"click" synthesis of nonsymmetrical bis(1,2,3-triazoles)

Article abstract of DOI:10.1021/ol1003127

Chemical Fig. Repretation Unsymmetrically 1,1'-disubstituted 4,4'-bis-1 H-1,2,3-triazoles 4 have been prepared from 4-ethynyl-1,2,3-triazoles 5 and azides. Following a "double-click" strategy, two complementary approaches were implemented for the preparation of the key 4-ethynyltriazole Intermediates 5: (a) the stepwise Swern oxidatlon/Ohira-Bestman alkynylation of readily available 4-hydroxymethyl-1,2,3-triazoles 8 and (b) the stepwise cycloaddition of TMS-1,4-butadiyne 9. The method is highlighted by Its compatibility with orthogonally protected and functlonallzed saccharide-peptide hybrids and its ability to be extended to the trlsubstituted counterparts 12.

Full text of DOI:10.1021/ol1003127

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1584-1587
“Click” Synthesis of Nonsymmetrical
Bis(1,2,3-triazoles)
Jesus M. Aizpurua,*,† Itxaso Azcune,† Raluca M. Fratila,*,‡ Eva Balentova,†
Maialen Sagartzazu-Aizpurua,† and Jose I. Miranda
Departamento de Qu´ımica Orga´nica-I, UniVersidad del Pa´ıs Vasco, Joxe Mari Korta
R&D Center, AVda Tolosa-72, 20018 San Sebastia´n, Spain, and Faculty of Science
and Technology, SupraMolecular Chemistry & Technology (SMCT), UniVersity of
Twente, 7500 AE Enschede, The Netherlands
jesusmaria.aizpurua@ehu.es; r.m.fratila@tnw.utwente.nl
Received February 5, 2010
ABSTRACT
Unsymmetrically 1,1′-disubstituted 4,4′-bis-1H-1,2,3-triazoles 4 have been prepared from 4-ethynyl-1,2,3-triazoles 5 and azides. Following a
“double-click” strategy, two complementary approaches were implemented for the preparation of the key 4-ethynyltriazole intermediates 5: (a)
the stepwise Swern oxidation/Ohira-Bestman alkynylation of readily available 4-hydroxymethyl-1,2,3-triazoles 8 and (b) the stepwise cycloaddition
of TMS-1,4-butadiyne 9. The method is highlighted by its compatibility with orthogonally protected and functionalized saccharide-peptide
hybrids and its ability to be extended to the trisubstituted counterparts 12.
Since the discovery and recent development of the Cu(I)-
catalyzed alkyne-azide “click” cycloaddition reaction,1 the
1,2,3-triazole heterocyclic motif has rapidly become one of
the most popular structures in conjugate chemistry finding
applications in the preparation of hybrid compounds, surface
modification of materials and biomaterials, and molecular
scaffolding.2,3
In contrast to this breakthrough in monocyclic triazole
chemistry, the bis(1,2,3-triazole) counterparts 1 and 2 (Figure
1) have received little attention, despite their evident
† Universidad del Pa´ıs Vasco.
‡ University of Twente.
(1) (a) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057–3064. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2598.
Figure 1. Symmetrically substituted bis(1,2,3-triazoles).
(2) For reviews, see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004–2021. (b) Kolb, H. C.; Sharpless,
K. B. Drug DiscoVery Today 2003, 8, 1128–1137. (c) Lutz, J.-F. Angew.
Chem., Int. Ed. 2007, 46, 1018–1025. (d) Moses, J. E.; Moorhouse, A. D.
Chem. Soc. ReV. 2007, 36, 1249–1262. (e) Lutz, J.-F.; Zarafshani, Z. AdV.
Drug DeliVery ReV. 2008, 60, 958–970. (f) Moorhouse, A. D.; Moses, J. E.
ChemMedChem 2008, 3, 715–723. (g) Tron, G. C.; Pirali, T.; Billington,
R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res. ReV. 2008,
similarities with biaryl compounds.4 In addition, 4,4′,5,5′-
tetrasubstituted bis(1,2,3-triazoles) 3 may display axial
28, 278–308
.
(4) (a) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38,
2447–2464. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV.
2003, 103, 893–930.
(3) QSAR Comb. Sci. 2007, 26(11)is a special issue on click chemistry
and its applications.
