Efficient Pd-catalyzed heterobenzylic cross-coupling using sulfonium salts as substrates and (PhO)3P as a supporting ligand

Article abstract of DOI:10.1021/jo982250s

S-(2-Furanylmethyl)tetramethylenesulfonium hexafluorophosphate, S-(2-thienylmethyl)tetramethylenesulfonium hexafluorophosphate, S-(3-thienylmethyl)tetramethylenesulfonium hexafluorophosphate, and S-(N-tert-butoxycarbonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluorophosphate have been conveniently prepared from the corresponding alcohols. These stable heterobenzylic sulfonium salts participate in palladium-catalyzed Stille cross-couplings with organostannanes. All but the last mentioned sulfonium salt are also active participants in palladium-catalyzed cross-coupling reactions with boronic acids and organozinc halides. Because the heterobenzylic cross-coupling reactants are potent alkylating agents, they scavenge the typical phosphines and arsines that otherwise could be used to stabilize the palladium catalyst over extended reaction times. This problem was overcome by the use of (PhO)₃P as a unique supporting ligand for the palladium-catalyzed cross-coupling of heterobenzylic sulfonium salts.

Full text of DOI:10.1021/jo982250s

2796
J . Org. Chem. 1999, 64, 2796-2804
Efficien t P d -Ca ta lyzed Heter oben zylic Cr oss-Cou p lin g Usin g
Su lfon iu m Sa lts a s Su bstr a tes a n d (P h O)3P a s a Su p p or tin g
Liga n d
Shijie Zhang, Daniel Marshall, and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory University, 1515 Pierce Drive, Atlanta, Georgia 30322
Received November 12, 1998
S-(2-Furanylmethyl)tetramethylenesulfonium hexafluorophosphate, S-(2-thienylmethyl)tetra-
methylenesulfonium hexafluorophosphate, S-(3-thienylmethyl)tetramethylenesulfonium hexafluoro-
phosphate, and S-(N-tert-butoxycarbonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluoro-
phosphate have been conveniently prepared from the corresponding alcohols. These stable
heterobenzylic sulfonium salts participate in palladium-catalyzed Stille cross-couplings with
organostannanes. All but the last mentioned sulfonium salt are also active participants in palladium-
catalyzed cross-coupling reactions with boronic acids and organozinc halides. Because the
heterobenzylic cross-coupling reactants are potent alkylating agents, they scavenge the typical
phosphines and arsines that otherwise could be used to stabilize the palladium catalyst over
extended reaction times. This problem was overcome by the use of (PhO)3P as a unique supporting
ligand for the palladium-catalyzed cross-coupling of heterobenzylic sulfonium salts.
In tr od u ction
preparation of heterobenzylic sulfonium salts and the
development of a general Pd-catalyzed cross-coupling
protocol. The results of cross-coupling of sulfonium salts
with organotin, -boron, and -zinc nucleophiles are re-
ported herein.
The formation of carbon-carbon and carbon-hetero-
atom bonds from a remarkably broad range of participat-
ing reactants using palladium- and nickel-catalyzed
cross-coupling processes has led to widespread acceptance
of these powerful protocols by synthetic chemists.1-14
Nevertheless, there is no general procedure for the
carbon-carbon bond cross-coupling of benzylic and hetero-
benzylic reactants, two important classes of molecules.15-19
The recent discovery that benzylic sulfonium salts are
effective participants in Stille and Suzuki cross-coupling
reactions20 provided the impetus to investigate heter-
obenzylic cross-couplings. That effort led to a convenient
Resu lts a n d Discu ssion
P r ep a r a tion of Heter oben zylic Su lfon iu m Sa lts.
Many heterobenzylic halides are too unstable to serve
in transition metal-catalyzed cross-couplings, and in
synthesis in general. For example, the published prepa-
ration of 2-(chloromethyl)furan contains the following
cautionary note: “This compound should always be stored
in solution (at -20 °C) because neat samples decompose
slowly, even at -20 °C, to give hydrogen chloride which
catalyzes polymerization of the furan ring with explosive
violence.”21 The isomeric 3-halomethylfuran darkens
within 15 min at room temperature and must be stored
in a freezer.
Stable benzylic sulfonium salts can be prepared from
the corresponding benzylic halides through nucleophilic
substitution with tetrahydrothiophene (THT) followed by
counterion exchange.20 A practical extension of the same
procedure to the preparation of electron-rich heteroben-
zylic sulfonium salts is not feasible because of the
instability of many of these heterobenzylic halides.
However, ionization of the stable, electron-rich hetero-
benzylic alcohols, such as 2-furanylmethanol, 2-thienyl-
methanol, 3-thienylmethanol, and N-Boc-2-pyrrolylmeth-
anol, with aqueous HPF6 (60%) at 0 °C in the presence
of excess THT produced good yields of the corresponding
crystalline, stable sulfonium salts. Of these, only the
preparation of the pyrrolylmethanol-derived sulfonium
salt 2 was optimized. The results are summarized in
Figure 1. Therefore, in distinct contrast to the instability
of electron-rich heterobenzylic halides, the corresponding
* To whom correspondence should be addressed. Tel: (404) 727-
6604. Fax: (404) 727-0845. E-mail: CHEMLL1@emory.edu.
(1) Kharasch, M. S.; Fields, E. K. J . Am. Chem. Soc. 1941, 63, 2316.
(2) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
J pn. 1976, 49, 1958.
(3) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340.
(4) Beletskaya, I. P. J . Organomet. Chem. 1983, 250, 551.
(5) Farina, V.; Krishnamurthy, V.; Scott, W. J . In Organic Reactions;
Paquette, L., Ed.; J ohn Wiley & Sons: New York, 1997; Vol. 50; p 1.
(6) Hatanaka, Y.; Hiyama, T. SynLett 1991, 845.
(7) Mitchell, T. N. Synthesis 1992, 803.
(8) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(9) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 6054.
(10) Ahman, J .; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(11) Wolfe, J . P.; Ahman, J .; Sadighi, J . P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367.
(12) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120,
3694.
(13) Mann, G.; Hartwig, J . F.; Driver, f. M. S.; Fernandez-Rivas, C.
J . Am. Chem. Soc. 1998, 120, 827.
(14) Baranano, D.; Mann, G.; Hartwig, J . F. Curr. Org. Chem. 1997,
1, 287.
(15) Milstein, D.; Stille, J . K. J . Am. Chem. Soc. 1979, 101, 4992.
(16) Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21,
2865.
(17) Vanasselt, R.; Elsevier: C. J . Organometallics 1994, 13, 1972.
(18) Lipshutz, B. H.; Bulow, G.; Lowe, R. F.; Stevens, K. L. J . Am.
Chem. Soc. 1996, 118, 5512.
(19) Lipshutz, B. H.; Bulow, G.; Lowe, R. F.; Stevens, K. L.
Tetrahedron 1996, 52, 7265.
(20) Srogl, J .; Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc.
1997, 119, 12376.
(21) Divald, S.; Chun, M. C.; J oullie´, M. M. J . Org. Chem. 1976, 41,
2835.
10.1021/jo982250s CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/24/1999

Pd-Catalyzed Heterobenzylic Cross-Coupling
J . Org. Chem., Vol. 64, No. 8, 1999 2797
Ta ble 1. Liga n d Effects in th e Stille-Cou p lin g of
Su lfon iu m Sa lt 3
GLC yielda
entry
Pd source
L
Pd:L
(%)
F igu r e 1. Preparation of stable, electron-rich heterobenzylic
sulfonium salts.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(PhCN)2Cl2 none
46
10
39
29
78
0
(2,4,6-trimethoxyphenyl)3P 1:2
(2,4,6-trimethylphenyl)3P
(cyclohexyl)3P
(o-tolyl)3P
(p-tolyl)3P
Ph3P
(p-fluorophenyl)3P
(2-furanyl)3P
Ph3As
(C6F5)3P
(EtO)3P
(p-methylphenoxy)3P
(p-nitrophenoxy)3P
(PhO)3P
(PhO)3P
(PhO)3P
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:2
1:4
1:2
heterobenzylic sulfonium salts possessing nonnucleo-
philic counterions (PF6-, BF4-, ClO4-) can be easily
prepared and are air and moisture stable in the solid
state (Figure 1). This set the stage for evaluation of these
compounds as substrates in transition metal-catalyzed
cross-coupling reactions.
0
0
78
54
100
36
48
2
84
97
0
Cr oss-Cou plin g of Heter oben zylic Su lfon iu m Salts.
Exp lor a tor y Rea ction s. In nonprotic solvents (THF,
CH3CN, NMP, or toluene) with various palladium pre-
catalysts and supporting ligands, sluggish to extremely
slow cross-coupling reactions did proceed between het-
erobenzylic sulfonium salts 1-4 and 4-MeC6H5SnBu3, in
most cases giving only very low yields of the cross-
coupling products. Reaction conditions previously opti-
mized for the Stille cross-coupling of benzylic sulfonium
salts (1% Pd2(dba)3, 4% tris(2-furanyl)phosphine, 1 equiv
of Bu4NOP(O)Ph2 in EtOH at room temperature)20 were
effective only for 3, the heterobenzylic sulfonium salts
displaying greatest stability in solution.
Pd2(dba)3
(PhO)3P
93
a
All GLC yields were measured using 1,3,5-trimethoxybenzene
as an internal reference.
cludes the use of typical phosphines and arsines that are
required to stabilize the catalyst over extended reaction
times.
