The intramolecular reaction of acetophenoneN-tosylhydrazone and vinyl: Br?nsted acid-promoted cationic cyclization toward polysubstituted indenes

Article abstract of DOI:10.1039/d0cc07966a

In the presence of TsNHNH₂, a Br?nsted acid-promoted intramolecular cyclization ofo-(1-arylvinyl) acetophenone derivatives was developed, leading to polysubstituted indenes with complexity and diversity in moderate to excellent yields. In sharp contrast with either the radical or carbene involved cyclization of aldehydicN-tosylhydrazone with vinyl, a cationic cyclization pathway was involved, whereN-tosylhydrazone served as an electrophile and alkylation reagent during this transformation.

Full text of DOI:10.1039/d0cc07966a

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The intramolecular reaction of acetophenone
N-tosylhydrazone and vinyl: Brønsted
acid-promoted cationic cyclization toward
polysubstituted indenes†
Cite this: Chem. Commun., 2021,
57, 1810
Received 8th December 2020,
Accepted 14th January 2021
ab
Zhixin Wang,a Yang Li,a Fan Chen,b Peng-Cheng Qian*b and Jiang Cheng
*
DOI: 10.1039/d0cc07966a
rsc.li/chemcomm
In the presence of TsNHNH2, a Brønsted acid-promoted intramolecular
In the base-induced reaction of N-tosylhydrazones to afford
cyclization of o-(1-arylvinyl) acetophenone derivatives was developed, alkenes, namely the Shapiro reaction, a carbocation mechanism
leading to polysubstituted indenes with complexity and diversity in may be involved under protic solvents.6 Indeed, N-tosylhydrazones
moderate to excellent yields. In sharp contrast with either the radical or were also electrophiles, serving as carbocation equivalents and
carbene involved cyclization of aldehydic N-tosylhydrazone with vinyl, alkylation reagents in a series of transformations.7
a cationic cyclization pathway was involved, where N-tosylhydrazone
This chemistry of N-tosylhydrazone spurred us to test the
served as an electrophile and alkylation reagent during this trans- feasibility of intramolecular cationic cyclization of the ketonic
formation.
analogues with vinyl toward indenes, which are ubiquious in
pharmaceutical and biologically active compounds,8 serving as
Recently, much attention has been paid to the development of antitumor,9 antiallergic,10 anti-inflammatory,11 and antimicrobial12
N-tosylhydrazones in organic synthesis since they can serve as reagents.
key building blocks in either transition-metal-catalyzed or metal-
Herein, we wish to report a metal-free intramolecular reaction
free organic reactions.1 In some cases, N-tosylhydrazones proved of acetophenone N-tosylhydrazone derivatives and vinyl toward
to be ideal diazo or carbene precursors.2 As expected, the
intermolecular reaction of N-tosylhydrazone with vinyl resulted
in the cyclopropanation products (eqn (1), Scheme 1).3
Alternatively, in the intramolecular type reaction, de Bruin
reported the cobalt-catalyzed radical approach leading to
indene, which involved the insertion of vinyl C–H into the
in situ formed carbene intermediate (eqn (2), Scheme 1).4 After-
ward, Wang developed a rhodium(II)- or copper(I)-catalyzed
formal intramolecular carbene insertion into vinylic C–H bonds
to access indenes (eqn (3), Scheme 1).5 The intramolecular
reaction of ketonic N-tosylhydrazone with vinyl allowed the
facile introduction of functional groups into the 1-position of
indene with complexity and diversity. However, no example of
this was reported or studied before, which was at least partly
due to the less activation and more hindrance than the aldehydic
analogues. To circumvent this, a mechanistically different pathway
should be developed.
a School of Petrochemical Engineering, and Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, Changzhou University, Changzhou 213164,
P. R. China
b Institute of New Materials & Industry Technology, College of Chemistry &
Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China.
E-mail: jiangcheng@cczu.edu.cn, qpc@wzu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 The reaction of N-tosylhydrazone with vinyl.
d0cc07966a
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Table 1 Selected results for screening the optimized reaction conditionsa
polysubstituted indenes in the presence of TsNHNH2 promoted
by a Brønsted acid (eqn (4), Scheme 1). In sharp contrast with
the aforementioned examples on the annulation of aldehydic
N-tosylhydrazone with vinyl, this procedure features: (1) less
active substrates with more hindrance toward polysubstituted
indenes with more complexity and diversity; (2) acidic reaction
conditions rather than basic conditions; (3) a mechanistically
different pathway involving a carbocation.
