Ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate: A bench-stable synthon for ethyl 3-oxopent-4-enoate (Nazarov's Reagent)

Article abstract of DOI:10.1055/s-0028-1083378

The easily available adducts of sodium p-toluenesulfinate to both acrylonitrile or acrylic acid were efficiently transformed through a two-step, high-yielding sequence into ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate, a convenient source for the popular Nazarov's reagent, ethyl 3-oxopent-4-enoate, which could be generated in situ by base-induced β-elimination and used for annulation reactions.

Full text of DOI:10.1055/s-0028-1083378

LETTER
2609
Ethyl 5-[(4-Methylphenyl)sulfonyl]-3-Oxopentanoate: A Bench-Stable
Synthon for Ethyl 3-Oxopent-4-enoate (Nazarov’s Reagent)
A
N
ew Syntho
i
n for
E
m
thyl-3-Oxopent-4-e
o
noate (Nazar
n
ov’s Reagen
e
t) tta Benetti,a Stefano Carli,b Carmela De Risi,*b Gian P. Pollini,b Augusto C. Veronese,b Vinicio Zaniratob
a
Dipartimento di Chimica, Via L. Borsari 46, 44100 Ferrara, Italy
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Fax +39(0532)455953; E-mail: drc@unife.it
b
Received 1 July 2008
Consequently, the development of suitable precursors al-
lowing the in situ generation of Nazarov’s reagents, there-
by eliminating the need for their isolation, may be
particularly useful.
Abstract: The easily available adducts of sodium p-toluenesul-
finate to both acrylonitrile or acrylic acid were efficiently trans-
formed through a two-step, high-yielding sequence into ethyl 5-[(4-
methylphenyl)sulfonyl]-3-oxopentanoate, a convenient source for
the popular Nazarov’s reagent, ethyl 3-oxopent-4-enoate, which
could be generated in situ by base-induced b-elimination and used
for annulation reactions.
In connection with our continuous interest in the synthesis
of new reagents acting as latent enone precursors,12 we en-
visaged the hitherto unknown ethyl 5-[(4-methylphe-
nyl)sulfonyl]-3-oxopentanoate (2) as a new synthon for 1,
a base-induced elimination of the g-keto sulfone moiety
being required for the introduction of the unsaturation
conjugated to the carbonyl group.
Key words: Nazarov’s reagent, annulations, tandem reactions,
bicyclic compounds, carbocycles
Ethyl 3-oxopent-4-enoate (1, Nazarov’s reagent,
Figure 1)1 is a well-known annulating agent extensively
used for several transformations, including Robinson an-
nulation of cyclic b-diketones,2 cycloalkanones3 or the
corresponding enamines,4 and cyclic imidates.5 More-
over, its versatility has been further extended to the syn-
thesis of 4-piperidones6 and carbocyclic b-keto esters.7
The preparation of 2 has been efficiently achieved by two
different synthetic routes13 starting from easily available
adducts 314 and 515 of sodium p-toluenesulfinate to acrylo-
nitrile or acrylic acid, respectively (Scheme 1).
The required two-carbon elongation has been accom-
plished through Blaise reaction of 3 with ethyl bromoace-
tate and in situ activated zinc by action of a catalytic
amount of methanesulfonic acid.16 The intermediate
b-aminoacrylate 4 was then hydrolyzed by aqueous HCl
solution to afford b-ketoester 2 in 75% overall yield.
