[3+2] Cross-coupling reactions of aziridines with isocyanates catalyzed by nickel(II) iodide

Article abstract of DOI:10.1021/ol052417l

Cycloaddition of aziridines with isocyanates proceeded smoothly in the presence of a nickel catalyst, and five iminooxazolidine derivatives were isolated in good yields. The best result was obtained when the reaction was carried out in the presence of NiI

Full text of DOI:10.1021/ol052417l

ORGANIC
LETTERS
2006
Vol. 8, No. 3
379-382
[3+2] Cross-Coupling Reactions of
Aziridines with Isocyanates Catalyzed
by Nickel(II) Iodide
Takeshi Munegumi,† Isao Azumaya,‡ Takako Kato,‡ Hyuma Masu,‡ and
Shinichi Saito*,†
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku, Tokyo, Japan 162-8601, and Faculty of Pharmaceutical
Sciences at Kagawa Campus, Tokushima Bunri UniVersity, Kagawa, Japan 769-2193
ssaito@rs.kagu.tus.ac.jp
Received October 6, 2005
ABSTRACT
Cycloaddition of aziridines with isocyanates proceeded smoothly in the presence of a nickel catalyst, and five iminooxazolidine derivatives
were isolated in good yields. The best result was obtained when the reaction was carried out in the presence of NiI2, and a longer reaction
time allowed the isomerization of the iminooxazolidine to the corresponding imidazolidinone derivatives.
Cycloaddition reactions of three-membered heterocycles with
heterocumulenes are efficient methods for the synthesis of
heterocyclic compounds. For example, Pd(PhCN)2Cl2 cata-
lyzed the cycloaddition of aziridines and carbodiimides to
form imidazolidinimine.1 The Pd-catalyzed2-5 or NaI-
catalyzed6-8 reactions of aziridines with phenyl isocyanate
have also been reported. In these reactions, imidazolidinones
were isolated as the major product. In the cycloaddition of
aziridine with carbon dioxide, the Ni(II)9 complex (electro-
chemical process) and LiI10 were efficient catalysts. Orga-
noantimony halides were also capable of catalyzing the
cycloadditions of aziridines with heterocumulenes such as
carbondioxide,carbondisulfide,andphenylisothiocyanate.11-13
Although a variety of catalysts have been developed, most
of the reactions were carried out at high temperature or for
a long period. Moreover, there are still few examples of
metal-catalyzed cycloaddition reactions involving aziridines
with isocyanates. Consequently, we investigated cycloaddi-
tion reactions of aziridines with isocyanates in the presence
of Ni catalysts.
The reaction of 1-benzylaziridine 1a with phenyl isocy-
anate 2a in the presence of a Ni catalyst proceeded at 100
°C to give the corresponding iminooxazolidine derivative
3aa and imidazolidinone derivative 4aa. We examined vari-
ous Ni catalysts, and the results are summarized in Table 1.
† Tokyo University of Science.
‡ Tokushima Bunri University.
(1) Baeg, J. O.; Alper, H. J. Am. Chem. Soc. 1994, 116, 1220-1224.
(2) Baeg, J. O.; Bensimon, C.; Alper, H. J. Am. Chem. Soc. 1995, 117,
4700-4701.
(3) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836-
11837.
(4) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65,
5887-5890.
(5) Dong, C.; Alper, H. Tetrahedron: Asymmetry 2004, 15, 1537-1540.
(6) Nadir, K. U.; Base, N. Tetrahedron Lett. 1992, 33, 7949-7952.
(7) Nadir, K. U.; Base, N. Tetrahedron 1993, 49, 7787-7792.
(8) Nadir, U. K.; Krishna, R. V.; Singh, A. Tetrahedron Lett. 2005, 46,
479-482.
(9) Tascedda, P.; Dun˜ach, E. Chem. Commun. 2000, 449-450.
(10) Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003, 44, 5457-
5460.
The reaction proceeded slowly in the presence of 10 mol
% Ni(PPh3)2Br2, and 3aa and 4aa were isolated as the major
products in 65% combined yield (entry 1). When we used
NiBr2 as a catalyst, a higher catalytic activity was observed
(11) Nomura, R.; Nakano, T.; Nishio, Y.; Ogawa, S.; Ninagawa, A.;
Matsuda, H. Chem. Ber. 1989, 122, 2407-2409.
(12) Matsuda, H.; Ninagawa, A.; Hasegawa, H. Bull. Chem. Soc. Jpn.
1985, 58, 2717-2718.
(13) Fujiwara, M.; Baba, A.; Matsuda, H. J. Heterocycl. Chem. 1988,
25, 1351-1357.
10.1021/ol052417l CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/17/2006

