Kumada coupling of aryl and vinyl tosylates under mild conditions

Article abstract of DOI:10.1021/jo051394l

Aryl and alkenyl tosylates are easily prepared, inexpensive and, thus, attractive for transition-metal-catalyzed couplings, but their reactivity is low. We report examples of mild, palladium-catalyzed coupling of aryl, alkenyl, and alkyl Grignard reagents with aryl and alkenyl tosylates. The resulting biaryls, vinylarenes, and alkylarenes were isolated in good to excellent yield. These couplings were conducted with a nearly equimolar ratio of the two reactants, and many examples were conducted at room temperature.

Full text of DOI:10.1021/jo051394l

Kumada Coupling of Aryl and Vinyl Tosylates under Mild
Conditions
Michael E. Limmert, Amy H. Roy, and John F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107
john.hartwig@yale.edu
Received July 6, 2005
Aryl and alkenyl tosylates are easily prepared, inexpensive and, thus, attractive for transition-
metal-catalyzed couplings, but their reactivity is low. We report examples of mild, palladium-
catalyzed coupling of aryl, alkenyl, and alkyl Grignard reagents with aryl and alkenyl tosylates.
The resulting biaryls, vinylarenes, and alkylarenes were isolated in good to excellent yield. These
couplings were conducted with a nearly equimolar ratio of the two reactants, and many examples
were conducted at room temperature.
SCHEME 1. Coupling of Aryl Grignard Reagents
with Aryl Tosylates at Room Temperature
Introduction
Transition-metal-catalyzed cross-coupling reactions
have become a common synthetic procedure for the
synthesis of organic compounds with sp2-sp2 linkages.1-3
Aryl bromides, chlorides, and triflates are used most
commonly for the synthesis of substituted arenes, in-
cluding biphenyls and vinylarenes.4-12 Aryl and vinyl
tosylates would be useful as electrophiles for cross-
coupling chemistry because they can be prepared easily
from phenols or ketones with reagents that are less
expensive than those used to prepare aryl and vinyl
triflates. Further, aryl and vinyl tosylates are more
convenient to use because they are more stable to water
than triflates and are highly crystalline. However, this
greater stability of the tosylates makes them less reactive
in palladium-catalyzed processes. Couplings of aryl
tosylates with nickel,13-17 copper,18 and palladium19-23 are
now known. The mildest C-C coupling reported with an
aryl tosylate occurred with boronic acids at room tem-
perature with the combination of Ni(COD)2 and PCy3.16
Because boronic acids are usually derived from Grig-
nard reagents, Kumada couplings offer a more direct
approach to the synthesis of biaryls when the substrates
tolerate the background reactivity of a Grignard reagent.
For this reason, interest in the coupling of organomag-
nesium reagents has been renewed in recent years.24-30
(13) Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531.
(14) Bolm, C.; Hildebrand, J. P.; Rudolph, J. Synthesis 2000, 911.
(15) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett.
2001, 3, 3049.
(1) Diederich, F.; P, S. Metal-catalyzed cross coupling reactions;
Wiley-VCH: Weinheim, 1998.
(2) Miyaura, N. Cross-Coupling Reactions: a Practical Guide; Topics
in Current Chemistry; Springer-Verlag: New York, 2002; Vol. 219.
(3) de Meijere, A.; Diederich, F. Metal-catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(4) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
(5) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A 2001, 173, 249.
(6) Beletskaya, I., P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(7) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(8) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
(9) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(10) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(11) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(12) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374.
(16) Tang, Z. Y.; Hu, Q. S. J. Am. Chem. Soc. 2004, 126, 3058.
(17) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org.
Chem. 2004, 69, 3447.
(18) Erdik, E.; Eroglu, F. Synth. React. Inorg. Met-Org. Chem. 2000,
30, 955.
(19) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369.
(20) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
1473.
(21) Kubota, Y.; Nakada, S.; Sugi, Y. Synlett 1998, 183.
