Direct access to acylated azobenzenes via Pd-catalyzed C-H functionalization and further transformation into an indazole backbone

Article abstract of DOI:10.1021/ol303434n

Azobenzenes were readily acylated at the 2-position through a Pd-catalyzed C-H functionalization from simple aromatic azo compounds and aldehydes in good yields. The obtained acylated azobenzenes could be efficiently converted into the corresponding indaz

Full text of DOI:10.1021/ol303434n

ORGANIC
LETTERS
2013
Vol. 15, No. 3
620–623
Direct Access to Acylated Azobenzenes
via Pd-Catalyzed CꢀH Functionalization
and Further Transformation into an
Indazole Backbone
Hongji Li,† Pinhua Li,† and Lei Wang*,‡
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
P.R. China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
leiwang@chnu.edu.cn
Received December 16, 2012
ABSTRACT
Azobenzenes were readily acylated at the 2-position through a Pd-catalyzed CꢀH functionalization from simple aromatic azo compounds and
aldehydes in good yields. The obtained acylated azobenzenes could be efficiently converted into the corresponding indazole derivatives in nearly
quantitative yields.
In the past decades, the emergence of transition-metal-
catalyzed CꢀH activation dramatically shortened the
pathway to the construction of CꢀC and Cꢀheteroatom
bonds, which led to much more efficient protocols for
the desired substances.1 A salient feature of the CꢀH
activation strategy is not requiring stoichiometric organo-
metallic reagents, and it has been widely used in organic
synthesis.1a,2 Undoubtedly, significant progress has been
achieved in catalytic CꢀH activation and subsequent
functionalization.3 Generally, most of the developed ap-
proaches to regioselective CꢀH activation often involve
using substrates containing heteroatoms as directing
groups and direct oxidation to a specific CꢀH bond within
molecules.4 Hence, the suitable combination of transition
metals and directing groups is key to realizing CꢀH
activation and its further transformation. From recent
elegant work on functional group-directed CꢀH activa-
tion, a variety of directing groups, such as pyridines,
amides, oximes, alcohols, amines, carboxylic acids, esters,
aldehydes, ketones, nitriles, and triazenes, have been
developed for ortho-selective CꢀH activations and func-
tionalizations.5 To our knowledge, the azo group with a
† Huaibei Normal University.
‡ Shanghai Institute of Organic Chemistry.
(1) For selected reviews, see: (a) Dyker, G. Handbook of CꢀH
Transformations: Applications in Organic Synthesis; WileyꢀVCH:
Weinheim, 2005. (b) Goldberg, K. I., Goldman, A. S., Eds. Activation and
Functionalization of CꢀH Bond; ACS Symposium Series 885; American
Chemical Society: Washington, DC, 2004. (c) Giri, R.; Shi, B.-F.; Engle,
K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (d) Yu, J.-Q.;
Shi, Z. J. CꢀH Activation; Springer: Berlin, Germany, 2010.
(2) (a) Naota, T.; Takaya, H.; Murahashi, S. I. Chem. Rev. 1998, 98,
2599. (b) Godula, K.; Sames, D. Science 2006, 312, 67. (c) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (d) Campeau,
L. C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (e) Chen,
X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094. (f) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g)
Mkhalid, I.; Barnard, J.; Marder, T.; Murphy, J.; Hartwig, J. Chem. Rev.
2010, 110, 890.
(3) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Conejero,
S.; Paneque, M.; Poveda, M. L.; Santos, L. L.; Carmona, E. Acc. Chem.
Res. 2010, 43, 572. (d) Daz-Requejo, M. M.; Prez, P. J. Chem. Rev. 2008,
108, 3379. (e) Herreras, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007,
107, 2546. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (h) Leow, D.;
Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
(4) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634. (b) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q.
