Synthesis of 1,3-oxazolidines by copper-catalyzed addition of acetone and ethyl diazoacetate to imines

Article abstract of DOI:10.1016/S0040-4039(01)00479-8

1,3-Oxazolidines are obtained in high yields by copper-catalyzed addition of ethyl diazoacetate to imines in the presence of acetone. Hydrolysis of the oxazolidines with 6N HCl yields 1,2-amino alcohols.

Full text of DOI:10.1016/S0040-4039(01)00479-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3487–3490
Synthesis of 1,3-oxazolidines by copper-catalyzed addition of
acetone and ethyl diazoacetate to imines
Seung-Han Lee,* Jin Yang and Tae-Dong Han
Department of Chemistry, Kyunghee University, Yongin 449-701, South Korea
Received 19 March 2001; accepted 22 March 2001
Abstract—1,3-Oxazolidines are obtained in high yields by copper-catalyzed addition of ethyl diazoacetate to imines in the presence
of acetone. Hydrolysis of the oxazolidines with 6N HCl yields 1,2-amino alcohols. © 2001 Elsevier Science Ltd. All rights
reserved.
1,3-Oxazolidines have been used often in organic syn-
thesis as intermediates in preparative pathways and as
chiral auxiliaries to direct diastereoselective transforma-
tions.1 These substances are typically prepared by con-
densation reactions of 1,2-amino alcohols with
aldehydes or nitriles,2 [3+2]-cycloadditions of azome-
thine ylides and carbonyl compounds,3 or other routes.4
Recently a new method to prepare 1,3-oxazolidines, via
metal-catalyzed addition of epoxides to imines, was
described.5 During the course of investigations into
probing methods for aziridine ring construction, we
observed that copper catalyzed reactions of ethyl diazo-
acetate with imines in the presence of acetone results in
the formation of 1,3-oxazolidines and 1,2-amino alco-
hols (Scheme 1). A detailed study of this process has led
to the development of a convenient and efficient proce-
dure to prepare 1,3-oxazolidines. Below, we report the
results of this study which demonstrates that 1,3-oxazo-
lidines and amino alcohols can be generated in high
yields by reaction of imines with ethyl diazoacetate in
the presence of 10 mol% copper tetrafluoroborate or
triflate.
Scheme 1.
Table 1. 1,3-Oxazolidine formation by Cu-catalyzed addition of ethyl diazoacetate to imines in the presence of acetone
Entry
Imine
Ar1
Ar2
Catalyst
2 (%)a (cis/trans)b
3 (%)
Total yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1c
1d
1e
1f
p-MethoxyPh
p-NitroPh
p-NitroPh
p-MethoxyPh
p-NitroPh
p-MethoxyPh
Ph
Ph
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
38 (2)
45 (3)
38 (2)
53 (2)
79 (1.5)
48 (1.3)
56 (1.1)
58 (1.7)
48
28
39
28
17
32
13
19
86
73
77
81
96
80
69
77
p-MethoxyPh
Ph
p-MethoxyPh
Ph
p-MethoxyPh
Ph
p-MethoxyPh
Ph
a Isolated yields.
b Ratios were determined by 1H NMR analysis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00479-8

3488
S.-H. Lee et al. / Tetrahedron Letters 42 (2001) 3487–3490
Table 2. 1,3-Oxazolidine formation by Cu-catalyzed addition of ethyl diazoacetate to imines in the presence of acetone and
molecular sieves
Entry
Imine
Ar1
Ar2
Catalyst
2 (%)a (cis/trans)b
3 (%)
Total yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1c
1e
1f
p-MethoxyPh
p-NitroPh
p-NitroPh
p-MethoxyPh
Ph
Ph
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuI/AgBF4
CuCl2/AgBF4
CuCl2/AgBF4
CuCl2/AgBF4
CuCl2/AgBF4
68 (1.2)
80 (2)
72 (3)
85 (1.2)
53 (1.2)
80 (1.2)
86 (1.5)
93 (1)
10
13
23
14
13
12
13
5
17
13
15
11
6
10
12
11
10
16
14
19
15
78
93
95
99
66
92
99
98
80
93
97
84
84
95
91
72
94
90
90
80
68
p-MethoxyPh
Ph
p-MethoxyPh
Ph
p-MethoxyPh
p-MethoxyPh
Ph
Ph
p-ChloroPh
p-MethoxyPh
p-MethoxyPh
p-NitroPh
p-NitroPh
p-MethoxyPh
Ph
9c
10
11
12
13
14
15
16
17
18
19
20
21
Ph
63 (3)
80 (2)
p-MethoxyPh
Ph
p-MethoxyPh
Ph
p-MethoxyPh
p-MethoxyPh
p-NitroPh
p-NitroPh
Ph
82 (2.8)
73 (1.4)
78 (1.5)
85 (2.8)
79 (1.6)
61 (1)
84 (1.5)
74 (1.6)
76 (2.2)
61 (2.2)
53 (1.7)
Ph
p-ChloroPh
Ph
p-MethoxyPh
p-MethoxyPh
p-NitroPh
Ph
Ph
Ph
Ph
p-MethoxyPh
a Isolated yields.
b Ratios were determined by 1H NMR analysis.
c Reaction was performed at 0°C.
