Synthesis of aminobenzoxazoles via simple, clean and efficient electrochemical redox reactions

Article abstract of DOI:10.1016/j.tetlet.2018.12.054

An efficient single step process for the construction of pharmaceutically relevant substituted aminobenzoxazoles have been described in this report. Various electrodes and electrolytes combinations have been carried out to harvest optimum coupling results. The presented C–N bond formation reaction methodology has applied for the synthesis of biologically active compounds. This methodology saves reaction steps over traditional functionalization reactions.

Full text of DOI:10.1016/j.tetlet.2018.12.054

Accepted Manuscript
Synthesis of aminobenzoxazoles via simple, clean and efficient electrochemical
redox reactions
Tanay Ghoshal, Vishal Nagar, Adilakshmi Vutla, Sharadsrikar Kotturi,
Sasikumar Kuttappan
PII:
S0040-4039(18)31505-3
https://doi.org/10.1016/j.tetlet.2018.12.054
TETL 50517
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 November 2018
18 December 2018
22 December 2018
Please cite this article as: Ghoshal, T., Nagar, V., Vutla, A., Kotturi, S., Kuttappan, S., Synthesis of
aminobenzoxazoles via simple, clean and efficient electrochemical redox reactions, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.12.054
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Tanay Ghoshala, Vishal Nagara, Adilakshmi Vutlaa, Sharadsrikar Kotturia and Sasikumar Kuttappana

1
Tetrahedron Letters
Synthesis of aminobenzoxazoles via simple, clean and efficient electrochemical redox
reactions#
Tanay Ghoshala, Vishal Nagara, Adilakshmi Vutlaa, Sharadsrikar Kotturia and Sasikumar Kuttappana
aPiramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India
#Dedicated to the memory of Professor Gilbert Stork (Columbia University, New York, USA)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient single step process for the construction of pharmaceutically relevant
substituted aminobenzoxazoles have been described in this report. Various electrodes and
electrolytes combinations have been carried out to harvest optimum coupling results. The
presented C-N bond formation reaction methodology has applied for the synthesis of
biologically active compounds. This methodology saves reaction steps over traditional
functionalization reactions.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Aminobenzoxazoles
Electrochemical reactions
Piperazines, piperidines and homopiperazines
Nitrogen heterocycles
1. Introduction
production of polymers and pigments over a century ago and the
methods have been lasting till today5. One of the very early
Aminobenzoxazoles are an integral part of pharmacophores1
in medicinal chemistry discovery programs. Some of the recently
disclosed biologically active benzoxazole compounds are shown
in Scheme 1. Pemafibrate2 is a potent PPARα agonist used for the
management of atherogenic dyslipidaemia. The other three
compounds3 shown in the Scheme 1 are active in serotonin
receptors. Easy access to such types of aminobenzoxazoles are
always an interesting portion of research for the medicinal
chemists.
notable applications of Kolbe electrolysis reaction has been
reported by Stork6 in the synthesis of -onocerin. Over the last
few years, significant amount of complex organic chemistry
transformations have been reported from the labs of Baran and
others7. Quite often, multiple chemical transformations occurs
under the electrochemical environments. Electrochemistry
provides a powerful tool for the late-stage functionalization of
many complex molecules. These electrochemical transformations
are considered to be clean, nonpolluting and atom economic.
Recent example from Fu and co-workers on the diazidation of
inactive olefin represents an excellent process8 indicating all
facets of electro organic chemistry. In this paper, a combination
of electrochemistry and organic catalysis transforms alkenes into
hard-to-make vicinal diamines. We were intrigued by the recent
report of benzoxazole coupling of morpholine9 and majority of
other amines does not participate in the coupling reactions. At
this point in time we planned to study amines of
pharmaceutically valued substrates to accelerate the synthesis of
advanced intermediates. We also planned to survey electrodes,
electrolytes and reaction solvents to get maximum output for
these reactions. Effect of input voltage also included in the
proposed studies.
