Efficient synthesis of highly functionalized vinylogous thiol esters

Article abstract of DOI:10.1016/j.tetlet.2010.10.129

A series of vinylogous thiol esters 2, 3 and 2,6-dioxo-1,2,5,6- tetrahydropyridines (cyclic vinylogous thiol esters) 4 were prepared in high to excellent yields from the tandem reaction of readily available α-alkenoylketene diethylthioacetals 1 and diethy

Full text of DOI:10.1016/j.tetlet.2010.10.129

Tetrahedron Letters 51 (2010) 6918–6920
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of highly functionalized vinylogous thiol esters
⇑
⇑
Jinglin Liu, Xianxiu Xu , Dongwei Li, Lei Zhang, Kun Zhang, Qun Liu
Department of Chemistry, Northeast Normal University, Changchun 130024, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of vinylogous thiol esters 2, 3 and 2,6-dioxo-1,2,5,6-tetrahydropyridines (cyclic vinylogous thiol
esters) 4 were prepared in high to excellent yields from the tandem reaction of readily available
alkenoylketene diethylthioacetals 1 and diethyl malonate. A plausible mechanism, which involves a base
catalyzed retro-Michael ring opening of cyclohexanenes 2 to give vinylogous thiol ester 3, is disclosed.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Received 28 August 2010
Revised 21 October 2010
Accepted 26 October 2010
Available online 30 October 2010
a
-
Keywords:
Vinylogous thiol esters
a-Alkenoylketene diethylthioacetals
Diethyl malonate
Retro-Michael addition
Michael addition
As versatile intermediates, functionalized ketene dithioacetals
and their analogues have found wide applications in organic
synthesis.1,2 During the course of our studies, we found that the
O
NHR2
O
O
S
O
R2
S
R2
R1
R1
SEt
readily available highly functionalized
a-alkenoylketene diethyl-
R1 EtS
SEt
thioacetals 1 and
a
-alkenoylketene cyclic dithioacetals 10 can serve
EtO2C CO2Et
as useful building blocks in the synthesis of various carbo- and het-
1
1'
2
erocyclic compounds (Fig. 1).2g,3–9 For example, the reactions of
O
O
R2
HO
NHR2
five-carbon 1,5-dielectrophilic a-alkenoylketene diethylthioacetals
HO
N
1 with carbon,2g,6 nitrogen,7 sulfur,8 and selenium nucleophiles9
can afford the corresponding six-membered ring compounds via
[5+1] annulation. In this communication, the efficient synthesis
of highly functionalized vinylogous thiol esters 2, 3 and 2,6-di-
oxo-1,2,5,6-tetrahydropyridines (cyclic vinylogous thiol esters) 4
from 1 is described (Fig. 1). In addition, a new strategy, which in-
volves a base catalyzed retro-Michael ring opening of cyclohexa-
nones 2 to give vinylogous thiol ester 3, is disclosed.
CO2Et
O
R1
EtS
CO2Et
R1
EtS
CO2Et
3
4
Figure 1.
a
-Alkenoylketene thioacetals 1, 10 and vinylogous thiol esters 2, 3 and
2,6-dioxo-1,2,5,6-tetrahydropyridines 4.
NHR2
O
R1
EtO2C
In the present research, the reactions of
a-alkenoylketene
O
diethylthioacetals 1 with diethyl malonate under basic conditions
were investigated. As a result, the desired products, cyclic vinylo-
gous thiol esters 2a–c, could be obtained in excellent yields from
the reactions of 1a–c (2.0 mmol) with diethyl malonate (2.2 mmol)
in DMF (10 mL) in the presence of K2CO3 (4.0 mmol) at ambient
temperature for 4 h via the [5C+1C] annulation process, involving
a tandem Michael addition followed by an intramolecular Michael
addition and elimination of ethylthiol (Scheme 1).6,2g
CH2(CO2Et)2
O
O
K CO
2
3
EtO2C
R1 EtS
SEt
SEt NHR2
DMF, r. t.