Ca ta lyst System Develop m en t a n d Ap p lica tion to
Or ga n osta n n a n e Cou p lin g. If the above analysis is
correct, then the key factor in developing a general
system for the cross-coupling of benzylic and heteroben-
zylic reactants is the discovery of an effective supporting
ligand for palladium that is not alkylated by heteroben-
zylic or benzylic sulfonium salts or halides. To that effect,
a variety of metal precatalysts and supporting ligands
with widely different steric and electronic character were
screened using the Stille cross-coupling model system
shown in Table 1. In the reaction of S-(2-thienylmethyl)-
tetramethylenesulfonium hexafluorophosphate (3) with
p-tolyltri-n-butylstannane (Table 1), the weak donors26
(C6F5)3P (entry 11) and (PhO)3P (entry 15) gave excellent
yields of the coupling product 5 within 24 h, while the
very weak donor tri(4-nitrophenyl) phosphite (entry 14)
was ineffective as a supporting ligand. The metal-to-
ligand ratio was a critical reaction parameter for this
specific cross-coupling. A dramatic difference was noted
between the use of 4.0 equiv of (PhO)3P per Pd (entry
17), which completely shut down the coupling reaction,
and 2.0 equiv of (PhO)3P per Pd (entry 16), which gave
the product in excellent yield. Although the coupling
product was produced in good yield by the use of 1 equiv
of (PhO)3P per Pd (entry 15), the ratio of 2.0 equiv of
(PhO)3P per Pd remained superior. A much earlier Pd
black formation was observed in the former situation,
which indicates a decreased catalyst stability at the lower
ligand-to-metal ratio. Clearly, a successful cross-coupling
reaction is dependent upon the competition between
product formation and catalyst and sulfonium salt deg-
radation, the rates of which are closely linked to the steric
It was apparent from the exploratory study that
conventional catalyst/ligand systems did not efficiently
catalyze a general cross-coupling process of heteroben-
zylic sulfonium salts with organometallic reagents. Con-
sideration of the factors necessary to support a successful
cross-coupling reaction provided insight into this failure.
A successful heterobenzylic cross-coupling reaction should
occur if an efficient rate of reaction can be sustained at
a temperature low enough to minimize interference from
both competitive decomposition of the thermally sensitive
heterobenzylic coupling partners and catalyst deactiva-
tion. Unfortunately, a lower reaction temperature re-
quires a longer reaction time, which necessarily increases
the opportunity for catalyst deactivation. Catalyst deac-
tivation has often been prevented by the use of strongly
bound supporting ligands, but supporting ligands that
bond strongly to the metal catalyst can also slow the rate
of cross-coupling by retarding transmetalation, which is
often the rate-limiting step of cross-coupling reactions.22,23
Of particular significance to the case of heterobenzylic
(and benzylic) cross-coupling, those ligands that are
effective at stabilizing palladium in varying oxidation
states (phosphines, arsines) are also effectively scavenged
from the reaction mixture by the heterobenzylic cross-
coupling reactants, since the latter are potent alkylating
agents!24,25 Herein lies the conundrum. The very reactiv-
ity of the heterobenzylic cross-coupling reactants pre-
(22) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(23) Farina, V.; Roth, G. P. Tetrahedron Lett. 1991, 32, 4243.
(24) Flowers, W. T.; Freitas, A. M.; Holt, G.; Purkiss, S. C. J . Chem.
Soc., Perkin Trans. 1 1981, 1119.
(25) Kim, S.; Park, J . H.; Kim, Y. G.; Lee, J . M. J . Chem. Soc., Chem.
Commun. 1993, 1188.
(26) Rahman, M. M.; Liu, H. Y.; Eriks, K.; Giering, W. P. Organo-
metallics 1989, 8, 1.

2798 J . Org. Chem., Vol. 64, No. 8, 1999
Zhang et al.
Ta ble 2. Su r vey of Som e Cr oss-Cou p lin g Rea ction
P a r a m eter s
F igu r e 2.
P/H/Sa
and electronic nature and stoichiometry of the supporting
ligand. Given the sensitivity of the reaction system to
many factors, the formation of some cross-coupling
product in the absence of a strong supporting ligand for
palladium (i.e., with Pd(PhCN)2Cl2, as used in entry 1 of
Table 1) is not inconsistent with our underlying premise
and claims. Here, the absence of supporting ligands
allows a fast initial palladium-catalyzed cross-coupling
reaction to occur, but catalyst decomposition cannot be
prevented and the process is not efficient.
entry
additive
CuI ligand solvent
1
2
3
4
5
6
7
Ph2P(O)O-BnMe3N+
Ph2P(O)O-BnMe3N+
Ph2P(O)O-BnMe3N+
Ph2P(O)O-BnMe3N+
none
X
X
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
THF
NMP
THF
NMP
NMP
NMP
NMP
0/100/0
94/6/0
30/11/59
55/23/22
0/100/0
9/24/66
20/18/62
X
X
X
LiCl
NaOAc
a
Ratios determined by GLC. P, H, S ) cross-coupling Product,
Homocoupling side product, Stannane substrate.
Note the addition of Ph2P(O)O-BnMe3N+ to these
reactions. Its use as a highly effective tri-n-butylstannyl
scavenger was derived from an earlier observation that
n-Bu3SnOP(O)Ph2 precipitated from concentrated solu-
tions and facilitated the copper-catalyzed Stille cross-
coupling reaction.27 The efficacy of Ph2P(O)O- in sluggish
Stille cross-coupling reactions has been confirmed in
other laboratories,28 suggesting its general consideration
as a useful co-reactant in Stille reactions.
Efficient Stille cross-coupling reactions with the
thiophene-derived sulfonium salts 3 and 4 did proceed
in the presence of the catalyst system 2% Pd(PhCN)2Cl2
and 2-4% (PhO)3P in THF at room temperature (Figure
2). Unfortunately, direct extension of the same conditions
to the corresponding 2-furanyl and N-Boc-pyrrolyl sys-
tems 1 and 2 was not feasible. Catalyst and substrate
decomposition predominated with these more sensitive
sulfonium salts. Since transmetalation is the rate-
determining step in most Stille cross-coupling reactions,
acceleration of this step could lead to an efficient and
general protocol for heterobenzylic cross-couplings, and
many means of accelerating the transmetalation step
have been disclosed.5,29 Polar, aprotic solvents such as
NMP increase the rate of cross-coupling by facilitating
the requisite loss of a ligand prior to the transmetalation
step.22 Also, the use of cocatalytic Cu(I) salts has been
shown to accelerate problematic Stille couplings.30-32
Used in conjunction, these two reaction parameters led
to a protocol in which sulfonium salts 1 and 2 cross-
coupled efficiently with organostannanes at room tem-
perature.
n-butyl)stannane led only to homocoupling of the orga-
nostannane (entry 1),33 while the same reaction in NMP
produced a 94:6 ratio of the cross-coupling product to the
organostannane homocoupling product (entry 2). In
either THF or NMP under similar conditions, but in the
absence of cocatalytic Cu(I), partial conversion of the
stannane to the desired product was observed along with
significant amounts of the homocoupling product (entries
3 and 4). Omission of the n-Bu3Sn scavenger Ph2P(O)O--
BnMe3N+ led exclusively to the stannane homocoupling
product (entry 5), while replacing Ph2P(O)O-BnMe3N+
with LiCl or NaOAc depressed the reaction rate and led
to mixtures of products (entries 6 and 7). Because of
decomposition of sulfonium salt 1 in solution, its fate was
not tracked for those cases where the yield of cross-
coupled product was low.
For optimum results, the study depicted in Table 2
indicated the use of NMP as solvent, Pd2(dba)3‚CHCl3/
(PhO)3P/CuI as the catalyst system, and Ph2P(O)O--
BnMe3N+ as a n-Bu3Sn scavenger. With this protocol, the
coupling of the most sensitive heterobenzylic sulfonium
salts, 1 and 2, with a variety of organostannanes was
investigated. The results are summarized in Table 3.
Under the optimized conditions, sulfonium salt 1 coupled
with p-tolyl(tri-n-butyl)stannane, 2-dibenzofuranyl(tri-n-
butyl)stannane, and 1-methylenecyclohexane(tri-n-bu-
tyl)stannane in yields of 97%, 92%, and 87%, respectively
(entries 1-3). However, when sulfonium salt 1 was
treated with (E)-2-styryltri-n-butylstannane under the
described conditions, considerable homocoupling of the
organostannane was observed. Since unhindered alk-
enylstannanes are inherently reactive in Stille coupling
reactions and also very sensitive to Cu(I)-induced
homocoupling,34-36 the cocatalyst CuI was omitted in this
To elucidate the impact of these two parameters in
heterobenzylic cross-coupling, a series of experiments was
conducted (Table 2). With 40 mol % of CuI as a cocatalyst
in THF, the reaction of sulfonium salt 1 with p-tolyl(tri-
(27) Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc. 1996, 118,
2748.
(28) Smith, A. B., III.; Ott, G. R. J . Am. Chem. Soc. 1998, 120, 3935.
(29) Farina, V.; Roth, G. P. In Advances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; J AI Press: Greenwich, CT, 1996; Vol. 5; p 1.
(30) Liebeskind, L. S.; Foster, B. F. J . Am. Chem. Soc. 1990, 112,
8612.
(33) The organostannane homocoupling product can form if there
is a slow transmetalation of the stannane to the palladium intermedi-
ate (formed by oxidative addition of the sulfonium salt to Pd). A related
process was described: Koo, S.; Liebeskind, L. S. J . Am. Chem. Soc.
1995, 117, 3389.
(34) Piers, E.; McEachern, E. J .; Gladstone, P. L. Can. J . Chem.
1997, 75, 694.
(31) Liebeskind, L. S.; Riesinger, S. W. J . Org. Chem. 1993, 58, 408.
(32) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905.
(35) Piers, E.; Wong, T. J . Org. Chem. 1993, 58, 3609.
(36) Zhang, S.; Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1997,
62, 2312.

Pd-Catalyzed Heterobenzylic Cross-Coupling
J . Org. Chem., Vol. 64, No. 8, 1999 2799
Ta ble 3. Stille-Cou p lin g of Heter oben zylic Su lfon iu m
Sa lts 1 a n d 2
variety of boronic acids (N-Boc-2-pyrroleboronic acid,
p-tolylboronic acid, (E)-2-styrylboronic acid, and 2-diben-
zofuranylboronic acid) were uniformly sluggish and gave
only low yields of the desired cross coupling products
(entries 5-7).
Or ga n ozin c R ea gen t Cou p lin gs. Cross-coupling
with organozinc reagents is a valuable procedure in
organic synthesis.3,37 The synthetic utility of sulfonium
salt/organozinc cross-coupling, demonstrated in an earlier
study,20 was explored using heterobenzylic sulfonium
salts 1-3 in the presence of 2% Pd(PhCN)2Cl2/2-4%
(PhO)3P in THF at room temperature. As depicted in
Table 5, the furan- and thiophene-derived sulfonium salts
participated in organozinc cross-coupling reactions in
acceptable yields (entries 3 and 4), but the problematic
pyrrole system 2 was ineffective (entry 2).
