Synthesis of 3-substituted 2-fluoro- And 2,2-difluoroaziridines

Article abstract of DOI:10.1021/ol071127x

A new route for the synthesis of stable 3-alkyl- and 3-aryl-2(,2)-(di) fluoroaziridines was developed by hydride reduction of novel α-bromo- and α-chloro-α(,α)-(di)fluoroketimines and subsequent ring closure of β-fluorinated β-chloro- and β-bromoamines. T

Full text of DOI:10.1021/ol071127x

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2935-2937
Synthesis of 3-Substituted 2-Fluoro- and
2,2-Difluoroaziridines
Eva Van Hende, Guido Verniest,§ Riccardo Surmont, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent UniVersity, Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@UGent.be
Received May 15, 2007
ABSTRACT
A new route for the synthesis of stable 3-alkyl- and 3-aryl-2(,2)-(di)fluoroaziridines was developed by hydride reduction of novel
-chloro- (, )-(di)fluoroketimines and subsequent ring closure of -fluorinated -chloro- and -bromoamines. This is the first report on the
synthesis of 2,2-difluoroaziridines sensu stricto.
r-bromo- and
r
r
r
â
â
â
Fluorinated heterocyclic compounds have become increas-
ingly important in pharmaceutical chemistry, and hence
numerous synthetic methods are being developed to incor-
porate the smallest and most electronegative halogen in
organic compounds.1 In addition, the effects of fluorine as a
substituent in organic compounds on chemical reactivity and
stability are worth exploring to gain a more profound insight
into fluorine chemistry. Our interest was drawn to R-fluor-
inated imines, which constitute a promising class of building
blocks for the synthesis of fluorinated heterocycles.2 In that
respect, efforts were made to use R-fluoroimines to synthe-
size fluorinated aziridines. Although these peculiar com-
pounds could serve as useful starting materials for further
organic transformations, fluorinated aziridines have received
only very limited attention in the literature. 2,2-Difluoro-
aziridines have previously not been synthesized at all, apart
from some perfluorinated and trifluoromethylated aziridines,
which are prepared via carbene or nitrene cycloaddition
reactions to specific imines or olefins.3 There are only a few
reports in the literature on the synthesis of monofluorinated
aziridines, most of which deal with fluorocarbene cyclo-
additions to imines.4 In the present report, a new approach
to synthesize fluorinated aziridines was developed, based on
reduction of the appropriate novel R-fluorinated R-bromo-
and R-chloroketimines and cyclization via intramolecular
substitution of the resulting â-bromo- and â-chloroamines.
* Corresponding author. Tel.: +32(0)9 264 59 51. Fax: +32(0)9 264
62 43.
(3) (a) Zeifman, Y. V.; Ter-Gabrielyan, E. G.; Gambaryan, N. P.;
Knunyants, I. L. Russ. Chem. ReV. 1984, 53, 256. (b) Lork, A.; Gard, G.;
Hare, M.; Mews, R.; Stohrer, W. D.; Winter, R. J. Chem. Soc., Chem.
Commun. 1992, 12, 898. (c) Krespan, C. G. J. Org. Chem. 1986, 51, 332.
(d) Petrov, V. A. J. Fluorine Chem. 2000, 106, 25. (e) Logothetis, A. L. J.
Org. Chem. 1964, 29, 3049. (f) Carpenter, W. R.; Haymaker, A.; Moore,
D. W. J. Org. Chem. 1966, 31, 789.
(4) (a) Khlebnikov, A. F.; Novikov, M. S.; Shinkevich, E. Y.; Vidovic,
D. Org. Biomol. Chem. 2005, 3, 4040. (b) Konev, A. S.; Novikov, M. S.;
Khlebnikov, A. F. Tetrahedron Lett. 2005, 46, 8337. (c) Usuki, Y.; Fukuda,
Y.; Ilo, H. ITE Lett. Batteries, New Technol. Med. 2001, 2, 237. (d) Seyferth,
D.; Woodruff, R. A. J. Org. Chem. 1973, 38, 4031. (e) Yamanaka, H.;
Kikui, J.; Teramura, K.; Ando, T. J. Org. Chem. 1976, 41, 3794. (f) Konev,
A. S.; Novikov, M. S.; Khlebnikov, A. F. Russ. J. Org. Chem. 2007, 43,
286.
§ Postdoctoral Fellow of the Research Foundation - Flanders (FWO -
Vlaanderen).
(1) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; John Wiley & Sons: New York, 1991. (b) Baasner, B.;
Hageman, H.; Tatlow, J. C. Organo-Fluorine Compounds. In Houben-Weyl
Methods of Organic Chemistry, E10a-c, additional and supplementary vol.
to the 4th ed.; Georg Thieme-Verlag, Stuttgart: New York, 1999; Vol.
E10a-c. (c) Olah, G. A.; Chambers, R. D.; Prakash, G. K. Surya. Synthetic
Fluorine Chemistry; John Wiley & Sons: New York, 1992. (d) Curran, D.
P.; Mikami, K.; Soloshonok, V. A. (Guest Eds.) J. Fluorine. Chem. 2006,
127, 456.
(2) Verniest, G.; Van Hende, E.; Surmont, R.; De Kimpe, N. Org. Lett.
2006, 8, 4767.
10.1021/ol071127x CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

