Direct palladium-catalyzed ortho-arylation of benzylamines

Article abstract of DOI:10.1021/ol061919b

Unsubstituted benzylamines and N-methylbenzylamine can be ortho-arylated under palladium catalysis at 130 °C. The reactions require the presence of trifluoroacetic acid and silver acetate.

Full text of DOI:10.1021/ol061919b

ORGANIC
LETTERS
2
006
Vol. 8, No. 23
211-5213
Direct Palladium-Catalyzed
Ortho-Arylation of Benzylamines
5
Anna Lazareva and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204
olafs@uh.edu
Received August 2, 2006
ABSTRACT
Unsubstituted benzylamines and N-methylbenzylamine can be ortho-arylated under palladium catalysis at 130
presence of trifluoroacetic acid and silver acetate.
°C. The reactions require the
Probably the most ubiquitous functional group in organic
chemistry is the C-H bond. The use of this group in selective
organic transformations offers advantages with respect to the
length of synthetic transformations and the availability of
starting materials. As a consequence, the development of
selective C-H bond functionalization has become a topic
developed a widely applicable method that allows the
arylation of various substrates functionalized with directing
groups. The reactions involve heating of an aryl iodide, the
6
substrate, and silver acetate in a carboxylic acid or without
solvent. Unique functional group tolerance is observed;
bromide is always tolerated, and occasionally even iodide
substituents are compatible with the reaction conditions.
1
of intense interest. Despite many recent successes, there are
still problems with respect to the selectivity and generality
6
a
6b
Acylated anilines, 2-aryl-, and alkylpyridines have been
shown to be reactive under these conditions. If an additional
of such processes. Only a handful of examples of unactivated
3
(
not benzylic or R to heteroatoms) sp C-H bond conver-
(3) (a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
sions to C-C bonds have been demonstrated in the litera-
Soc. 2002, 124, 5286. (b) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui,
K.; Mori, A. Org. Lett. 2005, 7, 5083. (c) Park, C.-H.; Ryabova, V.; Seregin,
I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (d) Bressy,
C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (e)
Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.
2
ture. An improvement in the generality of intermolecular
C-H activation reactions is desirable. There are a few
substrate classes where remarkable achievements in this
method have been demonstrated. For example, electron-rich
heterocycles can be both arylated and alkenylated under a
variety of conditions, allowing direct functionalization of
2006, 128, 4972. (f) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am.
Chem. Soc. 2005, 127, 18020.
(4) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue,
Y. Org. Lett. 2001, 3, 2579. (b) Ackermann, L. Org. Lett. 2005, 7, 3123.
(
(
c) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113.
d) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759. (e)
3
these important substrates. Additionally, pyridines, oxazo-
Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000,
1, 2655. (f) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J.
Am. Chem. Soc. 2005, 127, 7330. (g) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (h) Chen, X.;
Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
lines, anilides, and phenols are among substrates that may
be arylated or otherwise functionalized. Recently, several
4
4
examples of the alkylation or arylation of compounds without
5
strong directing groups have been demonstrated. We have
128, 78.
(
5) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
(
1) Reviews: (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97,
Chem. Soc. 2006, 128, 8754. (b) Faccini, F.; Motti, E.; Catellani, M. J.
Am. Chem. Soc. 2004, 126, 78. (c) Dong, C.-G.; Hu, Q.-S. Angew. Chem.,
Int. Ed. 2006, 45, 2289. (d) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.;
Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506. (e) Campeau, L.-C.;
Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857. (f) Shi, Z.; He, C. J.
Am. Chem. Soc. 2004, 126, 13596.
(6) (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44,
4046. (b) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (c) Zaitsev,
V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
2
879. (b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (c)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (d) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698.
(
2) (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. (b) Barder,
T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
005, 127, 4685. (c) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem.,
2
Int. Ed. 2003, 42, 5736. (d) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am.
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0.1021/ol061919b CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/14/2006

