Heterogeneous catalytic reactions "on Water" by using stable polymeric alkynylcopper(I) pre-catalysts: Alkyne/azide cycloaddition reactions

Article abstract of DOI:10.1002/ejoc.201001326

Dinuclear alkynylcopper(I) complexes have been found to be the active pre-catalysts in copper-catalysed cycloaddition of azides and terminal alkynes (CuAAC). These copper(I) ladderane polymers are used in "on water" CuAAC reactions, with loadings as low a

Full text of DOI:10.1002/ejoc.201001326

FULL PAPER
DOI: 10.1002/ejoc.201001326
Heterogeneous Catalytic Reactions “On Water” by Using Stable Polymeric
Alkynylcopper(I) Pre-Catalysts: Alkyne/Azide Cycloaddition Reactions
Benjamin R. Buckley,*[a] Sandra E. Dann,[a] Harry Heaney,[a] and Emma C. Stubbs[a]
Keywords: CuAAC / Azides / Alkynes / Copper / Iodoalkyne / Triazole
Dinuclear alkynylcopper(I) complexes have been found to be
the active pre-catalysts in copper-catalysed cycloaddition of
azides and terminal alkynes (CuAAC). These copper(I) lad-
derane polymers are used in “on water” CuAAC reactions,
with loadings as low as 1 mol-%.
The cycloaddition reactions of azides and terminal alk-
ynes (CuAAC reactions) have been studied in great detail
since the discovery of the rate enhancement and high re-
gioselectivity as a result of copper(I) catalysis,[10] as exem-
plified in Scheme 1.[10a] The topic has been reviewed a
number of times.[11,12] Only a small number of reports have
involved heterogeneous catalysts: three involve the use of
a polymer-supported copper(I) catalyst,[13] and two other
studies reported impressive yields with very high regioselec-
tivities by using supports impregnated with catalytic species,
which were generated by the thermal treatment of solutions
of copper(II) salts.[14] In addition, the copper(I) bromide/
thioanisole complex has been used in “on water” click reac-
tions.[15]
Introduction
Interest in organic synthesis “on water” has increased
rapidly and is the subject of recent reviews.[1] A large
number of reports have appeared, particularly since
Sharpless and co-workers highlighted the advantages of
carrying out reactions involving hydrophobic compounds
“on water”.[2] The advantages accruing when not using a
traditional organic solvent include: water’s unique stability,
safety resulting from the high heat capacity of water, and
the ease of isolation of products. The ecologically benign
nature of water is sometimes invoked,[3] though the fact that
solvents are frequently required in order to isolate products
reduces the value of using water as the reaction medium.
There are a number of additional advantages to the use of
heterogeneous catalysts, and many catalytic reactions are
carried out under such conditions:[4] the advantages include
ease of workup and purification, reduction in waste dis-
posal, and the ability to recycle catalysts or to use them in
supported flow-cell systems. Copper(I) iodide is frequently
used as the preferred CuI catalyst, and its use in organo-
cuprate reactions has been evaluated.[5] Protocols for the
purification of CuI iodide are available,[6] and a large
number copper-catalyzed reactions specify the use of such
material.[7] Our interest in heterogeneous “on water” cop-
per(I)-catalysed reactions results from our novel syntheses
of stable, insoluble, alkynylcopper(I) ladderane polymers.[8]
Owsley and Castro reported that phenylethynylcopper(I)
was stable at ambient temperatures for years when stored
under nitrogen in a brown bottle:[9] our experience with a
range of alkynylcopper(I) polymers is similar. This feature
removes the requirement for the purification of copper(I)
salts before use in catalytic reactions.
Scheme 1. Copper-catalysed cycloaddition reaction of azides and
terminal alkynes.
