Iodine-catalyzed convergent aerobic dehydro-aromatization toward benzazoles and benzazines

Article abstract of DOI:10.1039/c9ra10964a

An iodine-catalyzed aerobic dehydro-aromatization has been developed, providing straightforward and efficient access to various benzoazoles and benzoazines. The present transition-metal-free protocol enables the dehydro-aromatization of tetrahydrobenzazoles and tetrahydroquinolines with molecular oxygen as the green oxidant, along with some other N-heterocycles. Hence, a broad range of heteroaromatic compounds are generated in moderate to good yields under facile reaction conditions.

Full text of DOI:10.1039/c9ra10964a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Iodine-catalyzed convergent aerobic dehydro-
aromatization toward benzazoles and benzazines†
Cite this: RSC Adv., 2020, 10, 8348
*
Xiaolong Tuo, Shanping Chen, Pingyu Jiang, Penghui Ni, Xiaodong Wang
*
and Guo-Jun Deng
An iodine-catalyzed aerobic dehydro-aromatization has been developed, providing straightforward and
efficient access to various benzoazoles and benzoazines. The present transition-metal-free protocol
enables the dehydro-aromatization of tetrahydrobenzazoles and tetrahydroquinolines with molecular
oxygen as the green oxidant, along with some other N-heterocycles. Hence, a broad range of
heteroaromatic compounds are generated in moderate to good yields under facile reaction conditions.
Received 27th December 2019
Accepted 15th February 2020
DOI: 10.1039/c9ra10964a
rsc.li/rsc-advances
which can be employed for dehydro-aromatization of both
carbocycles and N-heterocycles to afford a diversity of hetero-
Introduction
aromatic compounds is highly desirable.
Benzazoles and benzazines have unique pharmacological and
biological activities and thus have many applications in natural
products and pharmaceutical drugs.1–3 As a result, chemical
researchers have been actively seeking new methodologies to
synthesize these compounds. In recent years, dehydrogenative
aromatization has emerged as a direct and efficient approach to
access heteroaromatic compounds, especially N-heterocycles.
This strategy produces a series of benzazines with high value4
and continues to be an attractive and signicant research object
in organic synthesis.
Our group has been focusing on synthesizing aromatic
heterocyclic compounds, using cyclohexanones as the aryl
source via a dehydrogenative aromatization sequence.19,20 In our
recent research, cyclohexanones coupled with amines to form
tetrahydrobenzimidazoles, which could not be dehydrogenated
to produce heteroaromatic compounds under these condi-
tions.21 As a follow up study, herein, we describe an iodine
The direct dehydro-aromatization methods were generally
achieved by using stoichiometric oxidants, such as SeO2, DDQ,
o-iodoxybenzoic acid (IBX) and sulfur (Scheme 1a).5,6 Recently,
transition metal catalysts combined with oxygen as the sole
sacricial reagent were used to enable oxidative dehydrogen-
ative aromatization, such as Au, Pt, Pd, Ru, Fe, and Co.7–9 On the
other hand, in view of the atom-economy requirement and
potential application for hydrogen storage, Ir, Ru, Fe and Co
catalyst were used for the acceptorless dehydrogenation reac-
tions of N-heterocycles.10–12 However, due to the involvement of
transition metals and other specialized catalysts or amounts of
oxidants, these dehydrogenation protocols are oen expensive
or not environmentally friendly. In recent years, Lewis acids,13
photoredox catalysis,14 electrocatalysis15 and graphene oxide
(GO)16 were used for the same goal (Scheme 1b). In addition,
potassium tert-butoxide17 and elemental sulfur18 also could
promote the dehydrogenation process. However, most of these
methods are mainly suitable for dehydro-aromatization of N-
heterocycles. Hence, developing a convergent catalytic system
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: spchen@xtu.edu.cn; gjdeng@xtu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10964a
Scheme 1 Kinds of dehydrogenative aromatization reactions.
