Benzyne click chemistry: Synthesis of benzotriazoles from benzynes and azides

Article abstract of DOI:10.1021/ol800675u

(Chemical Equation Presented) A variety of substituted benzotriazoles have been prepared by the [3 + 2] cycloaddition of azides to benzynes. The reaction scope is quite general, affording a rapid and easy entry to substituted, functionalized benzotriazoles under mild conditions.

Full text of DOI:10.1021/ol800675u

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2409-2412
Benzyne Click Chemistry: Synthesis of
Benzotriazoles from Benzynes and
Azides
Feng Shi, Jesse P. Waldo, Yu Chen, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50010
larock@iastate.edu
Received March 24, 2008
ABSTRACT
A variety of substituted benzotriazoles have been prepared by the [3 + 2] cycloaddition of azides to benzynes. The reaction scope is quite
general, affording a rapid and easy entry to substituted, functionalized benzotriazoles under mild conditions.
Recent years have seen rapid development of the Cu-
catalyzed [3 + 2] cycloaddition1 reaction between terminal
alkynes and azides, commonly referred to as “click chem-
istry”.2 Such chemistry has found wide applications not only
in synthetic organic chemistry3 but also in dendrimer and
polymer chemistry,4 the material sciences,5 bioconjugation
chemistry,6 and the pharmaceutical sciences.7
Although there have been several reports on the annulation
of arynes by azides,8 efforts to modernize this reaction are
certainly necessary. Early examples utilizing potentially
explosive diazotized anthranilic acid as the benzyne
precursor8a–c suffer from the use of a potentially explosive
reagent and dangerous reaction conditions, and more recent
examples utilizing o-(trimethylsilyl)aryliodonium salts8e,f
suffer from the limited availability and difficulties in
preparation of these reagents. Nowadays, arynes are more
readily and conveniently generated in situ by the fluoride-
promoted ortho-elimination of commercially available or
easily prepared o-(trimethylsilyl)aryl triflates.9 Arynes gener-
ated in this way retain their high reactivity toward nucleo-
philic additions and annulations.10
With our recent success in the development of benzyne
annulation chemistry,11 particularly the [3 + 2] cycloaddition
reaction between benzynes and diazo compounds,11a,12 we
envisioned the [3 + 2] annulation of benzynes by azides as
a very promising extension of the current click chemsitry.
Such chemistry should not only expand the scope and utility
(1) Huisgen, R. HelV. Chim. Acta 1967, 50, 2421–2439.
(2) For comprehensive reviews, see: (a) Moses, J. E.; Moorhouse, A. D.
Chem. Soc. ReV. 2007, 36, 1249–1262. (b) Gil, M. V.; Arevalo, M. J.; Lopez,
O. Synthesis 2007, 1589–1620.
(3) (a) Tilliet, M.; Lundgren, S.; Moberg, C.; Levacher, V. AdV. Synth.
Catal. 2007, 349, 2079–2084. (b) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu,
L.-Y.; Zhao, Y.-B.; Liang, Y.-M. Tetrahedron: Asymmetry 2007, 17, 3288–
3293. (c) Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P. J. Org.
Chem. 2006, 71, 9244–9247.
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Angew. Chem., Int. Ed. 2004, 43, 3928–3932. (b) Lee, J. W.; Kim, J. H.;
Kim, B.-K.; Kim, J. H.; Shin, W. S.; Jin, S.-H. Tetrahedron 2006, 62, 9193–
9200.
(5) (a) Nandivada, H.; Jiang, X.; Lahann, J. AdV. Mater. 2007, 19, 2197–
2208. (b) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018–1025.
(6) (a) Rozkiewicz, D. I.; Gierlich, J.; Burley, G. A.; Gutsmiedl, K.;
Carell, T.; Ravoo, B. J.; Reinhoudt, D. N. ChemBioChem 2007, 8, 1997–
2002. (b) Lutz, J.-F.; Boerner, H. G.; Weichenhan, K. Macromolecules 2006,
39, 6376–6383.
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Reynolds, G. A. J. Org. Chem. 1964, 29, 3733–3734. (c) Huisgen, R.; Knorr,
R.; Moebius, L.; Szeimies, G. Chem. Ber. 1965, 98, 4014–4021. (d) Mitchell,
G.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1987, 403–412. (e) Kitamura,
T.; Fukatsu, N.; Fujiwara, Y. J. Org. Chem. 1998, 63, 8579–8581. (f)
Kitamura, T.; Todaka, M.; Shin-machi, I.; Fujiwara, Y. Heterocycl.
Commun. 1998, 4, 205–208.
(7) (a) Sharpless, K. B.; Manetsch, R. Expert Opin. Drug DiscoVery
2006, 1, 525–538. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today
2003, 8, 1128–1137. (c) Whiting, M.; Muldoon, J.; Lin, Y.-C.; Silverman,
S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless,
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10.1021/ol800675u CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