10.1021/ol1003127  2010 American Chemical Society
Published on Web 03/02/2010

chirality, as demonstrated by Burgess.5 To the best of our
knowledge, however, only symmetrically substituted bis(1,2,3-
triazoles) 1-3 have been prepared to date,6 and no practical
method for the synthesis of the unsymmetrically substituted
counterparts is known.7
We reasoned that the desired 4-ethynyltriazoles 5 could
be obtained from the readily available 4-hydroxymethyl
derivatives 8 through a two-step procedure involving the
Swern oxidation followed by the Ohira-Bestmann alkyny-
lation.14 As disclosed in Table 1, the Cu(I)-catalyzed click
Herein we report an approach to unsymmetrically disub-
stituted bis-1,2,3-triazoles (Scheme 1) involving a “click”
Table 1. Stepwise Preparation of 4-Ethynyl-1,2,3-triazoles 5
Scheme 1. Retrosynthesis of 4,4′-Disubstituted
Bis(1,2,3-triazoles) 4 from 4-Ethynylmonotriazoles 5 and Azides
6
disconnection into 4-ethynyl-1,2,3-triazoles 5 and azides 6.
The synthesis of 4-alkynyl-1,2,3-triazoles 5 was itself
challenging. Not surprisingly, the thermal cycloaddition of
terminal diacetylenes with 1 equiv of benzyl azide resulted
in mixtures of 1,4- and 1,5-regioisomers of bis-triazoles
together with small amounts of the desired 4-ethynyl-1,2,3-
triazole.8 Tykwinski et al. have reported the regioselective
trapping of terminal di-, tri-, and tetraynes with benzyl azide
to afford alkynyl-, butadiynyl-, and hexatriynyltriazoles in
moderate to good yields.9 4-Ethynyl-1,2,3-triazoles or their
trimethylsilyl-protected counterparts were also prepared as
antibacterial agents10 or tachykinin receptor antagonists.11
On the other hand, Hawker et al. have employed the azide/
acetylene coupling of 1-trimethylsilyl-2-vinylacetylene12 or
propargyl alcohol13 with azides to prepare vinyl-1,2,3-
triazolyl monomers.
a CuSO4, Na ascorbate, t-BuOH/H2O: 1/1. b Yields of pure isolated
products. c TBTA (1 mol %) was used as an additive. d Spontaneous
debenzylation of 8f was observed during the alkynylation step to give the
corresponding triazolyl carboxylic acid instead of the expected benzyl ester.
Theacidwasthensubmittedtomethylationto5iwithtrimethylsilyldiazomethane.
e Yield of the methyl ester 5i (see Table 3).
(5) Angell, Y.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 3649–
3651.
(6) (a) Monkowius, U.; Ritter, S.; Ko¨nig, B.; Zabel, M.; Yersin, H. Eur.
J. Inorg. Chem. 2007, 459, 7–4606. (b) Fletcher, J. T.; Bumgarner, B.;
Engels, N. D.; Skoglund, D. A. Organometallics 2008, 27, 5430–5433.
(7) A stepwise double-click strategy has been applied successfully to
the preparation of R,ω-bis(1,2,3-triazolyl)peptides; see: (a) Aucagne, V.;
Leigh, D. A. Org. Lett. 2006, 8, 4505–4507. For an iterative synthesis of
triazolamers containing amino acids side chains, see: (b) Angelo, N. G;
Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134-17135and J. Org. Chem.
2007, 72, 7963-7967. Oligomeric peptidomimetic compounds were
synthesized from orthogonally protected 1,4-disubstituted-1,2,3-triazoles,
see: (c) Montagnat, O. D.; Lessene, G.; Hughes, A. B. Tetrahedron Lett.
2006, 47, 6971–6974.
reactions of propargyl alcohol 7 with different azides (6a-f)
proceeded in 72-99% yields, but catalytic amounts (1-5%)
of TBTA15 were required when sterically hindered azides
were used (entries 3, 4, and 6, Table 1). Alkynyltriazoles
5a-c were prepared in good overall yields; however, when
benzyl ester and O-acetyl protective groups were present,
the final alkynylation step was problematic, leading to
complicated reaction crudes and low yields of the expected
products (entries 4-6).
