A facile synthesis of difluoromethylaziridines

Article abstract of DOI:10.1016/S0040-4039(02)00205-8

Difluoromethylaziridines were synthesized by the reaction of dimethylsulfonium methylide with difluoroenamines which were easily prepared from trifluoromethylimines by magnesium-promoted defluorosilylation.

Full text of DOI:10.1016/S0040-4039(02)00205-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2069–2072
A facile synthesis of difluoromethylaziridines
Masayuki Mae, Makoto Matsuura, Hideki Amii and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Received 7 December 2001; revised 21 January 2002; accepted 25 January 2002
Abstract—Difluoromethylaziridines were synthesized by the reaction of dimethylsulfonium methylide with difluoroenamines which
were easily prepared from trifluoromethylimines by magnesium-promoted defluorosilylation. © 2002 Elsevier Science Ltd. All
rights reserved.
Introduction of fluorine into pharmacologically active
substances has become an important approach in the
design of more potent agonists or antagonists from the
point of isogeometric modification of enzyme substrates
with maximal shift of electron distribution.1 Special
attention has been paid to difluoromethyl containing
compounds because they have interesting biological
activities.2 Among the pharmacologically active com-
pounds, difluoromethylaziridines are one of the attrac-
92% yield instead of an expected cyclopropane deriva-
tive (Scheme 2, Eq. (1)).
It was suggested that desilylation of 1a followed by
aziridination of difluoromethylimine would give the
corresponding aziridine 2a. In fact, (i) desilylation of 1a
proceeded smoothly to give 3a in 5 min under the
experimental conditions;8 (ii) aziridination of
difluoromethylimine 3a, which was prepared by desilyl-
ation with hydrated TBAF in THF, proceeded
smoothly in DMSO to give corresponding
difluoromethyl aziridine 2a in 92% yield (Scheme 2, Eq.
(2)).
tive
key
compounds
because
their
parent
nonfluorinated aziridines are useful precursors for vari-
ous kinds of medicines, for example, prenylamine b-
blocker, catrone MAO inhibitor, and so on.3 However,
very few synthetic methods for fluorinated aziridines4
have been presented. One of the typical methods is a
ring closure of b-amino alcohols or their equivalents,
Meanwhile the ylide aziridination reaction remains
rather undeveloped. In this paper, we would like to
report one-pot synthesis of difluoromethylaziridines 2
by the reaction of dimethyloxosulfonium methylide
with difluoroenamines 1, which were prepared by mag-
nesium-promoted selective CꢀF bond cleavage of corre-
sponding trifluoromethylimines (Scheme 1).5
In general, it is well known that the reactivity of
common N-alkyl- and N-arylimines, especially with
electron-donating N-substituted groups, toward nucle-
ophiles is very low and can be improved in the presence
of either Lewis acids or phase-transfer catalyst, by the
modification of imine structure with electron-withdraw-
ing groups such as tosyl group on nitrogen atom or an
aromatic group on the imine carbon.9,10 Recently, the
first successful methylene transfer to the aliphatic unac-
tivated aldimines was reported by Reetz et al.10 How-
ever, the participating imines were not derived from
corresponding ketones but mostly from aromatic and
Reaction of difluoroenamine 1a with dimethyloxosulfo-
nium methylide6 gave difluoromethylaziridine 2a7 in
Scheme 1.
Keywords: aziridines; enamines; imines; amino acid and derivatives; ylides.
* Corresponding author. Tel.: +81 86 251 8075; fax: +81 86 251 8021; e-mail: uneyamak@cc.okayama-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00205-8