We recognized that the distances between the copper(I)
atoms, as established in the known structure of the phenyl-
ethynylcopper(I) ladder polymer,[16] were ideally positioned
to take part in CuAAC reactions as predicted by Ahlquist
and Fokin.[17] Our earlier mechanistic studies reported
CuAAC reactions carried out by using microwave irradia-
tion in acetonitrile,[8a] and CuAAC and organic azide/
iodoalkyne reactions carried out at ambient temperature in
tert-butyl alcohol/water:[8b] in both studies we showed that
the ladderane complexes were recoverable for reuse at the
end of the reactions. In our earlier study we also showed
that layers of the polymer were removed during the catalytic
cycle and replaced by interaction with the added alkyne as
the ladderane was regenerated.[8] We now report results of
reactions between terminal alkynes or iodoalkynes with or-
ganic azides carried out “on water” by using a number of
polymeric alkynylcopper(I) ladderane pre-catalysts.
[a] Department of Chemistry, Loughborough University,
Loughborough, Leicestershire, LE11 3TU, UK
Fax: +44-1509-223925
E-mail: b.r.buckley@lboro.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001326.
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Alkyne/Azide Cycloaddition Reactions
We carried out a reaction in which phenylacetylene
(10 mmol) and benzyl azide (6 mmol) together with phenyl-
ethynylcopper(I) (3) (10 mol-%) were vigorously stirred as
a suspension at 50 °C in water (10 mL) at ambient tempera-
ture to give the triazole 1 in 66% yield after 15 h. Reaction
conditions were optimized by using phenylacetylene
(10 mmol), benzyl azide (6 mmol) together with phenyleth-
ynylcopper(I) (3) under microwave irradiation at 100 °C (3
times 10 min with cooling between) in water (10 mL). A
reaction with 10 mol-% of phenylethynylcopper(I) (3) gave
the expected triazole 1, shown in Scheme 3 in 91% yield.
Lower pre-catalyst loadings resulted in lower yields of the
triazole 1; for example we obtained the triazole 1 in 81%
yield using 2.5 mol-% of pre-catalyst and in 68% yield using
1 mol-% of pre-catalyst. When we used 2.5 mol-% of phen-
ylethynylcopper(I) (3) and increased the irradiation time (to
6 times 10 min with cooling between), the triazole 1 was
obtained in 89% yield. Additional examples by using those
optimized reaction conditions are shown in Table 1 and in
the Supporting Information. In a reaction with phenyl-
acetylene (2 mmol) and benzyl azide (1 mmol) together with
the phenylethynylcopper(I) (10 mol-%) and N,N,NЈ,NЈ,NЈЈ-
pentamethyldiethylenetriamine as the catalyst system, un-
der the standardized reaction conditions, the yield of the
triazole 1 fell from 91% to 69%. It is perhaps important
that acetic acid is generated when, for example, phenyl-
ethynylcopper(I) is prepared from copper(II) acetate in
methanol. We observed that the addition of an equimolar
amount of acetic acid to phenylethynylcopper(I) resulted in
a more rapid production of the triazole 1.
Results and Discussion
We noted that in an earlier report of the use of copper(II)
salts in click reactions in water, copper(II) acetate was sig-
nificantly more efficient than copper(II) nitrate.[18] It is per-
haps important that acetic acid is generated when, for ex-
ample, phenylethynylcopper(I) is prepared from copper(II)
acetate in methanol.[8b] Although we have shown that cop-
per(II) nitrate and phenylacetylene do not give phenyleth-
ynylcopper(I) in methanol, it is possible that the reactions
were really reactions on water, and that in order to generate
the required copper(I) ladderane complex by Glaser reac-
tions, the solubility of the copper(II) salt in the organic re-
action phase was important: for example that in the mixture
of phenylacetylene and benzyl azide, copper(II) acetate
would be more soluble in the organic phase than is cop-
per(II) nitrate. We carried out two experiments using aque-
ous solutions of copper(II) acetate. In the first experiment
we added phenylacetylene, but found that after 72 h no re-
action had occurred; however, the addition of 1-benzyl-4-
phenyltriazole (1) as a potential ligand[19] did then result in
the formation of 1,4-diphenylbuta-1,3-diyne (2), as shown
