Tandem cross-Rauhut-Currier/cyclization reactions of activated alkenes to give densely functionalized 3,4-dihydropyrans

Article abstract of DOI:10.1016/j.tet.2011.01.036

A novel tandem cross-Rauhut-Currier/cyclization reaction between α,β-unsaturated ketones was developed. Using DABCO (20 mol %) as the catalyst, a series of densely functionalized 3,4-dihydropyrans were obtained in excellent yields and stereoselectivities (up to 98% yield, >99:1 dr). A tentative catalytic cycle was proposed with key intermediates confirmed by ESIMS studies.

Full text of DOI:10.1016/j.tet.2011.01.036

Tetrahedron 67 (2011) 1768e1773
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem cross-RauhuteCurrier/cyclization reactions of activated alkenes to give
densely functionalized 3,4-dihydropyrans
Wen Liu a, Jing Zhou b, Changwu Zheng b, Xingkuan Chen b, Hua Xiao a, Yingquan Yang a,
,b,
Yinlong Guo b, Gang Zhao a
*
a Department of Chemistry, University of Science and Technology of China, 96 JingZhai Road, Hefei, Anhui 230026, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Ling Ling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel tandem cross-RauhuteCurrier/cyclization reaction between
a,b-unsaturated ketones was de-
Received 13 December 2010
Received in revised form 11 January 2011
Accepted 14 January 2011
veloped. Using DABCO (20 mol %) as the catalyst, a series of densely functionalized 3,4-dihydropyrans
were obtained in excellent yields and stereoselectivities (up to 98% yield, >99:1 dr). A tentative catalytic
cycle was proposed with key intermediates confirmed by ESIMS studies.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 20 January 2011
Keywords:
RauhuteCurrier reaction
Cyclization reaction
Activated alkenes
3,4-Dihydropyrans
OH
EWG
EWG
RCHO
1. Introduction
EWG
EWG
R
EWG
Nucleophilic
catalyst
Nucleophilic
catalyst
The RauhuteCurrier (RC) reaction, which is also known as the
vinylogous MoritaeBayliseHillman (MBH) reaction, provides
a unique atom-economical way to create a new CeC bond between
two activated alkenes under the catalysis of nucleophilic catalysts
(Scheme 1).1 In comparison to the numerous researches on the
MBH reaction, the RC reaction is much less investigated. This is
partly attributable to the low reactivity of the substrates and the
problem of selectivity when two different activated alkenes were
involved. Recently, in the domain of intramolecular RC reaction,
where the above two problems are somewhat extenuated, signifi-
cant progress has been made, which also demonstrated the value of
the reaction in synthetic chemistry.2 However, the intermolecular
RC reaction between different activated alkenes remains a great
challenge.3 It goes without saying that a right choice of the two
reactants with appropriate reactivity would serve as a direct solu-
tion to this challenge. Nevertheless, partly due to the restriction of
the reactivity of commonly known substrates, very limited success
has been achieved with this strategy. Recently, Ma et al. attained
Rauhut-Currier
Morita-Baylis-Hillman
EWG: Electron-withdrawing group
Scheme 1. Comparison of MBH and RC reactions.
aldehydes as the other reaction partner (known as the latent eno-
late), which was followed by acetalization to give useful spiro-3,4-
dihydrofurans.4 In contrast, much less satisfactory results were
reported for reactions using cheap, simple activated alkenes, such
as methyl vinyl ketone (MVK) and acrylates as the reaction part-
ners, which are probably due to their relatively lower reactivity and
susceptibility to homodimerization.
As part of our ongoing project on the development of organo-
catalyzed reactions utilizing
synthetically useful structures, we report herein a novel tandem
cross-RauhuteCurrier/cyclization reaction featuring the use of
cyano- -unsaturated ketones 2 as the Michael acceptor, with
a,b-unsaturated ketones to construct
a
-
a success by using the highly activated
b
,
g-unsaturated
a-keto ester
a,b
as the Michael acceptor and cyclic
b
-halo- -unsaturated
a,b
which simple activated alkenes (MVK and acrylates) are well tol-
erated as reaction partners. The resultant densely functionalized
3,4-dihydropyrans 1 are a common structural unit present in many
biologically active compounds, and the construction of this kind of
structures has aroused many interests among chemists.5
* Corresponding author. Fax: þ86 21 64166128; e-mail address: zhaog@mail.
sioc.ac.cn (G. Zhao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.036

W. Liu et al. / Tetrahedron 67 (2011) 1768e1773
1769
Table 2
2. Results and discussion
Scope of the tandem reaction of enones 2 and MVK 3a
We assumed that a suitable Michael acceptor in this reaction
should have a proper electrophilicity for the Michael addition step,
whereas be less reactive with the nucleophilic catalyst. With our
experience with
a,b-unsaturated ketones, it seems the chalcone
derivative 2a bearing a doubly activated alkene may be a suitable
candidate. To our delight, when (E)-2-benzoyl-3-phenyl-
acrylonitrile 2a and MVK 3a were treated with DABCO (20 mol %) in
CH3CN at room temperature for 6 h, a 3,4-dihydropyran product 1a
was isolated in good yield as a single diastereoisomer (Table 1, entry
1).6 Apparently, the formation of 1a could result from the expected
cross-RauhuteCurrier followed by an intramolecular SN2 reaction.