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M. Mae et al. / Tetrahedron Letters 43 (2002) 2069–2072
Scheme 2.
aliphatic aldehydes. So, the present reaction is the first
successful aziridination of difluoromethyl aryl ketimines
by sulfur-ylide.
Interestingly, the reaction of difluoroenamines bearing
electron-withdrawing group on imine carbon with sul-
fur-ylide was drastically different from aziridination,
but it gave a-fluoro- a,b-unsaturated imines 5 in good
yields instead of difluoromethyl aziridines (Table 1,
entries 8–11). On the other hand, difluoromethyl-
aziridine 2f was obtained from the corresponding
difluoromethyl imine 3f in a good yield (entry 12).
Moreover, difluoromethylaziridine 2h was obtained
without accompanying a-fluoro-a,b-unsaturated imines
5 from the corresponding difluoromethyl imine 3h
(entry 13).12
These results shown in Scheme 1 prompted us to inves-
tigate
a
scope of the one-pot synthesis of
difluoromethylaziridines.
As shown in Table 1, various kinds of difluoromethyl-
aziridines 2 were prepared directly from corresponding
difluoroenamines 1 in good yields under mild condi-
tions. In the case of N-p-chlorophenyl and N-phenyl
enamines, the reaction proceeded smoothly to give cor-
responding difluoromethylaziridines 2a, 2b and 2c in
high yields, respectively (entries 1–3). Moreover,
difluoroenamine 1d, which was prepared from tri-
fluoromethyl aldimine with N-p-methoxyphenyl group,
gave corresponding difluoromethylaziridine 2d in a
good yield (entry 4). In the case of silylated difluoro-
enamine 1e, desilylated product 2d was obtained (entry
5). Meanwhile, enamines with p-methoxyphenyl and o,
p-dimethoxyphenyl groups on imine carbon gave 2f
and 2g in moderate yields along with 3f and 3g, respec-
tively (entries 6 and 7).
Although, the reaction mechanism is not clear at
present, it is likely that the reaction course was inten-
sively affected by the electronic nature of substituent
both on nitrogen and imino carbon as shown in Scheme
3. When either the anion on the nitrogen was stabilized
by electron-withdrawing group or the anion on the
a-carbon was unstabilized by electron-donating group,
the reaction proceeded through path A to give azirizi-
nes 2 via corresponding difluoromethyl imines 3. The
path A is highly dependent on the stabilization of the
anion on nitrogen (Table 1, entry 1 versus entry 8). On
Table 1. A facile synthesis of difluoromethylaziridinesa
Entry
Substrate
R
Ar
Yield (%)b
2/5
3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
p-MeOC6H4
C6H5
H
TMS
p-MeOC6H4
o,p-(MeO)2C6H3
C6H5
p-ClC6H4
2-Thienyl
CO2Et
p-ClC6H4
p-ClC6H4
C6H5
92 (2a)
90 (2b)
62 (2c)
78 (2d)
52 (2d)
32 (2f)
41 (2g)
48 (5h)d
41 (5i)d
36 (5j)d
79 (5k)
57 (2f)
70 (2h)
0
0
0
0
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
0
25 (3f)
42 (3g)
26 (3h)
25 (3i)
38 (3j)
0
9
10
11
12
13c
1j
1k
3f
p-MeOC6H4
C6H5
0
3h
8 (3h)
a The reactions were carried out by the procedure shown in Ref. 11.
b Isolated yield.
c The reaction was carried out for 9 h.
d A mixture of syn and anti isomer.

M. Mae et al. / Tetrahedron Letters 43 (2002) 2069–2072
2071
Scheme 3.
PMP
PMP
References
NH
N
CAN
MeCN/H2O
HF2C
PMP
HF2C
1. (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.;
Kobayashi, Y., Eds.; Elsevier: Amsterdam, 1982; (b)
Walsh, C. Tetrahedron 1982, 38, 871; (c) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
John Wiley & Sons: New York, 1990; (d) Organofluorine
Compounds in Medicinal Chemistry and Biomedical Appli-
cations; Filler, R.; Kobayashi, Y.; Yagupolski, L. M.,
Eds.; Elsevier Science: Amsterdam, 1993.
2. For example: (a) Kuo, D.; Rando, R. R. Biochemistry
1981, 20, 506; (b) Dibari, C.; Pastore, G.; Roscigno, G.;
Schechter, P. J.; Sjoerdsma, A. Ann. Intern. Med. 1986,
105, 83; (c) Seiler, N.; Jung, M. J.; Koch-Wester, J., Eds.
Enzyme-activated Irreversible Inhibitors, North-Holland:
Amsterdam, 1978; (d) Schirlin, D.; Gerhart, F.;
Hornsperger, J. M.; Hamon, M.; Wagner, J.; Jung, M. J.
J. Med. Chem. 1988, 31, 30.
3. Medicinal Chemistry, An Introduction; Tsuda, Y.;
Ninomiya, I.; Kaneto, H., Eds., Nankodo: Japan, 1996.
4. (a) Katagiri, T.; Ihara, H.; Kashino, S.; Furuhashi, K.;
Uneyama, K. Tetrahedron: Asymmetry 1997, 8, 2933; (b)
Bravo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J. Fluo-
rine Chem. 1999, 97, 27; (c) Katagiri, T.; Takahashi, M.;
Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem.
1999, 64, 7323.
8 (92%)
2f
Scheme 4.
the other hand, when both the anion on nitrogen was
unstabilized by electron-donating group and the anion
on the a-carbon was stabilized by electron-withdrawing
group, a,b-unsaturated imines 5 were obtained. In path
B, initial addition of sulfur-ylide to b-carbon of
difluoroenamine followed by elimination of fluoride
anion and subsequent the fluoride anion attack on silyl
group resulted in the formation of 5 as a final product.
It is noteworthy that ethyl 3-fluoro-2-imino-3-butenoate
(5k)13 was obtained predominantly from ethyl 2-amino-
3,3-difluoroacrylate (1k), in which anion on a-carbon in
strongly stabilized by ethoxycarbonyl group.
N-p-Methoxyphenyl group of 2f was easily and selec-
tively removed by the oxidation with CAN to give
N-nonsubstituted aziridine 8 in 92% yield, which would
be transformed to
a
variety of functionalized
5. (a) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K.
Chem. Commun. 1999, 1323; (b) Mae, M.; Amii, H.;
Uneyama, K. Tetrahedron Lett. 2000, 41, 7893; (c) Amii,
H.; Kobayashi, T.; Uneyama, K. Synthesis 2000, 2001;
(d) Amii, H.; Kobayashi, T.; Terasawa, H.; Uneyama, K.
Org. Lett. 2001, 3, 3103; (e) Amii, H.; Hatamoto, Y.; Seo,
M.; Uneyama, K. J. Org. Chem. 2001, 66, 7216.
difluoromethyl aziridines and amines (Scheme 4).
In summary, one-pot synthesis of difluoromethylaziridi-
nes by the reaction of difluoroenamines 1 with dimethyl-
oxosulfonium methylide was achieved where the favor-
able reaction course was controlled by electronic nature
of substituents both on nitrogen and imine carbon.
6. For reviews of sulfur ylides: (a) Trost, B. M.; Melvin, L.
S., Jr. Sulfur Ylides; Academic Press: New York, 1975;
(b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.
1965, 87, 1353; (c) Trost, B. M.; Bogdanowicz, M. J. J.
Am. Chem. Soc. 1973, 95, 5298.
Acknowledgements
7. Selected spectra data for compound 2a: 1H NMR (200
MHz, CDCl3) l 2.72 (s, 1H), 2.74 (dd, JH–F=1.8, 3.6 Hz,
1H), 5.56 (t, JH–F=54.6 Hz, 1H), 6.94 (d, J=9.0, Hz,
2H), 7.18 (d, J=9.0 Hz, 2H), 7.32–7.37 (m, 3H), 7.46–
7.52 (m, 2H); 19F NMR (188 MHz, CDCl3, C6F6 as an
internal standard) l 42.8 (dd, JH–F=54.6 Hz, JF–F=289.0
The authors are grateful to the Ministry of Education,
Science, Sports, and Culture of Japan (grant-in-aid for
scientific research No. 13555254) and Okayama Univer-
sity VBL for the financial supports and the SC-NMR
Laboratory of Okayama University for 1H and 19F
NMR analyses.