Having in hand a new method to synthesize R-fluorinated
imines via electrophilic fluorination of imines using NFSI,2
efforts were made to use these compounds for further R-func-
tionalization. Therefore, N-(2-fluoro-1-phenylethylidene)-
isopropylamine was treated with NCS in refluxing CCl4
yielding (E)-N-(2-chloro-2-fluoro-1-phenylethylidene)isopro-
pylamine 3a or (E)-N-(2,2-dichloro-2-fluoro-1-phenyleth-
ylidene)isopropylamine 3h, depending on whether one or two
equivalents of halogenating agent were used (Scheme 1). The
curred when R-fluoroacetophenone was treated with a large
excess of chlorine gas in acetic acid at 80 °C for 20 h yielding
95% R-chloro-R-fluoroacetophenone. Bromination of R-fluo-
roacetophenone using bromine and aluminum(III) chloride
yielded R-bromo-R-fluoroacetophenone, as reported in the
literature,5 but in this case, subsequent imine formation with
isopropylamine in the presence of titanium(IV) chloride to
obtain the corresponding R-bromo-R-fluoroimine failed.
However, the latter imine condensation protocol with tita-
nium(IV) chloride proved successful in the synthesis of (E)-
N-(2-bromo-2-fluoro-1-phenylpropylidene)isopropylamine 3e6
and (E)-N-(2-chloro-2-fluoro-1-(4-methoxyphenyl)ethylide-
ne)isopropylamine 3d, starting from the corresponding
ketones 2 (R1 ) MeO, H; R2 ) H, Me; X ) Cl, Br).
Scheme 1
The obtained novel R-bromo- and R-chloro-R-fluoroimines
3a-e were reduced using sodium cyanoborohydride in
methanol resulting in stable â,â-dihalogenated amines
4a-e, although as a mixture of both diastereomers. Attempts
to increase the diastereomeric excess by adding Lewis acids,
such as LiCl, TiCl4, or ZnCl2 instead of acetic acid to induce
a complexation between the metal and the halogen (Cl or
F), gave no significant improvement of the diastereomeric
excess, even when the reaction was performed at -78 °C.
Using R-bromoimine 3e, the reduction had to be carefully
controlled at -20 °C for 45 min to obtain a 3:1 mixture of
diastereomers 4e. Treatment of â-chloro- and â-bromo-â-
fluoroamines 4a-e with K2CO3 in DMSO at 75-140 °C
gave rise to new 2-fluoroaziridines 5a-e and 6a-e.
In some cases, the cis- and trans-isomers could be
separated via flash chromatography on silica gel. It was
observed that trans-aziridines 6 were not as stable on silica
gel as the cis-analogues 5, giving rise to purification problems
during chromatography. This observation is analogous to
non-fluorinated 2-methyl-3-phenylaziridines, where the cis-
isomer is also the most stable.6,7
The stereochemical assignment of the two isomers 5a-d
and 6a-d was based on the vicinal H,H- and H,F-coupling
constants in 1H NMR. No conclusions could be drawn from
NOE analysis results. In the case of cis-aziridine 5a, a vicinal
H,H-coupling of 4.4 Hz and a vicinal H,F-coupling of 2.5
Hz were measured, whereas the trans-isomer 6a gave
coupling constants of 0 and 6.1 Hz, respectively. The same
difference in H,F-coupling (3.3 and 9.1 Hz) was found in
the 1H NMR spectrum of aziridines 5e and 6e, which
provided a clear discrimination of both isomers and is in
accordance with literature data of other cis- and trans-
substituted fluoroaziridines.4c
a
ns ) not separable from the cis-isomer via flash chromatog-
Encouraged by the results described above, R-chloro-R,R-
difluoroimines 9a-d were used as substrates for the synthesis
of 3-substituted 2,2-difluoroaziridines 12, a virtually new
class of compounds. Because R,R-difluoroacetophenone
raphy.
same strategy led to the formation of R-brominated imines
3g and 3f by the use of NBS in CCl4. Because the
R-chlorination proceeded in higher yield as compared to the
R-bromination, further elaboration of the reactivity was
predominantly performed using R-chloro-R-fluoroimines.
The ease of R-chlorination of R-fluoroimines is in sharp
contrast with the difficulties which were observed to
chlorinate R-fluoroacetophenone. R-Chlorination only oc-
(5) Bergmann, F.; Kalmus, A.; Vromen, S. J. Am. Chem. Soc. 1955, 77,
2494.
(6) Synthesis of ketone 2e: De Kimpe, N.; Verhe´, R.; De Buyck, L.;
Schamp, N. Tetrahedron Lett. 1980, 21, 2257.
(7) (a) Taguchi, T.; Kojima, M. Chem. Pharm. Bull. 1959, 7, 103. (b)
Okada, I.; Ichimura, K.; Sudo, R. Bull. Chem. Soc. Jpn. 1970, 43, 1185.
(c) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. J. Org. Chem.
1980, 45, 5319.
2936
Org. Lett., Vol. 9, No. 15, 2007