8348 | RSC Adv., 2020, 10, 8348–8351
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
catalyzed dehydro-aromatization reaction using molecular methoxy and halogen (4b–4i). Bulky 1-(naphthalen-1-yl)-4,5,6,7-
oxygen as the green oxidant toward various benzazoles and tetrahydrobenzo[d]thiazole and 2-(naphthalen-1-yl)-4,5,6,7-tetra-
benzazines (Scheme 1c).
hydrobenzo[d]thiazole could also react well to afford the target
products in good yields (4j, 4k). The steric effect of groups was
not obvious on the reaction and the corresponding products were
obtained in 62–74% yields when the carbocycle with an substit-
uent (4l–4n). The desired product 4o could be obtained in 56%
yield when 1-benzyl-2-phenyl-4,5,6,7-tetrahydro-1H-benzo[d]
imida-zole was used as the substrate. Regrettably, 2-phenyl-
4,5,6,7-tetrahydrobenzo[d]oxazole could not be dehydrogenated
under the standard condition (4p). Subsequently, we investigated
the dehydrogenation of tetracycle-fused system. Benzo[d]benzo
[4,5]imidazo[2,1-b]thiazole 5a could be smoothly generated in
71% yield under the standard conditions when 7,8,9,10-tetrahy-
drobenzo[d]benzo[4,5]imida-zo[2,1-b]thiazole was used as the
substrate. The substrates bearing a substituent such as methyl
and halogen on the benzene ring afforded the corresponding
product in 63–70% yields (5b–5d). The dehydrogenative products
were gave in 64–71% yields when carbocycle was decorated by an
alkyl or aryl substituent (5e, 5f) (Tables 2 and 3).
To further extend the scope of the substrates, we tested
a variety of N-heterocycles under the standard reaction condi-
tion. Fortunately, most of them could give the desired products
in moderate to good yields. Quinoline 6a was generated in 67%
yield when 1,2,3,4-tetrahydroquinoline was used as the
substrate. Tetrahydroquinolines with a methyl located at 2-, 3-,
4-, or 8-position could afford the corresponding dehydrogena-
tion products in good yields (6b–6e). Strong electron-
Results and discussion
We commenced our studies by choosing 2-phenyl-4,5,6,7-tet-
rahydrobenzo[d]thiazole (1a) as the model substrate. The
desired product 4a was afforded in 36% in the presence of KI
and oxygen (Table 1, entry 1). Then, a series of iodide-
containing reagents such as NaI, NIS, elemental iodine, ICl
and NaIO4 were screened (entries 2–6).22 The best reaction yield
was achieved when elemental iodine was added as the catalyst
(entry 4). A control experiment showed that trace of desired
product was obtained in the absence of iodine reagent (entry 7).
Subsequently, several solvents were tested. All of them did not
give a higher yield (entries 8–13). The yield was up to 79% when
o-dichlorobenzene (o-DCB) and toluene were used as the mixed
solvent (entry 14). When the reaction atmosphere was changed
to air, the reaction yield dramatically decreased (entry 15). A
lower yield was obtained when the reaction was performed at
ꢀ
140 C (entry 16).
With the optimized conditions in hand, we explored the scope
of this dehydrogenative aromatization reaction. The model
reaction afforded the target product 4a in 75% isolated yield, and
68% isolated yield could be achieved in a gram-scale reaction.
The corresponding products were obtained in moderate to good
yields,
when
2-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole
substrates bearing with various substituents, such as alkyl, aryl,
Table 2 Dehydro-aromatization of tetrahydrobenzazolesa
Table 1 Optimization reaction conditionsa
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
KI
NaI
NIS
I2
NaIO4
ICl
—
I2
I2
I2
I2
I2
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
Chlorobenzene
Toluene
1,4-Dioxane
DMSO
NMP
DMA
o-DCB/toluene
o-DCB/toluene
o-DCB/toluene
36%
39%
52%
71%
68%
67%
Trace
51%
55%
23%
Trace
ND
9
10
11
12
13
14c
15c,d
16c,e
I2
I2
I2
I2
ND
79% (75%)f
48%
53%
a
Reaction conditions: 1a (0.2 mmol), catalyst (20 mol%), solvent (0.8
b
c
mL), 160 ꢀC, under O2 (sealed tube), 30 h. GC yield. o-DCB/toluene
d
e
f
a
(0.8 mL/0.2 mL). Under air. At 140 ꢀC. Isolated yield. o-DCB:o-
Conditions: 1 or 2 (0.2 mmol), I2 (20 mol%), o-DCB/toluene (0.8 mL/0.2
dichlorobenzene, ND: not detected.
