Room temperature palladium-catalyzed cross coupling of aryltrimethylammonium triflates with aryl grignard reagents

Article abstract of DOI:10.1021/ol1018739

Figure Presented. Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe₃OTf relative to PhCl, PhBr, PhI, and PhOTf.

Full text of DOI:10.1021/ol1018739

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4388-4391
Room Temperature Palladium-Catalyzed
Cross Coupling of
Aryltrimethylammonium Triflates with
Aryl Grignard Reagents
Jonathan T. Reeves,* Daniel R. Fandrick, Zhulin Tan, Jinhua J. Song,
Heewon Lee, Nathan K. Yee, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals,
Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
jonathan.reeVes@boehringer-ingelheim.com
Received August 10, 2010
ABSTRACT
Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with
aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and
diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe3OTf relative to PhCl, PhBr, PhI, and PhOTf.
The nickel- or palladium-catalyzed cross coupling of
Grignard reagents with aryl and vinyl halides, discovered
by Kumada and Corriu in 1972, is among the simplest
methods for biaryl synthesis.1 Numerous alternatives to
traditional aryl halide electrophiles have been employed in
this reaction, including aryl-oxygen (triflates,2 tosylates,3
mesylates,4 phosphates,5 alkyl ethers,6 O-carbamates,2 ac-
etates,7 diaryl sulfates,8 phenolic salts9) and aryl-sulfur10
(thiols,11 sulfides,11,12 sulfoxides,13 sulfones,11,13 O-alkyl
sulfonates,14 sulfonamides15) derivatives. Electrophiles de-
rived from aryl-nitrogen species, however, have received
comparatively little attention. In 1988, Wenkert and co-
workers reported the first cross coupling of aryltrimethyl-
ammonium iodides with aryl and alkyl Grignard reagents
(Scheme 1).16 This pioneering work demonstrated the
(8) Guan, B.-T.; Lu, X.-Y.; Zheng, Y.; Yu, D.-G.; Wu, T.; Li, K.-L.;
Li, B.-J.; Shi, Z.-J. Org. Lett. 2010, 12, 396.
(1) (a) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun.
1972, 144. (b) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374.
(9) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2010, 49, 4566.
(10) For a review on cross-coupling reactions of aryl-sulfur electrophiles
Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674.
(11) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc., Chem.
Commun. 1979, 637.
(2) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V.
J. Org. Chem. 1992, 57, 4066.
(3) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J.
Org. Chem. 1984, 49, 4894. (b) Roy, A. H.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 8704.
(12) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 20,
43.
(4) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895.
(5) Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M. Tetrahedron
Lett. 1981, 22, 4449.
(13) (a) Clayden, J.; Julia, M. J. Chem. Soc., Chem. Commun. 1993,
1682. (b) Clayden, J.; Cooney, J. J. A.; Julia, M. J. Chem. Soc. Perkin
Trans. 1 1995, 7.
(6) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem.
Soc. 1979, 101, 2246. (b) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.;
Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 12, 1437.
(7) Li, B.-J.; Xu, L.; Wu, Z.-H.; Guan, B.-T.; Sun, C.-L.; Wang, B.-Q.;
Shi, Z.-J. J. Am. Chem. Soc. 2009, 131, 14656.
(14) Cho, C.-H.; Yun, H.-S.; Park, K. J. Org. Chem. 2003, 68, 3017.
(15) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43,
888.
(16) Wenkert, E.; Han, A.-L.; Jenny, C.-J. J. Chem. Soc., Chem.
Commun. 1988, 975.
10.1021/ol1018739  2010 American Chemical Society
Published on Web 09/02/2010

