Pyridine-catalyzed double C-N coupling reaction of an isocyanate with two benzynes

Article abstract of DOI:10.1002/ejoc.201101251

A pyridine-catalyzed double C-N bond cross-coupling reaction involving two benzynes with an isocyanate was carried out. The coupling reaction proceeded through a unique pathway involving the formation of an unstable carbamic acid intermediate and facile decarboxylation. Subsequent nucleophilic addition/protonation of in situ prepared amines with benzynes afforded variously substituted diaryl- and triarylamines in moderate to good yields with tolerance of a variety of functional groups. Copyright

Full text of DOI:10.1002/ejoc.201101251

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101251
Pyridine-Catalyzed Double C–N Coupling Reaction of an Isocyanate with Two
Benzynes
Yi-Hsien Lee,[a] Yen-Chung Chen,[a] and Jen-Chieh Hsieh*[a]
Keywords: Benzyne / Amines / Arylation / Cross-coupling / Nucleophilic addition
A pyridine-catalyzed double C–N bond cross-coupling reac-
tion involving two benzynes with an isocyanate was carried
out. The coupling reaction proceeded through a unique path-
way involving the formation of an unstable carbamic acid
intermediate and facile decarboxylation. Subsequent nucleo-
philic addition/protonation of in situ prepared amines with
benzynes afforded variously substituted diaryl- and triaryl-
amines in moderate to good yields with tolerance of a variety
of functional groups.
mechanism, and this method is efficient for the synthesis of
diaryl- and triarylamine derivatives.
Introduction
Diaryl- and triarylamine derivatives are synthetically im-
portant compounds for their wide applications in biology[1]
and material science.[2,3] Most of them are prepared
through transition-metal-catalyzed C–N coupling method-
ology. Among the various transition-metal-catalyzed proto-
cols reported to date, copper- and palladium-catalyzed N-
arylation are the most common and efficient conditions; for
example, the copper-catalyzed Ullmann reaction[4] involv-
ing the coupling of amines with aryl halides is convenient
and air stable. Moreover, this reaction can be utilized for
large-scale preparation. However, high catalyst loadings[5]
and operation at high reaction temperatures[6] were usually
required. The palladium-catalyzed N-arylations developed
by Buchwald[7] and Hartwig[8] are effective for the labora-
tory-scale preparation of specific amines under milder con-
ditions with low catalyst loadings, and the substrate scope
is diverse. Nickel-catalyzed C–N coupling[9] is an alternative
process to the palladium- or copper-mediated reactions;
however, the prerequisite for the preparation of the starting
materials limits its application. The first transition-metal-
free N-arylation involving benzynes and amines was re-
ported by Larock.[10,11] Although their choice of benzyne
species was limited, their methodology provided a very sim-
ple procedure to generate diaryl- and triarylamine deriva-
tives. This encouraged us to explore another possibility for
the synthesis of diaryl- and triarylamines without the use
of a transition metal. Herein, we wish to report a facile,
transition-metal-free and low catalyst loading N-arylation
involving isocyanates and benzynes. This is the first exam-
ple of a double C–N cross-coupling reaction with a distinct
Results and Discussion
In our preliminary study, o-(trimethylsilyl)phenyl triflate
(1a)[12] was treated with cyclohexylisocyanate (2a) in the
presence of cesium fluoride (3.0 equiv.) in acetonitrile at
80 °C for 12 h to give the corresponding diphenylamine in
17% yield (Table 1, Entry 1). We observed that some of the
isocyanates that did not participate in the C–N coupling
Table 1. Optimization of reaction conditions.[a]
Entry
Base
H2O
[equiv.]
Temp
[°C]
Yield
[%][b,c]
1
2
3
4
5
6
7
8
none
none
none
none
none
none
none
NEt3
NEt3
none
0.8
1.0
1.2
1.4
1.2
1.2
none
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
80
80
80
80
80
70
60
80
70
70
70
70
70
70
70
70
17
36
41
49
46
51
41
21
71
63
73
84
72[d]
62
66
69
9
10
11
12
13
14
15
16
TMEDA
pyridine
2,6-lutidine
2,6-lutidine
DBU
DABCO
DIPEA
[a] Department of Chemistry, Tamkang University,
New Taipei City 25137, Taiwan (R.O.C.)
Fax: +886-2-26209924
[a] Reactions were carried out with o-(trimethylsilyl)phenyl triflate
(1a; 0.1 mmol, 2.0 equiv.), cyclohexylisocyanate (2a, 0.15 mmol),
base (2 mol-%), CsF (3.0 equiv.), and H2O (0–1.4 equiv.) in CH3CN
(0.4 mL) for 12 h. [b] 1H NMR yield based on internal standard
mesitylene. [c] Yields were calculated based on 1a. [d] 5 mol-% base.
E-mail: jchsieh@mail.tku.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101251.
Eur. J. Org. Chem. 2012, 247–250
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
247

