Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Bearing (S)-α-Methylbenzylamine from 2-Phosphonamides via Horner-Wadsworth-Emmons Reaction

Abstract

The highly stereoselective synthesis of (E)-α,β-unsaturated amides bearing (S)-α-methylbenzylamine was achieved from 2-phosphonamides via Horner-Wadsworth-Emmons reaction. The starting phosphonamides are easily prepared in two steps with ­excellent yields via the standard Arbuzov reaction of trimethyl­phosphite and α-bromoamides.

α,β-unsaturated amides - chiral phosphonamides - ­Horner-Wadsworth-Emmons reaction - (S)-α-methylbenzylamine

References

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6 Gotor V. Menéndez E. Mouloungui Z. Gaset A. J. Chem. Soc., Perkin Trans. 1  1993,  2453 

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8b Rein T. Reiser O. Acta Chem. Scand.  1996,  50:  369 

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12 The non-chiral diethoxyphosphoryl-N-(1-methyl-benzyl)acetamide has been obtained from diethoxyphos-phorylacetyl chloride and 1-methylbenzylamine and used in the preparation of (E)-N-(1-methylbenzyl)-4-phenyl-2-butenamide via the HWE reaction: Janecki T. Bodalski R. Wieczorek M. Bujacz G. Tetrahedron  1995,  51:  1721 

13 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183 

14 Similar HWE reactions using NaI, NaBr, and KI in the presence of DBU have been reported: Ando K. J. Org. Chem.  2000,  65:  4745 

