Molecular iodine/DMSO mediated oxidation of internal alkynes and primary alcohols using a one-pot, two step approach towards 2,4,5-trisubstituted imidazoles: Substrate scope and mechanistic studies

Article abstract of DOI:10.1016/j.tet.2020.131028

An efficient, eco-friendly and practical oxidation of internal alkynes and primary alcohols as key steps towards the synthesis of 2,4,5-trisubstituted imidazoles is reported. This green synthetic methodology employed an acid and metal-free molecular iodine/DMSO system, to afford a variety of substituted imidazoles in moderate to good yields, with a range of functionalities tolerated. Mechanistic studies revealed two distinct oxidation pathways, which ultimately form the diketone and aldehyde that serve as key intermediates in the multicomponent domino synthesis.

Full text of DOI:10.1016/j.tet.2020.131028

Journal Pre-proof
Molecular iodine/DMSO mediated oxidation of internal alkynes and primary alcohols
using a one-pot, two step approach towards 2,4,5-trisubstituted imidazoles: Substrate
scope and mechanistic studies
Shivani Naidoo, Vineet Jeena
PII:
S0040-4020(20)30135-6
https://doi.org/10.1016/j.tet.2020.131028
TET 131028
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 December 2019
Revised Date: 3 February 2020
Accepted Date: 6 February 2020
Please cite this article as: Naidoo S, Jeena V, Molecular iodine/DMSO mediated oxidation of internal
alkynes and primary alcohols using a one-pot, two step approach towards 2,4,5-trisubstituted
imidazoles: Substrate scope and mechanistic studies, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2020.131028.
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03 February 2020
Subject: Molecular Iodine/DMSO Mediated Oxidation of Internal Alkynes and Primary
Alcohols using a One-pot, Two Step Approach Towards 2,4,5-Trisubstituted Imidazoles:
Substrate Scope and Mechanistic Studies
Dear Professor Marek
Please find the graphical abstract for the above manuscript.
R1
R2
O
O
* Double Oxidation of Two Diverse Substrates
* Metal and Acid-Free
* Environmentally Benign
1
2
R
R
R1
N
I2/DMSO
I2
NH4OAc
R3
+
N
R2
H
R
OH
3
* Inexpensive Synthesis
* One-Pot Approach
R
3
O
Kind Regards
_________________________________________
Dr Vineet Jeena
School of Chemistry & Physics
College of Agriculture, Engineering and Science
Postal Address: Private Bag X01, Scottsville, 3209 South Africa
Telephone: +27 (0) 33 260 5327 Email: Jeenav1@ukzn.ac.za

Senior Lecturer: Organic Chemistry
University of KwaZulu-Natal
Pietermaritzburg
South Africa
+(27) 033 260 5327
Jeenav1@ukzn.ac.za
School of Chemistry & Physics
College of Agriculture, Engineering and Science
Postal Address: Private Bag X01, Scottsville, 3209 South Africa
Telephone: +27 (0) 33 260 5327 Email: Jeenav1@ukzn.ac.za

Molecular Iodine/DMSO Mediated Oxidation of
Leave this area blank for abstract info.
Internal Alkynes and Primary Alcohols using a One-pot,
Two Step Approach Towards 2,4,5-Trisubstituted Imidazoles: Substrate Scope and Mechanistic Studies
Shivani Naidoo and Vineet Jeena*
School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, 3209, South
Africa
R1
O
* Double Oxidation of Two Diverse Substrates
* Metal and Acid-Free
O
R2
* Environmentally Benign
1
2
R
R
R1
N
I2/DMSO
I2
NH4OAc
R3
+
N
R2
H
R
OH
3
* Inexpensive Synthesis
* One-Pot Approach
R
3
O

Molecular Iodine/DMSO Mediated Oxidation of Internal Alkynes and
Primary Alcohols using a One-pot, Two Step Approach Towards 2,4,5-
Trisubstituted Imidazoles: Substrate Scope and Mechanistic Studies
Shivani Naidoo and Vineet Jeena*
School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, 3209,
South Africa.
Jeenav1@ukzn.ac.za
Keywords: alcohols, alkynes, imidazoles, iodine, oxidation
.
Abstract
An efficient, eco-friendly and practical oxidation of internal alkynes and primary
alcohols as key steps towards the synthesis of 2,4,5-trisubstituted imidazoles is reported. This
green synthetic methodology employed an acid and metal-free molecular iodine/DMSO
system, to afford a variety of substituted imidazoles in moderate to good yields, with a range
of functionalities tolerated. Mechanistic studies revealed two distinct oxidation pathways,
which ultimately form the diketone and aldehyde that serve as key intermediates in the
multicomponent domino synthesis.
1. Introduction
The preparation of complex molecules using simple substrates while maintaining economic
and eco-friendly aspects constitutes a great challenge in modern, synthetic organic
chemistry.1 For many years, the general procedure for the synthesis of organic compounds
1

