α-alkenoyl ketene S,S-acetal-based multicomponent reaction: An efficient approach for the selective construction of polyfunctionalized cyclohexanones

Article abstract of DOI:10.1021/jo900217g

A versatile multicomponent reaction based on the new four-carbon synthons α-alkenoyl ketene S,S- acetals 1 has been developed. This three-component reaction of readily available α-alkenoyl ketene S,S- acetals 1 with aldehydes 2 and active methylene compou

Full text of DOI:10.1021/jo900217g

r-Alkenoyl Ketene S,S-Acetal-Based Multicomponent Reaction: An
Efficient Approach for the Selective Construction of
Polyfunctionalized Cyclohexanones
Yuhui Ma, Mang Wang,* Dan Li, Bahargul Bekturhun, Jun Liu, and Qun Liu*
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, P. R. China
wangm452@nenu.edu.cn
ReceiVed February 1, 2009
A versatile multicomponent reaction based on the new four-carbon synthons R-alkenoyl ketene S,S-
acetals 1 has been developed. This three-component reaction of readily available R-alkenoyl ketene S,S-
acetals 1 with aldehydes 2 and active methylene compounds 3 proceeds smoothly in acidic medium
(glacial acetic acid in tetrahydrofuran) to give various polyfunctionalized cyclohexanones 4, 5, and 6 in
a highly regio- and diastereoselective manner with good to excellent yields. The reaction can tolerate a
broad range of substituents in the three components involved and is proposed to proceed via a tandem
Knoevenagel-intermolecular Michael-intramolecular Michael sequence. As an extension of the synthetic
application of polyfunctionalized cyclohexanones obtained, unsymmetrical biaryls 7 were synthesized in
almost quantitative yields by simple transformations of the corresponding cycloadducts 6.
Introduction
acetals, a kind of 1,4-dien-3-ones4 bearing a variety of alkenoyl
substituents and a ketene dithioacetal subunit that have been
successfully used as five-carbon synthons in our previous
works,5 can be taken as new four-carbon synthons in multi-
component reactions.
The utility of functionalized ketene S,S-acetals 1 (Scheme 1)
as versatile intermediates in organic synthesis has been greatly
expanded over the past several decades.5-11 Generally, as 1,3-
bielectrophilic three-carbon synthons, R-oxo ketene S,S-acetals
have been widely applied in [3 + 3] annulation reactions for
the synthesis of six-membered carbo- (Scheme 1, Strategy 1)
and heterocyclic compounds.6,7 In our research on the chemistry
of functionalized ketene S,S-acetals,5,8-11 we have taken R-alk-
enoyl ketene S,S-acetals as five-carbon 1,5-bielectrophilic double
Michael acceptors in the [5 + 1] annulation strategy for
Multicomponent reactions (MCRs) have been refined in recent
years into powerful and useful tools in synthetic chemistry and
have attracted increasing attention because complex molecules
and drugs can be prepared from cheap and easily available
starting materials.1 In addition, the implementation of several
transformations in a single manipulation is highly compatible
with the goals of sustainable and “green” chemistry.2 From this
perspective and combined with combinatorial chemistry,3 the
development of versatile MCRs, especially those involving
synthons having multiple reactive sites (groups), is particularly
desirable.1 In this paper, we show that R-alkenoyl ketene S,S-
(1) For reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115–136. (b) In
Multicomponent Reactions; Zhu, J., Bienayme´, H. , Eds.; Wiley-VCH, Weinheim,
2005. (c) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000,
6, 3321–3329. (d) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
3210. (e) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
(f) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (g) Tejedor, D.; Garc´ıa-Tellado,
F. Chem. Soc. ReV. 2007, 36, 484–491.
(2) For reviews, see: (a) Trost, B. M. Science 1991, 254, 1471–1477. (b)
Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246.
(3) For reviews, see: (a) Kassel, D. B. Chem. ReV. 2001, 101, 255–268. (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123–131. (c) Gordon, E. M.; Gallop, M. A.; Patel,
D. V. Acc. Chem. Res. 1996, 29, 144–154.
(4) 1,4-Dien-3-ones are useful substrates in the Nazarov reaction; for reviews,
see: (a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193–2206. (b) Pellissier, H.
Tetrahedron 2005, 61, 6479–6517. (c) Frontiera, A. J.; Collison, C. Tetrahedron
2005, 61, 7577–7606.
