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A ruthenium-catalyzed alkenylation–annulation
Cite this: Org. Biomol. Chem., 2018,
approach for the synthesis of indazole derivatives
16, 5973 via C–H bond activation†
Maral Gholamhosseyni and Ebrahim Kianmehr *

Ruthenium catalyzed oxidative alkenylation of N-aryl pyridazinediones and N-aryl phthalazinediones with
Received 28th April 2018, acrylates and subsequent intramolecular cyclization of the resulting product in water as a green solvent
Accepted 23rd July 2018
were accomplished. Diverse derivatives of pyridazino[1,2-a]indazoles and indazolo[1,2-b]phthalazines
DOI: 10.1039/c8ob00999f were readily prepared in moderate to high yields by this methodology from easily accessible starting
rsc.li/obc materials via cascade directed C–H bond activation/annulation reactions.

Cross-dehydrogenative alkenylation of arenes and heteroarens

via the transition metal-catalyzed transformation of aromatic
carbon–hydrogen (C–H) bonds which avoids the need for func-
tionalized starting materials1 has been proven as a powerful
alternative to Heck type reactions2 and thus has emerged as a
straightforward and economical tool for the synthesis of
organic compounds. The current approach is advantageous in
that it enables the direct formation of target molecules
without requiring pre-functionalization of the starting
materials, thereby minimizing undesired waste in fewer reac-
tion steps.3 Although a wide variety of Pd and Rh-catalyzed oxi-
dative coupling reactions have been developed,4 there are few
examples of the less expensive ruthenium complexes.5
Fig. 1 Some examples of bioactive compounds with indazole structural
The indazole containing structural motif is frequently
motif.
present at the core of pharmaceuticals. It has been shown that
this class of compound exhibits a broad range of useful
pharmacological effects including antitumor,6 anti-inflamma-
1-aryl-1H-indazoles via copper-catalyzed coupling reactions in
tory,7 anti-HIV,8 anti-bacterial9 and contraceptive10 activity. For
2012 (Scheme 1).13 Rhodium(III)-catalyzed C–H bond addition
example, several indazolium alkaloids and indazolones were
of azobenzenes to aldehydes for the synthesis of indazoles was
reported to show antidiabetic11 (Fig. 1A and B) and anti-
reported by Lian in 2013 (Scheme 1).14 Rh(III)-Catalyzed C–H
inflammatory activities (Fig. 1C and D).12
cleavage of arylhydrazines as another approach for the syn-
Due to the need for efficient ways to synthesize more elabor-
thesis of 2,3-dihydro-1H-indazoles was reported separately by
ate structures possessing biological activity, the development
Kim and Liu in 2014 (Scheme 1).15a,b Wu et al. reported a
of novel and convenient methods for the preparation of the
Rh(III)-catalyzed [4 + 1] annulation of propargyl alcohols with
indazole core structure is of great interest to medicinal che-
various heterocyclic scaffolds under air atmosphere in 2018.15c
mists. Construction of the indazole unit, a recurring structural
As part of our ongoing interest in exploring C–C bond for-
motif found in many pharmaceuticals and functional
mations through CDC reactions,16 herein we report an efficient
materials, has rarely been reported. Aryl iodides and N-acyl-N′-
and highly regioselective procedure for oxidative C–H bond
substituted hydrazines were used by Ma for the synthesis of
alkenylation of N-aryl pyridazinediones and N-aryl phthalazine-
diones followed by an intermolecular Michael reaction in water as
a nontoxic and environmentally friendly reaction medium.
School of Chemistry, College of science, University of Tehran, Tehran 1417614411,
Iran. E-mail: kianmehr@khayam.ut.ac.ir
Our study commenced with probing various solvents, cata-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/ lysts, additives and oxidants for the envisioned oxidative alke-
c8ob00999f nylation of 1-phenyl-1,2-dihydropyridazine-3,6-dione 1a to

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Scheme 1 Selected approaches to synthesis of indazole derivatives.