Obviously, the conditions of the Swern oxidation step also
limited the method to azide residues (R1) bearing no
oxidation-sensitive groups (e.g., hydroxyl groups). To over-
come these important limitations, we implemented a different
synthetic approach starting from commercial 1,4-bis(trim-
ethylsilyl)butadiyne 9. Accordingly, chemoselective desily-
(8) Tikhonova, L. G.; Serebryakova, E. S.; Proidakov, A. G.; Sokolova,
I. E.; Vereshchagin, L. I. J. Org. Chem. USSR 1981, 17, 645–648.
(9) Luu, T.; McDonald, R.; Tykwinski, R. R. Org. Lett. 2006, 8, 6035–
6038.
(10) (a) Reck, F.; Zhou, F.; Girardot, M.; Kern, G.; Eyermann, C. J.;
Hales, N. J.; Ramsay, R. R.; Gravestock, M. B. J. Med. Chem. 2005, 48,
499–506. (b) Josyula, V. P. V. N.; Boyer, F. E., Jr.; Kim, J.-Y. PCT Int.
Appl. WO 2007/000644 A1.
(11) Amegadzie, A. K.; Gardinier, K. M.; Hembre, E. J.; Hong, J. E.;
Jungheim, L. N.; Muehl, B. S.; Remick, D. M.; Robertson, M. A.; Savin,
K. A. PCT Int. Appl. WO 03/091227 A1.
(12) Thibault, R. J.; Takizawa, K.; Lowenheilm, P.; Helms, B.; Mynar,
J.; Fre´chet, J. M. J.; Hawker, C. J. J. Am. Chem. Soc. 2006, 128, 12084–
12085.
(14) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
(15) Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA): Chan,
T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853–
2855.
(13) Takizawa, K.; Nulwala, H.; Thibault, R. J.; Lowenheilm, P.;
Yoshinaga, K.; Wooley, K. L.; Hawker, C. J. J. Polym. Sci., Part A 2008,
2897–2912.
Org. Lett., Vol. 12, No. 7, 2010
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lation with MeLi·LiBr complex afforded 1-trimethylsilylb-
utadiyne 1016 which was further submitted to click reaction
with azides 6d-h (Table 2). The use of the standard
Alternatively, we explored the possibility to conduct an
one-pot cascade fluoride-induced desilylation-double click
reaction between 1,4-bis(trimethylsilyl)butadiyne 9 and two
different azides in order to obtain the corresponding non-
symmetrical bis-triazoles in a single operation, but this
approach turned less convenient than the sequential double
click.18
Table 2. Synthesis of Triazoles 5d-f
Monotriazoles 5 were subsequently submitted to a second
click cycloaddition with different azides to give the expected
nonsymmetrical bis-triazoles 4 (Table 3). Both electron-donor
Table 3. Nonsymmetrical 1,1′-Disubsituted
4,4′-Bis-1H-1,2,3-triazoles 4a-h from 4-Ethynyltriazoles 5
a Overall yields of pure isolated products. b Symmetrical bis-triazole
was obtained in an additional 14% yield. c Symmetrical bis-triazole was
obtained in an additional 37% yield.
Sharpless conditions (CuSO4/Na ascorbate/THF/H2O) proved
unexpectedly troublesome, causing partial desilylation of the
intermediate 4-(trimethylsilylethynyl)-1,2,3-triazoles17 and
subsequent formation of mixtures containing up to 37% of
the symmetrical bis-triazoles (entries 2 and 3). Finally, when
the CuI/DIPEA system was used as catalyst the silylated
triazole was obtained as the single reaction product. Complete
desilylation was achieved upon in situ treatment with CsF
affording the expected 4-ethynyltriazoles 5 as pure products
in good overall yields. Following this methodology, per-
acetylated mannose 5d and amino acid benzyl esters 5e-f
were introduced in the core, albeit the sterically hindered
azide 6f showed low reactivity and extended reaction time
was necessary. This method could also be applied success-
fully to the preparation of cycloadducts from unprotected
saccharides like fucose 5g or from free carboxylic acid
peptides like 5h.
a Yield of pure isolated products. b Reaction conducted in the presence
of CuI and DIPEA. c TBTA (1 mol %) was used as an additive.
and electron-withdrawing groups were tolerated and densely
functionalized substituents could be appended to the central
bis(1,2,3-triazole) core. Only the reaction with aromatic azide
p-azidotoluene 6l failed (entry 6). In this case, tiny product
signals were detected by NMR analysis of the reaction crude,
but the reaction did not proceed further, despite the several
combinations of conditions tested: copper source (CuSO4/
Na ascorbate; CuI), solvent (t-BuOH/H2O, MeCN, DMF),
and warming to 70-100 °C.
