One-pot sequential azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA): Expanding the scope of in situ copper(I) regeneration in the presence of environmentally Benign reducing agent

Article abstract of DOI:10.1002/ejic.201001335

One-pot sequential reactions involving azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) catalyzed by [Cu^II(TPMA)X][X] {X = Br^- or Cl^-, TPMA = tris(2-pyridylmethyl)amine} in the presence of ascorbi

Full text of DOI:10.1002/ejic.201001335

FULL PAPER
DOI: 10.1002/ejic.201001335
One-Pot Sequential Azide–Alkyne [3+2] Cycloaddition and Atom Transfer
Radical Addition (ATRA): Expanding the Scope of In Situ Copper(I)
Regeneration in the Presence of Environmentally Benign Reducing Agent
Carolynne L. Ricardo[a] and Tomislav Pintauer*[a]
Keywords: ATRA / Copper / Radical reactions / Synthesis design / Cycloaddition
One-pot sequential reactions involving azide–alkyne [3+2]
cycloaddition and atom transfer radical addition (ATRA) cat-
alyzed by [CuII(TPMA)X][X] {X = Br– or Cl–, TPMA = tris(2-
pyridylmethyl)amine} in the presence of ascorbic acid as a
reducing agent are reported. Reactions with azidopropyl
methacrylate and 1-(azidomethyl)-4-vinylbenzene in the
presence of a variety of alkynes [phenylacetylene, (3,4-di-
fluorophenyl)acetylene, propargyl alcohol, 2-methyl-3-bu-
tyn-2-ol, methyl propiolate and ethyl propiolate] and alkyl
halides (carbon tetrachloride, carbon tetrabromide, ethyl tri-
chloroacetate, methyl trichloroacetate, ethyl dichloroacetate,
methyl dichloroacetate, dichloroacetonitrile and 2-bromopro-
pionitrile) proceeded efficiently to yield highly functionalized
(poly)halogenated esters and aryl compounds containing a
triazolyl group in the presence of as low as 0.5 mol-% of the
catalyst. It is envisioned that the presented methodology
could have further implications in the organic synthesis of
functionalized triazoles, which have recently been identified
as the lead targets for the screening of potential pharmaceu-
tical drugs.
the reaction of copper(I) acetylides with organic azides to
from triazolyl–copper intermediates,[8] which upon pro-
tonolysis yield the desired 1,2,3-triazole. This last step also
regenerates the copper(I) catalyst.
Introduction and Background
In 2001, reinvigoration of an old style of organic synthe-
sis was defined in response to the demands of modern
chemistry.[1] This was coined as “click chemistry” describ-
ing a faster and modular style of synthesis. Among the reac-
tions that met the stringent criteria, copper-catalyzed
Huisgen [3+2] cycloaddition popularized by the Meldal[2]
and Sharpless[3] laboratories was the first to achieve the
“click status”. To date, this reaction has emerged as the best
example of click chemistry due to its reliability, robustness,
functional-group tolerance, ability to withstand a wide
spectrum of solvents, and desirable properties of the tri-
azole.[1,2,4] Numerous applications of this type of chemistry
have been found in all aspects of bioconjugation, drug dis-
covery, and materials science.[4–6]
Mechanistically, the first step in the copper-catalyzed
[3+2] cycloaddition involves the formation of copper(I)
acetylides, which are formed from copper(I) [typically re-
generated from copper(II) in the presence of sodium as-
corbate], terminal alkynes, and a base (Scheme 1). The gen-
erated copper(I) acetylide species have a strong tendency to
form μ-coordinate bridged aggregates, the formation of
which is strongly dependent on the nature and type of com-
plexing ligand.[7] The second step in the catalytic cycle is
Scheme 1. Proposed mechanism for the copper-catalyzed [3+2] cy-
cloaddition.[9,10]
Other C–C bond-forming reactions that are becoming
synthetically more useful are the transition-metal-catalyzed
atom transfer radical addition (ATRA) and the intra-
molecular counterpart, atom transfer radical cyclization
(ATRC).[11–16] Traditionally, both were conducted in the
presence of high catalyst loadings, therefore facing issues in
product separation and catalyst recycling. A solution to
[a] Duquesne University, Department of Chemistry and
Biochemistry,
600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, PA 15282, USA
Fax: +1-412-396-5683,
E-mail: pintauert@duq.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201001335.
