Base-Mediated Syntheses of Di- and Trisubstituted Imidazoles from Amidine Hydrochlorides and Bromoacetylenes

Article abstract of DOI:10.1002/chem.201502707

A new transition metal-free method for the preparation of substituted imidazoles from easy-to-handle amidine hydrochlorides and bromoacetylenes has been developed. The reactions proceed in air and use inexpensive K₂CO₃ as base. Additions of 2,2′-bipyridine and water have beneficial effects on the product yields. Various di- and trisubstituted imidazoles have been prepared in good yields (up to 88%). A new transition metal-free method for the preparation of di- and trisubstituted imidazoles in good yields from easy-to-handle amidine hydrochlorides and bromoacetylenes has been developed. The reactions proceed in air and use inexpensive K₂CO₃ as base. Additions of 2,2′-bipyridine and water have beneficial effects on the product yields.

Full text of DOI:10.1002/chem.201502707

DOI: 10.1002/chem.201502707
Communication
&
Synthetic Methods
Base-Mediated Syntheses of Di- and Trisubstituted Imidazoles
from Amidine Hydrochlorides and Bromoacetylenes
Xiao Yun Chen,[a] Ulli Englert,[b] and Carsten Bolm*[a]
Abstract: A new transition metal-free method for the
preparation of substituted imidazoles from easy-to-handle
amidine hydrochlorides and bromoacetylenes has been
developed. The reactions proceed in air and use inexpen-
sive K2CO3 as base. Additions of 2,2’-bipyridine and water
have beneficial effects on the product yields. Various di-
and trisubstituted imidazoles have been prepared in good
yields (up to 88%).
Due to their occurrence in natural products and other bioac-
tive molecules, imidazole structures have long been a focus of
Scheme 1. Synthetic approaches towards substituted imidazoles starting
from amidines.
synthetic chemistry.[1,2] Compounds with substituted imidazole
cores include angiotensin receptor blockers,[3] agents with anti-
tumor[4] and anticancer activities,[5] antibacterial and potential
anti-HIV agents,[6] and drugs with antiparasitic activity.[7] Fur-
thermore, 2,4(5)-diarylimidazoles have been reported to be in-
hibitors of hNaV1.2 sodium channels.[8]
these results and considering our previous work,[21] as well as
findings by Li and co-workers,[22] we wondered about an alter-
native transition metal-free approach and hypothesized that
imidazole derivatives 3 could also result from base-mediated
reactions starting from easy-to-handle amidine hydrochlorides
1 and bromoacetylenes 2 (Scheme 1c). The realization of this
idea is reported herein.
After the first described imidazole synthesis in 1882,[9] many
methods for the preparation of imidazole derivatives have
been reported. Among them, methods that use 1,2-diketones,
amines, and aldehydes have been most prominent.[10–12] Fur-
thermore, Van Leusen-type reactions that provide imidazoles
from aldimines and isocyanides by [3+2] cycloaddition have
been developed.[13] More recent methods for building the het-
erocyclic core have relied on the use of copper,[14] rhodium,[15]
and gold catalysts.[16] In this context, our attention was caught
by work by the groups of Chen (Scheme 1a)[17] and Neuville
(Scheme 1,b),[18] who reported copper-catalyzed syntheses of
imidazoles starting from amidines. Both protocols required the
use of substantial amounts of copper salts (10 mol% and
20 mol%, respectively) and an atmosphere of dioxygen and
led to 1,2,4-trisubstituted products. Also of interest was the
multicomponent metal-free synthesis of imidazoles reported
by Wang and co-workers,[19] as it started from alkynes that
were suggested to be oxidized to diketone,s which subse-
quently reacted with in situ-formed amidines.[20] In light of
For the initial test reactions, benzamidine hydrochloride (1a)
and (4-methoxyphenyl)ethynyl bromide (2a) were selected as
representative starting materials (Table 1). To our delight, treat-
ment of a mixture of 1a and 2a with 4.0 equivalents of K2CO3
in dry toluene at 808C under an argon atmosphere did indeed
lead to the desired product (3a), but the yield was only 6%
(Table 1, entry 1).[23] The molecular structure of 3a was con-
firmed by X-ray crystallography of its hemihydrate (for details,
see the Supporting Information). Performing the reaction in air
afforded 3a in 21% yield (Table 1, entry 2). Further experimen-
tation led to the assumption that water played an important
role. Confirming this hypothesis, 3a was obtained in 61%
yield, when 2.5 equivalents of deionized water was added to
the reaction mixture (Table 1, entry 3).[24] Raising the reaction
temperature from 808C to 1008C improved the yield of 3a to
68% (Table 1, entry 4).
