Organocatalytic conjugate addition of malononitrile to conformationally restricted dienones

Article abstract of DOI:10.1021/jo200112r

Organocatalytic conjugate addition of malononitrile to conformationally restricted dienones has been studied. A series of chiral primary and tertiary amine catalysts were screened. A piperidine-based thiourea-tertiary amine was found to be the efficient c

Full text of DOI:10.1021/jo200112r

ARTICLE
pubs.acs.org/joc
Organocatalytic Conjugate Addition of Malononitrile to
Conformationally Restricted Dienones
Zhi-Peng Hu, Chun-Liang Lou, Jin-Jia Wang, Chun-Xia Chen, and Ming Yan*
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China
S Supporting Information
b
ABSTRACT: Organocatalytic conjugate addition of malononitrile
to conformationally restricted dienones has been studied. A series of
chiral primary and tertiary amine catalysts were screened. A
piperidine-based thiourea-tertiary amine was found to be the
efficient catalyst. Chiral pyran derivatives were obtained in
excellent yields and enantioselectivities via a cascade conjugate
additionꢀintramolecular cyclization pathway. The reaction is
remarkably different for the corresponding reaction of conforma-
tionally flexible dienones.
Scheme 1. Organocatalytic Conjugate Addition of Malono-
nitrile to Dienones
’ INTRODUCTION
In the recent decade, great progress has been achieved in
organocatalytic asymmetric reactions.1 Among various organo-
catalytic reactions developed so far, organocatalytic conjugate
additions have proven to be extremely powerful and diversified. A
large number of Michael acceptors and nucleophilic reagents
have been applied successfully.2 In addition, cascade reactions
triggered by organocatalytic conjugate addition provide highly
efficient and convenient methods to construct polycyclic chiral
compounds.3 Recently we found that organocatalytic conjugate
addition of malononitrile to dienones generated chiral cyclohex-
anones in excellent yields, diastereoselectivities, and enantios-
electivities (Scheme 1, eq 1).4 A mechanism of double conjugate
addition was suggested to explain the experimenal results.
Interestingly, in this study we observed only a trace amount of
single conjugate addition product. We proposed that the con-
sequent intramolecular conjugate addition proceeds faster than
the first intermolecular conjugate addition. Thus, we become
interested in the reaction of conformationally restricted die-
nones. When such substrates are adopted, the necessary con-
formation for the second intramolecular conjugate addition
cannot be achieved, and the reaction should stop after the first
conjugate addition. In this paper, we reported organocatalytic
conjugate addition of malononitrile to conformationally re-
stricted dienones. The reaction provided bicyclic pyran deriva-
tives via new cascade steps (Scheme 1, eq 2). In addition,
significantly different requirements of organocatalysts and reac-
tion conditions were observed.
conjugate addition of malononitrile to chalcones.5cꢀe Initially
we studied the reaction of 3,5-bis(benzylidene)-4-piperidone 1a
and malononitrile 2a. A series of organocatalysts 3a-3h
(Scheme 2) were screened and the results are summarized in
Table 1. 9-Amino-9-deoxyepiquinine (3a), which is the best
catalyst in our previous study of conformationally flexible
dienones,4 was examined first. As expected, the reaction did
not give the single conjugate addition product. Instead bicyclic
pyran 4a was obtained in poor yield and enantioselectivity
(Table 1, entries 1ꢀ2). The product 4a obviously generated
from the primary conjugate addition intermediate through an
’ RESULTS AND DISCUSSION
Recently malononitrile had been used as a useful nucleophilic
reagent in asymmetric organocatalytic conjugate additions.5
Moderate to good enantioselectivities were achieved for
Received: January 18, 2011
Published: April 05, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 2. Organocatalysts 3aꢀ3i
Table 1. Screening of Catalystsa
entry
catalyst
time (h)
yield (%)b
ee (%)c
1
2d
3
4
5
6
7
8
9
3a
3a
3b
3c
3d
3e
3f
96
48
96
72
72
72
96
36
72
24
37
30
52
89
95
95
97
95
21
6
2
34
85
79
77
81
96
3g
3h
a The reactions were carried out with 1a (0.100 mmol), 2a (0.105 mmol), and 3aꢀ3h (0.010 mmol) in toluene (1.0 mL) at room temperature. b Isolated
yields by centrifugation. c Determined by chiral HPLC. d The reaction was carried out with 20 mol % 3a and 40 mol % trifluoroacetic acid in CHCl3
according to the optimum reaction conditions in ref 4.
intramolecular addition of enolate oxygen anion to the nitrile
group and a consequent tautomerization. Similar cascade reaction
was also reported in base-promoted addition of malononitrile
to 1a.6 Compound 4a is almost insoluble in toluene and was
deposited as a white solid after the reaction. It could be readily
obtained by the centrifugation. Perumal and co-workers reported
that racemic 4a and its analogues showed significant inhibitive
activity against Mycobacterium tuberculosis and multidrug resistant
M. tuberculosis.6h To the best of our knowledge, homochiral 4a and
its analogues have never been prepared. Currently, the effect of the
chiral center on the biological activity of these compounds is
unknown. We extended our screening to bifunctional chiral
primary amine catalysts 3b7 and 3c.8 Again, only low yields and
enantioselectivities were achieved (Table 1, entries 3ꢀ4). We
turned our attention to chiral tertiary amine catalysts. Takemoto’s
catalyst 3d was demonstratedtobea betterchoicefor thisreaction.
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Table 2. Effect of Reaction Solventsa
Table 3. Effect of Reaction Conditionsa
entry
solvent
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9e
hexane
toluene
CH2Cl2
CHCl3
THF
72
72
72
72
72
72
72
72
72
56
95d
56
33
96
47
75
11
21
2
76
53
Et2O
49
entry
x
time (h)
yield (%)b
ee (%)c
CH3CN
EtOH
22
79
94 d
0
1
10
10
10
5
72
28
94
96
93
89
85
90
98
99
98
99
98
96
toluene
98
2d
3e
4
a The reactions were carried out with 1a (0.100 mmol), 2a (0.105
mmol), and 3h (0.010 mmol) in solvent (1.0 mL) at room temperature.
b Isolated yields by column chromatography. c Determined by
chiral HPLC. d Isolated yields by centrifugation. e Catalyst 3i was used.
12
96
5
6f
2.5
10
120
120
a The reactions were carried out with 1a (0.100 mmol), 2a (0.105
mmol), and 3i in toluene (1.0 mL) at room temperature. b Isolated yields
by centrifugation. c Determined by chiral HPLC. d 2a (0.150 mmol)
was used. e 2a (0.200 mmol) was used. f The reaction was carried out at
0 °C.
