Synthesis of unsymmetrical 1,1′-disubstituted bis(1,2,3-triazole)s using monosilylbutadiynes

Article abstract of DOI:10.1021/ol102852z

Bis(1,2,3-triazole)s have attracted recent interest as coordinating ligands for transition metals. Here we report a rapid, modular method for the synthesis of 1,1′-disubstituted-4,4′-linked unsymmetrical bis(1,2,3-triazole)s. The method employs sequential

Full text of DOI:10.1021/ol102852z

ORGANIC
LETTERS
2011
Vol. 13, No. 3
537-539
Synthesis of Unsymmetrical
1,1′-Disubstituted Bis(1,2,3-triazole)s
Using Monosilylbutadiynes
Bradley C. Doak, Martin J. Scanlon, and Jamie S. Simpson*
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash UniVersity, 381 Royal Parade, ParkVille, VIC, 3052, Australia
Jamie.Simpson@monash.edu
Received November 25, 2010
ABSTRACT
Bis(1,2,3-triazole)s have attracted recent interest as coordinating ligands for transition metals. Here we report a rapid, modular method for the
synthesis of 1,1′-disubstituted-4,4′-linked unsymmetrical bis(1,2,3-triazole)s. The method employs sequential copper catalyzed azide-alkyne
cycloaddition and deprotection steps on a monosilylbutadiyne. TMS (trimethylsilyl) and TIPS (triisopropylsilyl) were both investigated with
TIPS being the preferred protecting group due to increased stability. The reactions were amenable to one-pot synthesis, and an optimized
one-pot, three-step procedure was developed.
The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
was reported in 2002 independently by both the Meldal and
Sharpless groups and has come to be the quintessential click
reaction.1 It is generally high yielding and can be conducted
under mild conditions leading to its widespread application in
chemistry. The resulting triazole moiety has attracted attention
for its coordinating properties,2 including those of the sym-
metrical bis(1,2,3-triazole)s.3 Metal-coordinated triazoles have
been shown to be efficient catalysts and to form supramolecular
structures, and varying substituents plays an important role in
tuning these properties.4 Despite this interest, a flexible and
efficient synthesis of unsymmetrical 4,4′-linked bis(1,2,3-
triazole)s has had little attention until very recently.
Fiandanese et al.5a first reported the synthesis of a number
of simple unsymmetrical bistriazoles using mono TMS-
butadiyne (TMS, trimethylsilyl). Initial CuAAC with an azide
followed by deprotection with TBAF (tetrabutylammonium
fluoride) and subsequent CuAAC gave the desired unsym-
metrical bis(1,2,3-triazole)s. More recently Aizpurua et al.
reported a synthesis which employed a CuAAC with propargyl
alcohol, followed by conversion to the ethynyltriazole (Swern
oxidation, then Ohira-Bestmann homologation) and then
subsequent CuAAC to the unsymmetrical bis(1,2,3-triazole)s.5b
Recognizing the limitations associated with this method, Aiz-
purua et al. also employed the TMS-butadiyne method to
produce a number of unsymmetrical bis(1,2,3-triazole)s.
At the same time, our laboratory was investigating a TMS-
butadiyne based approach; however as we describe below,
we encountered limitations that drove us to develop a more
widely applicable approach to unsymmetrical 1,1′-disubsti-
tuted-4,4′-linked bis(1,2,3-triazole)s, which we report here.
Initially, we utilized the monodeprotection of bis-TMS-
butadiyne to give TMS butadiyne (1),6 and reaction with
benzyl azide under standard CuAAC conditions produced
the silyl protected ethynyltriazole 2,5 along with small
amounts of deprotected ethynyltriazole 3 and symmetrical
(1) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornoe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Meldal, M.; Tornoe,
C. W. Chem. ReV. 2008, 108, 2952.
(2) (a) Struthers, H.; Mindt, T. L.; Schibli, R. Dalton Trans. 2010, 39,
675. (b) Yano, M.; Tong, C. C.; Light, M. E.; Schmidtchen, F. P.; Gale,
P. A. Org. Biomol. Chem. 2010, 8, 4356. (c) Crowley, J. D.; Bandeen,
P. H.; Hanton, L. R. Polyhedron 2010, 29, 70. (d) Urankar, D.; Pinter, B.;
Pevec, A.; De Proft, F.; Turel, I.; Kossˇmrlj, J. Inorg. Chem. 2010, 49, 4820.
(3) (a) Monkowius, U.; Ritter, S.; Konig, B.; Zabel, M.; Yersin, H. Eur.
J. Inorg. Chem. 2007, 29, 4597. (b) Fletcher, J. T.; Bumgarner, B. J.; Engels,
N. D.; Skoglund, D. A. Organometallics 2008, 27, 5430. (c) Crowley, J. D.;
Bandeen, P. H. Dalton Trans. 2010, 39, 612.
(4) (a) Warsink, S.; Drost, R. M.; Lutz, M.; Spek, A. L.; Elsevier, C. J.
Organometallics 2010, 29, 3109. (b) Schuster, E. M.; Botoshansky, M.;
Gandelman, M. Angew. Chem., Int. Ed. 2008, 47, 4555. (c) Gower, M. L.;
Crowley, J. D. Dalton Trans. 2010, 39, 2371.
10.1021/ol102852z  2011 American Chemical Society
Published on Web 01/12/2011