of the present click chemistry but also potentially provide a
rapid entry to substituted, functionalized benzotriazoles,
which are known to possess important biological activity13
and exhibit utility as synthetic auxiliaries.14 Herein, we report
our preliminary results on the [3 + 2] annulation reaction
of benzynes and azides, new benzyne click chemistry.
We started our investigation using commercially available
benzyl azide (1a) and o-(trimethylsilyl)phenyl triflate (2a)
under a variety of different reaction conditions (Table 1).
conditions observed previously by us for the synthesis of
indazoles by the cycloaddition of diazo compounds to
arynes.11a We have thus chosen these conditions as our
general procedure for all subsequent work.15
We next tested different benzyne precursors in this reaction
(Table 2). As can be seen, the reaction shows good
Table 2. Reaction with Different Benzyne Precursorsa
Table 1. Reaction Optimizationa
entry fluoride source solvent T (°C) time (h) yieldb (%)
1
2
3
4
5
TBAF
TBAF
TBAF
CsF
THF
MeCN 0 to rt
DCM
THF
MeCN rt
0 to rt
3
3
5
18
18
37
45
34
37
76
0 to rt
rt
CsF
a All reactions were carried out on a 0.3 mmol scale in 0.1 M
concentration. b Isolated yield.
TBAF and CsF were chosen as fluoride sources, and the
reaction was examined in several dipolar aprotic solvents.
While most reaction conditions gave low yields (entries
1-4), the reaction carried out in acetonitrile using CsF as
the fluoride source afforded a superior yield of 76% (entry
5). These optimized conditions are identical to the optimal
a All reactions were carried out on a 0.3 mmol scale with 1.2 equiv of
benzyne precursor and 2.0 equiv of CsF. b Isolated yield. c The product
was assigned by a 2D-NOESY experiment; see the Supporting Information
for details.
compatibility with a range of different benzyne precursors.
Thus, benzyne precursors 2b and 2c gave comparable yields
of the desired benzotriazole products (entries 1 and 2).
However, the electron-poor benzyne precursor 2d gave only
a 56% yield (entry 3). An unsymmetrical benzyne precursor
2e afforded a single regioisomer in a 78% yield (entry 4),
which is consistent with our previous results.11a
A wide range of azides have also been screened (Table
3). Among them, aryl and heteroaryl azides are generally
good substrates, affording the desired benzotriazole products
in 83-90% yields (entries 1-8). The substrate scope includes
electron-rich (entries 2 and 3), electron-poor (entries 4-7),
sterically hindered (entries 2, 4, and 7), and heterocyclic
(entry 8) aryl azides. All of these substrates gave clean
reactions under mild conditions and tolerated functional
groups, such as ester, ether, cyano, and halogen groups. Alkyl
(10) For recent reports, see: (a) Yoshida, H.; Mimura, Y.; Ohshita, J.;
Kunai, A. Chem. Commun. 2007, 2405–2407. (b) Xie, C.; Zhang, Y. Org.
Lett. 2007, 9, 781–784. (c) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai,
A. J. Am. Chem. Soc. 2006, 128, 11040–11041. (d) Liu, Z.; Larock, R. C.
J. Org. Chem. 2006, 71, 3198–3209. (e) Liu, Z.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112–13113. (f) Yoshida, H.; Watanabe, M.; Ohshita, J.;
Kunai, A. Chem. Commun. 2005, 3292–3294. (g) Tambar, U. K.; Stoltz,
B. M. J. Am. Chem. Soc. 2005, 127, 5340–5341. (h) Yoshida, H.; Watanabe,
M.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049–4051.
(11) (a) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C.
J. Org. Chem. 2008, 73, 219–226. (b) Zhao, J.; Larock, R. C. J. Org. Chem.
2007, 72, 583–588. (c) Liu, Z.; Larock, R. C. Tetrahedron 2007, 63, 347–
355. (d) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223–232.
(12) For related indazole work, see: Jin, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 3323–3325.
´
(13) (a) Kopan´ska, K.; Najda, A.; Zeebrowska, J.; Chomicz, L.;
Piekarczyk, J.; Myjak, P.; Bretner, M. Bioorg. Med. Chem. 2004, 12, 2617–
2624. (b) He, F.-Q.; Liu, X.-H.; Wang, B.-L.; Li, Z.-M. J. Chem. Res. 2006,
809–811. (c) Caliendo, G.; Greco, G.; Grieco, P.; Novellino, E.; Perissutti,
E.; Santagada, V.; Barbarulo, D.; Esposito, E.; De Blasi, A. Eur. J. Med.
Chem. 1996, 31, 207–213. (d) Caliendo, G.; Di Carlo, R.; Greco, G.; Meli,
R.; Novellino, E.; Perissutti, E.; Santagada, V. Eur. J. Med. Chem. 1995,
30, 77–84. (e) Wynne, G. M.; Wren, S. P.; Johnson, P. D.; Price, P. D.; De
Moor, O.; Nugent, G.; Dorgan, C. R.; Tinsley, J. M.; Storer, R.; Mulvaney,
A.; Pye, R. PCT Int. Appl. WO 2007091107, 2007.
(15) General Procedure. To a solution of benzyne precursor (0.35
mmol) and azide (0.30 mmol) in 3 mL of dry MeCN was added CsF (0.60
mmol). The reaction vial was sealed, and the reaction mixture was stirred
at room temperature for 18-24 h before being poured into saturated aqueous
NaHCO3. The resulting mixture was extracted with EtOAc or DCM, and
the combined organic layers were dried over MgSO4 and evaporated. The
residue was purified by silica gel chromatography.
(14) (a) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem.
ReV. 1998, 98, 409–548. (b) Katritzky, A. R.; Rogovoy, B. V. Chem. Eur.
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N. K. Tetrahedron 2005, 61, 2555–2581. (d) Katritzky, A. R.; Lan, X. Chem.
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Aldrichim. Acta 1994, 27, 31–38.
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Org. Lett., Vol. 10, No. 12, 2008