(22) Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(23) Nguyen, H. N.; Huang, X. H.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11818.
(24) Korn, T. J.; Cahiez, G.; Knochel, P. Synlett 2003, 1892.
10.1021/jo051394l CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/13/2005
9364
J. Org. Chem. 2005, 70, 9364-9370

Kumada Coupling of Aryl and Vinyl Tosylates
SCHEME 2. Oxidative Addition of Aryl Tosylates at Room Temperature
Despite this renewed interest, the palladium-catalyzed
coupling of organomagnesium reagents with unactivated
aryl tosylates has not been reported outside of our
previously communicated work.31
tosylates, and conditions for the coupling of a series of
Grignard reagents with unactivated vinyl tosylates.
Results and Discussion
Progress has been made during the last several years
on the coupling of aryl and alkyl halides with sp3 carbon
nucleophiles.26,27,32-35 Fu¨rstner et al. developed an iron-
catalyzed Kumada coupling of aryl chlorides and acti-
vated aryl and heteroaryl tosylates with alkylmagnesium
chlorides.32,36 A similar process based on cobalt and
an iron-catalyzed coupling of aryl Grignard reagents
with vinyl halides were published by Knochel and co-
workers.24,37 Yet, few couplings of aryl tosylates with alkyl
Grignard reagents have been reported,32 and no coupling
of unactivated aryl tosylates23 with alkyl Grignard re-
gents has been reported.
Several years ago, we reported that palladium com-
plexes of a bulky, electron-rich Josiphos ligand38 catalyze
the coupling of aryl tosylates with amines19 and with
ketone enolates.20 More recently, we communicated that
palladium complexes of a bis-dialkylphosphino analogue
of the Josiphos ligand used in the original work catalyzed
the coupling of aryl tosylates with amines and aryl
Grignard reagents (Scheme 1) at room temperature.31
Moreover, we showed that oxidative addition of aryl
tosylates to complexes 3 and 4 in Scheme 2 occurred at
room temperature to generate isolable arylpalladium
tosylate complexes.
We first sought conditions to decrease the amount of
Grignard reagent and to reduce the amount of biaryl
produced from homocoupling of the Grignard reagent. To
probe the effect of varying several reaction parameters,
we studied the coupling of p-tolyl tosylate with p-
fluorophenylmagnesium bromide at room temperature in
toluene catalyzed by the combination of Pd2(dba)3‚CHCl3
and 1. This reaction occurred under our original condi-
tions in 70% yield. After testing various palladium
precursors and solvents, we found that reducing the
reagent concentrations from 0.50 to 0.25 M led to a
decrease in the amount of biaryl from homocoupling of
the Grignard reagent to between 5% and 10%. As a
result, the cross-coupling process occurred in high yield
with a nearly equimolar ratio of arylmagnesium bromide
and aryl tosylate (1.1-1 equiv). Under these conditions,
the scope of the coupling of aryl and vinyl tosylates was
investigated with aromatic, benzylic, and aliphatic Grig-
nard reagents.
Coupling of Aryl Tosylates with Arylmagnesium
Halides. The coupling of aryl tosylates with aryl-
magnesium halides is summarized in Table 1. In most
cases, reactions conducted under the less concentrated
conditions formed the coupled product in yields that are
higher than those communicated earlier.31 The coupling
of electron-rich, electron-neutral, and electron-deficient,
as well as ortho-substituted, aryl tosylates occurred in
good yields. The influence of substituents in the para
position was not large and was the opposite of that
usually observed for the coupling of aryl halides. Reac-
tions of aryl tosylates with electron-donating substituents
(OMe) occurred in yields that were higher than those of
reactions of electron-neutral aryl tosylates (Me, H), and
reactions of aryl tosylates with electron-withdrawing
groups (F, CF3) occurred in yields (Table 1, entries 7 and
11) that were lower than those of reactions of the
electron-neutral aryl halides.
