Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts

Article abstract of DOI:10.1016/j.tetlet.2011.01.054

Highly asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by chiral primary amine thiourea bifunctional catalysts was developed and a series of Michael adducts were obtained in excellent yields (up to 97%) and enantioselectivities (up to 95% ee). Optically pure S-warfarin was easily obtained in 99% ee after single recrystallization.

Full text of DOI:10.1016/j.tetlet.2011.01.054

Tetrahedron Letters 52 (2011) 1566–1568
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly effective and enantioselective Michael addition of 4-hydroxycoumarin
to a,b-unsaturated ketones promoted by simple chiral primary amine
thiourea bifunctional catalysts
Ren-Qiang Mei a,b, Xiao-Ying Xu a, Yan-Chun Li a,b, Ji-Ya Fu a,b, Qing-Chun Huang a, Li-Xin Wang a,
⇑
a Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly asymmetric Michael addition of 4-hydroxycoumarin to a,b-unsaturated ketones promoted by chi-
Received 9 November 2010
Revised 21 December 2010
Accepted 14 January 2011
Available online 20 January 2011
ral primary amine thiourea bifunctional catalysts was developed and a series of Michael adducts were
obtained in excellent yields (up to 97%) and enantioselectivities (up to 95% ee). Optically pure S-warfarin
was easily obtained in 99% ee after single recrystallization.
Ó 2011 Elsevier Ltd. All rights reserved.
The asymmetric Michael addition was considered as one of the
most powerful and efficient methods for C–C bond formation in or-
ganic synthesis.1 Particularly, the addition of 4-hydroxycoumarin
on this background, we envisioned that the primary amine thio-
urea catalysts (1a–h; Fig. 1), which can be easily prepared from
cheaply and commercially available chiral diamines, could activate
to
a
,b-unsaturated ketones is a straightforward method to access
the a,b-unsaturated ketones via an imine or enamine intermediate
S-warfarin 4a which is an effective and relatively safe agent for
preventing thrombosis and embolism and its anticoagulant activity
is 5–8 times higher than that of R-enantiomer.2 In 2003, Jørgensen
reported the first example of enantioselective Michael reaction of
and 4-Hydroxycoumarin via H-bonding pathway as a double and
synergetic catalysis. As part of our continuing interests in asym-
metric synthesis6 and pharmaceutical preparations,7 herein we
wish to report the enantioselective conjugate addition of 4-
cyclic 1,3-dicarbonyl compounds to
a,b-unsaturated ketones cata-
hydroxycoumarin to a,b-unsaturated ketones catalyzed by this
lyzed by imidazolindine in good enantioselectivities (up to 85%
ee).3a Chin demonstrated that chiral diamine using acetic acid as
co-catalyst could afford similar or better results (up to 92% ee)
compared with imidazolindine3b catalyst. Chen reported the high-
est enantioselectivity (99% ee) of S-warfarin and related analogues
for the same addition catalyzed by 9-amino-9-deoxyepiquinine at
0 °C for four days.3c Recently, Feng developed a new type of C2-
symmetric secondary amine amide catalysts and good (up to 89%
ee) enantioselectivies were obtained.3d Although several efficient
methods have been achieved by these systems,3 the highly efficient
protocols of asymmetric Michael addition of 4-hydroxycoumarin
kind of bifunctional catalysts to give S-warfarin and its analogues
in high yields (up to 97%) and enantioselectivities (up to 95% ee)
under mild conditions.
Initially, the reaction of 4-hydroxycoumarin (2) with benzyli-
deneacetone (3a) was used as a model reaction and a series of chi-
ral primary amine thiourea catalysts (1a–h; Fig. 1) were
investigated at room temperature in CH2Cl2, and the results are
summarized in Table 1. All catalysts gave moderate to good yields
(49–92%) and enantioselectivitites (48–92% ee). Relatively, cata-
lysts with 1,2-diphenylethane-1,2-diamine moiety (1c–h) gave
higher ee values (75–92% ee, Table 1, entries 3–8) than those with
diaminocyclohexane moiety (48% ee and 61% ee, Table 1, entries 1
and 2). Catalyst 1h, giving the highest enantioselectivity and good
yield (Table 1, entry 8, 92% ee, 87% yield), was selected for further
optimizations.
to
a,b-unsaturated ketones for the preparation of S-warfarin and
its analogues are still commercially needed. It is still desirable
and challenging to develop simple, cheap, and commercially avail-
able and effective catalytic systems for this conversion.
