Chemo- and regioselective preparation and reaction of a kinetic zinc enolate formed from a thiol ester and bis(iodozincio)methane

Article abstract of DOI:10.1002/anie.200602950

(Chemical Equation Presented) Reactive functionalized enolates that are otherwise difficult to obtain can be prepared in a simple procedure by the treatment of a thiol ester with bis(iodozincio)methane in the presence of a palladium catalyst (see scheme). The terminal zinc enolates thus formed are kinetically controlled and react with a variety of electrophiles, such as aldehydes, ketones, and acyl cyanides. FG = functional group.

Full text of DOI:10.1002/anie.200602950

Communications
Synthetic Methods
DOI: 10.1002/anie.200602950
Chemo- and Regioselective Preparation and
Reaction of a Kinetic Zinc Enolate Formed from a
Thiol Ester and Bis(iodozincio)methane**
Zenichi Ikeda, Takaharu Hirayama, and
Seijiro Matsubara*
Bis(iodozincio)methane (1), which has a methylene carbon
atom with two nucleophilic sites, has been used for a variety of
À
molecular transformations in which C C bond formation is
repeated at the same carbon atom.[1,2] In other words, it
functions as a zinciomethylation reagent. Such zinciomethy-
[*] Z. Ikeda, T. Hirayama, Prof. Dr. S. Matsubara
Department of Material Chemistry
Graduate School of Engineering, Kyoto University
Kyoutodaigaku-Katsura, Nishikyo, Kyoto 615-8501 (Japan)
Fax: (+81)75-383-2461
E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
[**] This work was supported financially by the Japanese Ministry of
Education, Science, Sports, and Culture and by the Chugai
Pharmaceutical Co., Ltd.
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lation of acylating reagents should afford the kinetic enolates
of ketones. Many functional groups should be tolerated
during the transformation because of the modest reactivity of
organozinc compounds.[3] However, in previous studies some
combinations of acylating reagents and 1, regardless of their
stoichiometric relationship, resulted in the formation of
symmetrical 1,3-diketones through a double acylation of 1.
For example, the treatment of benzoyl chloride with 1 in any
ratio in the presence of a palladium catalyst gave 1,3-
diphenylpropane-1,3-dione.[4a] The treatment of an acyl
cyanide with 1 gave a similar result.[4b] These highly reactive
acylating reagents react preferentially with the a-zincioke-
tone intermediate over bis(iodozincio)methane (1). A mild
and chemoselective transformation reported by Fukuyama
and co-workers in which thiol esters are converted into
ketones with alkyl zinc reagents in the presence of a
palladium catalyst[5–7] suggested to us that a thiol ester may
react with bis(iodozincio)methane (1)[2c] in the presence of a
palladium catalyst to give an a-zincioketone, that is, an
enolate[8] that would not readily undergo palladium-catalyzed
coupling with the thiol ester. The transformation should be
chemoselective because of the modest reactivity of 1.
Furthermore, the terminal enolate formed initially would
not isomerize to the corresponding thermodynamic enolate
under these reaction conditions (Scheme 1).
Tuning of the electron density of the aromatic ring of the thiol
improved the yield. The aldol product 3 was obtained
quantitatively when 4-nitrobenzenethiol was used to form
the thiol ester. The only other possible aldol product 3’, which
may result if the enolate formed initially isomerizes to the
thermodynamic enolate, was not observed. The use of
ethanethiol ester as a substrate[5] resulted in the recovery of
the starting material.
Various types of electrophiles can be added to the
prepared kinetic enolate as reactants, as shown in Scheme 3.
Treatment with acyl cyanides gave 1,3-diketones. Conjugate
addition was not observed in the reaction of (E)-Me-
=
CH CHCOPh with the kinetic enolate formed from 2’.
Scheme 3. Reaction of the kinetic enolate prepared from thiol ester 2’ with
various electrophiles.
