The enantioselective intramolecular Morita-Baylis-Hillman reaction catalyzed by amino acid-derived phosphinothiourea

Article abstract of DOI:10.1016/j.tet.2010.01.085

A series of chiral bifunctional phosphinothioureas derived from l-amino acids have been developed to promote the enantioselective intramolecular Morita-Baylis-Hillman reaction. The process afforded the cyclic hydroxyl enones with up to 84% ee and good yields under mild conditions.

Full text of DOI:10.1016/j.tet.2010.01.085

Tetrahedron 66 (2010) 2439–2443
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The enantioselective intramolecular Morita–Baylis–Hillman reaction
catalyzed by amino acid-derived phosphinothiourea
*
Jing-Jing Gong, Kui Yuan, Hong-Liang Song, Xin-Yan Wu
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral bifunctional phosphinothioureas derived from L-amino acids have been developed to
Received 21 November 2009
Received in revised form 25 January 2010
Accepted 26 January 2010
promote the enantioselective intramolecular Morita–Baylis–Hillman reaction. The process afforded the
cyclic hydroxyl enones with up to 84% ee and good yields under mild conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 1 February 2010
Keywords:
Enantioselective organocatalysis
Intramolecular Morita–Baylis–Hillman
reaction
Chiral phosphinothiourea
Amino acids
Enones
1. Introduction
Hillman reaction between acrylates and aromatic aldehydes. Ac-
cordingly, other bifunctional phosphinothiourea compounds are
The Morita–Baylis–Hillman (MBH) reaction,1 one of the most
fundamental and important processes for construction of C–C
bonds and allylic alcohols, has received considerable interest in
synthetic organic chemistry. In the last decades, there has been
significant progress in developing efficient chiral catalysts for the
enantioselective intermolecular MBH reactions.2 However, the
asymmetric intramolecular MBH reaction is in its infancy, only
a few reports are known so far.3 The first enantioselective intra-
high efficient in the intermolecular MBH reaction.5 For these rea-
sons, we thought that it would be of interest to employ phosphi-
nothiourea in the intramolecular Baylis–Hillman reaction. Herein,
we report our results on the intramolecular MBH reaction catalyzed
by amino acid-derived phosphinothioureas.
2. Results and discussion
´
molecular MBH reaction was reported by Frater’s group in 1992,
The phosphinothioureas 5a–f are easily accessible by conden-
sation of chiral amino-phosphines 46 with 1.1 equiv of the corre-
sponding isothiocyanate in CH2Cl2 at room temperature. The
amino-phosphines 4 were prepared by degradation of 2-oxazoli-
affording the product in 14% ee with 40% yield after a reaction time
of 10 days.3a Recently Miller and co-workers described an enan-
tioselective intramolecular MBH reaction using a co-catalyst sys-
tem involving pipecolinic acid and N-methylimidazole, the cyclic
MBH products were obtained with up to 84% ee.3b Hong et al.
reported a highly enantioselective intramolecular MBH reaction of
hept-2-enedial catalyzed by proline, and the addition of imidazole
as co-catalyst resulted in an inversion of enantioselectivity.3c
Therefore, development of asymmetric version of intramolecular
MBH reactions is still a challenge.
dinones 3.7 Amino alcohols 2,8 prepared by reduction of
L-amino
acids 1, were converted quantitatively into compounds 3 via the
addition with dimethylcarbonate (Scheme 1).
Initially the catalysts 5a–f were examined in the intramolecular
MBH reaction of substrate 6a9 in CH2Cl2 at 25 ꢀC. As shown inTable 1,
the chiral scaffold of the organocatalysts significantly affected the
enantioselectivity and the chemical yield. The L-phenylalanine-de-
rived catalyst 5c provided the desired product in higher ee and lower
yield than the corresponding phosphinothioureas 5a and 5b, which
In our previous work,4 we have successfully developed
L-valine-
derived phosphinothiourea 5a for the asymmetric Morita–Baylis–
derived from
and 2). The thiourea moiety of the catalysts also played an important
role in achieving good yield and enantioselectivity. The -phenylal-
anine-derived thiourea 5d bearing strong electron-withdrawing
L-valine and L-alanine, respectively (entry 3 vs entries 1
L
* Corresponding author. Tel.: þ86 21 64252011; fax: þ86 21 64252758.
