Guanidines as a nitrogen source for direct conversion of epoxides to aziridines

Article abstract of DOI:10.1021/jo048813j

Direct conversion of epoxides to aziridines was achieved with guanidines as a nitrogen source. Stereochemical inversion at the chiral centers of epoxides was observed without loss of optical purity.

Full text of DOI:10.1021/jo048813j

SCHEME 1. A Strategy for Direct Conversion of
Epoxides to Aziridines
Guanidines as a Nitrogen Source for Direct
Conversion of Epoxides to Aziridines
Yukiko Tsuchiya, Takuya Kumamoto, and
Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences,
Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
benti@p.chiba-u.ac.jp
Received July 13, 2004
Abstract: Direct conversion of epoxides to aziridines was
achieved with guanidines as a nitrogen source. Stereochem-
ical inversion at the chiral centers of epoxides was observed
without loss of optical purity.
Aziridines are some of the most versatile synthetic
intermediates for the synthesis of biologically active
N-containing compounds.1 Normally, aziridines are syn-
thesized via reactions of nitrenes and olefins or carbenes
and imines, and intramolecular cyclization of â-amino
alcohol derivatives.2 We have reported a unique method
for the synthesis of aziridines from guanidinium salts
derived from ureas such as 1,3-dimethylimidazolidin-2-
one (DMI; 1) and aromatic aldehydes, and its application
to asymmetric synthesis by using the corresponding
chiral template.3 The proposed reaction mechanism may
involve the formation of spiro intermediates (like 4b in
Scheme 1) from guanidinium ylides and aromatic alde-
hydes via betains (like 4a in Scheme 1), which undergo
acid catalysis fragmentation to yield aziridines and 1. We
would expect the reaction of guanidines 2, derived from
1, with epoxides 3 to afford analogous betain species 4a,
which would then produce the corresponding aziridines
5 and 1 via spiro intermediates 4b (Scheme 1). Until now,
a few examples of direct conversion of epoxides to
aziridines with iminophosphorane as a nitrogen source
have been reported;4 however, problems still remain in
partial racemization of the product.4c Now we describe
herein our preliminary approaches to direct conversion
of epoxides to aziridines using guanidine as a nitrogen
source.
according to the reported procedure.5 Several epoxides
were purchased or prepared by either simple epoxidation
of the corresponding olefins or methylenation of alde-
hydes with trimethylsulfonium ylide.6 Heating guanidine
2a and racemic styrene oxide [(()-3a] at 70 °C without
a solvent for 24 h afforded the expected aziridine (()-5a
in 16% yield together with urea 1 (15%) (entry 1, Table
1). Reactions in several solvents showed that the yields
depended on the solvent. When the reaction was carried
out in DMF or THF, the yield was not improved com-
pared with the solvent-free conditions (entries 2 and 3).
A higher yield was observed in CH3CN (entry 4). The use
of EtOH resulted in the formation of a complex mixture
that was formed because of the instability of 5a in EtOH
(entry 5). Chloroform gave the best result, in which 5a
was produced in 65% yield despite a long reaction time
(entry 6). The use of toluene resulted in low yield (entry
7).
1
The H NMR spectrum of the crude product obtained
with chloroform as a solvent showed lower field-shifted
signals assignable to the salt7 of 2a compared to the
original ones. Thus, reactions in the presence of a basic
additive were examined (Table 2); however, no improve-
ment was found (entries 1-4). On the other hand,
reaction in the presence of 10 mol % of p-toluenesulfonic
acid hydrate (TsOH‚H2O) in toluene afforded (()-5a in
77% yield (entry 5). Although a similar result was
obtained in replacement of the solvent from toluene to
benzene (entry 6), the yield was lowered when the
reaction was carried out under azeotropic conditions,
suggesting that a small amount of water is necessary for
this reaction (entry 7). Low yield was also observed in
chloroform under the acidic condition (entry 8). In the
previous paper3 it was noted that SiO2 played a crucial
role for the formation of aziridine products. However,
Guanidines 2 were prepared from 2-chloro-1,3-dimeth-
ylimidazolinium chloride (DMC) and primary amines
(1) Recent reviews: Mueller, P.; Fruit, C. Chem. Rev. 2003, 103,
2905-2919. Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
(2) (a) Aube, J. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 1, p 835. (b) Rosen,
T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 2, p 428. (c) Kemp, J. E. G. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 7, p 469. (d) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599-619. (e) Osborn, H. M. I.; Sweeney,
J. Tetrahedron: Asymmetry 1997, 18, 1693-1715. (f) Atkinson, R. S.
Tetrahedron 1999, 55, 1519-1559. (g) Mitchinson, A.; Nadin, A. J.
Chem. Soc., Perkin Trans. 1 2000, 2862-2892. (h) Cardillo, G.;
Gentilucci, L.; Tolomelli, A. Aldrichim. Acta 2003, 36, 39-50.
(3) Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa, T. J. Am. Chem.
Soc. 2001, 123, 7705-7706.
(5) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000, 65,
(4) (a) Katritzky, A. R.; Jiang, J.; Urogdi, L. Synthesis 1990, 565-
567. (b) Shahak, I.; Ittah, Y.; Blum, J. Tetrahedron Lett. 1976, 4003-
4004. (c) Kuhnau, D.; Thomsen, I.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 1996, 1167-1170.
7770-7773.
(6) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364.
(7) A trace of acid may generate from the chloroform used as solvent.
10.1021/jo048813j CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/30/2004
8504
J. Org. Chem. 2004, 69, 8504-8505