could not be R-chlorinated nor R-brominated and the
R-halogenation of its N-isopropylimine 10 turned out to be
extremely difficult (yield 4-7%), the corresponding R-chloro-
R,R-difluoroketones 88 were synthesized from R-chloro-R,R-
difluoroacetic acid 7.9 These R-chloro-R,R-difluoroketones
8 were subsequently treated with primary amines in the
presence of titanium(IV) chloride (Scheme 2) yielding imines
It was observed that 3-alkyl-2,2-difluoroaziridines 12a,b
were significantly more stable on silica gel as compared to
2,2-difluoro-3-phenylaziridines 12c,d, which tended to de-
compose upon purification by flash chromatography. Indeed,
although both 3-alkyl- and 3-aryl-2,2-difluoroaziridines were
stable for several days at room temperature, the degradation
of 2,2-difluoroaziridines 12c,d was observed even at low
temperature (-20 °C). In the presence of moist air, a
complete conversion toward R-fluoroamides 15 took place
via expulsion of a fluoride anion by nitrogen, subsequent
ring opening of the azirinium fluoride 13 by fluoride, and
nucleophilic addition of water across the imidoyl fluoride
14. 3-Alkyl-2,2-difluoroaziridines 12a,b did not show this
degradation but could be forced to undergo the same reaction
pathway toward 16a by treatment with aqueous HCl in
DMSO. Analogous reaction conditions (aqueous HCl in
CH3CN) also converted 2,2-difluoro-3-phenylaziridine 12c
toward the corresponding R-chloroamide 16b (Scheme 3).
Scheme 2
Scheme 3
9a-d. The compounds were reduced with sodium cyano-
borohydride in methanol in the presence of acetic acid toward
the corresponding â,â,â-trihalogenated amines 11 in high
yield. Subsequently, amine 11c was treated with K2CO3 in
DMSO, analogous to the synthetic procedure for monofluo-
roaziridines 5 and 6. These reactions did not yield any
difluoroaziridine 12c but instead gave rise to difluoroimine
10 via a 1,2-dehydrochlorination and subsequent enamine-
imine tautomerization. The same result was obtained when
using KOtBu in THF. Treatment of amines 11 with the more
sterically hindered and stronger base LDA did not result in
a 1,2-dehydrochlorination but gave 2,2-difluoroaziridines 12
in good yield. This is the first efficient synthesis of 2,2-
difluoroaziridines described in the literature.
In conclusion, it can be stated that useful synthetic
pathways were developed to access new 2-fluoro- and 2,2-
difluoroaziridines starting from halogenated mono- and
difluoroimines. It should be noted that, previously, no general
method to synthesize difluoroaziridines was available. The
obtained fluorinated aziridines were stable enough to isolate,
characterize, and store for several days, which is promising
for the further elaboration of these novel compounds.
Acknowledgment. The authors are indebted to the FWO
- Flanders, Ghent University (GOA, BOF), and Janssen
Pharmaceutica (Johnson & Johnson) for financial support.
Supporting Information Available: General experimen-
tal conditions and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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