Microwave-Assisted Synthesis of 2-Aminothiophene Derivatives via Improved Gewald Reactions

Abstract

In this paper, a new and efficient method was developed to prepare 2-aminothiophene derivatives through improved Gewald reaction. Thirty-one final products were synthesized under microwave radiation for 30 min with 57%-95% isolated yields. All the products could be used as building blocks in drug discovery.2-Aminothiophenes are important organic intermediates, which are often found in drug research. 1,2 Due to the broad activities of the derivatives including anti-microbial, anti-tumor, anti-oxidation, and anti-inflammatory, it has been greatly interested in development of new 2-aminothiophenes for organic chemists and medicinal chemists. [3][4][5] In 2013, Davis reported a new drug candidate CaCCinh-A01, 6 which was used as inhibitor for treatment of glioblastoma. In addition, Ballatore studied ATTZ-15 and 2-TCU 7 in the next year, which were performed significant effects in neurological diseases. Recently, Sim also developed a series of 2-aminothiophene-3-carboxamide derivatives as calcium-activated chloride ion channel blockers. 8

Efficient one-pot synthesis of dan-substituted organo- and silyl-boron compounds

“…Installation of a naphthalene-1,8-diaminato (dan) substituent on boron centers significantly diminishes the boron-Lewis acidity, 1 thus providing transmetalation-resistant properties to the respective organoboron compounds [R–B(dan)] that are conventionally synthesized by dehydration condensation of organoboronic acids [R–B(OH) 2 ] and 1,8-diaminonaphthalene (danH 2 ) (Scheme 1A). 2 The characteristic feature has been utilized for the boron-masking strategy in the iterative Suzuki–Miyaura coupling (SMC), 2 where the B(dan) moieties remain intact during the cross-coupling event at Lewis acidic B(OH) 2 or pinacol boronates [B(pin)].…”

Scalable Synthesis of Silacyclohexanones and Ready Access to Silicon Building Blocks

“…17 We then checked the utility of silaketones for the synthesis of fused thiophenes (application V). 18 Microwave assisted reaction of silacyclohexanones with ethylcyanoacetate and sulfur in the presence of pyrrolidine base delivered the sila-tetrahydro-2amino thiophene derivatives 15a−15c. Next, we turned our attention to the synthesis of nitrogen-containing 6-membered heterocycles.…”

“…Silicon incorporated fused pyrroles 13a – 13c were synthesized from silacyclohexanones 5a – 5c using aniline and ( E )-(2-nitrovinyl) benzene (53–74% yields, application IV) under heating conditions . We then checked the utility of silaketones for the synthesis of fused thiophenes (application V) . Microwave assisted reaction of silacyclohexanones with ethylcyanoacetate and sulfur in the presence of pyrrolidine base delivered the sila-tetrahydro-2-amino thiophene derivatives 15a – 15c .…”

Truly Catalytic Gewald Synthesis of 2-Aminothiophenes Using Piperidinium Borate (Pip Borate), a Conjugate Acid–Base Pair

“…(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(phenyl) methanone (4d) Yield: 1.18 gm, (87 %); yellow solid; mp 170-172°C (lit 30. 176-177 °C)13 Yield: 1.32 gm, (89 %); yellow solid; mp 123-125 °C (lit 32. 124-125 °C)1 H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.72 (s, 2H), 2.51 (t, J = 6.3 Hz, 2H), 1.80 (t, J = 6.1 Hz, 2H), 1.74 (dt, J = 12.3, 6.3 Hz, 2H), 1.49 (dt, J = 11.8, 6.1 Hz, 2H).…”