Decreasing the catalyst loading to 10 mol % slowed down the re-
action remarkably (Table 1, entry 2). When three other tertiary
amines DBU, DMAP, and Et3N were used instead of DABCO, much
less successful results were obtained (Table 1, entries 3e6). In ad-
dition, nucleophilic phosphine catalysts (n-Bu)3P and Ph3P also
proved unsuitable for this reaction (Table 1, entries 7e8). Polar
solvents were favored in the reaction, however, the other solvents
examined all gave inferior results to the originally used CH3CN
(Table 1, entries 9e14). Thus, the present reaction was best per-
formed with 20 mol % of DABCO in CH3CN at room temperature.
E
2 (R1, R2)
2a (R1¼R2¼Ph)
R3
T (h) Prod. dra
Yieldb
%
1
2
3
4
5
6
7
8
9
CN
CN
CN
CN
CN
CN
CN
CN
12
4
4
4
12
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
>99:1 86
>99:1 92
>99:1 95
>99:1 92
>99:1 98
>99:1 98
>99:1 96
>99:1 71
>99:1 87
>99:1 70
>99:1 96
2b (R1¼Ph, R2¼4-CleC6H4)
2c (R1¼Ph, R2¼4-BreC6H4)
2d (R1¼Ph, R2¼3-BreC6H4)
2e (R1¼Ph, R2¼2-BreC6H4)
2f (R1¼Ph, R2¼4-FeC6H4)
2g (R1¼Ph, R2¼4-MeOeC6H4)
2h (R1¼Ph, R2¼4-NO2eC6H4)
18
2
2i (R1¼Ph, R2¼2,4-dichlorophenyl) CN
12
12
24
72
12
12
12
72
10 2j (R1¼Ph, R2¼2-thienyl)
CN
1j
1k
1l
11 2k (R1¼Ph, R2¼N-methyl-3-indyl) CN
12 2l (R1¼Ph, R2¼PhCH2CH2)
13 2m (R1¼4-MeOeC6H4, R2¼Ph)
14 2n (R1¼4-MeeC6H4, R2¼Ph)
15 2o (R1¼4-BreC6H4, R2¼Ph)
16 2p (R1¼R2¼Ph)
CN
CN
CN
CN
H
d
n.r.c
1m
1n
1o
1p
1q
1r
>99:1 82
>99:1 84
>99:1 85
d
d
d
n.r.c
17 2q (R1¼R2¼Ph)
SO2Ph 72
CO2Me 72
n.r.c
n.r.c
18 2r (R1¼R2¼Ph)
Determined by 1H NMR assay. The relative configuration was determined by
a
Table 1
NOESY assay.
Screening of solvents and Lewis bases
b
c
Isolated yields.
The n.r. stands for no reaction.
O
Ph
O
Ph
O
O
Lewis base
solvent
was replaced by H, SO2Ph or CO2Me, basically no reaction took
place (Table 2, entries 16e18). In all of these cases examined, only
the trans diastereoisomer was observed (Fig. 1).6
NC
NC
H
Ph
H
Ph
2a
3a
1a
CN
H
E
Lewis base (equiv)
Solvent
T (h)
dra
Yieldb
%
O
Ph
1
2
3
4
5
6
DABCO (0.2)
DABCO (0.1)
DBU (0.2)
DBU (0.2)
DMAP (0.2)
Et3N (0.2)
CH3CN
CH3CN
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
6
24
48
12
48
48
48
48
48
48
12
48
48
48
>99:1
>99:1
d
84
73
Trace
Complex
52
Trace
Trace
Complex
45
70
75
R
H
H
d
NOE
>99:1
d
Fig. 1. Nuclear Overhauser effect.
7
Ph3P (0.2)
d
8c
9
n-Bu3P (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
d
To our delight, besides MVK, methyl acrylate 3b also partici-
pated in the reaction with 2a to give the corresponding products in
moderate to good yields, albeit with a long reaction time at room
temperature and a poor diastereoselectivity (Table 3, entry 1). In-
creasing the reaction temperature to 60 ꢀC could shorten the re-
action time dramatically and improve the dr value slightly (Table 3,
entry 2). The use of bulkier acrylates 3c and 3d provided inferior
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
10
11
12
13
14
DMF
CH2Cl2
CHCl3
Et2O
35
40
Trace
a
Determined by 1H NMR assay.
Isolated yields.
Run in the nitrogen atmosphere.
b
c
Table 3
Substrate scope of activated alkenes 3
Having established optimal reaction conditions, we next studied
the scope of the reaction with regard to different -cyano- -un-
Ph
Ph
NC
O
O
Ph
O
R4
H
R4
H
R4
a
a,b
DABCO ( 20 mol% )
CH3CN , 60 oC
saturated ketones 2 using MVK 3a. When R1 is a phenyl group
(2aek), the reaction proceeded smoothly to give the desired
products in good to excellent yields when R2 is also an aryl group,
including heterocyclic groups, such as 2-thienyl and 3-indyl groups
(Table 2, entries 1e11). Substrates bearing electron-withdrawing
substituents on the aryl group of R2 in general were significantly
more reactive than those with electron-donating ones. In addition,
substrates 2e and 2i with ortho substituents also seemed less re-
active probably due to steric reasons (Table 2, entries 5 and 9). The
reaction hardly proceeded when R2 is an alkyl group (Table 2, entry
12). In contrast, variation of the substituents with different elec-
tronic nature on the aryl group of R1 has little influence on the
reaction rate (Table 2, entries 13e15). Notably, the cyano group at
NC
NC
H
H
Ph
Ph
Ph
trans
1s-v
cis
1s'-v'
2a
3b-e
Entry
1c
2
3 (R4)
T (h)
Product
dra (trans/cis)
Total yieldb (%)
3b (CO2Me)
3b (CO2Me)
3c (CO2Et)
3d (CO2-t-Bu)
3e (COEt)
120
24
24
1s
1s
1t
1.5:1
2.4:1
1.4:1
d
71
78
61
Trace
81
3
4
120
12
1u
1v
5c
>99:1
Determined by 1H NMR analysis. The relative configuration was determined by
a
NOESY assay.
b
c
Isolated yields.