Scheme 1. Some of the biologically active aminobenzoxazoles.
Electrochemical reactions attracted considerable amounts of
interest over the years due to its versatility and applicability4. The
Based on the extensive study of common functional groups
present in FDA approved drugs (nitrogen containing hetero-
cycles) compiled by Njardarson and co-workers10, we focused
electrochemical processes have been utilized in the classical
———
 Corresponding author. Tel.: +919586467677; e-mail: sasikumar.kuttappan@piramal.com

2
Tetrahedron
our attention on the coupling reactions of piperidines and
Next, we focused our attention on the selection of best
piperazines in our proposed electrochemical reactions with
benzoxazoles and benzothiazoles. According to the above
mentioned mini perspective compiling all FDA approved drugs,
non-aromatic heterocycles are widely present in active
pharmaceutical ingredients. There are 72 drugs with piperidine
substructure, 59 drugs with piperazine moiety, 37 drugs with
pyrrolidine substructure, 13 drugs with morpholine subunit and
11 compounds with tetrahydroisoquinoline substructure10. We
planned a systematic study of the above mentioned subunits
under electrochemical coupling conditions.
electrolytes as shown in Table 2. Among five commonly used
electrolytes tried, tetrabutylammonium iodide (TBAI) furnished
the best results. The reactions were conducted at room
temperature and monitored periodically and then allowed to be
stirred overnight.
Table 3. Screening of conditions for solvents.
Entry
Cathode
Al
Al
Al
Al
Anode
Solvent
Acetone
DCM
Methanol
Acetonitrile 90
% Conversion Time
1
2
3
4
C
C
C
C
14
<5
<5
3 h
3 h
3 h
3 h
2. Results and Discussions
At the beginning of our investigation, we chose simple
benzoxazole (1) and N-Boc piperazine (2a) as our model
substrates. These nitrogen heterocycles were chosen aiming at the
possibility of further derivatization to get focused libraries of
aminobenzoxazoles.
Table 3 shows the optimal solvent as acetonitrile for the
electrochemical transformations.
Table 4. Study of pharmaceutically relevant secondary amines
and their coupling with benzoxazoles.
Scheme 2. Electrochemical coupling of benzoxazoles with
amines.
Our initial studies utilizing carbon electrodes and 9V batteries
were extremely encouraging and then later we used regular cell
phone charger (5V) as described by Aubé and co-workers11. The
undivided cells made from simple vials were safe and
economical and this simple set up produced reproducible results
with a variety of substituted amines. The successful reactions
were repeated with different electrodes, electrolytes and solvents
as shown in the following Tables 1-3.
Table 1. Screening of conditions for electrodes.
Entry
Cathode
Anode
C
C
C
C
Electrolyte
TBAI
TBAI
TBAI
TBAI
% Conversion Time
1
2
3
4
5
6
Cu
Al
Fe
C
Al
C
50
90
<5
<5
<5
<5
3 h
3 h
3 h
3 h
3 h
3 h
Fe
Al
TBAI
TBAI
As shown in Table 1, a wide variety of electrodes have been
screened for optimal conditions keeping TBAI as electrolyte and
entry 2 gave us the best conversion of starting material to the
product 3a. Other electrodes furnished poor results as compared
to aluminum as cathode and carbon rod as anode.
Conditions: Undivided cell, C anode/Al cathode, TBAI (10 mol %), HOAc (5
equiv.), Acetonitrile (20 mL) at RT. Isolated yields are shown.
It is evident from the above tables that the optimum condition for
this particular transformation is entry number 2 in Table 1. It
should also be noted that each experiments were carried out in
the presence of acetic acid (5 mmol). The best results obtained by
the use of aluminum rod as cathode, carbon rod as anode and
TBAI as electrolyte in acetonitrile solvent at room temperature.
