Lewis acid-catalyzed synthesis of aziridines

Full text of DOI:10.1021/jo961391w

8358
J . Org. Chem. 1996, 61, 8358-8359
Lew is Acid -Ca ta lyzed Syn th esis of
Azir id in es
(1)
Luis Casarrubios, J ulio A. Pe´rez,
Maurice Brookhart,* and J oseph L. Templeton*
Department of Chemistry, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
Treatment of an ethereal solution of N-benzilidene-
aniline (1a ) with variable amounts of BF3‚Et2O and 1.0
equiv of ethyl diazoacetate (EDA) resulted in the forma-
tion of aziridine 3a . In the absence of BF3‚Et2O, no
reaction was observed after a mixture of 1a and EDA
(1.0 equiv) was stirred for 48 h in ether at room
temperature. With equimolar amounts of imine,
BF3‚Et2O, and EDA, decomposition of the starting ma-
terials along with traces of aziridine 3a were detected
Received J uly 23, 1996 (Revised Manuscript Received
September 17, 1996)
Aziridines are useful intermediates in organic synthe-
sis.1,2 Classical methods for the synthesis of aziridines
are ring closure of amino alcohols,3 ring opening of
epoxides with sodium azide,4 and addition of R-halo ester
enolates to N-(trimethylsilyl)imines.5
1
Recently, methods for aziridine synthesis employing
transition metal catalysts have been reported. For
example, nitrene transfer to olefins from [N-(p-toluene-
sulfonyl)imino]phenyliodinane (PhIdNTs) in the pres-
ence of Cu(I) and Cu(II) salts has been demonstrated.6
An alternative route, involving carbene transfer to
imines, was reported by J acobsen.7 The reaction of
imines with EDA catalyzed by chiral Cu(I)-bis(dihydro-
oxazole) complexes produces aziridines in moderate yields
with ee’s up to 67%. J o¨rgensen8 was able to increase
aziridine yields to 80-90% using Cu(OTf)2 in combination
with either (-)-menthyl diazoacetate or (R)-(+)-2,2′-
isopropylidenebis(4-phenyl-2-oxazoline), but enantio-
selectivities were moderate. More recently, Espenson9
reported reaction of imines with EDA catalyzed by
methylrhenium trioxide.
by H NMR spectroscopy. When an ethereal solution of
imine 1a and a 10 mol % of BF3‚Et2O was treated with
1.0 equiv of EDA, the 1H NMR spectrum of the crude
reaction showed a mixture of aziridine 3a , plus 4a and
5a (eq 2).
(2)
Two reports describe the formation of aziridines fol-
lowing activation of imines with Lewis acids, but these
methods are not general. Thus, Bartnik10a reported the
reaction of imines with phenyldiazomethane catalyzed
by zinc iodide. Yields are moderate, and this method
failed when ethyl diazoacetate was the carbene source.
Aziridines have also been detected in the reaction of
diazopenicillanates with imines in the presence of
BF3‚Et2O.11
In an effort to minimize the formation of 4a and 5a ,
different solvents were tested (Table 1). After 1 h in the
presence of 0.10 equiv of BF3‚Et2O, the ratio of products
was determined by 1H NMR analysis of the crude
reaction mixtures. Our best results were obtained in
hexane.12 The reaction went to completion overnight, and
93% of pure cis aziridine 3a was isolated by column
chromatography (entry 1, Table 2).
We report here a convenient synthesis of aziridines
from various imines and ethyl diazoacetate catalyzed by
readily available Lewis acids (eq 1).
Ta ble 1a
(1) (a) Kump, J . E. G. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 469. (b)
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 7, p 47. (c) Ham, G. E. J . Org.
Chem. 1964, 29, 3052. (d) Dermer, O. C.; Ham, G. E. Ethyleneimine
and other aziridines; Academic: New York, 1969. (e) Dewar, M. J . S.;
Ford, G. P. J . Am. Chem. Soc. 1979, 101, 783.
(2) (a) Brimacombe, J . S.; Hanna, R.; Tucker, L. C. N. J . Chem. Soc.,
Perkin Trans. 1 1983, 2277. (b) Oppolzer, W.; Flaskamp, E. Helv. Chim.
