Thiol ester-boronic acid coupling. A mechanistically unprecedented and general ketone synthesis [18]

Full text of DOI:10.1021/ja005613q

11260
J. Am. Chem. Soc. 2000, 122, 11260-11261
Table 1. Copper Carboxylate Mediated Thiol Ester-Boronic Acid
Thiol Ester-Boronic Acid Coupling. A
Mechanistically Unprecedented and General Ketone
Synthesis
Cross-Couplinga
Lanny S. Liebeskind* and Jiri Srogl*
Department of Chemistry, Emory UniVersity
1515 Pierce DriVe, Atlanta, Georgia 30322
ReceiVed September 15, 2000
entry reactants
ketone (R1, R2)
Ph, o-MeOPh
Ph, m-MeOPh
Ph, 2-naphthyl
p-NO2Ph, 3,4-methylenedioxyphenyl
p-HOPh, Ph
2-pyrazyl, (E)-â-styryl
C11H23, m-NO2Ph
C11H23, o-CHO-p-MeOPh
adamantyl, 3,4-methylenedioxyphenyl
ClCH2, 2-naphthyl
AcOCH2, p-MeO2CPh
CF3, m-NO2Ph
yield, %
Highly discriminating activation of a stable carbon-sulfur bond
is achieved in the presence of a vast sea of oxygen and nitrogen
heteroatoms in various biochemical transformations.1,2 The Prin-
ciple of Hard-Soft Acids and Bases,3 e.g., the selective interaction
of a soft substrate with a soft activator in a hard environment
and vice versa, helps to rationalize Nature’s use of biologically
relevant thiophilic metals such as Ni to achieve selective
disconnection of the carbon-sulfur bond in water. Implicit in
this mode of C-S activation is the capacity of the biological
system to prevent the formation of refractory metal thiolates from
thiophilic metals.
Given the above considerations, new laboratory-based synthetic
processes that involve metal-catalyzed carbon-sulfur bond scis-
sion and lead to new carbon-carbon bond formation under very
mild conditions should be feasible. It is implicit in the discussion
above that metal-catalyzed turnover of organosulfur compounds
requires activation of the stable bond that forms between a
catalytically active metal and the soft sulfur atom.
1
2
3
4
5
6
7
8
9
10
11
12
13
1, 11
1, 12
1, 18
2, 16
3, 10
4, 17
5, 13
5, 15
6, 16
7, 18
8, 14
9, 13
9, 17
88
83
79
85
81
81
79
75
52
57
88
63
93
CF3, (E)-â-styryl
a Refer to Chart 1 for structures.
Chart 1. Thiol Ester and Boronic Acid Reactants
We have previously demonstrated the importance of sacrificial
ZnII in facilitating the cross-coupling of thioglycolate systems,4
and more recently described a thiol ester-boronic acid cross-
coupling using the principle of “alkylative activation”.5 The latter
draws on our earlier disclosures of sulfonium salts as highly
effective cross-coupling partners.6,7 We now report a mechanisti-
cally unique and unprecedented Pd-catalyzed coupling of thiol
esters8 with boronic acids to give ketones that proceeds in the
presence of CuI thiophene-2-carboxylate (CuTC)9 under strictly
nonbasic reaction conditions (Table 1, Chart 1). Although many
methods for the synthesis of ketones are known,10-12 none is
sufficiently general to allow the coupling of stable and functionally
rich reaction partners under neutral conditions. Some transforma-
tions of thiol esters to ketones are known; they proceed under
basic reaction conditions and are not general.13-18 Aroyl chlorides
do participate in couplings with neutral partners such as orga-
nostannanes19,20 and boronic acids,21,22 but acid chlorides are too
reactive to be broadly useful in sensitive, functionally rich
systems, and the boronic acid coupling is limited to acid chlorides
that can survive the basic conditions inherent in Suzuki-Miyaura
couplings.23
The examples in Table 1 demonstrate the generality and
efficiency of this new reaction. Although a variety of palladium
precatalysts/ligand systems were effective, the reaction was
surveyed using Pd2(dba)3‚CHCl3/tris(2-furyl)phosphine. Aromatic
and aliphatic S-alkyl and S-aryl thiol esters coupled efficiently
(52-93% yields) with a variety of functionalized boronic acids.
