Palladium-catalyzed direct arylation of aryl(azaaryl)methanes with aryl halides providing triarylmethanes

Article abstract of DOI:10.1021/ol0708119

Direct arylation of aryl(azaaryl)methanes with aryl halidas takes place at the benzylic position in the presence of a hydroxide base under palladium catalysis to yield triarylmethanes

Full text of DOI:10.1021/ol0708119

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2373-2375
Palladium-Catalyzed Direct Arylation of
Aryl(azaaryl)methanes with Aryl Halides
Providing Triarylmethanes
Takashi Niwa, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received April 4, 2007
ABSTRACT
Direct arylation of aryl(azaaryl)methanes with aryl halides takes place at the benzylic position in the presence of a hydroxide base under
palladium catalysis to yield triarylmethanes.
Transition-metal-catalyzed cross-coupling reactions are among
the most important reactions in organic synthesis.1 The
conventional cross-coupling procedure requires preparation
of organometallic reagents in advance of the reaction. Recent
progress in this area has allowed for direct use of organic
compounds bearing no metallic atoms as nucleophilic
coupling partners. Among them, direct conversion of sp2C-H
bonds into sp2C-sp2C bonds of biaryls is widely investi-
gated.2-5 On the other hand, examples of direct arylation of
sp3C-H bonds are relatively less pronounced.6-14 Here we
report a new repertoire of direct arylation of sp3C-H bonds,
direct arylation of diarylmethanes providing triarylmethanes.
(5) Direct arylation of electron-deficient arenes: (a) Lafrance, M.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496-16497. (b) Lafrance, M.;
Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
8754-8755. (c) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi,
M.; Ponde, D. E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809-
1812. (d) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020-18021.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004. (c) Cross-Coupling Reactions. A Practical Guide;
Miyaura, N., Ed.; Springer: Berlin, 2002. (d) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons:
New York, 2002.
(2) (a) Dyker, G., Ed. Handbook of C-H Transformations; Wiley-
VCH: Weinheim, Germany, 2005. (b) Godula, K.; Sames, D. Science 2006,
312, 67-72. (c) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345,
1077-1101. (d) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-
241. (e) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200-205. (f) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174-238.
(3) Direct ortho-arylation of phenols: (a) Satoh, T.; Inoh, J.; Kawamura,
Y.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998,
71, 2239-2246. (b) Cuny, G. D. Tetrahedron Lett. 2004, 45, 5167-5170
and refs cited therein.
(6) R-Arylation of carbonyls: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234-245. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382-12383. (c) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108-11109.
(7) Chelation-assisted direct arylations of sp3C-H bonds via Pd(IV)
intermediates: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154-13155. (b) Shabashov, D.; Daugulis, O. Org. Lett.
2005, 7, 3657-3659. (c) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org.
Lett. 2006, 8, 3391-3394. (d) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330-7331. (e) Giri, R.;
Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu,
J.-Q. J. Am. Chem. Soc. 2007, 129, 3510-3511.
(8) Chelation-assisted oxidative alkylation of sp3C-H bonds with
alkylboron reagents: Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 12634-12635.
(4) Direct arylation of electron-rich arenes: Yanagisawa, S.; Sudo, T.;
Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748-11749 and refs
cited therein. Also note that a large part of ref 2 describes this type of
transformation.
(9) Palladium-catalyzed cross-coupling reactions of 2,4,6-tri(tert-butyl)-
bromobenzene with arylboronic acids resulting in sp3C-H bond arylation:
Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4685-4696.
10.1021/ol0708119 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/12/2007

