A new tandem reaction of benzyne: One-pot synthesis of aryl amines containing anthracene

Article abstract of DOI:10.1021/ol063017g

(Chemical Equation Presented) The reaction of benzyne with N-substituted imidazoles affords a novel way to prepare arylamines containing anthracene under very mild conditions. This transformation is assumed to proceed via a tandem reaction involving a Die

Full text of DOI:10.1021/ol063017g

ORGANIC
LETTERS
2007
Vol. 9, No. 5
781-784
A New Tandem Reaction of Benzyne:
One-Pot Synthesis of Aryl Amines
Containing Anthracene
Chunsong Xie and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, PRC
yhzhang@zjuem.zju.edu.cn
Received December 14, 2006
ABSTRACT
The reaction of benzyne with N-substituted imidazoles affords a novel way to prepare arylamines containing anthracene under very mild
conditions. This transformation is assumed to proceed via a tandem reaction involving a Diels
coupling reaction.
−Alder reaction and an intermolecular nucleophilic
Aryl amines are fundamental building blocks in natural
products and functional materials.1,2 However, the classical
methods for the synthesis of aryl amines often suffer from
the harsh reaction conditions, which lead to severe limitations
in the general use of the reactions.3,4 As a consequence,
considerable attention has been paid to the development of
novel methods for the synthesis of aryl amines,5,6 and
currently, transition-metal-catalyzed C-N bond-forming
reactions have become the direct routes in the synthesis of
aryl amines.7,8
Arynes are one of the most important classes of organic
species9 and have been frequently used as the substrates in
a variety of reactions.10,11 In particular, their use in Diels-
Alder processes with heterocyclic compounds affords the
unique straightforward methods for the preparation of a wide
range of aromatic ring-containing heterocycles.12 Among the
reactions of aryne with various heterocyclic compounds, few
reports are available on the reaction of N-substituted imid-
azoles with aryne in the cycloaddition processes. In the
studies of N-substituted imidazoles with benzyne generated
in situ from o-trimethylsilyl aryltriflates, Yoshida et al. found
that N-alkyl-N′-aryl imidazolium salts, instead of cyclo-
addition products, were produced.13
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10.1021/ol063017g CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/06/2007

Herein, we describe our findings on the investigation of
benzyne with N-substituted imidazoles. The reaction was
assumed to proceed via a tandem Diels-Alder reaction of
benzyne with N-substituted imidazole and intermolecular
nucleophilic coupling reaction. The ratio of benzyne and
imidazole was crucial for the direction of the reaction, and
two important building blocks, aryl amine and anthracene,
were constructed in a single step under optimized conditions.
The aryl amines containing anthracene14 were separated as
the final products. This method provides a novel transition-
metal-free access to aryl amines containing anthracene under
very mild conditions.
We first examined the reaction of benzyne and N-
methylimidazole using the same reaction conditions reported
by Yoshida et al.,13 and N-methyl-N′-phenyl imidazolium
triflate was obtained. We noticed that in their experiments
the ratio of N-substituted imidazole and benzyne was 3:1.
We reasoned that the large excess of imidazole might make
the rate of nucleophilic addition of a nitrogen atom to
benzyne fast and lead to the production of imidazolium salt.
Accordingly, we carried out the reaction using benzyne and
imidazole in a 1:1 ratio at room temperature. As we expected,
the benzyne/imidazole ratio had a decisive influence on the
direction of the reaction, and the interesting tandem product
N-methyl-N′-phenylanthracen-10-amine (1c) was isolated in
23% yield after 24 h. The increase of the reaction temperature
was found to be beneficial to the tandem reaction, and the
best yield was obtained when the reaction temperature
achieved 50 °C for 12 h (Table 1, entries 1-3 and 6). Further
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Table 1. Optimization Studiesa
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entry
conditions
yieldb (%)
1
2
3
4
5
6
7
8
9
30 °C, 24 h, CH3CN
50 °C, 24 h, CH3CN
50 °C, 12 h, CH3CN
50 °C, 8 h, CH3CN
50 °C, 4 h, CH3CN
80 °C, 24 h, CH3CN
80 °C, 24 h, toluene
110 °C, 24 h, toluene
80 °C, 24 h, DME
67 °C, 24 h, THF
26
53
56
38
19
43
36
42
36
28
10
a
Reaction conditions: 1a (0.5 mmol), 1b (0.5 mmol), CsF (1.0 mmol).
Isolated yield.
b
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Org. Lett., Vol. 9, No. 5, 2007

