Preparation of 2-heteroatom substituted-4-oxo-4-arylbutanoates via thio- and aza-Michael addition

Article abstract of DOI:10.2298/JSC110526202L

Efficient regioselective conjugate additions of thiophenols and benzotriazole to 4-aryl-4-oxobut-2-enoates were achieved under mild conditions. Thus, a variety of 2-(arylthio)-4-oxo-4-arylbutanoates and 2-benzotriazolyl-4- oxo- -4-arylbutanoates were conveniently synthesized in good to excellent yields. 2012 Copyright (CC) SCS.

Full text of DOI:10.2298/JSC110526202L

J. Serb. Chem. Soc. 77 (5) 581–588 (2012)
JSCS–4291
UDC 544.412.1:547.56+547.53–
304.9:547.53.024+547.264
Original scientific paper
Preparation of 2-heteroatom substituted-4-oxo-4-arylbutanoates
via thio- and aza-Michael addition
*
*
HUILI LIU, XIN LV , LIEJIN ZHOU, RUIFENG YIN and XIAOXIA WANG
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and
Life Sciences, Zhejiang Normal University, Jinhua 321004, P. R. China
(Received 25 July, revised 11 November 2011)
Abstract: Efficient regioselective conjugate additions of thiophenols and ben-
zotriazole to 4-aryl-4-oxobut-2-enoates were achieved under mild conditions.
Thus, a variety of 2-(arylthio)-4-oxo-4-arylbutanoates and 2-benzotriazolyl-4-oxo-
-4-arylbutanoates were conveniently synthesized in good to excellent yields.
Keywords: Michael addition; thiophenol; benzotriazole; 4-aryl-4-oxobut-2-enoate.
INTRODUCTION
4-Aryl-4-oxobut-2-enoates, which can be readily prepared from low-cost and
1,2
readily available materials, have aroused great interest because of their bio-
3–6
logical activity and applications in the field of synthetic chemistry.
The con-
jugate addition using 4-aryl-4-oxobut-2-enoates as Michael acceptors has re-
ceived significant attention since the adducts are usually multi-functional com-
pounds and are potentially synthetically or medicinally valuable. The addition of
amino acids to 4-aryl-4-oxobut-2-enoates (γ-oxo-γ-phenylbutyrate) could produce
useful intermediates for the synthesis of angiotensin-converting enzyme (ACE)
7,8
inhibitors. Indoles underwent conjugate addition to 4-aryl-4-oxobut-2-enoates,
9
forming a C–C bond, catalyzed by a Lewis acid. The facile Michael addition of
other C-nucleophiles, such as active methylene compounds to 4-aryl-4-oxobut-2-
10
-enoates was also reported.
In our recent program focused on the selective reduction of 2-heteroatom-
substituted carbonyl compounds, some 2-heteroatom-substituted 4-oxo-4-aryl-
butanoates were required. Although thio-Michael addition has been intensively
11–19
studied,
only a few unusual approaches to certain specific 2-arylthio-4-oxo-
-4-arylbutanoates have been reported. Yoshimatsu et al. found that scandium(III)
triflate (Sc(OTf) ), i.e., scandium(III) trifluoromethanesulfonate, could facilitate
3
the reaction between trimethyl((1-phenylvinyl)oxy)silane and ethyl 2-fluoro-2-
*Corresponding authors. E-mail: lvxin@zjnu.cn (X. Lv); wangxiaoxia@zjnu.cn (X. Wang)
doi: 10.2298/JSC110526202L
581
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582
LIU et al.
20,21
-(phenylthio)acetate to afford ethyl 4-oxo-4-phenyl-2-(phenylthio)butanoate.
Mukaiyama et al. reported that methyl 4-oxo-4-phenyl-2-(phenylthio)butanoate
was synthesized in low yield (23 %) via Sn(OTf) -promoted rearrangement of a
2
22
β-keto sulfoxide. In addition, methyl 4-oxo-4-aryl-2-(arylthio)butanoates could
be prepared from the substitution between α-chloro-α-phenylthioketone and silyl
23,24
enol ethers.
Nevertheless, the above methods might suffer from special sub-
strates, expensive (or special) catalysts, low efficiency, and/or harsh conditions.
