Carboxylic acid-promoted copper(I)-catalyzed azide-alkyne cycloaddition

Article abstract of DOI:10.1021/jo101495k

In this article, we proved that all three key steps in the catalytic cycle of CuAAC can proceed in the presence of carboxylic acids and the latter two steps can be promoted significantly by carboxylic acids. Benzoic acid showed the best promotion activity, and the acids with strong chelating ability to Cu(I) ion could not serve for this purpose. Thus, the first carboxylic acid-promoted highly efficient CuAAC was established.

Full text of DOI:10.1021/jo101495k

pubs.acs.org/joc
SCHEME 1
Carboxylic Acid-Promoted Copper(I)-Catalyzed
Azide-Alkyne Cycloaddition
Changwei Shao, Xinyan Wang,* Jimin Xu, Jichen Zhao,
Qun Zhang, and Yuefei Hu*
Department of Chemistry, Tsinghua University,
Beijing 100084, People’s Republic of China
wangxinyan@mail.tsinghua.edu.cn; yfh@mail.tsinghua.edu.cn
Received July 29, 2010
Great attention has been paid to understand the mecha-
nism of CuAAC in past years. A widely recognized three-
key-step catalytic cycle was proposed by Sharpless in his first
CuAAC article.2 As shown in Figure 1, it starts from the
formation of Cu(I) acetylide (5) and finishes by the proton-
ation of the Cu-C bond in 5-Cu-substituted 1,2,3-triazole
(6). Actually, the intermediates 5 and 6 (as coordination
compounds) have been isolated and confirmed by 1H NMR
spectra.7
In this article, we proved that all three key steps in the
catalytic cycle of CuAAC can proceed in the presence of
carboxylic acids and the latter two steps can be promoted
significantly by carboxylic acids. Benzoic acid showed the
best promotion activity, and the acids with strong chelating
ability to Cu(I) ion could not serve for this purpose. Thus, the
first carboxylic acid-promoted highly efficient CuAAC was
established.
FIGURE 1
The original Huisgen 1,3-dipolar cycloaddition1 between
alkyne (1) and azide (2) usually requires higher temperatures
and provides a mixture of 1,4- (3) and 1,5-disubstituted 1,2,3-
triazoles (4) (Scheme 1). However, these drawbacks can be
overcome conveniently by using different Cu(I) catalysts.
This Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
was reported initially and independently by the groups of
Sharpless2 and Meldal3 in 2002, which could proceed under
mild conditions to give regioisomer 3 exclusively. Since then,
CuAAC has been categorized as a “click reaction” and
extensively studied and applied in the literature.4-6
The investigation shows that the formation of Cu(I) ace-
tylides (5) benefits from amine additives. For example, all
practical procedures for the preparation of [(PhCtCCu)2]n
(5a) proceed in ammonia solution.8 In fact, an amine addi-
tive is essential for the preparation of RCtCCuLn (5) in
many published CuAAC procedures.4 The amine additives
accelerate the formation of 5 by two factors: (a) as a ligand, it
could dissociate the stable clusters of Cu(I) salts to form the
active Cu(I) species; (b) as a base, it could help to deprotonate
the terminal acetylenes to form acetylides.
(6) For selected referencestoCuAAC applications in2010, see: (a) Sharma,
P.; Moses, J. E. Org. Lett. 2010, 12, 2860. (b) Struthers, H.; Mindt, T. L.;
Schibli, R. Dalton Trans. 2010, 39, 675. (c) Bakunov, S. A.; Bakunova, S. M.;
Wenzler, T.; Ghebru, M.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R. J. Med.
Chem. 2010, 53, 254. (d) Carvalho, I.; Andrade, P.; Campo, V. L.; Guedes,
P. M. M.; Sesti-Costa, R.; Silva, J. S.; Schenkman, S.; Dedola, S.; Hill, L.;
Rejzek, M.; Nepogodiev, S. A.; Field, R. A. Bioorg. Med. Chem. 2010, 18,
2412. (e) Goldup, S. M.; Leigh, D. A.; McGonigal, P. R.; Ronaldson, V. E.;
Slawin, A. M. Z. J. Am. Chem. Soc. 2010, 132, 315. (f) Ornelas, C.;
Broichhagen, J.; Weck, M. J. Am. Chem. Soc. 2010, 132, 3923. (g) Pellico,
D.; Gomez-Gallego, M.; Ramirez-Lopez, P.; Mancheno, M. J.; Sierra,
(1) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; pp 1-176.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596.