In the past few years, bifunctional chiral thiourea catalysts have
been proven to be effective in asymmetric Michael addition.4
Among them, chiral primary amine thiourea catalysts were consid-
ered as powerful tools in many asymmetric procedures for the
simultaneous activation of donors and acceptors and have been
extensively investigated in asymmetric Michael additions.5 Based
NH2
NH2
Ph
S
S
R
R
Ph
N
H
N
H
N
N
H
H
1c R = Ph
1f R = n-Bu
1g R = 1-adamantyl
1h R = Bn
1a R = 3,5-(CF3)2C6H3
1b R = 1-adamantyl
1d R = cyclohexyl
1e R = 3,5-(CF3)2C6H3
⇑
Corresponding author.
E-mail address: wlxioc@cioc.ac.cn (L.-X. Wang).
Figure 1. Primary amine thiourea catalysts.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.054

R.-Q. Mei et al. / Tetrahedron Letters 52 (2011) 1566–1568
1567
Table 1
Table 3
The screening of chiral bifunctional catalysts 1a–ha
Asymmetric Michael Addition of 4-hydroxycoumarin 2 to
a
,b-unsaturated ketones
3aa
OH
O
OH Ph
*
O
OH
OH R1
*
O
O
Cat. 20 mol %
+
1h, 20 mol %
R2
+
R1
R2
O
O
DCM, 25ºC, 55 h,
O
O
1,4-dioxane, 25ºC,55 h
O
2
O
O
O
2
3a
4a
3
4
Entry
Catalyst
Yieldb (%)
eec (%)
Entry
R1
Ph
3-FC6H4
4-FC6H4
R2 (3)
4
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
49
84
89
91
84
89
92
87
48 (R)d
61 (R)
86 (S)
88 (S)
89 (S)
75 (S)
89 (S)
92 (S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me (3a)
Me (3b)
Me (3c)
Me (3d)
Me (3e)
Me (3f)
Me (3g)
Me (3h)
Me (3i)
Me (3j)
Me (3k)
Me (3l)
Me (3m)
Me (3n)
Et (3o)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
97
92
89
95
92
93
89
96
87
80
90
87
88
83
96
95 (>99%)d
91
91
88
92
93
89
91
93
90
92
88
86
89
88
2-ClC6H4
4-ClC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
2-Furanyl
2-Thienyl
1-Naphthyl
Ph
1g
1h
a
Unless noted otherwise, the reactions were carried out with 2 (0.20 mmol) and
3a (0.24 mmol) in the presence of the catalyst (20 mol %) in CH2Cl2 (1.5 mL) at 25 °C
for 55 h.
b
Isolated yield.
Determined by chiral HPLC.
The absolute configuration was determined by comparing with the literature
c
d
(Ref. 8).
a
The reaction mixture of 2 (0.20 mmol) with 3 (0.24 mmol), 1h (0.04 mmol) in
1.5 mL 1,4-dioxane at 25 °C for 55 h.
b
To further improve the enantioselectivity, a series of solvents
and additives were investigated and the results were listed in Ta-
ble 2. The results indicated that solvents have remarkable effects
on the yields and enantioselectivities (Table 2, entries 1–12). Apro-
tic solvents, such as CH2Cl2, CHCl3, toluene and 1,4-dioxane gave
good to excellent enantioselectivities and moderate to excellent
yields (79–95% ee, 31–97% yield, Table 2, entries 1–9), whereas
protic solvents, such as CH3OH and t-BuOH gave moderate enanti-
oselectivities (50% ee and 18% ee, Table 2, entries 10 and 12).
Remarkably, when 1,4-dioxane was used, the highest yield (97%)
and enantioselectivity (95% ee, Table 2, entry 8) were observed.
