Diastereoselective Baylis-Hillman reaction using N-glyoxyloyl camphorpyrazolidinone as an electrophile: Synthesis of optically pure 2-hydroxy-3-methylene succinic acid derivative

Article abstract of DOI:10.1016/j.tetlet.2004.02.001

The camphorpyrazolidinone derived N-glyoxylate was efficiently prepared and used as an electrophile in the Baylis-Hillman reaction under classical DABCO catalyzed conditions. The corresponding 2-hydroxy-3-methylene succinic acid derivative was generally obtained with excellent diastereoselectivity and moderate chemical yields (51-75%).

Full text of DOI:10.1016/j.tetlet.2004.02.001

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2541–2543
Diastereoselective Baylis–Hillman reaction using N-glyoxyloyl
camphorpyrazolidinone as an electrophile: synthesis of optically
pure 2-hydroxy-3-methylene succinic acid derivative
Jia-Fu Pan and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, 116, Taiwan, ROC
Received 24 December 2003; revised 30 January 2004; accepted 2 February 2004
Abstract—The camphorpyrazolidinone derived N-glyoxylate was efficiently prepared and used as an electrophile in the Baylis–
Hillman reaction under classical DABCO catalyzed conditions. The corresponding 2-hydroxy-3-methylene succinic acid derivative
was generally obtained with excellent diastereoselectivity and moderate chemical yields (51–75%).
ꢀ 2004 Elsevier Ltd. All rights reserved.
Increasing attention has been focused on the coupling of
an aldehdyde with a,b-unsaturated carbonyls/nitriles in
the presence of a tertiary amine (Baylis–Hillman reac-
tion).1 The corresponding (a-methylene-b-hydroxy)car-
bonyl derivatives represent versatile intermediates in
organic chemistry.2 The asymmetric Baylis–Hillman
reaction has been studied extensively by several research
groups to achieve a wide range of stereoselectivities.3
The aza version of the Baylis–Hillman reaction using
aldimine derivatives instead of an aldehyde to generate
(a-methylene-b-amino)carbonyls has previously been
reported.4 Bauer and Tarasiuk reported on the use of
())-8-phenylmenthyl glyoxylate as an electrophile in the
Baylis–Hillman reaction using dimethyl sulfide in the
presence of titanium tetrachloride, which gave the cor-
responding adducts in high diastereoselectivity.5 How-
ever this reaction is limited to the use of a,b-unsaturated
cycloketones. The Baylis–Hillman reaction is notorious
for its extremely poor reaction rate, which requires long
reaction times to achieve synthetically useful yields of
the desired products. Numerous attempts have been
made to increase the rate of the reaction.6 In this con-
text, we wish to report a rapid and general protocol for
the formation of 2-hydroxy-3-methylene succinic acid
derivatives using N-glyoxyloyl camphorpyrazolidinone
(2) as a chiral electrophile in the Baylis–Hillman reac-
tion under classical DABCO catalyzed conditions. In
addition, excellent stereoselectivity was obtained when
the Baylis–Hillman adduct (4c) was treated with N-
aminophthalimide in the presence of lead tetraacetate.
The starting camphorpyrazolidinone (1) was designed
and synthesized in this laboratory and has proved to be
an efficient chiral auxiliary in asymmetric synthesis.3g;7
The synthesis of N-glyoxyloyl camphorpyrazolidinone
(2) is problematic at beginning, many synthetic routes
have been examined (e.g., ozonolysis of the camp-
horpyrazolidinone derived acrylate, the direct coupling
of camphorpyrazolidinone with glyoxylic acid and its
derivatives, the reduction of the camphorpyrazolidinone
derived a-carbonyl ester and etc.) and none have been
found to give the desired glyoxylate in a reasonable
material yield. Optimum conditions for this reaction are
finally defined.8 Treatment of camphorpyrazolidinone
with oxalyl chloride (10 equiv) in CH2Cl2 gave the
monoacylated product, which was reduced with Bu3SnH
(1.0 equiv) in benzene at room temperature for 10 min,
affording 2 in 84% overall yield (Scheme 1).
With theN-glyoxyloyl camphorpyrazolidinone in hand
we then turned our attention to the Baylis–Hillman
Me
Me
NH
Me
Me
1. Oxalyl chloride, CH2Cl2
2. Bu3SnH, PhH, rt
H
N
O
(84%)
O
O
N
Ph
N
Ph
O
Keywords: Diasteroselective Baylis–Hillman.