We began our investigation with the reaction of o-(1-arylvinyl)
acetophenone 1a (0.1 mmol), and TsNHNH2 (0.2 mmol) in
MeOH at 60 1C in the presence of base (2.0 equiv.) under a N2
atmosphere. However, no reaction took place at all (entries 1 and
2). Replacing the base with HOAc (2.0 equiv.), PivOH (2.0 equiv.)
and TsOHꢁH2O (2.0 equiv.), trace indene was detected (entries 3–5).
Fortunately, in the presence of TsOHꢁH2O (2.0 equiv.), indene was
isolated in 18% (4.4/1) yield (entry 6) and the yield was further
increased to 47% (4.1/1) (0.1 equiv.), 75% (4.4/1) (0.3 equiv.) and
78% (4.4/1) (0.5 equiv.), respectively (entries 7–9). Under elevated
reaction temperature (80 1C), the yield increased to 81% (2a/2a0 =
5.6/1, entry 11). Under air atmosphere, the yield slightly decreased
to 68% (5.6/1) (entry 9). Among the tested solvents, dioxane
(70%, 0.5/1), THF (67%, 1.8/1), DCE (52%, 1.8/1), MeCN (45%,
0.5/1) and EtOH (69%, 4.4/1) were all inferior to MeOH (entries
12–16). Other Brønsted acids, such as MsOH (41%, 8.4/1), HNTf2
(35%, 7.2/1), were tested, but all resulted in low yields (entries 17
and 18) (Table 1). The ratio of 2a and 2a0 changed under
increased temperature (3.4/1, 100 1C).
Entry
Additive (equiv.)
Solvent
Temperature
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3 (2.0)
Cs2CO3 (2.0)
HOAc (2.0)
PivOH (2.0)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Dioxane
THF
60
60
60
60
60
60
60
60
60
r.t.
80
80
80
80
80
80
80
80
N.R.
N.R.
Trace
Trace
Trace
18
HOTf (2.0)
TsOHꢁH2O (2.0)
TsOHꢁH2O (0.1)
TsOHꢁH2O (0.3)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
TsOHꢁH2O (0.5)
MsOH (0.5)
47
75
9
78/68b/57c
46
10
11
12
13
14
15
16
17
18
81
70
67
52
45
69
41
35
DCE
MeCN
EtOH
MeOH
MeOH
HNTf2 (0.5)
a
Reaction conditions: 1a (0.1 mmol), TsNHNH2 (0.2 mmol), solvent
b
c
(2.0 mL), under N2 for 6 h, isolated yields. Under air. TsNHNH2
(0.12 mmol). The ratio of 2a and 2a0 was determined by 1H NMR.
With the optimized catalytic system in hand, the scope of
o-(1-phenylvinyl) acetophenone with substituents attaching in
the carbonyl was studied, as shown in Fig. 1. As expected, the
ethyl analogue produced 2b in 87% yield (2b/2b0 = 5.6/1).
However, the iso-propyl (2c, 57%, 5.6/1), tert-butyl (2d, 52%,
2/1), and phenyl (2e, 48%) analogues delivered the cyclized
products in relatively lower yields, which was at least partly due
to the hindrance. n-Pentanyl and benzyl analogues ran
smoothly under the standard procedure, and 2f and 2g were
isolated in 74% (10/1) and 65% (5.6/1) yields, respectively.
Notably, the 2-cyclohexanyl substituted substrate was also a
suitable reaction partner, albeit in relatively low yield (2h, 35%,
4/1). Importantly, 2-(1-phenylvinyl) benzaldehyde worked under
the procedure, providing 2i in 38% yield (3.4/1).
Next, the scope of o-(1-phenylvinyl) acetophenone with sub-
stituents in both aryls was studied, as shown in Fig. 2. In the
case of substrates with functional groups in the phenyl sub-
stituted by acyl, the reaction tolerated fluoro (2k, 75%, 3.4/1;
2n, 69%, 5.6/1), methyl (2p, 78%, 6.7/1), and chloro (2j, 72%,
3.4/1; 2m, 62%, 5/1), which provided facile handles for
potential further functionalization. However, the ortho-
fluoride substrate provided 2o (42%, 3.4/1) in lower yields.
