Copper(I)-catalyzed cycloaddition of organic azides and 1-iodoalkynes

Article abstract of DOI:10.1002/anie.200903558

High fidelity: 1-Iodoalkynes react rapidly and selectively with organic azides in the presence of copper(I) catalysts (see scheme; TTTA=tris((1-tert- butyl-1H-1,2,3-triazolyl)methyl)amine). The reaction is compatible with many functional groups and solven

Full text of DOI:10.1002/anie.200903558

Communications
DOI: 10.1002/anie.200903558
Click Chemistry
Copper(I)-Catalyzed Cycloaddition of Organic Azides and
1-Iodoalkynes**
Jason E. Hein,* Jonathan C. Tripp, Larissa B. Krasnova, K. Barry Sharpless, and
Valery V. Fokin*
The copper-catalyzed azide–alkyne cycloaddition reaction[1]
(CuAAC; Scheme 1a) is known for its high fidelity in the
presence of many functional groups and under demanding
Scheme 2. Reactivity of organic azides with copper(I) acetylides.
differently substituted 1,2,3-triazoles would be a valuable
addition to the family of catalytic cycloaddition reactions.
Herein, we report that 1-iodoalkynes, which are stable and
readily accessible internal acetylenes, exhibit exceptional
reactivity in the copper-catalyzed annulation reaction with
organic azides (Scheme 1c). Indeed, their reactivity appears
to surpass that of terminal alkynes. As an added benefit, the
Scheme 1. Various routes to substituted 1,2,3-triazoles.
products of the reaction (5-iodo-1,2,3-triazoles) are versatile
reaction conditions.[2] The experimental simplicity and high
selectivity of this process have been exploited in many
applications in synthetic and medicinal chemistry,[3] biocon-
jugations,[4] materials science,[5] and polymer chemistry.[6] The
efficiency and selectivity of this transformation are a direct
consequence of the reactivity of in situ generated copper(I)
acetylides. Coordination of the organic azide to the copper
center of the acetylide increases the nucleophilicity of the
triple bond and initiates a sequence of steps which ultimately
synthetic intermediates that are amenable to further func-
tionalization. Although several syntheses of iodotriazoles are
known, the reactions require stoichiometric amounts of
copper catalysts and employ reactive electrophilic halogenat-
ing reagents (e.g., iodine monochloride, N-iodosuccini-
mide).[9] In addition, some procedures require extended
reaction times and generate mixtures of 5-H and 5-iodotria-
zoles.[10]
Disclosed here is a general, rapid, and operationally
simple method for the chemo- and regioselective synthesis of
5-iodo-1,4,5-trisubstituted-1,2,3-triazoles from organic azides
and iodoalkynes. The catalysis is effected by copper(I) iodide
in the presence of an amine ligand.
The initial survey of experimental conditions, which
included a broad array of copper(I) and copper(II) salts,
solvents, and ligands, revealed that the reaction of iodoalkyne
1 and azide 2 was catalyzed by copper(I) iodide–triethylamine
(TEA) in THF, and gave 5-iodo-1,2,3-triazole 3 as the major
product,[11] along with 5-proto- and 5-alkynyl triazoles 4 and 5,
respectively (Table 1, entry 2).
À
results in the formation of the new C N bond between the
nucleophilic b-carbon atom of the acetylide and the terminal,
electrophilic nitrogen atom of the azide (Scheme 2). Natu-
rally, internal alkynes are devoid of such reactivity, and
therefore CuAAC is limited to terminal acetylenes, which
produce only 1,4-disubstituted triazoles. Although the ruthe-
nium-catalyzed
azide–alkyne
cycloaddition
reaction
(Scheme 1b)[7] and methods for functionalization of the
triazole heterocycle itself[8] partially address these deficien-
cies, a general method for the regiocontrolled synthesis of
Inclusion of an amine ligand was crucial, as no reaction
was observed when TEA was omitted (Table 1, entry 1).