The effects of additives were also investigated and are summarized
in Table 2 (Table 2, entries 13–17). TFA has a significantly negative
effect on the yield (29%, Table 2, entry 13), contrary to the reported
Isolated yield.
Determined by chiral HPLC analysis.
After single recrystallization from EtOH.
c
d
results.3c Organic bases, such as DMAP and Et3N, were also used
and the same negative effects on the enantioselectivities of warfa-
rin were observed.
Those screenings showed that 20 mol % of catalyst 1h,
0.20 mmol of 4-hydroxycoumarin (2), 0.24 mmol of benzylidene-
acetone (3a) in 1.5 mL of 1,4-dioxane at 25 °C for 55 h may give
the best results in both yield and enantioselectivity and were se-
lected as the optimal parameters for further study.
Under the optimized reaction conditions, a wide range of
a,b-
unsaturated ketones were investigated and the results are shown
in Table 3. All the additions were performed smoothly to afford Mi-
chael adducts in excellent yields (up to 97%) and good to excellent
enantioselectivities (88–93% ee). Naphthyl
a,b-unsaturated ke-
Table 2
The screenings of solvents and additivesa
tones, as well as aromatic ,b-unsaturated ketones with electron-
a
withdrawing or electron-donating substituents afforded high
enantioselectivities (88–95% ee) and yields (80–97%), and substit-
uents on para- (Table 3, entries 3, 5, 6, 8, 10, 11), meta- (Table 3,
entries 2 and 7) or ortho- position (Table 3, entries 4 and 9) in
the aromatic ring slightly affected the yields and enantioselectivi-
OH
O
OH Ph
*
O
1h. 20 mol %
+
O
O
25ºC, 55 h
O
O
2
3a
4a
Yieldb (%)
eec (%)
ties. Heteroaromatic a,b-unsaturated ketones and bulkier alkyl en-
Entry
Solvent
Additive (mol %)
one also gave satisfactory yields and enantioselectivities (Table 3,
entries 12, 13 and 15).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Toluene
ClCH2CH2Cl
CH2Cl2
CHCl3
Et2O
EtOAc
THF
1,4-Dioxane
Acetonitrile
t-Butyl alcohol
DMF
—
—
—
—
—
—
—
—
—
—
—
—
68
81
87
69
76
84
63
97
31
25
31
76
29
94
92
90
95
92
86
92
87
87
90
90
95
79
18
18
50
90
91
80
89
92
Notably, the enantiomeric excess value of (S)-warfarin can be
enhanced from 95% to 99% by simple and single recrystallization
in ethanol, thus rendering this method potentially useful for indus-
trial applications.
In conclusion, a series of simple chiral primary amine thiourea
catalysts, easily prepared from cheaply and commercially available
chiral diamines, were successfully applied to catalyze the Michael
reaction of 4-hydroxycoumarins with
a,b-unsaturated ketones in
MeOH
excellent enantioselectivities (up to 95% ee) and yields (up to
97%). Optically pure S-warfarin was obtained in 99% ee after a sim-
ple and single recrystallization in alcohol, which provides a possi-
ble approach for the commercial production of S-warfarin.
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
TFA (40)
DMAP (20)
Et3N (40)
Et3N (20)
Et3N (10)
a
Unless noted otherwise, the reactions were carried out with 2 (0.20 mmol) and
Supplementary data
3a (0.24 mmol) in the presence of catalyst 1h (20 mol %) in solvent (1.5 mL) for
55 h.
b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.054.
Isolated yield.
c
Determined by HPLC analysis.

1568
R.-Q. Mei et al. / Tetrahedron Letters 52 (2011) 1566–1568
Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2010,
References and notes
352, 827–832; (o) Chen, J.-R.; Cao, Y.-J.; Zou, Y.-Q.; Tan, F.; Fu, L.; Zhu, X.-Y.; Xiao,
W.-J. Org. Biomol. Chem. 2010, 8, 1275–1279.
