Effects of a flexible alkyl chain on a ligand for CuAAC reaction

Article abstract of DOI:10.1021/ol101990d

Imidazole derivatives substituted by a normal alkyl group are shown to be efficient as a ligand for the copper(Δ)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. An alkyl chain on the imidazole ligands shows an efficient steric effect and benefits the reaction. Such functionalities of an alkyl chain allow a rapid CuAAC reaction of even a bulky alkyne, which has been difficult to perform under conventional conditions.

Full text of DOI:10.1021/ol101990d

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4988-4991
Effects of a Flexible Alkyl Chain on a
Ligand for CuAAC Reaction
Keisuke Asano and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoutodaigaku-katsura, Nishikyo, Kyoto 615-8510, Japan
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received September 9, 2010
ABSTRACT
Imidazole derivatives substituted by a normal alkyl group are shown to be efficient as a ligand for the copper(Ι)-catalyzed azide-alkyne cycloaddition
(CuAAC) reaction. An alkyl chain on the imidazole ligands shows an efficient steric effect and benefits the reaction. Such functionalities of an alkyl
chain allow a rapid CuAAC reaction of even a bulky alkyne, which has been difficult to perform under conventional conditions.
An alkyl chain is a part of many amphiphiles or other organic
materials and plays an important role in determining their
properties.1 Although it ordinarily has an extended form with
all anti configurations as its stable shape, it can readily
change its conformation in a host molecule to an unusual
one, such as coiled, folded, or U-shaped, to adjust its volume
to the cavity size.2 However, such a flexible nature of an
alkyl chain has rarely been noted as a special functionality
for synthetic reagents.3,4 In addition, a normal alkyl group
with a variety of conformations may have an appreciable
steric effect. On the basis of such a viewpoint, we sought to
utilize the latent functionalities of a normal alkyl group in
the design of a ligand for a transition metal catalyst. Herein
we describe the efficiency of imidazoles carrying a long alkyl
chain5,6 as a ligand for the copper(Ι)-catalyzed azide-alkyne
cycloaddition (CuAAC) reaction.7
The CuAAC reaction7 has been a representative of click
chemistry8 that has been utilized in various areas,9 and there
are a few examples where the reaction was accelerated by a
ligand.10-12 Polydentate ligands, such as tris(benzyltria-
(5) Cu(Ι)-imidazole systems have been well studied and shown to form
a stable complex with an affinity for π-acceptor compounds; see: (a)
Kitagawa, S.; Munakata, M. Bull. Chem. Soc. Jpn. 1986, 59, 2743. (b)
Kitagawa, S.; Munakata, M. Bull. Chem. Soc. Jpn. 1986, 59, 2751. (c)
Gaykema, W. P. J.; Hol, W. G. J.; Vereijken, J. M.; Soeter, N. M.; Bak,
H. J.; Beintema, J. J. Nature 1984, 309, 23. (d) Linzen, B.; Soeter, N. M.;
Riggs, A. F.; Schneider, H.-J.; Schartau, W.; Moore, M. D.; Yokota, E.;
Behrens, P. Q.; Nakashima, H.; Takagi, T.; Nemoto, T.; Vereijken, J. M.;
Bak, H. J.; Beintema, J. J.; Volbeda, A.; Gaykema, W. P. J.; Hol, W. G. J.
(1) (a) Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. J. Chem.
Soc., Faraday Trans. 2 1976, 72, 1525. (b) Holbrey, J. D.; Seddon, K. R.
J. Chem. Soc., Dalton Trans. 1999, 2133.
(2) For selected references, see: (a) Trembleau, L.; Rebek, J., Jr. Science
2003, 301, 1219. (b) Schramm, M. P.; Rebek, J., Jr. Chem.sEur. J. 2006,
12, 5924. (c) Purse, B. W.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 2530. (d) Rebek, J., Jr. Chem. Commun. 2007, 2777. (e) Ajami,
D.; Rebek, J., Jr. Nat. Chem. 2009, 1, 87. (f) Ko, Y. H.; Kim, H.; Kim, Y.;
Kim, K. Angew. Chem., Int. Ed. 2008, 47, 4106.
