Reaction of (Z)-1-aryl-3-hexen-1,5-diynes with sodium azide: Synthesis of 1-aryl-1H-benzotriazoles

Article abstract of DOI:10.1021/ol047563q

(Chemical Equation Presented) A novel tandem cascade reaction involving 1,3-dipolar cycloaddition reaction, anionic cyclization, and sigmatropic rearrangement for the synthesis of 1-aryl-1H-benzotriazoles 2 and 3 was accomplished by treatment of the (Z)-1

Full text of DOI:10.1021/ol047563q

ORGANIC
LETTERS
2005
Vol. 7, No. 3
475-477
Reaction of (Z)-1-Aryl-3-hexen-1,5-diynes
with Sodium Azide: Synthesis of
1-Aryl-1H-benzotriazoles
Zhong-Yi Chen and Ming-Jung Wu*
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical UniVersity,
Kaohsiung, Taiwan
mijuwu@kmu.edu.tw
Received November 28, 2004
ABSTRACT
A novel tandem cascade reaction involving 1,3-dipolar cycloaddition reaction, anionic cyclization, and sigmatropic rearrangement for the
synthesis of 1-aryl-1H-benzotriazoles 2 and 3 was accomplished by treatment of the (Z)-1-aryl-3-henen-1,5-diynes (1) with sodium azide in DMF
or DMSO at 80 °C for 12 h and gives 65−91% yields.
The 1H-benzotriazoles are an important class of compounds
because of their wide use in synthetic organic chemistry and
pharmaceutical science. They are useful synthons for the
Graebe-Ullmman reaction1 in some versions of the synthesis
of Ellipticine2 and pyridoacridine1g for preparations of
tetraazapentalenes3 and 1,1′-carbonylbisbenzotriazoles.4 1H-
Benzotriazoles are also found to exhibit a broad spectrum
of pharmacological activities such as antiinflammatory,
antifungal, antitumor, antineoplastic, and antidepressant
activities.5
They also serve as synthetic auxiliaries in insertion,
amidoalkylation, and imidoylation that have been applied
in many heterocyclic compound syntheses.6 Furthermore, 1H-
benzotriazole moieties are emerging as powerful RNA and
DNA labels in SERRS detectors.
1,3-Dipolar cycloaddition reactions are powerful methods
for the preparation of a variety of cyclic compounds. It is
well-known that the 1,3-dipolar cycloaddition of an azide
with an alkyne leads to the formation of 1,2,3-triazoles.8
Recently, we reported nucleophile-promoted anionic cyclo-
aromatization reactions of enediynes that would allow us to
prepare a variety of aromaric compounds such as phenan-
thridinones, biphenyls, dibenzofurans, and carbazoles.9 In
(1) (a) Graebe, C.; Ullmann, F. Justus Liebigs. Ann. Chem. 1896, 291,
16-17. (b) Burgess, E. M.; Carither, R.; McCullagh, L. J. Am. Chem. Soc.
1968, 90, 1923-1924. (c) Menta, L. K.; Parrick, J.; Payne, F. J. Chem.
Soc., Perkin Trans. 1 1993, 1261-1267. (d) Hagan, D. J.; Gimenez-Arnau,
E.; Schwalbe, C. H.; Stevens, M. F. J. Chem. Soc., Perkin Trans. 1 1997,
2739-2746. (e) Irina, P. B.; Dmitri, V. D.; Marcial, M. Tetrahedron Lett.
1998, 39, 5617-5620.
(2) Miller, R. B.; Stowell, J. G. J. Org. Chem. 1983, 48, 886-888.
(3) (a) Subramanian, G.; Stevens, E. D.; Boyer, J. H.; Buzatu, D.; Trudell,
M. L. J. Org. Chem. 1995, 60, 6110-6113. (b) Subramanian, G.; Stevens,
E. D.; Boyer, J. H.; Eck, G.; Trudell, M. L. J. Org. Chem. 1996, 61, 5801-
5803.
(4) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org. Chem. 1997,
62, 4155-4158.
(5) (a) Al-Soud, Y. A.; Al-Masoudi, N. A.; Ferwanah, A. S. Bioorg.
Med. Chem. 2003, 11, 1701-1708. (b) Katarzyna, K.; Najda, A.; Justyna,
Z.; Chomicz, L.; Piekarczyk, J.; Myjak, P.; Bretner, M. Bioorg. Med. Chem.
2004, 12, 2617-2624.
(6) (a) Katritzky, A. R.; Rogovoy, B. V. Chem. Eur. J. 2003, 9, 4586-
4593. (b) Katritzky, A. R.; Xie, L.; Serdyuk, L. J. Org. Chem. 1996, 61,
7564-7570. (c) Katritzky, A. R.; Drewniak, M. J. Chem. Soc., Perkin Trans.
1 1988, 2339-2344.
(7) (a) El-Kafrawy, S. A.; Zahran, M. A.; Pedersen, E. B.; Nielsen, C.
HelV. Chim. Acta 2000, 83, 1408-1416. (b) Graham, D.; Brown, R.; Simth,
W. E. Chem. Commun. 2001, 1002-1003.
(8) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909.
(9) (a) Lee, C. Y.; Lin, C. F.; Lee, J. L.; Chiu, C. C.; Lu, W. D.; Wu, M.
J. J. Org. Chem. 2004, 69, 2106-2110. (b) Wu, M. J.; Lin, C. F.; Lu, W.
D. J. Org. Chem. 2002, 67, 5907-5912. (c) Wu, M. J.; Lee, C. Y.; Lin, C.
F. Angew. Chem., Int. Ed. 2002, 41, 4077-4079. (d) Wu, M. J.; Lin, C. F.;
Chen, S. H. Org. Lett. 1999, 1, 767-768.
10.1021/ol047563q CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/12/2005

