Base-catalyzed stereoselective intermolecular addition of imidazoles onto alkynes: An easy access to imidazolyl enamines

Article abstract of DOI:10.1016/j.tetlet.2013.12.100

An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles 1a-f onto alkynes 2a-l to provide the Z- and E isomers of imidazolyl enamines 3a-q and 4a-d using catalytic amount of KOH is described. Stereoselectivity of the addition products (Z and E isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less reactive than pyrrole and more reactive than aniline towards hydroamination.

Full text of DOI:10.1016/j.tetlet.2013.12.100

Accepted Manuscript
Base-catalyzed stereoselective intermolecular addition of imidazoles onto al-
kynes: An easy access to imidazolyl enamines
Monika Patel, Rakesh K. Saunthawal, Akhilesh K. Verma
PII:
S0040-4039(13)02198-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.12.100
TETL 44014
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
16 October 2013
25 December 2013
26 December 2013
Please cite this article as: Patel, M., Saunthawal, R.K., Verma, A.K., Base-catalyzed stereoselective intermolecular
addition of imidazoles onto alkynes: An easy access to imidazolyl enamines, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.12.100
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Monika Patel, Rakesh K. Saunthawal and Akhilesh K. Verma*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Base-catalyzed stereoselective intermolecular addition of imidazoles onto
alkynes: An easy access to imidazolyl enamines
Monika Patel, Rakesh K. Saunthawal and Akhilesh K. Verma*
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles
1a–f onto alkynes 2a–l to provide the Z- and E isomers of imidazolyl enamines 3a–q and 4a–d
using catalytic amount of KOH is described. Stereoselectivity of the addition products (Z and E
isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less
reactive than pyrrole and more reactive than aniline towards hydroamination.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Hydroamination, Alkyne
Enamines, Imidazole
Stereoselective, N-Heterocycles, Regioselective
Nitrogen-containing molecules such as imidazoles are an
important class of heteroaromatic compounds due to their
presence in biologically active,1 pharmaceuticals and natural
products2. Imidazole nucleus is commonly found in biomolecules
and amino acids such as biotin, purine, histidine, histamine,
pilocarpine alkaloids,3 and other alkaloids, which have shown to
display remarkable biological activities i.e. anticryptococcal,
antimicrobial and various other cytotoxic activities.4 The
medicinal properties of imidazole which possess broad spectrum
of physiological and biological activities mainly includes
antibacterial,5 antifungal,6 and antimalarial activity.7 Imidazole
derivatives, for instant nitro-vinylimidazole (i),8 etomidate (ii),
and ketoconazole (iii) are common structural arrays that are
involved in a variety of inflammatory and immunological
disorders and also comprise an important application in drug
therapy.9
However in contrast, addition of N-heterocycles onto alkynes has
not been much explored. Knochel in 1999 reported the first
example for the addition of N-heterocycles onto phenylacetylene
using CsOH.H2O (Figure 2, ii). Recently we18 and Trofimov19
reported the base-mediated addition of electron-rich N-
heterocycles (indoles and pyrroles) onto alkynes.
Figure 2. (i) Hydroamination of alkynes using metal catalyst. (ii)
First hydroamination reported by Knochel.
With this limited work on hydroamination of N-heterocycles
on alkynes and as a part of our ongoing research on alkyne
chemistry,20 herein, we wish to report transition metal-free
hydroamination of electron-deficient imidazoles onto alkynes.
(Scheme 1).
Figure 1. Biologically active imidazole derivatives.
Hydroamination of alkynes represent an attractive
approach for the synthesis of nitrogen heterocycles, enamines and
imines. Inter- and intramolecular addition of alkynes onto aryl
amines using metal complexes has been well studied by
Bergman,10 Doye,11 Beller,12 Yamamoto,13
Knochel,14
Ackermann,15 Kondo,16 Kozmin17a (Figure 2, i) and others;17
* Corresponding author. Tel.: +91 1127666646 (Ext. 175)
E-mail address: averma@acbr.du.ac.in (Akhilesh K. Verma)
Scheme 1. Synthesis of Z-styryl enamines and E-styryl enamines.