has been the stepwise formation of single bonds in the target molecule, with work-up
procedures after each individual transformation.2 However, a more advantageous approach
would allow for the generation of multiple bonds, in the same reaction vessel, without the
isolation of the intermediates to ultimately produce the target molecule.3 With this objective
in mind, there are two common approaches known as the Tandem Oxidation Process (TOP)4
or the “Ireland” oxidative process,5 which have significantly advanced this methodology. The
tandem oxidation process involves mixing an alcohol, nucleophile and oxidant in a one-pot
reaction where the alcohol is oxidized to the aldehyde and immediately trapped by the
nucleophile to produce the target molecule. The “Ireland” oxidative process was reported by
Robert Ireland, over 30 years ago, in which a series of alcohols were oxidized to their
aldehyde derivatives, followed by the addition of the appropriate nucleophile, without
isolation of the aldehyde, to produce an array of valuable compounds.6 Both of these
synthetic approaches, have a number of advantages such as a decrease in reaction time, cost
effectiveness and produce the desired product in a higher yields when compared to traditional
syntheses.
Multicomponent reactions (MCRs) represent one of the most important processes for the
preparation of numerous compounds in synthetic organic chemistry. In a MCR, three or more
substrates are combined to form a single product in a one-pot reaction.7 These reactions offer
an array of possibilities for the efficient formation of highly complex heterocyclic molecules
in a single step, omitting the need for several work-up and purification steps, and aids in the
minimization of waste, labour, time and cost, while maximizing the yield of the final
product.8
2,4,5-Trisubstituted imidazoles have been studied since the 19th century9 and, remarkably,
continue to find new applications, such as exciting biological activity against Alzheimer’s
2

disease,10 diabetes mellitus11 and malaria12 to name but a few. The classic approach to
assemble these illustrious heterocycles occurs via the multicomponent reaction, between an
α-diketone, aldehyde and ammonium acetate in the presence of transition metal catalysts or
acidic media (Scheme 1a).13
(a) Traditional Imidazole Synthesis
R1
O
R1
R2
O
O
N
Metal/Acid
Catalyst
R3
NH4OAc
+
+
R3
H
N
H
R2
(b) Alcohol Oxidation Initiated Imidazole Synthesis
R1
R2
N
R1
O
O
O
Ru(II)
R3
NH4OAc
R3
OH
+
+
N
H
catalyst
R3
H
R2
(c) Hydroxy Ketone and Alcohol Initiated Imidazole synthesis
R1
R2
O
R1
Ionic
N
NH4OAc
+
+
OH
R3
R3
liquid
OH
N
H
R2
(d) Alkyne Oxidation Initiated Imidazole Synthesis
R1
O
R1
N
Pivalic
acid
R3
NH4OAc
+
+
R3
H
N
H
R2
R2
R1
R1
O
R1
R2
O
N
Iodine/
DMSO
NH4OAc
R3
+
H
+
R3
N
H
R2
O
R2
3

(e) This work
R1
R2
O
O
* Double Oxidation of Two Diverse Substrates
* Metal and Acid-Free
* Environmentally Benign
1
2
R
R
R1
N
I2/DMSO
I2
NH4OAc
R3
+
N
R2
H
R
OH
3
* Inexpensive Synthesis
* One-Pot Approach
R
3
O
Scheme 1: Various synthetic approaches to 2,4,5-trisubstituted imidazoles.
Recently, this approach has evolved using a number of diverse substrates as reactants for one-
pot imidazole synthesis. Rengan and co-worker extended the traditional imidazole synthesis
by commencing from a primary alcohol which was oxidized to the aldehyde using a Ru(II)
catalyst, followed by the addition of the diketone and ammonium acetate to produce a variety
of 2,4,5-trisubstituted imidazole derivatives (Scheme 1b).14 Mirjafari elaborated the standard
approach by mixing α-hydroxyketones, primary alcohols and ammonium acetate
simultaneously in a one-pot procedure, using the ionic liquid, 1-methyl-3H-imidazolium
nitrate [Hmim][NO3], as an oxidant and reaction medium under microwave irradiation that
successfully formed a series of 2,4,5-trisubstituted imidazoles (Scheme 1c).15 Wang and co-
workers adjusted their strategy towards the synthesis of 2,4,5-trisubstituted imidazoles by
commencing from an internal alkyne rather than the 1,2-diketone, to deliver 2,4,5-
trisubstituted imidazoles. Various internal alkynes were oxidized to their subsequent 1,2-
diketones, using a pivalic acid system in the presence of the aldehyde and ammonium acetate
resulting in the formation of numerous trisubstituted imidazoles (Scheme 1d).16 Our research
group extended this methodology by using an I2/DMSO oxidation system for transformation
4

of internal alkynes to 1,2-diketones, followed by the addition of numerous aldehydes and
ammonium acetate to produce a variety of trisubstituted imidazoles (Scheme 1d).17
The combined use of molecular iodine and DMSO, has emerged as a valuable tool for the
synthetic organic chemist and this system has been reported to perform in two ways: (i)
reactions catalyzed via I2 in a DMSO medium and (ii) I2/DMSO mediated oxidative
transformations.18 Some transformations exhibited by this powerful system include, the
oxidation of alkynes to glyoxals,19 the selective sulfenylation of electron rich arenes and
carbonyl compounds,20 the synthesis of unsymmetrical organochalcogenides,21 oxidative
cross-coupling,22 dehydrogenation23 and oxidative cleavage24 to name but a few. Using this
information, we were intrigued by the possibility of an iodine mediated double oxidation of
readily available starting materials (internal alkynes and primary alcohols) in the same
reaction vessel, which would lead to their respective intermediates (diketones and aldehydes)
that, in the presence of ammonium acetate, would ultimately converge to the desired 2,4,5-
trisubstituted imidazoles (Scheme 1e).
2. Results and Discussion
We initiated our study by examining a one-pot reaction between diphenylacetylene (1a),
benzyl alcohol (2a) and ammonium acetate (NH4OAc) in DMSO for 2 h, in the presence of 2
equivalents of I2, at 100 °C, however, the reaction failed to proceed, and no product was
detected (Table 1, entry 1). A similar result was observed when the reaction was repeated for
a longer duration (24 h) (Table 1, entry 2). Due to the failure of these two reactions, we then
attempted a one-pot, two-step approach in which, 1a and 2a were reacted in DMSO for 24 h
at 130 °C, in the presence of 2 equivalents of I2. Subsequently, ammonium acetate was added,
and the mixture was left to react for 2 h at 100 °C, however, only 12% of 3a was produced
(Table 1, entry 3). The synthesis of trisubstituted imidazoles are known to be solvent
5