Functional-group tolerance in the formation of the kinetic
enolate was examined (Scheme 4). Terminal alkyne (in 5d),
primary bromide (in 5e), silyl ether (in 5i), and ester (in 5j)
functionalities remained intact during the reaction. Neither a
bromophenyl (in 5 f) nor a sulfide (in 5g) group interfered
with the formation of the kinetic enolate, although these
functional groups often interact with palladium(0) catalysts.
The chemo- and regioselective preparation of the kinetic
enolate in the presence of a keto group was an attractive
goal.[10] Unfortunately, the treatment of a thiol ester contain-
ing a keto group with bis(iodozincio)methane (1) in the
presence of a palladium catalyst gave a polymeric compound
formed by an intermolecular reaction
Scheme 1. Preparation of a kinetic zinc enolate by zinciomethylation of
a thiol ester. FG=functional group.
Arene thiol esters[9] of 5-hexenoic acid, 2, were mixed with
bis(iodozincio)methane (1) in the presence of a palladium(0)
catalyst, which was prepared in situ from [Pd2(dba)3] (dba =
trans,trans-dibenzylideneacetone) and triphenylphosphane,
and treated subsequently with benzaldehyde (Scheme 2).
of the keto group with the enolate. The
addition of the electrophile to the
reaction mixture prior to the formation
of the enolate, however, prevented this
self-condensation. Mixtures of a thiol
ester with a keto group, 7, and benzoyl
cyanide were treated with the dizinc
reagent 1 in the presence of a palla-
dium catalyst (Scheme 5). The desired
triketones were formed in excellent
yields. The initially formed kinetic
enolate reacted with the electrophile
without being transposed to the other
methyl ketone in the same molecule, as
Scheme 2. Preparation of the kinetic zinc enolate from thiol esters 2 and reaction with
benzaldehyde.
shown by the reactions of 7d and 7e.
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bis(iodozincio)methane. The modest reactivity of the zinc
reagent makes the transformation chemo- and regioselective.
The method is simple, but provides access to reactive
functionalized enolates which are otherwise hard to obtain.
Experimental Section
Typical Procedure: Triphenylphosphane (0.02 mmol, 5.5 mg) was
added to a solution of [Pd2(dba)3] (0.005 mmol, 4.6 mg) in THF
(0.8 mL) at 258C. The mixture was stirred for 10 min, then cooled to
08C, whereupon the p-nitrobenzenethiol ester of 5-hexenoic acid
(1.0 mmol, 0.25 g) was added as a solution in THF (1.0 mL), followed
by bis(iodozincio)methane (1) in THF (0.45m, 1.2 mmol, 2.7 mL).
The resulting mixture was stirred for 5 min at 08C. A solution of
benzaldehyde (1.5 mmol, 0.16 g) in THF (1.0 mL) was then added,
and the reaction mixture was stirred for a further 5 min at 08C. A
saturated aqueous solution of ammonium chloride (1.0 mL) was
added, and the mixture was extracted with diethyl ether. The
combined organic layers were washed with saturated, aqueous
NaHCO3 and brine, then dried over anhydrous sodium sulfate.
After rapid column chromatography on silica gel with hexane/
ethyl acetate as the eluent, compound 3 was obtained in
quantitative yield.
Scheme 4. Chemoselectivity in the formation of the kinetic enolate.
[a] [Pd2(dba)3] (1.0 mol%) and PPh3 (4.2 mol%) were used.