pyridine or quinoline chelating group is present, then even
3
6c
sp C-H bonds are reactive. This method was recently used
Table 1. Arylation of Benzylaminesa
7
for the synthesis of modified amino acid derivatives.
On the other hand, the selective, palladium-catalyzed
ortho-arylation of benzylamines has yet to be demonstrated.
Reaction sequences leading to such compounds currently
require multiple steps, involving lithiation/boronation/cross-
8
coupling. We report here the direct ortho-arylation of
benzylamines by aryl iodides under palladium catalysis.
Although the ortho-palladation of N,N-dialkylbenzy-
9
lamines is well-known, the palladation of NH-containing
benzylamines is much less common.10 We wished to
determine if these compounds could be ortho-arylated using
our method; we note that the corresponding lithiation
chemistry would be difficult in this case due to acidic NH
protons. Given the solvent dependence of the previously
reported arylations,6 acetic and trifluoroacetic acids were
tested in the reaction of (R)-R-methylbenzylamine and
iodobenzene. The reaction was fast in trifluoroacetic acid,
and a slower process resulting in the formation of a mixture
of mono- and diarylation products was observed in acetic
acid. Importantly, the amount of acid strongly influenced
the results. Specifically, the reactions were the fastest when
about 5 equiv of trifluoroacetic acid was used. In only one
a,b
3
case were sp C-H bonds found to be reactive; 2-amino-
3,3-dimethylbutane was arylated by p-tolyl iodide, leading
to a mixture of mono- and diarylation products. It was not
possible to obtain selectively either the mono- or the
diarylated amine, and out of many alkylamines, only this
substrate was reactive. The attempted arylation of amines
possessing â-hydrogen substituents led to the immediate
formation of Pd(0), presumably by facile â-hydride elimina-
tion from the palladated intermediate. Consequently, we
concentrated our efforts on the arylations of benzylamines.
Analysis by GC-MS of the products formed from the
arylation of benzylamine revealed that, besides the expected
diarylation product, some (ca. 10%) of the N-trifluoroacetyl-
ated derivative was formed (Scheme 1). N-Methylbenzyl-
Scheme 1. Trifluoroacetamide Formation
a
Benzylamine (1 equiv), ArI (10 equiv), AgOAc (2.4 equiv), Pd(OAc)2
(
5 mol %), CF3CO2H (5 equiv), 1.5-4 h. Yields are isolated yields. See
the Supporting Information for details.
the reaction mixture. Thus, N-trifluoroacetylbenzylamine was
reacted with iodobenzene under the usual conditions. No
reaction was observed. To simplify the isolation procedure,
the reaction mixtures were treated with trifluoroacetic
anhydride (for unsubstituted benzylamines) or acetic anhydride/
triethylamine (for N-methyl derivatives).
Using GC standards, we found that the reactions proceed
in almost quantitative yields. However, upon attempted
amines were not trifluoroacetylated under these conditions.
A control experiment was performed to verify that benzy-
lamine trifluoroacetamides are not the species arylated in
(
9) (a) Cope, A. C.; Friedrich, E. C. J. Am. Chem. Soc. 1968, 90, 909.
Review: (b) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105,
527.
(10) Vicente, J.; Saura-Llamas, I.; Palin, M. G.; Jones, P. G.; Ram ´ı rez
de Arellano, M. C. Organometalics 1997, 16, 826.
2
(
7) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
8) Sundermann, B.; K o¨ gel, B.-Y.; Buschmann, H. WO 01/10816, 2001.
(
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Org. Lett., Vol. 8, No. 23, 2006

lamines. As expected, the reactions are faster for electron-
rich benzylamines. A competition experiment was carried
out by reacting N-methylbenzylamine with a mixture of
Table 2. Arylation of N-Methylbenzylaminea
4-iodotoluene and 4-iodobromobenzene. Approximately equal
reactivity was observed (see Supporting Information for
details). This feature is distinct from the usual Pd(0)-Pd-
(II) catalytic cycles where electron-poor aryl halides are more
reactive. For unsubstituted or 4-substituted benzylamines,
clean 2,6-diarylation is observed. Benzylamines substituted
at the 3-position are monoarylated (examples 6 and 7). As
in the case of pyridine and anilide arylation, bromine is
tolerated on the substrate (entries 4 and 5), and even iodide
is compatible with the reaction conditions, although in this
case the yield is somewhat reduced (entry 7).
N-Methylbenzylamine is also arylated successfully under
the optimized reaction conditions (Table 2). The reactions
are somewhat faster than in the case of unsubstituted
benzylamines. Because trifluoroacetylation of products was
not observed in these reactions, the arylated amines were
acetylated to facilitate the isolation. An X-ray structure of
the product of entry 3 in Table 2 was obtained (see
Supporting Information for details).
In conclusion, we have developed a useful method for the
direct ortho-arylation of benzylamines and N-methylbenzy-
lamine. The reactions require a slight excess of silver acetate,
about 5 equiv of trifluoroacetic acid, and temperatures of
1
30 °C. This presents a shorter and more convenient
alternative to our previously reported methodology that
requires a picolylamide directing group for benzylamine
arylation and is successful only for primary amine derivatives.6c
a
N-Methylbenzylamine (1 equiv), ArI (10 equiv), AgOAc (2.4 equiv),
Acknowledgment. We thank the Welch Foundation
(Grant No. E-1571) for supporting this research. A.L. is
grateful to the University of Houston for undergraduate
research scholarships (PURS, SURF). We thank Dr. James
Korp for collecting and solving the X-ray structure.
Pd(OAc)2 (5 mol %), CF3CO2H (5 equiv), 1-2 h. Yields are isolated yields.
See the Supporting Information for details.
chromatography of the trifluoroacetamides, variable yields
as low as 30% were observed. Reproducible yields were,
however, obtained upon treatment of trifluoroacetamides with
transition-metal scavenging resins before chromatography.
The acetylated N-methylbenzylamines did not require such
treatment.
Supporting Information Available: Detailed experi-
mental procedures, characterization data for new compounds,
and X-ray data for Table 2, entry 3. This material is available
free of charge via the Internet at http://pubs.acs.org.
The reactions proceed well with both electron-rich and
moderately electron-poor (Table 1, entries 4, 5, 7) benzy-
OL061919B
Org. Lett., Vol. 8, No. 23, 2006
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