J. Am. Chem. Soc. 2006, 128, 6790. (c) Zhao, L.; Basl, O.; Li, C.-J. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 4106. (d) Gao, K.; Lee, P. S.; Fujita,
T.; Yoshikai, N. J. Am. Chem. Soc. 2010, 132, 12249. (e) Wang, X.;
Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (f) Xie, P.;
Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012,
134, 9902.
r
10.1021/ol303434n
Published on Web 01/23/2013
2013 American Chemical Society

NꢀN doublebond, asa directing group, israrelystudied in
the CꢀH activation process.6
dehydrogenation of aryl amines, etc.12 However, the
above-mentioned methodologies usually suffer from a
narrow substrate scope and complex byproducts. Espe-
cially, it is worth noting that synthesis of the steric ortho-
substituted azo compounds and their further transforma-
tions are often ignored. To make up for this deficiency, a
transition metal-catalyzed CꢀH functionlization strategy
with one-step transformation and simple operation is
highly desirable.
It is well-known that indazole usually bears a benzo
five-membered heterocycle unit, which has been broadly
studied for its unique biological activity in medicinal
chemistry (Figure 1).13 Pursuing our interests in CꢀH
activation,14 herein we first report a novel approach to
the acylated azobenzenes through Pd-catalyzed acylation
of azobenzenes with aldehydes via azo-directed CꢀH
activation. It is important to note that the obtained
acylated azobenzenes can easily be converted into the
corresponding indazoles via an intramolecular reductive
cyclization process in nearly quantitative yields.
Figure 1. Representative biologically active indazoles as liver
X receptor agonist.13b
Aromatic azo compounds have been extensively inves-
tigated for their photochromic properties, which were
widely used as a light triggered switch in surface-modified
materials,7 polymers,8 molecular machines,9 and protein
probes.10 Additionally, azobenzene also frequently ap-
pears in food additives, industrial dyes, and nonlinear
optical devices.11 To date, many methodologies have been
established for the synthesis of azobenzene and its deriva-
tives, such as the coupling of diazo salts with aromatic
compounds, thereduction ofnitrocompoundsby reducing
agents, the transition-metal-catalyzed aerobic oxidative
Our initial studies focused on the model reaction of
azobenzene (1a) and benzaldehyde (2a). The optimization
of a Pd source and oxidant are summarized in Table 1.
Considering the stability of 1a, freshly distilled 1,2-
dichloroethane (DCE) and dried tert-butyl hydroperoxide
(TBHP) were necessary in the model reaction. We found
that the combination of azobenzene (1a, 1.0 equiv) with
benzaldehyde (2a, 1.1 equiv), TBHP (2.0 equiv), and Pd-
(PPh3)2Cl2 (5.0 mol %) in DCE at 80 °C for 12 h generated
the acylated product 3a in 26% yield (Table 1, entry 1).
However, Pd(PPh3)4 did not work in the model reaction
(Table 1, entry 2). When PdCl2 was used as the catalyst in
the reaction, 3a was obtained in 42% yield (Table 1, entry 3).
Meanwhile, acylation also proceeded in comparable
yield and efficiency in the presence of Pd(CH3CN)2Cl2
(Table 1, entry 4 vs 3). As expected, Pd(OCOCF3)2 gave 3a
in 69% yield (Table 1, entry 5). Gratifyingly, Pd(OAc)2
showed excellent activity among the tested Pd sources
(Table 1, entry 6). Further exploration of some commer-
cially available oxidants in the model reaction indicated
that dried TBHP was superior to the others, as also shown
in Table 1. When TBHP (70% in H2O) was used, 3a was
isolated in 56% yield (Table 1, entry 7). It is likely that the
existing H2O may be responsible for the partial decom-
position of azobenzene, leading to the lower yield of 3a.
Other oxidants, such as R,R-dimethylbenzyl hydroperoxide
(DBHP), di-tert-butyl peroxide (DTBP), dicumyl peroxide
(DCP), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), and
tert-butyl perbenzoate (TBPB), generated the desired
product 3a in 23ꢀ66% yields (Table 1, entries 8ꢀ12). It is
noteworthy to mention that inorganic oxidant (NH4)2S2O8
(5) (a) Boele, M. D. K.; Strijdonck, G. P. F.; Vries, A. H. M.; Kamer,
P. C. J.; Vries, J. G.; Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124,
1586. (b) Wang, D. H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010,
327, 315. (c) Lu, Y.; Wang, D. H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 5916. (d) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 3680. (e) Shi, B.-F.; Zhang, Y. H.; Lam, J. K.; Wang,
D. H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460. (f) Garcia-Rubia, A.;
Fernandez-Ibanez, M. A.; Arrayas, R. G.; Carretero, J. C. Chem.;Eur.