15

HWE Reaction Using DBU/LiCl in Anhydrous THF; General Procedure A solution of phosphonamides 2 or 3 (1 equiv) in anhyd THF (30 mL) was treated under nitrogen with DBU (3 equiv) and LiCl (3 equiv) at r.t. After stirring for 5 min, the aldehyde (1 equiv) was added and the reaction mixture was stirred for 4 h at r.t. The reaction was quenched by the addition of a sat. soln of NH₄Cl and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with H₂O (30 mL) followed by brine (30 mL), dried over Na₂SO₄, and concentrated. The E/Z ratio was determined by ¹H NMR spectroscopy of the crude product, and then the (E)-α,β-unsaturated amides 5a-f and 6a-f were purified by flash chromatography.
( E )-( S )- N -(1-Methylbenzyl)-3-phenylpropenamide 5a Yield: 96%; white solid; mp 146 °C; [α]_D -21.7 (c 2.2, CHCl₃). [22]
( E )-( S )- N -(1-Methylbenzyl)-3-( p -chlorophenyl)propen-amide ( 5b) Yield: 94%; white solid; mp 164-165 °C; [α]_D +2.1 (c 2.60, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.53 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 5.24 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 6.38 (d, J = 6.8 Hz, 1 H, NH), 6.42 (d, J _trans = 15.6 Hz, 1 H, =CHCO), 7.24-7.36 (m, 9 H, H_arom) 7.55 [d, J _trans = 15.6 Hz, 1 H, =CH(p-ClC₆H₄]. ¹³C NMR (100 MHz, CDCl₃): δ = 21.9 [CH₃(CH)Ph], 49.2 [CH(CH₃)Ph], 121.5, 126.4, 127.6, 128.9, 129.1, 129.2, 133.5, 135.6, 139.9, 143.2, 164.9 (C=O). HRMS (CI⁺): m/z calcd for C₁₇H₁₇ClNO (MH⁺): 286.0999; found: 286.0989. Anal. Calcd for C₁₇H₁₆ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C, 71.09; H, 5.60; N, 9.94.
( E )-( S )- N -(1-Methylbenzyl)-3-( p -methoxyphenyl)prop-enamide ( 5c) Yield: 90%; white solid; mp 149 °C; [α]_D +13.2 (c 2.43, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.52 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 3.79 (s, 3 H, CH₃O), 5.25 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 6.31 (d, J = 6.8 Hz, 1 H, NH), 6.33 (d, J _trans = 15.6 Hz, 1 H, =CHCO), 6.83 (AA′BB′ system, J = 8.8 Hz, 2 H, H_arom), 6.23-6.38 (m, 5 H, H_arom), 7.39 (AA′BB′ system, J = 8.8 Hz, 2 H, H_arom), 7.58 [d, J _trans = 15.6 Hz, 1 H, =CH(p-MeOC₆H₄]. ¹³C NMR (100 MHz, CDCl₃): δ = 21.9 [CH₃(CH)Ph], 49.0 [CH(CH₃)Ph], 55.5 (CH₃O), 114.3, 118.6, 126.4, 127.4, 127.7, 128.8, 129.5, 140.9, 143.4, 160.9, 165.6 (C=O). HRMS (EI): m/z calcd for C₁₈H₁₉NO₂ (M⁺): 281.1416; found: 281.1408. Anal. Calcd for C₁₈H₁₉NO₂: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.88; H, 6.80; N, 5.06.
( Z )-( S )- N -(1-Methylbenzyl)-4-methyl-2-pentenamide ( 5d) Yield: 42%; white solid; mp 80-81 °C, [α]_D -167 (c 3.13, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.94 [d, J = 6.4 Hz, 3 H, (CH₃)₂CH], 1.00 [d, J = 6.4 Hz, 3 H, (CH₃)₂CH], 1.50 [d, J = 6.4 Hz, 3 H, CH₃(CH)Ph], 3.61-3.70 [m, 1 H, (CH(CH₃)₂], 5.15 [quint, J = 6.4 Hz, 1 H, CH(CH₃)Ph], 5.55 (dd, J _cis = 11.6 Hz, J _1,4 = 0.8 Hz, 1 H, =CHCO), 5.78 [dd, J _cis = 11.6 Hz, J _1,3 = 10.0 Hz, 1 H, =CHCH(CH₃)₂], 5.80 (br, 1 H, NH), 7.22-7.36 (m, 5 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 22.0 [CH₃(CH)Ph], 22.8 [2 C, (CH₃)₂CH], 27.5 [CH(CH₃)₂], 48.7 [CH(CH₃)Ph], 120.0, 126.4, 127.5, 128.8, 143.5, 153.0, 165.7 (C=O). HRMS (EI): m/z calcd for C₁₄H₁₉NO (M⁺): 217.1467; found 217.1467. Anal. Calcd for C₁₄H₁₉NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 76.88; H, 8.84; N, 6.39.
