Novel synthesis of N-unsubstituted imidazoles via the cycloaddition of N-(tert-butylsulfinyl)imines and TosMIC

Article abstract of DOI:10.1016/j.tetlet.2020.151705

A facile and efficient method was developed for the synthesis of N-unsubstituted imidazoles via the cycloaddition of N-sulfinyl imines and p-toluenesulfonylmethyl isocyanide (TosMIC). This methodology is operationally simple and useful for the preparation of various aromatic and heteroaromatic imidazoles in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2020.151705

Journal Pre-proofs
Novel synthesis of N-unsubstituted imidazoles via the cycloaddition of N-(tert-
butylsulfinyl)imines and TosMIC
Manjunatha M. Ramaiah, Priya Babu Shubha, Hari Prasad, Nanjunda Swamy
Shivananju
PII:
S0040-4039(20)30128-3
DOI:
https://doi.org/10.1016/j.tetlet.2020.151705
TETL 151705
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
3 December 2019
28 January 2020
3 February 2020
Please cite this article as: Ramaiah, M.M., Babu Shubha, P., Prasad, H., Swamy Shivananju, N., Novel synthesis of
N-unsubstituted imidazoles via the cycloaddition of N-(tert-butylsulfinyl)imines and TosMIC, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151705
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Novel synthesis of N-unsubstituted imidazoles via
the cycloaddition of N-(tert-butylsulfinyl)imines and
TosMIC
Leave this area blank for abstract info.
Manjunatha M Ramaiah, Priya Babu Shubha*, Hari Prasad, Nanjunda Swamy Shivananju
O
N
S
N
tBu
TosMIC
Ar
K2CO3, MeOH
rt, 30 min
N
H
Ar
13 Examples
75-96%

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Novel synthesis of N-unsubstituted imidazoles via the cycloaddition of N-(tert-
butylsulfinyl)imines and TosMIC
Manjunatha M Ramaiaha, Priya Babu Shubha*a, Hari Prasada, Nanjunda Swamy Shivananjub
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India
bDepartment of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS Technical Institutions Campus, Mysore, India
Corresponding author. Mobile: +91-974392112; E-mail address: priyabs_chem@yahoo.com (Priya Babu Shubha)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and efficient method was developed for the synthesis of N-unsubstituted
imidazoles via the cycloaddition of N-sulfinyl imines and p-toluenesulfonylmethyl
isocyanide (TosMIC). This methodology is operationally simple and useful for the
preparation of various aromatic and heteroaromatic imidazoles in good to excellent
yields.
Available online
Keywords:
N-sulfinyl imines
TosMIC
Cycloaddition
Imidazoles
Introduction
method offers advantages such as operational simplicity, short
reaction times, high yields, simple work-up and mild reaction
Imidazoles and their derivatives are valuable scaffolds which
have attracted the attention of organic chemists due to their
significant biological and pharmacological properties [1-5]. With
their unique structural features, imidazoles represent an important
class of compounds, forming the core of many natural
products, such as vitamin B12, histidine, histamine, nucleic acid
[6-8] bases, alkaloids [9], biotin and many other bioactive
molecules. Their biological properties include, antifungal,
antibacterial, antimalarial [10-11], antinociceptive, anti-
inflammatory [12], anti-hypertensive [13], hypoxic cell therapy,
imaging agents [14], anticancer [15], and antiplasmodium
[16]. They have a wide range of applications in materials and
polymer sciences [17-18] and are also exploited as anion sensors,
optical materials, electronic and ionic liquids [19]. Consequently,
significant efforts have been invested in the synthesis of different
substituted imidazoles [20-25]. In this regard, several strategies
have been reported for the synthesis of N-unsubstituted
imidazoles using p-toluenesulfonylmethyl isocyanide (TosMIC)
derivatives and imines [26-28]. However these protocols suffer
from drawbacks such as high temperatures, long reaction times,
multi-step reaction sequences, moderate yields, limited substrate
scope and difficulty in accessing the starting materials.
Therefore, there is still scope for the development of mild and
efficient methods to address the drawbacks in the existing
protocols. To the best of our knowledge, the synthesis of 4(5)-
aryl-1H-imidazoles using N-(tert-butylsulfinyl) imines and
TosMIC in the presence of potassium carbonate has not been
reported.
conditions.
Results and Discussion
Recently, we reported the synthesis of N-(tert-butylsulfinyl)
imines from aldehydes and tert-butanesulfinamides in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [29]. In
continuation of our efforts regarding the development of novel
methodologies in organic synthesis, we discovered the formation
of N-unsubstituted imidazoles using N-benzylidene-2-
methylpropane-2-sulfinamide (1) and p-toluenesulfonylmethyl
isocyanide (TosMIC) as starting materials. In our preliminary
experiments, we examined the reactivity of N-benzylidene-2-
methylpropane-2-sulfinamide (1) and TosMIC in the presence of
different bases such as triethylamine (TEA), N,N-
diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), sodium carbonate (Na2CO3), cesium carbonate
(Cs2CO3), potassium phosphate tribasic (K3PO4) and potassium
carbonate (K2CO3) in methanol. After 60 minutes, the desired
product was not formed in the presence of TEA, DIPEA, DBU
and Na2CO3. On the other hand, formation of the desired product
4(5)-phenyl-1H-imidazole (2a) was observed with Cs2CO3,
K3PO4 and K2CO3 which was confirmed by TLC and LC-MS. To
determine the optimum reaction conditions, we further
investigated the influence of time, temperature, stoichiometry and
various solvents such as ethanol (EtOH), isopropanol (IPA) and
tetrahydrofuran (THF) (Table 1). The reaction was best
performed with 1 (1.0 mmol) and TosMIC (1.1 mmol) in the
presence of K2CO3 (2.5 mmol) and protic solvents (MeOH,
EtOH, IPA) at room temperature for 0.5 h (Table 1, entry 10).
Our methodology reports an alternate approach for the
synthesis of 4(5)-aryl-1H-imidazoles via a [2+3] cycloaddition
protocol at ambient temperature. This facile and highly efficient

