Pd-catalyzed C-H activation/C-N bond formation: A new route to 1-aryl-1H-benzotriazoles

Article abstract of DOI:10.1021/ol200523a

A method for the C-H activation of aryl triazene compounds followed by intramolecular amination is described. It involves the use of a catalytic amount of Pd(OAc)₂ that efficiently effects the cyclization to provide 1-aryl-1H-benzotriazoles at moderate temperature.

Full text of DOI:10.1021/ol200523a

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2102–2105
Pd-Catalyzed C-H Activation/C-N
Bond Formation: A New Route to
1-Aryl-1H-benzotriazoles
Rapolu Kiran Kumar, Md Ashif Ali, and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039,
India
tpunni@iitg.ernet.in
Received February 25, 2011
ABSTRACT
A method for the C-H activation of aryl triazene compounds followed by intramolecular amination is described. It involves the use of a catalytic
amount of Pd(OAc)2 that efficiently effects the cyclization to provide 1-aryl-1H-benzotriazoles at moderate temperature.
Recent advances in cross-coupling reactions using tran-
sition metal catalysis provide effective methods for C-N
bond formation.1 Among them, C-H activation and
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Figure 1. Examples of some biologically active 1-aryl-1H-
benzotriazoles.
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functionalization afford a simple and powerful tool for
an atom economical process. Notable progress has been
made using predominantly Ru,2 Rh,3 Pd,4 Ag,5 and Cu6
based systems. Herein, we report a new approach to the
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r
10.1021/ol200523a
Published on Web 03/10/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditions
entry
Pd source
base
solvent
DMSO
yield (%)a,b
1
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
KOH
36
2
DMSO
DMSO
DMF
30
3
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
15
4
65(80c)
23d
n.d.
n.d.
3
Figure 2. ORTEP diagram of 5,6-dimethyl-1-(3,4-
dimethylphenyl)-1H-benzo[d][1,2,3]triazole 2m. H-Atoms are
omitted for clarity.14
5
DMF
6
xylene
chlorobenzene
1,4-dioxane
DMF
7
8
9
12
10
11
12
13
14
15
16
DMF
72
DMF
5
Scheme 1. Proposed Catalytic Cycle
K3PO4
DMF
25
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
DMF
n.d.
55e
32f
n.d.
DMF
DMF
DMF
a (Phenylimino)-2-phenylhydrazine 1a (1 mmol), Pd source (10 mol
%), and base (2 mmol) were stirred at 110 °C in solvent (1 mL) under an
c
oxygen balloon. b Isolated yield. With MS 4 A (100 mg). d Pd(OAc)2
˚
(5 mol %) used. e 1.5 equiv of Cs2CO3 was used f Reaction temperature =
100 °C. n.d. = not detected.
synthesis of substituted 1-aryl-1H-benzotriazoles7 via Pd-
catalyzed intramolecular C-H amination of triazene moi-
eties. This method features the use of Pd(OAc)2 that
successfully effects C-H activation followed by C-N
cross-coupling to afford the cyclized products at moderate
temperatures.
1H-Benzotriazoles are among the most important
classes of heterocycles in biological and medicinal sciences.
For example, 1H-benzotriazoles are structural motifs of
many compounds that possess antibacterial, anticancer,
antidepressant, antifungal, and antimalarial activities
(Figure 1).8 They are also useful synthons in some versions
of the Graebe-Ullmann reaction,9 especially in the synth-
esis of pyridoacridine,10 carboline,11 and tetraazapental-
enes.12 1H-Benzotriazoles also serve as synthetic auxili-
aries in amidoalkylation, insertion, and imidoylation that
have been used for the synthesis of heterocyclic
compounds.10,11a,13 Development of newer methods for
the construction of the functionalized 1H-benzotriazoles is
thus important in synthetic organic chemistry.
First, the reaction conditions were optimized using
(phenylimino)-2-phenylhydrazine 1a as a model substrate
with different Pd sources, solvents, and bases at varied
temperature (Table 1). The reaction occurred to afford the
desired 1-aryl-1H-benzotrizole 2a in 36% yield when the
substratewas stirred with10mol % Pd(OAc)2 in DMSO at
(7) For some recent studies for 1-aryl-1H-benzotriazole synthesis,
see: (a) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409. (b) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587. (c) Chen, Z.-
Y.; Wu, M.-J. Org. Lett. 2005, 7, 475.
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V. J.; Jain, S.; Arora, S. K.; Sinha, N. Bioorg. Med. Chem. Lett. 2005, 15,
3002. (b) Mishra, N.; Arora, P.; Kumar, B.; Mishra, L. C.; Bhattachar-
ya, A.; Awasthi, S. K.; Bhasin, V. K. Eur. J. Med. Chem. 2008, 43, 1530.
(c) Rezaei, Z.; Khabnadideh, S.; Pakshir, K.; Hossaini, Z.; Amiri, F.;
Assadpour, E. Eur. J. Med. Chem. 2009, 44, 3064.
(9) (a) Graebe, C.; Ullmann, F. Justus Liebigs Ann. Chem. 1896, 291,
16. (b) Burgess, E. M.; Carithers, R.; McCullagh, L. J. Am. Chem. Soc.
1968, 90, 1923. (c) Mehta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc.,
Perkin Trans. 1 1993, 1261. (d) Mitchell, G.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1987, 403. (e) Borsche, W.; Feise, M. Chem. Ber. 1907,
40, 378.
(10) Hagan, D. J.; Gimenez-Arnau, E.; Schwalbe, C. H.; Stevens,
M. F. G. J. Chem. Soc., Perkin Trans. 1 1997, 2739.
(11) (a) Miller, R. B.; Stowell, J. G. J. Org. Chem. 1983, 48, 886. (b)
Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski, J. J.
Med. Chem. 1994, 37, 3503. (c) Molina, A.; Vaquero, J. J.; Garcia-
Navio, J. L.; Alvarez-Builla, J. Tetrahedron Lett. 1993, 34, 2673.
(12) (a) Kauer, J. C.; Carboni, R. A. J. Am. Chem. Soc. 1967, 89,
2633. (b) Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Barili, P. L. J.
Heterocycl. Chem. 1995, 32, 1709.
(13) For examples, see: Katritzky, A. R.; Rachwal, S. Chem. Rev.
2010, 110, 1564.
Org. Lett., Vol. 13, No. 8, 2011
2103