O
CO2Et
1
CN
CO2H
Figure 1
TolO2S
TolO2S
3
5
c, d
a
A number of preparations of 1 and its analogues has been
developed since the original work of Nazarov and
Zav’yalov in 1953,1a including b-elimination from latent
enone precursors,2b,4b,5a,8 pyrolysis,9a and rhodium(II)ace-
tate-catalyzed transformations of suitable a-diazo-b-hy-
droxy esters,9b,c as well as retro Diels–Alder reaction of
NH2
O
b
CO2Et
CO2Et
TolO2S
TolO2S
4
2
formal cyclopentadiene adducts.2c,10 The applicability of Scheme 1 Reagents and conditions: (a) Zn, BrCH2CO2Et, MsOH,
THF, reflux, 3 h; (b) HCl, THF, r.t., 2 h, 75% from 3; (c) 1,1¢-carbon-
yldiimidazole, THF, r.t., 4 h; (d) HO2C(CH2)CO2Et, Mg(OEt)2, THF,
r.t., 12 h, 80% from 5.
most of these protocols has been hampered either by poor
yields, difficulty accessible starting materials, and/or re-
quirement of special apparatus.
The most reliable procedure for the synthesis of 1 and its
analogues11 entailed on the oxidation of the b-hydroxy es-
ters derived by 1,2-addition of a lithioalkyl acetate to ac-
rolein and the red-written warning ‘the product is volatile
and will be lost by evaporation if care is not taken’ high-
lighted the main drawback of the checked protocol.11b
Alternatively, the b-ketoester 2 was obtained in 80% yield
through chain elongation of the acid derivative 5 via acti-
vation of the carboxyl group as imidazolide followed by
reaction with the neutral magnesium salt of monoethyl
malonate according to the procedure developed by
Masamune et al.17
The new reagent 2 is a white powder, bench-stable, that
can be stored indefinitely at room temperature without
special precautions.18
SYNLETT 2008, No. 17, pp 2609–2612
Advanced online publication: 01.10.2008
x
x
.x
x
.2
0
0
8
DOI: 10.1055/s-0028-1083378; Art ID: G21308ST
© Georg Thieme Verlag Stuttgart · New York

2610
S. Benetti et al.
LETTER
A preliminary investigation of its chemical behavior in the the first event leading to the formation of 1, which under-
presence of different bases led us to discover that a went an intermolecular base-induced Michael reaction
smooth transformation took place by treatment with po- producing the nonisolated intermediate 7 (Scheme 3).
tassium fluoride in MeOH at room temperature,19 leading This was eventually converted into 6 through an intramo-
to the formation of the cyclic b-ketoester 6, other basic re- lecular Morita–Baylis–Hillman reaction20 promoted by
agents being ineffective or causing polymerization fluoride-ion activation of the double bond.21
(Scheme 2).
In order to test the utility of 2 as source of 1, we next ex-
amined its behavior in several model reactions described
OH
in the literature in which 1 has been directly applied.2
KF, MeOH
12 h, r.t.
O
CO2Et
Thus, the annulated product 8 could be obtained when 2
was reacted with 2-methylcyclohexane-1,3-dione in
MeOH in the presence of potassium fluoride (Scheme 4),
the overall 50% yield of isolated product comparing well
with the existing data.2d–2f
CO2Et
TolO2S
40%
HO
2
6
EtO2C
Scheme 2
Surprisingly, we were unable to obtain the bicyclic ester
9
dione under the same conditions. However, the expected
annulation leading to 9 was successfully accomplished in
40% yield performing the reaction in boiling aqueous 0.1
N NaHCO3 according to a known procedure.2c
2a–2c by the reaction of 2 with 2-methylcyclopentane-1,3-
Interestingly, the highly functionalized cyclohexane de-
rivative 6 was also formed submitting freshly prepared 1
to identical reaction conditions.
A plausible mechanism to explain the formation of 6 is
likely to involve elimination of p-toluenesulfinic acid as
O
CO2Et
TolO2S
2
O
F
O–
F–
O
CO2Et
CO2Et
CO2Et
EtO2C
EtO2C
O
O
F
7
1
OH
O
O
CO2Et
CO2Et
CO2Et
HO
HO
–O
6
EtO2C
EtO2C
EtO2C
Scheme 3
O
O
, KF, MeOH
24 h, r.t.
O
O
O
50%
CO2Et
8
9
O
O
, NaHCO3, H2O
24 h, reflux
O
O
CO2Et
40%
TolO2S
2
CO2Et
NO2
O2N
BnN(Me)3+ –OMe
dioxane, 3 h, r.t.