by GC/MS, and a yellow insoluble product (Scheme 2). Evi-
dently, the copper(I) catalyst required in the click reactions
carried out by using the aqueous solutions of copper(II)
salts,[18] resulted from the formation of small amounts of
polymeric copper(I) pre-catalysts formed in precursor Gla-
ser reactions. In the second experiment we added phenyl-
acetylene and benzyl azide to an aqueous solution of cop-
per(II) acetate and noted a yellow material at the interface
between the organic and aqueous layers after 24 h. After
72 h, analysis of the extracted organic phase of the latter
experiment by GC/MS showed that 1,4-diphenylbuta-1,3-
diyne (2) and 1-benzyl-4-phenyltriazole (1) were both pres-
ent. In that experiment we conclude that benzyl azide acts
as a ligand to transport copper(II) across the water/organic
interface. We also carried out a reaction in which we added
phenylacetylene and benzyl azide to a vigorously stirred
aqueous suspension of the phenylethynylcopper(I) lad-
derane polymer 3, and after 72 h 1-benzyl-4-phenyltriazole
(1) was shown to be present. A recent publication reported
the pre-treatment reaction of copper(II) hydroxide sup-
ported on aluminium oxide by using phenylacetylene in or-
der to generate a catalyst; however, although 1,4-di-
phenylbuta-1,3-diyne (2) was reported to be formed, the
structure of the copper catalyst was not established.[20]
Scheme 3. “On water” CuAAC reaction.
Reactions of organic azides with 1-iodoalkynes catalysed
by copper(I) iodide have been shown to proceed with sig-
nificant rate enhancement, as compared to the CuAAC re-
actions of terminal alkynes, in the presence of amine li-
gands, to give 5-iodo-1,2,3-triazoles in good to excellent
yields in a variety of solvents, including water.[21] Having
previously established that alkynylcopper(I) ladderane com-
plexes could be used in reactions of iodoalkynes with azides
carried out in tetrahydrofuran in the presence of triethyl-
amine,[8b] we were also interested to establish whether the
same reactions could be carried out “on water” in micro-
wave-assisted reactions. Heterocoupling reactions of ter-
minal alkynes and 1-iodoalkynes have been reported by
using a water-soluble palladium catalyst system. Those re-
sults show that terminal alkynes and 1-iodoalkynes do not
undero exchange reactions in a mixture of acetonitrile and
water.[21] Reactions of iodophenylacetylene with a number
of azides and phenylethynylcopper(I) ladderane polymer (3)
Scheme 2. In-situ formation of copper(I) ladderane complexes “on
water” in the CuAAC reaction.
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B. R. Buckley, S. E. Dann, H. Heaney, E. C. Stubbs
Table 1. (Continued)
FULL PAPER
Table 1. “On water” CuAAC reactions with dinuclear copper(I)
ladderane complexes.[a]
[a] General conditions: [(CuCCR)2]n (10 mol-%), alkyne
(2.0 equiv.), azide (1.0 equiv.), H2O, 100 °C (microwaves), 10 min.
[b] Isolated yield. [c] 6ϫ10 min microwave irradiation. [d]
N,N,NЈ,NЈ,NЈЈ-Pentamethyldiethylenetriamine (10 mol-%) added.
[e] Acetic acid added (0.1 mmol) and reaction mixture irradiated at
100 °C for 1 min. [f] Acetic acid added (0.025 mmol) and reaction
mixture irradiated at 100 °C for 1 min.
in the presence of several bases were carried out by using a
program of 10 s pre-stirring and 3ϫ10 min at 100 °C with
cooling between irradiations. All of the reactions resulted in
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Alkyne/Azide Cycloaddition Reactions
the formation of significant amounts of the 5-protio-1,2,3- Table 2. “On water” CuAAC reactions of phenylethynylcopper(I)
ladderane complex with iodophenylacetylene.[a]
triazoles, shown in Scheme 4 and Table 2. In reactions of
iodophenylacetylene with 3-(trifluoromethyl)benzyl azide,
by using triethylamine as the base, changing the amount of
base (from 2 to 4 equiv.), resulted in an overall increase of
the two products 25a and 26a, from 30% and 39% to 73%
and 26%, respectively. The use of N,N,NЈ,NЈ,NЈЈ-penta-
methyldiethylenetriamine (2 equiv.) resulted in a further in-
crease of the amount of compound 25a; the yields of 25a
and 26a changed to 62% and 12%, respectively. In a reac-
tion with DMAP as the base the yields of 25a and 26a were
43% each.
