Azetidinones 4-allyl

A similar intramolecular nucleophilic capture of an allylic sulfenate generated thermally from the corresponding sulfoxide was also reported for the facile transformation of the azetidinone 61 into a new 3-acetylthio-2-thiacephem ring system 62 (equation 29)127. 

The reaction of 4-(phenylsulfonyl)azetidin-2-one (128) with nucleophiles such as dialkylcopper lithium and Grignard reagents gives 4-alkyl, 4-allyl, 4-vinyl or 4-ethynyl-azetidinon-2-one (129) in good yields (equation 99)83. The yields of several azetidin-2-ones obtained by this method are given in Table 10. The reaction apparently proceeds through an intermediate azetin-2-one 131 derived from the five-membered coordination complex (equation 100). 

The nonacarbonyldiiron-induced transformation of oxazabicyclo[2.2.2] octenes (12) into condensed azetidinones is intriguing mechanistically but will obviously have limited synthetic application (Scheme 15).37 The /(-lactam (14a), among other products, is isolated directly from the iron carbonyl reaction but the dimethyl analog (14b) is obtained by pyrolysis of an isolable intermediate <7-7r-allyl complex (13b). 

Indium mediated allylation of 4-acetoxy-2-azetidinones gave the products 57 in high yield <99SL447> and similar reactions with azetidin-2,3-diones gave 3-substituted 3-hydroxy-P-lactams 58 <98H97>. 

In 2006, the palladium-catalyzed carbonylative [2+2] cycloaddition of allyl bromide with heteroaryliden anilines was reported to afford 2-azetidinones... 

Azetidinones. CSI and allyl iodide undergo [2 + 2]cycloaddition to form the zctidine-2-one (1), which can be converted into 3, a potential precursor to carbapenams. 

Direct transformation of thiazoline-azetidinones 2 into 3 -thio-substituted cephalosporins 6 has been performed by ring opening of the thiazoline moiety with sulfenyl chloride followed by ring closure with ammonia in dimethylformamide and simultaneous displacement of the allylic chlorine atom with the leaving thiolates. 

Azetidinones with a 4-allyl alcohol substituent, for example, 309, which are readily available from /3-lactam 4-aldehyde by the Baylis-Hillman reaction, are converted by triphenyltin hydride plus AIBN without racemization in good yield to fused ring systems, 310 (n = 1-3). 

An unprecedented one-pot stereoselective synthesis of 2-azetidinone P-chlorinated allylic alcohols 23, which can also be considered as functionalized allylsilanes, has been developed, by tin(IV) chloride-mediated reaction of propargyltrimethylsilane and 4-oxoazetidine-2-carbaldehydes <02CEJ1719>. An explanation for the formation of P-chlorovinyl alcohols involves a stepwise process with the chlorination proceeding via a silicon stabilized carbocation. 

Indium-mediated allylation of 4-acetoxy-2-azetidinones affords 4-allyl-substituted azetidinones with retention of the stereochemistry (Equation (82)).320 An aminoalkoxy titanium complex is readily allylated with allylindium reagents to give homoallylic amines (Scheme 86).321... 

Geraniol or nerol can be converted to citronellol in 96-99% ee in quantitative yield without saturation of the C(6)-C(7) double bond (eq 6). The S C ratio approaches 50000. The use of alcoholic solvents such as methanol or ethanol and initial H2 pressure greater than 30 atm is required to obtain high enantioselectivity. Diastereoselective hydrogenation of the enantiomerically pure al-lylic alcohol with an azetidinone skeleton proceeds at atmospheric pressure in the presence of an (i )-BINAP-Ru complex to afford the (3-methyl product, a precursor of ip-methylcarbapenem antibiotics (eq 7). Racemic allylic alcohols such as 3-methyl-2-cyclohexenol and 4-hydroxy-2-cyclopentenone can be effectively resolved by the BINAP-Ru-catalyzed hydrogenation (eq 8). ... 

