Transition-metal-free synthesis of N-(1-Alkenyl)imidazoles by potassium phosphate-promoted addition reaction of alkynes to imidazoles

Article abstract of DOI:10.1002/asia.201301173

The addition reaction of alkynes to N-heterocycles by simply heating in DMSO with potassium phosphate is reported. Good yields with high stereoselectivity could be achieved for a range of substrates. The scope is quite general for both amines and phenylac

Full text of DOI:10.1002/asia.201301173

COMMUNICATION
DOI: 10.1002/asia.201301173
Transition-Metal-Free Synthesis of N-(1-Alkenyl)imidazoles by Potassium
Phosphate-Promoted Addition Reaction of Alkynes to Imidazoles
Linhua Lu, Hong Yan, Defu Liu, Guangwei Rong, and Jincheng Mao*[a]
Abstract: The addition reaction of alkynes to N-heterocycles
by simply heating in DMSO with potassium phosphate is re-
ported. Good yields with high stereoselectivity could be ach-
ieved for a range of substrates. The scope is quite general
for both amines and phenylacetylenes. In addition, internal
alkynes and a-bromostyrene were also examined in this re-
action. This process is efficient and useful for the synthesis
of (Z)-N-(1-alkenyl)imidazoles and related Z products.
Thus, the reaction is useful because of the importance of the
imidazole scaffold.
The reaction system, KOH/DMSO (DMSO=dimethyl
sulfoxide), has been extensively applied in many synthetic
reactions, including the addition of alkynes to pyrroles.[6e,f,7]
Therefore, we selected the addition of imidazole to phenyla-
cetylene in the presence of KOH/DMSO as the model reac-
tion. Unfortunately, the product could only be obtained in
34% yield (Z/E=75:25; Table 1, entry 1). Therefore, we de-
Table 1. Screening various catalytic conditions for the addition of phenyl-
acetylene to imidazole.[a]
N-(1-Alkenyl)imidazoles are versatile intermediates in or-
ganic synthesis and widely present in many biologically
active molecules.[1] The antifungal and antiparasitic proper-
ties of these compounds are widely applied in medicine and
agriculture.[2] Over the past few decades, a number of meth-
ods to synthesize such compounds have been reported.[3,4]
Among these methods, vinylation reactions of imidazoles
with vinyl halides were the most efficient and straightfor-
ward, because the traditional methods are not able to con-
trol the geometry of the double bond and suffer from harsh
reaction conditions.[4]
Recently, we were interested in the stereoselectivity of
the vinylation of imidazoles.[5] Interestingly, we found that
just 10 mol% of CuI could effectively catalyze the coupling
reaction of nitrogen-containing heterocycles with vinyl bro-
mides and chlorides to afford exclusive E products under
ligand-free and Pd-free conditions.[5a] However, when
10 mol% of FeCl3 was employed as the catalyst, Z products
were obtained predominantly.[5b] But how can we gain
access to the Z products exclusively? It is noteworthy that
the base is important for the stereoselectivity of the addition
reaction of alkynes and N-heterocycles, particularly for
Z products.[6]
Entry
Solvent
Base
t [h]
Z/E
Yield [%][b]
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
KOH
24
24
24
24
24
24
24
24
24
24
24
24
5
12
30
24
24
24
24
75:25
>99:1
>99:1
>99:1
35:65
–
83:17
–
–
34
26
91
94
9
0
26
0
K2CO3
Cs2CO3
K3PO4
tBuOK
Et3N
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
Toluene
NMP
9
0
0
10
11[c]
12[d]
13
14
15
16[e]
17[f]
18[g]
19
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
>99:1
>99:1
>99:1
>99:1
>99:1
75:25
75:25
65:35
–
68
19
78
83
84
91
78
80
NR
[a] Catalytic conditions: Phenylacetylene (0.4 mmol), imidazole
(0.48 mmol), solvent (2 mL), base (2 equiv), 24 h, 1208C, Ar. [b] Isolated
yield based on phenylacetylene. [c] 1008C. [d] 608C. [e] 1 equiv of K3PO4
was employed. [f] 3 equiv of K3PO4 was employed. [g] 0.2 equiv of K3PO4
was employed. NR=no reaction.
duced that the known protocol was not suitable for this ad-
dition reaction. In DMSO, different, commonly used bases
were investigated under similar reaction conditions (1208C
and 24 h), such as K2CO3, Cs2CO3, K3PO4, tBuOK, and Et3N
(Table 1, entries 2–6). To our surprise, a satisfactory result
was achieved when K3PO4 was used as the base (94% yield,
Z/E>99:1; Table 1, entry 4). Therefore, we deduced that the
inorganic bases are more suitable than the organic bases for
the addition reaction. Various solvents such as N,N-dime-
[a] L. Lu, H. Yan, D. Liu, G. Rong, Prof. Dr. J. Mao
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry
Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (P. R. China)
Fax : (+86)512-65880403
E-mail: jcmao@suda.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301173.