Furthermore, the reaction displayed a strong dependence on
the quantity of TEA used (Table 1, entries 1–4). Thus, 5-iodo-
triazole 3 was generated as the sole product in excellent yield
by simply using an excess (2 equiv) of TEA. This trend
extended to other tertiary amine ligands, although the desired
5-iodotriazole was obtained in lower yield (compare Table 1,
entry 4 with entries 6 and 8).
The observed rate and chemoselectivity of the reaction
were strongly dependent on the nature of the amine ligand.
For example, the efficiency of the reaction was markedly
lowered, and as a result 5-alkynyl-triazole 5 was formed as the
major product [12] when TEA was replaced with 1,2-diamines
[*] Dr. J. E. Hein, Dr. J. C. Tripp, Dr. L. B. Krasnova,
Prof. Dr. K. B. Sharpless, Prof. Dr. V. V. Fokin
Department of Chemistry
The Scripps Research Institute
La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7562
E-mail: fokin@scripps.edu
Homepage: http://www.scripps.edu/chem/fokin
[**] We gratefully acknowledge financial support from the National
Institutes of Health, National Institutes of General Medical
Sciences (GM28384 to K.B.S., GM087620 and GM083658 to V.V.F.)
and the Skaggs Institute for Chemical Biology. Postdoctoral
fellowships were provided by the NIH (J.C.T) and NSERC (J.E.H).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903558.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Solvent compatibility study.[a]
TTTA (5 mol%)
TEA (2 equiv)
Solvent
t [h]
Yield [%]
t [h]
Yield [%]
THF
MeCN
DMF
Water
EtOH
CH2Cl2
toluene
1
1
2
2
4
4
5
93
94
91
85
78
79
62
6
6
18
6
24
24
24
90
85
86
76
69
62
73
Entry
Additive
Equiv
3/4/5[b]
Yield [%][c]
1
2
3
4
5
6
7
8
–
TEA
TEA
TEA
DIPEA
DIPEA
2,6-lutidine
TMEDA
L1
–
0.5
1
2
0.5
2
0.5
0.5
0.5
0.5
0.05
0.05
–
n.r.
55
75
90
47
73
12
26
25
[a] General conditions: CuI (0.05 mmol) and ligand in solvent (5 mL), 1
(1.00 mmol), 2 (1.00 mmol). [b] Yield of isolated 3.DMF=N,N-dime-
thylformamide.
10:3: 1
25:2:1
1:0:0
15:1:2
1:0:0
30:1:0
20:1:0
1:1:15
–
affected, even when the reaction was performed in protic
solvents.
The CuI–TTTA catalyst system was applied to a series of
structurally and functionally diverse azides and 1-iodoalkynes
(Scheme 3). In all cases, the 5-iodo-1,2,3-triazoles were
obtained as the exclusive products. Because of the mild
reaction conditions, high chemoselectivity, and low copper
catalyst loading, the reaction workup was usually as simple as
trituration and subsequent filtration. As a result, this method
is highly amenable to scale-up, and representative 5-iodo-
triazoles 6 and 15 were prepared in multigram quantities. In
addition, the diverse array of functional groups tolerated by
this annulation stands out as a particularly exceptional
feature. Both sterically demanding (e.g., 10 and 22) as well
as functionally dense (e.g., 7 and 17) substrates could be
utilized. As such, the azide–iodoalkyne cycloaddition pro-
vides a highly orthogonal means of chemical ligation, similar
to the more conventional CuAAC reaction.
The utility of this cycloaddition was enhanced through the
development of a simple and highly efficient synthesis of 1-
iodoalkynes from terminal acetylenes (Scheme 4). Terminal
alkynes were treated with N-iodomorpholine[14] (23), in the
presence of CuI and gave the corresponding 1-iodoalkynes
within 30 to 60 minutes. The products could be isolated by
simply passing the reaction mixture through a pad of silica gel
or alumina, which yielded the desired 1-iodoalkynes in good
to excellent yield.
9
10
11
12
L2
L3
L4
n.r.
60[d]
93[d]
1:0:0
1:0:0
[a] General reaction conditions: CuI (0.02 mmol) and ligand in THF
(2 mL), 1 (0.40 mmol) 2 (0.40 mmol), room temperature, 6 h. [b] Pro-
duct ratio determined by HPLC-MS analysis. [c] Yield of isolated 3.