Acta 1977, 60, 204. (c) Martens, J .; Scheunemann, M. Tetrahedron Lett.
1991, 32, 1417.
(3) (a) Kelly, J . W.; Eskew, N. L.; Evans, S. A., J r. J . Org. Chem.
1986, 51, 95. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33,
599. (c) Kuyl-Yeheskiely, E.; Lodder, M.; van der Marel, G. A.; van
Boom, J . H. Tetrahedron Lett. 1992, 33, 3013.
(4) (a) Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211. (b)
Legters, J .; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989, 30, 4881.
(5) Cainelli, G.; Panunzio, M.; Giacomini, D. Tetrahedron Lett. 1991,
32, 121
(6) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J . Am. Chem. Soc. 1993, 115, 5328. (b) Li, Z.; Conser,
K. R.; J acobsen, E. N. J . Am. Chem. Soc. 1993, 115, 5326. (c) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T. J . Am. Chem. Soc. 1994, 116, 2742.
(7) Hansen, K. B.; Finney, N. S.; J acobsen, E. N. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 676.
(8) Rasmussen, K. G.; J ørgensen, K. A. J . Chem. Soc., Chem.
Commun. 1995, 1401.
(9) Zhu, Z.; Espenson, J . H. J . Org. Chem. 1995, 60, 7090.
(10) (a) Bartnik, R.; Mloston, G. Synthesis 1983, 924. (b) See also:
Bartnik, R.; Mloston, G. Tetrahedron 1984, 40, 2569.
(11) J ephcote, V. J .; J ohn, D. I.; Williams, D. J . J . Chem. Soc., Perkin
Trans. 1 1986, 2195.
solvent
3a :(4a + 5a )
cis-3a : trans-3a
3a :1a
CH2Cl2
Et2O
THF
toluene
hexane
66:34
74:26
69:31
57:43
94:6
cis only
cis only
cis only
cis only
90:10
no imine
94:6
97:3
95:5
75:25
a
Reaction conditions: 25 °C, 1 h, 10 mL of solvent, 0.55 mmol
of 1a , 0.05 mmol of BF3‚Et2O.
Similar reactions were also performed with the imines
1b-1f13 and different Lewis acids. The conditions and
results of this series of studies are listed in Table 2.
(12) The following experimental procedure for the preparation of
the aziridine 3a is representative: Imine 1a (2.00 g, 11.04 mmol) is
dissolved in 100 mL of anhydrous hexane, and the solution is treated,
under nitrogen, with 0.16 g (0.11 mmol) of BF3‚Et2O and 1.20 g (11.04
mmol) of ethyl diazoacetate. The mixture is stirred at room temper-
ature until the starting imine has been consumed (1H NMR). Workup
with water and chromatography on silica gel using hexane/ethyl
acetate as eluent yields aziridine 3a (2.73 g 93%).
(13) Imines 1d -f were obtained as follows: The corresponding
aldehyde (1.0 mmol) was dissolved in 20 mL of methylene chloride and
treated with an equimolar amount of aniline in the presence of 10 g of
MgSO4. The resulting mixture was stirred overnight. Filtration and
solvent removal yielded imines 1d -f (pure by 1H NMR), which were
used without further purification.
S0022-3263(96)01391-6 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 24, 1996 8359
Ta ble 2
solvent
entry
cat.
1
R1
R2
N2CHE (equiv)
time
15 h
48 h
15 h
1 h
24 h
15 min
2 h
0.5 h
15 h
2 h
15 min
48 h
15 h
48 h
3 h
3:(4 + 5)
cis:trans
3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
BF3
BF3
BF3
BF3
BF3
BF3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
a
b
c
d
e
f
a
b
c
d
f
a
b
c
d
f
Ph
Ph
Ph
Ph
hexane
hexane
Et2O
Et2O
Et2O
1.0
1.0
2.0
1.0
1.0
1.0
1.0
3.0
2.0
1.0
1.0
3.0
2.0
1.5
1.0
1.0
94:6
95:5
93:7
93
53
51
80
p-CH3OC6H4
PhCH2
cis only
cis only
82:18
73:24
88:12
0:100
55:45
65:35
66:34
67:33
82:18
88:12
63:37
52:48
76:24
79:21
90:10
p-NO2C6H4
p-CH3OC6H4
Ph
Ph
Ph
Ph
tBu
Ph
Ph
Ph
Et2O
38:62
98:2
cis only
cis only
82:12
28:72
89:11
cis only
cis only
74:26
61
56
57
45
62
58
62
44
42
83
62
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
CH2Cl2
hexane
Et2O
p-CH3OC6H4
PhCH2
p-NO2C6H4
Ph
Ph
Ph
tBu
Ph
Ph
Ph
p-CH3OC6H4
PhCH2
Ph
p-NO2C6H4
tBu
Ph
CH2Cl2
2 h
48:52
a
Yields are of pure isolated product (best of at least two experiments). In the case of 1f and 1a , both isomers were isolated.
