Synthesis and reactivity of 2-halo-2H-azirines towards nucleophiles

Article abstract of DOI:10.1016/S0040-4039(00)01239-9

Nucleophilic substitution reactions of 2-halo-2H-azirine with potassium phthalimide and aniline allowed the preparation of new substituted 2H-azirines. The reactions of 2-bromo-3-phenyl-2H-azirine-2-carboxylate with methylamine led to the synthesis of α-diimines and from the reaction with water, a 3-oxazoline was obtained. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01239-9

Tetrahedron Letters 41 (2000) 7217±7220
Synthesis and reactivity of 2-halo-2H-azirines towards
nucleophiles
Teresa M. V. D. Pinho e Melo,* Claudia S. J. Lopes and
Antonio M. d'A. Rocha Gonsalves
Â
Departamento de Quõmica, Faculdade de CieÃncias e Tecnologia, Universidade de Coimbra, Coimbra, Portugal
Received 16 June 2000; accepted 21 July 2000
Abstract
Nucleophilic substitution reactions of 2-halo-2H-azirine with potassium phthalimide and aniline allowed
the preparation of new substituted 2H-azirines. The reactions of 2-bromo-3-phenyl-2H-azirine-2-carboxylate
with methylamine led to the synthesis of a-diimines and from the reaction with water, a 3-oxazoline was
obtained. # 2000 Published by Elsevier Science Ltd.
Keywords: 2H-azirines; a-diimines; 3-oxazoline.
The chemistry of highly reactive 2H-azirines has been explored extensively for various synthetic
purposes.1 These heterocycles undergo reactions in which they can function either as a nucleo-
phile or as an electrophile. Reactions with nucleophiles always involve the initial addition to the
imine bond.1,2 In some cases the corresponding aziridine can be isolated but in other cases the
products result from the formation of aziridine followed by ring opening and further reactions.
The study of the reactivity of 2-halo-2H-azirines is of particular interest since this system can
also undergo halide displacement on reacting with nucleophiles. In contrast with other 2H-azirines
derivatives, the reactivity of 2-halo-2H-azirines is almost unexplored. However, studies of the
reactivity of 2-chloro-2,3-dimethyl-2H-azirine and 2-chloro-2,3-diphenyl-2H-azirine revealed the
great lability of chlorine in these systems.3
Having reported previously a general route to 2-halo-2H-azirines,4 in this paper we describe the
use of this synthetic methodology for the preparation of new 2-halo-2H-azirines, including the
®rst examples of 2-iodo-2H-azirines, and a study of their reactivity towards nucleophiles.
The 2-bromo-2H-azirines 3a4 and 3d were prepared from the alkenes 2a and 2d which were
obtained from the reaction of ylides 1a and 1c with N-bromosuccinimide and azidotrimethylsilane
(Scheme 1). The reaction of ylides 1a and 1b with N-iodosuccinimide and azidotrimethylsilane
* Corresponding author. Fax: +351 239 826068; e-mail: tmelo@lyra.ci.uc.pt
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01239-9

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gave the corresponding iodoazidoalkenes 2b and 2c. These compounds were converted to the
2-iodo-2H-azirines 3b and 3c.
Scheme 1.
We started with the study of the reactivity of 2-halo-2H-azirine using potassium phthalimide as
the nucleophile, which could allow the development of a methodology for the synthesis of new
amino acids. (Scheme 1). The reaction of 2-bromo-2H-azirine 3a led to the synthesis of ethyl
3-phenyl-2-phthalimido-2H-azirine-2-carboxylate 4a in high yield5 (96%). The same product (4a)
was obtained in 35% yield from the reaction of 2-iodo-2H-azirine 3b with potassium phthalimide.
It was expected that the iodo-2H-azirines would undergo halide displacement more easily than
the corresponding bromo derivatives. However, the lower stability of the 2-iodo-2H-azirine led to
a moderate yield of compound 4a. A new phthalimido-2H-azirine derivative (4b) was also
obtained in 28% yield from 2-iodo-2H-azirine 3c. The halide displacement reactions of 2-halo-
2H-azirine 3d led to the synthesis of the corresponding 2-substituted-2H-azirine derivatives 4c in
low yield.
2-Phenylamino-2H-azirine could also be prepared from the reaction of 2-bromo-2H-azirines 3a
and 3d with aniline.
To extend this chemistry the reaction of 2H-azirine 3a with methylamine was studied. The
product was not a substituted 2H-azirine but instead compound 6 was obtained6,7 (6%). The 2H-
azirine 3a underwent halide displacement and addition to the iminic double bond to give 5.
Opening of the aziridine ring and elimination of ammonia gave the a-diimine 6. In the presence of
a large excess of methylamine, using DMF or acetone as a solvent, compound 7 was obtained in
36 and 40% yield, respectively (Scheme 2).
Scheme 2.
The reactivity of 2-halo-2H-azirines towards water was studied. A solution of 2H-azirine 3a in
DMF/H2O gave no reaction after 6 days at room temperature. However, when this reaction was
carried out in an ultrasound bath for 2 days, 3-oxazoline 8 could be isolated in 30% yield7,8

