Intermolecular cycloaddition of ethyl glyoxylate O-tert- butyldimethylsilyloxime with alkenes

Article abstract of DOI:10.1055/s-2007-967939

Ethyl glyoxylate O-tert-butyldimethylsilyloxime, on treatment with various alkenes in the presence of BF₃·OEt₂, generated a C-ethoxycarbonyl N-boranonitrone intermediate, which underwent intermolecular cycloaddition to afford 3-(etho

Full text of DOI:10.1055/s-2007-967939

658
LETTER
Intermolecular Cycloaddition of Ethyl Glyoxylate O-tert-Butyldimethyl-
silyloxime with Alkenes
Cycloaddition of
E
s
thyl
G
lyo
a
xylate
O
-te
m
rt-Butyldimethylsily
u
loxime
w
ith Alken
T
e
s
amura,*a Nobuyoshi Morita,a Yuu Takano,a Kenji Fukui,a Iwao Okamoto,a Xin Huang,b
Yoshiyuki Tsutsumi,b Hiroyuki Ishibashi*b
a
Showa Pharmaceutical University, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
Fax +81(42)7211579; E-mail: tamura@ac.shoyaku.ac.jp
b
Division of Pharmaceutical Sciences, Graduate School of National Science and Technology, Kanazawa University, Kanazawa 920-1192,
Japan
Fax +81(76)2344476; E-mail: isibasi@p.kanazawa-u.ac.jp
Received 16 November 2006
BF2
Abstract: Ethyl glyoxylate O-tert-butyldimethylsilyloxime, on
treatment with various alkenes in the presence of BF3·OEt2,
generated a C-ethoxycarbonyl N-boranonitrone intermediate, which
underwent intermolecular cycloaddition to afford 3-(ethoxy-
carbonyl)isoxazolidines in moderate to high yields.
N
TBSO
R1
BF3·OEt2
N
O
X
3
X
R1
R2
TBSF
R2
Key words: cycloaddition, boron trifluoride, N-boranonitrone,
alkenes, cycloadducts
4
5
Scheme 2
Intramolecular oxime-olefin cycloaddition, so-called
IOOC, appears to be one of the operationally simplest
cycloadditions. Thus, heating oximes 1 bearing an olefin
moiety in the molecule give N-unsubstituted isoxazo-
lidines 3 via tautomerization from 1 to NH-nitrone 2.1,2
However, the cycloaddition often requires very high tem-
perature conditions because of the thermodynamically
unfavorable tautomerization (Scheme 1).3 In addition, in-
termolecular oxime-olefin cycloaddition is known to be
restricted to reactions of only a few oximes with N-meth-
yl- or N-phenylmaleimides.4,5
We envisioned the extension of this procedure to the inter-
molecular counterpart, and have now found that exposure
of ethyl glyoxylate O-TBS oxime (12) to BF3·OEt2 in the
presence of various alkenes 7 resulted in the intermolecu-
lar cycloaddition to afford cycloadducts 14 in moderate to
good yields.7,8
Our investigation began with the simplest extension of
the intramolecular cycloaddition to intermolecular ver-
sion (Scheme 3). When benzaldehyde O-TBS oxime 6
was treated with styrene (7a; 10 equiv) in the presence
of BF3·OEt2 (2.2 equiv) in 1,2-dichloroethane (DCE) at
60 °C for 24 hours, intermolecular cycloaddition
proceeded, however, to give only 40% yield of cyclo-
adduct 9.9
H
H
N
H
N
N
O
R1
HO
R1
X
X
X
O
R1
H
R2
R2
R2
1
2
3
N
Ph
7a
Ph
TBSO
Scheme 1
BF3·OEt2, DCE
6
24 h, 60 °C
Recently, we reported BF3-mediated cycloaddition of
O-tert-butyldimethylsilyloximes (O-TBS oximes) as an
alternative method for the efficient synthesis of isoxazol-
idines 3. Treatment of oximes 4 with BF3·OEt2 generates
N-boranonitrones 5, which undergo intramolecular cyclo-
addition affording the products 3 after extractive workup
(Scheme 2).6 This procedure is highly useful for synthesis
of isoxazolidine derivatives because the reaction proceeds
smoothly at room temperature using the strong N–B and
Si–F affinity and is applicable to various substrates giving
the corresponding products in good to high yields.