On the other hand, to the best of our knowledge, a method for the synthesis
of 2-benzotriazolyl-4-oxo-4-arylbutanoates is unknown. Although a variety of 2-
heterocycle (C–N bond) substituted 4-oxo-4-arylbutanoates could be synthesized
via 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzed redox isomerization of
ethyl 4-aryl-4-hydroxybut-2-ynoate, followed by aza-Michael addition of N-con-
taining heterocyclic compounds to the isomerized product, unfortunately the re-
action of benzotriazole failed and the desired 2-benzotriazolyl-4-oxo-4-arylbu-
25
tanoates could not be obtained.
Herein, the preparations of 2-(arylthio)-4-oxo-4-arylbutanoates and 2-benzo-
triazolyl-4-oxo-4-arylbutanoates via regioselective conjugate addition of thiophe-
nol and benzotriazole to 4-aryl-4-oxobut-2-enoates are reported.
RESULTS AND DISCUSSION
This investigation focused first on the catalytic conjugate addition of thio-
phenols to 4-aryl-4-oxobut-2-enoates. The conjugate addition between thiophenol
1a and ethyl 4-phenyl-4-oxobut-2-enoate 2a was employed as a model reaction.
It is of interest that all the examined bases (DBU, 1,4-diazabicyclo[2.2.2]octane
(DABCO), triethylamine (TEA), pyridine (PyH) and K CO ) led to the forma-
2
3
tion of the desired 3a (Scheme 1, Table I). Among them, TEA proved to be the
most efficient (Table I, entry 3). Furthermore, screening of the solvents showed
that in CH Cl an excellent yield of 3a was obtained (Table I, entry 7). There-
2
2
fore, CH Cl was chosen as the most suitable solvent.
2
2
Scheme 1. The catalytic conjugate addition of thiophenol to
ethyl 4-phenyl-4-oxobut-2-enoate.
With the optimized conditions in hand, various 4-aryl-4-oxobut-2-enoates
were employed as the substrates to test the generality of the reaction (Scheme 2).
The results are given in Table II.
Generally, aryls with electron-donating groups and electron-withdrawing
group at the 4-position of substrate 2 exerted little influence on the efficiency of
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PREPARATION OF 2-HETEROATOM SUBSTITUTED 4-OXO-4-ARYLBUTANOATES
583
the reaction (entries 3, 5, 7, 8 and 10, Table III). Exceptionally, 2-furyl caused
the corresponding substrate 2 to react more slowly and afforded a lower yield
(entry 6). The more nucleophilic p-methoxythiophenol was also employed, and
the desired product was smoothly obtained in a shorter reaction time (entry 7).
TABLE I. The catalytic conjugate addition of thiophenol to ethyl 4-phenyl-4-oxobut-2-enoate
under different conditions
Entry
Catalysta
Solvent
Yield, %b,c
1
2
3
4
5
6
7
DBU
DABCO
TEA
PyH
K2CO3
TEA
THF
THF
THF
THF
THF
EtOH
CH2Cl2
PhMe
76
65
82
49
37
57
90
52
TEA
TEA
8
a
b
c
Catalyst loading: 20 mol %; the runs were performed at room temperature for 6 h; isolated yields
Scheme 2. The catalytic conjugate addition of thiophenols to 4-aryl-4-oxobut-2-enoates.
TABLE II. TEA promoted conjugate addition of thiophenols to 4-aryl-4-oxobut-2-enoates (re-
action conditions: thiophenol 1 (1 mmol), 4-aryl-4-oxobut-2-enoate 2 (1 mmol), CH2Cl2 (10
mL), TEA (0.2 mmol, 20 mol %), room temeprature)
Entry
1
Ar1
Ar2
R
Et
Product
Time, h
6
Yield, %a
90
3a
2
Et
3b
6
95
3
4
5
Et
CH2Ph
Et
3c
3d
3e
6
6
6
89
93
92
6
7
Et
Et
3f
8
4
62
88
3g
a
Isolated yields
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LIU et al.
With the successful preparation of 2-(arylthio)-4-oxo-4-arylbutanoates, the
conjugate addition between 1H-benzotriazole (BtH) and 4-aryl-4-oxobut-2-eno-
ates was then explored.