Table 2. Cyclization of (Phenylimino)-2-phenylhydrazines with Various Substituents on the Aryl Ringsa
a
˚
Reaction conditions: substrate 1a-s (1 mmol), Pd(OAc)2 (10 mol %), Cs2CO3 (2 mmol), and MS 4 A (100 mg) were stirred in DMF (1 mL) at 110 °C
under an O2 balloon. b Isolated yield. c Single isomer. n.d. = not detected.
110 °C under an oxygen balloon. The catalytic activity of
the Pd sourceswerecompared, and Pd(OAc)2 was found to
be superior to PdCl2 and PdCl2(PPh3)2. Replacing the
solvent from DMSO to DMF gave 2a in 65% yield. The
˚
yield of 2a was further increased to 80% when a 4 A
(14) Recrystallization of 2m in CH2Cl2 gave single crystals whose
X-ray data were collected on a Bruker SMART APEX equipped with a
CCD area detector using Mo KR radiation in the scan range
1.47°-28.02°: C16H17N3, Mw = 251.3304, orthorhombic; Pbca; a =
molecular sieve was added as an additive. In contrast,
solvents such as xylene, chlorobenzene, and 1,4-dioxane
gave inferior results. The reaction was effective with
Cs2CO3, K2CO3, K3PO4, KOH, and Na2CO3, and Cs2CO3
yielded the best results. No product was obtained using
KOtBu as the base. Lowering of the reaction temperature
˚
˚
˚
13.2943(7) A, b = 7.4099(4) A, c = 27.6216(14) A; R = 90°, β = 90°, γ
3
= 90°; V = 2721.0(2) A ; Z = 8; Dcalcd = 1.227 mg m-3; T = 296(2) K;
˚
Scan range 1.47° < θ < 28.02°; crystal dimension 0.44 Â 0.36 Â 0.26
mm3; 3161 reflns, 1810 unique reflections (I > 2σ(I)); R1 = 0.0497; wR2
= 0.1191; GOF (on F2) = 0.995.
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Org. Lett., Vol. 13, No. 8, 2011