E-mail address: xinyanwu@ecust.edu.cn (X.-Y. Wu).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.085

2440
J.-J. Gong et al. / Tetrahedron 66 (2010) 2439–2443
Scheme 1. Synthetic route of the amino acid-derived phosphinothioureas.
substituent at phenyl group afforded the desired product in 83% yield
and 76% ee, and it was more efficient than the corresponding thio-
ureas 5c, 5e, and 5f (entry 4 vs entries 3, 5, and 6). By comparison, 5d
was the optimum catalyst among the screened phosphinothioureas.
The absolute configuration of the intramolecular MBH products is R-
configuration, which was assigned by comparing the optical rotation
value with those reported in the literature.3b
within 9 h in EtOH, the enantioselectivity was poor (entry 8). In other
screened solvents, the reactions afforded moderate yields (58–73%)
and lower enantioselectivities (29–48% ee). Thus CH2Cl2 was se-
lected as solvent for further investigation.
Furthermore, optimization of other reaction conditions, in-
cluding the reaction temperature, the substrate concentration and
the loading of catalyst were investigated (Table 3). The results in-
dicated that the enantioselectivity was not sensitive to the reaction
temperature, and the lower reaction temperature resulted in longer
reaction time (entries 1–3). Reducing the substrate concentration
from 0.2 M to 0.1 M, the enantioselectivity was decreased by only
2% ee (entry 1 vs entry 4). While the substrate concentration was
increased to 0.3 M, the enantioselectivity was reduced obviously
(entry 5). The loading of catalyst has a pronounced influence on
chemical yield and enantioselectivity (entry 1 vs entries 6 and 7). In
the presence of 5 mol % 5d, the reaction was laggard. Surprisingly,
using 20 mol % 5d led to lower chemical yield due to the side-
reaction. The results summarized in Table 3 prompted us to
choose the reaction conditions using 10 mol % 5d in CH2Cl2 at 25 ꢀC
to probe the scope of the intramolecular MBH reaction.
Table 1
Screening of the phosphinothioureas for the intramolecular MBH reaction of 6aa
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
48
12
60
12
84
84
73
72
50
83
50
45
18
16
67
76d
65
56
Table 3
Further optimization of reaction conditionsa
a
The reactions were conducted with 10 mol % of organocatalyst, 0.2 mmol 6a in
1 mL CH2Cl2 (0.2 M) at 25 ꢀC.
b
Isolated yield.
c
Determined by HPLC using Chiralcel OD-H column.
d
30
[
a]
þ20.0 (c 0.30, CHCl3).
D
Next, the solvents were investigated on this process with 5d as
the organocatalyst (Table 2). In CH2Cl2 and CHCl3, the reaction pro-
ceeded quickly to provide the corresponding product with good
yield and ee (entries 2 and 3). Although the reaction completed
Entry Temp (ꢀC) Concn (mol/L) 5d (mol %) Time (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
25
0
0.2
0.2
0.2
0.1
0.3
0.2
0.2
10
10
10
10
10
5
13
35
13
12
12
83
76
85
80
86
82
69
76
71
72
74
60
65
66
40
25
25
25
25
Table 2
The effect of the solvents on the intramolecular MBH reactiona
108
12
20
a
b
c
The reactions were conducted in CH2Cl2.
Isolated yield.
Determined by HPLC using Chiralcel OD-H column.
Entry
Solvent
Time (h)
Yieldb (%)
eec (%)
Under the established optimal reaction conditions, the scope of
1
2
3
4
5
6
7
8
9
Toluene
CHCl3
CH2Cl2
Ether
Ethyl acetate
THF
Acetone
EtOH
32
13
13
32
40
106
40
9
70
88
83
70
73
58
73
83
70
48
74
76
40
45
29
40
30
48
the substrates in terms of intramolecular MBH reaction was in-
vestigated. As the results summarized in Table 4, the substrates
with electron-rich substituent at the para-position of phenyl group
(entries 1 and 2) could afford better enantioselectivity than those
with electron-deficient substituent or without substituent at phe-
nyl group (entries 5–12). In addition, the substrates bearing sub-
stituent at the ortho-position of phenyl group provided the
products in excellent yields with poor enantioselectivity probably
due to the ortho effect (entries 4 and 9). The thiophene analogue
performed the MBH product with reduced yield and enantiose-
lectivity (entry 12).
CH3CN
32
a
The reactions were conducted with 10 mol % 5d, 0.2 mmol 6a in 1 mL solvent
(0.2 M) at 25 ꢀC.
b
Isolated yield.
