A photoinduced, benzyne click reaction

Article abstract of DOI:10.1021/ol500389t

The [3 + 2] cycloaddition of azides and alkynes has proven invaluable across numerous scientific disciplines for imaging, cross-linking, and site-specific labeling among many other applications. We have developed a photoinitiated, benzyne-based [3 + 2] cycloaddition that is tolerant of a variety of functional groups as well as polar, protic solvents. The reaction is complete on the minute time scale using a single equivalent of partner azide, and the benzyne photoprecursor is stable for months under ambient light at room tempurature. Herein we report the optimization and scope of the photoinitiated reaction as well as characterization of the cycloaddition products.

Full text of DOI:10.1021/ol500389t

Letter
pubs.acs.org/OrgLett
A Photoinduced, Benzyne Click Reaction
Adam W. Gann, Jon W. Amoroso, Vincent J. Einck, Walter P. Rice, James J. Chambers,
and Nathan A. Schnarr*
Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, Massachusetts 01003, United States
S
* Supporting Information
ABSTRACT: The [3 + 2] cycloaddition of azides and alkynes
has proven invaluable across numerous scientific disciplines for
imaging, cross-linking, and site-specific labeling among many
other applications. We have developed a photoinitiated,
benzyne-based [3 + 2] cycloaddition that is tolerant of a
variety of functional groups as well as polar, protic solvents.
The reaction is complete on the minute time scale using a
single equivalent of partner azide, and the benzyne photo-
precursor is stable for months under ambient light at room
tempurature. Herein we report the optimization and scope of the photoinitiated reaction as well as characterization of the
cycloaddition products.
evelopment of reliable click chemistry techniques is
D
without question one of the most important endeavors of
the past decade and remains an exciting and evolving area of
modern synthetic methodology.1−6 As the applications of this
chemistry become increasingly complex, so do the demands for
improved kinetics, specificity, and functional group tolerance.
The [3 + 2] cycloaddition of alkynes and azides remains the
gold standard in the area of conjugation chemistry, and more
recently developed approaches using strained alkynes to
eliminate the need for a copper catalyst have greatly expanded
the scope of target applications in both aqueous and organic
environments.7−10 However, these techniques are not without
their drawbacks. The direct correlation between lipophilicity
and reactivity coupled with often difficult syntheses of the
alkyne component may prove prohibitive as faster kinetics in
aqueous environments and readily available material become
increasingly desirable.11−14 With this in mind, we were tempted
to explore copper-free click chemistry from a different angle.
We were initially inspired by impressive work from Larock
and co-workers where benzyne served as the reactive alkyne
species for click chemistry via treatment of appropriately
functionalized benzene with a fluoride ion (Figure 1).15 Despite
generally good yields and a broad substrate scope, several hours
to days were required for completion, presumably due to
sluggish benzyne formation. Addition of crown ethers led to
faster reaction times, but most of these reactions still required
at least 1 h for completion.16 To improve kinetics, we
envisioned fast photochemical generation of benzyne in the
presence of an azide click partner to achieve the desired
coupling. The use of light as an initiator also offers the potential
for spatiotemporal control of the reaction, a highly desired
feature for examining dynamic systems. Several photochemical
click approaches have been developed including a light-induced
Diels−Alder reaction,17 azirine to alkene cycloaddition,18 and
nitrile ylide to alkene cycloaddition.19 Additionally, a similar
Figure 1. Comparison of fluoride-induced benzyne click reaction (A)
with a photochemical approach (B). Fast benzyne formation via
photolysis of appropriately substituted benzenes will vastly improve
click reaction kinetics.
approach to our proposed benzyne click reaction has been
developed where photochemical uncaging of cyclooctynes in
the presence of azide partners results in the desired
conjugation.20,21 However, the overall reaction remains
dependent on the relatively slow cycloaddition step. We
therefore hypothesized that our click reaction would take full
advantage of the benefits of each strategy, specifically, fast
photolysis and a very reactive benzyne intermediate.
Our goals for development of this reaction were (1) reaction
times on the minute scale, (2) reliable and synthetically
straightforward preparation of the benzyne photoprecursor, and
(3) yields consistent with those observed for the previously
reported chemical methods.15 Herein, we describe our initial
efforts toward establishing a photoinduced, benzyne-based click
reaction.
Following a substantial search for an appropriate benzyne
photoprecursor, 2-(3-acetyl-3-methyltriaz-1-en-1-yl)benzoic
acid (1) was deemed the best candidate for further exploration
and development.22,23 To our satisfaction, this compound was
Received: February 6, 2014
Published: March 13, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500389t | Org. Lett. 2014, 16, 2003−2005