2
Tetrahedron
In order to optimize the reaction condition for the
reaction, previously reported catalyst and reaction conditions for
the hydroamination18 of electron-rich heterocycles on alkynes,
was examined in the reaction of imidazole 1a with 3-
ethynylthiophene 2a (Table 1). When 20 mol % of KOH was
used as a catalyst in DMSO at 120°C for 0.5 h, (Z)-1-(2-
(thiophen-3-yl)vinyl)-1H-imidazole 3a was obtained in only 35%
yield (Table 1, entry 1). Increase in the reaction time from 0.5 h
to 1 h and then to 1.5 h, afforded the Z-addition product 3a in
62% and 84% yields respectively (entries 2–3). When reaction
was allowed to stir for 2 h, it led to the conversion of kinetically
stable Z-isomer into thermodynamically stable E-isomer (entries
4–5). We observed that after running the reaction for 3 h,
products 3a (Z-isomer) and 4a (E-isomer) were obtained in 10:90
stereoselectivity (entry 6). The similar result was obtained when
the reaction was run for 5 h (entry 7). Lowering the catalyst
loading from 20 mol % to 10 mol % provided the addition
product 3a in 59% yield (entry 8). Decrease in the reaction
temperature adversely affected the yield of the addition product
(entries 9–12). Using DMF and NMP as a solvent, the product 3a
was obtained in 30% and 45% yields respectively (entries 13–
14). No addition product was obtained when toluene and DMA
were used (entries 15–16). Use of CsOH provided the desired
product 3a in 60% yield (entry 17).
Figure 3. Tautomerization in 4-methylimidazole.
imidazole 3l was obtained in 70% yield (entry 12). However the
reaction of 1c with phenylacetylene 2i provided the mixture of E
and Z-styryl product 3m in 82% yield (entry 13). No tautomeric
alkenylation was observed with imidazole 1c, the probable reason
for the above fact might be due to the steric hindrance of the
methyl and ethyl groups present adjacent to the rear nitrogen.
Reaction of benzimidazole 1d with electron-rich alkynes 2b–c
provided the addition products 3n–o in 81% and 79% yields
respectively (entries 14-15). When of 2-methylimidazole 1e (a
regioisomer of 1b) was reacted with alkyne 2i and 2e, products
3p–q were obtained in 75% and 70% yield respectively (entries
16–17). However no desired addition product was obtained when
electron-withdrawing 4-nitroimidazole 1f was used as the
reactant (entry 18). The reactant 1f remained unchanged even
with longer reaction time.
Table 2. Synthesis of Z- styrylimidazoles.
Table 1. Optimization of reaction conditionsa
Entrya
Imidazole
Alkyne
Product
Yield (%)b
Yield (%)b
Base
(equiv)
Time (h)/
T oC
Entrya
Solvent
3a(Z):4a(E)
100:00
100:00
100:00
74:26
35:65
10:90
10:90
100:00
100:00
100:00
95:05
90:10
100:00
100:00
-
1
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.1
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
KOH/0.2
CsOH/0.2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0.5/120
1.0/120
1.5/120
2.0/120
2.5/120
3.0/120
5.0/120
1.5/120
1.5/60
35
62
84
78
76
80
77
59
10
30
42
60
30
45
-
1
84
2
3
2a
1a
1a
4
3a
3b
5
6
7
2
3
82
87
8
2b
9
10
11
12
13
14
15
16
17
1.5/80
3.0/80
3.0/100
1.5./120
1.5/120
1.5/110
1.5/120
1.5/120
NMP
1a
2c
Toluene
DMA
DMSO
-
60
-
100:00
3c
3d
3e
a
Reactions were performed using 2.0 equiv of imidazoles 1a, 1.0 mmol
of the alkyne 2a, and base in 1.5 mL of solvent.
bIsolated yield.
4
5
6
1a
1a
1a
80
85
79
2d
2e
The scope and limitations of the optimized reaction
conditions were next examined by using various substituted
terminal alkynes 2a–i and imidazoles 1a–c (Table 2). The
presence of electron-releasing thiophene, methyl and methoxy
groups on alkyne substrates afforded the addition products 3a–f
−
in 79−87% yields (entries 1 6). However, alkynes having n-butyl
substitution and electron-withdrawing group provided the desired
corresponding addition products 3g–h in moderate yields (entries
7−8). Reaction of imidazole with phenylacetylene 2i provided
the Z-styryl product 3i in 80% yield (entry 9). Unsymmetrically
substituted imidazoles are well known for the rapid
tautomerization (Figure 3).7d When 4-methyl-imidazole 1b was
used, mixtures of tautomeric addition products were obtained
(entries 10−11) (Figure 3). Interestingly, when 2-ethyl-4- methyl-
1H-imidazole 1c was reacted with alkyne 2j, only (Z)- styryl-
3f
2f
7
1a
76
2g
3g

3
During the optimization studies we observed that formation
of E and Z isomer depended upon reaction time. In Table 2, we
have reported the synthesis of Z-addition products. To further
extend the scope of the developed chemistry E-styrylimidazoles
4a–d were synthesized by tuning the reaction time by reacting
alkyne 2a and 2k with imidazoles 1a–c using KOH in DMSO at
120 °C for 3 h (Table 3). Alkyne 2a bearing electron-rich
thiophene ring afforded the Z-addition product 3a in 84% yield in
1.5 h; however after running the reaction for 3 h afforded the E-
addition product 4a in 80% yield. Alkyne 2k with an electron-
withdrawing CF3 group on aryl ring provided the E addition
products 4b–d comparatively in lower yields (entries 2−4).
Unfortunately when the reaction of 1e was performed using open
chain aliphatic alkyne 2l, no addition product was obtained (entry
5).
8
9
1a
1a
70
80
2h
3h
3i
2i
3j
10
2b
80
+
(50:50)
1b
Table 3. Synthesis of E-styrylimidazoles
3j'
Entrya
Imidazoles
Alkynes
Product
Yield(%)b
3k
71
+
11
1b
2g
(50:50)
1
1a
2a
80c
4a
3k'
2
1a
72
73
4b
12
13
70
2k
2k
2j
2i
1c
1c
3l
CF3
N
N
82
3
4
1b
1c
Me
4c
(50:50)
3m
2k
71
14
2b
81c
1d
4d
3n
3o
3p
NR
NR
79c
75c
5
1e
2l
15
16
2c
2i
1d
1e
a Reactions were performed using 2.0 equiv of Imidazoles 1, 1.0 mmol of the
alkyne 2, and KOH (20 mol %) in 1.5 mL DMSO at 120 °C for 3 h.
bIsolated yield.
c Along with 10% of Z- isomer.
17
18
1e
2e
2i
70c
3q
NR
NRc
1f
Unless otherwise noted, reactions were performed using 2.0 equiv of
a
Figure 4. Z and E Stereoselectivity.
imidazoles 1, 1.0 mmol of the alkyne 2, and KOH (20 mol %) in 1.5 mL of
DMSO at 120°C for 1.5 h.
bIsolated yield.
The Z and E stereoselectivity in the product was characterized
by the coupling constant of the styryl protons in 1H NMR
c Reaction was run for 3.0 h.
d Reaction was run for 8.0 h.