J. 2011, 17, 3567. (g) Patureau, F. W.; Besset, T.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 1064. (h) Dai, H. X.; Stepan, A. F.; Plummer,
M. S.; Zhang, Y. H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (i)
Garca-Rubia, A.; Urones, B.; Arrays, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2011, 50, 10927. (j) Huang, C. H.; Chattopadhyay, B.;
Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406. (k) Padala, K.;
Jeganmohan, M. Org. Lett. 2011, 13, 6144. (l) Mewald, M.; Schiffner,
J. A.; Oestreich, M. Angew. Chem., Int. Ed. 2012, 124, 1797. (m) Mewald,
M.; Schiffner, J. A.; Oestreich, M. Angew. Chem., Int. Ed. 2012, 51, 1763.
(n) Wang, C. M.; Chen, H.; Wang, Z. F.; Chen, J.; Huang, Y. Angew.
Chem., Int. Ed. 2012, 51, 7242.
(6) (a) Fahey, D. R. J. Chem. Soc., Chem. Commun. 1970, 417.
(b) Fahey, D. R. J. Organomet. Chem. 1971, 27, 283. (c) Dick, A. R.;
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.
(7) Ferri, V.; Elbing, M.; Pace, G.; Dickey, M. D.; Zharnikov, M.;
Samori, P.; Mayor, M.; Rampi, M. A. Angew. Chem., Int. Ed. 2008, 47,
3407.
(8) (a) Puntoriero, F.; Ceroni, P.; Balzani, V.; Bergamini, G.; Voegtle,
F. J. Am. Chem. Soc. 2007, 129, 10714. (b) Parker, R. M.; Gates, J. C.;
Rogers, H. L.; Smith, P. G. R.; Grossel, M. C. J. Mater. Chem. 2010, 20,
9118.
(9) (a) Murakami, H.; Kawabuchi, A.; Kotoo, K.; Kunitake, M.;
Nakashima, N. J. Am. Chem. Soc. 1997, 119, 7605. (b) Muraoka, T.;
Kinbara, K.; Aida, T. Nature 2006, 440, 512.
(10) (a) Banghart, M. R.; Mourot, A.; Fortin, D. L.; Yao, J. Z.;
Kramer, R. H.; Trauner, D. Angew. Chem., Int. Ed. 2009, 48, 9097. (b)
Kim, Y.; Phillips, J. A.; Liu, H.; Kang, H.; Tan, W. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 6489.
(11) (a) Chang, C.-W.; Lu, Y.-C.; Wang, T.-T.; Diau, E. W.-G.
J. Am. Chem. Soc. 2004, 126, 10109. (b) Patai, S. The Chemistry of the
Hydrazo, Azo and Azoxy Groups, Vol. 2; Wiley: Chichester, 1997; pp
729ꢀ730.
(13) (a) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem.
2008, 4073. (b) Steffan, R. J.; Matelan, E. M.; Bowen, S. M.; Ullrich,
J. W.; Wrobel, J. E.; Zamaratski, E.; Kruger, L.; Olsen Hedemyr, A. L.;
Cheng, A.; Hansson, T.; Unwalla, R. J.; Miller, C. P.; Rhonnstad, P. P.
U.S. Pat. Appl. Publ. US 2006030612 A1 20060209, 2006; Chem. Abstr.
2006, 144, 212770.
(14) (a) Li, C.; Wang, L.; Li, P.; Zhou, W. Chem.;Eur. J. 2011, 17,
10208. (b) Li, C.; Wang, L.; Li, P.; Yang, J.; Wang, L. Chem. Commun.
2012, 48, 4214. (c) Zhou, W.; Li, H.; Wang, L. Org. Lett. 2011, 14, 4594.
(12) (a) Barbero, M.; Degani, I.; Dughera, S.; Fochi, R.; Perracino, P.
Synthesis 1998, 1235. (b) Wenkert, K.; Wickberg, B. J. Am. Chem. Soc.
