Bis(dibenzylideneacetone)palladium(0)/tert-Butyl Nitrite- Catalyzed Cyclization of o-Alkynylanilines with tert-Butyl Nitrite: Synthesis and Applications of Indazole 2-Oxides

Article abstract of DOI:10.1002/adsc.201700456

An efficient method for the synthesis of 1-benzyl/arylindazole 2-oxides via a bis(dibenzylideneacetone)palladium(0) [Pd(dba)₂]/tert-butyl nitrite (TBN)-catalyzed reaction of o-alkynylaniline derivatives with TBN is reported. The overall transfo

Full text of DOI:10.1002/adsc.201700456

Title: Pd(dba)₂/<i>t</i>BuONO-Catalyzed Cyclization
of <i>o</i>-Alkynylanilines with <i>t</i>BuONO: Synthesis and
Applications of Indazole 2-oxides
Authors: Gopal Chandru Senadi, Ji-Qi Wang, Babasaheb Sopan Gore,
and Jeh-Jeng Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700456
Link to VoR: http://dx.doi.org/10.1002/adsc.201700456

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pd(dba)2/tBuONO-Catalyzed Cyclization of o-Alkynylanilines
with tBuONO: Synthesis and Applications of Indazole 2-oxides
Gopal Chandru Senadi,a Ji-Qi Wang,a Babasaheb Sopan Gore,a and Jeh-Jeng Wang a,b*
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd, Sanmin
district, Kaohsiung City, 807 (Taiwan). Tel: (886)-7-3121101, Fax: (886)-7-3125339, email: jjwang@kmu.edu.tw
b
Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Rd, Sanmin District,
Kaohsiung City, 807 (Taiwan).
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Furthermore, the direct synthesis of N-oxides from
Abstract. An efficient method for the synthesis of 1-
benzy/aryl-indazole 2-oxides via
a
bis(dibenzylidene in situ generated NO sources has been scarcely
reported in the literature.[8] Therefore, the
identification of new reaction conditions/strategies for
the synthesis of a variety of heterocyclic N-oxides is
still an unexplored area of research. In this context,
Kimachi et al. (2011) reported the synthesis of
acetone)palladium(0) (Pd(dba)2)/tert-butyl nitrite (TBN)-
catalyzed reaction of o-alkynylaniline derivatives with
TBN is reported. The overall transformation involved the
formation of three new bonds via N-nitrosation (N-NO), 5-
exo-dig cyclization (C-N) and oxidation (C=O). The
notable features were the mild reaction conditions, broad
substrate scope and dual role of TBN as a NO source and
redox co-catalyst. This strategy was implemented for the
synthesis of indazole-3-carbaldehyde derivatives and the
formal syntheses of pharmaceutically active YC-1, an
anticancer agent (lonidamine), and the male contraceptive
experimental drugs AF2785 and adjudin (AF-2364).
quinoxalinone-N-oxides
from
cyanoacetanilides
through the in situ generation of NO using a
combination of NaNO2/H2SO4/O2 (Scheme 1a).[8a] In
2014, Jiao et al. reported the efficient synthesis of
quinoxaline N-oxides using tert-butyl nitrite TBN as a
NO source via imidoyl C(sp3)-H and arene C(sp2)-H
bond functionalizations (Scheme 1b).[8b] Herein, we
discovered a new in situ NO source by synthesizing
3-acyl-indazole 2-oxides from o-alkynylaniline
derivatives with TBN in the presence of
Pd(dba)2/TBN as a catalytic system.[8c] The reaction
proceeded through a sequence of (i) N-nitroso
formation (N-NO); (ii) regioselective 5-exo-dig-
cyclization (C-N); and (iii) oxidation (C=O) (Scheme
1c).
Keywords: Indazole 2-oxides; palladium; tert-butyl nitrite;
catalysis; formal syntheses
Aza-heterocyclic compounds have widespread
applications in biology,[1] chemistry[2] and materials
science[3a]. In particular, N-oxides of these molecules
are ubiquitous structural motifs found in alkaloids[3b]
and bioactive compounds[3c] and have several
chemical applications.[3d] The classical approach to
synthesize N-oxides is from the corresponding aza-
heterocyclic molecules with oxidants, such as
peroxyacids.[4] However, this method has certain
limitations, such as the unselective over-oxidation of
other N-atoms present in the molecules, the excessive
amount of strong oxidant needed and the requirement
of previously prepared parent heterocycles. A brief
literature survey revealed that the modern/non-
classical methods for the synthesis of heterocyclic-N-
oxides are the electrophilic cyclization[5a-e]/[2,3]-
rearrangement to N-allenyl nitrones followed by 6π-3-
azatriene electrocyclization[5f] of oximes tethered with
alkynes,[5] the oxidative cyclization of oximes[6] and
the transition-metal-catalyzed C-H functionalization
of oximes with diazo compounds[7a-b]/1,4,2-dioxazol-
5-ones.[7c]
Scheme 1 Syntheses of heterocyclic N-oxides from in situ
NO sources.