(5) For representative examples, see: (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.;
Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578–4579. (b) Dong, D.; Bi, X.;
Liu, Q.; Cong, F. Chem. Commun. 2005, 3580–3582. (c) Bi, X.; Dong, D.; Li,
Y.; Liu, Q.; Zhang, Q. J. Org. Chem. 2005, 70, 10886–10889. (d) Hu, J.; Zhang,
Q.; Yuan, H.; Liu, Q. J. Org. Chem. 2008, 73, 2442–2445. (e) Tan, J.; Xu, X.;
Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, Epub ahead of print,
DOI: 10.1002/anie.200805703.
3116 J. Org. Chem. 2009, 74, 3116–3121
10.1021/jo900217g CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

Construction of Polyfunctionalized Cyclohexanones
SCHEME 1. Versatile Organic Intermediates:
Functionalized Ketene S,S-Acetals 1
SCHEME 2. Preparation of r-Alkenoyl Ketene S,S-Acetals 1
substrates, R-alkenoyl ketene S,S-acetals 1a-1j bearing either
aromatic or aliphatic R1 substituents and either acyclic or cyclic
dithioacetal groups, were prepared in high to excellent yields
by the condensation reaction of the corresponding R-acetyl
ketene S,S-acetals with aldehydes under basic conditions
(Scheme 2).5a-c,9b,11
Synthesis of Polyfunctionalized Cyclohexanone 4a by
the MCR of 1a, 2a, and 3a. On the basis of our previous work,
one of the difficulties in studying the MCR of compound 1 with
an aldehyde 2 and an active methylene component 3 is to avoid
the favorable formation of the 2:1 adducts via sequential C-C
coupling of 1 with aldehyde 2 in the presence of Lewis acids
(for example, adduct A in Table 1).10a,b,d The present research
started with the model reaction between R-cinnamoyl ketene
S,S-acetal 1a (1.0 mmol), formaldehyde 2a (5.0 mmol, 40%
aqueous), and dimedone 3a (1.2 mmol) mediated by simple
Brønsted acids (Table 1).9c However, extensive experimentation
revealed that, similar to the results using Lewis acid catalysis
in our previous research,10a,b,d the 2:1 adducts A together with
B were isolated, respectively, when hydrochloric acid (2.0 equiv,
36% aqueous) or sulfuric acid (2.0 equiv, 98% aqueous) was
selected as the catalyst in THF (4.0 mL) (Table 1, entries 1 and
2). Fortunately, with treatment of the above reaction mixture
with glacial acetic acid (2.0 equiv) in THF (4 mL), a cyclization
product, the highly substituted cyclohexanone 4a, was obtained
in 57% yield after 24 h of reaction at room temperature in the
open air (Table 1, entry 3). Thus, glacial acetic acid was selected
to give an acid medium for this selective MCR, and the
optimization of the reaction conditions with respect to the
amount of acid and the reaction temperature was investigated.
The results are described in Table 1. Clearly, a higher temper-
ature accelerated the reaction rate, and cyclohexanone 4a was
obtained in 77% yield within 2.5 h at reflux temperature in the
presence of 2.0 equiv of glacial acetic acid in 4.0 mL of THF.
The best result was achieved when the reaction proceeded at
80 °C (oil bath temperature) in 2.0 mL of glacial acetic acid
and 2.0 mL of THF and with a 1:5:1.2 ratio of 1a:2a:3a (Table
1, entry 8).
construction of cyclohexenones (Scheme 1, Strategy 3),5a
dihydropyridones,5b and dihydrothiopyranones.5c Recently, func-
tionalized ketene S,S-acetals were also applied as two-carbon
dipolar synthons for efficient preparation of coumarins (Scheme
1, Strategy 2)7c,10d and the multistep synthesis of polysubstituted
furans.9c Combining all above synthetic applications of func-
tionalized ketene S,S-acetals in organic synthesis5-10 with their
potential nucleophilicity of the R-carbon atom,9c,10 in our present
research a cyclization strategy was designed to evaluate the
efficiency of the R-alkenoyl ketene S,S-acetals 1 as four-carbon
synthons in MCRs (Scheme 1, Strategy 4). Fortunately, the
three-component [4 + 2] cycloaddition reaction of readily
available R-alkenoyl ketene S,S-acetals 1 with the Knoevenagel
adducts produced in situ from aldehydes 2 and active methylene
compounds 3 was achieved via a tandem Knoevenagel-
intermolecular Michael-intramolecular Michael sequence in the
presence of glacial acetic acid in tetrahydrofuran to afford
polyfunctionalized cyclohexanones 4, 5, and 6 in highly regio-
and diastereoselective fashion with good to excellent yields.
Based on this new strategy, a wide variety of polyfunctionalized
cyclohexanones, including extensive changes of SR, R1, R2,
EWG1 (EWG ) electron-withdrawing group), and EWG2, were
efficiently synthesized in a single step. The results are reported
in this paper.
