Regioselective conversion of arenes to N-aryl-1,2,3-triazoles Using C-H Borylation

Article abstract of DOI:10.1002/chem.201403021

A one-pot protocol for the synthesis of N-aryl 1,2,3-triazoles from arenes by an iridium-catalyzed C-H borylation/copper catalyzed azidation/click sequence is described. 1mol % of Cu(OTf)₂ was found to efficiently catalyze both the azidation and the click reaction. The applicability of this method is demonstrated by the late-stage chemoselective installation of 1,2,3-triazole moiety into unactivated molecules of pharmaceutical importance.

Full text of DOI:10.1002/chem.201403021

DOI: 10.1002/chem.201403021
Communication
&
Click Chemistry
Regioselective Conversion of Arenes to N-aryl-1,2,3-triazoles
Using CÀH Borylation
Rajavel Srinivasan,* Anthony G. Coyne, and Chris Abell*[a]
Abstract: A one-pot protocol for the synthesis of N-aryl
1,2,3-triazoles from arenes by an iridium-catalyzed CÀH
borylation/copper catalyzed azidation/click sequence is
described. 1 mol% of Cu(OTf)2 was found to efficiently cat-
alyze both the azidation and the click reaction. The applic-
ability of this method is demonstrated by the late-stage
chemoselective installation of 1,2,3-triazole moiety into
unactivated molecules of pharmaceutical importance.
The discovery of the CuI-catalyzed 1,3-dipolar cycloaddition be-
tween an alkyne and an azide independently by Sharpless and
co-workers[1a] and Meldal and co-workers[1b] and popularly
known as the “click” reaction is known for its fidelity and ro-
bustness. This reaction has found widespread application in
medicinal chemistry,[2a,b] chemical biology,[2c,d] and materials sci-
ence[2e,f] and consequently revived the use of azides. However,
Figure 1. Representative of arenes functionalized with N-aryl-1,2,3-triazoles
at meta position.
unlike other aryl functionalities, such as nitrile, halides, phe-
nols, amines, acids, and ethers, there are not many methods
available to synthesize aryl azides from fundamental or feed-
stock building blocks, such as an unactivated arene. This might
in part be due to a reluctance of the synthetic community to
work with azides, some of which are known to be “explosive”
under certain conditions.[3] This property of the azides has se-
verely limited their application. The ever-expanding application
of click chemistry mainly in the fields of drug discovery and
compound-library synthesis[4] creates demand for simple and
quick methods to generate diverse azides from readily avail-
able starting materials. Furthermore, approaches, in which the
azides could be generated and used in situ for the next reac-
tion without being isolated or purified, making the synthesis
safer, simpler, and quicker, may attract the attention of process
chemists.
just 1 mol% of Cu(OTf)2 using air as the sole oxidant. The
azides generated were not isolated or purified and were
“clicked” in situ with a range of alkynes to furnish 1,2,3-tri-
azoles in moderate to good yields. This is the first report, in
which an aryl CÀH is functionalized to a 1,2,3-triazole in a one-
pot sequence, adding new methodology to the tool box of
azide/click chemistry and bringing together the fields of click
chemistry and CÀH activation. Finally, the applicability of this
method is demonstrated by introduction of a 1,2,3-triazole into
more complex molecules and by derivatizing 3-azidonicotine
generated through the CÀH borylation/azidation sequence to
various functionalized products (Scheme 1).
Several groups have demonstrated the in situ generation of
azides and their trapping with alkynes in a one-pot or a multi-
component fashion to create 1,2,3-triazoles. For example,
Fokin and co-workers[6] and Lutz and co-workers[7] have used
There have been several examples of arenes functionalized
with 1,2,3-triazoles at the meta position (Figure 1).[5a–e] Herein,
we present a simple protocol for the regioselective conversion
of an aryl meta CÀH to the corresponding 1,2,3-triazole by
direct CÀH borylation followed by CuII-catalyzed azidation of
the aryl boronate. The azidation has been achieved by using
[a] Dr. R. Srinivasan, Dr. A. G. Coyne, Prof. Dr. C. Abell
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: chmraja@gmail.com
ca26@cam.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403021.
