Electrophilic Attack at Carbon

Nitration of 4-amino-6-methylpyridazin-3(2-ff)-one at C-5 was performed in two steps. Treatment with concentrated nitric acid affords 6-methyl-4-(nitroamino)pyridazin-3(2f/)-one whose rearrangement in concentrated sulfuric acid led to the formation of 4-amino-6-methyl-5-nitropyridazin-3(2/0-one 2001RJ01026 . 

Thiazole sulfonation requires forced conditions such as oleum at 250 °C for 3 

Nitration of thiazoles has not been reported to take place under the classical nitration conditions even under extreme condition. Thiazole itself is untouched by nitric acid or oleum at 160 °C, but methyl thiazoles are sufficiently activated to undergo substitution and preferentially yield the 5-nitro over the 4-nitro regioisomer.  

There is no reaction of unsubstituted 1,3-thiazole with chlorine or bromine in an inert solvent. However, when activated by a donor such as the amino group, bromination has been reported to take place. An example is shown below.  

Similarly, when there are two substituents on the thiazole, the unsubstituted position gets halogenated. Activation of thiazoles with the aid of donor groups has been documented. The reaction scheme shown below illustrates this point where electrophilic substitution of 2 -phenyl-4/ -2,4 -bisthiazoles has been studied in order to establish relationships between structure and reactivity of the two thiazole rings. 

This reaction has also been used in the syntheses toward diamidino 2,5-bis(aryl)thiazoles exhibiting antiprotozoal activity against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f), shown below. Here, the synthesis involved conversion of derivatized thiazoles to bromothiazoles as substrates for Suzuki cross-couplings.  

Treatment of l-(/-butoxylcarbonyl)-2-(methoxycarbonylmethylene)-4-(trifluoromethyl)azetidine 28 with potassium bis(trimethylsilyl)amide at — 78 °C followed by reaction with an alkyl halide or an aldehyde afforded 3-alkyl-substituted azetidine derivatives 29 (Equation 6) 20030L4101 . This procedure is of particular importance to the synthesis of azetidines with an alkyl substituent at the C-3 position. 

Electrophilic attack at carbon was well covered in CHEC-I 84CHEC-I(3B)1 . The electron deficient (benzo)pyridazine systems are not normally susceptible to electrophilic attack at ring carbons of the heterocyclic ring unless one or preferably two activating substituents (e.g., amino, hydroxy/keto) or an A-oxide function are present, and are quite stable under oxidizing conditions. The benzo rings 

In contrast to other (benzo)pyridazines, 1//-benzo[fi e]cinnolines show a marked susceptibility to electrophilic attack due to the pyrrole-like N-1 and, for example, 6-methoxy derivatives undergo formylation at C-7 and C-9 with Vilsmeier s reagent 81ZOR2444 and condenses with aldehydes at C-9 82ZOR415 . 

While chlorination of pyridazines is not very common, the 4-dicyanomethylidene-l//-pyridazine system (30) with sulfuryl chloride gives the 5-chloro derivative (49) in quantitative yield (Equation 

The 3-, 4-, 5- and 6-positions in the pyridazine nucleus are electron deficient due to the negative mesomeric effect of the nitrogen atoms. Therefore, electrophilic substitution in pyridazines is difficult even in the presence of one or two electron-donating groups. The first reported example is nitration of 4-amino-3,6-dimethoxypyridazine to yield the corresponding 5-nitro derivative. Nitration of 3-methoxy-5-methylpyridazine gives the 6-nitro-, 

4-nitro- and 4,6-dinitro derivatives. In the case of pyridazinones, however, several electrophilic reactions are known. Nitration of 4,5-dichloro-2-methylpyridazin-3(2//)-one occurs at position 6. 

Direct chlorination of 3,6-dichloropyridazine with phosphorus pentachloride affords 3,4,5,6-tetrachloropyridazine. The halogen is usually introduced next to the activating oxo group. Thus, 1,3-disubstituted pyridazin-6(l//)-ones give the corresponding 5-chloro derivatives, frequently accompanied by 4,5-dichloro compounds as by-products on treatment with chlorine, phosphorus pentachloride or phosphoryl chloride-phosphorus pentachloride. 

2-Disubstituted pyridazine-3,6(l//,2//)-diones add halogens to the 4,5-double bond, followed by dehydrohalogenation to give 4-halo derivatives. 1,2-Disubstituted 5-bromopyridazine-3,6(l//,2F0 diones react with bromine to give the corresponding 4,5-dibromo derivative. The Mannich reaction with 2-arylpyridazin-3(2//)-one occurs at position 4. 

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

The reactivities of the isoxazoles are compared with those of benzene and some five-membered ring heterocycles in Table 7. Isoxazole is more reactive than benzene (by 4.3 log units) and isothiazole (0.8) and is less reactive than 1-methylpyrazole, furan, thiophene and 1-methylpyrrole. A 5-methyl substituent activates the nucleus more than does a 

3-methyl substituent the activation provided by 3,5-dimethyl substituents is nearly the sum of the individual effects of the 3-methyl and 5-methyl groups considered separately. 

