Palladium-catalyzed direct arylation of nitro-substituted aromatics with aryl halides

Article abstract of DOI:10.1021/ol801839w

(Chemical Equation Presented) Direct arylation reactions of nitrobenzenes and aryl halides occur in good yield and high ortho regioselectivity. These reactions can be performed on gram scale with as few as 3 equiv of the nitro arene relative to the aryl halide. The synthetic utility of this method is demonstrated via rapid synthesis of a Boscalid intermediate.

Full text of DOI:10.1021/ol801839w

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4533-4536
Palladium-Catalyzed Direct Arylation of
Nitro-Substituted Aromatics with Aryl
Halides
Laurence Caron, Louis-Charles Campeau, and Keith Fagnou*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
keith.fagnou@uottawa.ca
Received August 7, 2008
ABSTRACT
Direct arylation reactions of nitrobenzenes and aryl halides occur in good yield and high ortho regioselectivity. These reactions can be
performed on gram scale with as few as 3 equiv of the nitro arene relative to the aryl halide. The synthetic utility of this method is demonstrated
via rapid synthesis of a Boscalid intermediate.
Metal-catalyzed cross-coupling reactions of aryl halides
with an organometallic reagent constitute the most widely
used route to prepare biaryl molecules.1 While these
transformations occur in excellent yield, chemists have
begun to question the need for stoichiometric preactivation
to achieve the necessary reactivity.2 A promising alterna-
tive is a class of reactions called direct arylation, where
one of the preactivated species is substituted with the
oxides8 have been shown to react with aryl halides under
palladium(0) catalysis in high yield, allowing a novel entry
point into reaction development. This reactivity has been
rationalizedtooccurthroughaconcertedmetalation-deprotonation
(CMD) pathway5d,j,9 which might benefit from the presence
of inductive electron-withdrawing groups on the arene ring.
This insight prompted us to explore the reactivity of other
electron-deficient substrates that may not have warranted
consideration under a different mindset.
simple arene itself (usually the organometallic).3-5
A
variety of arenes have been demonstrated to undergo reaction,
particularly electron-rich heterocycles.6 In contrast, electron-
deficient arenes have been less extensively investigated.
Recently, however, fluoroarenes,5k,7 and azine/diazine N-
(3) For general reviews on direct arylation, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (d) Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200. (e) Lewis, J. C.; Bergman, R. C.; Ellman, J. A.
Acc. Chem. Res. 2008, 41, 1013.
(1) For reviews on this topic, see: Hassan, J.; Se´vignon, M.; Gozzi, C.;
Shulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(4) For recent examples using Pd(0), see: (a) Ackermann, L.; Vicente,
R.; Born, R. AdV. Synth. Catal. 2008, 350, 741. (b) Lebrasseur, N.; Larrosa,
I. J. Am. Chem. Soc. 2008, 130, 2926. (c) Shabazhov, D.; Daugulis, O. J.
Org. Chem. 2007, 72, 7720. (d) Campeau, L.-C; Bertrand-Laperle, M.;
Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3276. (e) Derridj, F.; Gottumukkala, A. L.; Djebbar, S.; Doucet,
H. Eur. J. Inorg. Chem. 2008, 2250. (f) Chuprakov, S.; Chernyak, N.;
Dudnik, A.; Gevorgyan, V. Org. Lett. 2007, 9, 2333.
(2) For reviews on C-H activation, see: (a) Kalyani, D.; Dick, A. R.;
Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483. (b) Labinger,
J. A.; Bercaw, J. E. Nature 2002, 417, 507. (c) Ritleng, V.; Silin, C.; Pfeffer,
M. Chem. ReV. 2002, 102, 1731. (d) Jia, C.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 633. (e) Godula, K.; Sames, D. Science 2006,
312, 67. (f) Li, J.-J.; Giri, R.; Yu, J.-Q. Tetrahedron 2008, 64, 6979. (g)
Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron 2008, 64, 5987.
10.1021/ol801839w CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

