A novel procedure for the synthesis of multifunctional ketones through the Fukuyama coupling reaction employing dialkylzincs

Article abstract of DOI:10.1016/j.tetlet.2004.07.148

Treatment of thiol esters 1 with dialkylzincs 2 in the presence of zinc bromide, that was in situ prepared from zinc dust and bromine, provided various functionalized ketones 3 in high yields. The reaction mechanism, which may shift the Schlenk equilibrium from dialkylzincs 2 to reactive alkylzinc bromide 5, was postulated to account for the facile coupling reaction.

Full text of DOI:10.1016/j.tetlet.2004.07.148

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7343–7345
A novel procedure for the synthesis of multifunctional ketones
through the Fukuyama coupling reaction employing dialkylzincs
Yoshikazu Moria and Masahiko Sekib,
*
aProcess Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
bExport and Import Group, Purchasing Department, Logistics Division, Tanabe Seiyaku Co., Ltd, 3-2-10, Dosho-Machi,
Chuo-Ku, Osaka 541-8505, Japan
Received 1 July 2004; revised 29 July 2004; accepted 30 July 2004
Available online 19 August2004
Abstract—Treatment of thiol esters 1 with dialkylzincs 2 in the presence of zinc bromide, that was in situ prepared from zinc dust
and bromine, provided various functionalized ketones 3 in high yields. The reaction mechanism, which may shift the Schlenk equi-
librium from dialkylzincs 2 to reactive alkylzinc bromide 5, was postulated to account for the facile coupling reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
O
Multifunctional ketones have received considerable
attention due to the significance in the preparation of
drugs and natural products. Development of their effi-
cient synthetic method has thus been a subject of on-
going interest.1 We have reported a practical synthesis
of the ketones through heterogeneous Pd/C-catalyzed
Fukuyama coupling reaction2 of thiol esters with alkyl-
zinc iodides (RZnI).3 The use of dialkylzincs (R2Zn) for
the reactant can be an attractive alternative because of
the stability over the corresponding RZnX. However,
Fukuyama and co-workers have reported an unsuccess-
ful coupling reaction of thiol ester 1a with Et2Zn 2a
in the presence of homogeneous Pd catalyst,
PdCl2(PPh3)2.2 They unexpectedly got a reduction prod-
uct, that is, aldehyde 4, instead of the desired ketone 3a.
We have recently reported an improved Fukuyama cou-
pling reaction of thiolactone 1b with alkylzinc iodide 5a
in the presence of ZnBr2 and heterogeneous Pd/C, and
have postulated a mechanism involving a shift of the
Schlenk equilibrium from inactive R2Zn 2 to the active
RZnX 5 (X = Br) species by the addition of ZnX2
(X = Br) (Scheme 1).3d If the hypothesis is true, the
Fukuyama coupling reaction employing R2Zn 2 would
take place in the presence of ZnBr2. Reported herein
are the successful results of the Fukuyama coupling
reaction of R2Zn 2 with thiol esters in the presence of
ZnBr2.
O
BnN
NBn
IZn
R
CO2Et
O
MeO
S
1b
5a
1a: R = SEt
3a: R = Et
4: R = H
In our initial study, the reaction of Et2Zn with thiol ester
1a was tested under various conditions. Treatment of 1a
with Et2Zn 2a4 in the presence of Pd/C5 in a mixed sol-
vent of THF and toluene provided the desired ketone 3a
albeitin a poor yield (36%, Table 1, entry 1). To
improve the yield, addition of ZnBr2 to the reaction
mixture was examined. Into a mixture of ZnBr2
(1.0equiv), freshly prepared from zinc dust(2.0equiv)
and bromine (1.0equiv) in THF and toluene, were
added thiol ester 1a and Pd/C followed by Et2Zn 2a.
After an initial exothermic reaction and stirring at
20°C for 17h, the desired ketone 3a was obtained
expectedly in a much higher yield (84%) (Table 1, entry
2). Addition of DMF3a was effective for the coupling
R2Zn + ZnX2
2RZnX
5
2
active
inactive
*
Scheme 1. The Schlenk equilibrium of zinc reagents and the utility for
the Fukuyama coupling reactions.
Corresponding author. Tel.: +81 6 6205 5498; fax: +81 6 6205 5178;
e-mail: m-seki@tanabe.co.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.148