The ratios of the cis- to trans-oxazolidines produced in
these reactions were found to vary from 1:1 to 3:1. As
demonstrated by the addition of ethyl diazoacetate to
N-phenylanisaldimine 1a, reaction at 0°C versus 25°C
results in an increase (3:1 versus 1:1) in the cis/trans
ratio. However, the observation that the reaction does
not occur at −25°C rules out the use of even lower
temperatures to further enhance stereoselectivity.
A number of experiments were performed to maximize
the efficiency of the 1,3-oxazolidine forming reaction
(Table 1).6 In this effort, we found that reactions of
imines with ethyl diazoacetate using copper(I) iodide as
catalyst were unsuccessful. However, the addition pro-
cess catalyzed by copper(I) tetrafluoroborate, prepared
by reaction of copper(I) iodide with silver tetra-
fluoroborate, afforded the oxazolidines and corre-
sponding amino alcohols in high yields (Table 1, entries
5–8).7 In addition, copper(II) triflate serves as an effec-
tive catalyst for this process (Table 1, entries 1–4).
When the addition reactions are run in the absence of
molecular sieves, large quantities of 1,2-amino alcohols
are generated, presumably by hydrolysis of the initially
formed 1,3-oxazolidines. Inclusion of molecular sieves
in the reaction mixtures, however, prevents formation
of the amino alcohols and it results in enhanced oxazo-
lidine yields (Table 2).
The amino alcohols 3, formed as minor products in
these processes, were separated and converted to the
oxazolidines by acid catalyzed (p-toluenesufonic acid or
BF3·Et2O)8
reaction
with
acetone
or
2,2-
dimethoxypropane (Scheme 2). It is interesting that the
trans-oxazolidines are formed as major products (trans
to cis ratios ca. 1.5:1). In addition, the amino alcohols
are formed in moderate to high yields (60–97%) by
hydrolysis of 1,3-oxazolidines with 6N HCl (Scheme 3
and Table 3).9
The structures of 1,3-oxazolidine products were deter-
1
mined by using H, 13C NMR spectroscopy and ele-
1
mental analysis. For example, the H NMR spectra of
the cis-diastereomer of oxazolidine 2e, prepared from
N-phenylbenzaldimine, contained two singlets (1.48
(3H) and 1.89 (3H) ppm) assigned to the methyl groups
at C-2 and two doublets (4.49 (1H, J=7.6 Hz) and 5.05
(1H, J=7.6 Hz) ppm) corresponding to the vicinally
disposed ring protons. The oxazolidine diastereomers
were separated by column chromatography and
purified by recrystallization. Since the coupling con-
stants of ring protons in cis- and trans-oxazolidines are
nearly the same, stereochemical assignments to the
oxazolidines required the use of COSY spectra.
Scheme 2.
Scheme 3.

S.-H. Lee et al. / Tetrahedron Letters 42 (2001) 3487–3490
Table 3. Amino alcohols by hydrolysis of 1,3-oxazolidines
3489
Entry
Oxazolidine
Ar1
Ar2
Yield
(%)a
1
2
3
4
5
6
7
8
cis-2a
cis-2c
cis-2d
cis-2e
cis-2f
cis-2h
cis-2i
trans-2a
trans-2d
trans-2e
trans-2f
trans-2h
p-MethoxyPh
p-NitroPh
p-MethoxyPh
Ph
Ph
Ph
p-MethoxyPh
p-MethoxyPh
p-MethoxyPh
Ph
Ph
Ph
Ph
Ph
71
75
97
71
84
61
65
58
94
77
90
61
p-MethoxyPh
Ph
p-MethoxyPh
p-NitroPh
p-NitroPh
Ph
p-MethoxyPh
Ph
p-MethoxyPh
p-NitroPh
9
10
11
12
a Isolated yield.
Scheme 4.