Scheme 4. “On water” CuAAC reactions of iodophenylacetylene.
Perhaps the most interesting result was that obtained in
a reaction that was carried out in the absence of a base;
that reaction resulted in the formation of 25a and 26a in
44% and 20%, respectively, together with recovery of phen-
ylethynylcopper(I). This latter reaction appears to confirm
that, under the microwave-assisted reaction conditions, pro-
teolysis of iodophenylacetylene occurs, but that the 5-cup-
[a] General conditions: [(CuCCPh)2]n (3) (10 mol-%), iodoalkyne
(1.0 equiv.), azide (1.0 equiv.), H2O, 100 °C (microwaves),
rio-1,2,3-triazoles do not undergo proteolysis; and further,
that pre-catalyst regeneration can be achieved by the inter-
action of iodophenylacetylene with 5-cuprio-1,2,3-triazoles.
3ϫ10 min. [b] Isolated yield.
A mechanistic scheme is shown in Figure 1. It is also inter- water, where the copper ladder polymer is postulated in one
esting to note that the corresponding reactions carried out of their proposed mechanisms, does not afford protonated
with copper(I) iodide, reported by Hein and Fokin,[22] in triazole products.
Figure 1. Mechanistic outline for reactions of iodoalkynes with organic azides “on water”.
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773

B. R. Buckley, S. E. Dann, H. Heaney, E. C. Stubbs
FULL PAPER
water and then centrifuged for a further 15 min. The process was
then repeated by using ethanol and finally dichloromethane to af-
Conclusions
We have established that the copper(I) catalyst required ford the product as a pale green solid. The structure was then con-
firmed by powder X-ray diffraction (below) and found to be mono-
hydrated by combustion analysis. Cu2(OH)3OAc·H2O (255.17):
calcd. C 9.41, H 3.16; found C 9.31, H 2.86.
in triazole click reactions carried out with copper(II) salts
resulted from the formation of small amounts of polymeric
alkynylcopper(I) ladder complexes. We have shown that
polymeric alkynylcopper(I) ladder complexes can be used
as effective heterogeneous pre-catalysts in the “on water”
triazole click reaction with loadings as low as 1 mol-%, and
we have also shown that these catalysts can be used in the
corresponding iodo click reaction. Interestingly in the latter
reactions a significant level of proteolysis was observed, and
we have postulated a possible mechanism. Current work
within the group is aimed at further understanding this
transformation.
Representative Synthesis of the Ladder Polymers: Cu2(OH)3OAc
(0.20 g, 0.78 mmol) was suspended in acetonitrile (4 mL) in a
Biotage microwave tube. Phenylacetylene (0.24 g, 2.4 mmol) was
added. The reaction mixture was heated under microwave irradia-
tion at 100 °C for 10 min (with 20 s pre-stirring, set at normal ab-
sorbance). The mixture was diluted with dichloromethane (4 mL),
filtered and washed with dichloromethane. The yellow filter cake
was dried and analysed by X-ray powder diffraction and found to
be the ladder polymer 2 (0.12 g, 92%). The filtrate was concen-
trated under reduced pressure to afford the Glaser product as a
colourless solid (0.15 g, 95%).
