A modular approach to catalytic synthesis using a dual-functional linker for Click and Suzuki coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2010.05.104

The stable benzylazido-boronate ester 1 is presented as an example of a dual-functional linker that allows the synthetically valuable boronate motif to be clicked onto other molecules under mild conditions. The utility of the azido-boronate motif as a modular building block is demonstrated in the rapid synthesis of drug-like structures employing sequential catalytic azide-alkyne cycloaddition and Suzuki coupling reactions.

Full text of DOI:10.1016/j.tetlet.2010.05.104

Tetrahedron Letters 51 (2010) 3913–3917
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A modular approach to catalytic synthesis using a dual-functional linker
for Click and Suzuki coupling reactions
James R. White a, Gareth J. Price a, Stefanie Schiffers a, Paul R. Raithby a, Pawel K. Plucinski b,
Christopher G. Frost a,
*
a Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b Department of Chemical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The stable benzylazido-boronate ester 1 is presented as an example of a dual-functional linker that allows
the synthetically valuable boronate motif to be clicked onto other molecules under mild conditions. The
utility of the azido-boronate motif as a modular building block is demonstrated in the rapid synthesis of
drug-like structures employing sequential catalytic azide–alkyne cycloaddition and Suzuki coupling
reactions.
Received 9 April 2010
Revised 4 May 2010
Accepted 21 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The construction of structures of increasing size and often cor-
responding complexity from modular components lies at the heart
of not only synthetic chemistry but also the basis of many biolog-
ical processes essential to life.1 With this in mind, it is easy to see
why robust synthetic manipulations, which allow chemospecific
coupling of compounds containing other diverse motifs, attract
such interest.1b,c,2 An excellent example of this is the click-chemis-
try philosophy proposed by Sharpless et al., based on ‘highly spe-
cific and reliable reactions’ and a modular approach to tackling
the synthesis of drug-like molecules.1b The reactions are typically
air and water tolerant, high yielding and are straightforward in
their execution. The significant growth of click-chemistry and in
particular the copper-catalysed azide–alkyne cycloaddition reac-
tion3 (CuAAC) into the fields of macromolecular and surface sci-
ence highlights the fundamental necessity for a core group of
reproducible and broadly applicable reactions which may be em-
ployed across diverse disciplines of the physical sciences.4 Many
of the key features that make the CuAAC so popular are in fact
shared with the Suzuki–Miyaura coupling. The organoboron deriv-
atives employed frequently exhibit air and water stability at ambi-
ent temperature, show little toxicity when compared to other
ubiquitous organometallics and allow a range of other synthetic
manipulations to be performed in their presence.5
bench-stable, dual-functional linkers that incorporate azido-boro-
nate functionality amenable to both CuAAC and Suzuki couplings
(Scheme 1).8
As illustrated in Figure 1, a number of azido-boronate com-
pounds have been described in the literature, for example, the syn-
thesis of regioisomers of 10 by Fedorov et al.9 However, the true
potential of these materials in catalysis is only just starting to
emerge. Vasil’ev and co-workers have noted Suzuki couplings with
compound 1110 and Molander and Ham initially reported CuAAC
reactions on analogues of 12.11 In 2009, Harrity and co-workers de-
tailed an innovative route to access another novel motif, typified
by 14, formed via thermal-Huisgen cycloaddition.12 In this case
the assembled triazole units bear two sites for subsequent derivat-
isation, namely the TMS-triazole and boronate centres, thus
increasing their synthetic scope. Indeed, this group has more re-
cently reported the use of their substrates in the synthesis of a
small compound library, further supporting the potential that this
class of materials possess.13 Very recently, Fedorov and co-workers
employed 10 (and related compounds) in an elegant approach to-
wards the synthesis of coumarin-type compounds.14 Molander and
co-workers have utilised alternative azide-bearing organotrifluo-
roborates such as 13 in catalysis. This useful compound is formed
in situ via nucleophilic aromatic substitution using the azide an-
ion.15 It should be noted however that many of these compounds
also have issues associated with their synthesis, purification, han-
dling or storage. From observations in the respective publications
and our own experience with the synthesis and handling of boro-
nate derivatives, we envisaged that these issues could be ad-
dressed by informed design choices. We therefore selected 1 as
an ideal candidate which could be accessed using a modification
of the synthetic route employed by James and co-workers for the
synthesis of novel fluorescent saccharide sensor 15.16 The benzyl
Traditionally, high temperatures were required for Suzuki cou-
plings,5a,6 however, more recent reports have demonstrated viable
couplings at lower temperatures, wide substrate scope and the cat-
alytic ability of palladium at exceptionally low loadings.7 In many
respects this makes organoboronates ideal partners in the CuAAC
reaction methodology. In this Letter we present the synthesis of
* Corresponding author. Tel.: +44 (0) 1225 386142; fax: +44 (0) 1225 386231.