Excellent yield and good enantioselectivity could be obtained
(Table 1, entry 5).9 Quinine-derived thiourea catalyst 3e10 and
squaric acid-derived catalyst 3f11 were also examined. Although
excellent yields were obtained, no improvement in enantioselec-
tivity was achieved (Table 1, entries 6ꢀ7). Further optimization
was focused on the modifications of Takemoto’s catalyst. In a
recent study of organocatalytic conjugate addition of malonates to
3-nitro-2H-chromenes, we found that pyrrolidine-based catalyst
3g provided better enantioselectivity than Takemoto’s catalyst.12
The application of 3g in this transformation gave better yield but
lower enantioselectivity(Table 1, entry8). Furtheroptimization of
catalyst structure led to piperidine-based catalyst 3h. To our
delight, significant improvement in enantioselectivity was achieved
using 3h as the catalyst (Table 1, entry 9).
A number of reaction solvents were also examined and the
results are summarized in Table 2. The effect of reaction solvent
is significant. Low yield and enantioselectivity were obtained in
hexane (Table 2, entry 1). Both dichloromethane and chloro-
form gave inferior yields and enantioselectivities (Table 2, entries
3ꢀ4). Even lower enantioselectivities were obtained in THF and
ether (Table 2, entries 5ꢀ6). Polar solvent, such as ethanol and
acetonitrile are incompatible for the reaction and almost racemic
products were obtained (Table 2, entries 7ꢀ8). Catalyst 3i,
which is the enantiomer of 3h, was also prepared and examined in
the reaction. The enantiomeric product of 4a was obtained in
excellent yield and enantioselectivity (Table 2, entry 9).
The effect of other reaction conditions was also studied and
the results are summarized in Table 3. Slightly better yield and
enantioselectivity could be achieved by increasing the loading of
2a to 1.5 equivalents (Table 3, entry 2). Further increase of the
loading of 2a did not improve the reaction performance (Table 3,
entry 3). While the loadings of catalyst 3i were decreased to
5 mol % and 2.5 mol % respectively, longer reaction time was
required. The products were obtained with similar enantioselec-
tivities (Table 3, entries 4ꢀ5). The reaction was also examined at
0 °C, but inferior yield and enantioselectivity were obtained after
extended reaction time (Table 3, entry 6).
A variety of (3E,5E)-3,5-diarylmethylene-piperidin-4-ones
were examined and the results are summarized in Table 4. Para
substitutions of the benzene ring with methyl, methoxyl, and
halogen were tolerated very well (Table 4, entries 2ꢀ6).
p-Nitro substitution gave excellent yield, however with decreased
enantioselectivity (Table 4, entry 7). m-Chloro and m-nitro
substitutions led to excellent yields and good enantioselectivities
(Table 4, entries 8ꢀ9). o-Chloro and o-MeO substitution also
gave excellent yields and enantioselectivities (Table 4, entries
10ꢀ11). The replacement of phenyl groups with furanyl or
thiophenyl groups were also studied. The resulted dienones 1l
and 1m showed lower reactivity and longer reaction time was
necessary. 1l provided the product 4l in moderate yield and with
good enantioselectivity (Table 4, entry 12). 1m gave both
excellent yield and enantioselectivity (Table 4, entry 13).
Cinnamyl-methylene-substituted substrate 1n provided moder-
ate yield and enantioselectivity (Table 4, entry 14). 3,5-Dicyclo-
hexanylene-piperidin-4-one 1o is also applicable. Good yield
and enantioselectivity could be achieved using 40 mol % 3i
after extended reaction time (Table 4, entries 15). 1-Benzyl-3,
5-dibenzylidine-piperidin-4-one 1p gave excellent yield and
enantioselectivity (Table 4, entry 16). The results demonstrated
that N-substitution of 3,5-bis(benzylidene)-4-piperidone does not
exert a substantial effect on the reaction. While ethyl cyanoacetate 2b
was used, the expected product 4q wasobtainedinlowyieldandwith
excellent enantioselectivity (Table 4, entry 17).
The absolute configuration of the product 4e was assigned as R
on the basis of the X-ray diffraction analysis.13 The same absolute
configurations are assigned for other products analogously. A
number of conformationally restricted dienones 5aꢀ5e were
also examined, and the results are summarized in Table 5. 4-Oxa,
4-thio, and 4-methylene substrates 5aꢀ5c provided excellent
yields and good to excellent enantioselectivities (Table 5, entries
1ꢀ3). (2E,5E)-2,5-Dibenzylidenecyclopentan-one 5d also pro-
vided excellent yield and enantioselectivity (Table 5, entry 4).
However, the seven-membered ring analogue, 5e, showed lower
reactivity. Higher catalyst loading and extended reaction time
were required. The product 6e was obtained with excellent
enantioselectivity but in moderate yield (Table 5, entry 5).
Under the present reaction conditions, acyclic dienone 5f
provided the pyran product in only 5% yield (Table 5,
entry 6); instead chiral cyclohexanone (7, 70% yield, 94% ee)
was obtained via double conjugate addition.4
Furthermore, unsymmetrical dienones 8a and 8b were pre-
pared and examined in the reaction (Scheme 3). In the case of 7a,
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Table 4. Conjugate Addition of Malononitrile to Dienones
Table 5. Conjugate Addition of Malononitrile to Dienones
1aꢀ1p.a
5aꢀ5f. a
entry
R1
phenyl
R2
time (h)
yield (%)
ee (%)b
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
28
42
52
36
28
36
72
30
40
38
30
96
72
72
96
30
72
4a, 96c
4b, 98c
4c, 84c
4d, 99d
4e, 95d
4f, 94d
4g, 98d
4 h, 99d
4i, 99c
4j, 99d
4k, 99d
4l, 75d
4 m, 95 c
4n, 50d
4o, 93d
4p, 95d
4q, 48d
99
94
94
93
96
94
87
91
90
91
97
92
97
77
83
91
98
2
4-Me-phenyl
4-MeO-phenyl
4-Cl-phenyl
4-Br-phenyl
4-F-phenyl
4-NO2-phenyl
3-Cl-phenyl
3- NO2-phenyl
2-Cl-phenyl
2-MeO-phenyl
furan-2-yl
3
4
5
6
7
8
9
10
11
12
13
14
15e
16
17f
entry
5
time (h)
yield (%)
ee (%)b
1
2
3
4
5e
6
5a
5b
5c
5d
5e
5f
20
36
42
20
96
6
6a, 99c
6b, 99c
6c, 97c
6d, 97d
6e, 52d
6f, 5d
95
88
thiophen-2-yl
E-styryl
92
92
cyclohexanyl
phenyl
91
Ndf
phenyl
Me
a Reactions were carried out with 5aꢀ5f (0.10 mmol), 2aꢀ2b (0.15
a Reactions were carried out with 1aꢀ1p (0.10 mmol), 2a (0.15 mmol),
mmol), and 3i (0.01 mmol) in toluene (1.0 mL) at room temperature.
and 3i (0.01 mmol) in toluene (1.0 mL) at room temperature.
d
b Determined by chiral HPLC. c Isolated yields by centrifugation.
b Determined by chiral HPLC. c Isolated yields by centrifugation.
d
Isolated yields by flash column chromatography. e 3i (0.04 mmol)
Isolated yields by flash column chromatography. e 3i (0.04 mmol)
was used. f 2b (0.15 mmol) was used.
was used. f Not determined.
