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Synlett 2005(5): 0757-0760  
DOI: 10.1055/s-2005-863722
LETTER
© Georg Thieme Verlag Stuttgart · New York

Ammonia in Ugi Reactions - Four-Component versus Six-Component Couplings

Rigobert Pick, Michael Bauer, Uli Kazmaier*, Christina Hebach
Institut für Organische Chemie, Universität des Saarlandes, Postfach 151150, 66041 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
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Publication History

Received 5 January 2005
Publication Date:
09 March 2005 (online)

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Abstract

If ammonia is used as amine component in Ugi reactions, the desired peptide sometimes is obtained only as the minor product or in traces. Side reactions such as six-component couplings are ­responsible for this observation. These side reactions can be suppressed or favoured depending on the reaction conditions used.

Key words

ammonia - peptide - Ugi reactions - six-component coupling

9

4-Component vs. 6-Component Coupling.
Isobutyraldehyde (0.80 mL, 8.8 mmol) was added to a solution of ammonium benzoate (280 mg, 2.0 mmol) in methanol (6 mL) at 0 °C. After stirring for 30 min, ethyl isocyanoacetate (225 mg, 2.0 mmol) was added via syringe over a period of 5 min. The mixture was allowed to warm to 15 °C overnight. After stirring at r.t. for further 24 h, the solution was diluted with CH2Cl2 (30 mL) and washed with 1 N KHSO4 and sat. NaHCO3 solution. The organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography giving rise to 1a and 3a.

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Spectroscopic data of 2: 1H NMR (300 MHz, CDCl3): δ = 0.72 (d, J = 6.7 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 2.08 (m, 1 H), 2.98 (m, 1 H), 3.31 (s, 3 H), 3.59 (d, J = 11.2 Hz, 1 H), 3.70 (s, 3 H), 3.94 (dd, J = 15.2, 2.5 Hz, 1 H), 4.01-4.16 (m, 2 H), 7.32-7.40 (m, 5 H), 8.95 (br s, 1 H). 13C NMR (300 MHz, CDCl3): δ = 18.2 (q), 18.6 (q), 19.2 (q), 19.8 (q), 27.2 (d), 32.1 (d), 40.6 (t), 51.8 (q), 57.5 (d), 67.4 (q), 97.4 (d), 126.4 (d), 128.4 (d), 129.3 (d), 136.5 (s), 169.9 (s), 172.6 (s), 173.3 (s). Selected signals of the minor diastereomer: 13C NMR (300 MHz, CDCl3): δ = 30.7 (d), 40.7 (t), 52.1 (q), 169.8 (s).

11

Analytical and spectroscopic data of new 6-fold coupling products 3.
Compound 3a: mp 128 °C. 1H NMR (400 MHz, CDCl3): δ = 0.74 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.45 (m, 1 H), 3.06 (m, 1 H), 3.81 (d, J = 11.0 Hz, 1 H), 4.01 (dd, J = 17.9, 5.1 Hz, 1 H), 4.14 (dd, J = 17.9, 6.4 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 6.15 (d, J = 10.6 Hz, 1 H), 7.42-7.45 (m, 7 H), 7.61 (t, J = 7.6 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 2 H), 9.04 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 173.9 (s), 172.4 (s), 169.5 (s), 164.1 (s), 135.4 (s), 133.7 (d), 130.4 (d), 129.9 (2 d), 129.1 (s), 128.7 (2 d), 128.4 (2 d), 127.3 (2 d), 88.8 (d), 69.5 (d), 61.2 (t), 41.2 (t), 32.0 (d), 27.1 (d), 20.02 (q), 20.01 (q), 18.23 (q), 18.15 (q), 14.2 (q). Anal. Calcd for C27H34N2O6 (482.58): C, 67.20; H, 7.10; N, 5.81. Found: C, 67.18; H, 7.31; N, 5.74. HRMS (CI): m/z calcd for C27H35N2O6 [M + H]: 483.2495; found: 483.2490.
Compound 3c: mp 176 °C. 1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J = 6.6 Hz, 3 H), 0.78 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.54 (m, 1 H), 3.07 (m, 1 H), 3.74 (d, J = 11.3 Hz, 1 H), 3.91 (dd, J = 17.9, 4.5 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.25 (dd, J = 17.9, 7.0 Hz, 1 H), 5.89 (d, J = 10.5 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 2 H), 8.23 (d, J = 8.8 Hz, 2 H), 8.33-8.35 (m, 4 H), 8.59 (dd, J = 7.0, 4.5 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 171.7 (s), 171.4 (s), 169.5 (s), 162.8 (s), 151.1 (s), 148.7 (s), 141.2 (s), 134.0 (s), 131.0 (2 d), 128.4 (2 d), 123.8 (2 d), 123.4 (2 d), 89.4 (d), 69.6 (d), 61.3 (t), 41.1 (t), 31.6 (d), 27.2 (d), 19.96 (q), 19.91 (q), 18.27 (q), 18.23 (q), 14.2 (q). Anal. Calcd for C27H32N4O10 (572.57): C, 56.64; H, 5.63; N, 9.79. Found: C, 56.41; H, 5.89; N, 9.65. HRMS (CI): m/z calcd for C27H31N4O10 [M - H]: 571.2040; found: 571.2086.
Compound 3d: mp 123 °C (decomp.). Mixture of rotamers: 1H NMR (400 MHz, CDCl3): δ = 0.805 (t, J = 7.4 Hz, 3 H), 0.811 (t, J = 7.3 Hz, 3 H), 1.21-1.33 (sh, 4 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.98 (m, 1 H), 2.06 (m, 1 H), 2.13 (m, 1 H), 2.25 (m, 1 H), 3.87 (dd, J = 18.2, 4.8 Hz, 1 H), 4.18 (dd, J = 18.2, 6.8 Hz, 1 H), 4.19 (m, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 6.13 (dd, J = 7.3, 6.2 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 2 H), 7.85 (br s, 1 H), 8.17 (d, J = 8.9 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H), 8.33 (d, J = 8.7 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 172.4 (s), 171.4 (s), 169.6 (s), 163.2 (s), 151.1 (s), 148.7 (s), 141.6 (s), 134.1 (s), 130.8 (2 d), 128.8 (2 d), 123.9 (2 d), 123.8 (2 d), 84.9 (d), 61.5 (d), 61.3 (t), 41.3 (t), 34.9 (t), 32.3 (t), 20.4 (t), 18.2 (t), 14.1 (q), 13.8 (q), 13.3 (q). Anal. Calcd for C27H32N4O10 (572.57): C, 56.64; H, 5.63; N, 9.79. Found: C, 56.64; H, 6.24; N, 9.63. HRMS (CI): m/z calcd for C27H32N4O10 [M]: 572.2118; found: 572.2120.
Compound 3e: mp 89-90 °C. 1H NMR (400 MHz, CDCl3): δ = 0.69 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 2.06 (s, 3 H), 2.31 (m, 1 H), 2.35 (s, 3 H), 2.93 (m, 1 H), 3.35 (d, J = 11.1 Hz, 1 H), 3.93 (d, J = 5.8 Hz, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.27 (d, J = 10.2 Hz, 1 H), 8.62 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 173.1 (d), 172.3 (d), 169.9 (d), 169.5 (d), 87.5 (d), 68.7 (d), 61.1 (t), 41.0 (t), 30.6 (d), 27.0 (d), 23.1 (q), 20.3 (q), 19.7 (q), 19.6 (q), 18.4 (q), 17.8 (q), 14.1 (q). Anal. Calcd for C17H30N2O6 (358.44): C, 56.97; H, 8.44; N, 7.82. Found: C, 56.85; H, 8.33; N, 7.85. HRMS (CI): m/z calcd for C17H31N2O6 [M + H]: 359.2182; found: 359.2183.

12

1H NMR spectra of Ugi products 1.
Compound 1a: (400 MHz, DMSO-d 6): δ = 0.94 (d, J = 7.1 Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H), 2.14 (m, 1 H), 3.79 (dd, J = 17.2, 5.8 Hz, 1 H), 3.90 (dd, J = 17.2, 6.2 Hz, 1 H), 4.07 (q, J = 7.1 Hz, 2 H), 4.34 (dd, J = 8.8, 7.1 Hz, 1 H), 7.46 (dd, J = 7.3, 7.0 Hz, 2 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.89 (d, J = 7.0 Hz, 2 H), 8.30 (d, J = 8.8 Hz, 1 H) 8.48 (dd, J = 6.2, 5.8 Hz, 1 H).
Compound 1b: (400 MHz, CDCl3): δ = 0.99 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 2.19 (m, 1 H), 3.81 (s, 3 H), 3.88 (dd, J = 18.2, 5.1 Hz, 1 H), 4.11 (dd, J = 18.2, 5.7 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 4.56 (dd, J = 8.5, 7.2 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.16 (dd, J = 5.7, 5.1 Hz), 7.76 (d, J = 8.8 Hz, 2 H).
Compound 1d: (400 MHz, CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.39 (m, 2 H), 1.71 (m, 1 H), 1.87 (m, 1 H), 3.97 (dd, J = 18.2, 5.2 Hz, 1 H), 4.06 (dd, J = 18.2, 5.6 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.73 (ddd, J = 7.6, 6.6, 6.6 Hz, 1 H), 7.02 (dd, J = 5.6, 5.2 Hz), 7.49 (d, J = 7.6 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H).
Compound 1f: (400 MHz, CDCl3): δ = 0.95 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 2.12 (m, 1 H), 3.95 (dd, J = 18.2, 4.9 Hz, 1 H), 4.12 (dd, J = 18.2, 5.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.39 (dd, J = 8.5, 7.3 Hz, 1 H), 6.77 (dd, J = 5.7, 4.9 Hz, 1 H), 7.46 (d, J = 8.5 Hz, 1 H).

13

Crystal data of 3a: C27H34N2O6, M r = 482.58, triclinic, space group P-1, a = 9.490 (2) Å, b = 15.015 (3) Å, c = 19.527 (4) Å, α = 83.69 (3)°, β = 78.94 (3)°, γ = 78.15 (3)°, V = 2665.4 (9) Å3, Z = 4, ρcalcd = 1.203 Mg/m3, F(000) = 1032, l = 0.71073 Å, T = 293 K, m(MoKa) = 0.085 mm-1. Of the 16984 measured reflections 7822 were independent [R(int) = 0.0274]. The final refinement converged at R1 = 0.0404 for I > 2σ(I), wR2 = 0.1122 for all data. The data for structure 3a were collected on a Stoe IPDS difractometer, the structure was solved by direct methods (SHELXS-97) and refined with all data by full matrix least squares on F2.

15

A solution of pyridinium p-toluenesulfonate (PPTS, 503 mg, 2.00 mmol) in H2O (2 mL) was added to a suspension of 3a (483 mg, 1.00 mmol) in MeCN (2 mL) at r.t. After stirring overnight the suspension was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL). The organic layer was washed with sat. NaHCO3 (20 mL) solution and dried (Na2SO4). Evaporation of the solvent leads to analytically pure 1a (302 mg, 0.99 mmol, 99%) as a snow white powder.

16

An aq NaOH solution (2 mL, 1 mol/L) was added to a suspension of 3a (483 mg, 1.00 mmol) in MeCN (2 mL) at r.t. After stirring for 30 min the clear solution was diluted with H2O (20 mL) and washed with Et2O (20 mL). The aqueous layer was acidified by the addition of KHSO4 solution (2.5 mL, 1 mol/L) and extracted with CH2Cl2 repeatedly. The organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo. 1H NMR analysis of the crude product indicates the formation of 4a (0.67 mmol, 67%) and benzoic acid. Compound 4a: 1H NMR (500 MHz, CDCl3 + 10% DMSO-d 6): δ = 0.72 (d, J = 6.8 Hz, 3 H), 0.73 (d, J = 6.8 Hz, 3 H), 1.95 (m, 1 H), 3.64 (dd, J = 17.9, 5.5 Hz, 1 H), 3.68 (dd, J = 17.9, 5.5 Hz, 1 H), 4.29 (dd, J = 8.8, 7.0 Hz, 1 H), 7.13 (dd, J = 7.5, 7.4 Hz, 2 H), 7.20 (tt, J = 7.4, 1.3 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 7.55 (sh, 3 H).

17

Isobutyraldehyde (8.03 mL, 88 mmol) was added to a solution of ammonium benzoate (5.56 g, 40 mmol) in MeOH (40 mL) at 0 °C. After stirring for 30 min methyl isocyanoacetate (2.26 g, 20 mmol) was added. The mixture was allowed to warm to r.t. overnight. After evaporation of the solvent in vacuo the residue was suspended in a mixture of MeCN and H2O (1:1), acidified to pH 2 by dropwise addition of concd HCl and stirred overnight. The MeCN was evaporated in vacuo and the resulting aqueous suspension was treated with H2O and CH2Cl2 until two clear layers were formed. The organic layer was separated, washed with sat. NaHCO3, dried (Na2SO4) and concentrated in vacuo. The solid residue was washed with Et2O (50 mL) filtrated and dried, giving rise to analytically pure 1a (5.2 g, 17 mmol) as a snow white powder.