Electrochemical synthesis of isobenzofuran-1-imines using oxidative halocyclization ofo-alkynylbenzamides

Article abstract of DOI:10.1039/d1ob00953b

Electrochemical oxidative 5-exo-dig-oxo-halocyclization ofo-alkynylbenzamides was achieved using readily available NaX (X = Cl, Br and I) salts under mild reaction conditions. The use of a cheap and highly stable sodium halide as a halide ion source is im

Full text of DOI:10.1039/d1ob00953b

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Electrochemical synthesis of isobenzofuran-1-
imines using oxidative halocyclization of
o-alkynylbenzamides†
Cite this: Org. Biomol. Chem., 2021,
19, 6792
Received 16th May 2021,
Accepted 9th July 2021
Mandapati Bhargava Reddy, a Rajagopal Peri,b Muthuraaman Bhagavathiacharib
a
DOI: 10.1039/d1ob00953b
and Ramasamy Anandhan
*
rsc.li/obc
Electrochemical oxidative 5-exo-dig-oxo-halocyclization of oxidant and base, the development of a simple, mild and
o-alkynylbenzamides was achieved using readily available NaX (X = alternative method for the halogenated 5-exo-dig-oxy-cycliza-
Cl, Br and I) salts under mild reaction conditions. The use of a tion of o-alkynylbenzamides with high atom economy is highly
cheap and highly stable sodium halide as a halide ion source is desirable.
impressive for the synthesis of a variety of halogenated isobenzo-
Electrochemical synthesis has attracted significant atten-
furan-1-imines. This electrochemical protocol shows regio- tion in organic synthesis because it is environment friendly,
selectivity and excellent conversion to isobenzofuran-1-imines in shows excellent atom economy and replaces oxidants, tran-
good yields without the use of stoichiometric amounts of oxidants sition metals, and ligands.20–22 In particular, halogen-
and transition metal catalysts.
mediated electrochemical synthesis is an emerging area as it
involves the anodic oxidation of the halide anion into X+, X•
and X2 and the cathodic reduction of protons to hydrogen.23,24
Moreover, these halogen species are believed to play a key role
in the selective formation of C–C, C–N, C–O, and C–S bonds in
Introduction
The halocyclization of functionalized alkynes has been a versa-
tile tool for the synthesis of several important heterocyclic and
carbocyclic compounds.1–5 In general, this kind of cyclization
reaction is achieved by the reaction of alkynes with an electro-
phile followed by an intramolecular N- and O-nucleophilic
attack on the cationic intermediate via 5-exo- or 6-endo-dig
cyclization (Scheme 1, eqn (1)).6–13 Over the past decade, a
variety of halogenated oxo-cyclization reactions of o-alkynyl-
benzamides have been reported using electrophilic halogen
sources such as I2, ICl, and NBS, leading to both halogenated
isobenzofuran-1-imines (5-exo-dig) and isochromen-1-imines
(6-endo-dig) (eqn (2)).14,15 In recent years, the use of cheap and
highly stable halide salts as a halogen source has gained sig-
nificant attention in the cyclization reactions16 and also owing
to the structural importance of isobenzofuran-1-imines.5,17
Interestingly, Wang et al. have reported a regioselective 5-exo-
dig-oxy cyclization of o-alkynylbenzamides using TBAB and
TBAI with a stoichiometric amount of oxidant and base (eqn
(3)).18,19 To avoid the use of a stoichiometric amount of
aDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai
– 600 025, India. E-mail: ananthanramasamy@gmail.com
bDepartment of Energy, University of Madras, Guindy Campus, Chennai – 600 025,
India
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, and spectral data for all new compounds. See DOI: 10.1039/d1ob00953b
Scheme 1 5-exo-dig-oxo-cyclization of o-alkynylbenzamides.