’ EXPERIMENTAL SECTION
two regioisomeric pyran derivatives (9a/9a0) were obtained in
excellent yield and enantioselectivities. The reaction was slightly
favorable for the attack from the 4-MeO-phenyl-substituted side.
Dienone 8b with phenyl and cyclohexanyl substitutions showed
lower reactivity. Two regioisomeric pyran derivatives (9b/9b0)
were obtained in moderate yield after 72 h. The reaction
occurred preferentially at the cyclohexanyl-substituted side and
gave 9b as the major product. Good to moderate enantioselec-
tivities were obtained for 9b and 9b0, respectively.
General Information. All solvents were used as commercial
anhydrous grade without further purification. The flash column chro-
matography was carried out over silica gel (230ꢀ400 mesh). 1H and 13
C
NMR spectra were recorded on a 400 MHz spectrometer as solutions in
1
CDCl3. Chemical shifts in H NMR spectra are reported in parts per
million (ppm, δ) downfield from the internal standard Me4Si (TMS, δ =
0 ppm). Chemical shifts in 13C NMR spectra are reported relative to the
central line of the chloroform signal (δ = 77.0 ppm). Peaks are labeled as
singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). High-
resolution mass spectra were obtained with a LCMS-IT-TOF mass
spectrometer. Infrared (IR) are represented as frequency of absorption
(cmꢀ1). Enantiomeric excesses of compounds were determined by
HPLC using a Daicel Chiralpak AD-H column. (3E,5E)-3,5-Bis-
(arylmethylidene)-4-piperidones 1aꢀ1q and their analogues 5aꢀ5f
were prepared according to the reported procedures.6a,14 Organocata-
lysts 3a,15 3b,8 3c,8 3d,9 3e,10b 3f,11 3g,16 3h,12 and 3i12 were prepared
according to the literature, respectively.
General Procedure for the Synthesis of Racemic Products.
A mixture of (3E,5E)-3,5-dibenzylidene-1-methylpiperidin-4-one 1a
(28.9 mg, 0.1 mmol), malononitrile 2a (9.9 mg, 0.15 mmol), and
piperidine (8.5 mg, 0.1 mmol) in ethanol (1 mL) was stirred for 30
min at room temperature. The precipitate was filtered to provide
racemic 4a as a white solid (80% yield).
’ CONCLUSIONS
In conclusion, we have developed enantioselective organoca-
talytic addition of malononitrile to conformationally restricted
dienones. A bifunctional thiourea tertiary amine was identified as
the efficient catalyst. Generally excellent enantioselectivities and
yields were achieved for a variety of dienones with various
substitutents and different ring sizes. The results are significantly
different from the reaction of conformationally flexible dienones.
The chiral pyran derivatives obtained in high enantiopurity are
potential inhibitors against M. tuberculosis. Further studies on the
other related reactions and the determination of inhibitive
activity of chiral products are currently under way.
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Scheme 3. Reaction of Unsymmetrical Dienones
General Procedure for Organocatalytic Conjugate Addi-
tion of Malononitrile to Dienones. A mixture of (3E,5E)-3,5-
dibenzylidene-1-methylpiperidin-4-one 1a (28.9 mg, 0.1 mmol), mal-
ononitrile 2a (9.9 mg, 0.15 mmol), and thiourea 3i (4.5 mg, 0.01 mmol)
in toluene (1 mL) was stirred for 28 h at room temperature. The white
precipitate 4a was collected by centrifugation.
(R,E)-2-Amino-8-benzylidene-6-methyl-4-phenyl-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4a):6e
white solid, mp 191ꢀ194 °C. 1H NMR (400 MHz, CDCl3):
δ 7.39ꢀ7.21 (m, 10 H), 6.90 (s, 1 H), 4.56 (s, 2 H), 4.03 (s, 1 H),
3.58 (d, J = 13.8 Hz, 1 H), 3.38 (d, J = 13.6 Hz, 1 H), 2.97 (d, J = 16.0 Hz,
1 H), 2.75 (d, J = 15.8 Hz, 1 H), 2.26 (s, 3 H); 13C NMR (100 MHz,
CDCl3): δ 158.83, 142.14, 140.16, 136.23, 129.15, 128.94, 128.35,
127.88, 127.62, 127.25, 126.94, 122.90, 119.67, 112.68, 60.65, 55.38,
54.70, 44.85, 41.71; MS (ESI): m/z = 356.2 [M þ H]þ; [R]D20 = þ6.0
(c = 0.28, CH2Cl2); enantiomeric excess was determined by HPLC with
a CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 7.5 min, tr(minor) = 13.4 min.
(R,E)-2-Amino-6-methyl-8-(4-methylbenzylidene)-4-p-to-
lyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carboni-
trile (4b):6a,e white solid, mp 215 °C. 1H NMR (400 MHz, CDCl3):
δ 7.21ꢀ7.07 (m, 8 H), 6.86 (s, 1 H), 4.55 (s, 2 H), 3.98 (s, 1 H), 3.58
(d, J = 13.7 Hz, 1 H), 3.37 (d, J = 13.8 Hz, 1 H), 2.95 (d, J = 16.0 Hz,
1 H), 2.75 (d, J = 15.9 Hz, 1 H), 2.36 (s, 3 H), 2.33 (s, 3 H), 2.26 (s, 3 H);
MS (ESI): m/z = 384.2 [M þ H]þ; [R]D20 = þ16.7 (c = 0.08, CH2Cl2);
enantiomeric excess was determined by HPLC with a CHIRALPAK
AD-H column (i-PrOH/hexane = 30:70, 254 nm, 0.8 mL/min),
tr(major) = 6.8 min, tr(minor) = 14.2 min.
(R,E)-2-Amino-8-(4-bromobenzylidene)-4-(4-bromophe-
nyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
3-carbonitrile (4e):6g,17 white solid, mp 223ꢀ225 °C. 1H NMR (400
MHz, CDCl3): δ 7.50ꢀ7.47 (m, 4 H), 7.11 (dd, J = 22.0, 8.4 Hz, 4H),
6.81 (s, 1 H), 4.57 (s, 2 H), 4.00 (s, 1 H), 3.50 (d, J = 13.7 Hz, 1 H), 3.33
(d, J = 13.7 Hz, 1 H), 2.93 (d, J = 15.9 Hz, 1 H), 2.71 (d, J = 15.9 Hz, 1
H), 2.27 (s, 3 H); MS (ESI): m/z = 514.0 [M þ H]þ; [R]D20 = þ16.3 (c
= 0.10, CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 8.2 min, tr(minor) = 10.2 min.
