Benzyne click chemistry with in situ generated aromatic azides

Article abstract of DOI:10.1021/ol9002338

An efficient synthesis of substituted benzotriazoles using an azide-alkyne 1,3-dipolar cycloaddition "click reaction" is described. Key to the procedure is the in situ generation of the reactive aromatic azide and benzyne reaction partners.

Full text of DOI:10.1021/ol9002338

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1587-1590
Benzyne Click Chemistry with in Situ
Generated Aromatic Azides
Fengzhi Zhang and John E. Moses*
School of Chemistry, UniVersity of Nottingham, UniVersity Park,
Nottingham NG7 2RD, U.K.
john.moses@nottingham.ac.uk
Received February 3, 2009
ABSTRACT
An efficient synthesis of substituted benzotriazoles using an azide-alkyne 1,3-dipolar cycloaddition “click reaction” is described. Key to the
procedure is the in situ generation of the reactive aromatic azide and benzyne reaction partners.
The recent discovery of Cu(I)-catalyzed advancement1 of the
Huisgen 1,3-dipolar cycloaddition between azides and ter-
minal alkynes has brought about a renaissance of interest in
this useful and reliable bond-forming “click” reaction.2 This
chemistry has found wide application in various disciplines
including materials science,3 chemical biology,4 and me-
dicinal chemistry.5 In the absence of Cu(I) catalysis, the
Huisgen cyloaddition reaction is generally sluggish due to
the kinetic stability of the azide and alkyne functionality. In
such instances, elevated temperature or pressure are often
required to drive the process. This inertness renders the azide
and alkyne functional groups bioorthogonal and, as such,
highly attractive motifs for bioconjugation applications.
Strategies aimed at avoiding Cu(I) catalysis or harsh
reaction conditions have been developed in recent times.
These methods involve activated alkynes which readily react
with azides at ambient temperature, including alkynes in
conjugation with electron-withdrawing groups6 and strained
internal alkynes such as cyclooctyne.7 One particularly
important class of activated alkynes, arynes, have long been
known to undergo facile annulation with organic azides to
yield benzotriazoles.8 This pharmacologically significant
structural motif is found in many biologically active com-
pounds, including anticancer, antifungal, anti-inflammatory,
and antidepressant agents.9
The reactive aryne intermediates must be generated in situ,
and several methods have been developed for this purpose.
Early procedures utilized diazotized anthranilic acid as the
benzyne precursor,10 which is a reliable and convenient
strategy, especially considering the ready availability of the
starting materials. However, the diazo intermediates are
considered to be potentially explosive, and milder alternative
conditions have since been developed, including the use of
(1) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565–632.
(2) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8,
1128–1137. (b) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. Eur. J. Org.
Chem. 2006, 1, 51–68. (c) Meldal, M.; Tornøe, C. W. Chem. ReV. 2008,
108, 2952–3015. (d) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007,
36, 1249–1262. (e) Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.;
Moore, M.; Neidle, S.; Moses, J. E. J. Am. Chem. Soc. 2006, 128, 15972–
15973.
(6) Li, Z.; Seo, T. S.; Ju, J. Tetrahedron Lett. 2004, 45, 3143–3146.
(7) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc.
2004, 126, 15046–15047.
(3) (a) Nandivada, H.; Jiang, X.; Lahann, J. AdV. Mater. 2007, 19, 2197–
2208. (b) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid Commun. 2007,
28, 15–54. (c) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018–1025.
(4) Breinbauer, R.; Kohn, M. ChemBioChem 2003, 4, 1147–1149.
(5) (a) Hein, C. D.; Liu, X.-M.; Wang, D. Pharm. Res. 2008, 25, 2216–
2230. (b) Moorhouse, A. D.; Haider, S.; Gunaratnam, M.; Munnur, D.;
Neidle, S.; Moses, J. E. Mol. BioSyst. 2008, 4, 629–642. (c) Moorhouse,
A. D.; Moses, J. E. ChemMedChem 2008, 3, 715–723.
(8) (a) Mitchell, G.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1987,
403–412. (b) For benzyne chemistry, see the following review: Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701–730.
(9) (a) He, F.-Q.; Liu, X.-H; Wang, B.-L.; Li, Z.-M. J. Chem. Res. 2006,
12, 809–812. (b) Caliendo, G.; Greco, G.; Grieco, P.; Novellino, E.;
Perissutti, E.; Santagada, V.; Barbarulo, D.; Esposito, E.; Blasi, A. D. Eur.
J. Med. Chem. 1996, 31, 207–213.
(10) Reynolds, G. A. J. Org. Chem. 1964, 29, 3733–3734.
10.1021/ol9002338 CCC: $40.75
Published on Web 03/06/2009
2009 American Chemical Society

