Enantioselective synthesis of multifunctionalized 4H-pyran derivatives using bifunctional thiourea-tertiary amine catalysts

Article abstract of DOI:10.1016/j.tetasy.2009.02.054

A series of novel chiral multifunctionalized 4H-pyran derivatives were easily accessed via the one-pot asymmetric Michael addition-cyclization reaction between malononitrile and β,γ-unsaturated α-keto esters catalyzed by chiral bifunctional thiourea-terti

Full text of DOI:10.1016/j.tetasy.2009.02.054

Tetrahedron: Asymmetry 20 (2009) 1046–1051
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of multifunctionalized 4H-pyran derivatives
using bifunctional thiourea-tertiary amine catalysts
Sheng-Li Zhao a, Chang-Wu Zheng b, Gang Zhao b,
*
a Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, People’s Republic of China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, People’s Republic of 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 novel chiral multifunctionalized 4H-pyran derivatives were easily accessed via the one-pot
Received 20 January 2009
Accepted 12 February 2009
Available online 22 April 2009
asymmetric Michael addition-cyclization reaction between malononitrile and b,c-unsaturated a-keto
esters catalyzed by chiral bifunctional thiourea-tertiary amine catalysts. With the optimized reaction
conditions, the desired products were obtained with 50–68% yields and 72–88% ees.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
further investigation. However, the use of these catalysts failed
to improve the result (Table 1, entries 2–4). It is worthy to note
Multifunctionalized 4H-pyrans are important structural units
present in many natural or synthetic compounds with important
biological or pharmacological activities such as anti-coagulant,
anticancer, spasmolytic, and anti-anaphylactic activities.1–3 In
addition, some of these compounds could serve as useful interme-
diates for organic synthesis.4 Therefore, numerous efforts have
been devoted to the synthesis of these compounds.5 However, to
the best of our knowledge, catalytic enantioselective syntheses of
these types of compounds have rarely been reported.
the difference between the results of catalysts 1c and 1d, which
underscored the importance of the match of stereocontrol ele-
ments in catalysts. Then another two known thiourea-tertiary-
amine catalysts of different chiral architecture were also examined.
The quinine-derived catalyst 1e9 gave the desired product in 32%
ee (Table 1, entry 5) while the phenylalanine-derived catalyst 1f9
60% ee (Table 1, entry 6). In view of the fact that amino acids are
inexpensive, easily available, and ready for modular modification,
we then synthesized four new catalysts 1g–1j based on 1f. For cat-
alysts 1g and 1h with changes on the tertiary amine moiety, only
slightly higher ees were obtained compared with 1f (Table 1, en-
tries 7 and 8). A sharp drop in the ee value was observed in the in-
stance of catalyst 1i in which an adamantyl group was installed
instead of the 3,5-bis(trifluoromethyl)phenyl group in 1f (Table
1, entry 9). In addition, the C2-symmetric catalyst 1j with two ter-
tiary amine moieties also provided rather poor results (Table 1, en-
try 10). In light of the above results, further optimization efforts
were carried out with catalyst 1a. The use of several other solvents
such as CHCl3, CH3CN, THF, and MeOH all led to inferior results (Ta-
ble 1, entries 11–14). Increasing the loading of the catalyst to
10 mol % gave only a little improvement in the enantioselectivity,
while reducing the loading of the catalyst to 2 mol % deteriorated
the enantioselectivity remarkably (Table 1, entries 15 and 16). A
reduction in the ee value was also observed when the concentra-
tion of the substrates was doubled (Table 1, entry 17).10 To our de-
light, lowering the reaction temperature to ꢀ30 °C improved both
the yield and ee significantly (Table 1, entry 18). However, further
lowering of the reaction temperature to ꢀ78 °C gave no apparent
improvement, yet with a largely prolonged reaction time (Table
1, entry 19) (see Fig. 1).
Being interested in the utilization of b,c-unsaturated a-keto es-
ters as useful reaction components in organic synthesis,6 we have
realized the enantioselective synthesis of naphthopyran deriva-
tives7 using bifunctional chiral thiourea-tertiary-amine catalysts.8
As a continuation of our efforts in this field, we report herein the
preparation of some thiourea-tertiary-amine catalysts and their
applications to the asymmetric Michael addition–cyclization reac-
tion of malononitrile with b,c-unsaturated a-keto ester leading to
the synthesis of a series of chiral 4H-pyran derivatives.
2. Results and discussion
Firstly, the reaction of b,c-unsaturated a-keto ester 2a with
malononitrile was chosen as a model reaction to optimize the reac-
tion conditions and the results are summarized in Table 1. The use
of Takemoto’s catalyst 1a8c gave the desired product 4a in 39%
yield and 71% ee, along with some unidentifiable byproducts (Ta-
ble 1, entry 1). Encouraged by this result, we then synthesized an-
other three known catalysts 1b–1d9 structurally related to 1a for
With the optimized reaction conditionsinhand (Table 1, entry 18),
we then explored the generality of this reaction with a spectrum of
* Corresponding author. Fax: +86 21 64166128.