E-mail address: c.g.frost@bath.ac.uk (C.G. Frost).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.104

3914
J. R. White et al. / Tetrahedron Letters 51 (2010) 3913–3917
X
> 65% yield from 6
> 75% yield from 7
6 X = Br
(a)
85%
7 X = B(OH)2
(b)
99%
8 X = BPin
(c)
80%
O
O
B
2
4
BPin
(d)
Hal
99%
N
N
N
N
N
N
Br
9
1
3
5
Air and moisture insensitive
Thermally stable
Synthesis is reproducible,
scalable, and requires
no column chromatography
Scheme 1. Reagents and conditions: (a) (i) n-BuLi, THF, ꢀ78 °C; (ii) (i-PrO)3B, ꢀ78 °C to rt; (iii) H2O; (b) pinacol, CH2Cl2, MgSO4, rt; (c) NBS, cat. AIBN, MeCN, 90 °C; (d)
1.1 equiv NaN3, EtOH, rt.
BF3-K+
BF3-K+
ingly of all, we found that 1 crystallised as a high-purity solid, ideal
B(OH)2
B(OH)2
for easy handling and also allowing us to obtain a crystal structure
O
(Fig. 2). Organoazides have been known to exhibit photolytic
N3
behaviour;20 however, we were surprised to find that deliberate at-
N3
N3
tempts at inducing photodegradation of 1, using high intensity UV-
N3
light and monitoring the process in situ by single crystal X-ray dif-
fraction, were totally unsuccessful.21 Indeed, samples of 1 re-
mained unchanged over periods of greater than nine months,
even when stored open to the air; demonstrating a level of stability
beyond what we expected. Though a top-to-tail arrangement of
azide groups in the unit cell of the crystal was observed, the inter-
molecular azide–azide distance was not atypical,22 suggesting that
no abnormal stabilising interactions are responsible for this behav-
iour. The solubility profile of 1 is also impressive, being readily sol-
uble in solvents with such diverse polarities as methanol and
petroleum ether. This wide compatibility is particularly important
due to the significant increases in polarity when converting parent
azides into the corresponding triazoles.1c This allows 1 to be em-
ployed across a much broader polarity range than, for example,
quaternised borates.23
10
11
12
13
SiMe3
N
N
O
O
B(OH)2
B
N
N
N
O
B
N
Ph
O
Ph
N3
14
15
1
Figure 1. Representative examples of reported azido-boronates.
We then proceeded with initial attempts at forming 3a via the
CuAAC of 1 and phenylacetylene (2a). At both ambient and subse-
quently elevated temperatures, low conversions were observed
(Table 1, entries 1–3). These initial reactions did, however, demon-
strate that exposure to reasonably high copper loadings, without
attempts to preclude oxygen, had no detrimental effects on the
boronate group of 1. Whereas boronic acids could be anticipated
to undergo side reactions,18a 1 only reacted at the azide substituent
as desired. Consistent with the literature precedent an amine addi-
tive, in particular DIPEA, gave a significant improvement in reactiv-
ity (Table 1, entries 4–6).4c
azide of 1, easily formed from precursor 9, would, after both cou-
pling reactions, ultimately produce an inert benzyl-triazole core.17
As it would be desirable to use a slight excess of azide to drive the
substitution reaction, a pinacolboronate ester would be an ideal
partner due to the high lipophilicity and inhibition of azide coordi-
nation at the boron centre it imparts.5b,18 This combination should
ensure high yields, with correspondingly simple removal of haz-
ardous azide salts. After optimisation, we secured a route to 1 in
over 75% isolated yield from commercially available boronic acid
7.19 The synthesis also proved robust and scalable, allowing multi-
gram quantities of 1 to be produced, without the requirement for
purification by column chromatography (Scheme 1). Most pleas-
The low excess of alkyne and short reaction times prompted us
not to optimise the reaction conditions further, but to proceed with

J. R. White et al. / Tetrahedron Letters 51 (2010) 3913–3917
3915
Figure 2. Crystal structure diagram of 1 showing intermolecular azide–azide configuration (distances in Å). The thermal ellipsoids are drawn at 50% probability. Structure
deposited with the CCDC; entry number 747986.