These results might be described based on the higher
conductivity of aluminum metal and better solubility of TBAI in
acetonitrile solvent. This optimized condition has been used for
all our substrates described in this paper. It should also be noted
that all reactions were conducted using 5V cell phone charger as
the power source. We carried out control experiments with all
Table 2. Screening of conditions for electrolytes.
Entry
Electrolyte
% Conversion Time
1
2
3
Lithium perchlorate (LiClO4)
Sodium iodide (NaI)
Tetraethylammonium-p-
toluenesulphonate
<5
<5
60
16 h
16 h
16 h
4
5
Tetrabutylamonium
tetrafluoroborate (TBATFB)
Tetrabutylammonium iodide
(TBAI)
35
90
16 h
3 h

3
reagents and electrodes without passing electricity and as
expected, we have not detected any desired product formation. In
order to extend the utility of this user friendly procedure, we
started to couple medicinally relevant subunits with benzoxazoles
and benzothiazoles.
particular example is alogliptin15 which contains
aminopiperidine moiety. Under our electrochemical conditions,
both racemic as well as single enantiomers of N-Boc protected
aminopiperidines (3n, 81% and 3o, 78% respectively) produced
the same results as anticipated. Similar results were obtained with
N-Boc protected aminopyrrolidines.
Preliminary experiments were successful with N-Boc piperazine,
however the reactions with simple piperazine were only partially
successful (15% conversion to the product 3z) under a variety of
experimental conditions. We assumed that this might be due to
the poor solubility of piperazine under the regular electro-
chemical reaction conditions. This prompted us to choose soluble
substrates such as N-Boc or ester derivatives. From our initial
optimization studies, compound 3a was obtained in 93% isolated
yield with a clean reaction profile12. Our results are summarized
in Table 4. It has been proposed previously that the Schiff base
(Int-A) would undergo electrochemically initiated
It is interesting to note that acyclic secondary amines also very
well participated in electrochemical reactions as illustrated by
compounds 3p and 3q. Excellent yields were observed in these
cases, however the reactions failed to provide any results in the
case of primary amines.
Recent literature discloses that many compounds with homo-
piperazine moieties are biologically active especially as serotonin
antagonists3,16. As expected, the reactions between benzoxaxoles
and N-Boc homopiperazine went uneventful to furnish compound
3s with around 90% isolated yields. A slight decrease in yield
was noted in the case of compound 3r.
dehydrogenative oxidation to form the desired aminobenzoxazole
3a as shown in Scheme 39.
Tetrahydroisoquinolines constitute yet another major moiety in
approved drugs and we were interested in these groups as well.
The coupling reactions went well and the product 3w was
isolated in 76% yield. Homomorpholine also tolerated under our
electrochemical conditions (3v; 79% yield). All compounds
described in this paper have been fully characterized by NMR
and mass spectral analysis.
Since we have a robust methodology to attach secondary amines
to benzoxazoles, we planned to explore the scalability of some of
the reactions. We chose simple benzoxazole and morpholine as
substrates. The scale-up results are shown in Table 5 and the
reactions were consistent even at 10 g scale (Compound 3aa)
with a very clean profile. It should be scalable even at larger
scale and the profile should be clean as well17.
Scheme 3. Suggested direct electrochemical amination for the
formation of 2-aminobenzoxazoles.
The intermediate A was detected under the LC-MS conditions13
and as the reaction time increases, intermediate A would undergo
aromatization to yield the required product 3a.
Substrate scope of the benzoxazole moiety was immediately
considered and the reactions were as smooth as that of simple
unsubstituted benzoxazoles. Substitutions like chloro, nitro and
methyl groups were included in the present study. It has been
found that there is not much effect on the substitution patterns on
the overall reactivity of benzoxazoles towards electrochemical
reactions. Compounds 3b, 3c and 3d were isolated in >80%
yield. It should be noted that these products can be hydrolyzed to
the free amines under mild conditions and further quick SAR
developments are possible.
Scheme 4. Scale-up reaction of compound 3aa.
Table 5. Summary of scale-up reactions.