E-mail address: zhaog@mail.sioc.ac.cn (G. Zhao).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.054

S.-L. Zhao et al. / Tetrahedron: Asymmetry 20 (2009) 1046–1051
1047
Table 1
Screen of the optimal reaction conditions for the reaction of 5a and 6a
O
O
H2N
NC
O
OMe
OMe
catalyst 1
solvent
N
+
N
Ph
O
Ph
2a
3
4a
Entry
Solvent
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16e
17f
18g
19h
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CHCl3
CH3CN
THF
MeOH
Toluene
Toluene
Toluene
Toluene
Toluene
1a
1b
1c
1d
1e
1f
1g
1h
1i
39
39
39
38
38
40
39
40
39
39
39
38
41
33
39
35
40
64
65
71
56
40
0
32
60
61
64
26
8
58
23
34
7
72
40
48
78
80
1j
1a
1a
1a
1a
1a
1a
1a
1a
1a
a
Unless otherwise noted, the reaction was conducted with 0.1 mmol of 2a and 0.11 mmol of 3 in the presence of 5 mol % of 1 in 2.0 mL of solvent at room temperature
under nitrogen atmosphere, 4 h.
b
Isolated yields.
c
Determined by chiral HPLC analysis on a chiral OD column.
10 mol % of 1a was used.
2 mol % of 1a was used.
1.0 mL of toluene was used.
d
e
f
g
The reaction was conducted at ꢀ30 °C, 14 h.
h
The reaction was conducted at ꢀ78 °C, 36 h.
O
Ph
Ph
N
Ph
Ph
N
NHTos
NHTos
N
N
S
NH
NH
S
NH
NH
HN
S
NH
HN
HN
S
F3C
NH
S
NH
N
N
F3C
CF3
CF3
1a
1b
1c
1d
1e
N
Bn
S
N
N
N
HN
Bn
HN
HN
HN
HN
Bn
N
N
HN
S
HN
Bn
S
S
S
HN
Bn
N
H
N
Bn
H
F3C
CF3
F3C
CF3
F3C
CF3
1j
1g
1f
1i
1h
Figure 1. Thiourea-tertiary amine catalysts used in the study.
b,
c
-unsaturated
a
-keto esters and the results are summarized in Ta-
brought little influenceonthe yields and the enantioselectivities, irre-
spective of the electronic nature, bulk or positions of the substituents
onthe phenylring. Substrateswith differentR2 substituentsonthees-
ter moiety were also studied in the reaction (Table 2, entries 10–13).
ble 2. Firstly, several b,c-unsaturated a-keto esters 2a–i bearing dif-
ferent R1 substituents were tested (Table 2, entries 1–9). Except for
substrate 2f with a nitro group on the phenyl group, variation of R1

1048
S.-L. Zhao et al. / Tetrahedron: Asymmetry 20 (2009) 1046–1051
Table 2
Enantioselective synthesis of 4H-pyran derivatives catalyzed by 1aa
O
O
H2N
NC
O
R2
O
1a (5 mol %)
O
N
N
R1
R2
+
toluene, -30 ºC
O
R1
2
3
4
Entry
2
R1
R2
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
2,4-diClC6H3
4-NO2C6H4
4-EtOC6H4
2-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
4a
4b
4c
4d
4e
4f
4g
4h
4i
64
66
64
68
62
50
61
65
65
63
58
57
60
78
81
82
88
88
72
85
83
80
80
80
75
77
2,5-diMeOC6H3
2j
2k
2l
Ph
Ph
Ph
Ph
4j
4k
4l
4-BrBn
i-Pr
Allyl
2m
4m
a
Unless otherwise noted, the reaction was conducted with 0.1 mmol of 2a–m and 0.11 mmol of 3 in the presence of 5 mol % of 1a in 2.0 mL of toluene at ꢀ30 °C for 12 h.
Isolated yields.
Determined by chiral HPLC analysis on a chiral OD or AD column. The absolute configuration of 4d was determined to be R configuration by X-ray crystallographic
b
c
analysis.
H2N
NC
O
O
OMe
Br
Figure 2. X-ray structure of compound 4d.
Similarly, no significant difference in yields and enantioselectivities
were observed with these substrates (entries 10–13). The absolute
configuration of the product 4d was determined to be (R)- by X-ray
crystallographic analysis (Fig. 2).11
phosphomolybdic acid in ethanol followed by heating. The 1H
NMR spectra were recorded on a DPX-300 or Varian EM-360
(300 MHz). Allchemicalshifts (d)are givenin ppm. Dataare reported
as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, m = multiplet) and coupling con-
stants (Hz), integration. 13C NMR spectra were recorded on a DPX-
300 (100 MHz). Analytical high performance liquid chromatography
(HPLC)wascarriedouton WATERSequipmentusingachiralcolumn.
Melting points were determined on a SGW X-4 apparatus and were
uncorrected. Optical rotations were measured on a JASCO P-1030
Polarimeter at k = 589 nm. IR spectra were recorded on a Perkin–El-
mer 983G instrument. Mass spectra analyses were performed on API
200 LC/MS system (Applied Biosystems Co. Ltd).
3. Conclusions
In conclusion, we have developed a simple and novel method
for the enantioselective synthesis of a series of 4H-pyran deriva-
tives through the one-pot asymmetric addition-cyclization of mal-
ononitrile to b,
c
-unsaturated
a-keto ester catalyzed by
bifunctional thiourea-tertiary amines. The desired products could
be obtained with moderate yields and good enantioselectivities
(50–68% yields and 72–88% ees).
