Copper-Mediated, Palladium-Catalyzed Coupling of Thiol Esters with Aliphatic Organoboron Reagents

Article abstract of DOI:10.1021/jo049964p

Thiol esters and B-alkyl-9-BBN derivatives couple in the presence of a copper(I) carboxylate mediator and a palladium catalyst. In contrast to copper-mediated, palladium-catalyzed cross-couplings of thioorganics with boronic acids, the current coupling reaction of 9-BBN derivatives is facilitated by the addition of a base such as Cs₂CO₃. Under optimized conditions, a variety of thiol esters react with different B-alkyl-9-BBN derivatives giving ketones in moderate to excellent yields.

Full text of DOI:10.1021/jo049964p

SCHEME 1
Cop p er -Med ia ted , P a lla d iu m -Ca ta lyzed
Cou p lin g of Th iol Ester s w ith Alip h a tic
Or ga n obor on Rea gen ts
Ying Yu and Lanny S. Liebeskind*
Emory University, Department of Chemistry,
1515 Dickey Drive, Atlanta, Georgia 30322
are understood to depend on the ability of the copper(I)
carboxylate to activate the catalytic intermediate, R1-
COPdL2SR′, toward transmetalation by both boronic
acids and organotri-n-butylstannanes. In the case of the
boronic acid cross-couplings, the data support a dual
activation of both the palladium thiolate and the boronic
acid by the copper(I) carboxylate as implied in Figure
1.1a,b
chemll1@emory.edu
Received J anuary 5, 2004
Abstr a ct: Thiol esters and B-alkyl-9-BBN derivatives
couple in the presence of a copper(I) carboxylate mediator
and a palladium catalyst. In contrast to copper-mediated,
palladium-catalyzed cross-couplings of thioorganics with
boronic acids, the current coupling reaction of 9-BBN deriva-
tives is facilitated by the addition of a base such as Cs2CO3.
Under optimized conditions, a variety of thiol esters react
with different B-alkyl-9-BBN derivatives giving ketones in
moderate to excellent yields.
To date, copper-mediated, palladium-catalyzed cou-
plings of thioorganics have been successfully developed
for aromatic, heteroaromatic, and alkenylboronic acids
as well as for the analogous organotri-n-butylstannanes.
Noticeably missing from this new coupling procedure are
examples utilizing either aliphatic boron or tin reagents.
In fact, alkylboronic acids have been problematic in
traditional Suzuki cross-couplings and generally result
in low yields of coupling products. Recent studies, how-
ever, show promise of improving this situation.6 In
contrast to aliphatic boronic acids, B-alkyl 9-BBN re-
agents, readily prepared by hydroboration of alkenes,7
can be cross-coupled with various organic halides under
mild conditions.8 In these standard Suzuki-Miyaura
couplings, both a base and palladium catalyst are es-
sential for a successful reaction.9 Other efficient alkyl-
boron cross-coupling partners have also been reported,
such as borinate esters (generated from selective mo-
nooxidation of B-alkyl-9-BBN reagents with anhydrous
trimethylamine N-oxide),10,11 trialkylboranes,12 and po-
tassium alkyltrifluoroborates.13
Recent publications have demonstrated the efficient,
palladium-catalyzed, copper-mediated coupling of various
thioorganics (thiol esters, alkynyl thioethers, heteroaro-
matic thioethers) with both boronic acids1 and with
organotri-n-butylstannanes.2 As a case in point, thiol
esters react with boronic acids in a mild, efficient, and
general Pd-catalyzed, Cu(I) carboxylate-mediated cou-
pling to give ketones under nonbasic conditions (Scheme
1).1a,3 In contrast, the synthesis of ketones via noncar-
bonylative cross-coupling protocols typically requires acyl
moieties of greater reactivity than thiol esters (and thus
lower functional group compatibility), such as acid ha-
lides4 and anhydrides.5 These new thioorganic couplings
The thiol ester/boronic acid method of ketone synthesis