We now report a full set of studies on the coupling of
Grignard reagents with aryl and vinyl tosylates.39 We
report several improvements in the reaction procedures
and an increase in the reaction scope. We developed
conditions to conduct the couplings without an excess of
Grignard reagent, conditions to conduct reactions of alkyl
and benzylic Grignard reagents with unactivated aryl
(25) Holzer, B.; Hoffmann, R. W. J. Chem. Soc., Chem. Commun.
2003, 732.
(26) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, B. J. Am. Chem.
Soc. 2004, 126, 3686.
(27) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(28) Huang, J. K.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889.
(29) Yang, L. M.; Huang, L. F.; Luh, T. Y. Org. Lett. 2004, 6, 1461.
(30) Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63, 8922.
(31) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704.
(32) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem.
Soc. 2002, 124, 13856.
(33) Zhou, J. R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726.
(34) Zhou, J. R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527.
(35) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2002, 41, 4056.
The selectivity for reaction at an aryl chloride and aryl
tosylate linkage was probed. Reactions of PhMgBr with
an aryl tosylate with a 4-chloro substituent occurred to
cleave the aryl tosylate and to form the 4-chlorobiphenyl
in good yield (Table 1, entry 12). This selectivity contrasts
with that of the coupling of arylboronic acids with
palladium complexes of X-phos. These reactions of pal-
ladium complexes of X-phos occurred preferentially at the
aryl chloride over the aryl tosylate.23 Reactions of bis-
tosylates with 2 equiv of phenyl Grignard generated
triaryl compounds in good yields. However, reactions of
bis-tosylates with 1 equiv of aryl Grignard reagent were
(36) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
(37) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901.
(38) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
(39) For precedent in
a nickel-catalyzed coupling of Grignard
reagents with an aryl mesylate to form biaryl in 53% yield, along with
two homocoupling products and reduction products, see: Percec, V.;
Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895.
J. Org. Chem, Vol. 70, No. 23, 2005 9365

Limmert et al.
TABLE 1. Coupling of Aryl Tosylates with Arylmagnesium Halidesa
a Reaction conditions: ArOTs (1 equiv), Ar′MgBr (1.1 equiv), 1 mol % of Pd(P(o-tol)3)2 or Pd(dba)2, 1 mol % of 1; isolated yield is an
average of two runs. b Pd(dba)2 and 2 equiv of Ar′MgBr were used. c Gas chromatography yield.
not selective, and a mixture of products containing
predominantly the disubstitution product was obtained.
In most couplings of aryl Grignard reagents with aryl
tosylates in which one of the two reagents contained an
ortho substituent, 2 equiv of the magnesium reagent and
elevated temperatures were required for full conversion,
but reasonable yields were obtained (Table 1, entries
2-4). An excess of Grignard reagent was needed, regard-
less of whether the catalyst was generated from Pd2dba3
or Pd(P(o-tol)3)2. However, the reaction of 2-naphthyl-
tosylate with o-tolylmagnesium bromide occurred in
excellent yield with only 1 equiv of the magnesium
9366 J. Org. Chem., Vol. 70, No. 23, 2005

Kumada Coupling of Aryl and Vinyl Tosylates
SCHEME 3
a catalyst generated from ligand 2 formed larger amounts
of arene from hydrodesulfonylation than did reactions
conducted with a catalyst generated from ligand 1.
However, the coupling of the cyclohexylmagnesium bro-
mide occurred in higher yield with ligand 1 than with
ligand 2. This reaction also occurred in lower yields at
elevated temperatures than at room temperature.
