Highly efficient click reaction on water catalyzed by a ruthenium complex

Article abstract of DOI:10.1039/c4ra12960a

The highly efficient click reaction between terminal alkynes and azides has been achieved on water using ruthenium complex RuH₂(CO)(PPh₃)₃ as the catalyst, and the catalyst loading was decreased to 0.2 mol% on water from 5

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DOI: 10.1039/C4RA12960A
Graphic abstract
Reactivity of ruthenium-catalyzed click reaction is enhanced greatly by using H2O as the solvent.

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ARTICDLOI:E10.10T39/YC4RPA129E60A
Highly efficient click reaction on water catalyzed by ruthenium complex
Hai Xiao Siyang, Hui Ling Liu, Xin Yan Wu and Pei Nian Liu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
The highly efficient click reaction between terminal alkynes and azides has been achieved on water using
ruthenium complex RuH2(CO)(PPh3)3 as the catalyst, and the catalyst loading was decreased to 0.2 mol%
on water from 5 mol% in organic solvent. The RuH2(CO)(PPh3)3/H2O system also catalyzed the one-pot
click reaction of bromides, sodium azide and alkynes; in this process, azides formed in situ and then
underwent a click reaction with alkynes. In both aqueous processes, 1,4-disubstituted 1,2,3-triazoles were
10 obtained in 71-89% yield with high regioselectivity.
RuH2(CO)(PPh3)3, which we previously showed to catalyze the
click reaction in organic solvent to afford 1,4-disubstituted-1,2,3-
triazole with high regioselectivity.22 Here we report that the
50 RuH2(CO)(PPh3)3-catalyzed click reaction on water led to much
higher reactivity and proceeded efficiently at catalyst loadings as
low as 0.2 mol%. The synthetic usefulness of this catalytic
system was further demonstrated by achieving the one-pot
multicomponent cycloaddition of bromides, sodium azide and
55 alkynes.
Introduction
Water, which is unquestionably cheap, safe, non-toxic and readily
available,1 is becoming an increasingly popular medium for
organic reactions.2 Ever since Breslow adapted the Diels-Alder
15 reaction to water,3 extraordinary advances have been made in
performing organic chemistry in aqueous media.2,4 Chemists who
make use of water as a solvent are often confronted with
problems such as the antagonistic nature of water toward
nucleophilic organic compounds5 and the limited solubility of the
20 organic components. However, in some cases, using water as a
solvent can accelerate reaction rates and enhance yield and
selectivity compared to the same reaction in organic solvent,6
even when the reactants are only sparingly soluble or insoluble in
Results and discussion
We began our investigation of ruthenium-catalyzed cycloaddition
using benzyl azide (1a) and phenylacetylene (2a) as the model
substrates, and the resulting reaction mixture was analyzed by 1H
water. Various factors have been proposed to explain how water 60 NMR using PhSiMe3 as the internal standard (Table 1). Initially,
25 can cause these enhancements. These factors include the
hydrophobic effect,7 hydrogen bonding,8,9 and the method used to
mix reactants in water.10 Another advantage of conducting
reactions in aqueous solvent is that it facilitates the design of one-
1a and 2a were heated on water at 80 °C for 2 h in the presence
of RuH2(CO)(PPh3)3; this led to 100% conversion and 86% yield
of 1,4-disubstituted 1,2,3-triazole 3a with 100% regioselectivity
(entry 1). Encouraged by these results, we optimized the reaction
pot consecutive and multicomponent reactions (MCRs), which 65 by adding phase transformation catalyst (PTC), which can
30 tend to be more environmentally friendly and atom-economical
than conventional organic syntheses.11
solubilize organic materials or form emulsions with them on
water. In the presence of Bu4NBr, catalyst loading could be
reduced from 5 mol% to 0.2 mol% while maintaining a 100%
conversion and generating the 1,4-disubstituted 1,2,3-triazole 3a
One of the most ingenious examples of “click chemistry”12 is
the copper-catalyzed Huisgen 1,3-dipolar cycloaddition of azides
and alkynes (CuAAC), discovered by Meldal13 and Sharpless.14 70 in >86% yield with 100% regioselectivity (entries 2-6). Lowering
35 This click reaction is the most direct route to 1,4-disubstituted
1,2,3-triazoles,15 which are applied widely across various fields,
including biological science,16 synthetic organic chemistry,17
medicinal chemistry18 and material chemistry.19 Therefore,
catalyst loading below 0.1 mol% led to incomplete substrate
conversion (entry 7).
