Gewald Synthesis of Aminothiophene Carboxylic Acids Providing New Dipeptide Analogues

Abstract

A new multicomponent synthesis of 2-aminothiophene carbocyclic acids 4 by reaction of methyl 2-siloxycyclopropane-carboxylates 1, alkyl cyanoacetates, and elemental sulfur is reported. This version of the Gewald thiophene synthesis rapidly provides a new type of δ-amino acids, which can be considered as dipeptide analogues. Smooth protective-group manipulations allowed regio- and chemoselective couplings with l-phenylalanine derivatives furnishing new tripeptide analogues such as 5 and 8 or products of type 10.

Key words

multicomponent reaction - thiophenes - cyclopropanes - amino acids - peptide analogues

References and Notes

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9

Typical Procedure for the Synthesis of 2-Aminothio-phene 4a Using the One-Pot/One-Stage Procedure
Siloxycyclopropanecarboxylate 1a (0.209 g, 1.06 mmol), tert-butyl cyanoacetate (0.143 g, 1.01 mmol) and sulfur (0.032 g, 1.01 mmol) were suspended in MeOH (2 mL), then Et₂NH (0.11 mL, 1.01 mmol) was added. The mixture was refluxed for 7 h, and then stirred overnight at r.t. After addition of water and EtOAc the layers were separated and the aqueous layer was extracted two times with EtOAc. The combined organic layers were dried with Na₂SO₄, filtered, and concentrated. Column chromatography (SiO₂, hexane-EtOAc = 8:1 to 7:1 to 6:1) provided 0.180 g (66%) 4a as a brownish oil.
Analytical Data for tert -Butyl 2-Amino-5-(2-methoxy-2-oxoethyl)thiophene-3-carboxylate (4a)
^¹H NMR (500 MHz, CDCl₃): δ = 1.50 [s, 9 H, C(CH₃)₃], 3.56 (s, 2 H, CH₂), 3.68 (s, 3 H, OCH₃), 5.90 (br s, 2 H, NH₂), 6.70 (s, 1 H, CH). ^¹³C NMR (126 MHz, CDCl₃): δ = 28.3 [q, C(CH₃)₃], 35.0 (t, CH₂), 52.1 (q, OCH₃), 79.9 [s, C(CH₃)₃], 107.6 (s, C-2), 115.4 (s, C-5), 125.4 (d, C-4), 162.0 (s, C-3), 164.7, 170.9 (2 s, CO). IR (film): 3445-3255 (NH), 3070-2845 (CH), 1740, 1670 (C=O), 1590, 1500, 1455 (NH, CSNH) cm^-¹. MS (EI, 80 eV, 60 ˚C): m/z (%) = 271 (14) [M]⁺, 215 (59) [M - C₄H₉]⁺, 197 (33) [M - C₅H₁₂]⁺, 156 (100) [M - C₅H₁₂O₂]⁺, 138 (61), 57 (37) [C₄H₉]⁺. HRMS (EI, 80 eV, 60 ˚C): m/z calcd for C₁₂H₁₇NO₄S: 271.0878; found: 271.0880. Anal. calcd for C₁₂H₁₇NO₄S (271.3): C, 53.12; H, 6.32; N, 5.16; S, 11.82. Found: C, 53.37; H, 6.43; N, 5.16; S, 11.95.

10

We also prepared thiophene 4a in 61% yield starting from commercially available aldehyde 2a using a one-pot/one-stage Gewald procedure (method A). Although the result is comparable with the yield we achieved with cyclopropane 1a the very high cost of aldehyde 2a (100 mg, 77 ı) is almost prohibitive for large-scale preparations of 4a.

14

Alternatively, 7c was synthesized in 59% overall yield by a reversed reaction sequence.

21

During peptide couplings presented here we did not observe racemization of the amino acid moiety since subsequent couplings with a second amino acid provided only one diastereomer.