4.2. Preparation of catalysts 1g–1j
4. Experimental
4.1. General
Catalysts 1a8c, 1b9a, 1c9e, 1d9e, 1e9a, and 1f9d were synthesized
according to the literature.
Unless otherwise indicated, chemicals and solvents were pur-
chased from commercial suppliers and purified by standard tech-
niques. Flash column chromatography was performed using silica
gel (300–400 mesh). For thin-layer chromatography (TLC), silica
gel plates (HSGF 254) were used and compounds were visualized
by irradiation with UV light or by treatment with a solution of
4.2.1. (S)-1-(3,5-Bis(trifluoromethyl)phenyl)-3-(1-(diethyl-
amino)-3-phenylpropan -2-yl)thiourea 1g
This compound was prepared according to a known proce-
dure from (S)-N1,N1-diethyl-3-phenylpropane-1,2-diamine12 and
1-isothiocyanato-3,5-bis(trifluoromethyl)benzene as a pale yel-
low oil. Yield: 66%; ½a D22:1
¼ ꢀ32:5 (c 1.60, CHCl3); IR (neat)
ꢁ

S.-L. Zhao et al. / Tetrahedron: Asymmetry 20 (2009) 1046–1051
1049
m
= 3236, 2974, 1607, 1495, 1472 cmꢀ1
;
1H NMR (300 MHz,
NMR (300 MHz, CDCl3) d 7.38–7.24 (m, 5H), 6.30 (d, J = 4.2 Hz,
1H), 4.68 (s, 2H), 4.32 (d, J = 4.2 Hz, 1H), 3.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 160.6, 159.1, 141.8, 138.2, 128.9, 127.8,
127.7, 119.1, 115.6, 58.8, 52.6, 38.5, 30.8; LRMS (EI): m/e 77
(23.6), 119 (32.0), 131 (31.7), 179 (100), 197 (65.0), 256 (M+, 41);
HRMS (EI): 256.0854; Calcd for C14H12N2O3: 256.0848. The enan-
tiomeric ratio was determined by HPLC analysis, using a Chiralcel
OD column (25 °C, 254 nm, 1:4, hexane/2-propanol, 0.1 mL/min);
tmajor = 49.6 min, tminor = 52.7 min.
CDCl3) d 7.98 (s, 2H), 7.59 (s, 1H), 7.21–7.38 (m, 5H), 6.76 (br
s, 1H), 4.03 (br s, 1H), 3.01–3.05 (m, 1H), 2.62–2.80 (m, 5H),
2.46–2.57 (m, 2H), 0.94–0.99 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 182.9, 141.8, 136.3, 131.6 (J = 29.2 Hz), 129.0, 127.3,
123.3, 123.0 (J = 207.8 Hz), 117.7, 59.6, 57.0, 47.4, 39.7, 14.1,
10.7; LRMS (EI): m/e 58 (7.76), 86 (100), 91 (6.52), 271
(19.49), 477 (M+, 0.74); HRMS (EI): 477.1676; Calcd for
C22H25F6N3S: 477.1673.
4.2.2. (S)-1-(3,5-Bis(trifluoromethyl)phenyl)-3-(1-phenyl-3-
(pyrrolidin-1-yl)prop- an-2-yl) thiourea 1h
4.3.2. (R)-Methyl 6-amino-5-cyano-4-(4-fluorophenyl)-4H-pyran-
2-carboxylate 4b
White solid; yield: 66%. Mp 180–183 °C; ½a D22:1
¼ ꢀ68:1 (c 1.00,
ꢁ
This compound was prepared according to a known procedure
from (S)-1-phenyl-3-(pyrrolidin-1-yl)propan-2-amine10c and 1-
isothiocyanato-3,5-bis(trifluoromethyl)benzene as a white solid.
CHCl3); IR (KBr)
m = 3439, 3297, 2191, 1740, 1678, 1634,
1597 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.23 (t, 2H), 7.06 (t, 2H),
;
Yield: 68%; Mp 60–62 °C; ½a D22:1
ꢁ
¼ ꢀ23:8 (c 1.00, CHCl3); IR (KBr)
6.26 (d, J = 4.1 Hz, 1H), 4.68 (s, 2H), 4.31 (d, J = 4.1 Hz, 1H), 3.83 (s,
3H); 13C NMR (100 MHz, CDCl3) d 162.3 (J = 245.7 Hz), 160.3,
138.6, 137.9, 129.6 (J = 8.2 Hz), 119.2, 116.3, 115.5, 59.2, 52.2, 38.1,
31.2; LRMS (EI): m/e 101 (49.76), 149 (100), 179 (85.79), 215
(98.5), 274 (M+, 45.3); HRMS (EI): 274.0760; Calcd for C14H11FN2O3:
274.0754. The enantiomeric ratio was determined by HPLC analysis,
usinga ChiralcelODcolumn(25 °C, 254 nm, 1:4, hexane/2-propanol,
0.1 mL/min); tmajor = 50.7 min, tminor = 46.6 min.