For the substrates with groups in the phenyl attached in the
vinyl, o-chloro substrate 1t produced 2t (37%, 5.6/1) in lower
Fig. 1 The substrate scope of o-(1-phenylvinyl) acetophenone bearing
substituents on the carbonyl. Reaction conditions: o-(1-phenylvinyl)
acetophenone derivatives 1 (0.1 mmol), TsNHNH2 (0.2 mmol), TsOHꢁ
H2O (0.5 equiv.), MeOH (2.0 mL), under N2 for 6 h, isolated yields. The
ratio of 2 and 20 was determined by 1H NMR.
To get some insights into this reaction, more experiments
yield. However, the p-methyl (2q, 73%, 3.4/1), p-chloro (2r, 79%, were conducted. Under the standard procedure, 2a was isolated
5.6/1), and m-chloro (2s, 56%, 5.6/1), analogues all ran in 73% yield in the presence of styrene (1.0 equiv.), and no
smoothly under the standard procedure. As such, this proce- cyclopropanation product 3 was detected at all (eqn (1),
dure provided a facile pathway to access 1,3-difunctionalized Scheme 2). This result ruled out the possibility of the involve-
indenes with complexity and diversity.
ment of a carbene pathway. Meanwhile, TsOHꢁH2O could
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Scheme 3 A tentative mechanism.
subjected to the standard reaction conditions, and indene 2u was
isolated in 3% yield proceeding with a presumed carbocation
migration (eqn (3), Scheme 2). These two results clearly confirmed
the involvement of a carbocation pathway. However, 2-(1-phenyl-
vinyl)benzaldehyde, which has no hyperconjugation in the corres-
ponding cabocation, provided 2i (38%) in relatively lower yield.
Moreover, for substrates with an electron-withdrawing group
attached in the carbonyl, neither 2v nor 2w was detected at all
under the standard reaction (eqn (4), Scheme 2). These results were
also consistent with the carbocation pathway.
Based on the aforementioned experimental results, a tentative
mechanism was proposed (Scheme 3). First, in the presence of
TsNHNH2 and TsOHꢁH2O, o-(1-phenylvinyl) acetophenone 1a
converts into N-tosylhydrazone 5. Afterward, intermediate 5 trans-
forms into intermediate 6 under the acidic conditions. Second,
intermediate 7 is formed whereby 4-methylbenzenesulfinic acid is
released, which is detected by GC–MS (for details, see ESI†). Third,
after the extrusion of a proton in intermediate 7, the diazo
intermediate 8 is generated, which produces the carbocation
intermediate 9 in the presence of a proton. Fourth, the cation
cyclization takes place leading to intermediate 10. Finally, the
product 2a is formed after the releasing of one proton. Mean-
while, the isomer 2a0 is produced through the sequential addition
of a proton to 2a toward intermediate 11 and the extrusion of a
proton.
Fig. 2 The substrate scope of o-(1-phenylvinyl) acetophenone bearing
groups on the phenyl. Reaction conditions: o-(1-arylvinyl) acetophenone
derivatives 1 (0.1 mmol), TsNHNH2 (0.2 mmol), TsOHꢁH2O (0.5 equiv.),
MeOH (2.0 mL), under N2 for 6 h, isolated yields. The ratio of 2 and 20 was
determined by 1H NMR.
promote the annulation of 1-(2-(1-phenylvinyl) phenyl)ethan-1-ol 4
leading to indene 2a (8%, eqn (2), Scheme 2), indicating the
participation of the produced carbocation in the subsequent cycliza-
tion. Moreover, (E)-4-(2-(1-phenylvinyl) phenyl)but-3-en-2-one 1u was
In conclusion, we have developed a Brønsted acid-promoted
intramolecular cyclization of o-(1-arylvinyl) acetophenone deriva-
tives, leading to polysubstituted indenes with complexity and diver-
sity in moderate to excellent yields. A carbocation pathway was
involved during this procedure, which was different from either the
radical or carbene involved cyclization of aldehydic N-tosylhydrazone
with vinyl. In sharp contrast with the aforementioned examples on
the annulation of aldehydic N-tosylhydrazone with vinyl, this proce-
dure features: (1) less active substrates with more hindrance toward
polysubstituted indenes with more complexity and diversity; (2)
acidic reaction conditions rather than basic conditions; and (3) a
mechanismly different pathway involved carbocation.