As in the previously reported 1H-indazole synthesis,[21e] the
yield of 3a was affected by the addition of a catalytic amount
of a diamine, albeit, in this case, only to a minor extent
(Table 1, entries 5–7). Among diamines L1–L3, 2,2’-bipyridine
(bipy, L2) proved to be the most effective and application of
10 mol% of L2 gave 3a in 74% yield (Table 1, entry 6). Substi-
tuting K2CO3 by Cs2CO3 led to 3a in 65% yield, and with
Na2CO3 only a trace of product was formed (Table 1, entries 8
[a] Dr. X. Y. Chen, Prof. Dr. C. Bolm
Institut für Organische Chemie, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Carsten.Bolm@oc.RWTH-Aachen.de
[b] Prof. Dr. U. Englert
Institut für Anorganische Chemie, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502707.
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Communication
the reaction time from 24 h to 12 h and 6 h indicated that 12 h
were enough to provide 3a in good yield (Table 1, entries 24–
26). Taking all parameters into account, the optimal reaction
conditions required keeping a mixture of 1.5 equivalents of
amidine hydrochloride 1a, 1.0 equivalent of bromoacetylene
2a, 4.0 equivalents of K2CO3, 5 mol% of L2, and 2.5 equivalents
of deionized water in toluene at 1208C for 12 h, leading to 3a
in 74% yield (Table 1, entry 25).
Table 1. Optimization of the reaction conditions.[a]
Under the optimized reaction conditions, various aryl ami-
dine hydrochlorides were applied in the reaction with (4-me-
thoxyphenyl)ethynyl bromide (2a). All N,N’-unsubstituted de-
rivatives afforded the corresponding imidazoles in good yields
(Table 2, entries 1–8). The best result was achieved with imida-
Entry
Amine
Base
K2CO3
Solvent
t [h]
T [8C]
Yield [%]
1[b]
2[c]
3[d]
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[e]
20[f]
21[g]
22[f,h]
23[f,i]
24[f,h]
25[f,h]
26[f,h]
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
THF
DMF
DCE
dioxane 24
CH3CN
H2O
80
80
80
6
21
61
68
68
74
61
33
65
trace
34
62
66
59
trace
58
41
trace
71
75
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
120
120
L1
L2
L3
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
Table 2. Scope of amidine hydrochlorides.
Cs2CO3
Na2CO3
tBuOK
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
24
24
24
Entry
Ar
R
Product
Yield [%]
1
2
3
4
5
6
7
8
9
2-methoxyphenyl
4-methoxyphenyl
3,5-dimethoxyphenyl
4-methylphenyl
2-naphthyl
4-trifluoromethylphenyl
4-chlorophenyl
4-bromophenyl
phenyl
H
H
H
H
H
H
H
H
3b
3c
3d
3e
3 f
3g
3h
3i
55
66
84
71
68
62
74
59
27
24
24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 24
toluene 12
73
73
59
76
74
62
n-butyl
3j
zole 3d, derived from 3,5-dimethoxyphenyl amidine hydro-
chloride 1d (84% yield; Table 1, entry 3). Probably due to
steric effects, the use of 2-methoxyphenyl amidine hydrochlo-
ride 1b led to imidazole 3b in only 55% yield, corresponding
to the least productive transformation in this series (Table 1,
entry 1). Electronic effects seemed less relevant. Applying N-
substituted aryl amidine hydrochloride 1j led to 1,2,5-trisubsti-
tuted imidazole 3j, but unfortunately the yield was only 27%
(Table 2, entry 9).