specific,25 therefore, a range of solvents were added to encourage cyclization, however, no
reaction to low yields were observed when dimethylformamide (DMF), dichloromethane
(DCM), toluene (PhMe), acetonitrile (MeCN), water (H2O) and tetrahydrofuran (THF) were
added (Table 1, entries 4–9). Trisubstituted imidazole syntheses are known to proceed well in
the presence of an alcohol solvent,26 and encouragingly, when methanol (MeOH) was used,
the desired product was formed in an isolated yield of 65% (Table 1, entry 10) and, to our
delight, when ethanol (EtOH) was used as the solvent, 2,4,5-triphenyl imidazole was isolated
in a yield of 86% (Table 1, entry 11). The reaction failed to produce the expected product
when DMSO was replaced with THF, H2O and MeCN (Table 1, entries 12-14), suggesting
the crucial role of DMSO. Attempts were made to decrease the amount of iodine, however,
varied amounts of 1.5 to 0.2 equivalents, resulted in a decrease in product yield (65%-21%)
(Table 1, entries 15-18). Other iodine catalysts, such as iodine pentoxide (I2O5) and 2-
iodobenzoic acid (IBX) were also evaluated and both catalysts resulted in no product
formation (Table 1, entries 19-20). The reaction was attempted in the absence of I2 (Table 1,
entry 21) and DMSO (Table 1, entry 22), but failed to give 3a. Attempts were made to lower
the NH4OAc loading to 5 and 2 equivalents, which resulted in decreased product yields of
33% and 10% respectively (Table 1, entries 23-24). To conclude, the conditions described in
Table 1, entry 11, were found to be optimal and allowed for the maximum formation of the
desired product 3a.
6

Table 1: Screening of optimal reaction conditionsa
Ph
Ph
O
Ph
Ph
1a
Ph
Ph
O
N
Iodine Source/Solvent 1
NH4OAc, Solvent 2
Ph
+
O
+
o
o
N
H
130 C, 24 h
100 C, 2 h
Ph
OH
Ph
2a
Entry
1c
Iodine Source
Solvent 1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
Solvent 2
–
Yieldb
I2
I2
N.R
N.R
12
2d
–
I2
–
3
I2
DMF
DCM
PhMe
MeCN
H2O
Trace
N.R
18
4
I2
5
I2
6
I2
N.R
N.R
N.R
65
7
I2
8
I2
THF
9
I2
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
10
11
12
13
14
15e
16f
17g
18h
19
20
21
22
23i
24j
I2
I2
86
N.R
N.R
N.R
65
I2
H2O
I2
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
I2
I2
62
I2
43
I2
21
I2O5
IBX
–
N.R
N.R
N.R
N.R
33
I2
I2
DMSO
DMSO
I2
10
a Reaction conditions: Step 1: 1a (0.5 mmol), 2a (0.5 mmol), I2 (2 equiv.) solvent 1 (2 mL),
b
c
130 °C, 24 h. Step 2: NH4OAc (10 equiv.), solvent 2 (2 mL), 100 °C, 2 h. Isolated yield.
d
e
One-pot, one-step reaction, 100 °C, 2 h. One-pot, one-step reaction, 100 °C, 24 h. I2 (1.5
7

equiv.)/DMSO (2 mL). f I2 (1 equiv.)/DMSO (2 mL). g I2 (0.5 equiv.)/DMSO (2 mL). h I2 (0.2
equiv.)/DMSO (2 mL) i NH4OAc (5 equiv.). jNH4OAc (2 equiv.). N. R = No Reaction.
With the optimal reaction conditions in hand, we set out to explore the substrate generality of
these transformations and the results are summarized in Scheme 2. Various electron-
withdrawing and electron-donating para-substituted benzyl alcohol derivatives were reacted
with 1a and underwent smooth transformation, to afford the resulting 2,4,5- trisubstituted
imidazoles, 3a-3f, in good to excellent yields (70%-88%). Moderate to good imidazole
yields, 53%-78%, were obtained with benzyl alcohol derivatives substituted at the meta and
ortho positions (Scheme 2, 3g-3l). Motivated by these results, we decided to expand our
methodology, by assessing bulkier substrates such as, 2-naphthalenemethanol, which coupled
well with 1a to afford 2-(naphthalene-2-yl)-4,5-diphenyl-1H-imidazole in a 75% yield
(Scheme 2, 3m). The iodine/DMSO system was shown to be substrate dependent as steric
and electronic factors influenced the yield. Based on the successful results obtained by
substituted benzylic alcohols, we further explored heterocyclic and aliphatic substituted
primary alcohols such as; 2-furanmethanol, cyclohexylmethanol and 1-hexanol, to produce
3n and 3o in yields of 16% and 22% respectively, however, no product was obtained when 1-
hexanol was used, even with extended reaction times (Scheme 2, 3p).
8

