The first well-defined silver(I)-complex-catalyzed cycloaddition of azides onto terminal alkynes at room temperature

Article abstract of DOI:10.1002/chem.201103244

Silver(I)-catalyzed click chemistry: Substituted 1,2,3-triazoles are versatile intermediates with an expanding array of applications. The discovery and application of a general Ag^I-catalyzed azide-alkyne cycloaddition reaction (AAC) leading to

Full text of DOI:10.1002/chem.201103244

COMMUNICATION
DOI: 10.1002/chem.201103244
The First Well-Defined Silver(I)-Complex-Catalyzed Cycloaddition of Azides
onto Terminal Alkynes at Room Temperature
James McNulty,* Kunal Keskar, and Ramesh Vemula[a]
The copper(I)-catalyzed Huisgen dipolar cycloaddition of
terminal alkynes 1 with azides 2[1] to yield 1,4- and 1,4,5-sub-
stituted 1,2,3-triazoles 3 (azide–alkyne cycloaddition; AAC
reaction) has been transformed in recent years, since its de-
scription as the prototype “click” reaction,[2] to become a
general process with applications in diverse areas ranging
from functional materials[3] to biological chemistry.[4,5] The
generally accepted mechanism for the reaction, outlined in
Scheme 1,[5,6] involves a stepwise process initiated through
generation of a copper(I) acetylide complex I, which com-
plexes to the azide 2, undergoes the cycloaddition, generat-
ing a metalated triazole III, which is then protonated[6e] to
yield the product 3, regenerating the catalyst.
(and variations thereof), prior to the cycloadition. The inter-
mediacy of higher order Cu–oligomer complexes and in-
volvement of copper(II) species have also been reported.[6c,d]
While gold(I),[7a] silver(I)[6d,7c] and other[7b] acetylides are
known to participate in the AAC reaction, the addition of
copper(I) salts is required to effect the cycloaddition, in
accord with the p-complexation step. No competent silver(I)
or gold (I) species has been reported to catalyze the catalyt-
ic cycle alone, and several failed attempts at copper-free
AAC reactions with silver acetylides have been reported
(Scheme 2). For example, the stoichiometric addition of
Scheme 2. Previous work on the AgI-catalyzed AAC reaction. a) AAC
reaction in the absence of CuI. b) AgI-mediated AAC reaction. c) Other
AgI-catalyzed AAC reaction.
silver phenylacetylide to azides failed to promote cyclization
in the absence of copper.[6d] The silver-mediated desilylation
of a trimethylsilyl alkyne, producing the Ag–acetylide inter-
mediate, also did not react with azides on their own ac-
cord.[7c–e] These and other reports[3a,5b] have shown that de-
spite the efficacy of silver(I) species catalyzing other proc-
esees,[8] they do not catalyze the AAC reaction. In this
work, we report the first example of a well-defined silver(I)
complex as a viable catalyst for the copper-free, room-tem-
perature AAC reaction.
Scheme 1. Generally accepted mechanism for the copper(I)-catalyzed
azide–alkyne cycloaddition (AAC) reaction.
A bimetallic pathway has been proposed for the cycload-
dition step involving p-complexation of the copper(I) cata-
lyst to the Cu–acetylide/azide yielding the intermediate II
Our research group has recently investigated the develop-
ment of hemilabile and bidentate P,O- and P,N-type ligands
for a variety of [Pd(L2)]-catalyzed reactions.[9] Parallel to
this work, we became interested in the reactivity of isoelec-
tronic s0d10 silver(I) species. Well-defined species of type
[Ag+(L2)(XÀ)] have been reported with 2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl (BINAP) and thiaphosphines.[10]
[a] Dr. J. McNulty, K. Keskar, Dr. R. Vemula
Department of Chemistry and Chemical-Biology
McMaster University, 1280 Main Street West
Hamilton, Ontario, L8S 4M1 (Canada)
Fax : (+1)905-522-2509
E-mail: jmcnult@mcmaster.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103244.
Chem. Eur. J. 2011, 17, 14727 – 14730
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14727

