Rapid and Efficient Microwave-Assisted Amination of Electron-Rich Aryl Halides without a Transition-Metal Catalyst

Article abstract of DOI:10.1021/ol0353868

Equation presented. A rapid and direct amination of aryl halides has been developed in good to high yields under microwave irradiation without a transition-metal catalyst. This reaction is a particularly powerful method for the coupling of electron-rich aryl halides with various amines. In some cases, the excellent regioselectivity could be observed, which facilitated the preparation of meta-substituted anilines from ortho- or para-substituted phenylhalides. In addition, a mechanism via the interesting benzyne intermediate has been proposed.

Full text of DOI:10.1021/ol0353868

ORGANIC
LETTERS
2
003
Vol. 5, No. 19
515-3517
Rapid and Efficient Microwave-Assisted
Amination of Electron-Rich Aryl Halides
without a Transition-Metal Catalyst
3
Lei Shi, Min Wang, Chun-An Fan, Fu-Min Zhang, and Yong-Qiang Tu*
Department of Chemistry & State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received July 24, 2003
ABSTRACT
A rapid and direct amination of aryl halides has been developed in good to high yields under microwave irradiation without a transition-metal
catalyst. This reaction is a particularly powerful method for the coupling of electron-rich aryl halides with various amines. In some cases, the
excellent regioselectivity could be observed, which facilitated the preparation of meta-substituted anilines from ortho- or para-substituted
phenylhalides. In addition, a mechanism via the interesting benzyne intermediate has been proposed.
Amination of aryl halides has been an important and
frequently required reaction for the synthesis of the interest-
ing molecules containing the N-aryl moiety, which have wide
palladium catalyst. However, these reported methods usually
required high temperatures, long reaction times, or had a
relatively narrow application scope of substrates.2 In
particular, the use of transition metals leads to the generation
of waste and has a number of hazards associated with it.5
In the past few years, the utilization of microwave
irradiation in chemical transformations has attracted consid-
erable interest and is of significant importance in the search
-4
1
a
occurrence in many areas such as pharmaceuticals,
1b
1c
1d
1e
agrochemicals, photography, xeroxography, pigments,
1f
1g
electronic materials, and natural products. Compared with
the C-N cross-coupling of electron-poor aryl halides with
amines, that of aryl halides bearing electron-rich substituents
is not accessed easily under mild conditions. Over the years,
a number of cleverly designed and useful methods for
electron-rich aryl C-N bond formation have mainly included
6
for green synthesis and sustainable chemistry. More at-
tractively, many reactions that typically required hours or
days to complete full conversion with conventional heating
could be realized in several minutes utilizing microwave
irradiation. Microwave-mediated protocols have been widely
applied to the formation of a variety of carbon-heteroatom
2
3
the Ullmann reaction and the Goldberg reaction using Cu
4
reagent and the Buchwald-Hartwig amination utilizing
6
(1) (a) Negwer, M. Organic-Chemical Drugs and their Synonyms (An
and carbon-carbon bonds. To the best of our knowledge,
International surVey), 7th ed.; Akademie Verlag GmbH: Berlin, 1994. (b)
Montgomery, J. H. Agrochemicals Desk Reference: EnVironmental Data;
Lewis Publishers: Chelsea, MI, 1993. (c) Loutfy, R. O.; Hsiao, C. K.;
Kazmaier, P. M. Photogr. Sci. Eng. 1983, 27, 5. (d) Schein, L. B.
Electrophotography and DeVelopment Physics, 2nd ed.; Springer-Verlag:
Berlin, 1992. (e) Pigment Handbook; Lewis, P. A., Ed.; John Wiley &
Sons: New York, 1988; Vol. I. (f) D’Aprano, G.; Leclerc, M., Zotti, G.;
Schiavon, G. Chem. Mater. 1995, 7, 33. (g) He, F.; Foxman, B. M.; Snider,
B. B. J. Am. Chem. Soc. 1998, 120, 6417.
however, the direct metal-free amination of electron-rich aryl
halides using high-speed microwave techniques has not been
described. Herein we wish to report our preliminary inves-
tigation on the microwave-assisted C-N bond coupling of
aryl halides with various amines.
(4) Palladium-catalyzed N-arylation of amines, see: (a) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Wolfe, J. P.; Wagaw. S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Yang,
B. Y.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(5) Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed. 2003, 42, 1407.
(6) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717.
(
2) Ullmann reactions, see: (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903,
6, 2382. (b) Ma, D.-W.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459.
3) Goldberg reaction, see: (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906,
3
(
3
9, 1691. (b) Freeman, H. S.; Butler, J. R.; Freedman, L. D. J. Org. Chem.
978, 43, 4975.
1
1
0.1021/ol0353868 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/20/2003