Science 1985, 229, 519
.
(6) (a) Asano, K.; Matsubara, S. Org. Lett. 2009, 11, 1757. (b) Asano,
K.; Matsubara, S. Synlett 2009, 35. (c) Asano, K.; Matsubara, S. Synthesis
2009, 3219. (d) Gu¨ntensperger, M.; Zuberbu¨hler, A. D. HelV. Chim. Acta
1977, 60, 2584. (e) Asano, K.; Matsubara, S. Heterocycles 2010, 80, 989
.
(3) Hua, M.-Q.; Cui, H.-F.; Wang, L.; Nei, J.; Ma, J.-A. Angew. Chem.,
(7) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Meldal., M.; Tornøe,
C. W. Chem. ReV. 2008, 108, 2952. (d) Spiteri, C.; Moses, J. E. Angew.
Chem., Int. Ed. 2010, 49, 31.
Int. Ed. 2010, 49, 2772
.
(4) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054. (b)
Hamatani, T.; Matsubara, S.; Matsuda, H.; Schlosser, M. Tetrahedron 1988,
44, 2875
.
10.1021/ol101990d  2010 American Chemical Society
Published on Web 09/29/2010

zolylmethyl)amine (TBTA),10a,b are well-balanced to stabilize
Cu(Ι) and to accelerate the reaction.10 Monodentate ligands
with rigid backbones, such as an NHC (ICy or SIMes) or a
phosphoramidite, were also shown to have a high accelerating
effect.11 These previous instances suggest that bulky ligands
are desirable for an efficient catalyst. Indeed, during our
initial investigations of the CuAAC reaction between 1-azi-
dooctane (1a) and phenylacetylene (2a) under the conditions
in Table 1, bulky 1-(1-adamantyl)imidazole (4b) was shown
4b (Table 1, entries 9 and 10).6d We then investigated the
efficiency of imidazoles substituted by a normal alkyl group
in hopes of finding its steric effect. As expected, they proved
to be effective, and especially 1-decylimidazole (4d) showed
as good a result as 4b (Table 1, entries 11 and 12).13 With
4d, we also replaced CuI by some other Cu sources, and
CuI was shown to be the best among them (Table 2).
Table 2. CuAAC Reaction with 1-Decylimidazole (4d) and
Various Cu Sourcesa
Table 1. CuAAC Reaction between 1-Azidooctane (1a) and
Phenylacetylene (2a) with Various Ligandsa
entry
Cu
yield (%)b
1
2
3
4
5
6
CuI
96
63
38
54
31
34
entry
ligand
yield (%)b
CuBr
CuCl
CuCN
1
2
3
4
5
6
7
8
none
Et3N
4
15
37
18
6
29
35
99
61
51
63
96c
Cu(CH3CN)4PF6
n-Bu3N
EtNiPr2
CuSO4 with Na ascorbatec
a Reactions were run using 1a (1.0 mmol), 2a (1.05 mmol), a Cu salt
(0.005 mmol), and 4d (0.005 mmol). b Determined by 1H NMR. c 0.025
mmol (2.5 mol %) of Na ascorbate was used.
2,6-lutidine
DMAPd
4a (R ) CH3)
4b (R ) 1-ade)
5
9
10
11
12
6
We then applied the condition with 0.5 mol % of CuI and
0.5 mol % of 4d to some other azides and alkynes (Table 3).
4c (R ) n-C4H9)
4d (R ) n-C10H21
)
a Reactions were run using 1a (1.0 mmol), 2a (1.05 mmol), CuI (0.005
b
mmol), and a ligand (0.005 mmol). Determined by H NMR. c Isolated
1
yield. d DMAP ) N,N-dimethyl-4-aminopyridine. e ad ) adamantyl.
