Thiophene-3-carbonitrile

Stable 2,4-disubstituted thiophene-3-carbonitrile oxides 7 and 3,5-di(t-butyl)-thiophene-2-carbonitrile oxide 8 were synthesized from respective aldoximes by the similar one-pot procedure (33—35). 

Diamino-3,4-dicyanothiophene is thus converted by NaOH to 2-amino-3,4-dicyano-5-mercaptopyrrole (Scheme 132) (58JA2822). Here, prior to the recyclization of the intermediate (396), a rotation around the 4,5-bond has occurred. With other substrates such as (397), recyclization results in a thiophene, different from the precursor. Here the 3-substituent is involved in the cyclization and so a rotation around the 3,4-bond is mandatory. One can therefore postulate an intermediate of the type (398) in such reactions ring closure of this will lead to a thiophene-3-carbonitrile which could be either (399) or (400). Some examples are shown in Scheme 133 (75JPR861, 77JCR(S)294). 

It has been established that thiophenes undergo regiospecific oxidative cyanation at C-2 with TMSCN, as illustrated by the general transformation of 41 into 42 <05OL537>. Conversion of 3-bromobenzo[6]thiophene to benzo[6]thiophene-3-carbonitrile has been accomplished by treatment of the substrate with Zn(CN)2 in the presence of a catalytic system consisting of Pd/C, Zn dust, Br2, and PPhs in A/jA -dimetliylacetamide <05TL 1849>. 

Evidently, stable nitrile oxides can be investigated by spectral and X-ray methods using ordinary procedures. As examples, X-ray diffraction studies of o-sulfamoylbenzonitrile oxides (20), 5-methyl-2-(methylsulfonyl)-3-thiophene-carbonitrile oxide (21), (),( >-diphenylacrylonitrile oxide (22), and (dimorpholino-phosphoryl) carbonitrile oxide (23) can be cited. It should be underlined that structures of the latter compounds differ from those of classical stable 0,0 -disubstituted arylcarbonitrile oxides and tert-alkylcarbonitrile oxides. Therefore, not only purely steric shielding of the CNO group but also electrostatic or donor-acceptor interactions between the atoms of the latter and adjacent polar substituents (21, 23) and also electron delocalization in it-systems (20, 22) enhance the stability of nitrile oxide. 

Similarly, the conformation of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophene-carbonitrile (3) forms seven (if not more) polymorphs, the colour of which ranges from yellow to red depending on the molecular conformation [10-12]. 

Acetoacetic esters also exhibit the characteristics of an aldol intermediate with 2-amino-4,5-dihydro-3-thiophene-carbonitriles 281. In the first stage, the aldol adds to the nitrile group with the formation of... 

Different crystal forms are often recognized by differences in the colour and shape of crystals. A striking example of these two properties is provided by the differences in colour and form of the crystal forms of ROY (ROY=red, orange, yellow polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophene carbonitrile) [30,31]. Colour and shape are only some of the possible differences and Table 1 summarizes some major possible differences in chemical and physical properties between crystal forms and solvates of the same substance. In addition, one has to consider that new and different properties may derive from a change in the nature and chemical composition of the same molecule as a consequence of salt formation or co-crystallization. For each new crystal form obtained, a full characterization... 

Thiophene-2-carbonitrile, 3-azido-synthesis, 4, 807 Thiophene-2-carboxamide 3,5-disubstituted synthesis, 4, 9l9 5-substituted protonation, 4, 755... 

Nitrile oxides, RNCO, are derivatives of fulminic acid (R = H). They can be named as fulmido-substituted parent molecules, but usually their names are derived from corresponding nitriles, for example, benzonitrile oxide, mesitonitrile oxide, thiophene-2-carbonitrile oxide. 