depicted in Scheme 1 is effective with various substitu-
ents on the thiol ester (aromatic, heteroaromatic, ali-
phatic) and with aromatic, heteroaromatic, and alkenyl-
boronic acids. Unfortunately, under standard conditions
for the Cu(I) carboxylate-mediated, palladium-catalyzed
coupling of thiol esters with boronic acids,1 the coupling
* To whom correspondence should be addressed. Tel: (404) 727-
6604. Fax: (404) 727-0845.
(1) (a) Srogl, J .; Liebeskind, L. S. J . Am. Chem. Soc. 2000, 122,
11260. (b) Liebeskind, L. S.; Srogl, J . Org. Lett. 2002, 4, 979; Savarin,
C.; Srogl, J .; Liebeskind, L. S. Org. Lett. 2001, 3 (1), 91; Savarin, C.;
Liebeskind, L. S. Org. Lett. 2001, 3 (14), 2149. Srogl, J .; Liebeskind,
L. S. Org. Lett. 2002, 4 (6), 979. Kusturin, C. L.; Liebeskind, L. S.;
Neumann, W. L. Org. Lett. 2002, 4 (6), 983. Liebeskind, L. S.; Srogl,
J .; Savarin, C.; Polanco, C. Pure Appl. Chem. 2002, 74 (1), 115.
Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweizer,
B.; Srogl, J .; Neumann, W. L. Org. Lett. 2003, 5 (23), 4349.
(2) Egi, M.; Wittenberg, R.; Srogl, J .; Liebeskind, L. S. Org. Lett.
2003, 5, 3033-3035. Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801.
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet,
G. Org. Lett. 2003, 5, 803.
(3) By way of comparison, thiol esters are known to give ketones
upon reaction with Grignard reagents (Araki, M.; Sakata, S.; Takei,
H.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1974, 47, 1777), organocopper
compounds ((a) Anderson, R. J .; Henrick, C. A.; Rosenblum, L. D. J .
Am. Chem. Soc. 1974, 96, 3654. (b) Kim, S.; Lee, J . I. J . Chem. Soc.,
Chem. Commun. 1981, 1231), 1-alkynyltrimethysilanes (Kawanami,
Y.; Katsuki, I.; Yamaguchi, M. Tetrahedron Lett. 1983, 24, 5131), and
organozinc reagents (Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189). Heteroaromatic
thioethers participate in a palladium-catalyzed coupling with orga-
nozinc reagents (Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P.
Synlett. 2000, 905-907).
(6) (a) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020. (b) Zou, G.; Reddy, Y. K.; Falck, J . R. Tetrahedron Lett. 2001,
42, 7213. (c) Kirchhoff, J . H.; Netherton, M. R.; Hills, I. D.; Fu, G. C.
J . Am. Chem. Soc. 2002, 124, 13662. (d) Molander, G. A.; Yun, C.
Tetrahedron 2002, 58, 1465.
(7) Soderquist, J . A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1995;
Vol. 1, pp 622-630.
(8) Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, T. J . Am.
Chem. Soc. 1991, 113, 5402. Rivera, I.; Colberg, J . C.; Soderquist, J .
A. Tetrahedron Lett. 1992, 33, 6919. Bhagwat, S. S.; Gude, C.; Cohen,
D. S.; Dotson, R.; Mathis, J .; Lee, W.; Furness, P. J . Med. Chem. 1993,
36, 205. Netherton, M. R.; Dai, C.; Neuschuetz, K.; Fu, G. C. J . Am.
Chem. Soc. 2001, 123, 10099.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) Matos, K.; Soderquist, J . A. J . Org. Chem. 1998, 63, 461.
(11) (a) Moore, W. R.; Schatzman, G. L.; J arvi, E. T.; Gross, R. S.;
McCarthy, J . R. J . Am. Chem. Soc. 1992, 114, 360. (b) Matos, K.;
Soderquist, J . A. J . Org. Chem. 1998, 63, 461.
(4) Haddach, M.; McCarthy, J . R. Tetrahedron Lett. 1999, 40, 3109.
Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057.
(5) Kakino, R.; Yasumi, S.; Shimizu, I.; Yamamoto, A. Bull. Chem.
Soc., J pn. 2002, 75, 137-148. Goossen, L. J .; Ghosh, K. Angew. Chem.,
Int. Ed. 2001, 40, 3458-3460.
(12) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J . Am. Chem. Soc. 1989, 111, 314. (b) Old, D. W.; Wolfe,
J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722.
(13) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
10.1021/jo049964p CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/17/2004
3554
J . Org. Chem. 2004, 69, 3554-3557