Our attention was drawn to the potential utility of nitro
aromatics which are easily accessible via arene nitration with
high degrees of predictable regioselection. Many are com-
mercially available at low cost (for example, the cost of
nitrobenzene compares favorably to benzene itself). Further-
more, there are a wide range of methods for either removal
or derivatization of the nitro functionality following direct
arylation cross-coupling.10 Herein we show that nitro-
substituted aromatics exhibit useful reactivity in direct
arylation and may be used in the synthesis of a variety of
functionalized biaryl molecules. The successful inclusion of
nitroarenes in the array of aromatic direct arylation coupling
partners also demonstrates the value associated with a
consideration of CMD entry points into direct arylation.
Initial screens were performed with 3-bromoanisole in
conjunction with 10 equiv of nitrobenzene. In early evalu-
ations, the use of apolar solvents, such as mesitylene or
octane provided superior outcomes compared to the more
common use of polar aprotic solvents such as N,N-dimeth-
ylformamide (DMA). While complete consumption of the
limiting reagent, 3-bromoanisole was observed in each case,
improved regioselectivity in favor of reaction at the ortho-
position, and cleaner reactivity is obtained in apolar sol-
vents.11
(5) For recent examples using Pd(II), see: (a) Beck, E. M.; Hatley, R.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004. (b) Wang, D.-H.;
Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (c) Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (d) Chiong,
H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. For
recent examples using Rh(I), see: (e) Tsai, A. S.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2008, 130, 6316. (f) Proch, S.; Kempe, R. Angew.
Chem., Int. Ed. 2007, 46, 3135. (g) Ueura, K.; Satoh, T.; Miura, M. Org.
Lett. 2005, 7, 2229. (h) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J.
Am. Chem. Soc. 2006, 128, 11748. For recent examples using Ru, see: (i)
Ozdemir, I.; Demir, S.; C¸ etinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau,
C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156. (j) Ackermann, L.;
Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299. (k) Ackermann, L.;
Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115. (l) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (m) Do,
H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (n) Ackermann,
L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081.
(6) For reviews, see refs 3c and 3d. For recent examples, see: (a) Lane,
B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (b) Li, W. J.; Nelson, D. P.;
Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org.
Lett. 2003, 5, 4835. (c) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.;
Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003,
125, 1700. (d) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005,
127, 4996. (e) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (f)
Turner, G. L.; Morris, J. A.; Greany, M. F. Angew. Chem., Int. Ed. 2007,
46, 7996. (g) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007,
72, 8543. (h) Pozˇgan, F.; Rogerm, J.; Doucet, H. ChemSusChem 2008, 1,
404.
Further reaction optimization revealed the crucial role of
base in these transformations. For example, treatment of
3-bromoanisole with 10 equiv of nitrobenzene in the presence
of 5 mol % of Pd(OAc)2, 15 mol % of PtBu2MeHBF4, 1.3
equiv of base, and 0-0.3 equiv of pivalic acid in mesitylene
at 125 °C provides highly variable outcomes depending on
the choice of base and the presence/absence of pivalic acid.
While the use of K3PO4 (Table 1, entry 1) does not induce
11
Table 1. Effect of Base and Pivalic Acida,
regioselectivity
(o/(m+p))b
entry base additive % conversion % yieldc
1
2
3
4
5
6
7
8
K3PO4
Cs2CO none
K2CO3 none
CsOPiv none
KOPiv none
none
0
52
73
22
19
65
100
100
0
28
43
10
0
(7) (a) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097.
(b) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754.
27:1
5.1:1
1.7:1
1.8:1
6:1
(8) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006,
45, 7781. (c) Campeau, L.-C.; Schipper, D; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266. See also ref 4e.
7.2
K3PO4
PivOH
29
69
77
(9) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 10848. (b) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (e) Davies, D. L.;
Donald, S. M. A.; Al-Duaij, O.; Macgregor, S. A.; Polleth, M. J. Am. Chem.
Soc. 2006, 128, 4210. (c) Garcia-Cuadrado, D.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129,
6880.
Cs2CO3 PivOH
36:1
34:1
K2CO3
PivOH
a Conditions: PivOH (0 to 0.3 equiv), base (1.3 equiv), Pd(OAc)2 (5
mol %), and PtBu2MeHBF4 (15 mol %) were added sequentially to the
reaction vessel. ArBr (1.0 equiv), nitrobenzene (10 equiv), and mesitylene
(1.3 M) were added, and the reaction was heated to 125 °C for 16 h
(overnight). b Determined by GCMS analysis. c Isolated yield.
(10) For transformations of nitrobiphenyl into indole, see selected
examples: (a) Ragaini, F.; Rapetti, A.; Visentin, E.; Monzani, M.; Caselli,
A.; Cenini, S. J. Org. Chem. 2006, 71, 3748. (b) Bartoli, G.; Palmieri, G.
Tetrahedron Lett. 1989, 30, 2129. For transformations of nitrobiphenyl into
carbazole, see selected examples: (c) Sanz, R.; Escribano, J.; Pedrosa, M. R.;
Aguado, R.; Arna´iz, F. J. AdV. Synth. Catal. 2007, 349, 713. (d) Smitrovich,
J. H.; Davies, I. W. Org. Lett. 2004, 6, 533. For transformation of
nitrobiphenyl to 2-hyrdoxybiphenyl, see selected examples: (e) Boldt, P.;
Bruhnke, D.; Gerson, F.; Scholz, M.; Jones, J. G.; Ba¨r, F. HelV. Chim. Acta
1993, 76, 1739. For transformation of nitrobiphenyl into 2-aminobiphenyl,
see selected examples: (f) Tafesh, A. M.; Weiguny, J. Chem. ReV. 1996,
96, 2035. (g) McLaughlin, M. A.; Barnes, D. M. Tetrahedron Lett. 2006,
47, 9095. (h) Liu, Y.; Lu, Y.; Prashad, M.; Repie`, O.; Blacklock, T. J. AdV.
Synth. Catal. 2005, 347, 217. (i) Hanaya, K.; Muramatsu, T.; Kudo, H.;
Chow, Y. L. J. Chem. Soc., Perkin Trans. 1 1979, 10, 2409. (j) Vass, A.;
Dudas, J.; Toth, J.; Varma, R. S. Tetrahedron Lett. 2001, 42, 5347. (k)
Huber, D.; ermann, G.; Leclerc, G. Tetrahedron Lett. 1988, 29, 635. For
transformation of nitrobiphenyl into 2-cyanobiphenyl, 2-chlorobiphenyl and
2-bromobiphenyl, see selected examples: (l) Suzuki, N.; Azuma, T.; Kaneko,
Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1
1987, 3, 645. (m) Lee, J. G.; Cha, H. T. Tetrahedron Lett. 1992, 33, 3167.
(n) Doyle, M. P.; Siegried, B.; Dellaria, J. F., Jr. J. Org. Chem. 1977, 42,
2426. (o) Roe, A.; Graham, J. R. J. Am. Chem. Soc. 1952, 74, 6297.
reaction, the use of carbonate bases leads to partial conver-
sion (Table 1, entries 2 and 3). Similarly, the use of
stoichiometric potassium and cesium pivalate provides low
conversions and isolated yields (Table 1, entries 4 and 5).
In contrast, the combined use of a carbonate base and pivalic
acid (generating the metal pivalate in situ) provides 100%
conversion and synthetically useful isolated yields of the
o-arylated biaryl compound (Table 1, entries 7 and 8).
Interestingly, the ortho/(meta+para) selectivity is also strongly
influenced by these same parameters. While relatively poor
(11) Incompete peak separation of the meta and para isomers in the
crude GCMS analysis prevents a more precise measure of these two isomers
separately. In most cases, the meta/para ratio was ∼2:1.
4534
Org. Lett., Vol. 10, No. 20, 2008