Representative Click Reaction by Using the Copper(I) Ladder Com-
plexes
Experimental Section
1-Benzyl-4-(hydroxymethyl)-5H-1,2,3-triazole (11):[23] Water
(20 mL) was added to a large microwave tube (25 mL) fitted with
a stirrer bar; then propargyl alcohol (0.12 g, 2.1 mmol) was added,
followed by benzyl azide (0.14 g, 1.02 mmol) and the copper ladder
polymer (0.014 g, 0.1 mmol). The reaction mixture was then heated
under microwave irradiation at 100 °C for 3ϫ10 min (with pre-
stirring for 10 s). The reaction mixture was allowed to cool to room
temperature, and the water was removed by gravity filtration. The
filter cake was washed with ethyl acetate and the water extracted
with ethyl acetate. The organic phases were combined, dried with
magnesium sulfate, filtered, and concentrated under reduced pres-
General Details: All IR spectra were obtained with a Perkin–Elmer
Paragon 1000 or Spectrum 65 FT-IR spectrophotometer; thin film
1
spectra were acquired by using sodium chloride plates. All H and
13C NMR spectra were measured at 400.13 and 100.62 MHz with
a Bruker DPX 400 MHz or Avance 400 MHz spectrometer. The
solvent used for NMR spectroscopy was CDCl3 (unless stated
otherwise) with TMS (tetramethylsilane) as the internal reference.
Chemical shifts are given in parts per million (ppm), and J values
are given in Hertz (Hz). Analysis by GC–MS utilised a Fisons GC
8000 series (AS 800) with a 15 mϫ0.25 mm DB-5 column and an
electron-impact low-resolution mass spectrometer. Melting points
were recorded with a Stuart Scientific melting-point apparatus
SMP3 and are uncorrected. Microanalyses were performed with an
Exeter Analytical Inc. CE-440 Elemental Analyser. All chromato-
graphic manipulations used silica gel as the adsorbent. Reactions
were monitored by thin layer chromatography (TLC) on alumin-
ium-backed plates with Merck Kieselgel 60 F254 silica gel; visualis-
ation was carried out by UV radiation at a wavelength of 254 nm,
or staining upon exposure to an ethanolic solution of phosphomol-
ybdic acid (acidified with concentrated sulfuric acid), followed by
charring where appropriate. For purification by column chromatog-
raphy Merck Kieselgel 60 H silica was used as adsorbent. The reac-
tions requiring anhydrous conditions were carried out in flame-
dried glassware under nitrogen, unless otherwise stated. Reaction
solvents were obtained commercially dry, except for light petroleum
ether (b.p. 40–60 °C), which was distilled from calcium chloride
prior to use. Ethyl acetate was distilled from calcium sulfate or
chloride. Dichloromethane was distilled from calcium hydride.
Tetrahydrofuran (THF) was distilled under nitrogen from sodium/
benzophenone ketyl radical. Microwave reactions were performed
in a Biotage Initiator EXP 8 reactor in 2–5 or 20–25 mL crimped
vials. Powder diffraction data were recorded with a Bruker Avance
powder diffractometer operating with monochromated Cu-Kα1 ra-
diation over a 2θ range of 5–60° in 2θ = 0.0147° steps. Mass spectra
were recorded with a Thermo Fisher Exactive with an Ion Max
source and ESI probe fitted with an Advion Triversa Nanomate.
Mass range 20–2000 a.m.u. with a resolution of better than 100000.
sure to afford a colourless solid (0.20 g, 72%). IR (CDCl ): ν
=
˜
3
max
649.3, 733.1, 906.2, 1046.7, 1123.5, 1224.4, 1383.5, 1459.1, 2252.2,
1
3341.1 cm–1. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.46
(s, 1 H), 7.36–7.31 (m, 3 H), 7.28–7.25 (m, 2 H), 5.50 (s, 2 H), 4.75
(s, 2 H), 3.02 ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ
= 133.5, 128.1, 127.8, 127.3, 127.1, 120.9, 55.1, 53.2 ppm. MS:
calcd. for C10H11N3O [M + H]+ 190.0975; found 190.0970.
1-(4-Fluorobenzyl)-4-(hydroxymethyl)-5H-1,2,3-triazole (12):
Colourless solid (0.21 g, 98 %). M.p. 66.9–67.9 °C. IR (CDCl3):
ν
= 649.4, 733.1, 907.2, 1046.3, 1229.6, 1512.9, 1607.4, 2252.2,
˜
max
3341.2 cm–1. C10H10FN3O (207.20): calcd. C 57.97, H 4.86, N
20.28; found C 57.97, H 4.86, N 19.71. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 4.66 (s, 2 H), 5.44 (s, 2 H), 7.01 (t, JHF
= 8.4 Hz, 2 H), 7.24 (t, JHF = 6.8 Hz, 2 H), 7.51 (s, 1 H) ppm.