Table 1 Optimization of the reaction conditionsa

Entry Catalyst (5 mol%) Additive (10 mol%) Oxidant (1 equiv.) Solvent Yielda (%)

1 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O DCE 80

2 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O Toluene 21
3 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O PhCl 33
4 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O THF 79
5 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O CH3CN 50
6 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O DMSO 10
7 [{RuCl2(p-cymene)}2] KPF6 Cu(OAc)2·H2O H2O 95
8 [{RuCl2(p-cymene)}2] KPF6 AgOAc H2O 20
9 [{RuCl2(p-cymene)}2] KPF6 Ag2CO3 H2O 30
10 [{RuCl2(p-cymene)}2] KPF6 K2S2O8 H2O 10
11 [{RuCl2(p-cymene)}2] — Cu(OAc)2·H2O H2O 45
12 [{RuCl2(p-cymene)}2] AgSbF6 Cu(OAc)2·H2O H2O 93
13 RuCl2(PPh3)3 KPF6 Cu(OAc)2·H2O H2O 20
14 RuCl2(COD) KPF6 Cu(OAc)2·H2O H2O 54
15 Pd(OAc)2 KPF6 Cu(OAc)2·H2O H2O 52
16 — KPF6 Cu(OAc)2·H2O H2O 0
a
General reaction conditions: 1a (1 equiv., 0.5 mmol), 2a (3 equiv., 1.5 mmol), 2 mL solvent, 24 h, 120 °C.

furnish methyl-2-(6,9-dioxo-6,9-dihydro-11H-pyridazino[1,2-a] entries 1–7) so it proved to be the solvent of choice. To our

indazol-11-yl)acetate 3a (Table 1). Among representative sol- delight, with [{RuCl2( p-cymene)}2] as a catalyst, KPF6 as an
vents including DCE, toluene, H2O, PhCl, THF, CH3CN and additive and Cu(OAc)2·H2O as the oxidant, the product was
DMSO, H2O turned out to be the most appropriate (Table 1, obtained in 95% yield in water as the solvent (Table 1, entry 7).

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Table 2 Substrate scopea

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a
Reaction conditions: Substrate 1 (1 equiv., 0.5 mmol), acrylate derivatives 2 (3 equiv., 1.5 mmol), [{RuCl2(p-cymene)}2] (5 mol%), Cu(OAc)2·H2O
(1 equiv., 0.5 mmol), KPF6 (10 mol%) in water (2.0 mL) at 120 °C for 24 h. b DCE was used as the solvent.

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Scheme 2 Possible reaction mechanism.

The effects of oxidants, additives and catalysts on the reactivity On the basis of previous mechanistic reports,17 a plausible
were studied. An aerobic oxidative alkenylation with stoichio- mechanism for the ruthenium-catalyzed oxidative vinylation–
metric amounts of Cu(OAc)2·H2O proved to be effective among annulation is illustrated in Scheme 2. The reaction proceeds
various terminal oxidants. by N–H assisted C–H bond ruthenation of the substrate 1 to
The use of silver(I) salts such as AgOAc and Ag2CO3 pro- form a ruthenacycle complex A. Subsequent migratory inser-
vided less satisfactory results (Table 1, entries 8 and 9) and a tion of the acrylate, along with β-hydride-elimination leads to
poor result was obtained when K2S2O8 was used as an oxidant intermediate C which reductively eliminates to alkenylated
(Table 1, entry 10). Use of KPF6 and AgSbF6 as an additive product D. Finally the desired product (3a–t) is obtained by an
proved to be efficient in this reaction (Table 1, entries 11 and intramolecular aza-Michael addition reaction of D under the
12). Screening the catalyst yielded [{RuCl2( p-cymene)}2] as the reaction conditions.
best among RuCl2(PPh3)3, RuCl2(COD) and Pd(OAc)2 (Table 1,
entries 13–15). Decreasing the amount of catalyst below
5 mol% led to insufficient outcomes. Predictably, the reaction Conclusions
didn’t proceed in the absence of catalyst (Table 1, entry 16).
With the optimized reaction conditions identified, we next In summary, a highly efficient [{RuCl2( p-cymene)}2]/
examined the scope and versatility of this reaction using Cu(OAc)2·H2O/KPF6 system in water as an environmentally
different derivatives of N-aryl pyridazinediones and N-aryl benign, nontoxic reaction medium for tandem oxidative C–H
phthalazinediones (Table 2). The substrates with both elec- bond alkenylation, aza-Michael addition reactions of N-aryl
tron-donating and electron withdrawing groups on aryl rings pyridazinediones and N-aryl phthalazinediones with acrylates
reacted smoothly and resulted in the corresponding products has been reported in an atom- and step-economical fashion.
3a–q in moderate to high yields. The excellent chemo- and
site-selectivity of the ruthenium catalyst was illustrated by suc-
cessful C–H/N–H functionalization with substrates bearing a Conflicts of interest
range of substituents such as fluoro, bromo, and methyl. The There are no conflicts to declare.
reaction was not successful with methyl methacrylate (3u). To
further explore the potential of this methodology for the syn-
thesis of indazole derivatives, we investigated the reaction with Acknowledgements
pyrazolidinone backbone, 1-phenyl-3-pyrazolidinone, and the
corresponding indazole derivatives 3r and 3s were obtained in We gratefully acknowledge the financial support from the
moderate yields. Research Council of the University of Tehran and the Iran