Various other PTCs were then tested. Although CTAB gave
100% conversion and generated the desired 1,4-product in 95%
tremendous attention has been given to develop new protocols for 75 yield, it also generated the 1,5-product as by-product in 3% yield
40 the synthesis of various 1,2,3-triazoles.20 The ruthenium-
catalyzed azide-alkyne cycloaddition reaction (RuAAC) relying
on pentamethylcyclopentadienyl ruthenium chloride catalysts has
been reported to give 1,5-disubstituted-1,2,3-triazole with high
regioselectivity.21
(entry 8). Bu4NI, PEG2000, Cyclodextrin or Tween-80 were
inferior to Bu4NBr, giving either lower conversion or yields of
products and selectivity (entries 9-12). Eliminating the PTC
entirely led to poor conversion and yield (entry 13). Changing the
80 reactant ratio (1a : 2a) from 1:2 to 1:1.2 gave the desired 1,4-
product in 89% isolated yield (entry 14).
45
In an effort to adapt the RuAAC reaction to aqueous solvent,
we took advantage of ruthenium hydride complex,
a
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[journal], [year], [vol], 00–00 | 1

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Table 1 RuH2(CO)(PPh3)3-catalyzed click reaction of 1a and 2a
on water under various conditions.a
oC; 2 h. These conditions worked well for a variety of terminal
alkynes and azides (Table 2). All reactions of benzyl azide 1a
View Article Online
with aromatic alkynes containing electron-donating or electron-
DOI: 10.1039/C4RA12960A
withdrawing groups proceeded smoothly to afford 1,4-substituted
15 triazole products 3b-3g in 71-88% yield. The results illustrate that
the electronic properties of substituents on the benzene ring of
alkynes does not appreciably affect the aqueous click reaction.
Ferrocenylacetylene and alkyl alkyne were also effective in this
ruthenium complex-catalyzed click reaction, producing the
20 corresponding triazoles 3h and 3i in respective isolated yields of
80% and 82%. The reaction also proceeded with 3-
ethynylpyridine, giving 3j in 62% yield, while using 2-
ethynylthiophene gave 3k in 52% yield.
Next we examined the substrate scope of organic azides.
25 Benzyl azide bearing methyl, methoxy, or fluoride groups
underwent this transformation efficiently, giving products 3l-3n
in 86-89% isolated yield. Alkyl organic azides also reacted
efficiently, giving the desired products 3o-3q with high isolated
yields of 76-87%. The hydroxyl-functionalized azide was a good
30 reaction partner, generating triazole 3r with phenylacetylene in
82% yield. The reaction tolerated a substitution of the benzylic
methylene of benzyl azide with a methyl group, leading to
formation of 3s in 89% yield. This suggests that the reaction is
insensitive to steric hindrance of the azide.
Entry
S/C
PTC
Conv. (%)b
Yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
20
20
50
100
100
100
100
100
100
69
100
99
66
86
95
95
94
86
92
63
95
87
28
47
37
57
-
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
CTAB
100
200
500
1000
500
500
500
500
500
500
500
Bu4NI
PEG2000
Cyclodextrin
Tween-80
-
64
54
74
100
Bu4NBr
94 (89)e
a Reactions were performed in sealed tubes containing 1a (0.5 mmol), 2a (1.0
mmol), PTC (0.025 mmol) and water (0.5 mL) under N2 for 2 hours, unless
noted otherwise. b Conversions were estimated by integrating the area under
the peaks for triazole and unreacted azide in H NMR spectra. Based on the
integrated area of the peak for unreacted azide (1a) in H NMR spectra, using
1
c
35
Based on the above results, the RuH2(CO)(PPh3)3-catalyzed
click reactions on water gave yields similar to those of the
corresponding reactions in organic solvent. At the same time, the
use of aqueous solvent allowed us to reduce the catalyst loading
from 5 mol% to 0.2 mol%.
1
d
PhSiMe3 as the internal standard. 1a (0.5 mmol) and 2a (0.6 mmol) were
used. e Isolated yield is shown in parentheses.