CuI Y
mol % yield (%)
entry
X
R
1
2
3
4
5
6
7
8
9
O
O
O
O
p-tolyl
40
40
40
0
40
40
40
40
0
97
92
87
95
64
60
72
78
49
97
2-dibenzofuranyl
methylenecyclohexan-1-yl
(E)-2-styryl
N-Boc p-tolyl
N-Boc 2-furanyl
N-Boc 2-dibenzofuranyl
N-Boc 2-methyl-1-propenyl
N-Boc (E)-2-styryl
N-Boc (E)-2-styryl
Con clu sion s
10
10
Starting from readily available and inexpensive ma-
terials, a one-step method for the preparation of heter-
obenzylic sulfonium salts (derived from furan, thiophene,
and pyrrole) has been developed. In contrast to their
corresponding halides (which are often too unstable to
be preparatively useful), these novel sulfonium salts
undergo palladium-catalyzed cross-coupling with a va-
riety of organostannanes, organoboronic acids, and or-
ganozinc halides. The organostannane coupling reactions
proved most general, giving good to excellent yields of
cross-coupling products from furan-, thiophene-, and
pyrrole-derived sulfonium salts. The furan- and thiophene-
based sulfonium salts participated in efficient cross-
coupling with organoboron and organozinc reagents, but
the pyrrole-based reactant gave only low yields of prod-
ucts.
The reactivity of heterobenzylic cross-coupling reac-
tants as potent alkylating agents precludes the use of
nucleophilic phosphines and arsines to stabilize the metal
catalyst over extended reaction times. However, triphenyl
phosphite, an effective supporting ligand that is not
readily alkylated, was uniquely effective as ligand in
heterobenzylic cross-couplings. It, or electronically simi-
lar supporting ligands, could prove generally useful in
other cross-coupling protocols where one of the substrates
is also a potent alkylating agent, such as a benzylic halide
and R-halocarbonyl.
specific case, and the cross-coupling product was obtained
in 95% yield (entry 4).
Under the optimized conditions, the pyrrole-derived
sulfonium salt 2 coupled with p-tolyltri-n-butylstannane
(64%), 2-furanyltri-n-butylstannane (60%), 2-dibenzo-
furanyltri-n-butylstannane (72%), and 2-methyl(1-tri-n-
butylstannyl)propene (78%) (entries 5-8). Once again,
the coupling reaction with (E)-2-styryltri-n-butylstannane
was sensitive to the amount of cocatalytic CuI. With 40
mol % of CuI, only reductive homocoupling of the stan-
nane was observed, but omission of the copper cocatalyst
gave only 49% yield of the product (entry 9). However,
in the presence of 10 mol % CuI cocatalyst, the desired
cross-coupling product was formed in 97% yield (entry
10)! These results suggest that fine-tuning of the Cu-
Pd ratio will be essential in maximizing the cross-
coupling/homo-coupling ratio for those organostannanes
prone to homocoupling.
Bor on ic Acid Cou p lin gs. The Suzuki cross-coupling
reaction of heterobenzylic sulfonium salts 1-3 with
p-tolylboronic acid was assayed under a variety of condi-
tions. Exploratory reactions were carried out with Pd-
(dppf)Cl2, a catalyst used successfully in previous cou-
plings of sulfonium salts with boronic acids.20 In the
presence of various bases (tetra-n-butylammonium fluo-
ride, K2CO3, K2CO3‚H2O, KH2PO4, K2HPO4) and solvents
(THF, N-methylpyrrolidone, CH3CN) this catalyst system
did not lead to a general protocol. However, by using 2%
(PhO)3P as a supporting ligand for 2% Pd(PhCN)2Cl2 in
THF at room temperature, a successful cross-coupling
reaction with sulfonium salt 3 was achieved in a model
reaction (p-tolylboronic acid with K2CO3, 80%, GLC
monitoring using 1,3,5-trimethoxybenzene as the internal
standard).
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under an
atmosphere of dry N2 or Ar in flame-dried glassware unless
otherwise noted. THF and CH3CN were dried over 4 Å
molecular sieves and titrated for water level prior to use with
a Fisher Coulomatic K-F titrater. Anhydrous DMF and NMP
were obtained from Aldrich in Sure-Seal bottles and titrated
for H2O prior to use. Purification by flash chromatography was
performed using 32-63 µm SiO2 with compressed air as a
source of positive pressure. Analytical thin-layer chromatog-
raphy (TLC) was carried out using Merck Kieselgel 60F254
plates with visualization by UV, phosphomolybdic acid, or
iodine stain. Uncalibrated melting points taken on a Thomas-
Hoover melting point apparatus in open capillary tubes were
obtained from recrystallized samples or samples that crystal-
lized during concentration of the chromatography eluents. In
the latter case, no solvents of recrystallization are indicated.
1H NMR spectra were recorded at 300 or 400 MHz and were
The generality of this ligand system in the cross-
coupling of heterobenzylic sulfonium salts with orga-
noboronic acids was then investigated (Table 4). Sulfo-
nium salt 3 reacted with arylboronic acids to give cross-
coupling products in good yields (entries 1 and 2).
Sulfonium salt 1 coupled with p-tolylboronic acid in
moderate yield (55%) and with (E)-styrylboronic acid in
good yield (84%) (entries 3 and 4). S-(3-Thiophenemeth-
yl)tetramethylenesulfonium hexafluorophosphate, 4, was
also active in this reaction, producing the desired product
in 84% yield (entry 8). The reaction of S-(N-Boc-2-
pyrrolemethyl)tetramethylenesulfonium salt 2 with a
(37) Negishi, E.; Ay, M.; Gulevich, Y. V.; Noda, Y. Tetrahedron Lett.
1993, 34, 1437.

2800 J . Org. Chem., Vol. 64, No. 8, 1999
Ta ble 4. Cr oss-Cou p lin g of Heter oben zylic Su lfon iu m Sa lts w ith Bor on ic Acid s
Zhang et al.
Ta ble 5. Cr oss-Cou p lin g of Heter oben zylic Su lfon iu m Sa lts w ith Or ga n ozin c Ha lid es
yield
(%)
entry
X
RZnCl
p-tolyl
p-tolyl
3-methoxyphenyl
4-chlorophenyl
heteroaryl-CH2R
1
2
3
4
O
(2-furanyl)CH2(p-tolyl)
67
0
62
53
N-Boc
(N-Boc-2-pyrrolyl)CH2(p-tolyl)
(2-thienyl)CH2(3-methoxyphenyl)
(2-thienyl)CH2(4-chlorophenyl)
S
S
internally referenced to CHCl3 (7.26 ppm), acetone (2.05 ppm),
or DMSO (2.49 ppm); 13C NMR spectra were recorded at 75
and 80 MHz and were referenced to CDCl3 (77.0 ppm) or
DMSO-d6 (39.7 ppm). Infrared (IR) spectroscopy was per-
furan,44 N-Boc-pyrrolyl-2-methanol,45 and 3-methoxyphenyl-
magnesium bromide46 were prepared according to the litera-
ture procedures.
P r ep a r a tion of Ben zyltr im eth yla m m on iu m Dip h e-
n ylp h osp h in a te. Benzyltrimethylammonium methoxide (45
wt % MeOH solution, 54.384 g, 120.0 mmol, 1.00 equiv) and
diphenylphosphinic acid (26.183 g, 120.0 mmol, 1.00 equiv)
were mixed together in 100 mL of MeOH, and the majority of
the solvent was removed under reduced pressure, producing
a suspended white solid. After being filtered, the mixture was
evaporated to give benzyltrimethylammonium diphenylphos-
phinate (39.090 g, 104.4 mmol, 87%) as a white microcrystal-
line solid: mp 86-89 °C dec; IR (KBr pellet, cm-1) 3385 (sb),
3047 (s), 3016 (s), 2197 (w), 1961 (w), 1905 (w), 1818 (w), 1767
(w); 1H NMR ((CD3)2SO, 400 MHz) δ 7.70-7.67 (m, 4H), 7.55-
7.45 (m, 5H), 7.26 (bs, 6H), 4.59 (s, 2H), 3.58 (bs, 5H, H2O),
3.03 (s, 9H); 13C NMR ((CD3)2SO, 80.0 MHz) δ 132.9, 131.2 (d,
J ) 6.7 Hz 39P-13C coupling), 130.2, 128.8, 128.7, 128.5, 127.4,
127.2, 67.6, 51.6. Anal. Calcd for C22H26NO2P‚2.5H2O: C,
64.06; H, 7.58; N, 3.40. Found: C, 64.31; H, 7.25; N, 3.14.
formed on a Nicolet 510 FT-IR with a resolution of 4 cm-1
.
Sta r tin g Ma ter ia ls. Benzyltrimethylammonium methox-
ide, diphenylphosphinic acid, 2-furanylmethanol, 2-thiophe-
nylmethanol, 3-thiophenylmethanol, 3-furanylmethanol, 2-pyr-
rolecarboxaldehyde, tetrahydrothiophene, hexafluorophosphoric
acid, phenylboronic acid, p-tolylboronic acid, o-tolylboronic
acid, 2-tri-n-butylstannanylfuran, 4-methoxybenzyl chloride,
p-tolylmagnesium bromide (1 M in Et2O), 4-chlorophenylmag-
nesium bromide (1 M in Et2O), zinc chloride (1 M in THF),
tris(dibenzylideneacetone)dipalladium chloroform adduct, bis-
(benzonitrile)dichloropalladium(II), and all ligands were pur-
chased from Aldrich and used as received. 3-Methoxybenzene
boronic acid was purchased from Lancaster. 2-Dibenzofuran
boronic acid was graciously provided by Frontier Scientific.38
4-Chlorophenyltri-n-butylstannane,39 p-tolyltri-n-butylstan-
nane,40 (E)-â-styrylboronic acid,41 2-methyl-1-tri-n-butylstan-
nylpropene,42 (E)-â-tri-n-butylstannylstyrene,42 1-methylenecy-
clohexyl tri-n-butylstannane,43 2-tri-n-butylstannyldibenzo-
(43) Mascarenas, J . L.; Garcia, A. M.; Castedo, L.; Mourino, A.
Tetrahedron Lett. 1992, 33, 7589.
(44) Stang, P. J .; Tykwinski, R.; Zhdankin, V. V. J . Heterocycl. Chem.
1992, 29, 815.
(45) Davies, H. M. L.; Matasi, J . J .; Ahmed, G. J . Org. Chem. 1996,
61, 2305.
