Palladium-catalyzed benzylic arylation of N-benzylxanthone imine

Article abstract of DOI:10.1021/ol802070d

(Chemical Equation Presented) The direct benzylic arylation of N-benzylxanthone imine with aryl chloride proceeds under palladium catalysis, yielding the corresponding coupling product. The product is readily transformed to benzhydrylamine. Taking into consideration that the imine is readily available from benzylic amine, the overall transformation represents a formal cross-coupling reaction of aryl halide with α-aminobenzyl metal.

Full text of DOI:10.1021/ol802070d

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4689-4691
Palladium-Catalyzed Benzylic Arylation
of N-Benzylxanthone Imine
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 September 4, 2008
ABSTRACT
The direct benzylic arylation of N-benzylxanthone imine with aryl chloride proceeds under palladium catalysis, yielding the corresponding
coupling product. The product is readily transformed to benzhydrylamine. Taking into consideration that the imine is readily available from
benzylic amine, the overall transformation represents a formal cross-coupling reaction of aryl halide with r-aminobenzyl metal.
Transition-metal-catalyzed direct arylation at sp3-hybridized
carbons having acidic hydrogens has been emerging as one
of the recent remarkable advances in cross-coupling reac-
tion.1-5 In light of the importance of this transformation,
further progress should be made. We thus envisioned a new
application of the direct arylation, specifically, intermolecular
benzylic arylation of N-benzyl imines (Scheme 1). Imine 1,
Scheme 1. Concept of Benzylic Arylation of Benzylamine
(1) 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. (d) Gaertzen, O.; Buchwald, S. L. J.
Org. Chem. 2002, 67, 465–475. (e) Satoh, T.; Inoh, J.; Kawamura, Y.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
2239–2246. γ-Arylations of R,ꢀ-unsaturated carbonyl compounds: (f) Terao,
Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 6203–
6206. (g) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581–
7582
.
(2) Intermolecular arylation at the activated benzylic or allylic positions:
(a) Inoh, J.; Satoh, T.; Pivsa-Art, S.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1998, 39, 4673–4676. (b) Dyker, G.; Heiermann, J.; Miura, M.; Inoh,
J.; Pivsa-Art, S.; Satoh, T.; Nomura, M. Chem. Eur. J. 2000, 6, 3426–
3433. (c) Dyker, G.; Heiermann, J.; Miura, M. AdV. Synth. Catal. 2003,
345, 1127–1132. (d) Niwa, T.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007,
9, 2373–2375. (e) Mousseau, J. J.; Larive´e, A.; Charette, A. B. Org. Lett.
2008, 10, 1641–1643. (f) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am.
readily prepared from benzylamine and ketone, has benzylic
hydrogens of high acidity.6 Palladium-catalyzed arylation of
1 with aryl halide would afford 2. Hydrolysis of 2 should
finally yield 3. The overall transformation represents a formal
cross-coupling reaction of aryl halide with an R-aminobenzyl
metal.
Treatment of N-benzylxanthone imine (1a) with chlo-
robenzene in the presence of cesium hydroxide and a
palladium catalyst afforded the corresponding coupling
product 2a and its isomer 2a′ in a ratio of 7:3 (Scheme 2).
Chem. Soc. 2008, 130, 3266–3267
.
(3) Intramolecular arylative cyclization at the benzylic positions: (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. (c) Dong, C.-G.; Hu,
Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289–2292. (d) Hu, Q.-S. Synlett
2007, 1331–1345. (e) Catellani, M.; Motti, E.; Ghelli, S. Chem. Commun.
2000, 2003–2004. (f) Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008,
73, 3600–3603
(4) Arylation of N-tert-butylhydrazones as an acyl anion equivalent:
Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800–14801
.
.
10.1021/ol802070d CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society