Since BtH is also weakly acidic, the above base-catalyzed conditions for
thio-Michael addition was tentatively applied to the aza-Michael addition. How-
ever, the reaction of BtH (4) and ethyl 4-phenyl-4-oxobut-2-enoate (2a) under the
above optimized conditions, afforded 5a in only 53 % yield (Scheme 3) (Table
III, entry 1). Other bases, such as DBU, DABCO, PyH, cyclohexylamine, and
K CO were also tested, but the yield could not be improved (Table III, entries
2
3
2–6).
Scheme 3. The catalytic conjugate addition of BtH to ethyl 4-phenyl-4-oxobut-2-enoate.
TABLE III. The catalytic conjugate addition of BtH to ethyl 4-phenyl-4-oxobut-2-enoate under
different conditions
Entry
Catalysta
Solvent
Yield, %b,c
1
2
3
4
5
6
7
8
9
TEA
DBU
DABCO
PyH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
53
47
20
33
46
35
93
73
51
92d
80e
Cyclohexylamine
K2CO3
Quinine
Quinine
Quinine
Quinine
Quinine
PhMe
10
11
CH2Cl2
CH2Cl2
c
a
b
d
Catalyst loading: 20 mol %; the runs were performed at r.t. for 24 h; isolated yields; catalyst loading: 10
e
mol %; catalyst loading: 5 mol %
In light of the fact that quinine could promote many Michael additions due to
26–30
its special bi-functional structure,
it was introduced as a base catalyst for the
addition of BtH with 2a. Encouragingly, the yield of 5a increased to 93 % yield
with quinine as the catalyst (Table III, entry 7). Other solvents were also
screened. THF and toluene seemed to be inferior to CH Cl (entries 8–10). Re-
2
2
ducing the amount of the catalyst to 10 mol % had hardly any influence on the
efficiency (entry 10). However, the yield sharply decreased when the amount of
the catalyst was reduced to 5 mol % (entry 11).
Therefore, the conjugate addition of BtH to various substituted 4-oxobut-2-
-enoates was performed at room temperature in CH Cl with 10 mol % of qui-
2
2
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PREPARATION OF 2-HETEROATOM SUBSTITUTED 4-OXO-4-ARYLBUTANOATES
585
nine as the catalyst (Scheme 4). The results are summarized in Table IV. With
regard to the substituents on the aryl in substrate 2, the electron properties
seemed to only slightly affect the efficiency of the reactions and good to excel-
lent yield of product 5 could be isolated (Table IV, entries 1–6). The substrate
with 2-furyl substitution afforded a lower yield (entry 7). An alkyl substituted
substrate was also tried and moderate yield of the desired adduct was obtained
(entry 8).
Scheme 4. The catalytic conjugate addition of BtH to 4-phenyl-4-oxobut-2-enoates.
TABLE IV. Quinine promoted conjugate addition of BtH to 4-aryl-4-oxobut-2-enoates (reac-
tion conditions: thiophenol 1 (1 mmol), 4-aryl-4-oxobut-2-enoate 2 (1 mmol), in CH2Cl2 (10
mL) with TEA (0.2 mmol, 20 mol %) as catalyst, stirred at room temperature)
Entry
1
R1
R2
Et
Product
Yield, %a
92
5a
Et
5b
5c
5d
90
80
88
2
3
CH2Ph
CH2Ph
4
Et
5e
83
5
6
Et
Et
5f
90
57
5g
7
8
Me
Et
5h
62
a
Isolated yields
A plausible mechanism of this quinine catalyzed aza-Michael addition was
proposed (Fig. 1). The hydroxyl on the quinine could form a hydrogen bond with
the γ-carbonyl of the 4-aryl-4-oxobut-2-enoate, and the tertiary nitrogen of qui-
nine acts as a base, which deprotonates the BtH to give a benzotriazole anion
–
(Bt ). The combination of these factors could double-activate the aza-Michael
addition, thereby making the reaction highly efficient.
It is noteworthy that the above catalytic conjugate reactions exhibited com-
plete regioselectivity. The S- and N- nucleophiles selectively attacked the β-po-
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586
LIU et al.
sition of the ketone carbonyl. In addition, no product resulting from addition to
the β-position of the ester carbonyl was observed under the employed catalytic
conditions. Furthermore, attacks of S- and N- nucleophiles on the carbonyls were
not observed.
Fig. 1. Proposed mechanism for the conjugate addi-
tion between BtH and 4-aryl-4-oxobut-2-enoate.
