Azetidine formation

Analogous intramolecular additions have also been described. The importance of the trifluoromethyl group in influencing the course of a photoreaction has again been demonstrated in the conversion of 3-(but-3-enyl)-2-trifluoromethyl-4(3H)-quinazolinone (100) into the intramolecular adduct (101) the corresponding 2-unsubstituted quinazolinone is reported to be photostable. Intramolecular azetidine formation has also been... 

Azetidines under analogous reaction conditions to those above result in six-membered ring formation. However, diketene (472), an oxetan-2-one, offers considerable promise for five-membered heterocycle formation. With hydroxylamine the 3-methylisoxazolin-5-one (473) was formed. Phenylhydrazine gave the corresponding 3-methyl-l-phenylpyrazolin-5-one. 

Dialkylation of an amine or sulfonamide with a 1,3-dihalide provides a further route to azetidines <79CRV33l, 64HC( 19-2)88 5). Examples of this approach are the formation of N-tosylazetidine from tosylamide and l-bromo-3-chloropropane and the formation of N-alkylazetidinyl esters (36). The latter reaction works well except for R=Me the former provides a useful route to azetidine since the tosyl group can be removed by reductive methods. 

There are few examples of formation of simple azetidines from [2 + 2] fragments, although this type of approach is important for certain azetidine derivatives, e.g. azetidin-2-ones (see Section 5.09.3). Nitrogen analogues of the Paterno-Buchi route to oxetanes are rare an example involves the photoaddition of 3-ethoxyisoindolone (37) to the enol ether (38) (75JA7288, 72CC1144). 

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. 

Azetidin-2-one formation by N—C(4) ring closure has also been observed in the irradiation of cfs-a-phenylcinnamides (143) in degassed benzene. Both cis and trans lactams are formed (68JA2333). 

There appear to be few examples of the formation of azetidin-2-ones by closure of the C(2) —C(3) bond. One reaction which fits into this category involves reaction of the iron carbonyl lactone complexes (144) with an amine to give the allyl complexes (145) which on oxidation are converted in high yield to 3-vinyl-/3-lactams (146) (80CC297). 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments.208 Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the kcto-fi-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionalized hydroxy-ji-lactams (Eq. 8.82). 

Thermal isomerization of certain cis-l,3,4-trisubstituted azetidin-2-ones 76 provided the trans isomer in good yield . Bases caused the isomerization of cis-3-substituted-4-formylazetidin-2-ones and of sulfonic acid derivatives of 3-aminoazetidin-2-ones during the formation of a Schiff base <00T3985>. 4-Acyloxy-iV-o-azidobenzoyl-P-lactams underwent ring expansion to produce l,3-oxazin-6-ones 77 . 

This success encourages us to consider the other monocyclic tertiary amines for which there are enthalpies of formation. In particular, consider iV-(2-phenylethyl)azetidine (6),... 

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 reaction of alkoxy(aryl)carbene iron complexes with two equivalents of an isonitrile leads to the formation of azetidin-2-ylidene complexes [197]. For other reactions of Fischer-type carbene complexes with isonitriles see [198]. 

The only example known for the formation of azetidine 82 by direct intramolecular aza-Wittig reaction is the reaction of the /3-azidoketone 81 with triphenylphosphane (Scheme 41). Attempts to transfer this reaction to 83 and 84 were not successful (87NKK1250). This failure can be attributed to the formation of intermediates with highly energetic transition states, where the rate of intramolecular attack on the carbonyl function is so slow that oligo- and polymeric compounds are preferentially formed. 

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