m
= 3550, 2972, 2880, 1615, 1540, 1383 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.98 (s, 2H), 7.59 (s, 1H), 7.28–7.39 (m, 3H), 7.22 (d,
J = 6.9 Hz, 1H), 6.39 (br s, 1H), 4.01 (br s, 1H), 2.96–3.05 (m, 2H),
2.74–2.82 (m, 3H), 2.50–2.63 (m, 3H), 1.81 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 183.0, 142.4, 137.4, 136.5, 132.0 (J = 32.1 Hz),
129.2, 127.6, 124.8, 123.3 (J = 228.5 Hz), 117.9, 62.5, 56.8, 54.3,
40.0, 23.9; LRMS (EI): m/e 55 (4.55), 84 (100), 271 (7.84), 475
(M+, 0.32); HRMS (EI): 475.1515; Calcd for C22H23F6N3S: 475.1517.
4.3.3. (R)-Methyl 6-amino-4-(4-chlorophenyl)-5-cyano-4H-pyran-
4.2.3. 1-Adamantan-1-yl-3((S)-1-benzyl-2-dimethylamino-ethyl)-
thiourea 1i
2-carboxylate 4c
White solid; yield: 64%. Mp 210–212 °C; ½a D22:1
¼ ꢀ132:4 (c 1.00,
ꢁ
This compound was prepared according to a known proce-
dure9d from 1-adamantanamine and ((S)-2-isothiocyanato-3-
phenylpropyl)-dimethylamine13 as a white solid. Yield: 58%; Mp
CHCl3); IR (KBr) m ;
= 3449, 3296, 2194, 1739, 1680, 1640, 1597 cmꢀ1
1H NMR (300 MHz, CDCl3) d 7.35 (d, J = 6.9 Hz, 2H), 7.19 (d, J = 6.9 Hz,
2H), 6.25 (d, J = 3.9 Hz, 1H), 4.70 (s, 1H), 4.30 (d, J = 3.9 Hz, 1H), 3.83
(s, 3H);13C NMR(100 MHz, CDCl3)d160.8, 159.4, 140.5, 138.7, 134.0,
129.5, 129.5, 119.1, 115,2, 58.8, 53.0, 38.3, 31.2; LRMS (EI): m/e 119
(42.25), 165 (32), 179 (100), 231 (72.61), 290 (M+, 24.95); HRMS (EI):
290.0458; Calcd for C14H11ClN2O3: 290.0465. The enantiomeric ratio
was determined by HPLC analysis, using a Chiralcel OD column
(25 °C, 254 nm, 1:4, hexane/2-propanol, 0.1 mL/min); tmajor = 55.7 -
min, tminor = 48.8 min.
59–61 °C; ½a 2D2:1
ꢁ
¼ ꢀ12:9 (c 1.00, CDCl3); IR (KBr)
m = 3550, 2972,
2880, 1615, 1540, 1383 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.23–
7.33 (m, 5H), 6.06 (s, 1H), 4.11 (m, 1H), 3.16–3.17 (m, 1H), 2.81–
2.89 (m, 1H), 2.42–2.49 (m, 1H), 2.27–2.32 (m, 1H), 2.18 (s, 6H),
2.04–2.08 (m, 9H), 1.65–1.69 (m, 7H); 13C NMR (100 MHz, CDCl3)
d 180.8, 138.6, 129.7, 128.7, 126.6, 53.9, 45.4, 41.9, 36.4, 29.6;
LRMS (EI): m/e 58 (100), 91 (8.76), 135 (7.63), 161 (11.80), 371
(M+, 0.19); HRMS (EI): 371.2388; Calcd for C22H33N3S: 371.2395.
4.3.4. (R)-Methyl 5-Amino-3-(4-bromophenyl)-4-
4.2.4. 1-((R)-1-(Dimethylamino)-3-phenylpropan-2-yl)-3-((S)-
1-(dimethylamino)-3-phenylpropan-2-yl)thiourea 1j
cyanocyclohexa-1,4-dienecarboxylate 4d
White solid; yield: 68%. Mp 172–174 °C; ½a D22:1
¼ ꢀ50:7 (c 1.00,
ꢁ
This compound was prepared according to a known proce-
dure9d from (S)-N1,N1-dimethyl-3-phenylpropane-1,2-diamine
and ((S)-2-isothiocyanato-3-phenyl propyl)-dimethylamine13 as a
CHCl3); IR (KBr)
m = 3449, 3296, 2194, 1739, 1680, 1640,
1597 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.50 (d, J = 8.1 Hz, 2H),
;
colorless oil. Yield: 53%; ½a D22:1
ꢁ
¼ ꢀ18:5 (c 1.00, CHCl3); IR (neat)
7.26 (d, J = 8.2 Hz, 2H), 6.24 (d, J = 4.5 Hz, 1H), 4.72 (s, 2H), 4.29
(d, J = 4.3 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) d
171.6, 167.1, 160.7, 159.3, 141.1, 138.3, 132.9, 132.4, 130.6,
122.2, 115.1, 111.2, 58.9, 53.0, 38.3, 29.9; LRMS (EI): m/e 102
(76.37), 119 (36.99), 179 (100), 209 (44.88), 275 (46.98), 334
(M+, 25.51); HRMS (EI): 333.9950; Calcd for C14H11BrN2O3:
333.9953. The enantiomeric ratio was determined by HPLC analy-
sis, using a Chiralcel OD column (25 °C, 254 nm, 1:4, hexane/2-pro-
panol, 0.1 mL/min); tmajor = 56.6 min, tminor = 49.5 min.