We thank the National Natural Science Foundation of China
(no. 21971025), ‘‘Innovation & Entrepreneurship Talents’’
Introduction Plan of Jiangsu Province, Jiangsu Key Laboratory
of Advanced Catalytic Materials & Technology (BM2012110), the
Scheme 2 Mechanism study.
1812 | Chem. Commun., 2021, 57, 1810ꢀ1813
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(i) W. Wu, Z. Lin, C. Zhu, P. Chen, J. Li and H. Jiang, J. Org. Chem.,
2017, 82, 12746; ( j) X. Nie, Y. Wang, L. Yang, Z. Yang and T. Kang,
Tetrahedron Lett., 2017, 58, 3003.
4 B. G. Das, A. Chirila, M. Tromp, J. N. H. Reek and B. de Bruin, J. Am.
Chem. Soc., 2016, 138, 8968.
Foundation of Wenzhou Science & Technology Bureau (No.
W20170003), and Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center for financial supports.
5 Q. Zhou, S. Li, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2017,
56, 16013.
Conflicts of interest
6 For reviews, see: (a) W. Kirmse, Eur. J. Org. Chem., 1998, 201;
(b) R. M. Adlington and A. G. M. Barrett, Acc. Chem. Res., 1983,
16, 55; (c) J. P. Wolfe, Name Reactions for Functional Group Transfor-
mations, ed. J. J. Li and E. J. Corey, 2007, pp. 405–413; (d) J. J. Li,
Name Reactions: A Collection of Detailed Mechanisms and Synthetic
Applications, Spring Verlag, Berlin Heidelberg, 4th edn, 2011,
pp 16–17.
7 (a) F. Ye, X. Ma, Q. Xiao, H. Li, Y. Zhang and J. Wang, J. Am. Chem.
Soc., 2012, 134, 5742; (b) T. Wang, M. Wang, S. Fang and J. Y. Liu,
Organometallics, 2014, 33, 3941; (c) X. Zhao, G. Wu, Y. Zhang and
J. Wang, J. Am. Chem. Soc., 2011, 133, 3296; (d) T. Yao, K. Hirano,
T. Satoh and M. Miura, Angew. Chem., Int. Ed., 2012, 51, 775;
(e) Q. Xiao, L. Ling, F. Ye, R. Tan, L. Tian, Y. Zhang, Y. Li and
J. Wang, J. Org. Chem., 2013, 78, 3879; ( f ) A. K. Jha and N. Jain,
Chem. Commun., 2016, 52, 1831; (g) S. Xu, G. Wu, F. Ye, X. Wang,
H. Li, X. Zhao, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2015,
54, 4669.
8 For reviews, please see: (a) Q. He, Z. Yin, H. Chen, Z. Zhang, X. Wang
and G. Yue, Huaxue Jinzhan, 2016, 28, 801; (b) A. Rinaldi, D. Scarpi
and E. G. Occhiato, Eur. J. Org. Chem., 2019, 7401; (c) R. Pluskota and
M. Koba, Mini-Rev. Med. Chem., 2018, 18, 1321; (d) B. An,
Y.-M. Zhang, H.-B. Zhu, W. Teng and G.-J. Guo, Guangzhou Huagong,
2015, 43, 34.
9 (a) S. Guzelj, M. Gobec, D. Urbancic, I. Mlinaric-Rascan, E. Corsini
and Z. Jakopin, Eur. J. Med. Chem., 2020, 190, 112089; (b) D. Zhu,
H. Huang, D. M. Pinkas, J. Luo, D. Ganguly, A. E. Fox, E. Arner,
Q. Xiang, Z.-C. Tu and A. N. Bullock, et al., J. Med. Chem., 2019,
62, 7431.
There are no conflicts to declare.
