Thiol ester-boronic acid cross-coupling. Catalysis using alkylative activation of the palladium thiolate intermediate

Article abstract of DOI:10.1021/ol000231a

(matrix presented) Thiol esters and boronic acids do not participate in cross-coupling in the presence of palladium catalysts. However, efficient palladium-catalyzed thiol ester-boronic acid cross-coupling is observed when simple alkylating agents are present. Alkylative conversion of the very stable palladium-thiolate bond to a labile palladium-thioether bond is presumed to be crucial to the catalysis. Of the systems studied, 4-halo-n-butyl thiol esters were most effective in this cross-coupling.

Full text of DOI:10.1021/ol000231a

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3229-3231
Thiol Ester−Boronic Acid
Cross-Coupling. Catalysis Using
Alkylative Activation of the Palladium
Thiolate Intermediate
Cecile Savarin, Jiri Srogl,* and Lanny S. Liebeskind*
Emory UniVersity, Department of Chemistry, 1515 Pierce DriVe,
Atlanta, Georgia 30322
chemll1@emory.edu
Received August 11, 2000
ABSTRACT
Thiol esters and boronic acids do not participate in cross-coupling in the presence of palladium catalysts. However, efficient palladium-
catalyzed thiol ester−boronic acid cross-coupling is observed when simple alkylating agents are present. Alkylative conversion of the very
stable palladium−thiolate bond to a labile palladium−thioether bond is presumed to be crucial to the catalysis. Of the systems studied,
4-halo-n-butyl thiol esters were most effective in this cross-coupling.
New metal-catalyzed synthetic processes that involve carbon-
sulfur bond scission and lead to the formation of a new
carbon-carbon bond under mild conditions should be
feasible if carbon-sulfur oxidative addition is facile and the
formation of refractory metal thiolates from thiophilic, redox
active metals can be prevented.1 The oxidative addition of
organosulfur compounds to low-valent transition metal
species is well-known;2 therefore the key to catalytic turnover
with organosulfur compounds is activation of the very stable
bond that forms between the catalytically active metal (such
as Ni, Pd, Pt, Rh) and the soft sulfur atom.
From a synthetic perspective, the coupling of stable
organosulfur compounds with boronic acids would be a
singular boon to the synthetic chemist, since both reaction
partners are readily available and stable molecules of low
toxicity, and their coupling would provide a uniquely mild
method for the synthesis of highly functionalized organics.
Given the precedence for oxidative addition of thioorganics
to low valent nickel, palladium, and platinum mentioned
above, the conceptual key to this proposed coupling reaction
is transmetalation of the boronic acid to the metal thiolate
intermediate, with concomitant replacement of the thiolate
ligand. Unfortunately, the low thiophilicity of boron com-
bined with the low nucleophilic reactivity of organoboron
derivatives renders this transmetalation problematic.
(1) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem. Soc.
1999, 121, 9449-9450. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Lin,
S.-C.; Li, L.; Fukuyama, T. J. Braz. Chem. Soc. 1998, 9, 381-387.
Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 3189-3192. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem.
Soc. 1990, 112, 7050-7051. Wenkert, E.; Ferreira, T. W.; Michelotti, E.
L. J. Chem. Soc., Chem. Commun. 1979, 637-638. Okamura, H.; Miura,
M.; Takei, H. Tetrahedron Lett. 1979, 43-46. Han, Y.; Chorev, M. J. Org.
Chem. 1999, 64, 1972-1978.
(2) Wenkert, E.; Shepard, M.; McPhail, A. J. Chem. Soc., Chem.
Commun. 1986, 1390-1391. Gosselink, J. W.; Bulthuis, H.; Van Koten,
G. J. Chem. Soc., Dalton Trans. 1981, 1342-1348. Wackett, L. P.; Honek,
J. F.; Begley, T. P.; Shames, S. L.; Niederhoffer, E. C.; Hausinger, R. P.;
Orme-Johnson, W. H.; Walsh, C. T. In The Bioinorganic Chemistry of
Nickel; Lancaster, J. R., Jr., Ed.; VCH Publishers: New York, 1988. Jones,
W. D.; Dong, L. J. Am. Chem. Soc. 1991, 113, 559-564. Kuniyasu, H.;
Ogawa, A.; Miyazaki, S. I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem.
Soc. 1991, 113, 9796-9803. Wong, K. T.; Luh, T. Y. J. Chem. Soc., Chem.
Commun. 1992, 564-565. Deavenport, J. L.; Stubbs, R. T.; Powell, G. L.;
Sappenfield, E. L.; Mullica, D. F. Inorg. Chim. Acta 1994, 215, 191-198.
Kim, J. S.; Reibenspies, J. H.; Darensbourg, M. Y. Inorg. Chim. Acta 1996,
250, 283. Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei,
I. A. J. Am. Chem. Soc. 1998, 120, 9205-9219. Planas, J. G.; Hirano, M.;
Komiya, S. Chem. Lett. 1998, 123-124. Kuniyasu, H.; Ohtaka, A.;
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2375-2376.
10.1021/ol000231a CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

