Azetidines

Azetidines.—j8-Lactams, both natural and synthetic, have been the subject of a recently published book.  

Manhas and A. K. Bose, jff-Lactams Natural and Synthetic, Part I (New Dimensions in Organic Chemistry), Wiley-Interscience, New York, 1971. 

A number of CSl additions have been shown to produce much less stable j5-lactams. The azetidinone (51) was isolated from the reaction of cyclo-hexadiene with CSI for five minutes at room temperature, while after thirty hours (52) was formed, and the reaction in refluxing chloroform gave (53). Analogous reactions with bicyclo-octadiene did not involve the tautomeric cyclo-octatriene. Initial formation of a 1,4-dipolar intermediate was 

The initially formed /3-lactam (63) from the reaction of /3-pinene with CSI could also be observed by n.m.r. at —70 °C and its decomposition to (64) could be followed by the same technique at —40°C. The / -Iactam (65) from a-pinene is more stable and only decomposes slowly at room temperature to give (66) and (67) the different final products in this case are explained in terms of ring strain. 

The rra 5-azetidinone (71) and stilbene dimers were formed by the photocycloaddition of either cis- or /ra j-stilbene to phenyl isocyanate. The 

Azetidines, whose structures have been found in many natural products, constitute an important class of compounds, because of their interesting pharmacological activities and synthetic utility. Whereas the strain associated with the azetidine ring system leads to difficulties in its synthesis, functionalization 

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-Picrylazetidine (155) is found to be inert to attack by dinitrogen pentoxide, a consequence of the electron-withdrawing picryl group. The triazine (156) gave a 60 % crude yield of the energetic 1,3-nitramine-nitrate (157) which is an analogue of Tris-X. 

Another new -lactam synthesis proceeds via the hitherto unknown chloro-cyanoketene, obtained by thermolysis of various /8-azidoenones. Hence, when the crotonolactone (160) was refluxed in benzene in the presence of dicyclohexyl-carbodi-imide 88% of the adduct (161) was obtained similarly thermolysis of (160) with ethoxymethylene aniline gave 48% of (162). The reactions are stereospecific, and only one diastereoisomer was obtained. Thermolysis of 4-azidopyrrolin-3-one (163) in benzene gave 58% of the j8-lactam (165) directly, the zwitterion (164) being implicated without direct evidence such intermediates have already been proposed as precursors of jS-lactams when ketenes add to imines. The f -stereo- 

Huisgen, B. Davis, and M. Morikawa, Angew. Chem. Internat. Edn., 1968,7, 826. 

Spectroscopic observations of ketene-imine carboxylates, and their conversion into azetidindiones (166), have been made by Woodman and co-workers treat- 

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The reaction of the vinylcyclopropanedicarboxylate 301 with amines affords an allylic amine via the 7r-allylpalladium complex 302[50]. Similarly, three-membered ring A -tosyl-2-(l,3-butadienyl)aziridine (303) and the four-mem-bered ring azetidine 304 can be rearranged to the five- and six-membered ring unsaturated cyclic amines[183]. 

Serratia mane seem 3,4-dehydro-Pro prodegradation , thiazoline-4-carboxylate/ azetidine-2-carboxylate (transduction) 75 145... 

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. 

Azetidine N-oxides produce isoxazolidines by a thermal ring expansion (77AHC(21)207, 75GEP2365391), and nitrosobenzenes react with alkenes to provide isoxazolidines (77AHC(21)207, 79IZV1059). 

N-Inversion in azetidine and azetidin-2-one is rapid, even at —77 and -40 °C, respectively (B-73NMR144). Again, halo substituents on nitrogen drastically slow the inversion rate, so that Af-chloro-2-methylazetidine can be separated into two diastereomers (b-77SH(1)54). Substituent effects on N-inversion are much the same as in the aziridines Af-aryl and N- acyl... 

Scheme 1 H NMR shifts and coupling constants of azetidine derivatives...

Azetidine N shifts are similar to those of the aziridines. Unsubstituted azetidine has its N resonance (relative to anhydrous ammonia) at 25.3 p.p.m., and N-r-butylazetidine shows the signal at 52 p.p.m. (80JOC1277). 

Four-membered heterocycles prefer to cleave, upon ionization, into two fragments, each containing two of the ring atoms. Further cleavages commence from these initial fragments (Scheme 5). Specific details can be found as follows azetidines (B-71MS296), oxetanes... 

Electrophiles, such as C—Hal functions, contained in side chains may be well positioned for interaction with ring heteroatoms. Thus, Af-t-butyl-2-tosyloxymethylaziridine in ethanol displaces tosylate ion from the side chain, and nucleophilic opening of the resulting azabicyclobutanonium ion by solvent gives 3-hydroxy- and 3-ethoxy-azetidine (Section 5.09.2.3.2). 

While these rearrangements are used most often to prepare large rings, it should be noted that the expansion of cyclopropane derivatives to azetidines is also practical (Scheme 6 Section 5.09.3.3.3.a). 

Addition of trichloromethide ion to azirine (210) generates aziridine (230). When this aziridine was treated with base, cyclization and rearrangement occurred and the azetidine (233) was isolated (73JA2982). 

Vibrational spectra including Raman data of 3,3-dimethyldiaziridine and its hexadeutero compound were recorded in the gas phase and in the crystalline state. Assuming C2 symmetry and employing isotopic shifts and comparison with azetidine, a classification of bands which regarded 33 normal modes could be given (75SA(A)1509). 

In view of the uneven attention which azetidines, azetines and azetes have received and because of their lack of chemical similarity, they are treated separately in this chapter. Furthermore, because of the considerable literature on azetidin-2-ones, these have been dealt with in their own right, rather than as derivatives of azetidine. 

Azetidine (1) is a colourless, mobile liquid, b.p. 62.5 C/747 mmHg (56JA4917), which is completely miscible with water. Its density 4 = 0.8412 and refractive index d = 1.4278 (37HCA109). Table 1 gives b.p. and m.p. data for other representative azetidines. 

Azetidine itself has been studied by electron diffraction, which reveals a non-planar structure (Figure 1) (73CC772). The enhanced length of the bonds reflects the strain in the ring and the angle between the CCC and CNC planes of 37° is similar to that found for cyclobutane (35°), but quite different from that for oxetane (4°). 

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