X
O
30–35%
CO2Et
X
10a X = CH; 10b X = N
Scheme 4
Synlett 2008, No. 17, 2609–2612 © Thieme Stuttgart · New York

LETTER
A New Synthon for Ethyl-3-Oxopent-4-enoate (Nazarov’s Reagent)
2611
(8) (a) Gelin, S.; Gelin, R. Bull. Soc. Chim. Fr. 1969, 4091.
(b) Pichat, L.; Beaucourt, J.-P. Synthesis 1973, 537.
(c) Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974, 39, 2648.
(d) Ohta, S.; Shimabayashi, A.; Hatano, S.; Okamoto, M.
Synthesis 1983, 715.
Moreover, we extended the use of the masked Nazarov’s
reagent 2 as counterpart of b-nitrostyrenes in a tandem
Michael reaction promoted by benzyl trimethylammoni-
um methoxide producing in unoptimized moderate yields
diastereomeric mixtures of the completely enolized cyclic
b-ketoesters 10, which could be partially separated by si-
lica gel column chromatography.22
Interestingly, Takemoto et al.23 investigating the bifunc-
tional thiourea-catalyzed enantioselective double Michael
addition of 1 to nitroalkenes could not obtain either
Michael adducts or the desired cyclized product, the reac-
tion giving rise to a complex mixture owing to the insta-
bility of 1.
(9) (a) Wenkert, E.; Ceccherelli, P.; Fugiel, R. A. J. Org. Chem.
1978, 43, 3982. (b) Pellicciari, R.; Fringuelli, R.;
Ceccherelli, P.; Sisani, E. J. Chem. Soc., Chem. Commun.
1979, 959. (c) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org.
Chem. 1990, 55, 4144.
(10) Stork, G.; Guthikonda, R. N. Tetrahedron Lett. 1972, 27,
2755.
(11) (a) Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717.
(b) Zibuck, R.; Streiber, J. M. Org. Synth. 1993, 71, 236.
(12) (a) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini,
G. P.; Zanirato, V. Tetrahedron Lett. 1998, 39, 7591.
(b) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini,
G. P.; Zanirato, V. Eur. J. Org. Chem. 2001, 975.
(13) Typical Procedures for the Preparation of Compound 2
Method A: A stirred suspension of zinc dust (3.8 g, 58.1
mmol) in THF (28 mL) was treated with MsOH (0.14 mL,
2.2 mmol) and heated at reflux for 10 min. Ethyl
In conclusion, solid crystalline and bench-stable 5-[(4-
methylphenyl)sulfonyl]-3-oxopentanoate (2) was shown
to serve as an excellent precursor for Nazarov’s reagent 1.
Its facile preparation from easily available chemicals and
the mild conditions required for the in situ demasking of
the enone moiety make the new reagent an attractive tool
for obtaining a wide variety of carbo- and heterocyclic
compounds.
bromoacetate (1.0 mL, 9.0 mmol) was added dropwise until
it turned green, then 3 (4.0 g, 19.1 mmol) was added. Ethyl
bromoacetate (4.0 mL, 36.1 mmol) was successively
dropped over a period of 30 min. The reaction mixture was
refluxed for 3 h, cooled to 0 °C, and treated with 10% HCl
(28 mL). The solution was stirred at r.t. for 2 h, then the
solvent was concentrated in vacuo. The residue was
extracted with EtOAc (3 × 60 mL), the combined organic
phases were washed with brine (2 × 100 mL), and dried
(Na2SO4). The solvent was evaporated, and the residue was
purified by flash chromatography (EtOAc–PE, 1:2) to afford
2 (4.3 g, 75%).
Acknowledgment
This work was financially supported by MIUR (PRIN 2006) within
the project ‘Metodologie e strategie sintetiche orientate alla creazi-
one di diversità molecolare per la preparazione di molecole biologi-
camente attive’.