Results and Discussion
Preparation of r-Alkenoyl Ketene S,S-Acetals 1. According
to the procedures described in our previous reports, the selected
Possible Mechanism for MCR of 1a, 2a, and 3a. The
construction of suitably functionalized (or substituted) six-
(6) For reviews, see: (a) Dieter, R. K. Tetrahedron 1986, 42, 3029–3096.
(b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423–5506.
(7) For representative examples, see: (a) Gill, S.; Kocienski, P.; Kohler, A.;
Pontiroli, A.; Liu, Q. Chem. Commun. 1996, 1743–1744. (b) Kocienski, P. J.;
Pontiroli, A.; Liu, Q. J. Chem. Soc., Perkin Trans. 1 2001, 2356–2366. (c) Rao,
H. S. P.; Sivakumar, S. J. Org. Chem. 2006, 71, 8715–8723.
(8) For representative examples of intramolecular anti-Michael additions, see:
(a) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org. Chem. 2006, 71, 8006–8010. (b) Bi,
X.; Zhang, J.; Liu, Q.; Tan, J.; Li, B. AdV. Synth. Catal. 2007, 349, 2301–2306.
(9) For representative examples of other applications, see: (a) Liang, F.;
Zhang, J.; Tan, J.; Liu, Q. AdV. Synth. Catal. 2006, 348, 1986–1990. (b) Liu, J.;
Wang, M.; Li, B.; Liu, Q.; Zhao, Y. J. Org. Chem. 2007, 72, 4401–4405. (c)
Fu, Z.; Wang, M.; Ma, Y.; Liu, Q.; Liu, J. J. Org. Chem. 2008, 73, 7625–7630.
(10) For representative examples of C-C bond-forming reactions at the
R-position of functionalized ketene S,S-acetals, see: (a) Yin, Y.; Wang, M.; Liu,
Q.; Hu, J.; Sun, S.; Kang, J. Tetrahedron Lett. 2005, 46, 4399–4402. (b) Zhang,
Q.; Liu, Y.; Wang, M.; Liu, Q.; Hu, J.; Yin, Y. Synthesis 2006, 3009–3014. (c)
Yin, Y.; Zhang, Q.; Li, J.; Sun, S.; Liu, Q. Tetrahedron Lett. 2006, 47, 6071–
6074. (d) Yuan, H.-J.; Wang, M.; Liu, Y.-J.; Liu, Q. AdV. Synth. Catal. 2009,
351, 112–116.
(11) Yu, H.; Dong, D.; Ouyang, Y.; Liu, Q.; Wang, Y. Lett. Org. Chem.
2005, 2, 755–759.
J. Org. Chem. Vol. 74, No. 8, 2009 3117

Ma et al.
SCHEME 3. Proposed Mechanism for the MCR of 1a, 2a,
TABLE 1. Optimization of Reaction Conditions of the MCR of
1a, 2a, and 3aa
and 3a
entry
acid
THF (mL) T (°C)
time
24 h
24 h
24 h
4a (%)b
1
2
3
4
5
6
7
8
9
HCl (2.0 equiv)
H2SO4 (2.0 equiv)
AcOH (2.0 equiv)
AcOH (4.0 equiv)
AcOH (2.0 equiv)
AcOH (4.0 equiv)
AcOH (1.0 mL)
AcOH (2.0 mL)
AcOH (3.0 mL)
4.0
4.0
4.0
4.0
4.0
4.0
3.0
2.0
1.0
rt
rt
rt
rt
80
80
80
80
80
c
d
57
80
77
80
85
93
90
24 h
2.5 h
2.5 h
1.5 h
45 min
30 min
a 1a (1.0 mmol), 2a (5.0 mmol, 40% aqueous), 3a (1.2 mmol).
b Isolated yield. c 2:1 adducts A and B were isolated in 65% and 90%
yields, respectively. d 2:1 adducts A and B were isolated in 60% and
86% yields, respectively.
addition of 1a to I produces intermediate II, which is protonated
and further undergoes an intramolecular Michael addition to
generate cyclohexanone 4a. In our experiments, intermediate I
could not be isolated from the reaction mixture because of its
high reactivity toward nucleophiles.16 Adduct B, which was
proved not to react with 1a under the identical conditions (Table
1, entry 8), was isolated in 95% yield when the Knoevenagel
condensation of 2a (5.0 mmol) with 3a (1.0 mmol) was
performed in glacial acetic acid (2.0 mL) and THF (2.0 mL) at
80 °C (oil bath temperature) for only 5.0 min in the absence of
1a. The above results suggest that under the optimized reaction
conditions, the formations of the 2:1 adducts A and B (Table
1) can be effectively minimized so that the MCR product 4a
can be constructed through the very reactive intermediate I and
subsequent conjugate addition with 1a (Scheme 3).