(46) Ireland, R. E.; Thaisrinongs, S.; Dussalt, P. H. J . Am. Chem.
Soc. 1988, 110, 5768.
(38) Frontier Scientific Inc., P.O. Box 31, Logan, UT 84323-0031.
(39) Farina, V. J . Org. Chem. 1991, 56, 4985.
(40) Saa, J . M.; Martorell, G. J . Org. Chem. 1993, 58, 1963.
(41) Brown, H. C.; Gupta, S. K. J . Am. Chem. Soc. 1972, 94, 4371.
(42) Labadie, J . W.; Stille, J . K. J . Am. Chem. Soc. 1983, 105, 6129.

Pd-Catalyzed Heterobenzylic Cross-Coupling
J . Org. Chem., Vol. 64, No. 8, 1999 2801
P r ep a r a tion of Heter oben zylic Su lfon iu m Sa lts 1-4.
S-(2-Fu r a n ylm eth yl)tetr a m eth ylen esu lfon iu m Hexa flu o-
r op h osp h a te, 1. Aqueous HPF6 (60% by weight, 12.160 g, 50.0
mmol, 1.0 equiv) was slowly added to tetrahydrothiophene
(4.410 g, 50.0 mmol, 1.0 equiv) in 30 mL of ether at 0 °C
(CAUTION: exothermic!). The mixture was then slowly
transferred to a solution of furfuryl alcohol (5.400 g, 55.0 mmol,
1.1 equiv) and tetrahydrothiophene (4.41 g, 50.0 mmol, 1.0
equiv) in 100 mL of ether at 0 °C. After 1 h, the precipitated
solids were collected by filtration. This solid was washed with
30 mL of toluene, 30 mL of hexane, and 30 mL of ether and
then dried under vacuum. S-(2-Furanylmethyl)tetramethyl-
enesulfonium hexafluorophosphate was obtained as an off-
white solid (7.760 g, 24.7 mmol, 49%): mp 93 °C dec; 1H NMR
((CD3)2SO, 300 MHz) δ 7.83 (d, J ) 0.9 Hz, 1 H), 6.78 (d, J )
3.0 Hz, 1 H), 6.57 (m, 1 H), 4.72 (s, 2 H), 3.52 (pent, J ) 6.6
40.0, 28.1. Anal. Calcd for C9H13S2PF6: C, 32.73; H, 3.97; S,
19.42; P, 9.38; F, 34.51. Found: C, 33.82; H, 3.96; S, 19.32.
Liga n d Effects on th e Cr oss-Cou p lin g of Su lfon iu m
Sa lt 3 a n d p-tolyl(tr i-n -bu tyl)sta n n a n e (Ta ble 1 Stu d y).
S-(2-Thienylmethyl)tetramethylenesulfonium hexafluorophos-
phate (0.165 g, 0.500 mmol, 1.00 equiv) and benzyltrimethy-
lammonium diphenylphosphinate (0.202 g, 0.538 mmol, 1.08
equiv) were placed in an oven-dried 50 mL flask containing
10 mL of degassed THF and p-tolyltri-n-butylstannane (0.210
g, 0.525 mmol, 1.05 equiv). To this was added (PhCN)2PdCl2
(0.004 g, 0.010 mmol, 0.020 equiv) and ligand (0.020 mmol,
0.040 equiv). This mixture was stirred under N2 at room
temperature for 24 h. To the crude reaction mixture was added
0.50 mL of a 0.25 M solution of 1,3,5-trimethoxybenzene (0.125
mmol, 0.25 equiv) in THF as an internal standard, and the
reaction mixtures were analyzed by GLC (Hewlett-Packard
5890; column: J & W Scientific #128-5022; program: initial
temperature ) 80 °C static for 8 min, ramp 9 °C/min for 20
min to 260 °C).
4-Ch lor op h en yl-2-th ien ylm eth a n e. S-(2-Thienylmethyl)-
tetramethylenesulfonium hexafluorophosphate 3 (0.660 g, 2.00
mmol, 1.00 equiv) and benzyltrimethylammonium diphe-
nylphosphinate (0.81 g, 0.040 mmol, 1.10 equiv) were placed
in an oven-dried 25 mL flask containing 4-chlorophenyl(tri-
n-butyl)stannane (0.840 g, 2.100 mmol, 1.05 equiv) in 10 mL
of degassed THF. To this were added (PhCN)2PdCl2 (0.015 g,
0.039 mmol, 0.020 equiv) and (PhO)3P (10.1 µL, 0.012 g, 0.039
mmol, 0.020 equiv). This mixture was stirred under Ar at room
temperature for 36 h and then transferred to a flask containing
20 mL of EtOAc and 20 mL of deionized H2O. While the
biphasic mixture was being stirred excess KF was added. After
20 min, the mixture was filtered through a plug of Celite and
placed in a 60 mL separatory funnel. The organic phase was
washed with 20 mL of NaHCO3, 3 × 20 mL of H2O, and 1 ×
20 mL of brine. The organic phase was dried with MgSO4,
concentrated, and purified by SiO2 column chromatography
with a gradient of 0-2% Et2O/hexane to provide 4-chlorophe-
nyl-2-thienylmethane as a colorless oil (0.321 g, 1.54 mmol,
77%): 1H NMR (CDCl3, 300 MHz) δ 7.18-7.33 (m, 5 H), 6.97
(dd, J ) 5.1, 3.6 Hz, 1 H), 6.83 (dd, J ) 3.3, 0.9 Hz, 1 H), 4.15
(s, 2 H). 13C NMR (CDCl3, 75.5 MHz) δ 143.3, 138.8, 132.2,
129.9, 128.6, 126.8, 125.3, 124.1, 35.3. Anal. Calcd for C11H9-
ClS: C, 63.30; H, 4.35; Cl, 16.99; S, 15.36. Found: C, 63.54;
H, 4.48; Cl, 16.81; S, 15.17.
2-Diben zofu r a n yl-2-th ien ylm eth a n e. Following the pre-
viously described procedure, S-(2-thienylmethyl)tetramethyl-
enesulfonium hexafluorophosphate 3 (0.100 g, 0.300 mmol,
1.20 equiv), 2-tri-n-butylstannyldibenzofuran (0.114 g, 0.250
mmol, 1.00 equiv), benzyltrimethylammonium diphenylphos-
phinate (0.108 g, 0.300 mmol, 1.20 equiv), (PhCN)2PdCl2 (0.002
g, 0.005 mmol, 0.020 equiv), and (PhO)3P (1.3 µL, 0.005 mmol,
0.020 equiv) gave, after SiO2 chromatography with a gradient
of 0-5% Et2O/hexane, 2-dibenzofuranyl-2-thienylmethane as
an oil (0.040 g, 0.172 mmol, 61%): 1H NMR (CDCl3, 400 MHz)
δ 7.94 (ddd, J ) 7.6, 0.4, 0.4 Hz, 1 H), 7.83 (dd, J ) 6.0, 2.0
Hz, 1 H), 7.59 (dd, J ) 8.4, 0.8 Hz, 1 H), 7.45 (ddd, J ) 8.4,
8.4, 0.8 Hz, 1 H), 7.36-7.25 (m, 3 H), 7.15 (dd, J ) 4.8, 1.2
Hz, 1 H), 6.84 (m, 2 H), 4.53 (s, 2 H). 13C NMR (CDCl3, 80.0
MHz) δ 156.3, 154.4, 142.7, 127.6, 127.3, 127.1, 125.8, 124.7,
124.6, 124.3, 124.2, 123.1, 122.9, 120.9, 119.2, 112.0, 30.0.
2-Diben zofu r a n yl-3-th ien ylm eth a n e. Following the pre-
viously described procedure, S-(3-thienylmethyl)tetramethyl-
enesulfonium hexafluorophosphate 4 (0.100 g, 0.300 mmol,
1.20 equiv), 2-tri-n-butylstannyldibenzofuran (0.114 g, 0.250
mmol, 1.00 equiv), benzyltrimethylammonium diphenylphos-
phinate (0.108 g, 0.300 mmol, 1.20 equiv), (PhCN)2PdCl2 (0.002
g, 0.005 mmol, 0.020 equiv), and (PhO)3P (1.3 µL, 0.005 mmol,
0.020 equiv) gave, after SiO2 chromatography with a gradient
of 0-5% Et2O/hexane, 2-dibenzofuranyl-3-thienylmethane as
an oil (0.0643 g, 0.242 mmol, 97%): 1H NMR (CDCl3, 400 MHz)
δ 7.95 (ddd, J ) 7.6, 0.8, 0.4 Hz, 1 H), 7.83 (dd, J ) 7.2, 1.6
Hz, 1 H), 7.60-7.57 (m, 1 H), 7.47 (ddd, J ) 7.2, 7.2, 1.2 Hz,
1 H), 7.34 (ddd, J ) 7.6, 7.6, 1.2 Hz, 1 H), 7.30-7.23 (m, 3 H),
7.05-7.03 (m, 2 H), 4.35 (s, 2 H); 13C NMR (CDCl3, 80.0 MHz)
Hz, 2 H), 3.35 (pent, J ) 6.6 Hz, 2 H), 1.92-2.13 (m, 4 H); 13
C
NMR ((CD3)2SO, 75.5 MHz) δ 145.7, 142.8, 114.0, 111.7, 42.5,
38.2, 28.1. Anal. Calcd for C9H13OSPF6: C, 34.40; H, 4.17; O,
5.09; S, 10.20; P, 9.86; F, 36.28. Found: C, 34.51; H, 4.23; S,
10.32.