We focused on generating P,O-type silver complexes from
reaction of silver(I) species with amides of the tunable 2-di-
phenylphosphinobenzoic acid (SHOP) ligand 4 (R=Ph, X=
OH).[11] We were able to form a crystalline 1:1 complex (5)
of the diisopropylamide ligand 4 (R=Ph, X=NACTHNUGTRENUNG(iPr)2) with
silver acetate.
Crystals suitable for X-ray diffraction were readily depos-
ited from dichloromethane–pentane and the resulting struc-
ture depicted in Scheme 3. The complex is tetragonal, exhib-
Scheme 4. Silver-catalyzed AAC reaction. Standard reaction conditions:
Phenylacetylene (0.19 mmol, 1.0 equiv), benzyl azide (0.93 mmol,
4.8 equiv), catalyst 5 (20 mol%), caprylic acid (20 mol%), PhMe, RT
48 h.
cess provided the 1,4-triazole in 43–52% yield over 48 h at
room temperature. Increasing the catalyst loading to
20 mol% and excess azide (4.8 equiv) allowed the reaction
to go to completion and the triazole was isolated in 98%
yield (Table 1, entry 1).
These parameters were chosen as the “standard condi-
tion” and a wide range of functionalized azides (Table 1)
and phenylacetylenes (Table 2) were found to successfully
Table 1. Scope of azide participation in the Ag-AAC reaction.[a]
Azide
Product
Yield
[%]
Scheme 3. Synthesis of the SHOP amide: AgOAc (1:1) complex 5 and
ORTEP plot (lower).
1
2
3
4
5
6
7
98
95
99
99
99
90
99
À
iting a shorter Ag P contact (2.345 ꢁ) than the reported
BINAP complex (2.449 ꢁ).[10a] The Ag atom was also coor-
dinated to the oxygen atom of the amide as expected
(2.680 ꢁ), and asymmetrically bound to the acetate counter-
À
ion (Ag O contacts 2.167 and 2.669 ꢁ). Complex 5 proved
to be highly soluble in standard organic media (CH2Cl2,
PhMe, THF, etc) and poorly soluble in water. The complex
did not deposit silver chloride when shaken with brine and
was very stable thermally, melting with decomposition at
170–1908C. The crystals proved to be very air stable, nonhy-
groscopic and contain no solvate. The 31P NMR spectrum of
complex 5 exhibited sharp signals even at room temperature
in CDCl3 (d=4.57 ppm, d, J=712 Hz), fully in accord with a
tightly coordinated mononuclear species in solution.[10e]
We initially investigated the AAC reaction of phenylace-
tylene and benzyl azide (1:1 ratio) in the presence of
10 mol% of various silver(I) salts (AgOAc, Ag2O, AgNO3,
AgOTf) as well as complex 5 at room temperature in tolu-
ene. While the salts alone did not provide any adduct, to
our surprise, complex 5 was observed to catalyze the AAC
reaction regioselectively, at room temperature, slowly form-
ing the 1,4-triazole regioisomer 3 selectively in 9–10% yield
(Scheme 4).
8
99
Encouraged by this result, we screened several additives
known from the Cu-AAC process;[6b,e] in particular the addi-
tion of 10 mol% of benzoic acid or 20 mol% of caprylic
acid was found to facilitate the AgAAC reaction. This pro-
[a] Reaction conditions: phenylacetylene (0.19 mmol, 1.0 equiv), benzyl
azide (0.93 mmol, 4.8 equiv), catalyst
(20 mol%), PhMe (1 mL), 48 h, RT.
5 (20 mol%), caprylic acid
14728
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 14727 – 14730

Homogeneous Catalysis
COMMUNICATION
Table 2. Scope of the alkyne participation in the Ag-AAC reaction.[a]
presence of 20 mol% caprylic acid, but absence of complex
5, yielded no triazole product over 48 h. The same experi-
ment with the addition of silver acetate (20 mol%) led to
no reaction, while the silver triflate complex of ligand 4
(10 mol%) gave only 5% isolated yield of the triazole. In
contrast, the addition of 10 mol% of complex 5 resulted in
52% conversion to the triazole in 48 h.
Phenylacetylene
Azide
Product
Yield
[%]
These results indicate that a silver(I) source alone is not
sufficient, but that complex 5 is required for catalytic activi-
ty. Furthermore, the results are basically in agreement with
the earlier negative results shown in Scheme 2 and indicate
that catalyst 5 is exceptional in its ability to promote the
1
2
3
2a
72
90
99
Ag-AAC reaction. In
a
further control experiment
(Scheme 5), deuterated phenylacetylene (C6H5CCD,>99%
2a
2e
Scheme 5. AgAAC reaction with deuterium labeling. Reaction condi-
tions: a) Phenylacetylene (0.19 mmol, 1.0 equiv), benzyl azide
(0.93 mmol, 4.8 equiv), catalyst 5 (20 mol%), RT, 48 h in PhMe; isolated
yield 55%.
4
5
6
2a
2a
2c
99
99
99
D) was used in place of phenylacetylene under our standard
conditions yielding the triazole with 55% loss of deuterium.
This result is in accord with the intermediacy of a silver
acetylide, as opposed to an alkyne p-complexation pathway,
in which deuterium should be retained. Lastly, silver phenyl
acetylide was prepared quantitatively and several control re-
actions investigated with benzyl azide under standard condi-
tions (Scheme 6). In the absence of catalyst 5, no reaction
occurs, demonstrating that the role of 5 is not simply acety-
lide formation, but that it plays a role in further activation
of the intermediate in order to effect cyclization. This result
is in accord with a bimetallic p-complex species of type II
(Scheme 1), in which both metals are silver. In the absence
of catalyst 5, but addition of caprylic acid (0.20 equivalents),
very slow conversion to the 1,4-triazole is observed, leading
to 14% isolated yield after 48 h. This result demonstrates
that the carboxylic acid can play a minor role in the cycliza-
tion reaction itself as well as the final triazole protonation
step, most likely through activation of the alkyne bond in
the azide–acetylide complex. Although this acid-catalyzed
7
8
9
2h
2h
2g
97
99
99
[a] Reaction conditions: phenyl acetylene (0.19 mmol, 1.0 equiv), benzyl
azide (0.93 mmol, 4.8 equiv), Catalyst
(20 mol%), PhMe (1 mL), 48 h, RT.
5 (20 mol%), caprylic acid
undergo the Ag-AAC process efficiently under these mild
conditions. In all the cases, exclusive formation of the 1,4-re-
gioisomer was observed in 72–99% yield.
The general reaction was investigated in a series of con-
trol experiments. The reaction of phenylacetylene with
benzyl azide (1:1) in toluene at room temperature in the
Scheme 6. Silver phenylacetylide control reactions under the standard
conditions. Reaction conditions: a) Silver phenyl acetylide (0.09 mmol,
1.0 equiv), benzyl azide (0.45 mmol, 4.8 equiv), RT, 48 h in PhMe. 1) No
catalyst 5; 0% 3a. 2) Caprylic acid (0.20 equiv), no catalyst 5; 14% 3a.
3) Caprylic acid (0.20 equiv), catalyst 5 (0.20 equiv); 32% 3a.
Chem. Eur. J. 2011, 17, 14727 – 14730
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14729