bistriazole 4. Aizpurua et al. also noted isolation of sym-
metrical bistriazoles from some azides in this manner and
reported overcoming this by changing conditions to CuI,
EtN(i-Pr)2 in acetonitrile; in our hands these conditions also
gave similar amounts of symmetrical bistriazole. Deprotec-
tion with KF gave ethynyl triazole 3 in quantitative yield,
and subsequent CuAAC with a variety of azides then gave
a number of unsymmetrical bistriazoles 5a-e in moderate
to low yields (Table 1).
Scheme 1
.
Synthesis of Symmetrical Bistriazole 7, and
4-(TIPSethynyl)triazole 9a
Table 1. Initial Synthesis of Unsymmetrical Bistriazole with
TMS Protectiona
protected butadiyne (TIPS, triisopropylsilyl), in order to
retain the selective and modular nature of the synthesis but
with greater functional group tolerance.
TIPS-protected butadiyne 8 was prepared according to the
reported procedure in 70% yield over three steps.8
Subsequent CuAAC with azide 6 then gave silyl protected
ethynyl triazole 9a in 54 and 48% yield with copper iodide
and copper sulfate/sodium ascorbate procedures respectively;
no symmetrical bistriazole was observed. Given the moderate
yield of silyl protected ethynyl triazole 9a, optimization by
excluding oxygen and the addition of catalytic amounts of
tris-(benzyltriazolylmethyl)amine (TBTA) was undertaken,
improving the yield of 9a to 65% (Table 2).9 Both TBAF
and CsF were used to deprotect TIPS ethynyl triazole 9b in
Table 2. Synthesis of 4-Ethynyltriazoles with TIPS Protectiona
a Conditions: (a) CuSO4·5H2O, Na ascorbate, 2:1 t-BuOH/H2O; (b) CuI,
EtN(i-Pr)2, MeCN; (c) KF, MeOH. b Yield of isolated purified product.
In seeking to investigate a broader range of substitutents
in this reaction, we trialled the CuAAC with (S)-azidoben-
zylacetic acid (6) under standard conditions but found the
symmetrical bistriazole 7 as the major product in 40% yield
(Scheme 1). The increased yield of bistriazole was attributed
to the acidic nature of azide 6 leading to cleavage of the
TMS group. Noting the reported instability of the TMS group
to copper,7 we sought to utilize the more stable TIPS-
(5) (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo,
F. Tetrahedron 2009, 65, 10573. (b) Aizpurua, J. M.; Azcune, I.; Fratila,
R. M.; Balentova, E.; Sargartzazu-Azipurua, M.; Miranda, J. I. Org. Lett.
2010, 12, 1584.
a Conditions: (a) CuI, EtN(i-Pr)2, TBTA, under N2; (b) TBAF. b Yield
of isolated purified product. c Decomposed during purification. d CsF
procedure.
(6) Holmes, A. B.; Jennings-White, C. L. D.; Schulthess, A. H. Chem.
Commun. 1979, 840.
538
Org. Lett., Vol. 13, No. 3, 2011

97 and 80% yield respectively, demonstrating TBAF to be
the preferred fluoride source. A number of TIPS ethynyl
triazoles 9b-e were then synthesized by this method (Table
2), and some converted to bistriazoles (Table 3).
Scheme 2. One-Pot Two-Step Procedures
Table 3. Synthesis of Bis(1,2,3-triazole)sa
Table 4. One-Pot Three-Step Synthesis of Bistriazolesa
a Conditions: CuI, EtN(i-Pr)2, TBTA, under N2. b Isolated purified yield.
1
After TBAF deprotections, the H NMR spectrum of the
crude product showed that both the CuAAC and silyl
deprotection generally proceeded with high conversion and
gave only inoffensive byproducts. This suggested a one-pot
multistep procedure may also give the desired bistriazoles
while reducing time and the number of isolation and
purification steps required.
a Conditions: (a) CuI, EtN(i-Pr)2, TBTA, MeCN, under N2, 20 h; (b)
TBAF, 20 min then AcOH; (c) 16 h. b Isolated purified yield.
Initially, one-pot two-step procedures for the initial
CuAAC/TBAF deprotection and alternately the TBAF
deprotection/final CuAAC were conducted with good results;
in either case, the overall yield for the three steps was 45%
for bistriazole 11b (Scheme 2), compared to 43% overall
for the three separate reactions. Two additional one-pot click
and deprotection reactions (Scheme 2) gave similar results.
We next investigated a one-pot three-step procedure. The
one-pot three-step synthesis of bistriazole 11b gave a yield
of 49% for a slight improvement over the multipot ap-
proaches (Table 4, entry b). Two additional novel bistriazoles
were then synthesized via the one-pot procedure (Table 4),
demonstrating a viable synthetic approach involving a single
purification step.
In summary, an efficient and selective modular synthesis
of 1,1′-unsymmetrical-4,4′-linked bis(1,2,3-triazole)s from
silylbutadiynes was developed. This method is amenable to
a simple, one-pot three-step procedure.
Acknowledgment. We thank Monash Universtiy for
funding. B.C.D. was supported by an APA scholarship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all novel compounds and
key literature compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) Valverde, I. E.; Delmas, A. F.; Aucagne, V. Tetrahedron 2009, 65,
7597.
(8) Jiang, M. X.-W.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004,
126, 5970.
(9) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853.
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