Synthesis of 2-chloro-2-imidoylaziridines via aza-darzens-type reaction of 3,3-dichloro-1-azaallylic anions and N-(arylsulfonyl)imines

Article abstract of DOI:10.1021/jo060241a

3,3-Dichloro-1-azaallylic anions, generated by deprotonation of α,α-dichloroketimines 10 with lithium diisopropylamide, reacted with N-sulfonylaldimines 7 to produce the Mannich-type products N-[2,2-dichloro-3- (N-alkylimino)-1,3-diarylpropyl]benzenesulfo

Full text of DOI:10.1021/jo060241a

Synthesis of 2-Chloro-2-imidoylaziridines via Aza-Darzens-type
Reaction of 3,3-Dichloro-1-azaallylic Anions and
N-(Arylsulfonyl)imines
Nicola Giubellina,† Sven Mangelinckx,† Karl W. To¨rnroos,‡ and Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000 Ghent, Belgium, and Department of Chemistry, UniVersity of Bergen,
Allegaten 41, N-5007 Bergen, Norway
norbert.dekimpe@ugent.be
ReceiVed February 6, 2006
3,3-Dichloro-1-azaallylic anions, generated by deprotonation of R,R-dichloroketimines 10 with lithium
diisopropylamide, reacted with N-sulfonylaldimines 7 to produce the Mannich-type products N-[2,2-
dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11. The latter stable compounds were
hydrolyzed at the imino functionality to afford N-[2,2-dichloro-3-oxo-1,3-diarylpropyl]benzenesulfonamides
12 in excellent yields. N-[2,2-Dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11 were
cyclized to cis-3-aryl-2-chloro-2-imidoylaziridines 19 in 81-99% yield with high diastereoselectivity,
representing a novel and readily available class of stable 2-chloroaziridines. Finally, a highly stereoselective
entry to 2-(aminomethyl)-2-chloroaziridines 27 (70-98% yield; de > 95-99) was worked out from the
reaction of cis-3-aryl-2-chloro-2-imidoylaziridines 19 and sodium cyanoborohydride in the presence of
acetic acid. The latter 2-(aminomethyl)aziridines 27 represent stereochemically defined small azahetero-
cyclic rings which were scarcely reported in the literature.
SCHEME 1
Introduction
The Darzens reaction1 is arguably one of the most powerful
methods of epoxide formation, explaining that it has been widely
explored. R-Halogenated esters, amides, and ketones 1 have been
condensed with ketones (or aldehydes) in a basic medium to
give access to various functionalized oxiranes 3 (Scheme 1).
To a much more minor extent, the Darzens reaction has been
worked out with R-haloimines 1 (Z ) NR; R1 ) alkyl)2 and
cyclic imidates 1 (R1-Z ) O-C-C-N)3-6 to afford the
corresponding epoxides 3.
On the other hand, since Deyrup7 described the analogous
aza-Darzens reaction, where the electrophilic ketone 2 was
replaced by an imine (4) resulting in the synthesis of function-
alized aziridines 5 (Scheme 2), few reports on this item have
been reported in the literature.7-15 R-Halogenated esters, amides,
and ketones 1 have been condensed with imines 4 in a basic
medium in the synthesis of various functionalized aziridines 5
(Scheme 2).
* Corresponding author. Phone: +32-9-2645951. Fax: +32-9-2646243.
† Ghent University.
‡ University of Bergen.
(1) (a) Darzens, G. Compt. Rend. 1904, 139, 1214. (b) Darzens, G.
Compt. Rend. 1906, 142, 214.
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4457.
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9859.
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10.1021/jo060241a CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/04/2006
J. Org. Chem. 2006, 71, 5881-5887
5881

Giubellina et al.
SCHEME 2
2-methyl-3-phenyl-2H-azirine and 2-chloromethylenemalono-
nitrile derivatives gave rise to mixtures of chlorinated cis- and
trans-aziridines.20 Finally, 2,2-dimethyl-3-phenyl-2H-azirines
reacted with phthalimidoacetyl chloride in benzene to give
2-chloroaziridines in 62% yield.21 2-Haloaziridines were also
generated in poor yield by dichlorocarbene addition to ben-
zylideneamines, followed by chlorine extrusion induced by
methyllithium22 or lithium aluminum hydride (28% yield).23
Dehalogenation of 2,2-dihalo-1-phenylaziridines was also per-
formed with tri-n-butyltin hydride to give monohalogenated
aziridines.24 Nitrene chemistry was applied to the synthesis of
2-chloroaziridines, as exemplified for 1-ethoxycarbonyl-2-
chloroaziridines which were generated from the addition of
ethoxycarbonylnitrene, produced by thermolysis of the corre-
sponding azide, to vinyl chlorides.25 The reaction of (Z)-N-
trifluoromethylacetimidoyl fluoride with diazomethane afforded
N-trifluoromethyl-2-fluoroaziridines.26 1-Alkyl-2-sulfonylaziri-
dines incorporated a halogen at the 2-position when treated with
carbon tetrahalides (CCl4 or CBr4) in tert-butyl alcohol in the
presence of potassium hydroxide.27 In a similar way, aziridi-
nylphosphonates reacted with BuLi leading to 2-lithiated species
which were trapped with carbon tetrachloride to give 2-chlo-
roaziridinylphosphonates in good yields.28 A mixture of cis- and
trans-2-bromoaziridines was synthesized in poor yield (25%)
when thiohydroxamic acid anhydride was photolyzed in neat
CBrCl3.29 This protocol was applied to the synthesis of
2-bromoaziridine derivatives, which were used in the key step
of the synthesis of (+)-9a-desmethoxymitomycin A and mito-
mycin K.30
SCHEME 3
Therefore, the aza-Darzens reaction can still be considered a
useful and not fully investigated tool for the construction of
three-membered azaheterocycles, i.e., functionalized aziridines.