toluene
6
[a] Reaction conditions, unless otherwise stated: Benzamidine hydrochloride
(1a, 2.0 equiv), (4-methoxyphenyl)ethynyl bromide (2a, 1.0 equiv), base
(4.0 equiv), diamine (10 mol%), H2O (2.5 equiv), and solvent (1 mL). [b] Dry
toluene and dry K2CO3 were used under argon. [c] Dry toluene and dry
K2CO3 were used under air. [d] Dry toluene and dry K2CO3 were used under
air, with addition of 1 drop of H2O. [e] 2.5 mol% of L2. [f] 5 mol% of L2.
[g] 20 mol% of L2. [h] 1.5 Equivalents of benzamidine hydrochloride.
[i] 1.0 Equivalent of benzamidine hydrochloride.
Subsequently, the bromoacetylene component was varied
and various aryl- and alkyl-substituted derivatives were ap-
plied. Phenyl amidine hydrochloride (1a) served as reaction
partner. Again, all couplings proceeded well and, in general,
the yields of the corresponding imidazoles were good (reach-
ing 75%, 74%, and 74% for compounds 3k, 3p, and 3q, re-
spectively; Table 3, entries 1, 6, and 7). The lowest yield was
observed in a transformation providing 2-methoxyphenyl-sub-
stituted product 3l (50%), which might again be indicative of
a steric effect. Notably, compared to their aryl-containing coun-
terparts, cyclopropyl- and pentyl-substituted bromoacetylenes
2i and 2j gave higher yields of the corresponding imidazoles
3r (88%) and 3s (86%), respectively (Table 3, entries 8 and 9).
In light of these results and based on literature prece-
dence,[19,21,22,25] we considered two possible reaction pathways
(Scheme 2); either a base-mediated addition of the amidine to
the bromoacetylene took place, affording intermediates 4 and
4’, which, upon cyclization, led to the observed imidazole 3
and 9, respectively). With the more basic KOH or tBuOK instead
of K2CO3 3a was obtained in 33% and 34% yield, respectively
(Table 1, entries 10 and 11). With K3PO4 the yield of 3a was
62% (Table 1, entry 12).
Next, the influence of the solvent was investigated. Com-
pared to toluene, the use of DMF, THF, dioxane or CH3CN re-
sulted in slightly decreased yields of 3a ranging from 41% to
66% (Table 1, entries 13–17). In deionized water, only a trace of
3a was formed (Table 1, entry 18). Varying the amount of L2 in
the range of 2.5–20 mol% did not significantly affect the yield
of 3a (71–75%; Table 1, entries 19–21). Decreasing the amount
of amidine hydrochloride 1a from 2.0 to 1.5 and 1.0 equiva-
lents lowered the yield of 3a from 74% to 73% and 59%, re-
spectively (Table 1, entry 6 versus entries 22 and 23). With
1.5 equivalents of 1a, a reaction temperature increase from
1008C to 1208C had a positive effect on the yield of 3a, which
was now formed in 76% yield (Table 1, entry 24). Shortening
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Communication
Table 3. Scope of bromoacetylenes.
Entry
R
Educt
Product
Yield [%]
1
2
3
4
5
6
7
8
9
phenyl
2b
2c
2d
2e
2 f
2g
2h
2i
3k
3l
75
50
72
61
64
74
74
88
86
2-methoxyphenyl
3-methoxyphenyl
3-chlorophenyl
3-nitrophenyl
4-chlorophenyl
4-bromophenyl
cyclopropyl
3m
3n
3o
3p
3q
3r
n-pentyl
2j
3s
Scheme 3. Mechanism-related test reactions.
