Sulfur-assisted five-cascade sequential reactions for the convenient and efficient synthesis of allyl thiophen-2-yl acetates, propionates and ketones

Article abstract of DOI:10.1021/ol902690h

(Figure presented) A sulfur-assisted five-cascade sequential reaction, wherein the In situ-generated allenyl allyl sulfides undergo thio-Claisen rearrangement, intramolecular Michael addition, and 1,5-proton migratlon/aromatlzation to obtain allyl thlophen-2-yl acetates, propionates, and ketones as the final products, was reported. As a result of the ready availability of starting materials and the extremely simple and convenient operation, this type of reaction presented here has potential utility In organic synthesis. Application of this efficient method for the synthesis of potentially pharmaceutical compounds also might be useful for the pharmacists.

Full text of DOI:10.1021/ol902690h

ORGANIC
LETTERS
2010
Vol. 12, No. 2
356-359
Sulfur-Assisted Five-Cascade Sequential
Reactions for the Convenient and
Efficient Synthesis of Allyl Thiophen-2-yl
Acetates, Propionates, and Ketones
Hongwei Zhou,* Yongfa Xie, Lianjun Ren, and Rui Su
Department of Chemistry, Zhejiang UniVersity (Campus Xixi),
Hangzhou 310028, People’s Republic of China
zhouhw@zju.edu.cn
Received November 22, 2009
ABSTRACT
A sulfur-assisted five-cascade sequential reaction, wherein the in situ-generated allenyl allyl sulfides undergo thio-Claisen rearrangement,
intramolecular Michael addition, and 1, 5-proton migration/aromatization to obtain allyl thiophen-2-yl acetates, propionates, and ketones as the
final products, was reported. As a result of the ready availability of starting materials and the extremely simple and convenient operation, this
type of reaction presented here has potential utility in organic synthesis. Application of this efficient method for the synthesis of potentially
pharmaceutical compounds also might be useful for the pharmacists.
The preparation of polyfunctionalized heterocyclic com-
pounds has been of interest for the organic community over
the past half century. In this regard, thiophene-based
compounds are considered an important class due to their
intrinsic properties such as drug activity, wide range of
photobiological activity, luminescence, redox activity, and
Figure 1. The structure of tiaprofenic acid.
electron transport.1,2 2-(Thiophen-2-yl)acetic acids and pro-
panoic acids, as members of aryl acetic acids and propanoic
acids, play a role in the nonsteroidal anti-inflammatory drug
class. A famous example is Tiaprofenic acid, which is used
to treat pain, especially arthritic pain (Figure 1).
Thio-Claisen rearrangement (TCR), classically a [3,3]
sigmatropic rearrangement in the allyl vinyl sulfides leading
to a homoallyl thiocarbonyl unit, has received considerable
attention since its first appearance in the literature.3,4
(1) (a) Handbook of Oligo- and Polythiophenes; Fichou, D., Ed.; Wiley-
VCH: Weinheim, Germany, 1999. (b) PolythiophenessElectrically Conduc-
tiVe Polymers; Schopf, G., Kossmehl, G., Eds.; Springer: Berlin, Germany,
(3) Kwart, H.; Hackett, C. M. J. Am. Chem. Soc. 1962, 84, 1754.
(4) (a) Kwart, H.; Cohen, M. H. J. Org. Chem. 1967, 32, 3135. (b)
Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 413. (c) Kwart, H.; Cohen,
M. H. J. Chem. Soc. D 1968, 319, 1296. (d) Majumdar, K. C.; Ghosh, S.;
Ghosh, M. Tetrahedron 2003, 59, 7251. (e) Kwart, H.; Miles, W. H.;
Horgan, A. G.; Kwart, L. D. J. Am. Chem. Soc. 1981, 103, 1757. (f) Block,
E.; Ahmad, S. J. Am. Chem. Soc. 1985, 107, 6731.
1997
.
(2) (a) Ortiz, R. P.; Casado, J.; Hernande, V.; Navarrete, J. T. L.; Letizia,
J. A.; Ratner, M. A.; Facchetti, A.; Marks, T. J. Chem.sEur. J. 2009, 20,
5023. (b) Hom, D. H. S.; Lamberton, J. A. Aust. J. Chem. 1963, 16, 475.
(c) Cosimelli, B.; Neri, D.; Roncucci, G. Tetrahedron 1996, 52, 11281
.
10.1021/ol902690h  2010 American Chemical Society
Published on Web 12/10/2009

