A direct route to triazole boronic esters and their application in the synthesis of small molecule arrays

Article abstract of DOI:10.1016/j.tetlet.2009.07.085

Alkynylboronates represent useful substrates for the direct synthesis of triazole boronic esters by their thermal cycloaddition with azides. A telescoped cycloaddition-cross-coupling protocol is reported and its employment in the synthesis of a small tria

Full text of DOI:10.1016/j.tetlet.2009.07.085

Tetrahedron Letters 50 (2009) 5539–5541
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct route to triazole boronic esters and their application in the synthesis
of small molecule arrays
Jianhui Huang a, Simon J. F. Macdonald b, Anthony W. J. Cooper b, Gail Fisher b, Joseph P. A. Harrity a,
*
a Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
b GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkynylboronates represent useful substrates for the direct synthesis of triazole boronic esters by their
thermal cycloaddition with azides. A telescoped cycloaddition–cross-coupling protocol is reported and
its employment in the synthesis of a small triazole array is disclosed.
Received 26 June 2009
Accepted 17 July 2009
Available online 21 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Recent studies in our laboratories have focused on the develop-
ment of thermal- and metal-mediated cycloaddition reactions of
alkynylboronates for the synthesis of aromatic and heteroaromatic
boronic esters.1,2 A synthetically useful paradigm has emerged
whereby benzene- and azine-based boronic esters can be accessed
by cycloaddition–cycloreversion strategies,3 whilst azole-based
analogues are generated by direct cycloaddition.4,5 In the context
of this programme, we recently became interested in the synthesis
of triazole boronic esters by a direct cycloaddition route.6 The
1,2,3-triazole ring is regarded as an important pharmacophore in
drug discovery research and is common amongst a plethora of
compounds of biological significance.7 We therefore wished to
investigate the potential of the alkynylboronate cycloaddition con-
cept to deliver a range of fully substituted triazole boronic esters,
with a view to employing this chemistry in the synthesis of a small
library of heterocycles using standard array platform technologies.
We report herein the successful realisation of this idea.
mely unstable and could not be further purified by chromatogra-
phy. However, the compounds were isolated as relatively clean
crude mixtures in high yield. Unfortunately, once again, the regi-
oselectivity was found to be rather disappointing.
These preliminary observations highlighted the potential insta-
bility of triazole boronic esters and this prompted us to explore the
potential of in situ cross-coupling methods. Moreover, we were
mindful that this particular goal complemented our ultimate aim
of employing this technique in an array format. Accordingly, we
investigated a telescoped cycloaddition–cross-coupling procedure
for the synthesis and functionalisation of the unstable boronic es-
ters 7a, b and 8a, b. As outlined in Scheme 1, we were pleased to
find that performing the cycloaddition and subsequently cross-
coupling the crude boronic ester intermediates with iodobenzene
using Fu’s protocol9 provided the corresponding triazoles 9 and
10. Moreover, these compounds were stable to chromatography
Our preliminary goal was to establish the feasibility of the ther-
mally promoted azide 1,3-dipolar cycloadditions with alkynylbor-
onates.8 Indeed, we were pleased to find that heating a mixture of
benzyl azide and a small selection of boronate-substituted alkynes
provided the corresponding triazoles in high yield (Table 1). To our
surprise however, we observed significant differences in both the
reaction regioselectivity and the product stabilities. Specifically,
trimethylsilyl-substituted alkyne 1 underwent cycloaddition in
high yield to provide 5a as a single regioisomer. In contrast, phen-
ylacetylene substrate 2 furnished two regioisomers 6a, b with poor
levels of selectivity. Nonetheless, the regioisomers were separable
by chromatography and the regiochemical assignments of 6a, b
were made by HMBC NMR spectroscopy. On attempting to extend
this chemistry to alkyl-substituted alkynes 3 (R = CH2OMe) and 4
(R = Prn), we were surprised to find that the products were extre-
Table 1
O
R
R
B
N
O
B
O
N
1-4
N
O
BnN3
O
N
DCB, 150 oC, 24 h
N
B
Bn
O
N
R
Bn
5a-8a
5b-8b
Yield (a:b)
Entry
R
1a
2
3
Me3Si; 1
5; 84% (100:0)
6; 63% (2:3)
7; 99%b,c
Ph; 2
MeOCH2; 3
4
Prn; 4
8; 99%b,c
a
The reaction was conducted at 110 °C.