9

Scheme 2: Substrate scope of 2,4,5-trisubstituted-1H-imidazoles with various internal
alkynes and primary alcohols. Reaction conditions: Step 1: 1 (0.5 mmol), 2 (0.5 mmol), I2 (2
equiv.)/DMSO (2 mL), 130 °C, 24 h. Step 2: NH4OAC (10 equiv.), EtOH (2 mL), 100 °C, 2
h. b Isolated yield. c Step 2: 24 h.
This result is consistent with literature, as aliphatic aldehydes do not couple well in
trisubstituted imidazole synthesis and, when they do, often result in low yields.27 Next, the
coupling reactions between benzyl alcohol and various internal alkynes were examined.
Unfortunately, 1-phenyl-1-propyne and 2-butyne resulted in no product formation, which is
probably due to the reduced nucleophilicity of the reagents (Scheme 2, 3q-3r).28 The
coupling of 1-chloro-4-(phenylethynyl)benzene with benzyl alcohol and 4-fluorobenzyl
alcohol under the optimized reaction conditions, successfully afforded the trisubstituted
imidazoles, 3s and 3t in good yields of 66% and 56% respectively. Given the promising
biological activity of 2,4,5-trisubstituted imidazoles highlighted earlier in this manuscript, the
synthesis of novel imidazoles would be welcome addition to medicinal chemistry. As a result,
this methodology was used to prepare new 2,4,5-trisubstituted imidazoles, 3u to 3x, in yields
of 52% - 62%. Encouraged by the above results, we were curious to investigate the reaction
of 1,2-bis(4-bromophenyl)acetylene with 2a, which reacted smoothly to afford 4,5-bis(4-
bromophenyl)-2-phenyl-1H-imidazole in a modest yield of 48% (Scheme 2, 3y).
To gain insight into the reaction mechanism, several control experiments were conducted
(Scheme 3). In experiment 1, 1a and 2a were oxidized under standard conditions, to afford
benzil and benzaldehyde in isolated yields of 96% and 83%, respectively (Scheme 3, eqn.
(1)). This indicates that the diketone and the aldehyde are intermediates in this domino
synthesis. Next, the radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) was
10

added to the reaction mixture under standard conditions, however, 3a was not formed,
indicating that one (or both) of the substrates undergoes oxidation via a radical mediated
pathway (Scheme 3, eqn. (2)). To further, rationalize this observation, the oxidation of the
alkyne and alcohol was carried out individually.
Scheme 3: Control experiments for the I2/DMSO catalyzed trisubstituted imidazole synthesis.
Firstly, TEMPO was added to 1a in the I2/DMSO system resulting in the formation of benzil
in a 91% isolated yield, suggesting that the oxidation of the alkyne does not proceed via a
radical mediated pathway (Scheme 3, eqn. (3)). Under similar conditions, TEMPO was added
11

in the oxidation of 2a however, benzaldehyde was not detected but the TEMPO-iodine adduct
was identified (determined by mass spectroscopy). This result indicates that this
transformation may proceed via a radical mediated pathway (Scheme 3, eqn. (4)). On
completion of reactions 3 and 4, it was concluded that the synthesis of the trisubstituted
imidazoles, proceeds via two different oxidation methods viz. a non-radical oxidative
pathway for the internal alkyne and a radical mediated pathway for the primary alcohol.
To understand the mechanistic pathway of this double oxidation, multicomponent reaction, a
series of additional experimental reactions and spectroscopic analyses were performed. Our
initial studies focused on the synthesis of the diketone as we attempted to gain insight into its
formation. We had previously shown that the iodo-ketone may be a key intermediate in the
alkyne oxidation17 and we set about attempting to isolate this intermediate to prove its
existence in this reaction. However, despite various reaction conditions only the diketone was
observed with trace amounts of the iodo-ketone. Consequently, it was postulated that it is
difficult to isolate the iodoketone, if generated in the presence of a strong nucleophilic
solvent such as DMSO. This prompted us to alter the optimized reaction conditions to allow
for isolation of the iodinated intermediate using a variety of solvents (ESI, Table 1). Weak
nucleophilic solvents such as MeCN, THF, dichloroethane (DCE) and iso-propanol,
unfortunately resulted in no or minimal product formation. However, when EtOH was
employed; the iodoketone intermediate was obtained in an isolated yield of 28%, which
proved that the iodoketone is a key intermediate in the alkyne oxidation.
Secondly, we decided to probe the source of oxygen atoms in the final diketone and it was
evident that there were three sources of oxygen namely, (i) oxygen from the air, (ii) oxygen
from the trace water in the DMSO and (iii) DMSO itself (Scheme 4). 1a was reacted with I2
12

