Thermal, non-catalyzed Huisgen cycloaddition for the preparation of 4,5-bis(trimethylsilyl)-1H-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2012.11.019

The 1,2,3-triazole scaffold is an important pharmacophore and a versatile, increasingly leveraged, substructure in biochemical, materials, polymer, and metal-coordinating applications. Continuing advances in 1,2,3-triazole construction, by either non-catalyzed or metal-catalyzed azide/alkyne cycloaddition, foster further creative use. The work reported here establishes a general protocol for the synthesis of 4,5-bis(trimethylsilyl)-1H-1,2,3- triazoles via thermal Huisgen cycloaddition between azides and bis(trimethylsilyl)acetylene.

Full text of DOI:10.1016/j.tetlet.2012.11.019

Tetrahedron Letters 54 (2013) 272–276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thermal, non-catalyzed Huisgen cycloaddition for the preparation
of 4,5-bis(trimethylsilyl)-1H-1,2,3-triazoles
Ronald G. Brisbois a, , Alexandra M. Bergan b, Aubrey J. Ellison a, Percy Y. Griffin a, Kent C. Hackbarth a,
⇑
Steven R. Larson a
a Department of Chemistry, Macalester College, 1600 Grand Avenue, St. Paul, MN 55105-1899, USA
b Century Community College, 3300 Century Avenue North, White Bear Lake, MN 55110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,2,3-triazole scaffold is an important pharmacophore and a versatile, increasingly leveraged, sub-
structure in biochemical, materials, polymer, and metal-coordinating applications. Continuing advances
in 1,2,3-triazole construction, by either non-catalyzed or metal-catalyzed azide/alkyne cycloaddition,
foster further creative use. The work reported here establishes a general protocol for the synthesis
of 4,5-bis(trimethylsilyl)-1H-1,2,3-triazoles via thermal Huisgen cycloaddition between azides and
bis(trimethylsilyl)acetylene.
Received 16 October 2012
Revised 2 November 2012
Accepted 5 November 2012
Available online 20 November 2012
Keywords:
1,2,3-Triazole
Azide
Ó 2012 Elsevier Ltd. All rights reserved.
Bis(trimethylsilyl)acetylene
Cycloaddition
Introduction
fluorophores.10,12 We envisioned incorporation of 4,5-bis(trimeth-
ylsilyl)-1,2,3-triazole moieties into our targeted click-activated
The 1,2,3-triazole scaffold, which is chemically robust, can act
as a hydrogen bond acceptor, and imparts a significant local dipo-
fluorophores because of likely influence on solubility imparted by
trialkylsilyl substituents and because fluorophore derivatization
via metal-catalyzed cross coupling becomes possible upon replace-
ment of trialkylsilyl substituents by a halogen atom.13,14 We in-
tended to construct 4,5-bis(trimethylsilyl)-1,2,3-triazole moieties
via Huisgen cycloaddition between azide precursors and commer-
cially available bis(trimethylsilyl)acetylene (BTMSA), and our
search of the literature in this regard found only seven such scaf-
folds previously reported and no established general proce-
dure.13a,15,16 Thus, we decided to optimize a protocol for Huisgen
cycloaddition between azides and BTMSA and explore its scope
and limitations.
larity (l
= 5.2–5.6 D),1 has been known in the literature for about
120 years,2 and these heterocyclic aromatic systems have re-
mained valuable as pharmacophores in biologically active mole-
cules.3 Huisgen pioneered synthetic access to 1,2,3-triazoles by
demonstrating the effectiveness of thermal [3+2] dipolar cycload-
dition between azides and alkynes.4 In general, Huisgen cycloaddi-
tion is limited by the lack of regiocontrol obtained for reactions
between azides and unsymmetrically substituted alkynes. The
development of Cu-catalyzed Huisgen cycloaddition (the essen-
tially de facto example of a click reaction)5 and the complementary
Ru-catalyzed approach6 have furnished regiocontrol and facilitated
a renaissance extending 1,2,3-triazole synthesis and creative appli-
cation to biochemical ligating and tagging,7 polymers,8 metal coor-
dination complexes,9 and enhancement of photo-physical
properties (e.g., click-activated fluorescence).10 Such increased
attention in 1,2,3-triazole synthesis and application has also moti-
vated further, recent investigations of thermal Huisgen cycloaddi-
tion, with the so-called strained promoted reactions having gained
particular notarity.11
Results and discussion
Our preliminary optimization experiments were performed
with 2 equiv of BTMSA and 1 equiv of benzyl azide 1. We quickly
Among our interests regarding applications of Huisgen cycload-
dition, we have recently begun preparing novel, click-activated
⇑
Corresponding author. Tel.: +1 651 696 6270; fax: +1 651 696 6432.
E-mail address: brisbois@macalester.edu (R.G. Brisbois).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.019

Table 1
Entry
Azidea
4,5-Bis(TMS) productb (%yld)
Entry
11
Azidea
4,5-Bis(TMS) productb (%yld)
1
12c
2
3
4
5
13
14
15
(continued on next page)

Table 1 (continued)
Entry
Azidea
4,5-Bis(TMS) productb (%yld)
Entry
16
Azidea
4,5-Bis(TMS) productb (%yld)
6
7
17
8
9
18d
19
10
a
Alkyl azides were prepared from commercially available bromo or chloro precursors via O’Neil, E. J.; DiVittorio, K. M.; Smith, B. D. Org. Lett. 2007, 9, 199–202; 1-azidonaphthalene was prepared from commercially available
1-aminonaphthalene via Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811.
b
Isolated yields.
c
The mono-desilylated product was also isolated in 15% yield with respect to molar amount of the corresponding azide used.
d
Azide purchased from Sigma–AldrichÒ
.

