Synthesis of Functionalized Enamines: A Facile and Efficient Protocol toward N-Protected α,β-Dehydroamino Acid Derivatives

Yun Sun; Xiaozhao Wang; Xiufang Zheng; Kang Zhao

doi:10.1055/s-2008-1042901

LETTER

Synthesis of Functionalized Enamines: A Facile and Efficient Protocol toward N-Protected α,β-Dehydroamino Acid Derivatives

Yun Sun^a, Xiaozhao Wang^a,b, Xiufang Zheng^a, Kang Zhao*^a
^a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27890968; e-Mail: kangzhao@tju.edu.cn;
^b Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA

Abstract

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Abstract

α,β-Dehydroamino acid derivatives were synthesized in good yields from α-bromoketones or α-bromoesters and hydroxamates via a sequential procedure involving displacement of bromide by hydroxamate anion, followed by a base-induced elimination-isomerization reaction.

Key words

α,β-dehydroamino acid derivatives - functionalized enamines - substitution - elimination - electron-withdrawing group

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References

References and Notes

1a Meyers AI. Beverung WN. J. Chem. Soc., Chem. Commun. 1968, 877

1b Nakatsuka S. Tanino H. Kishi Y. J. Am. Chem. Soc. 1975, 97: 5008

1c Nicolaou KC. Zak M. Rahimipour S. Estrada AA. Lee SH. O’Brate A. Giannakakou P. Ghadiri MR. J. Am. Chem. Soc. 2005, 127: 15042

1d Armstrong RW. Moran EJ. J. Am. Chem. Soc. 1992, 114: 371

2 Chen DJ. Guo L. Liu JY. Kirtane S. Cannon JF. Li GG. Org. Lett. 2005, 7: 921

3a Harburn JJ. Lofius GC. Marples BA. Tetrahedron 1998, 54: 11907

3b Chang LC. Bhat KPL. Pisha E. Kennelly EJ. Fong HHS. Pezzuto JM. Kinghorn AD. J. Nat. Prod. 1998, 61: 1257

3c Kohno J. Nishio M. Kawano K. Nakanishi N. Suzuki SI. Uchida T. Komatsubara S. J. Antibiot. 1996, 49: 1212

4 Eervinka O. In The Chemistry of Enamines Part 1, Vol. 1: Rappoport Z. Wiley; New York: 1994.

5a Srinivasan M. Perumal S. Selvaraj S. ARKIVOC 2006, (x): 21

5b Liu JB. Li LC. Dai H. Liu Z. Fang JX. J. Organomet. Chem. 2006, 691: 2686

6 Weigel W. Henning H.-G. Chem. Commun. 1997, 19: 1893

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9b Pégurier C. Morellato L. Chahed E. Andrieux J. Nicolas J.-P. Boutin JA. Bennejean C. Delagrange P. Langlois M. Mathé-Allainmat M. Bioorg. Med. Chem. 2003, 11: 789

9c Romine JL. Martin SW. Meanwell NA. Epperson JR. Synthesis 1994, 846

10a Sivakumar PM. Seenivasan SP. Kumar V. Doble M. Bioorg. Med. Chem. Lett. 2007, 17: 1695

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11b Sai H. Ogiku T. Ohmizu H. Synthesis 2003, 201

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12b Trost BM. Dake GR. J. Am. Chem. Soc. 1997, 119: 7595

13

General Procedure for the Synthesis of α,β-Dehydroamino Acid Derivatives 4a-u
To a mixture of hydroxamate 2 (2.0 mmol) and Cs₂CO₃ (2.2 mmol) in anhyd MeCN (20 mL) was added α-bromoketone or α-bromoester 1 (2.2 mmol) in one portion under stirring at 40 °C. When the starting material 2 was totally consumed, the resulting mixture was cooled to r.t. and DBU (2.0 mmol) was added dropwise. When the intermediate 3 was not detected via TLC analysis any more, the solvent was evaporated under reduced pressure and the residue was purified by neutral Al₂O₃ chromatography or silica gel chromatography to afford the desired products 4a-u.

14

General Procedure for the Synthesis of α,β-Dehydroamino Acid Derivative 4v To a mixture of hydroxamate 2a (2.0 mmol) and Cs₂CO₃ (2.2 mmol) in anhyd MeCN (20 mL) was added α-bromoketone 1h (2.4 mmol) in one portion under stirring at 40 °C. When the starting material 2a had disappeared, DBU (2.0 mmol) was added dropwise and the temperature was raised to reflux. When the intermediate 3v was not detected via TLC analysis any more, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to afford the desired products 4v.