Determined by HPLC using Chiralcel OD-H column.
c

J.-J. Gong et al. / Tetrahedron 66 (2010) 2439–2443
2441
using CDCl3 as solvent. 13C NMR spectra were referenced to solvent
carbons (77.0 ppm for CDCl3). 31P NMR spectra were referenced to
an external H3PO4 signal (0.00 ppm). IR spectra were recorded on
Nicolet Magna-I 550 spectrometer. High Resolution Mass spectra
(HRMS) were recorded on Micromass GCT or KE465 LCT Premier/
XE spectrometer. HPLC analysis was performed on Waters 510
with 2487 detector using Daicel Chiralcel OD-H, Chiralpak AS-H or
Chiralpak AD-H column.
Table 4
The substrates scope of the intramolecular MBH reactiona
Entry
Ar
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-MeOC6H5
4-MeC6H5
3-MeC6H5
2-MeC6H5
C6H5
36
22
24
48
13
12
12
20
20
12
22
24
77
79
79
99
83
76
86
93
100
82
85
63
84
78
73
45
76
75
71
66
5
4.2. General procedure for synthesis of phosphinethiourea
catalysts 5a–f
To a solution of amino-phosphine compounds 46 (1.0 mmol) in
2.0 mL CH2Cl2 was added isothiocyanate (1.1 mmol) at room tem-
perature, and the corresponding mixture was stirred at this tem-
perature until the reaction completed (monitoring by TLC). The
solvent was removed under reduced pressure and the residue was
purified by column chromatography (petroleum ether/ethyl ace-
tate) to afford the chiral phosphinothiourea compounds 5a–f.
4-FC6H5
4-BrC6H5
3-BrC6H5
2-BrC6H5
4-ClC6H5
Naphtha-2-yl
Thiophen-2-yl
9
10
11
12
68
74
59
a
The reactions were conducted with 10 mol % 5d, 0.2 mmol 6 in 1 mL CH2Cl2
4.2.1.
L
-Valine-derived phosphinothiourea 5a.4 White solid, 60%
(0.2 M) at 25 ꢀC.
b
25
yield, mp: 54.6–55.7 ꢀC; [
a
]
þ32.1 (c 0.70, CHCl3); 1H NMR
Isolated yield.
D
c
Determined by HPLC using Chiralcel OD-H, Chiralpak AS-H or Chiralpak AD-H
(500 MHz, CDCl3):
d 7.80 (s, 1H), 7.49–7.42 (m, 4H), 7.40–7.35 (t,
column.
J¼7.7 Hz, 2H), 7.34–7.23 (m, 7H), 7.07 (d, J¼7.7 Hz, 2H), 5.97 (d,
J¼8.5 Hz, 1H), 4.59 (br, 1H), 2.44–2.38 (m, 1H), 2.32–2.24 (m, 1H),
2.17–2.09 (m, 1H), 0.87 (d, J¼6.8 Hz, 3H), 0.83 (d, J¼6.8 Hz, 3H); 13C
The proposed mechanism of the phosphinothiourea catalyzed
formation of cyclic hydroxyl enones is illustrated in Scheme 2. The
phosphine attacks b-position of the Michael acceptor to form an
enolate and the thiourea moiety activates the substrates 6 by
forming hydrogen-bonds with the aldehyde carbonyl. Then the
phosphinoyl associated enolate attacks the activated carbonyl from
the re-face to give the product in an R-configuration.
NMR (100 MHz, CDCl3):
d
180.1, 138.0, 136.2, 133.0 (d, J¼5.2 Hz),
132.8 (d, J¼5.2 Hz), 130.0, 128.9, 128.6–128.5 (m), 126.9, 125.1, 58.4
(d, J¼14.2 Hz), 31.8 (d, J¼8.6 Hz), 31.2 (d, J¼13.5 Hz), 18.9, 18.0; 31P
NMR (162 MHz, CDCl3, 85% H3PO4):
3229, 3056, 2957, 1598, 1540, 1494, 1043, 565; HRMS (EI) calcd for
C24H27N2PS ([M]þ) 406.1633, found: 406.1635.
d
ꢁ24.49; IR (KBr, cmꢁ1):
n
4.2.2.
yield, [
L-Alanine-derived phosphinothiourea 5b. Colorless oil, 72%
32
a]
þ50.5 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
d 8.59
D
(br, 1H), 7.55–7.47 (m, 2H), 7.45–7.27 (m, 10H), 7.28–7.20 (t,
J¼7.6 Hz,1H), 7.16 (d, J¼7.6 Hz, 2H), 6.22 (br,1H), 4.76 (br, 1H), 2.54–
2.45 (m, 1H), 2.41–2.32 (m, 1H), 1.30 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d
179.0, 138.3 (d, J¼11.8 Hz), 137.8 (d, J¼11.8 Hz),
136.4, 133.0, 132.9, 132.8, 132.7, 130.0, 128.9, 128.8, 128.7–128.2 (m),
126.8, 124.9, 49.6 (d, J¼16.9 Hz), 36.1 (d, J¼14.8 Hz), 21.7 (d,
J¼9.1 Hz); 31P NMR (162 MHz, CDCl3, 85% H3PO4):
ꢁ24.63; IR (KBr,
d
Scheme 2. Proposed mechanism of phosphinothiourea catalyzed intramolecular MBH
reaction.