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National Science Foundation (INSF, no. 96008622). We thank 4157; (k) T.-H. Chen, D. M. Reddy and Ch.-F. Lee, RSC Adv.,
Dr Karol Gajewski, Natural Resources Canada, for helpful com- 2017, 7, 30214–30220; (l) T. Balalas, A. Abdul-Sada,
ments on this work. D. J. Hadjipavlou-Litina and K. E. Litinas, Synthesis, 2017,
49, 2575–2583; (m) D. Wang and Sh. S. Stahl, J. Am. Chem.
Soc., 2017, 139, 5704–5707; (n) X.-B. Bu, Zh. Wang,
Notes and references Y.-H. Wang, T. Jiang, L. Zhang and Y.-L. Zhao, Eur. J. Org.
Published on 03 August 2018. Downloaded by Birla Institute of Technology & Science on 4/15/2023 1:26:35 PM.

Chem., 2017, 2017, 1132–1138; (o) S. K. R. Kotla,

1 (a) J. L. Bras and J. Muzart, Chem. Rev., 2011, 111, 1170– D. Choudhary, R. K. Tiwari and A. K. Verma, Tetrahedron
1214; (b) F. Bellina, R. Rossi and M. Lessi, Synthesis, 2010, Lett., 2015, 56, 4706–4710; ( p) D. Y. Li, H. J. Chen and
24, 4131–4153; (c) A. V. Vasil’ev, Russ. J. Org. Chem., 2009, P. N. Liu, Org. Lett., 2014, 16, 6176–6179; (q) D. Y. Li,
45, 1–17; (d) E. M. Beccalli, G. Broggini, M. Martinelli and X. F. Mao, H. J. Chen, G. R. Chen and P. N. Liu, Org. Lett.,
S. Sottocornola, Chem. Rev., 2007, 107, 5318–5365; 2014, 16, 3476–3479.
(e) C. Tirler and L. Ackermann, Tetrahedron, 2015, 71, 5 (a) L. Ackermann, Acc. Chem. Res., 2014, 47, 281–295;
4543–4551; (f ) L.-Y. Jiao, A. V. Ferreira and M. Oestreich, (b) H. Zhao, T. Zhang, T. Yan and M. Cai, J. Org. Chem.,
Chem. – Asian J., 2016, 11, 367–370; (g) Y. Qiu, W.-J. Kong, 2015, 80, 8849–8855; (c) S. Dana, A. Mandal, H. Sahoo,
J. Struwe, N. Sauermann, T. Rogge, A. Scheremetjew and S. Mallik, G. S. Grandhi and M. Baidya, Org. Lett., 2018, 20,
L. Ackermann, Angew. Chem., Int. Ed., 2018, 57, 5828–5832. 716–719; (d) D. Tyagi, Ch. Binnani, R. K. Rai, A. D. Dwivedi,
2 (a) J. Ruan and J. Xiao, Acc. Chem. Res., 2011, 44, 614–626; K. Gupta, P.-Zh. Li, Y. Zhao and S. K. Singh, Inorg. Chem.,
(b) D. M. Cartney and P. J. Guiry, Chem. Soc. Rev., 2011, 40, 2016, 55, 6332–6343; (e) E. J. Farrington, J. M. Brown and
5122–5150; (c) D. Haas, J. M. Hammann, R. Greiner and B. Rowsell, Angew. Chem., Int. Ed., 2002, 41, 169–171.
P. Knochel, ACS Catal., 2016, 6, 1540–1552; (d) A. Suzuki, 6 M. A. Jakupec, E. Reisner, A. Eichinger, M. Pongratz,
Angew. Chem., Int. Ed., 2011, 50, 6722–6737; (e) E. Negishi, V. B. Arion, M. Galanski, C. G. Hartinger and B. K. Keppler,
Angew. Chem., Int. Ed., 2011, 50, 6738–6764. J. Med. Chem., 2005, 48, 2831–2837.
3 (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 7 S. Caron and E. Vazquez, Org. Process Res. Dev., 2001, 5,
1215–1292; (b) L. Chao, Z. Hua, S. Wei and L. Aiwen, Chem. 587–592.
Rev., 2011, 111, 1780–1824; (c) S. H. Cho, J. Y. Kim, J. Kwak 8 J.-H. Sun, C. A. Teleha, J.-S. Yan, J. D. Rodgers and
and S. Chang, Chem. Soc. Rev., 2011, 40, 5068–5083; D. A. Nugiel, J. Org. Chem., 1997, 62, 5627–5629.
(d) M. C. Willis, Chem. Rev., 2010, 110, 725–748; 9 X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S. Margosiak,