o-(trimethylsilyl)aryliodonium salts11 and two-step deproto-
nation-dehalogenation of aromatic halogen compounds.12
These days, arynes are commonly prepared in situ by
fluoride-promoted ortho-elimination of o-(trimethylsilyl)aryl
triflates.13 Using this procedure, Larock et al.14 and others15,16
have reported the synthesis of a range of benzotriazoles by
the [3 + 2] cycloaddition of benzyne and organic azides.
Table 1. Reaction Optimization
Perhaps safer in terms of the preparation of the benzyne
component, these procedures still require the use of pre-
formed organic azides. Despite being stable under most
reaction conditions, organic azides with low molecular weight
can sometimes be explosive, and so-called “azidophobia”
may hinder the uptake of these potentially useful methodolo-
gies.17 Procedures which enable the in situ generation of
organic azides followed by their immediate reaction minimize
such hazards. In the context of “click” chemistry,18 several
procedures have already been reported, where in situ azide
formation is immediately followed by Cu(I)-catalyzed cy-
cloaddition with terminal alkynes to give the corresponding
1,4-triazole linkage.19
t-BuONO TMSN3 anthranilic
solvent
(T, °C)
yieldb
(%)
entrya
(equiv)
(equiv) acid (equiv)
1
2
3
4
2
1.1
1.1
1.1
1.1
2
2
2
2
acetone (57)
acetone (57)
THF (66)
2 + 2
2 + 2
2 + 2
34
60
88
CH3CN (82)
a All reactions were carried out at 1.0 mmol. b Isolated yield.
(entry 2). Changing the solvent from acetone to THF
improved the yield to 60% (entry 3). Gratifyingly, we found
if the solvent was changed to acetonitrile the yield could
reach 88%. These optimized conditions were chosen for all
subsequent work.21
Building upon our recent success in the development of
in situ “click” chemistry with aromatic azides,20 we envi-
sioned extending the scope of this methodology to include
in situ benzyne annulation. Herein we report a one-pot
synthesis of benzotriazoles using benzyne click chemistry
without the need for isolation of the aromatic azide substrate.
In order to explore the scope of this reaction, a range of
aromatic amines were reacted under the optimized conditions
with anthranilic acid (Table 2). Simple aromatic amines such
For convenience, we considered using a common alkyl
nitrite reagent for the in situ generation of both benzyne from
anthranilic acid and an aromatic azide fragment from aniline.
With this in mind, 1-azido-4-methoxybenzene was prepared
in situ from 4-methoxyaniline using an excess of t-BuONO
(2.0 equiv) and TMSN3 (1.1 equiv) in acetone.
Table 2. One-Pot Reaction with Different Aromatic Azides
This was followed by the addition of 2 equiv of anthranilic
acid at reflux (Table 1). Unfortunately, under these condi-
tions, the desired product was not observed (entry 1).
However, when additional t-BuONO (2.0 equiv) and an-
thranilic acid (2.0 equiv) were simultaneously added (over
25 min) to a mixture containing the in situ generated azide,
the target benzotriazole product was isolated in 34% yield
entrya
R1
R2
R3
R4
R5
yieldb (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
71
79
83
51
56
32
64
52
72
H
H
H
H
H
H
H
CH(CH3)2
CH2CH3
H
I
CH2CH3
H
H
H
H
H
H
H
H
H
H
CF3
NO2
CN
H
(11) (a) Kitamura, T.; Yamane, M. J. Chem. Soc., Chem. Commun. 1995,
983–984. (b) Kitamura, T.; Fukatsu, N.; Fujiwara, Y. J. Org. Chem. 1998,
63, 8579–8581.
(12) Wotiz, J. H.; Huba, F. J. Org. Chem. 1959, 24, 595–598.
(13) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 8,
1211–1214.
OMe
H
OMe OMe
a All reactions were carried out on a 1.0 mmol scale with 2.0 equiv of
(14) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409–2412.
benzyne precursor. b Isolated yield.
(15) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R. A.;
Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3461–3463
(16) Chandrasekhar, S.; Seenaiah, M.; Rao, C. L.; Reddy, C. R.
Tetrahedron 2008, 64, 11325–11327
.
.
as aniline and 4-isopropylaniline reacted smoothly to give
the benzotriazole products in 71% and 79% yields, respec-
tively (entries 1 and 2). Lower yields were observed with
stabilized aromatic amines containing deactivating substit-
uents (entries 4-7). These lower yields may be due to a
decrease in the rate of cycloaddition, thus enabling competing
reaction pathways of benzyne to occur. Indeed, these
reactions were generally more complex, with several uni-
dentified products obtained. Electron-rich substrates (entries
8 and 9), as well as sterically demanding anilines (entries 3
(17) (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188–5240. (b) Scriven, E. F. V.; Turnbull, K. Chem.
ReV. 1988, 88, 297–368.
(18) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
(19) (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6,
3897–3899. (b) Yadav, J. S.; Subba Reddy, B. V.; Madhusudhan Reddy,
G.; Narasimha Chary, D. Tetrahedron Lett. 2007, 48, 8773–8776. (c)
Chandrasekhar, S.; Basu, D.; Rambabu, C. Tetrahedron Lett. 2006, 47,
3059–3063.
(20) (a) Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9,
1809–1811. (b) Moorhouse, A. D.; Moses, J. E. Synlett 2008, 14, 2089–
2092.
1588
Org. Lett., Vol. 11, No. 7, 2009