[d] Reaction time was 45 min. Bn=benzyl, DIPEA=N,N-diisopropyle-
thylamine, n.r. =no reaction, THF=tetrahydrofuran, TMEDA=
N,N,N’,N’-tetramethylethylenediamine.
(Table 1, entries 8 and 9). Pyridines, such as 2,6-lutidine and
1,10-phenanthroline (L2), were also ineffective (Table 1,
entries 7 and 10). By contrast, tris((1,2,3-triazolyl)methyl)-
amine ligands[13] were found to be highly efficient in promot-
ing this cycloaddition. Both tris((1-benzyl-1H-1,2,3-triazolyl)-
methyl)amine (TBTA) and its tert-butyl analogue, tris((1-tert-
butyl-1H-1,2,3-triazolyl)methyl)amine
(TTTA;
Table 1,
entries 11 and 12) gave 5-iodotriazole 3 as the exclusive
product in excellent yield. In addition, these ligands markedly
accelerated the reaction, thus reducing the reaction time from
6 hours to 45 minutes.
The increased chemoselectivity of the reaction in the
presence of these ligands is a consequence of the rate
acceleration of the triazole-forming pathway. Both iodoal-
kyne 1 and 5-iodotriazole 3 slowly undergo reductive
dehalogenation in the presence of various copper salts, to
generate the corresponding terminal alkyne and 5-prototria-
zole 4. These pathways are likely to account for the
generation of the observed by-products, but are far too slow
in the presence of accelerating ligands.
Given the speed and fidelity with which the 1-iodoalkynes
could be synthesized, a one-pot, two-stage sequence was
developed (Scheme 5). The 1-iodoalkyne was partially puri-
fied by filtration through neutral alumina prior to the
introduction of the azide component.[15] This method gave
5-iodotriazoles 28–30 with efficiency comparable to that
observed with the isolated 1-iodoalkynes.
Based on these observations, TTTA emerged as the
optimum ligand for the rapid and chemoselective construc-
tion of 5-iodo-1,2,3-triazoles. Notably, both CuI–TTTA and
CuI–TEA systems were found to be compatible with a wide
variety of solvents (Table 2). Although some solvents did
have a large effect on the reaction rate the selectivity was not
This sequence could be further extended to the synthesis
of 1,4,5-triaryl-1,2,3-triazoles 31–33 (Scheme 6) by assembling
the 5-iodotriazole and immediately employing palladium(0)-
catalyzed cross-coupling with an appropriate arylboronic
acid.[16] This simple step-wise construction obviates purifica-
tion of any intermediates and simultaneously provides
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Scheme 3. Substrate scope for the copper(I)-catalyzed azide-iodoalkyne cycloaddition.[a,b] [a] General reaction conditions: azide (1.00 mmol), 1-
iodoalkyne (1.00 mmol), CuI (0.05 mmol), TTTA (0.05 mmol), THF (5 mL), room temperature, 2 h. [b] Values in parentheses represent yields of
isolated products. [c] Reaction time was 6 h. [d] Reaction was performed on a 10 mmol scale.
Scheme 6. One-pot, three-step synthesis of 1,4,5-triaryltriazoles.
PMP=p-methoxyphenyl, p-Tol=p-methylphenyl.
Scheme 4. Synthesis of 1-iodoalkynes using N-iodomorpholine·HI.
mechanistic proposals are outlined in Scheme 7. One possible
pathway is similar to that proposed for the CuAAC[1a,17] and
involves the formation of the s-acetylide complex 35 as the
first key intermediate (Scheme 7a).[18] Coordination of the
azide through the proximal nitrogen center and subsequent
cyclization to yield the cuprated triazoles 38. Copper
exchange through s-bond metathesis with iodoalkyne 34
completes the cycle, thus liberating iodotriazole 39 and
regenerating acetylide 35.