mL), 160 ꢀC, 30 h, under O2 (sealed tube), isolated yield. b 6 mmol scale.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 8348–8351 | 8349

View Article Online
RSC Advances
Paper
Table 3 Dehydro-aromatization of N-heterocyclesa
On the basis of relevant literatures,23 a possible reaction
mechanism is illustrated in Scheme 2. Initially, nitrogen-
centered radical A is formed via single-electron oxidation
process from 1a in the presence of elemental iodide, and
elemental iodide converts into iodine ion. Tautomerization of A
produces intermediate B. Subsequent single-electron oxidation
and deprotonation of B generates intermediate C, which can be
further transformed into intermediate D via a deprotonation.
Meanwhile, the second single-electron oxidative dehydrogena-
tion of D affords the intermediate G, followed by a deprotona-
tion to provide the desired product 4a. The iodide anion is
oxidized to form iodine in the presence of oxygen.
Conclusions
In conclusion, we have developed
a
direct dehydro-
aromatization of tetrahydrobenzazoles and N-heterocycles,
providing a straightforward and efficient approach to a variety
of benzazoles and benzazines. The present protocol is achieved
by use of elemental iodine as the catalyst and molecular oxygen
as the green oxidant, which could produce a broad range of
products in moderate to good yields under facile transition-
metal-free conditions.
a
Conditions: 3 (0.2 mmol), I2 (20 mol%), o-DCB/toluene (0.8 mL/0.2
mL), 160 ꢀC, 30 h, under O2, isolated yield.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (21871226, 21572194, 21372187),
the Collaborative Innovation Center of New Chemical Tech-
nologies for Environmental Benignity and Efficient Resource
Utilization.
Notes and references
1 (a) M. O. Chaney, P. V. Demarco, N. D. Jones and
J. L. J. Occolowitz, J. Am. Chem. Soc., 1974, 96, 1932; (b)
M. K. Sahoo, G. Jaiswal, J. Rana and E. Balaraman, Chem.–
Eur. J., 2017, 23, 14167; (c) O. Afzal, S. Kumar,
M. R. Haider, M. R. Ali, R. Kumar, M. Jaggi and S. Bawa,
Eur. J. Med. Chem., 2015, 97, 871.
Scheme 2 Possible reaction mechanism.
2 (a) N. Kumar, M. Alamgir, D. St and C. Black, Heterocycl.
Chem., 2007, 9, 87; (b) M. E. Doyle and J. M. Egan,
Pharmacol. Rev., 2003, 55, 105; (c) S. Meidute-Abaraviciene,
H. Mosen, I. Lundquist and A. Salehi, Acta Physiol., 2009,
195, 375.
3 (a) D. K. Kahlon, T. A. Lansdell, J. S. Fisk and J. Tepe, Bioorg.
Med. Chem., 2009, 17, 3093; (b) F. Touzeau, A. Arrault,
G. Guillaumet, E. Scalbert, B. Pfeiffer, M.-C. Rettori,
P. Renard and J.-Y. Merour, J. Med. Chem., 2003, 46, 1962;
(c) A. Masajtis-Zagajewska, J. Majer and M. Nowicki,
Hypertens. Res., 2010, 33, 348.
withdrawing groups, such as ester and nitro groups, attached at
tetrahydroquinoline substrates were well tolerated to give the
target products (6f–6h). The dehydrogenation reactions of
1,2,3,4-tetrahydroisoquinoline smoothly proceeded to give the
corresponding isoquinoline products in 67–87% yields (6i–6k).
Benzo[h]quinoline 6l was produced in 71% yield. In addition, 4-
phenylpiperidine and 2-phenylpiperidine could be oxidized to
form pyridine products in moderate yields under standard
conditions (6m, 6n). Furthermore, indole products could be
obtained in good yields when 1-(indolin-1-yl)ethanone and 5-
nitroindoline were used (6o, 6p).