S -(N -t er t -Bu t oxyca r b on yl-2-p yr r olylm e t h yl)t e t r a -
m eth ylen esu lfon iu m Hexa flu or op h osp h a te, 2. By the
same procedure used for sulfonium salt 1, aqueous HPF6 (60%
by weight, 10.270 g, 42.25 mmol, 1.69 equiv) and tetrahy-
drothiophene (2.210 g, 25.00 mmol, 1.0 equiv) in 30 mL of ether
at 0 °C (CAUTION: exothermic!) were slowly transferred to
a mixture of N-tert-butoxycarbonyl-2-pyrrolemethanol (4.93 g,
25.00 mmol, 1.0 equiv) and tetrahydrothiophene (4.40 g, 50.00
mmol, 2.0 equiv) in 100 mL of ether at 0 °C. After 6 h, the
precipitated solids were collected by filtration, washed with
30 mL each of toluene, hexane, and ether, and then vacuum-
dried. S-(N-tert-Butoxycarbonyl-2-pyrrolylmethyl)tetrameth-
ylenesulfonium hexafluorophosphate was obtained as a light
yellow solid (7.8 g, 18.870 mmol, 90%): mp 103 °C dec; IR (KBr
1
pellet, cm-1) 1740 (s); H NMR ((CD3)2CO, 300 MHz) δ 7.46
(dd, J ) 3.3, 1.5 Hz, 1 H), 6.71-6.72 (m, 1 H), 6.27 (app t, J )
3.3 Hz, 1 H), 4.93 (s, 2 H), 3.63-3.79 (m, 4 H), 2.38-2.57 (m,
4 H), 1.65 (s, 9 H); 13C NMR ((CD3)2CO, 75.5 MHz) δ 151.2,
125.7, 122.4, 120.5, 111.9, 86.6, 44.2, 43.0, 29.5, 28.1. Anal.
Calcd for C14H22NSPF6O2: C, 40.68; H, 5.36; N, 3.39; S, 7.76;
P, 7.49; F, 27.58; O, 7.74. Found: C, 40.79; H, 5.42; N, 3.40;
S, 7.72.
S-(2-Th ien ylm eth yl)tetr am eth ylen esu lfon iu m Hexaflu -
or op h osp h a te, 3. To a 100 mL round-bottomed flask charged
with 2-thiophenemethanol (8.390 g, 73.50 mmol, 1.05 equiv)
and tetrahydrothiophene (7.41 g, 84.00 mmol, 1.20 equiv) in
100 mL of ether at 0 °C was added slowly aqueous HPF6 (60%,
17.03 g, 70.00 mmol, 1.00 equiv). The flask was removed from
the cooling bath and stirred for 2 h at room temperature. The
white solid that precipitated was collected by filtration, washed
with 20 mL each of toluene and ether, and then dried under
vacuum, giving 14.53 g (43.99 mmol, 63%) of S-(2-thienylm-
ethyl)tetramethylenesulfonium hexafluorophosphate: mp 147.0
°C dec; 1H NMR ((CD3)2SO, 300 MHz) δ 7.72 (d, J ) 5.1 Hz, 1
H), 7.40 (d, J ) 3.6 Hz, 1 H), 7.14 (dd, J ) 5.1, 3.6 Hz, 1 H),
4.85 (s, 2 H), 3.35-3.54 (m, 4 H), 2.11-2.20 (m, 4 H); 13C NMR
((CD3)2SO, 75.5 MHz) δ 131.4, 130.3, 129.7, 128.0, 42.6, 40.5,
28.2. Anal. Calcd for C9H13S2PF6: C, 32.73; H, 3.97; S, 19.42;
P, 9.38; F, 34.51. Found: C, 32.89; H, 3.89; S, 19.34.
S-(3-Th ien ylm eth yl)tetr am eth ylen esu lfon iu m Hexaflu -
or op h osp h a te, 4. By the same procedure used to prepare
sulfonium salt 3, 3-thiophenemethanol (5.99 g, 52.5 mmol, 1.05
equiv) and tetrahydrothiophene (5.29 g, 60.0 mmol, 1.20 equiv)
in 60 mL of ether at 0 °C was treated slowly with aqueous
HPF6 (60%, 12.16 g, 50.0 mmol, 1.00 equiv) at 0 °C. The flask
was removed from the cooling bath and stirred for 2 h at room
temperature. The precipitated white solid was collected by
filtration, washed with 20 mL each of toluene and ether, and
then dried under vacuum to give 7.4 g (22.4 mmol, 45%) of
S-(3-thienylmethyl)tetramethylenesulfonium hexafluorophos-
1
phate: mp 98-100 °C; H NMR ((CD3)2SO, 300 MHz) δ 7.83
(m, 1 H), 7.70 (dd, J ) 4.8, 3.0 Hz, 1 H), 7.27 (d, J ) 4.8 Hz,
1 H), 4.57 (s, 2 H), 3.33-3.52 (m, 4 H), 2.14 (br s, 4 H); 13C
NMR ((CD3)2SO, 75.5 MHz) δ 129.3, 128.5, 128.4, 128.3, 42.4,

2802 J . Org. Chem., Vol. 64, No. 8, 1999
Zhang et al.
δ 156.3, 154.7, 140.3, 128.8, 127.7, 127.3, 125.8, 124.9, 124.8,
124.3, 123.1, 122.9, 121.8, 120.9, 118.9, 112.0, 30.5.
112.0, 110.5, 106.8, 28.4. Anal. Calcd for C17H12O2: C, 82.24;
H, 4.87; O, 12.89. Found: C, 82.04; H, 4.95.
En tr y 3. (2-F u r a n yl)(1-m eth ylen ecycloh exyl)m eth a n e.
S-(2-Furanylmethyl) tetramethylenesulfonium hexafluoro-
phosphate 1 (0.056 g, 0.180 mmol, 1.20 equiv), 1-methylenecy-
clohexyl tri-n-butylstannane (0.062 g, 0.160 mmol), Pd2(dba)3‚
CHCl3 (0.007 g, 0.007 mmol, 0.04 equiv), (PhO)3P (10.0 µL,
0.038 mmol, 0.24 equiv), benzyltrimethylammonium diphe-
nylphosphinate (0.065 g, 0.18 mmol, 1.20 equiv), and CuI
(0.012 g, 0.042 mmol, 0.40 equiv) were reacted for 12 h as
described in entry 1, above. Chromatography with a gradient
of 0-2% Et2O/hexanes provided (2-furanyl)(1-methylenecyclo-
hexyl)methane as a colorless oil (0.0244 g, 0.1380 mmol,
87%): IR (neat, NaCl, cm-1) 2925 (s), 2833 (s), 1453 (m), 1375
Oth er Rea ction P a r a m eter s (Ta ble 2 Stu d y). A 10 mL
round-bottomed flask containing 2.0 mL of degassed dry
solvent under Ar was charged with Pd2(dba)3‚CHCl3 (0.007 g,
0.007 mmol, 0.04 equiv) and (PhO)3P (10.0 µL, 0.038 mmol,
0.24 equiv). The mixture was stirred until a yellow hue
developed. The additive indicated in Table 2 (1.1 equiv) and
40 mol % CuI (for entries 1, 2, and 5-7) were introduced into
the reaction flask, followed by the addition of S-(2-furanylm-
ethyl)tetramethylenesulfonium hexafluorophosphate 1 (0.0560
g, 0.1800 mmol, 1.200 equiv). p-Tolyl(tri-n-butyl)stannane
(0.060 g, 0.160 mmol 1.00 equiv) in 1.0 mL of solvent was
immediately added, and the reaction mixture was stirred at
ambient temperature for 20 h. A portion of the reaction
mixture was taken from the flask, partitioned between Et2O
and saturated NH4Cl, and the organic phase was analyzed by
GC-MS (Shimadzu GC-17A, Shimadzu MS-QP-5000; col-
umn: Restek XTI-5, 30 m, 0.25 mmID; program: initial
temperature ) 80 °C ramp at 18 °C/min to 260 °C, 260 °C
static for 10 min, ramp at 10 °C/min to 310 °C; flow rate 2.2
mL/min) to determine the ratio of products (corrections for
response factors were not applied).
1
(w), 1261 (w), 1090 (w), 1019 (w), 791 (m); H NMR (CDCl3,
400 MHz) δ 7.31 (br s, 1 H), 6.27 (app t, J ) 1.6 Hz, 1 H), 5.96
(d, J ) 2.8 Hz, 1 H), 5.26 (app t, J ) 4.0 Hz, 1 H), 3.34 (d, J
) 7.6 Hz, 2 H), 2.20-2.17 (m, 2 H), 2.12 (br s, 2 H), 1.57-1.53
(m, 6 H); 13C NMR (CDCl3, 80.0 MHz) δ 156.6, 143.2, 142.0,
116.9, 111.2, 105.7, 38.1, 30.8, 29.8, 28.8, 27.9, 27.2; HRMS
(EI) calcd for C12H12O 176.1201, found: 176.1194 (error 3.97
ppm).
En tr y 4. 2-F u r a n yl-2-E-styr ylm eth a n e. S-(2-Furanylm-
ethyl)tetramethylenesulfonium hexafluorophosphate (0.056 g,
0.180 mmol, 1.06 equiv), â-tri-n-butylstannylstyrene (E/ Z 89:
11 by GC-MS; 90:10 by NMR) (0.068 g, 0.170 mmol, 1.0 equiv),
Pd2(dba)3‚CHCl3 (0.007 g, 0.007 mmol, 0.04 equiv), (PhO)3P
(10.0 µL, 0.0380 mmol, 0.22 equiv), and benzyltrimethylam-
monium diphenylphosphinate (0.065 g, 0.180 mmol, 1.06
equiv) were reacted for 14 h at room temperature as described
in entry 1, above. Purification by SiO2 column chromatography
with a gradient of 0-5% Et2O/hexanes provided 2-furanyl-2-
E-styrylmethane (E/Z 88:12 by GC-MS) as a colorless oil
(0.028 g, 0.152 mmol, 95%): IR (neat, NaCl, cm-1) 1595 (m);
1H NMR (CDCl3, 400 MHz) δ 7.42 (d, J ) 7.6 Hz, 0.18 H),
7.35-7.12 (m, 5.82 H), 6.94 (dd, J ) 12.0, 2.8 Hz, 0.8 H), 6.67-
6.58 (m, 0.2 H), 6.47 (d, J ) 16.0 Hz, 0.92 H), 6.32-6.25 (m,
0.8 H), 6.05 (d, J ) 2.8 Hz, 0.88 H), 5.87-5.80 (m, 0.12 H),
3.63 (d, J ) 7.2 Hz, 0.24 H), 3.53 (d, J ) 6.8 Hz, 1.76 H); 13C
NMR (CDCl3, 80.0 MHz) δ 154.1, 141.6, 137.4, 132.2, 131.1,
129.4, 128.9, 128.7, 128.5, 127.8, 127.5, 127.1, 126.6, 126.4,
125.8, 110.5, 105.8, 105.5, 32.0, 27.9. Anal. Calcd for C12H12O:
C, 84.75; H, 6.57. Found: C, 84.52; H, 6.60.
