Base-accelerated enantioselective substitution of morita-baylis-hillman carbonates with dialkyl phosphine oxides

Article abstract of DOI:10.1021/ol101601d

A base could accelerate the S_N2′ or S_N2′- S_N2′ reaction of Morita-Baylis-Hillman (MBH) carbonates with dialkyl phosphine oxides, but the judicial choice of an appropriate base would greatly depress this competitive S_N2′ reaction and allow for a highly enantioselective allylic substitution reaction with satisfactory yields and excellent enantioselectivities.

Full text of DOI:10.1021/ol101601d

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3914-3917
Base-Accelerated Enantioselective
Substitution of Morita-Baylis-Hillman
Carbonates with Dialkyl Phosphine
Oxides
Wangsheng Sun,† Liang Hong,† Chunxia Liu,† and Rui Wang*,†,‡
Key Laboratory of Preclinical Study for New Drugs of Gansu ProVince, State Key
Laboratory of Applied Organic Chemistry and Institute of Biochemistry and Molecular
Biology, Lanzhou UniVersity, Lanzhou 730000, China, and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity,
Kowloon, Hong Kong
wangrui@lzu.edu.cn
Received July 12, 2010
ABSTRACT
A base could accelerate the SN2′ or SN2′-SN2′ reaction of Morita-Baylis-Hillman (MBH) carbonates with dialkyl phosphine oxides, but the
judicial choice of an appropriate base would greatly depress this competitive SN2′ reaction and allow for a highly enantioselective allylic
substitution reaction with satisfactory yields and excellent enantioselectivities.
Chiral phosphorus compounds have been extensively em-
ployed in asymmetric metal-catalysis or organocatalysis.1
However, such compounds are expensive, and their prepara-
tions usually require a resolution or are limited to the use of
enantiopure starting materials.2 The synthesis of chiral
phosphine oxides through asymmetric catalysis is rare. Thus,
the development of more efficient catalytic methods for the
synthesis of optically active phosphine oxides is currently
of pressing importance.3 Previous studies in this area mainly
focused on the addition of reactive diaryl phosphine oxides to
various electrophiles4 or the use of phosphine oxide-containing
substrates in asymmetric addition5 to provide optically active
phosphine oxide compounds with high enantioselectivity.
(2) (a) Phosphorus Ligands in Asymmetric Catalysis: Synthesis and
Applications; Bo¨rner, A., Ed.; Wiley-VCH: Weinheim, Germany, 2008;
Vols. 1-3. (b) Pietrusiewicz, K. M.; Zablocka, M. Chem. ReV. 1994, 94,
1375. (c) Wiese, B.; Knu¨hl, G.; Flubacher, D.; Prieꢀ, J. W.; Ulriksen, B.;
Bro¨dner, K.; Helmchen, G. Eur. J. Org. Chem. 2005, 3246, and references
cited therein.
† Lanzhou University.
‡ The Hong Kong Polytechnic University.
(1) (a) ComprehensiVe Asymmetric Catalysis I-III, Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: New York, 1999. (b)
Asymmetric catalysis on industrial scale. Challenges, approaches, and
solutions; Blaser, H.-U., Schmidt, E., Eds.; Wiely-VCH: Weinheim,
Germany, 2004. (c) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (d)
Cre´py, K. V. L.; Imamoto, T. Top. Curr. Chem. 2003, 229, 1. Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (e) Methot, J. L.; Roush, W. R.
AdV. Synth. Catal. 2004, 346, 1035. (f) Benaglia, M.; Rossi, S. Org. Biomol.
Chem. DOI: 10.1039/c004681g . Published Online: June 21, 2010. (g)
Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org. Chem. 2006, 71, 6474.
(3) For reviews, see: (a) Glueck, D. S. Chem.sEur. J. 2008, 14, 7108.
(b) Glueck, D. S. Synlett 2007, 2627.
(4) (a) Feng, J.-J.; Chen, X.-F.; Shi, M.; Duan, W.-L J. Am. Chem. Soc.
2010, 132, 5562. (b) Fu, X.; Loh, W.-T.; Zhang, Y.; Chen, T.; Ma, T.; Liu,
H.; Wang, J.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 7387. (c) Leow,
D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed.
2008, 47, 5641. (d) Fu, X.; Jiang, Z.; Tan, C.-H. Chem. Commun. 2007,
5058. (e) Yamakoshi, K.; Harwood, S. J.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 1999, 40, 2565. (f) Albrecht, Ł.; Albrecht, A.; Krawczyk,
H.; Jørgensen, K. A. Chem.sEur. J. 2010, 16, 28.
10.1021/ol101601d  2010 American Chemical Society
Published on Web 08/03/2010