Yield of crude product.
A regioselectivity of 3:2 was observed although regiochemical assignments
b
c
* Corresponding author. Tel.: +44 114 222 9496; fax: +44 114 222 9346.
E-mail address: j.harrity@sheffield.ac.uk (J.P.A. Harrity).
were not made in this case.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.085

5540
J. Huang et al. / Tetrahedron Letters 50 (2009) 5539–5541
the triazole ring. Accordingly, we prepared a 4Â4Â3 component
O
O
array consisting of azides bearing alkyl, benzyl and 2-ethanoate
groups, alkynylboronates consisting of silyl, phenyl, alkyl and
propargylic ether groups and electron neutral, rich and deficient
cross-coupling partners. The general scheme and structures of
the cycloaddition substrates are highlighted in Figure 1.
R
B
1.
R
Ph
R
N
N
3-4
N
N
BnN3
DCB, 150 oC, 24 h
N
N
Ph
Bn
Bn
2. 5% Pd2(dba)3
12% tBu3P.HBF 4, PhI
K3PO4, MeCN, 50 oC
R=MeOCH2: 9a; 35% 9b; 44%
R=nPr: 10a; 33% 10b; 39%
The cycloadditions were carried out in 1,2-dichlorobenzene at
150 °C in reaction tubes using a Radleys GreenHouseTM parallel syn-
thesiser. After 24 hours, each crude cycloadduct was portioned be-
tween three reaction tubes and a mixture of Pd2dba3 (5 mol %),
tBu3PÁHBF4 (12 mol %), K3PO4 and aryl iodide in MeCN was added.
After stirring at 50 °C overnight, the crude reaction mixture was
purified using a Flashmaster platform on a 10 g ISOLUTEÒ flash
column to provide the corresponding triazole products. In the
event, the 4Â4Â3 array provided 30 members which had purities
P90%. Upon closer inspection, it is clear that the less effective
members of the array are largely those compounds that originate
from the cross-coupling of 4-iodoanisole. Whilst it is not the
purpose of this study to optimise the cross-coupling reaction of
this particular aryl halide, we would expect that catalyst screening
Scheme 1.
and the regioisomers could be isolated as separate compounds in
good overall yield.
Having established that the cycloaddition and cross-coupling
processes could be successfully telescoped, we next demonstrated
that this chemistry could be exploited to make available a small
library of triazoles, thereby making the cycloaddition–coupling
technique of potential utility in the discovery of small bioactive
compounds. Specifically, we decided to prepare a 48-membered
library of triazoles with variable substitution at all 3 positions of
Table 2
a
b
c
d
SiMe3
SiMe3
SiMe3
SiMe3
N
N
N
N
N
N
N
N
Ar
Ar
Ar
Ar
N
N
N
N
Bn
Oct
A
Tol- m
CO2Et
Ar:Ph; 53% (95%)
Ar:Ph; 32% (95%)
Ar:Ph; 39% (95%)
Ar:p-MeOC6H4; --b
Ar:Ph; 28% (95%)
Ar:p-MeOC6H4; 40% (70%)