One solution to this problem is found in the unusual
efficacy of tetrahydrothiophene-based sulfonium salts as
partners in nickel- and palladium-catalyzed cross-coupling
with organozinc, -tin, and -boron reagents, where it was
convincingly demonstrated that tetrahydrothiophene does not
interfere with palladium or nickel catalysis (Scheme 1).3 This
acetamide (DMA) at 90-95 °C for 12-24 h, various boronic
acids underwent cross-coupling with thiol esters 1a-c to give
the desired ketones, which were isolated in 50-88% yields.5
Tetrahydrothiophene was detected by GC/MS, which sup-
ports the hypothesis of sulfur scavenging by alkylative
displacement. The lower yield entries in Table 1 are
Scheme 1. Sulfonium Salts in Cross-Coupling
Table 1. Ketone Synthesis Using Thiol Esters and Boronic
Acids
led to the notion of “alkylative activation” of refractory metal
thiolate intermediates as a way to weaken the metal-sulfur
bond and overcome the low thiophilicity of boron. Applica-
tion of the principle to thiol ester-boronic acid cross-
coupling is depicted in Scheme 2.
R1
R2
product yield (%)
1
2
3
4
5
6
7
8
phenyl
phenyl
phenyl
phenyl
methyl
methyl
phenyl
5
6
88b
57b
78b
76b
100c
70b
80b
50b
3-methoxyphenyl
2-formyl-4-methoxyphenyl
2-naphthyl
7
8
9
phenyl
2-naphthyl
10
11
12
Scheme 2. Thiol Ester Cross-Coupling Using Alkylative
undecyl phenyl
undecyl 3-methoxyphenyl
Activation
a 5-10% trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalla-
dium(II),4 4-6 equiv of K2CO3, 20-45% NaI, DMA, 90-95 °C, 12-24
h. b Isolated yield. c GC/MS with n-decane as internal standard.
associated with electron-rich boron reagents.6 The acetyl and
lauroyl thiol esters also underwent the coupling reaction in
good to excellent yields (entries 5-8). For comparison,
certain acid chlorides can, under specific conditions, be
coupled with organoboron reagents,7 and Fukuyama8 and
Terfort9 have reported low yields of ketone from the
palladium-catalyzed coupling of a thiol ester with a boronic
acid.
To demonstrate the concept of alkylative activation,
4-halo-n-butyl and normal thiol esters (Figure 1) were
Interestingly, in the absence of catalytic NaI the bromo-
butyl-derived thiol ester 1a gave only traces of benzophenone
when treated with phenylboronic acid in the presence of 8%
trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipal-
ladium(II) in DMA at 95 °C for 22 h. The addition of NaI
was undertaken in order to transform the alkyl bromide to
the alkyl iodide and facilitate the postulated intramolecular
Figure 1. Thiol esters.
(5) Typical Procedure: 2-Benzoyl-4-methoxybenzaldehyde, 7. A
solution of 6% trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipal-
ladium(II) (14 mg, 0.03 mmol), K2CO3 (313 mg, 2.27 mmol, 4.3 equiv),
33% NaI (26 mg, 0.17 mmol), 2-formyl-4-methoxyphenylboronic acid (113
mg, 0.62 mmol, 1.2 equiv) in dry and degassed dimethylacetamide (2 mL)
was treated with 142 mg (0.52 mmol, 1.0 equiv) of thiol ester 1a for 17 h
at 95 °C to give 98 mg (0.41 mmol, 78%) of 7 as white needles. Mp 82-
84 °C (Et2O-hexanes). Complete characterization data are listed in the
Supporting Information.
(6) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(7) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109-
3112. Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057-
3060.
prepared and studied as substrates for palladium-catalyzed
cross-coupling with boronic acids. In the presence of 5-10%
trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipal-
ladium(II),4 20-45% NaI, 4-6 equiv K2CO3, in dimethyl-
(3) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376-12377. Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org. Chem.
1999, 64, 2796-2804.
(4) Herrmann, W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 1844-1847. Beller, M.; Fisher, H.; Herrmann, W. A.; Ofele, K.;
Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
(8) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189-3192.
(9) Zeysing, B.; Gosch, C.; Terfort, A. Org. Lett. 2000, 2, 1843-1845.
3230
Org. Lett., Vol. 2, No. 20, 2000