The in situ generation of NO was initially studied
with N-benzyl-2-(phenylethynyl)aniline 4aa and
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
TBN.[9] The desired product 5aa[10] was isolated in alkyne was tested with aryl (4ab-ai), heteroaryl (4aj),
25% yield along with 35% of the 6-endo-dig product alkyl (4ak-al) and silyl (4am) functionalities, as
1-benzyl-4-oxo-3-phenyl-1,4-dihydrocinnoline
2- shown in Table 2. The reaction worked well with o-
oxide 6aa in 1,4-dioxane at 80 °C over 24 h (entry 1, /m-/p-functional groups on the R group of the aryl
Table 1). The structures of compound 5aa and 6aa ring, affording products with various functionalities,
were confirmed by X-ray analyses.[11] The 5-exo such as o-MeO (5ab), m-MeO (5ac), m-Cl (5ad), m-
selectivity was increased when 5 mol % of CF3 (5ae), m-CN (5af), m-NO2 (5ag), p-Me (5ah) and
tetrabutylammonium bromide (TBAB) was used, p-MeO (5ai), in 45-96% yields irrespective of the
affording 45% 5aa and 24% 6aa (entry 2, Table 1). electronic properties. However, strong electron-
However, the best regioselectivity was obtained using donating functionalities on the aryl group gave 6-
5 mol % I2, albeit in low yields without any endo endo-dig products, such as o-Me (6ab), m-MeO (6ac)
product (entry 3, Table 1). Increasing the ratio of I2 to and p-MeO (6ai) products, in 26-39% yields. The
10 mol% also failed to increase the yield of 5aa likely reason could be the strong donating ability of
(Supporting Information, Table S1). When transition- the methoxy group, which stabilized the endo-vinyl
metal catalysts, such as Fe, Cu, Zn, Ag and Pd were
tested (Table S1), the desired 5-exo-dig product was Table 2 Scope of the R/R1/R2 functionalities to afford
obtained in 88% yield along with a trace amount of indazole 2-oxides.[a,b]
the endo-dig product using 5 mol % Pd(dba)2 as a
catalyst (entry 4, Table 1). Subsequent tests of the
solvents were studied using 4aa and TBN with 5
mol % Pd(dba)2 in DMSO, DMF, CH3CN, THF or
MeOH (Table S1). We found that DMSO and CH3CN
gave similar yields to that of 1,4-dioxane; however,
the endo-dig selectivity was slightly increased (entries
5-6, Table 1). A lower catalyst loading increased the
reaction time, and no notable changes were observed
upon increasing the loading of the catalyst (entry 7-8,
Table 1). Decreasing the reaction temperature to
60 °C resulted in a longer reaction time, whereas at
refluxing temperature, the selectivity was reduced
(Table S1). Reducing the quantity of TBN to 1.2
equiv resulted in some remaining unreacted N-nitroso
intermediates and a low yield (entry 9, Table 1). Thus,
the reaction conditions listed in entry 4, Table 1 were
chosen as the optimal conditions.
With the optimized reaction conditions in hand, the
scope of this in situ NO source reaction was
investigated. The scope of the R group attached to the
Table 1 Screening of the reaction conditions.[a]
Yield
(%)[b]
Catalyst
(mol %)
Entry
Solvent
t, h
5aa 6aa
1
2
3
4
5
6
7
8
---
1,4-dioxane 24
1,4-dioxane 24
1,4-dioxane 16
1,4-dioxane 1.5
25
45
30
88
80
78
82
73
60
35
24
0
<5
14
12
<5
10
<5
TBAB (5)
I2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (2)
DMSO
CH3CN
1,4-dioxane
1.5
1.5
4
a)
Reaction conditions: 4ab-ma (0.5 mmol), TBN (1.0
mmol), 5 mol % Pd(dba)2 and 1,4-dioxane (0.2 M) with
Pd(dba)2 (10) 1,4-dioxane 1.5
Pd(dba)2 (5) 1,4-dioxane 1.5
b)
9[c]
stirring under air for 1-4 h at 80 °C.
