Intramolecular cyclizations chloride

Benzotrithiadiazepine (12.14, R = H) is obtained as bright-yellow crystals by the reaction of benzo-l,2-bis(sulfenyl chloride) with McsSiNSNSiMcs (Eq. 12.4). The tetrafluoro derivative 12.14 (R = F) has been prepared by a similar procedure. The isomeric 1,2,4,3,5-benzotrithiadiazepine (12.15) is formed in the reaction of PhNSNSiMcs and S2CI2, followed by intramolecular cyclization (Eq. 12.5). " ... 

The intramolecular cyclization of 2-alkynylaryldiazonium salts (Richter reaction) leads not only to 4-hydroxy- but also to 4-bromo- and 4-chlorocinnolines. The behavior of alkynylpyrazolediazonium chlorides differs from that of their benzene analogs. The Richter reaction of the series of alkynylaminopyrazoles gives only 4-halo derivatives of l//-pyrazolo[3,4-c]pyridazines and l//-pyrazolo[4,3-c] pyridazines, and mainly hydroxy derivatives of 2//-pyrazolo[3,4-c]pyridazines. 

Reaction of 2-methoxytetrahydropyrrole with dioxalane-2,4-dione in presence of Et3N in benzene followed by treatment with MeONa in methanol afforded the monocyclic intermediate 185. Its treatment with BuLi followed by perfluorobenzoyl chloride gave 186 whose hydrolysis gave 187 which possess low or no antibacterial activity (96PHA805). Regiospecific intramolecular cyclization of 188 with sodium hydride yielded 189 as ester whose hydrolysis gave the respective acid (87JHC1537) (Scheme 35). 

Scheme 5.1-46 The intramolecular cyclization of alkyl chlorides and bromides.

The decomposition of 2-(2-phenylphenylsulfanyl)benzenesulfonyl chloride (5) at elevated temperatures leads to the formation of tribenzo[6,c/,/]thiepin(6) in 24% yield by an intramolecular cyclization pathway. Mechanistically, this thermolysis is comparable to the Pschorr reaction (cf. Houben-Weyl, Vol. 5/2b, p 420 Vol. 10/3, p 189) however, copper(I) chloride is now preferred as a catalyst, without any solvent.4 In the thermolysis of 5, 4-phenyldibenzothiophene (7) is formed as a byproduct in 14% yield. Octachloronaphthalene can also be employed as a catalyst however, the yield of 6 is somewhat lower (19%).4... 

The phthalide 25, obtainable by condensation of 4,4 -bisdimethyl-aminobenzophenone-2-carboxylic acid with 3-dimethylaminoacetanilide and subsequent hydrolysis, was diazotized in sulfuric acid and the resultant diazonium salt treated with copper powder to yield 26. However, better yields are reportedly obtained by carrying out ring closure of the diazonium salt in phosphoric acid.103 A further synthetic route has also been described in which phthalides undergo intramolecular cyclization in the presence of aluminum chloride and urea.104,105 Thus, Crystal Violet lactone (2) has been directly converted into phthalide 26.106... 

Treatment of a (l-t-butoxycarboxylic acid 18 with thionyl chloride gave an intermediate P-hydroxyacid chloride 19 which underwent intramolecular cyclization to oxetanone 20... 

Reaction in methanol yields the substituted diether 13 whereas, in methylene chloride, intramolecular cyclization to an ether cation takes place and attack by the nucleophilic F from the electrolyte yields a fluorinated cyclic ether 14 (cf also Reference 197). 

The Liebeskind group cross-coupled 4-chloro-2-cyclobutenone 69 with 2-tribuylstannyl-benzothiazole to synthesize a-pyridone-based azaheteroaromatics [48], The adduct 70 underwent a thermal rearrangement to afford a transient vinylketene 71, which then intramolecularly cyclized onto the C—N double bond of benzothiazole, giving rise to thiazolo[3,2-a]pyridin-5-one 72. In another case, 2-acetyl-4-trimethylstannylthizaole (73) was coupled with an acid chloride 74 to form the desired ketone 75 [49]. 

Ring closure of triazinyl diester 276 was reported by Moderhack etal. <2002M1165>. This compound was treated with hydrazonoyl chloride in the presence of triethylamine in refluxing benzene. Formation of the intermediate 277 was anticipated, which, upon intramolecular cyclization, afforded the fused triazole 278 in medium yield (42%). Syntheses of other related compounds via modified synthetic routes have also been described. 