It is interesting to speculate about the mechanism of
this 1,3-oxazolidine ring forming reaction. It has been
proposed that formation of aziridines in copper cata-
lyzed reactions of diazoacetates with imines involves the
intermediacy of carbene complexes and azomethine
ylides, or zwitterionic (Lewis acid catalyzed) species.10
In reactions proceeding via carbene complexes,
fumarate and/or maleate esters are commonly formed
as side products.11 However, reaction mixtures gener-
ated in the oxazolidine forming processes described
above were found not to contain either diethyl maleate
or diethyl fumarate. Thus, it is likely that this reaction
does not proceed via the intermediacy of metal carbene
complexes. Also, oxazolidines are known to be pro-
duced by cycloaddition reactions of carbonyl com-
pound such as ketene with azomethine ylides, generated
by thermal electrocyclic ring opening of aziridines.3b
But, if the above reactions were to proceed through
azomethine ylide intermediates A, it is expected that
ethyl 5,5-dimethyl-2,3-diphenyl-4-oxazolidinecarboxy-
late 4 (Scheme 4) would be formed. The 1H NMR
spectra of these substances, which are structural iso-
mers of the oxazolidines actually generated in the cop-
per catalyzed reactions of acetone, imines and the
diazoacetate ester, would characteristically contain two
singlets corresponding to the ring protons. Also, we
have prepared aziridines, representative of those that
are possible intermediates in the oxazolidine forming
reactions. Treatment of these aziridines with acetone
under the copper catalyzed reaction conditions did not
lead to generation of oxazolidine products. Recently,
1,3-oxazolidines were synthesized by using SmI2 or
Pd(0) catalyzed reactions between epoxides and imines.5
To determine if epoxides are intermediates in the reac-
tions described above, we treated acetone with ethyl
diazoacetate in the presence of copper catalyst and then
with imines. Here again, no oxazolidines were obtained.
The combined results suggest that the likely mechanism
for oxazolidine formation in copper catalyzed reactions
between ethyl diazoacetate, imines and acetone involves
formation of the zwitterionic (Lewis acid catalyzed)
intermediate B followed by acetone addition (Scheme
4).
Acknowledgements
Financial support for this work was provided by the
Brain Korea 21 Project, 2000.
References
1. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835–875; (b) Gordon, K.; Bolger, M.; Khan, N.;
Balasubramanian, S. Tetrahedron Lett. 2000, 41, 8621–
8625; (c) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem.
1997, 62, 3770–3771; (d) Dai, W.-M.; Zhu, H. J.; Hao,
X.-J. Tetrahedron: Asymmetry 1996, 7, 1245–1248; (e)
Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetra-
hedron 1997, 53, 14381–14396; (f) Le Bail, M.; Pe´rard, J.;
Aitken, D. J.; Bonin, M.; Husson, H.-P. Tetrahedron
Lett. 1997, 38, 7177–7180; (g) Alezra, V.; Bonin, M.;
Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P.
Tetrahedron Lett. 2000, 41, 1737–1740.
2. (a) Le´tinois, S.; Dumur, J.-C.; He´nin, F.; Muzart, J.
Tetrahedron Lett. 1998, 39, 2327–2330; (b) Henin, F.;
Le´tinois, S.; Muzart, J. Tetrahedron Lett. 1997, 38, 7187–
7190; (c) Tremblay, M. R.; Wentworth, Jr., P.; Lee, Jr.,
G. E.; Janda, K. D. J. Comb. Chem. 2000, 2, 698–709.
3. (a) Novikov, M. S.; Khlebnikov, A. F.; Krebs, A.;
Kostikov, R. R. Eur. J. Org. Chem. 1998, 133–137; (b)
Texier, F.; Carrie, R.; Jaz, J. J. Chem. Soc., Chem.
Commun. 1972, 199–200; (c) Hosomi, A.; Miyashiro, Y.;
Yoshida, R.; Tominaga, Y.; Yanagi, T.; Hojo, M. J. Org.
Chem. 1990, 55, 5308–5310; (d) Padwa, A.; Dent, W. J.
Org. Chem. 1987, 52, 235–244.
4. (a) Katritzky, A. R.; Feng, D.; Qi, M. Tetrahedron Lett.
1998, 39, 6835–6836; (b) Yli-Kauhaluoma, J. T.; Harwig,
C. W.; Wentworth, Jr., P.; Janda, K. D. Tetrahedron
Lett. 1998, 39, 2269–2272.
5. (a) Nishitani, T.; Shiraishi, H.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2000, 41, 3389–3393; (b) Shim, J.-G.;
Yamamoto, Y. Tetrahedron Lett. 1999, 40, 1053–1056; (c)
Shim, J.-G.; Yamamoto, Y. Heterocycles 2000, 52, 885–
895.
6. Acetone distilled from anhydrous K2CO3 under N2 was
used.

3490
S.-H. Lee et al. / Tetrahedron Letters 42 (2001) 3487–3490
7. General procedure for the three-component 1,3-oxazo-
K.; Hoppe, D. Tetrahedron Lett. 1994, 35, 7365–7368.