Although some acid-catalyzed methods for the aza-Darzens-
type reaction are known,9 the most common route involves the
use of a base.
In the present paper, the reactivity of R,R-dichloroketimines
6 and N-sulfonylaldimines 7 leading to the synthesis of 2-chloro-
2-imidoylaziridines 8 was investigated in a novel type of the
aza-Darzens-type reaction (Scheme 3).
These reactions should provide the corresponding 2-chloro-
2-imidoylaziridines 8 which represent a relevant example of
fairly stable 2-haloaziridines. The synthesis of 2-haloaziridines
has attracted the interest of organic chemists since the early
60s because these 2-heteroatom-substituted strained rings are
effective building blocks. Approaches to 2-chloroaziridines
included the reaction of 2H-azirines with hydrogen chloride or
acid chlorides (benzoyl chloride, acetyl chloride, ...), resulting
in the formation of mixtures of cis- and trans-aziridines.16 The
latter aziridines were used as starting products in the synthesis
of functionalized oxazoles17,18 and oxazolines.16,19 Reactions of
Results and Discussion
A preceding Darzens-type reaction of R-chloroimines with
ketones and aldehydes enabled the synthesis of 2-imidoylepoxide
derivatives.2 Remarkable to note is the lack of self-condensation
and side-reaction products during the deprotonation of R-chlo-
rinated and R,R-dichlorinated imines, a clear advantage in
contrast to, for instance, R-chlorinated oximes.31
Knowing that the condensation reaction of R-chlorinated
imine anions with an activated imine (e.g., N-sulfonylimine)
(9) (a) Casarrubios, L.; Pe´rez, J. A.; Brookhart, M.; Templeton, J. L. J.
Org. Chem. 1996, 61, 8358. (b) Xie, W.; Fang, J.; Li, J.; Wang, P. G.
Tetrahedron 1999, 55, 12929. (c) Antilla, J. C.; Wulff, D. W. J. Am. Chem.
Soc. 1999, 121, 5099. (d) Antilla, J. C.; Wulff, D. W. Angew. Chem., Int.
Ed. 2000, 39, 4519. (e) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 1612.
(10) (a) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249. (b)
Davis, F. A.; Wu, Y.; Hongxing, Y.; McCoull, W.; Prasad, K. R. J. Org.
Chem. 2003, 68, 2410. (c) Davis, F. A.; Ramachandar, T.; Wu, Y. J. Org.
Chem. 2003, 68, 6894.
(18) (a) Schmid, H.; Gilgen, P.; Heimgartner, H. HelV. Chim. Acta 1974,
57, 1393. (b) Sato, S.; Kato, H.; Ohta, M. Bull. Chem. Soc. Jpn. 1967, 40,
2938.
(19) For recent reviews on the rearrangement of 1-acylaziridines to
oxazole derivatives, see: (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.
Aldrichimica Acta 2003, 36, 39. (b) Hu, X. E. Tetrahedron 2004, 60, 2701.
(20) Lee, S. M.; Lai, T. F.; Sammes, M. P. J. Chem. Res., Synop. 1992,
266.
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2000, 30, 87.
(21) Eremeev, A. V.; El’kinson, R. S.; Imuns, V. Khim. Geterotsikl.
Soedin. 1981, 643; Chem. Abstr. 1981, 95, 97505.
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24, 797.
(24) Hiroki, Y.; Kikui, J.; Teramura, K.; Ando, T. J. Org. Chem. 1976,
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57, 1958.
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(b) Ziegler, F. E.; Berlin, M. Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2,
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3243. (b) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
5473. (c) Davis, F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997,
38, 5139. (d) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J. Org. Chem. 1999, 64, 7559. (e) Davis, F. A.; Zhang, Y.; Rao, A.;
Zhang, Z. Tetrahedron 2001, 57, 6345. (f) Davis, F. A.; Deng, J.; Zhang,
Y.; Haltiwanger, R. C. Tetrahedron 2002, 58, 7135.
(13) (a) Coutrot, P.; El Gadi, A. J. Organomet. Chem. 1985, 280, 11.
(b) Wartski, L. J. Chem. Soc., Chem. Commun. 1977, 602.
(14) Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.;
Hiraga, Y.; Koijma, S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998,
689.
(15) Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem. 2000,
65, 5498.
(16) (a) Fowler, F. W.; Hassner, A. J. Am. Chem. Soc. 1968, 90, 2875.
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Int. Ed. 2003, 42, 5613.