However, the use of less reactive dialkyl phosphine oxides as
P-nucleophiles is still a challenge and has been reported less.
Recently, another strategy, the substitution of Morita-
Baylis-Hillman (MBH) adducts with various nucleophiles, has
emerged as a very versatile approach to deliver multifunctional
allylic-substituted compounds.6 We envisaged that the asym-
metric substitution of MBH carbonates with dialkyl phosphine
oxides might be developed.
Phosphine oxides undergo an equilibrium in phosphine
oxide-phosphinite tautomerism in solution. The phosphinite
tautomer is thought to be the actual nucleophilic species in
the bond-forming step. However, under neutral conditions,
the equilibrium lies predominantly toward the left (Scheme
1).7 On the other hand, the higher pKa values of dialkyl
Herein, we describe that base could significantly accelerate
the organic Lewis base-catalyzed asymmetric substitution of
MBH carbonates with dialkyl phosphine oxides.
As part of our continuing interest in asymmetric phos-
phonylation,10 we recently reported the asymmetric allylic
substitution of MBH carbonates with diaryl phosphine
oxides.10a However, the reaction did not proceed when the
less reactive dialkyl phosphine oxides were employed. We
questioned whether inorganic bases, which have a relatively
weak basicity, would generate an active phosphinite tautomer
at an appropriate rate, thereby enhancing the substitution of
MBH carbonates with dialkyl phosphine oxides.
To test our hypothesis, our experiments began with the
addition of some inorganic bases to the catalytic system we
previously reported. In the control experiment, the reaction
did not occur without the addition of a base (Table 1, entry
Scheme 1. The Strategy for the Activation of Phosphine Oxides
Table 1. Optimization of the Reactiona
entry
Na2CO3
product
yieldb (%)
eec (%)
phosphine oxides relative to diaryl phosphine oxides makes
them less reactive in bond-forming.7c Thus, the activation
of dialkyl phosphine oxides is essential for achieving
sufficient reactivity. A simple strategy to address these issues
is the deprotonation of dialkyl phosphine oxides with an
appropriate base because the equilibrium could shift toward
the reactive phosphinite tautomer under basic conditions
(Scheme 1).8 However, because phosphine oxides should be
deprotonated by a base, the pKa difference between phos-
phine oxide and phosphinite could alter the degree of
asymmetric induction. Therefore, the basicity of the base
should be optimized, and the judicial choice of an appropriate
base seems to be of great importance.9
1
2
3
4
5
6
7
8e
none
NaOH
Na2CO3
Li2CO3
K2CO3
Cs2CO3
NaHCO3
Na2CO3
3a
4a
4a
4a
4a
4a
4a
78
81
73
77
<10
63
73
92
88
87
ndd
86
95
a Unless noted otherwise, all reactions were performed with 0.20 mmol
of 1a, 0.50 mmol of 2a, 0.30 mmol of base, and 0.04 mmol of quinidine in
1.0 mL of toluene at room temperature for 48 h. b Isolated yield.
c Determined by chiral HPLC on a Chiralpak AD column. d Not determined.
e The reaction was performed at 0 °C for 72 h.
(5) (a) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.; Hayashi, T. J. Am.
Chem. Soc. 2006, 128, 2556. (b) Kawamoto, T.; Hirabayashi, S.; Guo, X.-
X.; Nishimura, T.; Hayashi, T. Chem. Commun. 2009, 3528. (c) Nishimura,
T.; Guo, X.-X.; Hayashi, T. Chem. Asian J. 2008, 3, 1505.
1). The addition of sodium hydroxide led to the SN2′ product
3a as the main product (3a:4a ) 9:1) (Table 1, entry 2).
This was probably because the basicity is too strong, and a
direct SN2′ reaction occurred without the assistance of the
nucleophilic catalyst (Table 1, entry 2 and Scheme 2a).11
(6) For selected examples, see: (a) Cui, H.-L.; Feng, X.; Peng, J.; Lei,
J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737. (b) Jiang,
Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (c) Cui,
H.-L.; Peng, J.; Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C. Chem.sEur. J.
2009, 15, 1574. (d) Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed.
2004, 43, 6689. (e) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.; Spek,
A. L.; van Maarseveen, J. H.; Hiemstra, H. AdV. Synth. Catal. 2007, 349,
281. (f) Du, Y.; Han, X.; Lu, X. Tetrahedron Lett. 2004, 45, 4967. (g)
Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004, 6, 1337. (h) Jiang,
K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009, 3955. (i) Cui,
H.-L.; Huang, J.-R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C.
Org. Lett. 2010, 12, 720.
Scheme 2
. SN2′ Reaction (path a) vs SN2′-SN2′ Reaction (path
b) of MBH Carbonate 1a with Diethyl Phosphine Oxide 2a
(7) (a) Doak, G. O.; Freedman, L. D. Chem. ReV. 1961, 61, 31. (b) Pietro,
W. J.; Hehre, W. J. J. Am. Chem. Soc. 1982, 104, 3594. (c) Li, J.-N.; Liu,
L.; Fu, Y.; Guo, Q.-X. Tetrahedron 2006, 62, 4453.
(8) (a) Suyama, K.; Sakai, Y.; Matsumoto, K.; Saito, B.; Katsuki, T.
Angew. Chem., Int. Ed. 2010, 49, 797. (b) Uraguchi, D.; Ito, T.; Ooi, T.
J. Am. Chem. Soc. 2009, 131, 3836. (c) Nakamura, S.; Hayashi, M.;
Hiramatsu, Y.; Shibata, N.; Funahashi, Y.; Toru, T. J. Am. Chem. Soc. 2009,
131, 18240.
(9) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997,
36, 1236. (b) Shibasaki, M.; Iida, T.; Yamada, Y. M. A. J. Synth. Org.
Chem., Jpn. 1998, 56, 344.
Org. Lett., Vol. 12, No. 17, 2010
3915

