Spiro-azetidines

Primary and secondary amines are found to cleave the 1,2,3-dithiazole ring in spiro azetidin-l,2,3-dithiazoles 76 to afford azetidintrisulfides 77 in good to excellent yields (Equation 14) <2001CC1412>. 

Methyleneazetidines, readily obtainable form 4-chloro-3,3-di-methylbutan-2-one, undergo [3+2]cycloaddition of an azide (RN3) to yield the spiro-compounds (13). The triazoline (13) loses diazomethane readily to give the cyclic amidine (14) (94JOC5189). Other spiro-azetidines include (15) (94H1879). 

Powdered crystals of 1, well ground and sandwiched by Pyrex glass plates, were irradiated with 500-W Hg lamp at 0 °C for 2 h, which led to the exclusive production of optically active / -thiolactam, l-benzyl-4-phenyl-azetidine-2-tliione-3-spiro-T-cyclohexane 2, in 96% yield at 58% conversion. The material was purified by column chromatography, and the structure was determined by spectroscopy. As expected, the thiolactam 2 showed optical activity ([a]D+109° c 1.0 CHC13, 94% ee). 

Joshi et al. [81] have incorporated azetidin-2-one moiety into indole nucleus and synthesized several fluorine containing spiro-(3-lactams (Scheme 9). The synthesis involved the condensation of primary amines with an appropriate indole-2,3-dione... 

The synthesis of antiviral spiro-(3-lactam 51 begins with the benzylation of isatin 45 to give 1-benzylisatin 46, which affords Schiff s base 47 on reaction with anisidine in ethanol. The Schiff s base 47 on treatment with methoxyacetyl chloride by the chloride-imidate cycloaddition [85] route afforded a mixture of spiro E- and Z-azetidin-2-ones 48 and 49, which were separated by chromatography. The (Z)-N-arylazetidin-2-one 49 was further converted to desired 4-spiro-(3-lactam 51 by treatment with ceric ammonium nitrate and subsequently with tetrabutylammonium bromide in THF in the presence of pulverized KOH (Scheme 13). 

Durst and Sharma [86] have reported the stereospecific synthesis of 3-spiro-epoxyazetidin-2-ones 55 (Scheme 14). The oxidation of the diastereoisomers of compound 52 with PCC provided a single acetyl compound 3-acetyl-3-benzyloxy-azetidin-2-one 53. Nonchelation controlled L-Selectride reduction of 53 gave the isomerically pure 3-hydroxyethylazetidin-2-one as the sole reduced product, which was further converted to tosylate 54 using NaH/tosylimidazole. The debenzylation-oxirane formation sequence was conveniently performed as a single pot operation with ammonium formate, 5% Pd/C in refluxing methanol as the hydrogen transfer reagent combination. 

Scheme 23 Incorporation of 3-(prop-2-enylidene)azetidin-2-one for the synthesis of spiro-...

Otto and Ruf [96] have incorporated the 3-(prop-2-enylidene)azetidin-2-one derivatives 85 for the synthesis of spiro-(3-lactams 86 via Diels-Alder reactions (Scheme 23). The reaction of (Z)-85 with highly reactive tetracyanoethylene (TCNE) was performed in THF at refluxing temperature, which afforded spiro-(3-lactams 86. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Scheme 25 Intramolecular alkylation of azetidin-2-ones to access spiro-P-lactams...

Treatment of bis-spirocyclopropanated isoxazolidines 551 with trifluoroacetic acid in acetonitrile furnishes 3-spiro-cyclopropanated azetidin-2-ones 552 in excellent yields (Equation 226) <2004EJ04158>. 

The formation of the azetidin-one ring is by a [2 + 2] imine-acid chloride cycloaddition via the insitu formation of methoxy ketene. Other jS-lactams have been prepared using this route (1) as illustrated in Eq. 1. Spiro[3.5] jS-lactams have also been prepared in this manner and are discussed (2). 

Adamantan 1-Acetamino- E5, 995 (Umaminier.), 1032/1034 (H - NH-Ac), 1037 (OH - NH-AC) l-Aza-spiro 4.5 dec-6-en 7-Methoxy-l-methyl-3-methylen- E19a, 768 (Cycloaddition/Desilylierung) 3H-Azepin 2-Hexyloxy- E9d, 158 (02N —Ar + R3P R —OH) Azetidin l-Cyclohexyl-4-ethyl-3-methylen-2-oxo- E16b, 136 (aus HO-A-CO-NHR) Butanol 2-(Methylamino-methyl)-2-phenyl- IV/ld, 133... 

Arylimino-4-chloro-57/-l,2,3-dithiazole 558 reacts with (chloro)phenylketene in CH2CI2 at room temperature affording spiro compounds 559, which undergo decomposition in the presence of primary and secondary alkylamines giving bis(2-oxo-azetidin-4-yl)trisulfides, which, in turn, with an excess of -propylamine are converted into the isothiazolones 560 <2001CC1412>. 

The photoisomerisation kinetics and other properties of the 1 1 inclusion complexes formed between aromatic derivatives of norbomadiene and P-cyclo-dextrin have been measured." (S)- or (R)-2-Chloropropiophenone affords partially racemised (S)- or (R)-2-phenylpropionic acid respectively by a photo-induced rearrangement via what is probably an ion or radieal intermediate," and (Z)-N-substituted benzoyl-a-dehydrophenylalanines such as (7) are photo-isomerised to 1-azetidine derivatives (8) by a 1,3-acyl migration. Irradiation of 9,9 -bifluorene-9,9 -diol (9) gives a mixture of fluoren-9-one and spiro[9H-fluorene-9,9 (10 -H)-phenanthren]-10 -one (10) whose composition is solvent dependent with the more polar solvents favouring (10). Laser flash photolysis shows the presence of two transients, one of which can be identified with the 9-fluorenyl cation (11), and which originates from photoheterolysis of the diol (9). There is also evidence to support the view that unimolecular rearrange-... 

Hussain and Nizamuddin [97] combined the 1,3-dithiolane moieties with azetidin-2-ones for the study of different biological activities. The spiro-p-lactams I (Fig. 10) have been screened against A. niger, P. oryzae, F. oxysporum, and... 

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