Thiophenes reactions with nucleophiles

Mansuy D, Valadon P, Erdelmeier I, et al. Thiophene S-oxides as new reactive metabolites formation by cytochrome P450 dependent oxidation and reaction with nucleophiles. J Am Chem Soc 1991 113(20) 7825—7826. 

The 2,3-double bond in benzo[6]thiophene-1,1-dioxides undergoes addition reactions with nucleophiles in a manner comparable to that of other a,/9-unsaturated sulfones no aromatic properties are detectable in this way for the thiophene ring.718-723 For example, thiophenol and p-thiocresol give the adducts (340 R = H or Me) in the presence of base.723 However, if the aryl mercaptan and the sulfone are heated together, a radical reaction occurs to give the corresponding 2-substituted compound.723 In contrast to the behavior of aryl mercap-... 

Thiophene-1-oxides Thiophene-1,1 -dioxides. 2.1 Reaction with nucleophiles. 2.2 Cycloaddition reactions. 2.3 Other reactions Thiophene S,N-ylides and S,C-ylides. 3.1 Cycloaddition reactions of S,N-ylides and S,C-ylides. 3.2 Cyclopropanation reactions of S,C-ylides. 3.3 Thermal transformations of thiophene S,N- and S,C-ylides Oxothiophenes Tautomeric with Hydroxythiophenes. 4.1 Tautomerism. 4.2 Alkylation and acylation. 4.3 Condensation reactions at the methylene group. 4.4 Halogenation. 4.5 Oxidative coupling. 4.6 Cycloaddition. 4.7 2,3-Diones 4 Sulfoxides and sulfones. 4.9 Photochemistry. 4.10 Macrocyclic polyethers... 

Several 2-(haloethenyl)benzo[Z>]thiophene-1,1-dioxides have been prepared and their reaction with nucleophiles studied <89JOC331l>. Thus the dichlorofluoro compound (209) reacts with amines by initial addition at position 3, followed by 1,4-elimination of HCl (Scheme 36). Alkoxide acts in a similar manner. Thiophenol leads to the bis (phenylthio) product. 

Complexes 79 show several types of chemical reactions (87CCR229). Nucleophilic addition may proceed at the C2 and S atoms. In excess potassium cyanide, 79 (R = R = R" = R = H) forms mainly the allyl sulfide complex 82 (R = H, Nu = CN) (84JA2901). The reaction of sodium methylate, phenyl-, and 2-thienyllithium with 79 (R = R = r" = R = H) follows the same route. The fragment consisting of three coplanar carbon atoms is described as the allyl system over which the Tr-electron density is delocalized. The sulfur atom may participate in delocalization to some extent. Complex 82 (R = H, Nu = CN) may be proto-nated by hydrochloric acid to yield the product where the 2-cyanothiophene has been converted into 2,3-dihydro-2-cyanothiophene. The initial thiophene complex 79 (R = R = r" = R = H) reacts reversibly with tri-n-butylphosphine followed by the formation of 82 [R = H, Nu = P(n-Bu)3]. Less basic phosphines, such as methyldiphenylphosphine, add with much greater difficulty. The reaction of 79 (r2 = r3 = r4 = r5 = h) with the hydride anion [BH4, HFe(CO)4, HW(CO)J] followed by the formation of 82 (R = Nu, H) has also been studied in detail. When the hydride anion originates from HFe(CO)4, the process is complicated by the formation of side products 83 and 84. The 2-methylthiophene complex 79... 

Cases of the S-coordinated rhodium and iridium are quite scarce. To complete the picture, we next consider the possibilities of S-coordination using complicated derivatives of thiophene. 2,5-[Bis(2-diphenylphosphino)ethyl]thiophene is known to contain three potential donor sites, two phosphorus atoms and the sulfur heteroatom, the latter being a rather nucleophilic center (93IC5652). A more typical situation is coordination via the phosphorus sites. It is also observed in the product of the reaction of 2,5-bis[3-(diphenylphosphino)propyl]thiophene (L) with the species obtained after treatment of [(cod)Rh(acac)] with perchloric acid (95IC365). Carbonylation of [Rh(cod)L][C104]) thus prepared yields 237. Decarbonylation of 237 gives a mixture of 238 and the S-coordinated species 239. Complete decarbonylation gives 240, where the heterocycle is -coordinated. The cycle of carbonylation decarbonylation is reversible. 