Although the result was less than satisfactory, an interest-
ing finding was that diethyl phosphine oxide could be
activated by a base. At this stage, it was thought that an
appropriate base which could activate the dialkyl phosphine
oxides, and depress the SN2′ reaction would facilitate the
substitution reaction. We next tested some alkaline metal
carbonates. It was found that the addition of 1.5 equiv of
sodium carbonate significantly accelerated the asymmetric
substitution in moderate yield and good enantioselectivity
(Table 1, entry 3). Lithium carbonate and potassium carbon-
ate each increased the reaction, but showed lower enanti-
oselectivities (Table 1, entries 4 and 5). The addition of
cesium carbonate resulted in significantly diminished yield
due to the background reaction (Table 1, entry 6). Of the
base tested, sodium carbonate showed the most promising
result. Compared with our previous protocols, the addition
of 4 Å MS and the use of xylenes as the solvent had no
positive effect. By lowering the reaction temperature to 0
°C, the ee was improved to 95% (Table 1, entry 8).
Having established that the system quinidine12/Na2CO3 can
accelerate the substitution reaction, we next examined the
scope and limitation of the reaction (Table 2). Generally, a
wide range of MBH carbonates 1 and dialkylphosphine
oxides 2 were suitable for the reaction, affording allylic
phosphine oxides 4 in moderate yields and excellent enan-
tioselectivities. It appears that the position and electronic
properties of substituents on aromatic rings have a limited
effect on the efficiency of this process (Table 2, entries
1-10). Unfortunately, when 2-furyl-substituted MBH car-
bonate was used, only moderate ee was obtained (Table 2,
entry 11). For less reactive alkyl-substituted MBH carbon-
ates, the reaction showed much lower reactivity.13 Moreover,
the scope of the reaction can be successfully extended
utilizing other dialkyl phosphine oxides 2b-d, and high
enantioselectivities were generally achieved (Table 2, entries
12-14).
Table 2. Scope of the Reactiona
entry
1, R1
1a, Ph
1b, 2-FPh
1c, 2-ClPh
2, R2
product yieldb (%) eec (%)
1
2
3
2a, Et
2a, Et
2a, Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
73
66
63
61
80
87
75
78
76
83
48
81
63
92
95
91
95
90
94
95
92
96
95
96
71
90
98
90
4
5
6
1d, 2-MeOPh 2a, Et
1e, 3-ClPh 2a, Et
1f, 3-MeOPh 2a, Et
7
8
9
1g, 4-FPh
1h, 4-ClPh
1i, 4-BrPh
2a, Et
2a, Et
2a, Et
10
11
12
13
14
1j, 4-MeOPh 2a, Et
1k, 2-furyl
1a, Ph
2a, Et
2b, n-Pr
2c, n-Bu
2d, allylic
1a, Ph
1a, Ph
a All reactions were performed with 0.20 mmol of 1, 0.50 mmol of 2,
0.30 mmol of Na2CO3, and 0.04 mmol of quinidine in 1.0 mL of toluene
at 0 °C for 72 h. b Isolated yield. c For analysis of the ee values of the
products, see the Supporting Information.
Table 3. Control Experimentsa
entry
catalyst
base
yieldb (%)
eec (%)
1
2
3
4
5
none
Na2CO3
none
Na2CO3
Na2CO3
Na2CO3
quinidine
quinidine
cinchonine
QD-TMSd
81
78
21
92
88
nde
a All reactions were performed with 0.20 mmol of 1a, 0.50 mmol of
2a, 0.30 mmol of base, and 0.04 mmol of catalyst in 1.0 mL of toluene at
room temperature for 48 h. b Isolated yield. c Determined by chiral HPLC
on a Chiralpak AD column. d The hydroxyl group of quinidine was protected
by TMSCl. e Not determined.
To provide more insight into the mechanism, control
experiments were performed. As shown in Table 3, neither
quinidine nor Na2CO3 on its own was effective enough to
accelerate the substitution of MBH carbonate with diethyl
phosphine oxide (Table 3, entries 1 and 2). Only when these
two were used synergistically in a double-activation way
could this transformation perform excellently (Table 3, entry