Table 2 RuH2(CO)(PPh3)3-catalyzed cycloaddition of various
5
alkynes and organic azides on water.a,b
40 Table 3 Optimization of conditions for the RuH2(CO)(PPh3)3-
catalyzed, one-pot click reaction of benzyl bromide, sodium azide,
and phenylacetylene on water.a
O
OMe
Ph
Me
F
Entry
S/C
PTC
Conv. (%)b
Yield (%)c
Ph
N
N
N
N
N
N
N
N
N
Ph
Ph
N
Ph
1
2
3
4
5
6
7
20
50
100
200
1000
50
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NBr
-
100
100
71
22
21
63
79 (84)d
49
N
N
N
N
N
3d, 88%
3b, 87%
3c, 80%
3e, 71%
3a, 89%
CO2Et
NH2
Ph
22
22
54
42
N
Ph
Fe
3
Ph
Ph
N
N
N
N
N
N
N
N
N
N
75
81
N
N
N
Ph
Ph
Ph
N
N
3j, 62%
3h, 80%
3i, 82%
3g, 75%
3f, 74%
50
a
Reactions were performed in sealed tubes containing benzyl bromide (0.5
mmol), sodium azide (0.55 mmol), phenylacetylene (0.6 mmol), PTC (0.025
mmol) and water (0.5 mL) under N2 for 2 hours. Conversion rates were
estimated by integrating the area under the peaks for triazole and unreacted
benzyl bromide in 1H NMR spectra. c Based on the integrated area of the peak
for unreacted benzyl bromide in 1H NMR spectra, using PhSiMe3 as the
internal standard. d Isolated yield is shown in parentheses.
Ph
Ph
Me
OMe
F
S
b
N
N
N
N
N
N
N
N
Ph
N
N
N
N
3m, 89%
3n, 86%
Ph
3k, 52%
3l, 88%
Ph
Ph
Ph
Ph
N
N
N
N
N
N
OH
( )4
N
N
N
N
N
( )11
N
N
N
N
45 Multicomponent reactions (MCRs) involve connecting three or
more starting materials in a single synthetic operation with high
atom economy and bond-forming efficiency.23 This allows the
construction of high molecular diversity and complexity in a
relatively rapid and straightforward manner.24 One-pot MCRs
50 often involve shorter reaction times and higher overall yields than
multi-step syntheses, thereby reducing energy and manpower
3s, 89%
3o, 87%
3r, 82%
3p, 76%
3q, 76%
a
Reaction conditions: azide (0.5 mmol), alkyne (0.6 mmol), RuH2CO(PPh3)3
b
(0.001 mmol), Bu4NBr (0.025 mmol), 80 °C, 2 h, 0.5 mL of water. Isolated
yields are reported.
Encouraged by the reaction efficiency, we examined its scope
using the following optimized conditions: 1a : 2a, 1:1.2;
10 RuH2(CO)(PPh3)3, 0.2 mol%; Bu4NBr, 5 mol%; H2O, 0.5 mL; 80
2
| Journal Name, [year], [vol], 00–00
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Page 4 of 6
requirements.25 Given the desirability of eliminating the need to 35 Using water as the reaction medium, we have developed a highly
store or manipulate organic azides, we envisaged a one-pot MCR
involving an alkyne, sodium azide and bromide. Our plan was to
generate organic azides in situ from suitable precursors, which
would then undergo RuH2(CO)(PPh3)3-catalyzed azide-alkyne
efficient RuH2(CO)(PPh3)3-catalyzed click reaction between
View Article Online
terminal alkynes and organic azides to afford various 1,4-
DOI: 10.1039/C4RA12960A
disubstituted triazoles in good to excellent yield. Catalyst loading
(0.2 mol%) was much lower than that required in organic solvent
5
cycloaddition on water, thereby forming 1,2,3-triazoles. In this 40 (5 mol%). This catalytic system proved suitable for one-pot,
one-pot approach, we wished to avoid the need for interim
purification of potentially unstable organic azide intermediates.
First, we screened various conditions for this one-pot MCR by
three-component reactions of bromides, sodium azide, and
alkynes, eliminating the need for interim purification of in situ-
generated organic azides as well as significantly improving
overall efficiency. We believe this protocol will offer a good
10 taking as our model reaction the standard three-component click
reaction of benzyl bromide and sodium azide with 45 option as an efficient click reaction and contribute substantially to
phenylacetylene. As we envisaged, the ruthenium complex
RuH2(CO)(PPh3)3 was amenable to this one-pot MCR on water,
displaying high activity towards this multicomponent reaction to
15 generate 1,4-disubstituted 1,2,3-triazoles from simple substrates.