However, due to the instability of thials and thiones, most
of the reports about TCR focused on the access to thioamides
and dithioesters.5 Although less attention was paid, the thials
and thiones having an R-proton could be used as useful
“Michael attackers” via the thermodynamically stable enethi-
ols. Thus, the appropriate substrate design may allow the
thione as an intermediate, which is trapped in situ by an
intramolecular electrophile.
As a first attempt, we chose ethyl 6-(allylthio)hept-2-en-
4-ynoate (1a)10 as the starting material and initiated our study
by testing the reaction of 1a in the presence of various bases
and examining the solvent effect. Weak bases such as
triethylamine or K2CO3 could not trigger the reaction whereas
strong bases such as t-BuOK or EtONa gave an unidentified
mixture. DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN
(1,5-diazabicyclo[4.3.0]non-5-ene.) were suitable options and
gave ethyl 2-(4-allyl-5-methylthiophen-2-yl)acetate (2a) as
the product in acceptable yields at room temperature. Further
study showed that there were only slight solvent and
temperature effects (Table 1).
Sulfur-assisted propargyl-allenyl isomerization has been
a useful and efficient method to thio-allenes.6,7 The allene
moiety could be thought of as an “activated olefin”, which
generally enhances the diversity of the reaction possibility
compared with that of a normal olefin. Thus, it is hypoth-
esized that the allenyl allyl sulfides should undergo TCR
more smoothly than allyl vinyl sulfides, giving allyl-ene-
thiones as the intermediates (Scheme 1).
Table 1. Base and Solvent Effects on the Sequential Reactiona
Scheme 1
entry
base
Et3N
Et3N
K2CO3
K2CO3
solvent
THF
toluene
THF
temp (°C)
yield of 2a (%)b
NR
NR
NR
1
2
3
4
reflux
reflux
reflux
reflux
rt
Combining two or more reactions into one sequential
reaction, which usually involves a series of inter- or
intramolecular processes wherein the product of one
reaction is programmed to be the substrate for the next,
represents an elegant and efficient way to access novel
and complex molecules from simple, readily available
starting materials.8,9 However, the complexity and diversity
of the sequential reaction increases with the number of
cascades, which offers a more challenging and exquisite task
for organic chemists bent on reaction design. Herein we wish
to report a sulfur-assisted five-cascade sequential reaction,
wherein the in situ-generated allenyl allyl sulfides undergo
thio-Claisen rearrangement, leading to 2-allyl-2-ene-thiones.
That rearrangement is followed by a thione enolization, an
intramolecular Michael addition, and 1,5-proton migration/
aromatization to give allyl thiophenes as the final products.
toluene
NR
5
t-BuOK THF
unidentified mixture
6
7
8
9
10
11
12
13
EtONa THF
rt
rt
rt
rt
rt
rt
rt
50
unidentified mixture
DBN
DBN
DBU
DBU
DBU
DBU
DBU
toluene
THF
toluene
THF
1,4-dioxane
Et2O
36
48
42
63
55
46
52
THF
a Conditions: substrate 1a (0.5 mmol) and base (0.6 mmol) in solvent
(2 mL) under a N2 atmosphere. b Isolated yields.
Inspired by this result, we examined the scope of the
reaction and obtained allyl thiophenes in moderate to good
yields under mild conditions (Table 2).
As shown in Table 2, the substituent group R3 must have
an R-proton, which allows the enolization of the intermediate
enethione to enethiol. Thus, starting materials with no
substituent, or tert-butyl and phenyl group on R3 cannot reach
the expected products (entries 22-24).
(5) (a) Liu, Z.; Qu, H.; Gu, X.; Min, B. J.; Nyberg, J.; Hruby, V. J.
Org. Lett. 2008, 10, 4105. (b) Nowaczyk, S.; Alayrac, C.; Reboul, V.;
Metzner, P.; Averbuch-Pouchot, M. T. J. Org. Chem. 2001, 66, 7841. (c)
Liu, Z.; Qu, H.; Gu, X.; Min, B. J.; Nyberg, J.; Hruby, V. J. Org. Lett.
2009, 11, 497. (d) Lemieux, R. M.; Meyers, A. I. J. Am. Chem. Soc. 1998,
120, 5453.
It is notable that a substituent at C3 of the allyl group
prevents the reaction, probably because the transition state
of the key step (TCR) is sensitive to steric hindrance (Scheme
2).
(6) For recent allene reviews, please see: (a) Ma, S. Acc. Chem. Res.
2003, 36, 284. (b) Ma, S. Chem. ReV. 2005, 105, 2829. (c) Ma, S. Acc.
Chem. Res. 2003, 36, 701. (d) Kim, H.; Williams, L. J. Curr. Opin. Drug
DiscoVery DeV. 2008, 11, 870
.
(7) (a) Garratt, P. J.; Neoh, S. B. J. Am. Chem. Soc. 1975, 97, 3255. (b)
Sromek, A. W.; Gevorgyan, V. Top. Curr. Chem. 2007, 274, 77. (c) Kim,
J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98.
(d) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.;
(10) The substrates (1a-u) could be easily prepared via a Sonogashira
reaction with iodoethenes (3) and allyl propargyl sulfanes (4) as the
materials: to a solution of 3 (2.0 mmol) and 4 (2.4 mmol) in 10 mL of
THF were added CuI (10 mg. 0.05 mmol) and PdCl2(PPh3)2 (35mg,
0.05mmol), then 1 mL of diisopropylamine under N2 atmosphere was added
at room temperature for 1 h. The reaction mixture was quenched with water,
extracted with Et2O, and dried over anhydrous Na2SO4. After evaporation
of the Et2O, chromatography on silica gel (eluent: EtOAc/petroleum ether
) 1:20) of the crude product afforded 1, generally in a yield higher than
80%.
Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440
(8) (a) Ho, T. L. Tandem Organic Reactions; John Wiley & Sons: New
York , 1992. (b) Tietze, L. F.; Brasche, G.; Gericke K. M. Domino Reaction
.
in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006
.
(9) (a) Posner, G. H. Chem. ReV. 1986, 86, 831. (b) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Padwa, A.;
Weingarten, M. D. Chem. ReV. 1996, 96, 223. (d) Tietze, L. F. Chem. ReV.
1996, 96, 115
.
Org. Lett., Vol. 12, No. 2, 2010
357