The reaction was run at room temperature.
the a-position of enone 2a was essential for the reaction. When it

1770
W. Liu et al. / Tetrahedron 67 (2011) 1768e1773
(2) A solution of
a,b-unsaturated ketones 2a (0.0025 mmol),
results (Table 3, entries 3 and 4), while the homolog of MVK, ethyl
vinyl ketone gave the product with a good yield, and only the trans
diastereoisomer was detected (Table 3, entry 5).
Based on previous studies on the RC reaction, a tentative catalytic
cycle was proposed for the current tandem reaction (Scheme 3).
Conjugate addition of DABCO to the activated alkene 3b provided
methyl acrylate 3b (0.0025 mmol) and DABCO (0.0025 mmol)
in CH3CN (6 mL) was stirred at room temperature. In the first
5 min, intermediate ions 5 (m/z 199) were detected (Fig. 2b); at
20 min, inter-mediate ions 5 (m/z 199) and 8 (m/z 432) were
detected (Fig. 2c); at 40 min, ions 9 formed from the product 1
started to appear while intermediate ions 5 and 8 existed
(Fig. 2c). After 5 h, the signal of ion 5 and 8 became very weak,
and strong signals of ions 9 could be detected. All these in-
termediate ions were structurally characterized by tandem
mass spectrometric (MS/MS) analysis.
intermediate 4, which would add onto a,b-unsaturated ketone 2a to
afford intermediate 7. The latter then underwent an intramolecular
SN2 reaction to yield dihydropyran 1s with regeneration of the
amine catalyst. And another possible reaction path was that the
intermediate 7 first underwent elimination of the DABCO moiety,
then the pyranyl ring 1 was generated from 10 by means of a 6-endo-
trig-O-1,4-addition. Given the several neutral zwitterionic in-
termediates in this proposed mechanism,7 which are suitable for
detection by ESIMS in their protonated/cationic forms,8 we also
employed this technique to gain some insight into this reaction.
With the standard procedure for MS detection, possible in-
termediates in the model reaction between 2a and 3bwere captured
by gradual addition of the reactants (Scheme 2). All the in-
termediates in the catalytic cycle were found in ESIMS analysis,
which supported the speculation (Fig. 2).
3. Conclusion
In conclusion, we have discovered an efficient, amine-catalyzed
tandem cross-RauhuteCurrier coupling/cyclization reaction of ac-
tivated alkenes and investigated the mechanism with ESIMS. The
mild reaction conditions, good to excellent yields, and easily
available substrates make this reaction an attractive method for the
preparation of densely functionalized 3,4-dihydropyrans. Efforts
toward the development of an asymmetric variant of this reaction
are ongoing in our laboratory.
N
Ph
O
Ph
O
O
NC
Ph
N
OMe
4. Experiment section
OMe
NC
O
Ph
4.1. General information
2a
3b
1s
Unless otherwise indicated, all compounds and reagents were
purchased from commercial suppliers and used without further
Scheme 2. Model reaction for ESIMS study.
Ph
O
NC
OMe
Ph
O
1s
O
-O
9: [M+Na]+ m/ z: 342
OMe
N
Ph
NC
O
3b
N
[M+H]+ m/ z: 87
[M+H]+ m/ z: 113
MeO
10
-O
OH
O
O
NC
Ph
NC
O
O
Ph
OMe
ESI-MS
ESI-MS
OMe
MeO
N
MeO
N
N+
N+
N+
N+
N
4
N
5
7
Ph
O
+
8
C
10H19N2O2
m/z: 199
+
C
26H30N3O3
m/z: 432
NC
Ph
2+a
6
: [M+H] m/z: 234
Scheme 3. Proposed catalytic cycle for the cross-RauhuteCurrier/cyclization reaction of 2a and 3b.
purification. 1H nuclear magnetic resonance spectra are recorded at
400 MHz. All chemical shifts ( ) are given in parts per million. Data
(1) A solution of activated alkene 3b (0.0025 mmol) and DABCO
(0.0025 mmol) in CH3CN (6 mL) was stirred at room temper-
d
ature. After 1 min, 5
with 100 L of CH3CN and transferred into the ESI source by
a syringe pump at a flow rate of 10
L minꢁ1 for the MS de-
tection. After this standard treatment, the signal of in-
termediate ions 5 (m/z 199), a protonated form of the proposed
intermediate 4, was detected (Fig. 2a).
mL of the solution was taken and diluted
are reported as follows: chemical shift, integration, multiplicity
(s¼single, d¼doublet, t¼triplet, q¼quartet, m¼multiplet), and
coupling constants (Hz). 13C NMR spectra were recorded on Bruker
AMX-400 NMR spectrometer. IR spectra were recorded on a Per-
kineElmer 983 G instrument. MS or HRMS was recorded on a HP-
5989A spectrometer.
m
m

W. Liu et al. / Tetrahedron 67 (2011) 1768e1773
1771
4.3. General procedure for the synthesis of 2aeo10
Adry50 mLroundflaskequippedwithamagneticstirringbarwas
charged with a solution of 3-oxo-3-phenylpropanenitrile (0.87 g,
6.0 mmol), benzaldehyde (0.61 mL, 6.0 mmol), piperidine (0.12 mL,
0.2 equiv), and acetic acid (0.069 mL, 0.2 equiv) in toluene (20 mL).