2
Table 1. Optimization of the reaction conditions.
Mechanistic insights for the synthesis of 4(5)-aryl-1H-
imidazoles were previously reported by ten Have and co-workers
[28].
O
O
Table 2. Synthesis of N-unsubstituted imidazoles.a
S
N+ C-
O
S
O
N
S
N
N
tBu
TosMIC
TosMIC (1.1 equiv.)
K2CO3, MeOH
rt, 30 min
N
tBu
Base, MeOH
Ph
R
N
H
2a
N
Ph
R
H
1
2a-m
Yield 2a
MeO
NC
Entry
Base (equiv.)
T (°C)
Solvent
Time (min)
(%)a
H
H
H
N
N
N
1
TEA (1.5)
25
25
25
25
25
25
25
25
25
25
25
25
50
50
25
25
25
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
60
60
60
60
60
60
60
30
30
30
30
15
30
15
30
30
30
0
N
N
(90%)
N
(93%)
2
DIPEA (1.5)
DBU (1.5)
0
2c
2a
(91%)
2b
3
0
4
Na2CO3 (1.5)
Cs2CO3 (1.5)
K3PO4 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (2.5)
K2CO3 (3.0)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
0
Br
F
5
61
52
62
64
75
91
90
68
82
78
85
50
0
H
N
H
N
H
N
6
F
7
N
N
N
(91%)
2f
(82%)
8
2e
(78%)
2d
9
Br
Br
10
11
12
13
14
15
16
17
H
F
H
N
N
H
O
H
N
N
S
N
N
N
N
I
N
(96%)
2i
(87%)
2j
(93%)
2h
(85%)
2g
O
H
N
IPA
H
N
N
H
N
THF
N
N
a Isolated yield after chromatographic purification.
NH
N
Br
N
2m
(75%)
2l
(91%)
2k
(94%)
With the optimized conditions in hand, we then explored the
scope of this method. Diversified N-sulfinyl imines having
different substitutions at various positions on the aromatic ring
were reacted with TosMIC. Initially, N-benzylidene-2-
methylpropane-2-sulfinamide (Table 2, entry 1) was reacted with
TosMIC in the presence of K2CO3 in methanol at room
temperature. The cycloaddition between electron-withdrawing
and electron-donating sulfinyl imines (Table 2, entries 2 and 3)
provided the corresponding imidazoles 2b and 2c in excellent
yields. The reaction was explored with substrates bearing para
and meta substituents (Table 2, entries 4 and 6) which gave the
corresponding imidazoles in high yields. Sterically hindered N-
sulfinyl imines (Table 2, entries 5 and 7) provided 2e and 2g in
78% and 96% yield, respectively. The reaction scope was further
a
Reagents and conditions: N-sulfinyl imines (1.0 mmol), TosMIC (1.1 mmol),
MeOH (3 mL), K2CO3 (2.5 mmol), rt, 0.5 h. b Isolated yield after chromatographic
purification.
Conclusion
In conclusion, we have developed a new methodology for the
synthesis of 4(5)-aryl-1H-imidazoles via the cycloaddition of
p-toluenesulfonylmethyl isocyanide (TosMIC) and N-(tert-
butylsulfinyl)imines in the presence of potassium carbonate at
room temperature. This methodology provides easy access to N-
unsubstituted imidazoles, with advantages such as short reaction
times, high yields, mild reaction conditions and simple work-up.
This method was shown to be appropriate for a broad range of
sulfinyl imines containing aromatic, heteroaromatic, sterically
hindered, electron-rich, electron-deficient and bicyclic
substituents. Unfortunately this method was not suitable for
aliphatic N-sulfinyl imines.
examined with
a
variety of five- and six-membered
heteroaromatic N-sulfinyl imines (Table 2, entries 8-11). Upon
cycloaddition with TosMIC the corresponding imidazoles 2h, 2i,
2j and 2k were obtained in high yields. Bicyclic N-sulfinyl
imines proceeded smoothly to furnish the desired compounds (2l
and 2m) in 91% and 75% yield, respectively. To further
demonstrate the scope of this method, the optimized conditions
were applied to aliphatic N-sulfinyl imines with tert-butyl,
cyclopropyl and cyclohexyl groups, but no product formation
was observed by TLC and LCMS and the starting materials were
unreacted.
Acknowledgements
The authors wish to thank Srinivasaiah and Pavan Kumar
Prabhala for their support.

3
Supplementary Material
1
Experimental details, H, 13C NMR and HRMS spectra of
compounds 2a-m are available in the supporting information.
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Graphical abstract
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H
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13 Examples
75-96%
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Highlights

4
 Facile and efficient approach for the
synthesis of 4(5)-aryl-1H-imidazoles.
 Transition-metal-free, mild reaction
conditions with operational simplicity.
 Short reaction times with higher yields.