Rhodium(NHC)-catalyzed amination of aryl bromides

Article abstract of DOI:10.1021/ol100437j

(Figure Presented) A rhodium-catalyzed amination reaction of aryl halides with amines has been developed with the use of a N-heterocyclic carbene (NHC) ligand (I/Pr = 1,3-diisopropylimidazol-2-ylidene). The active metal species responsible for the reaction progress was identified. The developed procedure of the Rh-catalyzedW-arylation is convenient to carry out under mild reaction conditions displaying a wide range of substrate scope and high degree of functional group tolerance.

Full text of DOI:10.1021/ol100437j

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1640-1643
Rhodium(NHC)-Catalyzed Amination of
Aryl Bromides
Min Kim and Sukbok Chang*
Department of Chemistry and Molecular-LeVel Interface Research Center, Korea
AdVanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
sbchang@kaist.ac.kr
Received February 22, 2010
ABSTRACT
A rhodium-catalyzed amination reaction of aryl halides with amines has been developed with the use of a N-heterocyclic carbene (NHC) ligand
(IiPr ) 1,3-diisopropylimidazol-2-ylidene). The active metal species responsible for the reaction progress was identified. The developed procedure
of the Rh-catalyzedN-arylation is convenient to carry out under mild reaction conditions displaying a wide range of substrate scope and high
degree of functional group tolerance.
Metal-facilitated C-N bond formation has been significantly
advanced in recent years.1 In particular, the palladium-2 or
copper-catalyzed3 N-arylation of aryl halides with amines
is most extensively explored. The catalytic amination reaction
has been comprehensively studied to reveal its mechanistic
and synthetic aspects.4 Despite these achievements, there is
still room for the exploration of new catalytic systems that
can display different views of reactivity, functional group
tolerance, and diversity.5
droamination of alkenes/alkynes,6 C-H amination via
nitrene transfer,7 and C-H amination via decomposition
of azide moieties.8
(5) For selected examples of N-arylation with metal species other than
Pd or Cu, see: Ni catalysis: (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 6054. (b) Gradel, B.; Brenner, E.; Schneider, R. L.; Fort,
Y. Tetrahedron Lett. 2001, 42, 5689. (c) Omar-Amrani, R.; Thomas, A.;
Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311. (d) Gao, C. Y.;
Cao, X. B.; Yang, L. M. Org. Biomol. Chem. 2009, 7, 3922. Fe catalysis:
(e) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862. (f) Correa,
A.; Mancheno, O. G.; Bolm, C. Chem. Soc. ReV. 2008, 37, 1108. (g) Correa,
A.; Carril, M.; Bolm, C. Chem.sEur. J. 2008, 14, 10919. (h) Guo, D. L.;
Huang, H.; Xu, J. Y.; Jiang, H. L.; Liu, H. Org. Lett. 2008, 10, 4513. Co
catalysis: (i) Toma, G.; Fujita, K.; Yamaguchi, R. Eur. J. Org. Chem. 2009,
4586. (j) Teo, Y. C.; Chua, G. L. Chem.sEur. J. 2009, 15, 3072.
On the other hand, rhodium-catalyzed C-N bond
formation has flourished mainly by the advent of hy-
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Hartwig,
J. F. Nature 2008, 455, 314.
(2) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41,
1534. (c) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338.
(6) (a) Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2225. (b) Hartung, C. G.; Tillack, A.; Trauthwein, H.;
Beller, M. J. Org. Chem. 2001, 66, 6339. (c) Utsunomiya, M.; Kuwano,
R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608. (d)
Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042. (e)
Fukumoto, Y.; Asai, H.; Shimizu, M.; Chatani, N. J. Am. Chem. Soc. 2007,
129, 13792. (f) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570.
(7) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.
(b) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378. (c) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007,
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7558. (e) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061.
(3) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (b) Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (c) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793. (d) Ma, D.; Cai, Q. Acc. Chem.
Res. 2008, 41, 1450. (e) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
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Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.;
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10.1021/ol100437j  2010 American Chemical Society
Published on Web 03/05/2010

