2-Hydroxymethyl- 5- thiophene

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Hydroxymethylation and alkylation of furans, thiophenes, and pyrroles in the presence of H" " cations 98KGS3. 

Di- and tetraynes with hydrogen sulfide in an alkaline medium at 20-80°C form systems containing linked thiophene cycles. Thus, l,4-dithienylbuta-l,3-diyne (47) forms 2,5-di(2-thienyl)thiophene (48) in 78% yield, whereas octa-2,4,6-tiiyn-l-ol (49) under the same conditions gives 5-hydroxymethyl-2-prop-1-ynylthiophene (50) in 50% yield (77HOU947). 

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

The formyl group in orthoformylselenophenecarboxylic acids on reduction to an hydroxymethyl group undergoes ring closure to lactones.100 To obtain 2,4-disubstituted selenophenes, 4-bromo-2-formylselenophene was prepared by the swamping catalyst method.101 Selenopheno[2,3-b]thiophene derivatives may be prepared from compound 84.102 Another route to substituted... 

The use of 2-(hydroxymethyl)furan or 2-(hydroxymethyl)thiophene as aUyhc alcohols gives rise to a-(trifluoromethyl)-a-(2-heteroaryl)glycine derivatives 125 after hydrolysis of the corresponding oxazolone 124 as shown in Scheme 7.35. ... 

The fouling bryozoan Dakaira subovoidea has been shown to contain two thiophene compounds, 1 -hydroxymethyl-6-oxo-6//-anthra[ 1,9-... 

When 2-hydroxymethyl-5,6-methylenedioxybenzo[6]thiophene is heated in a polar solvent with a catalytic amount of mineral acid, the polycyclic compound (166) is formed in 75% yield, probably by way of the intermediate (251).190 3-Hydroxymethylbenzo[6]thiophene and di(3-benzo[6]thienyl)methane react together in the presence of boron trifluoride to give a compound with the probable structure 252.486... 

Nitration of 2-acetoxymethylbenzo[6]thiophene, followed by acidic hydrolysis of the product, affords 2-hydroxymethyl-3-nitrobenzo[6]-thiophene.518... 

HjO / pH - 5) are 2- and 3-mercaptopropionic-, furan-, and thiophene carboxylic acids, which amount to 40 to 80 % of the volatile Maillard products. The furan- and thiophene carboxylic acids are formed via 3-deoxyosone and the mercaptoacids via 1-deoxyosone (Figure 6). By dehydration, addition of H 0 (or by Strecker degradation of Cys) and reduction of the carbonyl group, furfuryl-mercaptan (the impact component of roasted coffee) results. 2-Hydroxymethyl-4-thiolanone, which may be formed by the same route, was identified for the first... 

Isomer yields have been determined in the chloroethylation of some thiophenes (62MI2). Hydroxymethylation has been used to determine the position of substitution in indole (51G613). 

Phenol 6-Hydroxymethyl-4-methyl-2-thiocyanatomethyl- IX, 858 3H-Pyrrol 3-Phenylsulfonyl-4,5-dihydro-Ell, 1254 (C,C-Aufbau) Thiophen 4-Cyan-2-ethoxycarbonyl-5-ethyl-3-hydroxy- E6a, 297 [HS-CH2-COOR + RO-C(C2H 5) = C(CN) - COOR]... 

Chart 3.1 Chemical structures of 6-(N,N-di- -propyl)amino-4,5,6,7-tctrahydrobcnzo /)]thiophene (34), 2-fomiyl-6-(N,N-di- -propyl)amino-4,5,6,7-tctrahydrobcnzo /> thiophene (65), 2-hydroxymethyl-6-(N,N-di- -propyl)amino-4,5,6,7-tctrahydrobcnzo /> thiophenc (66),... 

The most potent and selective compound is derivative 66 with a hydroxymethyl moiety on the 2-position. Introduction of an extra interaction point on the 2-position of 6-(N,N-di- -propyl)aminotetrahydrobenzo[/>]thiophene has a negative effect on the affinity for the dopamine D2 receptor and no or a positive effect on the affinity for the dopamine D3 receptor. 

Hydroxymethyl-6-(N,N-di- -propyl)aminomethyl-4,5,6,7-tetrahydrobenzo /> thiophene (71). This compound was synthesised according to the method used for compound 66 starting with 0.25 g crude 2-formyl -6-(N,N-di -//-propyl )ami nomethyl -... 

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