Twofold CH Functionalization: Palladium-Catalyzed Ortho

Arylation of Anilides
Citation
Brasche, Gordon, Jorge Garcia-Fortanet, and Stephen L.
Buchwald. Twofold CH Functionalization: Palladium-Catalyzed
Ortho Arylation of Anilides. Org. Lett. 10, no. 11 (June 2008):
22072210. 2008 American Chemical Society.
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Twofold C-H Functionalization:
Palladium-Catalyzed Ortho Arylation of
Anilides
Gordon Brasche, Jorge Garc a-Fortanet, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received March 17, 2008
ABSTRACT
The ortho arylation of anilides to form biphenyls via a twofold C-H functionalization/C-C bond-forming process is described. The oxidative
coupling takes place in the presence of 5-10 mol % of Pd(OAc)
2
, 10-20 mol % of DMSO, and 4-11 equiv of the aryl substrate in TFA under
an oxygen atmosphere. No metal-containing cocatalyst is required.
Organic chemists are faced with the challenges of accessing
complex organic molecules efciently, producing a mini-
mum amount of waste and handling nonrenewable or
natural resources as economically as possible. In that
context, the growing number of reports of catalytic, direct
functionalization of C-H bonds by transition metals
represents a promising advance.
1,2
The application of C-H
bond functionalization to the synthesis of biaryls, molecules
with important applications in the polymer and pharmaceuti-
cal sciences, illustrates the potential utility of these protocols.
3
As shown in Scheme 1, biaryl synthesis via C-H bond
activation has been achieved via simple
4
and, most recently,
via twofold
5
C-H functionalization approaches. High regi-
oselectivities have generally been observed only when
electron-rich arenes
5ce
ordirecting groups (DG)
6
such as
(1) For recent reviews of C-H functionalization, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b) Godula, K.; Sames,
D. Science 2006, 312, 67. (c) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731.
(2) For selected examples using palladium as a catalyst, see: (a)
Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
3276. (b) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K.
Org. Lett. 2007, 9, 2931. (c) Cai, G.; Fu, Y.; Le, Y.; Wan, X.; Shi, Z.
J. Am. Chem. Soc. 2007, 129, 7666. (d) Delcamp, J. H.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 15076. (e) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao,
S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. (f) Grimster,
N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2005, 44, 3125. (g) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 14560. (h) Boele, M. D. K.; van Strijdonck, G. P. F.;
de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen,
P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586.
(3) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Moore, R. E., Eds.; Springer: New York, 2001; Vol. 82,
pp 1-293.
(4) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (b) Yang, S.; Li, B.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (c) Chiong, H. A.;
Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (d) Daugulis,
O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
Scheme 1. Palladium-Catalyzed Simple and twofold C-H
Functionalization in the Presence of a Directing Group
ORGANIC
LETTERS
2008
Vol. 10, No. 11
2207-2210
10.1021/ol800619c CCC: $40.75 2008 American Chemical Society
Published on Web 05/09/2008
anilides or pyridine are used as one of the coupling partners.
Despite substantial practical advances, however, important
limitations such as the need for Cu or Ag salts as cooxidants
(oftentimes in stoichiometric amounts)
5a,4d
and the require-
ment of up to a 100 equivalent excess of arene coupling
partner limit the synthetic utility of these methods. Fewer
examples have been reported of palladium-catalyzed C-H
functionalization using molecular oxygen as the only oxi-
dant.
7
In one elegant example, Stoltz and co-workers
described the oxidative annulation of indoles using a catalytic
system of Pd(II)/ligand/O
2
(1 atm).
8
During our investigations in C-H activation-type reac-
tions, we found that a twofold C-H functionalization occurs
between anilides and arenes to form substituted biaryls using
5-10 mol % of Pd(OAc)
2
and 4-11 equiv of the aryl
coupling partner in the presence of oxygen as the terminal
oxidant.
Initially, we studied the coupling of 2-methylpivalanilide
(1a) with benzene (2a) in the presence of Pd(OAc)
2
and
oxygen (1 atm) to afford 3a (Table 1).