F IGURE 1.
the protodeborylation product,14 was also observed. The
latter observation suggested that the B-alkyl-9-BBN
reagent, although more effective than the corresponding
alkylboronic acid, was not sufficiently reactive in trans-
metalation with the RCOPd(L)2SR′ intermediate. B-Styryl-
9-BBN gave results similar to those for B-undecyl-9-BBN.
TABLE 1. P d (0)-Ca ta lyzed , Cu TC-Med ia ted Cou p lin g of
Ben zoyl Th iol Ester w ith B-u n d ecyl-9-BBN
Although the presence of an oxygen base is often
crucial for the success of traditional Suzuki-Miyaura
reactions, such bases were shown to be deleterious to the
copper carboxylate-mediated, palladium-catalyzed cou-
plings of boronic acids with thioorganics referred to
earlier in this paper.1 In contrast to those boronic acid
couplings, the addition of 1 equiv of Cs2CO3 to the
couplings of thiol esters and B-alkyl-9-BBN reagents
greatly improved the product yields. Among the common
bases used in the coupling reactions, Cs2CO3 was the
best. K2CO3 and K3PO4 were also effective, although
quantities greater than 1 equiv were required. A sto-
ichiometric amount of Cu(I) and catalytic amount of Pd-
(0) were both essential for the couplings. As copper
sources both CuTC1a and CuMeSal15 were effective in
mediating the couplings, while other Cu(I) species such
as CuOAc and CuX (X ) Cl, I) resulted in much lower
yields. THF, DMA, and 1,4-dioxane were all suitable
solvents for the reaction. The couplings even proceeded
in EtOH, although ethyl esters were formed as byprod-
ucts. As depicted in Table 2, the optimized conditions
could be extended to a variety of B-alkyl-9-BBN deriva-
tives and thiol esters, which produced the desired aryl-
alkyl or alkyl-alkyl ketones in moderate to excellent
yields. B-Alkyl-9-BBN derivatives prepared from long
chain primary alkenes, dienes, and styrene and its
derivatives worked well in the coupling reactions. B-(2-
Hexanonyl)-9-BBN and B-(3,3-dimethoxypropyl)-9-BBN
were relatively sluggish in the coupling reaction, but still
gave the desired ketones in modest yields.
thiol ester
boron (equiv)
product yielda (%)
1a
1b
1c
1.5
1.5
1.2
1.5
2.0
30
48
29
41
48
a
GLC yield using nonadecane as an internal standard.
of n-BuB(OH)2 with PhCOS-p-tolyl failed to produce any
ketone. Nor was 2-n-butyl-4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolane (the corresponding boronate ester prepared
from n-butyl boronic acid and pinacol) effective as a
coupling agent. Suspecting that transmetalation of an
aliphatic group from boron to palladium is slower than
the corresponding transfer of C-sp2 and C-sp moieties,
an investigation of the more reactive B-alkyl-9-BBN
reagents was undertaken.
The preparation of B-alkyl-9-BBN derivatives was
easily achieved by reaction of alkenes with commercially
available 0.5 M 9-BBN in THF.7 Hydroboration proceeded
smoothly at room temperature with almost exclusive
selectivity for introduction of boron at the less hindered
side of the double bond. The resulting B-alkyl-9-BBN
reagents in THF can be stored under an inert atmosphere
at 0 °C for weeks without obvious decomposition. In the
first set of experiments, benzoyl thiol esters 1a -c were
heated with B-undecyl-9-BBN, a stoichiometric amount
of Cu(I) thiophene-2-carboxylate (CuTC), and 5% Pd-
(PPh3)4 at 45 °C in THF. The reaction gave dodecano-
phenone as the desired product, but only in 25-48%
yields (Table 1). Control experiments revealed that both
Cu(I) and the Pd(0) catalyst were essential for the
couplings. Although not shown in Table 1, various
combinations of thiol esters, Cu(I) compounds, Pd cata-
lysts, solvents, and temperature were also screened using
B-undecyl-9-BBN as the boron reagent, but none of these
variations led to promising improvements. In most cases,
unreacted thiol esters could be recovered and undecane,
The method is ideal for synthesizing alkyl-alkyl
ketones and aryl-alkyl ketones with various functional
groups that can withstand basic reaction conditions.
Other alkylboron coupling partners, such as BEt3, 2-n-
butyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, B-undec-
yl-9-oxa-10-borabicyclo[3,3,2]decane, and potassium n-
butyltrifluoroborate were also investigated in the cou-
pling reaction with thiol esters, but the desired ketone
product was not formed.
Unfortunately, not all thiol esters could be successfully
coupled with aliphatic boron reagents. The basic reaction
(14) Control experiments showed that heating B-undecyl-9-BBN
with 1 equiv of CuTC in THF for 3 h produced undecane as the
protodeborylation product in more than 90% yield.
(15) See the Supporting Information for: Savarin, C.; Srogl, J .;
Liebeskind, L. S. Org. Lett. 2001, 3 (1), 91-93.
J . Org. Chem, Vol. 69, No. 10, 2004 3555

