Thiophenes reaction with aldehydes

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

Aldehyde (46) has also been converted into diazole-fused thiophenes. Reaction with hydrazine derivatives gave hydrazones (50), which on treatment with acid were converted to diazoles (51). Unfortunately, the nitrogen substituent was sometimes scrambled, leading to mixtures of (51) and (52). The final sulfur oxidation was uniformly high yielding [28,29] (Scheme 6.13, Table 6.3). 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

This 1,3-migration of hydrogen was also observed when 40 reacted with Lawesson s reagent to produce the dithiolactone 41. However, when y-hydroxy-a,P-unsaturated aldehyde 42 was reacted under similar conditions, thiophene 43 was prepared efficiently. These results are not surprising considering that the oxidation state of 42 is equivalent to the traditional saturated 1,4-dicarbonyl substrates of the Paal thiophene reaction via tautomerization of the double bond, and aromaticity is reestablished in the fully conjugated 43. 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

The greatest difference observed between the side-chain reactivities of selenophene and thiophene derivatives was in the reaction of aldehydes with aniline (cf. Eq. 13), a ratio of 4.2. 

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. 

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)]. 

The condensation of thiophene with ketones in presence of 70% H2S04 gives di-2-thienylmethane derivatives (63AHC(l)l). Thus acetone leads to (85). Intramolecular versions of such acid-catalyzed condensations with aldehydes and ketones are known (Scheme 14) (73JOC1056, 70AHC(11)177). The Bradsher reaction has been used for the synthesis of thienobenzothiophenes in low to moderate yields (Scheme 15) (70CC1094). 

Thiophene-2-carbaldehyde has become extremely cheap and easily available through the Vilsmeier formylation of thiophene. The reactions of thiophene substrates with several iminium salts have been investigated (B-76MI31400). 3-Phenylthiophene gives 4-phenylthiophene-2-carbaldehyde with chloromethylene iminium ion. In the case of 2-methoxy-5-methylthiophene, a dealkylation takes place above 50-70 °C. If the intermediate iminium salt (91) is formed at 20 °C and then hydrolyzed, the aldehyde (92) is obtained. 

The Vilsmeier-Haack reaction of ketones forms chlorovinyl aldehydes, which can add thiols readily. The reaction with a-tetralone gave the chlorovinyl aldehyde (230), and reaction with ethyl thioglycolate in ethanolic ethoxide solution formed the dihydro derivative (231), easily dehydrogenated to naphtho[l,2-6]thiophene-2-carboxylate (73JCS(P1)2956). 

Thieno[2,3-6]thiophene (7), upon reaction with DMF-POCb, was readily formylated at C-2 to give the aldehyde (54). Less than 0.1% of the C-3 substituted product was detectable by GC when exactly one equivalent of POCl3 was used. The orientation of the substituent was confirmed by conversion to the known acid (55) by oxidation, and by reduction to the known 2-methyl derivative (56 Scheme 12) (76AHC(19)123). 

The use of 4-bromo-3-formylthiophene (175) led to the third classical thieno[3,4-6]thiophene (8) via analogous reactions. The aldehyde (175) was protected by ketalization, and then subjected to bromine-metal exchange with n-butyllithium to give a lithio derivative which was reacted with sulfur, followed by methyl chloroacetate. The resulting ester-aldehyde derivative (176a) was condensed under the influence of base to give, after decarboxylation, thieno[3,4-6]thiophene (8 Scheme 61) <76AHC(19)123). 

Reaction of 2-benzo[6]thienyllithium (and its 7-methyl derivative 90) with aldehydes 486,5fl4, 620 or ketones 467 483 affords a secondary or tertiary alcohol, respectively. Treatment of 2-benzo[6]thienyl-lithium with acetyl chloride gives mainly l,l-di(2-benzo[6]thienyl)-ethylene.132 Side-chain alcohols in positions other than the 2-position are most easily prepared by reaction of the appropriate benzo[6]-thienylmagnesium halide with aldehydes 460,471 or ketones,186,3o9, 349, 4 7,466,479,498 or foy reaction of a benzo[fe]thiophene aldehyde, ketone, or ester with an alkylmagnesium halide.358,427 465 The preparation of alcohols from 2- and 3-benzo[6]thienylmethyl-magnesium chloride485,528 is discussed in Section VI, D, 4. 

Finally, SchifTs bases of other heterocyclic aldehydes can also be reacted with p-tolyl-substituted benzo[6]- (see Table III) and naphtho-[2, l-i]thiophenes.38,37,58 Thus, 2-(p-tolyl)naphtho[2,l-A]thiophene (116) gives, on reaction with the anil derived from 3-formyldibenzofuran and p-chloroaniline, the styryl compound 117.36... 

As pointed out by Togni and Pastor, enantioselectivities in the gold-catalyzed aldol reaction of aldehydes containing an a-heteroatom are significantly different from those of simple aldehydes (Table 8B1.3) [15,16]. Low enantioselectivities for rrani-oxazolines are observed in the aldol reactions of 2-thiophene-, 2-furan-, and 2-pyridinecarboxaldehyde (entries 2, 4,7). In the reactions of the 2-furan- and 2-pyridinecarboxaldehyde, cA-oxazolines with fairly high enantiomeric purities are formed as the minor product but in a rather low trans/cis ratio. A similar a-heteroatom effect is also observed in the aldol reaction of 2,3-Oisopropylidene-D-glyceraldehyde. 

For the thiophen mentioned above, all the carbon atoms stemmed from cysteine, carbohydrate apparently not having a role. On the other hand, theoretically, thiophens can be derived from furans simply by reaction with H2S. Belitz and Grosch251 postulate derivation from 2-mercaptoethanal (Strecker aldehyde from cysteine) and acrolein or butenal (aldol condensation product from acetaldehyde). Vemin and Parkanyi216... 

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