m
= 3550, 2972, 2880, 1615, 1540, 1383 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.17–7.33 (m, 10H), 2.88 (s, 4H), 2.08–2.42 (m, 20H);
13C NMR (100 MHz, CDCl3) d 181.4, 136.6, 128.6, 127.4, 125.6,
61.3, 53.2, 44.2, 37.9; LRMS (EI): m/e 58 (100), 91 (36.61), 161
(92.81), 238 (47.32), 398 (M+, 2.03); HRMS (EI): 398.2507; Calcd
for C23H34N4S: 398.2504.
4.3. General procedure for the asymmetric synthesis of 4H-pyran
derivatives 4a–4m
4.3.5. (S)-Methyl 6-amino-5-cyano-4-(2,4-dichlorophenyl)-4H-
To a solution of b,c-unsaturated a-keto ester (0.1 mmol) and
pyran-2-carboxylate 4e.
White solid. yield: 62%. Mp 165–168 °C; ½a D22:1
¼ ꢀ189:5 (c 1.00,
ꢁ
malononitrile (0.11 mmol) in 2.0 mL of toluene, 1a (0.005 mmol)
was added. The mixture was sealed and stirred at ꢀ30 °C for the
time indicated in Table 2 (monitored by TLC). Then the solvent
was removed under reduced pressure and the crude product was
purified by column chromatography on silica gel (hexane/ace-
tate = 5:1) to afford the corresponding products.
CHCl3); IR (KBr) m ;
= 3461, 3429, 2190, 1745, 1683, 1642, 1596 cmꢀ1
1H NMR (300 MHz, CDCl3) d 7.17(s, 1H), 7.29–7.30 (m, 2H), 6.28 (d,
J = 4.5 Hz, 1H), 4.85–4.86 (m, 3H), 3.82 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 160.4, 160.3, 138.8, 137.2, 134.3, 133.5, 130.8, 129.7,
128.1, 118.7, 113.6, 56.5, 52.8, 35.0, 30.0; LRMS (EI): m/e 119
(25.97), 136 (23.90), 179 (100), 199 (58.57), 265 (43.44), 324 (M+,
23.89); HRMS (EI): 324.0059; Calcd for C14H10Cl2N2O3: 324.0068.
The enantiomeric ratio was determined by HPLC analysis, using a
Chiralcel OD column (25 °C, 254 nm, 1:4, hexane/2-propanol,
0.1 mL/min); tmajor = 54.3 min, tminor = 48.2 min.
4.3.1. (R)-Methyl 6-amino-5-cyano-4-phenyl-4H-pyran-2-car-
boxylate 4a
White solid. yield: 64%. Mp 171–173 °C; ½a D22:1
ꢁ
¼ ꢀ105:6 (c 1.00,
CHCl3); IR (KBr)
m
= 3437, 2197, 1740, 1683, 1644, 1590 cmꢀ1 1H
;

1050
S.-L. Zhao et al. / Tetrahedron: Asymmetry 20 (2009) 1046–1051
4.3.6. (R)-Methyl
6-amino-5-cyano-4-(4-nitrophenyl)-4H-
134.8, 129.0, 128.7, 127.9, 127.8, 119.1, 115.8, 67.6, 59.0, 38.6,
pyran-2-carboxylate 4f.
30.9; LRMS (EI): m/e 66 (27.16), 77 (29.19), 91 (100), 131 (14.47),
197 (29.53), 255 (24.04), 332 (M+, 10.13); HRMS (EI): 332.1169;
Calcd for C20H16N2O3: 332.1161. The enantiomeric ratio was deter-
mined by HPLC analysis, using a Chiralcel AD column (25 °C,
254 nm, 4:1, hexane/2-propanol, 0.5 mL/min); tmajor = 47.8 min,
tminor = 38.5 min.
Yellow solid; yield: 50%. Mp 223–225 °C; ½a D22:1
¼ ꢀ10:3 (c 1.00,
ꢁ
CHCl3); IR (KBr)
m = 3438, 3200, 2194, 1736, 1681, 1648,
1589 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.25 (d, J = 9 Hz, 2H), 7.44
;
(d, J = 9 Hz, 2H), 6.26 (d, J = 4.2 Hz, 1H), 4.79 (s, 2H), 4.45 (d,
J = 4.3 Hz, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, acetone-d6) d
160.2, 160.2, 150.4, 147.4, 139.1, 129.1, 123.9, 118.4, 113.8, 55.8,
52.0, 38.5; LRMS (EI): m/e 119 (33.28), 179 (100), 196 (11.70), 242
(57.59), 301 (M+, 38.95); HRMS (EI): 301.0697; Calcd for
C14H11N3O5: 301.0699. The enantiomeric ratio was determined by
HPLC analysis, using a Chiralcel OD column (25 °C, 254 nm, 1:4, hex-
ane/2-propanol, 0.1 mL/min); tmajor = 64.0 min, tminor = 58.3 min.
