Conjugate addition of thiols and malonates to thiocinnamates under PTC conditions

Article abstract of DOI:10.1081/SCC-120003641

Addition of thiols or diethylmalonate to thiocinnamate, under solid-liquid PTC conditions, afforded the corresponding 1,4-adducts in moderate to good yields. A 2-pyrrolidinone was obtained using diethyl N-acetamidomalonate as Michael donor, via intramolecular cyclization of the parent adduct.

Full text of DOI:10.1081/SCC-120003641

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CONJUGATE ADDITION OF THIOLS AND MALONATES TO
THIOCINNAMATES UNDER PTC CONDITIONS
a
a
a
a
Liliana Marzorati , Marcos Carlos de Mattos , Blanka Wladislaw & Claudio Di Vitta
a
Instituto de Química, Universidade de São Paulo, P.O. Box 26.077, CEP. 05513–970, São
Paulo, S.P., Brazil
Version of record first published: 17 Aug 2006.
To cite this article: Liliana Marzorati , Marcos Carlos de Mattos , Blanka Wladislaw & Claudio Di Vitta (2002): CONJUGATE
ADDITION OF THIOLS AND MALONATES TO THIOCINNAMATES UNDER PTC CONDITIONS, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:9, 1427-1435
To link to this article: http://dx.doi.org/10.1081/SCC-120003641
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SYNTHETIC COMMUNICATIONS, 32(9), 1427–1435 (2002)
CONJUGATE ADDITION OF THIOLS AND
MALONATES TO THIOCINNAMATES
UNDER PTC CONDITIONS
y
Liliana Marzorati,* Marcos Carlos de Mattos,
Blanka Wladislaw, and Claudio Di Vitta
Instituto de Quı
´
Box 26.077, CEP. 05513-970, Sa
˜
mica, Universidade de Sao Paulo – P.O.
o Paulo, S.P. – Brazil
˜
ABSTRACT
Addition of thiols or diethylmalonate to thiocinnamate, under
solid–liquid PTC conditions, afforded the corresponding 1,4-
adducts in moderate to good yields. A 2-pyrrolidinone was
obtained using diethyl N-acetamidomalonate as Michael
donor, via intramolecular cyclization of the parent adduct.
Key Words: Thiocinnamates; Conjugate addition; Phase
transfer catalysis; Pyrrolidinone
Conjugate addition to a,b-unsaturated aldehydes, ketones and
carboxylic acid esters is one of the most valuable methods for carbon–
1
carbon and carbon–heteroatom bond formation. Stereochemical and
mechanistic aspects of these classical reactions have been object of intense
*
Corresponding author. Fax: 55 11 38155579; E-mail: lmarzora@iq.usp.br
y
Corresponding author. Current address: Departamento de Quı
nica, Universidade Federal do Ceara C.P. 12.200–CEP. 60541-970,
Fortaleza, Ceara–Brazil. E-mail: mcdmatto@ufc.br
´
mica Orgaˆ nica e
Inorga
ˆ
´
,
´
1
427
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
428
MARZORATI ET AL.
investigation, mainly focused on the direct addition of enolates or stabilized
2
carbanions.
In this communication we wish to report on the 1,4-addition of several
thiols, diethylmalonate and diethyl N-acetamidomalonate to thiocinnam-
ates, in a solid–liquid system, using TEBAC as phase transfer catalyst. It
should be mentioned that a,b-unsaturated thiolesters were seldom used as
acceptors in conjugate additions, and previously reported examples refer to
3
,4
reactions performed in homogeneous media.
,4-Addition of thiols to thiocinnamates: In our laboratory, the
conjugate addition of a series of thiols to thiolesters 1a–d was performed
1
Scheme 1.
5
using in situ generated benzyltriethylammonium fluoride as catalytic phase
transfer agent, and toluene as solvent (Scheme 1).
The reaction of thiocinnamate 1a with four aromatic thiols afforded the
expected 3-arylsulfanyl-3-phenyl-thiopropanoates in approximately the same
yield (Table 1, Entries 1–4). As for compounds 1b–d, good results could be
1
2
obtained only if the R and R groups were the same (Table 1, Entries 5–7). If
2
1
different thiols (R
6
¼R ) were allowed to react with thiocinnamates 1b–d,