Scheme 1
.
Wenkert’s Ni-Catalyzed Cross Coupling of
Table 1. Counterion Screening with NiCl2(dppp)a
Ar-NMe3I and Our Pd-Catalyzed Cross Coupling of
Ar-NMe3OTf
entry
salt
mol % catalyst
time [h]b
yield [%]c
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1a
1a
10
10
10
10
10
2.5
1.0
2
2
58
56
19
12
5
48d
48d
48d
2
60
61
4
a Reaction conditions: PhNMe3X 1 (1.0 mmol), THF (1 mL),
NiCl2(dppp), 4-MeO(C6H4)MgBr 2 (2.2 mL, 0.5 M in THF, 1.1 equiv), rt.
b Time for complete conversion of 1 by HPLC analysis. c HPLC assay yield.
d Complete conversion of 1 not achieved after 48 h.
feasibility of oxidative addition of a Ni(0) species into a C-N
bond. The low yields obtained, high reaction temperature
(benzene reflux), long reaction time (14 h), and functional
group intolerance (methoxy and fluoro groups were com-
petitively coupled) left room for improvement, however. In
2003, MacMillan and co-workers reported the Ni(cod)2/IMes-
catalyzed Suzuki cross coupling of aryltrimethylammonium
triflates.17 While this procedure gave high yields, the air-
sensitive nature of Ni(cod)2 was a concern for large-scale
applications. We recently became interested in using arylt-
rimethylammonium salts in cross-coupling reactions with aryl
Grignard reagents. In this communication we report our
findings on the dramatic effect of the counterion on reactivity
and the subsequent development of conditions which allow
for the first time a palladium-catalyzed cross coupling of
aryltrimethylammonium triflates with grignard reagents.
The counterion effect on reactivity was examined first. The
reaction of phenyltrimethylammonium salts 1a-e with
4-methoxyphenylmagnesium bromide 2 was chosen as a
model reaction. Salts 1a and 1b were prepared from N,N-
dimethylaniline in high yields as shown in Scheme 2. Salts
1c-e were purchased from commercial sources.
triflate salt 1a suggested that the catalyst loading could be
lowered; this was indeed possible and the reaction proceeded
equally as fast with 1 mol % catalyst (entry 7).
Having established the greater reactivity of triflate 1a over halide
salts, we next explored alternative catalysts in an effort to further
increase the yield of 3. The results are summarized in Table 2.
Table 2. Catalyst Screening Resultsa
entry
catalyst
time [h]b
yield [%]c
1
2
3
4
5
6
7
8
none
NiCl2
24d
24
4
2
2
1
5
24
24
1
1
5
30
24d
2
3
34
61
65
65
69
60
12
14
81
93
65
88
5
NiCl2(dppp)
NiCl2(dppe)
NiCl2(dppf)
NiCl2(PPh3)2
NiCl2(PCy3)2
PdCl2
Scheme 2. Preparation of Triflate and Tetrafluoroborate Salts
9
Pd(OAc)2
10
11
12
13
14
15
PdCl2(dppf)
PdCl2(PPh3)2
PdCl2[P(o-tolyl)3]2
Pd(PPh3)4
PdCl2(PCy3)2
CoCl2 + 2PPh3
Employing Wenkert’s catalyst, NiCl2(dppp)14 (10 mol %),
with 1.1 equiv of Grignard 2, we were gratified to observe
a fast reaction at room temperature with salts 1a and 1b
(Table 1, entries 1 and 2). In contrast, the iodide, bromide,
and chloride salts 1c-e reacted much more slowly at room
temperature (entries 3-5). The exceptional reactivity of the
30
a Reaction conditions: PhNMe3OTf 1a (1.0 mmol), THF (1 mL), catalyst
(1.0 mol %), 4-MeO(C6H4)MgBr 2 (2.2 mL, 0.5 M in THF, 1.1 equiv), rt.
b Time for complete conversion of 1a by HPLC analysis unless noted otherwise.
c HPLC assay yield. d Complete conversion of 1a not achieved after 24 h.
With no catalyst (entry 1), little background reaction was
observed. By using ligand free NiCl2 (entry 2), a low yield
(17) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
6046.
Org. Lett., Vol. 12, No. 19, 2010
4389