continuation of our interest in the chemistry of enediynes,
we now report a novel one-pot reaction of (Z)-1-aryl-3-
hexen-1,5-diynes (1) with sodium azide to give 4-butyl-1-
aryl-1H-benzotriazoles (2) and 7-butyl-1-aryl-1H-benzotri-
azoles (3).
Figure 1. ORTEP Plots for X-ray Crystal Structures of 2a.
The preparation of the precursors, (Z)-1-aryl-3-hexen-1,5-
diynes 1a-h, is outlined in Scheme 1. The Sonogashira
solvents were also examined, and the results are summarized
in Table 1. Replacing the solvent from DMF to DMSO
afforded 2a in 19% yield and 3a in 72% yield. Using HMPA
as the solvent afforded 2a in 25% yield and 3a in 70% yield.
No product was obtained using CH3CN, THF, CH2Cl2 and
toluene as the solvent in this reaction.
Scheme 1. Synthesis of the Precursors
(Z)-1-Aryl-3-hexen-1,5-diynes 1a-h from
cis-1,2-Dichloroethene
Table 1. Solvent Effects on the Synthesis of
1-Aryl-1H-benzotriazole
isolated yields [%]
entry
solvent
time [h]
2a
3a
1
2
3
4
5
6
7
8
DMF
12
24
32
144
52
52
54
19
25
19
20
72
70
62
DMSO
HMPA
NMP
THF
no reaction
no reaction
no reaction
no reaction
CH3CN
CH2Cl2
toluene
46
56
cross-coupling reaction of cis-1,2-dichloroethene (4) with
trimethylsilylacetylene (5) using palladium as a catalyst gave
enyne 6 in 68% yield. Palladium-catalyzed coupling reaction
of 6 with 1-hexyne provided enediyne 7 in 62% yield.
Desilylation of 7 with potassium carbonate in methanol gave
8 in 86% yield. Finally, reaction of aryl iodides with 8 using
palladium as a catalyst gave (Z)-1-aryl-3-hexen-1,5-diynes
1a-h in 52-84% yields, respectively.
Our first attempt of the new type of cyclization reaction
was carried out by treatment of (Z)-1-aryl-3-hexen-1,5-diynes
1a with sodium azide in DMF at 25 °C for 48 h. No reaction
took place. However, when the reaction was heated to 80
°C and stirred for 12 h, 4-butyl-1-(4-trifluoromethylphenyl)-
1H-benzotriazole (2a) was obtained in 54% yield along with
20% yield of 7-butyl-1-(4-trifluoromethylphenyl)-1H-benzo-
triazole (3a). The structure of 2a was unambiguously
determined by single-crystal X-ray analysis (Figure 1). Other
Various (Z)-1-aryl-3-hexen-1,5-diynes 1b-e bearing elec-
tron-withdrawing or -donating groups have also been carried
out for the reaction with sodium azide, and the results are
summarized in Table 2. The results indicated that the
substituent effect has no influence on this reaction. However,
the solvent plays an important role in this cyclization
reaction. When DMF was employed in this reaction,
compounds 2b-e were obtained as the major products, and
using DMSO as the solvent, compounds 3b-e became the
major products. However, when (Z)-1-aryl-3-hexen-1,5-
diynes 1f-h bearing a substituent at the ortho position on
the aryl group were used, compounds 2f-h were obtained
as the major products either in DMF or in DMSO. (Table 3)
A plausible mechanism for the formation of compounds
2 and 3 is proposed as shown in Scheme 2. The [3 + 2]
476
Org. Lett., Vol. 7, No. 3, 2005

