Sulfonium Salts. Participants par Excellence in Metal-Catalyzed Carbon-Carbon Bond-Forming Reactions

Full text of DOI:10.1021/ja9726926

12376
J. Am. Chem. Soc. 1997, 119, 12376-12377
Table 1. Metal-Catalyzed Cross-Coupling with
Tetramethylenesulfonium Salts
Sulfonium Salts. Participants par Excellence in
Metal-Catalyzed Carbon-Carbon Bond-Forming
Reactions
Jiri Srogl, Gary D. Allred, and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center
Emory UniVersity
1515 Pierce DriVe, Atlanta, Georgia 30322
ReceiVed August 4, 1997
During the past decade, novel biological roles have been
identified for metalloenzyme-induced transformations at the
carbon-sulfur bond of biomolecules. Since metal-mediated
rupture of a carbon-sulfur bond is a key step in a number of
these processes,1-3 new and synthetically useful transformations
of organosulfur compounds mediated by metals might be
discovered by following nature’s example.4 Consider, for
example, the sulfonium salt.5,6 Although certain “onium”
reagents7,8 have been used in transition metal-mediated cross-
coupling reactions,9-14 it is surprising, given their biological
relevance,15 that sulfonium salts have been neglected in the
search for useful partners in this very powerful metal-catalyzed
process.16
Sulfonium salts possess unique attributes that set them apart
from other cross-coupling agents. Typically they are crystalline
solids with excellent shelf-lives, they are easily and economi-
cally prepared by a variety of procedures, and they may well
be superior to iodides or triflates in various applications. With
appropriate non-nucleophilic counterions (PF6, BF4, ClO417),
they possess good solubility and stability in both aprotic and
protic solvents. As synthetically versatile cationic cross-
coupling reactants, they offer a reactivity advantage through
participation in attractive Coulombic interactions with approach-
ing nucleophiles, and although cationic, sulfonium salts can
coordinate to (and be activated by) a metal catalyst through the
-
-
a ClO4 as counterion; all others were PF6
.
b Catalysts. A: 0.2%
generated in situ from Pd2dba3/8 trifurylphosphine. B: 0.1% catalyst
generated in situ from Pd2dba3/8 trifurylphosphine with copper(I)
diphenylphosphinate. C: 0.4-0.5% Pd(dppf)Cl2, excess K2CO3. D:
0.9% Pd(PPh3)4. E: Ni(dppf)Cl2. F: 4% Pd(dppf)Cl2, 1 equiv of freshly
ground K2CO3‚H2O. c GLC yield.
* Corresponding author. Phone: (404) 727-6604. FAX: (404) 727-0845.
E-mail: CHEMLL1@emory.edu.
nonbonding pair of electrons on sulfur.18,19 These attractive
features and the biological relevance of metal-mediated carbon-
sulfur bond cleavage led to the current study, documented herein,
which revealed the synthetic power of sulfonium salts in metal-
catalyzed cross-coupling reactions (see Table 1).
(1) Hausinger, R. P. In Biochemistry of Nickel; Plenum Press: New York,
1993; p 147.
(2) Ferry, J. G. Annu. ReV. Microbiol. 1995, 49, 305.
(3) Ragsdale, S. W.; Kumar, M. Chem. ReV. 1996, 96, 2515.
(4) Metal-catalyzed cross-coupling between Grignard reagents and aryl
and alkenyl sulfides is known: Fiandanese, V., Marchese, G., Naso, F.
and Ronzini, L. J. Chem. Soc., Chem. Commun. 1982, 647. Wenkert, E.,
Leftin, M. and Michelotti, E. L. J. Chem. Soc., Chem. Commun. 1984, 617.
Okamura, H., Miura, M. and Takei, H. Tetrahedron Lett. 1979, 43. In
addition, Luh and co-workers have extensively studied the nickel-catalyzed
cross-coupling of Grignard reagents with various dithiane derivatives: Luh,
T. Y. Acc. Chem. Res. 1991, 24, 257.
A wide variety of tetramethylenesulfonium salts were easily
prepared (Scheme 1). Various benzylic and heterobenzylic
sulfonium salts (either PF6- or ClO4-) were generated from the
corresponding alcohols or halides and tetrahydrothiophene, while
aromatic and heteroaromatic thiols were readily converted into
tetramethylenesulfonium salts by reaction with Et3N/1,4-di-
bromobutane in methyl tert-butyl ether or diethyl ether followed
by counterion exchange with NH4PF6 in acetone.20 Although
few alkenylsulfonium salts are known,5,6 three representative
alkenylsulfonium salts were prepared for this study (4, 5, and
6) from alkenes upon reaction with Br2/tetrahydrothiophene
(THT) followed by elimination of HBr and counterion exchange
(see Scheme 1).21-24 With optimization, good synthetic po-
tential should result from this stereocontrolled synthesis of
(5) The Chemistry of the Sulphonium Group. Part 1; Stirling, C. J. M.,
Ed.; John Wiley & Sons: New York, 1981; Vol. 1, p 385.