A similar intramolecular cyclization of 3-arylamino-2-chloropropanonitriles under basic conditions to yield l-aryl-2-cyanoaziridines (Scheme 5.2) also proceeds more smoothly when benzyltriethylammonium chloride is added to the reaction mixture [20], The procedure is not suitable, however, for the preparation of /V-alkyl analogues. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Chloro-4-cyanobutane undergoes a high-yielding intramolecular cyclization under basic solidrliquid two-phase conditions in the presence of tetra-n-butylammo-nium chloride to form cyclobutyl cyanide 1-chloro-4,8-dicyanooctane is formed as a by-product (ca. 10%). No cyclization occurs in the absence of the ammonium salt or when aqueous sodium hydroxide is used [29]. Attempts to produce the cyclobutyl derivative in a one-pot reaction of 1,4-dichlorobutane with sodium cyanide/sodium hydroxide gave only a 9% yield, with 1,4-dicyanobutane (63%) and l-chloro-4-cyanobutane (18%). A similar intramolecular cyclization of (3-chloropropyl-thio)acetonitrile yields 2-cyanotetrahydrothiophene (80%) [30]. 

Electrogenerated nickel(I) salen has been employed catalytically for the reduction of benzal chloride [152] and for the reductive coupling of 2-bromo- and 2-iodoethanol to prepare 1,4-butanediol [153]. Electrogenerated nickel(I) cyclams have been used as catalysts for the reductive intramolecular cyclizations of o-haloaryl... 

Curtius degradation of the acyl azide and subsequent transesterification with tert-butanol and hydrolysis resulted in the A/-BOC amino acid 156. Compound 156 was readily cyclized with thionyl chloride, resulting in anhydride 157 diendo, R = H, Me diexo, R = H) in one step. In the cyclization step, acid chlorides were formed first and thereafter an intramolecular cyclization took place with loss of hydrogen chloride (93BSB227,93T1985). 

A Bischler-Napieralski intramolecular cyclization involving aryl acetyl chlorides in phosphoryl chloride affords 4-arylmethyl-4H-pyrrolo[l,2-fl][l,4]benzo-diazepines 236 (Scheme 50 (1995EJM593)). 

A variety of other reaction conditions have been examined for acylation of alkenes by acyl chlorides. With the use of Lewis acid catalysts, reaction typically occurs to give both enones and jS-halo ketones.7 The latter reaction has been most synthetically useful in intramolecular cyclizations. The following reactions are illustrative. 

The importance of intramolecular cyclization was emphasized when Butler and coworkers found that the radical polymerization of N, N, N, /V-diallyldimethylammonium chloride (DADMAC) gave soluble, uncrosslinked polymers with little or no unsaturation (Eq. 6-101) [Butler and Angelo, 1957 Butler and Ingley, 1951 Wandrey et al., 1999]. There is a very low tendency for radical IV to propagate intermolecularly and undergo crosslinking. The predominant reaction is intramolecular cyclization, and the product is a linear product with cyclic structures in the backbone. The reaction is referred to as alternating intra/intermolecular polymerization or cyclopolymerization. 

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

As it has been shown, there are many ways to assemble the 1,4-(oxa/thia)-2-azole ring. Most of them are performed by inter- or intramolecular cyclization of suitable acyclic precursors. Some of them are found to be suitable for the synthesis of various ring systems, by using readily available, and properly modified reactants. Of particular importance are the following (a) the cyclizations of sulfenamides leading to (oxa/thia)azolium salts (Scheme 33) (b) the cyclization of hydroxamic acids (Scheme 39) (c) the dipolar cycloaddition methodology (Scheme 40) (d) the cyclizations of chlorosulfenyl chlorides (Scheme 46) and (e) the cyclizations of chloromethane sulfonamides (Schemes 47 and 48). Other cyclizations reported are preparative ways used mainly for the synthesis of specific compounds and the scope of these reactions has not been widely studied. 

Ley and Murray have developed a short synthesis of hirsutine in which the key step involves intramolecular cyclization of a P-oxoester to an alkene with N-phenylselenophthalimide and stannic chloride (Scheme LXVII) ° ... 

Synthetic endeavours have continued in the diterpenoid series. The cyclization of geranylgeranic acid chloride to derivatives of cembrene, and their conversion into cembrene itself, have been described. Some further extensions of the route to macrocyclic diterpenoids based on the intramolecular cyclization of epoxysulphides and the subsequent modification of the macrocylic product have been described. ... 

A recent report on trifluoromethylsulfenylation of (3-keto acids and derivatives describes isolation of 29 in good yield from reaction of 27 with trifluoromethyl-sulfenyl chloride (Scheme 6.10). Mechanistically, this was rationalized via electrophilic attack of trifluoromethylsulfenyl chloride on the enamine tautomer 27a to generate 28 followed by intramolecular cyclization through the imide oxygen with concomitant loss of CF3SH to produce 29. The product was characterized spectroscopically. 

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