Hetero-Type Benzannulation Leading to Substituted Benzothio-Phenes

TiCl4 (or SnCl4)-promoted hetero-type benzannulation reactions using various (2,2-dichlorocyclopropyl)(thiophen-2-yl)methanols proceeded smoothly to produce uniquely substituted 4-chlorobenzothiophenes (five examples). The present approach involves the first distinctive thiophene formation from thiophene cores, in contrast to traditional methods of thiophene formation from benzene cores. The stereocongested (less reactive) Cl position in the obtained 4-chlorobenzothiophenes functioned successfully as the partners of three cross-coupling reactions: (i) a Suzuki–Miyaura cross-couplings using Pd(OAc)2/SPhos/K3PO4 catalysis (seven examples; 63–91%), (ii) a hydroxylation using KOH/Pd(dba)2/tBu-XPhos catalysis (85%), and (iii) a borylation using a B2(pin)2/Pd(dba)2/XPhos/NaOAc catalysis-provided 4-(pin)B-benzothiophene (58%).

Next, the regiocontrol aspect of the present hetero-benzannulation is d (Scheme 6). Following the reported procedure for the preparation of AACM-2 (Sc [10], the sequential introduction of Ar groups and a 1-thienyl group to acid ch provided stereodefined alcohols 13a and 13b in good yield with excellent stereose through ketones 12a [26] and 12b, respectively. The stereochemical course of the oselective addition accounts for the reported mechanistic speculation based on t rule [25][26][27]; the thienyl anion attacks the less hindered side of the more stabl conformer of ketones 12 to afford stereodefined alcohols 13 with >95:5 de. The distinctive hetero-type benzannulation procedure using 13a and 13b suc produced 6-arylbenzothiophenes 14a and 14b in 47% and 58% yields, respectiv The TiCl 4 -promoted hetero-type benzannulation using alcohol 3 proceeded successfully, affording the desired 4-chloro-6-methyl-7-(thiophen-2-yl)benzothiophene (5) in 75% yield. Although the reaction of alcohol 4 using TiCl 4 unfortunately resulted in complex mixtures, a substitution with SnCl 4 successfully afforded the corresponding benzothiophene 6 in 54% yield.
Hetero-type benzannulation using diastereoisomeric (2,2-dichloro-1,3-dimethylcyclopropyl) di(thiophen-2-yl)methanols 9 and 10 afforded intriguing results (Scheme 5). Alcohol 9 was prepared from methyl angelate by the addition of stereospecific syn-dichlorocarbene and the subsequent addition of the two molar 1-lithiated thiophene through methyl ester 7. In a similar procedure, isomeric methyl tiglate was converted to alcohol 10 through methyl ester 8. The identical TiCl 4 -mediated and SnCl 4 -mediated reactions using 9, however, yielded only complex mixtures. To our delight, 10 successfully underwent hetero-benzannulation to afford 11 in 48% yield. This outcome is in clear contrast to the benzannulations for naphthalene formation, wherein methyl angelate was employed as a starting compound [9,10]. The reason for the contrast switching results using diastereomeric substrates is not clear at present. Hetero-type benzannulation using diastereoisomeric (2,2-dichloro-1,3-dimethylcyclopropyl)di(thiophen-2-yl)methanols 9 and 10 afforded intriguing results (Scheme 5). Alcohol 9 was prepared from methyl angelate by the addition of stereospecific syn-dichlorocarbene and the subsequent addition of the two molar 1-lithiated thiophene through methyl ester 7. In a similar procedure, isomeric methyl tiglate was converted to alcohol 10 through methyl ester 8. The identical TiCl4-mediated and SnCl4-mediated reactions using 9, however, yielded only complex mixtures. To our delight, 10 successfully underwent hetero-benzannulation to afford 11 in 48% yield. This outcome is in clear contrast to the benzannulations for naphthalene formation, wherein methyl angelate was employed as a starting compound [9,10]. The reason for the contrast switching results using diastereomeric substrates is not clear at present. Next, the regiocontrol aspect of the present hetero-benzannulation is discussed (Scheme 6). Following the reported procedure for the preparation of AACM-2 (Scheme 3) [10], the sequential introduction of Ar groups and a 1-thienyl group to acid chloride 2 provided stereodefined alcohols 13a and 13b in good yield with excellent stereoselectivity through ketones 12a [26] and 12b, respectively. The stereochemical course of the diastereoselective addition accounts for the reported mechanistic speculation based on the Cram rule [25][26][27]; the thienyl anion attacks the less hindered side of the more stable s-trans conformer of ketones 12 to afford stereodefined alcohols 13 with >95:5 de.
The distinctive hetero-type benzannulation procedure using 13a and 13b successfully produced 6-arylbenzothiophenes 14a and 14b in 47% and 58% yields, respectively, with high regiocontrol (Electronic Supporting Information of Free Energy Calculations: see SI). Next, the regiocontrol aspect of the present hetero-benzannulation is discussed (Scheme 6). Following the reported procedure for the preparation of AACM-2 (Scheme 3) [10], the sequential introduction of Ar groups and a 1-thienyl group to acid chloride 2 provided stereodefined alcohols 13a and 13b in good yield with excellent stereoselectivity through ketones 12a [26] and 12b, respectively. The stereochemical course of the diastereoselective addition accounts for the reported mechanistic speculation based on the Cram rule [25][26][27]; the thienyl anion attacks the less hindered side of the more stable s-trans conformer of ketones 12 to afford stereodefined alcohols 13 with >95:5 de. With these successful results in hand, we investigated the functionalization of th obtained benzothiophenes 5, 11, and 14a to demonstrate the utility for synthesizing seve 4-aryl-substituted benzothiophene derivatives 15-21. As depicted in Figure 1, the Suzuki Miyaura cross-couplings proceeded smoothly at the congested (less reactive) 4-Cl-pos tion using Pd(OAc)2/SPhos/K3PO4 catalysis to produce a variety of uniquely substitute benzothiophenes 15-21 in good to excellent yield. The use of K3PO4 was superior to tha of K2CO3 (70%) and i-Pr2NEt (65%). As a further distinctive extension, a couple of heteroatom groups [OH-and (pin)B were successfully introduced into benzothiophene 5 using recently developed cross-cou pling methods; KOH/Pd(dba)2/tBu-XPhos catalysis [29] provided 4-hydroxybenzothio Scheme 6. Regiocontrolled hetero-type benzannulation.
The distinctive hetero-type benzannulation procedure using 13a and 13b successfully produced 6-arylbenzothiophenes 14a and 14b in 47% and 58% yields, respectively, with high regiocontrol (Electronic Supporting Information of Free Energy Calculations: see SI).
Colorless oil; Rf = 0.63 (hexane/AcOEt = 10:1); 1  stirred at the same temperature for 1 h. Acid chloride 2 (937 mg, 5.0 m mL) was added to the mixture at 0-5 °C, which was stirred at 20-25 °C aqueous solution was added to the mixture, which was extracted twice combined organic phase was washed with water, brine, dried (Na2SO4) The obtained crude oil was purified by SiO2 column chromatography 30:1) to give the desired product 12b (1.06 g, 80%).