4.3.11. (R)-4-Bromobenzyl
6-amino-5-cyano-4-phenyl-4H-
pyran-2-carboxylate 4k.
White solid; yield: 58%. Mp 137–139 °C; ½a D22:1
¼ ꢀ50:1 (c 1.00,
ꢁ
CHCl3); IR (KBr)
m = 3440, 3392, 3315, 2189, 1732, 1677, 1599,
1481 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.22–7.51 (m, 9H), 6.30
;
(d, J = 4.5 Hz, 1H), 5.22 (q, 2H), 4.67 (s, 2H), 4.31 (d, J = 4.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 160.3, 159.4, 142.0, 138.4,
134.0, 132.1, 1305, 128.0, 123.1, 119.3, 116.3, 67.0, 59.2, 38.9,
30.6; LRMS (EI): m/e 90 (38.62), 131 (18.39), 171 (100), 197
(77.84), 335 (17.14), 411 (M+, 7.18); HRMS (EI): 410.0268; Calcd
for C20H15BrN2O3: 410.0266. The enantiomeric ratio was deter-
mined by HPLC analysis, using a Chiralcel OD column (25 °C,
254 nm, 4:1, hexane/2-propanol, 0.5 mL/min); tmajor = 56.6 min,
tminor = 48.4 min.
4.3.7. (R)-Methyl6-amino-5-cyano-4-(4-ethoxyphenyl)-4H-
pyran-2-carboxylate 4g.
White solid; yield: 61%. Mp 137–139 °C; ½a D22:1
¼ ꢀ96:1 (c 1.00,
ꢁ
CHCl3); IR (KBr)
m = 3437, 3299, 2195, 1739, 1679, 1640, 1599,
1511 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.14 (d, J = 8.4 Hz, 2H),
;
6.88 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 4.8 Hz, 1H), 4.65 (s, 2H), 4.25
(d, J = 4.8 Hz, 1H), 4.01 (q, 2H), 3.82 (s, 3H), 1.41 (t, 3H); 13C NMR
(100 MHz, CDCl3) d 161.0, 159.3, 138.3, 134.3, 129.0, 119.5,
116.1, 115.2, 63.7, 59.4, 52.9, 38.0, 15.0; LRMS (EI): m/e 119
(80.74), 179 (95.42), 241 (100), 300 (M+, 97.25); HRMS (EI):
300.1112; Calcd for C16H16N2O4: 300.1110. The enantiomeric ratio
was determined by HPLC analysis, using a Chiralcel OD column
(25 °C, 254 nm, 1:4, hexane/2-propanol, 0.1 mL/min); tmajor = 61.7 -
min, tminor = 48.1 min.
4.3.12. (R)-Isopropyl 6-amino-5-cyano-4-phenyl-4H-pyran-2-
carboxylate 4l.
White solid; yield: 57%. Mp 198–200 °C; ½a D22:1
¼ ꢀ63:0 (c 1.00,
ꢁ
CDCl3); IR (KBr)
m = 3447, 3333, 2193, 1722, 1678, 1637,
1597 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.25–7.38 (m, 5H), 6.25
;
(d, J = 4.5 Hz, 1H), 5.13 (m, 1H), 4.71 (s, 2H), 4.30 (d, J = 4.8 Hz,
1H), 1.26–1.31 (m, 6H); 13C NMR (100 MHz, CDCl3) d 160.0,
159.5, 142.3, 138.9, 129.3, 128.1, 119.5, 115.2, 59.2, 38.9, 31.2,
21.9; LRMS (EI): m/e 131 (62.43), 165 (90.73), 197 (100), 284
(M+, 41.95); HRMS (EI): 284.1167; Calcd for C16H16N2O3:
284.1161. The enantiomeric ratio was determined by HPLC analy-
sis, using a Chiralcel OD column (25 °C, 254 nm, 1:4, hexane/2-pro-
panol, 0.1 mL/min); tmajor = 59.7 min, tminor = 49.7 min.
4.3.8. (S)-Methyl
6-amino-4-(2-bromophenyl)-5-cyano-4H-
pyran-2-carboxylate 4h.
White solid; yield: 65%. Mp 181–183 °C; ½a D22:1
¼ ꢀ173:5 (c
ꢁ
1.00, CHCl3); IR (KBr)
m = 3467, 3340, 2194, 1729, 1686, 1644,
1601 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.57 (d, J = 8.1 Hz, 1H),
;
7.27–7.39 (m, 2H), 7.16 (t, 1H), 6.33 (d, J = 4.8 Hz, 1H), 4.92 (s,
2H), 4.89 (d, J = 4.5 Hz, 1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.9, 160.5, 140.4, 138.7, 133.5, 130.4, 129.6, 128.7, 123.3,
119.1, 114.6, 57.2, 53.0, 38.1; LRMS (EI): m/e 102 (50.57), 130
(33.91), 179 (100), 255 (51.98), 334 (M+, 11.78); HRMS (EI):
333.9965; Calcd for C14H11BrN2O3: 333.9953. The enantiomeric ra-
tio was determined by HPLC analysis, using a Chiralcel OD column
(25 °C, 254 nm, 1:4, hexane/2-propanol, 0.1 mL/min); tmajor = 51.1 -
min, tminor = 68.7 min.