1962, 84, 4914. (c) Goldstein, S. L.; McNelis, E. J. Org. Chem. 1973, 38,
183. (d) Krageloh, K.; Anderson, G. H.; Stang, P. J. J. Am. Chem. Soc.
1984, 106, 6015. (e) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49,
6174. (f) Grirrane, A.; Corma, A.; Garca, H. Science 2008, 322, 1661.
Org. Lett., Vol. 15, No. 3, 2013
621

Table 1. Optimization of Pd Source and Oxidanta
Scheme 1. Scope of the Acylation of Azobenzenes with
Aldehydesa
entry
Pd source
oxidant
TBHP
yield (%)b
1
Pd(PPh3)2Cl2
Pd(PPh3)4
PdCl2
26
0
2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DBHP
DTBP
DCP
3
42
46
69
78
56c
66
30
43
23
57
0
4
Pd(CH3CN)2Cl2
Pd(OCOCF3)2
Pd(OAc)2
5
6
7
Pd(OAc)2
8
Pd(OAc)2
9
Pd(OAc)2
10
11
12
13
Pd(OAc)2
Pd(OAc)2
DDQ
Pd(OAc)2
TBPB
(NH4)2S2O8
Pd(OAc)2
a Reaction conditions: azobenzene (1a, 0.20 mmol), benzaldehyde
(2a, 0.22 mmol), Pd source (5.0 mol %), TBHP (0.40 mmol) dried over
4 A MS prior to use, DCE (1.0 mL), 80 °C, sealed tube, N2, 12 h. b Isolated
˚
yields. c TBHP (70% in H2O).
a Reaction conditions: azobenzene (1, 0.20 mmol), aldehyde (2,
˚
0.22 mmol), Pd(OAc)2 (5.0 mol %), TBHP (0.40 mmol, dried over 4 A
MS prior to use), DCE (1.0 mL), 80 °C, sealed tube, N2, 12 h. b Isolated
was ineffective in the reaction (Table 1, entry 13). In
addition, the solvent also played an important role and
the results demonstrated that DCE was the best reaction
medium among the solvents tested in the model reaction
(see Table S1, Supporting Information).
yields. c 18 h.
When azobenzene was treated with furaldehyde (2s) under
the present reaction conditions, 3s was isolated in 66% yield.
Pleasingly, aliphatic aldehydes, for example cyclohexanecar-
baldehyde and n-butyraldehyde, also reacted with azoben-
zene to generate the corresponding products 3t and 3u in 59
and 64% yields. In order to expand the scope of azobenzenes,
three representative 4,40-disubstituted azobenzenes, 4,40-di-
methoxyazobenzene (1b), 4,40-dimethylazobenzene (1c),
and 4,40-dichloroazobenzene (1d) were surveyed. It was
found that the oxidative acylation reactions of 1b, 1c, and
1d with benzaldehyde were clean and gave the corre-
sponding 3v, 3w, and 3x in 81, 83, and 76% yields,
respectively.
Withthe obtained acylatedazobenzenes (3aꢀx) in hand,
their further transformation into important substances is
desirable. Having the unique biological activity of inda-
zoles in mind, we tried to construct the backbone of
indazole using acylated azobenzenes as starting materials.