Table 2. Synthesis of Allyl Thiophenesa
Scheme 3. Proposed Mechanism
entry
R1
R2
R3
R4
yield of 2b
1
2
3
4
5
6
7
8
OEt
Ph
Ph
n-Pr
n-Pr
OEt
Ph
n-Pr
OEt
H
H
H
H
Me
Me
n-Pr
Me
n-Pr
Me
Me
Me
n-Pr
Me
Me
n-Pr
n-Pr
Me
Me
Me
n-Pr
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
2a (63%)
2b (68%)
2c (65%)
2d (60%)
2e (70%)
2f (73%)
2g (62%)
2h (71%)
2i (80%)
2j (62%)
2k (65%)
2l (63%)
2m (78%)
2n (68%)
2o (66%)
2p (62%)
2q (80%)
2r (60%)
2s (66%)
2t (63%)
2u (62%)
0
H
Me
Me
Me
Me
H
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ph
OEt
Me
Me
H
H
H
H
H
Me
H
Me
H
Me
Me
Me
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Me
Me
Me
4-Cl-C6H4
4-Me-C6H4
OEt
4-Me-C6H4
4-Me-C6H4
Ph
4-Cl-C6H4
Ph
t-Bu
OEt
OEt
OEt
Oet
Further control experiments conducted might be helpful
for supporting this pathway. We treated 1p with 1.2 equiv
of DBU and 10 equiv of D2O in 2 mL of THF at room
temperature for 1 h (compared with entry 16) and obtained
deuterated 2p. However, only the protons of the thiophene
ring and the R-carbon of the carbonyl group were deuterated
and the protons on the methyl group adjacent to the thiophene
ring were not exchanged, demonstrating that the intermediate
(C) experiences a 1,5-proton migration, instead of the
deprotonation-aromatization on C2 in the presence of DBU
(Scheme 4).
Me
H
H
t-Bu
Ph
0
0
H
a Standard conditions: 1 (0.5 mmol) and DBU (0.6 mmol) in THF (2
mL) at room temperature for 1 h under a N2 atmosphere. b Isolated yields.
Scheme 4. Control Experiment
We propose a plausible pathway as shown in Scheme 3.
At first 1, via a propargyl-allenyl isomerization in the
presence of DBU, gives intermediate A,7c which undergoes
a TCR to afford enethione B. Then the enethiol anion via
deprotonation of the R-proton of the enethione (B) undergoes
an intramolecular Michael addition, giving the intermediate
5-methylene-2,5-dihydrothiophene (C). In the intermediate
(C), a 1,5-proton migration occurs to finish the last step:
aromatization to afford 2.
Unlike the R-protons of the carbonyl group, the thiophene
proton of 2p, due to the very weak acidity, could not undergo
H-D exchange after the completion of the reaction. Treat-
ment of 2p under the same conditions as shown in Scheme
4 gave a product undeuterated on the thiophene ring, showing
that the deuteration on the thiophene ring occurs in the step
of propargyl-allenyl isomerization through the deprotonation
by DBU (Scheme 5).
Scheme 2
.
The Influence of Substituent at C3 of the Allyl
Group
In summary, we developed a sulfur-assisted five-cascade
sequential reaction for the synthesis of allyl thiophen-2-yl
acetates, propionates, and ketones. As a result of the ready
availability of starting materials and the extremely simple
358
Org. Lett., Vol. 12, No. 2, 2010

efficient method for the synthesis of potentially pharmaceuti-
cal compounds also might be useful for pharmacists.
Scheme 5. Control Experiment
Acknowledgment. This paper is dedicated to Prof. John
Warkentin on the occasion of his 80th birthday. Financial
support was received from the Natural Science Foundation
of China (Nos. 20702046 and 20972134) and the Natural
Science Foundation of Zhejiang Province (R405066).
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
and convenient operation, this type of reaction presented here
has potential utility in organic synthesis. Application of this
OL902690H
Org. Lett., Vol. 12, No. 2, 2010
359