(R,E)-2-Amino-8-(4-fluorobenzylidene)-4-(4-fluorophen-
yl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
3-carbonitrile (4f):6e white solid, mp 197ꢀ198 °C. H NMR (400
1
MHz, CDCl3): δ 7.24ꢀ7.17 (m, 4 H), 7.08ꢀ7.02 (m, 4 H), 6.86 (s,
1 H), 4.55 (s, 2 H), 4.03 (s, 1 H), 3.52 (d, J = 13.4 Hz, 1 H), 3.36 (d, J =
13.0 Hz, 1 H), 2.95 (d, J = 15.9 Hz, 1 H), 2.72 (d, J = 15.4 Hz, 1 H), 2.28
(s, 3 H); MS (ESI): m/z = 392.2 [M þ H]þ; [R]D20 = þ6.0 (c = 0.10,
CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 7.5 min, tr(minor) = 10.6 min.
(R,E)-2-Amino-6-methyl-8-(4-nitrobenzylidene)-4-(4-nitro-
phenyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-car-
bonitrile (4g):6g,17 yellow solid, mp 214ꢀ217 °C. 1H NMR
(400 MHz, CDCl3): δ 8.25 (d, J = 8.6 Hz, 4 H), 7.45 (d, J = 8.7 Hz,
2 H), 7.38 (d, J = 8.7 Hz, 2 H), 6.96 (s, 1 H), 4.69 (s, 2 H), 4.20 (s, 1 H),
3.53 (d, J = 14.3 Hz, 1 H), 3.40 (d, J = 14.6 Hz, 1 H), 3.01 (d, J = 16.2 Hz,
1 H), 2.72 (d, J = 16.4 Hz, 1 H), 2.29 (s, 3 H); MS (ESI): m/z = 446.2
[M þ H]þ; [R]D20 = þ69.6 (c = 0.09, CH2Cl2); enantiomeric excess
was determined by HPLC with a CHIRALPAK AD-H column (i-PrOH/
hexane = 30:70, 254 nm, 0.8 mL/min), tr(major) = 19.2 min, tr(minor) =
22.4 min.
(R,E)-2-Amino-8-(4-methoxybenzylidene)-4-(4-methoxy-
phenyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyri-
dine-3-carbonitrile (4c):6a,e white solid, mp 185ꢀ187 °C. 1H NMR
(400 MHz, CDCl3): δ 7.18ꢀ7.15 (m, 4 H), 6.91ꢀ6.86 (m,
4 H), 6.83 (s, 1 H), 4.52 (s, 2 H), 3.97 (s, 1 H), 3.83 (s, 3 H), 3.80 (s,
3 H), 3.57 (d, J = 13.7 Hz, 1 H), 3.37 (d, J = 13.8 Hz, 1 H), 2.94 (d, J =
15.8 Hz, 1 H), 2.74 (d, J = 15.8 Hz, 1 H), 2.27 (s, 3 H); MS (ESI): m/z =
(S,E)-2-Amino-8-(3-chlorobenzylidene)-4-(3-chlorophe-
nyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
1
3-carbonitrile (4h): white solid, mp 172ꢀ175 °C. H NMR (400
MHz, CDCl3): δ 7.32ꢀ7.23 (m, 5 H), 7.21 (s, 1 H), 7.14 (dt, J = 6.8,
1.9 Hz, 1 H), 7.10 (d, J = 7.4 Hz, 1 H), 6.83 (s, 1 H), 4.60 (s, 2 H), 4.01
(s, 1 H), 3.53 (d, J = 13.8 Hz, 1 H), 3.35 (d, J = 14.0 Hz, 1 H), 2.96 (d,
J = 16.0 Hz, 1 H), 2.73 (d, J = 15.9 Hz, 1 H), 2.29 (s, 3 H); 13C NMR
(100 MHz, CDCl3): δ 158.97, 144.18, 140.08, 137.91, 134.88, 134.26,
130.23, 129.63, 129.01, 128.01, 127.95, 127.38, 127.23, 126.17, 121.82,
119.36, 112.79, 59.82, 55.20, 54.45, 44.84, 41.53; IR (KBr): 3440, 3329,
2191, 1681, 1637, 1591, 1475, 1390, 1106, 787, 728, 689 cmꢀ1; HRMS
(ESI) calcd for C23H20Cl2N3Oþ [M þ H]þ: 424.0983, found: 424.0973;
[R]D20 = þ4.7 (c = 0.09, CH2Cl2); enantiomeric excess was determined
by HPLC with a CHIRALPAK AD-H column (i-PrOH: hexane =30: 70,
254 nm, 0.8 mL/min), tr(major) = 6.3 min, tr(minor) = 11.9 min.
(R,E)-2-Amino-6-methyl-8-(3-nitrobenzylidene)-4-(3-nitro-
phenyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-car-
bonitrile (4i):6e yellow solid, mp 200ꢀ202 °C. 1H NMR (400 MHz,
20
416.2 [M þ H]þ; [R]D = þ10.2 (c = 0.09, CH2Cl2); enantiomeric
excess was determined by HPLC with a CHIRALPAK AD-H column
(i-PrOH/hexane = 30:70, 254 nm, 0.8 mL/min), tr(major) = 12.4 min,
tr(minor) = 24.0 min.
(R,E)-2-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophe-
nyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
3-carbonitrile (4d):6e white solid, mp 205ꢀ207 °C. 1H NMR (400
MHz, CDCl3): δ 7.35ꢀ7.32 (m, 4 H), 7.21ꢀ7.13 (m, 4 H), 6.84 (s,
1 H), 4.57 (s, 2 H), 4.02 (s, 1 H), 3.51 (d, J = 13.8 Hz, 1 H), 3.35 (d, J =
13.6 Hz, 1 H), 2.94 (d, J = 16.0 Hz, 1 H), 2.72 (d, J = 16.0 Hz, 1 H), 2.27
(s, 3 H); MS (ESI): m/z = 424.1 [M þ H]þ; [R]D20 = þ17.0 (c = 0.11,
CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 7.6 min, tr(minor) = 9.7 min.
3801
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The Journal of Organic Chemistry
ARTICLE
CDCl3): δ 8.20ꢀ8.09 (m, 4 H), 7.63 ꢀ 7.55 (m, 4 H), 6.98 (s, 1 H), 4.70
(s, 2 H), 4.21 (s, 1 H), 3.57 (d, J = 13.0 Hz, 1 H), 3.40 (d, J = 13.2 Hz,
1 H), 3.04 (d, J = 15.6 Hz, 1 H), 2.72 (d, J = 15.4 Hz, 1 H), 2.30 (s, 3 H);
MS (ESI): m/z = 446.2 [M þ H]þ; [R]D20 = þ67.4 (c = 0.13, CH2Cl2);
enantiomeric excess was determined by HPLC with a CHIRALPAK
AD-H column (i-PrOH/hexane = 30:70, 254 nm, 0.8 mL/min),
tr(major) = 11.8 min, tr(minor) = 28.8 min.