H
N
BF2
Ph
O
+
N
Ph
–
O
9 (40%)
Ph
8
(single isomer)
Scheme 3
From the viewpoint of the electrophilic nature of N-bora-
nonitrone, replacement of the phenyl group in nitrone 8 by
an ester group was examined to activate the intermediary
N-boranonitrone.10 The requisite O-TBS oxime 12 was
readily prepared from chloral hydrate (10) which reacted
with hydroxyammonium sulfate in the presence of MgCl2
in ethanol solution to furnish glyoxylate oxime 1111
SYNLETT 2007, No. 4, pp 0658–0660
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967939; Art ID: U13606ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cycloaddition of Ethyl Glyoxylate O-tert-Butyldimethylsilyloxime with Alkenes
659
Table 1 Intermolecular Cycloaddition of O-TBS Oxime 12 with
Alkenes 7a–e in the Presence of BF3·OEt2
HO
CCl3
NH3OH·HSO3
a
N
CO2Et
HO
MgCl2, EtOH
OH
Entry Alkene 7
Time Product 14
Yield (%)
10
11
H
N
TBSCl
imidazole, DMF
N
CO2Et
CO2Et
TBSO
O
71
(5:1)
Ph
1
2 h
12
7a
Ph
Scheme 4
14a
H
N
(Scheme 4). Silylation of ethyl glyoxylate oxime (11)
afforded ethyl glyoxylate O-TBS oxime (12) in 86%
yield.12
CO2Et
O
78
(77:1)
n-Bu
2
18 h
7b
n-Bu
14b
The intermolecular cycloadditions of the starting O-TBS
oxime 12 with various alkenes 7 were carried out in the
presence of 2.2 equivalents of BF3·OEt2 in 1,2-dichloro-
ethane under argon at 60 °C (Scheme 5, Table 1). In con-
trast to the reaction of benzaldehyde oxime 6, reaction of
oxime 12 with styrene (7a) smoothly proceeded to give
the corresponding cycloadduct 14a in 71% yield, proba-
bly via nitrone 13 as active intermediate (entry 1).13 Reac-
tion of aliphatic terminal alkenes 7b and 7c also afforded
the cycloadducts 14b and 14c in 78% and 61% yields as
77:1 (14b) and 7:1 (14c) mixture of diastereomers,
respectively (entries 2 and 3). As expected, 1,1-disub-
stituted alkene 7d reacted with nitrone 13, giving rise to
5,5-disubstituted isoxazolidine 14d in low yield (entry 4).
This low yield may be due to polymerization of alkene 7d
during the reaction. Reaction of 1-methylcyclopentene
(7e) afforded bicyclic product 14e in 79% yields as 3.4:1
mixture of diastereomers (entry 5).
H
N
CO2Et
O
61
MeO
4
3
22 h
(7:1)
MeO
7c
4
14c
H
N
CO2Et
O
4
3 h
28
7d
14d
H
N
CO2Et
O
79
Me
H
5
2 h
(3.4:1)
7e
14e
alkene 7 (10 equiv)
a All reactions were carried out with BF3·OEt2 (2.2 equiv) in 1,2-
dichloroethane at 60 °C.
N
CO2Et
TBSO
BF3·OEt2 (2.2 equiv)
DCE
12
H
N
dichloroethane at 60 °C for 15 hours, cycloadduct 14f was
obtained in 53% yield as a 7:1 mixture of diastereomers.
This reaction would be applicable for syntheses of natu-
rally occurring 4-hydroxy-4-substituted glutamic acids.14
BF2
N
CO2Et
O
CO2Et
O
R2
R1
13
14
In conclusion, we have developed a novel intermolecular
cycloaddition of O-TBS oxime 12 with various alkenes 7
via N-boranonitrone 13 as active intermediate, giving the
corresponding isoxazolidines 14. To the best of our
knowledge, the present reaction is the first example of
intermolecular cycloaddition of oxime derivatives that
can react with various alkenes. Further work will be
devoted to the extension of the procedure to the other
functionalized oximes and alkenes, as well as to the appli-
cation of the procedure in natural product synthesis.