Stille Cr oss-Cou p lin g of Heter oben zylic Su lfon iu m
Sa lts 1 a n d 2. Ta ble 3 Stu d y. En tr y 1. Rep r esen ta tive
Stille Cr oss-Cou p lin g P r oced u r e of Su lfon iu m Sa lts 1 or
2. (2-F u r a n yl)-4-tolylm eth a n e. A 10 mL round-bottomed
flask containing 2.0 mL of dry NMP under Ar was deoxygen-
ated four times with a freeze-thaw cycle and then charged
with Pd2(dba)3‚CHCl3 (0.007 g, 0.007 mmol, 0.04 equiv) and
(PhO)3P (10.0 µL, 0.038 mmol, 0.24 equiv). The mixture was
stirred until a yellow hue developed. Benzyltrimethylammo-
nium diphenylphosphinate (0.065 g, 0.180 mmol, 1.20 equiv)
and CuI (0.012 g, 0.042 mmol, 0.40 equiv) were added, and
then S-(2-furanylmethyl) tetramethylenesulfonium hexafluo-
rophosphate 1 (0.056 g, 0.180 mmol, 1.20 equiv) was intro-
duced. This was immediately followed by the addition of
p-tolyltri-n-butylstannane (0.060 g, 0.160 mmol 1.00 equiv) in
1.0 mL of NMP, which had been deoxygenated four times with
a freeze-thaw cycle. The reaction mixture was stirred at
ambient temperature for 12 h and then transferred to a flask
containing 20 mL of EtOAc and 10 mL of deionized H2O.
Excess KF was added while the biphasic mixture was being
stirred. After 20 min, the mixture was filtered through a plug
of Celite and placed in a 60 mL separatory funnel. The organic
phase was washed 20 mL of NaHCO3, 3 × 20 mL of H2O, and
1 × 20 mL of brine. The organic phase was dried with MgSO4,
concentrated, and purified by SiO2 chromatography with a
gradient of 0-5% Et2O/hexanes to provide 2-furanyl-4-tolyl-
methane as a colorless oil (0.027 g, 0.156 mmol, 97%): 1H NMR
(CDCl3, 300 MHz) δ 7.39 (app s, J ) Hz, 1 H), 7.20 (s, 4 H),
6.35 (dd, J ) 2.4, 1.8 Hz, 1 H), 6.07 (d, J ) 2.4 Hz, 1 H), 4.00
(s, 2 H), 2.41 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 154.8,
141.4, 135.9, 135.0, 129.1, 128.5, 110.2, 106.0, 34.0, 21.0.
HRMS (EI) calcd for C12H12O 172.0888, found 172.0882. Anal.
Calcd for C12H12O: C, 83.69; H, 7.02; O, 9.29. Found: C, 82.30;
H, 7.14.
En tr y 5. 2-(P yr r ole-1-ca r boxylic a cid ter t-bu tyl ester )-
4-tolylm eth a n e. S-(N-tert-Butoxycarbonyl-2-pyrrolylmethyl)-
tetramethylenesulfonium hexafluorophosphate (0.073 g, 0.180
mmol, 1.20 equiv), p-tolyltri-n-butylstannane (0.060 g, 0.160
mmol, 1.00 equiv), Pd2(dba)3‚CHCl3 (0.007 g, 0.007 mmol, 0.04
equiv), (PhO)3P (10.0 µL, 0.038 mmol, 0.24 equiv), benzyltri-
methylammonium diphenylphosphinate (0.065 g, 0.180 mmol,
1.20 equiv), and CuI (0.012 g, 0.063 mmol, 0.40 equiv) were
reacted for 12 h as described in entry 1, above. Purification
by SiO2 chromatography with a gradient of 0-5% Et2O/
hexanes provided 2-(pyrrole-1-carboxylic acid tert-butyl ester)-
4-tolylmethane as a colorless oil (0.028 g, 0.102 mmol, 64%):
1
IR (neat, NaCl, cm-1) 1737 (s); H NMR (CDCl3, 400 MHz) δ
7.24 (dd, J ) 3.2, 1.6 Hz, 1 H), 7.10 (d, J ) 8.0 Hz, 2 H), 7.06
(d, J ) 8.4 Hz, 2 H), 6.07 (app t, J ) 3.2 Hz, 1 H), 5.74 (dd, J
) 3.2, 1.2 Hz, 1 H), 4.17 (s, 2 H), 2.33 (s, 3 H), 1.52 (s, 9 H);
13C NMR (CDCl3, 80.0 MHz) δ 149.8, 136.8, 135.7, 135.0, 129.1,
129.0, 121.5, 113.1, 110.2, 83.7, 34.9, 28.2, 21.3. Anal. Calcd
for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; O, 11.79. Found:
C, 75.06; H, 7.83; N, 5.03.
E n t r y 2. 2-Dib en zofu r a n yl-2-fu r a n ylm et h a n e. S-(2-
Furanylmethyl)tetramethylenesulfonium hexafluorophosphate
1 (0.056 g, 0.180 mmol, 1.200 equiv), 2-tri-n-butylstannyldiben-
zofuran (0.073 g, 0.160 mmol, 1.00 equiv), Pd2(dba)3‚CHCl3
(0.007 g, 0.007 mmol, 0.040 equiv), (PhO)3P (10.0 µL, 0.038
mmol, 0.24 equiv), benzyltrimethylammonium diphenylphos-
phinate (0.065 g, 0.180 mmol, 1.20 equiv), and CuI (0.012 g,
0.042 mmol, 0.40 equiv) were reacted for 12 h as described in
entry 1, above. Chromatography with a gradient of 0-5% Et2O/
hexanes provided 2-dibenzofuranyl-2-furanylmethane as a
colorless oil (0.036 g, 0.147 mmol 92%): 1H NMR (CDCl3, 400
MHz) δ 7.96 (d, J ) 7.6 Hz, 1 H), 7.85 (app pent, J ) 4.0 Hz,
1 H), 7.60 (d, J ) 8.4 Hz, 1 H), 7.47 (ddd, J ) 7.2, 7.2, 1.2 Hz,
1 H), 7.37-7.33 (m, 2 H), 7.30 (d, J ) 5.2 Hz, 2 H), 6.32 (dd,
J ) 3.2, 1.2 Hz, 1 H), 6.11 (dd, J ) 3.2, 0.8 Hz, 1 H), 4.37 (s,
2 H); 13C NMR (CDCl3, 80.0 MHz) δ 156.3, 154.6, 153.5, 141.7,
127.7, 127.3, 124.7, 124.3, 123.1, 122.9, 122.4, 120.9, 119.2,
En tr y 6. 2-(P yr r ole-1-ca r boxylic a cid ter t-bu tyl ester )-
2-fu r a n ylm eth a n e. S-(N-tert-Butoxycarbonyl-2-pyrrolylmeth-
yl)tetramethylenesulfonium hexafluorophosphate (0.073 g,
0.180 mmol, 1.20 equiv), 2-tri-n-butylstannylfuran (57.1 g,
0.160 mmol, 1.00 equiv), Pd2(dba)3‚CHCl3 (0.007 g, 0.007 mmol,
0.04 equiv), (PhO)3P (10.0 µL, 0.038 mmol), benzyltrimethy-
lammonium diphenylphosphinate (0.065 g, 0.180 mmol, 1.20
equiv), and CuI (0.012 g, 0.063 mmol, 0.40 equiv) were reacted
for 12 h as described in entry 1, above. Purification by SiO2
chromatography with a gradient of 0-20% Et2O/hexanes
provided 2-(pyrrole-1-carboxylic acid tert-butyl ester)-2-fura-
nylmethane as a colorless oil (0.024 g, 0.096 mmol, 60%): IR

Pd-Catalyzed Heterobenzylic Cross-Coupling
J . Org. Chem., Vol. 64, No. 8, 1999 2803
(CH2Cl2, KCl, cm-1) 1738 (s); 1H NMR (CDCl3, 400 MHz) δ
7.33 (d, J ) 0.8 Hz, 1 H), 7.24 (dd, J ) 3.2, 1.2 Hz, 1 H), 6.29
(dd, J ) 2.0, 0.8 Hz, 1 H), 6.09 (app t, J ) 3.6 Hz, 1 H), 5.96
(d, J ) 3.2 Hz, 1 H), 5.92 (d, J ) 1.2 Hz, 1 H), 4.22 (s, 2 H),
1.52 (s, 9 H); 13C NMR (CDCl3, 75.5 MHz) δ 153.7, 149.6, 141.2,
131.3, 121.7, 113.1, 110.2, 106.2, 83.9, 29.9, 28.4, 28.1. Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66; O, 19.41.
Found: C, 68.23; H, 6.94; N, 5.50.
(w); 1H NMR (CDCl3, 400 MHz) δ 7.43 (d, J ) 7.6 Hz, 0.12 H),
7.36-7.17 (m, 5.88 H), 6.99-6.91 (m, 0.08 H), 6.68-6.64 (m,
0.08 H), 6.58 (d, J ) 11.6 Hz, 0.28 H), 6.44-6.33 (m, 1.56 H),
6.09 (app t, J ) 2.0 Hz, 0.94 H), 6.04-6.03 (m, 0.28 H), 6.01-
6.00 (m, 0.62 H), 5.92-5.85 (m, 0.24 H), 3.85 (d, J ) 7.6 Hz,
0.42 H), 3.75 (d, J ) 4.8 Hz, 1.58 H), 1.57 (s, 7.1 H), 1.55 (s,
1.9 H); 13C NMR (CDCl3, 80.0 MHz) δ 149.7, 137.8, 134.1,
131.6, 131.5, 131.4, 128.8, 127.8, 125.7, 127.7, 127.2, 126.4,
126.2, 121.5, 121.3, 112.1, 111.9, 110.3, 110.2, 83.7, 32.7, 32.6,
32.6, 28.8, 28.3, 28.2. Anal. Calcd for C18H21NO2: C, 76.30; H,
7.47; N, 4.94; O, 11.29. Found: C, 76.11; H, 7.42; N, 4.80.