15

All melting points were determined on a Kofler hot-plate microscope apparatus and were uncorrected. ¹H NMR, ¹³C NMR, and NOE spectra were recorded on a Varian Inova 500 MHz instrument. High-resolution electrospray ionization mass spectra (HR-ESI-MS) were obtained using an IonSpec Ultima 7.0T FTICR ESI mass spectrometer.

16

Compound 4v: crystallized in triclinic, space group P1 with cell parameters: a = 0.951 (3) nm, b = 0.104 (3) nm, c = 0.109 (3) nm, α = 110.184 (4)°, β = 93.423 (5)°, γ = 98.428 (4)°, V = 0.999 (5) nm³, D _c = 1.287 g/cm³, Z = 2; CCDC 672176.

17

Compound 4a: yellow solid, mp 167-168 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.29 (s, 3 H), 2.41 (s, 3 H), 3.84 (s, 3 H), 6.89 (d, J = 9.0 Hz, 2 H), 6.94 (br s, 1 H), 7.08 (s, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.90 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.50, 21.58, 55.36, 113.99, 125.44, 127.62, 128.95, 129.09, 129.12, 129.46, 133.43, 133.80, 136.15, 140.95, 142.72, 143.97, 161.71, 193.47. HRMS: m/z calcd for C₂₄H₂₃NNaO₄S⁺ [M + Na]⁺: 444.1240; found: 444.1235.
Compound 4b: yellow solid, mp 142-144 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.41 (s, 3 H), 3.84 (s, 3 H), 6.89 (d, J = 8.5 Hz, 2 H), 6.97 (br s, 1 H), 7.13 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.86, 55.64, 114.32, 125.45, 128.88, 129.31, 129.33, 129.35, 129.36, 133.64, 133.95, 137.93, 139.86, 141.62, 143.25, 162.06, 193.58. HRMS: m/z calcd for C₂₃H₂₀ClNNaO₄S⁺ [M + Na]⁺: 464.0694; found: 464.0691.
Compound 4c: yellow solid, mp 197-198 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.42 (s, 3 H), 3.85 (s, 3 H), 6.91 (d, J = 9.0 Hz, 2 H), 7.01 (br s, 1 H), 7.20 (s, 1 H), 7.23 (d, J = 7.5 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 8.01 (d, J = 8.5 Hz, 2 H), 8.19 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.86, 29.93, 55.66, 114.46, 124.21, 125.19, 128.30, 129.10, 129.39, 129.47, 133.83, 142.37, 143.61, 145.24, 150.33, 162.24, 193.37. HRMS: m/z calcd for C₂₃H₂₀N₂NaO₆S⁺ [M + Na]⁺: 475.0934; found: 475.0930.
Compound 4d: white solid, mp 103-104 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.44 (s, 3 H), 3.10 (s, 3 H), 3.83 (s, 3 H), 6.45 (br s, 1 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.05 (s, 1 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.66, 42.00, 55.39, 114.36, 125.17, 129.20, 129.65, 130.01, 132.63, 134.48, 138.89, 143.35, 161.42, 194.19. HRMS: m/z calcd for C₁₈H₁₈NO₄S^- [M - H]^-: 344.0962; found: 344.0970.
Compound 4e: yellow solid, mp 112-114 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (br, 3 H), 2.42 (s, 3 H), 3.83 (s, 3 H), 4.11 (br, 2 H), 6.71 (br s, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 7.5 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.64, 21.89, 55.57, 62.10, 114.46, 126.61, 129.21, 129.90, 130.65, 131.15, 131.54, 134.76, 143.18, 154.35, 160.58, 193.63. HRMS: m/z calcd for C₂₀H₂₁NNaO₄ ⁺ [M + Na]⁺: 362.1363; found: 362.1361.
Compound 4f: yellow solid, mp 130-132 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.39-1.46 (br, 9 H), 2.42 (s, 3 H), 3.83 (s, 3 H), 6.58-6.67 (br, 2 H), 6.91 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.88, 28.30, 55.57, 81.19, 114.40, 126.82, 129.16, 129.28, 129.88, 130.08, 131.53, 134.83, 143.08, 153.24, 160.44, 193.72. HRMS: m/z calcd for C₂₂H₂₅NNaO₄ ⁺ [M + Na]⁺: 390.1676; found: 390.1680.
Compound 4g: yellow solid, mp 179-181 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.21 (t, J = 7.0 Hz, 3 H), 2.39-2.42 (m, 5 H), 3.83 (s, 3 H), 6.75 (s, 1 H), 6.90 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.45 (br s, 1 H), 7.75 (d, J = 8.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 9.62, 21.88, 29.81, 55.56, 114.39, 126.67, 129.13, 130.05, 131.44, 131.50, 131.85, 134.67, 143.19, 160.55, 172.54, 193.96. HRMS: m/z calcd for C₂₀H₂₁NNaO₃ ⁺ [M + Na]⁺: 346.1414; found: 346.1410.