CDCl3): δ 5.57 (d, J = 9.6 Hz, 1 H), 4.55 (s, 2 H), 3.36 (d, J = 13.6 Hz,
1 H), 3.10 (d, J = 15.2 Hz, 1 H), 2.95 (d, J = 15.5 Hz, 1 H), 2.74 (d, J = 1.9
Hz, 1 H), 2.41 (s, 3 H), 2.24ꢀ2.14 (m, 1 H), 1.80ꢀ0.99 (m, 21 H); 13C
NMR (100 MHz, CDCl3): δ 161.42, 141.44, 128.80, 123.55, 121.52,
110.93, 56.44, 56.31, 53.80, 45.03, 43.59, 41.34, 36.59, 33.02, 32.97,
30.53, 27.95, 26.78, 26.43, 26.30, 25.91, 25.81; IR (KBr): 3431, 3423,
2945, 2191, 1682, 1638, 1600, 1465, 1390, 1103, 1025, 908, 781,
735 cmꢀ1; HRMS (ESI) calcd for C23H34N3Oþ [M þ H]þ:
(R,E)-2-Amino-8-(2-chlorobenzylidene)-4-(2-chlorophe-
nyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
20
368.2702, found: 368.2684; [R]D = þ15.9 (c = 0.09, CH2Cl2);
3-carbonitrile (4j):6e white solid, mp 208ꢀ210 °C. H NMR (400
1
enantiomeric excess was determined by HPLC with a CHIRALPAK
AD-H column (i-PrOH/hexane = 20:80, 254 nm, 0.8 mL/min),
tr(major) = 5.3 min, tr(minor) = 5.9 min.
MHz, CDCl3): δ 7.35ꢀ7.32 (m, 4H), 7.20ꢀ7.13 (m, 4H), 6.84 (s, 1 H),
4.57 (s, 2 H), 4.02 (s, 1 H), 3.51 (d, J = 13.7 Hz, 1 H), 3.35 (d, J =
13.9 Hz, 1 H), 2.94 (d, J = 16.0 Hz, 1 H), 2.72 (d, J = 16.0 Hz, 1 H),
2.27 (s, 3 H); MS (ESI): m/z = 424.1 [M þ H]þ; [R]D20 = þ9.0 (c =
0.12, CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 7.6 min, tr(minor) = 9.7 min.
(R,E)-2-Amino-6-benzyl-8-benzylidene-4-phenyl-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4p):6g,17
white solid, mp 193ꢀ194 °C. 1H NMR (400 MHz, CDCl3):
δ 7.35ꢀ7.15 (m, 13 H), 7.10 (dd, J = 6.5, 2.8 Hz, 2 H), 6.91 (s, 1 H),
4.56 (s, 2 H), 3.95 (s, 1 H), 3.76 (d, J = 14.0 Hz, 1 H), 3.53ꢀ3.43 (m, 2
H), 3.46 (d, J = 13.9 Hz, 1 H), 3.03 (d, J = 16.2 Hz, 1 H), 2.85 (d, J = 16.3
Hz, 1 H); MS (ESI): m/z = 432.2 [M þ H]þ; [R]D20 = ꢀ18.4 (c = 0.10,
CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 20:80, 254 nm,
0.8 mL/min), tr(major) = 14.9 min, tr(minor) = 17.3 min.
(R,E)-2-Amino-8-(2-methoxybenzylidene)-4-(2-methoxy-
phenyl)-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyr-
idine-3-carbonitrile (4k):6e white solid, mp 179ꢀ180 °C. 1H NMR
(400 MHz, CDCl3): δ 7.29ꢀ7.20 (m, 3 H), 7.09 (dd, J = 7.4, 1.1 Hz,
1H), 6.99ꢀ6.88 (m, 5 H), 4.65 (s, 1 H), 4.51 (s, 2 H), 3.853 (s, 3 H),
3.845 (s, 3 H), 3.45 (d, J = 13.7 Hz, 1 H), 3.31 (d, J = 13.8 Hz, 1 H), 3.01
(d, J = 16.1 Hz, 1 H), 2.78 (d, J = 16.0 Hz, 1 H), 2.23 (s, 3 H); MS (ESI):
(R,E)-Ethyl 2-amino-8-benzylidene-6-methyl-4-phenyl-5,
6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carboxylate
m/z = 416.2 [M þ H]þ; [R]D = ꢀ43.5 (c = 0.11, CH2Cl2);
20
1
(4q): white solid, mp 191ꢀ193 °C. H NMR (400 MHz, CDCl3):
enantiomeric excess was determined by HPLC with a CHIRALPAK
AD-H column (i-PrOH/hexane = 30:70, 254 nm), 0.8 mL/min),
tr(major) = 9.0 min, tr(minor) = 13.2 min.
δ 7.38ꢀ7.17 (m, 10 H), 7.00 (s, 1 H), 6.29 (brs, 2 H), 4.16 (s, 1 H), 4.01
(qd, J = 7.1, 1.1 Hz, 2H), 3.69 (d, J = 13.7 Hz, 1 H), 3.49 (d, J = 13.7 Hz,
1 H), 3.21 (d, J = 15.7 Hz, 1 H), 2.91 (d, J = 16.1 Hz, 1 H), 2.41 (s, 3 H),
1.09 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.43,
159.71, 145.59, 139.27, 136.60, 129.15, 128.98, 128.27, 128.12, 127.40,
126.96, 126.37, 122.05, 115.89, 78.55, 59.28, 55.58, 54.62, 44.78, 41.05,
14.22; IR (KBr): 3421, 3312, 2979, 1743, 1690, 1614, 1525, 1454, 1300,
1255, 1093, 702 cmꢀ1; MS (ESI): m/z = 403.2 [M þ H]þ; HRMS
(R,E)-2-Amino-4-(furan-2-yl)-8-(furan-2-ylmethylene)-6-
methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-car-
bonitrile (4l):6e white solid, mp 181ꢀ183 °C. H NMR (400 MHz,
1
CDCl3): δ 7.45 (d, J = 1.5 Hz, 1 H), 7.36 (d, J = 1.1 Hz, 1 H), 6.58 (s,
1 H), 6.44 (dd, J = 3.3, 1.8 Hz, 1 H), 6.34ꢀ6.32 (m, 1 H), 6.22 (d, J = 3.2
Hz, 1 H), 4.61 (s, 2 H), 4.20 (s, 1 H), 3.86 (d, J = 14.8 Hz, 1 H), 3.52 (d,
J = 14.8 Hz, 1 H), 3.08 (d, J = 15.9 Hz, 1 H), 2.91 (d, J = 15.9 Hz, 1 H),
2.39 (s, 3 H); MS (ESI): m/z = 336.2 [M þ H]þ; [R]D20 = ꢀ48.8 (c =
0.08, CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 20:80, 254 nm,
0.5 mL/min), tr(major) = 18.5 min, tr(minor) = 19.9 min.
