Chemo-, regio- and stereoselective preparation of silyl enol ethers from thiol esters and bis(iodozincio)alkane

Article abstract of DOI:10.1039/b709456f

Treatment of thiol ester with bis(iodozincio)alkane in the presence of palladium catalyst followed by silylation affords Z-silyl enol ether chemo-, regio- and stereoselectively. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709456f

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COMMUNICATION
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Chemo-, regio- and stereoselective preparation of silyl enol ethers from
thiol esters and bis(iodozincio)alkane{
Akihiro Ooguri, Zenichi Ikeda and Seijiro Matsubara*
Received (in Cambridge, UK) 21st June 2007, Accepted 20th August 2007
First published as an Advance Article on the web 31st August 2007
DOI: 10.1039/b709456f
was tuned to 2 : 1.{ Silyl triflate gave the best yield among the used
silylation reagents. The reactions of 1,1-bis(iodozincio)ethane (2b)7
caused some interest in the E/Z-selectivities of the formed enolate
3. Use of tert-butyldimethylsilyl chloride, cyanide and triflate gave
the Z-enolate more diastereoselectively (runs 2, 7, 9 and 11).
As shown in Table 2, various thiol esters were examined for the
preparation of silyl enol ethers as starting materials. Thiol esters
carrying terminal alkyne (run 2), ester (runs 5, 9), or aryl bromide
(runs 8, 10), were transformed into the corresponding silyl enol
ethers in good yields. When 1,1-bis(iodozincio)ethane was used,
the produced silyl enol ethers had Z-configuration exclusively.8
The preparation of a silyl enol ether which carries a keto group
in the same molecule is one of the most difficult applications of this
method. As shown in Scheme 2, several thiol esters carrying keto
groups were treated with bis(iodozincio)methane and the palla-
dium catalyst in the presence of chlorotrimethylsilane. The thiol
esters9 were converted into the corresponding silyl enol ethers.
The reaction pathway can be explained as shown in Scheme 3.
The palladium-catalyzed cross-coupling reaction of thiol ester and
gem-dizinc will afford an a-zincioketone regio- and chemoselec-
tively. The isomerization of the a-zincioketone to zinc enolate may
give the sterically less hindered Z-enolate stereoselectively, which
will be trapped with silylation reagent.
Treatment of thiol ester with bis(iodozincio)alkane in the
presence of palladium catalyst followed by silylation affords
Z-silyl enol ether chemo-, regio- and stereoselectively.
While silyl enol ethers have been important reagents especially for
cross-aldol reactions,1 the selective preparation of those com-
pounds are still challenging. For example, their regioselective
preparations from 2-hexanone can be performed easily by
adapting thermodynamic or kinetic control.2 On the contrary, it
is not so easy to realize the regioselective preparation from an
internal ketone, such as 3-hexanone. An alternative route to get the
corresponding product may provide a solution in one case,3 but a
more general method, which would also lead to further selectivities
such as chemo- and stereoselectivities possible, is desirable. We had
reported a series of synthetic applications of a gem-dizinc reagent.
As the gem-dizinc reagent can achieve zincioalkylation by a single
cross-coupling reaction, it gives a route to prepare an organozinc
reagent through homologation of an electrophile.4 We had also
shown that the palladium-catalyzed cross-coupling reactions of
bis(iodozincio)methane with several thiol esters affords the zinc
enolate selectively which corresponds to the terminal enolate of
methyl ketone.5,6 In this communication, we report on the chemo-,
regio- and stereoselective preparation of silyl enol ethers based on
the cross-coupling reaction of gem-dizincioalkane and various thiol
esters (Scheme 1).
Table 1 Use of various silylation reagentsa
As shown in Table 1, thiol ester 1 was treated with gem-
dizincioalkanes 27 in the presence of palladium catalyst and the
mixture were quenched with various silylation reagents. The
palladium catalyst was prepared from Pd2dba3 and tris(2-furyl)-
phosphine in THF. The molar ratio of phosphine to palladium
Run
RCH(ZnI)2
R93SiX
Yieldb (%)
Z : E
1
2
3
4
5
6
7
8
CH2(ZnI)2
Me3SiCl
Me3SiCl
Me3SiCN
Me3SiOTf
PhMe2SiCl
t-BuMe2SiCl
t-BuMe2SiCl
t-BuMe2SiCN
t-BuMe2SiCN
t-BuMe2SiOTf
t-BuMe2SiOTf
96
93
92
.99
34
32
34
92
60
89
72
—
CH3CH(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH3CH(ZnI)2
CH2(ZnI)2
CH3CH(ZnI)2
CH2(ZnI)2
CH3CH(ZnI)2
79 : 21
—
—
70 : 30
—
96 : 4
—
93 : 7
—
93 : 7
9
Scheme 1 Selective preparation of silyl enol ether based on cross-
coupling of gem-dizinc reagent with thiol ester.
10
11
a
Thiol ester (2.0 mmol), dizinc (0.5 M in THF, 3.0 mmol), R93SiX
