3-Thienylboronic acid

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

A simple method for the synthesis of maleic anhydride derivative 165 starting from 2,5-dimethyl-3-thienylboronic acid and commercially available inexpensive mucobromic acid 168 was reported (04IZV2238) (Scheme 52). The starting boronic acid was prepared in good yield from 2,5-dimethyl-3-iodothiophene. 

Di- and poly-thienyls can be prepared by cross-coupling of 2- and 3-thienylboronic acids in the presence of Pd° catalyst. Another similar method is the cross-coupling of iodothiophenes with stannylthiophenes (Scheme 80). 

Dibromide 124 undergoes regioselective and sequential Suzuki reactions to afford 125 and then 126 [63], A double coupling of 124 with 3-thienylboronic acid yields... 

Synthesis of arylboronic acids by in situ quench procedure with n-BuLi and triisopropyl borate Preparation of 3-thienylboronic acid (364) 11481... 

A 50 ml round-bottomed flask equipped with a temperature probe, a magnetic stirrer and a septum was charged with toluene (16 ml) and THF (4 ml) and put under a nitrogen atmosphere. The flask was further charged with triisopropyl borate (2.8 ml, 12 mmol,1.2 eq.) and 3-bromothiophene (365, 1.63 g, 10 mmol). The mixture was cooled to -70 °C using a dry ice / acetone bath. -Butyllithium (2.5 M in n-hexane, 4.8 ml, 12 mmol, 1.2 eq.) was added dropwise via a syringe pump over 1 h, and the mixture was stirred for additional 0.5 h, while the temperature was held at -70 "C. The acetone / dry ice bath was removed, and the reaction mixture was then allowed to warm to -20 °C before 2 M aqueous sodium hydroxide solution (10 ml) was added. When the mixture reached room temperature, it was transferred to a 100 ml separatory funnel and the layers were separated. The organic layers were evaporated in vacuo to provide solids which were recrystallized from acetonitrile to yield 1.16 g (91%) of 3-thienylboronic acid (364). 

The Suzuki-Miyaura coupling of 3-thienylboronic acid 64 with aryl bromides 65 is possible with extremely low catalyst loadings of only 0.1% using the catalytic system... 

Other types of HIV-1 protease inhibitors have also been prepared using microwave-promoted Suzuki reaction [37]. The symmetric cyclic sulfamide (3K,4S,5S,6it)-3,6-bis(phenoxymethyl)-2,7-bis[4-(2-thienyl)benzyl]-l,2,7-thi-adiazepane-4,5-diol 1,1-dioxide, for instance, was synthesized via cross-couphng of (3aS,4R,8it,8aS) - 5,7 - bis(4 - bromobenzyl) - 2,2 - dimethyl - 4,8 - bis-(phenoxymethyl) hexahydro [1,3] dioxolo [4,5 - d] [ 1,2,7 ] - thiadiazepine 6,6 - dioxide with 2-thienylboronic acid for 3 min at 45 W (Scheme 19). 

Thienylboronic acids are useful building blocks for preparing biaryls and heterobiaryls employing the Suzuki reaction. In one case, a Suzuki coupling between thiophene-3-boronic... 

Treatment of thiophene r-butyl sulfonamide (59) with 2 equivalents of n-BuLi formed a dianion in which the second anion resided at the C(5) position. Quenching the resulting dianion with triisopropylborate followed by acidic workup furnished thienylboronic acid 60, which was then coupled with p-bromobenzyl alcohol under basic conditions to afford arylthiophene 61 [49]. 

The synthesis of radioactive ketones with C in carbonyl was achieved by carbonylative cross-coupling of aryl iodides or triflates with methyl-, phenyl-, or 2-thienylboronic acids under elevated pressure of CO. To ensure fast reaction, harsh conditions were used. Interestingly, under such conditions the addition of a base is not necessary (Equation (18))." ... 

Thieno-pyridopyridine isomers were prepared by the coupling of a halogenated aminopyridine derivative and formyl-thienylboronic acid. The coupling of the unprotected reagents led to the concomitant formation of the carbon-nitrogen and carbon-carbon bonds in good yield (4.2.),3... 

Hydrolysis of the product from the reaction between 2-benzo[6]-thienyllithium and methyl borate with acid is said to give 2-benzo[6]-thienylboronic acid.394... 

Nettekoven and coworkers exploited the Suzuki reaction to synthesize a key intermediate used in their synthesis 5-thienyl triazolopyridines series [73]. These compounds have the potential to act as antagonists of adenosine 2a (A2a) receptor, an important receptor in certain neurodegenerative diseases. The pivotal coupling was accomplished by using 2-thienylboronic acid and the 5-iodotriazolopyridine 96 in the presence of Pd(dppf)Cl2 dichloromethane complex to afford the triazolopyridine 97 in 83% yield. Compound 97 was subsequently acylated with a series of acyl chlorides to deliver the target triazolopyridines 98. 

Thienylboronic acids are useful building blocks for preparing biaryls and heterobiaryls employing the Suzuki reaction. In one case, a Suzuki coupling between thiophene-3-boronic acid and iodocyclopropane 99 was promoted by cesium fluoride to furnish the adduct 100 with retention of configuration [74]. In another example, the union between thiophene-3-boronic acid and 5-bromo-2,2-dimethoxy-l,3-mdandione (101) provided ninhydrin derivative 102 [75]. 

The Suzuki reaction of j9-chlorobenzoyl chloride and thiophene-2-boronic acid was carried out under anhydrous conditions to furnish ketone 118 [81], providing an alternative synthesis of ketones. Behaving like simple aryl halides, iodothiophenes served as coupling partners with phenylboronic acid [82] and thienylboronic acid [83] to deliver biaryls 119 and 120, respectively. 

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