(3) Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(4) For references to CuAAC and its applications, see reviews: (a) Mamidyala,
S. K.; Finn, M. G. Chem. Soc. Rev. 2010, 39, 1252. (b) Hua, Y.; Flood, A. H.
Chem. Soc. Rev. 2010, 39, 1262. (c) Le Droumaguet, C.; Wang, C.; Wang, Q.
Chem. Soc. Rev. 2010, 39, 1233. (d) Hanni, K. D.; Leigh, D. A. Chem. Soc.
Rev. 2010, 39, 1240. (e) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39,
1302. (f) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39, 1325.
(g) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (h) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(5) For selected references of CuAAC reactions in 2010, see: (a) Shao, C.;
Cheng, G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv. Synth. Catal. 2010, 352,
1587. (b) Buckley, B. R.; Dann, S. E.; Harris, D. P.; Heaney, H.; Stubbs, E. C.
Chem. Commun. 2010, 46, 2274. (c) He, Y.; Bian, Z.; Kang, C.; Cheng, Y.;
Gao, L. Chem. Commun. 2010, 46, 3532. (d) Gonda, Z.; Novak, Z. Dalton
Trans. 2010, 39, 726.
M. A.; Torres, M. R. Chem. Eur. J. 2010, 16, 1592. (h) Meyer, A.; Spinelli,
;
N.; Dumy, P.; Vasseur, J.-J.; Morvan, F.; Defrancq, E. J. Org. Chem. 2010,
75, 3927.
(7) (a) Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47,
8881. (b) Nolte, C.; Mayer, P.; Straub, B. F. Angew. Chem., Int. Ed. 2007, 46,
2101.
(8) For selected references, see: (a) Shi, W.; Luo, Y.; Luo, X.; Chao, L.;
Zhang, H.; Wang, J.; Lei, A. J. Am. Chem. Soc. 2008, 130, 14713. (b) Woon,
E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill, M. D. Tetrahedron 2006, 62,
4829. (c) Owsley, D. C.; Castro, C. E. Org. Synth. 1972, 52, 128.
7002 J. Org. Chem. 2010, 75, 7002–7005
Published on Web 09/17/2010
DOI: 10.1021/jo101495k
r
2010 American Chemical Society

Shao et al.
JOCNote
SCHEME 2
SCHEME 3
However, an amine additive is associated with two draw-
backs: (a) it caused low efficiency in the protonation of the
Cu-C bond of intermediate 6; (b) it induced a byproduct by
promoting the self-coupling of intermediate 5. In fact, the
low yields and byproduct have been reported by Sharpless in
his first CuAAC article when Et3N was used as an additive.2
This may be the reason that the most common catalytic
system to date for CuAAC is CuSO4/NaAsc in neutral
aqueous t-BuOH.
Recently, Straub reported that the protonation of the
Cu-C bond of 6 was inefficient using H2O or RCtCH as
a proton source, but it proceeded extremely fast (few
minutes) in HOAc.7b This study clearly indicated that “step
III” (see Figure 1) could not be improved even by using
catalytic system CuSO4/NaAsc in aqueous t-BuOH. It also
strongly implied that a highly efficient CuAAC may be
achieved if “step I” and “step II” could be influenced
efficiently by HOAc.
However, there are no such reports in the literature where
Cu(I) acetylides (5) can be prepared (step I) or carried out a
1,3-cycloaddition with azides (step II) in the presence of
HOAc. Herein, we would like to report our recent efforts to
understand the mechanistic cycle of CuAAC, by which the
first carboxylic acid-promoted highly efficient CuAAC was
established.
In the past years, two mechanistic concepts for CuAAC
have been developed: (a) the catalytic CuAAC has a strict
second-order dependence on Cu(I);9 (b) the dinuclear or tetra-
nuclear alkynyl-Cu(I) intermediate remarkably enhances the
reactivity of CuAAC.10 In our recent work, copper(I) acetate
(7a) {a structurally well-defined dinuclear Cu(I) complex
polymer [(MeCO2Cu)2]n}-catalyzed highly efficient CuAAC
was established based on these concepts.5a As shown in
Scheme 2, with 0.01 equiv of 7a, phenylethyne (1a) and benzyl
azide (2a) carried out a CuAAC to give the desired product 3a
in 98% yield in 8 min. Further stoichiometric experiments
provided two facts: (a) the catalyst 7a reacted with 1a to
quickly yield [(PhCtCCu)2]n (5a), while an equimolar amount
of HOAc (8a) was produced; (b) the “bare” 5a (i.e., with no
exogenous ligands) is not an active intermediate, but its
cycloaddition with 2a proceeded efficiently in the presence of
HOAc (8a).