reioselectivity is obtained with either K2CO3 (5.1: 1) or
KOPiv (1.8: 1), when K2CO3 is combined with a substo-
ichiometric quantity of KOPiv, excellent regioselectivity is
obtained (34:1). The reasons for this change in selectivity
are a focus of ongoing mechanistic evaluation.
yield is influenced principally by the ease or difficulty with
which the major isomer could be separated in pure form from
the small amounts of the other minor isomers by chroma-
tography and is a property that may improve when working
on larger scale.
Illustrative examples of direct arylation employing ni-
trobenzene are shown in Table 2. Most cross-coupling pairs
Table 3. Scope of Substituted Nitrobenzenea
Table 2. Scope of Nitrobenzene and Various Aryl Bromidesa
a Conditions: PivOH (0.3 equiv), K2CO3 (1.3 equiv), Pd(OAc)2 (5 mol
%), PtBu2MeHBF4 (15 mol %), and nitroarene (5.0 equiv) were added
sequentially to the reaction vessel. ArBr (1.0 equiv) and mesitylene (1.3
M) were added, and the reaction was heated to 125 °C for 16 h (overnight).
b Isolated yield. c Reaction was performed on a 1 g scale using 3.0 equiv
of nitrobenzene.
a Conditions: PivOH (0.3 equiv), K2CO3 (1.3 equiv), Pd(OAc)2 (5 mol
%), and PtBu2MeHBF4 (15 mol %) were added sequentially to the reaction
vessel. ArBr (1.0 equiv), nitrobenzene (10 equiv) and mesitylene (1.3 M)
were added and the reaction was heated to 125 °C for 16 h (overnight).
b Isolated yield. c 0.5 equiv of Ag2CO3 added.
A range of functional groups are tolerated on the aryl
halide including electron poor (Table 2, entries 5, 6, 8, and
9) and electron rich (entries 2, 4, and 7) substrates. The use
of an aryl iodide (entry 2) is tolerated when 0.5 equiv of
silver carbonate is used. This diminished reactivity with aryl
went to 100% conversion and provided moderate to good
isolated yields of pure o-arylated compound. This isolated
Org. Lett., Vol. 10, No. 20, 2008
4535