5882 J. Org. Chem., Vol. 71, No. 16, 2006

2-Chloro-2-imidoylaziridines Via Aza-Darzens Reaction
SCHEME 4
was not yet explored (vide supra), we attempted the synthesis
of 2-chloro-2-imidoylaziridines. The combination of a carbon-
nitrogen double bond and a halogen atom in one molecule offers
the potential to provide access to new aziridine derivatives when
condensed to N-sulfonylaldimines, via the aza-Darzens reaction.
For instance, R,R-dichloroketimines 6 can be deprotonated with
strong nonnucleophilic bases and then condensed with N-
sulfonylimines 7 giving rise to the synthesis of â-imidoylsul-
fonamides, which can be ring closed to 2-imidoylaziridine
derivatives 8 (Scheme 3).
Up to now, only a few reports described the addition of an
imine anion (1-azaenolate) toward an activated imine or an
aldehyde, resulting in the aldol-type reaction.32 These facts
confirm that the previously designed aza-Darzens strategy is
worth working out because of its synthetic potential. Natural
products containing an aziridine ring have attracted much interest
because the biological activity of these compounds is often
attributed to the aziridine ring.33 In the following text, the
successful efforts to synthesize chlorinated â-imidoylsulfon-
amides and 2-chloro-2-imidoylaziridines in a highly stereose-
lective way will be highlighted.
dichloro-â-iminosulfonamides 11a-f in 34-95% yield via an
aza-aldol-type reaction (Scheme 4).
N-(2,2-Dichloro-3-iminopropyl)benzenesulfonamides 11a-f
represent novel structures, suitable for further elaboration. They
are the aza analogues of O-(2,2-dichloro-3-iminopropyl)meth-
anesulfonates, aldol adducts previously explored by our research
group in the synthesis of functionalized cis-2,4-diaryl-3,3-di-
chloroazetidines.37 Aza-aldol adducts 11a-f are crystalline com-
pounds that showed a great stability, as they can be stored for
over one year in sealed bottles at -20 °C. In addition they could
be produced on a multigram scale (up to 0.04 mol) without
changes in the reaction yields. Mannich-type products 11a-c
were hydrolyzed at the imino functionality in aqueous hydro-
chloric acid, giving the corresponding dichlorinated â-aminoke-
tone derivatives 12a-c (92-99% yields) that can be considered
as precursors of R-dione derivatives.38 Finally, â-aminoketones
12 can be considered as a precursor of 3-amino alcohol deriv-
atives, of which fluoxetine (antidepressant) is an example.39
Attempts to synthesize 2-chloroaziridines starting from â-
ketosulfonamide 12a by treatment with potassium hydroxide
(1 equiv) in aqueous tetrahydrofuran at room temperature failed
because the retro-aldol reaction was preferred over the aziridine
formation. R,R-Dichloroketone 9a, benzaldehyde 13, and ben-
zenesulfonamide 14 were formed in quantitative yield under
these conditions (Scheme 5).
Dehalogenation of â-aminoketone 12b with tributyltin hydride
and a catalytic amount of 2,2′-azobisisobutyronitrile in warm
carbon tetrachloride failed, and the starting material was
recovered instead (Scheme 6). However, reaction of â-ami-
noketone 12b in carbon tetrachloride-toluene (1:1) under reflux
for 6 h afforded the retro-aldol-type reaction leading to R,R-
dichloroketone 9b and N-sulfonylimine 7a (100% yield).
â-Aminoketimines 11a-d proved to be better substrates for
the synthesis of cis-2-chloro-2-imidoylaziridines 19 (Scheme
7) because the retro-aldol reaction was not observed anymore.
R,R-Dichloroketimines 10a-c were prepared by condensation
of the corresponding R,R-dichloroketones 9 with primary amines
in the presence of titanium(IV) chloride in diethyl ether (Scheme
4).34-36 Deprotonation of R,R-dichloroimines 10a-c with
stoichiometric amounts of lithium diisopropylamide in THF at
0 °C gave 3,3-dichloro-1-azaallylic anions, which reacted as
carbon nucleophiles with N-sulfonylimines 7 to afford R,R-
(32) (a) Hayashi, K.; Kogiso, H.; Sano, S.; Nagao, Y. Synlett 1996, 1203.
(b) Hou, X.-L.; Luo, Y.-M. L.; Dai, L.-X. J. Chem. Soc., Perkin Trans. 1
2002, 1487.
(33) (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.,
Padwa, A., Eds.; Elsevier: New York, 1996; Vol. 1A, p 1. (b) Kump, J. E.
G. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 7, p 469.
(34) (a) De Kimpe, N.; Sulmon, P.; Schamp, N. Angew. Chem., Int. Ed.
Engl. 1985, 10, 881. (b) De Kimpe, N.; Sulmon, P.; Schamp, N. Angew.
Chem. 1985, 97, 878. (c) De Kimpe, N.; Verhe´, R. In The Chemistry of
R-Haloketones, R-Haloaldehydes and R-Haloimines; Patai, S., Rappoport,
Z., Eds.; J. Wiley & Sons: Chichester, 1988.