(16) (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetra-
hedron Lett. 2003, 44, 9087–9090. (b) Holmes, A. B.; Jennings-White,
C. L. D.; Schulthess, A. H.; Akinde, B.; Walton, D. R. M. J. Chem. Soc.,
Chem. Commun. 1979, 840–842. (c) Holmes, A. B.; Jones, G. E.
Tetrahedron Lett. 1980, 21, 3111–3112.
(17) A test reaction pointed out that 1,4-bis(trimethylsilyl)butadiyne 9
remained unchanged after several days upon treatment with CuSO4/Na
ascorbate in THF/H2O.
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Org. Lett., Vol. 12, No. 7, 2010

The scope and synthetic potential of the double-click
approach was apparent from the examples quoted in entries
9-11 of Table 3 and in Figure 2. Fragments scaffolded
the ꢀ-D-fucose/RGD hybrid (4m) obtained by clicking the
alkynyl triazole 5g and the tripeptide azide Boc-Arg(Pbf)-
Gly-Asp(OtBu)-OCH2CH2N3.
Finally, the potential of the method was explored to
prepare polysubstituted bis(1,2,3-triazoles), and as a proof
of principle, we prepared the trisubstituted derivative 12.
Accordingly, the 4-ethynyltriazole 5a was first submitted to
an iodinative “click” cycloaddition19 with 4-tert-butylbenzyl
azide 6j, N-bromosuccinimide, and a stoichiometric amount
of CuI to afford the halogenated bis-triazole 11 in 50%
isolated yield (Scheme 2). Then, the palladium acetate-
Scheme 2
.
Trisubstituted Bis(1,2,3-triazoles) from
4-Ethynyltriazole 5a
Figure 2. Nonsymmetrically substituted bis(1,2,3-triazoles). Pbf:
2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl.
around the bis-triazole moiety included (a) orthogonally
protected amino esters and carbohydrates (4h-j), (b) an R-L-
mannose/ꢀ-D-fucose disaccharide mimetic (4k); (c) a fully
deprotected Gly-Phe peptide-saccharide hybrid (4l), and (d)
catalyzed Heck reaction of 11 with methyl acrylate provided
the trisubstituted bis-triazole 12 in 66% isolated yield.
(18) We found that desilylation of 9 with 0.4 equiv of TBAF (1 M,
THF) in the presence of benzyl azide 6a and CuI/DIPEA led to the exclusive
formation of symmetric bis-triazole 1a, whereas replacement of the copper(I)
catalyst by the Sharpless system in aqueous-organic medium resulted in
the formation of 5-ethynyltriazole 5a as the major reaction product.
Importantly, the one-pot sequential “click” cycloaddition of 9 with azide
6a, followed by the addition of 6e or 6j, provided reaction mixtures
containing, respectively, the unsymmetrically substituted bis-triazoles 4d
and 4b as major products. Unfortunately, the chromatographic isolation of
the products from symmetrical byproducts was laborious and afforded the
desired compounds in modest yields.
In conclusion, the combination of two methods to syn-
thesize 4-ethynyl-1,2,3-triazoles, followed by click attach-
ment of a second azide, allows for the efficient preparation
of 1,1′-disubsituted 4,4′-bis-1H-1,2,3-triazoles in good to
excellent yields. The procedure is simple, applicable to a
large variety of azides, and can be used for the preparation
of mixed structures, as demonstrated by the synthesis of
several amino acid (peptide)-sugar and sugar-sugar hybrids.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (MEC, Spain) (Project No. CTQ2006-13891/
BQU), UPV/EHU, and Gobierno Vasco (ETORTEK-inano-
GUNE IE-08/225) for financial support and SGIker UPV/
EHU for NMR facilities. Predoctoral grants from Gobierno
Vasco to I.A. and M.S.-A. are acknowledged.
Supporting Information Available: Preparation proce-
dures, physical and spectroscopic data for compounds 4a-m,
5a-h, 6h,n, 8a-f, 11, and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Li, L.; Zhang, G.; Zhu, A.; Zhang, L. J. Org. Chem. 2008, 73,
3630–3633.
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