J. McNulty et al.
Chem. Eur. J. 2009, 15, 8146–8162; c) J. F. Lutz, Angew. Chem.
2007, 119, 1036–1043; Angew. Chem. Int. Ed. 2007, 46, 1018–1025.
[4] a) A. Wang, N. W. Nairn, R. S. Johnson, D. A. Tirrell, K. Grabstein,
ChemBioChem 2008, 9, 324–330; b) F. Amblard, J. H. Cho, R. F.
Schinazi, Chem. Rev. 2009, 109, 4207–4220; c) T. Fekner, X. Li,
M. M. Lee, M. K. Chan, Angew. Chem. 2009, 121, 1661–1663;
Angew. Chem. Int. Ed. 2009, 48, 1633–1635; d) E. M. Sletten, C. R.
Bertozzi, Acc. Chem. Res. 2011, 44, 666–676; e) M. D. Best, M. M.
Rowland, H. E. Bostic, Acc. Chem. Res. 2011, 44, 686–698.
[5] For a selection of recent reviews and contributions see: a) L. Acker-
mann, H. K. Potukuchi, Org. Biomol. Chem. 2010, 8, 4503–4513;
b) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302–1315;
c) M. Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952–3015;
d) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51–68; e) S. Dꢂez-Gonzꢄlez, Catal. Sci. Technol. 2011,
1, 166–178; f) E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin,
K. B. Sharpless, S. Chang, Angew. Chem. 2005, 117, 1515; Angew.
Chem. Int. Ed. 2005, 44, 1491.
[6] For select mechanistic and theoretical investigations see: a) V. O.
Rodionov, V. V. Fokin, M. G. Finn, Angew. Chem. 2005, 117, 2250–
2255; Angew. Chem. Int. Ed. 2005, 44, 2210–2215; b) B. F. Straub,
Chem. Commun. 2007, 3868–3870; c) B. R. Buckley, S. E. Dann,
D. P. Harris, H. Heaney, E. C. Stubbs, Chem. Commun. 2010, 46,
2274–2276; d) I. P. Silvestri, F. Andemarian, G. N. Khairallah, S. W.
Yap, T. Quach, S. Tsegay, C. M. Williams, R. A. R. OꢅHair, P. S.
Donnelly, S. J. Williams, Org. Biomol. Chem. 2011, 9, 6082–6088;
e) C. Shao, X. Wang, J. Xu, J. Zhao, Q. Zhang, Y. Hu, J. Org. Chem.
2010, 75, 7002–7005.
[7] a) Gold acetylide: D. V. Partyka, L. Gao, T. S. Teets, J. B. Updegraff
III, N. Deligonul, T. G. Gray, Organometallics 2009, 28, 6171–6182;
b) Aluminum acetylide: Y. Zhou, T. Lecourt, L. Micouin, Angew.
Chem. 2010, 122, 2661–2664; Angew. Chem. Int. Ed. 2010, 49, 2607–
2610; c) V. Aucagne, D. A. Leigh, Org. Lett. 2006, 8, 4505–4507;
d) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman,
K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210–216.
[8] a) U. Halbes-Letinois, J. Weibel, P. Pale, Chem. Soc. Rev. 2007, 36,
759–769; b) M. Naodovic, H. Yamamoto, Chem. Rev. 2008, 108,
3132–3148; c) Y. Yamamoto, Chem. Rev. 2008, 108, 3199–3222;
d) M. ꢆlvarez-Corral, M. Munoz-Dorado, I. Rodriguez-Garcia,
Chem. Rev. 2008, 108, 3174–3198.
pathway is not efficient, to our knowledge this is the first
report on the role of acid in promoting the AAC reaction
with a silver acetylide. Finally, preformed silver phenyl ace-
tylide reacted under the standard conditions with addition
of caprylic acid (0.20 equiv) and catalyst 5 (0.20 equiv) to
generate the 1,4-triazole in 32% yield, in contrast to 98%
yield when catalyst 5 is used alone. This result indicates that
the SHOP-amide ligand plays a pivotal role on both the ter-
minal acetylide component in addition to further p-com-
plexation to the alkyne (Scheme 1, II in which Ln =N,N-dii-
sopropyl-2-phenylphosphinobenzamide 4).