9
The effects of
different palladium sources, additives, and temperature were
systematically examined. Low conversion of 1a to 3a was
observed in the presence of 5 mol % of Pd(OAc)
2
and 11
equiv (1 mL) of benzene (2a) under an oxygen atmosphere
at 80 C (entry 1). Similar results were obtained when 5
equiv of acetic acid (AcOH) were added (entry 2). The
substitution of triuoroacetic acid (TFA) for AcOH resulted
in better yields, but these results were not fully reproducible.
After some experimentation we found that loss of active
catalyst through palladium black formation could be slowed
by the addition of DMSO (10 mol %), thus affording the
expected biaryl in excellent yield (entry 4). The best results
were nally obtained at 90 C, at which temperature 3a was
isolated in 92% yield (entry 7).
The reaction could also be carried out with only 4 equiv
of 2a by increasing the amount of TFA to 10 equiv, although
the corresponding yield was lower. During the course of our
work, an elegant related paper by Shi appeared.
5a
In this
disclosure, a single example of twofold C-H functionaliza-
tion using 6 equiv of arene coupling partner was reported.
10
As shown in entry 9, oxygen could be replaced effectively
by air, but lower conversions were generally achieved under
these conditions. Poor results were obtained if Pd(OAc)
2
was
substituted by other palladium salts such as Pd(O
2
CCF
3
)
2
or
PdCl
2
(entries 5 and 6).
Using these optimized conditions, we next explored the
scope and generality of this process using benzene (2a) as
an arylating reagent. As shown in Table 2 (entry 1),
acetanilides, as well as pivalanilides, can be efciently
arylated using our protocol. Nonetheless, due to their greater
stability and selectivity at higher temperatures, we decided
to focus our attention on pivalanilides.
Neutral or electron-rich substituents on the anilide afforded
arylated products in good yields of up to 91% (entries 2-5).
In the case of the slightly electron-decient uorinated
compound 1g the temperature had to be raised to 100 C to
obtain a satisfactory yield of 68% (entry 6). However, even
(5) (a) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed.
2008, 47, 1115. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007,
129, 11904. (c) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 12072. (d) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(e) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org.
Lett. 2007, 9, 3137.
(6) (a) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041.
(b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva,
A. Synlett 2006, 3382.
(7) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am.
Chem. Soc. 2006, 128, 2528. (b) Stahl, S. Angew. Chem., Int. Ed. 2004,
43, 3400. (c) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew.
Chem., Int. Ed. 2003, 42, 3512. (d) Hagelin, H.; Oslob, J. D.; kermark,
B. Chem. Eur. J. 1999, 5, 2413. (e) Shue, R. S. J. Chem. Soc. Chem.
Commun. 1971, 1510.
(8) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578.
(b) Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron 2008, doi:10.1016/
j.tet.2008.01.052.
(9) Unsubstituted pivalanilide gave rise to a variable mixture of mono-
and bis-ortho arylated products. Similar results were observed by Daugulis
et al. See ref 4d for details.
(10) According to the Supporting Information of ref 5a, most of the
examples use 28-37 equiv of arene counterpart.
Table 1. Screening Results of the Arylation of 2-Methylpivalanilide with Benzene
entry
a
2a (equiv) Pd catalyst additive(s) gas T (C) convn
b
(%) yield
b
(%)
1 11 Pd(OAc)
2
O
2
80 8 3
2 11 Pd(OAc)
2
5 equiv of HOAc O
2
80 11 3
3
c
11 Pd(OAc)
2
5 equiv of TFA O
2
80 66 64
4 11 Pd(OAc)
2
5 equiv of TFA, 10 mol % of DMSO O
2
80 91 87
5 11 Pd(O
2
CCF
3
)
2
5 equiv of TFA, 10 mol % of DMSO O
2
80 20 16
6 11 PdCl
2
5 equiv of TFA, 10 mol % of DMSO O
2
80 8
7 11 Pd(OAc)
2
5 equiv of TFA, 10 mol % of DMSO O
2
90 100 92
d
8 4 Pd(OAc)
2
10 equiv of TFA, 10 mol % of DMSO O
2
100 97 78
9
e
11 Pd(OAc)
2
5 equiv of TFA, 10 mol % of DMSO air 80 82 76
a
Reactions carried out on a 1.0 mmol scale.
b
Corrected GC data with dodecane as internal standard.
c
Reaction was carried out multiple times with
signicantly varying results.
d
Isolated yield: 90% (average of two runs).
e
Reaction carried out on a 0.2 mmol scale.