1292
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One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and ATRA
these problems was found for the mechanistically similar
atom transfer radical polymerization (ATRP),[17,18] in
Since the azide–alkyne [3+2] cycloaddition (Scheme 1)
[1,3,4]
and ATRA (Scheme 2)[14,26,27] are both catalyzed by
which reducing agents were utilized to continuously regen- copper(I) complexes, our attention has focused on the pos-
erate the activator or copper(I) complex.[19–22] Catalyst-re- sibility of mediating these reactions in a one-pot sequential
generation technique has also been shown to be highly ef- manner (Scheme 3). Such a sequence would lead to the for-
ficient in ruthenium-[23] and copper-catalyzed[14,24–27] mation of compounds with both triazole and halogen func-
ATRA and ATRC reactions. The presence of the reducing tionalities. The latter one is particularly attractive, because
agents (free-radical diazo initiators, magnesium or ascorbic it opens up the possibilities for numerous organic transfor-
acid) successfully allowed the reduction of the amount of mations such as elimination, displacement, conversion to a
the transition metal complex, and as a result, these reac- Grignard reagent, etc. Also, on the other hand, the halogen
tions can now be conducted by using very low amounts of functionality could serve as further radical precursor. A
the catalyst.[28–40]
combination of copper-catalyzed azide–alkyne [3+2] cyclo-
Additionally, the methodology was also extended to in- addition and mechanistically similar ATRP was first ex-
clude sequential organic transformations involving ATRA/ plored by the group of Matyjaszewski in a two-pot two-step
ATRC.[41–43]
manner consisting of converting the halogen end-groups in
The proposed mechanism for the copper-catalyzed well-defined polymers to azides and subsequently to tri-
ATRA in the presence of reducing agents is shown in azoles.[44,45] The methodology was also successfully ex-
Scheme 2. The role of the reducing agent is to continuously tended to a one-pot simultaneous reaction in which propar-
regenerate copper(I) from the copper(II) complex that ac- gyl methacrylate and alkyl azides were allowed to react to
cumulates in the reaction mixture as a result of unavoidable yield highly functionalized and well-defined polymeric ma-
and often diffusion-controlled radical–radical termination terials.[46,47] However, to the best of our knowledge, the two
reactions. The copper(I) complex starts a catalytic cycle by reactions were never applied to small-molecule synthesis.
homolytically cleaving an alkyl–halide bond to produce an
alkyl radical that adds across a carbon–carbon double bond
of an alkene. The generated secondary radical then irrevers-
ibly abstracts a halogen atom from the copper(II) complex
to form the desired monoadduct. This step regenerates the
activator or copper(I) complex, completing the catalytic cy-
cle. As indicated in Scheme 2, the competing side reactions
in this process besides radical terminations by either cou-
pling or disproportionation include repeating radical ad-
ditions to the alkene to form oligomers/polymers.
Scheme 3. Copper-catalyzed sequential azide–alkyne [3+2] cycload-
dition and atom transfer radical addition (ATRA).
In this article, we report on one-pot sequential reactions
involving azide–alkyne [3+2] cycloaddition and atom trans-
fer radical addition (ATRA) catalyzed by [CuII(TPMA)X]-
[X] [X = Br– or Cl–, TPMA = tris(2-pyridylmethyl)amine]
in the presence of ascorbic acid as a reducing agent.