Scope of the MCRs. With optimized conditions in hand, the
scope and limitations of this new MCR were examined in regard
to the three components involved. According to the results of
the MCRs of 1 with 2a and 3a (Table 2), it was found that all
selected R-alkenoyl ketene S,S-acetals 1 bearing aromatic
substituents (entries 1-7) reacted efficiently with 2a and 3a to
give the corresponding cyclohexanones 4 in high yields. In the
case of 1h bearing a bulky aliphatic substituent (t-Bu), an acyclic
product IIa, same as intermediate II described in Scheme 2,
was obtained (Table 2, entry 8). In addition, both 1i (with cyclic
dithioacetal group) and 1j (with acyclic dithioacetal group) also
allowed the formation of 4h and 4i in 77% and 60% isolated
yields, respectively (Table 2, entries 9 and 10).
membered carbocycles is of great interest for the synthesis of
natural products and pharmaceutically attractive molecules.12
Therefore, the development of simple and efficient approaches
for the construction of them is desired.13 Although MCRs have
been widely applied for the preparation of a diverse array of
polysubstituted heterocyclic compounds,1 the synthesis of six-
membered carbocycles via MCRs are less well developed. In
this context, remarkable progresses have been achieved in the
four-component cyclization of Fischer carbene complexes,
lithium enolates, allylmagnesium bromide with carbon monox-
ide,14 and Barbas three-component cycloaddition of 3-buten-
2-ones, aldehydes, and active methylene compounds via a
domino Knoevenagel/Diels-Alder sequence.15
In the present work, the regioselective MCR of R-cinnamoyl
ketene S,S-acetal 1a, formaldehyde 2a, and dimedone 3a leading
to cyclohexanone 4a provides an alternative approach for the
construction of six-membered carbocycles. This reaction should
be reasonably described as a three-component [4 + 2] cycload-
dition. As shown in Scheme 3, the reaction begins with the in
situ formation of methylidenedimedone I via Knoevenagel
condensation of 2a with 3a. Then, intermolecular Michael
(12) (a) Hazama, N.; Irie, H.; Mizutani, T.; Shingu, T.; Takada, M.; Uyeo,
S.; Yoshitake, A. J. Chem. Soc. C: 1968, 2947–2953. (b) Ho, T. L. In Carbocycle
Construction in Terpene Synthesis; Wiley-VCH: Weinheim, 1988.
(13) For recent examples of the synthesis of six-membered carbocycles, see:
(a) Tanaka, K.; Fu, G. C. Org. Lett. 2002, 4, 933–935. (b) Halland, N.; Aburel,
P. S.; Jøgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272–1277. (c)
DeGraffenreid, M. R.; Bennett, S.; Caille, S.; Gonzalez-Lopez de Turiso, F.;
Hungate, R. W.; Julian, L. D.; Kaizerman, J. A.; McMinn, D. L.; Rew, Y.; Sun,
D.; Yan, X.; Powers, J. P. J. Org. Chem. 2007, 72, 7455–7458. (d) Zhang, G.;
Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814–1815.
(14) Barluenga, J.; Pe´rez-Sa´nchez, I.; Suero, M. G.; Rubio, E.; Flo´rez, J.
Chem. Eur. J. 2006, 12, 7225–7235.
(15) (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2003, 42, 4233–4237. (b) Ramachary, D. B.; Anebouselvy, K.; Chowdari,
N. S.; Barbas, C. F., III. J. Org. Chem. 2004, 69, 5838–5849. (c) Ramachary,
D. B.; Barbas, C. F., III. Chem. Eur. J. 2004, 10, 5323–5331. (d) Ramachary,
D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1577–1580. (e) Ramachary, D. B.;
Reddy, Y. V.; Prakash, B. V. Org. Biomol. Chem. 2008, 6, 719–726.
The versatility of the above MCR was further demonstrated
with the successful preparation of the corresponding cyclohex-
anones 5 by treatment of various aldehydes 2 (1.2 mmol) with
selected R-alkenoyl ketene S,S-acetals 1 (1.0 mmol) and
dimedone 3a (1.2 mmol) under the identical conditions as
described in Table 1, entry 8. As shown in Table 3, all of the
aromatic aldehydes, including benzaldehyde (entries 1-3),
aromatic aldehydes bearing either electron-withdrawing (entries
(16) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1970, 101, 824–828.