4 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257.
8350 | RSC Adv., 2020, 10, 8348–8351
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
5 (a) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y. L. Wong, 14 (a) S. Kato, Y. Saga, M. Kojima, H. Fuse, S. Matsunaga,
H. J. Chen, A. K. Courtney and S. F. Martin, J. Am. Chem.
Soc., 2002, 124, 8584; (b) K. C. Nicolaou, C. J. N. Manthison
and T. Montagnon, J. Am. Chem. Soc., 2004, 126, 5192.
A. Fukatsu, M. Kondo, S. Masaoka and M. Kanai, J. Am.
Chem. Soc., 2017, 139, 2204; (b) K.-H. He, F.-F. Tan,
C.-Z. Zhou, G.-J. Zhou, X.-L. Yang and Y. Li, Angew. Chem.,
Int. Ed., 2017, 56, 3080; (c) M. F. Zheng, J. L. Shi, T. Yuan
and X. C. Wang, Angew. Chem., Int. Ed., 2018, 57, 5487; (d)
S. Chen, Q. Wan and A. K. Badu-Tawiah, Angew. Chem., Int.
Ed., 2016, 55, 9345; (e) F. Su, S. C. Mathew, L. Mçhlmann,
M. Antonietti, X. Wang and S. Blechert, Angew. Chem., Int.
Ed., 2011, 50, 657.
´
6 (a) M. Zhao, L. Bi, W. Wang, C. Wang, M. Baudy-Floch, J. Ju
and S. Peng, Bioorg. Med. Chem., 2006, 14, 6998; (b) M. Cain,
O. Campos, F. Guzman and J. M. Cook, J. Am. Chem. Soc.,
1983, 105, 907; (c) K. C. Nicolaou, C. J. N. Mathison and
T. Montagnon, Angew. Chem., Int. Ed., 2003, 42, 4077.
7 (a) M. H. So, Y. Liu, C. M. Ho and C. M. Che, Chem.–Asian J.,
2009, 4, 1551; (b) D. V. Jawale, E. Gravel, N. Shah, V. Dauvois, 15 Y. Wu, H. Yi and A. Lei, ACS Catal., 2018, 8, 1192.
H. Li, I. N. Namboothiri and E. Doris, Chem.–Eur. J., 2015, 21, 16 J. Y. Zhang, S. Y. Chen, F. F. Chen, W. S. Xu, G.-J. Deng and
7039; (c) D. Ge, L. Hu, J. Wang, X. Li, F. Qi, J. Lu, X. Cao and
H. Gu, ChemCatChem, 2013, 5, 2183.
8 (a) S. Furukawa, A. Suga and T. Komatsu, Chem. Commun.,
H. Gong, Adv. Synth. Catal., 2017, 359, 2358.
17 T. T. Liu, K. K. Wu, L. D. Wang and Z. K. Yu, Adv. Synth.
Catal., 2019, 361, 3958.
2014, 50, 3277; (b) A. E. Wendlandt and S. S. Stahl, J. Am. 18 T. B. Nguyen and P. Retailleau, Adv. Synth. Catal., 2018, 360,
Chem. Soc., 2014, 136, 11910. 2389.
9 (a) X. Cui, Y. Li, S. Bachmann, M. Scalone, A.-E. Surkus, 19 (a) X. X. Cao, X. F. Cheng, Y. Bai, S. W. Liu and G.-J. Deng,
K. Junge, C. Topf and M. Beller, J. Am. Chem. Soc., 2015,
137, 10652; (b) A. E. Wendlandt and S. S. Stahl, J. Am.
Chem. Soc., 2014, 136, 506; (c) A. V. Iosub and S. S. Stahl,
Org. Lett., 2015, 17, 4404.
Green Chem., 2014, 16, 4644; (b) Y. F. Liao, Y. Peng,
H. G. Qi, G.-J. Deng, H. Gong and C.-J. Li, Chem. Commun.,
2015, 51, 1031; (c) J. J. Chen, G. Z. Li, Y. J. Xie, Y. F. Liao,
F. H. Xiao and G.-J. Deng, Org. Lett., 2015, 17, 5870.
10 (a) R. Yamaguchi, C. Ikeda, Y. Takahashi and K. Fujita, J. Am. 20 (a) J. Wu, Y. J. Xie, X. G. Chen and G.-J. Deng, Adv. Synth.
