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Synlett 2006(10): 1507-1510  
DOI: 10.1055/s-2006-944184
LETTER
© Georg Thieme Verlag Stuttgart · New York

New, Simple and Versatile Synthesis of Protected α-Alkylidene-β-amino Acids from Activated Vinylphosphonates

Tomasz Wąseka, Jacek Olczakb, Tomasz Janecki*a
a Institute of Organic Chemistry, Technical University of Łódź, Żeromskiego 116, 90-924 Łódź, Poland
Fax: +48(42)6365530; e-Mail: tjanecki@p.lodz.pl;
b TriMen Chemicals Sp. z o.o., Al. Pisudskiego 141, 92-318 Łódź, Poland
e-Mail: olczak@trimen.pl;
Further Information

Publication History

Received 16 March 2006
Publication Date:
12 June 2006 (online)

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Abstract

A two-step route to Boc-protected α-alkylidene-β-amino esters was developed by addition of sodium tert-butylcarbamate to ethyl 2-diethoxyphosphoryl-2-alkenoates followed by the Horner-Wadsworth-Emmons olefination of aldehydes using intermediate 2-diethoxyphosphoryl-3-tert-butoxycarbonylaminoalkanoates.

Key words

α-Alkylidene-β-amino acids - Michael addition - vinyl­phosphonates - Wittig-type reaction - tert-butylcarbamate

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Typical Experimental Procedure for Ethyl 3- tert -Butoxycarbonylamino-2-diethoxyphosphoryl-3-phenylpropionate ( 4d).
A solution of BocNH2 (0.225 g, 1.92 mmol) in THF (3 mL) was added dropwise to a stirred suspension of NaH (84.5 mg, 3.52 mmol) in THF (6 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and a solution of ethyl 2-(diethoxyphosphoryl)-3-phenylacrylate (2d, 0.50 g, 1.6 mmol) in THF (5 mL) was added. The mixture was then warmed to r.t. and stirred for 24 h. After this time the reaction mixture was quenched with H2O (5 mL), acidified to pH ca. 4.5 with 3 M HCl and extracted with CHCl3 (3 × 15 mL). The organic extracts were dried (MgSO4) and evaporated to give crude 4d, which was purified by column chromatography (EtOAc-hexane, 7:3). A 55:45 mixture of diastereoisomers was obtained. IR (film): 3344, 1736, 1708, 1240, 1056 cm-1. 1H NMR (250 MHz, CDCl3): d (major isomer) = 1.10 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2OC), 1.18-1.37 [m, 6 H, (CH 3 CH2O)2], 1.38 [s, 9 H, (CH 3 )3C], 3.37-3.50 (m, 1 H, PCHCH), 3.98-4.30 [m, 6 H, (CH3CH 2 O)2, CHCH 2 OC], 5.19-5.46 (m, 1 H, PCHCH), 6.04 (br s, 1 H, NHCO), 7.20-7.56 (m, 5 H, C6 H 5 ); d (minor isomer) = 1.08 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2O), 1.18-1.37 [m, 6 H, (CH 3 CH2O)2], 1.42 [s, 9 H, (CH 3 )3C], 3.37-3.50 (m, 1 H, PCHCH), 3.98-4.30 [m, 6 H, (CH3CH 2 O)2, CH3CH 2 O], 5.19-5.45 (m, 1 H, PCHCH), 6.43 (d, ³ J HH = 7.50 Hz, 1 H, NHCO), 7.20-7.56 (m, 5 H, C6 H 5 ). 13C NMR (62.9 MHz, CDCl3): δ = 13.60 (s), 13.67 (s), 15.95 (2d, ³ J CP = 6.2 Hz), 16.15 (2d, ³ J CP = 6.2 Hz), 28.11 (s), 28.16 (s), 50.90 (d, ¹ J CP = 130.25 Hz), 51.84 (d, ¹ J CP = 132.14 Hz), 51.93 (s), 53.50 (s), 61.35 (s), 61.50 (s), 62.63 (d, ² J CP = 6.64 Hz), 62.79 (d, ² J CP = 6.40 Hz), 62.99 (d, ² J CP = 6.70 Hz), 63.21 (d, ² J CP = 6.94 Hz), 79.26 (s), 79.48 (s), 125.92 (s), 126.68 (s), 127.30 (s), 127.49 (s), 128.20 (s), 128.30 (s), 140.18 (s)140.23 (s), 154.63 (s), 154.68 (s), 166.50 (d, ² J PC = 4.50 Hz), 167.86 (s). 31P NMR (101 MHz, CDCl3): δ = 18.97 (major), 20.09 (minor).