3118 J. Org. Chem. Vol. 74, No. 8, 2009

Construction of Polyfunctionalized Cyclohexanones
TABLE 2. MCRs for the Synthesis of Cyclohexanones 4:
TABLE 4. MCRs for the Synthesis of Cyclohexanones 6:
Variation of Active Methylene Compounds 3a
Variation of the r-Alkenoyl Ketene S,S-Acetals 1a
entry
1
R1
R,R or R
4
time
yield (%)b
1
2
3
4
5
6
7
8
9
1a C6H5
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
4a
4b
4c
4d
4e
4f
45 min
6.0 h
93
77
88
91
80
71
86
66
77
60
1b 4-NO2C6H5
1c 4-ClC6H5
1d 4-MeOC6H4
1e 4-MeC6H4
45 min
25 min
35 min
45 min
15 min
1f
3,4-CH2O2C6H3 (CH2)2
1g 2-furyl
1h t-Bu
(CH2)2
(CH2)2
(CH2)3
Et
4g
IIa 1.5 h
4h
4i
1i
1j
C6H5
C6H5
25 min
1.4 h
10
a 1 (1.0 mmol), 2a (5.0 mmol, 40% aqueous), 3a (1.2 mmol), AcOH
(2.0 mL), THF (2.0 mL), 80 °C. b Isolated yield.
a 1a (1.0 mmol), 2a (5.0 mmol, 40% aqueous), 3 (1.2 mmol), AcOH
(2.0 mL), THF (2.0 mL), 80 °C. b Isolated yield. c Performed in a
mixture of AcOH (1.0 mL) and THF (3.0 mL) at 80 °C. d 6e was
obtained as one diastereoisomer out of the two possible ones. e 2:1
adduct A was obtained in 61% yield.
TABLE 3. MCRs for the Synthesis of Cyclohexanones 5:
Variation of Aldehydes 2a
reactions provide an efficient and divergent approach to a variety
of cyclohexanones 5.
Notably, it was found that the above reactions proceed in a
highly diastereoselective manner, giving cyclohexanones 5 in
76-99% de (Table 3, entries 1-13). The major isomer was
further determined as the cis-isomer by single-crystal X-ray
diffraction study of 5e.17 This is in accordance with the evidence
that the cis-isomer of 3,5-diaryl-substituted cyclohexanones is
thermodynamically stable.15b,18
Next, the reactions of R-cinnamoyl ketene S,S-acetal 1a and
formaldehyde 2a with a variety of active methylene compounds
3 were examined (Table 4). As expected, under the optimized
conditions as indicated in Table 4, entry 1, cyclopentane-1,3-
dione 3b reacted with 1a and 2a to afford the cyclohexanone
6b in 98% yield within 40 min (Table 4, entry 2). Compara-
tively, initial treatment of Meldrum’s acid 3c with 1a and 2a
led to a complex mixture due to probable hydrolysis of
Meldrum’s acid under acid conditions at elevated temperature.
The cycloadduct 6c could be obtained in good yield by
decreasing the amount of acetic acid to 1.0 mL (in 3.0 mL of
THF) at reflux temperature (Table 4, entry 3). In the cases of
acyclic active methylene components, several features of the
MCR are noteworthy. Generally, the reaction rates were slower
than those of the cyclic active methylene compounds and the
product yields were relatively lower. For instance, cyclohex-
time yield
(h)
de
entry
1 R1
1a C6H5
1c 4-ClC6H4
1d 4-MeOC6H4 2b C6H5
2 R2
2b C6H5
2b C6H5
5
(%)b (%)c
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
4.0
8.0
4.0
1.0
2.0
2.0
2.5
3.0
3.0
3.5
3.0
4.0
71
51
70
83
86
89
80
72
69
78
60
70
50
nrd
nrd
99
81
92
95
96
97
99
99
84
99
76
99
88
1a C6H5
1c 4-ClC6H4
2c 4-NO2C6H4
2c 4-NO2C6H4
1d 4-MeOC6H4 2c 4-NO2C6H4
1a C6H5
1a C6H5
1c 4-ClC6H4
2d 4-ClC6H4
2e 4-MeC6H4
2e 4-MeC6H4
9
10
11
12
13
14
15
1d 4-MeOC6H4 2e 4-MeC6H4
5j
5k
5l
1a C6H5
1a C6H5
1a C6H5
1a C6H5
1a C6H5
2f 4-MeOC6H4
2g 4-pyridyl
2h E-PhCHdCH 5m 11.5
2i Me
2j Cy
24
24
a 1 (1.0 mmol), 2 (1.2 mmol), 3a (1.2 mmol), AcOH (2.0 mL), THF
(2.0 mL), 80 °C. b Isolated yield. c Diastereomeric excesses determined
by H NMR. d No reaction.
