Heck reaction thiophenes

Scheme 7.5 Heck reactions of dihydrofuran with phenyl- or cyclohexenyl-triflates with (benzo)thiophene-containing phosphinooxazoline ligands.

Scheme 7.6 Intramolecular Heck reaction with thiophene-containing phosphinoox-azoline ligands.

Synthesis of dithieno[2,3-A2,3-,7]thiophene derivatives 122 has been accomplished through the Heck reaction of 3-(4-bromo-2-thienyl)acrylic acid 302 to afford 3-(2,4-thienylene)diacrylic acid 303 which was cyclized with thionyl chloride and a catalytic amount of pyridine to the dichloride 120 in 75% yield (Scheme 56) <2005MOL279>. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

Ohta s group investigated the heteroaryl Heck reaction of thiophenes and benzothiophenes with aryl halides [127] and chloropyrazines [128]. Addition of the electrophiles invariably took place at C(2) as exemplified by the formation of arylbenzothiophene 156 from the reaction of benzothiophene and p-bromobenzaldehyde [127]. As expected, the heteroaryl Heck reaction of 2-thienylnitrile, an activated thiophene, with iodobenzene afforded the arylation product 157 [129],... 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many rt-electron-rich heteroaryls including furan, thiophene, benzo[ ]furan and benzo[6] thiophene [42, 43]. In reactions of chloropyrazines with furan, thiophene and pyrrole, disubstituted heterocycles were also isolated albeit in low yields. 

Heck reactions of chloropyrazine 57 with benzo[fc]furan and benzo[b]thiophene produced 61 and 62, respectively. 

Walker and associates described a heteroaryl Heck reaction of 2,4-dimethoxy-5-iodopyrimidine with thiophene [78], They found that it was advantageous to carry out the thienylation in the presence of water as opposed to anhydrous conditions. Thienylation of less reactive 2,4-dimethoxy-5-bromopyrimidine gave the product in a lower yield (38%). 

The Heck reaction was also efficient in the construction of furane and thiophene rings. These processes start form the appropriate o-halophenyl ether or sulphide. 2-Butenyl-(2 -iodophenyl)-sulfide, for example, was converted to 3-methyl-benzothiophene under standard conditions in 70% yield (3.21.).27... 

The Heck reactions of thiophenes, particularly in the 2-position are well documented. In a recent example 2-bromothiophene was converted into a thienyl-vinylboronic acid derivative using a conventional palladium-triphenylphosphine catalyst and tributylamine as base (6.59.),... 

The heteroaryl Heck reaction is an efficient tool for the introduction of other five membered heteroaromatic systems too (for more details see Chapter 6.4.). Chloropyrazines reacted readily with oxazole to give the coupled product (7.57.), consisting solely of the 5-oxazolyl isomer.77 Extension of the reaction to imidazole led to a similar observation,78 and the expected 5-pyrazyl-imidazole derivative was isolated in acceptable yield. Reactions using thiophene as the masked olefin gave similar results. Under forcing conditions the 2,5-diarylation of fiiran was also observed.77... 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

The direct arylation (Heck) of thiophene by means of aryl halides and substituted thiophenes has been extensively studied by Lemaire and co-workers <1997TL8867, 1998JOM(567)49,2002TL1829, 2004T3221>. EWGs facilitate the reaction. With a 3-substituted thiophene, the major product was the 2-aryl derivative with 2-substituted thiophenes, the only product was the 5-aryl derivative. Yields ranged from 40% to 95%. The reaction has been extended to the synthesis of 2-arylbenzo[3]thiophenes as well (Equations 22 to 25). The yield improved on replacing the quaternary ammonium bromide by dicyclohexyl-18-crown-6. 

The 2-indolinone system has been found in a large number of pharmaceutically active compounds. This framework could be constructed by a tandem Heck-Suzuki reaction sequence [137]. Intramolecular Heck reaction of 390 afforded a cyclized intermediate that, in situ, reacted with boronic acid 187 to produce 391 in a single pot sequence. The reaction made use of copper thiophene-2-carboxylic acid (CuTC) to generate base-free conditions for the Suzuki reaction. 

The second type of intramolecular Heck reactions involves conversion of an aryl halide into a furan. Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 161 furnishes benzofuran 162 [140], Such an approach has become a popular means of synthesizing fused furans. 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many K-clcctron-rich heteroaryls including furan, thiophene, benzo [A] furan, and benzo[Z ] thiophene [81, 82]. In reactions of chloropyrazines with furan, thiophene, and pyrrole, disubstituted heterocycles were also isolated, albeit in low yields. Along with the disubstituted furan 161, the mono-arylation product 160 was isolated when 2-chloro-3,6-diethylpyrazine and furan were refluxed in the presence of Pd(Ph3P)4 and KOAc. In the case of 2-chloro-3,6-dimethylpyrazine and thiophene, monothienylpyrazine 162 was the sole product. When 2-chloro-3,6-diisobutylpyrazine was used as substrate, 9% of the disubstituted thiophene was detected. Analogous to the couplings with furan and thiophene, the heteroaryl Heck reactions of chloro-3,6-diethylpyrazine with benzo[Z ]furan and benzo[Z ]thiophene produced 163 and 164, respectively. 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

The electron-rich nature of heterocycles such as indoles, furans and thiophenes allows a different type of Heck reaction to be carried out. In this oxidative modification, the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. 

The electron-rich nature of heterocycles such as indoles, furans, and thiophenes allows a different type of Heck reaction to be carried out. " In this oxidative modification the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. This process is not catalytic in the standard way, but can be made so by the addition of a reoxidant selective for Pd(0) note, that the catalytic Pd(0) could not effect the first (electrophilic) ring palladation. " ... 

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