(35) (a) Weingarten, H.; Chupp, J. P.; White, W. A. J. Org. Chem. 1967,
32, 3246. (b) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Moe¨ns, L.; Schamp,
N. Synthesis 1982, 43.
(37) Aelterman, W.; De Kimpe, N.; Declercq, J.-P. J. Org. Chem. 1998,
63, 6.
(38) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. J. Org. Chem.
1978, 43, 2933.
(39) (a) Robertson, D. W.; Jones, N. D.; Swartzendruber, J. K.; Yang,
K. S.; Wong, D. T. J. Med. Chem. 1988, 31, 185. (b) Robertson, D. W.;
Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31,
1412.
(36) De Kimpe, N.; Coppens, W.; Welch, J.; De Corte, B. Synthesis 1990,
675.
J. Org. Chem, Vol. 71, No. 16, 2006 5883

Giubellina et al.
SCHEME 5
SCHEME 6
SCHEME 7
room temperature for 6-24 h, resulting in a complete diaste-
reoselective entry to cis-3-aryl-2-chloro-2-imidoylaziridines
19a-d in 81-99% yield after recrystallization (Scheme 7). No
1
trans isomer 17 was found either during the analysis of the H
NMR of the crude reaction mixtures or after the purification
procedure. During the course of our investigation, it was found
that sodium hydroxide or organic bases (DBU, DABCO) in an
organic solvent (tetrahydrofuran, acetonitrile) were not efficient
reagents for the ring closure of â-aminoketones 11. Moreover,
no heating was allowed to prevent the retro-aldol-type reaction.
The synthesis of 2-benzimidoyl-2-chloroaziridine 19d required
a longer reaction time (24 h) during the ring closure procedure
(see transition state, 18d; R ) c-Hex), originating from the
sterical hindrance exerted by the N-cyclohexyl substituent,
without registering any significant changes in the reaction yield
(81%). The latter aziridines 19 showed a great deal of confor-
mational stability, whereas no nitrogen inversion was detected
(1H NMR analysis).
Finally, attempts to synthesize the aliphatic 2-acetimidoyl-
2-chloroaziridine 22 were made. During the condensation of
N-(2,2-dichloro-1-methylethylidene)isopropylamine 20 with N-
benzenesulfonylimine 7a, the retro-aldol reaction was faster than
the ring closure, as compared to the previously studied cases.
In fact, the use of analogous reaction conditions, as previously
described for the synthesis of 2-benzimidoyl-2-chloroaziridines
19a-d, led to the recovery of the starting material. As a result,
during the reaction of N-(2,2-dichloro-1-methylethylidene)-
isopropylamine 20 with N-benzenesulfonylimine 7a, the tem-
perature was lowered to -60° and slowly increased to -20 °C
during 6 h. The reaction resulted in a crude (1:1) mixture of
cis- and trans-aziridines 22, along with unidentified reaction
1
products, judging from the H NMR spectrum of the crude
reaction mixture (Scheme 8). The purification of the latter via
flash chromatography gave a poor yield of an inseparable
mixture of the corresponding hydrolyzed 2-acyl-2-chloroaziri-
dine 23 (one isomer) along with an equal amount of the ring-
opened product 24.
As a conclusion, the aza-Darzens reaction of R,R-dichlori-
nated imines 10 and 20 was studied, leading to novel 2-chloro-
2-imidoylaziridines 19 and 22. In particular, the presented
protocol involved the formation of stable and stereochemically
defined 2-chloro-2-imidoylaziridines in preparative amounts.
Treatment of aziridines 19 with hydride reagents is of in-
terest to produce 2-(aminomethyl)-2-chloroaziridines with three
stereocenters. Previously, the diastereoselective reduction at the
CdO group of aziridinyl ketones has been investigated, for
Cis-2-chloro-2-imidoylaziridines 19 are interesting chemicals
difficult to access otherwise. The synthesis of ketimines derived
from 2-acylaziridines cannot be performed at high temperature,
i.e., in hot toluene or benzene, because intramolecular rear-
rangement to oxazole derivatives is in competition with the
imine condensation.40 Moreover, reactions at the carbonyl group
of 2-acyl- and 2-formylaziridines are more difficult because of
the inactivation caused by hyperconjugation of the adjacent
aziridine ring.41 These problems were partially overcome when
a PPE-hydrolysate42 was used in a catalytic amount during the
condensation of aziridinyl ketones and tosylhydrazine.43
â-Imidoylsulfonamides 11a-d were stirred in water-tet-
rahydrofuran (1:1) in the presence of 1.2 equiv of 2 N KOH at
(41) (a) Cromwell, N. H.; Graff, M. A. J. Org. Chem. 1952, 17, 414. (b)
Pohland, A. E.; Badger, R. C.; Cromwell, N. H. Tetrahedron Lett. 1965, 6,
4369. (c) Nagel, D. L.; Woller, P. B.; Cromwell, N. H. J. Org. Chem. 1971,
36, 3911. (d) Tarbutron, P.; Kingsbury, C. A.; Sopchik, A. E.; Cromwell,
N. H. J. Org. Chem. 1978, 43, 1350. (e) Crimaldi, K.; Lichter, R. L. J.
Org. Chem. 1980, 45, 1277.