THIOCINNAMATES UNDER PTC CONDITIONS
Table 1. Addition of Thiols to Thiocinnamates
1429
1
2
PhCH(SR )CH
1
COSR 2
PhCH¼CHCOSR
2
1
R
2
R
a
Yield (%)
Entry
1
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1c
1d
Me
Ph
Ph
2a (76)
2b (73)
2c (70)
2d (68)
2e (87)
2f (82)
2g (73)
C
C
C
6
6
6
H
H
H
4
4
4
-Me (p)
-Cl (p)
-OMe (p)
Ph
C
C
6
6
H
H
4
-Me (p)
-OMe (p)
C
C
6
6
H
H
4
-Me (p)
-OMe (p)
4
4
1
3
a
C NMR Chemical Shifts for Chalcone and 1a–d
Table 2.
Compound
d
C-a
d
C-b
d
C¼O
PhCH ¼ CHCOPh
122.0144.4
124.9
124.4
124.4
124.3
189.9
1
1
1
1
a
b
c
140.2
141.8
141.6
141.5
190.0
188.1
188.6
189.1
d
a
3
ppm/CDCl .
complex mixtures of mixed adducts were formed, probably due to the nucleo-
fugality of the arylsulfanyl group at the thiolester moiety.
It is noteworthy that, in all cases, blank experiments, performed in the
absence of catalyst, led to complete recovery of starting materials.
1,4-Addition of malonates to thiocinnamates: The conjugate addition of
malonates to hindered Michael acceptors has been performed under PTC
6
conditions, in the absence of solvent. In particular, for additions to
chalcone, this methodology proved to be superior to classical ones. In
view of these findings, we became interested in investigating the reactivity
of unsaturated thiolesters 1a–d towards diethylmalonate and diethyl
N-acetamidomalonate, under the same reaction conditions.
1
3
It should be mentioned that considering the similarity of C NMR
chemical shifts of carbonyl and double bond carbons for compounds 1a–d,
as compared to chalcone (Table 2), a similar trend of reactivity would be
expected for the unsaturated ketone and thiolesters.
Results for the addition of diethylmalonate to acceptors 1a–d, in the
presence of catalytic amount to potassium hydroxide and in the absence of

1
430
MARZORATI ET AL.
Table 3. Michael Addition of Diethylmalonate to Thiolesters 1a–d
a
Yield (%)
1
R
TEBAC
No PTC Catalyst
1
1
1
1
a
b
c
Me
Ph
3a
3b
3c
3d
7040
46
44
6043
38
37
C
C
6
H
H
4
-Me (p)
d
6
4
-OMe (p)
a
Isolated pure product after column chromatography on silica, using
benzene as eluent.
solvent, are summarized in Table 3. As can be noted, the uncatalyzed
interfacial process led to products in roughly the same yield, independently
of the sulfur substituent at the thiolester group. However, some significant
differences were observed under PTC conditions.
However, analogous reaction using diethyl N-acetamidomalonate
instead of diethylmalonate, afforded a mixture of N-acetyl-4-phenyl-5,5-
dicarbethoxy-2-pyrrolidinone 4 and b-sulfanylated thiolester 2 (Scheme 2).
Scheme 2.
The formation of the heterocyclic ring can be attributed to an
intramolecular cyclization of the former Michael adduct. Competitive 1,4-
addition of the liberated thiolate anion to the starting thiolester could be
partially responsible for the low yield of compound 4 (Table 4).