underwent cyclization to give the corresponding benzo-
triazoles 2f-n in 55-88% yield. Recrystallization of 2m in
CH2Cl2 gave single crystals whose structure was confirmed
by X-ray analysis (Figure 2). The substrates 1e and 1l with
a Br group provided the debrominated products 2a and 2f
exclusively.4a These results suggest that the cyclization is
controlled by both steric and electronic factors on the aryl
rings.
Table 3. Cyclization of Unsymmetrical (Phenylimino)-2-
phenylhydrazinesa
Finally, to reveal the regioselectivity, the reactions of the
unsymmetrical substrates 1t-u were studied (Table 3).
Both of the substrates underwent cyclization to provide a
2:1 mixture of the regioisomers 2o and 2p in 75% yield. In
both of the substrates, the cyclization occurred preferen-
tially on the nonsubstituted aryl ring. These results suggest
that the isomerization of triazenes can occur easily under
the conditions used in this system.
The proposed catalytic cycle is shown in Scheme 1.4a The
substrates 1a-l may undergo coordination with Pd(II) to
give intermediate a that could lead to the formation of b in
the presence of base. The latter may undergo C-H activa-
tion to give the six-membered palladacycle c that could
afford the target 1-aryl-1H-benzotriazole and Pd(0). The
reduced Pd could be oxidized in the presence of oxygen to
complete the catalytic cycle.
In summary, a novel protocol for the synthesis of 1-aryl-
1H-benzotriazole is developed via C-H activation fol-
lowed by intramolecular amination employing a Pd(II)
catalyst under relatively milder conditions. Further study
to understand the precise mechanism as well as to expand
the range of substrates is currently underway in our
laboratory.
a Reaction conditions: substrate 1t-u (1 mmol), Pd(OAc)2 (10 mol
%), Cs2CO3 (2 mmol), and MS 4 A (100 mg) were stirred in DMF (1 mL)
˚
at 110 °C under an O2 balloon. b Regioisomeric ratio was determined by
400 MHz 1H NMR of the crude reaction mixture. c Isolated yield.
(100 °C) ortheamountofthecatalyst(5 mol %) or the base
(1.5 equiv) gave 2a in <55% yield. Control experiments
confirmed that no product was obtained in the absence of
the palladium source. In summary, the optimal conditions
in DMF include Pd(OAc)2 (10 mol %) and Cs2CO3 (2
equiv) at 110 °C for 25 h under an oxygen balloon.
Next, the scope of the protocol was studied for the
substrates having substituents on the aryl rings (Table 2).
(Phenylimino)-2-phenylhydrazines 1b, 1e-g, and 1i hav-
ing two 3-NO2, 4-Cl, 4-Et, and 4-Me substituents pro-
ceeded in the C-H amination to afford the benzotriazoles
2b and 2c-e in 70-85% yield. In contrast, the substrates
1c-d and 1h with two 4-COMe, 4-CO2Et, and 4-OMe
groups showed no cyclization and the starting materials
were recovered, whereas (phenylimino)-2-phenylhydra-
zines 1j-s having Cl, Me, and Et substituents readily
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, and Council of Scientific and
Industrial Research, New Delhi, for financial support.
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra (1H and
13C) of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
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