iodides has been observed in other direct arylation reactions
and may be due to competitive iodide inhibition of the
palladium catalyst.8b,12 Chlorides may also be employed, but
lower yields are obtained under the current conditions when
compared to the use of aryl bromides (entry 2).
Scheme 1. Boscalid Intermediate
The effect of substitution on the nitroarene was also
examined; in many cases, high levels of regioselection were
obtained (Table 3). When an ortho substituent is present,
1,2,3-trisubstituted arenes are generated in moderate to good
yields (entries 1-3, 5, and 7). Similarly, a para substituent
may also be present (entry 10). Interestingly, when meta-
functionalized nitroarenes are employed, the regiochemical
outcome of direct arylation is governed by both substituents.
For example, when a m-methyl or methyl ester group is
present, arylation occurs ortho to the nitro substituent at the
more sterically accessible position (entries 4, 6, and 9). On
the contrary, when a meta nitrile functionality is present,
arylation occurs at the more sterically encumbered position
between the two substituents indicating that other influences
on regioselectivity must be at play (entry 8).
While the initial reactions employing substituted nitroben-
zenes were performed with 5-10 equiv of the nitroarene, it
was subsequently discovered that as few as 3 equiv of the
nitroarene may be employed while maintaining good yields.
For example, treatment of 1 g of 3-bromoanisole with 3 equiv
of 3-methylnitrobenzoate under the standard reaction condi-
tions produces the o-arylated product in 72% isolated yield
(Table 3, entry 9).
quantity of methylbenzoate, and in another, in the presence
of anisole. In both instances, arylation of nitrobenzene is
highly favored.14 These observations as well as the experi-
mentally observed reversal in regioselectivity are a focus of
ongoing experimental and computational analysis. Nonethe-
less, the successful inclusion of electron-deficient nitroben-
zenes in palladium-catalyzed direct arylation reactions, and
the observed preferential reactivity over both ester and
methoxy-substituted benzenes point to a useful and poten-
tially broad reaction scope outside the traditional nucleophilic
arene substrate class. Important from a practical perspective,
these reactions have been scaled to gram levels and may be
performed with a slight excess of the nitrobenzene if desired.
As the mechanism of direct arylation becomes better
understood, it is anticipated that many, otherwise disregarded
arenes will emerge as useful coupling partners in the
preparation of useful biaryl building blocks for use in
medicinal chemistry and materials science.
To further investigate the potential utility of this chemistry,
we investigated its use in the rapid preparation of a key
intermediate 23 in the synthesis of Boscalid, a commercially
available agrochemical compound.13 4′-Chlorobiphenyl-2-
amine 23 is easily prepared in 60% isolated yield (over two
steps) by treatment of nitrobenzene with 4-bromochloroben-
zene under the standard conditions followed by reduction
of the nitro group to the amine by treatment of the crude
reaction mixture with SnCl2 and concentrated HCl.
Acknowledgment. We thank NSERC, the Research
Corporation, the Sloan Foundation, the ACS (PRF AC),
Merck Frosst, Merck Inc, Amgen, Eli Lilly, Astra Zeneca
and Boehringer Ingelheim for financial support. We thank
Professor Tom K. Woo for the use of computing facilities
funded by the CFI and the ORF.
To probe the reactivity imparted by the nitro functionality,
two competition reactions were performed. In one case,
nitrobenzene was reacted in the presence of an equimolar
Supporting Information Available: Complete charac-
terization data for all new biaryl products as well as
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581
.
OL801839W
(13) (a) Ehrenfreund, J.; Lamberth, C.; Tobler, H.; Walter, H. WO pat.
2004, 058723. (b) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006,
313, 662.
(14) See the Supporting Information for details.
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Org. Lett., Vol. 10, No. 20, 2008