Hydroxylamine-O-sulfonic acid converts thiophene-2-carbaldehyde into the nitrile in high yield under mild conditions. 3-Azidothiophene-2-carbonitrile has been prepared thus and used for synthesizing many types of fused thiophenes (80JHC1765). Vapour-phase ammoxidation of thiophene-2-carbaldehyde to the nitrile has also been described (78CPB2838) the Mo-Bi-Sb (molar ratio 3 5 2) mixed oxide catalyst was found most suitable. 

In addition to identifying the molecular ion of the dithiadiazole cation, major fragments corresponding to the loss of NS and NS2 were also observed. Fragmentations for the dithiatetrazocines see a loss of thiophene-2-carbonitrile or furan-2-carbonitrile, with N, N2S, and N2S2. 

Yamagata etal. (86CPB516) found that condensation of 2-acetamido(or benzamido)-4,5-dihydrothiophene 3-carbonitriles 61 (R = Me or Ph) with ethyl cyanoacetate in the presence of sodium hydride afforded ethyl a-cyano-4-[2-(methyl or phenyl)thienopyrimidine]acetates 83a. Thiophenes 61 (R = Me or Ph) also reacted with malononitrile in a similar way, to yield the corresponding malononitriles 83b. 

Thiophenes are also readily available by treatment of 3-halocinnamonitriles with a-haloacetic acid derivatives in the presence of sodium sulfide and a base. In a stepwise route, the precursor 4 was converted to the intermediate 5, which was finally subjected to base induced cyclization giving the thiophene 6 <07SC1133>. Related annulation methodology has been used for construction of a series of 3-amino-5-arylthiophene-2-carbonitriles <07S1027>, and thieno[3,2-Z>]pyridine-5(477)-ones <07S2153>. 

Alternatively, thiophenes have been accessed by base induced reactions involving thioacetaldehyde dimer and active methylene compounds under microwave irradiation, as illustrated by synthesis of 2-aminothiophene-3-carbonitrile 7 <07TL5261>. 

If the 2-position is blocked, cyanation occurs at the 3-position. Similarly, cyanation of 1-methylpyrazole gives a mixture of the 4- and 5-carbonitrile [228]. The efficient substitution observed for many pyrroles, imidazoles [229], and indoles contrasts markedly the addition reactions observed for furans (cf. Chapter 16) and thiophenes [230]. However, this difference may only be apparent. At least for two of the cases already cited [226], it has been demonstrated [231] that the cyanosubstituted pyrroles arise as a result of elimination during workup of the 2,5-addition product originally formed. For benzo[b]thiophenes, cyanation leads predominantly to substitution products [232] ... 

To achieve a further benzannelation, benzo(b)thiophen-7-carbonitrile (196 b) has been converted by a four-step sequence — hydrolysis by KOH in cellosolve (150°, 1 h), reduction of the acid by sodium bis(methoxyethoxy)aluminiumdi-hydride, action of thionyl chloride on the carbinol, and reaction of the chloromethyl compound with sodium cyanide in DMSO — in a 75% overall yield to the oily benzo(b)thiophen-7-acetonitrile (197), which finally afforded the naphtho(l,2-b)-thiophen-9-carbonitriles (198a, b) ... 

Alkenylcyclopropane-l -carbonitriles were obtained in moderate to good yields, in some cases even with good diastereoselectivity, by the photolysis of 3/f-pyrazole-5-carbonitriles in unsaturated solvents (Table 4). On UV irradiation, the pyrazoles isomerize to jS,> -unsaturated a-diazocarbonitriles, which cannot be isolated but decompose rapidly to l-alkenyl(cyano)car-benes, which then either cyclize to cyclopropenecarbonitriles 1 or react with the alkene substrate to give 1 -alkenylcyclopropane-1 -carbonitriles 2. As a rule, the cyclopropanation of electron-rich alkenes, dienes, thiophene, and furan dominates the intramolecular carbene reaction. A generalized procedure can be found in Houben-Weyl, Vol. 19b, p 1209. 

In a novel synthesis of 5-R-substituted benzo[b]thiophene-7-carbonitriles,... 

---