the E configuration of the imine moiety were confirmed
(Figure 1).16
Table 1. Ni-Catalyzed Cross-Coupling Reactions of 1a with 2a
yield of
catalyst
(mol %)
time
(h)
3aa + 4aa
ratio
(3:4)b
entry
(%)a
1
2
3
4
5
6
7
8
9
Ni(PPh3)2Br2 (10)
NiBr2 (10)
Ni(PPh3)2I2 (10)
NiI2 (10)
NiI2 (1.0)
LiI (1.0)
TBAI (1.0)
NaI (10)
no catalyst
88
40
16
1.0
2.5
2.5
2.5
1.0
3.0
65
70
99
92
95
97
30c
6.3c
25c
5:1
6:1
22:1
35:1
.50:1
.50:1
3:1
Figure 1. ORTEP view of 1-benzyl-2-phenyliminooxazolidine
(3aa).
1.5:1
6:1
We next examined the reaction of various aziridines in
the presence of NiI2. The iminooxazolidine derivative 3 was
isolated as the single or the major product, and the results
are summarized in Table 2.
a Isolated yield of 3 + 4. b Determined by NMR. c Contaminated with a
small amount of a byproduct.
(entry 2). The rate as well as selectivity of the reaction
improved when the reaction was carried out in the presence
of Ni(PPh3)2I2 or NiI2 14 (entries 3 and 4). The reaction was
catalyzed efficiently even in the presence of 1 mol % of
NiI2: the reaction was completed in 2.5 h, and the cycload-
duct was isolated in 95% yield (entry 5). We further
examined the catalytic activity of other iodides, such as LiI,
tetra-n-butylammonium iodide, and NaI, and found that LiI
was also a good catalyst, whereas other iodides were less
efficient (entries 6-8). Although the reaction proceeded
slowly even in the absence of the catalyst, the acceleration
of the reaction by NiI2 was obvious (entries 5 and 9).
Table 2. NiI2-Catalyzed Cross-Coupling Reactions of
Aziridines (1a-h) with 2a
time yield of 3 yield of 4
Though we assumed that Lewis acids could be efficient
catalysts for the reaction and we carried out this reaction
in the presence of some Lewis acids such as BF3‚OEt2,
Ni(OTs)2, and Ni(OTf)2, the reaction did not proceed
efficiently. As the catalytic activity of LiI10 was reported in
the literature, the high catalytic activity of NiI2 indicates that
the iodide plays an important role for this catalytic reaction.15
At the same time, however, the countercation seems to have
a significant effect on the catalytic activity. Because the
unique catalytic activity of NiI2 was observed in some
reactions (vide infra), we selected NiI2 as the catalyst and
carried out further studies.
entry compd
R1
benzyl
n-butyl
t-butyl
TBSOCH2CH2
benzyl
n-butyl
Ph
R2
(h)
(%)
(%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
H
H
H
1.0
1.0
0.25
5.0
92
89
78a
75
82
86
20b
5a
Ph 1.0
Ph 0.5
14
5
5
1g
1h
H
H
72
72
Ts
a Determined by NMR. b Aziridine did not disappear.
When n-butylaziridine 1b, tert-butylaziridine 1c, and tert-
butyldimethylsiloxyethylaziridine 1d were used, the reaction
We also examined the effect of the solvents on the
reaction. Although the reaction proceeded smoothly when
1,4-dioxane, DMF, and DMSO were used as the solvents,
the best result was obtained when the reaction was carried
out in toluene. The structure of 3aa was analyzed by an X-ray
diffraction study, and the iminooxazolidine framework and
(16) X-ray data were collected on a Bruker Smart1000 CCD detector.
The crystal structure was solved by direct methods SHELXS-97 (Sheldrick,
1997) and refined by full-matrix least-squares SHELXL-97 (Sheldrick,
1997). All non-hydrogen atoms were refined anisotropically. All hydrogen
atoms were included as their calculated positions. Crystal data for 3aa:
C16H16N2O; M ) 252.31 g mol-1; monoclinic; P21/n; colorless prism
measuring 0.3 × 0.3 × 0.3 mm; T ) 300 K; a ) 8.0158(16), b ) 6.5155-
(13), c ) 26.090(5) Å; â ) 90.072(3)°; V ) 1362.6(5) Å3; Z ) 4; Dc )
1.230 Mg m-3; µ ) 0.078 mm-1; Tmax ) 0.9770, Tmin ) 0.9770, GOF on
F2 ) 0.712; R1 ) 0.0394, wR2 ) 0.0825 ([I > 2σ(I)], R1 ) 0.0876, and
wR2 ) 0.0895 (all data). CCDC-280438.
(14) Although the reaction proceeded when we carried out the reaction
at lower temperature (50 °C or 80 °C), a longer reaction time was required.
(15) The catalytic activity of Ni(0) complexes such as Ni(PPh3)2(cod)
and Ni(PPh3)4 was also very low.
380
Org. Lett., Vol. 8, No. 3, 2006