and DMSO under an N2 atmosphere, affording the 1,2-diketone in a 90% isolated yield, thus
indicating that the reaction is not dependent on O2 from the atmosphere. Next, a water and
toluene biphasic solvent mixture was used, however the reaction did not proceed and only
starting material was obtained, suggesting that the trace amount of H2O found in DMSO does
not play a role in the alkyne oxidation. Finally, the test reaction was carried out in freshly
distilled, anhydrous DMSO, which resulted in the formation of the 1,2-diketone in a 91%
isolated yield, implying that DMSO is the source of oxygen in the isolated diketone.
Scheme 4: Control experiment determining the source of oxygen for benzil formation.
To further substantiate this result, we carried out an additional study. During the oxidation of
internal alkynes, DMSO is, predicted to be reduced to dimethyl sulfide (DMS) however,
DMS is a volatile species and attempts at its isolation would be challenging. This prompted
us to use diphenyl sulfoxide (DPSO) as a surrogate nucleophile, as its reductive product,
diphenyl sulfide (DPS) can easily be isolated and analyzed spectroscopically.29 The reaction
of 1a with I2 and DPSO in dioxane, rendered benzil in an isolated yield of 86% and 0.87
mmol of DPS was obtained. The mole ratio of DPS: benzil (0.87: 0.43), is approximately 2:
1, which suggests that two molecules of DMSO are required to oxidize one molecule of the
internal alkyne and that both oxygen atoms on the diketone arise from the DMSO (Scheme
5).
13

Scheme 5: Oxidation of alkyne with DPSO under optimized conditions.
We then turned our attention to the alcohol oxidation and, as proposed from the control
studies, the primary alcohol oxidation is expected to proceed via a radical mediated pathway
consequently, Electron Paramagnetic Resonance (EPR) was used to detect any radical
species. The addition of benzyl alcohol, I2/DMSO and 5,5-dimethylpyrroline-N-oxide
(DMPO) resulted in the appearance of a 1:2:2:1 quartet with a coupling constant of 14.09
Gauss, characteristic of a phenoxyl radical (Figure 1)30 which implies homolytic cleavage of
the O–H bond.
Figure 1: EPR spectrum showing the DMPO-trapped phenoxyl radical.
14

This observation suggests that upon heating, the I–I bond is cleaved homolytically to produce
iodine radicals, which initiate the homolytic cleavage of the O–H bond to generate a
phenoxyl radical.
Based on our experimental observations and previous literature reports,31 we propose a
mechanistic pathway to rationalize the trisubstituted imidazole formation via a double
oxidation (Scheme 6). The reaction begins with the activation of the triple bond of the alkyne
1 by iodine to furnish the iodonium intermediate A. The addition of DMSO on A allows for
the formation of iodide intermediate B, followed by the removal of weakly basic DMS. The
newly formed iodoketone C, is immediately trapped by a molecule of DMSO, to produce
intermediate D, which further proceeds to form the diketone E through the expulsion of a
second molecule DMS. Concurrently, a proton is abstracted from the hydroxy of the primary
alcohol 2 by an iodine radical to afford the corresponding phenoxyl radical intermediate F.
Thereafter, iodination affords the corresponding iodo intermediate G, followed by
deprotonation which delivers the aldehyde H, while expelling a molecule of HI. Finally,
intermediates E and H are activated by iodine and upon reaction with ammonium acetate,
form imine intermediates I and J which undergo cyclocondensation to afford the desired
2,4,5-trisubstituted imidazole 3.
15

R2
I
I
I2
R1
R2
R2
R1
O
1
A
R1
B
O
S
S
DMS + HI
I
S
S
O
R2
DMS + HI
R2
R2
I
O
O
I
R1
O
R1
R1
O
O
D
E
C
+
R1
R2
O
NH3
H2O
H2O
NH
R1
R2
N
R3
I
NH4OAc
N
H
+
NH
5
R3
H
I
J
O
+
NH4OAc
NH3
R3
H
HI
H
R3
I
O
O
G
HI
I
I
R3
R3
F
O H
4
2 I
I
I
Scheme 6: Plausible mechanism for the double oxidation, multicomponent domino synthesis
of trisubstituted imidazoles.
16

3. Conclusions
In conclusion, we have developed an innovative method for the synthesis of 2,4,5-
trisubstituted imidazoles from internal alkynes and primary alcohols, via a simple, efficient,
eco-friendly and inexpensive double oxidation, domino sequence. The developed system is
applicable to a wide variety of substrates, making this an alternate synthetic approach that
could replace conventional trisubstituted imidazole synthesis. Control and mechanistic
studies predict that the internal alkyne undergoes oxidation to the diketone via the iodoketone
intermediate while the primary alcohol undergoes oxidation via a radical mediated pathway.
Further insight into the mechanism was provided through the judicious use of spectroscopy
and the isolation of key intermediates to provide valuable information into this sophisticated
synthetic procedure.
4. Experimental Details
1
13
All reagents were purchased and used without further purification. All H and C Nuclear
Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance III spectrometer
operating at 400 MHz. Chemical shifts (δ) were reported in ppm using the Dimethyl
1
13
Sulfoxide-d6 (DMSO-d6) residual peak (δ 2.50) for H NMR. Chemical shifts of C NMR
were reported, relative to DMSO-d6 (δ 39.51). The following abbreviations were used to
describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. Coupling constants, J, were reported in Hertz unit (Hz).
High-resolution/Low-resolution electron-spray ionization (ESI) mass spectra were recorded
on a time-of-flight (TOF) micromass spectrometer. Infra-Red (IR) spectra were recorded on
Carey 630 FTIR. Absorption maxima are expressed in wavenumbers (cm-1). Melting points
were determined using Kofler hot-stage melting apparatus. EPR measurements were
conducted using a Bruker EMX Ultra X spectrometer.
17