( E ) - ( S )- N -(1-Methylbenzyl)-4-methyl-2-pentenamide ( 5d) Yield: 50%; white solid; mp 94-95 °C, [α]_D -123 (c 3.30, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 1.00 [d, J = 7.0 Hz, 3 H, (CH₃)₂CH], 1.01 [d, J = 7.0 Hz, 3 H, (CH₃)₂CH], 1.45 [d, J = 7.0 Hz, 3 H, CH₃(CH)Ph], 2.33-2.42 [m, 1 H, (CH(CH₃)₂], 5.17 [quint, J = 7.0 Hz, 1 H, CH(CH₃)Ph], 5.80 (dd, J _trans = 15.6 Hz, J _1,4 = 1.2 Hz, 1 H, =CHCO), 6.62 (br, 1 H, NH), 6.79 [dd, J _trans = 15.6 Hz, J _1,3 = 6.8 Hz, 1H, =CHCH(CH₃)₂], 7.21-7.30 (m, 5 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 21.6 [2 C, (CH₃)₂CH], 21.9 [CH₃(CH)Ph], 30.9 [CH(CH₃)₂], 48.7 [CH(CH₃)Ph], 121.0, 126.2, 127.1, 128.5, 143.4, 150.9, 165.5 (C=O). HRMS (EI): m/z calcd for C₁₄H₁₉NO (M⁺): 217.1467; found: 217.1460. Anal. Calcd for C₁₄H₁₉NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.28; H, 8.79; N, 6.38.
( Z )-( S )- N -(1-Methylbenzyl)-5-methyl-2-hexenamide ( 5e) Yield: 25%; colorless oil; [α]_D -156.9 (c 3.06, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 0.91 [d, J = 6.8 Hz, 3 H, (CH₃)₂CH], 0.92 [(d, J = 6.8 Hz, 3 H, (CH₃)₂CH], 1.49 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 1.69 [m, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.54 [dddd, J _gem = 14.6, J _1,3 = 7.4 Hz, J _1,4 = 1.8 Hz, 2 H, CH₂CH(CH₃)₂], 5.15 (quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 5.72 (dt, J _cis = 11.6 Hz, J _1,4 = 1.8 Hz, 1 H, =CHCO), 5.92 (br, 1 H, NH), 5.99 (dt, J _cis = 11.6 Hz, J _1,3 = 7.4 Hz, 1 H, =CHCH₂ i-Pr), 7.26-7.36 (m, 5 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 22.0 [CH₃(CH)Ph], 22.5 [2 C, (CH₃)₂CH], 28.8 [CH₂CH(CH₃)₂], 37.6 [CH(CH₃)₂], 48.6 [CH(CH₃)Ph], 123.0, 126.4 (C _ortho ), 127.4 (C _para ), 128.8 (C _meta ), 143.5 (C _ipso ), 144.9, 165.9 (C = O). HRMS (EI): m/z calcd for C₁₅H₂₁NO (M⁺): 231.1623; found: 231.1625.
( E )-( S )- N -(1-Methylbenzyl)-5-methyl-2-hexenamide ( 5e) Yield: 67%; white solid; mp 95 °C; [α]_D -118.5 (c 2.23, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.89 [d, J = 6.8 Hz, 3 H, (CH₃)₂CH], 0.90 [d, J = 6.8 Hz, 3 H, (CH₃)₂CH], 1.51 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 1.73 [m, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.04 [td, J _1,3 = 7.4 Hz, J _1,4 = 1.4 Hz, 2 H, CH₂CH(CH₃)₂], 5.20 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 5.76 (dt, J _trans = 15.2 Hz, J _1,4 = 1.4 Hz, 1 H, CHC=O), 5.84 (d, J = 6.8 Hz, 1 H, NH), 6.83 [dt, J _trans = 15.6 Hz, J _1,3 = 7.4 Hz, 1 H, CHCH₂CH(CH₃)₂], 7.24-7.34 (m, 5 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 21.9 [CH₃(CH)Ph], 22.7 [2 C, (CH₃)₂CH], 28.1 [CH₂CH(CH₃)₂], 41.6 [CH(CH₃)₂], 48.9 [CH(CH₃)Ph], 124.6, 126.4, 127.4, 128.8, 143.3, 144.1, 165.1 (C=O). HRMS (EI): m/z calcd for C₁₅H₂₁NO (M⁺): 231.1623; found: 231.1627. Anal. Calcd for C₁₅H₂₁NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.91; H, 9.14; N, 6.15.
( E )-( S )- N -(1-Methylbenzyl)-4,4-dimethyl-2-pentenamide ( 5f) Yield: 93%; white solid; mp 94-95 °C; [α]_D -120 (c 2.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.05 [s, 9 H, (CH₃)₃C], 1.51 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 5.21 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 5.67 (d, J _trans = 15.6 Hz, 1 H, =CHCO), 5.92 [d, J = 6.8 Hz, 1 H, NH], 6.85 [d, J _trans = 15.6 Hz, 1 H, =CHC(CH₃)₃], 7.25-7.34 (m, 5 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 21.9 [CH₃(CH)Ph], 29.1 [(CH₃)₃C], 33.7 [C(CH₃)₃], 48.9 [CH(CH₃)Ph], 119.0, 126.5, 127.6, 128.9, 143.5, 155.1, 165.7 (C=O). HRMS (EI): m/z calcd for C₁₅H₂₁NO (M⁺): 231.1623; found: 231.1635. Anal. Calcd for C₁₅H₂₁NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.76; H, 9.08; N, 6.12.