Scheme 5
The N-boranonitrone 13 was found to react with 2-substi-
tuted acrylate (Scheme 6). When oxime 12 was treated
with ethyl acrylate 7f in the presence of BF3·OEt2 in 1,2-
7f
EtO2C
H
N
CO2Et
N
CO2Et
O
BF3·OEt2 (2.2 equiv)
TBSO
Acknowledgment
DCE, 60 °C, 15 h
12
CO2Et
14f (53%, 7:1)
Financial support of this study by a Grant-in-Aid for Scientific
Research on Priority Area ‘Creation of Biologically Functional
Molecules’ from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan is gratefully acknowledged.
Scheme 6
Synlett 2007, No. 4, 658–660 © Thieme Stuttgart · New York

660
O. Tamura et al.
LETTER
TBSO
N
H
H
References and Notes
H
H
N
NTs
R2
BF3·OEt2
NTs
(1) For pioneering works, see: (a) Oppolzer, W.; Keller, K.
Tetrahedron Lett. 1970, 1117. (b) Wildman, W. C.;
Slabaugh, M. R. J. Org. Chem. 1971, 36, 3202.
+
Me
O
NTs
NH
R1
O
R1
15a: R1 = Me, R2 = H
15b: R1 = H, R2 = Me
(2) For recent examples, see: (a) Abiko, A.; Liu, J.-F.; Wang,
G.; Masamune, S. Tetrahedron Lett. 1997, 38, 3261.
(b) Baskaran, S.; Aurich, H. G. Synlett 1998, 277.
(c) Sharma, G. V. M.; Srinivas, R. I.; Goverdhan, R. V.;
Rama, R. A. V. Tetrahedron: Asymmetry 1999, 10, 229.
(d) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck,
A.; Gottlieb, H. E. J. Org. Chem. 1999, 64, 498.
(e) Dransfield, P. J.; Moutel, S.; Shipman, M.; Sik, V. J.
Chem. Soc., Perkin Trans. 1 1999, 3349. (f) Noguchi, M.;
Okada, H.; Tanaka, M.; Matsumoto, S.; Kakehi, A.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 917.
(g) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem.
Soc., Perkin Trans. 1 2001, 452. (h) Singh, S.; Ishar, M. P.
S.; Singh, G.; Singh, R. Can. J. Chem. 2005, 83, 260.
(3) For a theoretical study on oximenitrone isomerization, see:
Long, J. A.; Harris, N. J.; Lammertsma, K. J. Org. Chem.
2001, 66, 6762.
(4) (a) Grigg, R.; Thianpantagul, S. J. Chem. Soc., Perkin Trans.
1 1984, 653. (b) Shirai, M.; Kuwabara, H.; Matsumoto, S.;
Yamamoto, H.; Kakehi, A.; Noguchi, M. Tetrahedron 2003,
59, 4113.
(5) For related palladium-catalyzed cycloaddition of oximes,
see: Frederickson, M.; Grigg, R.; Thornton-Pett, M.;
Redpath, J. Tetrahedron Lett. 1997, 38, 7777.
16
17
Scheme 7
(11) Adachi, I.; Yamamori, T.; Hiramatsu, Y. Jpn. Patent, 50939,
1977.
(12) Preparation of Ethyl 2-[tert-Butyldimethylsilyl-
oxyimino]acetate (12): The mixture of ethyl 2-hydroxy-
iminoacetate (11;11 0.91 g, 7.8 mmol), tert-butylchloro-
dimethylsilane (1.77 g, 11.8 mmol), and imidazole (1.60 g,
23.5 mmol) in DMF (12 mL) was stirred at r.t. for 46 h. The
reaction mixture was poured into H2O and extracted with
Et2O. The combined organic phases were washed with brine
and dried with MgSO4. The solvent was removed by rotary
evaporation and the crude product was purified by column
chromatography on silica gel with hexane–Et2O (20:1) to
afford 12 (1.77 g, 98%) as a colorless oil. IR: 2934, 1749,
1728 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.62 (s, 1 H),
4.30 (q, J = 7.1 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H), 0.95 (s, 9
H), 0.23 (s, 6 H). 13C NMR (75 MHz, CDCl3): d = 162.3,
146.1, 61.3, 25.7, 18.0, 14.0, –5.4. LRMS: m/z = 231.14.