The mixture was heated at 60 ꢀC for 12 h. After cooling to room
temperature, the mixture was washed with water (10 mL) and the
aqueousphasewasextractedwithethylacetate(3ꢂ10 mL).Thecrude
mixture was subjected to column chromatography (PE/EA 98:2) to
yield 0.68 g (2.9 mmol, 48%) of the desired product as a white solid.
4.3.1. 2-Benzoyl-3-(1-methyl-1H-indol-3-yl)acrylonitrile (2k). Orange
solid; mp: 139e141 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.95 (3H, s),
7.32e7.44 (3H, m), 7.51 (2H, t, J¼7.2 Hz), 7.60 (1H, t, J¼7.2 Hz), 7.78
(1H, d, J¼8.0 Hz), 7.88e7.90 (2H, m), 8.63 (2H, d, J¼16.4 Hz) ppm; 13C
NMR (100 MHz, CDCl3)
d 34.16, 101.27, 110.56, 110.73, 118.58, 120.07,
122.94, 124.19, 128.46, 128.70, 128.92, 132.47, 135.18, 137.12, 137.45,
147.14, 189.19 ppm; IR (KBr):
n 3117, 3060, 2928, 2203, 1650, 1549,
1517, 1472, 1325, 1263, 1124, 1074, 741, 720, 654 cmꢁ1; HRMS (EI)
calcd for C19H14N2O (Mþ) 286.1106. Found 286.1100.
4.4. General procedure for the tandem cross-RauhuteCurrier/
cyclization reactions
To a mixture of enone 2 (0.10 mmol) and MVK 3 (0.30 mmol) in
acetonitrile (1.0 mL), DABCO (0.02 mmol) was added at ambient
temperature. After stirring for 6 h, the solvent was concentrated,
the crude product was directly purified by flash column chroma-
tography on silica gel (PE/EA 95:5 to 90:10) to afford the desired
product 1 as a solid.
4.4.1. 3-Acetyl-4,6-diphenyl-3,4-dihydro-2H-pyran-5-carbonitrile
(1a). White solid; mp: 124e125 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.07 (3H, s), 3.05 (1H, m), 4.15 (1H, d, J¼6.0 Hz), 4.36e4.38 (2H,
m), 7.30e7.33 (3H, m), 7.37e7.47 (5H, m), 7.78 (2H, m) ppm; 13C
NMR (100 MHz, CDCl3) 29.77, 42.00, 53.23, 65.93, 87.21, 119.10,
127.99, 128.08, 128.30, 128.46, 129.23, 131.14, 132.53, 140.26, 165.70,
d
205.46 ppm; IR (KBr):
n 3063, 3023, 2206, 1713, 1618, 1492, 1449,
1359, 1150, 769, 698 cmꢁ1; HRMS (EI) calcd for C20H17NO2 (Mþ)
303.1259. Found 303.1263.
4.4.2. 3-Acetyl-4-(4-chlorophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
5-carbonitrile (1b). White solid;mp: 131e132 ꢀC;1HNMR(400 MHz,
CDCl3)
d
2.10 (3H, s), 3.03 (1H, m), 4.16 (1H, d, J¼6.8 Hz), 4.31e4.42
(2H, m), 7.24 (2H, d, J¼8.8 Hz), 7.36 (2H, d, J¼8.0 Hz), 7.42e7.48 (3H,
m), 7.77 (2H, d, J¼7.2 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 29.86,
41.37, 53.20, 66.01, 86.91,119.16,124.50,128.27,128.50,129.45,131.29,
Fig. 2. ESIMS carried out with the standard procedure for MS detection for the sample
taken from the reaction mixture of -unsaturated ketones 2a (0.0025 mmol), methyl
acrylate 3b (0.0025 mmol), and DABCO (0.0025 mmol) in CH3CN (6 mL) stirred at room
a,
b
132.29, 133.95, 138.74, 165.90, 204.93 ppm; IR (KBr): n 2988, 2923,
2206, 1714, 1614, 1489, 1455, 1361, 1151, 1082, 697 cmꢁ1; HRMS (EI)
temperature at the reaction time of (a) 5 min, (b) 20 min, and (c) 40 min.
calcd for C20H17ClNO2 ([MþH]þ) 338.0942. Found 338.0947.
4.2. General procedure for the synthesis of 3-oxo-3-phenyl
propanenitrile9
4.4.3. 3-Acetyl-4-(4-bromophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
5-carbonitrile (1c). White solid; mp: 141e142 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
2.12 (3H, s), 3.03 (1H, m), 4.15 (1H, d, J¼6.8 Hz),
A dry and nitrogen-flushed 150 mL three-neck flask equipped
with a magnetic stirring bar was charged with a solution of sodium
hydride (60%) (3.8 g, 1.5 equiv) and ethyl benzoate (9.2 mL,
64 mmol) in dry toluene (100 mL). The reaction mixture was stirred
at 90 ꢀC, and acetonitrile (8.0 mL) was dropped with stirring in 1 h,
thereafter, the solvent was stirred at 90 ꢀC for 6 h. Then saturated
NH4Cl (10 mL) and 70 mL of water were added at 0 ꢀC to quench the
reaction. The suspension was extracted with ethyl acetate
(3ꢂ100 mL), the solvent was evaporated and the crude mixture was
recrystallized to yield 6.0 g (41 mmol, 64%) of the desired product
as a yellow solid.