Addition of amines to a,/J-unsaturated sulfones has been used in synthesis of key intermediates of biotin. In this reaction, benzylamine serves first as a base in the reaction with 60 to afford thiophene 1,1-dioxide (61) and also as a nucleophile to introduce two amino groups (equation 57)49. 

The maleimide group can undergo a variety of chemical reactions. The reactivity of the double bond is a consequence of the electron withdrawing nature of the two adjacent carbonyl groups which create a very electron-deficient double bond, and therefore is susceptible to homo- and copolymerizations. Such polymerizations may be induced by free radicals or anions. Nucleophiles such as primary and secondary amines, phenates, thiophenates, carboxylates, etc. may react via the classical Michael addition mechanism. The maleimide group furthermore is a very reactive dienophile and can therefore be employed in a variety of Diels Alder reactions. Bisdienes such as divinylbenzene, bis(vinylbenzyl) compounds, bis(propenylphenoxy) compounds and bis(benzocyclobutenes) are very attractive Diels Alder comonomers and therefore some are used as constituents for BMI resin formulations. An important chemical reaction of the maleimide group is the ENE reaction with allylphenyl compounds. The most attractive comonomer of this family is DABA particularly when tough bismaleimide resins are desired. 

Vinyl ethers and amines disclose little tendency to revert to type thus, the intermediate formed by reaction with an electrophilic reagent reacts further by adding a nucleophilic species to yield an addition compound cf the sequence (8) — (11). Thiophene and pyrrole have a high degree of aromatic character consequently the initial product formed by reaction of thiophene or pyrrole with an electrophilic species subsequently loses a proton to give a substituted compound cf the reaction sequence (12) — (15). Furan has less aromatic character and often reacts by overall addition as well as by substitution. In electrophilic addition, the first step is the same as for substitution, i.e. the formation of a tr-complex (e.g. 13), but instead of losing a proton this now adds a nucleophile. 

The sulfur atom of thiophenes is weakly nucleophilic and can act in some cases as the site for attack of an electrophilic reagent. In strongly acidic solutions the a-carbon atom is protonated (66RTC1072) this could be a thermodynamically controlled product, however. Reaction of thiophene with powerful alkylating agents provides the thiophenium salt (56),... 

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

As well as the previous chapter on the Hammett equation,1 the importance of the approach has found expression in specific areas in other contributions to these volumes side chain reactivities of thiophenes 17 tautomerism 18 reactions of azines with nucleophiles 19,20 formation of benzofuroxans by decomposition of o-nitrophenyl azides 21 acid dis-... 

When a cyclization reaction leads to mixtures of two isomeric benzo[6]thiophenes, their relative proportions are readily estimated by examination of the 1H NMR spectrum of the mixture.96 104-106 Mixtures obtained by acetylation98 and bromination 76,90 reactions and by Baeyer-Villiger oxidation of acetylbenzo[6]thiophenes107 have been similarly analyzed. The 19F NMR spectra of several polyfluoro-benzo[6]thiophenes have been examined,103,108-m and used to study the reaction of 4,5,6,7-tetrafluorobenzo[6]thiophene with nucleophiles.108 The tautomerism of 2-amino-,112-114 3-N-phenylamino-,116 and 3-hydroxybenzo[6]thiophene109,116-117 derivatives has been studied by 7H NMR spectroscopy. 

An example of transfer of electron from nucleophile to substrate is seen in the formation of the radical anions (observable by ESR) of 5-halo-2A/,3W-benzotf>]thiophene-2,3-diones on treatment with nucleophiles.20 It has been proposed in some cases, that this single-electron transfer step takes place through a charge transfer complex between the nucleophile and the aromatic substrate.21-22 Some reactions occur spontaneously, i.e. without any catalysts or reagents other than the substrate and the nucleophile, but the initiation process is usually, although not invariably, photostimulated (near-ultraviolet radiation, 300-... 

Cyclizations can occur with heteroatoms present in the tether as long as the groups are not strongly nucleophilic. Decomposition of a-diazo- 3-arylmethanesulfonyl esters (173) resulted in the formation of 1,3-dihydrobenzo[c]thiophene 2,2-dioxides (174 equation 38),143 which are valuable precursors to o-quinodimethanes. Reaction with /V-aryldiazoamides (175) has been shown to be a useful method for preparing 2(3//)-indolinones (176 equation 39),22a while reaction of a-diazo-(3-keto esters (177) has been developed as a process to synthesize 3-acetylbenzofiiran-2(3//)-ones (178 equation 40).144... 

---