During the course of our studies on the C-N bond
formation reactions,9 we were interested in the new reactivity
of N-heterocyclic carbene (NHC)-bound rhodium complexes
in the N-arylation reaction.10 Described herein is our study
on the development and scope of a Rh(NHC)-catalyzed
amination of aryl bromides with amines.
Scheme 1. Crystallographic Structure of Rh(cod)(IiPr)Cl (4)
With the use of bromobenzene (1a) and morpholine (2a) as
test substrates, optimization of an intermolecular N-arylation
was first tried (Table 1). While no conversion was observed
Table 1. Optimization of the Reaction Conditionsa
mentioned that the stable Rh complex 4 could also be
prepared in a large scale by a more convenient procedure at
ambient conditions (eq 2).11
While the isolated Rh species 4 turned out to be less
reactive for the N-arylation reaction (entry 6), the reactivity
was significantly increased upon the addition of catalytic
amounts of AgBF4 salt (entry 7), strongly suggesting that
the actiVe species would be the corresponding cationic
complex [Rh(cod)(IiPr)]+. A full conversion was also
achieved with use of a Rh precursor and NHC upon the
addition of a silver salt (entry 8).12
entry
conditions
RhCl(PPh3)3
time (h) convn (%)b
1
2
3
4
24
24
12
12
12
12
12
12
<1
<1
>99
<1
<1
50
Rh(cod)2BF4
Rh(cod)2BF4 + IiPr·HCl
Rh(cod)2BF4 + IMes·HCl
Rh(cod)2BF4 + PCy3
Rh(cod)(IiPr)Cl (4)
Rh(cod)(IiPr)Cl (4) + AgBF4
[Rh(cod)Cl]2 + IiPr·HCl + AgBF4
5
6
Under the optimized conditions, the substrate scope was
subsequently investigated (Table 2). In general, electronic
variation on aryl bromides bearing different types of sub-
stituents displayed negligible effects on the reaction ef-
ficiency (3a-e). Not only polyaryl but also heteroaryl
bromides smoothly underwent the amination reaction to
afford the desired N-morpholinyl (hetero)arene derivatives
in high yields (3f-h).
7c
8c
>99
>99
a Conditions: 1a (0.2 mmol), 2a (3 equiv), Rh species (2 mol %), additive
(4 mol %), t-BuONa (2 equiv), and 1.2-dimethoxyethane (0.2 mL) at 80
°C. b GC-MS conversion with 1,3-benzodioxole as an internal standard.
c AgBF4 (10 mol %) was used.
with rhodium species in the absence of NHC (entries 1-2),
addition of a N,N′-diisopropyl NHC precursor (IiPr·HCl)
resulted in a full conversion at 80 °C in the presence of t-BuONa
(entry 3). It turned out that structure of NHCs displayed
significant effects on the resulting Rh catalyst’s activity as
demonstrated in entry 4. It was interesting that no reaction was
observed when tricyclohexylphosphine was employed as an
external ligand instead of IiPr (entry 5).
While anilines having either neutral or electron-withdraw-
ing substituents were facile reactants (3i-j), reaction of
electron-rich anilines gave a rather moderate yield (3k). On
the other hand, excellent product yields were obtained from
the reaction of bromobenzene with a wide range of aliphatic
amines such as benzyl (3l), n-pentyl (3m), cyclohexyl (3n),
ꢀ-substituted alkyl (3o), or pyrrolidine (3p) moieties with
high efficiency. It should be mentioned that, in contrast to
(9) (a) Ko, S.; Han, H.; Chang, S. Org. Lett. 2003, 5, 2687. (b) Lee,
J. M.; Ahn, D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S.
J. Am. Chem. Soc. 2006, 128, 12954. (c) Chang, S.; Lee, M. J.; Jung, D. Y.;
Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366. (d)
Han, H.; Park, S. B.; Kim, S. K.; Chang, S. J. Org. Chem. 2008, 73, 2862.
(e) Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73,
9454. (f) Kim, J.; Chang, S. Chem. Commun. 2008, 3052. (g) Cho, S. H.;
Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127.
(10) (a) Kim, M.; Lee, J.; Lee, H.-Y.; Chang, S. AdV. Synth. Catal. 2009,
351, 1807. (b) Kim, M.; Kwak, J.; Chang, S. Angew. Chem., Int. Ed. 2009,
48, 8935.
(11) See the Supporting Information for details.
A neutral NHC-bound rhodium species Rh(cod)(IiPr)Cl
(4) could be isolated under the reaction conditions (eq 2)
and its structure was confirmed by 1H and 13C NMR, and an
X-ray crystallographic analysis (Scheme 1).11 It should be
(12) While the amination reaction took place smoothly and reproducibly
when the in situ generated Rh(cod)2BF4 species was used, reactions with
the rhodium complex purchased commercially showed rather unreproducible
results especially in the case of secondary amines. This can be attributed
to the purity of certain bottles of the Rh species (confirmed by ICP-AES
analysis). For a similar example of the effects of purity of commercial
products on the reaction efficiency, see: Tobisu, M.; Hyodo, I.; Chatani, N.
J. Am. Chem. Soc. 2009, 131, 12070.
(8) Shen, M.; Leslie, B. E.; Driver, T. G. Angew. Chem., Int. Ed. 2008,
47, 5056.
Org. Lett., Vol. 12, No. 7, 2010
1641