TABLE 1. Synthesis of Aziridine (()-5a from Guanidine
2a and Racemic Styrene Oxide [(()-3a]
yield (%)a
FIGURE 1. Epoxides examined for the conversion.
entry
solvent
conditions
(()-5a
1
SCHEME 2. Reaction of Guanidine 2a and Chiral
1
2
3
4
5
6
7
none
70 °C, 24 h
75 °C, 41 h
reflux, 7 d
reflux, 40 h
rt, 2 d
reflux, 7 d
75 °C, 41 h
16
9
10
48
b
15
15
7
23
b
Styrene Oxide (R)-3aa
DMF
THF
CH3CN
EtOH
CHCl3
toluene
65
2
72
8
a Calculated yields by 1H NMR, but not optimized. b Complex
mixture.
a Reagents and conditions: (a) TsOH‚H2O (1 molar equiv),
toluene reflux, 90 h (41%).
TABLE 2. Effects of Additives on the Reaction of
Guanidine 2a and Epoxide (()-3a
yield (%)a
guanidine (entry 3). The reaction was sluggish with
N-phenylguanidine because of low nucleophilicity (entry
4). No acceleration was observed even when electron-rich
styrene oxides were used (entries 5-8). Unfortunately,
reactions were retarded with use of 1,1-disubstituted 3b,
1,2-disubstituted epoxides 3c-e, and aliphatic epoxides
3f and 3g shown in Figure 1.
entry
solvent
additive
conditions
of (()-5a
1
2
3
4
5
6
7e
8
9
CHCl3
CHCl3
CHCl3
CHCl3
toluene
benzene
benzene
CHCl3
CH3CN
Et3Nb
reflux, 4 d
reflux, 54 h
reflux, 7 d
reflux, 7 d
reflux, 80 h
reflux, 7 d
reflux, 7 d
reflux, 5 d
reflux, 35 h
51
53
pyridineb
TMGb,c
53
b
K2CO3
38
TsOH‚H2Od
TsOH‚H2Od
TsOH‚H2Od
TsOH‚H2Od
77
68
A trial with chiral (R)-styrene oxide8 (R)-3a afforded
(S)-aziridine (S)-5a in 41% yield (Scheme 2). The absolute
configuration of the product was determined by optical
22
21
f
SiO2
<10
rotation {[R]24 +69.2 (c 2.0, EtOH)},9 showing that
a Calculated yields by 1H NMR, but not optimized. b 1 molar
equiv. c 1,1,3,3-Tetramethylguanidine. d A catalytic amount (0.1
molar equiv). e Using Dean-Stark apparatus. f 1 g per 1 mM.
D
inversion of configuration occurred during the reaction.
Optical purity of the product was estimated as ca. 96%
ee from chiral HPLC analysis (DAICEL CHIRALCEL
OD-H, hexane only, 254 nm, 1.2 mL/min). Thus, high
retention of chirality should be expected in this direct
conversion of epoxides to aziridines.
TABLE 3. Substituent Effects on the Aziridine
Formation
In summary, we have established a direct conversion
method of epoxides to aziridines with guanidine as a
nitrogen source. This reaction proceeds via inversion of
configuration at the asymmetric carbon on styrene oxides
with high chirality control. Detailed mechanistic studies
and the application of aziridines10 to the synthesis of
natural products are under way in our laboratory.
Ar in
yield (%)b
entry
R in 2
(()-3
conditionsa
of (()-5
1
2
3
4
5
6
7
8
allyl
Ph
A
A
A
B
B
B
B
B
60
t
CH2CO2 Bu
Ph
54
iPr
Ph
29
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (14370717) from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan. Dainippon Ink and Chemicals Award
in Synthetic Organic Chemistry, Japan are acknowl-
edged by T.K.
Ph
Ph
no reaction
CH2Ph
CH2Ph
CH2Ph
CH2Ph
o-MeOPh
p-MeOPh
p-MePh
p-ClPh
46
61c
40c
55c
a A: reflux in toluene with TsOH‚H2O (0.1 molar equiv) for 3.5
d. B: reflux in CHCl3 for 7 d. b Isolated yields, but not optimized.
c Calculated yields by 1H NMR, but not optimized.
Supporting Information Available: Experimental pro-
cedures for this work. This material is available free of charge
via the Internet at http://pubs.acs.org.
utilization of SiO2 resulted in a trace amount of produc-
tion of 5a due to the instability of 5a against SiO2 (entry
9).
We next examined the reaction using substrates with
a different substituent (Table 3). Guanidines with a
primary alkyl group on the imino nitrogen gave aziridine
products (entries 1 and 2), but the reaction was sup-
pressed in the case of a secondary alkyl-substituted
JO048813J
(8) Purchased from Aldrich, 95% ee.
(9) Kawamoto et al. reported the optical rotation of (R)-5a with 98%
ee to be [R]20 -49.4 (c 2.0, EtOH) [Kawamoto, A.; Wills, M. Tetrahe-
D
dron: Asymmetry 2000, 11, 3257-3261]. The lower value may be due
to the lability of 5a in EtOH.
(10) Furuta, Y.; Kumamoto, T.; Ishikawa, T. Synlett 2004, 362-
364.
J. Org. Chem, Vol. 69, No. 24, 2004 8505