(6) The Chemistry of the Sulphonium Group. Part 2; Stirling, C. J. M.,
Ed.; John Wiley & Sons: New York, 1981; Vol. 2, p 847.
(7) Bumagin, N. A.; Sukhomlinova, L. I.; Igushkina, S. O.; Banchikov,
A. N.; Tolstaya, T. P.; Beletskaya, I. P. Bull. Russ. Acad. Sci. Ch-Engl. Tr.
1992, 41, 2128.
(8) Moriarty, R. M.; Epa, W. R. Tetrahedron Lett. 1992, 33, 4095.
(9) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
Jpn. 1976, 49, 1958.
(10) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340.
(11) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(12) Hatanaka, Y.; Hiyama, T. SynLett 1991, 845.
(18) Taube, H.; Stein, C. A. J. Am. Chem. Soc. 1978, 100, 336.
(19) Adams, R. D.; Blankenship, C.; Segmu¨ller, B. E.; Shiralian, M. J.
Am. Chem. Soc. 1983, 105, 4319.
(13) Mitchell, T. N. Synthesis 1992, 803.
(14) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(15) S-Adenosylmethionine, nature’s premier methylating agent, is a
sulfonium salt that acts as an alkylating agent for numerous biological
molecules, and it is responsible for C-alkylations (The Biochemistry of
Adenosylmethionine; Salvatore, F., Borek, E., Zappia, V., Williams-Ashman,
H. G., Schlenk, F., Eds.; Columbia University Press: New York, 1977).
(16) Gendreau, Y.; Normant, J. F.; Villieras, J. J. Organomet. Chem.
1977, 142, 1.
(20) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H. Tetrahedron Lett.
1994, 35, 8659.
(21) Doering, W. v. E.; Schreiber, K. C. J. Am. Chem. Soc. 1955, 77,
514.
(22) Caserio, M. C.; Pratt, R. E.; Holland, R. J. J. Am. Chem. Soc. 1966,
88, 5747.
(23) Batty, J. W.; Howes, P. D.; Stirling, C. J. M. J. Chem. Soc., Perkin
Trans. 1 1973, 59.
(17) Sulfonium salts possessing perchlorate counterions are easily and
economically prepared by substituting NaClO4 for NaPF6 or NH4PF6 in
the experimental procedures described in the Supporting Information.
(24) Chow, Y. L.; Bakker, B. H.; Iwai, K. J. Chem. Soc., Chem. Commun.
1980, 521.
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Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 50, 1997 12377
Scheme 1
benzylic sulfonium salts also participated in cross-coupling
reactions with aryl- and heteroarylboronic acids (Table 1, entries
9-13); however, the use of K2CO3 in these reactions required
an empirical match of substrate with solvent in order to minimize
base-induced side reactions of the sulfonium salt (2,3-sigma-
tropic rearrangement of the sulfur ylide, nucleophilic opening
of the tetramethylenesulfonium ring). (5) Of the few sulfonium
salt/organozinc cross-coupling reactions attempted to date, the
examples in Table 1, entries 14 and 22, suggest that this system
will also prove useful, in particular in other benzylic cross-
coupling reactions.
Aryl and heteroarylsulfonium salts also underwent efficient
palladium-catalyzed cross-coupling reactions (Table 1, entries
15-19). However, in contrast to the benzylic and hetero-
benzylic substrates just described, where both organotin and
-boron reagents were useful cross-coupling partners, boronic
acids were noticeably superior to their organostannane counter-
parts in metal-catalyzed cross-coupling reactions with aryl- and
heteroarylsulfonium salts. As before, the use of K2CO3 with
the boronic acid reactants required an empirical match with
solvent in order to achieve maximum efficiency of the reaction.
Three alkenylsulfonium salts have been studied as cross-
coupling reaction partners (Table 1, entries 20-25). All three
reactions of the S-R-styrylsulfonium salt 4 proceeded unevent-
fully (entries 20-22), and the sulfonium salt 5, bearing a (Z)-
S-(4-octen-4-yl) residue (generated stereospecifically from (E)-
4-octene), participated in efficient and stereospecific cross-
coupling reactions with 3-methoxyphenyl- and 2-thienylboronic
acid (entries 23 and 24). However, a single attempt to induce
a similar cross-coupling of the isomeric sulfonium salt 6
(prepared stereospecifically from (Z)-4-octene) failed (entry 25),
perhaps a consequence of the greater steric demand of this
system on oxidative addition. Metal catalysts with supporting
ligand systems of lower steric requirements will be explored as
a means of overcoming this current limitation.