(e) L. Ackermann and H. K. Potukuchi, Org. Biomol. Chem., V. Nikulin, J. Levin, K. G. Sprankle, M. E. Tedder,
2010, 8, 4503–4513; (f ) W. J. Yoo and C.-J. Li, Top. Curr. R. Almassy, K. Appelt and K. M. Yager, J. Med. Chem., 2003,
Chem., 2010, 292, 281–302; (g) O. Daugulis, Top. Curr. 46, 5663–5673.
Chem., 2010, 292, 57–84; (h) D. A. Colby, R. G. Bergman 10 G. Corsi, G. Palazzo, C. Germani, P. S. Barcellona and
and J. A. Ellman, Chem. Rev., 2010, 110, 624–655; B. Silvestrini, J. Med. Chem., 1976, 19, 778–783.
(i) K. Fagnou, Top. Curr. Chem., 2010, 292, 35–56; 11 T. Yuan, P. Nahar, M. Sharma, K. Liu, A. Slitt, H. A. Asia
( j) D.-W. Gao, Q. Gu and S.-L. You, J. Am. Chem. Soc., 2016, and N. P. Seeram, J. Nat. Prod., 2014, 77, 2316–2320.
138, 2544–2547; (k) W. Liu, Y. Yu, B. Fan and C. Kuang, 12 Kh. A. M. Abouzid and H. S. EI-Abhar, Arch. Pharmacal.
Tetrahedron Lett., 2017, 58, 2969–2971; (l) T. Maegawa, Res., 2003, 26, 1–8.
R. Mizui, M. Urasaki, K. Fujimura, A. Nakamura and 13 X. Xiong, Y. Jiang and D. Ma, Org. Lett., 2012, 14, 2552–
Y. Miki, ACS Omega, 2018, 3, 5375–5381; (m) G. S. Kumar, 2555.
D. Singh, M. Kumar and M. Kapur, J. Org. Chem., 2018, 83, 14 Y. Lian, R. G. Bergman, L. D. Lavis and J. A. Ellman, J. Am.
3941–3951. Chem. Soc., 2013, 135, 7122–7125.
4 (a) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 15 (a) S. Han, Y. Shin, S. Sharma, N. Kumar Mishra, J. Park,
2001, 34, 633–639; (b) M. Wasa, K. M. Engle and J.-Q. Yu, M. Kim, M. Kim, J. Jang and I. S. Kim, Org. Lett., 2014, 16,
Isr. J. Chem., 2010, 50, 605–616; (c) X. Chen, K. M. Engle, 2494–2498; (b) J. Yao, R. Feng, C. Lin, Z. Liu and Y. Zhang,
D. H. Wang and J. Q. Yu, Angew. Chem., Int. Ed., 2009, 48, Org. Biomol. Chem., 2014, 12, 5469–5476; (c) X. Wu and
5094–5115; (d) K. Neog, A. Borah and P. Gogoi, J. Org. H. J, J. Org. Chem., 2018, 83, 4650–4656.
Chem., 2016, 81, 11971–11977; (e) T. Satoh and M. Miura, 16 (a) E. Kianmehr, M. Torabi, M. Rezazadeh Khalkhali,
Chem. – Eur. J., 2010, 16, 11212–11222; (f ) D. A. Colby, N. Faghih and Kh. M. Khan, Eur. J. Org. Chem., 2015, 2015,
R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 2796–2800; (b) E. Kianmehr, Sh. Kazemi and A. Foroumadi,
624–655; (g) D. A. Colby, A. S. Tsai, R. G. Bergman and Tetrahedron, 2014, 70, 349–578; (c) E. Kianmehr,
J. A. Ellman, Acc. Chem. Res., 2012, 45, 814–825; M. Fardpour and Kh. M. Khan, Eur. J. Org. Chem., 2017,
(h) M. Yamaguchi, K. Omata and M. Hirama, Tetrahedron 2017, 2661–2266; (d) E. Kianmehr, M. Fardpour and
Lett., 1994, 35, 5689–5692; (i) X. Yu, W. Yao, H. Wan, Zh. Xu A. N. Kharat, Eur. J. Org. Chem., 2017, 2017, 3017–3021.
and D. Wang, J. Organomet. Chem., 2016, 822, 100–103; 17 (a) A. Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz,
( j) S. Zhang, Zh. Chen, Sh. Qin, Ch. Lou, A. M. Senan, C. Kornhaaß and L. Ackermann, Angew. Chem., Int. Ed.,
R.-Zh. Liao and G. Yin, Org. Biomol. Chem., 2016, 14, 4146– 2016, 55, 264–267; (b) W. Ma and L. Ackermann, ACS