Scheme 1. Comparison between the existing methods and the CÀH activa-
tion method to generate 1,2,3-triazoles.
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alkyl and aryl halides, respectively, for the in situ generation of
azides and have “clicked” them with alkynes. Moses and co-
workers[8] used anilines, whereas Wittmann and co-workers[9]
used aliphatic amines for this purpose. More recently, Guo and
co-workers[10a] and Yang et al.[10b] have demonstrated the gen-
eration of azides from commercially available boronic acids by
Chan–Lam-based oxidative coupling[11] and used them in situ
to make 1,2,3-triazoles. Even though all the above-mentioned
methods are simple and attractive, they all need arenes with
a functionalized handle, such as a halide, amine, or boronic
acid(ester), to generate the azide. The commercial availability
and substrate scope of these azide precursors limit the applica-
bility of the methods. Another drawback of all the existing ap-
proaches to generate aryl azides from aryl boronic acids is the
requirement of high loading of copper catalyst (10 mol%), and
in some cases, the use of additives, such as CsF[12] and higher
temperatures for effective conversion.[10b] It should be noted
that the use of higher concentrations of copper catalyst in the
presence of an anionic azide source, such as sodium azide or
trimethylsilyl azide, results in the generation of higher concen-
trations of copper(II) azide, which is shock sensitive when dry,
potentially making the reaction more hazardous particularly on
a large scale.[13]
Table 1. Optimization of one-pot conversion of the crude CÀH borylated
intermediate to 1,2,3-triazole.
Entry Catalyst[a]
Solvent t
Conv. of 1B to 1Az Yield of triazole 2a
[%][c]
[h] [%][b]
1
2
3
4
5
Cu(OTf)2
CuSO4·5H2O ethanol
ethanol
4
6
6
6
8
94
89
68
48
31
75
71
n.d.[e]
n.d.
n.d.
Cu(OAc)2
Cu(acac)2
copper(II)
d-gluconate
Cu(OTf)2
Cu(OTf)2
–
ethanol
ethanol
ethanol
6
7
8
9[d]
THF
CH3CN 24
ethanol 24
24
14
21
0
n.d.
n.d.
0
Cu(OTf)2
ethanol
9
33
n.d.
[a] Catalyst (1.0 mol%) was used. [b] Conversion was determined by
1H NMR spectroscopy. [c] Isolated yields after silica-gel chromatography.
[d] Reaction was performed under N2. [e] n.d.=not determined.
Iridium-catalyzed direct CÀH borylation has proven to be
a successful approach to functionalize unactivated (hetero)ar-
enes.[14] The use of the [Ir(cod)(OMe)]2/dtdpy (dtdpy=4,4’-di-
tert-butyl-2,2’-dipyridyl; cod=1,5-cyclooctadiene) catalytic
system developed by Hartwig and co-workers remains the
most common choice for CÀH borylation.[14a] The regiochemis-
try of this reaction is controlled by steric factors rather than
electronic or directing effects, and the borylation occurs at the
arene carbon, which is least hindered.[14f,g,h] This selectivity has
been exploited for the regioselective derivatization of an aryl
CÀH to phenol,[15a] amino and ether,[15b] halide,[15c,d] nitrile,[15e]
trifluoromethyl,[15f,g] alkyl,[15h] and aryl[15i,j,k] groups in a one-pot
fashion, which are difficult to access by traditional chemical
methods. However, this method has not been explored for the
synthesis of 1,2,3-triazoles via an azide intermediate, which we
describe herein.