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Jincheng Mao et al.
thylformamide (DMF), toluene, N-methyl pyrrolidone
(NMP), and 1,4-dioxane were tested (Table 1, entries 7–10),
and DMF afforded the desired product in low yield (Table 1,
entry 7). Next, we optimized the reaction conditions in
terms of temperature, time, and the amount of K3PO4 em-
ployed (Table 1, entries 11–18). In a control experiment, no
product was detected in the absence of base, as expected
(Table 1, entry 19). Finally, the best reaction conditions were
those shown in entry 4 (Table 1).
and the results are shown in Table 2. We were delighted to
find that the addition reaction of phenylacetylene to various
N-heterocycles proceeded smoothly to give the Z isomers in
good to excellent yields (83–99%; Table 2, entries 1–6). In-
terestingly, unsymmetrically substituted 4-methylimidazole
afforded a mixture of 1,4- and 1,5-trisubstituted imidazoles,
but the overall conversion of the reaction was good (97%;
Table 2, entry 5).[8] Subsequently, other N-heterocycles, such
as pyrrole (38%; Table 2, entry 8), indole (84%; Table 2;
entry 2), benzimidazole (78–83%; Table 2; entries 6 and 7),
and benzotriazole (13%; Table 2; entry 9) were also tested
as substrates and afforded the desired products. It was dem-
onstrated that our method can be successfully applied for
various N-containing heterocycles. However, the addition
reactions of phenylacetylene to aliphatic amines including
morpholine, diisopropylamine, or aniline were unsuccessful
(Table 2, entries 10–12).
Under these optimized reaction conditions, a variety of
amine substrates were examined in the addition reaction
Table 2. Addition reactions of phenylacetylene to various amines under
transition metal-free conditions.[a]
Entry Amine
Product
Z/E
Yield
[%][b]
Furthermore, the addition reactions of phenylacetylene to
alcohols or carboxylic acids were investigated. However,
only when n-octanol was employed as the addition reagent,
the desired product could be obtained in 20% yield, as
shown in Scheme 1.
1
>99:1
94
84
2
>99:1
3
4
>99:1
>99:1
92
>99
55:45
5
6
(or vice
versa)
97
83
Scheme 1. Addition reaction of phenylacetylene to various alcohols or
acid using the K3PO4/DMSO system.
>99:1
The scope of this addition reaction is substantially extend-
ed to both aromatic and aliphatic alkynes, as shown in
Table 3. The addition products were not obtained when ali-
phatic alkynes were used as the substrates (Table 3, entries 1
and 5). However, the addition products of imidazole to aro-
matic alkynes were obtained with good yields (73–85%;
Table 3, entries 2–4) and the addition reactions of 2-methyli-
midazole with aromatic alkynes afforded the desired prod-
ucts in moderate to good yields (43–99%, Table 3, entries 6–
8). Interestingly, unsymmetrically substituted 4-methylimida-
zole afforded a mixture of 1,4- and 1,5-trisubstituted imida-
zoles. However, the overall conversion of the reaction was
good (88%; Table 3, entry 9).[8]
7
8
9
>99:1
>99:1
>99:1
78
38
13
10
–
NR
Imidazole- or benzimidazole-fused isoquinoline polyheter-
oaromtaic compounds showed biological activities, such as
anticancer and antifungal properties.[9] Retrosynthetic analy-
sis showed that these compounds came from N-(1-alkenyl)i-
11
12
iPr2NH
–
–
trace
trace
À
midazoles through two sequential C H activations. Recent-
ly, Bao and co-workers reported an N-arylation of (Z)-b-
bromostyrene and N-heterocycles with good yields.[10]
Herein, our alternative to prepare N-(1-alkenyl)imidazoles
is through the direct addition of readily available alkynes to
N-heterocycles, as shown in Scheme 2.
[a] Reaction conditions: Phenylacetylene (0.4 mmol), amine (0.48 mmol),
DMSO (2 mL), K3PO4 (2 equiv), 24 h, 1208C, Ar. [b] Yield of isolated
product based on phenylacetylene. NR=no reaction.
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Jincheng Mao et al.