4.31e4.43 (2H, m), 7.18 (2H, d, J¼8.8 Hz), 7.42e7.53 (5H, m), 7.77
(2H, d, J¼7.6 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 29.83, 41.35,
53.12, 65.98, 86.74, 118.93, 122.02, 128.28, 128.51, 129.82, 131.32,
132.27, 132.39, 139.32, 165.95, 204.92 ppm; IR (KBr):
n 3063, 2925,
2206, 1715, 1615, 1472, 1360, 1151, 776, 696 cmꢁ1; HRMS (EI) calcd
for C20H16BrNO2 (Mþ) 381.0364. Found 381.0370.
4.4.4. 3-Acetyl-4-(3-bromophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
5-carbonitrile (1d). White solid; mp: 142e143 ꢀC; 1H NMR
(400 MHz, CDCl3)
d 2.13 (3H, s), 3.02 (1H, m), 4.17 (1H,
d, J¼6.0 Hz), 4.36e4.38 (2H, m), 7.24e7.26 (2H, m), 7.42e7.48 (5H,

1772
W. Liu et al. / Tetrahedron 67 (2011) 1768e1773
m), 7.78 (2H, d, J¼6.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
118.90, 125.40, 126.79, 127.29, 128.34, 128.45, 131.22, 132.33, 143.69,
d
29.58, 41.29, 53.12, 65.76, 86.43, 118.88, 123.28, 126.92, 128.31,
165.26, 204.61 ppm; IR (KBr): n 2956, 2854, 2203, 1714, 1614, 1495,
128.51, 130.76, 131.06, 131.23, 131.32, 132.26, 142.75, 166.05,
1463,1456,1361,1154,1186,1081, 968, 693 cmꢁ1; HRMS(EI) calcd for
204.66 ppm; IR (KBr):
n
3001, 2933, 2206, 1716, 1611, 1512, 1460,
C18H15NO2SNa ([MþNa]þ) 332.0716. Found 332.0726.
1359, 1249, 1150, 833, 776 cmꢁ1; HRMS (EI) calcd for C20H16BrNO2
(Mþ) 381.0364. Found 381.0364.
4.4.11. 3-Acetyl-4-(1-methyl-1H-indyl-3-yl)-6-phenyl-3,4-dihydro-
2H-pyran-5-carbonitrile (1k). Orange solid; mp: 169e171 ꢀC; 1H
4.4.5. 3-Acetyl-4-(2-bromophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
NMR (400 MHz, CDCl3) d 2.17 (3H, s), 3.27 (1H, m), 3.77 (3H, s),
5-carbonitrile (1e). White solid; mp: 148e149 ꢀC; 1H NMR
4.38e4.48(3H, m), 6.99 (1H, s), 7.13 (1H, t, J¼7.2 Hz), 7.28e7.35 (2H, m),
(400 MHz, CDCl3)
d 2.33 (3H, s), 3.02 (1H, s), 4.14e4.17 (1H, dd,
7.43e7.45 (3H, m), 7.56 (1H, m), 7.79 (2H, d, J¼6.8 Hz) ppm; 13C NMR
3J¼11.6 Hz, 4J¼2.4 Hz), 4.61e4.67 (2H, m), 7.23 (1H, m), 7.38e7.51
(100 MHz, CDCl3) d 30.23, 31.44, 33.71, 51.25, 65.96, 87.25, 109.86,
(5H, m), 7.67 (1H, d, J¼8.0 Hz), 7.82e7.84 (2H, d, J¼7.2 Hz) ppm; 13C
113.56, 118.47, 119.55, 122.25, 125.73, 128.29, 128.35, 128.44, 131.00,
NMR (100 MHz, CDCl3)
d
28.03, 40.46, 50.56, 64.27, 84.65, 119.24,
132.73, 137.78, 165.19, 205.82 ppm; IR (KBr): n 2925, 2854, 2205, 1712,
124.11, 128.06, 128.26, 128.46, 129.50, 130.37, 131.20, 132.45, 133.86,
1613,1467,1360,1327,1282,1150,1081, 969, 909, 739, 697 cmꢁ1;HRMS
139.43, 166.58, 204.03 ppm; IR (KBr):
n
3059, 2998, 2206, 1713,
(EI) calcd for C23H20N2O2Na ([MþNa]þ) 379.1417. Found 379.1423.
1621, 1464, 1445, 1361, 1153, 768, 697 cmꢁ1; HRMS (EI) calcd for
C20H16BrNO2 (Mþ) 381.0364. Found 381.0369.
4.4.12. 3-Acetyl-6-(4-methoxyphenyl)-4-phenyl-3,4-dihydro-2H-py-
ran-5-carbonitrile (1m). White solid; mp: 121e123 ꢀC; 1H NMR
4.4.6. 3-Acetyl-4-(4-fluorophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
5-carbonitrile (1f). White solid;mp:121e123 ꢀC;1HNMR(400 MHz,
(400 MHz, CDCl3) d 2.07 (3H, s), 3.04 (1H, m), 3.84 (3H, s), 4.14 (1H,
d, J¼7.2 Hz), 4.34e4.38 (2H, m), 6.93 (2H, d, J¼9.2 Hz), 7.26e7.38
CDCl3)
d
2.14 (3H, s), 3.05e3.10 (1H, m), 4.20 (1H, d, J¼7.2 Hz),
(5H, m), 7.75 (2H, d, J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
4.38e4.44 (2H, m), 7.12 (2H, t, J¼8.8 Hz), 7.30e7.50 (5H, m), 7.81 (2H,
d 29.87, 42.15, 53.41, 55.42, 65.92, 85.78, 113.80, 119.55, 124.79,
d, J¼6.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d
29.70, 41.34, 53.32,
127.93, 128.06, 129.19, 129.96, 140.44, 161.83, 165.43, 205.60 ppm;
66.06, 87.24, 116.20 (d, JFeC¼21.2 Hz), 118.93, 128.27, 128.49, 129.71
(d, JFeC¼8.2 Hz), 131.25, 132.33, 135.90 (d, JFeC¼3.3 Hz), 162.40 (d,
IR (KBr): n 2956, 2926, 2853, 2204, 1715, 1608, 1512, 1455, 1256,
1176, 1150, 1029, 837, 701 cmꢁ1; HRMS (EI) calcd for C21H19NO3Na
JFeC¼246.9 Hz), 165.77, 205.18 ppm; IR (KBr):
n
2958, 2920, 2207,
([MþNa]þ) 356.1257. Found 356.1261.