General Procedure for the Synthesis 2,4,5-Trisubstituted Imidazoles (3).
Alkyne (0.5 mmol, 1 equiv.), primary alcohol (0.5 mmol, 1 equiv.), I2 (1 mmol, 253.8 mg, 2
equiv.) and DMSO (2 mL) were mixed in a round bottom flask and heated at 130 °C for 24 h.
Thereafter, ammonium acetate (5 mmol, 385.4 mg, 10 equiv.) and EtOH (2 mL) was added to
the mixture and heated at 100 °C for 2 h. After cooling, a solution of 1% Na2S2O3 was added
dropwise to the mixture to form a precipitate which was filtered and dried. The crude product
was recrystallized from EtOH to afford spectroscopically pure imidazole 3.
2,4,5-Triphenyl-1H-imidazole (3a).16,32
This compound was prepared as described in the general procedure to produce the target
compound as a white solid. Yield 86% (127.4 mg).
mp: 271 – 272 °C.
IR (cm-1) 3757, 3037, 1586, 1461, 1484, 1126.
1H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.12-8.10 (d, J = 7.58 Hz, 2H), 7.65-7.41
(m, 8H), 7.39-7.25 (m, 5H).
13C NMR (100 MHz, DMSO-d6): δ 146.0, 137.6, 135.7, 131.6, 130.9, 129.1, 128.9, 128.7,
128.65, 128.2, 127.6, 127.0, 125.7.
HRMS (ESI) calculated for C21H16N2: 297.1392, found 297.1398.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (3b).33, 34
This compound was prepared as described in the general procedure. White solid. Yield 85%
(140.6 mg).
18

mp: 261-263 °C.
IR (cm-1) 2841, 1483, 1127, 766.
1H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 8.13 – 8.11 (d, J = 8.25 Hz, 2H), 7.57 –
7.55 (m, 6H), 7.46 – 7.41 (m, 3H), 7.32 – 7.26 (m, 3H).
13C NMR (100 MHz, DMSO-d6): δ 144.9, 137.8, 135.5, 133.2, 131.4, 129.7, 129.2, 129.1,
128.9, 128.7, 128.3, 127.6, 127.3, 127.1.
HRMS (ESI) calculated for C21H15N2Cl: 329.0846, found 329.0846.
2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (3c).33,34
This compound was prepared as described in the general procedure. White solid. Yield 83%
(155.7 mg).
mp: 254-256 °C.
IR (cm-1) 2965, 2085, 1597, 1481, 1125, 766.
1H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 8.06-8.04 (d, J = 9.08 Hz, 2H), 7.71-7.69
(d, J = 8.64 Hz, 2H), 7.57-7.51 (m, 4H), 7.48-7.44 (m, 2H), 7.42-7.40 (m, 1H), 7.34-7.30 (m,
2H), 7.26-7.24 (s, 1H);
13C NMR (100 MHz, DMSO-d6): δ 145.0, 137.8, 135.5, 132.1, 131.4, 130.0, 129.13, 129.1,
128.9, 128.7, 128.3, 127.6, 127.1, 121.9.
HRMS (ESI) calculated for C21H15N2Br: 373.0340, found 373.0344.
2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole (3d).33,34
This compound was prepared as described in the general procedure. White solid. Yield 70%
(110.0 mg).
19

mp: 262-264 °C.
IR (cm-1) 2647, 1655, 1499, 1225, 1160.
1H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.16 – 8.12 (m, 2H), 7.55 – 7.53 (m, 4H),
7.36 – 7.31 (m, 8H).
13C NMR (100 MHz, DMSO-d6): δ 163.8, 161.4, 145.2, 137.6, 135.6, 131.5, 129.1, 128.9,
128.7, 128.2, 127.8 (d, Jc,f = 8.2 Hz), 127.5 (d, Jc,f = 3.4 Hz), 127.0, 116.2 (d, Jc,f = 21.6 Hz).
HRMS (ESI) calculated for C21H15N2F: 313.1141, found 313.1135.
2-(4-Methylphenyl)-4,5-diphenyl-1H-imidazole (3e).34,35
This compound was prepared as described in the general procedure. White solid. Yield 80%
(124.1 mg).
mp: 230-232 °C.
IR (cm-1) 3755, 2840, 1585, 1487, 1437.
1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1H), 8.00 – 7.98 (d, J = 8.57 Hz, 2H), 7.58 –
7.53 (m, 4H), 7.45 – 7.44 (m, 4H), 7.31 – 7.29 (m, 4H), 2.37 (s, 3H).
13C NMR (100 MHz, DMSO-d6): δ = 146.3, 138.3, 136.1, 135.5, 134.6, 132.6, 131.4, 130.4,
129.7, 129.6, 129.2, 129.0, 128.7, 128.4, 128.2, 128.0, 127.7, 127.2, 125.7, 21.4.
HRMS (ESI) calculated for C22H18N2: 309.1392, found 309.1398.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (3f).32
This compound was prepared as described in the general procedure. White solid. Yield 88%
(143.6 mg).
mp: 230-233 °C.
20