Yields in the
parentheses refer to the 6-endo-dig product. c) Trace refers
to 2-5% of the 6-endo-dig product, which was not isolated.
d) Reaction was stopped at N-nitrosoyl intermediate.
a)
Reaction conditions: 4aa (0.5 mmol), TBN (1.0 mmol),
catalyst and solvent (0.2 M) unless otherwise noted.
Yields of the isolated product. The amount of TBN was
b)
c)
changed to 1.2 equiv.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
palladium complex. The reaction underwent smooth indazole 2-oxide 5na. Interestingly, the reaction
derivatives, under the standard conversion with a proceeded smoothly with N-phenyl substituent 4oa to
thiophenyl derivative to get compound 5aj in 98% afford the desired 5-exo-product in 48% yield albiet in
yield. The structure of compound 5aj was confirmed moderate selectivity along with the formation of 33%
by X-ray analysis.[11] However, with alkyl derivatives, of 6-endo-product.
such as cyclopropyl and butyl conditions gave
This methodology was applied to the synthesis of
considerable amounts of the endo products along with indazole-3-carbaldehyde derivatives (Scheme 2).
desired products 5ak-al, albeit in low yields. These Indole-3-carbaldehyde, an alkaloid isolated from a
results suggest that an electron-donating R group species of Vibrio marine bacteria in the red sea,
increases the ratio of the endo product. Interestingly, possesses antibacterial activity against Gram-positive
the reaction proceeded smoothly with a trimethylsilyl bacteria and is also cytotoxic to mice lymphocytic
derivative to produce compound 5am in 62% yield.
leukemia and Jurkat-T-cell leukemia cells.[1a] The
Next, the scope and limitations of this reaction representative indazole-3-carbaldehye derivatives
were tested on the R1 and R2 groups of the o- 8am and 8km were produced from terminal alkynes
alkynylanilines 4ba-oa, as shown in Table 2. The under the standard conditions of Table 2, as shown in
reaction underwent smoothly when the R1 group was Scheme 2a. Furthermore, the formal synthetic
substituted with p-Me, p-F, p-Cl and p-Br to afford precursor of YC-1 was achieved through the
the corresponding derivatives 5ba-ea in 60-69% reduction of compound 8am in the presence of
yields. However, electron-withdrawing groups at the Fe/NH4Cl to get compound 9am in 85% yield
R1 position gave moderate regioselectivities due to (Scheme 2b).[12a] YC-1 is an important pharmaceutical
the formation the 6-endo-dig products 6ca-da in 20- active compound that inhibits platelet aggregation,
25% yields. Then, the scope of the R2 group was smooth muscle proliferation[12b] and hepatocellular
investigated with benzyl derivatives with different carcinoma cell proliferation.[12c] With this successful
electronic and steric properties, such as o-MeO-Bn, o- outcome, we next explored the formal synthesis of
Br-Bn, p-Me-Bn, p-tert-butyl-Bn, p-MeO-Bn, p-F-Bn, lonidamine, an anticancer and antifertility drug.[12d]
2,4-di-Cl-Bn and 2-(bromomethyl)naphthalene. The The key steps involved were the reductions of the N-
reaction worked well irrespective of the o/m/p oxide (8lm) and the aldehyde functional groups (9lm)
positions or the electron-donating/withdrawing (Scheme 2c). Then, compound 10lm was converted to
properties to get the desired compounds 5fa-ma in lonidamine by the reported Jones oxidation.[12f]
55-91% yields. The structure of compound 5ga was Similarly, the male contraceptive experimental drug
13a]
confirmed by X-ray analysis.[11] However, a 2,4- adjudin[12e,
was prepared in two steps from
dichloro benzyl derivative exhibited an average lonidamine via esterification[13b] and a nucleophilic
regioselectivity, producing 24% of the endo-dig displacement reaction with hydrazine hydrate.[13c-d]
product 6la. Changing the R2 functionality from Additionally, AF2785[13e] was prepared from a basic
benzyl derivative to methyl substitutent under condensation reaction with malonic acid and aldehyde
standard conditions gave the corresponding nitroso 9lm.[13f]
intermediate 4na, rather than the desired N-methyl
Scheme 2 Synthesis of indazole-3-carbaldehyde derivatives; formal syntheses of YC-1, lonidamine, AF-2785 and Adjudin
(AF 2364).
