Azetidine

Azetidine was previously called trimethyleneimine. The activation energy of the ring inversion is 5.5 kJ mol and is therefore only slightly below the value for cyclobutane (6.2 kJ mol 0- The 

Azetidines are thermally stable and less reactive than aziridines. They behave in their reactions almost like secondary alkylamines. The value of azetidine is 11.29 and so it is more basic than aziridine (pAT = 7.98) and even dimethylamine ( Ka = 10.73). Azetidines unsubstituted on the N-atom react with alkyl halides to give 1-alkylazetidines which can react further to give quaternary azetidinium salts. With acyl halides, they produce acylazetidines and with nitrous acid, they give 1-nitrosoazetidines. 

The synthesis of azetidines can be accomplished starting with r-substituted amines or 1,3-dihaloalkanes  

The yields are lower than in the analogous aziridine synthesis. The Mitsunobu reagent (see p 30) [7] is suitable for the cyclodehydration of amino alcohols. 

The tosyl group can be reductively removed from the 1-tosylazetidine. 

1 -(2-Carbethoxyethyl)azetidine. A solution of 150 g. (2.0 mol es) of 3-amino-1-propanol in 500 g. (5.0 moles) of ethyl acrylate (Note 1) is refluxed for 2 hours in a 1-1. round-bottomed flask. Subsequent vacuum stripping of the excess ethyl acrylate at steam temperature furnishes 548 g. (99%) of crude diethyl 3-N-(3-h ydroxypropyl)iminodipropionate. A stirred, cooled solution of this material (548 g.) in 1 1. of chloroform and 10 ml. of dimethjrlformamide is treated dropwise with 262 g. (2.2 moles) of thion yl chloride. By cooling with an ice bath and controlling the addition rate, the reaction temperature is maintained below 40° (Note 2). After the addition is complete, the reaction m i xture is stirred for 30 minutes at room temperature and poured 

Azetidine. A stirred mixture of 38 g. (0.68 mole) of potassium hydroxide pellets in 100 ml. of white mineral oil (Note 8) is heated to 140-150° in a four-necked 500-ml. round-bottomed flask, fitted with an air-driven Hershberg stirrer, a thermometer, a dropping funnel, and a 6-in. Vigreux column fitted with a vacuum-distillation head. The flask is removed from the heat source, and 50 g. (0.32 mole) of purified l-(2-carbethoxyethyl)azetidine is added dropwise at a rate sufficient to maintain the reaction temperature at 150° (Note 9). After addition is complete, the reaction mixture is heated to 200° at 50 mm. to remove all traces of ethanol (Note 10). The flask is fitted with a distillation head and a nitrogen bubbler, and the distillation is resumed at atmospheric pressure until azetidine distills (210° maximum pot temperature) (Note 11). The resulting product (19.6 g., 85% purity) is dried over potassium hydroxide and redistilled through a short Vigreux column to furnish 14.5-15.8 g. (80-87%) of purified azetidine, b.p. 62-63° (Note 12). 

Eastman Organic Chemicals, practical grade, 3-amino-1-propanol, and ethyl acrylate were used. The checkers used 3-amino-1-propanol, FLUKA purum. 

If the reaction temperature is not controlled, a tarry by-product is formed. By dissolving the crude aminochloride in petroleum ether, the impurity is separated as an insoluble tar. 

Considerable foaming occurs during neutralization, which is best accomplished in a 4-1. beaker with rapid stirring. 

Azete 6 crystallizes as reddish needles of mp 37°C. In its chemical properties, 6 shows analogies to cyclobutadienes. Its flash pyrolysis at 700°C gives di-tert-butyl acetylene and tBu-CN AG for this decomposition is very high, since a concerted (2 + 2)-cycloreversion is not allowed according to the Woodward-Hoffman rules  

Azete 6 dimerizes thermally to the 1,3-diazetidine system 7, which can be isomerized to the 1,5-diazocine 7. Azete 6 shows numerous cycloaddition reactions, especially with activated acetylenes and phosphaalkines for its transformations to the pyridine valence tautomers see p. 364. 

A positive charge on the N-atom destabiHzes the ring, as is the case with the aziridines. Ring-opening by nucleophiles proceeds with acid catalysis. Hydrogen chloride yields 

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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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