Exocyclic products

Harmata et al. have developed a tandem Sonogashira/nitrogen-addition reaction of acetylenes 261 to sulfonamide 262 to prepare S(vi)-oxidized compounds 263 and 264 (Scheme 36) <20050L143>. When R = alkyl (e.g., Pr"), the 1,2-thiazine 263 is the major product (70%) formed via a endocyclization process, along with a minor amount (20%) of exocyclized product 264, while the five-membered ring product 264 (81%) is preferred when R= Ph. 

Analogous reactions have been achieved recently with molecular oxygen as the sole stoichiometric oxidant by employing (-)-sparteine (sp) as the chiral ligand [153,163]. Stoltz and coworkers demonstrated asymmetric oxidative cychzation of a 2-allylphenol substrate (Eq. 34). A stoichiometric quantity of the sp hgand was necessary, perhaps because it also serves as a base in the reaction. Enantioselective oxidative tandem cychzation of 2-allyl anilides was achieved by Yang and coworkers (Eq. 35). The reactions proceed exclusively to the five-membered exocyclization products. 

With a-phenylselenolactones, endocyclic elimination is preferred if the syn elimination is possible (equation 44), perhaps because the conformation leading to the exocyclic product involves greater dipole-dipole interaction between the selenoxide and the carbonyl group. However, a-methylenelactones are obtained if syn elimination cannot be achieved (equation 45). The conjugate addition of sodium phenylselenide has been recommended for the protection of ot-methylenelactones, the double bond being reintroduced by selenoxide elimination. ... 

Cyclization of penta-3,4-dien-l-ol (36) affords a mixture of exocyclic products (51). However, cyclization of the isomeric pent-4-yn-l-ol (37) forms methylene tetrahydrofurane exclusively (52) [191]. The reaction can also be applied to... 

Diels-Alder reactions. The product of the cyclization is a bicyclooctene isomer, where endocyclic and exocyclic products are possible with respect to the orientation of the ester group. Of major significance is that the host framework enhances selectivity for the endoisomer over the exoproduct. In the absence of the host, these reactions typically proceeded with a preference for the endoisomer (87 13). but in some cases, the presence of the host would push the selectivity to the point where virtually only the endoisomer was obtained. 

The crucial 3-mercurated cyclic peroxide precursors of can be prepared by mercuric nitrate initiated cyclization of unsaturar-ted hydroperoxides (15). Yields are excellent and the compounds (as the bromide derivatives) can be purified by high pressure liquid chromatography (hplc). Exocyclic products are formed in cyclizations of and 6 with none of the 6-endo products being... 

Thompson points out that there is no evidence that adducts give other than acetates on thermolysis. The exocyclic methylene intermediate (iv) postulated by Robinson could arise by proton abstraction from a Wheland intermediate analogous to (vll) above, rather than from the adduct (in). Similarly its decomposition does not necessarily require the intermediacy of the adduct (v). The fact that i -methyl-4-nitromethylnaphthalene is the product even when the nitrating medium is nitric acid and nitromethane would then require no separate explanation. 

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

Reactions of the 2-amino-4,5-substituted thiazole (52) in acetic acid with ethylene oxide has been reported to give the N-exocyclic disubstitution product (S3) (201) in a 40% yield (Scheme 38). The reactive species in this reaction is probably the carbocation generated in acetic acid by ethvlene oxide. 

If the medium is sufficiently basic to generate the arabident anion 31. mixtures of products resulting from N-nng and N-exocyclic reactivity are observed. Here again steric effects can preferentially orient the whole reaction toward one of the two nitrogens. A general study clearly delineating the rules of behavior for 31 accordine to the nature of R. the... 

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

Benzoyl chloride and derivatives acylate 2-amino-4-aryithiazoles in dioxane in yields of 80 to 90% (249, 250). The location of the acyl group on the exocyclic N has been demonstrated by the fact that the benzoyla-tion product is identical to the benzamidothiazole synthesized from benzamide and 2-bromothiazole (251). 3-Indolyl acetic acid chloride (89) acylates 2-aminothiazole in pyridine (Scheme 62) (81). 

Picryl halides react with 2-amino-4-methylthiazole. Again, the exocyclic nitrogen is the reactive center (288). and the product formed (128) is... 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

Amino-5-methylthiazole does not react with diazotized p-nitroaniline in solutions acidified with acetic or hydrochloric acid (391). 2-Amino-4,5-dimethylthiazole with the diazonium salts of para-substituted anilines, however, gives product 193, involving reactivity of the exocyclic nitrogen (Scheme 122) (399). 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

With secondary amines such as piperidine or dimethylamine the formal products (169) of cine substitution are obtained with primary amines e.g. /-butylamine), in addition to the displacement product (173), a rearranged product (174) is obtained in which the nitrogen-bearing methyl becomes exocyclic 80CC123). Earlier studies on the reaction of... 

The configuration of pairs of isomeric 4-aryIidene-5-pyrazoIones, (Z)- and (E)-(117), was determined by H NMR data (72G491). When R is H, the E configuration is preferred when it is a methyl or a phenyl group, the Z configuration predominates. The presence of an exocyclic sulfur atom as in (118) lowers the interconversion barrier and the products... 

The mesomeric anion (157 Scheme 10) reacts readily with electrophilic reagents such as alkyl or acyl halides at N-2, C-4 and the exocyclic oxygen atom. The percentages of the different products formed are controlled by the HSAB principle. The acylium ion (hard) attacks preferentially at oxygen (hard), whilst the softer alkylating agents attack the nitrogen atom. 

The C-nor-D-homosteroid rearrangement was discovered by Hirschmann and co-workers at the time that Wintersteiner and his collaborators established that the steroid alkaloids jervine and veratramine incorporate a 14 (1312) abeo-nng system. This was the predecessor of the family of simultaneous ring contraction-expansion reactions. Solvolysis of the 12j5-methanesulfonate (144a) gives mainly the kinetic reaction product, the C-nor-D-homo exocyclic olefin (145) along with some 13(17)-ene (146a). 

The dehydrobromination and dequaternization of l,l,3-trimethyl-2-bromomethylpyrrolidinium bromide (158) has been accomplished by dry distillation from potassium acetate (123). Since the product was isolated as the perchlorate salt, no conclusion can be drawn as to whether the original reaction mixture contained the exocyclic enamine (159) or the endocyclic enamine (160) ora mixture of both. 

Reaction of 2-aminopyridine and its 4-methyl derivative and diethyl alkylidenemalonates 356 at 175°C for 1.5-2.5h yielded 3-vinyl derivatives 358, after the isomerization of the exocyclic double bond in 357 (99ACS901). Reaction of 2-amino-4-methylpyridine and bis(2,4,6-trichlor-ophenyl) benzylidenemalonate in the presence of NEt3 afforded only non-cyclised product 359. 2-Aminopyridine and its 4-methyl derivative with diethyl benzylidene- and hexylidenemalonates at 190 °C did not give cyclized products (99ACS901, 99MI29). 

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