* Corresponding author. Tel.: +886-2-89315831; fax: +886-2-293242-
49; e-mail: kchen@scc.ntnu.edu.tw
1
2
Scheme 1. The synthesis of N-glyoxyloyl camphorpyrazolidinone (2).
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.001

2542
J.-F. Pan, K. Chen / Tetrahedron Letters 45 (2004) 2541–2543
reaction. The reaction of a-naphthyl acrylate with N-
glyoxyloyl camphorpyrazolidinone in CH3CN in the
presence of DABCO (0.3 equiv) for 2 h gave the desired
Baylis–Hillman product in 30% yield (entry 1). A survey
of various solvents was undertaken in an attempt to
increase the efficiency of the reaction. To this end, the
use of CH2Cl2 and benzene resulted in low material
yields while the use of MeOH further decreased the
reactivity (entries 2–4). The reaction rate could, how-
ever, be improved when a polar aprotic solvent was
employed (entry 6). Thus, treatment of 2 with a-naph-
thyl acrylate in DMSO affords the desired product in a
51% material yield in a 10 min reaction. The chemical
yield was further improved to 65% yield when DMSO/
H2O 10:1 was used (entry 7). In this homogeneous
DMSO/H2O medium, although the reactivity is lower,
side reactions that complicate product purification are
minimized. The diastereoselectivity was determined to
be in excess of 90% de based on 1H NMR analysis of the
relevant peaks. The absolute stereochemistry of the
newly generated stereogenic center was determined to
have an S configuration by single crystal X-ray analysis
of one of the analogous adducts (4e) (Table 1).
the Michael acceptors effect efficiency, while a relative
slow reaction rate was observed when acrylonitrile was
used (entries 12–14). The observed enhanced reaction
rate of the present system can be attributed to the
greater electrophilicity of the N-glyoxylate toward the
addition of ammonium enolate.
The stereochemical bias of the present study can be
rationalized by the conformational preference of the
glyoxylate moiety in the transition state. Similar to N-
glyoxyloyl-(2R)-bornane-10,2-sultam, the CO/CHO s-cis
planar conformation (A) in 2 is electronically favored
over its s-trans conformer (A0) with the carbonyl group
oriented toward the phenyl moiety.9 A series of confor-
mational analyses of the camphorpyrazolidinone derived
a,b-unsaturated amides indicate that for a-unsubstituted
N-enones the planar, s-cis arrangement dominate while
the nonplanar s-trans-like conformation is energetically
favored for a-substituent and a,b-disubstituents in the
solid state conformation. These are confirmed by single
crystal X-ray analyses of various N-enoylcamphorpyr-
azolidinones. The N-glyoxyloyl camphorpyrazolidinone
(2) is believed to be in analogy to its counter a-unsub-
stituted N-enones.10 The initially formed aza enolate
then attacks the formyl group from the less hindered
bottom si face with the subsequent elimination of
DABCO to afford the desired adduct (Fig. 1).
To further determine the feasibility of the system, a
range of Michael acceptors were tested under the opti-
mum reaction conditions. The use of b-naphthyl acryl-
ate affords the adduct with high diastereoselectivity in
30 min (entry 8). The use of phenyl acrylate and benzyl
acrylate to provide comparable results (entries 9 and
10). The reactivity decreased when methyl acrylate was
used (entry 11). The use of a,b-unsaturated ketones as
The structural array of the corresponding 2-hydroxy-3-
methylene succinic acid derivative 4 can be further
transformed to synthetic useful intermediates. An initial
investigation involved the reaction of 4c with N-amino-
Table 1. Reaction of N-glyoxyloyl camphorpyrazolidinone (2) with various a,b-unsaturated carbonyls (3a–g) and acrylonitrilea
Me
Me
Me
Me
O
OH O
H
DABCO, solvent
N
N
R
+
R
O
O
O
N
Ph
O
N
Ph
O
3a-g
4a-h
2
Entry
R
Solvent
t (min)
Product
Yield (%)b
Drc
Absolute configurationd
1
–O-a-Naphthyl
–O-a-Naphthyl
–O-a-Naphthyl
–O-a-Naphthyl
–O-a-Naphthyl
–O-a-Naphthyl
–O-a-Naphthyl
–O-b-Naphthyl
–OPh
CH3CN
CH2Cl2
C6H6
2 h
24 h
24 h
2 d
24 h
10
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
30
<10
<10
<10
35
Nde
2
Nde
3
Nde
Nde
4
MeOH
THF
5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
S
S
S
S
S
S
S
S
S
S
6
DMSO
51
65
7
DMSO/H2Of
DMSO/H2Of
DMSO/H2Of
DMSO/H2Of
DMSO/H2Of
DMSO/H2Of
DMSO/H2Of
DMSOg
30
30
8
67
70
9
60
30
10
11
12
13
14
–OBn
–OMe
66
61
6 h
20
–CH3
–CH2CH3
Acrylonitrile
71
75
20
60
4g
4h
54
a All reactions were carried out using 2 (0.32 mmol), activated alkene (1.3 equiv), DABCO (0.3 equiv) in the solvent indicated.
