2- Chloro-5-methylthiophene

Aiming at better 1,2-di(thien-3-yl)ethenes, compounds with different substituents on the cyclopentene ring were targeted. Thus, the idea of acylating 2-bromo-5-methylthiophene (44, R=Br) emerged. Unfortunately, the desired product was not obtained, and instead, the bromine substituent migrated to C-3, and acylation took place at C-2. However, 2-chloro-5-methylthiophene (44, R=C1) was smoothly converted into the desired diketcme giving a 98% yield under Friedel-Crafts conditions (Scheme 48) [63, 66],... 

Dihydrothiophene as a bridging unit was also investigated instead of cyclopentene [70]. In this case, acetylation of 2-chloro-5-methylthiophene in the presence of AICI3 gave C-4-acylated product in 78% yield (Scheme 52) [70]. 

The synthesis of nonsymmetric cyclopentenes, containing both thien-3-yl and benzo[Z7]thien-3-yl units, was aimed at more sophisticated photochromic molecules (Scheme 54) [73]. By the application of glutaric anhydride with 2-chloro-5-methylthiophene and 5-bromo-2-methylbenzo[h]thiophene in the presence of AICI3, keto acids 52 and 53 were obtained. Conversion of the keto acids into acid anhydrides then Friedel-Crafts acylations produced the desired diketone albeit in only 31% yield (over 2 steps) in the first case and in 14% yield (over two steps) in the second case (Scheme 54) [73]. 

A. Z-Thienylmethylhexamethylenetetrammonium chloride. In a 1-1. round-bottomed flask are placed 67 g. (0.5 mole) of 2-chloro-methylthiophene (p. 31), 400 ml. of chloroform, and 70 g. (0.5 mole) of hexamethylenetetramine. The flask is fitted with a reflux condenser, and the mixture is boiled gently for 30 minutes. The mixture is cooled, and filtered on a Buchner funnel. The precipitate is washed with 100 ml. of cold chloroform, drained thoroughly, and air-dried. I hc yield is 128-136 g. (94 99%j) of a white iiowder. 

Thenoic acid has been prepared in low yield by oxidation of 3-methylthiophene with potassium permanganate,2-4 dilute nitric acid, chromic acid, and hydrogen peroxide,4 and by reductive dechlorination of chloro-3-thenoic acid.4 Starting with 3-iodothiophene, which is difficult to obtain, good yields are obtained by the Grignard procedure 6 or with cuprous cyanide and potassium cyanide in a sealed tube.6... 

Substituted 3-hydroxythiophenes are convenient starting-points for the synthesis of the thieno[3,2-Mthiophene system. Shvedov et obtained 50% of 3-chloro-3-ethoxycarbonyl-5-methylthiophene-2-aldehyde (110) from 3-ethoxycarbonyl-4-hydroxy-2-methylthiophene (109) by Vilsmeier formylation at 100°. Reaction with thioglycolic ter formed 3-ethoxycarbonyl-5-methoxycarbonyl-2-methylthieno[3,2-6]-thiophene (111) [. (36)]. 

Marino and Linda130 have measured the relative rates of 2-chloro-thiophene, thiophene, and 2-methylthiophene in the reaction with acetic anhydride and tin tetrachloride in dichloroethane. Additional measurements on two other thiophene derivatives have been made... 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCU-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with AT-bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chloro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with f-butyl chloride in the presence of FeClg, only 5-f-butyl monosubstituted and... 

Thiophene and alkylthiophenes are readily chlorinated in the a-position by the reagent. Thus thiophene affords 2-chlorothiophene (43%) and 2,5-dichlorothio-phene 3-methylthiophene gives 2-chloro-3-methylthiophene in 79% yield. Sulfuryl chloride is an excellent reagent for the selective chlorination of 2-thenylamines in the. 5-position. ... 

The simplest possible case involves formaldehyde and thiophene, and 2,2 -dithienylmethane is formed as a by-product in the chloromethylation of thiophene with formaldehyde-hydrochloric acid7,8 replacement of the hydrochloric acid by hydrofluoric acid causes the dithienylmethane to become the major product (52%).9 Under the normal chloromethylation conditions 2-methylthiophene gave only a minor amount (4%) of 2-chloro-... 

Thiophenes substituted at C-2 were selectively halogenated at C-5 under biphasic conditions, though in the case of 2-methylthiophene, 10% of isomeric 2-methyl-3-chlorothiophene was also identified [96]. In this way, thiophenes with mixed halogens can be obtained. Chlorination and bromination of 2-iodothiophene gave 2-chloro-5-iodothiophene and 2-bromo-5-iodothiophene, respectively (Scheme 63). 

Bromo-5-chloro-2-methylthiophene (56) was an intermediate for the synthesis of the photochromic diaryl perfluorocyclopentene 57 (Scheme 66) [99, 100], 2-Methyl-thiophene was selectively chlorinated by NCS at C-5, followed by bromi-nation ortho to the tdkyl group. Subsequent selective reaction at the C-Br bond finally gave 57, which in turn could be further modified at the thiophene ring by substitution of chlorine (Scheme 66) [99, 100]. 

Bromo-3-methylthiophene-2-carbonyl chloride was required as an intermediate for the synthesis of an insecticide, 5-(4-bromo-3-methylthien-2-yl)-3-(2-chloro-6-fluorophenyl)-l-methyl-l//-l,2,4-triazole (XR-693) [113]. 3-Methyl-thiophene was selected as a starting material it could be selectively 2-brominated with NBS or exhaustively brominated by bromine to 2,3,5-tribromo-4-methyl-thiophene as shown in Scheme 73 [113]. 

Electron-withdrawing and electron-donating groups on the pyridine moiety were compatible. It is worth noting that ster-ics and electronics play an inportant role in governing C2- vs. C6-selectivity for C3-substituted pyridines sterically hindered substrates, such as C3-pivalamido, phenyl, and ester substrates, preferred C6-arylation, whereas, due to electronic effects, C3-chloro- and fluoro-substrates favored C2-arylation. Other azines could also be cross-coupled with 2-methylthiophene including pyrimidine, quinoline, quinoxaline, pyridine, and pytidazine. 

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