1
4-7) or electron-donating substituents (entries 8-11), het-
eroaromatic aldehyde (entry 12), and unsaturated aldehyde (entry
13), furnished the corresponding cyclohexanones 5 in good to
high yields. Interestingly, although formaldehyde 2a can be
successfully applied to this MCR (Table 2), the aliphatic
aldehydes, such as acetaldehyde (Table 3, entry 14) and
cyclohexanecarbaldehyde (Table 3, entry 15), could not afford
the desired product, probably because of their lower reactivity.
Nevertheless, it is clear that the above three-component tandem
(17) Crystal data for 5e: C28H26ClNO5S2, yellow, M ) 556.09, orthorhombic,
space group Pbca, a ) 10.9199 (10), b ) 13.5197 (2), c ) 40.2340 (5) Å, V )
5939.90 (13) Å3, R ) 90.00°, ꢀ ) 90.00°, γ ) 90.00°, Z ) 4, T ) 296 (2) K,
F000 ) 3135, R1 ) 0.0488, wR2 ) 0.1424.
(18) Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.; Winemiller, M. D.;
Chamberlin, M. J.; Czulada, G.; Johnson, S. D.; Sabat, M. J. Org. Chem. 1998,
63, 4359–4365.
J. Org. Chem. Vol. 74, No. 8, 2009 3119

Ma et al.
SCHEME 4. Synthesis of Unsymmetrical Biaryls 7 from 6a
one10a,d,11 (160 mg, 1.0 mmol) and furfural (0.09 mL, 1.1 mmol)
in EtOH (5.0 mL) was added NaOH (80 mg, 2.0 mmol) in one
portion at room temperature. The reaction mixture was stirred for
2.0 h. After the starting material 1-(1,3-dithiolan-2-ylidene)propan-
2-one was consumed as indicated by TLC, the resulting mixture
was quenched by ice-water (20 mL) under stirring and neutralized
with concentrated hydrochloric acid. The precipitate was collected
by filtration, washed with water (20 mL), and dried in vacuo to
afford the product (E)-1-(1,3-dithiolan-2-ylidene)-4-(furan-2-yl)but-
3-en-2-one (1g) (205 mg, 90%) as a yellow crystal. Mp 144-146
1
°C. H NMR (500 MHz, CDCl3) δ 3.36 (t, J ) 6.5 Hz, 2H), 3.46
(t, J ) 6.5 Hz, 2H), 6.46-6.47 (dd, J ) 2.0, 3.0 Hz, 1H), 6.61 (d,
J ) 3.0 Hz, 1H), 6.68 (d, J ) 15.5 Hz, 1H), 6.78 (s, 1H), 7.40 (d,
J ) 15.5 Hz, 1H), 7.47 (s, 1H). 13C NMR (125 MHz, CDCl3) δ
184.1, 166.5, 151.7, 144.4, 127.9, 124.4, 114.8, 112.4, 112.3, 38.9,
35.4. IR (KBr, cm-1) 3057, 2984, 2928, 1577, 1495. ES-MS m/z
239.0 [(M + 1)]+. Anal. Calcd for C11H10O2S2: C, 55.44; H, 4.23.
Found: C, 55.69; H, 4.11.
Representative Procedure for the MCRs of 1, 2, and 3.
Synthesis of Cyclohexanones 4 and 6 (Reaction of 1a, 2a, and
3a as Example). To a solution of 1a (248 mg, 1.0 mmol), 2a (0.37
mL, 5.0 mmol, 40% aqueous), and 3a (168 mg, 1.2 mmol) in THF
(2.0 mL) was added AcOH (2.0 mL) at 80 °C. The mixture was
stirred for 45 min at 80 °C and then quenched with water (50 mL).
The resulting mixture was neutralized with saturated aqueous
NaHCO3 and extracted with CH2Cl2 (3 × 15 mL). The combined
organic phase was washed with water (20 mL), dried over
anhydrous MgSO4, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, petroleum ether/
ether 3/1, v/v) to give 4a (372 mg, 93%) as a light yellow crystal.
Synthesis of Cyclohexanones 5 (Reaction of 1c, 2c, and 3a
As example). To a solution of 1c (282 mg, 1.0 mmol), 2c (181
mg, 1.2 mmol), and 3a (168 mg, 1.2 mmol) in THF (2.0 mL) was
added AcOH (2.0 mL) at 80 °C. The mixture was stirred for 2.0 h
at 80 °C and then quenched with water (50 mL). The resulting
mixture was neutralized with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3 × 15 mL). The combined organic phase
was washed with water (20 mL), dried over anhydrous MgSO4,
and concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ether 3/1, v/v) to give
a mixture of cis- and trans-isomers 5e (505 mg, 91%, de, 96%).