Table 3. Transition-metal-free addition reactions of various terminal alkynes to 1H-imidazoles.[a]
To extend the application of
our method, we applied the
K3PO4/DMSO catalytic system
to other addition reactions,
such as the addition of a-bro-
mostyrene to imidazole. To our
delight, the desired product
could also be afforded in 80%
yield, as shown in Scheme 4.
Although the actual active
species is unknown until now,[6]
one can deduce from the above
results that both solvent and
base play an important role in
the chemical reactivity and the
stereoselectivity of this addition
reaction. For this reaction,
K3PO4 was employed not only
as the base but also as the cata-
lyst. In those cases where the
combination of K3PO4 and
DMSO exclusively affords the
Z products, we propose that
these adducts are initially
formed as the Z isomers owing
to kinetic control, according to
the classic trans-nucleophilic
addition rule.[11] Then, as
a result of thermodynamic con-
trol, in some instances, the
Z isomers isomerized to give
the E isomers until reaching
a state of equilibrium. Studies
on the reaction mechanism
were performed in our labora-
tory.
Entry
1
Alkyne
Product
Z/E
Yield [%][b]
NR
–
2
3
4
5
6
7
8
>99:1
>99:1
>99:1
–
85
73
74
trace
>99
84
>99:1
>99:1
>99:1
43
60:40
(or vice versa)
9
88
[a] Reaction conditions: alkyne (0.4 mmol), amine (0.48 mmol), DMSO (2 mL), K3PO4 (2 equiv), 24 h, 1208C,
Ar. [b] Yield of isolated product based on alkyne.
Scheme 3. Addition reaction of diphenylacetylene to imidazoles using
the K3PO4/DMSO system.
Scheme 2. Retrosynthetic analysis of imidazole- or benzimidazole-fused
isoquinoline compounds.
Scheme 4. Addition of a-bromostyrene to imidazole using the K3PO4/
DMSO system.
To further expand the range of substrates, addition reac-
tions of internal alkynes to imidazoles were examined. As
shown in Scheme 3, when diphenylacetylene was used as an
alkyne substrate, a single isomer was obtained successfully.
In summary, an efficient ligand-free and transition-metal-
free protocol has been developed for the addition reaction
of alkynes to N-heterocycles. These reactions were opera-
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Jincheng Mao et al.
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Experimental Section
General experimental
All reactions were carried out under an atmosphere of argon. Various al-
kynes and N-heterocycles were purchased from Aldrich, Acros, or Alfa.
Column chromatography was generally performed on silica gel (100–
200 mesh) and reactions were monitored by thin-layer chromatography
(TLC) using UV light (254 nm) to visualize the course of the reactions.
The 1H (300 MHz or 400 MHz) and 13C NMR spectroscopic (75 MHz or
100 MHz) data were recorded on Varian 300MHz or 400MHz spectrom-
eters, respectively, using CDCl3 as a solvent. The chemical shifts (d) are
1
reported in ppm and coupling constants (J) in Hz. H NMR spectra were
recorded with tetramethylsilane (d=0.00 ppm) as an internal reference;
13C NMR spectra were recorded with CDCl3 (d=77.000 ppm) or
[D6]DMSO (d=39.500 ppm) as an internal reference. ESI-MS and
HRMS were performed by the State-authorized Analytical Center in
Soochow University.
General procedure for the transition-metal-free addition of
phenylacetylene to imidazole
A mixture of phenylacetylene (43.9 mg, 0.4 mmol), imidazole (33.3 mg,
0.48 mmol), K3PO4 (171.2 mg, 2 equiv), and DMSO (2 mL) in a Schlenk
tube was stirred under an argon atmosphere at 1208C for 24 h. Then, the
mixture was poured into ethyl acetate, washed with water, extracted with
ethyl acetate, dried by anhydrous Na2SO4, filtered, and evaporated under
vacuum, and then the residue was purified by flash column chromatogra-
phy (petroleum ether or petroleum ether/ethyl acetate, 1:2) to afford the
corresponding coupling products.
Acknowledgements
We are grateful to the grants from the International Science and Technol-
ogy Cooperation Program of Jiangsu Province (BZ2010048), the Scientif-
ic Research Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry, the Priority Academic Program Development
of Jiangsu Higher Education Institutions, and the Key Laboratory of Or-
ganic Synthesis of Jiangsu Province.
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Keywords: alkynes · imidazoles · nitrogen heterocycles ·
nucleophilic addition · synthetic methods
Received: August 29, 2013
Published online: October 21, 2013
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