1. For an overview of asymmetric Michael additions: (a) Christoffers, J. Eur. J. Org.
Chem. 1998, 7, 1259–1266; (b) Sibi, M.; Manyem, P. S. Tetrahedron 2000, 56,
8033–8061; (c) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171–196; (d)
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–1894; (e)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–1690; (f) Notz, W.
F.; Tanaka, C. F.; Barbas, III. Acc. Chem. Res. 2004, 37, 580–591; (g) Ballini, R.;
Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933–972; (h)
Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633–639; (i) Almasi, D.; Alonso, D. A.;
Najera, C. Tetrahedron: Asymmetry 2007, 18, 299–365; (j) Vicario, J. L.; Badia, D.;
Carrillo, L. Synthesis 2007, 2065–2092; (k) Sulzer-Mossé, S.; Alexakis, A. Chem.
Commun. 2007, 3123–3135; (l) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–
1716; (m) Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2008, 37, 1218–1228; (n) Liu, P.-
M.; Chang, C.; Reddy, R. J.; Ting, Y.-F.; Kuan, H.-H.; Chen, K. Eur. J. Org. Chem.
2010, 42–46.
2. Selected examples: (a) ÓReilly, R. A. N. Engl. J. Med. 1976, 295, 354; (b) Wingard,
L. B.; ÓReilly, R. A.; Levy, G. Clin. Pharmacol. Ther. 1978, 23, 212; (c) Rang, H. P.;
Dale, M.; Ritter, J. M.; Gardner, P. Pharmacology, fourth ed.; Churchill
Livingstone: Philadelphia, 2001; (d) Thomassigny, C.; Prim, D.; Greck, C.
Tetrahedron Lett. 2006, 47, 1117–1119.
3. Selected examples: (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 4955–4957; (b) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006,
8, 5239–5242; (c) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen,
Y.-C. Org. Lett. 2007, 9, 413–415; (d) Dong, Z.-H.; Wang, L.-J.; Chen, X.-H.; Liu, X.-
H.; Lin, L.-L.; Feng, X.-M. Eur. J. Org. Chem. 2009, 5192–5197; (e) Yang, H.-M.;
Gao, Y.-H.; Li, L.; Jiang, Z.-Y.; Lai, G.-Q.; Xia, C.-G.; Xu, L.-W. Tetrahedron Lett.
2010, 51, 3836–3839.
5. For selected studies on primary amine thiourea catalyst asymmetric Michael
addition: (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451–1453; (b)
Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170–7171; (c) Laloude, M.
P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366–6370; (d)
Sheng, W.-W.; Yalaov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121,
151–157; (e) Zhang, X.-J.; Liu, S.-P.; Li, X.-M.; Yan, M. A.; Chan, S. C. Chem.
Commun. 2009, 833–835; (f) Jiang, X.-X.; Zhang, Y. F.; Albert, S.; Chan, C.; Wang,
R. Org. Lett. 2009, 11, 153–156; (g) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.;
Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem. Eur. J.
2009, 15, 7846–7849; (h) Li, B.-Y.; Wang, Y.-F.; Luo, S.-P.; Zhong, A.-G.; Li, Z.-B.;
Du, X.-H.; Xu, D.-Q. Eur. J. Org. Chem. 2010, 656–662; (i) Zhu, Q.; Lu, Y.-X. Chem.
Commun. 2010, 2235–2237; (j) Uehara, H.; Barbas, C. F., III Angew. Chem., Int. Ed.
2009, 48, 9948–9952; (k) Wang, Y.-Y.; Yang, H.-T.; Yu, J.-P. Adv. Synth. Catal.
2009, 351, 3057–3062; (l) Li, X.; Deng, H.; Zhang, B.; Li, J.-Y.; Zhang, L.; Luo, S.-Z.;
Cheng, J.-P. Chem. Eur. J. 2010, 16, 450–455.
6. (a) Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang, Q.-C.; Xu, X.-Y.; Wang, L.-X. Chem.