compound (6%) was also detected. CuSO4·5H2O catalyzed
89% conversion of 1B to 1Az in 6 h. In contrast, other copper-
(II) sources, such as Cu(OAc)2 and Cu(acac)2 (acac=acetylaceto-
nate), gave much poorer conversion of 68 and 48%, respec-
tively. Copper(II) d-gluconate gave the lowest conversion of
only 31%. When the solvent was varied, it was found that eth-
anol gave the best conversions, ahead of THF, which in turn
was better than acetonitrile. Halogenated solvents, such as
CH2Cl2 and CHCl3, were avoided, considering the risk of forma-
tion of highly sensitive azidomethanes in the presence of
sodium azide.[3d] In the absence of any copper source, azide
1Az was not detected even after 24 h of reaction (by NMR
spectroscopy). When the reaction was performed under N2, the
conversion was poor (33% after 9 h compared to 96% in 4 h
when carried out open to air). Having optimized conditions for
the in situ conversion of the aryl boronate 1B to aryl azide
1Az, the click reaction was then initiated by adding phenyl
acetylene and 3 mol% of aqueous sodium ascorbate solution
to the same reaction pot containing the aryl azide. No addi-
tional copper catalyst was added, because the reaction mixture
already contained 1 mol% of the catalyst. After 8 h, complete
conversion of azide 1Az to 1,4-substituted-1,2,3-triazole 2a
was achieved in an overall yield (for three steps) of 75%
(entry 1, Table 1). The presence of the iridium catalyst and
other by-products from the borylation step did not appear to
greatly affect either the azidation reaction or the click reaction.
Importantly, only the expected 1,4-disubstituted regioisomer
was formed in the click reaction.
3-Chloroanisole was used as the substrate in the optimiza-
tion studies because of the presence of both electron-with-
drawing and electron-donating groups on the same molecule.
At first, 3-chloroanisole was subjected to a CÀH borylation re-
action by using the standard conditions as described by Hart-
wig and co-workers by using B2Pin2 as the borylation agent in
the presence of 0.25 mol% of [Ir(OMe)(cod)]2 and 0.5 mol% of
dtdpy in THF, heating at 808C for 18 h (Scheme 2). After the
1
completion of the reaction (as was monitored by H NMR spec-
troscopy), the volatiles were removed, and the reaction mix-
ture was subjected to the screening conditions summarized in
Table 1. Various copper catalysts were assessed to determine
the most effective conversion of aryl boronate 1B to aryl azide
1Az. Sodium azide was used as the azide source. Among the
conditions screened, it was found that just 1 mol% of copper-
(II) triflate in ethanol at 408C in the presence of air as an oxi-
By using the optimized conditions, various 1,2,3-triazoles
were synthesized as summarized in Scheme 2. Initially, the
arenes were subjected to the CÀH borylation (Hartwig’s condi-
tions)[14a] to give the aryl boronates (see the Supporting Infor-
1
dant could effect 94% conversion by H NMR analysis (entry 1
in Table 1) of 1B to 1Az in just 4 h. The protodeboronated
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ents, such as CH3, CF3, CN, OCH3,
OCF3, CO2R, NR2, F, Cl, and Br,
were tolerated under these reac-
tion conditions. Arenes contain-
ing electron-withdrawing and/or
electron-donation groups per-
formed well. Heterocycles, such
as pyridines and quinolones,[14h,i]
underwent the reaction se-
quence in modest yields (en-
tries 2q, 2r, and 2s). Alkynes
with different steric and elec-
tronic properties underwent the
click reaction effectively (see the
Supporting Information).
The minor drawbacks of this
approach are: 1) the low yield
(Scheme 2, entry 2b) in the case
of a volatile azide intermediates
(such as 1-azido-3,5-dimethyl-
benzene), which could be lost
during the azidation sequence,
which was performed open
under air; and 2) contamination
by pinacol (<3%) in a few final
compounds even after chroma-
tographic purification. This con-
tamination can be removed
azeotropically with water on
a rotary evaporator.[15l] A control
reaction was performed between
the purified azide and alkyne in
the presence of the iridium-cata-
lytic system, but in the absence
of any copper source. This con-
firmed that iridium did not have
any effect on the click reaction.
Late-stage modification of
complex molecules is of interest
to pharmaceutical companies
seeking to develop structure–ac-
tivity relationships (SAR), but at
the same time presents a signifi-
cant challenge to synthetic
chemists. By using the approach
described herein, (Æ)-a-toco-
pherol nicotinate and (À)-nico-
tine were each modified with
a 1,2,3-triazole moiety selectively
Scheme 2. Conversion of (hetero)arenes to 1,2,3-triazoles. [a] Isolated yields after silica-gel chromatography.