We focused on aryl(azaaryl)methanes as substrates to
achieve our project. On the basis of the structural similarity
between imines and azaarenes as well as the fact that direct
R-arylation of carbonyl compounds proceeds efficiently,6 it
would be feasible that aryl(azaaryl)methanes undergo direct
arylation at the benzylic position. This was indeed the case,
and treatment of chlorobenzene (2a) with 2-benzylpyrimidine
(1a) in the presence of cesium hydroxide15 under PdCl2/
tricyclohexylphosphine (PCy3) catalysis16 in refluxing xylene
provided 2-(diphenylmethyl)pyrimidine (3a) in high yield
(Table 1, entry 1). A plausible reaction mechanism includes
Electron-rich 4-chloroanisole (2d) reacted with the aid of
PCy3 to yield the corresponding triarylmethane in excellent
yield (entry 4). The reaction of 4-chloro-N,N-dimethylaniline
(2e) required prolonged reaction time and an excess of the
base to proceed to completion (entry 5). The reaction of
4-chlorostyrene (2f) provided the desired product 3f (entry
6), although 2f can alternatively undergo self-contained
Mizoroki-Heck reactions which lead to oligo(4-phenyl-
enevinylene).17 Unfortunately, attempted reactions of electron-
deficient 2g resulted in incomplete conversion. The highest
yield was obtained when di(tert-butyl)(2-phenylphenyl)-
phosphine was used as a ligand (entry 7). The reaction of
2g would proceed via [4-(tert-butoxycarbonyl)phenyl][phen-
yl(pyrimidyl)methyl]palladium, which would suffer from
slow reductive elimination because of the electron-withdraw-
ing nature of the carbonyl group. In addition, cleavage of
the ester bond was observed.
Table 1. Pd-Catalyzed Arylation of 2-Benzylpyrimidinea
Other aryl(azaaryl)methanes were subjected to the aryl-
ation reaction (Table 2). The reaction of 2- or 4-benzylpy-
entry
R
2
time/h
3
yield/%
Table 2. Pd-Catalyzed Phenylation of Aryl(azaaryl)methanesa
1
2
3
4
5
6
7
H
2a
2b
2c
2d
2e
2f
3
2
2
8
18
5
3a
3b
3c
3d
3e
3f
86
96
94
86
63b
62
29c
(1-naphthyl)
2-Me
4-OMe
4-NMe2
4-CHdCH2
t
4-CO2 Bu
2g
24
3g
a
A mixture of 1a (0.50 mmol), 2 (0.60 mmol), PdCl2(MeCN)2 (0.025
mmol), PCy3 (0.075 mmol), and CsOH‚H2O (1.0 mmol) was boiled in
b
c
xylene (1.0 mL). CsOH‚H2O (1.5 mmol) was used. Di(tert-butyl)(2-
phenylphenyl)phosphine was used. 30% of 1a was recovered. t-Butyl
benzoate (4%) and 2g (6%) were detected. The yields are based on 1H
NMR.
oxidative addition, deprotonation of 1a with cesium hydrox-
ide, transmetalation of phenyl(2-pyrimidyl)methylcesium
with an arylpalladium chloride (or hydroxide) intermediate,
and reductive elimination.
A variety of aryl chlorides underwent the arylation
reaction. Aryl chloride 2c having a methyl group at the 2
position participated in the reaction similarly (entry 3).
(10) Direct arylations of R,â-unsaturated carbonyl compounds at the
γ-position and of 4-alkylnitrobenzenes were reported. In the latter report,
an example of direct arylation of 4-methylpyrimidine yielding 4-(diaryl-
methyl)pyrimidine was reported: (a) Terao, Y.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron Lett. 1998, 39, 6203-6206. (b) Inoh, J.; Satoh,
T.; Pivsa-Art, S.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 4673-
4676.
a
A mixture of 1 (0.50 mmol), chlorobenzene (0.60 mmol), PdCl2(MeCN)2
(11) Ruthenium-catalyzed arylation: Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220-14221.
(12) Copper-catalyzed oxidative functionalization: Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 6968-6969.
(0.025 mmol), PCy3 (0.075 mmol), and CsOH‚H2O (1.0 mmol) was boiled in
xylene (1.0 mL). b Triphenyl(4-pyridyl)methane (8%) was obtained. c Iodo-
benzene and KOH were used instead of chlorobenzene and CsOH‚H2O,
respectively.
(13) Pd-catalyzed arylation of cyclopentadienes: (a) Dyker, G.; Heier-
mann, J.; Miura, M.; Inoh, J.; Pivsa-Art, S.; Satoh, T.; Nomura, M. Chem.-
Eur. J. 2000, 6, 3426-3433. (b) Dyker, G.; Heiermann, J.; Miura, M. AdV.
Synth. Catal. 2003, 345, 1127-1132.
ridine proceeded smoothly (entries 1 and 2). It is worth noting
that we could obtain tetraarylmethane, triphenyl(4-pyridyl)-
(14) Pd-catalyzed intramolecular arylative cyclization: (a) Ren, H.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462-3465. (b) Ren, H.; Li,
Z.; Knochel, P. Chem. Asian J. 2007, 2, 416-433.
(15) The effect of base is summarized in the Supporting Information.
(16) The result of the ligand screening is tabulated in the Supporting
Information.
(17) Heitz, W.; Brugging, W.; Freund, L.; Gailberger, M.; Greiner, A.;
Jung, H.; Kampschulte, U.; Niessner, N.; Osan, F.; Schmidt, H. W.; Wicker,
M. Makromol. Chem. 1988, 189, 119-127.
2374
Org. Lett., Vol. 9, No. 12, 2007