1715, 1615, 1506, 1449, 1223, 1146, 695 cmꢁ1; HRMS (EI) calcd for
C20H16FNO2Na ([MþNa]þ) 344.1057. Found 344.1066.
4.4.13. 3-Acetyl-4-phenyl-6-p-tolyl-3,4-dihydro-2H-pyran-5-car-
bonitrile (1n). White solid; mp: 122e123 ꢀC; 1H NMR (400 MHz,
4.4.7. 3-Acetyl-4-(4-methoxyphenyl)-6-phenyl-3,4-dihydro-2H-py-
CDCl3)
d
2.07 (3H, s), 3.13 (3H, s), 3.05 (1H, m), 4.14 (1H, d, J¼6.4 Hz),
ran-5-carbonitrile (1g). Yellow solid; mp: 123e124 ꢀC; 1H NMR
4.35e4.38 (2H, m), 7.22e7.25 (2H, m), 7.28e7.31 (3H, m), 7.36e7.39
(400 MHz, CDCl3)
d
2.07 (3H, s), 3.04 (1H, m), 3.80 (3H, s), 4.08 (1H,
(2H, m), 7.68 (2H, d, J¼8.4 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 21.50,
d, J¼6.8 Hz), 4.33e4.41 (2H, m), 6.91 (2H, d, J¼8.8 Hz), 7.21 (2H, d,
29.87, 42.01, 53.31, 65.93, 86.59, 119.32, 127.95, 128.07, 128.22, 129.14,
J¼8.4 Hz), 7.43e7.50 (3H, m), 7.77 (2H, d, J¼7.2 Hz) ppm; 13C NMR
129.21, 129.66, 140.34, 141.59, 165.82, 205.59 ppm; IR (KBr):
n 3036,
(100 MHz, CDCl3)
d
30.01, 41.44, 53.26, 55.32, 66.12, 87.71, 114.64,
2925, 2849, 2205, 1716, 1609, 1454, 1360, 1189, 1150, 824, 701 cmꢁ1
;
119.19, 128.28, 128.44, 129.12, 131.09, 132.05, 132.56, 159.30, 165.45,
HRMS (EI) calcd for C21H19NO2Na ([MþNa]þ) 340.1308. Found 340.1317.
205.82 ppm; IR (KBr):
n 2956, 2926, 2204, 1715, 1608, 1512, 1455,
1256, 1176, 1029, 837, 701 cmꢁ1; HRMS (EI) calcd for C21H19NO3
(Mþ) 333.1365. Found 333.1362.
4.4.14. 3-Acetyl-6-(4-bromophenyl)-4-phenyl-3,4-dihydro-2H-py-
ran-5-carbonitrile (1o). White solid; mp: 138e139 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
2.09 (3H, s), 3.06 (1H, m), 4.14 (1H, d, J¼6.8 Hz),
4.4.8. 3-Acetyl-4-(4-nitrophenyl)-6-phenyl-3,4-dihydro-2H-pyran-
4.37e4.39 (2H, m), 7.26e7.41 (5H, m), 7.57 (2H, d, J¼8.8 Hz), 7.66 (2H,
5-carbonitrile (1h). Yellow solid; mp: 146e147 ꢀC; 1H NMR
d, J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 29.81, 41.98, 53.08,
(400 MHz, CDCl3)
d
2.17 (3H, s), 3.10 (1H, m), 4.33e4.38 (2H, m),
66.01, 87.71, 118.78, 125.68, 128.02, 128.10, 129.28, 129.80, 131.31,
4.48 (1H, m), 7.47e7.53 (5H, m), 7.80 (2H, d, J¼8.0 Hz), 8.27 (2H, d,
131.74,140.00,164.49, 205.31 ppm;IR(KBr):n2955, 2924,2852, 2206,
J¼8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d
29.36, 41.43, 53.11,
1715, 1621, 1615, 1487, 1455, 1150, 1010, 831, 701, 674 cmꢁ1; HRMS (EI)
65.99, 86.05, 123.99, 124.44, 128.28, 128.60, 129.21, 131.57, 131.93,
calcd for C20H16NO2BrNa ([MþNa]þ) 404.0257. Found 404.0267.
147.69, 166.42, 203.93 ppm; IR (KBr): n 2957, 2925, 2206, 1715, 1614,
1597, 1519, 1494, 1348, 1151, 969, 696 cmꢁ1; HRMS (EI) calcd for
4.4.15. Methyl 5-cyano-4,6-diphenyl-3,4-dihydro-2H-pyran-3-car-
boxylate (1s). The title compound was obtained according to the
generalprocedure(78%yield)anda mixtureof twodiastereoisomers
(major and minor); dr: trans/cis¼2.4:1. Yellow solid; 1H NMR
C20H17N2O4 ([MþH]þ) 349.1183. Found 349.1195.