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General Experimental Procedure.
A mixture of alkanoate 4 (0.815 mmol), t-BuOK (0.10 g, 0.896 mmol) and paraformaldehyde (0.122 g, 4.07 mmol) in THF (10 mL) was refluxed for 2 h. After cooling to r.t. H2O (5 mL) was added. Then, THF was evaporated and the residue was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were dried (MgSO4) and the solvent was removed. The crude 5 were purified by column chromatography.
Analytical Data. Ethyl 2-(tert-Butoxycarbonylaminomethyl)acrylate (5a): oil (CHCl3-EtOAc = 95:5 as eluent). IR (film): 1716, 1684 cm-1. 1H NMR (250 MHz, CDCl3): δ = 1.31 (t, ³ J HH = 7.25 Hz, 3 H, CH 3 CH2O), 1.44 [s, 9 H, (CH 3 )3C], 3.95 (br d, ³ J HH = 6.25 Hz, 2 H, CH 2 NH), 4.23 (q, ³ J HH = 7.25 Hz, 2 H, CH3CH 2O), 4.95 (br s, 1 H, CHNH), 5.77 (s, 1 H, CHHCH2NH), 6.25 (s, 1 H, CHHCH2NH). 13C NMR (62.9 MHz, CDCl3): δ = 14.02 (s), 28.23 (s), 41.48 (s), 60.69 (s), 79.28 (s), 125.74 (s), 137.38 (s), 155.57 (s), 166.05 (s). Anal. Calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.78; H, 8.24; N, 6.03.
Ethyl 2-(tert-Butoxycarbonylamino-isopropyl-methyl)acrylate (5b): oil (CHCl3-hexane = 7:3 as eluent). IR (film): 3384, 1712, 1684, 1628 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.84 (d, ³ J HH = 7.00 Hz, 3 H, CH 3 CH), 0.93 (d, ³ J HH = 7.00 Hz, 3 H, CH 3 CH), 1.31 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2O), 1.43 [s, 9 H, (CH 3 )3C], 1.89-2.01 [m, 1 H, (CH3)2CH], 4.08 (t, ³ J HH = 9.00 Hz, ³ J HH = 9.00 Hz, 1 H, CHNH), 4.22 (q, ³ J HH = 7.00 Hz, 2 H, CH3CH 2O), 5.27 (br d, ³ J HH = 9.00 Hz, 1 H, CHNH), 5.67 (s, 1 H, CHHC), 6.21 (s, 1 H, CHHC). 13C NMR (62.9 MHz, CDCl3): δ = 13.95 (s), 18.62 (s), 20.00 (s), 28.21 (s), 31.01 (s), 59.63 (s), 60.49 (s), 78.88 (s), 126.47 (s), 139.65 (s), 155.31 (s), 165.98 (s). Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.16; H, 9.39; N, 5.19.
Ethyl 2-[tert-Butoxycarbonylamino(1′-methyl-butane)methyl]acrylate (5c): oil (CHCl3-hexane = 7:3 as eluent); a 60:40 mixture of diastereomers was obtained. IR (film): 3392, 1716, 1628 cm-1. 1H NMR (250 MHz, CDCl3): δ (major isomer) = 0.79-1.30 (m, 10 H, CH 3 CHCH 2CH 2CH 3), 1.31 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2O), 1.43 [s, 9 H, (CH 3 )3C], 1.70-1.92 (m, 1 H, CH3CHCH2CH2CH3), 4.22 (q, ³ J HH = 7.00 Hz, 2 H, CH3CH 2O), 4.44 (dd, ³ J HH = 9.50 Hz, ³ J HH = 9.50 Hz, 1 H, CHNH), 5.10 (br d, ³ J HH = 9.50 Hz, 1 H, CHNH), 5.64 (s, 1 H, CHHC), 6.22 (s, 1 H, CHHC); δ (minor isomer) = 0.79-1.30 (m, 10 H, CH 3 CHCH 2CH 2CH 3), 1.26 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2O), 1.43 [s, 9 H, (CH 3 )3C], 1.70-1.92 (m, 1 H, CH3CHCH2CH2CH3), 4.08-4.13 (m, 1 H, CHNH), 4.12 (q, ³ J HH = 7.00 Hz, 2 H, CH3CH 2O), 5.25 (br d, ³ J HH = 9.50 Hz, 1 H, CHNH), 5.66 (s, 1 H, CHHC), 6.20 (s, 1 H, CHHC). 13C NMR (62.9 MHz, CDCl3): δ = 13.99 (s), 14.14 (s), 14.80 (s), 16.86 (s), 19.74 (s), 19.93 (s), 28.25 (s), 34.57 (s), 35.00 (s), 35.55 (s), 36.09 (s), 57.20 (s), 58.79 (s), 60.52 (s), 79.00 (s), 125.85 (s), 126.54 (s), 139.60 (s), 140.09 (s), 155.32 (s), 166.04 (s). Anal. Calcd for C16H29NO4: C, 64.18; H, 9.76; N, 4.68. Found: C, 64.01; H, 9.80; N, 4.55.
Ethyl 2-(tert-Butoxycarbonylaminophenyl-methyl)acrylate (5d): white prisms (from Et2O), mp 81-83 °C (CHCl3 as eluent). IR (film): 3392, 1716, 1684, 1630 cm-1. 1H NMR (250 MHz, CDCl3): δ = 1.18 (t, ³ J HH = 7.25 Hz, 3 H, CH 3 CH2O), 1.45 [s, 9 H, (CH 3 )3C], 4.11 (q, ³ J HH = 7.25 Hz, 2 H, CH3CH 2O), 5.47 (d, ³ J HH = 8.00 Hz, 1 H, CHNH), 5.68 (d, ³ J HH = 8.00 Hz, 1 H, CHNH), 5.89 (s, 1 H, CHHC), 6.37 (s, 1 H, CHHC), 7.21-7.31 (m, 5 H, C6 H 5 ). 13C NMR (62.9 MHz, CDCl3): δ = 13.83 (s), 28.24 (s), 55.99 (s), 60.66 (s), 79.61 (s), 125.95 (s), 126.49 (s), 127.30 (s), 128.38 (s), 139.94 (s), 140.28 (s), 154.81 (s), 165.51 (s). Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.69; H, 7.52; N, 4.68.
Ethyl 2-(tert-Butoxycarbonylamino-1-naphthyl-methyl)acrylate (5e): oil (CHCl3 as eluent). IR (film): 3360, 1724, 1684, 1632 cm-1. 1H NMR (250 MHz, CDCl3): δ = 1.04 (t, ³ J HH = 7.00 Hz, 3 H, CH 3 CH2O), 1.45 [s, 9 H, (CH 3 )3C], 4.06 (q, ³ J HH = 7.00 Hz, 2 H, CH3CH 2O), 4.98 (d, ³ J HH = 8.00 Hz, 1 H, CHNH), 5.89 (s, 1 H, CHHC), 6.50 (s, 1 H, CHHC), 6.56 (br d, ³ J HH = 8.00 Hz, 1 H, CHNH), 7.31-8.20 (m, 7 H, C10 H 7). 13C NMR (62.9 MHz, CDCl3): δ = 13.76 (s), 28.22 (s), 51.14 (s), 60.64 (s), 79.75 (s), 123.41 (s), 123.96 (s), 124.99 (s), 125.24 (s), 125.79 (s), 126.49 (s), 128.56 (s), 131.00 (s), 133.93 (s), 135.86 (s), 141.11 (s), 154.59 (s), 165.73 (s). Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found: C, 70.76; H, 7.14; N, 3.84.