In conclusion, tetramethylenesulfonium salts are easily pre-
pared and are effective participants in palladium- and nickel-
catalyzed cross-coupling reactions with organoboron, -tin, and
-zinc reagents under mild conditions. Furthermore, stable
sulfonium salts can be prepared and used in cross-coupling
reactions from those substrates for which the corresponding
halide or triflate would be unstable (various benzylic and
heterobenzylic systems). It is notable that efficient palladium-
and nickel-catalyzed processes occur even though tetrahydro-
thiophene is generated as a stoichiometric byproduct of the
cross-coupling reaction, suggesting that other metal-catalyzed
reactions of sulfonium salts are worth investigating (Heck
reactions, carbonylations, allylic cross-couplings).
alkenylsulfonium salts from geometrically pure alkenes by an
anti addition-anti elimination sequence.
The sulfonium salts participated in efficient cross-coupling
with a variety of organotin and -boron reagents (Pd-catalyzed)
and organozinc reagents (Ni-catalyzed) (Table 1).25 Attention
is drawn to a number of special features of these cross-coupling
reactions. (1) Of particular note is the observation that a wide
range of benzylic and some heterobenzylic sulfonium salts are
effective participants in cross-coupling reactions under mild
conditions (Table 1, entries 1-14). This extends the scope of
the cross-coupling protocol to a historically problematic, but
significant, class of substrates.26-29 (2) Very low levels of
palladium catalyst (0.01-0.5% Pd2dba3/8 TFP; dba ) di-
benzylideneacetone, TFP ) tri-2-furylphosphine) are required
to support acceptable rates of benzylic and heterobenzylic
sulfonium/organostannane cross-coupling in ethanol at 42 °C
(entries 1-8). (3) The efficiency of these organostannane cross-
couplings was significantly improved by the use of Ph2P(O)O-
n-Bu4N+ as a “n-Bu3Sn” scavenger.30 (4) Benzylic and hetero-
(25) Representative Procedure. 2-(4-Fluorobenzyl)thiophene. NH4PF6
(20.3 g, 124.5 mmol) in 50 mL of acetone was added to 4-fluorobenzyl
chloride (10.0 g, 69.17 mmol) and tetrahydrothiophene (18.29 g, 207.5
mmol) in acetone (10 mL). After the solution was stirred for 16 h at 35 °C,
the precipitated NH4Cl was removed and washed with acetone. Evaporation
of solvents and recrystallization of the residue from minimal acetone and
Et2O gave S-(4-fluorobenzyl)tetramethylenesulfonium hexafluorophosphate
as colorless crystals (15.71 g, 66%): mp 118-120 °C. See the Supporting
Information for characterization details. Next, n-BuLi (2.19 mmol, 1.14
mL of 2.5 M in hexanes) was added by syringe to thiophene (0.19 g, 2.22
mmol) in THF (7 mL) at 0 °C. After the solution was stirred for 15 min,
ZnCl2 (2.22 mmol, 2.22 mL of 1.0 M in ether) was added, and the mixture
was warmed to room temperature. After 10 min, Ni(dppf)Cl2 (2%, 0.02 g,
0.030 mmol; dppf ) (diphenylphosphino)ferrocene) and S-(4-fluorobenzyl)-
tetramethylenesulfonium hexafluorophosphate (0.506 g, 1.48 mmol) were
added. The mixture was stirred at room temperature for 6 h, then diluted
with ether (100 mL), and washed with water (2 × 100 mL) and brine (100
mL). The organic layer was dried over Na2SO4, solvents were removed,
and the crude product was purified by chromatography (Chromatotron, 4
mm SiO2 rotor, 100% hexanes) to give 0.212 g (75%) of 2-(4-fluorobenzyl)-
thiophene as a colorless oil (Stoner, E. J.; Cothron, D. A.; Balmer, M. K.;
Roden, B. A. Tetrahedron 1995, 51, 11043).
(26) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992.
(27) Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 2865.
(28) Vanasselt, R.; Elsevier, C. J. Organometallics 1994, 13, 1972.
(29) Lipshutz, B. H.; Bulow, G.; Lowe, R. F.; Stevens, K. L. Tetrahedron
1996, 52, 7265.
(30) Certain counterions facilitate the copper-mediated Stille cross-
coupling reaction (Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996,
118, 2748). The observation that n-Bu3SnOP(O)Ph2 precipitates from
concentrated solutions led to the use of Ph2P(O)O- in the current study.
Acknowledgment. This investigation was supported by Grant No.
CA40157, awarded by the National Cancer Institute, DHHS, and by
partial funding from Bristol-Myers Squibb. We acknowledge the use
of a VG 70-S mass spectrometer purchased through funding from the
National Institutes of Health, Grant S10-RR-02478. This paper is
dedicated to Professor Albert Padwa, colleague and confidant, on the
occasion of his recent birthday.
Supporting Information Available: A complete description of the
synthesis and characterization of all compounds in the paper (22 pages).
See any current masthead page for ordering and Internet access
instructions.
JA9726926