Electrochemical access to benzimidazolone and quinazolinone derivatives: Via in situ generation of isocyanates

Article abstract of DOI:10.1039/d0cc07125k

Isocyanates are the key intermediates for several organic transformations towards the synthesis of diverse pharmaceutical targets. Herein, we report the development of an oxidant-free protocol for electrochemical in situ generation of isocyanates. This strategy highlights expedient access to benzimidazolones and quinazolinones and eliminates the need for exogenous oxidants. Furthermore, detailed mechanistic studies provide strong support towards our hypothesis of in situ isocyanate generation. This journal is

Full text of DOI:10.1039/d0cc07125k

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Electrochemical Access to Benzimidazolone and Quinazolinone
Derivatives via in situ Generation of Isocyanates
Debarshi Saha,a Irshad Maajid Taily,a Sumitra Naik a and Prabal Banerjee a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Isocyanates are the key intermediates for several organic are extensively studied for their antitumor, anticancer, anti-
transformations towards the synthesis of diverse pharmaceutical inflammatory, anti-HIV, and other multifarious biological
targets. Herein, we report the development of an oxidant-free activities.4b Hence, many efficacious protocols have been
protocol for electrochemical in situ generation of isocyanates. The disclosed for their construction.8 In spite of the landmark
strategy highlights expedient access to benzimidazolones and advancement in the synthesis of these vital structural scaffolds,
quinazolinones and eliminates the need for exogenous oxidants. modern methodologies which are green and environmentally
Furthermore, detailed mechanistic studies provide strong support benign has always fascinated the scientific community. In
towards our hypothesis of in situ isocyanate generation.
recent times, electroorganic chemistry has bestowed us an
appealing tool for various redox transformations.5 Employing
electrons as the reagent makes this methodology green and
sustainable6 and has intrigued the organic chemists to adopt
this promising technology.7a Allured by this elegant technology,
recently, Xu et al. established an electrosynthetic procedure for
the construction of benzimidazolones and benzoxazoles.9a
Isocyanates, discovered in 1848 by Wurtz, are one of the most
prevalent intermediates in organic chemistry.1 Currently, the
global isocyanate market surge of more than 5% per year
underlines its importance towards the synthesis of structural
scaffolds like biurets, allophanate, and most widespread
polyurethanes.2a Notably, isocyanates are often derived from
the reaction of toxic phosgene with amines.2a Phosgene, being
hazardous to health, difficult to store, and handling issues, has
made the synthetic community to think about its alternative. In
2018, Rousseaux and co-workers turned up with a phosgene
and metal free synthesis of unsymmetrical ureas and
carbamates where they employed isocyanate as an
intermediate.2b Despite the importance and significant research
efforts, isocyanate intermediates still suffer from one of the
most significant challenges, i.e., sensitivity towards moisture.2b
To overcome this, blocked isocyanates,3 which contains a
protected isocyanate, were introduced. Manoeuvring these
isocyanates, many groups have demonstrated their utility
towards the synthesis of many nitrogen containing biologically
active heterocycles. Being highly valuable and pivotal
intermediate, chemists persuade their in situ generation. An
example of this was demonstrated by Beauchemin et al.,
whereby engaging an N-substituted isocyanate, cascade
synthesis of aminohydantoin was conducted.4a Among the
nitrogen heterocycles, quinazolinones and benzimidazolones
a) Li et al. (Adv. synth. catal. 2020, 362,1977)
R1
R1
N
H
N
N
RVC(+)/Pt(-), CCE
Me4NBF4, NaOMe
MeOH, 60 °C, 8 h
undivided cell
R
R2
+
H2
R2
O
O
N
R= Ar, OMe
R
R1= Me, Et
R2= EDG, EWG
b) This work: Electrochemical in situ generation of isocyanate
C(+)/C(-), CCE
X
0-1 X
0-1
X
R3
R3
R3
0-1
N
H2
O
+
Bu4NBF4 (2.0 equiv.)
Cp2Fe (0.5 equiv.)