Ar:p-MeOC6H4; 29% (50%)
Ar:p-MeOC6H4; 47% (20%)
Ar:p-NO2C6H4; 30% (95%)
Ar: -NO2C6H4; 37% (50%)
p
Ar: -NO2C6H4; 23% (20%)
p
Ar:p-NO2C6H4; 37% (95%)
Ph
N
Ph
N
Ph
N
Ph
N
N
N
N
N
Ar
N
Ar
N
Ar
Ar
N
N
Bn
Oct
B
Tol-m
CO2Et
Ar:Ph; 26% (95%)
Ar:p-MeOC6H4; --b
Ar:Ph; 22% (95%)
Ar:Ph; 19% (90%)
Ar:Ph; 30% (95%)
Ar:p-MeOC6H4; 23% (30%)
Ar:p-NO2C6H4; 18% (90%)
25% (90%)c
Ar:p-MeOC6H4; 18% (30%)
Ar:p-NO2C6H4; 32% (60%)
Ar:p-MeOC6H4; 14% (95%)
Ar:p-NO2C6H4; 21% (50%)
Ar:p-NO2C6H4; 15% (90%)
nPr
N
nPr
N
nPr
N
nPr
N
N
N
N
N
Ar
N
Ar
N
Ar
Ar
N
N
C
Bn
Oct
Tol- m
CO2Et
Ar:Ph; 15% (95%)
24% (95%)c
Ar:p-MeOC6H4; 37% (60%)d
Ar:p-NO2C6H4; 16% (95%)
22% (40%)c
Ar:Ph; 27% (95%)d
Ar:p-MeOC6H4; 26% (85%)d
Ar:p-NO2C6H4; 21% (95%)
23% (95%)c
Ar:Ph; 20% (95%)
Ar:Ph;16% (95%)
18% (90%)c
Ar:p-MeOC6H4; 45% (60%)d
Ar:p-NO2C6H4; 16% (95%)
14% (95%)c
17% (95%)c
Ar:p-MeOC6H4; 33% (60%)d
Ar:p-NO2C6H4; 12% (95%)
OMe
N
OMe
N
OMe
N
OMe
N
N
N
N
N
Ar
N
Ar
N
Ar
N
Ar
N
Bn
Oct
D
Tol- m
Ar:Ph; 10% (95%)
27% (80%)c
CO2Et
Ar:Ph; 20% (95%)
24% (95%)c
Ar:Ph;21% (95%)
25% (95%)c
Ar:Ph; --b
Ar: -MeOC H ; 11% (95%)
p
6
4
Ar: -MeOC H ; 23% (95%)
p
27% (40%)c
6
4
Ar:p-MeOC6H4; 15% (95%)
19% (95%)c
Ar:p-MeOC6H4; 16% (90%)
15% (90%)c
19% (90%)c
Ar:p-NO2C6H4; 13% (95%)
16% (95%)c
Ar:p-NO2C6H4; 43% (85%)d
Ar: -NO2C6H4; 22% (95%)
p
Ar: -NO2C6H4; 27% (95%)
p
30% (95%)c
22% (95%)c
a
b
c
Compound purities indicated in parentheses, as judged by LC–MS and NMR spectroscopy.
The desired compounds were not isolated in this case.
Yield (purity) of separated regioisomers. Regiochemical assignment was not carried out.
Yield (purity) of inseparable regioisomeric mixtures.
d

J. Huang et al. / Tetrahedron Letters 50 (2009) 5539–5541
5541
Acknowledgements
O
O
R2
B
1.
R2
R3
N
N
We are grateful to the EPSRC (EP/E016898/1) and GlaxoSmithK-
line for financial support.
R1N3
N
N
DCB, 150 oC, 24 h
2. 5% Pd2(dba)3, R3I
12% tBu3P.HBF 4
R3
R2
N
N
R1
R1
Supplementary data
K3PO4, MeCN, 50 oC
Supplementary data (synthetic procedures, 1H and 13C NMR
spectra of all compounds and LC–MS spectra of compounds listed
in Table 2) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.07.085.
O
O
O
Me3Si
B
Ph
B
O
References and notes
A
B
D
1. For recent overviews see: (a) Hilt, G.; Bolze, P. Synthesis 2005, 2091; (b)
Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209.
2. For recent examples of the synthesis of aromatic and heteroaromatic boronic
esters by alkynylboronate cycloadditions, see: (a) Davies, M. W.; Johnson, C. N.;
Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525; (b) Hilt, G.; Smolko, K. I. Angew.