proceeded smoothly and the corresponding coupling products
were isolated in good yields (entries 1-4). However, in the
reaction of butylaziridine 1c, the selectivity of the reaction
decreased (entry 3). Disubstituted aziridines such as 1e and
1f were also good substrates for the [3+2] coupling reaction,
and the corresponding iminooxazolidine derivatives 3 were
isolated in good yields (entries 5 and 6). The selective
cleavage of the benzylic C-N bond was observed in the
reactions of 2-phenyl-substituted aziridines. In these reac-
tions, however, a small amount of 4 was also isolated. When
phenylaziridine 1g was used as the substrate, the progress
of the reaction was very sluggish, and the yields of the
products were low (entry 7). The cycloaddition reaction did
not proceed when tosylaziridine 1h was selected as the
substrate (entry 8).
Table 4. Relationship between Reaction Time and Ratio of the
Product in the Reaction of 1f with 2a
yield (%)a
entry
time (h)
3fa
4fa
1
2
3
0.5
4.0
16
86
57
0
5
32
84
We also examined the reaction of benzylaziridine 1a
with various isocyanates (Table 3). The reaction of 1a with
a Isolated yields.
Table 3. NiI2-Catalyzed Cross-Coupling Reactions of 1a with
Isocyanates (2a-e)
(Scheme 1). Although the isomerization of 3fa did not
proceed and 3fa was recovered unchanged when the reaction
was carried out in the absence of NiI2, the reaction proceeded
smoothly in the presence of NiI2 and 4fa was isolated in
84% yield. Although the isomerization of 3fa proceeded in
the presence of LiI, the rate of the conversion was slower
and a 53:47 mixture of 3fa and 4fa was formed (91% total
yield) under the same condition. To the best of our
knowledge, iminooxazolidine derivatives isomerized to imi-
dazolidinone derivatives at 220-240 °C,17 and our study
revealed that NiI2 was also an efficient catalyst for the
isomerization.
time
(h)
yield of 3
entry
compd
R
(%)
1
2
3
4
5
2a
2b
2c
2d
2e
phenyl
benzyl
p-methoxyphenyl
p-acetylphenyl
1-naphthyl
1.0
3.0
1.0
1.0
1.0
92
74
78
82
91
Scheme 1. NiI2-catalyzed Isomerization of 3fa
benzyl isocyanate 2b proceeded smoothly, and compound
3ab was isolated in 74% yield (entry 2). The reaction of
other isocyanates also proceeded efficiently, and the prod-
ucts were isolated in high yields (entries 3-5). It is
noteworthy that the formation of 4 was not observed in those
reactions.
During the study, we observed that the ratio of 3 to 4
depended on the reaction time in some experiments. We
carried out the reaction of 1f with 2a to examine the
relationship between the reaction time and the ratio of the
products. The results are summarized in Table 4.
When the reaction was carried out for a shorter period
(0.5 h), the iminooxazolidine derivative 3fa was isolated as
the major product (entry 1); the yield of 3fa decreased and
that of 4fa increased to 32% when the reaction time was 4
h (entry 2). The iminooxazolidine 3fa disappeared, and the
imidazolidinone 4fa was isolated as the major product when
the reaction was carried out for 16 h (entry 3).
We proposed the mechanism of this reaction as shown in
Scheme 2. Thus, NiI2 would act as a Lewis acid and as an
iodide source. The aziridine ring would be cleaved by the
nucleophilic attack of the iodide.10 The selective cleavage
of the benzylic C-N bond in the reaction of 1e-f could be
explained in terms of the stabilization of the transition state
by the phenyl group,18,19 and similar results have been
reported in the literature.10 A nickel amide 5 would be a
We hypothesized that 3 isomerized to 4 in the presence
of Ni catalysts, and we examined the isomerization of 3fa
(17) Beachell, H. C.; Ngoc Son, C. P.; Tinh, N. H. J. Org. Chem. 1972,
37, 422-425.
Org. Lett., Vol. 8, No. 3, 2006
381

Scheme 2. A Possible Mechanism for the Formation of 3 and 4
strong nucleophile and would attack the isocyanate 2 to give
the iminooxazolidine 3.
In summary, we found that the cycloaddition of aziridines
with isocyanates proceeded smoothly in the presence of
nickel catalysts and five-membered heterocycles were iso-
lated in good to high yields. NiI2 was a very effective catalyst
for the reaction. We also found that iminooxazolidine
derivatives isomerized to imidazolidinone derivatives in the
presence of NiI2. The study provided an efficient method
for the selective preparation of five-membered heterocycles.
The isomerization of 3 would proceed by the coordination
of NiI2 to the imine moiety of 3, followed by the cleavage
of the C-O bond of 3.20 A carbocation 7 or an aziridinium
ion 8 would be formed, and the imidazolidinone 4 would be
isolated as the final product by the recyclization of the
cationic intermediate 7 or 8.
Supporting Information Available: Detailed experi-
mental procedures, spectral data of 3 and 4, and X-ray
crystallographic data (CIF) for 3aa. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Hedley, S. J.; Moran, W. J.; Price, D. A.; Harrity, J. P. A. J. Org.
Chem. 2003, 68, 4286-4292.
(19) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2000, 65, 1344-
1348.
(20) Alternatively, the iodide may react as a nucleophile in this
process. The stereochemical study of this reaction will distinguish the
processes.
OL052417L
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Org. Lett., Vol. 8, No. 3, 2006