Zinc mediated azide-alkyne ligation to 1,5- and 1,4,5-substituted 1,2,3-triazoles

Article abstract of DOI:10.1021/ol402225d

A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.

Full text of DOI:10.1021/ol402225d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Zinc Mediated AzideꢀAlkyne Ligation to
1,5- and 1,4,5-Substituted 1,2,3-Triazoles
Christopher D. Smith and Michael F. Greaney*
School of Chemistry, University of Manchester, Manchester, M13 9PL, U.K.
michael.greaney@manchester.ac.uk
Received August 5, 2013
ABSTRACT
A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature
and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the
intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.
The 1,2,3-triazolehasrisen toprominence inrecent years
as a superbly versatile heterocycle, with the 1,4-isomer
being readily prepared from azide and alkyne components
using copper-catalyzed azide alkyne cycloaddition (CuAAC).1
This reaction reliably functions under mild conditions,
displays superb substrate scope, and has driven a vast range
of triazole application across the chemical, biological, and
materials sciences.2 Methods for accessing the alternate 1,5-
isomer, by contrast, are far less developed. The synthesis of
both triazole geometrical isomers has conventionally been
achieved using the thermal Huisgen cycloaddition between
azides and alkynes to afford a mixture of the 1,4- or 1,5-
substituted 1,2,3-triazoles.3 However, the separation of
these products is frequently a tedious and sometimes in-
surmountable challenge.4 Existing methods for the exclusive
construction of 1,5-triazoles require strongly basic condi-
tions, utilizing alkali5 or magnesium6 acetylides, and have
proven too demanding for many useful substrate classes.
Alternatively, bulky ruthenium catalysts7 are capable of
forming the desired 1,5-triazole (also 1,4,5-substituted
triazoles). However, the cost of using a noble metal catalyst
in this RuAAC procedure is an impediment to the develop-
ment of a general, cost-effective application.8
With these concerns in mind, a milder and more eco-
nomical route toward 1,5-substituted triazoles is sorely
(4) Landge, K. P.; Seo, Y. W.; Kwak, J.; Park, W. K.; Gong, J. Y.;
Lee, H. Y.; Koh, H. Y. Bull. Korean Chem. Soc. 2011, 32, 3101–3104.
(5) (a) Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.;
(1) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
~
Fokin, V. V. Org. Lett. 2010, 12, 4217–4219. (b) Meza-Avina, M. E.;
Patel, M. K.; Lee, C. B.; Dietz, T. J.; Croatt, M. P. Org. Lett. 2011, 13,
2984–2987. (c) Wu, L.; Chen, Y.; Tang, M.; Song, X.; Chen, G.; Song,
X.; Lin, Q. Synlett 2012, 1529–1533. (d) Hong, L.; Lin, W.; Zhang, F.;
Liu, R.; Zhou, X. Chem. Commun. 2013, 49, 5589–5591.
(2) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–
1262. (b) Meldal, M. Macromol. Rapid Commun. 2008, 29, 1016–1051. (c)
Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015. (d) Baxen-
dale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed.
2009, 48, 4017–4021. (e) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem.;
Asian J. 2011, 6, 2696–2718. (f) Beale, T. M.; Bond, P. J.; Brenton, J. D.;
Charnock-Jones, D. S.; Ley, S. V.; Myers, R. M. Bioorg. Med. Chem. 2012,
20, 1749–1759. (g) Lewandowski, B.; De Bo, G.; Ward, J. W.; Papmeyer,
M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P. M. E.; Heckmann, D.;
Goldup, S. M.; D’Souza, D. M.; Fernandes, A. E.; Leigh, D. A. Science
2013, 339, 189–193. (h) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K.
Chem. Rev. 2013, 113, 4905–4979.
ꢀ
(6) (a) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237–1240. (b) Akao, A.; Tsuritani, T.; Kii, S.; Sato, K.; Nonoyama, N.;
Mase, T.; Yasuda, N. Synlett 2007, 31–36.
(7) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998–
15999. (b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923–8930.
Correction: J. Am. Chem. Soc. 2008, 130, 14900. (c) Lamberti, M.;
Fortman, G. C.; Poater, A.; Broggi, J.; Slawin, A. M. Z.; Cavallo, L.;
Nolan, S. P. Organometallics 2012, 31, 756–767.
(3) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565–598.
r
10.1021/ol402225d
XXXX American Chemical Society