Table 3. Reaction Scope with Different Azidesa
a All reactions were carried out on a 0.3 mmol scale with 1.2 equiv of 2a and 2.0 equiv of CsF. b Isolated yield. c The reaction was allowed to run for
24 h. d A trace of unreacted starting azide remained even after 24 h. e Other unidentified products were present. f The reaction was carried out using 2.4 equiv
of 2a and 5.0 equiv of CsF.
azides are also good substrates. Other than benzyl azide (1a),
functionalized benzylic (entry 9) and allylic (entry 10) azides
also have afforded excellent yields of the desired products.
Sterically demanding adamantyl azide (1l) (entry 11) reacted
smoothly to afford a 78% yield as well. Azides with
functional groups can be easily transformed into the corre-
sponding benzotriazoles. Thus, ethyl azidoacetate (1m)
reacted cleanly to give a quantitative yield of the corre-
sponding benzotriazole (entry 12). Coumarin-derived azide
1n also afforded the desired product in a moderate 51% yield
(entry 13). An alkyne moiety is well tolerated under the
reaction conditions, as seen in the smooth reaction of alkyne
1o with benzyne, affording the alkynyl benzotriazole 3s
(entry 14). A free hydroxyl group is tolerated, although an
additional, unidentified side product was observed (entry 15).
Although the reaction tolerates alkenes quite well (see entries
10 and 13), the vinylic azide 1q was not a suitable substrate
in this annulation process (entry 16). After the reaction was
complete, a complex mixture was obtained. After isolation,
purification, and identification, the product was found in only
a 20% yield, and we were unable to identify the rest of the
products. Trimethylsilyl azide (1r) was also examined in this
reaction (entry 17). Surprisingly, the reaction did not stop
at the [3 + 2] cycloaddition stage but underwent further
desilylation, followed by phenylation with another equivalent
of 2a to afford 3f as the final product. The same reaction
afforded unidentified products when MeOH was used as a
cosolvent.16 The current limitation on the scope of the azide
substrate is that azides bearing electron-withdrawing groups
directly attached to the azide moiety do not work in this
annulation. Thus, the reaction of sulfonyl azide 1s did not
give any annulation product.17
In conclusion, we have developed a facile, efficient, and
general method for the synthesis of substituted, functionalized
benzotriazoles by the 1,3-dipolar cycloaddition of benzynes
with azides under very mild reaction conditions. The reaction
Org. Lett., Vol. 10, No. 12, 2008
2411

has good substrate scope and tolerates a board range of
functional groups. It provides a useful new route to benzo-
triazoles in much the same manner as present “click”
chemistry affords triazoles. We believe that this methodology
should find broad applications in synthetic organic chemistry,
as well as the combinatorial, pharmaceutical, and polymer
sciences.
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM079593 and GM070620) and the Kansas
University NIH Center of Excellence in Chemical Methodol-
ogy and Library Development (P50 GM069663) for their
generous financial support. We also thank Mr. Donald C.
Rogness at Iowa State University for his help in the
preparation of the benzyne precursors.
Supporting Information Available: Preparation of azide
starting materials, experimental details, and characterization
of the final products, including full 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) In a similar reaction between benzyne 2a and TMS diazomethane
to form indazole, MeOH was needed as a co-solvent; see ref 11a.
(17) We have also unsuccessfully carried out a reaction with an acyl
azide (2-iodobenzoyl azide). However, we observed severe spontaneous
decomposition of this azide simply upon standing. Thus, not surprisingly,
under our reaction conditions, the reaction between this azide and 2a
afforded a complex mixture. Other acyl azides will be investigated, and
results will be published in due course.
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