2208 Org. Lett., Vol. 10, No. 11, 2008
with 10 mol % of Pd(OAc)
2
, this reaction could not be driven
to completion. Furthermore, the arylated product 3h could
be isolated in only 59% yield after 96 h at 55 C (entry 7).
In the case of the chlorinated example 1h, the reaction had
to be carried out at a lower temperature to prevent reduction
of the aryl chloride and the immediate formation of palladium
black. Electron-decient substrates such as those substituted
by CF
3
, CO
2
Me, or NO
2
groups underwent either no or only
trace amounts of arylation.
Prompted by these results, we next examined the arylation
of anilides with arenes other than benzene (Table 3). Either
electron-neutral or electron-rich arenes were equally effective
using 7.5-10 mol % of Pd(OAc)
2
. The use of toluene as
coupling partner, however, afforded a mixture of ortho, meta,
and para regioisomers (Table 3, entry 1). The regioselectivity
was improved by employing anisole or arenes with several
substituents. In particular, the use of veratrole as the arene
coupling partner exclusively afforded the arylation product
4d in excellent yield as the only regioisomer.
Although the electronic effects of the substituents on the
arene are considerable in determining the substitution pattern
of the product (Table 3, entries 1, 3, 5, 7 vs 2, 4, 6, 8), steric
hindrance appears to play a more important role. For
example, when 1,3-dimethoxybenzene was used as the arene
coupling partner (entry 6), the 1,2,3-regioisomer arising from
coupling of the most electron-rich carbon, was not observed.
Indeed, with all substrates tested, arylation at less hindered
positions was observed almost exclusively. In line with these
results, the arylation of 1,4-dimethoxybenzene was consis-
tently sluggish. These results are in accord with the results
recently described by Sanford and co-workers.
5b
Because of the excellent regioselectivity observed using
veratrole 2d as the arene coupling partner, we next turned
our attention to the reaction of this substrate with pivalanil-
ides with different substituents (Table 4). As expected, a
single regioisomer was observed in all cases, yielding the
corresponding biaryls in good yield.
It is worth mentioning that reactions employing uoroben-
zene derivatives, such as 1,3-diuorobenzene or pentauo-
robenzene, as the arene coupling partner resulted in notably
low conversions under these conditions. The signicant
acidity of the ortho proton to the uorine atom make these
substrates particularly reactive in a proton abstraction-type
mechanism. Thereby, our results suggest that another mech-
anism may be operative under our reaction conditions.
5b,11
Table 2. Arylation of Anilides with Benzene
a
Isolated yield, average of two runs.
b
Incomplete conversion of the
starting material.
c
Reaction run for 96 h.
Table 3. Arylation of Anilides with Different Aryls
a
The ratio of the regioisomers was detemined by GC.
b
Isolated yield
for the mixture of all regioisomers, average of two runs.
c
The ratio of the
regioisomers was calculated by
1
H NMR.
d
Incomplete conversion.
e
5 equiv
of TFA were used.
Org. Lett., Vol. 10, No. 11, 2008 2209
In summary, we have developed a practical and mild
method for the synthesis of biaryl compounds from simple
and readily accessible anilides and arenes via twofold C-H
functionalization using molecular oxygen at atmospheric
pressure as the only oxidant. Further mechanistic studies are
currently underway.
Acknowledgment. We thank the National Institutes of
Health (GM46059) for support of this work. G.B. and J.G.-
F. thank the German Academic Exchange Service (DAAD)
and the Spanish MEC for postdoctoral fellowships. BASF
is acknowledged for a generous gift of Pd(OAc)
2
. We also
thank Amgen, Merck, and Boehringer Ingelheim for ad-
ditional unrestricted funds. The Varian NMR instruments
used for this publication were purchased with funds from
the NSF (CHE 9808061 and DBI 9729592).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800619C
(11) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
Table 4. Arylation of Anilides with Veratrole 2d
a
Isolated yield, average of two runs.
b
Incomplete conversion.
2210 Org. Lett., Vol. 10, No. 11, 2008