Organic Letters
Letter
prepared in four straightforward steps from o-aminobenzyl
alcohol without the need for chromatographic purification of
any synthetic intermediates (Scheme 1). With the target
product (9) (Figure 2). These lower yields are potentially due
to formation of nitrenes upon photolysis of the azides.24−26
Scheme 1. Synthesis of 2-(3-Acetyl-3-methyltriaz-1-en-1-
a
yl)benzoic Acid
a
The target compound 1 is available in four straightforward synthetic
steps from commercially available o-aminobenzyl alcohol in 40%
overall yield. See Supporting Information for experimental details.
compound in hand, we began to explore optimal parameters for
the photoclick reaction using benzyl azide as a coupling partner
for 1 (Table 1). To our delight, the reaction nears completion
Table 1. Reaction Optimization
Figure 2. Scope of our photoinduced, benzyne click reaction. All
reactions were executed on 15 mM (0.75 μM compound 1) scale at
room temperature using an LED light source (3 min irradiation) and 1
equiv of azide. Yields were obtained from fitting spectroscopic data to
standard curves for each compound. Each yield is an average of three
reactions (see Supporting Information).
irraditation time
(min)
azide
equivalents
yield
a
entry
solvent
(%)
1
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
chloroform
chloroform
chloroform
chloroform
dioxane
3
3
3
3
3
3
3
3
3
3
3
3
0.1
1
3
5
3
3
3
1
2
3
3
2
Overall, the reaction appears to be quite tolerant of common
functional groups including alcohols, amides, esters, alkenes,
and ethers, and in all cases both LC retention times and mass
profiles matched perfectly with authentic standards prepared via
the Larock method.15
3
5
13
23
47
56
65
61
25
28
39
46
2
4
10
1
5
6
2
7
5
With an eye for potential downstream applications, we were
motivated to examine the water tolerance of this chemistry
(Figure 3). In our hands, the fluoride induced benzyne click
reaction was effectively stalled when even small amounts
(∼5%) of water were introduced presumably due to fluoride
sequestration (data not shown). Therefore, we were pleasantly
surprised to find detectable product formation in acetonitrile
solution with up to 70% water content, the limit of solubility for
compound 1. As above, these results were obtained using only
1 equiv of azide, which bodes well for future development of
this chemistry aimed at applications in aqueous environments.
In summary, we have developed a photoinitiated, benzyne
click reaction. The reaction is complete on the minute time
scale in acetonitrile using a simple LED light source and a single
equivalent of azide although higher azide equivalents do lead to
increased efficiency. A wide variety of functional groups are
tolerated, and yields are generally good with the exception of
phenyl azides as coupling partners. In addition, the benzyne
photoprecursor is very stable at room temperature under
ambient light (see Supporting Information) and is available in
four synthetic steps from commercially available starting
materials without the need for chromatographic purification
of any synthetic intermediates. Finally, unlike chemically
induced benzyne click reactions, the photochemical process is
quite tolerant of water with observable product yields generated
8
10
1
9
10
11
12
13
14
15
16
17
18
19
dioxane
2
dioxane
5
dioxane
10
1
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
1
56
82
83
90
97
98
1
1
2
5
10
a
All yields were calculated from fitting HPLC peak area to a standard
curve for the click product (see Supporting Information for details).
after only 3 min of irradiation and good yields can be achieved
using a mere 1 equiv of azide. Yields can be improved by using
higher azide equivalents when necessary. In addition, a variety
of solvents are tolerated although acetonitrile appears the most
suitable of those examined.
Satisfied with the optimized reaction conditions, we set out
to explore the reaction scope. Yields were generally good (68−
88%) with the notable exception of the phenyl azide series with
p-nitrophenyl azide managing only a 3% yield of the expected
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Organic Letters
Letter
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Figure 3. Water tolerance of our photoinduced, benzyne click
reaction. Benzotriazole yields were obtained as above in acetonitrile
solution with increasing water percentage. Above 70% water, the
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization of compounds, raw
data for yield calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schnarr@chem.umass.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by start-up funding from the
University of Massachusetts, Amherst (to N.A.S. and J.J.C.).
The authors would like to thank Mr. Thomas Sullivan
(Berkshire Community College) for assistance in assembly
and use of the LED light source.
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dx.doi.org/10.1021/ol500389t | Org. Lett. 2014, 16, 2003−2005