Azetidine-2-amides

Shibasaki et al. reported on a direct awri-selective catalytic asymmetric Mannich-type reaction of a-ketoanilides 191122 puj- ermore, they transformed the anti Mannich adduct 192 into a-hydroxy-y-amides 193, which under asymmetric alkylative cyclization produces azetidine-2-amides 194 in good yield and excellent stereoselectivity (Scheme 40.40). 

Xu Y, Lu G, Matsunaga S, Shibasaki M. Direct anti-selective catalytic asymmetric Mannich-type reactions of a-ketoanilides for the synthesis of -Y-amino amides and azetidine-2-amides. Angew. Chem. Int. Ed. 2009 48(18) 3353 3356. 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

The preparation of isothiazolidin-3-one 5-oxide and 5,5-dioxide derivatives of azetidin-3-ones was described (99EUP100069), starting from penicillanic acid sulfoxide amides in the presence of halogenating agents in anhydrous inert solvents or even without them. Through rearrangement and oxidation with conventional methods, compounds 73 could be obtained. For some derivatives the usefulness, as intermediates for the preparation of novel p-lactam analogs or active substances in formulations for antimicrobial therapy, is claimed. 

The electrophilicity of alane is the basis for its selective reaction with the amide group. Alane is also useful for reducing azetidinones to azetidines. Most nucleophilic hydride reducing agents lead to ring-opened products. DiBAlH, A1H2C1, and A1HC12 can also reduce azetinones to azetidines.100... 

The oxetane tertiary amides 15 on treatment with methyl triflate in anhydrous nitrobenzene at 150 °C undergo ring expansion to the cyclic acetals 16 and, if the groups R and R2 are sufficiently bulky, the acetals undergo a ring contraction to form the azetidines 17 . 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

The rotational barriers of A-nitroso-, A-formyl and A-(A,A-dimethylcarbamoyl)-azetidines, compared with those of analogous acyclic amides, suggest that amide conjugation is weaker when the nitrogen is part of an azetidine ring (87KGS912). 

More recently, the direct reaction of amines and amino esters with azetidin-2,3-diones 128 at 90°C, Scheme 43, leading to peptides 130, has also been reported. The reaction is believed to occur through formation of an aziridine intermediate 129 which then rearranges to the amino amide with coextrusion [119, 120]. 

Treatment of l-(/-butoxylcarbonyl)-2-(methoxycarbonylmethylene)-4-(trifluoromethyl)azetidine 28 with potassium bis(trimethylsilyl)amide at — 78 °C followed by reaction with an alkyl halide or an aldehyde afforded 3-alkyl-substituted azetidine derivatives 29 (Equation 6) <20030L4101>. This procedure is of particular importance to the synthesis of azetidines with an alkyl substituent at the C-3 position. 

The cycloaddition of keteniminium triflates 195, formed from tertiary amides by the action of triflic anhydride, with imines formed the azetidine iminium salts 196 (Equation 51) <1996JOC8480>. 

Diphenylsilane is compatible with the ester group at C-4 in azetidin-2-ones 203 and reduces only the amide carbonyl group affording azetidin-2-carboxylates 204 (Equation 55) <2004TL2193>. Removal of the />-methoxy-benzyl group from azetidin-2-carboxylates 204 allowed the preparation of conformationally strained amino ester hydrochlorides. 

The oxetane /-amides 222 undergo a ring expansion-contraction sequence in the presence of a Lewis acid to azetidine derivatives 223 (Equation 60) <2000JOC2253>. The overall reaction sequence has been described as double isomerization . The four-membered oxetane ring first enlarged to a [2.2.2]-dioxazabicycle, which in turn rearranged to the final azetidine derivatives. 

A novel N(l)-C(4) cleavage of azetidin-2-one 320 or 321 forming a-alkoxy-7-keto amides 322 has been observed by addition of 2-(trimethylsilyl)thiazole to cis- or /ra r 4-formylazetidin-2-ones (Equation 111) <20040L1765>. 

A selective amide cleavage of proline-tethered azetidin-2-one 329 with sodium methoxide followed by cyclization of the resulting /3-amino ester resulted into formation of the ring-expanded indolizidine derivative 330 (Equation 115) <2005JOC8890>. 

The /3-amino esters 387, obtained by hydrolysis of the corresponding /3-amino amides, have been cyclized in the presence of lithium hexamethyldisilazide (LHMDS)/THF to furnish the /ram-3,4-disubstituted azetidin-2-ones (Scheme 58) <2001JOC9030>. 

Carboxylic amides or related substrates, substituted with leaving groups at the /3-position, are suitable substrates for the synthesis of azetidin-2-ones. Relatively stable or labile, in situ generated, leaving groups can be applied. Selective activation of 3-hydroxy-2-hydroxymethyl-2-methylpropanamide 388 with P(NMe2)3-KPF6 and subsequent... 

The amides derived from /3-hydroxy-a-amino acids, obtained from the reaction of the latter with resin-bound hydroxylamine, have been cyclized under the Mitsunobu conditions to afford 3-aminoazetidin-2-ones. The free azetidin-2-ones were cleaved from the resin by reduction with samarium iodide <20010L337>. 

The reaction of iV-benzylidene l-methoxyaniline with the lithium enolate derived from ethyl 3-ferrocenylpropanoate 472 provided an easy access to azetidin-2-ones 473 and 474 with ferrocene tethered to the C-3 position through a methylene group (Equation 192) <2001JOC8920>. However, the azetidin-2-one 475, formed in the reaction of an enolate with the imine of ferrocene carbaldehyde, furnished an amide 476 by N(l)-C(4) cleavage (Scheme 66). 

The azetidin-2-one 475 bearing a ferrocene moiety at C-4 undergoes deprotonation to form 2-azetine 599, which undergoes ring cleavage to afford the amide 476 (Scheme 79) <2001JOC8920>. 

An unusual example of an acid-catalyzed rearrangement of oxetanes is the reaction of /W-amide-substituted oxetanes with MeOTf at high temperatures to give ester-substituted azetidines (e.g., 29 Scheme 4) <2000JOC2253>. The tertiary amide oxetanes can readily be prepared using a six-step sequence from trimethylolethane. 

Fig. 20 CD spectra of a carbacepham derivative at different temperatures. The chromophore related to the CD band at 220 nm is the amide group of the azetidin-2-one ring. Data to prepare the plot were taken from [253]...

---