cmꢁ1):
n 3370, 3208, 3048, 2964, 1595, 1528, 1494, 1478, 1449, 1429,
1318, 1248, 738, 693; HRMS (EI) calcd for C22H23N2PS ([M]þ)
378.1320, found: 378.1321.
3. Conclusion
4.2.3.
68% yield, mp: 45.8–46.9 ꢀC; [
(500 MHz, CDCl3):
L-Phenylalanine-derived phosphinothiourea 5c. White solid,
In summary, a series of chiral phosphinothioureas have been
31
a
]
þ20.5 (c 1.00, CHCl3); 1H NMR
D
synthesized starting from different amino acids, including
-alanine, and -phenylalanine. These bifunctional phosphino-
thioureas could promote the enantioselective intramolecular MBH
reactions of -formyl- -unsaturated carbonyl compounds, and
L-valine,
d
7.78 (s, 1H), 7.51–7.43 (m, 2H), 7.40–7.26 (m,
L
L
10H), 7.25–7.14 (m, 4H), 7.08 (d, J¼6.5 Hz, 2H), 6.90 (d, J¼7.6 Hz,
2H), 5.96 (d, J¼7.0 Hz, 1H), 4.59–4.55 (m, 1H), 3.20–2.59 (m, 2H),
u
a,b
2.37 (d, J¼6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 179.4, 138.1–
the cyclic MBH products were obtained in up to 84% ee with good-
to-excellent yields in dichloromethane at room temperature. Fur-
ther efforts are underway with a focus on improving the reaction
enantioselectivity and probing the full scope of this reaction.
137.8 (m), 137.4, 136.2, 133.1–132.8 (m), 130.0, 129.5, 128.9, 128.7,
128.6, 126.9, 126.7, 125.1, 54.2 (d, J¼15.9 Hz), 40.6 (d, J¼8.7 Hz), 33.1
(d, J¼14.9 Hz); 31P NMR (162 MHz, CDCl3, 85% H3PO4):
ꢁ24.51; IR
d
(KBr, cmꢁ1):
n 3373, 3195, 3053, 3025, 2932, 1595, 1529, 1494, 1451,
1432, 1309, 1244, 733, 699; HRMS (EI) calcd for C28H27N2PS ([M]þ)
454.1633, found: 454.1634.
4. Experimental
4.1. General methods
4.2.4.
75% yield, mp: 109.6–111.0 ꢀC; [
(400 MHz, CDCl3): d 8.73 (br, 1H), 7.68 (s, 1H), 7.60 (s, 2H), 7.48–7.35
L-Phenylalanine-derived phosphinothiourea 5d. White solid,
31
a
]
D
þ8.3 (c 0.90, CHCl3); 1H NMR
Melting points were taken without correction. Optical rota-
tions were measured on a WZZ-2A digital polarimeter at the
wavelength of the sodium D-line (589 nm). 1H, 13C, and 31P NMR
spectra were recorded on Bruker 500 or 400 spectrometer. 1H
NMR spectra were referenced to tetramethylsilane (0.00 ppm)
(m, 4H), 7.35–7.23 (m, 9H), 7.19 (d, J¼6.8 Hz, 2H), 6.37 (br, 1H), 4.95
(br, 1H), 3.29–2.95 (m, 2H), 2.66–2.49 (m, 1H), 2.46–2.27 (m, 1H);
13C NMR (100 MHz, CDCl3):
d
179.6, 138.7, 137.6, 137.5, 137.1, 136.9,
136.8, 132.9, 132.8, 132.7, 132.6, 129.3, 129.1, 129.0, 128.7 (d,

2442
J.-J. Gong et al. / Tetrahedron 66 (2010) 2439–2443
J¼7.2 Hz), 127.0, 124.2, 123.9, 121.5, 119.2, 54.7, 40.9, 32.9; 31P NMR
2.22 (m, 2H), 1.97–1.85 (m, 3H), 1.70–1.63 (m, 1H). HPLC analysis
(AD-H column,
(162 MHz, CDCl3, 85% H3PO4):
d
ꢁ25.19; IR (KBr, cmꢁ1):
n
3212,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow
30
3035, 1540, 1496, 1471, 1455, 1384, 1335, 1289, 1176, 1127, 737, 695;
HRMS (EI) calcd for C30H25F6N2PS ([M]þ) 590.1380, found:
590.1385.
rate: 1.0 mL/min): tR¼14.7 min (major), 16.1 min (minor); [
a]
D
þ42.3 (c 0.26, CHCl3, 78% ee).