CH3CN:H2O (4.5:0.5)
C
NH
N
H
O
O
NH
OR4
in situ isocyanate generation
2-4 h, rt
O
Ts
OR4
OH
NH
X=
N
H
N
H
Scheme 1. Electrochemical synthesis of benzimidazolones and
quinazolinones.
In continuation of the endeavour, very recently, Li’s group
achieved an electrochemical intramolecular oxidative C-N
coupling from simple aryl ureas towards the synthesis of
benzimidazolones9b (Scheme 1a). Motivated by the incredible
,
utility of this chemistry towards C-C7b,7c C-X7d-7g bond
formation, we envisaged that this process can be exploited
towards in situ generation of isocyanates and the same could be
further exploited towards the sustainable synthesis of
benzimidazolones and quinazolinones (Scheme 1b). In line with
a. Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road,
Rupnagar, Punjab-140001, India. E-mail: prabal@iitrpr.ac.in.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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our thought, we found, in 2014, seminal work by Jeffrey et al. supporting electrolytes like Et4NBF4, Bu4NClO4, Bu4NBr, and
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DOI: 10.1039/D0CC07125K
encountered an isocyanate intermediate in the presence of Bu4NBF4 were varied (entry 2-5). We found that Bu4NBF4 (2.0
iodobenzene diacetate (PhI(OAc)2), while attempting [4+3] equiv.) served as a better supporting electrolyte. Among others,
cycloaddition reaction via diazaoxy-allylic cation.10 Although Et4NBF4 proved equally efficient, whereas Bu4NClO4 and Bu4NBr
hypervalent iodine reagents are used in various resulted in diminished yields. Although the reaction worked
transformations, and suffer from several limitations such as the well with the dry CH3CN (entry 6) but incorporating a trace
stoichiometric generation of waste, large scale preparation, amount of H2O enhanced the yield to 60% (entry 1). Further,
etc.11 We contend that electrochemical in situ generation of replacement of CH3CN with DCM, MeOH, DMF (entry 7) was
isocyanate remains fully unexplored. In this particular context, found fatal. Usage of TEMPO (entry 8) instead of Cp2Fe
herein, we report an unprecedented in situ electrochemical furnished a decent yield. The choice of the electrode materials
generation of isocyanate pathway for the synthesis of was found critical because replacing the graphite anode with
benzimidazolone and quinazolinones.
the platinum anode (entry 10) showed lower efficiency.
However, the usage of Pt cathode has no profound effect on the
yield (entry 9). Furthermore, increasing or decreasing the
current from 3.0 mA (entry 11-12) resulted in compromised
yield. Control experiments demonstrated electricity and Cp2Fe
as (entry 13) crucial parameters for the electrolysis. Moreover,
to ascertain the role of electricity, the reaction (in the absence
of electricity) was also performed in the presence of
stoichiometric amount of bases like NaH, NaOH, and K2CO3
(entry 14), but no product formation was observed.
Table 1: Optimization of reaction conditions
OBn
O
NH
NH
NH
electrodes, 2.5-3.0 mA
electrolyte (2.0 equiv.)
H
N
O
Mediator (0.5 equiv.)
solvent, rt
N
OBn
N
OBn
O
H
O
N
H
Single crystal X-ray structure
CCDC No. 1983427
1a
2a
OR2
Entr
y
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Variation from standard conditionsa
Yieldb
O
C(+)/C(-), 3 mA
Bu4NBF4 (2.0 equiv.)
Cp2Fe (0.5 equiv.)
R1
O
NH
X
OR2
H
N
X=
N
H
N
O
NH
H
R1
O
N
H
None
60
15
14
17
45
44
n.r.