C5H9)3, P(n-Bu)3, and P(t-Bu)3, were used instead of P(c-
C6H11)3, the reaction was sluggish (30-50% combined yields
of 2a and 2a′) and a mixture of unidentified byproducts was
obtained. Use of triarylphosphines in the arylation of 1a with
bromobenzene also led to low combined yields of 2a and
2a′ (30-50%), along with byproducts and recovered 1a
(10-30%). The 1:4 molar ratio of Pd/P(c-C6H11)3 led to the
highest catalytic activity. The combined yield of 2a and 2a′
was less than 20% when a Pd/P(c-C6H11)3 ratio was 1:3. As
the precursor of the catalyst, other palladium complexes, such
as Pd(acac)2, PdCl2(PhCN)2, and Pd(OAc)2, showed com-
parable yet slightly lower catalytic activity. A temperature
as high as 140 °C was essential: a similar reaction in
refluxing toluene failed to afford 2a and 2a′. The choice of
base is quite important, and the use of KOH, t-BuOK, and
Cs2CO3 gave only traces of 2a and 2a′.
Scheme 2. Phenylation of N-Benzylxanthone Imine
A variety of aryl chlorides participated in the reaction
(Table 1). Both electron-rich (entries 1-3) and electron-
Table 1. Arylation of 1a and Isolation of Benzhydrylamine
Derivativesa
Facile deprotonation of initially formed 2a at the benzylic
position took place in situ, which led to the formation of a
mixture of 2a and 2a′. Hydrolysis of the mixture of 2a and
2a′ afforded a mixture of desired 3a and undesired amine 4.
Hence, the mixture of imines 2a and 2a′ was reduced with
sodium cyanoborohydride to afford 5a, which was then
hydrolyzed under acidic conditions to provide benzhydry-
lamine (3a) and 6.7 Oxygen-bridged xanthone is a suitable
precursor of N-benzyl imine 1 because the exclusive forma-
tion of highly delocalized and thus stable 9-xanthenyl cation
allowed the regioselective hydrolysis of 5a, producing 3a.
After acid/base extraction in a separatory funnel, the product
3a was isolated as its hydrochloride salt 3a·HCl in 83%
overall yield. Notably, each step was high yielding, and no
chromatographic purification was needed during the process.
Bromobenzene reacted with 1a as smoothly as chloroben-
zene to yield 3a·HCl in 80% yield. On the other hand, the
use of iodobenzene resulted in the formation of a complex
mixture. When other trialkylphosphines, such as PMe3, P(c-
entry
Ar-Cl
product
overall yield (%)
1
2
3
4
5c
6
7
4-MeC6H4Cl
4-MeOC6H4Cl
3b·HCl
3c·Bzb
73
75
82
73
47
71
80
4-Me2NC6H4Cl
2-MeC6H4Cl
4-CH2dCHC6H4Cl
4-Me2NC(dO)C6H4Cl
2-chloropyridine
3d·2HCl
3e·HCl
3f·Bzb
3g·Bzb
3h·2HCl
a The reaction conditions are the same as shown in Scheme 2. b Instead
of treatment with HCl, 3c, 3f, and 3g were benzoylated for chromatographic
isolation. c Formic acid was used instead of hydrochloric acid for the removal
of the xanthenyl group.
(5) Other C(sp3)-H arylation involving cleavage of less acidic hydrogens:
(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. (f) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–
4696. (g) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006,
128, 14220–14221. (h) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 14570–14571. (i) Watanabe, T.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2008, 10, 1759–1762.
deficient (entry 6) aryl chlorides reacted smoothly to yield
the corresponding benzhydrylamine derivatives in good
yields. 2-Chlorotoluene underwent the reaction similarly,
irrespective of the steric hindrance of the 2-methyl group
(entry 4). The reaction of 4-chlorostyrene provided the
desired product 3f·Bz in moderate yield (entry 5), although
the aryl chloride can alternatively undergo self-contained
Mizoroki-Heck reaction, forming oligo(4-phenylenevi-
(6) The pKa value of the benzylic protons of Ph2CdNCH2Ph was
reported to be 24.3 in dimethyl sulfoxide at 25 °C. See: Bordwell, F. G.
Acc. Chem. Res. 1988, 21, 456–463.
4690
Org. Lett., Vol. 10, No. 20, 2008

nylene).8 Installation of heteroarene at the benzylic position
was satisfactory (entry 7). Not only N-benzyl imine 1a but
also other N-arylmethyl imines 1b-d were arylated (Scheme
3). However, 1e having an electron-donating group suffered
Scheme 4. Synthesis of Fluorenylamine
Scheme 3. Scope of N-(Arylmethyl)xanthone Imines
of 9. The transformation from 1f and 7 to 9 thus offers a
new route to 9-fluorenylamine derivatives.
By converting benzylamine to N-benzylxanthone imine,
metalation at the benzylic position becomes facile. The
present method provides a new concept for transition-metal-
catalyzed functionalization of aminated carbons.
from very low conversion, probably due to the slower
deprotonation.
The Suzuki-Miyaura cross-coupling reaction of 1f with
arylboronic acid 7 afforded biaryl 8 in high yield (Scheme
4). The intramolecular benzylic arylation of 8 created
fluorenylamine skeleton, eventually leading to the formation
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and GCOE Research from
MEXT and JSPS. T.N. acknowledges JSPS for financial
support.
Supporting Information Available: Experimental pro-
cedure and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Xanthene (6) was formed through the reduction of xanthenyl cation
with the remaining sodium cyanoborohydride in the same pot. No xanthenyl
alcohol, which could be generated by the nucleophilic attack of hydroxide
to the cation, was observed.
(8) 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.
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