Chem., Int. Ed. 2003, 42, 2795; (c) Yamamoto, Y.; Ishii, J.-i.; Nishiyama, H.; Itoh,
K. J. Am. Chem. Soc. 2004, 126, 3712; (d) Gandon, V.; Leca, D.; Aechtner, T.;
Vollhardt, K. P. C.; Malacria, M.; Aubert, C. Org. Lett. 2004, 6, 3405; (e) Gandon,
V.; Leboeuf, D.; Amslinger, S.; Vollhardt, K. P. C.; Malacria, M.; Aubert, C. Angew.
Chem., Int. Ed. 2005, 44, 7114; (f) Sato, S.; Isobe, H.; Tanaka, T.; Ushijima, T.;
Nakamura, E. Tetrahedron 2005, 61, 11449; (g) Barluenga, J.; Barrio, P.; Riesgo,
L.; López, L. A.; Tomas, M. J. Am. Chem. Soc. 2007, 129, 14422.
O
O
O
Prn
B
B
O
MeO
C
BnN3 OctnN3
EtO2CCH2N3
N3
a
b
d
c
3. (a) Moore, J. E.; York, M.; Harrity, J. P. A. Synlett 2005, 860; (b) Helm, M. D.;
Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2005, 44, 3889; (c)
Delaney, P. M.; Moore, J. E.; Harrity, J. P. A. Chem. Commun. 2006, 3323; (d)
Gomez-Bengoa, E.; Helm, M. D.; Plant, A.; Harrity, J. P. A. J. Am. Chem. Soc. 2007,
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Tetrahedron 2008, 64, 866; (f) Delaney, P. M.; Huang, J.; Macdonald, S. J. F.;
Harrity, J. P. A. Org. Lett. 2008, 10, 781.
Figure 1.
would ultimately overcome this issue. Significantly however, there
are no such trends with respect to the azide/alkynylboronate com-
binations, suggesting that there is potential for these cycloaddi-
tions to be widely applied on the array platform.10 Moreover, the
yield would likely be generally higher if any given analogue was re-
peated as a single reaction (compare yields of 9a, b in Scheme 1
with array grid point DÂaÂPh in Table 1 and 10a, b with grid point
CÂa ÂPh) (Table 2).
4. (a) Moore, J. E.; Goodenough, K. M.; Spinks, D.; Harrity, J. P. A. Synlett 2002,
2071; (b) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow, R. A. J.; York,
M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron 2005, 61, 6707.
5. For a recent cycloaddition–cycloreversion route to pyrazoles see: (a) Browne,
D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2007, 46, 8656;
(b) Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. J. Am.
Chem. Soc. 2009, 131, 7762.
6. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565; (b) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1963, 2, 633; (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008,
108, 2952.
7. Fan, W.-Q.; Katritzky, A. R.. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 4, pp 1–126.
8. For a preliminary account of this work see: Huang, J.; Macdonald, S. J. F.;
Harrity, J. P. A. Chem. Commun. 2009, 436.
9. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
10. The presence of regioisomers ultimately provides >48 compounds and these
were generally separable by LC–MS. In some cases both regioisomers could not
be isolated in sufficient yield and only a single compound is noted where
appropriate. Nonetheless, the solution phase studies outlined herein suggest
that all processes should give rise to an approximately equal ratio of
regioisomers, except in the case of the trimethylsilyl alkynylboronate 1.
In summary, we have reported a direct route to novel triazole
boronic esters by the thermal cycloaddition of alkynylboronates
and azides. Alkynes bearing a range of alkyl/aryl groups undergo
cycloaddition in good yield but with poor regiocontrol. In sharp
contrast, the trimethylsilyl-substituted alkynes react with a range
of azides to provide the corresponding triazoles in high yield and
with excellent regiocontrol. Furthermore, the power of this chem-
istry to prepare libraries of triazoles using standard protocols for
the assembly of small molecule arrays has been exemplified.