Preparation of 8a: Triphenylphosphane (0.042 mmol,
11.3 mg) was added to a solution of [Pd2(dba)3] (0.01 mmol,
9.2 mg) in THF (1.0 mL) at 258C, and the mixture was stirred
for 10 min. After the reaction mixture was cooled to 08C,
benzoyl cyanide (0.5 mmol, 0.066 g) was then added as a
solution in THF (0.5 mL), followed by a solution of the p-
nitrobenzenethiol ester of 7-oxooctanoic acid (1.0 mmol,
0.29 g) in THF (1.0 mL) at 08C. A solution of bis(iodozincio)-
methane (1) in THF (0.45m, 1.5 mmol, 3.3 mL) was then added
dropwise, and the reaction mixture was stirred for a further 1 h
at 08C. A saturated aqueous solution of ammonium chloride
(2.0 mL) was then added, and the mixture was extracted with
diethyl ether. The combined organic layers were washed with
saturated, aqueous NaHCO3 and brine, and dried over anhy-
drous sodium sulfate. After rapid column chromatography on
silica gel with hexane/ethyl acetate as the eluent, compound 3
was obtained in 92% yield. Triketones 8d (94%) and 8e (79%)
were obtained in the same way, although P(2-furyl)3 was used
instead of PPh3 in the preparation of 8e.
Scheme 5. Preparation of triketones 8 by the treatment of benzoyl cyanide with
enolates that contain a keto group. [a] P(2-furyl)3 was used instead of PPh3.
8a: 1H NMR (500 MHz, CDCl3): d = 7.8–8.0 (m, 2H), 7.4–
7.6 (m, 3H), 6.17 (s, 1H, enol form), 2.43 (t, J = 7.5 Hz, 2H),
2.14 (s, 3H), 1.70 (tt, J = 5.5, 5.5 Hz, 2H), 1.62 (tt, J = 5.5,
5.5 Hz, 2H), 1.56 (brs, 1H), 1.3–1.41 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d = 209.0, 196.7, 183.4, 134.9, 132.2, 128.6, 127.0,
96.1, 43.4, 39.0, 29.9, 28.7, 25.5, 23.4 ppm.
The formation from the thiol esters and reaction of the
enolates proceeded chemo- and regioselectively.
No loss of enantiomeric purity was observed in the
transformation of the enantiomerically pure thiol ester 9 into
the diketone 10.[11] The thiol ester 9 was prepared readily from
l-proline. The chiral 1,3-diketone is a potentially useful
compound for organic synthesis (Scheme 6).
8d: 1H NMR (500 MHz, CDCl3): d = 7.8–8.0 (m, 2H), 7.4–7.6 (m,
3H), 6.17 (s, 1H, enol form), 3.11 (tq, J = 7.5, 7.5 Hz, 1H), 2.93 (dd,
J = 16.0, 8.0 Hz, 1H), 2.44 (dd, J = 16.0, 5.5 Hz, 1H), 2.25 (s, 3H), 1.61
(bs, 1H), 1.18 ppm (d, J = 5.5, 5.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d = 211.0, 196.6, 181.0, 134.3, 132.3, 128.6, 126.9, 96.7, 42.8,
42.3, 28.5, 16.6 ppm.
Thus, these results allow us to propose a novel method for
the preparation of a kinetic zinc enolate from a thiol ester and
8e: 1H NMR (500 MHz, CDCl3): d = 7.8–8.0 (m, 2H), 7.4–7.6 (m,
3H), 6.23 (s, 1H, enol form), 3.08 (ddq, J = 8.0, 7.0, 5.0 Hz, 1H), 3.01
(dd, J = 18.0, 8.0 Hz, 1H), 2.50 (dd, J = 18.0, 5.0 Hz, 1H), 2.18 (s, 3H),
1.60 (brs, 1H), 1.18 ppm (d, J = 5.5, 5.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d = 206.9, 201.2, 181.3, 134.4, 132.2, 128.6, 126.9, 95.4, 46.5,
38.7, 30.3, 17.9 ppm.
Received: July 22, 2006
Published online: November 14, 2006
Scheme 6. Conversion of thiol ester 9, prepared from enantiomerically
pure l-proline, into the enantiomerically pure 1,3-diketone 10.[11]
Boc=tert-butoxycarbonyl.
Keywords: chemoselectivity · cross-coupling · enolates ·
regioselectivity · zinc
.
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4.23 min.
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