Recrystallization of the isomer mixture in acetone/petroleum ether
(1/2, v/v) afforded cis-isomer 5e (478 mg, 86%) as a yellow crystal.
10-(1,3-Dithiolan-2-ylidene)-3,3-dimethyl-7-phenylspiro[5.5]-
undecane-1,5,9-trione (4a). Mp 224-226 °C. 1H NMR (500 MHz,
CDCl3) δ 0.86 (s, 3H), 0.88 (s, 3H), 1.95 (d, J ) 16.0 Hz, 1H),
2.37 (d, J ) 16.0 Hz, 1H), 2.40-2.45 (m, 2H), 2.60 (dd, J ) 5.0,
18.0 Hz, 1H), 2.80 (d, J ) 16.0 Hz, 1H), 2.97 (dd, J ) 10.0, 18.0
Hz, 1H), 3.11 (d, J ) 16.0 Hz, 1H), 3.36-3.44 (m, 4H), 3.70 (dd,
J ) 5.0, 10.0 Hz, 1H), 7.04 (d, J ) 7.5 Hz, 2H), 7.26-7.30 (m,
3H). 13C NMR (125 MHz, CDCl3) δ 210.1, 209.0, 191.4, 160.6,
138.5, 128.8 (2C), 128.4 (2C), 128.1, 118.3, 66.8, 54.3, 53.0, 47.4,
39.9, 39.4, 36.1, 35.0, 30.1, 30.0, 27.7. IR (KBr, cm-1) 3035, 2954,
1723, 1694, 1617, 1459. ES-MS m/z 401.0 [(M + 1)]+. Anal. Calcd
for C22H24O3S2: C, 65.97; H, 6.04. Found: C, 65.68; H, 6.11.
a Reaction conditions: (1) 4 (1.0 mmol), NaBH4 (0.5 equiv), MeOH (5.0
mL), rt; (2) dilute HCl (0.2 mL, 10% aqueous), THF (5.0 mL), rt; (3) DBU
(0.1 mL), DMF (5.0 mL), rt. b 6f was prepared from the MCR of 1d, 2a,
and 3f in 51% yield. c 6g was prepared from the MCR of 1f, 2a, and 3f in
53% yield.
anones 6d and 6e (Table 4, entries 4 and 5) were obtained in
moderate yields from the reaction of acetylacetone 3d and ethyl
nitroacetate 3f with 1a and 2a, respectively, under the above
conditions. For benzoylacetone 3e, the reaction furnished the
acyclic cross-coupling product IIb within 2.0 h (Table 4, entry
6). Prolonging the reaction time did not give the desired
cyclohexanone product. When ethyl acetoacetate 3g was
subjected to the identical conditions, the reaction resulted in a
complex mixture (Table 4, entry 7). In the case of malononitrile
3h as substrate, 2:1 adduct A was isolated from the reaction
mixture in 61% yield after reacting for 24 h (Table 4, entry 8).
Application of Polyfunctionalized Cyclohexanones in
the Synthesis of Unsymmetrical Biaryls. As presented above,
we have developed a novel MCR with a broad scope of the
three components and provided a practical method for the
synthesis of diverse densely functionalized cyclohexanones 4,
5, and 6 with an R-oxo ketene S,S-acetal unit.5-11 Thus, these
cyclohexanones are expected to react with various of 1,3-
bielectrophiles for the library synthesis and screening of bio/
pharmacologically interesting compounds.5 As an extension of
the synthetic application of polyfunctionalized cyclohexanones
obtained above, the synthesis of unsymmetrical biaryls19 was
designed. As shown in Scheme 4, via a sequential reduction of
6e-g with NaBH4, followed by acid-catalyzed dehydration and
elimination of nitrous acid in the presence of DBU,5a function-
alized unsymmetrical biaryls 7a-c were produced in almost
quantitative yields.
Conclusion
In conclusion, we have developed an efficient multicomponent
reaction for the regio- and diastereoselective synthesis of a
combinatorial library of polyfounctionalized cyclohexanones.
This reaction has several attractive features: the use of R-alk-
enoyl ketene S,S-acetals as new four-carbon synthons in
multicomponent reactions, relatively mild reaction conditions,
good functional tolerance, good to excellent yields and high
regio- and diastereoselectivity in most cases, and potential
applications of the polyfunctionalized products. Future studies
focused on the development of the MCR are in progress.