4.3.4. (R)-(6-Hydroxycyclohex-1-enyl)(3-tolyl)methanone. 1H NMR
(400 MHz, CDCl3): 7.47–7.43 (m, 2H), 7.36–7.30 (m, 2H), 6.73 (t,
4.2.5.
60% yield, mp: 53.1–54.7 ꢀC; [
(400 MHz, CDCl3):
L
-Phenylalanine-derived phosphinothiourea 5e. White solid,
d
31
a
]
D
þ29.5 (c 1.00, CHCl3); 1H NMR
J¼4.0 Hz, 1H), 4.74 (d, J¼2.4 Hz, 1H), 3.51 (d, J¼2.4 Hz, 1H), 2.41 (s,
d
8.80 (br, 1H), 7.54–7.44 (m, 2H), 7.44–7.36 (m,
3H), 2.39–2.20 (m, 2H), 1.97–1.82 (m, 3H), 1.69–1.60 (m, 1H); 13C
2H), 7.36–7.28 (m, 6H), 7.28–7.23 (m, 5H), 7.15 (d, J¼6.8 Hz, 2H),
NMR (100 MHz, CDCl3):
d 199.5, 146.8, 140.1, 138.0, 137.8, 132.7,
6.90 (d, J¼8.4 Hz, 2H), 6.06 (br, 1H), 4.95 (br, 1H), 3.17–2.99 (m, 2H),
129.7, 128.0, 126.5, 63.9, 29.8, 26.3, 21.3, 17.4; IR (KBr, cmꢁ1):
n
2.53–2.37 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
179.4, 138.0–137.6
3448, 2934, 2864, 1636, 1601, 1420, 1277, 1201, 1056, 986, 756;
(m), 137.3, 134.8, 133.0, 132.9, 132.8, 132.7, 132.2, 130.0, 129.5, 128.9,
128.8–128.4 (m),126.8,126.3, 54.3 (d, J¼15.5 Hz), 40.6 (d, J¼8.5 Hz),
33.5 (d, J¼14.3 Hz); 31P NMR (162 MHz, CDCl3, 85% H3PO4):
HRMS (ESI) calcd for C14H16O2Na ([MþNa]þ): 239.1048, found:
239.1046. HPLC analysis (AS-H column,
l
¼254 nm, eluent: hex-
ane/2-propanol¼90/10, flow rate: 0.9 mL/min): tR¼7.1 min (ma-
d
ꢁ24.66; IR (KBr, cmꢁ1):
n
3371, 3265, 3054, 2917, 1521, 1489, 1456,
jor), 23.1 min (minor).
1430, 1093, 737, 695; HRMS (EI) calcd for C28H26ClN2PS ([M]þ)
488.1243, found: 488.1245.
4.3.5. (R)-(6-Hydroxycyclohex-1-enyl)(2-tolyl)methanone.3b 1H NMR
(400 MHz, CDCl3):
d 7.36–7.32 (m, 1H), 7.24–7.19 (m, 3H), 6.60 (t,
4.2.6.
65% yield, mp: 59.1–60.4 ꢀC; [
(400 MHz, CDCl3):
L
-Phenylalanine-derived phosphinothiourea 5f. White solid,
J¼4.0 Hz, 1H), 4.79 (s, 1H), 3.51 (s, 1H), 2.31 (s, 3H), 2.34–2.15 (m,
þ23.5 (c 1.00, CHCl3); 1H NMR
2H), 1.92–1.80 (m, 3H), 1.67–1.61 (m, 1H). HPLC analysis (AS-H
31
a
]
D
d
8.33 (br, 1H), 7.54–7.44 (m, 2H), 7.44–7.34 (m,
column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate:
27
2H), 7.34–7.26 (m, 6H), 7.26–7.15 (m, 3H), 7.11 (d, J¼6.8 Hz, 2H), 6.90
(d, J¼8.4 Hz, 2H), 6.83 (d, J¼8.4 Hz, 2H), 5.89 (br, 1H), 4.93 (br, 1H),
3.79 (s, 3H), 3.13–2.94 (m, 2H), 2.40 (d, J¼6.8 Hz, 2H); 13C NMR
0.9 mL/min): tR¼6.4 min (major), 12.6 min (minor); [
a]
þ13.3 (c
D
0.30, CHCl3, 45% ee).