Less electron-rich aryl tosylates, such as 4-trifluoro-
methylphenyl tosylate and 2-naphthyltosylate, also un-
derwent coupling with alkyl Grignard reagents. The
yields from coupling of the modestly activated naphthyl
tosylate were higher than those of the more activated
trifluoromethylphenyl tosylate, and the naphthyl elec-
trophile reacted in excellent yield with linear or â-branched
Grignard reagents and with benzylic Grignard reagents
at room temperature in the presence of a palladium
catalyst generated from 1. However, the reaction of the
trifluoromethylphenyl tosylate did not occur to comple-
tion with 1 mol % of palladium, even after 8 h. The
coupling of ortho-substituted aryl tosylates is also chal-
lenging. Two equivalents of Grignard reagent, elevated
temperatures, and long reaction times were required. The
yield of the coupling of the o-anisyl tosylate with iso-
butylmagnesium chloride was estimated as 65% by GC
methods.
Coupling of secondary alkylmagnesium halides with
a methyl group adjacent to the nucleophilic carbon, such
as sec-butylmagnesium chloride or phenethylmagnesium
bromide occurred in low yield. The major product from
reaction of sec-butyl Grignard was arene. This product,
presumably, forms by â-hydride elimination of the alkyl
group and C-H bond-forming reductive elimination.
Some product from rearrangement of the branched to the
linear alkyl prior to reductive elimination was also
observed (Scheme 4).
Kumada and Hayashi proposed43 a relationship be-
tween the P-Pd-P bite angle of bis-phosphines and the
amount of product from rearrangement of the branched
alkyl group. This isomerization was suppressed by con-
ducting the reactions of branched alkyl Grignard re-
agents with catalysts derived from 1,1′-bis(diphenylphos-
phino)ferrocene (DPPF). DPPF generates complexes with
a P-Pd-P angle of about 99°. Although the 98° bite angle
of the coordinated Josiphos ligand could similarly lead
to a suppression of the isomerization, the difference in
steric and electronic properties of this ligand and DPPF
apparently allow â-hydrogen elimination and isomeriza-
tion of the branched to linear alkyl group to compete with
C-C bond-forming reductive elimination.
Coupling of Alkenyl Tosylates with Arylmagne-
sium Halides. Previous procedures for the synthesis of
vinyl tosylates from ketones were conducted with lithium
diisopropylamide (LDA) as base and 2 equiv of p-
toluenesulfonic anhydride. This procedure yielded sub-
stantial amounts of sulfonamide byproduct, and this
sulfonamide can be difficult to separate from the vinyl
tosylate. Thus, we prepared the vinyl tosylates by depro-
tonation of the ketone with lithium hexamethyldisilazide
(LiHMDS)44 at -78 °C and addition of tosic anhydride
reagent (Table 1, entry 14). Aryl tosylates that are
substituted in both the 2- and 6-position reacted in lower
yields. In addition to the products from cross-coupling
and homocoupling of the Grignard reagent, a biaryl
containing the p-tolyl group of the tosylate was observed,
as shown in Scheme 3, perhaps from coupling of a
sulfone18,40,41 generated by cleavage of the tosylate.
Coupling of aryl halides containing ester and nitrile
groups did not occur, and coupling of functionalized
Grignard reagents42 could not be accomplished because
the couplings did not occur below room temperature.
Unfortunately, reactions of nitrogen-containing hetero-
cycles such as quinolines also did not occur.
Biaryl couplings catalyzed by complexes generated
from this hindered Josiphos ligand are, thus far, limited
to reactions of organomagnesium compounds. Phenylzinc
bromide reacted with phenyl tosylate to give only traces
of biphenyl, and arylboronic acids did not react to give
any biaryl products. Because oxidative addition of aryl
tosylates to the Pd(0) species containing the Josiphos
ligand is facile, transmetalation of these complexes with
arylboronic acids and arylzinc halides is apparently slow.