11-(4-Chlorophenyl)-8-(1,3-dithiolan-2-ylidene)-3,3-dimethyl-
7-(4-nitrophenyl)spiro[5.5]undecane-1,5,9-trione (5e). Mp 188-190
1
°C. H NMR (500 MHz, CDCl3) δ -0.23 (s, 3H), 0.57 (s, 3H),
0.99 (d, J ) 16.5 Hz, 1H), 2.07 (d, J ) 16.5 Hz, 1H), 2.18 (t, J )
19.0 Hz, 2H), 2.56 (d, J ) 18.5 Hz, 1H), 3.00-3.07 (m, 2H),
3.15-3.24 (m, 3H), 3.62 (d, J ) 12.0 Hz, 1H), 5.33 (s, 1H), 7.04
(d, J ) 8.0 Hz, 2H), 7.33-7.36 (m, 4H), 8.00 (d, J ) 8.0 Hz, 2H).
13C NMR (125 MHz, CDCl3) δ 210.4, 208.3, 192.3, 162.5, 147.1,
146.4, 135.6, 134.5 (2C), 133.4, 130.1 (3C), 129.1, 123.1, 122.8
(2C), 72.9, 55.4, 53.8, 51.8, 48.3, 38.6, 38.1, 37.1, 31.0, 29.1, 26.1.
IR (KBr, cm-1) 3028, 2954, 1683, 1512, 1491, 1346. ES-MS m/z
556.0 [(M + 1)]+. Anal. Calcd for C28H26ClNO5S2: C, 60.48; H,
4.71; N, 2.52. Found: C, 60.61; H, 4.82; N, 2.55.
Experimental Section
General Procedure for Preparation of 1a-1j (1g as Exam-
ple).5a–c,9–11 To a solution of 1-(1,3-dithiolan-2-ylidene)propan-2-
(19) (a) Bringmann, G.; Gunther, C.; Schupp, O.; Tesler, S. In Progress in
the Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W.,
Moore, R. E., Eds.; Springer-Verlag: New York, 2001; Vol. 81, pp 1-293. (b)
Bonesi, S. M.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2008, 47, 10022–
10025.
3120 J. Org. Chem. Vol. 74, No. 8, 2009

Construction of Polyfunctionalized Cyclohexanones
Typical Procedure for the Transformation of 6 to 7 (7a as
Example). A mixture solution of 6e (393 mg, 1.0 mmol) and
NaBH4 (19 mg, 0.5 mmol) in MeOH (5.0 mL) was stirred for 20
min at room temperature and then quenched with water (20 mL).
The mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic phase was concentrated in vacuo to yield a yellow oil which
was redissolved in THF (5.0 mL) and treated with dilute hydro-
chloric acid (0.2 mL, 10% aqueous) for 20 min at room temperature.
Then, this mixture was diluted with 20 mL of water and neutralized
with saturated aqueous NaHCO3. After extraction with CH2Cl2 (3
× 15 mL) and sequential removing of CH2Cl2 in Vacuo, the yellow
residual oil was obtained and further treated with DBU (0.1 mL)
in DMF (5.0 mL) for 30 min at room temperature. The resulting
mixture was diluted with water (50 mL), neutralized with dilute
hydrochloric acid and extracted with CH2Cl2 (3 × 15 mL). The
combined organic phase was washed with water (30 mL), dried
over anhydrous MgSO4 and concentrated in vacuo to give ethyl
4-(1,3-dithiolan-2-yl)biphenyl-2-carboxylate (7a) (326 mg, 99%)
7.0 Hz, 2H), 5.69 (s, 1H), 7.28-7.40 (m, 6H), 7.69-7.71 (m, 1H),
7.94 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 168.5, 142.1, 141.0,
140.0, 131.3, 130.9, 130.6, 129.3, 128.3 (2C), 128.0 (2C), 127.2,
61.0, 55.4, 40.4 (2C), 13.6. IR (KBr, cm-1): 3058, 2993, 1708,
1516, 1292. ES-MS: m/z 331.0 [(M + 1)]+. Anal. Calcd for
C18H18O2S2: C, 65.42; H, 5.49; Found: C, 65.21; H, 5.58.
Acknowledgment. Financial support of this research by the
Ministry of Education of China (108044), NNSFC-20872015,
NENU-STC08007/07007 and JLSTD-20070549/20082212 are
greatly acknowledged.
Supporting Information Available: Experimental details;
spectral and analytical data for compounds 4, 5, 6, 7, and II;
1
copies of H NMR and 13C NMR spectra of new compounds;
and crystallographic data for 5e in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
as a light yellow oil. H NMR (500 MHz, CDCl3) δ 0.98 (t, J )
7.0 Hz, 3H), 3.37-3.42 (m, 2H), 3.51-3.56 (m, 2H), 4.07 (q, J )
JO900217G
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