(E )-( S )- N -(1-Methylbenzyl)-2-methyl-3-phenyl-propenamide ( 6a) Yield: 90%; white solid; mp 113-114 °C; [α]_D -4.0 (c 1.94, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.57 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 2.08 (d, J = 1.6 Hz, 3 H, CH₃C=CH), 5.25 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 6.21 (d, J = 6.8 Hz, 1 H, NH), 7.25-7.39 (m, 11 H, 10 × H_arom, H_vinyl). ¹³C NMR (100 MHz, CDCl₃): δ = 14.6 (CH₃C=CH), 21.9 [CH₃(CH)Ph], 49.3 [CH(CH₃)Ph], 126.4, 127.5, 127.9, 128.4, 128.8, 129.4, 132.1, 134.0, 136.2, 143.3, 168.7 (C=O). HRMS (CI⁺, CH₄): m/z calcd for C₁₈H₁₉NO (M⁺): 265.1466; found: 265.1479. Anal. Calcd for C₁₈H₁₉NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.56; H, 7.22; N, 5.38.
( E )-( S )- N -(1-Methylbenzyl)-2-methyl-3-( p -chloro-phenyl)propenamide ( 6b) Yield: 96%; white solid; mp 118-119 °C; [α]_D +5.9 (c 2.34, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.57 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 2.06 (d, J = 1.2 Hz, 3 H, CH₃C=CH), 5.24 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 6.18 (d, J = 6.8 Hz, 1 H, NH), 7.23 (AA′BB′ system, J = 8.4 Hz, 2 H, H_arom), 7.26-7.37 (m, 8 H, 7 × H_arom, H_vinyl). ¹³C NMR (100 MHz, CDCl₃): δ = 14.6 (CH₃C=CH), 21.9 [CH₃(CH)Ph], 49.4 [CH(CH₃)Ph], 126.3, 127.5, 128.7, 128.8, 130.7, 132.7, 132.8, 133.7, 134.6, 143.2, 168.4 (C=O). HRMS (CI⁺, CH₄): m/z calcd for C₁₈H₁₉ClNO (MH⁺): 300.1155; found: 300.1146. Anal. Calcd for C₁₈H₁₈ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C, 71.89; H, 6.07; N, 4.83.
( E )-( S )- N -(1-Methylbenzyl)-2-methyl-3-( p -methoxy-phenyl)propenamide ( 6c) Yield: 86%; white solid; mp 117-118 °C; [α]_D +14.8 (c 2.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.56 [d, J = 6.8 Hz, 3 H, CH₃(CH)Ph], 2.09 (d, J = 1.2 Hz, 3 H, CH₃C=CH), 3.81 (s, 3 H, CH₃O), 5.24 [quint, J = 6.8 Hz, 1 H, CH(CH₃)Ph], 6.16 (d, J = 6.8 Hz, 1 H, NH), 6.89 (AA′BB′ system, J = 8.4 Hz, 2 H, H_arom), 7.28 (AA′BB′ system, J = 8.4 Hz, 2 H, H_arom), 7.29-7.39 (m, 6 H, 5 × H_arom, H_vinyl). ¹³C NMR (100 MHz, CDCl₃): δ = 14.5 (CH₃C=CH), 21.9 [CH₃(CH)Ph], 49.3 [CH(CH₃)Ph], 55.5 (CH₃O), 114.0, 126.5, 127.5, 128.9, 129.0, 130.5, 131.1, 133.7, 143.6, 159.5, 169.1 (C=O). HRMS (CI⁺, CH₄): m/z calcd for C₁₉H₂₂NO₂ (MH⁺): 296.1651; found: 296.1653. Anal. Calcd for C₁₉H₂₁NO₂: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.40; H, 7.23; N, 4.91.

16

The E and Z isomers for 5d and 5e were easily separable by flash chromatography.

17

When the minor diastereomer was not detected, an E/Z ratio 98:02 is shown in Tables [1] and [3] .

18

The coupling constant between the olefinic protons of compound 5a-f was J = 15 Hz for E and J = 11 Hz for Z; this is in agreement with the average literature values.

19 Sano S. Takemoto Y. Nagao Y. Arkivoc  2003,  (viii):  93 

20 Thompson SK. Heathcock CH. J. Org. Chem.  1990,  55:  3386 

Phosphonamides bearing amino acids have been used in the HWE reaction:

21a

Ordóñez, M.; Bustos-Salgado, P.; Bautista-de la Cruz, R.; Hernández-Fernández, E.; Rojas-Cabrera, H. manuscript in preparation

21b Coutrot Ph. Grison C. Gérardin-Charbonnier C. Lecouvey M. Tetrahedron Lett.  1993,  34:  2767 

22 For the R enantiomer: mp 144-146 °C, [α]_D +20.2 (c 1.0, CHCl₃), see: Gotor V. Menéndez E. Mouloungui Z. Gaset A. J. Chem. Soc., Perkin Trans. 1  1993,  2453