3
4
13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 53.4, 55.9, 115.9–
116.2 (2JCF = 86.4 Hz), 122.0, 130.0–130.1 (3JCF = 33.2 Hz), 130.4–
130.5 (4JCF = 13.2 Hz), 148.5, 161.5–164.0 (1JCF = 986 Hz) ppm.
MS: calcd. for C10H10FN3O [M + H]+ 208.0881; found 208.0874.
1-(4-Methylbenzyl)-4-(hydroxymethyl)-5H-1,2,3-triazole (13):
Colourless solid (0.18 g, 87 %). M.p. 90.7–91.7 °C. IR (CDCl3):
ν
= 649.2, 743.7, 907.4, 1046.1, 1121.8, 1223.6, 1382.2, 1461.7,
˜
max
1515.5, 2252.0, 3328.9 cm–1. C11H13N3O (203.24): calcd. C 65.01,
H 6.45, N 20.68; found C 64.99, H 6.41, N 20.30. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 2.32 (s, 3 H), 4.69 (s, 2 H),
5.41 (s, 2 H), 7.14 (s, 4 H), 7.45 (s, 1 H) ppm. 13C NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 21.2, 53.9, 56.0, 121.8, 128.2, 129.7,
131.5, 138.7, 148.3 ppm. MS: calcd. for C17H17N3O2 [M + H]+
204.1131; found 204.1126.
Synthesis of Cu2(OH)3OAc·H2O: Cu(OAc)2·H2O (4.00 g,
20.1 mmol) was dissolved in H2O (200 mL), and the mixture was
stirred at room temperature. NaOH (200 mL, 0.1 m) was added
slowly with vigorous stirring. The reaction mixture was stirred for
7 d. The reaction mixture was centrifuged at 2000 rpm for 15 min.
The aqueous phase was decanted and replaced with deionised
[1-(4-Fluorobenzyl)-5H-1,2,3-triazol-4-yl]methyl Benzoate (15):
Colourless crystals (0.25 g, 78 %). M.p. 148.9–149.9 °C. IR
(CDCl ): νmax = 649.6, 734.3, 908.3, 1110.1, 1272.9, 1512.8, 1606.0,
˜
3
774
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Alkyne/Azide Cycloaddition Reactions
1715.8, 2253.6 cm–1. C17H14FN3O2 (311.31): calcd. C 65.59, H 6.86 (dt, J = 9.2, 2.4 Hz, 2 H), 7.14 (s, 4 H), 7.50 (s, 1 H) ppm. 13
C
4.53, N 13.50; found C 65.37, H 4.43, N 13.40. 1H NMR NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 21.2, 54.0, 55.7, 62.7,
(400 MHz, CDCl3, 25 °C, TMS): δ = 5.44 (s, 2 H), 5.49 (s, 2 H), 114.7, 115.9, 122.6, 128.4, 129.5, 131.6, 138.7, 144.7, 152.4,
7.05 (t, J = 8.4 Hz, 2 H), 7.27 (t, J = 6.0 Hz, 2 H), 7.41 (t, J =
154.2 ppm. MS: calcd. for C18H19N3O2 [M + H]+ 310.1550; found
7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.63 (s, 1 H), 8.01 (d, J = 310.1538.
7.2 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
Methyl {4-[(4-Methoxyphenyl)methyl]-5H-1,2,3-triazol-1-yl}acetate
(24): Colourless crystals (0.20 g, 66 %). M.p. 96.2–97.2 °C. IR
(CDCl ): νmax = 732.3, 826.2, 907.9, 1040.1, 1226.8, 1439.7, 1466.0,
53.5, 58.0, 116.1–116.3 (2JCF = 86.8 Hz), 123.8, 128.4, 129.70,
129.73, 130.0–130.1 (3JCF = 33.6 Hz), 130.3 (4JCF = 13.2 Hz),
133.2, 143.5, 161.7–164.1 (1JCF = 987 Hz), 166.4 ppm. MS: calcd.
for C17H14FN3O2 [M + H]+ 312.1143; found 312.1131.