Entry Compound 1
Compound 2aa
Isolated yield of 3aa
1
2
3
4
50 mg, 0.42 mmol 73 mg, 0.84 mmol 79 mg; 92%
500 mg, 4.2 mmol 730 mg, 8.4 mmol 746 mg; 87%
Subsequently we focused our attention on another abundant
functional groups in the list of approved drugs namely piperidine
moiety. Though simple piperidine should be able to produce the
required compounds, our aim is to functionalize further to
generate more SAR points. In this situation, we chose pipecolic
ester as our major substrate hoping to derivatize further. The
reaction under our standard conditions afforded compound 3h in
73% isolated yield. This compound is proved to be amenable to
further functionalization at the acid functional group to generate
focused libraries of amide compounds for direct SAR studies.
Methyl substitutions on the piperidine moiety was also studied.
Recent literature on the incorporation of oxetanes14 in drug
molecules prompted us to study this functional group as well. It
has been found that the oxetane functional group tolerated well
under the electrochemical conditions. Compound 3j was isolated
in 63% isolated yield. Substituted pyrrolidines were also afforded
aminobenzoxazoles in reasonable yield (Compound 3k, 50%
yield).
2.5 g, 21.0 mmol
10 g, 84.0 mmol
3.65 g, 42 mmol
16.6 g, 168 mmol
3.6 g; 84%
14.6 g; 85%
Another interesting result is that we were able to attach one of the
marketed drugs such as rasagiline18 to benzoxazoles in a single
step with 59% isolated yield as shown in Scheme 5. This
methodology could be utilized for the late stage functionalization
of pharmaceutically relevant compounds containing secondary
nitrogen moieties. More SAR studies would be generated from
this simple one step reaction set up. Further work is in progress
to explore the substrate scope of this versatile chemistry that
includes benzothiazoles and benzimidazoles and the results will
be published in due course.
We studied N-Boc protected amino piperidines, hoping to
develop a strategy for further functionalization at the 3 or 4-
position of the piperidine ring. These pharmacophores were
valuable in many commercial drugs existing in the market. One
Scheme 5. Electrochemical coupling of rasagiline with
benzoxazole.

4
Tetrahedron
(c) Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem.
Rev. 2008, 108, 2265. (d) Kärkäs, M. D. Chem. Soc. Rev. 2018,
47, 5786.
Shown below are some of the unsuccessful substrates attempted
in our electrochemical reactions. These subunits are present in
some of the biologically active compounds and may require
further rigorous methodology developments.
8. Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Science, 2017, 357,
575.
9. Gao, W-J.; Li, W-C.; Zeng, C-C.; Tian, H-Y.; Hu, L-M.; Little, R.
D. J. Org. Chem. 2014, 79, 9613.
10. Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257.
11. Frankowski, K. J.; Liu, R.; Milligan, G. L.; Moeller, K. D.; Aubé,
J. Angew. Chem. Int. Ed. 2015, 54, 10555.
12. Typical electrochemical experimental details are shown here.
Compound 3a (tert-Butyl 4-(benzo[d]oxazol-2-yl)piperazine-1-
carboxylate): A 30 mL screw capped vial with a septum was
inserted carbon anode and aluminum cathode (CAUTION:
Electrodes should not come in contact with each other). The
electrodes were connected to a cell phone charger (5V) by use of
alligator clips. To the reaction vial were added benzoxazole 1
(119 mg, 1 mmol), N-Boc piperazine 2a (372 mg, 2 mmol), acetic
acid (300 mg, 5 mmol, 5 equiv.) and TBAI (37 mg, 10 mol %) and
the mixture was dissolved in 20 mL of acetonitrile and stirred
gently at room temperature. Electric current was passed through
the reaction vial at room temperature for 3 hours. The progress of
the reaction was monitored by TLC and LC-MS. After the
completion of the reaction, the solvent was removed in vacuo and
the crude material was re dissolved in ethyl acetate (25 mL) and
then washed with saturated aqueous sodium carbonate solution
(3X10 ml). The organic layer was separated, washed with water
and then dried over sodium sulfate. The product was purified by
column chromatography using hexane and ethyl acetate as eluent
to afford 282 mg of compound 3a (93% yield).