7219
(Scheme 3). 2H-Azirine 3a underwent halide displacement giving 3-hydroxy-2H-azirine 9. Part of
this azirine underwent ring opening and hydrolysis leading to 10. The reaction of this compound
with the remaining 3-hydroxy-2H-azirine 9 gave 3-oxazoline 8. This synthesis is an alternative
route to the known synthetic strategies for the preparation of 3-oxazolines using 2H-azirines as
starting material.9a,9b,10
Scheme 3.
In conclusion, we have described the results obtained from the reactions of halo-2H-azirines
with nucleophiles. With potassium phthalimide and aniline the products resulted from the halide
displacement and there was no evidence of nucleophilic addition to the iminic double bond. Thus,
the reaction of 2-halo-2H-azirines with these nucleophiles can be used as a source of new 2H-
azirine derivatives.
The reactions of 2-bromo-2H-azirine 3a with methylamine allowed the preparation of a-
diimines, important intermediates for the synthesis of heterocycles and in coordination chem-
istry.11 A useful approach to the synthesis of 3-oxazolines was also achieved. They are interesting
heterocyclic compounds since several derivatives show biological activity.9
Acknowledgements
We thank Chymiotechnon for ®nancial support.
References
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5. General procedure for the halide displacement of 2-halo-2H-azirines with potassium phthalimide or aniline. The
2-halo-2H-azirine (1 mol) was dissolved in DMF (10 ml) and potassium phthalimide or aniline (1 mol) was added.
The reaction mixture was stirred at room temperature for 18 h. Water (35 ml) was added and the solution was
extracted with chloroform (3Â10 ml). The combined organic phases were washed with water (20 mL) and dried
(MgSO4). The solvent was evaporated giving the azirine. Ethyl 2-phthalimido-3-phenyl-2H-azirine-2-carboxylate 4a
(96% from 2H-azirine 3a and 35% from 2H-azirine 3b). M.p. 144±145ꢀC. 1H NMR (CDCl3, 300 MHz): 1.21 (3H,
t), 4.25 (2H, q), 7.60±7.78 (5H, m, Ar-H), 7.85±7.89 (2H, m, Ar-H), 8.22±8.25 (2H, m, Ar-H); 13C NMR (CDCl3,
75.5 MHz): 14.1, 42.9 (C-2), 62.7, 121.1, 123.8, 129.2, 131.6, 131.8, 134.5, 134.49, 159.2 (C-3), 167.2 and 167.6; MS
(EI) 334 (M+, 18%), 306 (33), 277 (20), 132 (9) and 105 (100).

7220
6. Ethyl 1,4-diaza-1,4-dimethyl-3-phenyl-1,3-butadiene-2-carboxylate 6. The 2H-azirine 3a (0.59 g, 2.2 mmol) was
dissolved in DMF (10 ml) and methylamine (68.2 mg, 2.2 mmol) was added. The reaction mixture was stirred at
room temperature for 5 days. The solvent was evaporated and the residue was subjected to ¯ash chromatography
[with hexane:ethyl acetate (2:1)] giving the compound 6 (16 mg, 6.2%) as a solid. M.p. 62.5±64ꢀC (from ethyl
1
ether±hexane). H NMR (CDCl3, 300 MHz): 1.30 (3H, t, J 7.2 Hz), 3.34 (3H, s), 3.39 (3H, s), 4.31 and 4.32 (2H,
2Âq, 7.2 Hz), 7.40±7.43 (3H, m, Ar-H) and 7.61±7.65 (2H, m, Ar-H); 13C NMR (CDCl3, 75.5 MHz): 13.9, 41.1,
42.2, 62.3, 126.4, 128.8, 130.9, 134.9, 161.6, 161.8, 163.6; MS (EI) 232 (M+, 20%), 231 (40), 203 (6), 158 (12), 118
(100) and 77 (100); HRMS (EI) 231.1128 [M^H]+ (C13H15N2O2 M^H+, 231.1134).
7. The structures of this a-diimine 6 and 3-oxazoline 8 were established by X-ray crystallography. These results will
be disclosed in a joint paper by the authors together with Beja, A. M.; Paixao, J. A.; Silva, M. R.; Alte da Veiga,
L. (Departamento de Fõsica, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, Portugal).
8. Diethyl 2-benzoyl-5-hydroxy-4-phenyl-3-oxazoline-2,5-dicarboxylate 8. The 2H-azirine 3a (0.52 g, 1.94 mmol) was
dissolved in DMF (10 ml) and water (60 mg, 3.3 mmol) was added. The reaction mixture was stirred in an
ultrasound bath for 2 days. The solvent was evaporated and the residue was subjected to ¯ash chromatography
[with hexane:ethyl acetate (3:1)] giving 8 (0.117 g, 30%) as a solid. M.p. 99.7±102ꢀC (from ethyl ether±hexane).
1
Anal. calcd for C22H21NO7: C, 64.23; H, 5.14; N, 3.40. Found: C, 63.86; H, 5.25; N, 3.28. H NMR (CDCl3, 300
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7.55 (10H, m, Ar-H), 7.58±7.62 (2H, m, Ar-H), 7.96±8.02 (4H, m, Ar-H) and 8.18±8.26 (4H, m, Ar-H); 13C NMR
(CDCl3, 75.5 MHz): 13.45, 13.69, 62.64, 63.27, 63.54, 63.61, 105.17, 105.47, 109.85, 110.17, 128.23, 128.29, 128.44,
128.47, 126.71, 126.74, 128.95, 129.83, 129.86, 132.54, 132.59, 133.58, 133.70, 133.96, 165.51, 166.74, 167.34,
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