Table 1
Table 2
Initial CuAAC reactivity of 1 with phenylacetylene (2a)a
CuAAC reactivity of 1 with selected terminal alkynesa
Ph
R
PinB
PinB
PinB
PinB
2a
2
N
N
N
N
N3
N3
Ph
R
N
N
20 mol% CuI
1.1 eq. alkyne
1.1 eq. additive
20 mol% CuI
1.1 eq. alkyne
1.1 eq. DIPEA
60 °C, 1 h
1
3a
1
3
Entry
Solvent
Additive
% Conversionb
Entry
Alkyne
Product
% Yieldb
1
2
3
4
5
6
H2O
1,4-Dioxane
EtOH
—
—
—
Et3N
DIPEA
DIPEA
20c
20c
12c
56d
93d
93d
1
2
2a
2a
3a
3a
72
95c
Ph
H2O
H2O
O
1:1 t-BuOH/H2Oe
3
2b
3b
78
OEt
a
All reactions performed in sealed tubes under air atmosphere using 0.50 mmol
4
5
2c
3c
92
90
of 1 in 1.0 ml of solvent.
b
Determined by 1H NMR spectroscopy.
Reaction run at rt for 18 h, then at 60 °C for 6 h.
Reaction run at 60 °C for 1 h.
Used to aid mixing.
OH
c
2d
3d
d
e
6
7
2e
2f
3e
3f
(30)d
52e
TMS
a
All reactions performed in sealed tubes under air atmosphere using 1.0 mmol of
1 in 2.0 ml of 1:1 t-BuOH/H2O as solvent.
the reaction of 1 with a selection of representative terminal al-
kynes (Table 2). The only alkyne which exhibited particularly low
reactivity was trimethylsilyl acetylene (2e) (Table 2, entry 6),
which gave incomplete conversion into a mixture of 3e and in
situ-de-silylated 3f.24 Furthermore, 3e exhibited lower crystallinity
when compared with other 1,2,3-triazoles, such that it was not
possible to separate from 1 by recrystallisation. Given these fac-
tors, we realised the potential that acetylene gas would have in
giving direct access to mono-substituted 1,2,3-triazoles such as
3f, which could otherwise be produced via uneconomic silyl depro-
tection of 3e (Scheme 2).25 Indeed Liang and co-workers reported
the use of acetylene gas (2f) sourced from pressured cyclinders.26
However, our approach was to generate discrete amounts of acet-
ylene, formed upon contact of water with calcium carbide and
introduced into the reaction solution via a cannula.27 This route
to 4H-1,2,3-triazoles proved more than competitive with that
using trimethylsilyl acetylene (Table 2, entries 6 and 7; Scheme 2).
Subsequent Suzuki couplings using 3a as a model substrate un-
der typical conditions for the coupling of boronate esters were then
investigated.28 Pleasingly, a range of aryl and heteroaryl bromides
all gave complete conversion into the corresponding products
(Table 3, entries 3–7); the variations in yield being due principally
to differences in the ease of purification.
b
Isolated yields after purification.
Performed on 3.0 mmol of 1 using 20 mol % CuSO4/40 mol % sodium ascorbate,
c
24 h, rt, see Supplementary data for details.
d
Using 2.0 equiv of 2e, 2 h, 60 °C. 1H NMR spectroscopic analysis revealed a
mixture containing unreacted 1 (45%), 3e (30%) and 3f (25%).
e
See Scheme 2.
CaC2 + H2O
1
(c)
(a)
TMS
~55%
N
N
(b) TBAF
N
N
N
N
(c): 52% yield
TMS
(a),(b): 50% yield
3e
3f
In situ
~25%
Scheme 2. Alternative routes to mono-substituted triazole 3f. Reagents and
conditions: (a) (see Table 2, entry 6); (b) TBAF, THF, rt; (c) twice reacted for 1 h
at 60 °C, after purging with acetylene; conditions otherwise as (a).29

3916
J. R. White et al. / Tetrahedron Letters 51 (2010) 3913–3917
Table 3
Rufinamide ® (16)
Suzuki coupling reactivity of 3a with aryl- and heteroaryl halidesa
F
N
O
N
R
X
(4)
(1.5 eq.)
N
PinB
R
NH2
N
N
N
N
F
Ph
Ph
N
N
2 mol% Pd(OAc)2
5 mol% S-Phos
N2, 100 °C, 2 h
3a
X
5
N
X
N
N
Diversity through
boronate couplings
Entry
Aryl halide
Product
% Yield
54b
Alkyne variation
and post-CuAAC
modification
XnB
R
1
4a0 (X = Cl)
5a
2
3
4a0
4a (X = Br)
5a
5a
81c,d
89d
Catalyst controlled
regioselectivity
Core variations
Br
4
4b
5b
99
Figure 3. Analogues of
1 provide multiple points of synthetic divergence for
building pharmacologically active compounds such as rufinamideÒ (16).