In summary, we report the synthesis of a novel silver(I)a-
cetate complex ligated to a 2-diphenylphosphino-N,N,-diiso-
propylcarboxamide ligand and identified the first general
purely silver azide–alkyne cycloaddition (Ag-AAC) process
catalyzed by this well-defined species. Control experiments
show that the reaction proceeds via silver acetylide forma-
tion, but that further activation of the acetylide–azide inter-
mediate is necessary to effect cyclization. These features are
in accord with the generally accepted mechanism of the cop-
per(I)-catalyzed process described in Scheme 1. Silver(I)
salts alone are not sufficient to promote the cycloaddition
indicating that an important role is played by the hemilabile
P,O-type ligand. The hemilabile nature of this ligand may
play a role in opening coordination sites on silver for azide
À
complexation (cleavage of the Ag O bond) and returning
electron density to the alkyne bond through the metal to
effect the cyclization. Structure–activity studies with a series
of related ligands to probe the ligand effect and applications
of this mildly Lewis acidic silver(I) species—soluble in or-
ganic solvents—in promoting other reactions are in prog-
ress.
[9] a) E. Ullah, J. McNulty, A. Robertson, C. Kennedy, Org. Biomol.
Chem. 2011, 9, 4421–4424; b) E. Ullah, J. McNulty, V. Larichev, A.
Robertson, Eur. J. Org. Chem. 2010, 6824–6830; c) E. Ullah, J.
McNulty, A. Robertson, Tetrahedron Lett. 2009, 50, 5599–5602.
[10] a) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126,
5360–5361; b) C. Nꢄjera, M. de G. Retamosa, J. M. Sansano, Org.
Lett. 2007, 9, 4025–4028; c) M. Ohkouchi, D. Masui, M. Yamaguchi,
T. J. Yamagishi, J. Mol. Catal. A 2001, 170, 1–15; d) L. Lettko, J. S.
Wood, M. D. Rausch, Inorg. Chim. Acta 2000, 308, 37–44.
Acknowledgements
We thank NSERC and Cytec Canada for financial support of this work.
Keywords: alkynes · azides · click chemistry · cycloaddition ·
homogeneous catalysis · silver
[11] The parent ligand was first developed at Shell for the Ni-mediated
higher olefins process (ethylene oligomerization) and is known as
the SHOP ligand, see: a) R. S. Bauer, P. W. Glockner, W. Keim, H.
van Zwet, H. Chung, U. S. Pat. 3, 644,563, 1972; b) W-M. Dai, Y.
Zhang, Tetrahedron Lett. 2005, 46, 1377–1381; c) F. Y. Kwong, W. H.
Lam, C. H. Yeung, K. S. Chan, A. S. C. Chan, Chem. Commun.
2004, 1922–1923; d) B. M. Trost, F. D. Toste, J. Am. Chem. Soc.
1998, 120, 815–816.
[1] a) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67,
3057–3064; b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.
Sharpless, Angew. Chem. 2002, 114, 2708–2711; Angew. Chem. Int.
Ed. 2002, 41, 2596–2599.
[2] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113,
2056–2075; Angew. Chem. Int. Ed. 2001, 40, 2004–2021.
ˇ
[3] a) M. Jurꢂcek, P. H. J. Kouwer, A. E. Rowan, Chem. Commun. 2011,
47, 8740–8749; b) J. M. Casas-Solvas, E. Ortiz-Salmerꢃn, I. Fernꢄn-
Received: October 13, 2011
dez, L. Garcꢂa-Fuentes, F. Santoyo-Gonzꢄlez, A. Vargas-Berenguel,
Published online: November 28, 2011
14730
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 14727 – 14730