b Isolated yield. An unidentified material (<10%) was generally isolated with the substrates investigated.
c Determined by 1H NMR analysis of the relevant peaks from the crude products.
d The absolute stereochemistry of the newly generated stereogenic center was determined to have an S configuration by single crystal X-ray analysis
of 4e. The absolute stereochemistry of 4c was further confirmed from compound 5 while the rest of the adducts are assigned by analogy.
e Not determined.
f 10:1.
g Slow reaction rate was observed when DMSO/H2O 10:1 was used.

J.-F. Pan, K. Chen / Tetrahedron Letters 45 (2004) 2541–2543
2543
2. (a) Martinez, I.; Andrews, A. E.; Emch, J. D.; Ndakala, A.
J.; Wang, J.; Howell, A. R. Org. Lett. 2003, 5, 399; (b)
Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S.
Chem. Commun. 2001, 2030; (c) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42,
7867.
Me
Me
Me
Me
H
O
N
N
O
H
O
O
N
Ph
N
Ph
O
O
O
A
R3N
OR
A'
3. For enantioselective Baylis–Hillman reaction, see: (a)
Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett.
2003, 5, 3741; (b) Yang, K. S.; Lee, W.-S.; Pan, J.-F.;
Chen, K. J. Org. Chem. 2003, 68, 915; (c) Iwabuchi, Y.;
Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219; (d) Barrett, A. G. M.; Cook,
A. S.; Kamimura, A. Chem. Commun. 1998, 2533; (e)
Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem.
Commun. 1998, 1271; (f) For diastereoselective Baylis–
Hillman reaction, see: Krishna, P. R.; Ilangovan, A.;
Sharma, G. V. M. Tetrahedron: Asymmetry 2001, 12, 829;
(g) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729; (h)
Evans, M. D.; Kaye, P. T. Synth. Commun. 1999, 29, 2137;
(i) Basavaiah, D.; Gowriswari, V. V. L.; Sarma, P. K. S.;
Rao, P. D. Tetrahedron Lett. 1990, 31, 1621.
Figure 1. Proposed mechanism of the Baylis–Hillman reaction.
Me
Me
Me
Me
H2NNPth
Pb(OAc)4
OH O
OH O
N
N
OPh
OPh
NPth
O
(81%)
O
N
Ph
N
Ph
O
O
4c
5 (>95% de)
Scheme 2. Further functional group transformation of the Baylis–
Hillman adduct 4c.
4. (a) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2003, 5, 3103; (b) Shi, M.; Xu,
Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4503; (c) Shi, M.;
Xu, Y.-M. Eur. J. Org. Chem. 2002, 696; (d) Shi, M.; Xu,
Y.-M.; Zhao, G.-L.; Wu, X.-F. Eur. J. Org. Chem. 2002,
3666; (e) Aggarwal, V. K.; Castro, A. M. M.; Mereu, A.;
Adams, H. Tetrahedron Lett. 2002, 43, 1577; (f) Shi, M.;
Xu, Y.-M. Chem. Commun. 2001, 1876; (g) Balan, D.;
Adolfsson, H. J. Org. Chem. 2001, 66, 6498; (h) Richter,
H.; Jung, G. Tetrahedron Lett. 1998, 39, 2729.
phthalimide in the presence of lead tetraacetate, which
provides the corresponding N-phthalimidoaziridine (5)
in excellent diastereoselectivity. The structure of 5 was
initially assigned by 1H, 13C NMR, and HRMS analyses
and further confirmed by single crystal X-ray analysis
(Scheme 2).