4.3.13. (R)-Allyl
6-amino-5-cyano-4-phenyl-4H-pyran-2-car-
boxylate 4m.
White solid; yield: 60%. Mp 156–158 °C; ½a D22:1
¼ ꢀ99:5 (c 1.00,
ꢁ
CDCl3); IR (KBr)
m = 3438, 3317, 2199, 1741, 1682, 1646,
1594 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.24–7.40 (m, 5H), 6.31
;
(d, J = 4.2 Hz, 1H), 5.87–5.99 (m, 1H), 5.27–5.38 (m, 2H), 4.70–
4.73 (m, 4H), 4.31 (d, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 159.9, 159.2, 141.9, 138.3, 131.2, 129.1, 127.9, 127.8, 119.5,
119.2, 115.7, 66.4, 58.8, 38.6, 29.7; LRMS (EI): m/e 131 (58.52),
197 (100), 205 (82.99), 282 (M+, 44.34); HRMS (EI): 282.1000;
Calcd for C16H14N2O3: 282.1004. The enantiomeric ratio was deter-
mined by HPLC analysis, using a Chiralcel AD column (25 °C,
254 nm, 4:1, hexane/2-propanol, 0.5 mL/min); tmajor = 33.0 min,
tminor = 24.8 min.
4.3.9. (S)-Methyl 6-amino-5-cyano-4-(2,5-dimethoxyphenyl)-
4H-pyran-2-carboxylate 4i.
White solid; yield: 65%. Mp 133–135 °C; ½a D22:1
¼ ꢀ153:8 (c
ꢁ
1.00, CHCl3); IR (KBr)
m = 3310, 3002, 2958, 2184, 1740, 1661,
1503, 1465 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.68 (s, 1H), 7.19
;
(m, 2H), 6.73 (d, J = 5.4 Hz, 1H) 5.17 (d, J = 5.4 Hz, 1H), 5.14 (s,
2H), 4.23(s, 3H), 4.22 (s, 3H), 4.18 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 161.1, 160.4, 154.3, 151.0, 138.6, 131.0, 112.0, 115.9,
115.8, 112.9, 111.9, 57.4, 56.3, 56.0, 52.8, 32.1; LRMS (EI): m/e
158 (100), 191 (69.04), 289 (69.75), 316 (M+, 89.06); HRMS (EI):
316.1056; Calcd for C16H16N2O5: 316.1059. The enantiomeric ratio
was determined by HPLC analysis, using a Chiralcel OD column
(25 °C, 254 nm, 1:4, hexane/2-propanol, 0.1 mL/min); tmajor = 62.3 -
min, tminor = 50.0 min.
References
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4.3.10. (R)-Benzyl 6-amino-5-cyano-4-phenyl-4H-pyran-2-car-
boxylate 4j.
White solid. yield: 63%. Mp 140–142 °C; ½a D22:1
¼ ꢀ55:6 (c 1.00,
ꢁ
CHCl3); IR (KBr)
m = 3437, 3407, 3326, 2186, 1741, 1676, 1636,
1599 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.22–7.36 (m, 10H), 6.30
;
(d, J = 4.5 Hz, 1H), 5.24 (q, 2H),4.73 (s, 2H), 4.29 (d, J = 4.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 160.1, 159.1, 141.8, 138.3,

S.-L. Zhao et al. / Tetrahedron: Asymmetry 20 (2009) 1046–1051
1051
5. For recent examples: (a) Jin, T. S.; Zhang, J. S.; Liu, L. B.; Wang, A. Q.; Li, T. S.
Synth. Commun. 2006, 36, 2009; (b) Zhang, A. Q.; Zhang, M.; Chen, H. H.; Chen,
J.; Chen, H. Y. Synth. Commun. 2007, 37, 231; (c) Foroumadi, A.; Dehghan, G.;
Samzadeh-Kermani, A.; Arabsorkhi, F.; Sorkhi, M.; Shafiee, A.; Abdollahi, M.
Asian J. Chem. 2007, 19, 1391; (d) Kumar, R. R.; Perumal, S.; Senthilkumar, P.;
Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2007, 17, 6459; (e) Peng, Y.
Q.; Song, G. H. Catal. Commun. 2007, 8, 111; (f) Shanthi, G.; Perumal, P. T.
Tetrahedron Lett. 2007, 48, 6785; (g) Elinson, M. N.; Dorofeev, A. S.; Merkulova,
V. M.; Stepanov, N. O.; Miloserdov, F. M.; Ogibin, Y. N.; Nikishin, G. I.
Tetrahedron 2007, 63, 10543; (h) Guo, S. B.; Wang, S.-X.; Li, J.-T. Synth. Commun.