and 8), reacted efficiently to give the desired products with
good yields.
We next tested several substituted anthranilic acid benzyne
precursors using this one-pot “click” procedure (Table 3).
Table 4. One-Pot Reaction under Microwave Conditions
Table 3. One-Pot Reaction with Different Substituted
Anthranilic Acids
entrya
R1
R2
R3
R4
R5
yield (%) (A:B)c
1
2
3
4
5
6
7
H
H
H
H
Cl
H
H
OMe
OMe
OMe
OMe
NO2
NO2
CN
H
H
H
H
Cl
H
H
H
H
CF3
H
H
H
Me
H
F
H
H
H
86
69 (1:1)
65 (>95:1)
52 (1:1)
41
29
42
entrya
R1
R2
R3
R4
yield (%) (A:B)c
H
H
1
2
3
4
5
6
7
8
H
H
H
CF3
H
Me
H
OMe
-CHCHCHCH-
H
H
F
H
H
H
Me
H
36
a All reactions were carried out at 0.5 mmol with 2.0 equiv of benzyne
precursor. b Isolated yield. c The regioisomeric ratio was determined by 1H
NMR spectroscopic analysis of the crude product.
H
Cl
H
H
34 (3:1)
33 (1:1)
61 (>95:1)
H
H
H
H
H
H
NO2
H
74 (1:1)
77 (1:1)
75 (1:0)d
significant change in the product yields (Table 4).20b,22
Following in situ formation of the aromatic azide fragment,
the corresponding anthranilic acid-benzyne precursor and
t-BuONO were added to the same flask. The reaction mixture
was placed in a microwave reactor and irradiated for 15 min
at 150 °C. These conditions favored electron-rich azides
(entries 1-3), whereas lower yields were observed with
electron-poor substrates (entries 5-7).
We were intrigued to investigate alternative strategies for
benzyne generation and determine the compatibility with our
in situ protocol. We turned to the popular method of fluoride
promoted ortho-elimination of o-(trimethylsilyl)phenyl tri-
flates (Table 5), recently utilized by Larock14 and Ferringa.15
H
H
a All reactions were carried out at 1.0 mmol with 2.0 equiv of benzyne
precursor. b Isolated yield. c The ratio was determined by 1H NMR
spectroscopic analysis of the crude product. d Regiochemistry determined
by NOE.
When 4-methoxyaniline and 3-amino-2-naphthoic acid were
used as the substrates, the corresponding napthotriazole
product was isolated in 36% yield (entry 1). With a chlorine
substituent at R3, or fluorine at R4, the unsymmetrical aryne
intermediates resulted in a 3:1 and 1:1 mixture of regioiso-
mers, respectively, with moderate yields (entries 2 and 3).
With deactivating CF3 at R1, a >95:1 mixture of regioisomers
was obtained in 61% yield (entry 4). However, when
2-amino-5-nitrobenzoic acid was used as the benzyne precur-
sor, no product formation was observed (entry 5). With a
methyl substituent at R4 or R1, the reactions gave a 1:1
mixture of separable regioisomers (entries 6 and 7). In the
case of 2-amino-3-methoxybenzoic acid, a single regioisomer
was obtained (entry 8) with the aromatic ring on nitrogen
remote to the substituent, which is consistent with Larock’s
observations.1
Table 5. One-Pot Reaction with o-(Trimethylsilyl)phenyl
Triflate as Benzyne Precursors
Interestingly, reaction times could be significantly reduced