Br
Br
O
5
6
4c
5c
99
the reaction time to five hours, a comparable yield to the aryl bro-
mide was achieved (Table 3, entry 2).
4d
5d
82d
N
The rapid and divergent nature of this protocol suggests signif-
icant potential for use in drug discovery.30 Here the wide availabil-
ity of aryl and heteroaryl halides in particular allows a large
number of products to be obtained from a single stable dual-func-
tional starting material.31 This is particularly relevant given the re-
cent approval of rufinamideÒ (16) as an anti-epilepsy agent, which
critically shares its benzyl-triazole core with 1 (Fig. 3).32
It can be envisaged that a small selection of varied cores could
be employed to build large compound libraries, using a selection of
robust and cost-attractive transformations (Fig. 3).
74d
Br
7
4e
5e
S
a
All reactions performed using 0.5 mmol of 3a, 3.0 equiv of K3PO4 and 2.0 ml of
9:1 DMF/H2O.
b
32% of unchanged 1 was also recovered.
Reaction run at 100 °C for 5 h.
c
d
Purification resulted in disproportionate attrition of the yield, though conver-
sions were complete by 1H NMR spectroscopy; see Supplementary data for details.
To demonstrate this we synthesised F-1 (Scheme 3), which
bears a single aryl-fluoro substituent. Compound F-1 was prepared
in a manner analogous to 1, in 64% overall yield from F-6 (see
Supplementary data for details). To ascertain the CuAAC reactivity
of F-1 we subjected it to reaction with 2d and with a 95% yield
The use of the appropriate aryl chloride (Table 3, entry 1) in the
synthesis of 5a under the standard Suzuki coupling conditions gave
a lower yield than the corresponding aryl bromide (Table 3, entry
3), though the majority of the unreacted boronate was recovered
intact, exhibiting remarkable stability. Consequently, by extending
Br
F
PinB
F
N
95% yield
OH
N
N
2d
F-6
F-3d
64%
overall yield
(a)
94% yield
PinB
F
PinB
F
N
O
N
N3
O
N
X
F-1
OH
2g
47% overall yield
over four steps
(unoptimised)
17 X = OH
18 X = Cl
(b)
(c)
56% over
two steps
N
(d)
90% yield
F
N
O
19 X = NEt2
N
N
4d
NEt2
20
Scheme 3. Proof-of-concept use of F-1 as a synthetic building block for the preparation of 5H-rufinamide derivative 20. Reagents and conditions: (a) 1.2 equiv 2g, 1:1 t-
BuOH/H2O (2.0 ml), 10 mol % Cu(OAc)2, 20 mol % sodium ascorbate, 18 h, rt; (b) oxalyl chloride, cat. DMF, CH2Cl2, 0 °C to rt, 18 h; then: (c) Et2NH, CH2Cl2, 0–10 °C; (d) 19
(0.44 mmol scale), otherwise as Table 3, entry 6. Compound F-3d was synthesised in an analogous manner to 3d (Table 2, entry 5).

J. R. White et al. / Tetrahedron Letters 51 (2010) 3913–3917
3917
Wiley-VCH: Weinheim, 2005; (c) Kotha, S.; Lahiri, K. Eur. J. Org. Chem. 2007,
1221–1236; (d) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–
3658; (e) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085.
6. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685–4696.
obtained of F-3d found it to be equally amenable to this type of
chemistry (compared with 3d; Table 2, entry 5). We therefore set
out to synthesise a proof-of-concept target, starting with the cou-
pling of F-1 with propiolic acid (2g), which gave the triazole-4-car-
boxylic acid 17 in 94% yield. Although we ideally aimed for a
protected secondary amide synthesised in parallel to F-1, our ini-
tial attempts, though not exhaustive, were problematic and we
therefore opted in this instance to incorporate a tertiary amide
after the CuAAC. Pleasingly, N,N-diethylamide 19 was obtained in
56% yield in an unoptimised one-pot procedure from 17. With this
final intermediate in hand we subjected it to reaction with 4d un-
der the same Suzuki coupling conditions as used previously for 3a;
obtaining our target compound 20, bearing a 3-pyridyl motif, in a
respectable 90% yield. 5H-rufinamide derivative 20 was thus syn-
thesised in a 47% overall yield in four unoptimised steps, starting
from 1.0 mmol of azido-boronate F-1.