Particular attention is drawn to the direct preparation of a
chloromethyl ketone from the corresponding thiol ester 7 (Entry
(1) Huxtable, R. J., Ed. Biochemistry of Sulfur; Plenum Press: New York,
1986.
(2) Oae, S.; Okuyama, T. Organic Sulfur Chemistry: Biochemical Aspects;
CRC Press: Boca Raton, FL, 1992.
(3) Pearson, R. G. Chemical Hardness; Wiley-VCH Verlag GmbH:
Weinheim, 1997.
(4) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem. Soc.
1999, 121, 9449-9450.
(5) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2000, 2 (20), 3229-
3231.
(6) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376-12377.
(7) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org. Chem. 1999, 64,
2796-2804.
(8) Thiol esters have evolved as important acyl building blocks in biological
systems (Lynen, F. In Enzymes; Smellie, R. M. S., Ed.; Academic Press: New
York, 1970; p 1) because they are stable under protic conditions, and yet can
be selectively activated (by biologically relevant metals) for reaction in the
presence of oxygen- and nitrogen-based functionality.
(9) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312-
2313.
(15) Kawanami, Y.; Katsuki, I.; Yamaguchi, M. Tetrahedron Lett. 1983,
24, 5131-5132.
(16) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetra-
hedron Lett. 1998, 39, 3189-3192.
(17) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1974, 47, 1777-1780.
(18) Kim, S.; Lee, J. I. J. Chem. Soc., Chem. Commun. 1981, 1231-1232.
(19) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
Paquette, L., Ed.; John Wiley & Sons: New York, 1997; Vol. 50, pp 1-652.
(20) Mitchell, T. N. Synthesis 1992, 803-815.
(10) Dieter, R. K. Tetrahedron 1999, 55, 4177-4236.
(11) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-40.
(12) O’Neill, B. T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 397-458.
(13) Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. J. Am. Chem. Soc.
1974, 96, 3654-3655.
(21) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109-
3112.
(22) Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057-
(14) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Ronzini, L. Tetra-
hedron Lett. 1987, 28, 2053-2056.
3060.
(23) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
10.1021/ja005613q CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/26/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11261
Scheme 1
directly from the acylpalladium thiolate-CuTc complex. If prior
transmetalation from boron to the S-bound CuI does occur,
protodemetalation from this intermediate must be slow relative
to a fast internal transfer from copper to palladium. Mixed
anhydrides are not intermediates in the process: PhCOSCH2-
CONMe2, 1, does not react with CuTC to give a mixed anhydride,
either alone or catalyzed by palladium.
Both the copper cation and the carboxylate anion are critical
to the reaction. CuI halides and CuCN were ineffective. Coupling
to ketone was not observed when PhCOSCH2CONMe2 and PhB-
(OH)2 were exposed to 1% Pd2(dba)3 and K2CO3 or KOAc in
the absence of a thiolate scavenger. Nor was ketone efficiently
formed in the presence of added ZnII carboxylates (low yields of
the desired ketonic product were observed in some reaction
mixtures), even though ZnII salts functioned as metal-thiolate
activator/scavengers in nickel-catalyzed cross-coupling reactions
of thio-organics with organozinc reagents.4
10), the easy generation of trifluoromethyl ketones from tri-
fluoromethyl thiol ester 9 (Entries 12 and 13), and the simple
synthesis of a heterocyclic ketone (Entry 6). The special properties
of PhCOSCH2CONMe2 (1) are also noted: it undergoes coupling
with boronic acids more efficiently and in a greater range of
solvents when compared to the simple thiol esters.
Unlike the traditional Suzuki-Miyaura cross-coupling of
boronic acids and organic halides, where the presence of a base
is essential,23 base was deleterious in the current chemistry.