˜
3
1508.3, 1754.9, 2253.2, 2835.6, 2957.0, 3003.1, 3153.4 cm–1
.
C13H15N3O4 (277.28): calcd. C 56.31, H 5.45, N 15.15; found C
56.13, H 5.40, N 14.92. 1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 3.74 (s, 3 H), 3.77 (s, 3 H), 5.14 (s, 2 H), 5.15 (s, 2 H), 6.83 (dt,
J = 9.2, 2.4 Hz, 2 H), 6.90 (dt, J = 9.2, 2.4 Hz, 2 H), 7.74 (s, 1 H)
ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 50.7, 53.0,
55.7, 62.6, 114.9, 115.9, 124.3, 144.7, 151.6, 154.2, 166.8 ppm. MS:
calcd. for C13H15N3O4 [M + H]+ 278.1135; found 278.1125.
[1-(4-Methylbenzyl)-5H-1,2,3-triazol-4-yl]methyl Benzoate (16):
Colourless crystals (0.23 g, 73%). M.p. 94.2–95.2 °C. IR (CDCl3):
ν
˜
= 650.7, 730.7, 907.5, 1110.4, 1273.4, 1716.3, 2254.4 cm–1
.
max
C18H17N3O2 (307.35): calcd. C 70.34, H 5.58, N 13.67; found C
70.24, H 5.60, N 13.57. 1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 2.34 (s, 3 H), 5.43 (s, 2 H), 5.47 (s, 2 H), 7.17 (s, 4 H), 7.40 (t,
J = 12.0 Hz, 2 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 8.01 (d,
J = 8.0 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 21.2, 54.1, 58.1, 123.7, 128.2, 128.4, 129.7, 129.8, 131.4, 133.2,
138.8, 143.3, 166.4 ppm. MS: calcd. for C18H17N3O2 [M + H]+
308.1394; found 308.1383.
General Procedure for the Reaction of 1-Iodophenylacetylene and a
Range of Benzyl Azides: Water (20 mL) was added to a large micro-
wave tube (25 mL) fitted with stirrer bar; then 1-iodophenyl-
acetylene (1.0 mmol) was added, followed by the azide (1.0 mmol),
the base (x mmol; as outlined in Table 2), and the copper ladder
polymer (0.1 mmol). The reaction mixture was then heated under
microwave irradiation at 100 °C for 3ϫ10 min (with pre-stirring
for 10 s). The reaction mixture was then allowed to cool and the
water removed by gravity filtration. The filter cake was washed with
ethyl acetate and the water extracted with ethyl acetate. The organic
phases were combined, dried with magnesium sulfate, filtered, and
concentrated under reduced pressure to afford the crude products.
Analytically pure samples were prepared by column chromatog-
raphy.
1-(4-Fluorobenzyl)-4-(phenoxymethyl)-5H-1,2,3-triazole (18):
Colourless crystals (0.26 g, 87%). M.p. 82.3–83.3 °C. IR (CH2Cl2):
ν
= 907.0, 1049.2, 1230.7, 1494.1, 1512.1, 1599.8, 1710.2,
˜
max
2251.6 cm–1. C16H14FN3O (283.30): calcd. C 67.83, H 4.98, N
14.83; found C 67.71, H 4.95, N 14.51. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 5.14 (2 H s), 5.44 (s, 2 H), 6.92–6.96 (m,
3
3 H), 7.01 (t, JHF = 8.8 Hz, 2 H), 7.20–7.28 (m, 4 H), 7.54 (s, 1
H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 53.4, 61.9,
114.8, 116.0–116.2 (2JCF = 86.8 Hz), 121.3, 122.7, 129.6, 130.1–
130.2 (3JCF = 32.4 Hz), 130.5 (4JCF = 13.2 Hz), 144.7, 158.2, 161.6–
164.1 (1JCF = 986 Hz) ppm. MS: calcd. for C16H14FN3O
[M + H]+ 284.1194; found 284.1183.
