Thiophenes with benzaldehyde

The ion (97), acting as an electrophilic reagent, can also attack another molecule of the heterocyclic compound. Thiophene with benzaldehyde or chloral gives the dinuclear product (100 R = Ph, CC13). Pyrrole and furan react with acetone to form tetranuclear derivatives of type (101 Z = NH, O). Pyrroles with a single free position react analogously to thiophene e.g. two molecules of 3-ethoxycarbonyl-2,4-dimethylpyrrole with formaldehyde afford the dipyrromethane (102). 

In a variation of the usual reaction conditions for oxidising furfuraldehyde to 2-furoic acid with hypochlorite, the aldehyde was added dropwise to a 10% excess of commercial sodium hypochlorite solution at 20-25°C, but without the inclusion of additional sodium hydroxide. When aldehyde addition was almost complete, a violent explosion occurred. Subsequent investigation showed that the pH of the reaction mixture fell progressively with addition of aldehyde, and at pH 8.5 the reaction mixture erupted violently, the temperature increased by 70°C and the pH fell to 2. Similar results were seen with benzaldehyde, but not with thiophene-2-aldehyde. 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

The C-thioacylation of l-alkyl-2-methyltetrahydropyrimidines and 1,2-dimethyl-dihydroimidazole has been achieved by reaction with thiophene-2-carbaldehydes in the presence of sulfur (Scheme 115) (82T1673). The yield of product is better with thiophene-2-carbaldehydes (30-40%) than with benzaldehyde. 

The incorporation of cyclic substituents, such as propane-1,3-diyldioxy, its ethyl and benzyl derivatives substituted at the (1-thiophene carbons of 21,23-dithiaporphyrins 240b and 21-monothiaporphyrins 241b (Scheme 95), has also been reported (04BCJ1173) by condensing the substituted thiophene diols 239b with benzaldehyde and pyrrole. The cyclic substituents at the (5-thiophene carbon atoms alter electronic properties of porphyrin. 

In addition to furan, other heterocycles have been examined." Thiophene undergoes efficient photocycloaddition with benzaldehyde to afford a single exo photoproduct (183) in 60% yield. As reported by Jones and coworkers,the photolysis of IV-methylpyrrole in the presence of aldehydes or ketones yields the corresponding 3-hydroxyalkyl derivative (184), even when the reaction mixture is free from any trace of acid. In order to use the pyrrole nucleus for stereoselective alkaloid synthesis (cf. caesalpinine, 185) in the fashion developed with the furan nucleus, pyrrole substituents that stabilize the presumed intermediate bicyclic oxetane must be discovered. 

The hydroxy thiophenes which exist predominantly as the thiolen-2-ones also show reactions characteristic of the enol form. They can be methylated at the oxygen with dimethyl sulfate of diazomethane and they can also be acylated. " They also react as thio-lene-2-ones showing a reactive methylene group which can be condensed with benzaldehyde. The danger of using chemical reactivity data for drawing conclusion as to the physical state of these tautomerizable systems has been pointed out. ... 

Homologs of pyridine, quinoline, thiophen, and various other heterocycles can be oxidized to carboxylic acids generally without destruction of the hetero ring in the pyrrole series, however, this cannot be done directly but requires intervention of an intermediate (see Fischer et al.A05). More circuitous routes are also sometimes preferable in the quinoline series for instance, in their total synthesis of hydroquinine Rabe et a/.406 obtained the 4-carboxylic acid from 6-methoxy-4-methylquinoline by oxidizing the 4-styryl derivative (obtained by reaction with benzaldehyde) instead of oxidizing the methyl compound directly. Alkyl groups at positions 2 and 4 of pyridine are more easily oxidized than those at position 3. 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

By introducing reasonable values (about 2 for nitrogen, 4 for oxygen) for the electron affinity parameter relative to carbon, 8, and for the induced electron affinity for adjacent atoms (32/8i = Vio), we have shown that the calculated permanent charge distributions for pyridine, toluene, phenyltrimethylammonium ion, nitrobenzene, benzoic acid, benzaldehyde, acetophenone, benzo-nitrile, furan, thiophene, pyrrole, aniline, and phenol can be satisfactorily correlated qualitatively with the observed positions and rates of substitution. For naphthalene and the halogen benzenes this calculation does not lead to results... 

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

Dihydro-2,5-dimethoxyfuran 824 reacts neat at 24°C with TCS 14 via the intermediate 825, the 2-trimethylsilyloxyfuran 826 (which can also be readily prepared from 5H-furan-2-one), and 827-829 to give the crystalline trimer 830 in 20% yield [21]. In the presence of aldehydes such as thiophen-2-aldehyde 831a or benzaldehyde 831b, however, 824 reacts via 832 to give the condensation products 833 a and 833 b, which are obtained in 30 and 62% yield, respectively [22, 23] (Scheme 6.11). Because it is postulated 2-trimethylsilyloxyfuran 826 is a intermedi-... 

Standard transformations at the a-carbon, as discussed in CHEC-II(1996) <1996CHEC-II(4)179>, proceed without incident. Selected recent examples (Scheme 19 Equation 22) include the conversion of the esters 153 into the hydrazides 154 and thence into the methylene carbohydrazides 155 <2005HC029>, a process that has been shown by the same workers to apply to other aldehydes (benzaldehyde, 4-A Ar-dimethylaminobenzaldehyde, furfuralde-hyde, or thiophene 2-carboxaldehyde) with equal success <1999FES747>, and the conversion of the ester 156 into amide 157 <2005NN1919>, a process that demonstrates the robustness of the 1,2,4-oxadiazole ring. 

A recent extension of this methodology includes condensation of 44 with a variety of substituted benzaldehydes, furfurals, and thiophene carboxaldehydes afforded analogues of 48 in good to excellent yield as shown in Table 6.2 (Fig. 6.6). These products were completely characterized spectroscopically with an excellent discussion of the effects of substituents on the corresponding UV, IR, MS, and NMR spectra. Neutralization of 48 with sodium bicarbonate in aqueous ethanol produced the corresponding free bases uneventfully. These compounds were evaluated both as cyanine dyes and for biological activity. Condensation of 44 with ( )-3-(5-methylfuran-2-yl)-2-propenal affords the expected E, )-dienes 49a and 49b in 50 and 90% yield, respectively (Fig. 6.7). 

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