Addition of 1 equiv of KOAc to the reaction of PhCOSCH2-
CONMe2 with PhB(OH)2 in the presence of 1% Pd2(dba)3‚CHCl3/
TFP (tris-2-furylphosphine) and CuTC significantly suppressed
the yield of ketone. In a dramatic demonstration, 2-naphthyl
phenyl ketone was formed in 60% yield from naphthalene-2-
boronic acid and thiol ester PhCOSCH2CONMe2 in acetic acid
as solVent! These “baseless” conditions should open new pos-
sibilities for the synthesis of base-sensitive compounds. In addition
to THF (the solvent of choice), ethanol and 2-propanol are
acceptable, although some competitive alcoholysis of the thiol
ester takes place in these solvents. Coordinating solvents (DMA,
NMP, acetonitrile) and coordinating ligands (NaI, LiCl, alkyl
sulfide) negatively affect the reaction outcome, completely
preventing the reaction in many cases.
The mechanistic key to this new reaction is the selective
activation of a catalytically generated acylpalladium-thiolate in
a way that facilitates transmetalation from boron to palladium,
while retaining compatibility with all other components of the
reaction system. Although a detailed understanding of this cross-
coupling is not currently in hand, the process requires transmeta-
lation from boron to palladium mediated by CuTC (Scheme 1).
A number of observations are significant: Although naphthalene-
2-boronic acid (18) suffers rapid (2 h) protodeborylation to
naphthalene upon treatment with 1 equiv of CuTC in THF at room
temperature, the protodeborylation is suppressed with high
efficiency in the presence of 1 equiv of thiol ester 1, PhCOSCH2-
CONMe2. Therefore, a thiol ester-CuTC complex is deemed
important in the cross-coupling. Presumably then, cross-coupling
of the thiol ester with the boronic acid is initiated by oxidative
addition of the CuTC-bound thiol ester to the Pd(0) catalyst.
(Efficient chelation of CuTC to PhCOSCH2CONMe2 helps
rationalize the special reactivity of this thiol ester in the cross-
coupling chemistry. The coordinating solvent DMA inhibited the
cross-coupling of S-alkyl and S-aryl thiol esters, but not PhCOSCH2-
CONMe2.) Transmetalation from boron to palladium must occur
next, either preceded by boron to copper transmetalation or
Since CuI halides and CuCN are ineffective, the carboxylate
counterion is clearly important in facilitating transmetalation from
boron, possibly through direct coordination to trivalent boron. If
this mechanistic speculation is correct, then any solvent or added
ligand that binds to copper and blocks formation of the requisite
thiol ester CuI complex will interfere with Cu-mediated trans-
metalation. Furthermore, any added base may bind to boron and
retard reaction by blocking coordination of the CuI carboxylate
to the trivalent boron.
In conclusion, a mild and general method for the palladium-
catalyzed, copper-mediated coupling of thiol esters and boronic
acids under “baseless” conditions has been developed. The general
availability of both reaction partners and the nonbasic reaction
condition suggest new possibilities for the synthesis of highly
functionalized and base-sensitive compounds under these cross-
coupling conditions. Additional investigation of the scope and
limitation of this chemistry (heteroaromatic and alkylboron reagent
couplings; amino acid thiol esters as reactants), as well as of the
origin of carbon-boron bond activation, is in progress in our
laboratory. Extension of this new reaction to polymer-supported
reactions is obvious and also under study.
Acknowledgment. The National Cancer Institute, DHHS supported
this investigation through grant No. CA40157. We are most grateful to
Dr. Paul Reider of Merck Pharmaceutical Co. for his interest in and
generous support of this work and to Dr. Gary Allred of Frontier
Scientific, Inc. of Logan, Utah for facilitating this study with a generous
supply of boronic acids. We thank Ms. Heather Petralia for her
experimental assistance with this project, and Ms. Cecile Savarin for her
expert proofreading of the manuscript.
Supporting Information Available: A complete description of the
synthesis and characterization of all compounds prepared in this study
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org..
JA005613Q