58
R1
Ts
X
N
H
CH3CN:H2O (4.5:0.5)
2-4 h
X
R1= Me, OMe
Observed for
Bu4NPF6 instead of Bu4NBF4
Bu4NBr instead of Bu4NBF4
Bu4NClO4 instead of Bu4NBF4
Et4NBF4 instead of Bu4NBF4
Dry CH3CN instead of CH3CN:H2O
DCM, CH3OH and DMF instead of CH3CN:H2O
TEMPO instead of Cp2Fe
Pt cathode instead of Carbon
Pt anode instead of Carbon
At constant current of 5.0 mA
At constant current of 1.5-2.0 mA
Without electricity or Cp2Fe
Without electricity in the presence of NaH,
NaOH and K2CO3
2a-2l
1a-1l
2d,2e & 2f
H
H
H
N
O
N
H
N
N
N
O
O
O
N
N
N
O
O
O
O
BnO
BnO
H3CO
N
O
N
N
H
N
H
H
H
2d
2c
2b
2a
80% (1:1), 2.3 h
60%, 2.3 h
57%, 3.0 h
60%, 3.0 h
H
H
N
H
N
O
N
H
N
O
N
56
O
O
O
N
N
N
trace
trace
24
n.r.
n.r.
O
O
O
H3CO
BnO
N
O
N
BnO
N
H3CO
N
H
H
H
H
2h
2g
2f
2e
59%, 2.3 h
87%, 2.2 h
70% (1:1), 2.2 h
78% (1:1), 2.2 h
H
H
N
H
N
H
N
N
O
N
O
O
O
N
N
N
N
O
S
O
O
O
O
BnO
N
H3CO
N
H3CO
N
aUnless otherwise stated, all the reactions were performed at a
constant current of 3.0 mA with carbon as both anode and
cathode, Cp2Fe as
electrolyte, and CH3CN:H2O as a solvent with 1a (0.1 mmol).
bisolated yield. n.r. = no reaction.
H
H
H
2l
2k
2i
2j
61%, 3.2 h
44%, 4.0 h
68%, 2.1 h
66%, 3.0 h
a mediator, Bu4NBF4 as supporting
Scheme 2. Substrate scope of benzimidazolone derivatives.
Once the optimized conditions were established, the substrate
scope was investigated. Initially, the effect of (un)substituted
benzyloxy group was screened (2a and 2b). To our delight, para-
isopropylbenzyloxy derivative (2b) furnished moderate yield.
Further, no profound effect on the yield was observed on
replacing the benzyloxy group with the methoxy group (2c).
Next, substituted ortho-phenylene diamines having electron
donating groups delivered the product in moderate yields (2d-
2h). In the case of para-methyl (2d and 2e) and para-methoxy
phenylene diamines (2f), NMR data revealed the formation of
two inseparable regioisomers (1:1). Although the dimethyl
substituents (2g and 2h), irrespective of their position, rendered
the single regioisomers in good yields. To resolve the issue of
regioselectivity, the reaction of the unsymmetrical substrate
To test our hypothesis, we initially took 1,1'-(1,2-
phenylene)bis(3-(benzyloxy)urea) 1a as a model substrate,
Cp2Fe (0.5 equiv.) as a mediator, and Bu4NPF6 (2.0 equiv.) as a
supporting electrolyte in an undivided cell equipped with
graphite electrodes. The electrolysis was performed at a
constant current of 3.0 mA (cell potential during the reaction
lies in the range of 2.23-2.90 V), and gratifyingly N-(benzyloxy)-
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide
2a
was obtained in low yields. The structure of 2a was confirmed
by single-crystal X-ray structure analysis. Encouraged by this
result, we screened the reaction conditions for the following
transformation which are summarized in Table 1. Initially,
2 | J. Name., 2012, 00, 1-3
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(2i) evinced the formation of a single regioisomer. However, (2,2,3,3-tetrafluoro-1-propanol).10 The substrate 1l initially
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DOI: 10.1039/D0CC07125K
electron withdrawing substituents on the aryl ring of the undergoes anodic oxidation followed by a nucleophilic attack of
corresponding diamines proved incompatible, possibly due to TFP to form adducts I and II with a trace amount of product
compromised nucleophilicity. On the other hand, the formation. The adduct I and II (detected by HRMS) describe the
replacement of the aryl group with naphthalene moiety (2j) in situ generation of isocyanate intermediate (Scheme 5a).
proved compatible. Heterocyclic motif, like pyridine-2,3- Moreover, the electrolysis failed in the absence of nitrogen of
diamine (2k), gave the single regioisomer with slightly inferior diamines (Scheme 5b).
yield due to the decreased nucleophilicity of the amine group.