S-alkylative activation. To support this hypothesis, the iodo
substrate PhCOS(CH2)3CH2I 2 easily coupled with phenyl-
boronic acid under the same conditions, but in the absence
of NaI, to give benzophenone in 56% yield. As a suitable
control experiment, only a trace of p-tolyl phenyl ketone was
formed when the simple thiol ester 4-MePhCOSMe, 3, was
treated with phenylboronic acid in the presence of NaI under
the standard reaction conditions.
Scheme 3. Anionic Acylpalladate as an Intermediate
Although less efficient than the intramolecular system,
intermolecular alkylative activation was also feasible. For
example, undecylCOSEt, 4, was transformed into undecyl
phenyl ketone (48%) when treated with PhB(OH)2 and 1,4-
dibromobutane in the presence of 6% trans-di(µ-acetato)-
bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), 30% NaI,
and 4.1 equiv of K2CO3 in DMF at 90 °C for 18 h. While
1,4-dibromobutane was a reasonably effective activator, other
alkylating agents were not (1,2-dibromoethane, 1-bromo-
hexane). In all cases employing intermolecular alkylative
activation, varying amounts of starting material were recov-
ered. Finally, among Pd(PPh3)4, Pd2(dba)3/tris(2-furylphos-
phine), and trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)-
benzyl]dipalladium(II), the latter was most efficient. In the
absence of catalyst, no product was formed.
conditions, thiol esters participated in Miyaura-Suzuki6
cross-coupling reactions with boronic acids to give ketones.
Intramolecular palladium-sulfur alkylative activation was
more efficient than the intermolecular variant.
Acknowledgment. The National Cancer Institute, DHHS
supported this investigation through Grant CA40157. We
thank Dr. Paul Reider of Merck Pharmaceutical Co. and Dr.
Gary Allred of Frontier Scientific, Inc. for their interest in
and support of this work.
The mechanism of this cross-coupling is presumed to
follow the pathway depicted above in Scheme 2. One role
of NaI is therefore to catalytically generate the alkyl iodide
from the alkyl bromide; in addition, iodide might ligate the
palladium and generate an anionic acylpalladate providing
increased electron density for the alkylative activation step
(Scheme 3). Although no evidence was obtained for genera-
tion of an acyl iodide or a highly reactive acyl sulfonium
salt prior to oxidative addition, these intermediates cannot
be ruled out.10
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL000231A
(10) Minato, H.; Miura, T.; Kobayashi, M. Chem. Lett. 1977, 609-614.
Oishi, T.; Mori, M.; Ban, Y. Chem. Pharm. Bull. 1971, 19, 1863-1870.
Chaves das Neves, H. J.; Machete, M. F. Tetrahedron Lett. 1977, 2, 187-
190. Minato, H.; Kodama, H.; Miura, T.; Kobayashi, M. Chem. Lett. 1977,
413-416. Minato, H.; Takeda, K.; Miura, T.; Kobayashi, M. Chem. Lett.
1977, 1095-1098.
In conclusion, the possibility of “alkylative activation” of
a palladium thiolate intermediate under catalytic carbon-
carbon bond-forming conditions was elucidated. Using these
Org. Lett., Vol. 2, No. 20, 2000
3231