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 5973–5978 | 5977
 View Article Online

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Catal., 2015, 5, 2822–2825; (c) S. I. Kozhushkova and Savarimuthu, R. Senthil Kumaran, C. M. Nagarajad and
L. Ackermann, Chem. Sci., 2013, 4, 886–896; T. Gandhi, Chem. Commun., 2016, 52, 2509–2512;
(d) L. Ackermann, L. Wang, R. Wolfram and A. V. Lygin, (h) W. Ma, P. Gandeepan, J. Lid and L. Ackermann, Org.
Org. Lett., 2012, 14, 728–731; (e) L. Ackermann and Chem. Front., 2017, 4, 1435–1467; (i) S. Singh, H. H. Butani,
J. Pospech, Org. Lett., 2011, 13, 4153–4155; D. D. Vachhani, A. Shahb and E. V. Van der Eycken, Chem.
(f) S. Mayakrishnan, Y. Arun, Ch. Balachandran, N. Emi, Commun., 2017, 53, 10812–10815; ( j) R. Prakash,
Published on 03 August 2018. Downloaded by Birla Institute of Technology & Science on 4/15/2023 1:26:35 PM.

D. Muralidharan and P. Thirumalai Perumal, Org. Biomol. B. R. Bora, R. C. Boruah and S. Gogoi, Org. Lett., 2018, 20,
Chem., 2016, 14, 1958–1968; (g) S. Rajkumar, S. Antony 2297–2300.

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