3). These results showed that both the activation of diethyl
phosphine oxide and the assistance of the nucleophilic
catalyst were essential for the substitution reaction.14 Next,
we investigated the role of the C-6-OMe of quinidine, which
showed little effect on the reaction. When cinchonine was
used as the catalyst, similar result was observed (Table 3,
entry 3 vs 4). Furthermore, protection of C-9-OH of quinidine
gave a poor result (Table 3, entry 5). This result showed
that hydrogen bonding between the hydroxyl group and
sodium phosphinite plays a key role in the reaction.15 On
(10) (a) Hong, L.; Sun, W.; Liu, C.; Zhao, D.; Wang, R. Chem. Commun.
2010, 46, 2856. (b) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.;
Wang, R. Org. Lett. 2010, 12, 1880. (c) Zhao, D.; Yuan, Y.; Chan, A. S. C.;
Wang, R. Chem.sEur. J. 2009, 15, 2738. (d) Zhao, D.; Wang, Y.; Mao,
L.; Wang, R. Chem.sEur. J. 2009, 15, 10983.
(11) For selected examples of base-catalyzed SN2′ reaction, see: (a)
Reddy, L. R.; Hu, B.; Prashad, M.; Prasad, K. Angew. Chem., Int. Ed. 2009,
48, 172. (b) Im, Y. J.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2002, 43, 4675. (c) Kim, J. N.; Chung, Y. M.; Im, Y. J. Tetrahedron Lett.
2002, 43, 6209. (d) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim, H. S.
Tetrahedron Lett. 2001, 42, 3737.
(14) For the mechanism of substitution reaction of MBH carbonates
catalyzed by a nucleophilic catalyst, see: Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811, and ref 6.
(15) For selected examples of Cinchona alkaloids as bifunctional
catalysts, see: (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (b) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2005, 127, 8948. (c) Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006,
8, 1391. (d) Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.;
Wang, W. AdV. Synth. Catal. 2007, 349, 1052. (e) Bartoli, G.; Bosco, M.;
Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.;
Melchiorre, P. Angew. Chem. Int. Ed. 2006, 45, 4966. (f) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
(12) For a review on modified Cinchona alkaloids, see: Tian, S.-K.;
Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621.
(13) The same phenomenon was observed in other allylic nucleophilic
substitution of alkyl-substituted MBH carbonates, see refs 6a, c, h and
10a.
3916
Org. Lett., Vol. 12, No. 17, 2010

the basis of all these observations, we proposed a tentative
transition state for the substitution of MBH carbonate with
diethyl phosphine oxide using the system quinidine/Na2CO3
(Figure 1).
direct access to optically allylic phosphine oxides with
satisfactory yields and excellent enantioselectivities. Al-
though the competitive SN2′ reaction would occur under basic
conditions, the judicial choice of an appropriate base would
greatly depress this competitive reaction and allow for a
highly enantioselective allylic substitution reaction. In this
catalytic system, the less reactive dialkyl phosphine oxides
can be activated by Na2CO3 because the equilibrium could
shift toward the reactive phosphinite tautomer under such
conditions. Further applications of the current methodology
are ongoing in our laboratory.
Acknowledgment. We gratefully acknowledge financial
support from NSFC (20932003, 90813012) and the National
S&T Major Project of China (2009ZX09503-017).
Figure 1. Proposed transition state.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have found that a base could significantly
accelerate the enantioselective allylic substitution of MBH
carbonates with dialkylphosphine oxides, which provides
OL101601D
Org. Lett., Vol. 12, No. 17, 2010
3917