Y.-H. Lee, Y.-C. Chen, J.-C. Hsieh
SHORT COMMUNICATION
reaction were converted into the corresponding iso- dition, a phenyl ring with an electron-withdrawing group
cyanurate 4[13] (Scheme 1) through fluoride-promoted significantly reduced the yields (Table 2, Entries 7 and 8),
cyclotrimerization.[14] Thus, we employed an excess amount especially for p-acetylphenylisocyanate (2h). Because
of isocyanate to ensure that benzyne precursor 1a was com- strongly electron-withdrawing substituents weaken the nu-
pletely consumed. We also noticed by GC–MS analysis that cleophilicity of the resulting secondary amine, single C–N
a small amount of phenanthridinone derivative 5[15,16] was bond coupling derivative 3hЈ predominated over the double
formed, and this renders our current target under investiga-
tion. To the best of our knowledge, this is the first C–N
coupling reaction giving arylamines from benzynes and iso-
cyanates.
Table 2. Pyridine-catalyzed cross-coupling of benzynes with isocy-
anates.[a]
Scheme 1. Side products of the cross-coupling reaction.
To optimize the reaction conditions, we first tested the
reaction with different amounts of water at different tem-
peratures (Table 1, Entries 2–7). We discovered that water
was necessary to increase the yield of 3a and to inhibit the
formation of 5. Another competitive reaction took place to
afford product 6[10b,17] (Scheme 1) from a molecule of H2O
and two benzyne molecules. Reactions carried out in
CH3CN at 70 °C were optimal; neither increased nor de-
creased temperatures improved the reaction yields. We no-
ticed that an additional basic additive was effective in im-
proving the yields of both 3a and 4 (Table 1, Entry 8).
Among the investigated bases, we found that the pyridine-
promoted reactions gave higher yields than those promoted
by amines and imidazole (Table 1, Entries 9–16). It was
found that 2,6-lutidine was the best for this coupling reac-
tion, which exhibited a greatly improved yield of 84%.
When a less-hindered pyridine was used as the catalyst, the
formation of 7[18] was also detected by GC–MS; however,
the 2,6-dimethyl groups of 2,6-lutidine provided greater
steric hindrance, thus preventing the approach of cyano-
methanide. Moreover, a higher loading of 2,6-lutidine ef-
ficiently catalyzed the formation of product 4 and reduced
the yield of 3a (Table 1, Entry 13).
The scope of the pyridine-catalyzed C–N coupling reac-
tion was evaluated with variously substituted isocyanates
and benzynes (Table 2). All the alkyl isocyanates reacted
smoothly with benzynes under the optimized conditions.
Reactions with primary alkyl groups (Table 2, Entries 2 and
3) gave slightly poorer yields than the reaction with a sec-
ondary alkyl group (Table 2, Entry 1) due to their lower
electron densities; however, the strongly hindered tertiary
isocyanate (Table 2, Entry 4) showed poorer reactivity to-
ward benzyne. Our results revealed that the performance of
this coupling reaction strongly depends on the electronic
[a] Reactions were carried out with benzyne precursor 1 (0.5 mmol,
2.0 equiv.), isocyanate 2 (0.75 mmol), 2,6-lutidine (2 mol-%), CsF
(3.0 equiv.), and H2O (1.2 equiv.) in CH3CN (2.0 mL) at 70 °C for
12 h. [b] Isolated yields after column chromatography. [c] Yields
were calculated based on benzyne precursor 1. [d] GC yields, de-
effects of the aliphatic and aromatic substituted isocyanates.
Thus, phenylisocyanate (2e) and p-tolylisocyanate (2f)
worked well in this coupling reaction and produced the cor-
responding triarylamine derivatives 3e and 3f in 70 and
75% yield, respectively (Table 2, Entries 5 and 6). In ad- tected and calculated by GC–MS. [e] Yields of 3Ј.
248 Eur. J. Org. Chem. 2012, 247–250
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Pyridine-Catalyzed Double C–N Coupling Reaction
C–N coupling compound 3h. The triethoxysilyl group was
also well tolerated in this coupling reaction to form com-
pound 3i (Table 2, Entry 9), which was difficult to obtain
by other synthetic pathways, and this compound should be
stored in the refrigerator due to its ease of decomposition
at high temperatures.
By using the same protocol, we were able to carry out
the C–N coupling reaction of isocyanates with variously