4
Tetrahedron
spectroscopy. The J-value of the two styryl protons in products
In conclusion, we have described an efficient approach for
the regio-and stereoselective addition of imidazoles (electron-
deficient heterocycle) onto alkynes to provide a broad range of
synthetically and biologically important (Z)- and (E)-imidazolyl
enamines selectively in good yields. This transition-metal and
ligand-free methodology utilizes a basic system of KOH/DMSO
for the addition of imidazoles onto alkynes. The competitive
experiments clearly demonstrates that imidazole is less reactive
than pyrrole and more reactive than aniline. From a synthetic
point of view, the developed approach is general, cost effective
and could be used for the synthesis of vide range of imidazolyl
enamines of biological importance.
3a−q lies between 8.0−9.5 Hz which supports the Z-
stereoselectivity in the products; however products 4a−d with
coupling constant between 14.6−16.7 Hz conforms the E-
stereoselectivity in the addition products (Figure 4).
Scheme 2. Hydroamination with dialkyne.
Acknowledgments
We further explore the possibility of the reaction with a
dialkyne. More fascinatingly, when 1,4-diethynylbenzene 5 was
reacted with 4.0 equiv of 1a using KOH (40 mol %) at 120 °C,
for 3.5 h, the thermodynamically stable 1,4-bis((E)-2-(1H-
imidazol-1-yl)vinyl)benzene 6 was obtained in 49% yield
(Scheme 2). Reaction monitoring at incessant interval of time
showed that the addition of the imidazole onto alkyne takes place
very rapidly, leading to the transformation of kinetically stable Z-
isomer to thermodynamically stable E-isomer followed by the
attack on another alkyne group present in the substrate 5.
In order to validate the reactivity behavior of the imidazole
1a and pyrrole 7 on alkyne, we performed a control experiment.
We carried out the reaction of 1a (2.0 equiv), pyrrole (2.0 equiv),
with alkyne 2c (1 mmol) using 20 mol % of KOH in 2 mL of
DMSO at 120 °C for 15 min (Scheme 3). The results demonstrate
that the product 9 (addition of pyrrole on alkyne) was obtained in
72% yield, whereas product 3c (addition of imidazole on alkyne)
was formed only in 6% yield. This clearly reveals that imidazole
1a is less reactive than pyrrole and afforded the products in lower
yields along with unreacted alkyne. When the hydroamination
was performed using internal alkyne 8, imidazole fails to afford
the desired addition product 10; however highly reactive pyrrole
gave the hydroaminated product 11 in 73 % yield.
We thank CSIR and DU-DST-PURSE grant for the financial
support and USIC, University of Delhi for the use of
Instrumentation facility. MP and RKS are thankful to DST and
UGC for Fellowship.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
125.
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General procedure for the synthesis of substituted Z-styryl-1H-
imidazole (3b). An oven-dried Schlenk tube with a teflon screw valve
was charged with 2.0 equiv of imidazole 1a–c, 1.0 mmol of the
alkyne 2b, and KOH (20 mol %) in DMSO (2.0 mL). The Schlenk
tube was capped with a rubber septum and then evacuated and
backfilled with nitrogen. The reaction mixture was heated to 120 °C
until alkyne 2b had been completely consumed (as determined by
TLC) and was allowed to cool to room temperature. The reaction
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silica gel (ethylacetate and hexane 4:6). (Z)-1-(4-Methylstyryl)-1H-
imidazole (3b).The product was obtained as orange semi-solid : 1H
NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.03 (d, J = 8.0 Hz, 2H),
6.99 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H), 6.63 (d, J = 8.8
Hz, 1H), 6.28 (d, J = 9.5 Hz, 1H), 2.27 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 138.2, 136.8, 130.5, 129.3, 129.2, 128.3, 123.8, 121.6,
118.4, 21.1. HRMS ESI: [M+] Calcd for C12H12N2: 184.1000; found:
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