Coupling of Aryl Tosylates with Alkenyl- and
Alkylmagnesium Halides. The coupling of aryl tosyl-
ates with alkenyl, benzylic, and aliphatic magnesium
halides was also investigated in the presence of the
catalyst generated from a Pd(0) precursor and the Josi-
phos ligands 1 and 2. Reactions of aryl tosylates with
these Grignard reagents are summarized in Table 2. In
general, reactions catalyzed by complexes of the bulkier
and more electron-rich phosphine 2 occurred faster and
in higher yield than reactions catalyzed by complexes of
ligand 1. However, the optimal reaction conditions were
not identical with each class of Grignard reagent. For
example, the coupling with 2-methylpropenylmagnesium
chloride (Table 2, entry 1) required heating, while the
coupling of isobutyl- and cyclohexylmagnesium bromide
occurred at room temperature.
Nevertheless, alkenyl, n-alkyl, â-branched alkyl, cyclo-
alkyl ,and benzyl Grignard reagents all coupled with the
electron-rich anisyl tosylate in good to excellent yields.
Reactions of this aryl tosylate generally occurred in
higher yield with a catalyst generated from the more
electron-rich ligand 2 than with a catalyst generated from
the less electron-rich ligand 1. Reactions conducted with
(40) Clayden, J.; Julia, M. Chem. Commun. 1993, 1682.
(41) Clayden, J.; Cooney, J. J. A.; Julia, M. Chem. Commun. 1995,
7.
(42) Bonnet, V.; Mongin, F.; Trecourt, F.; Queguiner, G.; Knochel,
P. Tetrahedron 2002, 58, 4429.
(43) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
(44) Cox, R. A.; McAllister, M.; Roberts, K. A.; Stang, P. J.; Tidwell,
T. T. J. Org. Chem. 1989, 54, 4899.
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Limmert et al.
TABLE 2. Coupling of Aryl Tosylates with Alkylmagnesium Halidesa
a Reaction conditions: ArOTs (1 equiv), RMgX (1.1 equiv, R ) alkenyl, alkyl; X ) Br, Cl), 1 mol % of Pd(P(o-tol)3)2, 1 mol % of 1 or 2;
isolated yields are an average of two runs.
SCHEME 4. Coupling of 2-Naphthyltosylate with
sec-Butylmagnesium Bromide
LiHMDS consisted predominantly of the E configuration
instead of a mixture of E and Z isomers, as was obtained
from reactions with LDA as base. The tosylate obtained
from 2-methylcyclohexanone (Table 3, entry 2) contained
about 5-10% of the more substituted vinyl tosylate.
Reactions of the vinyl tosylates with Grignard reagents
are summarized in Table 3. We studied reactions of
tosylates with different steric properties (Table 3, entries
1-4) and different electronic properties (Table 3, entries
5-7). Sterically hindered and unhindered cyclic alkenyl
tosylates (Table 3, entries 1 and 2) reacted readily with
p-tolylmagnesium bromide at elevated temperatures and
in good yields.
to the resulting enolate.45,46 This procedure provided
several benefits. First, the remaining disilazide or any
silyl-substituted sulfonamide hydrolyzed and did not
elute during chromatography. Second, the alkenyl
tosylates formed after deprotonation of the ketone with
The reaction of 2-methyl-3-tosyloxy-3-propene (Table
3, entry 3) with p-tolyl Grignard, however, generated a
coupled product resulting from isomerization. The mech-
anism of this isomerization is not clear. Although isomer-
ization that leads to migration of a metal center between
contiguous carbons in an alkyl group is common, migra-
tion of a metal from one vinyl carbon to another is less
common. â-Hydrogen elimination from an alkyl group to
form an olefin hydride complex and reinsertion to gener-
ate a new alkyl species accounts for migration of a metal
(45) The following recent reference on coupling of amides with vinyl
tosylates reported the preparation of vinyl tosylates by a similar
procedure.
(46) Klapars, A.; Campos, K. R.; Chen, C. Y.; Volante, R. P. Org.
Lett. 2005, 7, 1185.