Scheme 5. One-pot, two-step synthesis of 5-iodo-1,2,3-triazoles.
complete control over the placement of substituents around
the 1,2,3-triazole core, thus allowing facile access to all
regioisomeric permutations of triaryltriazoles 31–33. This
achievement is notable, as a similar regiocontrolled synthesis
would not be possible by thermal or ruthenium-catalyzed 1,3-
dipolar cycloaddition owing to the high degree of similarity
between the aryl groups (phenyl, tolyl, and p-methoxy-
phenyl).
Although this newly discovered copper(I)-catalyzed
cycloaddition clearly shares some similarities with the
CuAAC process, the modes of activation of iodo and terminal
alkynes by copper are likely to be distinctly different. Our
Scheme 7. Proposed mechanisms for the copper(I)-catalyzed azide–
iodoalkyne cycloaddition.
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Alternatively, copper may activate the iodoalkyne
Keywords: azides · click chemistry · copper · cycloaddition ·
iodoalkynes · iodotriazoles
.
through the formation of
a
p-complex intermediate
(Scheme 7b), which then engages the azide to produce
complex 41. Cyclization then proceeds via a vinylidene-like
transition state 42 to give iodotriazole 39. A similar transition
state has been proposed to explain the involvement of
dicopper intermediates in the CuAAC reaction.[19] The
[1] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41,
2596; b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057.
[2] a) P. Wu, V. V. Fokin, Aldrichimica Acta 2007, 40, 7; b) M.
Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952.
À
distinctive feature of this pathway is that the C I bond is
never severed during the catalysis.
[3] a) H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 8,
1128; b) M. Whiting, J. C. Tripp, Y. C. Lin, W. Lindstrom, A. J.
Olson, J. H. Elder, K. B. Sharpless, V. V. Fokin, J. Med. Chem.
2006, 49, 7697; c) B. L. Wilkinson, L. F. Bornaghi, T. A. Houston,
S.-A. Poulsen, in Drug Design Research Perspectives (Ed.: S. P.
Kaplan), Nova, Hauppauge, 2007, p. 57.
[4] a) A. J. Link, D. A. Tirrell, J. Am. Chem. Soc. 2003, 125, 11164;
b) Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless,
M. G. Finn, J. Am. Chem. Soc. 2003, 125, 3192; c) J.-F. Lutz, Z.
Zarafshani, Adv. Drug Delivery Rev. 2008, 60, 958.
[5] C. J. Hawker, V. V. Fokin, M. G. Finn, K. B. Sharpless, Aust. J.
Chem. 2007, 60, 381.
Although a detailed examination of the mechanism has
not been completed, we currently favor pathway b based on
our preliminary studies and the results from the optimization
experiments carried out in the reaction. The main argument in
support of this hypothesis is the exclusive formation of the 5-
iodotriazole: even when the reaction is performed in protic
solvents (Table 2) or with the substrates containing acidic
protons (Scheme 3, compounds 11, 15, and 22). If pathway a
was operational, the cuprated triazole intermediate 38 could
be trapped with other electrophiles, including a proton,
thereby producing a mixture of the 5-iodo and 5-prototria-
zoles. The absence of the latter products supports our
proposal that pathway a is not dominant.
[6] a) R. A. Evans, Aust. J. Chem. 2007, 60, 384; b) J. A. Johnson,
J. T. Koberstein, M. G. Finn, N. J. Turro, Macromol. Rapid
Commun. 2008, 29, 1052.
The new catalytic cycloaddition reaction enables rapid,
controlled, and practical synthesis of 1,4,5-trisubstituted-
1,2,3-triazoles. This reaction displays broad substrate scope,
excellent functional group and solvent compatibility, as well
as remarkably high rates which may exceed those of the more
familiar CuAAC. In addition to these immediate practical
benefits, the unprecedented and exquisite reactivity, as well as
facile synthesis of 1-iodoactylenes disclosed here will serve as
a powerful tool to probe the mechanism of other copper-
catalyzed transformations of alkynes, including the CuAAC
reaction.
[7] a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B.
Sharpless, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127,
15998; b) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang,
H. Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130,
8923.
[8] a) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan, Org.