Scheme 1. Optimized Reaction Conditions and Substrate Scope
a Standard conditions but 2.4 equiv azide and 3.0 equiv ZnEt2. b As standard but 72 h. c As standard but 2.5 equiv ZnEt2 and 72 h.
needed, as is a suitable method for the further functiona-
lization of the 4-position. Such reactions could see signifi-
cant application, as the alternative 1,5-linkage would afford
molecules and materials with new and contrasting proper-
ties to 1,4-triazoles synthesized via CuAAC. In response to
these demands we have investigated a zinc-mediated method
for triazole synthesis, inspired by significant advances in the
formation of zinc acetylides and their further reaction with
carbonyl functional groups.9 It was anticipated that the less
nucleophilic zinc reagents (with respect to magnesium or
lithium) would permit a much wider substrate scope and
permit further functionalization.
We quickly discovered that simple addition of stoichio-
metric ZnEt2 [1 M in hexanes] to a THF/toluene solution
of alkyne 1 and azide 2 would exclusively form the desired
(9) (a) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider,
P. J. Synthesis 1999, 1453–1458. (b) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757–824. (c) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett.
2002, 4, 2605–2606. (d) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org.
Chem. 2006, 71, 1558–1562. (e) Yang, F.; Xi, P.; Yang, L.; Lan; Xie, R.;
You, J. J. Org. Chem. 2007, 72, 5457–5460. (f) Turlington, M.; Pu, L.
Synlett 2012, 649–684. (g) Trost, B. M.; Bartlett, M. J.; Weiss, A. H.; J.
von Wangelin, A.; Chan, V. S. Chem.;Eur. J. 2012, 18, 16498–16509.
(8) (a) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71,
8680–8683. (b) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.; Thuery,
ꢀ
P.; Rousseau, B.; Cintrat, J.-C. Tetrahedron 2007, 63, 8094–8098. (c)
Nulwala, H.; Takizawa, K.; Odukale, A.; Khan, A.; Thibault, R. J.;
Taft, B. R.; Lipshutz, B. H.; Hawker, C. J. Macromolecules 2009, 42,
6068–6074. (d) Zhang, J.; Kemmink, J.; Rijkers, D. T. S.; Liskamp,
R. M. J. Chem. Commun. 2013, 49, 4498–4500.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Further Functionalization of the Aryl Zinc Reagent (4)
Figure 1. X-ray crystal structures of 3a and 3x proving the 1,5
and 1,4,5 configurations of the triazole products. Thermal
ellipsoids at 50%.13
1,5-substituted triazole isomer (Scheme 1). Proof of the
geometry was initially determined by comparison with the
1,4-isomer formed under CuAAC, followed by single
crystal X-ray crystallography of 3a (Figure 1) and an
analog (3x) subsequently prepared (vide infra). However,
repeating the reaction with resynthesized 2 gave no reac-
tion at all, with only starting materials observed. We
surmised that a catalytic base could be required to form
the zinc acetylide and that residual aniline from the azide
synthesis10 was promoting the reaction. Addition of 10%
N-methylimidazole (NMI) promptly restored reactivity,
and screening could continue.11 A range of solvents were
found to be suitable including CH2Cl2, 1,4-dioxane, MeCN,
PhCF3, i-PrOAc, and PhMe; although THF afforded a better
purity profile and is readily available anhydrously. A con-
centration of 0.125 M was utilized to ensure all the zinc species
remained in solution, and a slight excess of alkyne and ZnEt2
were used to drive the reaction to completion. The reaction
was typically complete after 18 h at ambient temperature or in
2 h at 100 °C in a microwave reactor. Yields were lower in the
latter case due to the formation of an azide derived aniline
byproduct (typically ∼10%). The final optimized conditions
are outlined in Scheme 1 and afforded the 1,5-product (3) in
an isolated yield of 75% on a 1 mmol scale. The reaction was
then directly scaled up to 10 mmol and afforded just over of 2
g of 3a in a very similar 76% isolated yield.
a Standard conditions with quench added directly. b Standard con-
ditions with third component addition to reaction as a THF solution and
stirred for 18 h at rt.
including esters (entries 3f, 3i, and 3l), amides (3m), ketones
(3n), nitriles, nitros (3k), aryl iodides (3o), heterocycles (3p
and 3q), andortho-substituents (3c and 3d). Diynes(3r) were
also suitable starting materials, suggesting this method
could find application in polymer or dendrimer synthesis.12
These substrates are not productive in the RuAAC method
due to the formation of unreactive ruthenacycles.7
Alkyl azides were not generally suitable as substrates,
although benzyl azide could be reacted in good yield using
extended reaction times (72 h) at ambient temperature (3s).
Efforts to accelerate the reaction through heating resulted in
poor yields and significant decomposition of starting mate-
rials. Further difficult examples included substrates with
free alcohols. Nevertheless, a successful reaction could be
achieved by the addition of extra ZnEt2 and extended
reaction times (72 h) at ambient temperature (3t and 3u).
Formation of triazole 3t via the zinc method is of particular
interest, representing the successful functionalization of the
The alkyne substrate range encompasses both alkyl and
aryl terminal alkynes (Scheme 1) including enyne (3d) and
silylated (3e) functionalities. Further success was found
with propargylic ethers (3g), esters (3i), and thioethers
(3q) although 1,2-diphenyl acetylene, tosyl azide, and
(iodoethynyl)benzene failed to provide the desired product.
Important substrate classes unsuitable for the magnesium
system were able to withstand our zinc mediated conditions
(12) Astruc, D.; Liang, L.; Rapakousiou, A.; Ruiz, J. Acc. Chem. Res.
2011, 45, 630–640.
(13) CCDC 931414 and CCDC 931415 contain the crystallographic
data for 3a and 3x respectively. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. ORTEP-3 was used to produce the thermal
ellipsoid plots: Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(10) Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9,
1809–1811.
ꢀ
ꢀ
(11) (a) Clegg, W.; Garcıa-Alvarez, J.; Garcıa-Alvarez, P.; Graham,
D. V.; Harrington, R. W.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E.;
Russo, L. Organometallics 2008, 27, 2654–2663. (b) Du, Y.; Turlington,
M.; Zhou, X.; Pu, L. Tetrahedron Lett. 2010, 51, 5024–5027.
Org. Lett., Vol. XX, No. XX, XXXX
C