(100 MHz, CDCl3):
d
180.0, 158.7, 138.4–137.7 (m), 137.3, 133.1, 132.9
4.3.6. (R)-(4-Fluorophenyl)(6-hydroxycyclohex-1-enyl)meth-
anone. 1H NMR (400 MHz, CDCl3):
7.74–7.70 (m, 2H), 7.13 (t,
(d, J¼5.8 Hz), 132.7, 129.5, 128.8 (d, J¼2.1 Hz), 128.7–128.4 (m),
d
127.6, 126.6, 115.1, 55.6, 54.0 (d, J¼16.0 Hz), 40.5 (d, J¼8.7 Hz), 33.1
J¼8.4 Hz, 2H), 6.70 (t, J¼4.0 Hz, 1H), 4.74 (s, 1H), 3.42 (s, 1H), 2.41–
(d, J¼14.5 Hz); 31P NMR (162 MHz, CDCl3, 85% H3PO4):
d
ꢁ24.67; IR
2.23 (m, 2H), 1.97–1.86 (m, 3H), 1.71–1.64 (m, 1H); 13C NMR
(KBr, cmꢁ1):
n
3368, 3190, 3054, 2959, 2830, 1608, 1509, 1430, 1239,
(100 MHz, CDCl3):
d
197.7, 165.1 (d, J¼251.8 Hz), 146.3, 140.0, 133.9
1164, 1027, 740, 702; HRMS (EI) calcd for C29H29N2OPS ([M]þ)
484.1738, found: 484.1736.
(d, J¼3.2 Hz), 131.8 (d, J¼8.9 Hz), 115.3 (d, J¼21.7 Hz), 63.9, 29.8,
26.3,17.4; IR (KBr, cmꢁ1):
n 3440, 2940, 2859,1645,1598,1506,1271,
1228, 987, 767; HRMS (ESI) calcd for C13H13O2FNa ([MþNa]þ):
4.3. General procedure for the intramolecular MBH reaction
243.0797, found: 243.0801. HPLC analysis (AD-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate: 0.8 mL/
30
To a solution of phosphinothiourea 5d (0.02 mmol, 11 mg) in
CH2Cl2 (1.0 mL) was added substrates 6 (0.2 mmol) at 25 ꢀC. The
reaction mixture was stirred at 25 ꢀC until the reaction completed
(monitoring by TLC). The solvent was removed under reduced
pressure and the residue was purified by a flash column chroma-
tography to afford the intramolecular Baylis–Hillman adducts. The
ee values were determined by HPLC analysis with a chiral column.
min): tR¼12.7 min (minor), 14.0 min (major); [
a
]
þ25.0 (c 0.32,
D
CHCl3, 75% ee).
4.3.7. (R)-(4-Bromophenyl)(6-hydroxycyclohex-1-enyl)methanone.3b
1H NMR (400 MHz, CDCl3):
d
7.60 (d, J¼8.4 Hz, 2H), 7.54 (d,
J¼8.4 Hz, 2H), 6.71 (t, J¼4.0 Hz, 1H), 4.75 (s, 1H), 2.57 (br s, 1H),
2.40–2.23 (m, 2H), 1.98–1.83 (m, 3H), 1.71–1.63 (m, 1H). HPLC
analysis (AD-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/
4.3.1. (R)-(6-Hydroxycyclohex-1-enyl)(phenyl) methanone.9 1H
10, flow rate: 1.0 mL/min): tR¼19.4 min (minor), 22.7 min (major);
30
NMR (500 MHz, CDCl3):
d
7.66 (d, J¼7.2 Hz, 2H), 7.54 (t, J¼7.2 Hz,
[a]
D
þ16.7 (c 0.24, CHCl3, 71% ee).
1H), 7.44 (t, J¼7.2 Hz, 2H), 6.73 (t, J¼4.0 Hz, 1H), 4.74 (d, J¼1.2 Hz,
1H), 3.51 (d, J¼1.2 Hz, 1H), 2.39–2.22 (m, 2H), 1.97–1.84 (m, 3H),
4.3.8. (R)-(3-Bromophenyl)(6-hydroxycyclohex-1-enyl)methan-
one. 1H NMR (400 MHz, CDCl3):
1.69–1.66 (m, 1H). HPLC analysis (OD-H column,
l¼254 nm, eluent:
d
7.78 (s, 1H), 7.66 (d, J¼8.0 Hz, 1H),
hexane/2-propanol¼95/5, flow rate: 1.0 mL/min): tR¼9.9 min
7.57 (d, J¼8.0 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H), 6.73 (t, J¼4.0 Hz, 1H),
30
(major), 11.8 min (minor); [
a
]
þ20.0 (c 0.30, CHCl3, 76% ee).