TABLE 2. B-Alk yl-9-BBN Der iva tives: Th iol Ester s Cou p lin g u n d er Ba sic Con d ition s
a
b
Isolated yields. Intramolecular aldol-dehydration product (43%) was formed under the basic conditions.
conditions required to induce the coupling of the B-alkyl-
9-BBN reactants led to decomposition of some thiol
esters, such as those shown in Figure 2. Neither did
B-sec-alkyl-9-BBN reagents (i.e., prepared from cyclo-
hexene) react with thiol esters to give the desired ketones.
For example, neither B-cyclohexyl-9-BBN nor R-Alpine
Borane returned any ketonic product upon reaction with
thiol ester 1c.
During earlier studies of the copper carboxylate-
mediated, palladium-catalyzed coupling of thioorganics
with boronic acids, it was noted that boronic acids were
much superior to boronate esters as reactants. This and
3556 J . Org. Chem., Vol. 69, No. 10, 2004

pling of thioorganics with boronic acids, the presence of
a base (Cs2CO3) was required in the current reagent
system in order to provide activation of the boron
reagents. Aryl-alkyl and alkyl-alkyl ketones with a
variety of functional groups have been synthesized in
moderate to excellent yields.
F IGURE 2.
other observations led to the proposal that the copper(I)
carboxylate functioned as a unique dual activator, acting
through the soft Cu(I) ion as a thiophilic agent to help
polarize the palladium thiolate bond while simulta-
neously providing borophilic activation through the hard
carboxylate counterion. The much greater reactivity of
boronic acids over boronate esters and the deleterious
effect of added oxygen bases on the coupling reaction led
to the proposal of the hydrogen bonded, ternary complex
depicted in Figure 1, above, as the reactive intermediate.
A low energy reaction path proceeding through this
ternary complex would most likely be sensitive to steric
effects and depend on the presence of hydrogen bonds
from the boronic acid to the carboxylate counterion. The
inability to form hydrogen bonds to the copper carboxy-
late may account for the poor reactivity of boronate esters
in the palladium-catalyzed, copper-mediated coupling of
thioorganics.
Like boronate esters, the greater steric demand of the
B-alkyl-9-BBN reagents should render reaction through
the dual activation, ternary complex pathway quite
difficult, and as confirmed above, B-alkyl-9-BBN reac-
tants participate only sluggishly under the nonbasic
cross-coupling conditions. Nevertheless, stepwise, sepa-
rate activation of the palladium thiolate by Cu(I) and of
the B-alkyl-9-BBN by Cs2CO3 is still feasible; hence, the
9-BBN system is susceptible to base-induced activation.
In summary, through the use of B-alkyl-9-BBN deriva-
tives the Pd(0)-catalyzed, Cu(I) carboxylate-mediated
cross-coupling of thiol esters has been broadened to
include aliphatic boron reagents. In contrast to the
palladium-catalyzed, copper carboxylate-mediated cou-
Exp er im en ta l Section
Gen er a l P r oced u r e for P r ep a r in g B-Alk yl-9-BBN Re-
a gen ts. To a round-bottomed flask was added alkene (5.0 mmol),
and then the mixture was cooled to 0 °C under the protection of
argon. 9-BBN (10 mL, 0.5 M) in THF (5.0 mmol) was added
slowly via syringe. The reaction solution was stirred at 0 °C for
1 h and then room temperature for another 2 h. The resulting
B-alkyl-9-BBN reagent solution (0.5 mmol/mL) was stored below
0 °C before using.
Gen er a l P r oced u r e for Cr oss-Cou p lin g Rea ction . Thiol
ester (0.40 mmol), CuTC (91 mg, 0.48 mmol), Cs2CO3 (130 mg,
0.40 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) were added into
a Schlenk tube and then degassed with argon. The B-Alkyl-9-
BBN reagent (0.96 mL, 0.5 mmol/mL, 0.48 mmol) in THF was
added via syringe. Then dry and degassed THF (4 mL) was
added. The dark brown suspension was stirred under the
protection of argon at 45 °C for 16 h. Then Et2O (10 mL) was
added, and the reaction was quenched with 2 M HCl followed
by 1 M NH3‚H2O and then brine. After evaporation of the
solvent, the residue was purified by silica gel chromatography
or preparative plate silica chromatography (SiO2, 500 µm,
gradient of hexanes/Et2O) to give the desired product.
Ack n ow led gm en t. The National Institutes of Gen-
eral Medical Sciences, DHHS supported this investiga-
tion through Grant No. GM066153. We thank Dr. J iri
Srogl for his advice and interest in this project.
Su p p or tin g In for m a tion Ava ila ble: A complete descrip-
tion of the synthesis and characterization data of all com-
pounds prepared in this study. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O049964P
J . Org. Chem, Vol. 69, No. 10, 2004 3557