), 4.36 (d, J = 10.0 Hz, 1 H), 4.12 (d, J = 15.0 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.45 (br s, 1 H), 2.73-2.84 (m, 2 H), 1.30 (d, J = 6.5 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 166.65, 147.85, 147.63, 133.81, 131.49, 128.49, 126.97, 125.04, 123.97, 111.13, 109.32, 56.94, 55.80, 55.45, 33.13, 18.69. MS (ESI): m/z = 327.1 [M + H]⁺. 3i (trans): mp 184-186 °C. ¹H NMR (CDCl₃): δ = 7.71 (d, J = 7.5 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 6.82 (br s, 1 H), 6.68 (s, 1 H), 6.57 (s, 1 H), 4.31 (br s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.46 (br s, 1 H), 2.77-2.82 (m, 1 H), 2.67 (dd, J = 3.5, 16.5 Hz, 1 H), 1.93-2.00 (m, 1 H), 1.73-1.80 (m, 1 H), 1.56-1.63 (m, 1 H), 1.40 (m, 1 H), 1.27 (d, J = 6.5 Hz, 3 H), 0.90 (t, J = 6.0 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 167.18, 147.67, 147.60, 134.21, 131.53, 128.68, 128.43, 126.92, 110.92, 109.34, 64.22, 56.06, 55.85, 35.84, 35.19, 19.82, 18.31, 14.57. MS (ESI): m/z = 369.3 [M + H]⁺. 3i (cis): mp 183-184 °C. MS (ESI): m/z = 369.3 [M + H]⁺. 3k (trans): mp 170-172 °C. ¹H NMR (CDCl₃): δ = 7.59 (d, J = 7.0 Hz, 2 H), 7.48-7.51 (m, 1 H), 7.39-7.42 (m, 2 H), 7.23-7.26 (m, 4 H), 7.14-7.17 (m, 1 H), 7.01 (br s, 1 H), 6.53 (s, 1 H), 6.46 (s, 1 H), 4.73 (br s, 1 H, H_a), 3.84 (s, 3 H), 3.63 (s, 3 H), 3.54-3.56 (m, 1 H, H_e), 3.28 (dd, J _ee = 5.0 Hz, J _ea = 14.0 Hz, 1 H, H_e), 3.09 (dd, J _aa = 6.5 Hz, J _ae = 14.0 Hz, 1 H, H_a), 2.65 (dd, J _aa = 11.0 Hz, J _ae = 16.0 Hz, 1 H, H_a), 2.59 (dd, J _ea = 3.5 Hz, J _ea = 16.0 Hz, 1 H, H_e), 1.23 (d, J = 6.0 Hz, 3 H).
¹³C NMR (CDCl₃): δ = 167.14, 147.41, 147.20, 139.87, 133.79, 131.61, 129.61, 129.03, 128.59, 128.30, 126.87, 126.81, 126.04, 110.63, 109.99, 66.23, 55.82, 55.69, 55.06, 43.72, 36.26, 20.04. MS (ESI): m/z = 417.3 [M + H]⁺. 3m: mp 195-196 °C. ¹H NMR (CDCl₃): δ = 7.44-7.51 (m,
3 H + 1 H′), 7.71 (d, J = 7.5 Hz, 2 H, cis), 7.34-7.37 (m, 2 H, trans), 7.41 (t, J = 7.5 Hz, 2 H, cis), 7.26 (d, J = 4.0 Hz, 1 H, trans), 7.31 (d, J = 4.0 Hz, 1 H, cis), 7.19 (br s, 1 H, 2 isomers), 7.11 (d, J = 3.0 Hz, 1 H, trans), 6.84 (d, J = 3.0 Hz, 1 H, cis), 6.91 (dd, J = 3.5, 5.5 Hz, 1 H, trans), 6.98 (dd, J = 3.5, 5.5 Hz, 1 H, cis), 6.58 (s, 1 H, trans), 6.63 (s, 1 H, cis), 6.32 (s, 1 H, trans), 6.48 (s, 1 H, cis), 6.17 (br s, 1 H, trans), 5.50 (s, 1 H, cis), 4.11 (br s, 1 H, trans), 3.42-3.49 (m, 1 H, cis), 3.86 (s, 1 H, trans), 3.88 (s, 1 H, cis), 3.64 (s, 1 H, trans), 3.75 (s, 1 H, cis), 2.84-2.96 (m, 1 H, 2 isomers), 2.80 (dd, J = 3.5, 15.5 Hz, 1 H, 2 isomers), 1.30 (d, J = 6.5 Hz, 3 H, trans), 1.24 (d, J = 6.5 Hz, 3 H, cis). ¹³C NMR (CDCl₃): δ (trans/cis)= 167.85/166.05, 147.87/148.48, 147.24/147.60, 133.88/133.92, 131.49/131.58, 128.58/128.61, 127.47/127.00, 126.75/126.55, 125.96/125.92, 125.85/125.36, 110.96/111.11, 110.37/110.58, 63.68/62.86, 55.80/55.85, 49.77/54.66, 38.11/34.52, 19.74/18.78. MS (ESI): m/z = 409.4 [M + H]⁺. 3n (trans): mp 192-194 °C. ¹H NMR (CDCl₃): δ = 8.44 (d, J = 5.5 Hz, 2 H), 7.61 (br s, 1 H), 7.43-7.55 (m, 3 H), 7.30-7.34 (m, 2 H), 7.27-7.28 (m, 2 H), 6.61 (s, 1 H), 6.02 (s, 1 H), 5.86 (br s, 1 H), 4.00 (br s, 1 H), 3.85 (s, 3 H), 3.58 (s, 3 H), 2.95 (br s, 1 H), 2.82 (dd, J = 3.5, 15.5 Hz, 1 H), 1.27 (d, J = 6.0 Hz, 3 H). MS (ESI): m/z = 404.4 [M + H]⁺.