hindered propargyl alcohol mestranol (a commercial
estrogen) in excellent yield. The reaction evidently has the
capacity for late stage elaboration of sterically hindered,
chiral molecules and biologically important scaffolds.
Further insight into the mechanism of the reaction was
discovered when the mixture was quenched with D2O/
D3CCO2D rather than with NH4Cl (aq).14 1H NMR and
LCMS determined an 89% deuterium incorporation at the
triazole 4-position (3v, Table 1). Implying that a stoichio-
metric aryl-zinc intermediate (Scheme 2, 4) was formed in
the reaction in a way analogous to the previously described
magnesium methods.6 This aryl-zinc reagent (4) was then
used for further elaboration to afford a number of 1,4,5-
trisubstituted 1,2,3-triazoles and to demonstrate this tech-
nology’s potential for the synthesis of highly diverse
libraries through three-component coupling. The initial
exploration successfully incorporated bromine (3w) and
thus offers a partner for palladium catalyzed cross-cou-
pling at some later stage. Conversely, the aryl-zinc itself
easily underwent palladium mediated cross-coupling with
iodobenzene (3x) and thus offers a myriad of opportunities
for biaryl synthesis. The ketone and alcohol products (3y
and 3z) present significant opportunities for further mole-
cular diversity through a ‘capping’ step to incorporate four
distinct components in only a few steps.
With our accrued observations we have proposed a
reaction mechanism in Scheme 2 to help explain the observed
reactivity of this system. It is reasonable to assume from
previous reports that the transformation passes through the
initial metalation of the alkyne-H, mediated by the amine
base, to form the zinc acetylide 5.9f,g,11 Reversible precoor-
dination between the azide and zinc acetylide could be
expected to occur before the [3 þ 2]-cycloaddition can take
place, explaining the necessity for stoichiometric quantities
of ZnEt2 in the reaction and the formation of the aryl-zinc
intermediate 4. Harnessing the further reactivity of this aryl-
zinc species (4) has been demonstrated by the trapping
experiments set out in Table 1.
Scheme 2. Proposed Mechanistic Pathway
In conclusion we present a significant addition to the
regioselective formation of 1,5-substiuted 1,2,3-triazoles, a
method that has proved successful across a wide range of
azido/alkynyl substrates. Additionally, the 4-position can
be further functionalized through the intermediate aryl-
zinc to accommodate a diverse three-component coupling
strategy. The inherently benign nature and efficient con-
struction of these triazoles make this protocol ideal for
both library synthesis and the late stage functionalization
of complex molecules. Equally, the procedure is opera-
tionally straightforward, eminently scalable, and expected
to be of interest across the chemical community.
Acknowledgment. We thank the Wellcome Trust
(Grant WT094899MA) and the EPSRC (Leadership
Fellowship to MFG) for funding. Dr. Achim Schnaufer
(University of Edinburgh) and Prof. Rommie Amaro
(University of California, San Diego) are thanked for
helpful discussions.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Akula, H. K.; Lakshman, M. K. J. Org. Chem. 2012, 77, 8896–
8904.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX