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

Rigobert Pick; Michael Bauer; Uli Kazmaier; Christina Hebach

doi:10.1055/s-2005-863722

LETTER

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;

Abstract

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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

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References

1a Wagner I. Musso H. Angew. Chem., Int. Ed. Engl. 1983, 22: 816 ; Angew. Chem. 1983, 95, 827

1b

Annual reports in: Amino Acids, Peptides and Proteins, Specialist Periodical Reports, Chem. Soc., London.

1c Faulkner DJ. Nat. Prod. Rep. 2002, 19: 1

2 Gräfe U. Biochemie der Antibiotika Spektrum; Heidelberg: 1992.

3a Ugi I. Isonitrile Chemistry Academic Press; New York: 1971.

3b Ugi I. Chem.-Ztg. 1997, 74: 9

3c Dömling A. Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168 ; Angew. Chem. 2000, 112, 3300 and references cited therein

4a Ugi I. Steinbrückner C. Chem. Ber. 1961, 94: 2797

4b Keating TA. Armstrong RW. J. Org. Chem. 1998, 63: 867

5 Hebach C. Kazmaier U. Chem. Commun. 2003, 596

6a Miller SJ. Grubbs RH. J. Am. Chem. Soc. 1995, 117: 5855

6b Clark TD. Ghadiri MR. J. Am. Chem. Soc. 1995, 117: 12364

6c Miller SJ. Blackwell HE. Grubbs RH. J. Am. Chem. Soc. 1996, 118: 9606

6d Williams RM. Liu J. J. Org. Chem. 1998, 63: 2130

6e Gao Y. Lane-Bell P. Vederas JC. J. Org. Chem. 1998, 63: 2133

6f Cabrejas LMM. Rohrbach S. Wagner D. Kallen J. Zenke G. Wagner J. Angew. Chem. Int. Ed. 1999, 38: 2443 ; Angew. Chem. 1999, 111, 2595

7 Kazmaier U. Hebach C. Synlett 2003, 1591

8 Floyd CD. Harnett LA. Miller A. Patel S. Saroglou L. Whittaker M. Synlett 1998, 637

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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).

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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.

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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, ρ_calcd = 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.

14a Ruch E. Ugi I. Theor. Chim. Acta 1966, 4: 287

14b Ruch E. Ugi I. Top. Stereochem. 1969, 4: 99

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.