4.74 (s, 1H), 3.37 (s, 1H), 2.42–2.23 (m, 2H), 1.97–1.81 (m, 3H), 1.69–
D
1.63 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
197.4, 147.7, 140.0, 139.7,
4.3.2. (R)-(6-Hydroxycyclohex-1-enyl)(4-methoxyphenyl)-
methanone. 1H NMR (400 MHz, CDCl3):
134.8, 132.0, 129.8, 127.8, 122.4, 63.7, 29.7, 26.5, 17.4; IR (KBr, cmꢁ1):
d
7.71 (d, J¼8.8 Hz, 2H), 6.94
n 3446, 2925, 2855, 1652, 1636, 1418, 1078; HRMS (ESI) calcd for
(d, J¼8.8 Hz, 2H), 6.66 (t, J¼4.0 Hz, 1H), 4.71 (s, 1H), 3.88 (s, 3H),
C13H13O2BrNa ([MþNa]þ): 302.9997, found: 302.9983. HPLC anal-
3.60 (br s, 1H), 2.39–2.22 (m, 2H), 1.95–1.85 (m, 3H), 1.69–1.65 (m,
ysis (AD-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10,
1H); 13C NMR (100 MHz, CDCl3):
d
198.1, 163.0, 144.7, 139.8, 131.8,
flow rate: 1.0 mL/min): tR¼11.9 min (minor),13.5 min (major); [
a]
D
28
130.2, 113.5, 64.2, 55.4, 29.8, 26.2, 17.4; IR (KBr, cmꢁ1):
n
3440, 2936,
þ11.3 (c 0.40, CHCl3, 66% ee).
1635, 1599, 1509, 1257, 1173, 1028, 767; HRMS (ESI) calcd for
C14H16O3Na ([MþNa]þ): 255.0997, found: 255.0992. HPLC analysis
4.3.9. (R)-(2-Bromophenyl)(6-hydroxycyclohex-1-enyl)meth-
anone. 1H NMR (400 MHz, CDCl3):
(AS-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow
d
7.59 (d, J¼8.0 Hz, 1H), 7.38–
30
rate: 1.0 mL/min): tR¼12.0 min (major), 29.1 min (minor); [
a
]
7.24 (m, 3H), 6.60 (t, J¼4.0 Hz, 1H), 4.80 (t, J¼4.4 Hz, 1H), 3.33 (s,
D
þ57.5 (c 0.20, CHCl3, 84% ee).
1H), 2.35–2.15 (m, 2H), 1.96–1.71 (m, 3H), 1.70–1.60 (m, 1H); 13C
NMR (100 MHz, CDCl3):
d
198.5, 150.4, 140.6, 140.2, 133.0, 130.9,
3446,
4.3.3. (R)-(6-Hydroxycyclohex-1-enyl)(4-tolyl)methanone.10 1H NMR
(400 MHz, CDCl3):
7.59 (d, J¼8.0 Hz, 2H), 7.25 (d, J¼7.6 Hz, 2H),
6.71 (t, J¼4.0 Hz, 1H), 4.73 (s, 1H), 2.91 (br s, 1H), 2.42 (s, 3H), 2.40–
128.6, 127.0, 119.4, 63.0, 29.7, 26.8, 17.4; IR (KBr, cmꢁ1):
n
d
2939, 2859, 1653, 1634, 1429, 1287, 1056, 986, 767. HRMS (ESI) calcd
for C13H13O2BrNa ([MþNa]þ): 302.9997, found: 303.0005. HPLC

J.-J. Gong et al. / Tetrahedron 66 (2010) 2439–2443
2443
analysis (AS-H column,
10, flow rate: 1.0 mL/min): tR¼7.9 min (major), 17.2 min (minor).
l
¼254 nm, eluent: hexane/2-propanol¼90/
Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (20772029) and the Program for New
Century Excellent Talents in University (NCET-07-0286).