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M. Mae et al. / Tetrahedron Letters 43 (2002) 2069–2072
Hz, 1F), 44.9 (dd, JH–F=54.6 Hz, JF–F=289.0 Hz, 1F);
extracted with ether. The extracts were washed with
brine, dried over MgSO4 and evaporated. The crude
product was purified by silica gel column chromatogra-
phy (ether/hexane=1/9) to give difluoromethylaziridine
2a in 92% yield as yellow oil.
IR (neat) 1494 cm−1. GC/MS m/z 279 (M+, 44), 278
(100), 227 (27). Anal. calcd for C15H12ClF2N: C, 64.41;
H, 4.32; N, 5.01. Found: C, 64.13; H, 4.32; N, 5.12.
8. Desilylative imine formation from 1a occurred in DMSO,
NaH/DMSO or Me3S(O)I/DMSO.
12. Difluoromethylaziridine 2k (R=CO2Et) was not
obtained because desilylation of ethyl 2-amino-3,3-
difluoroacrylate (1k) gave the corresponding enamine 4k
(R=CO2Et) rather than the imine 3k (R=CO2Et). Like-
wise, ethyl 3,3-difluoro-2-hydroxy acrylate is known to be
isolated. Osipov, S. N.; Golubev, A. S.; Sewald, N.;
Michel, T.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. J.
Org. Chem. 1996, 61, 7521.
9. (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev.
1997, 97, 2341; (b) Tewari, R. S.; Awasthi, A. K.;
Awasthi, A. Synthesis 1983, 330; (c) Aggarwal, V. K.;
Stenson, R. A.; Jones, R. V. H.; Fieldhouse, R.; Blacker,
J. Tetrahedron Lett. 2001, 42, 1587; (d) Aggarwal, V. K.;
Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni,
M. Angew. Chem., Int. Ed. 2001, 40, 1443.
10. Reetz, M. T.; Lee, W. K. Org. Lett. 2001, 3, 3119.
11. Typical procedure was as follows: To a mixture of
sodium hydride (1.7 mmol, prewashed with n-hexane)
and trimethyloxosulfonium iodide (1.7 mmol) was added
DMSO (5.0 mL) at room temperature. Vigorous gas
evolution was observed. The mixture was stirred at room
temperature for 30 min. A solution of difluoroenamine 1a
(1.0 mmol) in DMSO (5.0 mL) was added at room
temperature. After being stirred for 3 h, the mixture was
poured onto cold ice–water. The biphasic mixture was
13. Selected spectra data for compound 5k: 1H NMR (200
MHz, CDCl3) l 1.07 (t, J=7.2 Hz, 3H), 3.80 (s, 3H), 4.15
(q, J=7.2 Hz, 2H), 5.26 (dd, JH–H=3.9, JH–F=45.7 Hz,
1H), 5.41 (dd, JH–H=3.9, JH–F=15.0, Hz, 1H), 6.85 (d,
J=9.2 Hz, 2H), 6.94 (d, J=9.2 Hz, 2H); 19F NMR (188
MHz, CDCl3, C6F6 as an internal standard) l 46.8 (dd,
J
H–F=15.0, 45.7 Hz, 1F) IR (neat) 1738 cm−1; GC/MS
m/z 251 (M+, 1), 92 (74), 77 (100). Anal calcd for
C13H14FNO3: C, 62.14; H, 5.62; N, 5.57. Found: C,
61.92; H, 5.71; N, 5.53.