O
C
N
F
H
F
F
F
O
N
Pleasingly, when the phenylene diamine was replaced by rac-
cyclohexane-1,2-diamine our protocol furnished rac-N-
methoxy-2-oxooctahydro-1H-benzo[d]imidazole-1-
O
O
F
OMe
OMe
a)
H
N
O
C
NH
NH
NH
NH
C(+)/C(-), 3 mA
O
N
H
O
F
Bu4NBF4, Cp2Fe
CH3CN:TFP (1:1)
3 h
N
F
O
F
MeO
O
N
N
carboxamide (2l) with 61% yield.
O
O
F
H
H
F
I
II
2l
F
F
1l
To extend the generality of our concept, the synthesis of
quinazolinone derivatives was also attempted, and four
different derivatives were obtained (Scheme 3). Similar yields
were observed when the benzyl substituents were varied (2m-
Detected by HRMS
Detected by HRMS
Trace
OBn
b)
HN
C(+)/C(-), 3 mA
O
O
No reaction
Bu4NBF4, Cp2Fe
CH3CN:H2O (4.5:0.5)
HN
5 h
OBn
3
2q).
The
structure
of
N-(benzyloxy)-2-oxo-1,2-
Scheme 5. Mechanistic studies.
dihydroquinazoline-3(4H)-carboxamide (2m) was confirmed by
single-crystal X-ray structure analysis. Next, the protocol was
attempted with unsymmetrical substrates (2p and 2q), which
resulted in significant improvement of the yield. Pleasingly, the
synthesis of diverse heterocyclic scaffolds like N-tosylated
quinazolinones (2p) and oxazinone (2q) was accomplished by
employing this methodology.
Furthermore, cyclic voltammetry experiments (see supporting
information) could figure out the role of Cp2Fe in lowering the
oxidation peak of 1c (2.53 V v/s Ag/AgCl) to 2.27 V, indicating
that Cp2Fe acts as a mediator. Also, to determine the role of
water the experiment was performed in the presence of 0.1 M
NaOH, which enhanced the catalytic current between [Cp2Fe]+
and 1c. Henceforth, the generation of -OH is one of the key steps
for this protocol. Based on the experimental results and
literature reports, we proposed a plausible mechanism (Scheme
6). The process gets initiated with the synergistically paired
electrolytic cycles as suggested by Luo et al.12 These two
processes further facilitate the oxidation of 1c to generate
nitrenium intermediate B via the formation of intermediate A.
O
C(+)/C(-), 3 mA
OR2
X
X =
Bu4NBF4 (2.0 equiv.)
Cp2Fe (0.5 equiv.)
N
H
H
N
N
X
H
(2m-2o)
NH
NH
1m-1q OR2
CH3CN:H2O (4.5:0.5)
0.5-2.3 h
N
O
(2p)
(2q)
Ts
H
O
OH
2m-2q
O
O
OBn
O
N
N
N
N
H
H
N
O
N
H
O
H
Subsequently, nitrenium intermediate
B underwent the
2n
2m
CCDC No. 1965927
59%, 2.3 h
formation of isocyanate C and eliminates nitrene intermediate
D, which is followed by 5-exo cyclization instead of 7-exo
cyclization which leads to the formation of 2c.
60%, 2.3 h
O
Ts
O
O
OCH3
N
N
N
H
N
H
O
N
N
O
H
H
H
2o
2p
95%, 0.5 h
2q
O
N
OCH3
OCH3
OCH3
57%, 2.2 h
88%, 1.0 h
NH
NH
(-)
H2
O
Scheme 3. Formation of quinazolinones and oxazinone.
O
N
1c
H
(+)
O
N
-OH
Salubrious with the above result, we attempted the synthesis of
N-methoxy-2-oxo-2,3-dihydro-1H-perimidine-1-carboxamide
(2r). Surprisingly, the N-methoxy amide group got hydrolyzed
during the reaction, and we obtained perimidinone (2r’) as a
product (Scheme 4), which has been reported for anxiolytic
effects.11
NH
NH
Cp2Fe2+
OCH3
O
N
H
A
H
N
H2
O
O
N
OCH3
OCH3
Cp2Fe3+
O
N
N
O
-OH
NH
H3CO
N
H
B
O
N
Cathode
2c
O
O
O
O
O
H
C(+)/C(-), 3 mA
Bu4NBF4 (2.0 equiv.)