2007, 37, 2111; (i) Costa, M.; Areias, F.; Abrunhosa, L.; Venncio, A.; Proena, F. J.
Org. Chem. 2008, 73, 1954; (j) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Rahmati,
A. Synth. Commun. 2008, 38, 274; (k) Babu, N. S.; Pasha, N.; Rao, K. T. V.; Prasad,
P. S. S.; Lingaiah, N. Tetrahedron Lett. 2008, 49, 2730; (l) Gonzalez, R.; Martin, N.;
Seoane, C.; Marco, J. L.; Albert, A.; Cano, F. H. Tetrahedron Lett. 1992, 33, 3809.
Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625; (e) Sohtome, Y.; Tanatani, A.;
Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589; (f) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119;
(g) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894; (h)
Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (i) Tan, K. L.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315; (j) Zhou, W. M.; Liu, H.; Du,
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2008, 691.
9. (a) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603; (b)
Tsogoeva, S. B.; Huthmacher, K. Eur. J. Org. Chem. 2005, 4995; (c) Ishihara, K.;
Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504; (d) Andrés, J. M.; Anzano, R. M.;
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Wu, X. J. Chem. Commun. 2008, 1431.
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2008, 1208.
6. For recent examples utilizing b,
c
-unsaturated
a
-keto ester as electrophiles,
11. CCDC-716175 contains the supplementary crystallographic data for 4d. These
data can be obtained free of charge from the Cambridge Crystallographic Data
centre via www.ccdc.cam.ac.uk/data_request/cif.
see: (a) Zhou, J.; Tang, Y. Org. Biomol. Chem. 2004, 2, 429; (b) Tardy, S.;
Tatibouët, A.; Rollin, P.; Dujardin, G. Synlett 2006, 1425; (c) Desimoni, G.; Faita,
G.; Mella, M.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2007, 1529; (d)
Gohier, F.; Bouhadjera, K.; Faye, D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.;
12. This compound was prepared according to Ref. 10c. Characterizing data:
colorless oil; ½a D22:1
¼ þ44:2 (c 2.00, CDCl3); IR (film) m = 3373, 2968, 2931,
ꢁ
Dhal, R. Org. Lett. 2007, 9, 211; (e) Herrera, R. P.; Monge, D.; Elolsa, M. Z.;
1602, 1495 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.18–7.29 (m, 5H), 3.37 (s, 2H),
;
´
Fernández, R.; Lassaletta, J. M. Org. Lett. 2007, 9, 3303; (f) Wang, Q. G.; Deng, X.
M.; Zhu, B. H.; Ye, L. W.; Sun, X. L.; Li, C. Y.; Zhu, C. Y.; Shen, Q.; Tang, Y. J. Am.
Chem. Soc. 2008, 130, 5408; (g) Wang, J.; Yu, F.; Zhang, X. J.; Ma, D. W. Org. Lett.
2008, 10, 2561; (h) Zheng, C.; Wu, Y.; Wang, X.; Zhao, G. Adv. Synth. Catal. 2008,
350, 2690; (i) Wang, H.-F.; Zheng, C.-W.; Yang, Y.-Q.; Chai, Z.; Zhao, G.
Tetrahedron: Asymmetry 2008, 19, 2608.
3.11–3.37 (m, 1H), 2.37–2.79 (m, 8H), 0.99 (t, J = 7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 138.7, 129.2, 128.5, 126.3, 58.8, 50.8, 47.4, 41.0, 11.8; LRMS
(EI): m/e 58 (9.72), 72 (11.70),86 (100), 91 (7.88), 206 (M+, 0.56); HRMS (EI):
206.1779; Calcd for C13H22N2: 206.1783.
13. This compound was prepared according to Ref. 10b. Characterizing data: white
solid; M.p. 86–88 °C; ½a D22:1
ꢁ
¼ ꢀ47:0 (c 1.50, CDCl3); IR (KBr)
m = 3085, 3062,
7. (a) Wang, X.-S.; Yang, G.-S.; Zhao, G. Tetrahedron: Asymmetry 2008, 19, 709;
(b) Wang, X. -S.; Zheng, C. -W.; Zhao, S. -L.; Chai, Z.; Zhao, G.; Yang, G. -S.
Tetrahedron: Asymmetry 2008. doi:10.1016/j.tetasy.2008.11.025.
8. For asymmetric reactions promoted by urea or thiourea catalysts, see: (a)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901; (b) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012; (c) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (d) Okino, T.; Nakamura, S.;
2100, 1603, 1535, 1454 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.22–7.37 (m, 5H),
;
3.91–3.40 (m, 1H), 2.97–3.03 (m, 1H), 2.81–2.88 (m, 1H), 2.50–2.57 (m, 1H),
2.41–2.47 (m, 1H), 2.29 (s, 6H); 13C NMR (100 MHz, CDCl3) d 135.6, 131.9,
128.5, 127.6, 126.1, 62.2, 57.3, 44.8, 38.9; LRMS (EI): m/e 42 (7.76), 58 (100), 91
(9.55), 129 (24.43), 220 (M+, 4.93); HRMS (EI): 220.1034; Calcd for C12H16N2S:
220.1036.