Compound 4h: yellow solid, mp 156-158 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.61-1.66 (m, 6 H), 2.42 (s, 3 H), 3.46 (t, J = 5.0 Hz, 3 H), 3.83 (s, 3 H), 6.64 (s, 1 H), 6.68 (br s, 1 H), 6.89 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 7.5 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.85, 24.71, 26.13, 45.68, 55.53, 114.35, 127.32, 128.98, 129.42, 130.20, 131.19, 133.47, 134.87, 142.88, 154.99, 160.16, 194.81. HRMS: m/z calcd for C₂₃H₂₆N₂NaO₃ ⁺ [M + Na]⁺: 401.1836; found: 401.1836.
Compound 4i: white solid, mp 131-133 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.14 (d, J = 7.0 Hz, 2 H), 2.28 (s, 3 H), 3.85 (s, 3 H), 6.54 (q, J = 7.5 Hz, 1 H), 6.84-6.86 (m, 3 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 9.0 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.61, 21.70, 55.71, 113.71, 127.63, 128.58, 129.74, 131.61, 134.05, 136.38, 142.24, 144.14, 163.25, 191.73. HRMS:
m/z calcd for C₁₈H₁₉NNaO₄S⁺ [M + Na]⁺: 368.0927; found: 368.0926.
Compound 4j: white solid, mp 125-126 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.15 (d, J = 7.0 Hz, 2 H), 3.86 (s, 3 H), 6.61 (q, J = 7.0 Hz, 1 H), 6.86-6.89 (m, 3 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.43 (d, J = 9.0 Hz, 2 H), 7.76 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.62, 55.73, 113.88, 128.45, 129.07, 129.40, 131.62, 133.66, 137.95, 139.79, 142.77, 163.44, 191.51. HRMS: m/z calcd for C₁₇H₁₆ClNNaO₄S⁺ [M + Na]⁺: 388.0381; found: 388.0382.
Compound 4k: white solid, mp 170-171 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.18 (d, J = 7.0 Hz, 2 H), 3.85 (s, 3 H), 6.70 (q, J = 7.0 Hz, 1 H), 6.86-6.89 (m, 3 H), 7.43-7.46 (m, 2 H), 8.00-8.04 (m, 2 H), 8.21-8.23 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.77, 55.76, 114.02, 124.31, 128.21, 128.92, 131.60, 133.13, 143.92, 145.22, 150.36, 163.65, 191.11. HRMS: m/z calcd for C₁₇H₁₅N₂O₆S^- [M - H]^-: 375.0656; found: 375.0650.
Compound 4l: white solid, mp 101-102 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.11 (d, J = 7.0 Hz, 2 H), 3.00 (s, 3 H), 3.89 (s, 3 H), 6.35 (br s, 1 H), 6.63 (q, J = 7.0 Hz, 1 H), 6.95-6.98 (m, 2 H), 7.72-7.75 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.32, 41.32, 55.77, 114.06, 129.26, 131.99, 134.29, 141.63, 163.62, 192.41. HRMS: m/z calcd for C₁₂H₁₅NNaO₄S⁺ [M + Na]⁺: 292.0614; found: 292.0612.
Compound 4m: white solid, mp 98-99 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.25 (t, J = 7.0 Hz, 3 H), 1.88 (d, J = 7.0 Hz, 3 H), 3.87 (s, 3 H), 4.15 (q, J = 7.0 Hz, 2 H), 6.14 (q, J = 6.5 Hz, 1 H), 6.63 (br s, 1 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.78 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.33, 14.65, 55.66, 61.77, 113.71, 129.63, 131.86, 132.01, 134.98, 154.24, 163.24, 192.17. HRMS: m/z calcd for C₁₄H₁₇NNaO₄ ⁺ [M + Na]⁺: 286.1050; found: 286.1056.
Compound 4n: white solid, mp 158-160 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.42 (s, 9 H), 1.86 (d, J = 7.5 Hz, 3 H), 3.86 (s, 3 H), 6.05 (br s, 1 H), 6.46 (br s, 1 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.11, 28.34, 55.66, 80.87, 113.67, 114.02, 129.79, 131.84, 132.02, 135.44, 153.26, 163.21, 192.19. HRMS: m/z calcd for C₁₆H₂₁NNaO₄ ⁺ [M + Na]⁺: 314.1363; found: 314.1357.