þ
(ESI) calcd for C25H27N2O3 [M þ H]þ: 403.2022, found: 403.
20
2027; [R]D = ꢀ26.9 (c = 0.13, CH2Cl2); enantiomeric excess was
determined by HPLC with a CHIRALPAK AD-H column (i-PrOH/
hexane = 30:70, 254 nm, 0.8 mL/min), tr(major) = 9.8 min, tr(minor) =
18.5 min.
(R,E)-2-Amino-8-benzylidene-4-phenyl-4,5,7,8-tetrahydro-
pyrano[4,3-b]pyran-3-carbonitrile (6a): white solid, mp 225ꢀ
230 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.43ꢀ7.21 (m, 10 H), 6.94
(s, 1 H), 6.91 (s, 2 H), 4.61 (d, J = 14.2 Hz, 1 H), 4.50 (dd, J = 14.2,
1.1 Hz, 1 H), 4.17 (d, J = 15.8 Hz, 1 H), 4.11 (s, 1 H), 3.73 (d, J = 15.5
Hz, 1 H), 13C NMR (100 MHz, DMSO-d6): δ 159.75, 143.05, 138.09,
135.29, 128.92, 128.75, 128.53, 127.47, 127.22, 126.26, 121.35, 120.27,
113.19, 65.21, 65.00, 55.79; IR (KBr): 3430, 3335, 2191, 1682, 1640,
(S,E)-2-Amino-6-methyl-4-(thiophen-2-yl)-8-(thiophen-2-
ylmethylene)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
3-carbonitrile (4m):6e white solid, mp 172ꢀ174 °C. 1H NMR (400
MHz, CDCl3): δ 7.35 (d, J = 4.9 Hz, 1 H), 7.24 (d, J = 4.7 Hz, 1 H),
7.08ꢀ7.04 (m, 2 H), 6.99 (s, 1 H), 6.95ꢀ6.93 (m, 2 H), 4.61 (s, 2 H),
4.37 (s, 1 H), 3.76 (d, J = 14.4 Hz, 1 H), 3.48 (d, J = 14.4 Hz, 1 H), 3.05
(d, J = 15.9 Hz, 1 H), 2.95 (d, J = 15.8 Hz, 1 H), 2.38 (s, 3 H); MS (ESI):
20
m/z = 368.1 [M þ H]þ; [R]D = þ23.7 (c = 0.23, CH2Cl2);
1621, 1596, 1489, 1453, 1393, 1362, 1158, 1101, 949, 716, 702 cmꢀ1
;
enantiomeric excess was determined by HPLC with a CHIRALPAK
AS-H column (i-PrOH/hexane = 20:80, 254 nm, 0.8 mL/min), tr-
(major) = 19.6 min, tr(minor) = 23.6 min.
MS (ESI): m/z = 343.1 [M þ H]þ; HRMS (ESI) calcd for C22H19-
N2O2þ [M þ H]þ: 343.1447, found: 343.1431; [R]D20 = ꢀ21.6 (c =
0.09, CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 20:80, 254 nm,
0.8 mL/min), tr(major) = 11.8 min, tr(minor) = 17.6 min.
(R,E)-2-Amino-6-methyl-8-((E)-3-phenylallylidene)-4-styr-
yl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carboni-
trile (4n):6e red solid, mp 169ꢀ181 °C. 1H NMR (400 MHz, CDCl3):
δ 7.45ꢀ7.24 (m, 10 H), 6.96 (dd, J = 15.3, 11.6 Hz, 1 H), 6.70 (d, J =
15.4 Hz, 1 H), 6.55 (d, J = 11.8 Hz, 1 H), 6.51 (d, J = 15.7 Hz, 1 H), 5.99
(dd, J = 15.6, 8.9 Hz, 1 H), 4.58 (s, 2 H), 3.62 (d, J = 8.9 Hz, 1 H), 3.57 (d,
J = 14.0 Hz, 1 H), 3.38 (d, J = 13.9 Hz, 1 H), 3.14 (d, J = 16.2 Hz, 1 H),
3.02 (d, J= 16.0 Hz, 1 H), 2.44 (s, 3 H); MS (ESI): m/z = 408.2 [M þ H]þ;
[R]D20 = þ15.4 (c = 0.42, CH2Cl2); enantiomeric excess was determined by
HPLC with a CHIRALPAK OD-H column (i-PrOH/hexane = 20:80,
254 nm, 0.8 mL/min), tr(major) = 21.9 min, tr(minor) = 16.6 min.
(R,E)-2-Amino-4-cyclohexyl-8-(cyclohexylmethylene)-6-me-
thyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbo-
nitrile (4o): white solid, mp 185ꢀ188 °C. 1H NMR (400 MHz,
(S,Z)-2-Amino-8-benzylidene-4-phenyl-4,5,7,8-tetrahydro-
thiopyrano[4,3-b]pyran-3-carbonitrile (6b): white solid, mp
228ꢀ230 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.44ꢀ7.23 (m,
10 H), 7.16 (s, 1 H), 6.87 (s, 2 H), 4.08 (s, 1 H), 3.68ꢀ3.58 (m,
2 H), 3.26 (d, J = 17.1 Hz, 1 H), 2.90 (d, J = 17.0 Hz, 1 H); 13C NMR
(100 MHz, DMSO-d6): δ 159.65, 143.42, 141.39, 135.84, 129.13,
128.74, 128.51, 127.51, 127.39, 127.16, 126.35, 124.39, 120.23,
114.04, 55.97, 43.21, 27.20, 27.15; IR (KBr): 3428, 3331, 2190, 1682,
1640, 1621, 1596, 1489, 1453, 1393, 1361, 1158, 1101, 948, 716,
700 cmꢀ1; MS (ESI): m/z = 359.1 [M þ H]þ; HRMS (ESI)
calcd for C22H19N2OSþ [M þ H]þ: 359.1218, found: 359.1219;
20
[R]D = ꢀ54.7 (c = 0.09, CH2Cl2); enantiomeric excess was
3802
dx.doi.org/10.1021/jo200112r |J. Org. Chem. 2011, 76, 3797–3804

The Journal of Organic Chemistry
ARTICLE
determined by HPLC with a CHIRALPAK AD-H column (i-PrOH/
hexane = 20:80, 254 nm, 0.8 mL/min), tr(major) = 11.2 min, tr(minor) =
28.5 min.