4.3.10. (R)-(4-Chlorophenyl)(6-hydroxycyclohex-1-enyl)meth-
anone.3b 1H NMR (400 MHz, CDCl3):
d
7.62 (d, J¼8.4 Hz, 2H), 7.43 (d,
J¼8.4 Hz, 2H), 6.71 (t, J¼4.0 Hz, 1H), 4.74 (s, 1H), 2.51 (br s, 1H),
2.42–2.24 (m, 2H), 1.98–1.88 (m, 3H), 1.71–1.64 (m, 1H). HPLC
analysis (AS-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/
References and notes
10, flow rate: 1.0 mL/min): tR¼7.3 min (major), 12.4 min (minor);
30
[a]
D
þ23.3 (c 0.30, CHCl3, 68% ee).
1. For reviews, see: (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–
4670; (b) Ciganek, E. Org. React. 1997, 51, 201–350; (c) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (d) Langer, P. Angew. Chem., Int.
Ed. 2000, 39, 3049–3052; (e) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811–891.
4.3.11. (R)-(6-Hydroxycyclohex-1-enyl)(naphthalen-2-yl)meth-
anone. 1H NMR (400 MHz, CDCl3):
8.18 (s, 1H), 7.96–7.89 (m, 3H),
d
7.79–7.77 (m, 1H), 7.62–7.55 (m, 2H), 6.81 (t, J¼4.0 Hz, 1H), 4.82 (s,
2. For recent reviews on enantioselective Morita–Baylis–Hillman reaction, see: (a)
Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581–1588; (b)
Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614–4628;
(c) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–2916; (d) Declerck, V.;
Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1–48; (e) Krishna, P. R.; Sachwani,
R.; Reddy, P. S. Synlett 2008, 2897–2912; (f) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y.
Chem. Commun. 2009, 5496–5514.
3. (a) Roth, F.; Gygax, P.; Fra´ter, G. Tetrahedron Lett. 1992, 33, 1045–1048; (b) Ar-
oyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2005, 7, 3849–3851; (c) Chen,
S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron Lett. 2005, 46, 8899–8903.
4. Gong, J.-J.; Yuan, K.; Wu, X.-Y. Tetrahedron: Asymmetry 2009, 20, 2117–2120.
5. (a) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129–2135; (b) Yuan, K.; Zhang,
L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49, 6262–6264; (c) Yuan,
K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron 2009, 65, 8185–8190.
6. Ito, M.; Osaku, A.; Kobayashi, C.; Shiibashi, A.; Ikariya, T. Organometallics 2009,
28, 390–393.
1H), 3.54 (s, 1H), 2.43–2.27 (m, 2H), 2.03–1.87 (m, 3H), 1.74–1.67 (m,
1H); 13C NMR (100 MHz, CDCl3):
d
199.2, 146.6, 140.3, 135.1, 135.0,
132.2, 130.6, 129.2, 128.2, 128.1, 127.8, 126.8, 125.4, 64.0, 29.9, 26.4,
17.5; IR (KBr, cmꢁ1):
n 3441, 2937, 1635, 1456, 1354, 1283,1231,1056,
989, 762; HRMS (ESI) calcd for C17H17O2 ([MþH]þ): 253.1229,
found: 253.1214. HPLC analysis (OD-H column,
l
¼254 nm, eluent:
hexane/2-propanol¼95/5, flow rate: 1.0 mL/min): tR¼13.5 min
30
(major), 17.4 min (minor); [
a
]
þ31.4 (c 0.35, CHCl3, 74% ee).
D
4.3.12. (R)-(6-Hydroxycyclohex-1-enyl)(thiophen-2-yl)methanone.3b
1H NMR (400 MHz, CDCl3):
d
7.67 (d, J¼4.8 Hz, 1H), 7.63 (d,
J¼2.8 Hz, 1H), 7.15–7.12 (m, 1H), 6.96 (t, J¼4.0 Hz, 1H), 4.69 (s, 1H),
7. Benoit, D.; Coulbeck, E.; Eames, J.; Motevalli, M. Tetrahedron: Asymmetry 2008,
19, 1068–1077.
8. Mckennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568–3571.
9. Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P. M.; Gelbrich, T.;
Hursthouse, M. B. Tetrahedron 2001, 57, 7771–7784.
2.70 (s, 1H), 2.43–2.25 (m, 2H), 1.98–1.80 (m, 3H), 1.72–1.65 (m, 1H).
HPLC analysis (AS-H column,
l
¼254 nm, eluent: hexane/2-prop-
anol¼90/10, flow rate: 1.0 mL/min): tR¼9.5 min (major), 17.0 min
30
(minor); [a]
D
þ33.3 (c 0.24, CHCl3, 59% ee).
10. Seidel, F.; Gladysz, J. A. Synlett 2007, 986–988.