En tr y 7. 2-Diben zofu r an yl-2-(pyr r ole-1-car boxylic acid
ter t-bu tyl ester )m eth a n e. S-(N-tert-Butoxycarbonyl-2-pyr-
rolylmethyl)tetramethylenesulfonium hexafluorophosphate
(0.073 g, 0.180 mmol, 1.20 equiv), 2-tri-n-butylstannyldiben-
zofuran (0.073 g, 0.160 mmol, 1.00 equiv), Pd2(dba)3‚CHCl3
(0.007 g, 0.007 mmol, 0.04 equiv), (PhO)3P (10.0 µL, 0.038
mmol, 0.24 equiv), benzyltrimethylammonium diphenylphos-
phinate (0.065 g, 0.180 mmol, 1.20 equiv), and CuI (0.012 g,
0.063 mmol, 0.40 equiv) were reacted for 12 h as described in
entry 1, above. Purification by SiO2 chromatography with a
gradient of 0-20% Et2O/hexanes provided 2-dibenzofuranyl-
2-(pyrrole-1-carboxylic acid tert-butyl ester)methane as an oil
(0.040 g, 0.115 mmol, 72%): IR (CH2Cl2, KCl, cm-1) 1731 (s);
1H NMR (CDCl3, 400 MHz) δ 8.06-8.04 (m, 0.1 H), 7.96 (d, J
) 6.8 Hz, 1 H), 7.83 (dd, J ) 7.6, 0.8 Hz, 0.9 H), 7.58 (d, J )
8.4 Hz, 1 H), 7.40 (ddd, J ) 7.2, 7.2, 1.2 Hz, 1 H), 7.36-7.32
(m, 2 H), 7.31 (app t, J ) 7.6 Hz, 1 H), 7.11 (d, J ) 7.6 Hz, 1
H), 6.09 (app t, J ) 3.2 Hz, 1 H), 5.79 (dd, J ) 3.2, 1.2 Hz, 1
H), 4.58 (s, 2 H), 1.44 (bs, 9 H); 13C NMR (CDCl3, 80.0 MHz)
δ 156.2, 154.7, 149.8, 132.6, 127.4, 127.1, 124.8, 124.3, 124.0,
123.0, 121.8, 121.7, 120.9, 118.9, 118.8, 113.6, 112.1, 112.0,
En tr y 1. 3-An isyl-2-th ien ylm eth a n e. A freshly prepared
0.01 M solution of (PhO)3P (0.008 g, 0.02 mmol, 0.02 equiv) in
THF (2 mL) was added to a flask charged with a freshly made
solution of (PhCN)2PdCl2 (0.006 g, 0.02 mmol, 0.02 equiv) in
THF (2 mL, 0.01 M). The solution turned from orange-brown
to light yellow as the (PhO)3P was added. This catalyst system
was then transferred to a flask charged with S-(2-thienylm-
ethyl)tetramethylenesulfonium hexafluorophosphate (0.33 g,
1.000 mmol, 1.00 equiv), 3-methoxyphenylboronic acid (0.167
g, 1.10 mmol, 1.10 equiv), and K2CO3 (0.690 g, 5.00 mmol, 5.00
equiv) in THF (6 mL) under nitrogen at room temperature.
To avoid the formation of considerable amounts of the homo-
coupling product of the arylboronic acid, the mixture was
deoxygenated using three cycles of a vacuum-nitrogen purge.
After 36 h, the mixture was diluted with 20 mL of Et2O/hexane
(1:1), filtered through a plug of silica gel, and concentrated.
Purification by SiO2 chromatography with hexane (100 mL)
and then 2% Et2O/hexane provided 3-anisyl-2-thienylmethane
as a colorless oil (0.147 g, 0.720 mmol, 72%): 1H NMR (CDCl3,
300 MHz) δ 7.26 (t, J ) 7.8 Hz, 1 H), 7.17 (dd, J ) 5.1, 1.2 Hz,
1 H), 7.96 (dd, J ) 7.8, 2.4 Hz, 1 H), 6.79-6.89 (m, 4 H), 4.16
(s, 2 H), 3.81 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 159.7,
143.7, 141.9, 129.5, 126.8, 125.1, 123.9, 120.9, 114.3, 111.8,
55.1, 36.0. Anal. Calcd for C12H12OS: C, 70.55; H, 5.92; O, 7.83;
S, 15.70. Found: C, 70.52; H, 5.93.
110.3, 110.2, 83.9, 29.9, 29.5, 18.1, 28.0. Anal. Calcd for C22H21
-
NO3: C, 76.06; H, 6.09; N, 4.03; O, 13.82. Found: C, 76.23; H,
6.15; N, 3.88.
En tr y 8. 3-(2-Meth yl-1-bu ten yl)-2-(p yr r olyl-1-ca r boxy-
lic a cid ter t-bu tyl ester ). S-(N-tert-Butoxycarbonyl-2-pyrro-
lylmethyl)tetramethylenesulfonium hexafluorophosphate
2
(0.073 g, 0.1800 mmol, 1.20 equiv), 2-methyl-1-tri-n-butylstan-
nylpropene (0.055 g, 0.160 mmol, 1.00 equiv), Pd2(dba)3‚CHCl3
(0.007 g, 0.007 mmol, 0.04 equiv), (PhO)3P (10.0 µL, 0.038
mmol, 0.238 equiv), benzyltrimethylammonium diphenylphos-
phinate (0.065 g, 0.180 mmol, 1.20 equiv), and CuI (0.012 g,
0.042 mmol, 0.40 equiv) were reacted for 12 h as described in
entry 1, above. Purification by SiO2 chromatography with a
gradient of 0-20% Et2O/hexanes provided 3-(2-methyl-1-
butenyl)-2-(pyrrolyl-1-carboxylic acid tert-butyl ester) as a
En tr y 2. 2-(Th ien yl)p h en ylm eth a n e. Following the pro-
cedure, workup, and purification described in entry 1, above,
S-(2-thiophenemethyl)tetramethylenesulfonium hexafluoro-
phosphate 3 (0.33 g, 1.00 mmol, 1.00 equiv), o-tolylboronic acid
(0.15 g, 1.10 mmol, 1.10 equiv), K2CO3 (0.690 g, 5.00 mmol,
5.00 equiv), (PhCN)2PdCl2 (0.008 g, 0.02 mmol, 0.02 equiv),
and (PhO)3P (5.1 µL, 0.02 mmol, 0.02 equiv) at room temper-
ature for 72 h provided 2-(thienyl)phenylmethane as a colorless
oil (0.152 g, 0.81 mmol, 81%): 1H NMR (CDCl3, 300 MHz) δ
7.28 (s, 4 H), 7.22 (dd, J ) 5.1, 0.9 Hz, 1 H), 7.01 (dd, J ) 5.1,
3.3 Hz, 1 H), 6.82 (dd, J ) 3.3, 0.9 Hz, 1 H), 4.24 (s, 2 H), 2.41
(s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 143.6, 138.4, 136.2,
130.3, 129.4, 126.8, 126.7, 126.1, 124.9, 123.6, 33.7, 19.4. Anal.
Calcd for C12H12S: C, 76.55; H, 6.42; S, 17.03. Found: C, 76.47;
H, 6.44; S, 17.12.
colorless oil (0.029 g, 0.125 mmol, 78%): IR (neat, NaCl, cm-1
)
1745 (s), 1596 (w); 1H NMR (CDCl3, 400 MHz) δ 7.19 (dd, J )
3.2, 1.2 Hz, 1 H), 6.07 (app t, J ) 3.2 Hz, 1 H), 5.93 (m, 1 H),
5.36 (m, 1 H), 3.53 (d, J ) 6.8 Hz, 2 H), 1.75 (br d, J ) 0.8 Hz,
3 H), 1.66 (s, 3 H), 1.59 (s, 9 H); 13C NMR (CDCl3, 80.0 MHz)
δ 135.5, 133.4, 121.2, 121.1, 111.1, 110.2, 83.5, 28.3, 28.1, 26.0,
17.9. Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95;
O, 13.60. Found: C, 71.35; H, 9.04; N, 5.84.
En tr y 9. 2-(P yr r olyl-1-ca r boxylic a cid ter t-bu tyl ester )-
(2-E-st yr yl)m et h a n e. S-(N-tert-Butoxycarbonyl-2-pyrrolyl-
methyl)tetramethylenesulfonium hexafluorophosphate 2 (0.072
g, 0.180 mmol, 1.20 equiv), â-tri-n-butylstannyl styrene (E/Z
89:11 by GC-MS; 90:10 by NMR) (0.068 g, 0.170 mmol, 1.0
equiv), Pd2(dba)3‚CHCl3 (0.007 g, 0.007 mmol, 0.04 equiv),
(PhO)3P (10.0 µL, 0.038 mmol, 0.22 equiv), and benzyltrim-
ethylammonium diphenylphosphinate (0.065 g, 0.180 mmol,
1.06 equiv) were reacted for 14 h at room temperature as
described in entry 1, above. At this point, 1H NMR analysis of
the crude reaction product indicated an E/ Z ratio of 87:13.
Purification by SiO2 chromatography with a gradient of 0-20%
Et2O/hexanes provided 2-(pyrrolyl-1-carboxylic acid tert-butyl
ester)(2-E-styryl)methane as a colorless oil (E/Z 79:21 by 1H
NMR) (0.024 g, 0.783 mmol, 49%). Data are presented with
the next entry.
En tr y 10. 2-(P yr r olyl-1-car boxylic acid ter t-bu tyl ester )-
(2-E-styr yl)m eth a n e. This experiment was run as described
in entry 9, but with the addition of CuI (0.003 g, 0.015 mmol,
0.10 equiv). Chromatography with a gradient of 0-20% Et2O/
hexanes provided 2-(pyrrolyl-1-carboxylic acid tert-butyl ester)-
(2-E-styryl)methane as a colorless oil (0.046 g, 0.155 mmol,
97%) (E/Z 79:21 by NMR): IR (neat, NaCl, cm-1) 1738 (s), 1595
En tr y 3. (2-F u r a n yl)p h en ylm eth a n e. Following the pro-
cedure, workup, and purification described in entry 1, above,
S-(2-furanylmethyl)tetramethylenesulfonium hexafluorophos-
phate (0.310 g, 1.00 mmol, 1.00 equiv), p-tolylboronic acid
(0.150 g, 1.100 mmol, 1.10 equiv), K2CO3 (0.690 g, 5.00 mmol,
5.00 equiv), (PhCN)2PdCl2 (0.008 g, 0.02 mmol, 0.02 equiv),
and (PhO)3P (5.1 µL, 0.02 mmol, 0.02 equiv) at room temper-
ature for 48 h provided (2-furanyl)phenylmethane as a color-
less oil (0.094 g, 0.550 mmol, 55%). See entry 1 in Table 3 data,
above, for characterization data.
