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Volumn , Issue 20, 2008, Pages 3145-3148

Gewald synthesis of aminothiophene carboxylic acids providing new dipeptide analogues

Author keywords

Amino acids; Cyclopropanes; Multicomponent reaction; Peptide analogues; Thiophenes

Indexed keywords


EID: 58149331873     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-0028-1087243     Document Type: Article
Times cited : (20)

References (39)
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    • For a review on the synthesis of 2-aminothiophenes by Gewald reaction, see: (a) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333.
    • For a review on the synthesis of 2-aminothiophenes by Gewald reaction, see: (a) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333.
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    • For a review on multicomponent reactions of carbonyl compounds and derivatives of cyanoacetic acid, see: b
    • For a review on multicomponent reactions of carbonyl compounds and derivatives of cyanoacetic acid, see: (b) Shestopalov, A. M.; Shestopalov, A. A.; Rodinovskaya, L. A. Synthesis 2008, 1.
    • (2008) Synthesis , pp. 1
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    • 58149331578 scopus 로고    scopus 로고
    • Typical Procedure for the Synthesis of 2-Aminothiophene 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
    • 4S (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.
  • 24
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    • 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 €) is almost prohibitive for large-scale preparations of 4a.
    • 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 €) is almost prohibitive for large-scale preparations of 4a.
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    • For a review on recent development of peptide coupling reagents in organic synthesis, see
    • (a) For a review on recent development of peptide coupling reagents in organic synthesis, see: Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
    • (2004) Tetrahedron , vol.60 , pp. 2447
    • Han, S.-Y.1    Kim, Y.-A.2
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    • For a review on chemical synthesis of natural product peptides, see
    • (b) For a review on chemical synthesis of natural product peptides, see: Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
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    • Humphrey, J.M.1    Chamberlin, A.R.2
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    • Alternatively, 7c was synthesized in 59% overall yield by a reversed reaction sequence.
    • Alternatively, 7c was synthesized in 59% overall yield by a reversed reaction sequence.
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    • 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
    • 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.


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