6792 | Org. Biomol. Chem., 2021, 19, 6792–6796
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
electrochemical processes and dehydrogenation in atom econ- reduce the reaction performance (Table 1, entries 9–11). There
omical and sustainable methods.25–32 Recently, our group has is no significant improvement in the yield of 3ac when repla-
developed visible light initiated cyclization reactions via a cing the electrodes, C(+)|Pt(−), RVC(+)|Pt(−) and C(+)|C(−)
radical pathway.33–35 To the best of our knowledge, there is no (Table 1, entries 12–14). Notably, no product was observed
report on the synthesis of these target molecules via dehydro- without an electric current. The result indicates the need for a
genative cyclization under electrochemical conditions. We constant current in the reaction.
wish to report an oxidative 5-exo-dig-oxy-cyclization of o-akynyl-
Encouraged by these promising results, a diverse array of
benzamides for the synthesis of isobenzofuran-1-imines using 3-iodo-isobenzofuran-1-imine derivatives were explored using
NaX salts under electrochemical conditions (Scheme 1).
different substituted o-alkynylbenzamides with NaI 2aa under
the optimized conditions as shown in Table 2. The substrate
scope of various N-substituted (R1) derivatives was examined. A
variety of aliphatic (1a–1e) N-substituted o-alkynylbenzamides
smoothly underwent intramolecular cyclization with NaI 2aa,
affording the corresponding products 3aa–3ae in 79–84%
yields. Different aryl group N-substituted o-alkynylbenzamides
(1f–1l) also reacted smoothly to furnish the corresponding pro-
ducts 3af–3al in 66–74% yields. Furthermore, we studied the
substituent effect of the alkyne (R2) group in o-alkynylbenza-
mides; both aliphatic (1m–1p) and aromatic (1q–1s) alkynes
were reacted with NaI to afford the corresponding 3-iodo-iso-
benzofuran-1-iminines 3am–3as in 68–78% yields. Bromo sub-
stituted o-alkynylbenzamide 1t also gave the product 3at in
69% yield. In contrast, o-alkynylbenzamide 1au and N,N′-di-
substituted o-alkynylbenzamide 1av failed to produce 3au and
3av, respectively.
Next, we investigated the scope of different o-alkynylbenza-
mides with NaBr 2ba for the synthesis of 3-bromo-isobenzo-
furan-1-imines and the results are shown in Table 3. The
various N-substituted (R1) o-alkynylbenzamides (1a–1g) were
successfully tested with NaBr 2ba under electrolytic con-
ditions, affording the corresponding 3-bromo-isobenzofuran-1-
iminines 3ba–3dg in 61–77% yields. Furthermore, different
alkyne (R2) substituted o-alkynylbenzamides also smoothly
reacted with NaBr 2ba to yield the corresponding products
3bh–3bk in 66–71% yields. Furthermore, we screened halogen
substituted o-alkynylbenzamides in this electrochemical cycli-
zation to afford the corresponding products 3bl and 3bm with
good yields. Notably, NaBr 2ba shows less efficiency for halocy-
clization under the optimized conditions and also produced
slightly lower yields than NaI 2aa.
The synthetic utility of 3-halo-isobenzofuran-1-imines 3ae
and 3be was studied by coupling them with phenylacetylene in
a palladium-catalyzed Sonogashira cross-coupling reaction,
which afforded the coupled product 4 in good yields, respect-
ively. The acid hydrolysis of 3ae and 3be afforded the corres-
ponding isobenzofuran products 5 and 6 with good yields
(Scheme 2).
The scale-up reaction was performed for the halogen
mediated electrochemical halocyclization reaction. Under the
optimized conditions, 1.24 g of 1c (4.0 mmol) afforded the
product 3ac in 71% (1.23 g) yield (Scheme 3).
