ETHYL 5-[(4-METHYLPHENYL)SULFONYL]-3-OXOPENTANOATE 1

Ethyl 5-[(4-Methylphenyl)sulfonyl]-3-oxopentanoate

CO2Et

O

SO O

H3C

[1093348-62-9] C14H18O5S (MW 298.36)InChI = 1S/C14H18O5S/c1-3-19-14(16)10-12(15)8-9-20(17,18)

13-6-4-11(2)5-7-13/h4-7H,3,8-10H2,1-2H3InChIKey = APRUPJUUTCSBAE-UHFFFAOYSA-N

(reagent used as a convenient source for Nazarov’s reagent inannulation reactions)1,2

Physical Data: mp 44–45 ◦C.Solubility: sol in most organic solvents, insol in H2O.Form Supplied in: white solid.Analysis of Reagent Purity: IR, NMR.Preparative Methods: the reagent has been prepared by two dif-

ferent synthetic routes (Method A and Method B) starting fromadducts 13 and 24 and in turn derived by the addition of sodiump-toluenesulfinate to acrylic acid and acrylonitrile, respectively.

Method A: Compound 1 has been converted into the corres-ponding imidazolide and eventually progressed to ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate via treatment with theneutral magnesium salt of monoethyl malonate according toMasamune’s procedure5 (eq 1).

1. CDI, THF, rt

2. HO2C(CH2)CO2Et

Mg(OEt)2, THF, rt

(1)

180%

CO2Et

O

SO O

H3C

CO2HS

O O

H3C

Method B: Ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoatehas been produced through HCl hydrolysis of β-aminoacrylate 3,readily obtained by zinc-catalyzed Blaise reaction of 2 with ethylbromoacetate and methanesulfonic acid6 (eq 2).

Zn, BrCH2CO2Et, MsOH

THF, reflux

(2)HCl

THF, rt

75% from 2

2

CO2Et

O

SO O

H3C

CNS

O O

H3C

3

SO O

H3CNH2

CO2Et

Purification: isolated by flash chromatography and crystallizedfrom n-hexane.

Handling, Storage, and Precautions: the reagent is bench sta-ble and can be stored indefinitely at room temperature withoutspecial precautions.

Annulation Reactions. Ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate proves to act as a synthetic equivalent ofNazarov’s reagent, namely, ethyl 3-oxopent-4-enoate 4. This canbe generated in situ by elimination of the β-sulfone moiety underbasic conditions (eq 3) and used in annulation reactions leadingto functionalized mono- and bicyclic carbocycles.

CO2Et

O

SO O

H3C

H B

CO2Et

O

4

(3)

The application of ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate has the advantage of avoiding the isolation ofNazarov’s reagent that has been reported to be problematic due tothe compound’s high volatility.7–17

Cyclic β-ketoesters are readily obtained when the maskedNazarov’s reagent is used as the counterpart of trans-β-nitrostyrenes in base-promoted tandem Michael/Michaelsequences. For example, nitroalkene 5 reacts with ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate at room temperatureunder the action of benzyl trimethylammonium methoxide togive 6 as a diastereomeric mixture in 35% yield (eq 4).

CO2Et

O

SO O

H3C

(4)

6

O

CO2Et

O2N

N

N 5

NO2

dioxane, rt

35%

OMeBnN(Me)3

2 ETHYL 5-[(4-METHYLPHENYL)SULFONYL]-3-OXOPENTANOATE

Treatment of ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopenta-noate with cyclic β-diketones in basic medium provides goodyields of bicyclic carbocycles via a Robinson annulation route.In particular, the reaction with 2-methylcyclohexane-1,3-dione inmethanol at room temperature in the presence of potassium fluo-ride gives rise to compound 7 in 50% yield (eq 5), whereas adduct8 is obtained in 40% yield by heating the masked annulating agentand 2-methylcyclopentane-1,3-dione with aqueous sodium bicar-bonate solution (eq 6).

CO2Et

O

SO O

H3C

KF, MeOH, rt50%

O

O

H3C

H3C

O

CO2Et

7

O

(5)

CO2Et

O

SO O

H3C

H3CO

O

NaHCO3, H2O

reflux

H3C O

O

CO2Et

40%

(6)

8

These results assess the usefulness of ethyl 5-[(4-methyl-phenyl)sulfonyl]-3-oxopentanoate as a synthon for Nazarov’sreagent 4. In fact, experimental outcomes compare well with theexisting data, and in turn obtained when 4 directly participates inthe same model reactions (eqs 7–9).

KF, MeOH, rt58%

(7)CO2Et

O

4

H3C

O

CO2Et

7

O

O

H3CO

0.1 M NaHCO3, 100 °C

60%

(8)CO2Et

O

4

H3CO

O

H3C O

O

CO2Et

8

2. chromatographic purification

46%

(9)

N

O

CO2Et

O2N

N

CO2Et

O

4

Cl

NO2

Cl

1.

9

10

OMe, dioxane, rtBnN(Me)3

Indeed, Robinson annulations of 4 with 2-methylcyclohexane-1,3-dione18 and 2-methyl-cyclopentane-1,3-dione15 furnish bi-cyclic derivatives 7 and 8 in 58% and 60% yield, respectively(eqs 7 and 8), while a double Michael reaction between 4 andnitroalkene 9, followed by chromatographic purification of thecrude reaction mixture, gives access to cyclic β-ketoester 10 in46% yield (eq 9).19

Furthermore, treatment of ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate with potassium fluoride in MeOH at roomtemperature results in a Michael/Morita–Baylis–Hillman tandemreaction providing cyclohexenone 11 (eq 10), this product beingalso obtained on exposure of freshly prepared Nazarov’s reagentto the same reaction conditions.

CO2Et

O

SO O

H3C

MeOH, rt

40%

OH

CO2Et

HO

CO2Et

(10)

11

KF

Interestingly, a similar tandem Michael/Morita–Baylis–Hillman sequence leading to chiral cyclohexane derivativesstructurally related to 11 has been reported to occur whenNazarov’s reagent 4 is reacted with α,β-unsaturated aldehy-des in the presence of catalytic amounts of (S)-diphenylprolinolTMS ether (eq 11).20

ETHYL 5-[(4-METHYLPHENYL)SULFONYL]-3-OXOPENTANOATE 3

55%

CO2Et

O

4

O

Ph

OH

CO2Et

HO

(11)

12

Ph

NH

Ph

OTMSPh

(10 mol %)

PhCO2H (10 mol %)

toluene, rt

+

94% ee

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12. Orsini, F.; Pelizzoni, F.; Destro, R., Gazz. Chim. Ital. 1983, 693.

13. Stork, G.; Guthikonda, R. N., Tetrahedron Lett. 1972, 27, 2755.

14. Wenkert, E.; Ceccherelli, P.; Fugiel, R. A., J. Org. Chem. 1978, 43, 3982.

15. Caselli, A. S.; Collins, D. J.; Stone, G. M., Aust. J. Chem. 1982, 35, 799.

16. Zibuck, R.; Streiber, J. M., J. Org. Chem. 1989, 54, 4717.

17. Zibuck, R.; Streiber, J. M., Org. Synth. 1993, 71, 236.

18. Watson, A. T.; Park, K.; Wiemer, D. F.; Scott, W. J., J. Org. Chem. 1995,60, 5102.

19. Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;Romagnoli, R.; Zanirato, V., Tetrahedron Lett. 1994, 35, 9297.

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Carmela De RisiUniversitá degli Studi di Ferrara, Ferrara, Italy