R. G. Brisbois et al. / Tetrahedron Letters 54 (2013) 272–276
275
learned that a greater excess of BTMSA was required and used
5 equiv for all subsequent optimization experiments (Scheme 1),
which varied solvent, reaction temperature, and, ultimately, even
reaction glassware. Although the desired reaction would proceed
in polar solvent (e.g., THF, THF–H2O (1:1), CHCl3), we observed
varying degrees of desilylation in product mixtures. Less polar sol-
vent (e.g., toluene or xylene) suppressed the formation of desilylat-
ed products, and we found toluene preferable because it provided
an adequate range for temperature variation while also being eas-
ily removed via rotary evaporation. Typical of many non-catalyzed
Huisgen cycloadditions, the reaction required elevated tempera-
tures to form desired products, with little or no product formed be-
low 80 °C. Even at reflux in toluene, the reaction is slow, as well as
impacted by the low boiling point and volatility of BTMSA. Addi-
tionally, as reaction temperature was raised, we obtained increas-
ingly darkened reaction mixtures for reactions run in standard
glassware (i.e., round-bottomed flask, jacketed condenser, gas
take-off adapter for connection to a double manifold) even when
an argon atmosphere was maintained. When we used a thick-
walled re-sealable tube (with threaded Teflon cap),17 and gently
degassed18 the reaction mixture prior to heating at 100 °C (oil
bath) for 72 h, the reaction proceeded cleanly and with virtually
no discoloration, providing an optimized protocol (Scheme 1) that
was used to explore scope and limitations.
Nineteen additional cases were explored, as shown in Table 1.
Except in the case of 2-azidoacetophenone (Table 1, entry 12),
for which the crude reaction mixture became significantly dark-
ened and slightly tarry, we did not observe nor isolate other desi-
lylated products. For the other cases, the reactions were generally
clean, easily purified, and typically formed desired products with
very good isolated yield. We did obtain an attenuated—but service-
able—yield for a benzimidazole-derived azide (Table 1, entry 7),
while a quinazolinone-derived azide (Table 1, entry 8) reacted to
give a low yield of the corresponding product. In contrast to those
heterocyclic aromatic scaffolds, an indole-derived azide (Table 1,
entry 14) reacted very well, as did an isoxazole-derived azide (Ta-
ble 1, entry 9). Circumstantially, the downward trend in isolated
yield from indole (Table 1, entry 14) to benzimidazole (Table 1, en-
try 7) to quinazolinone (Table 1, Entry 8) tracks with the decreas-
ing pKa of the corresponding N–H sites for each. For that matter,
the results for azidoacetophenone (Table 1, entry 12), which fea-
tures an active methylene site, might also reveal additional sub-
tlety in the overall reaction profile as a function of the starting
azide pKa. Curiously, a simple aliphatic ester azide (Table 1, entry
15) reacted with a moderate—but serviceable—yield, whereas a
tris-acetylated tetrahydropyran-derived azide (Table 1, entry 18)
reacted to provide very good isolated yield, illustrating the poten-
tial for preparing other 4,5-bis(trimethylsilyl)-1,2,3-triazolyl mod-
ified sugars. Pleasingly, two bis-azide compounds (Table 1, entries
10 and 11) reacted quite efficiently and raised the possibility of no-
vel applications. For example, in the case of the biphenyl bis-azide
(Table 1, entry 10), invocation of an analogous, but enantiopure,
binaphthyl bis-azide suggests the likelihood of generating a chiral
bidentate ligand for potential metal ligation and catalyst design.
In a related sense, the bis(1,2,3-triazolyl)quinoxaline product (Ta-
ble 1, entry 11) directly provides a scaffold for potential metal
coordinating applications, considering it features two neutral,
bidentate binding sites. (We note that, in complement, the 1,2,3-
triazolylbenzimidazole product (Table 1, entry 7) offers, upon
deprotonation, the possibility of an anionic, bidentate site for me-
tal ligation applications). Representative of aryl azides, 1-azido-
naphthalene (Table 1, entry 19) reacted smoothly to form the
corresponding product with effectively double a previously re-
ported yield.16d
3-triazoles via thermal Huisgen cycloaddition between azides
and commercially available bis(trimethylsilyl)acetylene. Both
mono and bis-azide precursors have been shown to react
smoothly. This work complements the existing literature docu-
menting 1,2,3-triazole synthesis by establishing a general protocol
that others can apply directly or leverage as a dependable starting
point for fine tuning in the specific way a novel synthetic situation
might require and/or laboratory equipment holdings allow.19
Experimental procedure
General synthetic protocol
To an oven-dried 15 mL Ace Glass re-sealable pressure tube
(# 8648), a dried 1-inch teflon-coated magnetic stir bar is added.
Argon-sparged anhydrous toluene (5 mL) is added to the re-
sealable pressure tube via syringe. The previously prepared azide
is massed using either a sheet of weighing paper for solids or a
glass Pasteur pipette (cut with a diamond DremelÒ tool to fit with-
in the balance housing) for liquid azides of unknown density. In the
latter case, a portion of the total 5 mL of anhydrous toluene is used
to rinse through the glass Pasteur pipette to ensure quantitative
transfer. While stirring, the azide (0.075–0.100 g, 1 equiv) is added
to the toluene. The re-sealable pressure tube is then capped with
two septum stoppers: first a 19/22–19/38 Chemglass septum
(CG-3022-26) is fitted in the standard way and then a 24/40–24/
25 Chemglass septum (CG-3022-28) is placed—upside down—over
the 19/22–19/38 septum. Using a needle-tipped line from a vac-
uum/gas double manifold (needle = B–DÒ PrecisionGlideÒ 21 G
#305167), the reaction mixture is subjected to three gentle vac-
uum (house vacuum @ 150–200 mm Hg for 5 s)/argon back-fill cycles.
Via a Kloehn™ syringe with a fixed needle, bistrimethylsilylacetylene
(5 equiv) is then added to the re-sealable pressure tube. The two septa
are removed and quickly replaced with the re-sealable pressure tube’s
screw cap. The re-sealable pressure tube is then submerged in either a
mineral oil bath or a silicone oil bath at 100 °C and allowed to react for
72 h with rapid stirring. After 72 h, the re-sealable pressure tube is re-
moved from the oil bath, cooled to room temperature, and TLC analy-
sis is performed, using Dragendorf-Munier solution20 to obtain highly
diagnostic (orange) staining of 1,2,3-triazole products. Using 25–30 mL
of methyl tert-butyl ether to aid quantitative transfer of the reaction
mixture to a separatory funnel, a liquid–liquid extractive work-up is
performed in which the organic layer is washed with 2 Â 15 mL de-
ionized H2O. The aqueous layer is salted out using solid NaCl and then
back-extracted using 15 mL of methyl tert-butyl ether. The combined
organic layers are washed with 1 Â 25 mL of saturated NaCl solution.
Anhydrous Na2SO4 is then used to dry the combined organic layers,
prior to filtration through a fluted paper filter and concentration on
a rotary evaporator. Flash column chromatography21 is performed to
purify products.
Acknowledgements
R.G.B. thanks Macalester College and the National Science Foun-
dation (CHE-1062944) for the financial support to purchase equip-
ment and materials. A.M.B. and S.R.L. thank the National Science
Foundation (CHE-1062944) for undergraduate research stipend
support. PYG and KCH thank the Macalester College Beltmann
Fund for undergraduate research stipend support. A.J.E. thanks
the Macalester College Leonard Fund for undergraduate research
stipend support. We thank Professor J. Thomas Ippoliti (University
of St. Thomas, St. Paul, MN) for generously providing us access to a
Biotage Initiator™ Microwave Synthesizer. We also thank Rob Ros-
si for numerous forms of assistance provided via his role as the
Chemistry Department Laboratory Supervisor.
In summary, we have reported an experimentally straightfor-
ward method for the preparation of 4,5-bis(trimethylsilyl)-1,2,