Results and Discussion
Copper-Catalyzed Azide–Alkyne [3+2] Cycloaddition
In our previous reports we demonstrated that copper(II)
complexes with the TPMA ligand {[CuII(TPMA)X][X], X
= Br– or Cl–} in the presence of reducing agents such as
free-radical diazo initiators or ascorbic acid were highly
active in ATRA, ATRC, and domino or cascade-type reac-
tions.[24,25,30,40,41] The next logical step was to determine
whether the same complexes could also catalyze azide–al-
kyne [3+2] cycloadditions, particularly taking into account
Scheme 2. Proposed mechanism for the copper-catalyzed atom
transfer radical addition (ATRA) in the presence of a reducing
agent.
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that the tetradentate nature of the TPMA[48] ligand could Table 1. [CuII(TPMA)Cl][Cl]-catalyzed azide–alkyne [3+2] cycload-
dition in the presence of ascorbic acid as a reducing agent.
block the coordination of the alkyne to the copper(I) center,
which is an important step in the reaction mechanism
(Scheme 1).[6,49,50] Series of reactions involving azidopropyl
methacrylate (AzPM) and various alkynes (Scheme 4 and
Table 1) were performed in the presence of [CuII(TPMA)]-
[Cl][Cl] and ascorbic acid as a reducing agent.
Scheme 4. Structures of alkynes used in the azide–alkyne [3+2] cy-
cloaddition and atom transfer radical addition.
Although sodium ascorbate is widely used for in situ re-
generation of CuI from CuII salts in azide–alkyne cycload-
dition,[6] its insolubility in MeOH shifted our choice
Entry[a]
Alkyne
PhA
Product [CuII][b]
t [h]
Yield [%][c]
towards ascorbic acid.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1
1.0
0.25
0.25
0.2
1
1
6
6
24
1
2
3
18
18
3
3
6
3
24
24
1
1
3
ca. 100
93
96
90
83
ca. 100
92
ca. 100
92
93
ca. 100
90
76
ca. 100
91
56
ca. 100
95
90
81
ca. 100
97
93
As indicated in Table 1, cycloaddition reactions between
AzPM and the alkynes phenylacetylene (PhA), (3,4-difluo-
rophenyl)acetylene (DFPhA), propargyl alcohol (PrOH) 2-
methyl-3-butyn-2-ol (MBOH), methyl propiolate (MPr)
and ethyl propiolate (EPr) (Entries 1, 6, 11, 14, 17, and 21)
in the presence of 1.0 mol-% of [CuII(TPMA)Cl][Cl] and
10–25 equiv. of ascorbic acid (relative to CuII complex) af-
forded the formation of the corresponding triazoles in ne-
arly quantitative yields. Encouraged by these results, the ex-
tent of catalyst loading was further examined. In previous
reports, azide–alkyne [3+2] cycloaddition reactions cata-
lyzed by copper(I) in conjunction with the TPMA ligand
required at least 10 mol-% of the complex relative to the
azide.[44,49] Surprisingly, with DFPhA, MPr, and EPr tri-
azoles were synthesized in 93%, 81%, and 86% yields
(Table 1, Entries 10, 20 and 24), respectively, by using as
low as 0.2 mol-% of the copper catalyst. An even lower cat-
alyst loading (0.1 mol-%) was suffiecient for the reaction
between AzPM and PhA (Entry 5). To the best of our
knowledge, these are one of the lowest amounts of cop-
per(II) complexes required to efficiently catalyze azide–
alkyne [3+2] cycloaddition.
0.1
1.0
DFPhA
2
0.5
0.5
0.25
0.20
1.0
0.50
0.25
1.0
0.50
0.25
1.0
PrOH
MBOH
MPr
3
4
5
0.50
0.25
0.20
1.0
3
3
3
3
EPr
6
0.50
0.25
0.20
3
86
[a] All reactions were performed in CH3OH at 60 °C by using
[AzPM]0/[Alkyne]0 = 1:1, [AzPM]0 = 0.50 m. The amount of ascor-
bic acid in each system ranged between 20 and 25 equiv. relative to
that of the copper(II) complex. For alkyne structures, see Scheme 4.
[b] mol-% relative to AzPM. [c] The yield is based on the formation
of the triazole and was determined by 1H NMR spectroscopy using
p-dimethoxybenzene as internal standard (relative errors are
Ϯ15%).