Scheme 2. Proposed Mechanism for the Formation of
1-Aryl-1H-benzotriazoles.
Table 2. Direct Synthesis of 1-Aryl-1H-benzotriazoles by the
Reaction of 1-Aryl-3-(Z)-hexen-1,5-diynes with Sodium Azide
entry
Ar
solvent time [h] product, yield [%]
1
2
3
4
5
6
7
8
1b, p-NO2C6H4 DMF
1c, p-MeOC6H4 DMF
12
72
72
14
24
64
52
16
2b, 70
2c, 54
2d, 56
2e, 65
2b, 19
2c, 22
2d, 19
2e, 16
3b, 19
3c, 18
3d, 20
3e, 19
3b, 61
3c, 43
3d, 56
3e, 67
1d, C6H4
1e, pyridinyl
DMF
DMF
1b, p-NO2C6H4 DMSO
1c, p-MeOC6H4 DMSO
1d, C6H4
1e, pyridinyl
DMSO
DMSO
cycloaddition between (Z)-1-aryl-3-hexen-1,5-diyne 1 and
sodium azide would produce the triazole 9. An anionic
cascade cyclization of 9 would lead to the formation of the
corresponding 3a-arylbenzo[d][1,2,3]triazole 10. The inter-
mediate 10 could undergo a 1,5-aryl-shift to give 11 or
undergo another 1,5-shift followed by protonation during the
workup to produce the 1-aryl-7-butyl-1H-benzotriazole 3. On
the other hand, intermediate 11 would undergo a 1,5-aryl-
shift, and then protonation to give the 1-aryl-4-butyl-1H-
benzotriazole 2.
with intermediate 11. Since intermediate 11 is considered
to be a more stable intermediate, the equilibration would lead
to the more stable intermediate 11. After the 1,5-aryl shift,
the thermodynamic product 2 would form as the major
product.
In conclusion, we have developed an efficient as well as
novel example of the construction of 1-ary-1H-benzotriazoles
from enediynes. This reaction not only produces the products
in high yield but also involves a tandem anionic cascade
cyclization reaction and sigmatropic rearrangement in the
benzotriazole systems. We believe that this finding would
have a great impact to the chemistry of enediynes. Further
study of the reaction mechanism and the application of this
methodology to the synthesis of biological active 1-aryl-1H-
benzotriazoles are currently under investigation.
We believe that upon using a polar solvent such as DMSO,
intermediate 10 would undergo a fast 1,5-aryl-shift to form
the kinetic product 3. However, under a less polar solvent
such as DMF, intermediate 10 could form an equilibration
Table 3. Substituent Effect on the Synthesis of
4-Butyl-1-aryl-1H-benzotriazoles
Acknowledgment. We would like to thank the National
Science Council of the Republic of China for financial
support of this work.
entry
Ar
solvent time [h] product, yield [%]
1
2
3
4
5
6
1f, o-CF3C6H4
1g, o-NO2C6H4
1h, o-MeOC6H4 DMF
1f, o-CF3C6H4
1g, o-NO2C6H4
1h, o-MeOC6H4 DMSO
DMF
DMF
48
44
72
42
44
66
2f, 85
2g, 82
2h, 76
2f, 68
2g, 68
2h, 65
Supporting Information Available: Full experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
DMSO
DMSO
OL047563Q
Org. Lett., Vol. 7, No. 3, 2005
477