9368 J. Org. Chem., Vol. 70, No. 23, 2005

Kumada Coupling of Aryl and Vinyl Tosylates
TABLE 3. Coupling of Alkenyl Tosylates with Aryl- and Alkylmagnesium Halidesa
a Reaction conditions: ROTs (1 equiv), 4-MeC6H4MgBr/iBuMgCl (1.1 equiv), 1 mol % of Pd2(dba)3‚CHCl3, 1 mol % of 1 or 2; isolated
yield is an average of two runs. b The parent tosylate already consists of two isomers; hence, the product is obtained as a mixture with
about 6% of the higher substituted alkene.
along an alkyl chain, but â-hydrogen elimination from a
vinyl group to form an alkyne hydride complex has less
precedent. Isomerization induced by the reaction of a
strong base, like the elimination of vinyl triflates to give
alkynes,47 may also account for the isomerization. In any
case, the mechanism of the formation of the rearranged
product is speculative at this time.
R-Styryl tosylates (Table 3, entries 5-7) also coupled
with alkyl and aryl Grignard reagents. The products from
coupling of alkenyl Grignard reagents were isolated in
30-87% yields (Table 3, entries 5-7). In contrast to the
reaction of the vinyl tosylate in entry 3, the electronically
distinct but sterically similar 1-phenylpropenyl tosylate
(Table 3, entry 6) did not undergo isomerization during
the coupling process. Although the products from cou-
pling with aryl Grignard reagents were not separated
from some of the side products of similar low polarity,
yields for coupling of the vinyl tosylates of entries 5-7
with p-tolyl Grignard were estimated by GC to range
from 70 to 80%.
cases of the coupling of alkenyl tosylates with alkylmag-
nesium halides we tested, catalysts generated from
phenyl ligand 1 formed the coupled product in higher
yield than catalysts generated from cyclohexyl ligand 2.
Depending on the degree of steric hindrance, the reaction
proceeded quickly at room temperature (Table 3, entries
4-6) or required heating (Table 3, entry 7). The less
substituted vinyl tosylate in entry 5 of Table 3, however,
reacted in lower yield than the more substituted vinyl
tosylates. Hydrodesulfonylation apparently competed
with substitution and diminished the yield. Styrene was
detected by GC-MS, and the evolution of a gas from the
reaction mixture, presumably isobutene, was observed.
Conclusion
We have shown that catalysts containing strongly
electron-donating and sterically hindered bisphosphines
of the Josiphos class allow for Kumada couplings to be
conducted with aryl and vinyl tosylates. Previous cou-
plings of aryl and vinyl sulfonates have been conducted
predominantly with triflates, but we show that the less
expensive and more easily handled tosylates can also
react under mild conditions. The Kumada couplings of
tosylates catalyzed by a combination of a Pd(0) precursor
and the Josiphos ligands generates biaryl and styrenyl
The coupling of alkenyl tosylates with aliphatic Grig-
nard reagents was also accomplished with catalysts
generated from the hindered Josiphos ligands. In all
(47) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.; Kerekes, A.
D. Tetrahedron Lett. 1998, 39, 8613.
J. Org. Chem, Vol. 70, No. 23, 2005 9369

Limmert et al.
solvent, the crude product was purified using flash column
chromatography (silica gel, hexanes, ethyl acetate 95:5) to give
164.6 mg (83%) of 4-methoxy-4′-methylbiphenyl: 1H NMR
(CDCl3) δ 2.41 (s, 3H), 3.87 (s, 3H), 7.00 (d, J ) 8.8 Hz, 2H),
7.25 (d, J ) 8.0 Hz, 2H), 7.48 (d, J ) 8.0 Hz, 2H), 7.54 (d, J )
8.8 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 55.8, 114.6, 127.0, 128.4,
129.9, 134.2, 136.8, 138.4, 159.4.
