Thiophenes Mannich reaction

The benzo[6] heterocycles are generally less reactive than their monocyclic counterparts. Thus benzo[6]thiophene unlike thiophene does not undergo Vilsmeier formylation or the Mannich reaction. 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

Oxyiminium cations formed from iV,0-diaIkyhydroxylamines and formaldehyde are sufficiently reactive for Mannich reactions with activated arenes. Mannich reactions of oxyiminium cations with indoles (e.g. 74, equation 48) " as well as pyrroles and furans but not phenol and thiophene have been reported. 

Mannich reaction Pyrrole and alkyl substituted furan undergo the Man-nich reaction. Thiophene also undergoes this reaction, but, instead of acetic acid, hydrochloric acid is used. 

However, Mannich reactions on the thiophene nucleus are rare 2- and 3-methoxythio-phenes underwent this reaction in good yield to produce the Mannich bases (88) and (89) respectively (75SC59). 

Alternative synthetic techniques towards TB derivatives were reported by Becker (93TL1889) and Cekavicus (01TL4239). Becker prepared a highly functionalized TB derivative by heating methyl 5-chloro-4-[(ethoxyoxoacetyl)amino]-2-methoxybenzo-ate in DMSO at 180°C. Cekavicus reported that the novel heterocyclic system 3 arose via the intermolecular Mannich reaction of l,l-dioxo-l,2-dihydro-ben-zo[i]thiophen-3-one (Scheme 4). 

Thiophene, alkyl-substituted furans, and especially pyrrole, undergo Mannich reactions. 

Thiophene itself undergoes Mannich reactions more sluggishly than furan or pyrrole. The Mannich reaction of 3-alkoxythiophenes and 3,4-dialkoxythiophenes has been investigated in detail <2001J(P1)2595>. The reaction of 3-methoxythiophene with secondary amines and formaldehyde in acetic acid at room temperature led to the... 

In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or V-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in. 

Furane and thiophene derivatives are poorly reactive substrates thiophenes in particular require the presence in the ring of electron donors such as, for example, the methoxy group, in order to undeigo the Mannich reaction successfully. The preferred site of attack is again in the a position with respect to the heteroatom. - -35i,4i6,4i7,427 interestingly, the reaction takes place at position a-2 in the 3-substituted derivatives, rather than at the less hindered a-5 position. - ... 

Aminomethylation of thiophene was reported long before the more common Mannich reaction -dimethylaminomethylation - which, although it can be achieved under routine conditions with methoxy-thiophenes, requires the use of Me2N =CH2 Cl ( Eschemnoser s salt is the iodide) for thiophene and alkyl thiophenes. ... 

Another device for bringing thiophenes into reaction with Mannich intermediates is to utilise thiophene boronic acids - the Petasis reaction primary aromatic amines can also be used as the amine component. ... 

Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 C give the relative rates thiophene (1.0), furan (1.4 x 10 ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). Similar values, thiophene (1.0), furan (3.0 x 10 ) and pyrrole (5.0 x 10 ) are obtained for reactions with [C6H7Fe(CO)3]. We have already discussed the fact that thiophene does undergo the Mannich reaction using preformed methyleneiminium salts and therefore it is not surprising that furan also affords the aminomethyl derivatives in reactions with iminium salts. 

Acylamido-4,5,6,7-tetrahydrobenzo[b]thiophenes undergo the Mannich reaction,375 Vilsmeier-Haack formylation,376 diazo coupling,377 and thiocyanation378 to give the 3-CH2NHR, 3-CHO, 3-N=NAr, and 3-SCN derivatives, respectively the last can be cyclized to 95 (X = S, Y = NHAc).378... 

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