4.4.9. 3-Acetyl-4-(2,4-dichlorophenyl)-6-phenyl-3,4-dihydro-2H-py-
ran-5-carbonitrile (1i). Pale yellow solid; mp: 143e144 ꢀC; 1H NMR
(400 MHz, CDCl3) d 2.97 (m, 1H; major), 3.31 (m, 1H; minor), 3.55
(400 MHz, CDCl3)
d
2.26 (3H, s), 3.00 (1H, d, J¼2.4 Hz), 4.15 (1H, dd,
(s, 3H; minor), 3.71 (s, 3H; major), 4.23e4.27 (m, 1H; both di-
astereoisomers), 4.32(d,1H, J¼11.6 Hz; minor), 4.36 (d,1H, J¼3.2 Hz;
major), 4.46e4.51 (m,1H; both diastereoisomers), 7.23e7.48 (m, 8H;
both diastereoisomers), 7.80e7.84 (m, 2H; both diastereoisomers)
3J¼11.6 Hz, 4J¼2.4 Hz), 4.58e4.62 (2H, m), 7.28e7.30 (2H, m),
7.43e7.47 (4H, m), 7.77 (2H, d, J¼8.8 Hz) ppm; 13C NMR (100 MHz,
CDCl3)
d 28.16, 37.85, 50.30, 64.50, 84.24, 119.05, 127.75, 128.26,
128.50, 130.34, 131.08, 131.37, 132.25, 134.31, 134.53, 136.52, 166.75,
ppm; 13C NMR (100 MHz, CDCl3)
d 41.86, 42.00, 42.77, 46.21, 52.55,
203.79 ppm; IR (KBr):
n
3054, 3002, 2206, 1715, 1613, 1557, 1471,
62.94, 65.62, 85.37, 86.25, 119.25, 119.36, 127.93, 128.10, 128.17,
128.29, 128.34, 128.45, 128.49, 128.69, 129.10, 129.12, 131.12, 132.59,
1385, 1154, 1103, 696 cmꢁ1; HRMS (EI) calcd for C20H15Cl2NO2 (Mþ)
371.0480. Found 371.0478.
132.68,137.39,140.35,165.64,165.85,169.42,170.64 ppm; IR (KBr):
n
3054, 3026, 2954, 2925, 2854, 2207, 1737, 1617, 1494, 1453, 1437,
1345, 1246, 1203, 1152, 1080, 1011, 975, 771, 698 cmꢁ1; HRMS (EI)
calcd for C20H17NO3 (Mþ) 319.1208. Found 319.1205.
4.4.10. 3-Acetyl-6-phenyl-4-(thienyl-2-yl)-3,4-dihydro-2H-pyran-5-
carbonitrile (1j). Yellow solid; mp: 95e96 ꢀC; 1H NMR (400 MHz,
CDCl3)
m), 7.28 (1H, d, J¼4.8 Hz), 7.41e7.47 (3H, m), 7.75 (2H, d, J¼6.8 Hz)
ppm; 13C NMR (100 MHz, CDCl3)
29.24, 36.83, 53.52, 65.83, 87.44,
d 2.21 (3H, s), 3.12 (1H, m), 4.46e4.49 (3H, m), 6.99e7.03 (2H,
4.4.16. Ethyl 5-cyano-4,6-diphenyl-3,4-dihydro-2H-pyran-3-carbox-
ylate (1t). The title compound was obtained according to the
d

W. Liu et al. / Tetrahedron 67 (2011) 1768e1773
1773
general procedure (61% yield) and
astereoisomers (major and minor); dr: trans/cis¼1.4:1. Yellow solid;
1H NMR (400 MHz, CDCl3)
J¼3.0 Hz; major), 2.95 (m, 1H; major), 3.28 (m, 1H; minor),
3.96e4.00 (m, 1H; both diastereoisomers), 4.14e4.25 (m, 2H; both
diastereoisomers), 4.30e4.37 (m, 1H; both diastereoisomers),
4.46e4.50 (m, 1H; both diastereoisomers), 7.23e7.42 (m, 5H; both
diastereoisomers), 7.44e7.55 (m, 3H; both diastereoisomers),
7.79e7.84 (m, 2H; both diastereoisomers) ppm; 13C NMR (100 MHz,
a
mixture of two di-
References and notes
1. (a) Rauhut, M.; Currier, H. (American Cyanamide). U.S. Patent 3,074,999, 1963;
Chem. Abstr. 1963, 58, 11224a; (b) Baylis, A.B.; Hillman, M.E.D. German Patent
2155113, 1972; Chem. Abstr. 1972, 77, 34174q For reviews, see: (c) Aroyan, C. E.;
Dermenci, A.; Miller, S. J. Tetrahedron 2009, 65, 4069; (d) Methot, J. L.; Roush,
W. R. Adv. Synth. Catal. 2004, 346, 1035; (e) Ma, G.-N.; Jiang, J.-L.; Shi, M. Chem.
Commun. 2009, 5496.
2. For recent intramolecular RC reaction, see: (a) Erguden, J. K.; Moore, H. W. Org.
Lett. 1999, 1, 375; (b) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
2002, 124, 2404; (c) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 2402 For enantioselective variants of RC
reaction, see: (d) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256; (e)
d
1.13 (t, 3H, J¼3.0 Hz; minor), 1.21 (t, 3H,
CDCl3)
d 13.93, 14.09, 41.97, 42.01, 42.81, 46.30, 61.02, 61.57, 63.04,
65.79, 85.50, 86.33, 119.28, 119.40, 127.90, 128.13, 128.17, 128.26,
128.44,128.48,128.62,128.76,128.80,128.84,129.08,129.26,131.08,
132.66, 132.72, 137.41, 140.32, 165.58, 165.85, 168.99, 170.18 ppm; IR
ꢀ
Seidel, F.; Gladysz, J. A. Synlett 2007, 986; (f) Lopez, E. M.; Herrera, R. P.; Marks,
€
T.; Jacobs, W. C.; Konning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett.