substituted benzynes (Table 2, Entries 10–12). When
benzynes 1b and 1c with electron-donating groups were em-
ployed, the corresponding diarylated products 3j and 3k
were obtained in a moderate yield 59 and 54%, respectively
(Table 2, Entries 10 and 11). Electron-deficient difluoro-
benzyne 1d under the same conditions also provided di-
arylated product 3l in moderate yield, but in good total
yields including 3lЈ. Benzyne 1d and isocyanate 2h with
strong electron-withdrawing substituents afford the re-
sulting N-arylated secondary amines 3hЈ and 3lЈ, which ex-
hibit poor nucleophilicity; thus, the second coupling reac-
tion is suppressed and the corresponding double C–N cou-
pling adducts are not obtained.[18,19] Compared with pre-
vious reports,[10,11] these reaction conditions are closer to
neutral and tolerate a wider scope of substituents because
isocyanates were employed in the N-arylation instead of
primary or secondary amines.
Scheme 3. Possible mechanism.
idine or fluoride was necessary to promote the reaction and
the formation of compound 4.[22,23] Actually, alkyl isocyan-
ates are inert under mild conditions and require a pre-nu-
cleophile to assist its nucleophilic addition.[14,22,23]
To understand the mechanism of this C–N coupling reac-
tion, a control experiment was investigated by replacing
H2O with D2O. It was observed that both phenyl groups
were deuterated by D2O (Scheme 2) and compound 3aa was
generated in 73% yield.
Scheme 4. An alternative pathway for the coupling reaction.
Scheme 2. Deuteration of 3a.
Conclusions
Although a more detailed study is required to fully
understand the mechanism of this pyridine-catalyzed
double C–N bond coupling reaction, a tentative pathway
can be proposed. Active zwitterion A[20] was generated by
nucleophilic addition of pyridine to isocyanate 2 (Scheme 3)
and subsequent N-arylation then occurred by A with elec-
tron-deficient benzyne 1. The accompanied hydrolysis re-
leased pyridine and afforded a very unstable intermediate
carbamic acid B,[21] which underwent facile decarboxylation
to form secondary amine derivative 3Ј. A second N-aryl-
ation of an additional benzyne with compound 3Ј provided
diarylamine derivative 3. This proposed mechanism well ex-
plains the formation of 3aa, 3hЈ, and 3lЈ.
In conclusion, we have developed a novel pyridine-cata-
lyzed method for the cross-coupling reaction of two
benzynes with an isocyanate. This method can efficiently
provide diaryl- and triarylamine derivatives in moderate to
good yields and withstands a variety of functional groups.
Further studies to extend the scope of the catalytic reac-
tions as well as the cyclization of benzyne with isocyanate
are currently underway.
Experimental Section
Typical Procedure for the C–N Cross-Coupling Reaction: To a
screw-capped vial was added CsF (227 mg, 1.5 mmol). The vial was
sealed with a septum and flushed several times with nitrogen. o-
(Trimethylsilyl)phenyl triflate (1a; 0.5 mmol, 149 mg), cyclohex-
ylisocyanate (2a; 0.75 mmol, 94 mg), 2,6-lutidine (0.01 mmol,
1.2 μL), H2O (0.6 mmol, 10.8 μL), and acetonitrile (2.0 mL) were
injected into the reaction mixture with a syringe. The septum was
removed, and the vial was sealed with a screw cap. The reaction
mixture was stirred at 70 °C for 12 h. The crude reaction mixture
In the absence of pyridine (Table 1, Entries 2–7), prod-
ucts 3 and 3Ј were generated by fluoride-promoted nucleo-
philic addition of isocyanate to benzyne[14] or through an
alternative pathway involving the reaction of an isocyanate
with a molecule of H2O and the release of CO2 to form the
corresponding amine derivative (2Ј, Scheme 4). The subse-
quent addition to the benzynes afforded products 3Ј and
3.[10] However, this suggestion failed to explain why pyr- was diluted with CH2Cl2, filtered through a thin pad of Celite, and
Eur. J. Org. Chem. 2012, 247–250
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Y.-H. Lee, Y.-C. Chen, J.-C. Hsieh
SHORT COMMUNICATION
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Received: August 27, 2011
Published Online: November 21, 2011
250
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Eur. J. Org. Chem. 2012, 247–250