(42) Kanaoka, Y.; Machida, M.; Yonemitsu, O.; Ban, Y. Chem. Pharm.
Bull. 1965, 13, 1065.
(43) (a) Morioka, M.; Kato, M.; Yoshida, H.; Ogata, T. Heterocycles
1996, 43, 1759. (b) Morioka, M.; Kato, M.; Yoshida, H.; Ogata, T.
Heterocycles 1996, 43, 305.
(40) (a) Padwa, A. E.; Eisenhardt, W. Chem. Commun. 1968, 380. (b)
Lown, J. W.; Moser, J. P. Chem. Commun. 1970, 247. (c) Prosyanik, A.
V.; Belov, P. N.; Markov, V. I. Khim. Geterotsikl. Soedin. 1984, 1688;
Chem. Abstr. 1985, 102, 113352.
5884 J. Org. Chem., Vol. 71, No. 16, 2006

2-Chloro-2-imidoylaziridines Via Aza-Darzens Reaction
SCHEME 8
SCHEME 9
noaziridines 27a-c with high diastereoselection (Scheme 9).
The aziridinylketimine 19a did not react with 2 equiv of NaBH4
in ethanol at room temperature for 16 h as the starting product
was recovered completely. Preliminary attempts to revert the
reductive amination of 2-imidoylaziridines in favor of the anti
isomer by the use of sodium borohydride (1-10 equiv) and 1
equiv of Lewis acid (ZnCl2, TiCl4, CeCl3) failed, giving poor
yields of a mixture of complex reaction products.
CHART 1
The reaction scale of the reductive amination of aziridine 19c
was increased to 10 mmol (compared to 1 mmol for the previous
examples). Therefore, 1 equiv of acetic acid was added to a
solution of the aziridine 19c and sodium cyanoborohydride (4
equiv) in methanol at 0 °C, and then the suspension was stirred
at room temperature for 6 h (Scheme 10). In that case, three
compounds were isolated after flash chromatographic purifica-
tion. These compounds were identified as the syn-methylami-
noaziridine 27c, the anti-aziridine 28, existing in two inver-
tomers, and the aziridine 29. The stereochemistry of aziridine
29 was deduced from the coupling constant of both aziridine
protons (J ) 6.5 Hz; CDCl3) along with NOE experiments,
which revealed that the substituents at the aziridine ring adapted
a cis configuration.
Also, the stereochemistry of aziridine 27c was confirmed by
NOE experiments (Chart 2). Irradiation of the proton at C-3 of
the aziridine 27c gave a NOE of 9.5% on the methine of the
methylamino substituent. Vice versa, irradiating the CH proton
of the methylamino substituent resulted in a NOE of 23.5% on
the proton at carbon 3 of the aziridine. Normally, such a large
NOE, i.e., 23.5%, is registered only between geminal and vicinal
protons. From the previous NOE experiments, it can be deduced
that the benzenesulfonyl group is lying on the same side of the
space as the aminomethyl functionality and the aziridinyl C-3
proton, as previously described for 1-alkyl-3-aryl-2-benzoyl-
aziridines, where the trans isomer exists in a preferred confor-
mation with the N-alkyl group syn to the carbonyl.41 Finally,
the structure of 2-(aminomethyl)-2-chloroaziridine 27c was
secured by X-ray analysis.
instance, in tetrahydrofuran with L-Selectride44 and sodium
borohydride in the presence of ZnCl2 to give precursors of 1,2-
amino alcohols.45 On the other hand, only one preceding
example described the reductive amination of aziridinylketimine
derivatives, and this required a zinc chelate to induce a
stereofacial attack.46 The previously described 2-imidoylaziri-
dines 19 are ideal substrates for this type of reaction, where a
stereocenter can be stereoselectively created. Because of that,
NaBH4 was used in a mixture of 9:1 methanol-tetrahydrofuran
at room temperature for the reduction of the aziridinylimine
19a, resulting in unreacted starting product along with minor
amounts of unidentified reaction products. During the course
of our investigation, it was revealed that sodium cyanoboro-
hydride in methanol was a better reagent for the reduc-
tive amination of aziridinylketimines. A nearly quantitative
diastereoselective reduction of imidoylaziridines (de ) 95.0-
99.9%) was accomplished by the use of 3 equiv of NaBH3CN
along with a stoichiometric amount of acetic acid in methanol.
A Felkin-Anh model, 26, can be recalled to explain the
stereoselective reduction of the imino moiety having a neighbor-
ing aziridine ring,45,46 considering that this model also results
in better orbital overlap of the chlorine σ*-antibonding and the
CdN π-bonding (Chart 1). The borohydride adds to the CdN
only from the less-hindered side, that is, from the opposite side
of the sulfonyl group (26).