[b] Azidation carried out by using methanol as solvent. [c] Cu(OTf)2 (3 mol%) was used in the azidation sequence.
[d] Azidation and click reaction carried out in 0.5 mol% scale. [e] [Ir(cod)(OMe)]2 (3 mol%) and dtdpy (6 mol%)
used in the borylation sequence, and Cu(OTf)2 (3 mol%) in the azidation sequence.
mation). Volatiles were then removed in vacuo, and the residue
was dissolved in ethanol and added to a mixture of sodium
azide (1.5 equiv) and 1 mol% of Cu(OTf)2, and heated at 408C
for a period of 4–12 h in the presence of air to give the aryl
azide. Thereafter, 3 mol% of sodium ascorbate and 1.2 equiva-
lent of alkyne was added, and the resulting mixture was stirred
at room temperature for 12 h. The 1,4-disubsituted-1,2,3-tri-
azoles (click product) were isolated in 33–88% yield. Substitu-
in the meta-position, without the need to introduce a handle
for the modification. A number of compounds containing the
1,2,3-triazole scaffold are pharmaceutically active.[2a] We have
synthesized a resveratrol analogue[16a] and an intermediate en
route to a combretastatin analogue[16b] in 71 and 42% yield, re-
spectively, from arene precursors by using our approach. Both
the above-mentioned compounds are anti-cancer leads
(Scheme 3).
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The method was further evaluated for scale-up starting with
10 mmol (1.81 g) of 1,2,3-trichlorobenzene by using the stan-
dard conditions outlined in Scheme 2. The azide formed was
trapped in situ by using N,N-dimethyl propargyl amine to give
the desired 1,2,3-triazole in 78% isolated yield (Scheme 5).
Scheme 5. Evaluation of a scale-up reaction.
To conclude, we have demonstrated the first one-pot proto-
col for the conversion of an aryl CÀH bond to a 1,2,3-triazole
in a regioselective manner utilizing the CÀH borylation/azida-
tion/click sequence. Only 1 mol% of Cu(OTf)2 was required to
catalyze both the azidation, as well the subsequent click reac-
tion, making it a safer process. The method was applied to the
direct synthesis of known medicinally important compounds
and late-stage modification of more complex molecules. The
ease of generating an aryl azide regioselectively from the CÀH
of an (hetero)arene and derivatizing the azide into various
functionalities was demonstrated by using (À)-nicotine. We be-
lieve this methodology will simplify the ways to make polysub-
stituted aryl azides/1,2,3-triazoles and may be amenable for
scale-up chemistry.
Scheme 3. Late-stage modification/synthesis of medicinally important
compounds.
Apart from making 1,2,3-triazoles, azides are also versatile in-
termediates for a number of chemical transformations. We
chose (À)-nicotine to demonstrate this. (À)-Nicotine and its de-
rivatives are known to be powerful ligands, which modulate
nicotinic acetylcholine receptors and have potential effects on
the central nervous system.[17a] Moreover, every year, 2800 tons
of nicotine is used as an insecticide.[17b] We subjected (À)-nico-
tine to CÀH borylation/azidation sequence and isolated the
only regioselective product 3-azidonicotine formed in 62%
yield. The azido group was transformed into a variety of func-
tionalities including amine, amide,[18a] sulfonamide, 1,5-substi-
tuted triazole,[18b] and 5-iodo-1,2,3-triazole[18c] (Scheme 4). All
the nicotine derivatives synthesized herein were previously un-
known and may have potential application in medicine and
agriculture.
Acknowledgements
We thank Dr. John Skidmore for proofreading this manuscript.
A.C. would like to thank the BBSRC for funding (Grant code
BB/I019669/1).
Keywords: azidation · CÀH borylation · click chemistry ·
synthetic methods
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Received: April 10, 2014
Published online on July 22, 2014
Chem. Eur. J. 2014, 20, 11680 – 11684
www.chemeurj.org
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