1
2
R1
O
EtO2C
EtO2C
O
A
SEt NHR2
EtS
Interestingly, it was found that the highly functionalized vinyl-
ogous thiol ester 3a could be produced in 90% isolated yield simply
by stirring the reaction mixture of 1a (2.0 mmol) and diethyl
2a, R1 = 4-MeC6H4, R2 = 4-ClC6H4, 95%
, R = 4-MeOC6H4, R2 = Ph, 85%
1
2b
2c, R1 = 4-MeOC6H4, R2 = 2,4-Me2C6H3, 81%
Scheme 1. Synthesis of cyclic vinylogous thiol esters 2.
⇑
Corresponding authors. Tel.: +86 431 8509 9759; fax: +86 431 8509 9769 (X.X.).
E-mail address: xuxx677@nenu.edu.cn (X. Xu).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All
rights reserved.

J. Liu et al. / Tetrahedron Letters 51 (2010) 6918–6920
6919
malonate (2.2 mmol) in DMF (10 mL) in the presence of K2CO3
O
O
NHR2
O
NHR2
CO2Et
HO
(4.0 mmol) first at room temperature for 4 h to complete consump-
tion of 1a (monitored by TLC) and then at about 80 °C for addi-
tional 1 h (Table 1, entry 1). In another case, vinylogous thiol
ester 3a was obtained in 92% yield from the ring-opening of cyclo-
hexanone 2a (1.0 mmol) catalyzed by K2CO3 (5 mol %) in DMF
(5 mL) at 80 °C for 1 h. The above results indicate that the reaction
of 1 with diethyl malonate could be controlled to exclusively yield
2 or 3 by varying the reaction temperature. The above reaction pro-
ceeded in a chemo- and stereoselective manner. The structure of
vinylogous thiol ester 3a, which contains an highly functionalized
conjugated triene units, was established by the X-ray single crystal
analysis (Fig. 2)10 and the 1H NMR and 13C NMR spectra (for details,
please see Supplementary data).
CH2(CO2Et)2
Base
R1 EtS
SEt
DMF, 80 C R1
º
EtS
CO2Et
1
3
2
R1
O
O
NHR
O
2
EtO2C
EtO2C
O
R1
SEt
EtS SEt NHR2
EtO2C CO2Et
A
B
Scheme 2. Proposed mechanism for the formation of 3.
Dieter et al. have reported the chemo- and stereoselective
synthesis of vinylogous thiol esters through the reactions of
organocuprates with
a-oxoketene dithioacetals via a conjugate
addition–alkylthio elimination pathway.11a Other methods for the
preparation of vinylogous thiol esters involved transition-metal-
catalyzed acetylthiolation of alkynes,11b reaction of cyclic vinylo-
gous esters with thiols,11c and the radical reaction of aromatic
disulfides, alkynes, and isonitriles under photolytic conditions.11d
Table 2
Synthesis of 2,6-dioxo-1,2,5,6-tetrahydropyridines 4
R2
O
O
NHR2
CO2Et
HO
HO
N
PTSA
O
toluene
reflux
Therefore, the transformation of
etal 1a into vinylogous thiol ester 3a represents a new efficient ac-
a-alkenoylketene diethylthioac-
R1
R1
EtS
CO2Et
EtS
CO2Et
3
4
cess to highly functionalized vinylogous thiol esters starting from
Entry
3
R1
R2
4
Yield (%)
Table 1
1
2
3
4
5
6
a
b
c
d
e
j
4-MePh
4-MeOPh
3,4-O2CH2Ph
Ph
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Ph
a
b
c
d
e
f
91
86
88
81
83
90
One-pot Synthesis of highly functionalized vinylogous thiol esters 3
O
2
O
NHR
O
2
HO
NHR
CH (CO Et)
2
2
2
CO Et
2
4-MeOPh
K CO , DMF
2
3
R
º
r. t. to 80 C
EtS
CO Et
2
R
EtS
SEt
1
1
3
1
the easily available substrates. Under identical conditions as
shown in Table 1, entry 1, a series of vinylogous thiol esters 3 were
synthesized and the results are showed in Table 1. The results in
Table 1 clearly indicate the scope and generality of the reaction
with respect to various R1 groups of substrate 1, including aromatic
rings with electron-donating (entries 1–3) or electro-withdrawing
group (entry 5), heteroaromatic (entries 6 and 7), and aliphatic
group (entry 8). In addition, the R2 group (substituted phenyl)
shows little effect on the yields of vinylogous thiol esters 3 (entries
9–12).
