Thiophenes, acylation formylation

It is thus apparent that the selectivity of a reagent toward thiophene and benzene can differ appreciably, and this difference in selectivity is also strongly noticeable in the proportions of 2- and 3-isomers formed. Although in certain reactions no 3-isomer has been detected, appreciable amounts have been found in other reactions. Thus 0.3% of the 3-isomer has been found in the chlorination of thiophene.- Earlier results indicated that 5-10% 3-nitrothiophene is formed in the nitration of thiophene and a recent gas-chromatographic analysis by Ostman shows that the mononitrothiophene fraction contains as much as 16% of the 3-isomer. It appears that gas-chromatographic analysis should be very useful for the detection of small amounts of 3-isomers in other substitution reactions. However, from routine analyses of IR spectra, it appears to the present author that the amount of 3-isomers formed in acylation, formylation, and bromina-tion of thiophene are certainly less than a few per cent. 

Acylation. To achieve acylation of thiophenes, acid anhydrides with phosphoric acid, iodine, or other catalysts have been widely used. Acid chlorides with AlCl, SnCl, ZnCl2, and BF also give 2-thienylketones. AH reactions give between 0.5 and 2.0% of the 3-isomer. There has been much striving to find catalyst systems that minimize the 3-isomer content attempting to meet to customer specifications. The standard procedure for formylation is via the Vil smeier-H a ack reaction, using phosphoms o xycbl o ri de / /V, / V- dim e tb yl fo rm a m i de (POCl /DMF) or /V-m ethyl form an i1 i de. 

In glatter Reaktion werden Formyl- bzw. Acyl-thiophene mit Triathyl-siliciumhydrid in Trifluoressigsaure zu Alkyl-tetrahydro-thiophenen reduziert (s, S. 99). 

Substrates 47 and 48 have also been used to study the relative reactivities of selenophene and thiophene and of selenophene and benzene.71 The higher reactivity of the selenophene ring was demonstrated by the fact that upon formylation 59% of compound 49a was formed and upon acylation 63% of derivative 49b. Acylation of 48 gave exclusively 2-acetyl-5-benzylselenophene. Structures of the products were determined by H NMR. 

Acetylbenzo[6]tellurophene is also formed in isolable quantities. Benzo[6]selenophene is converted into 2-acyl derivatives by reaction with acid chlorides in the presence of aluminum chloride, whereas similar Friedel-Crafts acylation of benzo[6]thiophene yields 3-substituted products. When the 2-position is blocked, formylation can be directed into the 3-position. Thus treatment of 2-bromobenzo[6]selenophene with dichloromethyl butyl ether (Cl2CHOBu) and titanium tetrachloride yields the 3-formyl derivative (72BSF3955). If the 2- and 3-positions of benzo[6]selenophene are blocked with methyl groups, acylation under Friedel-Crafts conditions occurs in the 6-position (78CR(C)(287)333>. 

Methoxybenzo[J>]thiophene undergoes Friedel-Crafts acylation in the 7-position if this position is blocked, then substitution occurs exclusively in the 2-position.614 It undergoes Vilsmeier-Haack formylation to give its 7-formyl derivative.93... 

In contrast with benzofuran (and with thiophene itself), benzothiophene is substituted preferentially at the )3 position. Bromina-tion,77, 226, 227 formylation,228, 229 acylation,77, 221, 230-232 chlorination,233 chloromethylation,234 sulfonation,235 mercuration,236 and iodination237 give exclusively or prevalently the 3-substituted isomers. Anomalous orientation (in position 2) has been observed in iso-propylation,238 but it is possible that isomerization occurs under the conditions reported. 

Formyl and acyl derivatives of thiophene 86HC(44,3)309. Halothiophenes 86HC(44,2)159. 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

Thiophene is chlorinated by CI2 or SO2CI2. Bromination occurs by Br2 in acetic acid or with N-bromosuccinimide. Nitration is effected by concentrated nitric acid in acetic acid at 10°C. Further substitution predominantly yields 2,4-dinitrothiophene. Sulfonation with 96% H2SO4 occurs at 30°C within minutes. Benzene reacts extremely slowly under these conditions. This provides the basis for a method to remove thiophene from coal tar benzene (see p 77). Alkylation of thiophenes often gives only poor yields. However, more efficient procedures are the Vilsmeier-Haack formylation, which yields thiophene-2-carbaldehyde, and acylation with acyl chlorides in the presence of tin tetrachloride, to give 2-acylthiophenes. Like furan, thiophene is mercurated with mercury(II) chloride. 

In contrast with benzofuran (and with thiophene itself), benzothiophene is substituted preferentially at the 3 position. Bromina-tion, formylation, acylation,230-232 chlorina-... 

Ch. 3 Formyl and Acyl Derivatives of Thiophenes and Their Reactions... 

Analysis of the above methods for the synthesis of thienothiophenes and their analogues based on thiophene derivatives demonstrates that mono- and dibromo-substituted thiophenes are most often successfully used as the starting compounds. It should be noted that intramolecular cyclization of compounds derived from the above-mentioned thiophenes serves as the key step. In this step, vicinal carbonyl functions (generally, formyl or acyl) interact with fragments containing an activated methylene group. 

Thiophen Analogues of Phenanthrene.— Electrophilic substitutions of naphtho[2,l-6]thiophen (434) such as nitration, formylation, and acylation occur, in contrast to those in benzo[6]thiophen, in the thiophenic a-position (2-position). Bromination gives a mixture of the 2-bromo- and 2,5-dibromo-derivatives. That the 5-position is the second most reactive... 

Acylation can be conducted efficiently (a) with acid chlorides and SnCfi as catalyst to give 2-acylthiophenes and (b) by application of the Vilsmeier formylation to give thiophene-2-carbaldehydes ... 

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