Table 3. CuAAC Reaction with 1-Decylimidazole (4d)a
entry
R1
R2
3
yield (%)b
1
2
3
4
5
6
7
8
9
PhCH2 (1b)
p-CH3OC6H4CH2 (1c) Ph (2a)
p-CF3C6H4CH2 (1d) Ph (2a)
t-BuOCOCH2 (1e)
cyclohexyl (1f)
PhCH2 (1b)
PhCH2 (1b)
PhCH2 (1b)
PhCH2 (1b)
Ph (2a)
13ba
3ca
3da
3ea
3fa
99
99
99
97
99
99
99
97
99
to be excellent as a ligand and much more efficient than
1-methylimidazole (4a) (Table 1, entries 1-8). 1,2-Dimeth-
ylimidazole (5) and 1,4-dimethylimidazole (6) also gave 3aa
in higher yields than the case of 4a, but they are not up to
Ph (2a)
Ph (2a)
p-CH3OC6H4 (2b) 3bb
p-CF3C6H4 (2c)
CH3OCO (2d)
n-C8H17 (2e)
3bc
3bd
3be
(8) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
a Reactions were run using 1 (1.0 mmol), 2 (1.05 mmol), CuI (0.005
(9) For selected reviews, see: (a) Kolb, H. C.; Sharpless, K. B. Drug
DiscoVery Today 2003, 8, 1128. (b) Lutz, J.-F. Angew. Chem., Int. Ed. 2007,
46, 1018. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007, 36,
1249. (d) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid Commun. 2007,
28, 15. (e) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba,
G.; Genazzani, A. A. Med. Res. ReV. 2008, 28, 278.
mmol), and 4d (0.005 mmol). b Isolated yields.
Reactions with various substrates afforded excellent yields.
(10) (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853. (b) Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.;
White, J. M.; Williams, S. J. Chem. Commun. 2008, 2459. (c) Rodionov,
V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem.
Soc. 2007, 129, 12696. (d) Rodionov, V. O.; Presolski, S. I.; D´ıaz, D. D.;
Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12705. (e) Tanaka,
K.; Kageyama, C.; Fukase, K. Tetrahedron Lett. 2007, 48, 6475. (f)
Candelon, N.; Laste´coue`res, D.; Diallo, A. K.; Aranzaes, J. R.; Astruc, D.;
Vincent, J.-M. Chem. Commun. 2008, 741. (g) Ozc¸ubukc¸u, S.; Ozkal, E.;
Jimeno, C.; Perica`s, M. A. Org. Lett. 2009, 11, 4680. (h) Baron, A.; Ble´riot,
Y.; Sollogoub, M.; Vauzeilles, B. Org. Biomol. Chem. 2008, 6, 1898.
Azides with benzyl groups (1b, 1c, 1d), an ester group (1e),
(11) (a) D´ıez-Gonza´lez, S.; Correa, A.; Cavallo, L.; Nolan, S. P.
Chem.sEur. J. 2006, 12, 7558. (b) D´ıez-Gonza´lez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2008, 47, 8881. (c) Campbell-Verduyn, L. S.; Mirfeizi, L.;
Dierckx, R. A.; Elsinga, P. H.; Feringa, B. L. Chem. Commun. 2009, 2139.
(12) (a) Pe´rez-Balderas, F.; Ortega-Mun˜oz, M.; Morales-Sanfrutos, J.;
Herna´ndez-Mateo, F.; Calvo-Flores, F. G.; Calvo-As´ın, J. A.; Isac-Garc´ıa,
J.; Santoyo-Gonza´lez, F. Org. Lett. 2003, 5, 1951. (b) Gonda, Z.; Nova´k,
Z. Dalton Trans. 2010, 39, 726.
¨
Org. Lett., Vol. 12, No. 21, 2010
4989

and a cyclohexyl group (1f) showed rapid reactions (Table
3, entries 1-5). Acetylenes with phenyl groups (2b, 2c), an
ester group (2d), and a primary alkyl group (2e) were also
applicable (Table 3, entries 6-9).