the weak acid HOAc (8a). However, to understand the role
of HOAc (8a) in the conversion of 5a into 3a, a group of
control experiments were conducted (Scheme 3). (a) When
the mixture of 5a and 2a was stirred for 24 h in the medium in
which 5a was prepared (a reference method),8b a new mixture
of 3a and the coupling product 9 was obtained. (b) When the
mixture was stirred in H2O, t-BuOH, or t-BuOH/H2O for
5 h, 5a was recovered in almost quantitative yield. (c) When
the mixture was treated with a solution of NaOAc in t-BuOH/
H2O for 5 h, 3a was obtained in 6% yield. (d) When the
mixture was treated with HOAc (8a) in t-BuOH/H2O for
20 min, 3a was obtained in 98% yield. (e) When the mixture
was treated with DOAc (8a-d1) in cyclohexane for 5 min, the
deuterium-labeled 5-D-1,2,3-triazole (3a-d1, 97% D) was
produced in 98% yield.
Although the expected intermediate 6a or its analogues were
not isolated, some conclusions may be drawn from Scheme 3.
Experiments (a) and (b) proved that the cycloaddition of 5a
and 2a was retarded in base or neutral medium. Experiment (c)
proved that acetate itself could not accelerate the cycloaddition
at all, even though it has been reported to enhance CuAAC
(but it was not sufficiently investigated).11 Experiment (d)
proved that both cycloaddition and protonation of the Cu-C
bond could be promoted by HOAc (8a). Experiment (e) not
only showed that the cycloaddition can be promoted by DOAc
(8a-d1) but also implied that the intermediate 6a or its ana-
logues may exist because 3a-d1 was obtained exclusively.
Thus, HOAc (8a)-promoted CuAAC was studied further.
As shown in Table 1, when 1a and 2a were treated by CuSO4/
NaAsc for 24 h under the reference conditions,12 3a was
obtained in 21% yield (entry 1) or in 99% yield with an amine
ligand (entry 2). To our delight, when the same mixture of
(11) (a) Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.;
Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954. (b) Reddy, K. R.; Rajgopal,
K.; Kantam, M. L. Synlett 2006, 957. (c) Zhu, L.; Lynch, V. M.; Anslyn, E. V.
Tetrahedron 2004, 60, 7267.
(12) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853.
The results of Scheme 2 preliminarily indicate that all three
key steps in the catalytic cycle of CuAAC can proceed in the
presence of HOAc (8a). The formation of 5a can be easily
understood because 7a, in fact, is a strong conjugate base of
(13) (a) Sevryugina, Y.; Vaughn, D. D., II; Petrukhina, M. A. Inorg.
Chim. Acta 2007, 360, 3103. (b) Sugiura, T.; Yoshikawa, H.; Awaga, K.
Inorg. Chem. 2006, 45, 7584. (c) Cotton, F. A.; Dikarev, E. V.; Petrukhina,
M. A. Inorg. Chem. 2000, 39, 6072. (d) Ogura, T.; Mounts, R. D.; Fernando,
Q. J. Am. Chem. Soc. 1973, 95, 949. (e) Edwards, D. A.; Richards, R.
J. Chem. Soc., Dalton Trans. 1973, 2463.
(9) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2210.
(10) (a) Straub, B. F. Chem. Commun. 2007, 3868. (b) Ahlquist, M.;
Fokin, V. V. Organometallics 2007, 26, 4389.
J. Org. Chem. Vol. 75, No. 20, 2010 7003

Shao et al.
JOCNote
TABLE 1. HOAc (8a)-Promoted CuAAC between 1a and 2aa
entry
HOAc (8a) (equiv)
NaAsc (equiv)
solvent (mL)
time
24 h
yield of 3a (%)b
1
2
3
4
5
6
7
0.04
0.04
0.04
0.04
0.04
0.02
0.02
0.02
0.02
0.02
3
3
3
3
3
3
1
1
1
1
21c
99c
96
97
97
98
98
98
26
97
d
24 h
0.5
0.4
0.3
0.4
0.4
0.2
40 min
20 min
35 min
21 min
6 min
4 min
24 h
8
9e
10e
0.2
5 min
aThe mixture of 1a (1 mmol), 2a (1.05 mmol), CuSO4 5H2O (0.01 mmol), NaAsc, and HOAc (8a) in t-BuOH/H2O (1:2 v/v) was stirred at room
3
temperature. bIsolated yields. cThe data were cited from ref 12. d0.1 equiv of 1-benzyl-4-aminomethyl-1,2,3-triazole was used as a ligand.12
eCu(OAc)2 H2O (0.01 mmol) was used as a Cu(I) source.