J = 13.7 Hz, 1H), 3.37 (d, J = 13.7 Hz, 1H), 2.98 (d, J = 15.8 Hz, 1H),
2.66 (d, J = 15.7 Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 159.18, 158.99, 148.77, 144.57, 140.95, 134.12, 130.57, 129.98, 128.46,
124.85, 123.48, 122.87, 122.83, 119.14, 113.89, 110.19, 59.51, 55.29,
55.22, 54.70, 44.89, 41.65; IR (KBr): 3359, 2924, 2187, 1677, 1637,
1604, 1531, 1510, 1465, 1352, 1251, 1097, 824, 695 cmꢀ1; HRMS
(ESI) calcd for C24H23N4O4þ [M þ H]þ: 431.1719, found: 431.1710;
[R]D20 = þ5.4 (c = 0.20, CH2Cl2); enantiomeric excess was determined
by HPLC with a CHIRALPAK AS-H column (i-PrOH/hexane = 30:70,
254 nm, 0.8 mL/min), tr(major) = 18.5 min, tr(minor) = 22.1 min.
(R,E)-2-Amino-8-benzylidene-4-phenyl-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6c):6b,18 white solid, mp 221ꢀ
224 °C. 1H NMR (400 MHz, CDCl3): δ 7.37ꢀ7.24 (m, 10 H), 6.88 (s,
1 H), 4.50 (s, 2 H), 3.97 (s, 1 H), 2.74ꢀ2.70 (m, 1 H), 2.60ꢀ2.56 (m,
1 H), 2.04ꢀ1.92 (m, 2 H), 1.63ꢀ1.60 (m, 2 H); MS (ESI): m/z = 341.2
[M þ H]þ; [R]D20 = ꢀ29.8 (c = 0.10, CH2Cl2); enantiomeric excess
was determined by HPLC with a CHIRALPAK AD-H column
(i-PrOH/hexane = 20:80, 254 nm, 0.8 mL/min), tr(major) = 9.1 min,
tr(minor) = 22.3 min.
’ ASSOCIATED CONTENT
(R,E)-2-Amino-7-benzylidene-4-phenyl-4,5,6,7-tetrahydro-
cyclopenta[b]pyran-3-carbonitrile (6d):6b,18,19 white solid, mp
210ꢀ214 °C. 1H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.20 (m, 10 H),
6.46 (s, 1 H), 4.64 (s, 2 H), 4.26 (s, 1 H), 2.97ꢀ2.28 (m, 2 H),
2.42ꢀ2.36 (m, 1 H), 2.27ꢀ2.21 (m, 1 H); MS (ESI): m/z = 327.1 [M þ
S
Supporting Information. X-ray structural data (CIF),
b
NMR spectra and HPLC chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.org.
20
H]þ; [R]D = ꢀ25.5 (c = 0.10, CH2Cl2); enantiomeric excess was
’ AUTHOR INFORMATION
determined by HPLC with a CHIRALPAK AD-H column (i-PrOH/
hexane = 20:80, 254 nm, 0.8 mL/min), tr(major) = 9.3 min, tr(minor) =
13.6 min.
Corresponding Author
yanming@mail.sysu.edu.cn
(R,E)-2-Amino-9-benzylidene-4-phenyl-4,5,6,7,8,9-hexahy-
drocyclohepta[b]pyran-3-carbonitrile (6e):19 white solid, mp
175ꢀ179 °C. 1H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.25 (m, 10 H),
6.99 (s, 1 H), 4.48 (s, 2 H), 3.94 (s, 1 H), 2.71ꢀ2.65 (m, 1 H),
2.54ꢀ2.47 (m, 1 H), 2.18ꢀ2.11 (m, 1 H), 2.06ꢀ1.99 (m, 1 H),
1.81ꢀ1.67 (m, 3 H), 1.65ꢀ1.60 (m, 1 H); MS (ESI): m/z = 355.2
[M þ H]þ; [R]D20 = ꢀ61.5 (c = 0.10, CH2Cl2); enantiomeric excess
was determined by HPLC with a CHIRALPAK AD-H column
(i-PrOH/hexane = 10:90, 254 nm, 0.5 mL/min), tr(major) = 8.4 min,
tr(minor) = 10.0 min.
’ ACKNOWLEDGMENT
Financial supports from National Natural Science Foundation
of China (Nos. 20772160, 20972195), Ministry of Health of
China (No. 2009ZX09501-017), and Fundamental Research
Funds for the Central Universities are gratefully acknowledged.
’ REFERENCES
trans-4-Oxo-2,6-diphenylcyclohexane-1,1-dicarbonitrile
(1) For the general reviews of organocatalysis, see: (a) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 36, 2178; (b) Dondoni, A.; Massi,
A. Angew. Chem. 2008, 120, 4716; Angew. Chem., Int. Ed. 2008, 47, 4638.
(c) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH: Weinheim,
2007. (d) Pellissier, H. Tetrahedron 2007, 63, 9267. (e) Guillena, G.;
Nꢀajera, C.; Ramꢀon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249.
(2) For the reviews of organocatalytic asymmetric conjugate
addition, see: (a) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
11, 1701. (c) Sulzer-Mossꢀe, S.; Alexakis, A. Chem. Commun. 2007, 3123.
(d) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007, 2065.
(3) For the reviews of organocatalytic cascade reactions, see: (a)
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167; (b) Alba,
A. N.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009,
13, 1432; (c) Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem.
2007, 119, 1590; Angew. Chem., Int. Ed. 2007, 46, 1570.
4
1
(7): white solid, mp 174ꢀ176 °C. H NMR (400 MHz, CDCl3):
δ 7.46ꢀ7.37 (m, 6 H), 7.34ꢀ7.26 (m, 4 H), 3.82 (dd, J = 7.4, 6.0 Hz,
2 H), 3.10 (qd, J = 16.8, 7.0 Hz, 4 H); 13C NMR (100 MHz, CDCl3):
δ 204.7, 135.2, 129.7, 129.3, 129.1, 113.9, 45.8, 45.1, 42.5; IR (KBr):
3453, 2191, 1642, 1596, 1410 cmꢀ1; MS (ESI): m/z = 299.1 [MꢀH]ꢀ;
HRMS (ESI) calcd for C20H16N2Oꢀ [M ꢀ H]ꢀ: 299.1184, found:
20
299.1191; [R]D = þ3.0 (c = 1.00, CHCl3); enantiomeric excess
was determined by HPLC with a CHIRALPAK IC column (i-PrOH/
hexane = 40:60, 220 nm, 0.8 mL/min), tr(major) = 18.1 min, tr(minor) =
7.8 min.