Scheme 6. Some of the unreacted amines in coupling reaction.
The aminobenzoxazole compounds obtained (e.g. 3h, 3n and 3s)
from our studies are amenable to further chemical
transformations. Scheme 7 shows our plans to derivatize these
newly synthesized aminobenzoxazoles to make focused libraries
of amides, sulfonamides, ureas, reductive amination products and
so on.
Scheme 7. Further transformations of compounds 3h, 3n and 3s
The compound 3a was characterized by NMR and mass spectral
analysis. 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, J = 8 Hz,
1H), 7.30-7.32 (d, J = 8 Hz, 1H), 7.20-7.24 (t, 1H), 7.06-7.10 (t,
1H), 3.70-3.73 (t, 4H), 3.59-3.62 (t, 4H), 1.53 (s, 9H). LC-MS
(m/z): 304.7 [M+1]+.
3. Conclusion
In conclusion, we have presented that pharmaceutically relevant
amino substituted benzoxazoles can be synthesized in a single
step that is clean, environmentally friendly and atom economic.
Moreover, the process eliminates the use of toxic reagents and
the reactions are easily scalable.
13. Intermediate A was observed in the LC-MS and as the reaction
proceeds, intermediate A converts completely to the product 3a
over a period of time. See supplementary details for crude LC-MS
trace and analytical details.
14. Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla,
I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J. Med. Chem., 2010,
53, 3227.
Acknowledgements
We thank Mr. Vivek Sharma (Piramal Enterprises Limited) for
valuable support.
15. Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor, S. W.;
Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.;
Takeuchi, K.; Xu, R.; Webb, D. R.; Gwaltney, S. L. J. Med.
Chem., 2007 50, 2297.
16. Peprah, K.; Zhu, X. Y.; Eyunni, S. V. K.; Etukala, J. R.; Setola,
V.; Roth, B. L.; Ablordeppey, S. Y. Bioorg. Med. Chem., 2012,
20, 1671.
Supplementary Material
Supplementary data associated with this article can be found in
the online version.
17. Scale-up of Compound 3aa (2-Morpholinobenzo[d]oxazole): A
250 mL three neck flask was equipped with carbon anode and
aluminum cathode (CAUTION: Electrodes should not come in
contact with each other). The electrodes were connected to a cell
phone charger (5V) by use of alligator clips. To the reaction flask
were added benzoxazole 1 (10.0 g, 84 mmol), morpholine 2aa
(16.6 g, 168 mmol), acetic acid (25.2 g, 5 equiv.) and TBAI (3.1 g,
10 mol %) and the mixture was dissolved in 150 mL of
acetonitrile and stirred gently at room temperature. Electric current
was passed through the reaction flask at room temperature for
overnight. The progress of the reaction was monitored by TLC
and LC-MS. The work up was done according to ref. 12. The
product was purified by column chromatography using hexane and
ethyl acetate as eluent to afford 14.6 g of compound 3aa (85%
yield). 1H NMR (400 MHz, CDCl3) δ 7.41-7.42 (d, J = 7.6 Hz,
1H), 7.30-7.32 (d, J = 7.6 Hz, 1H), 7.20-7.24 (t, 1H), 7.07-7.10 (t,
1H), 3.85-3.88 (t, 4H), 3.72-3.75 (t, 4H). LC-MS (m/z): 205.1
[M+1]+.
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Note: Use of 12V adaptor furnished less clean reaction profile as
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5
Highlights:
 Substituted aminobenzoxazoles play an
integral role in medicinal chemistry and
drug development.
 Single step synthesis of aminobenzoxazoles
from benzoxazoles using electrochemical
conditions.
 These electrochemical transformations are
simple, clean and scalable with a broad
substrate scope and functional group
tolerance.