Commun. 2010, 46, 8064–8066; (b) Bai, J.-F.; Peng, L.; Wang, L.-L.; Xu, X.-Y.;
Wang, L.-X. Tetrahedron 2010, 66, 8928–8932; (c) Peng, L.; Xu, X.-Y.; Wang, L.-L.;
Huang, J.; Bai, J.-F.; Huang, Q.-C.; Wang, L.-X. Eur. J. Org. Chem. 2010, 1849–1853;
(d) Wang, L.-L.; Xu, X.-Y.; Huang, J.; Peng, L.; Huang, Q.-C.; Wang, L.-X. Lett. Org.
Chem. 2010, 7, 367–372; (e) Fu, J.-Y.; Huang, Q.-C.; Wang, Q.-W.; Wang, L.-X.;
Xu, X.-Y. Tetrahedron Lett. 2010, 51, 4870–4873; (f) Wang, Q.-W.; Peng, L.; Fu, J.-
Y.; Huang, Q.-C.; Wang, L.-X.; Xu, X.-Y. ARKIVOC 2010, 2, 340–351; (g) Bai, J.-F.;
Xu, X.-Y.; Huang, Q.-C.; Peng, L.; Wang, L.-X. Tetrahedron Lett. 2010, 51, 2803–
2805; (h) Fu, J.-Y.; Xu, X.-Y.; Li, Y.-C.; Huang, Q.-C.; Wang, L.-X. Org. Biomol.
Chem. 2010, 8, 4524.
4. For reviews concerning bifunctional thiourea organocatalysts: (a) Takemoto, Y.
Org. Biomol. Chem. 2005, 3, 4299–4306; (b) Connon, S. J. Chem. Eur. J. 2006, 12,
5418–5427; (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543; (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743;
For selected bifunctional chiral thiourea catalyzed reactions, see: (e) Pan, S. C.;
Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007, 46, 612–614; (f) Tillman, A. L.; Ye, J.-
X.; Dixon, D. J. Chem. Commun. 2006, 1191–1193; (g) Yalalov, D. A.; Tsogoeva, S.
B.; Schmatz, S. Adv. Synth. Catal. 2006, 348, 826–832; (h) Herrera, R. P.; Sgarzani,
V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576–6579; (i) Sohtome,
Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643–1648; (j) Cao,
C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904; (k) Wang, C.-J.;
Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Comm. 2008, 1431–1433; (l) Wang, C.-
J.; Zhang, Z.-H.; Dong, X.-Q.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130,
8606–8607; (m) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Tetrahedron: Asymmetry 2009, 20, 2397–2402; (n) Liao, Y.-H.; Chen, W. B.;
7. (a) Huang, J.; Wang, W.; Wang, L.-X. Org. Process Res. Dev. 2010, 14, 1464–1468;
(b) Wang, L.-X.; Shen, J.-F.; Tang, Y.; Chen, Y.; Wang, W.; Cai, Z.-G.; Du, Z.-J. Org.
Process Res. Dev 2007, 11, 487–489; c Wang, L.-X.; Tang, Y.; Chen, Y.; Tian, F. EP
Patent EP1942110;
d Wang, L. X.; Tang, Y.; Chen, Y.; Tian, F. U.S. Patent
US20080249311.;
WO2007028337.;
e
f
Wang, L.-X.; Tang, Y.; Chen, Y.; Tian, F. World Patent
Wang, L.-X.; Tang, Y.; Chen, Y.; Tian, F. CN Patent
ZL200510060721.2, 2007; Chem. Abstr. 2007, 146, 337870;
Tang,Y.; Chen, Y.; Tian, F. CN Patent ZL200510061230.X, 2007; Chem. Abstr.
2007, 146, 337870.; Wang, L.-X.; Tang, Y.; Chen, Y.; Tian, F. CN Patent
g Wang, L.-X.;
h
ZL200510061231.4, 2007; Chem. Abstr. 2007, 146, 337870.; Wang, L.-X.; Peng,
Q.-H.; Du, Z.-J; Lan, H.-F. Chinese Patent CN200610027596.X, 2006; Chem. Abstr.
2006, 148, 121716.
8. West, B. D.; Preis, S.; Schroeder, C. H.; Link, K. P. J. Am. Chem. Soc. 1961, 83, 2676–
2679.