THIOCINNAMATES UNDER PTC CONDITIONS
1431
Table 4. Michael Addition of Diethyl N-Acetamido-
malonate to Thiolesters 1a–d
a
a,b
4
Yield
(%)
2 Yield
(%)
Thiolester
c
c
c
c
d
1
1
1
1
a
b
c
33 (4)
36 (8)
44 (12)
47 (6)
14
16
8
d
a
Column chromatography on silica using hexane/acetone
9:2).
(
b
After recrystallization from hexane.
In the absence of catalyst.
c
d
Not isolated.
A better insight on the limitations of this new methodology for build-
ing the g-lactam ring resulted from an experiment employing 100% molar
excess of 1b. For the same reaction time (1 h), no improvement in yield was
observed. However, when the same reaction was performed adding an extra
catalytic amount of TEBAC after 30min, the yield of isolated pure pyrro-
lidinone 4 increased to 66%. A possible explanation for this result relies on
the known ability of thiolate ions in promoting dealkylation of quaternary
7
,8
ammonium salts, leading to catalyst deactivation.
In summary, we have demonstrated that a,b-unsaturated thiolesters
react chemoselectively (1,4-addition) with thiols and malonates. Moreover,
a new route to a functionalized pyrrolidinone could be improved by circum-
venting in situ catalyst decomposition.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker AC-200 spectro-
meter, using tetramethylsilane as internal standard. Melting points were
determined using an Electrothermal model 9100 apparatus and are uncor-
rected. Microanalyses were performed on a Perkin Elmer 2400 B CHN
elemental analyzer. Gravity column chromatography was performed on
Merck Kieselgel 60(7 0– 230mesh). Thiocinnamates
9
1a–d were prepared
according to literature procedures.
Addition of thiols to thiocinnamates 1a–d. General procedure: Thiol
(
5.0mmol) and thiocinnamate (6.3 mmol) were added, under N atmosphere
2

1
432
MARZORATI ET AL.

THIOCINNAMATES UNDER PTC CONDITIONS
1433

1
434
MARZORATI ET AL.
and magnetic stirring, to dry toluene (12.5 mL) containing TEBAC
0.02 mmol) and potassium fluoride (7.5 mmol). The resulting mixture was
(
further stirred for 4 h, and then diluted with dichloromethane. The organic
extract was treated with 10% aqueous sodium hydroxide and water,
and dried over anhydrous magnesium sulfate. The solvent was removed
under reduced pressure and the residue was recrystallized from hexane.
(
See Table 5).
Addition of malonates to thiocinnamates 1a–d. General procedure: A
mixture of thiocinnamate (1.40mmol), malonate (1.40mmol), KOH
0.14 mmol) and TEBAC (0.14 mmol) was vigorously stirred at 60 C for
h. The reaction mixture was diluted with dichloromethane (30mL), the
ꢀ
(
1
organic extract was treated with aqueous HCl (10%) and water, and then
dried over anhydrous magnesium sulfate. After removal of solvent under
reduced pressure, the crude product was purified by column chromatog-
raphy using (A) benzene or (B) hexane/acetone (9 : 2 v/v). (See Table 6).
ACKNOWLEDGMENTS
˜
We are grateful to ‘‘Funda c¸ ao de Amparo a Pesquisa do Estado de
`
Sa
Cientı
˜
o Paulo—FAPESP’’ and ‘‘Conselho Nacional de Desenvolvimento
´
fico e Tecnolo
´
gico—CNPq’’ for grants and financial support.
REFERENCES
1
2
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(
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3
4
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6
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1988, 18(4), 367.

THIOCINNAMATES UNDER PTC CONDITIONS
1435
7. Nicolas, P.P. A.C.S. Symposium Series, 326, Halpern, M.E., Ed.; 1987,
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8
9
. Shama, M.; Deno, N.C.; Remar, T.F. Tetrahedron Lett. 1966, 13, 1375.
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ꢀ
Pharm. Soc. Jpn. 1956, 76, 436. Compound 1d: m.p. 103–106 C (from
1
ethanol); H NMR (CDCl ) 3.83 (s, 3H); 6.78 (d, 1H, J ¼ 16 Hz); 6.96 (d,
3
2
H); 7.37–7.41 (m, 5H); 7.53–7.58 (m, 2H); 7.66 (d, 1H, J ¼ 16 Hz).
Anal. calcd. for C H O S: C, 71.11; H, 5.18. Found: C, 71.03; H, 5.18.
16 14 2
Received in the USA May 4, 2001