Chem. Soc., 2009, 131, 8410; (b) K. Fujita, Y. Tanaka,
M. Kobayashi and R. Yamaguchi, J. Am. Chem. Soc., 2014,
136, 4829; (c) J. Wu, D. Talwar, S. Johnston, M. Yan and
J. Xiao, Angew. Chem., Int. Ed., 2013, 52, 6983; (d) R. Xu,
Catal., 2016, 358, 3206; (b) Y. J. Xie, J. Wu, X. G. Che,
Y. Chen, H. W. Huang and G.-J. Deng, Green Chem., 2016,
18, 667; (c) S. P. Chen, L. R. Wang, J. Zhang, Z. R. Hao,
H. W. Huang and G.-J. Deng, J. Org. Chem., 2017, 82, 11182.
S. Chakraborty, H. Yuan and W. D. Jones, ACS Catal., 2015, 21 (a) Y. J. Xie, X. G. Chen, Z. Wang, H. W. Huang, B. Yi and
5, 6350.
G.-J. Deng, Green Chem., 2017, 19, 4294; (b) X. G. Chen,
Z. Wang, H. W. Huang and G.-J. Deng, Adv. Synth. Catal.,
2018, 360, 4017.
11 (a) S. Muthaiah and S. H. Hong, Adv. Synth. Catal., 2012, 354,
3045; (b) S. Chakraborty, W. W. Brennessel and W. D. Jones,
J. Am. Chem. Soc., 2014, 136, 8564; (c) G. Jaiswal, 22 (a) Y. Su, X. J. Zhou, C. L. He, W. Zhang, X. Ling and X. Xiao,
V. G. Landge, D. Jagadeesan and E. Balaraman, Nat.
Commun., 2017, 8, 2147.
12 (a) R. H. Crabtree, ACS Sustainable Chem. Eng., 2017, 5, 4491;
(b) Y. H. Han, Z. Y. Wang, R. R. Xu, W. Zhang, W. X. Chen,
L. R. Zheng, J. Zhang, J. Luo, K. L. Wu, Y. Q. Zhu, C. Chen,
Q. Peng, Q. Liu, P. Hu, D. S. Wang and Y. Li, Angew.
J. Org. Chem., 2016, 81, 4981; (b) S. Tang, K. Liu, Y. Long,
X. T. Qi, Y. Lan and A. W. Lei, Chem. Commun., 2015, 51,
8769; (c) H. Cao, J. W. Yuan, C. Liu, X. Q. Hu and
A. W. Lei, RSC Adv., 2015, 5, 41493; (d) W.-H. Bao, M. He,
J.-T. Wang, X. Peng, M. Sung, Z. L. Tang, S. Jiang, Z. Cao
and W.-M. He, J. Org. Chem., 2019, 84, 6065.
Chem., Int. Ed., 2018, 57, 11262; (c) C. Deraedt, R. Ye, 23 (a) V. Humne, Y. Dangat, K. Vanka and P. Lokhande, Org.
W. T. Ralston and F. D. Toste, J. Am. Chem. Soc., 2017, 139,
18084.
Biomol. Chem., 2014, 12, 4832; (b) J. Zhao, H. Huang,
W. Wu, H. Chen and H. Jiang, Org. Lett., 2013, 15, 2604; (c)
S. P. Chen, Y. X. Li, P. H. Ni, B. C. Yang, H. W. Huang and
G.-J. Deng, J. Org. Chem., 2017, 82, 2935.
¨
13 (a) A. F. G. Maier, S. Tussing, T. Schneider, U. Florke,
Z.-W. Qu, S. Grimme and J. Paradies, Angew. Chem., Int.
Ed., 2016, 55, 12219; (b) M. Kojima and M. Kanai, Angew.
Chem., Int. Ed., 2016, 55, 12224.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 8348–8351 | 8351