In summary, we have developed an operationally simple
method for the preparation of di- and trisubstituted imidazoles
from easy-to-handle amidine hydrochlorides and bromoacety-
lenes with inexpensive K2CO3 as base in air. Beneficial effects
on the product yield observed on the additions of bipy and
water were most likely due to enhanced solubilities of the
ionic reagents. Various synthetically interesting products were
obtained in good yields, and those can now serve as molecular
platforms for subsequent synthetic transformations.
Scheme 2. Possible reaction pathways.
Experimental Section
(path A), or, alternatively, bromoacetylene 2 hydrolyzed afford-
ing a highly reactive 2-bromoketone 5, which, by reacting with
the amidine, resulted in the formation of the isolated product
3 (path B). This pathway would easily explain the experimental-
ly observed important role of water needed to achieve a high
product yield.
The amidine hydrochloride (0.75 mmol), K2CO3 (276 mg, 2 mmol)
and bipy (3.9 mg, 0.025 mmol, 5 mol%) were added to a sealed
tube. Then, toluene (1 mL) and the bromoacetylene (0.5 mmol)
were added, followed by deionized water (22 mg, 1.25 mmol).
After sealing the tube tightly, the reaction mixture was heated to
1208C for 12 h. After cooling to room temperature, acetone (5 mL)
was added to the reaction mixture and the resulting mixture was
passed through a pad of SiO2, which was subsequently washed
with acetone (20 mL). The volatiles were removed under reduced
pressure, and the product was obtained after column chromatog-
raphy on silica gel.
To distinguish between both pathways and to shed light on
some mechanistic details, a number of test reactions were car-
ried out (Scheme 3). Firstly, the possible formation of 2-bromo-
ketone 5 as part of path B was tested. The result was clear:
Under the standard reaction conditions, bromoacetylene 2a
did not lead to significant amounts of 2-bromoketone 5
(Scheme 3a)[26] and, furthermore, 5 decomposed when applied
as a starting material (Scheme 3b). In light of these results,
path B seemed unlikely. Path A, in contrast, was supported by
the isolation of 7 (74%) and 9 (20%) resulting from additions
of N,N-dimethyl benzamidine hydrochloride (6) and diphenyl
imine (8) to bromoacetylenes 2a and 2b, respectively (Sche-
me 3c,d).[27] Thus, we conclude that the aforementioned imida-
zole synthesis most likely proceeds through the mechanism
depicted as path A in Scheme 2. In this scenario, the positive
effect of water would be attributed to the enhanced solubili-
ties of the involved salts (amidine hydrochloride and K2CO3) in
the otherwise less homogeneous reaction mixture.
Acknowledgements
X.Y.C. thanks the China Scholarship Council (CSC) for a predoc-
toral scholarship of the Science Foundation of China and we
acknowledge helpful discussions with Dr. C. Räuber, Dr. S. X.
Dong and R. A. Bohmann (all RWTH Aachen University), as well
as Dr. J. Wang (Sun Yat-sen University). We also thank I. Kalf
(RWTH Aachen University) for assistance with crystallization.
Keywords: alkynes
· amidines · base · heterocycles ·
imidazoles
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[1] a) L. De Luca, Curr. Med. Chem. 2006, 13, 1; b) N. B. Narasimhan, D.
Sharma, P. Kumar, Med. Chem. Res. 2011, 21, 1119; c) L. Zhang, X.-M.
Peng, G. L. V. Damu, R.-X. Geng, C.-H. Zhou, Med. Res. Rev. 2014, 34, 340.