Entry
1
R1
R2
Timea (h)
3
Yield (%)
1
2
3
4
5
a
b
c
d
e
f
4-MePh
4-MeOPh
3,4-O2CH2Ph
Ph
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
2-MeOPh
Ph
2,4-Me2Ph
2-MePh
4.0
4.5
3.5
4.0
4.0
6.0
10.0
12.0
4.0
4.0
4.0
a
b
c
d
e
f
g
h
i
90
87
92
81
86
70
76
65
76
80
78
78
4-ClPh
6
2-thienyl
3-pyridyl
PhCH@CH
4-MePh
4-MePh
4-MePh
4-MePh
7
8
9
g
h
i
Based on above results, the one-pot synthesis of vinylogous thiol
esters 3 could involve a retro-Michael ring opening of cyclic vinyl-
ogous thiol esters 2. Thus, the mechanism of formation of vinylo-
10
11
12
j
k
l
j
k
l
4.0
a
gous thiol esters
3 involves three steps: an intermolecular
Time for room temperature.
Michael reaction, an intramolecular reaction, and finally a retro-Mi-
chael reaction (Scheme 2).12 To our knowledge, this transformation
is the first example of base induced ring opening of cyclohexenone
derivatives, although the corresponding retro-oxa Michael ring
opening of chromones has been well established.13
With the easily available vinylogous thiol esters 3 at hand, our
attention was then turned to the intramolecular cyclization to pre-
pare the 2,6-dioxo-1,2,5,6-tetrahydropyridines 4 (Table 2). It was
found that no reaction occurred when 3a was treated in toluene
for 6 h at reflux. Whereas in the presence of catalytic amount of
p-toluenesulfonic acid (PTSA, 10 mol %), product 4a was obtained
in 91% yield by the reaction of 3a (1.0 mmol) in toluene (5 mL)
for 4 h at reflux (Table 2, entry 1). Under above conditions, 2,6-di-
oxo-1,2,5,6-tetrahydropyridines 4b–f were prepared in high yields
(Table 2, entries 2–6).
In conclusion, we have developed a convenient synthesis of a
series of highly functionalized vinylogous thiol esters 2, 3 and
2,6-dioxo-1,2,5,6-tetrahydropyridines 4 from the easily available
Figure 2. ORTEP drawing of 3a.

6920
J. Liu et al. / Tetrahedron Letters 51 (2010) 6918–6920
Kang, J.; Liang, F.; Sun, S.-G.; Bi, X.-H.; Liu, Q. Org. Lett. 2006, 8, 2547; (g) Fu, Z.;
a-alkenoylketene diethylthioacetals 1 and diethyl malonate. The
Wang, M.; Dong, Y.; Liu, J.; Liu, Q. J. Org. Chem. 2009, 74, 6105.
3. Wang, M.; Han, F.; Yuan, H.; Liu, Q. Chem. Commun. 2010, 46, 2247 (synthesis of
highly substituted cyclopentadienes from 1’).
4. (a) Bi, X.; Zhang, J.; Liu, Q.; Tan, J.; Li, B. Adv. Synth. Catal. 2007, 349, 2301; (b) Li,
Y.; Xu, X.; Tan, J.; Liao, P.; Zhang, Z.; Liu, Q. Org. Lett. 2009, 11, 244 (synthesis of
tetramic acid derivatives from 10).; (c) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org. Chem.
2006, 71, 8006 (synthesis of multisubstituted thiophene derivatives from 10).;
(d) Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong, D. Synlett 2005, 49
(synthesis of tetronic acid derivatives from 10)..