2009, 11, 4116; (g) Aroyan, C. E.; Dermenci, A.; Miller, S. J. J. Org. Chem. 2010,
75, 5784.
(KBr): n 3065, 3027, 2961, 2925, 2853, 2207, 1707, 1598, 1492, 1459,
3. For recent examples of the cross-RC reaction, see: (a) Sun, X.; Sengupta, S.;
Peterson, J. L.; Wang, H.; Lewis, J. P.; Shi, X. Org. Lett. 2007, 9, 4495; (b) Reynolds,
T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10, 2449; (c) Zhong, C.; Chen,
Y.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. Angew. Chem., Int. Ed. 2009, 48, 1279.
4. For pioneering studies on tandem processes involving RC reaction, see: (a)
Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394; (b) Stark, L.;
Pekari, M. K.; Sorensen, E. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12064; (c)
Yao, W.-J.; Wu, Y.-H.; Wang, G.; Zhang, Y.-P.; Ma, C. Angew. Chem., Int. Ed.
2009, 14, 9713.
5. (a) Brimble, M. A.; Prabaharan, H. Tetrahedron 1998, 54, 2113; (b) Jørgensen, K.
A. Angew. Chem., Int. Ed. 2000, 39, 3558; (c) Tang, Y.; Oppenheimer, J.; Song, Z.;
You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785; (d) Kumar, S.;
Malachowski, W. P.; DuHadaway, J. B.; LaLonde, J. M.; Carroll, P. J.; Jaller, D.;
Metz, R.; Prendergast, G. C.; Muller, A. J. J. Med. Chem. 2008, 51, 1706; (e) Han, B.;
Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C. Angew. Chem., Int. Ed. 2008, 47, 9971; (f)
Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem., Int. Ed. 2008, 47, 3046; (g)
Franke, P. T.; Richter, B.; Jørgensen, K. A. Chem.dEur. J. 2008, 14, 6317.
6. The relative configuration of 1a was determined by NOESY spectroscopy.
7. For a review on zwitterions, see: Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520.
1449, 1341, 1247, 1186, 1153, 1081, 1029, 771, 699 cmꢁ1; HRMS (EI)
calcd for C21H19NO3 (Mþ) 333.1365. Found 333.1369.
4.4.17. 4,6-Diphenyl-3-propionyl-3,4-dihydro-2H-pyran-5-carbon-
itrile (1v). Pale yellow solid; mp: 115e116 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
0.93 (3H, t, J¼7.2 Hz), 2.13 (1H, m), 2.44 (1H, m), 3.07 (1H,
m), 4.13 (1H, d, J¼7.8 Hz), 4.29e4.42 (2H, m), 7.26e7.47 (8H, m),
7.78 (2H, d, J¼6.8 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 7.23, 36.37,
42.65, 52.49, 66.57, 87.65, 119.01, 128.00, 128.29, 128.44, 129.20,
131.09, 132.56, 140.05, 165.67, 208.46 ppm; IR (KBr):
n 3060, 3023,
2924, 2854, 2206, 1715, 1614, 1575, 1494, 1455, 1308, 1214, 1151,
1078, 1029, 969, 768, 698 cmꢁ1; HRMS (EI) calcd for C21H19NO2
(Mþ) 317.1416. Found 317.1419.
8. For studies on key intermediates intercepted by ESIMS monitoring, see: (a)
Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N. Angew.
Chem., Int. Ed. 2004, 43, 4330; (b) Qian, R.; Guo, H.; Liao, Y.; Guo, Y.; Ma, S.
Angew. Chem., Int. Ed. 2005, 44, 4771; (c) Guo, H.; Qian, R.; Liao, Y.; Ma, S.; Guo,
Y. J. Am. Chem. Soc. 2005, 127, 13060; (d) Marquez, C.; Metzger, J. O. Chem.
Commun. 2006, 1539; (e) Marquez, C. A.; Fabbretti, F.; Metzger, J. O. Angew.
Chem., Int. Ed. 2007, 46, 6915; (f) Bao, H.; Zhou, J.; Wang, Z.; Guo, Y.; You, T.;
Ding, K. J. Am. Chem. Soc. 2008, 130, 10116; (g) De Souza, R.; da Penha, E. T.;
Milagre, H. M. S.; Garden, S. J.; Esteves, P. M.; Eberlin, M. N.; Antunes, O. A. C.
Chem.dEur. J. 2009, 15, 9799; (h) Amarante, G. W.; Benessi, M.; Milagre, H. M.
S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.; Coelho, F. Chem.dEur. J. 2009, 15,
12460.
Acknowledgements
The generous financial support from National Basic Research
Program of China (973 Program, 2010CB833300), the National
Natural Science Foundation of China (No. 21032006, 20875097, and
21002118), and Excellent Young Scholars Foundation of NNSF is
gratefully acknowledged.
9. (a) Drauz, K.; Kleemann, A.; Wolf-Heuss, E. U.S. Patent 4,728,743, Mar 1, 1988.
(b) Chen, Y. P.; Sieburth, S. M. Synthesis 2002, 2191; (c) Ji, Y. H.; Trenkle, W. C.;
Vowles, J. V. Org. Lett. 2006, 8, 1161; (d) Yu, W. Q.; Du, Y. F.; Zhao, K. Org. Lett.
2009, 11, 2417.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.01.036.
10. Cope, A. C. J. Am. Chem. Soc. 1937, 59, 2327.