(R,E)-2-amino-4-(4-methoxyphenyl)-6-methyl-8-(3-nitro-
benzylidene)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
1
3-carbonitrile (9a): kelly green solid, mp 147ꢀ149 °C. H NMR
(400 MHz, CDCl3): δ 8.14 ꢀ 8.11 (m, 1 H), 8.07 (s, 1 H), 7.54 (d, J =
6.1 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.88 (s,
1 H), 4.61 (s, 2 H), 4.01 (s, 1 H), 3.81 (s, 3 H), 3.53 (d, J = 13.8 Hz, 1 H),
3.38 (d, J = 13.8 Hz, 1 H), 2.97 (d, J = 16.1 Hz, 1 H), 2.78 (d, J = 16.1 Hz,
1 H), 2.28 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 158.12, 158.48,
148.26, 139.44, 137.93, 134.89, 133.98, 129.58, 129.36, 128.90, 123.71,
121.95, 120.19, 119.52, 114.91, 114.37, 60.97, 55.29, 55.25, 54.45, 44.91,
40.89; IR (KBr): 3354, 2925, 2183, 1679, 1637, 1604, 1530, 1510, 1462,
(4) Li, X.-M.; Wang, B.; Zhang, J.-M.; Yan, M. Org. Lett. 2010,
13, 374.
(5) (a) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. J. Am. Chem. Soc.
2006, 128, 9413. (b) Zhao, S.-L.; Zheng, C.-W.; Zhao, G. Tetrahedron:
Asymmetry 2009, 20, 1046. (c) Li, X.-F.; Cun, L.-F.; Lian, C.-X.; Zhong,
L.; Chen, Y.-C.; Liao, J.; Zhu, J.; Deng, J.-G. Org. Biomol. Chem. 2008,
6, 349. (d) Russo, A.; Perfetto, A.; Lattanzi, A. Adv. Synth. Catal. 2009,
351, 3067. (e) Ren, Q.; Gao, Y.-J.; Wang, J. Chem.—Eur. J. 2010,
16, 13594.
(6) For the selected publications of base-promoted addition of
malononitrile to enones, see: (a) Tyndall, D. V.; Al Nakib, T.; Meegan,
M. J. Tetrahedron Lett. 1988, 29, 5330. (b) Al-saleh, F. S.; Kandeel, E. M.
Indian J. Heterocycl. Chem. 1994, 3, 273. (c) Alsaleh, F. S.; El-Din,
A. Y. G.; Kandeel, E. M. Microbios 1995, 82, 87. (d) El-Subbagh, H. I.;
Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Al-Obaid, A. M. J. Med.
Chem. 2000, 43, 2915. (e) Wang, X.-S.; Shi, D.-Q.; Du, Y.; Zhou, Y.; Tu,
S.-J. Synth. Commun. 2004, 34, 1425. (f) Jin, T.-S.; Liu, L.-B.; Zhao, Y.; Li,
T.-S. Synth. Commun. 2005, 35, 1859. (g) Al-Omar, M. A.; Youssef,
K. M.; El-Sherbeny, M. A.; Awadalla, S. A. A.; El-Subbagh, H. I. Arch.
þ
1352, 1250, 1098, 824, 695 cmꢀ1; HRMS (ESI) calcd for C24H23N4O4
20
[M þ H]þ: 431.1719, found: 431.1710; [R]D = ꢀ19.8 (c = 0.086,
CH2Cl2); enantiomeric excess was determined by HPLC with a
CHIRALPAK AD-H column (i-PrOH/hexane = 30:70, 254 nm,
0.8 mL/min), tr(major) = 9.7 min, tr(minor) = 16.7 min.
(R,E)-2-Amino-8-(4-methoxybenzylidene)-6-methyl-4-(3-
nitrophenyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
1
3-carbonitrile (9a0): yellow solid, mp 151ꢀ153 °C. H NMR (400
MHz, CDCl3): δ 8.16 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J = 7.6
Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7
Hz, 2H), 6.89 (s, 1 H), 4.69 (s, 2H), 4.17 (s, 1H), 3.83 (s, 3H), 3.59 (d,
3803
dx.doi.org/10.1021/jo200112r |J. Org. Chem. 2011, 76, 3797–3804

The Journal of Organic Chemistry
ARTICLE
Pharm. 2005, 338, 175. (h) Kumar, R. R.; Perumal, S.; Senthilkumar, P.;
Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2007, 17, 6459. (i)
Rostom, S. A. F.; Hassan, G. S.; El-Subbagh, H. I. Arch. Pharm. 2009,
342, 584. (j) Han, Z.-G.; Tu, S.-J.; Jiang, B.; Yan, S.; Zhang, X.-H.; Wu,
S.-S.; Hao, W.-J.; Cao, X.-D.; Shi, F.; Zhang, G.; Ma, N. Synthesis
2009, 1639.
(7) Zhang, X.-J.; Liu, S.-P.; Li, X.-M.; Yan, M.; Chan, A. S. C. Chem.
Commun. 2009, 833.
(8) Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.; Chan,
A. S. C. Tetrahedron: Asymmetry 2009, 20, 1451.
(9) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119.
(10) (a) Zhang, H.; Syed, S.; Barbas, C. F. Org. Lett. 2010, 12, 708;
(b) McCooey, S. H.; Connon, S. J. Angew. Chem. 2005, 117, 6525;
Angew. Chem., Int. Ed. 2005, 44, 6367.
(11) (a) Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong,
A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem.—Eur. J. 2010, 16, 4177. (b) Malerich,
J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416.
(12) Nie, S.-N.; Hu, Z.-P.; Xuan, X.-N.; Wang, J.-J.; Li, X.-M.; Yan,
M. Tetrahedron: Asymmetry 2010, 21, 2055.
(13) CCDC-794045 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(14) (a) McElvain, S. M.; Rorig, K. J. Am. Chem. Soc. 1948, 70, 1820.
(b) Leonard, N. J.; Locke, D. M. J. Am. Chem. Soc. 1955, 77, 1852. (c)
Vatsadze, S.; Manaenkova, M.; Sviridenkova, N.; Zyk, N.; Krut’ko, D.;
Churakov, A.; Antipin, M.; Howard, J.; Lang, H. Russ. Chem. Bull. 2006,
55, 1184.
(15) Brunner, H.; B€ugler, J.; Nuber, B. Tetrahedron: Asymmetry
1995, 6, 1699.
(16) Berkessel, A.; Mukherjee, S.; M€uller, T. N.; Cleemann, F.;
Roland, K.; Brandenburg, M.; Neud€ofl, J. M.; Lex, J. Org. Biomol. Chem.
2006, 4, 4319.
(17) Wang, S.-L.; Han, Z.-G.; Tu, S.-J.; Zhang, X.-H.; Yan, S.; Hao,
W.-J.; Shi, F.; Cao, X.-D.; Wu, S.-S. J. Heterocycl. Chem. 2009, 46, 828.
(18) (a) Wang, X.-S.; Shi, D.-Q.; Tu, S.-J. Chin. J. Chem. 2004,
22, 122. (b) Jin, T.-S.; Liu, L.-B.; Zhao, Y.; Li, T.-S. Synth. Commun.
2005, 35, 1859.
(19) Otto, H. H. Arch. Pharm. 1974, 307, 422.
3804
dx.doi.org/10.1021/jo200112r |J. Org. Chem. 2011, 76, 3797–3804