The way the acetic acid was added was important for the
outcome of the reaction. When 1 equiv of acetic acid was added
dropwise at 0 °C to the aziridinylketimine 19a followed by 4
equiv of NaBH3CN and stirring was continued at room
temperature for 2 h, the starting product was isolated (60%)
along with a 1:1 ratio of syn- and anti-(aminomethyl)aziridines
27 (30%) and side-reaction products (10%). The addition of 1
equiv of acetic acid to the solution of the aziridine 19a and
NaBH3CN (3 equiv) in methanol gave instead the methylami-
A preceding report disclosed how the stereoselective ring
opening of 3-aryl-2-(hydroxymethyl)aziridines was accom-
plished with aluminum hydrides, namely, LiAlH4.47 The hydride
was directed toward C-2 through chelation of the nucleophile.47
Therefore, (aminomethyl)aziridine analogues 27 could be
promising reagents in the synthesis of 1,3-diaminopropane
derivatives through hydride nucleophiles. The use of NaBH4 in
methanol or LiAlH4 in dry diethyl ether resulted in the unreacted
starting material, and increasing the amounts of the hydrides
did not give any clean reaction mixture, as instead complex
mixtures were obtained upon workup. Although this preliminary
account displays a reluctant behavior of 2-(aminomethyl)-
(44) (a) Kim, B. C.; Lee, W. K. Tetrahedron 1996, 52, 12117. (b) Lee,
W. K.; Ha, H.-J. Aldrichimica Acta 2003, 36, 57.
(45) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J. J. Org.
Chem. 2003, 68, 7675.
(46) Bartnik, R.; Laurent, A.; Lesniak, S. J. Chem. Res., Synop. 1982,
287.
(47) (a) Tanner, D.; Gautun, O. R. Tetrahedron 1995, 51, 8279. (b) Davis,
F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997, 38, 5139.
J. Org. Chem, Vol. 71, No. 16, 2006 5885

Giubellina et al.
SCHEME 10
CHART 2. NOE Experiments on
2-(Aminomethyl)-2-chloroaziridine 27c
brown solution was stirred for 30 min at 0 °C. The temperature
was lowered to -40 °C, and the N-benzenesulfonylimine 7a (41
mmol, 10.05 g), dissolved in 15 mL of tetrahydrofuran, was added
dropwise. The resulting mixture was kept at the same temperature
for 2 h and then brought to room temperature for 12 h. Upon
quenching with 0.5 mL of 0.5 N NH4Cl, the mixture was washed
with an additional 100 mL of 0.5 N sodium hydroxide solution
and extracted with diethyl ether (3 × 50 mL). The combined organic
layers were dried over K2CO3-MgSO4 (1:1) and evaporated to
afford a red-brown residue N-[2,2-dichloro-3-(isopropylimino)-1,3-
diphenylpropyl]benzenesulfonamide 11a (18.50 g, 95%) that was
purified by recrystallization (methanol) to afford pale yellow
crystals. During the synthesis of 2,2-dichloro-3-(isopropylimino)-
1,3-diarylpropylsulfonamide 11c, after the N-sulfonylimine addition,
the reaction mixture was stirred at -40 °C and then the temperature
was increased to 0 °C over a period of 3.5 h. The reaction was
quenched at 0 °C (the reaction was performed at a 5 mmol scale).
aziridines 27 to ring opening by hydride, further reactions will
be reported in due course to clarify their reactivity over
nucleophilic displacement.
In conclusion, 3,3-dichloro-1-azaallylic anions have been
reacted with N-sulfonylaldimines 7 to produce the Mannich-
type products N-[2,2-dichloro-3-(alkylimino)-1,3-diarylpropyl]-
benzenesulfonamides 11. The latter sulfonamides 11 proved to
be useful reagents as they were hydrolyzed at the imino
functionality to afford N-[2,2-dichloro-3-oxo-1,3-diarylpropyl]-
arylsulfonamides 12 in excellent yields and as they were
diastereoselectively ring closed to cis-3-aryl-2-chloro-2-imi-
doylaziridines 19, which represents a novel entry to 2-chloro-
2-imidoylaziridines via the aza-Darzens-type reaction. Despite
the facts that a few examples which included the synthesis of
2-chloro-N-sulfonylaziridines started from the intramolecular
substitution of N-(2,2-dichloro-1,2-diarylethyl)benzenesulfon-
amides induced by NaOH in DMF48 and that the aza-Darzens-
type reaction was successful in the synthesis of chlorinated
N-phenylaziridines,13,49 these syntheses did not reveal a straight-
forward approach to 2-chloro-2-imidoyl-1-sulfonylaziridines.
The approach disclosed in the present report instead gave rise
to a novel class of stable chlorinated aziridines, i.e., cis-3-aryl-
2-chloro-2-imidoylaziridines 19, which were elaborated to
2-(aminomethyl)-2-chloroaziridines 27 with sodium cyanoboro-
hydride and acetic acid in methanol. The latter 2-(aminomethyl)-
aziridines 27 represent stereochemically defined small azahet-
erocyclic rings which are scarcely represented in the literature.