En tr y 4. (2-F u r a n yl)-(2-E-styr yl)m eth a n e. Following the
procedure, workup, and purification described in entry 1,
above, S-(2-furanylmethyl)tetramethylenesulfonium hexafluo-
rophosphate 2 (0.31 g, 1.00 mmol, 1.0 equiv), (E)-â-styrylbo-
ronic acid (0.160 g, 1.10 mmol, 1.10 equiv), K2CO3 (0.690 g,
5.00 mmol, 5.00 equiv), (PhCN)2PdCl2 (0.008 g, 0.020 mmol,
0.02 equiv), and (PhO)3P (0.006 g, 0.020 mmol, 0.02 equiv) at
room temperature for 24 h provided (2-furanyl)-(2-E-styryl)-
methane as a colorless oil (0.155 g, 0.840 mmol, 84%): 1H NMR
(CDCl3, 300 MHz) δ 7.24-7.52 (m, 6 H), 6.55 (d, J ) 14.7 Hz,
1 H), 6.32-6.42 (m, 2 H), 6.13-6.14 (m, 1 H), 3.61 (d, J ) 6.6
Hz, 2 H); 13C NMR (CDCl3, 75.5 MHz) δ 153.8, 141.3, 137.2,

2804 J . Org. Chem., Vol. 64, No. 8, 1999
Zhang et al.
131.9, 128.4, 127.2, 126.2, 125.5, 110.3, 105.6, 31.7. Anal. Calcd
for C13H12O: C, 84.75; H, 6.57; O, 8.68. Found: C, 84.70; H,
6.54.
removal of the ice bath. Stirring was stopped, and 2.5 mL of
dry hexane was added to precipitate the magnesium salts. The
solution was separated from the salts and transferred to a flask
containing S-(2-thiophenemethyl)tetramethylenesulfonium
hexafluorophosphate (0.157 g, 0.50 mmol, 1.00 equiv) and a
freshly prepared solution of (PhCN)2PdCl2 (0.004 g, 0.010
mmol, 0.02 equiv) and (PhO)3P (2.6 µL, 0.01 mmol, 0.02 equiv)
in 4 mL of THF. The reaction mixture was subjected to three
cycles of a vacuum-nitrogen purge, stirred for 36 h at room
temperature, and then quenched with 10 mL of saturated NH4-
Cl. The resulting biphasic mixture was diluted with 10 mL of
ether and partitioned in a 60 mL separatory funnel. The
organic phase was washed with 1 × 20 mL of brine and dried
with MgSO4. Chromatography with 0-2% Et2O/hexanes gave
(2-furanyl)-4-tolylmethane (0.057 g, 0.335 mmol, 67%); see
entry 1 in Table 3 data for characterization.
En tr y 2. 4-(N-Boc-2-p yr r olyl)tolu en e. S-(N-tert-Butoxy-
carbonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluo-
rophosphate (0.207 g, 0.50 mmol, 1.00 equiv), 1.0 M p-tolyl-
magnesium bromide solution in ether (0.750 mL, 0.750 mmol,
1.50 equiv), 1.0 M ZnCl2 solution in ether (0.750 mL, 0.750
mmol, 1.50 equiv), (PhCN)2PdCl2 (0.004 g, 0.010 mmol, 0.02
equiv), and (PhO)3P (5.2 µL, 0.02 mmol, 0.02 equiv) were
subjected to the reaction conditions and workup described in
entry 1. No coupling product was isolated.
En tr y 3. 3-An isyl-2-th ien ylm eth a n e. S-(2-Furanylmeth-
yl)tetramethylenesulfonium hexafluorophosphate (0.157 g,
0.50 mmol, 1.00 equiv), 0.3 M 3-methoxyphenylmagnesium
bromide solution in THF (2.50 mL, 0.750 mmol, 1.50 equiv),
1.0 M ZnCl2 solution in ether (0.750 mL, 0.750 mmol, 1.50
equiv), (PhCN)2PdCl2 (0.004 g, 0.010 mmol, 0.02 equiv), and
(PhO)3P (2.6 µL, 0.01 mmol, 0.02 equiv) in 5 mL of THF were
subjected to the reaction conditions and workup described in
entry 1 to give 3-anisyl-2-thienylmethane (0.057 g, 0.335 mmol,
62%) as a colorless oil: see entry 1 in Table 4 data for
characterization.
En tr y 5. (2-P yr r olyl-1-ca r boxylic a cid ter t-bu tyl ester )-
(4-tolyl)m eth a n e. Following the procedure, workup, and
purification described in entry 1, above, S-(N-tert-butoxycar-
bonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluoro-
phosphate (0.207 g, 0.50 mmol, 1.00 equiv), p-tolylboronic
anhydride (0.124 g, 0.350 mmol, 0.07 equiv), K2CO3 (0.345 g,
2.50 mmol, 5.00 equiv), (PhCN)2PdCl2 (0.004 g, 0.01 mmol, 0.02
equiv), and (PhO)3P (2.6 µL, 0.01 mmol, 0.02 equiv) at room
temperature for 24 h provided (2-pyrrolyl-1-carboxylic acid tert-
butyl ester)(4-tolyl)methane (0.0033 g, 0.13 mmol, 26%). See
entry 5 in Table 3 data, above, for characterization data.
En tr y 6. 2-(P yr r olyl-1-ca r boxylic a cid ter t-bu tyl ester )-
(2-E-styr yl)m eth a n e. Following the procedure, workup, and
purification described in entry 1, above, S-(N-tert-butoxycar-
bonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluoro-
phosphate 2 (0.207 g, 0.50 mmol, 1.00 equiv), (E)-â-styrylbo-
ronic acid (0.080 g, 0.563 mmol, 1.12 equiv), K2CO3 (0.345 g,
2.50 mmol, 5.00 equiv), (PhCN)2PdCl2 (0.004 g, 0.01 mmol, 0.02
equiv), and (PhO)3P (2.6 µL, 0.01 mmol, 0.02 equiv) at room
temperature for 24 h provided 2-(pyrrolyl-1-carboxylic acid tert-
butyl ester)(2-E-styryl)methane (0.015 g, 0.055 mmol, 11%).
See entry 10 in Table 3 data, above, for characterization data.
En tr y 7. 2-Diben zofu r an yl-2-(pyr r olyl-1-car boxylic acid
ter t-bu tyl ester )m eth a n e. Following the procedure, workup,
and purification described in entry 1, above, S-(N-tert-butoxy-
carbonyl-2-pyrrolylmethyl)tetramethylenesulfonium hexafluo-
rophosphate (0.207 g, 0.50 mmol, 1.00 equiv), 2-dibenzofura-
nylboronic acid (0.127 g, 0.60 mmol, 1.20 equiv), K2CO3 (0.345
g, 2.50 mmol, 5.00 equiv), (PhCN)2PdCl2 (0.004 g, 0.01 mmol,
0.02 equiv), and (PhO)3P (2.6 µL, 0.012 mmol, 0.02 equiv) at
room temperature for 24 h provided 2-dibenzofuranyl-2-
(pyrrolyl-1-carboxylic acid tert-butyl ester)methane (0.024 g,
0.07 mmol, 14%). See entry 7 in Table 3 data, above, for
characterization data.
En tr y 4. 4-Ch lor op h en yl-2-th ien ylm eth a n e. S-(2-Thio-
phenemethyl)tetramethylenesulfonium hexafluorophosphate
(0.660 g, 2.00 mmol, 1.00 equiv), 1.0 M p-chlorophenylmag-
nesium bromide solution in ether (3.00 mL, 3.00 mmol, 1.50
equiv), 1.0 M ethereal solution of ZnCl2 (3 mL, 3.00 mmol, 1.50
equiv), (PhCN)2PdCl2 (0.038 g, 0.10 mmol, 0.05 equiv), and
(PhO)3P (26 µL, 0.031 g, 0.10 mmol, 0.05 equiv) in 4 mL of
THF were subjected to the reactions conditions and workup
described in entry 1 to give 4-chlorophenyl-2-thienylmethane
as a colorless oil (0.220 g, 1.06 mmol, 53%); refer to Table 1
data, above, for characterization.
En tr y 8. P h en yl-3-th ien ylm eth a n e. Following the pro-
cedure, workup, and purification described in entry 1, above,
S-(3-thiophenemethyl)tetramethylenesulfonium hexafluoro-
phosphate (0.330 g, 1.00 mmol, 1.00 equiv), phenylboronic acid
(0.130 g, 1.100 mmol, 1.10 equiv), K2CO3 (0.690 g, 5.00 mmol,
5.00 equiv), (PhCN)2PdCl2 (0.008 g, 0.02 mmol, 0.02 equiv),
and (PhO)3P (5.1 µL, 0.02 mmol, 0.02 equiv) at room temper-
ature for 24 h provided phenyl-3-thienylmethane as a colorless
oil (0.146 g, 0.84 mmol, 84%): 1H NMR (CDCl3, 300 MHz) δ
7.28-7.41 (m, 6 H), 7.00 (app d, J ) 4.2 Hz, 2 H), 4.07 (s, 2
H); 13C NMR (CDCl3, 75.5 MHz) δ 141.4, 140.5, 128.7, 128.4,
127.1, 126.1, 125.5, 121.2, 36.5; HRMS (EI) calcd for C11H10
S
Ack n ow led gm en t. The National Cancer Institute,
DHHS supported this investigation through Grant No.
CA40157. We gratefully acknowledge Dr. Gary D. Allred
of Frontier Scientific, Inc. (Logan, UT) for a generous
supply of arylboronic acids and Dr. J iri Srogl for his
useful advice and long-standing interest in this project.
174.0503, found 174.0496. Anal. Calcd for C11H10S: C, 75.82;
H, 5.78; S, 18.40. Found: C, 76.68; H, 5.96; S, 17.36.
En tr y 1. (2-F u r a n yl)-4-tolylm eth a n e. To a 10 mL oven-
dried flask under Ar was placed 1.0 M p-tolylmagnesium
bromide in ether (0.750 mL, 0.750 mmol, 1.50 equiv). The
solution was cooled to 5 °C, and a 1.0 M ZnCl2 solution in ether
(0.750 mL, 0.750 mmol, 1.50 equiv) was added in a dropwise
fashion. The mixture was allowed to stir for 30 min after
J O982250S