In conclusion, we have demonstrated that azido-boronate esters
such as 1 have the potential to undergo sequential coupling reactions
in high overall yield. The isolation and storage of 1 makes positive
improvements to process safety by eliminating contamination from
the azide anion, which is dangerously incompatiblewith a widerange
of common solvents, metal salts and acids.8 Finally, the successful
synthesis of 20 demonstrates the potential these substrates possess
for diversity-oriented synthesis of drug-like molecules. We are cur-
rentlyinvestigatingalternativecoresandfurtherapplicationsofthese
privileged structures.
7. (a) Bedford, R. B.; Nakamura, M.; Gower, N. J.; Haddow, M. F.; Hall, M. A.; Huwe,
M.; Hashimoto, T.; Okopie, R. A. Tetrahedron Lett. 2009, 50, 6110–6111; (b)
Torborga, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027–3043.
8. For selected discussions on the incompatibility, stability and safety of azides,
see Refs. 3a and 1b; Conrow, R. E.; Dean, W. D. Org. Process Res. Dev. 2008, 12,
1285–1286.
´
9. Fedorov, A. Yu.; Shchepalov, A. A.; Bolshakov, A. V.; Shavyrin, A. S.; Kurskii, Yu.
A.; Finet, J. P.; Zelentsov, S. V. Russ. Chem. Bull., Int. Ed. 2004, 53, 370–375.
10. Sviridov, S. I.; Vasil’ev, A. A.; Sergovskaya, N. L.; Chirskaya, M. V.; Shorshnev, S.
V. Tetrahedron 2006, 62, 2639–2647.
11. Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767–2770.
12. Huang, J.; Macdonald, S. J. F.; Harrity, J. P. A. Chem. Commun. 2009, 436–438.
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Tetrahedron Lett. 2009, 50, 5539–5541.
14. Naumov, M. I.; Nuchev, A. V.; Sitnikov, N. S.; Malysheva, Y. B.; Shavyrin, A. S.;
Beletskaya, I. P.; Gavryushin, A. E.; Combes, S.; Fedorov, A. Yu. Synthesis 2009,
1673–1682.
15. Cho, Y. A.; Kim, D.-S.; Ahn, H. R.; Canturk, B.; Molander, G. A.; Ham, J. Org. Lett.
2009, 11, 4330–4333.
16. Scrafton, D. K.; Taylor, J. E.; Mahon, M. F.; Fossey, J. S.; James, T. D. J. Org. Chem.
2008, 73, 2871–2874.
17. Loren, J. C.; Krasin´ ski, A.; Fokin, V. V.; Sharpless, K. B. Synlett 2005, 2847–2850.
18. (a) Jin, S.; Choudhary, G.; Cheng, Y.; Dai, C.; Li, M. Chem. Commun. 2009, 5251–
5253; (b) Significant binding should reduce the rate of substitution, which was
comparable when employing either 1 or 4-bromobenzyl bromide. 11B NMR
analysis was also consistent with this conclusion.
19. p-Tolylboronic acid (7) was synthesised as detailed, or purchased from Frontier
Scientific Europe, product code T6078; see Supplementary data for full details.
20. Abbenante, G.; Le, G. T.; Fairlie, D. P. Chem. Commun. 2007, 4501–4503.
21. After 3 h of irradiation (100 W Blak-Ray B100 UV lamp) the single-crystal X-ray
structure was unchanged, further details are available in the Supplementary
data.
Acknowledgements
22. (a) Párkányi, L.; Besenyei, G. J. Mol. Struct. 2004, 691, 97–106; (b) Chesterton, A.
K. S.; Jenkinson, S. F.; Jones, N. A.; Fleet, G. W. J.; Watkin, D. J. Acta Crystallogr.,
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23. Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288–325.
24. For use of TMS-acetylene in CuAAC reactions and in situ de-silylation of the
products, see: Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron Lett. 2008,
49, 7030–7032.
We are grateful to the EPSRC for funding. Dr. Stephen Flower is
thanked for helpful discussions.
Supplementary data
25. For discussions on atom-economy and protecting groups, see: (a) Clark, J. H.
Green Chem. 1999, 1–8; (b) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature
2007, 446, 404–408.
26. Wu, L.-Y.; Xie, Y.-X.; Chen, Z.-S.; Niu, Y.-N.; Liang, Y.-M. Synlett 2009, 1453–
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27. Though no particular efforts to scrub any hydroxides from the stream were
made, no significant detrimental effect on the boronate was observed. A similar
procedure was recently reported: Jiang, Y.; Kuang, C.; Yang, Q. Synlett 2009,
3163–3166.
Supplementary data (experimental procedures, compound
characterisation data, and X-ray crystal structure data for 1) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.05.104.
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