N-[(3E)-2,2-Dichloro-3-(isopropylimino)-1,3-diphenylpropyl]-
1
phenylsulfonamide 11a. H NMR (CDCl3, 300 MHz): δ ) 1.16
(d, 3H, J ) 6.1 Hz, CH3), 1.09 (d, 3H, J ) 6.1 Hz, CH3), 3.26
(sept, 1H, J ) 6.1 Hz, CHNd), 5.55 (d, 1H, J ) 8.5 Hz, CHNH),
6.87 (brs, 1H, NH), 6.96-7.34 (m, 13H, CHarom.), 7.57 (m, 2H,
CHarom.). 13C NMR (CDCl3, 75 MHz): δ ) 23.2, 23.3, 54.4, 67.9,
90.5, 127.0, 127.6, 127.8, 128.1, 128.3, 128.6, 129.0, 130.6, 132.2,
133.8, 134.9, 140.9, 165.7. IR (KBr): ν ) 3262 (NH), 1642 (Cd
N), 1327 and 1171 (SdO). MS (ES+): m/z (%) ) 475/477/479
(MH+, 20), 246 (100), 230/232/234 (75). Mp (MeOH) ) 136.6-
138.9 °C. Yield ) 75%. Pale yellow crystals. Anal. Calcd for
C24H24Cl2N2O2S: C, 60.63; H, 5.09; N, 5.89. Found: C, 60.49; H,
5.21; N, 5.72.
Synthesis of N-(2,2-Dichloro-3-oxo-1,3-diarylpropyl)phen-
ylsulfonamides 12. The synthesis of N-(2,2-dichloro-3-oxo-1,3-
diphenylpropyl)phenylsulfonamide 12a is representative. To
N-[2,2-dichloro-3-(isopropylimino)-1,3-diphenylpropyl]phenylsulfon-
amide 11a (0.47 g, 1 mmol) in tetrahydrofuran (15 mL) was added
an equal amount of water (15 mL) and a solution of 2 N hydrogen
chloride in water (0.75 mL, 1.5 mmol). After stirring for 14 h at
room temperature, the reaction was neutralized with a 0.5 N aqueous
sodium hydroxide solution (15 mL) and extracted with diethyl ether
(15 mL × 3), then washed with brine. After drying the combined
organic phases over MgSO4 and removal of the solvent in vacuo,
a crude solid material was obtained. Recrystallization from metha-
nol gave pure N-(2,2-dichloro-3-oxo-1,3-diphenylpropyl)phenyl-
sulfonamide 12a as white crystals in 92% yield.
Experimental Section
Synthesis of N-[2,2-Dichloro-3-(alkylimino)-1,3-diarylpropyl]-
benzenesulfonamides 11. The synthesis of the N-[2,2-dichloro-3-
(isopropylimino)-1,3-diphenylpropyl]benzenesulfonamide 11a is
representative. Diisopropylamine (57 mmol, 5.76 g) was placed in
a 250 mL two-necked round-bottomed flask along with 10 mL of
dry tetrahydrofuran, and a 2.5 N n-butyllithium solution in hexane
(53.3 mmol, 21.32 mL) was added at 0 °C under nitrogen
atmosphere. Then, R,R-dichloroimine 10a (41 mmol, 9.39 g) was
added dropwise in 10 mL of tetrahydrofuran, and the resulting red-
N-(2,2-Dichloro-3-oxo-1,3-diphenylpropyl)phenylsulfon-
amide 12a. H NMR (CDCl3, 300 MHz): δ ) 5.52 (d, 1H, J )
1
10.2 Hz, CHNH), 5.83 (d, 1H, J ) 10.2 Hz, NH), 7.10-7.28 (m,
6H, CHarom.), 7.35-7.45 (m, 3H, CHarom.), 7.55-7.60 (m, 3H,
CHarom.), 8.99-7.02 (m, 2H, CHarom.). 13C NMR (CDCl3, 75
MHz): δ ) 65.9, 87.9, 127.1, 128.0, 128.3, 128.7, 129.9, 130.5,
132.5, 132.5, 132.9, 133.0, 140.0, 188.6. IR (KBr): ν ) 3254 (NH),
1697 (CdO), 1328 and 1164 (SdO). MS (ES+): m/z (%) ) 434/
436/438 (MH+, 8), 246 (100). Mp (MeOH) ) 149.6-152.3 °C.
Yield ) 92%. White crystals. Anal. Calcd for C21H17Cl2NO3S: C,
58.07; H, 3.95; N, 3.22. Found: C, 57.98; H, 4.11; N, 3.32.
(48) Rozentsveig, G. N.; Rozentsveig, I. B.; Levkovskaya, G. G.;
Albanov, A. I.; Mirskova, A. N. Russ. J. Org. Chem. 2003, 39, 1801; Chem.
Abstr. 2004, 141, 260462.
(49) Mamedov, V. A.; Litvinov, I. A.; Sibgatullina, F. G.; Kataeva, O.
N.; Nuretdinov, I. A. Khim. Geterotsikl. Soedin. 1994, 2, 189; Chem. Abstr.
1995, 122, 265191.