Lett. 2007, 9, 2333; b) S.-I. Fukuzawa, E. Shimizu, K. Ogata,
Heterocycles 2009, 78, 645.
[9] a) Y. M. Wu, J. Deng, Y. Li, Q. Y. Chen, Synthesis 2005, 1314;
b) L. Li, G. Zhang, A. Zhu, L. Zhang, J. Org. Chem. 2008, 73,
3630.
[10] a) I. Perez-Castro, O. Caamano, F. Fernandez, M. D. Garcia, C.
Lopez, E. De Clercq, Org. Biomol. Chem. 2007, 5, 3805;
b) Kuijpers et al. recently reported an elegant synthesis of 5-
bromo-1,2,3-triazoles from 1-bromoalkynes, however reactions
required 40 mol% CuI/CuII, elevated temperature or 16–50 h to
reach completion; B. H. M. Kuijpers, G. C. T. Dijkmans, S.
Groothuys, P. J. L. M. Quaedflieg, R. H. Blaauw, F. L. van Delft,
F. P. J. T. Rutjes, Synlett 2005, 3059.
[11] The regiochemistry of 3 was assigned by reducing the 5-iodo
center to give 5-H-triazole 4. See the Supporting Information for
details.
[12] B. Gerard, J. Ryan, A. B. Beeler, J. A. Porco, Jr., Tetrahedron
2006, 62, 6405.
Experimental Section
Typical procedure for the synthesis of 1-iodoalkynes—synthesis of 1-
iodo-phenylacetylene (1): Phenylacetylene (8.17 g, 80.0 mmol) was
dissolved in THF (200 mL) and treated with CuI (0.762 g, 4.00 mmol)
and N-iodomorpholine (30.0 g, 88.0 mmol). The reaction mixture was
stirred at room temperature for 45 min, after which time a fine white
precipitate had formed. The suspension was poured onto a pad of
activated neutral alumina (400 mL) and the filtrate was collected
under vacuum. The solid phase was washed with CH2Cl2 (4 ꢀ 100 mL)
and the combined organic fractions were concentrated by evapora-
tion to give 1 (16.6 g, 72.8 mmol, 91%) as a yellow oil. This material
was used without further purification.
[13] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
2004, 6, 2853.
[14] R. V. Rice, G. D. Beal, US Patent 2,290,710, 1943.
[15] Addition of electrophilic iodinating reagents (N-iodomorpho-
line, ICl, N-iodosuccinimide, etc.) to a solution containing CuI–
TTTA, the target azide and terminal alkyne rapidly gave the
corresponding 1-iodoalkyne, but failed to promote the subse-
quent cycloaddition. This failure is likely to be a result of the
disruption of the catalytically active complex, either through
oxidation of the metal or displacement/destruction of the ligand.
[16] J. Deng, Y.-M. Wu, Q.-Y. Chen, Synthesis 2005, 2730.
[17] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman,
K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210.
[18] P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem. 2000,
112, 2740; Angew. Chem. Int. Ed. 2000, 39, 2632.
Typical procedure for the synthesis of 5-iodotriazoles—synthesis
of 5-iodo-4-phenyl-1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazole
(3): CuI (9.52 mg, 0.050 mmol) and TTTA (0.021 g, 0.050 mmol)
were stirred in THF (4.5 mL) at room temperature for 20 min, after
which time a homogeneous solution was obtained. 1 (0.228 g,
1.00 mmol) and 2 (0.201 g, 1.00 mmol) were dissolved in THF
(0.5 mL) and added in a single portion to the catalyst solution. The
reaction mixture was stirred for 45 min, and then quenched by adding
1 mL of 10% NH4OH solution. The volatile components were
removed by evaporation, and the resulting residue was suspended in
water and diethyl ether. A precipitate formed upon vigorous stirring
and was isolated by filtration to give 3 (0.399 g, 0.930 mmol, 93%) as a
fine white powder.
[19] a) M. Ahlquist, V. V. Fokin, Organometallics 2007, 26, 4389;
b) B. F. Straub, Chem. Commun. 2007, 3868.
Received: June 30, 2009
Published online: September 22, 2009
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