In summary, the Baylis–Hillman reaction of N-glyo-
xyloyl camphorpyrazolidinone (2) with various a,b-
unsaturated carbonyls/nitrile proceeds smoothly to give
the corresponding 2-hydroxy-3-methylene succinic acid
derivative 4 in excellent diastereoselectivity. A pre-
liminary investigation of the 2-hydroxy-3-methylene
succinic acid derivative using 4c has demonstrated its
potential as a synthetic scaffold. A multifunctional array
of 2-hydroxy-3-methylene succinic acid derivatives can
be used for the construction of complex molecular
structures. This extends the synthetic application to the
versatile and general utility of chiral auxiliary 1. Further
applications of 5 and its derivatives are currently
underway.
5. Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12,
1741.
6. (a) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002,
4, 4723; (b) Aggarwal, V. K.; Dean, D. K.; Mereu, A.;
Williams, R. J. Org. Chem. 2002, 67, 510; (c) Lee, W.-D.;
Yang, K.-S.; Chen, K. Chem. Commun. 2001, 1612.
7. (a) Fang, C. L.; Lee, W.-D.; Teng, N. W.; Sun, Y.-C.;
Chen, K. J. Org. Chem. 2003, 68, 9816; (b) Fang, C. L.;
Lee; Reddy, G. S.; Chen, K. J. Chin. Chem. Soc. 2003, 50,
1047; (c) Yang, K. S.; Chen, K. J. Org. Chem. 2001, 66,
1676; (d) Yang, K. S.; Lain, J. C.; Lin, C. H.; Chen, K.
Tetrahedron Lett. 2000, 41, 1453; (e) Lin, C. H.; Yang, K.
S.; Pan, J. F.; Chen, K. Tetrahedron Lett. 2000, 41, 6815.
8. Typical procedure for the preparation of N-glyoxyloyl
camphorpyrazolidinone (2): To a solution of oxalyl chlo-
ride (10.0 mL, 117 mmol) in CH2Cl2 (50 mL) was added a
solution of camphorpyrazolidinone (1) (3.0 g, 11.7 mmol)
in CH2Cl2 dropwise at room temperature. The excess of
oxalyl chloride was removed in vacuo after stirring for
10 min and the residue was dried under high vacuum. The
residue was dissolved in benzene (20 mL) and Bu3SnH
(3.15 g, 11.7 mmol) was added dropwise at room temper-
ature. The reaction mixture was quenched with aqueous
NaHCO3 (200 mL) and extracted with CH2Cl2 (50 mL · 3).
The organic layers were combined and washed (brine),
dried (MgSO4), filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatogra-
phy on silica gel, using hexanes/ethyl acetate 2:1 to give
N-glyoxyloyl camphorpyrazolidinone (3.07 g, 84%).
9. (a) Bauer, T.; Chapuis, C.; Jezewski, A.; Kozak, J.;
Jurczak, J. Tetrahedron: Asymmetry 1996, 7, 1391; (b)
Bauer, T.; Chapuis, C.; Kozak, J.; Jurczak, J. Helv. Chim.
Acta 1989, 72, 482; (c) Jurczak, J.; Tkacz, M. J. Org.
Chem. 1979, 44, 3347.
Acknowledgements
This work is supported by the National Science Council
of the Republic of China (NSC 92-2113-M-003-017 and
NSC 92-2751-B-001-014-Y) and the National Taiwan
Normal University (ORD 91-2). The X-ray crystal data
are collected and processed by Taipei Instrumentation
Center, College of Science, National Taiwan University,
and National Taiwan Normal University are gratefully
acknowledged.
References and notes
1. For reviews of the Baylis–Hillman reaction, see: (a)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811; (b) Langer, P. Angew. Chem., Int. Ed.
2000, 39, 3049; (c) Ciganek, E. Org. React. 1997, 51, 201;
(d) Basavaiah, D.; Rao, D. P.; Hyma, R. S. Tetrahedron
1996, 52, 8001; (e) Drewes, S. E.; Roos, G. H. P.
Tetrahedron 1988, 44, 4653.
10. However, for camphorpyrazolidinone derived glyoxylic
oxime ether the s-trans conformation favored in the solid
state as indicated by single crystal X-ray analysis. Chen,
K. Unpublished results.