After screening various catalyst loadings and PTCs, we obtained
3a in 84% isolated yield in the presence of 2 mol% catalyst after
incubating the reaction for 2 h at 80 oC (Table 3).
Then we tested the scope of this one-pot RuAAC MCR (Table
20 4). A broad range of aromatic alkynes containing electron-
donating or electron-withdrawing groups and heterocyclic
alkynes were compatible with this reaction, affording the desired
products 3a-3k in 50-88% isolated yield. Various bromides
including aromatic and alkyl substrates were also compatible with
25 the reaction, providing 71-88% yields of the desired products 3l-
3s. These results demonstrate that the one-pot, three-component
click reactions were comparable to the click reactions of alkynes
and azides, although the one-pot format required increasing the
catalyst loading of RuH2(CO)(PPh3)3 to 2 mol%.
the rapid growth in applications of click chemistry.
Experimental section
General information
All manipulations were carried out under a nitrogen atmosphere
50 using standard Schlenk techniques, unless otherwise stated.
RuH2(CO)(PPh3)3 was prepared as described.26 Freshly distilled
water was used as solvent. Alkynes and other chemicals were
purchased from Aldrich. Mass spectra were collected on an API
QSTAR XLSystem (ESI) or GCT PremierTM Mass Spectrometer
55 (CI). 1H and 13C{1H} NMR spectra were collected on a Bruker
AV 400 MHz NMR spectrometer. 1H and 13C NMR chemical
shifts were determined relative to TMS or residue of deuterium
solvents.
60 Typical procedure for the RuH2(CO)(PPh3)3-catalyzed click
reaction of various terminal alkynes and organic azides on
water with low catalyst loading. To a mixture of azide (0.5
mmol), alkyne (0.6 mmol), and H2O (0.5 mL) were added
catalyst RuH2(CO)(PPh3)3 (0.001 mmol) and phase
65 transformation catalyst (PTC) Bu4NBr (0.025 mmol). The
resulting solution was stirred at 80 °C for 2 h. Then the reaction
mixture was extracted three times with 1 mL CHCl3. The organic
phases were combined, the solvent was evaporated under reduced
pressure, and the residue was subjected to flash column
70 chromatography on silica gel to afford the desired product. All
the compounds reported here are known, except for 3i and 3r (see
Supporting Information).
30 Table 4 RuH2(CO)(PPh3)3-catalyzed, one-pot click reaction of
various bromides, sodium azide, and various alkynes.a
O
OMe
Ph
Me
F
Ph
N
N
N
N
N
N
N
N
Ph
N
N
Ph
Ph
N
N
N
N
N
3c, 80%
3a, 84%
3b, 87%
3d, 88%
3e, 71%
CO2Et
Typical procedure for RuH2(CO)(PPh3)3-catalyzed one-pot
75 click reaction of benzyl bromide, sodium azide, and
phenylacetylene on water. To a mixture of bromide (0.5 mmol),
sodium azide (0.55 mmol), alkyne (0.6 mmol) and H2O (0.5 mL)