Method B: 1,1¢-Carbonyldiimidazole (3.5 g, 21.6 mmol)
was added to a solution of the acid 5 (4.0 g, 17.5 mmol) in
THF (100 mL). The mixture was stirred at r.t. for 4 h, then
the magnesium salt of monoethyl malonate [prepared by
stirring monoethyl malonate (4.54 mL, 38.5 mmol) and
magnesium ethoxide (2.8 g, 24.5 mmol) in THF (80 mL) for
1 h at r.t.] was added and stirring was continued at r.t.
overnight. The solvent was removed at reduced pressure and
the residue treated with 1.5 N HCl (80 mL) and extracted
with EtOAc (100 mL). The aqueous phase was further
extracted with EtOAc (2 × 100 mL), the combined extracts
were washed with aq sat. NaHCO3 soln and dried (Na2SO4).
Evaporation of the solvent and purification of the oily
residue by flash chromatography (EtOAc–PE, 1:2) gave 2
(4.2 g, 80%).
References and Notes
(1) (a) Nazarov, I. N.; Zav’yalov, S. I. Zh. Obshch. Khim. 1953,
23, 1703; J. Gen. Chem. USSR; 1953, 23, 1793; Chem.
Abstr. 1954, 48, 13667h. (b) Kaur, T. Synlett 2006, 2853.
(2) (a) Nominé, G.; Amiard, G.; Torelli, V. Bull. Soc. Chim. Fr.
1968, 3664. (b) Collins, D. J.; Tomkins, C. W. Aust. J.
Chem. 1977, 30, 443. (c) Caselli, A. S.; Collins, D. J.; Stone,
G. M. Aust. J. Chem. 1982, 35, 799. (d) Watson, A. T.;
Park, K.; Wiemer, D. F.; Scott, W. J. J. Org. Chem. 1995, 60,
5102. (e) Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong,
B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem.
2001, 66, 8843. (f) Ghosh, S.; Rivas, F.; Fischer, D.;
González, M. A.; Theodorakis, E. A. Org. Lett. 2004, 6, 941.
(3) Schkeryantz, J. M.; Luly, J. R.; Coghlan, M. J. Synlett 1998,
723.
(4) (a) Könst, W. M. B.; Witteveen, J. G.; Boelens, H.
Tetrahedron 1976, 32, 1415. (b) Orsini, F.; Pelizzoni, F.;
Destro, R. Gazz. Chim. Ital. 1978, 108, 693.
(5) (a) Célérier, J.-P.; Eskénazi, C.; Lhommet, G.; Maitte, P.
J. Heterocycl. Chem. 1979, 16, 953. (b) Watanabe, T.;
Nakashita, Y.; Katayama, S.; Yamauchi, M. Heterocycles
1980, 14, 1433. (c) Jong, L.; Zaveri, N.; Toll, L. Bioorg.
Med. Chem. Lett. 2004, 14, 181.
(14) Kamogawa, H.; Kusaka, H.; Nanasawa, M. Bull. Chem. Soc.
Jpn. 1980, 53, 3379.
(15) Bonete, P.; Nájera, C. J. Org. Chem. 1994, 59, 3202.
(16) Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.;
Lee, K. W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629.
(17) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 72.
(18) Selected Analytical Data for Compound 2
White solid, mp 44–45 °C (n-hexane). IR: 1740, 1718, 1597
cm–1. 1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3
H), 2.45 (s, 3 H), 3.04 (t, J = 7.2 Hz, 2 H), 3.37 (t, J = 7.2 Hz,
2 H), 3.46 (s, 2 H), 4.17 (q, J = 7.2 Hz, 2 H), 7.36 (d, J = 8.4
Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): d = 14.11, 21.72, 35.66, 49.12, 50.52, 61.76,
128.07, 130.13, 135.87, 145.18, 166.56, 198.68. Anal. Calcd
for C14H18O5S: C, 56.36; H, 6.08. Found: C, 56.20; H, 6.23.