Sequential Azide–Alkyne [3+2] Cycloaddition and Atom
Transfer Radical Addition (ATRA)
Having demonstrated the efficiency of [CuII(TPMA)Cl]-
[Cl] to catalyze the azide–alkyne [3+2] cycloaddition in the
presence of ascorbic acid as a reducing agent, optimization ynes, nearly quantitative yields of the triazolyl haloalkyl
studies were conducted to maximize the yield of the esters were obtained by using 1.0 mol-% of the copper cata-
1
monoadduct in the second sequential step involving ATRA lyst (Entries 1, 5, 8, 12, 16, and 20). Typical H and 13C
of CCl4. The results are summarized in Table 2. For all alk- NMR spectra of the reaction product (6a) are shown in
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One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and ATRA
Table 2. Sequential azide–alkyne [3+2] cycloaddition and atom to notice that the reaction mixtures containing as low as
0.25 mol-% of [CuII(TPMA)Cl][Cl] still proceeded ef-
transfer radical addition (ATRA) of carbon tetrachloride catalyzed
by [CuII(TPMA)Cl][Cl] in the presence of ascorbic acid as a reduc-
ficiently to afford the final product in yields higher than
ing agent.
80% (Entries 7, 10, 18 and 22).
Entry[a] Alkyne Product [CuII][b] t [h][c]
Yield [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
PhA
1a
1.0
0.50
0.25
0.20
1.0
0.50
0.25
1.0
0.50
0.25
0.20
1.0
0.50
0.25
0.20
1.0
0.50
0.25
0.20
1.0
0.50
0.25
0.20
2
3
3
3
3
4
6
3
3
3
3
3
3
3
3
1
1
1
1
3
3
3
3
ca. 100 (91)[e]
90
78
70
96
1
Figure 1. H (a) and 13C NMR (CDCl3, 298 K) spectra of 6a.
DFPhA
PrOH
2a
3a
90
83
The results presented in Tables 1 and 2 clearly indicate
that copper(II) complexes with the TPMA ligand, in con-
junction with ascorbic acid, are very efficient catalysts for
both azide–alkyne [3+2] cycloaddition and ATRA. In order
to further demonstrate the synthetic usefulness of this se-
quential sequence of reactions, additional experiments were
performed by using a variety of alkyl halides including
carbon tetrabromide (CBr4), ethyl trichloroacetate
(CCl3CO2Et), methyl trichloroacetate (CCl3CO2Me), ethyl
dichloroacetate (CCl2HCO2Et), methyl dichloroacetate
(CCl2HCO2Me), dichloroacetonitrile (CCl2HCN), and 2-
bromopropionitrile [CHBr(CH3)CN]. The results for azi-
dopropyl methacrylate (AzPM) and 1-(azidomethyl)-4-vi-
nylbenzene (AzMVB) are summarized in Table 3. As ex-
pected, for AzPM excellent yields of the final monoadduct
were obtained by using CBr4 and catalyst loadings as low
as 0.50 mol-% (Entries 2 and 12). The corresponding mo-
lecular structure of the product in the case of methyl pro-
piolate is shown in Figure 2. Sequential azide–alkyne [3+2]
cycloaddition and ATRA also worked reasonably well for
tri- and dihalogenated substrates by using 1.0 mol-% of the
catalyst. The monohalogenated alkyl halide 2-bromopro-
pionitrile yielded only 35 and 75% of the monoadduct in
the case of phenylacetylene (Entry 10) and methyl pro-
95 (86)[e]
86
83
73
ca. 100
86
74
72
98
MBOH
MPr
4a
5a
6a
91
86
72
ca. 100 (89)[e]
ca. 100
85
EPr
65
[a] All reactions were performed in CH3OH at 60 °C by using
[AzPM]0/[Alkyne]0 = 1:1, [AzPM]0 = 0.50 m. The amount of ascor-
bic acid in each system ranged between 20 and 25 equiv. relative to
that of the copper(II) complex. For alkyne structures, see Scheme 4.