group tolerance as seen in the Pd-catalyzed N-arylation,2a
we scrutinized a milder base to replace t-BuONa. Among
various organic and inorganic bases examined, it was found
that, similar to the Pd systems,14 the employment of Cs2CO3
as a base greatly improved the functional group compatibility
of the reaction (Table 3).
Table 2. Amination of Aryl Bromides with Various Aminesa b
,
Table 3. Amination with Cs2CO3 as a Mild Basea b
,
a Conditions: 1 (0.4 mmol), 2 (3 equiv), Rh(cod)2BF4 (2 mol %), IiPr·HCl
(4 mol %), and Cs2CO3 (2 equiv) in 1,2-dimethoxyethane (0.4 mL) at 90
°C for 12 h. b Isolated yield. c The reaction was conducted at 120 °C. d 2
(1.5 equiv) and t-BuONa (1.5 equiv) were used for 6 h.
We were pleased to observe a high degree of functional
group tolerance under the new conditions employing
Cs2CO3. In fact, various base-labile groups such as ester,
nitrile, or ketone were tolerated to afford the desired
aniline derivatives in high yields albeit at slightly higher
temperatures (entries 1-3). It is also noteworthy that the
pinacolboronate group was intact in the Rh-catalyzed
amination (entry 4) while such substrate could be prob-
lematic in the Pd-catalyzed reaction. In addition, a silyl
group was completely compatible to the reaction condi-
tions (entry 5).
a Conditions: 1 (0.4 mmol), 2 (3 equiv), Rh(cod)2BF4 (2 mol %), IiPr·HCl
(4 mol %), and t-BuONa (2 equiv) in 1,2-dimethoxyethane (0.4 mL) at 80
°C for 12 h. b Isolated yield.
some cases of palladium catalysis,13 oVer arylation of
primary amines was not obserVed at all in the present Rh-
catalyzed amination route.
Due to the fact that the use of a strong base such as
t-BuONa may lead to a relatively low level of functional
(14) (a) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
(b) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722. (c) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(13) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369. (b) Harris, M. C.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5327.
1642
Org. Lett., Vol. 12, No. 7, 2010

N-phenyl glycine tert-butyl ester with synthetically acceptable
yield (Scheme 2).
Scheme 2. N-Arylation of Amino Acid Ester
In summary, we have disclosed, to the best of our
knowledge, the first example of the Rh(NHC)-catalyzed
amination of aryl halides. The reaction is convenient to carry
out under mild conditions displaying a wide range of
substrate scope and high degree of functional group tolerance.
Detailed studies on the mechanistic aspects and synthetic
applications are now in progress.
Acknowledgment. This research was supported by the
KRF (2008-C00024, Star Faculty Program) and the SRC
program (MIRC). We also thank Mr. Kang Mun Lee
(Department of Chemistry, KAIST) for the crystal struc-
ture analysis.
It is notable to achieve a selective amination on an
arylbromo moiety in the presence of a chloro group (entry
6) although the N-arylation of activated chloroarenes was
also possible albeit at 120 °C (entry 7). In addition, labile
functional groups such as Boc-protected piperazine un-
derwent the N-arylation without difficulty (entry 8).
Additionally, the arylation protocol was briefly examined
to see whether the scope can be extended in arylation of
amino acid esters. It was observed that the reaction of
bromobenzene with glycine tert-butyl ester hydrochloride
proceeded smoothly under the developed conditions to afford
Supporting Information Available: Experimental pro-
cedure and characterization data including copies of 1H and
13C NMR spectra of obtained compounds and CIF file of 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100437J
Org. Lett., Vol. 12, No. 7, 2010
1643