7344
Y. Mori, M. Seki / Tetrahedron Letters 45 (2004) 7343–7345
Table 1. The Fukuyama coupling reaction of thiol ester 1a with Et2Zn
2a
The present method was applied to the coupling reac-
tion of various substrates (Table 2). Thiol esters 1b,c
and 1e carrying a ketone, an ester and Cl group were
applicable to the coupling reaction to afford the corre-
sponding ethyl ketones 3b,c and 3e in high yields
(Table 2, entries 1, 2 and 4). Aromatic thiol esters 1d,
1e and 1f were less reactive than aliphatic counterparts
1a,b and 1c: longer reaction periods were required to ob-
tain a sufficient conversion (compare Table 1, entry 3
and Table 2, entries 1–2 with Table 2, entries 3–5). An
odorless thiol ester 1g,7 prepared from dodecane thiol,
gave the desired ethyl ketone 3a in good yield as well
(Table 2, entry 6). The use of sterically more hindered
diisopropylzinc 2b furnished isopropyl ketone 3g albeit
in a moderate yield (Table 2, entry 7).
Et2Zn 2a (1 equiv)a
O
O
Pd/C (5 mol%)a
Et
SEt
Additive
THF, toluene
MeO
MeO
20oC, 17 h
1a
3a
Entry
Additive (equiv)b
Yield (%)c
1
2
3
––
ZnBr2 [Zn (2.0)/Br2 (1.0)]
ZnBr2 [Zn (2.0)/Br2 (1.0)], DMF (4.9)
36
84
95
a Equivalent relative to thiol ester 1a.
bEquivalent relative to Et2Zn 2a.
c Isolated yield.
In conclusion, a novel and efficient synthesis of function-
alized ketones through a coupling reaction of dialkyl-
zincs with thiol esters was worked out. Although
preparation of the ketones employing dialkylzincs in
the presence of homogeneous Pd or Cu catalyst has been
reaction: a complete conversion of the reaction was
accomplished by the addition of 4.9equiv of DMF to
the reaction mixture, providing 3a in an excellentyield
(95%) (Table 1, entry 3).6
Table 2. The Fukuyama coupling reaction employing R2Zn
Zn (2.0 equiva), Br2 (1.0 equiva)
O
O
Pd/C (5 mol%)b
R32Zn
+
R1
R3
R1
SR2
THF, toluene, DMF (4.9 equivb)
3
1
2
20oC
Entry
1
Thiol ester 1
R2Zn 2 (1equivb)
Ketone 3c
Period (h)
17
Yield (%)d
95
O
O
SEt
Et
Et2Zn
2a
O
O
1b
3b
O
O
SEt
Et
MeO
MeO
2
3
Et2Zn
2a
17
48
Quant.
85
O
O
1c
3c
Et
SEt
Et2Zn
2a
O
O
1d
3d
Et
SEt
Cl
S
Cl
4
5
Et2Zn
2a
48
48
83
57
O
3e
O
1e
S
SEt
Et
Et2Zn
2a
O
1f
O
3f
MeO
MeO
MeO
S(CH2)11CH3
S(CH2)11CH3
Et
6
7
Et2Zn
2a
48
48
72
56
O
O
O
3a
3g
1g
MeO
i-Pr2Zne
2b
i-Pr
O
1g
a Equivalent relative to R2Zn 2.
b Equivalent relative to thiol ester 1.
c All new compounds were fully characterized by IR, NMR and MS spectra.
d Isolated yield.
e 2.0 M toluene solution of i-Pr2Zn was employed for the reaction.