(19) Typical Procedure for the Preparation of Compound 6
A solution of 2 (0.2 g, 0.67 mmol) and KF (0.16 g, 2.75
(6) Dodd, D. S.; Oehlschlager, A. C.; Georgopapadakou, N. H.;
Polak, A.-M.; Hartman, P. G. J. Org. Chem. 1992, 57, 7226;
and references cited therein.
(7) Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini,
G. P.; Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1994,
35, 9297.
Synlett 2008, No. 17, 2609–2612 © Thieme Stuttgart · New York

2612
S. Benetti et al.
LETTER
(22) Selected Analytical Data for Compounds 10a and 10b
mmol) in MeOH (10 mL) was stirred at r.t. for 12 h. The
solvent was evaporated under reduced pressure, and the
crude residue was purified by flash chromatography
(EtOAc–PE, 1:3) yielding 6 as a colorless oil (76 mg, 40%).
IR: 3474, 1697, 1655, 1584 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.2 Hz, 3
H), 1.72–1.84 (m, 1 H), 1.90–2.00 (m, 1 H), 2.18–2.30 (m, 1
H), 2.48–2.52 (m, 1 H), 2.53–2.58 (m, 2 H), 4.13–4.30 (m, 4
H), 4.47 (s, 1 H), 5.73 (s, 1 H), 6.02 (s, 1 H), 12.09 (s, enol
OH). 13C NMR (100 MHz, CDCl3): d = 14.13, 14.24, 19.95,
34.02, 42.04, 60.81, 61.06, 71.04, 97.80, 115.83, 143.56,
162.24, 172.52. Anal. Calcd for C14H20O6: C, 59.14; H, 7.09.
Found: C, 59.20; H, 7.00.
Compound 10a: colorless oil. IR: 1706, 1650, 1620, 1545
cm–1. 1H NMR (400 MHz, CDCl3): d (less polar isomer) =
0.95 (t, J = 7.2 Hz, 3 H), 2.00–2.12 (m, 1 H), 2.36–2.70 (m,
3 H), 3.96–4.08 (m, 2 H), 4.56–4.63 (m, 1 H), 4.70–4.76 (br,
1 H), 7.17–7.37 (m, 5 H), 12.55 (s, enol OH). 13C NMR (100
MHz, CDCl3): d (less polar isomer) = 13.70, 20.87, 24.83,
42.46, 60.62, 85.99, 96.79, 127.31, 127.60, 128.77, 141.34,
171.41. Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88.
Found: C, 61.91; H, 5.80.
Compound 10b: colorless oil. IR: 1710, 1660, 1610, 1550
cm–1. 1H NMR (400 MHz, CDCl3): d (more polar isomer) =
0.96 (t, J = 7.2 Hz, 3 H), 2.00–2.13 (m, 1 H), 2.40–2.76 (m,
3 H), 3.93–4.10 (m, 2 H), 4.50–4.60 (m, 1 H), 4.70–4.80 (br,
1 H), 7.20–7.30 (m, 1 H), 7.46–7.53 (m, 1 H), 8.46–8.56 (br,
2 H), 12.56 (s, enol OH). 13C NMR (100 MHz, CDCl3):
d (more polar isomer) = 13.81, 21.24, 25.02, 40.45, 60.94,
85.67, 96.04, 123.66, 135.15, 137.03, 148.89, 149.53,
170.98, 171.98. Anal. Calcd for C14H16N2O5: C, 57.53; H,
5.52. Found C, 57.50; H, 5.60.
(20) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511; and
references cited therein.
(21) For an organocatalytic asymmetric tandem Michael and
Morita–Baylis–Hillman reaction between a,b-unsaturated
aldehydes and Nazarov’s reagents leading to cyclohexane
derivatives structurally related to 6, see: Cabrera, S.;
Alemán, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2008, 47, 121.
(23) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y.
Tetrahedron 2006, 62, 365.
Synlett 2008, No. 17, 2609–2612 © Thieme Stuttgart · New York

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