Nitration of alkylisoxazoles and phenylisoxazoles has received considerable attention (71JCS(B)2365, 75JCS(P2)1627). Alkylisoxazoles underwent nitration as the free base at the 4-position of the isoxazole nucleus the non-reactivity under similar conditions of the 

Under carefully controlled conditions, nitration of 3,5-diphenylisoxazole in AC2O/HNO3 at 20°C gave 4-nitro-3,5-diphenylisoxazole. However, 3,5-diphenylisoxazole in HNO3 underwent nitration first at the para position of the 5-phenyl substituent and then at the meta position of the 3-phenyl group (74KGS597). 

The parent isoxazole was nitrated under strictly controlled conditions (35-40 °C) in only 3.5% yield whereas 3,5-dimethylisoxazole was nitrated in mixed acid at 100 °C to give 

Svoboda and co-workers studied substitution reactivity of thieno[3,2- ][l]benzofuran 61 1997CCG1468 in comparison with the isomeric [l]benzothieno[3,2-. ]furan 60, which was already described 1993CCC2983 . They discovered that under electrophilic substitution conditions, the system 61 is more stable than 60. 

Electrophilic substitution and metallation reactions of [l]benzothieno[3,2-3][l]benzofuran 63 were studied 2000CCC58 . Bromination, acetylation, benzoylation, formylation, and nitration usually afforded inseparable mixtures of 2- and 7-substituted derivatives as the main products. Disubstitution reactions preferably led to 2,7-disubstituted derivatives. [l]Benzothieno[3,2-3][l]benzofuran-10,10-dioxide 64 and [l]benzothieno[3,2-3][l]ben-zofuran-lO-oxide 65 can be selectively obtained by oxidation of 63. Mononitration of 64 and 65 led selectively to corresponding 7-nitro derivatives, respectively. Only sulfoxide 65 was successfully reduced. 

The influence of catalysts (AICI3 and SnCU) acid chlorides, and solvents (dichloroethane, nitromethane) in the acylation of methyl 2-methyl-4/f-thieno[3,2- ]pyrrole-5-carboxylate 75 was studied. Conditions for the regioselective acylation processes were found and four types of compounds 76a-f, 77a-e, and 78 were obtained. 

The reactions and reactivities of thieno[3,2- ]thiophene (12) have been described in detail 84CHEC-1(4)1037). 

The nitration of ethyl 4/f-thieno[3,2- ]pyrrole-5-carboxylate (68 R = C02Et) has been carried out 84JHC215 using cupric nitrate in acetic anhydride with low yields obtained after purification by column chromatography (69 R = C02Et) 34%, (70 R = C02Et) 42%, (71 R = C02Et) 3%. 

Vilsmeier reaction of ethyl 1 -methyl-4/f-pyrrolo[3,2- ]pyrrole-2-carboxylate (72) gave a mixture of C-5 (73) and C-6 (74) formylated products 89TL1655 . 

The l-methylbenzo 7 ]furo-, benzo[ ]thieno-, and benzo[ ]selenolo[3,2- ]pyrroles (75), (76), and (77) were prepared 83JHC49 and the influence of annelation and of the heteroatom upon reactivity was tested toward acetylation and lithiation 83JHC6l . The l-methylbenzo[ ]furo[3,2- ]pyrrole (75) was acetylated at C-2. 

4-Acetyl-2-arylfuro[3,2-6]pyrroles (88) and (89) 86CCC106 yield 5-formylated products (90) and 

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Electrophilic Attack at Carbon. Electiopliilic attack at a C-atom in pyiidines is paiticulaily difficult unless one oi mote strong... 

Aminating agents 3.14 Other Lewis acids Electrophilic Attack at Carbon... 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

It is apparent from simple valence bond considerations as well as from calculations of rr-electron density, " that isoindoles should be most susceptible to electrophilic attack at carbon 1. This preference is most clearly evident when the intermediate cations (85-87) from electrophilic attack (by A+) at positions 1, 4, and 5 are considered. The benzenoid resonance of 85 is the decisive factor in favoring this intermediate over its competitors. 

Heterolytic cleavage of the tin-carbon bond is reviewed in references (94-96). Cleavage by electrophiles (e.g, HgXj or halogen) is dominated by electrophilic attack at carbon, and cleavage by nucleophiles principally involves nucleophilic attack at tin. Much of the interest in these processes centers on the intermediate mechanisms that may exist between these extremes, in which electrophilic attack is accompanied by some nucleophilic assistance, and vice versa. Allylic, al-lenic, and propargylic compoimds show a special reactivity by a special (Se2 or SE2y) mechanism. 

The 1,2,4-oxadiazole ring is almost inert to electrophilic attack at carbon and there are no further examples to supplement those few important exceptions reported previously in CHEC-II(1996) <1996CHECII-(4)179>. 

Electrophilic attack at carbon or sulfur is well documented in CHEC(1984) <1984CHEC(6)513> and in CHEC-11(1996) <1996CHEC-II(4)355>. No recent work has been reported. 

Electrophilic attack at carbon is a well-documented reaction which occurs regioselectively at the C-3 position. It was illustrated by numerous examples, including nitrations, halogenations, acylations, and Mannich reactions in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249>. Table 1 reports some additional recent examples. It should be noted that all these synthetic transformations were carried out in the field of medicinal chemistry. 

Electrophilic attack at carbon occurs regioselectively at the C-l position, although the reaction shown in Scheme 34 might interfere to give small amounts of C-3-substituted product. This was illustrated by some examples in CHEC(1984). Additional recent examples include acylations under Friedel-Crafts conditions <1998H(48)1015, 2001CPB799>. 

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