Generation and cycloadditions of azirinium difluoromethanides - Strained azomethine ylides

Article abstract of DOI:10.1016/S0040-4039(02)02076-2

The reaction of 3-aryl-2H-azirines with difluorocarbene involves the formation of azirinium difluoromethanides - the first strained azomethine ylides which undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate, giving rise to fluorinated

Full text of DOI:10.1016/S0040-4039(02)02076-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8523–8525
Generation and cycloadditions of azirinium
difluoromethanides—strained azomethine ylides
Alexander F. Khlebnikov,* Mikhail S. Novikov and Amer A. Amer
Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Petrodvorets, Russia
Received 22 June 2002; revised 7 September 2002; accepted 20 September 2002
Abstract—The reaction of 3-aryl-2H-azirines with difluorocarbene involves the formation of azirinium difluoromethanides—the
first strained azomethine ylides which undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate, giving rise to
fluorinated fused azirinopyrrole derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
The chemistry of azirines has long attracted consider-
able interest because of the high reactivity of these
strained nitrogen unsaturated heterocycles towards elec-
trophiles, nucleophiles, as well as dipoles and dienes, in
cycloaddition reactions.1 However, the reactions of
azirines with electrophilic carbenes, which might give
rise to unusual strained azomethine ylides—azirinium
methanides, are practically unknown. No evidence has
so far been reported for the existence of systems in
which the carbonꢀnitrogen bond of a 1,3-dipole is
incorporated into a three-membered ring. There has
been a sole work of Hassner et al. who showed that the
reaction of dichlorocarbene with azirines proceeds with
opening of the three-membered ring to provide N-vinyl-
N-dichloromethyleneamines, presumably through for-
mation of the corresponding azirinium dichloro-
methanides and subsequent rearrangement of the latter,
directly or through cyclization, into transient 1-azabicy-
clobutane.2 Trapping of dichloro-substituted ylides by
1,3-dipolar cycloaddition often fails because of their
tendency for 1,3-cyclization into aziridines.
Quantum-mechanical calculations revealed that intro-
duction of two geminal fluorine atoms influences the
ylide geometry, and this shows up in a great difference
in reactivity between iminiodifluoromethanides and
their close analogue iminiochlorofluoromethanides and
iminiodichloromethanides.4 Actually, as predicted by
the calculations difluoroylides (irrespective of sub-
stituent at nitrogen) undergo 1,3-dipolar cycloaddition
onto multiple bonds rather than cyclization into aziridi-
nes,5 and with dichloroylides and chlorofluoroylides the
situation is the opposite.6 These findings led us to
suppose that difluorocarbene would react with azirines
to give the corresponding azirinium difluoromethanides
which might be fixed as adducts of 1,3-dipolar cycload-
ditions to suitable dipolarophiles.
We found that the reaction of 3-aryl-2H-azirines with
difluorocarbene proceeds through formation of
difluorosubstituted azirinium ylides—the first strained
azomethine ylides which can be trapped with DMAD
and benzaldehyde as dipolarophiles to obtain fused
azirinopyrrole or azirinoxazole derivatives. Difluorocar-
bene was produced by reduction of CF2Br2 with active
lead in the presence of tetrabutylammonium bromide.5d
Earlier we found that reaction pathways of halogeno-
carbene-derived ylides are highly halogen-dependent.3
Scheme 1.
Keywords: azirines; difluorocarbene; strained azomethine ylides; cycloaddition; azirinopyrroles.
* Corresponding author. E-mail: alexander.khlebnikov@pobox.spbu.ru
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02076-2