To understand the preliminary reaction mechanism, min (Scheme 3, eq 1). Then, the N-nitroso
a few control experiments were carried out, as shown intermediate was reacted under the standard
in Scheme 3. The key N-nitroso intermediate 4aa’ conditions in the presence of TEMPO. The desired
was prepared by reacting compound 4aa with TBN compound 5aa was obtained in 75% yield along with
(1.2 equiv) in 1,4-dioxane at room temperature for 10 10% of the endo product (Scheme 3, eq 2). This ruled
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
out the possibility of a radical intermediate after the D could be generated by the regioselective 5-exo-dig
N-nitroso formation reaction. Then, the N-nitroso cyclization of N-nitroso intermediate C. Reductive
intermediate was treated with TBN (2.0 equiv) elimination of D could result in the vinyl ether
without Pd(dba)2, and the reaction showed poor exo intermediate E with the expulsion of the Pd(0)
vs endo regioselectivity (Scheme 4, eq 3). catalyst. Then, Pd(0) could oxidize to Pd(II) in the
Furthermore, the reaction did not proceed to presence of NO2 and 1/2O2 for the next catalytic
completion using Pd(dba)2 as a catalyst in the absence cycle.[14] Finally, intermediate E could undergo
of TBN (Scheme 3, eq 4). Finally, when 4aa’ was hydrolysis to afford the carbonyl intermediate F,[15]
treated with 5 mol % Pd(dba)2 and 20 mol% TBN in and the base-mediated elimination of the proton from
1,4-dioxane at 80 °C for 3 h, the desired compound F could afford compound 5.[16]
was obtained in 83% yield along with trace 6aa
(Scheme 3, eq 5). These results suggest that TBN
plays a key catalytic role along with Pd(dba)2 in the
reaction.
Scheme 4 Plausible mechanism for the synthesis of
indazole 2-oxides.
In summary, we developed a novel Pd(dba)2/TBN-
catalyzed approach for the synthesis of 1-benzyl-
indazole 2-oxides that involved the formation of three
new N-NO, C-N and C-O bonds. The key features
were the dual role of TBN as a NO source/redox co-
catalyst, which was shown for the first time, the broad
functional group tolerance and the mild reaction
conditions.
The
synthetic
application
was
demonstrated for the synthesis of indazole-3-
carbaldehyde alkaloid derivatives and the formal
syntheses of pharmaceutically active YC-1, an
anticancer agent (lonidamine), and the male
contraceptive experimental drugs AF2785 and
Scheme 3 Control studies.
A plausible mechanism is proposed based on the adjudin (AF-2364).
preliminary control studies and previous literature
reports, as shown in Scheme 4.[8,14,15] Initially, TBN
could decompose into a tert-butoxy radical and an NO
Experimental Section
radical.[8b] o-Alkynylaniline radical A could be
generated by the abstraction of a hydrogen atom by
the tert-butoxy radical.[8b] Then, intermediate A could
react with the NO radical to form intermediate B.
General procedure for the synthesis of compound 5. To
a stirred solution of compound 4 (0.5 mmol) in 1,4-dioxane
(0.2 M), tert-butyl nitrite (1.0 mmol) was added, followed
by the addition of Pd(dba)2 (5 mol %). The resulting
From the control studies (eq 4 & 5), TBN is necessary solution was stirred under air at 80 °C. Upon completion of
the reaction (~1.5-4 h), the reaction mixture was diluted
for the catalytic conversion. Based on these above
with ice water and extracted with ethyl acetate (3x20 mL).
results, we presume that Pd(dba)2 will oxidize to
The combined organics were washed with brine (1x20 mL),
Pd(dba)2(t-BuO)2 with tert-butanol (t-BuOH) in the
presence of the nitrite generated in situ from TBN,[14]
which eventually serves as the active catalyst
responsible for the product formation. The
coordination of the Pd(II) catalyst to intermediate B
could increase the regioselectivity and electrophilicity
of the alkyne intermediate C. The cyclic intermediate
dried over Na2SO4 and concentrated in vacuo. The crude
material was purified by column chromatography using 6-
10% EA/hexane for compound 5 and 10-15% EA/hexane
for compound 6.