Scheme 1.
CuAAC Reaction in the Presence of Watera
The efficiency of the catalyst for click chemistry should
stay relatively constant in a wide range of reaction media.8
As shown in Table 4, 4d was also useful in the reactions
Table 4. CuAAC Reaction Using 1-Decylimidazole (4d) and
1-Methylimidazole (4a) with Various Solventsa
yield (%)b
a Reactions were run using 1 (1.0 mmol), 2 (1.05 mmol), CuI (0.005
mmol), 4d (0.005 mmol), and H2O (0.5 mL). b Run in the presence of H2O
(0.1 mL) and t-BuOH (0.4 mL).
entry
solvent
with 4d
with 4a
11
2
3
4
5
6
7
8
hexane
CHCl3
CH2Cl2
DMSO
CH3CN
CH3OH
t-BuOH
H2O
71
85
99
53
85
26
40
97
2
46
99
23
82
7
without any protection of hydroxyl groups (1h) could also
be used for the reaction by using a mixture of water and
t-BuOH as a solvent (Scheme 1, 3ha).10h,17
10
34
We further investigated the reaction between 1a and 2a
with various amounts of imidazole derivatives in a shorter
reaction time (Scheme 2).18 As a result, the use of more than
a Reactions were run using 1a (1.0 mmol), 2a (1.05 mmol), CuI (0.005
mmol), 4 (0.005 mmol), and a solvent (0.5 mL). b Determined by 1H NMR.
using a variety of solvents, and the effect of the long alkyl
chain on 4d was observed in almost solvents. 4d was much
more effective than 4a in hexane (Table 4, entry 1), and the
efficiency of 4d was also seen in CHCl3 and DMSO (Table
4, entries 2 and 4). In CH2Cl2 or CH3CN, 4d and 4a gave
similarly good results (Table 4, entries 3 and 5).14,15
Although alcoholic solvents retarded the reaction, the ac-
celerating effect of 4d was still available (Table 4, entries 6
and 7). In addition, 4d maintained the activity even in the
presence of water, and its large accelerating effect was
observed (Table 4, entry 8).16
Scheme 2. CuAAC Reaction between 1-Azidooctane (1a) and
Phenylacetylene (2a) with Various Amounts of
1-Decylimidazole (4d) and 1-Hexadecylimidazole (4e)
Such a broad utility of the ligand expands the scope of
substrates. For example, although the substrates having a
hydroxyl group (1g, 2f) showed a significant inhibition of
the reaction under the neat condition, we could perform their
reactions efficiently in the presence of water, which may
interrupt the coordination of a hydroxyl group to a Cu
catalyst (Scheme 1, 3ga and 3bf). A similar enhancement
by water was also seen in the reaction of methyl propargyl
ether (2g) (Scheme 1, 3bg), and even the glucosyl azide
1.5 mol % of 4d brought about a further acceleration, and
the reaction using 2.0 mol % of 4d proceeded to completion
within only 15 min. Furthermore, with 1-hexadecylimidazole
(4e), carrying an even longer alkyl chain, only 1.0 mol %
was enough to gain a similar acceleration. The additional
drastic acceleration can be attributed to the effect of free
imidazole molecules not coordinating to a Cu catalyst and
working as a base to deprotonate from a terminal alkyne in
forming a copper-acetylide intermediate.7a,14 The longer alkyl
chain probably has a larger steric effect to repulse the
multiple coordination of 4e, and released 4e might work as
a base.
(13) In this case, the steric effect of the alkyl chain might keep the
reactivity of copper-acetylide intermediates; otherwise, copper acetylide
species are known to become an inactive polymeric form; see: Stephens,
R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313
(14) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210
.