To our delight, most of them (3aꢀq and 3sꢀx) could
be efficiently transformed into the indazoles (4aꢀq and
4sꢀx) through a Zn/NH4Cl/MeOH reducing system at rt
within 5 min in nearly quantitative yields (results listed
in Scheme 2). It should be noted that although the nitro
group on the benzene ring remarkably influenced the
transformation, excellent yields of 4h and 4p were also
obtained in the mixed solvent MeOH/DCM (3:1) along
with the reduction of NO2 into NH2. However, the more
steric acylated azobenzene 3r could not be transformed
into the corresponding product 4r. Compared to the
Based on the optimized reaction conditions, the scope of
the oxidative acylation of azobenzenes was examined. As
can be seen from Scheme 1, the reactions of azobenzenes
withvariousaldehydescould proceedwelland generatethe
desired acylated products in good yields. A wide range of
aromatic aldehydes bearing substituents on the benzene
rings were investigated. The results demonstrated that
both electron- and electron-withdrawing groups were tol-
erated in the acylation reactions. The para-substituted
benzaldehydes with electron-donating groups, such as
MeO and Me, reacted with azobenzene smoothly and
afforded the corresponding acylated products 3b and 3c
in 71 and 77% yields respectively. Meanwhile, with the
exception of F, electron-withdrawing groups such as Br,
Cl, CN, and NO2 also reacted with azobenzene well and
generated 3d, 3e, 3g, and 3h in 80ꢀ85% yields. When [1,10-
biphenyl]-4-carbaldehyde and 1-naphthaldehyde were used
to couple with azobenzene, 3i and 3j were obtained in 82 and
86% yields respectively. A slight steric effect was observed
when meta- and ortho-substitued benzaldehydes (2l and 2m
vs 2c, 2n vs 2e, and 2o vs 2f) as coupling reagents reacted
with azobenzene, and inferior yields of the products 3kꢀo
were obtained. Similarly, disubstituted benzaldehydes in-
cluding 4-chloro-3-nitrobenzaldehyde (2p), 3,5-dimethoxy-
benzaldehyde (2q), and 2-chloro-6-fluorobenzaldehyde(2r)
also coupled with azobenzene smoothly to afford the acylated
product 3p, 3q, and 3r in 82, 74, and 41% yields, respectively.
622
Org. Lett., Vol. 15, No. 3, 2013

Scheme 2. Synthesis of Indazoles from Acylated Azobenzenesa
Scheme 3. Proposed Reaction Mechanism
the reductive elimination of II, with the release of the
acylated product. In the presence of a radical scavenger,
TEMPO (2,2,6,6-tetramethyl-piperidyl-1-oxyl) up to
1.0 equiv, no acylated product was observed.18
a Reaction conditions: acylated azobenzenes (3, 0.20 mmol), zinc dust
(0.40 mmol), NH4Cl (0.60 mmol), CH3OH (0.50 mL), room tempera-
ture, 5 min. b Isolated yields. c MeOH/DCM (3:1, v/v), 50 °C, 6 h.
In conclusion, we have developed a novel and simple
Pd-catalyzed protocol for the synthesis of acylated azoben-
zenes from aromatic azo compounds and aldehydes via
an azo-directed CꢀH bond activation process and with
TBHP as an oxidant. The obtained acylated azobenzenes
can be efficiently transformed into the corresponding
indazoles through a Zn/NH4Cl/MeOH reduction at rt
within 5 min in nearly quantitative yields in most cases.
Further investigations into the photochromic properties,
scope, and synthetic application of these azobenzene deri-
vatives are now in progress.
well-established method for the synthesis of indazole
derivatives,15 this transformation is more efficient and
economical.
A possible mechanism for the Pd-catalyzed CꢀH func-
tionalization is proposed in Scheme 3. Initially, a five-
membered cyclopalladated intermediate I was generated
through chelate-directed CꢀH activation of azobenzene.
In fact, a similar metalocycle was obtained through the use
of a coordinating group that helps direct the subsequent
transition-metal CꢀH bond insertion.6b,16 In contrast, the
reaction of benzaldehyde with TBHP generated a reactive
benzoyl radical, which next reacted with intermediate I to
realize the oxidation of Pd(II) to dimeric Pd(III) or Pd(IV)
II.17 Finally, the Pd(II) species was regenerated through
Acknowledgment. This work was financially supported
by the National Science Foundation of China (No.
21172092).
Supporting Information Available. Analytical data and
spectra (1H and 13C NMR) for all the products; typical
procedure. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) (a) Wheeler, R. C.; Baxter, E.; Campbell, I. B.; Macdonald,
S. J. F. Org. Process Res. Dev. 2011, 15, 565. (b) Wray, B. C.; Stambuli,
J. P. Org. Lett. 2010, 12, 4576.
(16) Kleinman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(17) (a) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131,
11234. (b) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem.
Soc. 2009, 131, 10974. (c) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.;
Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488. (d) Sibbald, P. A.;
Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 15945.
(18) (a) Warren, J. J.; Mayer, J. M. J. Am. Chem. Soc. 2010, 132,
7784. (b) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737.
The authors declare no competing financial interest.
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