were added catalyst RuH2(CO)(PPh3)3 (0.01 mmol) and PTC
Bu4NI (0.025 mmol). The resulting solution was stirred at 80 °C
80 for 2 h. Then the reaction mixture was extracted three times with
1 mL CHCl3. The organic phases were combined, the solvent was
evaporated under reduced pressure, and the residue was subjected
to flash column chromatography on silica gel to afford the desired
product. All the compounds reported here are known (see
85 Supporting Information), except for 3i and 3r.
NH2
N
Ph
3
Fe
Ph
Ph
N
N
N
N
N
N
Ph
N
N
N
N
N
N
N
Ph
Ph
Ph
N
N
3h, 80%
3i, 82%
Ph
3j, 61%
3g, 75 %
3f, 74%
Ph
OMe
Me
F
S
N
N
N
N
N
N
Ph
Ph
N
N
N
N
N
N
3l, 88%
3m, 82%
Ph
3n, 84%
3k, 50%
Ph
Ph
Ph
N
N
N
N
N
N
OH
( )4
N
N
N
N
( )11
N
N
N
N
N
3s, 85%
3q, 76%
3r, 82%
3o, 87%
3p, 71%
a
The reaction was carried out using bromide (0.5 mmol), sodium azide (0.55
1-Benzyl-4-(3-phenyl-propyl)-1H-1,2,3-triazole (3i). Mp: 60-
62.5 oC; 1H NMR (400 MHz, CDCl3, 25 oC) δ 7.34-7.37 (m, 3H),
7.24-7.26 (m, 4H), 7.15-7.19 (m, 4H), 5.49 (s, 2H), 2.64-2.74 (dt,
90 4H), 1.94-2.02 (m, 2H); 13C NMR (100.6 MHz, CDCl3, 25 oC) δ
148.4, 141.9, 135.0, 129.1, 128.6, 128.5, 128.4, 128.0, 125.9,
mmol), alkyne (0.6 mmol) and Bu4NI (0.025 mmol) in the presence of
RuH2CO(PPh3)3 (0.01 mmol) on water (0.5 mL) at 80 oC for 2 h.
Conclusions
This journal is © The Royal Society of Chemistry [year]
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65 11 (a) K. Kumaravel and G. Vasuki, Curr. Org. Chem., 2009, 13, 1820;
120.7, 54.0, 35.4, 31.3, 25.3; HRMS (ESI, TOF) calcd for
C18H20N3 [M+H]+ 278.1562, found 278.1567.
(b) V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc. Rev.,
2010, 39, 4402; (c) Y. Gu, Green Chem., 2012, 14, 2091.View Article Online
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12 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem. Int. Ed.,
4-(4-phenyl-1,2,3-triazol-1-yl)-butan-1-ol (3r). Mp: 88-90 °C;
1H NMR (400 MHz, CDCl3, 25 oC) δ 7.82 (m, 2H), 7.78 (s, 1H),
2001, 40, 2004.
5
7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 4.47 (t, J = 7.1 70 13 C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002,
67, 3057.
Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 2.04-2.12 (m, 2H), 1.60-1.66
14 V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem. Int. Ed., 2002, 41, 2596.
15 (a) 1,3-Dipolar cycloaddition chemistry, (Ed: A. Padwa), WILEY-
(m, 3H); 13C NMR (100.6 MHz, CDCl3, 25 oC) δ 147.8, 130.6,
128.9, 128.2, 125.7, 119.6, 61.9, 50.2, 29.3, 27.0; HRMS (ESI,
TOF) calcd for C12H16N3O [M+H]+ 218.1288, found 218.1287.
75
VCH, New York, 1984; (b) Synthetic applications of 1,3 dipolar
cycloaddition chemistry toward heterocycles and natural products,
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W. Lwowski, In 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 (Ed: A.
Padwa), WILEY-VCH, New York, 1984, pp. 559.
10 Acknowledgements
This work was supported by NSFC/China, NCET (NCET-13-
0798), the Basic Research Program of the Shanghai Committee of
Sci. & Tech. (Project No. 13NM1400802), and the Fundamental
Research Funds for the Central Universities.
80 16 Selected examples, see: (a) M. J. Genin, D. A. Allwine, D. J.
Anderson, M. R. Barbachyn, D. E. Emmert, S. A. Garmon, D. R.
Graber, K. C. Grega, J. B. Hester, D. K. Hutchinson, J. Morris, R. J.
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15 Notes and references
a Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab
for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, Meilong Road 130, Shanghai
200237, China, Fax: (+) 86-21-64250552, E-mail: liupn@ecust.edu.cn
20 † Electronic Supplementary Information (ESI) available: analytical data
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R. G. Syvret, B. Twamley and J. M. Shreeve, Org. Lett., 2007, 9,
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Hänni, D. A. Leigh, P. J. Lusby and D. B. Walker, J. Am. Chem. Soc.,
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90
for all known products (melting point, H and 13C NMR, MS), copies of
1
1H NMR spectra of all products, copies of 13C NMR spectra of 3i and 3r.
See DOI: 10.1039/b000000x/
95
1
2
S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb and K.
B. Sharpless, Angew. Chem. Int. Ed., 2005, 44, 3275.
25
30
35
40
45
50
55
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