Table 2. Tandem Reaction of Benzyne with Imidazolesa
a
Reaction conditions: the reaction was conducted in N2 using 0.5 mmol of 1a, 1.0 mmol of CsF, and 0.5 mmol of imidazole at 50 °C (bath temperature)
b
for 12 h. Isolated yield.
We next examined the scope of the tandem reaction, and
a variety of aryl amines containing anthracene were obtained
as described in Table 2. The N-alkyl-substituted imidazoles,
such as N-ethylimidazole and N-butylimidazole, were found
to readily undergo the tandem reaction, and N-ethyl-N-
phenylanthracene-10-amine as well as N-butyl-N-phenyl-
anthracene-10-amine were afforded in 60% and 62% yields,
respectively (Table 2, entries 1 and 2). N-Benzylimidazole
and N-allylimidazole carried out the reaction smoothly and
delivered the desired product in 62% and 55% yields (Table
2, entries 3 and 4). Besides the N-alkyl-substituted imid-
azoles, the N-aryl-substituted imidazoles also reacted with
benzyne, and asymmetric triaryl amines containing an-
thracene were produced (Table 2, entries 5-9). The electron-
releasing substituents on aryl facilitated the reaction, and
higher yields were obtained (Table 2, entries 6 and 7). On
the other hand, the lower yields were obtained with the
N-arylimidazoles bearing electron-withdrawing substituents
on aryl (Table 2, entries 8 and 9). It should be noted that
1,2-disubstituted imidazoles reacted smoothly with benzyne
and afforded the aryl amines with substituents on anthracene
(Table 2, entries 10 and 11).
On the basis of our results, an alternative mechanism is
proposed as shown in Scheme 1. The benzyne generated from
flourine-induced elimination of o-trimethylsilyl aryltriflate
undergoes the Diels-Alder reaction with substituted imid-
azole to produce the nitrogen-bridged isoquinoline intermedi-
ate A. Subsequent retro Diels-Alder reaction leads to the
loss of nitrile and generates the intermediate B, which
undergoes the second Diels-Alder reaction with benzyne
to give the intermediate C. The intermolecular nucleophilic
addition of intermediate C to benzyne affords the final
product of aryl amine containing anthracene.15
(15) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198-3209.
Org. Lett., Vol. 9, No. 5, 2007
783

The reaction solution was analyzed by GC-MS, and benzo-
nitrile was indeed detected (shown in Supporting Informa-
tion), which showed the implications of the expulsion of
benzonitrile from intermediate A to B from the retro Diels-
Alder reaction.
Scheme 1
In conclusion, we have developed a mild, direct, and
transition-metal-free process for the synthesis of aryl amines
containing anthracene, which would otherwise be difficult
to obtain. The reaction is believed to undergo an unusual
tandem process of benzyne with N-substituted imidazoles
to produce the aryl amines in a single step. Further studies
on other heterocycles are in progress.
Acknowledgment. We thank the support of the Natural
Science Foundation of China (No. 20571063).
Supporting Information Available: The experimental
procedures and spectroscopic data (1H NMR, 13C NMR,
FTIR, and HRMS) for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
To obtain further evidence to support the mechanism, we
allowed 1-ethyl-4-phenyl-1H-imidazole to react with ben-
zyne, and the desired product of N-ethyl-N-phenylanthracene-
10-amine was generated in 61% yield (Table 2, entry 12).
OL063017G
784
Org. Lett., Vol. 9, No. 5, 2007