Synthesis of N-[(1E)-1-(cis-2-Chloro-3-aryl-1-sulfonylaziri-
din-2-yl)(aryl)methylidene] Alkylamines 19. The synthesis of
N-[(1E)-1-(cis-2-chloro-3-phenyl-1-sulfonylaziridin-2-yl)(phenyl)-
methylidene]-N-isopropylamine 19a is representative. [2,2-Dichloro-
5886 J. Org. Chem., Vol. 71, No. 16, 2006

2-Chloro-2-imidoylaziridines Via Aza-Darzens Reaction
3-(isopropylimino)-1,3-diphenylpropyl]benzenesulfonamide 11a (10
mmol, 4.74 g) was dissolved in tetrahydrofuran (50 mL), and water
(50 mL) was added, followed by aqueous 2 N KOH (12 mmol, 6.0
mL). The reaction was vigorously stirred at room temperature for
48 h. Upon washing with water, diethyl ether, and brine, the
combined organic layers were dried (MgSO4). Evaporation of the
solvents in vacuo gave a crude pale yellow solid N-[(1E)-1-(cis-
2-chloro-3-phenyl-1-sulfonylaziridin-2-yl)(phenyl)methylidene]-N-
isopropylamine 19a (4.38 g), which was recrystallized over MeOH
to afford white crystals (4.17 g, 9.49 mmol) in 95% yield.
N-{(1E)-1-[cis-2-Chloro-3-phenyl-1-(phenylsulfonyl)aziridin-
2-yl](phenyl)methylidene}isopropylamine 19a. 1H NMR (CDCl3,
300 MHz): δ ) 1.13 (d, 3H, J ) 6.3 Hz, CH3), 1.28 (d, 3H, J )
6.3 Hz, CH3), 3.66 (sept, 1H, J ) 6.3 Hz, CHNd), 4.93 (s, 1H,
CHPh), 7.08-7.10 (m, 2H, CHarom.), 7.20-7.26 (m, 3H, CHarom.),
7.42-7.52 (m, 8H, CHarom.), 8.00 (m, 2H, CHarom.). 13C NMR
(CDCl3, 75 MHz): δ ) 22.9, 23.4, 50.9, 53.5, 73.4, 127.5, 128.0,
128.4, 128.5, 129.1, 131.6, 133.6, 134.8, 140.0, 159.5. IR (KBr):
ν ) 1638 (CdN), 1347 and 1168 (SdO). MS (ES+): m/z (%) )
439/441 (MH+, 20), 298/300 (100). Mp (MeOH) ) 38.0-40.7 °C.
Yield ) 95%. White crystals. Anal. Calcd for C24H23ClN2O2S: C,
65.67; H, 5.28; N, 6.38. Found: C, 65.49; H, 5.40; N, 6.49.
Synthesis of 2-(Aminomethyl)aziridines 27. Aziridine 19 (1
mmol) was dissolved in 5 mL of methanol at 0 °C, and then
NaBH3CN (3 mmol, 0.19 g) was added portionwise, followed by
dropwise addition of acetic acid (1 mmol, 60 mg). The reaction
was slowly allowed to reach room temperature and stirred up to
consumption of the starting product (3-6 h, TLC, flash chroma-
tography, petroleum ether-EtOAc 9:1). Workup was done by
pouring the reaction mixture into ice-cold water (10 mL) and
extraction with dichloromethane (3 × 60 mL). After drying the
combined extracts with potassium carbonate and evaporation of
the solvent in vacuo, the crude residue was recrystallized from
methanol.
The reduction of imidoylaziridine 19c (10 mmol, 4.72 g) gave a
crude mixture which was purified by flash chromatography
(petroleum ether-EtOAc 9:1), giving aziridine 27c (68% yield)
and aziridines 28 (16% yield) and 29 (6% yield).
syn-N-{1-[cis-2-Chloro-1-(phenylsulfonyl)-3-phenylaziridin-
2-yl](phenyl)methyl}isopropylamine 27a. 1H NMR (CDCl3, 300
MHz): δ ) 1.09 (d, 3H, J ) 6.3 Hz, CH3), 1.15 (d, 3H, J ) 6.3
Hz, CH3), 2.16 (brs, 1H, CHNH), 2.79 (sept, 1H, J ) 6.3 Hz,
Me2CHNH), 4.38 (s, 1H, CCHPh), 4.80 (s, 1H, NHCHPh), 6.69-
6.71 (m, 2H, CHarom.), 7.06-7.16 (m, 3H, CHarom.), 7.31-7.40 (m,
3H, CHarom.), 7.45-7.68 (m, 5H, CHarom.), 8.06-8.08 (m, 2H,
CHarom.). 13C NMR (CDCl3, 75 MHz): δ ) 21.8, 24.4, 46.1, 52.4,
64.0, 76.8, 127.8, 128.2, 128.5, 128.6, 128.6, 129.3, 131.2, 134.0,
139.2, 139.6. IR (KBr): ν ) 3321 (NH). MS (ES+): m/z ) 441/
443 (MH+). Mp (MeOH) ) 160.0-161.8 °C. Yield ) 91%. White
crystals. Anal. Calcd for C24H25ClN2O2S: C, 65.37; H, 5.71; Cl,
8.04; N, 6.35. Found: C, 65.08; H, 5.75; N, 6.26.
Acknowledgment. The authors are indebted to Ghent
University (GOA) for financial support of this research.
Supporting Information Available: General information,
experimental procedures and data for compounds 7, 10, and 20,
spectroscopic data for compounds 11b-f, 12b,c, 19b-d, 27b,c,
28, and 29, and X-ray structure of compound 27c. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060241A
J. Org. Chem, Vol. 71, No. 16, 2006 5887