IR (cm-1) 2645, 2104, 1609, 1492, 1243, 1175.
1H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.04 – 8.02 (d, J =8.60 Hz, 2H), 7.53 –
7.31 (m, 10H), 7.07 – 7.05 (d, J = 8.10 Hz, 2H), 3.83 (s, 3H).
13C NMR (100 MHz, DMSO-d6): δ 159.4, 145.6, 136.8, 135.3, 131.2, 128.6, 128.3, 128.1,
127.6, 127.57, 127.0, 126.7, 126.4, 123.1, 114.1, 55.2.
HRMS (ESI) calculated for C22H18N2O: 325.1341, found 325.1349.
2-(3-Chlorophenyl)-4,5-diphenyl-1H-imidazole (3g).34,36
This compound was prepared as described in the general experiment procedure. White
crystalline solid. Yield 64% (105.9 mg).
mp: 231-233 °C.
IR (cm-1) 3028, 2103, 1682, 1578, 1458, 1023, 846, 769.
1H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 8.17 – 8.16 (t, J = 1.71 Hz, 1H), 8.07 – 8.05
(m, 1H), 7.55 – 7.50 (m, 5H), 7.45 – 7.39 (m, 7H).
13C NMR (100 MHz, DMSO-d6): δ = 145.1, 138.4, 136.5, 134.3, 133.4, 132.8, 131.6, 131.2,
130.4, 129.5, 129.3, 129.0, 128.8, 127.7, 127.4.
HRMS (ESI) calculated for C21H15N2Cl: 329.0846, found 329.0847.
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (3h).33,34
This compound was prepared as described in the general procedure. Yellow solid. Yield 57%
(97.3 mg).
mp: 301-302 °C.
IR (cm-1) 2858, 1585, 1522, 1476, 1418, 1346, 1252, 1072.
21

1H NMR (400 MHz, DMSO-d6): δ 13.14 (s, 1H), 8.97 (s, 1H), 8.55 – 8.51 (d, J = 8.01 Hz,
1H), 8.25 – 8.20 (d, J = 7.61 Hz, 1H), 7.82 – 7.76 (t, J = 7.62 Hz, 1H), 7.59- 7.54 (m, 4H),
7.41 – 7.36 (m, 6H).
13C NMR (100 MHz, DMSO-d6): δ = 148.9, 143.9, 132.4, 131.7, 130.9, 129.0, 128.2, 123.0,
119.9.
HRMS (ESI) calculated for C21H15N3O2: 340.1086, found 340.1076.
2-(2-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (3i).32
This compound was prepared as described in the general procedure. White solid. Yield 78%
(127.3 mg).
mp: 210-211 °C.
IR (cm-1) 3067, 2841, 1588, 1528, 1473, 1392.
1H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.09-8.07 (d, J = 7.20 Hz, 1H), 7.56 (m,
2H), 7.50 (m, 2H), 7.45-7.42 (m, 2H), 7.40-7.38 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.21 (m,
1H), 7.19-7.17 (m, 1H), 7.10-7.07 (m, 1H), 3.94 (s, 3H).
13C NMR (100 MHz, DMSO-d6): δ 156.5, 143.6, 136.9, 135.8, 131.7, 130.2, 129.3, 129.1,
128.6, 128.1, 127.9, 127.6, 126.9, 121.1, 119.4, 112.1, 56.1.
HRMS (ESI) calculated for C22H18N2O: 325.1341, found 325.1344.
2-(2-Methylphenyl)-4,5-diphenyl-1H-imidazole (3j).37
This compound was prepared as described in the general procedure. White solid. Yield 70%
(108.6 mg).
mp: 201-204 °C.
22

IR (cm-1) 3101, 2987, 2101, 1660, 1400, 1315.
1H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 7.74-7.72 (m, 1H), 7.54 (m, 4H), 7.36-7.31
(m, 9H), 2.50 (s, 3H).
13C NMR (100 MHz, DMSO-d6): δ 146.6, 136.8, 131.6, 130.5, 129.2, 129.1, 128.7, 128.0,
127.5, 126.9, 126.2, 21.6.
HRMS (ESI) calculated for C22H18N2: 309.1392, found 309.1389.
2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (3k).38
This compound was prepared as described in the general procedure. Yellow solid. Yield 56%
(95.6 mg).
mp: 268-272 °C.
IR (cm-1) 2959, 1583, 1523, 1479, 1410, 1301, 1071.
1H NMR (400 MHz, DMSO-d6): δ 12.95 (s, 1H), 8.02-8.00 (d, J = 6.4 Hz, 1H), 7.95-7.92 (d,
J = 7.0 Hz, 1H), 7.82-7.78 (t, J = 7.0 Hz, 1H), 7.67-7.63 (t, J = 6.55 Hz, 1H), 7.51-7.49 (m,
4H), 7.39 (m, 6H).
13C NMR (100 MHz, DMSO-d6): δ 148.8, 141.5, 132.6, 130.3, 130.0, 129.0, 124.5, 124.0.
HRMS (ESI) calculated for C21H15N3O2: 340.1086, found 340.1080.
2-(2-Fluorophenyl)-4,5-diphenyl-1H-imidazole (3l).39
This compound was prepared as described in the general procedure. White solid. Yield 53%
(83.3 mg).
mp: 239-240 °C.
IR (cm-1) 3047, 1580, 1473, 1218, 1097, 759.
23