of 3 was obtained. Bidentate (entries 3-5) and monodentate
(entries 6-7) ligands on nickel gave similar yields, with
NiCl2(PPh3)2 being optimal (69% assay yield of 3). Interest-
ingly, NiCl2(PCy3)2, which has been shown to be a powerful
catalyst for many difficult cross-coupling reactions, was
significantly slower (5 h) than the other arylphosphine-based
catalysts. Next, palladium catalysis was investigated. Non-
ligated Pd gave slow reactions and low yields (entries 8 and
9). Using PdCl2(dppf), however, gave complete reaction in
<1 h and an excellent yield (81%). The best result (93%
assay yield) was obtained with PdCl2(PPh3)2 (entry 11).
Variation to a more bulky (entry 12) or more electron-rich
(entry 14) phosphine gave lower yields. Interestingly, Pd-
(PPh3)4 also gave an excellent assay yield of 88%, but
proceeded much more slowly, requiring 30 h for complete
conversion of 1a (entry 13). Catalysis by cobalt proceeded
in low yield (entry 15).
Table 3. Pd-Catalyzed Coupling of Aryltrimethylammonium
Triflates with Aryl Grignard Reagentsa
The scope of the cross-coupling reaction was explored with
use of the optimized reaction conditions (Table 3). Para-,
meta-, and ortho-substituted aryl Grignard reagents all
coupled with salt 1a in excellent yields (entries 1-4).
Notably, the presence of chloro groups was well tolerated
under the reaction conditions (entries 3 and 14). The sterically
hindered 2-mesitylmagnesium bromide coupled only slowly
at rt, but on heating to 60 °C for 2 h, an excellent yield of
biaryl 9 was obtained (entry 6). The functional group
compatibility of the reaction extended to alkyl esters (entries
7 and 8), an aryl ester (entry 9), and nitriles (entries 10 and
11). In addition, a methyl thioether was tolerated (entry 10).
A terphenyl could be produced by employing the 4-biphenyl
salt 22 (entry 14). Finally, the 2-pyridyl salt 24 also coupled
smoothly (entry 15).
Given the nearly quantitative nature of the methylation
reaction of N,N-dimethylanilines with methyl triflate, we
suspected the methylation and cross-coupling reactions could
be telescoped into a one-pot process. Thus, treatment of N,N-
dimethylaniline with a slight excess of methyl triflate in
CH2Cl2 gave the salt 1a. Subsequent addition of THF,
PdCl2(PPh3)2, and finally 4-fluorophenylmagnesium bromide
gave biaryl 4 in 88% isolated yield (Scheme 3). The reaction
time was longer for this one-pot protocol (5 h vs 1 h for the
direct reaction of 1a), but the yield was nonetheless com-
parable.
While the examples in Table 3 demonstrated the present
reaction conditions are tolerant of several functional groups
which have been shown to be competent electrophiles in
various Ni- and Pd-catalyzed cross-coupling reactions (F,18
Cl,19 OMe,6 OCF3,20 OPiv,21 SMe,9,10 CN22), we sought to
establish reactivity trends relative to the most common
electrophiles. A set of competition experiments, outlined in
Table 4, was conducted. Thus, an equimolar mixture of salt
a See the Supporting Information for procedures for preparation of
ArNMe3OTf and for all cross-coupling reactions. b Isolated yield after
chromatography on SiO2. c Reaction run at 60 °C for 2 h.
(18) Bohm, V. P. W.; Gstottmayer, C. W. K.; Weskamp, T.; Herrmann,
W. A. Angew. Chem., Int. Ed. 2001, 40, 3387.
(19) Bohm, V. P. W.; Weskamp, T.; Gstottmayer, C. W. K.; Herrmann,
W. A. Angew. Chem., Int. Ed. 2000, 39, 1602.
(20) Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428.
(21) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008,
130, 14422.
1a and PhX (X ) Cl, Br, I, or OTf) and 1 mol %
PdCl2(PPh3)2 in THF at rt was treated with 1 equiv of
4-fluorophenylmagnesium bromide. The reactions were
(22) Yu, D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.;
Shi, Z.-J. Org. Lett. 2009, 11, 3374.
4390
Org. Lett., Vol. 12, No. 19, 2010

were quenched with MeOH and HPLC assay yields of
product 4, residual 1a and residual PhX were obtained. The
salt 1a reacted much faster than PhCl or PhBr, as nearly
complete consumption of 1a was observed in both cases,
along with nearly complete recovery of PhCl and PhBr
(entries 1 and 2). The experiment with PhI, however, showed
a slight preference in reactivity of PhI over 1a (53% of 1a
recovered vs 41% of PhI recovered; entry 3). Finally, the
experiment employing PhOTf showed a preferential reaction
of 1a (22% of 1a recovered vs 80% of PhOTf recovered;
entry 4). From these experiments the relative reactivities,
under the present reaction conditions, can be ascribed as
follows: PhI is slightly more reactive than PhNMe3OTf,
which is in turn slightly more reactive than PhOTf, and much
more reactive than either PhBr or PhCl.
Scheme 3. One-Pot Methylation/Cross Coupling of
N,N-Dimethylaniline
Table 4. Competition Experiments in the Coupling of 1a and
Phenyl Electrophiles with 4-Fluorophenylmagnesium Bromidea
In conclusion, we have demonstrated that aryltrimethyl-
ammonium triflates and tetrafluoroborates are highly reactive
electrophiles for Pd-catalyzed cross coupling with aryl
Grignard reagents. Palladium was found to be more efficient
than nickel for catalysis of this process. The reaction proceeds
under mild reaction conditions (rt) and with only a slight
excess of Grignard reagent, and therefore is tolerant of a
wide range of functional groups. The methylation of N,
N-dimethylaniline and subsequent cross coupling may be
combined into a one-pot operation while maintaining a high
yield of biaryl product. Finally, the reactivity of PhNMe3OTf
relative to the most common cross-coupling electrophiles was
established through competition experiments.
recovery of
entry PhX yield of 4b [%] recovery of 1ab [%] PhXb [%]
1
2
3
4
PhCl
PhBr
PhI
94
94
93
91
0
4
53
22
97
92
41
80
PhOTf
a Reaction conditions: PhNMe3OTf 1a (1.0 mmol), PhX (1.0 mmol),
THF (2 mL), PdCl2(PPh3)2 (1.0 mol %), 4-F(C6H4)MgBr (1.0 mL, 1.0 M
in THF, 1.0 equiv), rt. b HPLC assay yield.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for all products and unknown substrates. This material
is available free of charge via the Internet at http://pubs.acs.org.
monitored by HPLC for complete consumption of 4-fluo-
rophenylmagnesium bromide. Upon completion, the reactions
OL1018739
Org. Lett., Vol. 12, No. 19, 2010
4391