3
TABLE 2. Carboxylic Acid-Promoted CuAAC between 1a and 2aa
entry
RCO2H (8)
time (min) yield of 3a (%)b
1
2
3
4
5
6
7
8
MeCO2H (8a)
HCO2H (8b)
MeCH2CH2CO2H (8c)
Me2CHCO2H (8d)
Me3CCO2H (8e)
H2CdCH(CH2)8CO2H (8f)
CF3CO2H (8g)
C6H5CO2H (8h)
HO2CCH2CH2CO2H (8i)
1,3,5-C6H3(CO2H)3 (8j)
trans-HO2CCHdCHCO2H (8k)
cis-HO2CCHdCHCO2H (8l)
4.0
3.5
3.5
3.5
3.0
4.0
98
97
96
96
98
95
30
94c
98
1.0
1.5
3.0
2.5
9
96
96
95
trace
10
11
12
120
aThe mixture of 1a (1 mmol), 2a (1.05 mmol), CuSO4 5H2O (0.01
mmol), NaAsc (0.02 mmol), and RCO2H (8a-8l, 0.2 mmol) in t-BuOH/
H2O (1:2 v/v, 1.0 mL) was stirred at room temperature. bIsolated yields.
c0.02 equiv of CF3CO2H (8g) was used.
FIGURE 2. Selected chelate carboxylic acids and non-carboxylic
acids.
3
was obtained in 98% yield within 1.0 min (entry 8). Succinic
acid (8i) and benzene-1,3,5-tricarboxylic acid (8j) also gave
excellent results because they have multicarboxylic acid
groups (entries 9 and 10). Since trans-but-2-enedioic acid
(8k) showed high promotion activity (entry 11) but its cis-
isomer (8l) had no activity (entry 12), the carboxylic acids
with strong chelating ability to Cu(I) ion may not serve for
this purpose.
More experiments showed that all selected chelate car-
boxylic acids (8m-8r in Figure 2) did not have acceptable
promotion activity for CuAAC. This result is in agreement
with the phenomenon reported in the literature.14 As was
expected, non-carboxylic acids 8s-8v were inert to CuAAC.
For example, in the presence of 8s-8v, no intermediate 5a
(characterized by a bright yellow color) was observed in
catalytic CuAAC. When preformed 5a was used as a sub-
strate, it was decomposed by 8s-8v within 5 min.
Interestingly, by using an equimolar mixture of 8v and
NaOAc (in situ formation of 8a), 5a was quickly produced
and converted into product 3a in 91% yield within 18 min.
Since the inert5a,b,9 polymer15 5a could be activated by 8a but
not by 8v or NaOAc alone, 8a may play dual roles in the
activation of 5a as an acidic reagent and a bidentate ligand.
As shown in Scheme 4, an active intermediate5b was proposed
entry 1 was treated with 0.5 equiv of 8a, 3a was obtained in
96% yield for 40 min (entry 3). By using 0.4 equiv of 8a, the
reaction finished in 20 min (entry 4), but a prolonged
reaction time was needed when using 0.3 equiv of 8a (entry 5).
We interestingly observed that the reaction rate was signifi-
cantly influenced by the ratio of HOAc, NaAsc, and solvent
(entries 6-8). When their ratio was 0.2 (equiv):0.02 (equiv):1.0
(mL), the reaction finished within 4 min to give 3a in 98% yield
(entry 8). There was no advantage to replacing CuSO4 5H2O
3
with Cu(OAc)2 H2O (entries 9 and 10).
3
The investigation showed that all structurally well-defined
Cu(I) carboxylates are dinuclear or polynuclear complexes.14
Four of them have been proved to be excellent catalysts for
CuAAC,5a such as [(MeCO2Cu)2]n (7a), (PhCO2Cu)4 (7b),
[(CF3CO2Cu)4]n (7c), and [(t-BuCO2Cu)5]n (7d). Therefore,
the other carboxylic acids may be expected to have similar
properties as HOAc (8a). As shown in Table 2, different
carboxylic acids were tested, and the aliphatic acids 8a-8f
showed highly efficient promotion activity (entries 1-6).
However, CF3CO2H (8g) could not afford the desired prod-
uct at higher loading (0.2 equiv), but it gave comparable
promotion activity at lower loading (0.02 equiv) (entry 7). To
our surprise, PhCO2H (8h) gave the best result, by which 3a
(15) Dinuclear polymeric structure of [(PhCtCCu)2]n (5a): Chui, S. S. Y.;
Ng, M. F. Y.; Che, C.-M. Chem. Eur. J. 2005, 11, 1739.
;
(14) Xie, J.; Seto, C. T. Bioorg. Med. Chem. 2007, 15, 45.