(15 h to 15 min) using microwave conditions without
entrya
R1
R2
R3
R4
R5
yieldb (%)
1
2
3
4
5
6
7
H
H
H
OMe
H
H
Me
H
H
H
H
H
OMe
H
Br
H
Me
H
OMe
H
Cl
H
H
H
H
H
H
H
89
64
67
59
53
73
76
(21) General Procedure. The corresponding amine (1.0 mmol) was
dissolved in CH3CN (3.0 mL) in a 25 mL round-bottomed flask. To this
stirring mixture was added t-BuONO (0.24 mL, 2.0 equiv) followed by
TMSN3 (0.14 mL, 1.05 equiv) dropwise. The resulting solution was stirred
at room temperature for 1 h. Two solutions, t-BuONO (0.24 mL, 2 equiv)
in CH3CN (1.0 mL) and the corresponding anthranilic acid benzyne
precursor (2 equiv) in CH3CN (3.0 mL), were prepared. Over a period of
25 min, these two solutions were simultaneously added dropwise to the
refluxing reaction. When the addition was complete, the mixture was stirred
under reflux overnight. The reaction mixture was allowed to cool to room
temperature. Saturated NaHCO3 solution (10 mL) was then added. The
mixture was extracted with EtOAc (2 × 50 mL). The combined organic
layers were washed with water (10 mL) and brine (10 mL) and dried over
anhydrous sodium sulfate. The solvent was removed and the crude residue
purified by silica gel chromatography (PE/EtOAc).
Cl
H
H
H
H
NO2
H
a All reactions were carried out at 1.0 mmol with 1.5 equiv of benzyne
precursor. b Isolated yield.
Following in situ formation of the azide fragment, the
benzyne precursor o-(trimethylsilyl)phenyl triflate and CsF
Org. Lett., Vol. 11, No. 7, 2009
1589

were added to the same flask, and the reaction mixture
stirred at rt for 15 h. A range of aromatic amines, including
electron rich (entries 2-4), electron poor (entries 5-7),
and sterically hindered (entries 4 and 6), were tested. All
of the substrates gave clean reactions under mild condi-
tions and offered yields comparable to or better than those
previously reported.14
over current methodologies in terms of safety, ease of
execution, and efficiency.
Acknowledgment. We thank the Association of Interna-
tional Cancer Research (AICR), EPSRC, and The University
of Nottingham (UoN) for funding J.E.M. and F.Z. We thank
Dr. Pallavi Sharma (UoN) for fruitful discussions.
In summary, a simple and efficient one-pot benzyne click
reaction has been described that enabled access to a range
of functionalized benzotriazoles. The method avoids isolation
and handling of potentially explosive aromatic azides and
uses readily available and inexpensive substituted anthranilic
acid or o-(trimethylsilyl)phenyl triflate as benzyne precursor.
Heating the reaction using microwave irradiation dramatically
decreased reaction times from hours to minutes with in-
creased yields in some case. This procedure offers advantages
Supporting Information Available: Full characterization
data and copies of 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9002338
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