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Typical Experimental Procedure for Ethyl 2-( tert -Butoxycarbonylaminomethyl)-4-methyl-2-pentenoate ( 6a).
To a suspension of NaH (0.024 g, 1.0 2 mmol) in THF (5 mL) a solution of alkanoate 4a (0.300 g, 0.85 mmol) in THF (3 mL) at 0 °C was added and the reaction mixture was stirred under an argon atmosphere for 0.5 h. Next, a solution of isobutyric aldehyde (0.093 mL, 1.02 mmol) in THF (1 mL) was added. The mixture was warmed to r.t. and refluxed for 4.5 h. After cooling to r.t. the reaction mixture was quenched with H2O (5 mL) and THF was evaporated. Extraction with CH2Cl2 (3 × 15 mL), drying (MgSO4) and evaporation of the solvent yielded crude 6a, which was purified by column chromatography (eluent, CHCl3-hexane 6:4). A mixture of diastereomers (E:Z = 83:17) was obtained; oil; yield 0.095 g (41%). IR (film): 3384, 1720,1700, 1655 cm-1. 1H NMR (250 MHz, CDCl3): δ (E isomer) = 1.01 [d, ³ J HH = 6.64 Hz, 6 H, (CH 3 )CH], 1.31 (t, ³ J HH = 7.25 Hz, 3 H, CH 3 CH2O), 1.44 [s, 9 H, (CH 3 )3C], 3.21-3.35 [m, 1 H, (CH3)CH], 3.86 (d, ³ J HH = 6.00 Hz, 2 H, CH 2 NH), 4.21 (q, ³ J HH = 7.25 Hz, 2 H, CH3CH 2O), 4.89 (br s, 1 H, CHNH), 5.96 (d, ³ J HH = 10.25 Hz, 1 H, (CH3)CHCH); δ (Z isomer) = 1.04 [d, ³ J HH = 6.64 Hz, 6 H, (CH 3 )CH], 1.32 (t, ³ J HH = 7.25 Hz, 3 H, CH 3 CH2O), 1.43 [s, 9 H, (CH 3 )3C], 2.75-3.10 [m, 1 H, (CH3)CH], 3.97 (d, ³ J HH = 6.25 Hz, 2 H, CH 2 NH), 4.21 (q, ³ J HH = 7.25 Hz, 2 H, CH3CH 2O), 5.05 (br s, 1 H, CHNH), 6.66 [d, ³ J HH = 10.5 Hz, 1 H, (CH3)CHCH]. 13C NMR (62.9 MHz, CDCl3): δ = 14.13 (s), 22.25 (s), 22.37 (s), 28.14 (s), 28.30 (s), 36.46 (s), 44.19 (s), 60.28 (s), 60.61 (s), 79.16 (s), 126.36 (s), 127.03 (s), 152.02 (s), 152.32 (s), 155.52 (s), 166.86 (s). Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.05; H, 9.33; N, 5.29.