7004 J. Org. Chem. Vol. 75, No. 20, 2010

Shao et al.
JOCNote
SCHEME 4
SCHEME 5
TABLE 3. PhCO2H (8h)-Promoted CuAAC between 1a and 2aa
entry PhCO2H (equiv) solvent (mL) time (min) yield of 3a (%)b
1
2
3
4
5
0.2
0.1
0.05
0.02
0.02
2.0
2.0
2.0
2.0
0.2
1.0
4.0
20
40
3.0
97
98
98
98
98
aThe mixture of 1a (2 mmol), 2a (2.1 mmol), CuSO4 5H2O (0.02
mmol), NaAsc (0.04 mmol), and PhCO2H (8h) in t-BuOH/H2O (1:2 v/v)
3
was stirred at room temperature. bIsolated yields.
SCHEME 6
(its structure remains unclear), which may be produced from
the dissociation of 5a by using 8a as an acidic reagent fol-
lowed by coordination with acetate by using 8a as a bidentate
ligand.
Thus, the combination of CuSO4/NaAsc just served as a
Cu(I) species producer. Once the Cu(I) species is produced
in situ, it quickly coordinated with RCO2H to generate a highly
active catalyst [(RCO2Cu)m]n. Thus, the method actually is
still a Cu(I) carboxylate-catalyzed CuAAC reaction, but of
greater advantage by its use of a cheap and stable Cu(II)
source and alterable solvents.
On the basis of the results in Table 2, PhCO2H (8h) was
chosen as a promoter in practice. As shown in Table 3, it was
so powerful that 0.1 equiv was good enough to give excellent
results (entry 2). The results in entries 3-5 indicated that the
reaction rate has been significantly accelerated by decreasing
the amount of solvent. Finally, entry 2 was assigned as our
standard conditions (rather than entry 1) for safety reasons
because CuAAC is a highly exothermic reaction.
efficient CuAAC, and the dual functions (acid reagent and
bidentate ligand) of carboxylic acids in CuAAC were discussed.
Experimental Section
Typical Benzoic Acid-Promoted CuAAC Procedure for the
Preparation of 1-Benzyl-4-phenyl-1H-[1,2,3]trizole (3a). To a
solution of CuSO4 5H2O (5.0 mg, 0.02 mmol), sodium ascor-
3
bate (7.9 mg, 0.04 mmol), and PhCO2H (24.4 mg, 0.2 mmol) in
t-BuOH/H2O (1:2 v/v, 2.0 mL) was added a mixture of phenyl-
ethyne (1a, 204 mg, 2 mmol) and benzyl azide (2a, 280 mg,
2.1 mmol) at room temperature. The resultant mixture was
stirred continuously until the reaction system solidified completely
(ca. 4 min). Then CH2Cl2 (20 mL) was added to dissolve the crude
product. The organic layer was washed with H2O and brine and
dried over anhydrous Na2SO4. Removal of the solvent yielded a
residue, which was purified by a short chromatography (silica gel,
EtOAc/PE, 1:3) to give 3a (461 mg, 98%) as an off-white solid.
A similar procedure was used in the preparation of products
3b-3q.
As shown in Scheme 5, excellent results were obtained
between the reaction of phenylethyne (1a) and different
azides (2a-2e, 2g, 2i, 2j, 2l) under the standard conditions.
However, 0.2 equiv of PhCO2H (8h) was recommended to
accelerate the reaction rate for the cases of substrates 2f, 2h,
and 2k.
As shown in Scheme 6, the reactions between benzyl azides
(2a) and different alkynes (1b-1d and 1f) also gave excellent
results. Under the standard conditions, more than 6 h was
required for the substrate 1e. However, the same conversion could
be achieved within 2 h when 0.2 equiv of PhCO2H (8h) was used.
In conclusion, on the basis of the results of the control and
the isotopic labeling experiments, we confirmed that all three
key steps in the catalytic cycle of CuAAC can proceed in the
presence of carboxylic acids. In fact, the later two key steps
can be promoted significantly by carboxylic acids. Among
the different types of carboxylic acids scanned, PhCO2H (8h)
showed the best promotion activity. The carboxylic acids
with strong chelating ability to Cu(I) ion and non-carboxylic
acids could not serve for this purpose. To the best of our
knowledge, this is the first carboxylic acid-promoted highly
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (21072112).
Note Added after ASAP Publication. Scheme 4 and Table 3
contained errors in the version published ASAP September 17,
2010; the correct version reposted September 22, 2010.
Supporting Information Available: Experiments, character-
1
ization, H NMR and 13C NMR spectra for products 3a-3q,
and 1H NMR spectrum of 3a-d1. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 20, 2010 7005