Acknowledgements
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and acknowledge the
Centre for Research and Development of Kaohsiung Medical
University for the 400 MHz NMR, LC-MS and GC-MS analyzes.
synthesis of pyrazole N-oxides using stoichiometric
amount of AgNO2, See: B. Yuan, F. Zhang, Z. Li, S.
Yang, R. Yan, Org. Lett. 2016, 18, 5928−5931.
[9] For selected reactions of TBN, see: a) Z. Shu, Y. Ye, Y.
Deng, Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 2013,
52, 10573–10576; b) S. Manna, S. Jana, T. Saboo, A.
Maji, D. Maiti, Chem. Commun. 2013, 49, 5286-5288;
c) S. Maity, T. Naveen, U. Sharma, D. Maiti, Org. Lett.
2013, 15, 3384-3387; d) T. Shen, Y. Yuan, N. Jiao,
Chem. Commun. 2014, 50, 554-556; e) U. Dutta, S.
Maity, R. Kancherla, D. Maiti, Org. Lett. 2014, 16,
6302−6305; f) U. Dutta, D. W. Lupton, D. Maiti, Org.
Lett. 2016, 18, 860-863; g) X.-F. Wu, J. Schranck, H.
Neumann, M. Beller, Chem. Commun. 2011, 47,
12462–12463.
References
[1] For selected reviews, see: a) L. M. Blair, J. Sperry, J.
Nat. Prod. 2013, 76, 794−812; b) N. Siddiqui, A. S.
Bawa, R. Ali, O. Afzal, M. J. Akhtar, B. Azad, R.
Kumar, J. Pharm. Bioall. Sci. 2011, 3, 194-212; c) M.
Baumann, I. R. Baxendale, Beilstein J. Org. Chem.
2013, 9, 2265–2319.
[2] For selected reviews, see: a) F. Fache, E. Schulz, M. L.
Tommasino, M. Lemaire, Chem. Rev. 2000, 100, 2159-
223; b) K. M. Engle, J.-Q. Yu, J. Org. Chem. 2013, 78,
8927−8955; c) M. N. Hopkinson, C. Richter, M.
Schedler, F. Glorius, Nature, 2014, 510, 485-496.
[10] For synthesis of acyl arenes see: X.-F. Wu, Chem. Eur.
J. 2015, 21, 12252–12265.
[11] CCDC numbers for the compounds 5aa (1537749),
5aj (1537750), 5ga (1537751) and 6aa (1537752).
[3] a) D. Chen, S.-J. Su, Y. Cao, J. Mater. Chem. C. 2014,
2, 9565–9578; b) J. D. Phillipson, Xenobiotica, 1971, 1,
419-447; c) A. M. Mfuh, O. V. Larionov, Curr. Med.
Chem. 2015, 22, 2819–2857; d) Y. Kondo, Top.
Heterocycl. Chem. 2014, 37, 155-178 and references
cited therein.
[12] a) Compound 9am can be converted to YC-1 via the
formal synthesis, see: A. Palmieri, S. Gabrielli, R.
Ballini, Chem. Commun. 2010, 46, 6165–6167; b) D. A.
Tulis, K. S. Bohl Masters, E. A. Lipke, R. L. Schiesser,
A. J. Evans, K. J. Peyton, W. Durante, J. L. West, A. I.
Schafer, Biochem. Biophys. Res. Commun. 2002, 291,
1014 –1021; c) S.-W. Wang, S.-L. Pan, J.-H. Guh, H.-L.
Chen, D.-M. Huang, Y.-L. Chang, S.-C. Kuo, F.-Y. Lee,
C.-M. Teng, J. Pharmacol. Exp. Ther. 2005, 312, 917-
925; d) H. Pelicano, D. S. Martin, R.-H. Xu, P. Huang,
Oncogene, 2006, 25, 4633–4646 and references cited
therein; e) J. S. Tash, B. Attardi, S. A. Hild, R.
Chakrasali, S. R. Jakkaraj, G. I. Georg, Biol. Reprod.
2008, 78, 1127–1138; f) M. Tang, Y. Kong, B. Chu, D.
Feng, Adv. Synth. Catal. 2016, 358, 926 – 939.
[4] a) S. Youssif, ARKIVOC, 2001, i, 242-268; b) A. Albini,
S. Pietra, Heterocyclic N-Oxides; CRC Press: Boca
Raton, FL, 1991; c) X. Cai, M. Sha, C. Guo, R. M. Pan,
Asian J. Chem. 2012, 24, 3781-3784.