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoutodaigaku-Katsura, Nishikyo, Kyoto, 615-8501,
Japan. E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp;
Fax: (+81)75-3832461
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b709456f
(3.0 mmol), Pd2dba3 (0.02 mmol) and phosphine (0.84 mmol) were
b
used. Yields were determined by 1H NMR using bromoform as an
internal standard. The product was also isolated by bulb-to-bulb
distillation in runs 1–4, and by short silica gel column
chromatography in runs 5–11.
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Table 2 Preparation of silyl enol ethers from various thiol estersa
Run
R
R9CH(ZnI)2
R03SiX
Productb,c
1
2
3
4
5
6
7
8
H2CLCH(CH2)3–
HCMC(CH2)3–
Ph–
PhCH2SCH2–
EtO2C(CH2)5–
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH2(ZnI)2
CH3CH(ZnI)2
CH3CH(ZnI)2
CH3CH(ZnI)2
CH3CH(ZnI)2
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
t-BuMe2SiOTf
t-BuMe2SiOTf
t-BuMe2SiOTf
t-BuMe2SiOTf
94 (3c)
94 (3d)
70 (3e)
79 (3f)
96 (3g)
79 (3h)
88 (3i)
PhO(CH2)10
Br(CH2)7–
–
p-BrC6H4(CH2)2–
EtO2C(CH2)5–
p-BrC6H4(CH2)2–
CH3CH2CH2–
76 (3j)
9
67 (3k, 93 : 7d)
65 (3l, 93 : 7d)
58 (3m, 95 : 5d)
66 (3n, 90 : 10d)
10
11
12
a
H2CLCH(CH2)3–
Thiol ester (2.0 mmol), dizinc (0.5 M in THF, 3.0 mmol), R03SiX (3.0 mmol), Pd2dba3 (0.02 mmol), and phosphine (0.84 mmol) were used.
b
Yields (%) were determined by 1H NMR using bromoform as an internal standard. The product was also isolated by bulb-to-bulb distillation
in runs 1–8 and by short silica gel column chromatography in runs 9–12. The reaction period after an addition of R03SiX was as follows: 15
c
d
min for runs 1–8; 6 h for runs 9–12. Z : E Ratio of the product.
bonding highly selectively. Such an introduction is not easily
performed by conventional halogen–metal exchange or deproto-
nation reactions.
Notes and references
{ Gem-dizinc reagents 2 were prepared as a THF solution following the
procedure of ref. 7. The thiol esters were obtained from a mixed anhydride
and a thiol following the reported procedure.9
Preparation of 3: Tri(2-furyl)phosphine (0.082 mmol) in THF (1.0 mL)
was added at 25 uC to a solution of Pd2dba3 (0.02 mmol) in THF (1.0 mL)
and the mixture was stirred for 15 min. 1,1-Bis(iodozincio)ethane in THF
(2b, 0.40 M, 3.0 mmol) and p-nitrobenzene thiol ester of carboxylic acid (1,
2.0 mmol, 0.18 g) in THF (1.0 ml) were added subsequently at 0 uC. The
resulting mixture was stirred for 15 min at the same temperature. Silylation
reagent (3.0 mmol) was added to the reaction mixture. The resulting
mixture was stirred for 6 h at 25 uC. Et3N (1.0 mL) was added to the
mixture. A saturated aqueous solution of sodium bicarbonate (5.0 mL) was
Scheme 2 Preparation of silyl enol ether carrying keto group.
added to the reaction mixture and the mixture extracted with diethyl ether.
The combined organic layers were washed with sat. aq. NaHCO3 and
brine, and dried over anhydrous sodium sulfate. After rapid column
chromatography on silica gel with hexane–ethyl acetate as the eluent, 3 was
obtained.
Preparation of 5: To a solution of Pd2dba3 (0.02 mmol) in THF (1.0 mL),
tri(2-furyl)phosphine (0.082 mmol) in THF (1.0 mL) was added at 25 uC.
The mixture was stirred for 10 min. To this solution, chlorotrimethylsilane
(3.0 mmol, 0.4 mL) and p-nitrobenzene thiol ester of keto acid (2.0 mmol)
in THF (2.0 mL) were added subsequently at 0 uC and a solution of
bis(iodozincio)methane in THF (2a, 0.40 M, 3.0 mmol) was added
dropwise at 0 uC. The resulting mixture was stirred for 5 min at the same
temperature and then stirred for an additional 15 min at 25 uC. Et3N
(1.0 mL) was added to the mixture. A saturated aqueous solution of
sodium bicarbonate (5.0 mL) was added to the reaction mixture and the
mixture extracted with diethyl ether. The combined organic layers were
washed with brine, and dried over anhydrous sodium sulfate. The product
was isolated by bulb-to-bulb distillation.
Scheme 3 Plausible pathway of the reaction.
1 (a) C. H. Heathcock, in Comprehensive Organic Synthesis, ed. B. M.
The method mentioned above is quite an easy and efficient
procedure to produce silyl enol ethers regio-, chemo- and
stereoselectively. The synthetic utility of silyl enol ethers has
already been emphasized.1–3 The cross-coupling reaction by a gem-
dizinc reagent is a convenient method to introduce C–metal
Trost, Pergamon, Oxford, 1991, vol. 2, ch. 15; (b) T. Mukaiyama and
J. Matsuo, in Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH,
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Synthesis, 1977, 91; (e) P. Brownbridge, Synthesis, 1983, 1;
P. Brownbridge, Synthesis, 1983, 85.
4762 | Chem. Commun., 2007, 4761–4763
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