1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1H), 8.03-8.00 (t, J = 15.30, 5.9 Hz, 1H), 7.54-
7.52 (m, 4H), 7.50-7.45 (m, 2H), 7.40-7.33 (m, 7H).
13C NMR (100 MHz, DMSO-d6): δ 160.6, 158.1, 141 (d, JC,F = 1.75 Hz), 137.7, 135.5, 131.4,
130.8 (d, JC,F = 8.26 Hz), 130.1 (d, JC,F = 2.59 Hz), 129.0, 128.7, 128.3, 127.6, 127.0, 125.2
(d, JC,F = 3.28 Hz), 119.2 (d, JC,F = 12.56 Hz), 116.8 (d, JC,F = 21.60 Hz).
HRMS (ESI) calculated for C21H15N2F: 313.1141, found 313.1135.
2-(2-Naphthyl)-4,5-diphenyl-1H-imidazole (3m).40
This compound was prepared as described in the general procedure. White solid. Yield 75%
(129.9 mg).
mp: 274-275 °C.
IR (cm-1) 3050, 1586, 1445, 1407, 1340, 1262, 1069.
1H NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H), 8.65 (s, 1H), 8.31-8.29 (d, J = 8.29 Hz, 1H),
8.04-7.95 (m, 3H), 7.59-7.56 (m, 6H), 7.41 (m, 6H).
13C NMR (100 MHz, DMSO-d6): δ 146.0, 133.5, 133.2, 128.9, 128.7, 128.6, 128.3, 128.2,
127.2, 126.8, 124.2, 124.0.
HRMS (ESI) calculated for C25H18N2: 345.1392, found 345.1393.
2-(2-Furanyl)-4,5-diphenyl-1H-imidazole (3n).16
This compound was prepared as described in the general procedure. White solid. Yield 16%
(22.9 mg).
mp: 225-230 °C.
IR (cm-1) 2818, 2721, 1599, 1442, 1071.
24

1H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.81 (m, 1H), 7.54-7.51 (m, 4H), 7.45-7.42
(m, 2H), 7.39-7.37 (m, 1H), 7.33-7.29 (m, 2H), 7.25-7.24 (m, 1H), 6.99-6.98 (d, J = 3.25 Hz,
1H), 6.66 – 6.65 (m, 1H).
13C NMR (100 MHz, DMSO-d6): δ = 146.6, 143.9, 139.5, 137.9, 135.8, 131.7, 129.5, 129.3,
129.1, 128.7, 128.4, 128.0, 127.5, 112.8, 108.3.
HRMS (ESI) calculated for C25H18N2: 286.3272, found 285.0739.
2-Cyclohexyl-4,5-diphenyl-1H-imidazole (3o).32
This compound was prepared as described in the general procedure. White solid. Yield 22%
(33.3 mg).
mp: 240-243 °C.
IR (cm-1) 3050, 1586, 1445, 1407, 1340, 1262, 1108.
1H NMR (400 MHz, DMSO-d6): δ 11.91 (s, 1H), 7.49-7.47 (d, J = 7.56 Hz, 2H), 7.42-7.36
(m, 4H), 7.32-7.24 (m, 3H), 7.19-7.16 (m, 1H), 2.74-2.68 (m, 1H), 2.00-1.97 (m, 2H), 1.82-
1.79 (m, 2H), 1.72-1.69 (m, 1H), 1.65-1.56 (m, 2H), 1.41-1.24 (m, 3H).
13C NMR (100 MHz, DMSO-d6): δ 153.3, 136.7, 135.9, 132.6, 129.5, 128.9, 128.7, 128.1,
127.8, 127.0, 126.7, 38.1, 32.3, 26.6, 26.4, 21.6.
HRMS (ESI) calculated for C25H18N2: 301.1705, found 301.1700.
5-(4-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3s).41
This compound was prepared as described in the general procedure. White solid. Yield 66%
(109.2 mg).
mp: 242-245 °C.
25

IR (cm-1) 3043, 1583, 1483, 1462, 1404, 1092.
1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 8.11-8.09 (d, J = 9.11 Hz, 2H), 7.57-7.50
(m, 6H), 7.42-7.38 (m, 6H).
13C NMR (100 MHz, DMSO-d6): δ = 145.9, 145.7, 137.7, 135.8, 134.9, 134.0, 132.3, 131.0,
130.8, 130.3, 130.0, 129.8, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2, 128.0, 127.3, 126.9,
126.8, 125.2.
HRMS (ESI) calculated for C21H15N2Cl: 331.1002, found 331.1002.
5-(4-Chlorophenyl)-2-(4-fluorophenyl)-4-phenyl-1H-imidazole (3t).42
This compound was prepared as described in the general procedure. White solid. Yield 56%
(97.7 mg).
mp: 247-249 °C.
IR (cm-1) 2967, 2786, 1601, 1538, 1484, 1442, 1221, 1089, 770.
1H NMR (400 MHz, DMSO-d6): δ 12.76-12.73 (m, 1H), 8.15-8.12 (m, 2H), 7.58-7.47 (m,
6H), 7.37-7.31 (m, 5H).
13C NMR (100 MHz, DMSO-d6): δ 163.9, 161.5, 145 (d, JC,F = 15.09 Hz), 138.2, 136.3,
135.4, 134.4, 132.7, 131.0 (d, JC,F = 23.5 Hz), 130.4 (d, JC,F = 12.8 Hz), 130.1, 129.3 (d, JC,F
=
7.4 Hz), 129.0 (d, JC,F = 4.1 Hz), 128.7, 128.5, 127.9 (d, JC,F = 8.23 Hz), 127.7, 127.4 (d, JC,F
= 2.88 Hz), 127.3, 116.2 (d, JC,F = 22.6 Hz).
HRMS (ESI) calculated for C21H15N2F: 347.0751, found 347.0743.
5-(4-Chlorophenyl)-4-phenyl-2-(p-tolyl)-1H-imidazole (3u).
26