9. General procedure for the 1,3–oxazolidine hydrolysis. A
solution of 1,3-oxazolidine (1.0 mmol) in acetone (3 mL)
and 6N HCl (1 mL) was stirred at 25°C for 1 h, concen-
trated, washed with saturated aq. NaHCO3, and
extracted with dichloromethane. The dichloromethane
extracts were concentrated and the residue was subjected
to chromatography on silica gel (ethyl acetate: hexane=
3:1) to give the amino alcohol products. Representative
1H NMR spectroscopic properties of the amino alcohols.
Ethyl 2-hydroxy-3-(p-nitrophenyl)amino-3-phenylpropano-
ate (3h from cis-oxazolidine): 1H NMR (200 MHz,
CDCl3): l 8.04–7.96 (m, 2H), 7.36–7.25 (m, 5H), 6.57–
6.49 (m, 2H), 5.73 (d, J=7.5 Hz, 1H), 4.89 (dd, J=7.9,
3.4 Hz, 1H), 4.69 (dd, J=7.1, 3.4 Hz, 1H), 4.28–4.12 (m,
2H), 2.99 (d, J=7.4 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H); IR
(KBr) 3498, 3380, 3031, 2982, 1736, 1600, 1504, 1475,
1312, 1112 cm−1. Ethyl 2-hydroxy-3-(p-nitrophenyl)amino-
lidine-forming reaction. To a stirred solution of AgBF4
(0.08 mmol, 0.1 equiv.) in acetone (5 mL), containing
,
suspended molecular sieves 4 A, at 25°C was added CuI
(0.08 mmol, 0.1 equiv.). After a white precipitate formed,
imine (0.8 mmol, 1.0 equiv.) and ethyl diazoacetate (0.8
mmol, 1.0 equiv.) were added. After stirring for 30 min,
the mixture was concentrated, diluted with ether, and
filtered through silica gel. The ethereal filtrate was con-
centrated in vacuo and the residue was subjected to
chromatography on silica gel (EA:hexane=1:5) to give
the oxazolidine product. Representative spectroscopic
properties of the oxazolidines. Ethyl 3-p-methoxyphenyl-
2,2-dimethyl-4-p-nitrophenyl-5-oxazolidine
carboxylate
1
(cis-2b): H NMR (300 MHz, CDCl3): l 8.09 (d, J=9.0
Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0 Hz,
2H), 6.74 (d, J=9.3 Hz, 2H), 5.28 (d, J=7.8 Hz, 1H),
4.96 (d, J=7.8 Hz, 1H), 3.83 (dq, J=14.4, 7.2 Hz, 1H),
3.71 (s, 3H), 3.58 (dq, J=14.4, 7.2 Hz, 1H), 1.87 (s, 3H),
1.29 (s, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): l 169.2, 155.7, 147.5, 145.0, 135.6, 129.1,
123.7, 123.3, 114.3, 97.7, 78.1, 64.9, 60.8, 55.3, 29.1, 22.9,
13.7; IR (KBr) 2981, 2927, 2836, 1753 cm−1. Anal. calcd
for C21H24N2O6: C, 62.99; H, 6.04; N, 7.00. Found: C,
63.04; H, 6.13; N, 6.93. Ethyl 3-p-methoxyphenyl-2,2-
dimethyl-4-p-nitrophenyl-5-oxazolidine carboxylate (trans-
1
3-phenylpropanoate (3h from trans-oxazolidine): H NMR
(200 MHz, CDCl3): l 8.10–7.97 (m, 2H), 7.38–7.30 (m,
5H), 6.57–6.49 (m, 2H), 5.55 (d, J=6.2 Hz, 1H), 5.01 (d,
J=5.8 Hz, 1H), 4.55 (s, 1H), 4.28 (q, J=7.1 Hz, 2H),
3.20 (s, 1H), 1.24 (t, J=7.1 Hz, 3H); IR (KBr) 3483,
3375, 3030, 2981, 1733, 1600, 1504, 1476, 1310, 1112
cm−1
.
1
10. For review of aziridine synthesis: Jacobsen, E. N. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer–Verlag: New
York, 1999; Vol. 2, p. 607.
11. (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. Engl. 1995, 34, 676–678; (b) Rasmussen,
K. G.; Jo*rgensen, K. A. J. Chem. Soc., Chem. Commun.
1995, 1401–1402.
2b): H NMR (300 MHz, CDCl3): l 8.12 (d, J=8.7 Hz,
2H), 7.62 (d, J=8.7 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H),
6.73 (d, J=8.7 Hz, 2H), 5.05 (d, J=7.8 Hz, 1H), 4.38 (d,
J=8.1 Hz, 1H), 4.29–4.25 (m, 2H), 3.70 (s, 3H), 2.04 (s,
3H), 1.71 (s, 3H), 1.28 (t, J=7.2 Hz, 3H); IR (KBr) 2981,
2933, 2830, 1750 cm−1
.
8. (a) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48,
8631–8644; (b) Harder, T.; Lo¨hl, T.; Bolte, M.; Wagner,
.