[2] a) Z. Jin, Nat. Prod. Rep. 2011, 28, 1143; b) K. V. Sashidhara, G. R. Palnati,
R. P. Dodda, S. R. Avula, P. Swami, Synlett 2013, 24, 1795.
[17] D. Tang, P. Wu, X. Liu, Y.-X. Chen, S.-B. Guo, W.-L. Chen, J.-G. Li, B.-H.
Chen, J. Org. Chem. 2013, 78, 2746.
[18] J. Li, L. Neuville, Org. Lett. 2013, 15, 1752.
[19] C.-Y. Chen, W.-P. Hu, P.-C. Yan, G. C. Senadi, J.-J. Wang, Org. Lett. 2013,
15, 6116.
[3] a) G. Agelis, A. Resvani, S. Durdagi, T. Tumova, J. Slaninov, P. Giannopou-
los, K. Spyridaki, G. Liapakis, D. Vlahakos, T. Mavromoustakos, J. Matsou-
kas, J. Pept. Sci. 2012, 18, 116; b) G. Agelis, A. Resvani, C. Koukoulitsa, A.
Afantitis, G. Melagraki, A. Siafaka, E. Gkini, T. Tumova, K. Spyridaki, D. Ka-
lavrizioti, M. E. Androutsou, J. Slaninova, G. Liapakis, D. Vlahakos, T. Mav-
romoustakos, J. Matsoukas, J. Pept. Sci. 2012, 18, 123.
[4] a) H. Shang, H. Chen, D. Zhao, X. Tang, Y. Liu, L. Pan, M. Cheng, Arch.
Pharm. 2012, 345, 43; b) L.-X. Liu, X.-Q. Wang, J.-M. Yan, Y. Li, C.-J. Sun,
W. Chen, B. Zhou, H.-B. Zhang, X.-D. Yang, Eur. J. Med. Chem. 2013, 66,
423; c) W. Chen, L.-J. Yang, Y. Li, X.-Q. Wang, S.-J. Wang, W.-C. Wan, H.-B.
Zhang, X.-D. Yang, Lett. Drug Des. Discovery 2013, 10, 561.
[5] X.-Q. Wang, L.-X. Liu, Y. Li, C.-J. Sun, W. Chen, L. Li, H.-B. Zhang, X.-D.
Yang, Eur. J. Med. Chem. 2013, 62, 111.
[6] S. Ganguly, V. V. Vithlani, A. K. Kesharwani, R. Kuhu, L. Baskar, P. Mitrama-
zumder, A. Sharon, A. Dev, Acta Pharmac. 2011, 61, 187.
[7] H. B. Tatipaka, J. R. Gillespie, A. K. Chatterjee, N. R. Norcross, M. A. Hul-
verson, R. M. Ranade, P. Nagendar, S. A. Creason, J. McQueen, N. A.
Duster, A. Nagle, F. Supek, V. Molteni, T. Wenzler, R. Brun, R. Glynne, F. S.
Buckner, M. H. Gelb, J. Med. Chem. 2014, 57, 828.
[20] For metal-free imidazole syntheses by [2+2+1] annulation reactions,
see: A. Saito, Y. Kambara, T. Yagyu, K. Noguchi, A. Yoshimunra, V. V.
Zhdankin, Adv. Synth. Catal. 2015, 357, 667.
[21] a) Y. Yuan, I. ThomØ, S. H. Kim, D. Chen, A. Beyer, J. Bonnamour, E. Zui-
dema, S. Chang, C. Bolm, Adv. Synth. Catal. 2010, 352, 2892; b) A. Beyer,
C. M. Reucher, C. Bolm, Org. Lett. 2011, 13, 2876; c) I. ThomØ, C. Bolm,
Org. Lett. 2012, 14, 1892; d) A. Beyer, J. Buendia, C. Bolm, Org. Lett.
2012, 14, 3948; e) I. ThomØ, C. Besson, T. Kleine, C. Bolm, Angew. Chem.
Int. Ed. 2013, 52, 7509; Angew. Chem. 2013, 125, 7657.