[5] Syntheses of N-oxides from oximes see: a) M. Gulla, L.
Bierer, L. Redcliffe, S. Schmidt, V. Jäger, ARKIVOC
2006, vii, 76-88; b) Z. Huo, H. Tomeba, Y. Yamamoto,
Tetrahedron Lett. 2008, 49, 5531–5533; c) Q. Ding, J.
Wu, Adv. Synth. Catal. 2008, 350, 1850–1854; d) H.-S.
Yeom, S. Kim, S. Shin, Synlett, 2008, 6, 924–928; e)
H.-S. Yeom, Y. Lee, J.-E. Lee, S. Shin, Org. Biomol.
Chem. 2009, 7, 4744–4752; f) I. Nakamura, D. Zhang,
M. Terada, J. Am. Chem. Soc. 2010, 132, 7884–7886.
[13] a) C. Y. Cheng, B. Silvestrini, J. Grima, M.-Y. Mo, L.-
J. Zhu, E. Johansson, L. Saso, M.-G. Leone, M.
Palmery, Mruk, D. Biol. Reprod. 2001, 65, 449–461; b)
US 20070015771A1, 2007; c) V. S. Arava, Gogireddy.
P. K. Dubey, Der. Pharma Chemica, 2012, 4, 1371-
1374; d) US6001865A, 1999; e) X. D. Gong, P. Y.
Wong, D. J. Membrane Biol. 2000, 178, 225–233; f) A.
Veerareddy, G. Surendrareddy, P. K. Dubey, Synth.
Commun. 2013, 43, 2236–2241.
[6] Oxidative cyclization of oximes, see: a) A. J. Maroulis,
K. C. Domzaridou, C. P. Hadjiantoniou-Maroulis,
Synthesis, 1998, 12, 1769-1772; b) R. Aggarwal, G.
Sumran, A. Saini, S. P. Singh, Tetrahedron Lett. 2006,
47, 4969-4971; c) K. Wang, X. Fu, J. Liu, Y. Liang, D.
Dong, Org. Lett. 2009, 11, 1015–1018; d) M. J. Raihan,
V. Kavala, P. Mujjamil Habib, Q.-Z. Guan, C.-W. Kuo,
C.-F. Yao, Org. Chem. 2011, 76, 424–434; e) M. G.
Kociolek, O. Hoermann, Synth. Commun. 2012, 42,
2632-2638; f) R. Aggarwal, C. Rani, G. Sumran, Synth.
Commun, 2013, 44, 923-928.
[14] a) K. J. Stowers, A. Kubota, M. S. Sanford, Chem. Sci.
2012, 3, 3192–3195; b) C. Song, H. Yi, B. Dou, Y. Li,
A. K. Singh, A. Lei, Chem. Commun. 2017, 53, 3689-
3692; c) X.-M. Chen, X.-S. Ning, Y.-B. Kang, Org. Lett.
2016, 18, 5368−5371.
[7] a) Z. Shi, D. C. Koester, M. Boultadakis-Arapinis, F.
Glorius, J. Am. Chem. Soc. 2013, 135, 12204−12207; b)
R. S. Phatake, P. Patel, C. V. Ramana, Org. Lett. 2016,
18, 292−295; c) Q. Wang, F. Wang, X. Yang, X. Zhou,
X. Li, Org. Lett. 2016, 18, 6144−6147.
[15] T. H. Fife, J. Am. Chem. Soc. 1965, 87, 1084–1089.
[16] See Supporting Information for the endo-dig product
mechanism.
[8] a) Y. Kobayashi, M. Kuroda, N. Toba, M. Okada, R.
Tanaka, T. Kimachi, Org. Lett, 2011, 13, 6280-6283; b)
F. Chen, X. Huang, X. Li, T. Shen, M. Zou, N. Jiao,
Angew. Chem. Int. Ed. 2014, 53, 10495 –10499; c)
While preparing our manuscript Yan et al reported the
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700456
Advanced Synthesis & Catalysis
COMMUNICATION
Pd(dba)2/tBuONO-Catalyzed Cyclization of o-
Alkynylanilines with tBuONO: Synthesis and
Applications of Indazole 2-oxides
Adv. Synth. Catal. Year, Volume, Page – Page
Gopal Chandru Senadi, Ji-Qi Wang, Babasaheb
Sopan Gore, and Jeh-Jeng Wang*
6
This article is protected by copyright. All rights reserved.