.
(15) It was reported that CH3CN could be an efficient ligand for CuAAC
reactions; see ref 14.
(16) As for the reaction in the presence of water, further investigations
corresponding to Table 1 were also performed. See Supporting Information
for details, Table S1.
(17) See Supporting Information for more details, Scheme S1.
(18) Similar investigations were also performed with 4a and 4b. See
Supporting Information for details, Scheme S2.
4990
Org. Lett., Vol. 12, No. 21, 2010

The imidazole ligands with a long alkyl chain in particular
were efficient for the reactions of bulky alkynes. A bulky
alkyne is a relatively unfavorable substrate in the CuAAC
reaction under mild conditions. Actually the reactions of tert-
butylacetylene (2h) or cyclohexylacetylene (2i) with 1b under
the condition using 0.5 mol % of 4d as in Table 3 resulted
in low yields (6% and 0%, respectively),19 and previous
research also suggests that such reactions should be per-
formed under harsher conditions.10f,20 This may be caused
by the difficulty of a bulky alkyne to form a stable π-complex
due to its steric hindrance, which would lead to a higher
pKa of its terminal proton than in the other cases;14 thus a
base catalyst would be required for a rapid reaction.
However, the use of a large amount of a small amine will
saturate the coordination spaces of a Cu catalyst and suppress
the catalytic activity.5b,10a Meanwhile, with 1.5 mol % of
4d or 4e, carrying a long alkyl chain, the reaction of even
2h could be performed smoothly to give 3bh in high yields,
and the use of the same amount of 4a or even 4b was less
efficient (Scheme 3). Besides, more noteworthy is that in
the case of 2i, only 4e gave a prominent result (Scheme 3).
These results suggest that the steric effect of 4e might leave
a free imidazole acting as a base while keeping a coordina-
tively unsaturated Cu catalyst.21 In addition, the fact that
the rigid backbone of 4b also disturbed the reaction despite
its sufficient steric effect indicates that the flexible alkyl chain
must be present to create a favorable environment around a
Cu center, even for a bulky substrate.22
Scheme 3
.
CuAAC Reaction of Acetylenes with Bulky
Substituents
imidazoles worked not only as a ligand but also as a base.
Furthermore, the flexible alkyl chain could provide a
favorable environment around a Cu center for a variety of
substrates. These results suggest a new concept for an
efficient ligand of transition metal catalysis. Further studies
on the detailed clarification of the role of the alkyl chain
and the application of this methodology to the other catalytic
processes are currently underway in our laboratory.
Acknowledgment. This work was supported financially
by the Japanese Ministry of Education, Culture, Sports,
Science and Technology. The authors acknowledge the
support by the Global COE Program “Integrated Materials
Science” (B-09). K.A. also acknowledges the Japan Society
for the Promotion of Science for Young Scinetists for the
fellowship support.
In summary, we have showed the efficiency of N-
alkylimidazoles as a ligand to achieve a rapid CuAAC
reaction. The alkyl chain gave an efficient steric effect, and
(19) The use of CH3CN or CH2Cl2 as a solvent was also not effective
for those reactions. See Supporting Information for details, Scheme S3.
(20) (a) Chassaing, S.; Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale,
P.; Sommer, J. Chem.sEur. J. 2008, 14, 6713. (b) Alonso, F.; Moglie, Y.;
Radivoy, G.; Yus, M. Tetrahedron Lett. 2009, 50, 2358. (c) Chan, T. R.;
Supporting Information Available: Experimental pro-
cedures including spectroscopic and analytical data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Fokin, V. V. QSAR Comb. Sci. 2007, 26, 1274
.
(21) Dureen, M. A.; Stephan, D. W. J. Am. Chem. Soc. 2009, 131, 8396.
(22) Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.;
Hoveyda, A. H. Nature 2008, 456, 933.
OL101990D
Org. Lett., Vol. 12, No. 21, 2010
4991