5. (a) Ma, Y.; Wang, M.; Li, D.; Bekturhum, B.; Liu, J.; Liu, Q. J. Org. Chem. 2009, 74,
3116 (synthesis of polyfunctionalized cyclohexanones from 10); (b) Liu, J.;
Wang, M.; Han, F.; Liu, Y.; Liu, Q. J. Org. Chem. 2009, 74, 5090 (synthesis of
polyfunctionalized unsaturated d-lactones/lactams from 10); (c) Tan, J.; Xu, X.;
Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, 48, 2868.
6. (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127,
4578; (b) Zhang, L.; Liang, F.; Cheng, X.; Liu, Q. J. Org. Chem. 2009, 74, 899.
7. (a) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Commun. 2005, 3580; (b) Zhao, L.;
Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org. Chem. 2006, 71, 1094.
one-pot synthesis of highly functionalized vinylogous thiol esters
3 involves a novel mechanism of base induced ring opening of
cyclohexenone derivatives 2. The simplicity of execution, high
yields, and promising synthetic applications of the products make
the protocol very attractive.14,15 Further studies are in progress.
Acknowledgments
Financial supports of this research provided by the NNSFC
(20872015), the Science Foundation for Young Teachers of NENU
(20090404), the Young Scientific Research Foundation of Jilin Prov-
ince (20090149) and China Postdoctoral Science Foundation
(20080431049) are greatly acknowledged.
8. Bi, X.; Dong, D.; Li, Y.; Liu, Q. J. Org. Chem. 2005, 70, 10886.
9. Li, D.; Xu, X.; Liu, Q.; Dong, S. Synthesis 2008, 1895.
Supplementary data
10. CCDC 675097 (3a) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ddcd.cam.ac.uk/data_request/cif.
11. (a) Dieter, R. K.; Silks, L. A., III; Fishpaugh, J. A.; Kastner, M. E. J. Am. Chem. Soc.
1985, 107, 4679; (b) Minami, Y.; Kuniyasu, H.; Miyafuji, K.; Kambe, N. Chem.
Commun. 2009, 3080; (c) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed.
2006, 45, 3109; (d) Leardini, R.; Nanni, D.; Zanardi, G. J. Org. Chem. 2000, 65,
2763.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.129.
References and notes
1. For reviews, see: (a) Dieter, R. K. Tetrahedron 1986, 42, 3029; (b) Ila, H.;
Junjappa, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423.
12. Rao, H. S. P.; Jothilingam, S. J. Chem. Sci. 2005, 117, 27.
13. (a) Appel, B.; Saleh, N. N. R.; Langer, P. Chem. Eur. J. 2006, 12, 1221; (b) Adeel,
M.; Nawaz, M.; Villinger, A.; Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2009,
65, 4099.
14. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260; (b) Aguilar-
Aguilar, A.; Liebeskind, L. S.; Pena-Cabrera, E. J. Org. Chem. 2007, 72, 8539.
15. For a review on the chemistry of sulfinyl and sulfonyl enones, see: Nenajdenko,
V. G.; Krasovskiy, A. L.; Balenkova, E. S. Tetrahedron 2007, 63, 12481.
2. For recent reports, see: (a) Savant, M. M.; Pansuriya, A. M.; Bhuva, C. V.;
Kapuriya, N.; Patel, A. S.; Audichya, V. B.; Pipaliya, P. V.; Naliapara, Y. T. J. Comb.
Chem. 2010, 12, 176; (b) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48, 2929; (c)
Yuan, H.-J.; Wang, M.; Liu, Y.-J.; Liu, Q. Adv. Synth. Catal. 2009, 351, 112; (d)
Zhao, Y.-L.; Li, D.-Z.; Han, X.-D.; Chen, L.; Liu, Q. Adv. Synth. Catal. 2008, 350,
1537; (e) Liang, F.; Li, D.; Zhang, L.; Gao, J.; Liu, Q. Org. Lett. 2007, 9, 4845; (f)