Azetidine alkylation

Azete, trisdimethylamino-isolation, 7, 278 Azetes, 7, 237-284, 278-284 benzo fused, 7, 278 benzodiazepine fused applications, 7, 284 fused ring, 7, 341-362 structure, 7, 360 2,3-naphtho fusion, 7, 278 reactivity, 7, 279 structure, 7, 278 synthesis, 7, 282-283 Azetidine, acylring expansion, 7, 241 synthesis, 7, 246 Azetidine, 3-acyl-irradiation, 7, 239 synthesis, 7, 246 Azetidine, N-acyl-synthesis, 7, 245 Azetidine, alkyl-synthesis, 7, 246 Azetidine, 3-alkylthio-synthesis, 7, 246 Azetidine, 3-amino-synthesis, 7, 246 Azetidine, N-amino-oxidation, 7, 241 synthesis, 7, 246 Azetidine, aryl-synthesis, 7, 246... 

Table 2 summarizes some of the transformations of substituents which have been carried out on azetidines without effect on the ring <79CRV33l). Other transformations of interest are the base catalyzed epimerization, H exchange and alkylation of the activated H-3 in azetidines (26) (69JHC153) and the nitration, reduction, diazotization and hence further modification of the aromatic ring in 3-phenyl-fV-acetylazetidine (27) (61LA 647)83). 

O-Alkylation of A-unsubstituted /3-lactams to give the corresponding 2-alkoxy-l- etines can be achieved by reaction of the azetidin-2-ones with hard electrophiles (trialkyloxonium tetrafluoroborates) followed by treatment with base (cf. Section 5.09.4.3.1) (67JHC619, 69LA(725)124). In contrast, reaction of the A-unsubstituted azetidin-2-ones (73) or their derived anions with a variety of softer electrophiles results in A-substitution, and some representative reactions are illustrated in Scheme 7. 

O-Alkylation of the readily available iV-unsubstituted azetidin-2-ones (/3-lactams) constitutes a versatile route to 2-alkoxy-l-azetines (cf. Section 5.09.3.2.3). Thus treatment of the /3-lactams (266) with trialkyloxonium tetrafluoroborates followed by basification affords the 2-alkoxy-l-azetines (267) in moderate yields (67JHC619,69LA(725)124). Similar treatment of the azetidine-2-thiones (268) (available from thiation of the corresponding /3-lactams with phosphorus pentasulfide) affords the analogous 2-ethylthio-1-azetines (269) (67JHC619), which are generally more stable than their 2-alkoxy analogues. 

Azetidines, 7, 237-284, 238-246 addition compounds with trimethylboron, 7, 240 AT-alkylation, 7, 240 applications, 7, 246 AT-arylation, 7, 240 azetidin-2-ones from, 7, 263 bicyclic... 

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). 

Scheme 2.92. Three-component asymmetric synthesis of 3-alkyl-4-methoxycarbonyl-azetidin-2-ones 2-386 from chiral crotonyl derivatives.

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

As mentioned in chapter 4.2.3, aliphatic imines are photochemically rather unreactive. When the C—N double bond is conjugated to an electron withdrawing group (e.g. carbonyl group), as in O-alkyl derivatives of succinimide and phthalimide, the reactivity increases and azetidines are obtained in cycloadditions to olefins486). A somehow similar example is the photoaddition of a 6-azauracil derivative to 2,3-dimethyl-2-butene... 

Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-P-lactams . 

The reaction of azetidines with dinitrogen pentoxide is found to reflect the reduced ring strain in this system compared to aziridines.Accordingly, while the carbamate and V-alkyl... 

A -(2-Aminobenzoyl)-peptides undergo acid-catalyzed cyclization to 1 -benzodiazepine, 5-diones. 187 Thus, Boc-Abz-Xaa-OH, where Xaa corresponds to various A-alkyl-amino acids such as Pro, Hyp, Thz, Pip, and azetidine-2-carboxylic acid and their methyl esters are readily converted into the corresponding l,4-benzodiazepine-2,5-diones in the acidolytic Boc-cleavage step by treatment with 95% aq TFA or 100% TFA (rt, 1 h). 

NRR = NH2, NHCy, NMe2, NEt2, aziridin-l-yl, azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl Y = alkyl, Ph, 2-futyl, 2-thienyl... 

The interception of suitably substituted Dewar pyridinones (IV-alkyl-3-oxo-2-azabicyclo[2.2.0]hex-5-enes) is increasingly being exploited as a route to novel /3-lactams (Scheme 223) (81JCS(P1)2620). In another approach, 4-methoxypyridin-2-one has been used as a source of substituted azetidin-2-one (306) which is a precursor of potential carbapenam antibiotics (Scheme 224) (82H(19)89). 

In ahnlicher Weise lassen sich l-(co-Brom-alkyl)-2-oxo-azetidine nitrieren2 ... 

Azetidine can be considered as a fairly typical cyclic amine. Strain in the four-membered ring is less than that in the three-membered aziridine system, and as a result azetidines show few, if any, of the exceptional properties associated with aziridines. Thus, ring cleavage reactions occur with greater ease than in larger ring cyclic amines, but much less readily than with aziridine for example, unlike aziridines, azetidines do not function as alkylating... 

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