General Procedure 2: Coupling of Aryl Tosylates with
Alkenyl- and Alkylmagnesium Halides and Coupling of
aLkenyl Tosylates with Aryl- and Alkylmagnesium Ha-
lides. The reaction conditions and average yields for each
reaction are shown in Tables 2 and 3. A typical procedure is
given for Table 2, entry 1.
compounds in good to excellent yields, often at room
temperature. An equimolar ratio of vinyl or aryl tosylate
and Grignard reagent is sufficient for many cross-
couplings with activated, deactivated, and certain steri-
cally hindered substrates. Furthermore, we conducted
successfully the first alkylations of electron-rich aryl and
vinyl tosylates.
The Kumada coupling has advantages and disadvan-
tages, relative to other types of couplings. The Kumada
coupling requires no synthesis of boronic acids or organo-
tin reagents, but they occur with less functional group
tolerance than Suzuki or Stille reactions. Thus, we are
also seeking conditions to couple aryl tosylates with
organozinc reagents or organoboron reagents with cata-
lysts bearing the Josiphos ligands. At the same time, we
are seeking systems that will further improve the turn-
over numbers of the coupling of Grignard reagents and
that will exploit the chirality of the Josiphos ligand for
enantioselective couplings.
1-Methoxy-4-(2-methylpropenyl)benzene.49 Into a small
vial were placed 3.6 mg of Pd(P(o-tol)3)2 (0.0050 mmol), 2.8
mg of 2 (0.0050 mmol), and 139 mg of 4-MeOC6H4OTs (0.500
mmol). The solids were dissolved in 1.5 mL of toluene. With a
syringe, 1.1 mL of a 0.5 M solution of 2-methylpropenyl-
magnesium bromide (0.55 mmol) in tetrahydrofuran was
added to the well-stirred solution at room temperature. The
vial was sealed with a poly(tetrafluoroethylene) septum,
removed from the glovebox, and stirred at 80 °C for 4 h.
The resulting orange to brown suspension was diluted in
100 mL of hexanes and filtered. After evaporation of the
solvent, the crude product was purified using flash column
chromatography (silica gel, hexanes, ethyl acetate 99:1) to give
71 mg (87%) of 1-methoxy-4-(2-methylpropenyl)benzene: 1H
NMR (CDCl3) δ 1.86 (d, J ) 1.3 Hz, 1H), 1.90 (d, 1.3 Hz, 1H),
3.82 (s, 3H), 6.23 (broad, 1H), 6.88 (d, 8.5 Hz, 2H), 7.18 (d, 8.5
Hz, 2H); 13C NMR (CDCl3) δ 18.3, 25.8, 54.2, 112.4, 123.5,
127.6, 128.7, 130.3, 132.0, 132.9, 156.6.
Experimental Section
General Procedure 1: Coupling of Aryl Tosylates with
Arylmagnesium Bromides. The reaction conditions and
average yields for each reaction are shown in Table 1. A typical
procedure is given for entry 1.
4-Methoxy-4′-methylbiphenyl.48 Into a small vial were
placed 7.2 mg of Pd(P(o-tol)3)2 (0.010 mmol), 5.4 mg of 1 (0.010
mmol), and 278 mg of 4-MeOC6H4OTs (1.00 mmol). The solids
were dissolved in 3 mL of toluene. With a syringe, 1.1 mL of
a 1.0 M solution of p-tolylmagnesium bromide (1.10 mmol) in
diethyl ether was added to the well-stirred solution at room
temperature. The vial was closed, and the solution was stirred
at room temperature in the glovebox for 4 h. The resulting
orange suspension was removed from the glovebox, hydrolyzed
with 1.0 M HCl, and extracted three times with dichloro-
methane. The combined organic layers were washed with
brine, dried over MgSO4, and filtered. After evaporation of the
Acknowledgment. We thank the NIH-NIGMS (R-
O1 58108) for support of this work. We also thank
Boehringer-Ingelheim for an unrestricted gift.
Supporting Information Available: Details of experi-
mental procedures and characterization of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051394L
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9370 J. Org. Chem., Vol. 70, No. 23, 2005