276
R. G. Brisbois et al. / Tetrahedron Letters 54 (2013) 272–276
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Supplementary data (general experimental details and 1H and
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2) associated with this article can be found, in the online version,
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19. Although we do not possess
completely reasonable urgings of
assistance in this regard from colleague at
a
laboratory-grade microwave reactor, the
reviewer motivated us to obtain
different university. For
a
a
a
example, using a Biotage Initiator™ microwave synthesizer, the reaction of
benzyl azide 2 (1 equiv) and BTMSA (5 equiv) in toluene (and degassed as
described under experimental procedure) was driven to completion by
microwave heating at 165 °C for 20 min. Thus, researchers working in
laboratories equipped with microwave reactors have the option to test that
alternative mode of heating when running reactions between azides and
BTMSA.
20. Dragendorf-Munier Recipe used: dissolve 10 g KI in 40 mL de-ionized H2O.
Dissolve 20 g tartaric acid in 80 mL de-ionized H2O. Mix these solutions, with
stirring, in an Erlenmeyer flask prior to adding 1.5 g Bi(NO3)3Á5H2O. Continue
stirring the entire mixture 15 min before filtering through a fluted paper filter.
Essentially instantaneous (orange) staining of 1,2,3-triazole products is
obtained by quickly dipping the TLC plate into the solution.
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