methane, in 8% yield, in the reaction of 1c. Further
optimization of the reaction conditions will allow us to
prepare tetraarylmethane through a cross-coupling methodol-
ogy.18 Unfortunately, 3-benzylpyridine (1d) resisted the
reaction (entry 3). Di(2-pyridyl)methane (1e) and 2-ben-
zylquinoline (1f) readily reacted to proceed to completion
within 6 h (entries 4 and 5). The reactions of 2-benzylben-
zoxazole and -benzothiazole were successful by using KOH19
as a base, albeit with prolonged reaction times (entries 6 and
7). The reactions of 2-picoline and of diphenylmethane
resulted in no conversion. The acidity of the protons to be
substituted by an aryl group is probably a decisive factor
for the success of the reaction. The pKa values of the acidic
protons of 1b, 1c, 1d, diphenylmethane, and water in DMSO
were reported to be 28.2, 26.7, 30.15, 32.2, and 32,
respectively.20 A hydroxide ion would fail to deprotonate
1d and diphenylmethane under the reaction conditions. An
attempted reaction of 4-benzylbenzonitrile resulted in hy-
drolysis of the nitrile group to yield 4-benzylbenzoic acid
(83%).
Azaarenes can find many applications in various fields of
chemical science. We have found a new method to synthesize
triarylmethanes23 having at least one azaaryl group through
the palladium-catalyzed direct benzylic arylation of aryl-
(azaaryl)methanes.
The present method is concise and reliable enough to offer
a straightforward route to highly azaarylated structures in
one pot. The reactions of 1,4-dibromobenzene (5a) and 1,3,5-
tribromobenzene (5b) with 1e afforded new multicoordinat-
ing molecular structures 6a and 6b (eqs 1 and 2). They are
potentially useful in constructing supramolecular architecture
not only as they are21 but also as their anionic forms upon
deprotonation of the methyne protons.22
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and COE Research from
MEXT and JSPS.
Supporting Information Available: Experimental pro-
cedure and characterization data of new compounds (pdf).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The Friedel-Crafts arylation reaction of triarylmethanols or their
analogues with aniline is the most popular method. (a) Zimmermann, T. J.;
Mu¨ller, T. J. J. Synthesis 2002, 1157-1162. (b) Su, D.; Menger, F. M.
Tetrahedron Lett. 1997, 38, 1485-1488. (c) Grimm, M.; Kirste, B.; Kurreck,
H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1097-1098.
(19) In the case that CsOH‚H2O was used, we obtained moderate yields
of 4f and 4g with contamination by byproducts. The byproducts were likely
formed by ring opening of the oxazole and thiazole units.
OL0708119
(20) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(23) Triarylmethanes are typically prepared by (1) addition of aryl
Grignard reagents to carbonyls yielding triarylmethanols and subsequent
reduction of the hydroxy group under acidic conditions or (2) Friedel-
Crafts arylaton of diarylmethanols. Muthyala, R.; Katritzky, A. R.; Lan, X.
Dyes Pigm. 1994, 25, 303-324 and refs cited therein.
(21) Use of di(2-pyridyl)methane: Steel, P. J.; Sumby, C. J. Dalton 2003,
4505-4515 and refs cited therein.
(22) Gornitzka, H.; Catherine, H.; Bertrand, G.; Pfeiffer, M.; Stalke, D.
Organometallics 2000, 19, 112-114 and refs cited therein.
Org. Lett., Vol. 9, No. 12, 2007
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