Notes and references
1 For reviews: (a) Y. Xia and J. Wang, J. Am. Chem. Soc., 2020,
142, 10592; (b) Y. Zhang and J. Wang, Top. Curr. Chem., 2012,
327, 239; (c) Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560;
(d) D. Qiu, F. Mo, Y. Zhang and J. Wang, Adv. Organomet. Chem.,
2017, 67, 151; (e) D. Arunprasath, B. D. Bala and G. Sekar, Adv. Synth.
Catal., 2019, 361, 1172; ( f ) H. Wang, Y.-H. Deng and Z. Shao,
Synthesis, 2018, 2281; (g) Y. Xia and J. Wang, Chem. Soc. Rev.,
2017, 46, 2306; (h) A. P. Jadhav, D. Ray, V. U. B. Rao and
R. P. Singh, Eur. J. Org. Chem., 2016, 2369; (i) K. Xu, C. Shen and
S. Shan, Youji Huaxue, 2015, 35, 294; ( j) Z. Liu and J. Wang, J. Org.
Chem., 2013, 78, 10024; (k) Z. Liu, Y. Zhang and J. Wang, Youji
Huaxue, 2013, 33, 687; (l) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem.
Res., 2013, 46, 236; (m) J. Barluenga and C. Valdes, Angew. Chem., Int.
Ed., 2011, 50, 7486; (n) J. R. Fulton, V. K. Aggarwal and J. de Vicente,
Eur. J. Org. Chem., 2005, 1479.
2 For selected examples: (a) H. Xiong, X. Wu, H. Wang, S. Sun, J.-T. Yu
and J. Cheng, Adv. Synth. Catal., 2019, 361, 3538; (b) V. S. Ostrovskii,
I. P. Beletskaya and I. D. Titanyuk, Org. Lett., 2019, 21, 9080;
(c) K. Ishitobi, K. Muto and J. Yamaguchi, ACS Catal., 2019,
9, 11685; (d) L. Zhu, X. Ren, Y. Yu, P. Ou, Z.-X. Wang and
X. Huang, Org. Lett., 2020, 22, 2087.
3 (a) D. F. Taber, P. Guo and N. Guo, J. Am. Chem. Soc., 2010,
132, 11179; (b) J. Barluenga, N. Quinones, M. Tomas-Gamasa and
M.-P. Cabal, Eur. J. Org. Chem., 2012, 2312; (c) J. S. Kapure,
C. N. Reddy, P. R. Adiyala, R. Nayak, V. L. Nayak, J. B. Nanubolu,
K. K. Singarapu and R. A. Maurya, RSC Adv., 2014, 4, 38425;
(d) M. Lawson, J. Bignon, J.-D. Brion, A. Hamze and M. Alami, Asian
J. Org. Chem., 2015, 4, 1144; (e) T. Iwai, F. Matsumoto, K. Hida,
K. Moriwaki, Y. Takao, T. Ito, T. Mizuno and T. Ohno, Synlett, 2015,
960; ( f ) R. Barroso, A. Jimenez, M. C. Perez-Aguilar, M.-P. Cabal and
10 H. Lim, S. Y. Lee, K. R. Lee, Y. S. Kim and H. P. Kim, Biomol. Ther.,
2012, 20, 477.
11 (a) S. Sanivarapu, N. Vaddiraju and L. Velide, Med. Chem. Res., 2019,
28, 1461; (b) S. S. Undare, N. J. Valekar, A. A. Patravale, D. K. Jamale,
S. S. Vibhute, L. S. Walekar, G. B. Kolekar, M. B. Deshmukh and
P. V. Anbhule, Bioorg. Med. Chem. Lett., 2016, 26, 814.
12 (a) N. Akhter, C. Pan, Y. Liu, Y. Shi and B. Wu, Nat. Prod. Res., 2019,
33, 2939; (b) N. Sudhapriya, P. T. Perumal, C. Balachandran,
S. Ignacimuthu, M. Sangeetha and M. Doble, Eur. J. Med. Chem.,
2014, 83, 190.
´
C. Valdes, Chem. Commun., 2016, 52, 3677; (g) P. Cyr, A. Cote-Raiche
and S. M. Bronner, Org. Lett., 2016, 18, 6448; (h) C. Zhu, J. Li,
P. Chen, W. Wu, Y. Ren and H. Jiang, Org. Lett., 2016, 18, 1470;
This journal is The Royal Society of Chemistry 2021
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