5-Iodo-4-phenyl-1-[3-(trifluoromethy)benzyl]-1H-1,2,3-triazole
(26c):[22] Prepared according to the representative procedure from
3-(trifluoromethyl)benzyl azide (0.20 g, 1.00 mmol). Colourless so-
1
1-Benzyl-4-[(4-methoxyphenyl)methyl]-5H-1,2,3-triazole (21):
lid (0.38 g, 88%). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
Colourless crystals. M.p. 112.0–113.2 °C. IR (film): ν
= 3054.3,
˜
max
5.73 (s, 2 H), 7.40–7.53 (m, 5 H), 7.60–7.64 (m, 2 H), 7.94 (d, J =
8.6 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
53.8, 76.4, 122.4, 124.8 (q, J = 3.8 Hz), 125.5 (q, J = 3.7 Hz), 127.4,
128.6, 128.8, 129.6, 130.0, 131.2, 131.5, 135.3, 150.4 ppm.
2986.1, 2305.8, 1506.4, 1265.1, 1230.7, 1040.0 cm–1. C17H17N3O2
(295.34): calcd. 69.14, H 5.80, N 14.23; found C 69.09, H 5.77, N
14.12. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.52 (s, 1 H),
7.35–7.37 (m, 3 H), 7.26–7.27 (m, 2 H), 6.89–6.91 (m, 2 H), 6.80–
6.84 (m, 2 H), 5.53 (s, 2 H), 5.13 (s, 2 H), 3.76 (s, 3 H) ppm. 13C
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 154.2, 152.3, 144.9,
134.5, 129.2, 128.8, 128.1, 122.5, 115.9, 114.7, 62.9, 55.7, 54.2 ppm.
MS: calcd. for C17H18N3O2 [M + H]+ 296.1394; found 296.1391.
Supporting Information (see footnote on the first page of this arti-
1
cle): Full experimental procedures and H and 13C NMR spectro-
scopic data.
Acknowledgments
1-(4-Fluorobenzyl)-4-[(4-methoxyphenyl)methyl]-5H-1,2,3-triazole
(22): Colourless crystals (0.21 g, 66%). M.p. 108.7–109.7 °C. IR
We thank Professor Lei Zhu (FSU, Tallahassee) for interesting dis-
cussions on the role of carboxylates in CuAAC reactions and Pro-
fessor Valery Fokin (Scripps Institute, CA) for his insights. B. R. B.
would like to thank the Research Councils (UK) for an RCUK
fellowship and the Loughborough University for funding a PhD
studentship (E. C. S.).
(CDCl ): νmax = 649.8, 742.0, 911.6, 1046.2, 1230.8, 1465.2, 1507.6,
˜
3
1607.3, 2253.2, 2836.7, 3003.8, 3155.9 cm–1. H NMR (400 MHz,
1
CDCl3, 25 °C, TMS): δ = 3.74 (s, 3 H), 5.11 (s, 2 H), 5.47 (s, 2 H),
6.82 (dt, J = 9.2, 2.4 Hz, 2 H), 6.86 (dt, J = 9.2, 2.4 Hz, 2 H), 7.01
(t, J = 8.4 Hz, 2 H), 7.23 (m, 2 H) 7.54 (s, 1 H) ppm. 13C NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 53.4, 55.7, 62.7, 114.6, 115.8,
116.0–116.2 (2JCF = 86.4 Hz), 122.6, 129.9–130.0 (3JCF = 33.2 Hz),
134.4–130.5 (4JCF = 13.2 Hz), 144.9, 152.3, 154.2, 161.6–164.1
(1JCF = 986 Hz) ppm. MS: calcd. for C17H16FN3O2 [M + H]+
314.1299; found 314.1286.
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Eur. J. Org. Chem. 2011, 770–776
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: September 22, 2010
Published Online: December 16, 2010
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Eur. J. Org. Chem. 2011, 770–776