Y. Mori, M. Seki / Tetrahedron Letters 45 (2004) 7343–7345
7345
6. A typical procedure for the Fukuyama coupling reaction
employing dialkylzinc, synthesis of ethyl ketone 3a from thiol
ester 1a: Into a suspension of zinc dust (584mg, 8.93mmol)
in THF (2.5mL) and toluene (2.5mL) was added dropwise
bromine (0.23mL, 4.46mmol) at<30 °C. Thiol ester 1a
(1.00g, 4.46mmol) in toluene (1mL) was then added to the
mixture at 20°C followed by Pd/C5 (20wt%, 123mg,
0.23mmol). Into the mixture was added dropwise Et2Zn
(1.1M toluene solution, Aldrich, 4.05mL, 4.46mmol) at
<25°C followed by DMF (1.7mL). The mixture was stirred
at20 °C for 17h. Into the suspension was carefully added
18% aq HCl (10mL) at<30 °C to dissolve excess zinc dust.
The mixture was filtered and the filtrate was separated. The
resulting organic phase was washed three times with water,
dried over anhydrous MgSO4 and evaporated. The residue
was purified by silica gel column chromatography (hexane
to hexane/AcOEt = 30:1) to afford ethyl ketone 3a (814mg,
reported, they require unstable and corrosive acid chlo-
ride as the substrates.8 The presentmehtod can be an
attractive alternative to these methods. While, at the
present time, the dialkylzincs employed are limited to
simple commercially available one, that is, Et2Zn and
i-Pr2Zn, it should find a wide application to a practical
synthesis of functionalized ketones, when combined
with the recently developed versatile synthesis of dialkyl
and diarylzincs.9
Acknowledgements
The authors wish to thank Degussa Japan Co., Ltd for
disclosing the chemical properties of the Pd/C catalyst.
95%) as a yellow oil. IR (ATR) m = 1712cmÀ1 1H NMR
;
References and notes
(CDCl3) d 7.10 (d, J = 8.7Hz, 2H), 6.82 (d, J = 8.7Hz, 2H),
3.78 (s, 3H), 2.87–2.82 (m, 2H), 2.72–2.67 (t, J = 7.6Hz,
2H), 2.39 (q, J = 7.3Hz, 2H), 1.04 (t, J = 7.3Hz, 3H); EI
m/z 192 (M+).
1. (a) Larock, R. C. Comprehensive Organic Transformations;
John Wiley & Sons: New York, 1999; p 1197–1620; (b)
Dieter, R. K. Tetrahedron 1999, 55, 4177, and references
cited therein.
7. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T.
Synlett 2004, 477.
2. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama,
T. Tetrahedron Lett. 1998, 39, 3189.
3. (a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429;
(b) Mori, Y.; Seki, M. Heterocycles 2002, 58, 125; (c) Mori,
Y.; Seki, M. J. Org. Chem. 2003, 68, 1571; (d) Kimura, M.;
Seki, M. Tetrahedron Lett. 2004, 45, 1635.
8. (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984,
106, 3368; (b) Oshino, H.; Nakamura, E.; Kuwajima, I. J.
Org. Chem. 1985, 50, 2804; (c) Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 83; (d) Nakamura, E.; Sekiya,
K.; Kuwajima, I. Tetrahedron Lett. 1987, 28, 337; (e)
Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwa-
jima, I. J. Am. Chem. Soc. 1987, 109, 8056; (f) Rozema, M.
J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956;
(g) Langer, F.; Devasagayaraj, A.; Chavant, P.-Y.; Kno-
chel, P. Synlett 1994, 410; (h) Devasagayaraj, A.; Schwink,
L.; Knochel, P. J. Org. Chem. 1995, 60, 3311.
4. 1.1M toluene solution of Et2Zn (Aldrich) was employed for
the coupling reaction.
5. The Pd/C catalyst employed in this study was purchased
from Degussa Japan Co., Ltd and has the following
chemical properties: impregnation depth, 200–500nm
(thick shell); reduction degree, 0–25%; Pd dispersion,
35%; water content, less than 3wt%. The catalyst is
commercially available atDegussa Japan Co., Ltd.
9. (a) Micouin, L.; Knochel, P. Synlett 1997, 327; (b) Kneisel,
F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed.
2004, 43, 1017.