[22] J. Peng, G. Shang, C. Chen, Z. Miao, B. Li, J. Org. Chem. 2012, 77, 1242.
[23] In most cases, the products were obtained with high tautomeric prefer-
ence (as revealed by NMR spectroscopy). A detailed NMR study of imi-
dazole 3s confirmed the shown substitution pattern (for details, see
the Supporting Information). To maintain consistent nomenclature in
this manuscript, we chose 1,2,5-trisubstituted product 3j as a reference
point for the atom assignments.
[24] Figure 3 in the Supporting Information shows the effect of water on
the product formation in detail. Varying the amount from 1.0 equivalent
to 5.0 equivalents had almost no impact on the yield of 3a. More or
less water, however, hampered the product formation.
[8] M. Fantini, M. Rivara, V. Zuliani, C. L. Kalmar, F. Vacondio, C. Silva, A. R.
Baheti, N. Singh, E. C. Merrick, R. S. Katari, G. Cocconcelli, C. Ghiron,
M. K. Patel, Bioorg. Med. Chem. 2009, 17, 3642.
[25] B. Li, C. K. F. Chiu, R. F. Hank, J. Murry, J. Roth, H. Tobiassen, Org. Process
Res. Dev. 2002, 6, 682.
[9] B. Radziszewski, Ber. Dtsch. Chem. Ges. 1882, 15, 1493.
[10] a) S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel, R. J. Lahoti, K. V.
Srinivasan, Tetrahedron 2005, 61, 3539; b) V. Zuliani, G. Cocconcelli, M.
Fantini, C. Ghiron, M. Rivara, J. Org. Chem. 2007, 72, 4551; c) G. Bratules-
cu, Synthesis 2009, 2319.
[26] Analyzing the product mixture obtained from the reactions depicted in
Scheme 3a,b by electrospray ionization (ESI) mass spectrometry re-
vealed the presence of small amounts of phenylglyoxal, which, in the
case of Scheme 3a, appeared to stem from a degradation of 5, formed
as a minor product.
[11] M. Adib, S. Ansari, S. Feizi, J. A. Damavandi, P. Mirzaei, Synlett 2009,
3263.
[12] a) B. Krieg, L. Brandt, B. Carl, G. Manecke, Chem. Ber. 1967, 100, 4042;
b) H. Neunhoeffer, B. Lehmann, H. Ewald, Justus Liebigs Ann. Chem.
1977, 1421.
[13] a) A. M. Van Leusen, J. Wildeman, O. H. Oldenziel, J. Org. Chem. 1977,
42, 1153; b) V. Gracias, A. F. Gasiecki, S. W. Djuric, Org. Lett. 2005, 7,
3183.
[27] We suggest that products 7 and 9 have Z configuration at the double
bonds. This assumption is based on the work by Li (ref. [22]) and relat-
ed studies, including a) M. Yamagishi, K. Nishigai, T. Hata, H. Urabe, Org.
Lett. 2011, 13, 4873; b) M. Yamagishi, K. Nishigai, A. Ishii, T. Hata, H.
Urabe, Angew. Chem. Int. Ed. 2012, 51, 6471; Angew. Chem. 2012, 124,
6577; c) M. Li, H. Yuan, B. Zhao, F. Liang, J. Zhang, Chem. Commun.
2014, 50, 2360; d) G. A. Burley, D. L. Davies, G. A. Griffith, M. Lee, K.
Singh, J. Org. Chem. 2010, 75, 980.
[14] For copper catalysis, see: C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am.
Chem. Soc. 2006, 128, 10662.
[15] For rhodium catalysis, see: T. Horneff, S. Chuprakov, N. Chernyak, V. Ge-
vorgyan, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 14972.
Received: July 10, 2015
[16] For gold catalysis, see: Y. Xiao, L. Zhang, Org. Lett. 2012, 14, 4662.
Published online on August 21, 2015
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