In contrast to most other C-N bond-forming protocols,2-4
the valuable features of our reported reaction include (i) a
Table 2. Direct Amination of Aryl Halides and Aminesa
7
shorter reaction time and a high yield; (ii) a broader substrate
7
scope; and (iii) the eradication of the transition-metal
catalyst.
As a starting point for the development of our direct
amination, we initially studied the microwave-assisted
coupling of PhBr with morpholine for optimizing reaction
conditions, and the results are presented in Table 1. Of the
Table 1. Optimization Studiesa
entry
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
K3PO4
K2CO3
NaOH
NaOMe
DMSO
DMSO
DMSO
DMSO
DMSO
benzene
toluene
CCl4
<1
<1
<1
74
t
KO Bu
94
t
KO Bu
<1
<1
<1
<1
<1
67
t
KO Bu
t
KO Bu
t
KO Bu
CH3CN
DME
DMF
t
1
1
0
1
KO Bu
t
KO Bu
a
All reactions were carried out within 5 min under the following
conditions: PhBr, 1.0 mmol; morpholine, 1.5 mmol; base, 1.5 mmol; and
b
solvent 5 mL. Yields of isolated products.
t
bases and solvents screened, KO Bu as the base and DMSO
as the solvent proved to be the most effective for this
coupling. Additionally, this reaction was found to be insensi-
tive to air and moisture; hence, there was no need for an
inert atmosphere.
Intrigued by the above-described results, we further
investigated the coupling reaction of different aryl halides
and amines. From the results shown in Table 2, it can be
seen that various secondary aliphatic and aromatic amines,
including bulky amines (entries 4-7), and less basic amines
such as aniline (entry 1) and indole (entry 9) were effective
for this C-N coupling reaction (entries 2-9). The yield for
a
For a detailed experimental operation, see Supporting Information.
b
d
c
Yields of isolated products. Trace meta-substituted aniline was obtained.
Trace para-substituted aniline was obtained. e Yield was based on the
recovered starting material ArX.
8
high yields and short reaction times (entries 12-19), and a
wide range of functional groups were also tolerated in this
reaction except for the acetyl group (entry 19). Even when
there was a free OH or NH group (entries 16 and 18) directly
2
bound to the aromatic ring, which was difficult to couple
under conventional conditions, a considerable yield was
provided in 20 min. Most notably, the steric effects and
electronic effects of the substituents on aryl bromides resulted
in the distinct regioselective amination
in some examples (entries 12 and 16-18).
employing primary amines (entry 1) is moderate and requires
2
the use of 4-fold excess of the PhNH in this coupling
reaction, because of the formation of undesired tertiary amine
9
(
(Ph)
3
N) as a byproduct. Additionally, both aryl chloride
(e.g., entry 10) and aryl iodide (e.g., entry 11) are effective
for this direct amination. Furthermore, we investigated the
influence of the structure of substrates on this C-N bond
coupling. Various electron-rich aryl bromides were chosen
to probe whether this coupling could be easily accessed in
the presence of morpholine. As expected, they still exhibited
10,11
that was observed
From the results shown above (entries 12-14 and 16-
8), the cine substitution
1
0,11
1
could be observed unambigu-
(
7) Some direct aminations were conducted in low yields and with a
(9) (a) Klapars, A.; Antilla, J. C.; Huang, X.-H.; Buchwald, S. L.J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.-H.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 7421.
long reaction time; see: (a) Heaney, H. Chem. ReV. 1962, 62, 81. (b)
Djakovitch, L.; Wagner, M.; K o¨ hler, K. J. Organomet. Chem. 1999, 592,
2
25.
(10) Bunnett, J. F.; Zahler, R. E. Chem. ReV. 1951, 49, 273.
(11) March, J. AdVanced Organic Chemistry, Reactions, Mechanisms and
Structure, 4th ed.; John Wiley & Sons: New York, 1992; p 641.
(8) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
1
24, 11684.
3516
Org. Lett., Vol. 5, No. 19, 2003

ously. Consequently, we proposed this direct amination of
aryl halides bearing electron-rich substituents most likely
proceeded via a benzyne intermediate.11 Further direct
evidence for the identification of benzyne intermediate was
provided by an additional experiment, where the trapping
of the benzyne intermediate was successfully conducted using
furan through [2 + 4] cycloaddition reaction.12 According
to the proposed benzyne intermediate, the steric or electronic
effect of a substituent on aromatic ring could be interpreted.
For example, the direct amination of ortho-methyl phenyl-
bromide (entry 12) only gave the meta-amination product,
possibly because the steric effects of the methyl group of
the benzyne intermediate resulted in the less sterically
hindered meta-attack of the nucleophilic amines. However,
the para-substituted analogues with a strong electron-donating
product, for reasons that are still unclear. For the example
of entry 19, formation of the same product as that in entry
5 of Table 1 could be explained via the benzyne intermediate
formed through the elimination of ortho-acetyl group.
In summary, we have established a rapid and direct
amination method without a transition-metal catalyst that
could be performed in good to excellent yields under
microwave irradiation. Particularly valuable features of this
method included the short reaction time, high yield, and
broad substrate scope, as well as convenient operation.
Additionally, the reaction was developed to meet the
increasing demand for environmentally benign chemical
processes. Efforts to expand the scope of the method in
combination with its application to the synthesis of phar-
maceutical molecules are ongoing in our laboratory.
2 3 2
group such as OH, NH , or N(CH ) give, with excellent
regioselectivity, the meta-amination product (entries 16-18),
Acknowledgment. This work was supported by NSFC
Grants 29925205 and 30271488 and QT program), FUK-
TME of China, the Young Teachers’ Fund of Ministry of
Education and the Fund of Ministry of Education (Grant
9209).
(
which is consistent with electronic effects of the electron-
11
rich substituent. In contrast, meta- or para-methyl phenyl-
bromide (entry13 and 14), where there was no distinct steric
effect or electronic effect, provided a mixture of meta- and
para-amination products. Unexpectedly, para-methoxy phen-
ylbromide (entry 15) gave the predominant para-amination
9
Supporting Information Available: Experimental details
and data on the C-N cross-coupling reaction. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Chapman, O. L.; Mattes, K.; McIntosh, C. L.; Pacansky, J.; Calder,
G. V.; Orr, G. J. Am. Chem. Soc. 1973, 95, 6134.
OL0353868
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