A large number of 3-lactams have been prepared - by this method (equations 56-61). Cycloadditions of CSI with 1,5-hexadiene, allyl iodide and vinyl acetate - yield azetidinones which have been used as starting materials in the synthesis of carbapenems and penems. In some cases the cycloaddition must be conducted at low temperature to avoid open-chain products (equations 61 and 62). 

Silver(I) compounds are often used as promoters for substitution reactions of aliphatic halides with carbon nucleophiles. A cyclic (8-bromo ether 29 can be reacted with allyltrimethylsilane (30) imder the influence of AgBp4, yielding a mixture of ally-lated products 31 and 32 (Sch. 7) [15]. Product 31 is formed by direct substitution of the bromine atom in ether 29 by an allyl group and isomeric ether 32 arises from the carboxonium ion which is generated by debromination and subsequent [l,2]-hydrogen shift. A synthesis of optically active 4-allylazetidinone 33 (Ft = phthalimido) has also been achieved by employing the silver-promoted substitution reaction of 4-chloro-azetidinone 34 with allylsilane 30 [16]... 

Durst, T., Van den Elzen, R., LeBelle, M. J. Base-induced ring enlargements of 1-benzyl- and 1-allyl-2-azetidinones. J. Am. Chem. Soc. 1972, 94, 9261-9263. 

Indium-mediated allylation of 4-acetoxy-2-azetidinones affords 4-aUyl-substituted... 

Allyl-2-azetidinones are synthesized by displacement of the corresponding acetoxy derivatives, A preparation of homoallylic amines can take advantage of the reactivity of allylindium reagents on iminium species that are formed in situ. ... 

Since many other functional groups are tolerated in this reaction, a great variety of useful synthetic intermediates have been assembled 4-styryl-2-azetidinones, 4,5-diphenyl-3-styryloxazolin-2-ones, jS-alkoxystyrenes, allylic and homoallylic alcohols. " The coupling between vinylic iodides and tertiary allylic alcohols to construct isoprenoid segments has also been demonstrated."... 

Three other groups reported alternative methods for the synthesis of 3-alkenyl-substituted P-lactams. Durst [71] prepared these compounds via a Peterson olefination reaction. Thus, for example, treatment of 3-trimethylsilyl-azetidinone 116 with lithium diisopropyl amide followed by addition of pro-pionaldehyde gave a mixture of 117 and 118 in 66% yield. Tanaka [72] converted allylic stannanes 119 to bromides 120 which were smoothly cyclized to P-lactams 121 in good yield. Ley [73] treated 7i-allyltricarbonyliron complexes with benzylamine in the presence of Lewis acids to afford the corresponding lactam complexes. Oxidation with cerric ammonium nitrate served to liberate the desired P-lactams (Scheme 14). 

Selected apphcations are shown in Scheme 60. The reaction is highly stereoselective, imines from a-ketoaldehydes yielding mostly or exclusively c -azetidinones, whereas imines from benzaldehydes yield only tron -isomers. The approach has been extended to benzyl electrophiles in place of allyl phosphates. A synthesis of cephems using this novel [2 + 2] cycloaddition has been reported by Zhou and Alper. This method represents a potential entry into the medicinally important class of /3-lactam antibiotics, and further applications are expected. 

A soln. of N-bromo-4-methyl-2-azetidinone in methylene chloride added with stirring and UV-irradiation by a high-pressure Hg-lamp during 5-10 min. to a refluxing mixture of allyl chloride (or another olefin such as 4-methyl-l-pentene or isoprene) and methylene chloride, refluxing with irradiation continued 0.5-1 hr. / -bromoisopropyl isocyanate. Y 93%. F. e. and procedures s. K. D. Kampe, A. 752, 142 (1971). 

Other glycosides of significance in medicinal chemistry to have been obtained by application of the allylic rearrangement reaction to alcohols are 42 (R = OAc, = H) [60] and 43 (R = H, R = OAc) [61]. In the former case reaction occurs selectively at the secondary alcohol site, and in the latter the glycosyla-tion has been used to resolve racemic 3-hydroxy-2-azetidinones, the illustrated enantiomer being required for synthesis studies on taxol. 

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