HRMS (EI): m/z calcd for C10H21NO3Si: 231.1291; found:
231.1270.
(6) (a) Tamura, O.; Mitsuya, T.; Ishibashi, H. Chem. Commun.
2002, 1128. (b) Tamura, O.; Mitsuya, T.; Huang, X.;
Tsutsumi, Y.; Hattori, S.; Ishibashi, H. J. Org. Chem. 2005,
70, 10720.
(7) For a review on related N-metalloazomethine ylides, see:
Husineca, S.; Savic, V. Tetrahedron: Asymmetry 2005, 16,
2047.
(13) Typical Procedure for the Cycloaddition: To a solution of
12 (300 mg, 1.3 mmol) in DCE (10 mL) were added 7e (1.1
mL, 13 mmol) and BF3·OEt2 (310 mL, 2.9 mmol) at r.t., and
then the mixture was heated at 60 °C for 2 h. The reaction
was monitored by TLC. After cooling, the reaction mixture
was poured into sat. NaHCO3 solution and was extracted
with CHCl3. The combined organic layers were washed with
brine and dried with MgSO4. The residue was concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel with hexane–EtOAc (3:2) to
give two diastereomers, 14e (160 mg, 61%) and 14e¢ (47 mg,
18%) as light brown oils. 14e: IR (neat): 1733 cm–1. 1H NMR
(300 MHz, CDCl3): d = 5.90 (br s, 1 H), 4.23 (q, J = 7.1 Hz,
2 H), 4.12 (d, J = 7.5 Hz, 1 H), 2.73 (dd, J = 7.0, 14.5 Hz, 1
H), 1.82–1.72 (m, 4 H), 1.59–1.45 (m, 2 H), 1.40 (s, 3 H),
1.29 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d =
164.4, 95.5, 66.0, 61.1, 55.7, 39.5, 28.2, 26.4, 24.8, 14.2.
LRMS: m/z = 199. HRMS (EI): m/z calcd for C10H17NO3:
199.1208; found: 199.1187. 14e¢: 1H NMR (300 MHz,
CDCl3): d = 5.93 (br s, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.56
(d, J = 6.6 Hz, 1 H), 2.49 (br s, 1 H), 1.92–1.65 (m, 6 H),
1.45–1.32 (m, 3 H), 1.29 (t, J = 7.1 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 171.3, 96.1, 70.2, 61.4, 59.5, 38.5, 32.2,
24.4, 23.5, 14.1.
(8) For related cycloaddition of acylhydrazones, see:
(a) Wilson, R. M.; Rekers, J. W. J. Am. Chem. Soc. 1979,
101, 4005. (b) Kobayashi, S.; Shimizu, H.; Yamashita, Y.;
Ishitani, H.; Kobayashi, J. J. Am. Chem. Soc. 2002, 124,
13678. (c) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.;
Ishitani, H.; Yamashita, Y. Tetrahedron Lett. 2003, 44,
3351. (d) Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc.
2004, 126, 11279. (e) Shirakawa, S.; Lombardi, P. J.;
Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974.
(9) For completion of the cycloaddition, 2 equiv of BF3·OEt2 are
essential. See ref. 6.
(10) During study on the intramolecular cycloaddition of N-
boranonitrone, we observed the tendency that electron-rich
carbon atom in the olefin attacks the nitrone-carbon. For
example, reaction of oxime 15a with BF3·OEt2 afforded
cycloadduct 16 bearing a bicyclo[3.3.0] system, whereas a
similar reaction of oxime 15b afforded cycloadduct 17
having a bicyclo[3.2.1] system (Scheme 7). See ref 6b.
(14) (a) Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653.
(b) Tamura, O.; Shiro, T.; Ogasawara, M.; Toyao, A.;
Ishibashi, H. J. Org. Chem. 2005, 70, 4569.
Synlett 2007, No. 4, 658–660 © Thieme Stuttgart · New York