8524
A. F. Khlebniko6 et al. / Tetrahedron Letters 43 (2002) 8523–8525
cycloaddition of unstrained fluorinated azomethine
The reaction of 3-aryl-2H-azirines 1a–f with difluoro-
carbene in the presence of dimethyl acetylenedicarboxyl-
ate as a dipolarophile yields azirino[1,2-a]pyrroles
3a,b,d–f (Scheme 1) which were fully characterised
using standard spectral and analytical methods.7 The
modest yields of the products can be rationalised by
their partial decomposition on silica during chromato-
graphic purification. In fact, the primary products of
cycloaddition of difluorosubstituted azomethine ylides
to multiple carbon–carbon bonds are usually not
isolable compounds because of their propensity to
dehydrofluorinate into pyrroles5a,5c,5e or hydrolyse into
lactams.5b,5d,5e In contrast, gem-difluorinated azirinopyr-
roles 3 being isolated as solids or an oil are fairly stable
and can be stored indefinitely at −20°C. However, when
kept at room temperature they quantitatively trans-
formed to 2-fluoropyridines7 4 by ring expansion and
dehydrofluorination (Scheme 2). Of all the azirines
studied, only azirine 1c gave a cycloadduct which
proved to be not stable enough to withstand chromato-
graphic work-up and directly transforms into pyridine
4c (isolable yield 36%).
ylides.5c
An important feature of the 2,2-difluoro-1-azabicy-
clo[3.1.0]hex-3-enes 3 synthesised is their ability to
undergo transformations with preservation of the three-
membered ring. Thus, azirinopyrroles 3 react with pri-
mary amines with preservation of the strained bicyclic
skeleton (Scheme 4). The products are amino-substi-
tuted azirinopyrroles 8 which are probably formed by
tele-substitution (SN2% reaction) of one fluorine in com-
pounds 3 with amine, followed by ipso-substitution of
the second fluorine through the addition-elimination
sequence. The structure of the products was proved by
1H, 13C NMR and IR spectroscopy and elemental
analysis.7 The trans-arrangement of the aryl and
methoxycarbonyl groups follows from the chemical
shifts of CH3O protons6a,8 and the NOESY spectrum of
compound 8a.
In conclusion, we have demonstrated that a new type
of azomethine ylide, strained azirinium difluoro-
methanides, can be generated by the reaction of
difluorocarbene with 3-aryl-2H-azirines. The azirinium
methanides can be used as synthetic equivalents both of
-C+-N-C− and -C+-C-N-C−-synthons in the carbene-
derived ylide methodology of preparation of heterocy-
cles containing an unusual combination of structural
fragments: a strained ring and fluorine.
Cycloaddition of azirinium difluoromethanide 2a to
benzaldehyde proceeds completely regioselectively.
However, the corresponding primary cycloadduct 5 is
unstable and undergoes hydrolysis to give 42% of
morpholinone7 7, probably through the 3-fluoro-
morpholine derivative 6 (Scheme 3). The regioselectivity
of cycloaddition of azirinium difluoromethanides to
carbonyl group is the same as in intermolecular
A typical experimental procedure of the reaction of
azirines 1 with difluorocarbene in the presence of di-
polarophiles is as follows. A flask containing a freshly
prepared active lead (1.7 g, 8.2 mmol) and methylene
chloride (20 cm3) was charged with Bu4NBr (2.79 g,
10.5 mmol), imine 1a (0.52 g, 4.44 mmol), DMAD (1.89
g, 13.3 mmol), and CBr2F2 (1 cm3, 10.9 mmol). The
flask was tightly stopped, and the mixture was magnet-
ically stirred at 45°C until the lead was consumed
completely (ca. 4 h). The solvent was removed under
reduced pressure, and the residue was separated by
chromatography on silica gel.
Scheme 2.
Scheme 3.
Scheme 4.

A. F. Khlebniko6 et al. / Tetrahedron Letters 43 (2002) 8523–8525
8525
Acknowledgements
Buyck, L.; Vehre, R.; Schamp, N.; Declery, J. P.; Van
Meerssehe, M. J. Chem. Res. 1984, 82–83.
7. Data for selected compounds: 3a mp 70–72°C (Et2O/pen-
We gratefully acknowledge the Russian Foundation for
Basic Research (Project 02-03-32735a) and the Ministry
of Education of Russian Foundation (Project E00-5.0-
371) for financial support of this research.
tane); IR wmax (CCl4): 1670, 1755 cm−1 1H NMR (300
;
MHz, CDCl3): 7.41–7.36 (m, 5H, PhH), 3.85 (s, 3H,
MeO), 3.76 (s, 3H, MeO), 2.85 (d, JH-F=1.5 Hz, 1H, 1-H),
2.69 (d, JH-F=2.5 Hz, 1H, 1-H); 13C NMR (75 MHz,
CDCl3): 162.3 (CꢁO), 159.7 (t, CꢁO, JC-F=2.6 Hz), 154.8
(t, C5, JC-F=4.5 Hz), 124.0 (dd, C4, JC-F=30, 38 Hz),
129.1 (dd, C3, JC-F=245, 255 Hz), 131.2 (d, CPh, JC-F=3.5
Hz), 129.0, 128.5, 127.8 (CPh), 55.0 (t, C5a, JC-F=2.9 Hz),
49.2 (t, C1, JC-F=3.5 Hz), 52.6, 52.4 (MeO). Anal. Calcd
for C15H13F2NO4: C, 58.26; H, 4.24; N, 4.53. Found: C,
58.11; H, 4.34; N, 4.34: 4a (mp 68°C, EtOH); IR wmax
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