The control experiments were carried out to study the reac-
tion mechanism as shown in Scheme 4. First, the optimized
reaction was performed with the addition of 2,2,6,6-tetramethyl-
piperidinooxy (TEMPO) as a radical scavenger, which afforded
the product 3ac in 0% yield (Scheme 4a). The results imply that
Results and discussion
We chose N-benzyl-2-(phenylethynyl)benzamide (1c) and NaI
(2aa) as the model substrates to explore the electrochemical
conditions in an undivided cell (Table 1). Initially, the reaction
was performed in an undivided cell at a constant current of
10 mA in the presence of LiClO4 as the electrolyte and CH3CN
as a solvent. After 5 h, the desired product halogenated iso-
benzofuran-1-imine 3ac was obtained with 84% yield (Table 1,
entry 1). Other iodide salts, such as KI and nBu4NI, were found
to be less efficient than NaI (Table 1, entries 2 and 3). Also, the
effect of solvents including THF, ACN : H2O, and MeOH was
tested under the optimized conditions, affording a moderate
yield of 3ac (Table 1, entries 4–6). Furthermore, on replacing
the electrolyte LiClO4 with nBu4NClO4, 3ac was obtained in
44% yield. However, the absence of electrolytes also afforded
product 3ac in 34% yield. Changing the current was found to
Table 1 Optimization table for the synthesis of isobenzofuran-1-imines
from o-alkynylbenzamidesa,b
Entry
Variation from the standard conditions
Yieldb (%)
1
2
3
None
84c
81
78
KI instead of NaI
nBu4NI instead of NaI
4
5
6
7
THF instead of ACN
45
31
Trace
44
34
ACN : H2O (1 : 1) instead of ACN
MeOH instead of ACN
nBu4NClO4 instead of LiClO4
Absence of LiClO4
8
9
5 mA instead of 10 mA
8 mA instead of 10 mA
12 mA instead of 10 mA
C(+)|Pt(−) instead of Pt(+)|Pt(−)
RVC(+)|Pt(−) instead of Pt(+)|Pt(−)
C(+)|C(−) instead of Pt(+)|Pt(−)
Without an electric current
55
71
84
46
44
38
n.r.
10
11
12
13
14
15
a Reaction conditions: 0.15 mmol (1c), 0.22 mmol (2aa), LiClO4 (0.3
M), ACN (8.0 mL), a Pt disk (80 mm × 6.3 mm × 2 mm) anode, a Pt
wire (70 mm × 6.3 mm × 0.5 mm) cathode, rt, 10 mA, 12 F mol−1
.
b Yields were determined after the purification of the compound.
c Current efficiency η = 27%. n.r. = no reaction.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6792–6796 | 6793

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Substrate scope of o-alkynylbenzamides for the synthesis of
3-iodo-isobenzofuran-1-iminesa,b
Table 3 Substrate scope of o-alkynylbenzamides for the synthesis of
3-bromo-isobenzofuran-1-iminesa,b
a All reactions were carried out with 0.15 mmol (1), 0.22 mmol (2ba),
LiClO4 (0.3 M), ACN (8.0 mL), Pt(+)|Pt(−), rt, 5 h. b Yields were deter-
mined after the purification of the compound.
Scheme 2 Synthetic transformations of 3-halo-isobenzofuran-1-
a All reactions were carried out with 0.15 mmol (1), 0.22 mmol (2aa),
imines. Reagents and conditions: (a) Phenyl acetylene (1.2 equiv.),
LiClO4 (0.3 M), ACN (8.0 mL), Pt(+)|Pt(−), rt, 5h. b Yields were deter- PdCl2(PPh3)2 (5 mol%), CuI (2 mol%), Et3N, 6 h, 70 °C, 4, X = I, 89% and
mined after the purification of the compound.
4, X = Br, 78%; (b) HCl (37% aq, 0.5 ml), THF : H2O (1 : 1), 2 h, rt, 5, X = I,
82% and 6, X = Br, 81%.
the reaction might have proceeded via a radical pathway.
Interestingly, NaCl 2ca also reacted with 1a, affording the (−) electrode system with Ag/AgCl (in saturated KCl solution)
corresponding cyclized product 3ca in 41% yield (Scheme 4b). as a reference electrode. Curve b, 1c (in the absence of 2aa)
Cyclic voltammetry (CV) experiments were performed to showed no oxidation and redox peaks. The CV of 2aa alone
investigate the reaction mechanism using the attained redox had two oxidation peaks (curve c). The first peak at +0.365 mV
potentials and the possible iodine-related active species corresponds to the conversion of iodide to triiodide and the
(Fig. 1). All the experiments were conducted using a Pt(+)|Pt second peak at +0.695 mV corresponds to the oxidation of
6794 | Org. Biomol. Chem., 2021, 19, 6792–6796
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 3 Gram-scale synthesis of isobenzofuran-1-imines.
Scheme 5 Plausible mechanism pathway for the electrochemical halo-
cyclization reaction.