Cp2Fe (0.5 equiv.)
Anode
OMe
MeO
OMe
HN
NH
HN
N
N
N
NH HN
N
N-OCH3
H
H3CO
N
N
OCH3
H
H
CH3OH
N2
H+
N
CH3CN:H2O (4.5:0.5)
D
N
H
N
O
N
N
C
O
Path 2
-H+
O-
Path 1
C
O-
C
2r
2r'
57%, 2.3 h
1r
N
OCH3
N
NH
5- exo cyclization
favored
N
H
NH
OCH3
7- exo cyclization
Disfavored
+H+
OCH3
NH
O
O
NH
OCH3
O
Obtained
Expected product
O
C
Not formed
Formation of isocyanate intermediate
Scheme 4. Formation of perimidinone.
Scheme 6. Plausible Mechanism.
To investigate the reaction pathway, the reaction was
performed in the presence of a stoichiometric amount of TFP
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J. Name., 2013, 00, 1-3 | 3
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Further, the nitrene intermediate D dimerizes to an unstable
hyponitrite ester, subsequently loses nitrogen, and forms
methanol.13 Although among the two nitrogen functionality,
the one having aryl/alkyloxy group is more nucleophilic, as
demonstrated by our group.14 But in this case, the one which is
less nucleophilic attacks, i.e., path 2 is preferred over path 1,
suggesting that the nitrogen which is in close proximity with
isocyanate could attack easily in comparison to the more
nucleophilic one, in addition to the fact that 5-membered ring
is thermodynamically more stable.
To evaluate the practicality of our protocol, the electrolysis was
performed at a gram-scale, and the reaction demonstrated
scalability with a moderate yield of 40% (Scheme 7a).
Furthermore, derivatization of 2c was performed by reaction
with chlorosulfonic acid to obtain 2ca, which was further
treated with (4-bromophenyl)hydrazine to furnish 5-((2-(4-
bromophenyl)hydrazinyl) sulfonyl)-N- methoxy-2-oxo-2,3-
dihydro-1H-benzo[d]imidazole-1-carboxamide (2cb) (Scheme
7b). Delightfully, the synthesized molecule bears structural
similarity to the molecule which is reported to have antitumor
activity.15
Notes and references
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1
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a) Gram scale synthesis
OMe
O
NH
C(+)/C(-), 3 mA
Bu4NBF4 (2.0 equiv.)
Cp2Fe (0.5 equiv.)
H
N
NH
O
N
CH3CN:H2O (4.5:0.5)
20 h
OMe
NH
N
O
H
O
NH
OMe
2c
1c
1 g
0.326 g, 40%
b) Late stage derivatization
H
N
H
N
ClO2S
ClSO2OH,
O
O
N
DCM, 18 h, rt
OMe
N
OMe
N
N
O
H
O
H
2c
H
2ca
, 60%
N
NH2
59
Ueng et al. ( J. Med. Chem. 2016, , 419)
Et3N, DMF
rt, 12 h
Br
Br
Br
8
9
(a) S. Li, R. Khan, X. Zhang, Y. Yang, Z. Wang, Y. Zhan, Y. Dai, Y.
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H
O
N
H
O
N
H
N
N
S
N
S
N
H
O
H
O
O
O
N
N
Scheme 7. Synthetic Application.
Conclusions
2cb
, 74%
NH
O
OMe
In summary, we disclosed an electrochemical pathway for in
situ generations of isocyanate under oxidant-free conditions. It
involves a straightforward, general protocol towards the
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construction
of
benzimidazolones,
quinazolinones,
perimidinone, and oxazinones. This methodology demonstrates
an inexpensive Cp2Fe as a redox catalyst with the release of H2
gas, thereby eliminating the need for expensive
transition/noble metal catalyst and hypervalent iodine
reagents. Furthermore, the synthetic applications of this work
highlight scalability and also involves the synthesis of a drug-like
molecule.
Conflicts of interest
There is no conflict of interest to declare
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