tion of EDA results in formation of intermediate 6.15
Subsequent ring closure and loss of N2 provides aziridines
3. Byproducts 4 and 5 result from 1,2 migration of either
the R1 substituent or H to the incipient carbocation to
yield initially 4′ and 5′.16 For aromatic imines, the ratio
of aziridines to migration products is strongly dependent
of the nature of the aryl ring. For Ar ) -C6H5, the ratio
of 3:(4 + 5) is ca. 65:35, while for the electron-withdraw-
ing p-NO2C6H4 system the ratio increases to 82:18 and
for the electron-donating substituent p-CH3OC6H4 only
traces of aziridine are observed, in keeping with the usual
migratory aptitudes for these substituted aryl groups in
electron-deficient rearrangements.
Sch em e 1
t
The conversion of imine 1f (R1 ) Bu) to aziridines is
much faster than for N-aryl-substituted imines. This
may be explained by the higher nucleophilicity of the
imine nitrogen when R ) alkyl. In this case, in addition
to aziridines, only the hydride migration product in the
iminic tautomeric form, 5f′, is observed.
In summary, we have shown that simple Lewis acids
catalyze the reaction of EDA with imines to form a
variety of aziridines. The mechanism for aziridine
formation shown in Scheme 1 may also apply to some
transition metal-catalyzed additions17 and must be con-
sidered when analyzing such results. We are currently
investigating the use of chiral Lewis acids in these
reactions.
Ack n ow led gem en t is made to the National Insti-
tutes of Health (Grant No. GM28938) and the National
Science Foundation (Grant No. CH9208207). L.C. and
J .A.P. also thank the Ministerio de Educacion y Ciencia
(Spain) and the Fulbright Foundation for a research
fellowship.
In no case have products derived from carbene coupling
(e.g., diethyl fumarate or maleate)7 been detected. The
absence of carbene coupling products suggests that no
metal carbenoid species are involved in the transfer
process.
Identification of 4 and 5 was possible on the basis of
comparison of their NMR data with similar compounds.14
Enamines 4 show a broad doublet (δ ) 8.60-10.34; J )
12.0-13.0 Hz) assigned as the NH resonance. This low-
field shift is compatible with the existence of a hydrogen
bond to the carbonyl group of the ester, and the large
vicinal coupling is consistent with a trans periplanar
relationship between the vicinal hydrogens.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for cis-3a , trans-3a , 4a , 5a ,
cis-3b, 4b, cis-3c, 4c, 5c, cis-3d , 5d , cis-3f, trans-3f, and 5f′
(5 pages).
J O961391W
Scheme 1 illustrates a mechanism consistent with the
results in Table 2. Activation of the imine by complex-
ation with the Lewis acid followed by nucleophilic addi-
(15) Similar intermediates have been proposed; see refs 10a and 11.
(16) The possibility of an equilibrium between aziridines 3 and
imines 4 and 5 was also tested. Pure cis-3a and pure trans-3a (R1
)
R2 ) Ph) were stirred separately for 15 h in hexanes in the presence
of BF3‚Et2O. After workup, no formation of 4 or 5 was detected.
(17) Pe´rez, J . A.; Templeton, J . L.; Brookhart, M. Unpublished
results.
(14) Speziale, A. J .; Tung, C. C.; Ratts, K. W.; Yao, A. J . Am. Chem.
Soc. 1965, 87, 3460.