Scheme 4 Control experiments.
is oxidized to X• by the loss of a single electron, which is
further oxidized to X+ by one more loss of a single electron.
Then, o-alkynylbenzamide reacted with the in situ generated X+
by electrophilic addition to afford alkenyl cation B (path B). At
the same time, o-alkynylbenzamide reacted with the in situ
generated X• by radical addition to form alkene radical A (path
A), which on further oxidation reaction on the anodic surface
afforded alkenyl cation B by the loss of a single electron.
Finally, alkenyl cation B undergoes intramolecular cyclization
via O-nucleophilic attack, affording products 3 by the loss of a
proton. Meanwhile, the cathodic reduction of the proton led to
the formation of hydrogen.
Conclusions
In conclusion, we have developed an electrochemical oxidative
5-exo-dig-oxo-halocyclization of o-alkynylbenzamides for the
synthesis of isobenzofuran-1-imines using readily available
NaX salts. A simple and cheaper NaX (X = Cl, Br and I) salt acts
as the halogen source under an applied current. This electro-
chemical protocol replaces the use of a stoichiometric amount
of oxidants and transition metals. Owing to its simple oper-
ation, high atom economy, and excellent regioselectivity, this
electrochemical protocol is an efficient approach and it can be
an alternative method to avoid the use of oxidants and tran-
sition metals.
Fig. 1 Cyclic voltammograms of a mixture in 0.03 M LiClO4/CH3CN
using a Pt disk (80 mm × 6.3 mm × 2 mm) working electrode, Pt wire
(70 mm × 6.3 mm × 0.5 mm) and Ag/AgCl (in saturated KCl solution) as
counter and reference electrodes at a scan rate of 100 mV s−1: (a) back-
ground, 0.3 M LiClO4; (b) 1c (0.15 mmol); (c) 2aa (0.22 mmol); (d) 1c
(0.15 mmol) + NaI (0.22 mmol).
triiodide to iodine.22,27 Notably, the CV of a mixture of 1c and
2aa (curve d) showed similar oxidation peaks with slightly
lower potentials (+0.352 mV and +0.680 mV). Therefore, the CV
studies clearly showed that NaI was oxidized by an electric
current acting as an iodine source.
Based on all the aforementioned experimental studies, CV
measurements, and literature reports, a plausible mechanism
Conflicts of interest
is proposed in Scheme 5.20,36 On the surface of the anode, X− There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6792–6796 | 6795

View Article Online
Communication
Organic & Biomolecular Chemistry
15 C. Schlemmer, L. Andernach, D. Schollmeyer, B. F. Straub
Acknowledgements
and T. Opatz, J. Org. Chem., 2012, 77, 10118–10124.
The authors RA and MB thank DST-SERB for a research grant 16 P. Ghosh, B. Ganguly and S. Das, Org. Biomol. Chem., 2021,
(vide grant no: EMEQ/2018/001129 and ECR/2016/000481) and 19, 2146–2167.
DST-FIST for providing NMR and HRMS facilities to the 17 F. Araniti, R. Mancuso, I. Ziccarelli, F. Sunseri,
Department of Organic Chemistry. MBR acknowledges
CSIR-SRF and RG thanks CSIR (80(0093)/20/EMR-II) for the
financial support.
M. R. Abenavoli and B. Gabriele, Molecules, 2014, 19, 8261–
8275.
18 Y. H. Wang, J. B. Liu, B. Ouyang, H. Zhou and G. Qiu,
Tetrahedron, 2018, 74, 4429–4434.
19 R. X. Wang, S. T. Yuan, J. B. Liu, J. Wu and G. Qiu, Org.
Biomol. Chem., 2018, 16, 4501–4508.
20 D. Pollok and S. R. Waldvogel, Chem. Sci., 2020, 11, 12386–
12400.
21 M. D. Kärkäs, Chem. Soc. Rev., 2018, 47, 5786–5865.
22 P. Xiong and H. C. Xu, Acc. Chem. Res., 2019, 52, 3339–
3350.
Notes and references
1 X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2005, 127,
12230–12231.
2 S. Mehta and R. C. Larock, J. Org. Chem., 2010, 75, 1652–
1658.