Compound 4o: white solid, mp 83-85 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.22 (t, J = 2.5 Hz, 3 H), 1.85 (d, J = 7.0 Hz, 3 H), 2.40 (q, J = 7.5 Hz, 2 H), 3.86 (s, 3 H), 6.24 (q, J = 7.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.48 (br s, 1 H), 7.78 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 9.68, 14.85, 29.76, 55.47, 113.53, 129.30, 131.94, 133.39, 134.40, 163.11, 171.93, 192.35. HRMS: m/z calcd for C₁₄H₁₇NNaO₃ ⁺ [M + Na]⁺: 270.1101; found: 270.1107.
Compound 4p: white solid, mp 128-130 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.60-1.62 (m, 6 H), 1.85 (d, J = 8.5 Hz, 3 H), 3.45-3.47 (m, 4 H), 3.86 (s, 3 H), 6.11 (q, J = 7.0 Hz, 1 H), 6.59 (br s, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.79 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.57, 24.66, 25.91, 45.54, 55.65, 113.60, 129.81, 130.60, 132.24, 136.33, 155.09, 163.12, 193.32. HRMS: m/z calcd for C₁₇H₂₂N₂NaO₃ ⁺ [M + Na]⁺: 325.1523; found: 325.1516.
Compound 4q: white solid, mp 67-69 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.90 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.5 Hz, 3 H), 1.45-1.31 (m, 4 H), 2.29 (q, J = 7.5 Hz, 2 H), 3.87 (s, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 5.98 (t, J = 7.0 Hz, 1 H), 6.55 (br s, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 7.79 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.07, 14.63, 22.73, 28.19, 30.86, 55.65, 61.77, 113.71, 129.72, 132.08, 133.74, 136.59, 154.42, 163.27, 192.26. HRMS: m/z calcd for C₁₇H₂₃NNaO₄ ⁺ [M + Na]⁺: 328.1519; found: 328.1522.
Compound 4r: white solid, mp 160-162 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.19 (br, 3 H), 4.10-4.12 (m, 2 H), 6.71 (s, 2 H), 7.35-7.43 (m, 3 H), 7. 52-7.62 (m, 4 H), 7.89-7.98 (m, 4 H), 8.42 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.61, 62.28, 125.68, 127.04, 128.07, 128.57, 128.60, 129.14, 129.29, 129.47, 129.68, 129.70, 131.37, 132.54, 133.57, 134.03, 134.44, 135.57, 154.32, 193.59. HRMS:
m/z calcd for C₂₂H₁₉NNaO₃ ⁺ [M + Na]⁺: 368.1257; found: 368.1252.
Compound 4s: white solid, mp 115-117 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.18 (br, 3 H), 4.11 (br, 2 H), 6.81 (br s, 1 H), 6.86 (s, 1 H), 7.47-7.53 (m, 4 H), 7.57-7.60 (m, 1 H), 7.66-7.68 (m, 1 H), 7.81-7.85 (m, 3 H), 7.90-7.92 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.64, 62.27, 126.25, 126.90, 127.38, 127.98, 128.40, 128.66, 129.50, 129.81, 130.12, 130.20, 131.63, 132.73, 133.37, 133.44, 133.63, 137.25, 154.11, 193.76. HRMS: m/z calcd for C₂₂H₁₉NNaO₃ ⁺ [M + Na]⁺: 368.1257; found: 368.1260.
Compound 4t: white solid, mp 84-86 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (br, 3 H), 3.86 (s, 3 H), 4.13 (q, J = 7.0 Hz, 2 H), 6.26 (br s, 1 H), 7.31-7.39 (m, 4 H), 7.53 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.63, 52.89, 62.04, 124.68, 128.82, 129.61, 129.92, 131.56, 134.00, 154.33, 166.11. HRMS: m/z calcd for C₁₃H₁₅NNaO₄ ⁺ [M + Na]⁺: 272.0893; found: 272.0899.
Compound 4u: oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.06 (d, J = 6.5 Hz, 6 H), 1.27 (t, J = 7.0 Hz, 3 H), 2.68-2.76 (m, 1 H), 3.78 (s, 3 H), 4.18 (q, J = 7.0 Hz, 2 H), 5.94 (br s, 1 H), 6.46 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.66, 21.83, 27.80, 52.51, 61.75, 123.73, 145.09, 155.01, 165.72. HRMS: m/z calcd for C₁₀H₁₇NNaO₄ ⁺ [M + Na]⁺: 238.1050; found: 238.1046.
Compound 4v: white solid, mp 152-154 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.14 (s, 9 H), 2.39 (s, 3 H), 3.85 (s, 3 H), 6.87 (br s, 1 H), 6.90 (d, J = 9.0 Hz, 2 H), 7.20 (s, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.72, 29.08, 43.08, 55.58, 114.21, 125.66, 127.62, 128.13, 129.50, 133.28, 136.11, 136.13, 144.07, 161.50, 203.59. HRMS: m/z calcd for C₂₁H₂₅NNaO₄S⁺ [M + Na]⁺: 410.1397; found: 410.1398.