Thiophenol was more nucleophilic towards 4-aryl-4-oxobut-2-enoate than
BtH. Thus, by employing simple TEA as the base catalyst, thiolphenol underwent
efficient regioselective thio-Michael addition and 2-arylthio-4-oxo-4-arylbuta-
noates were prepared in good to excellent yields. Using quinine as the catalyst,
the regioselective aza-Michael addition between BtH and 4-aryl-4-oxobut-2-
-enoate proceeded efficiently and afforded the desired 2-benzotriazolyl-4-oxo-4-
-arylbutanoates in satisfactory yields.
EXPERIMENTAL
Reagents were commercially available and used without further purification unless other-
wise indicated. 4-Aryl-4-oxobuten-2-oic acid,31 and the corresponding esters 2 were prepared
according to literature procedures.32 TLC was performed on silica gel plates with F-254 indi-
cator; viewing was by UV light (254 nm). Flash column chromatography was performed on
1
silica gel (200–300 mesh), using ethyl acetate/petroleum ether mixtures as eluents. The H-
and 13C-NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer with CDCl3
as the solvent and TMS as the internal standard. The elemental analyses were recorded on a
Varian-ELIII elemental analyzer. The HRMS spectra were obtained on a Bruker APEXIII 7.0
Tesla FTMS.
General procedure for the conjugation of thiophenols 1 to 4-aryl-4-oxobut-2-enoates 2.
Synthesis of compounds 3
To a solution of 4-aryl-4-oxobut-2-enoate 2 (1 mmol) and thiophenol 1 (1 mmol) in CH2Cl2
(10 mL) was added TEA (0.20 mmol, 20 mol %) at room temperature. The mixture was stir-
red at room temperature and monitored by TLC. After the starting material 2 had been com-
pletely consumed, the solvent was evaporated under vacuum and the residue purified by flash
column chromatography on silica gel to give the desired product 3.
General procedure for the conjugation of BtH 4 to 4-aryl-4-oxobut-2-enoates 2. Synthesis of
compounds 5
To a solution of 4-aryl-4-oxobut-2-enoate 2 (1.0 mmol) and BtH 4 (1.0 mmol) in CH2Cl2
(10 mL) was added quinine (0.1 mmol, 10 mol %). The mixture was stirred at room tempera-
ture and monitored by TLC. After the starting material 2 had been completely consumed, the
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PREPARATION OF 2-HETEROATOM SUBSTITUTED 4-OXO-4-ARYLBUTANOATES
587
reaction was quenched by aq. HCl. The mixture was extracted with ethyl acetate. The com-
bined organic layers were washed with aq. Na2CO3 and then with saturated NaCl. The ob-
tained organic layer was dried over anhydrous Na2SO4. After the solvent had been evaporated
under vacuum, the residue was purified by flash column chromatography on silica gel to give
the desired product 5.
CONCLUSIONS
In summary, efficient and facile conjugate addition reactions of thiophenols
and benzotriazole to various 4-aryl-4-oxobut-2-enoates were developed. The ob-
tained multi-functionalized adducts might be valuable for synthetic or pharma-
ceutical utilization. The addition reactions proceeded with complete regioselecti-
vity and tolerated various substituents. The readily available materials, simplicity
of the procedure, high efficiency, and potentially valuable adducts make the
method convenient and useful to synthetic chemists.
SUPPLEMENTARY MATERIAL
Spectral data of the products are available electronically from http://
//www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgement. This work was financially supported by the National Natural Science
Foundation of China (No. 20802070).
И З В О Д
СИНТЕЗА 2-ХЕТЕРОАТОМ-СУПСТИТУИСАНИХ 4-ОКСО-4-АРИЛБУТАНОАТA
ТИО- И АЗА-МАЈКЛОВОМ АДИЦИЈОМ
HUILI LIU, XIN LV, LIEJIN ZHOU, RUIFENG YIN и XIAOXIA WANG
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences,
Zhejiang Normal University, Jinhua 321004, P R China
Развијен је ефикасан поступак региоселективне коњуговане адиције тиофенола и бен-
зотриазола, под благим реакционим условима, при чему су добијени 4-арил-4-оксобут-2-
-еноати. Овим поступком добијени су различити 2-(арилтио)-4-оксо-4-арилбутаноати и
2-бензотриазолил-4-оксо-4-арилбутаноати у добром до одличном приносу.
(Примљено 25. јула, ревидирано 11. новембра 2011)
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