23 K. Liu, C. Song and A. Lei, Org. Biomol. Chem., 2018, 16,
2375–2387.
3 K. G. Ji, H. T. Zhu, F. Yang, A. Shaukat, X. F. Xia, Y. F. Yang,
X. Y. Liu and Y. M. Liang, J. Org. Chem., 2010, 75, 5670–
5678.
4 T. Aggarwal, S. Kumar and A. K. Verma, Org. Biomol. Chem.,
2016, 14, 7639–7653.
5 R. Sanz, A. Martínez, P. García-García, M. A. Fernández-
Rodríguez, M. A. Rashid and F. Rodríguez, Chem. Commun.,
2010, 46, 7427–7429.
24 F. Marken, Encycl. Electrochem., 2006, 273–302.
25 B. K. Malviya, P. K. Jaiswal, V. P. Verma, S. S. Badsara and
S. Sharma, Org. Lett., 2020, 22, 2323–2327.
26 H. D. Zuo, H. D. Zuo, W. J. Hao, C. F. Zhu, C. F. Zhu,
C. Guo, S. J. Tu and B. Jiang, Org. Lett., 2020, 22, 4471–
4477.
27 J. Li, X. Liu, J. Deng, Y. Huang, Z. Pan, Y. Yu and H. Cao,
Chem. Commun., 2020, 56, 735–738.
28 J. Strehl and G. Hilt, Org. Lett., 2020, 22, 5968–5972.
29 B. Huang, C. Yang, J. Zhou and W. Xia, Chem. Commun.,
2020, 56, 5010–5013.
6 X. Bantreil, A. Bourderioux, P. Mateo, C. E. Hagerman,
M. Selkti, E. Brachet and P. Belmont, Org. Lett., 2016, 18,
4814–4817.
7 C. Yang, X. Zhang, D. Zhang-Negrerie, Y. Du and K. Zhao,
J. Org. Chem., 2015, 80, 5320–5328.
30 S. Liang, C. C. Zeng, H. Y. Tian, B. G. Sun, X. G. Luo and
F. Z. Ren, J. Org. Chem., 2016, 81, 11565–11573.
31 K. Hu, Y. Zhang, Z. Zhou, Y. Yang, Z. Zha and Z. Wang,
Org. Lett., 2020, 22, 5773–5777.
8 D. Brahmchari, A. K. Verma and S. Mehta, J. Org. Chem.,
2018, 83, 3339–3347.
9 R. Liu, M. Li, W. Xie, H. Zhou, Y. Zhang and G. Qiu, J. Org.
Chem., 2019, 84, 11763–11773.
32 X. Meng, H. Xu, X. Cao, X. M. Cai, J. Luo, F. Wang and
S. Huang, Org. Lett., 2020, 22, 6827–6831.
33 M. Bhargava Reddy and R. Anandhan, Chem. Commun.,
2020, 56, 3781–3784.
10 R. Liu, M. Yang, W. Xie, W. Dong, H. Zhou, S. Yadav,
V. I. Potkin and G. Qiu, J. Org. Chem., 2020, 85, 5312–5320.
11 Y. H. Wang, B. Ouyang, G. Qiu, H. Zhou and J. B. Liu, Org.
Biomol. Chem., 2019, 17, 4335–4341.
34 M. Bhargava Reddy, K. Prasanth and R. Anandhan, Org.
Biomol. Chem., 2020, 18, 9601–9605.
12 D. Ding, T. Mou, J. Xue and X. Jiang, Chem. Commun.,
2017, 53, 5279–5282.
35 M. Bhargava Reddy, N. Neerathilingam and R. Anandhan,
Org. Chem. Front., 2021, 8, 87–93.
13 Y. Madich, R. Álvarez and J. M. Aurrecoechea, Eur. J. Org.
Chem., 2014, 6263–6271.
36 K. Yu, X. Kong, J. Yang, G. Li, B. Xu and Q. Chen, J. Org.
Chem., 2021, 86, 917–928.
14 S. Mehta, T. Yao and R. C. Larock, J. Org. Chem., 2012, 77,
10938–10944.
6796 | Org. Biomol. Chem., 2021, 19, 6792–6796
This journal is © The Royal Society of Chemistry 2021