[b] mol-% relative to alkyne. [c] Reaction time for azide–alkyne cy-
cloaddition [time for ATRA reaction was 8 h for all substrates with
(AzPM)0/(CCl4)0 = 1:1.25]. [d] The yield is based on the formation
of the product and was determined by 1H NMR spectroscopy by
using p-dimethoxybenzene as internal standard (relative errors are
Ϯ15%). [e] Isolated yield for the large-scale reaction.
Figure 1. Further decrease in catalyst loading to 0.5 mol-% piolate (Entry 25), respectively. The decreased yield can be
still resulted in very high yields of the desired monoadduct attributed to monoadduct reactivation resulting in the for-
(Entries 2, 6, 9, 13, 17, and 21). It is particularly important mation of oligomers/polymers. Furthermore, as indicated in
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C. L. Ricardo, T. Pintauer
FULL PAPER
Table 3, the results for AzMVB were similar to AzPM. 30, 31, 35 and 37), but significantly decreased for dihaloge-
Generally, with 1.0 mol-% of the catalyst relative to azide, nated ones (Entries 39, 40 and 41). Lastly, the monoadduct
yields higher than 80% were obtained by using CCl4 (En- formed from the azide–alkyne [3+2] cycloaddition of
tries 27 and 32). Respectable yields of the monoadduct were methyl propiolate to AzMVB followed by sequential ATRA
still observed by using trihalogenated alkyl halides (Entries of 2-bromopropionitrile was attained in only 26% yield.
Table 3. Sequential azide–alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) of various alkyl halides catalyzed by
[CuII(TPMA)X][X] (X = Br– or Cl–) in the presence of ascorbic acid as a reducing agent.
Entry[a]
Alkyne
RX
[CuII][b]
t1 [h]/t2 [h][c]
Product
Yield
[%][d]
1
2
3
4
5
6
7
8
PhA
CBr4
1.0
0.50
0.25
1.0
0.50
1.0
0.50
1.0
0.50
1.0
2/8
2/8
6/8
7a
99 (90)[e]
96
80
82
72
80
65
85
70
CCl3CO2Et
CCl2HCO2Et
CCl2HCN
2/24
2/24
2/24
2/24
2/24
2/24
2/24
2/8
8a
9a
10a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
CHBr(CH3)CN
CBr4
11a
12a
35
MPr
1.0
100 (86)[e]
0.50
0.25
1.0
0.50
1.0
0.50
1.0
0.50
0.25
1.0
0.50
1.0
0.50
1.0
2/8
6/8
94
78
81
75
91
CCl3CO2Et
CCl3CO2Me
CCl2HCO2Et
1/24
1/24
2/24
2/24
2/24
2/24
2/24
2/24
2/24
2/24
2/24
2/24
2/24
13a
14a
15a
81
80 (73)[e]
75
64
83
70
83
78
75
74
CCl2HCO2Me
CCl2HCN
16a
17a
18a
CHBr(CH3)CN
0.50
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
PhA
MPr
CCl4
1.0
0.50
0.25
1.0
1.0
1.0
0.50
0.25
1.0
0.50
1.0
0.50
1.0
1.0
3/8
3/8
6/8
6/24
6/24
2/8
19a
85 (86)[e]
83
32
45
CCl3CO2Et
CCl3CO2Me
CCl4
20a
21a
22a
57
92 (90)[e]
73
2/8
2/8
47
87
83
CCl3CO2Et
CCl3CO2Me
2/24
2/24
2/24
2/24
2/24
2/24
2/24
1/24
2/24
23a
24a
82 (84)[e]
78
CCl2HCO2Et
CCl2HCO2Me
CCl2HCN
CHCl3
CHBr(CH3)CN
25a
26a
27a
28a
29a
43
48
46
42
1.0
1.0
1.0
26
[a] All reactions were performed in CH3OH at 60 °C by using [AzPM or AzMVB]0/[Alkyne]0 = 1:1, [AzPM or VBAz]0 = 0.50 m. The
amount of ascorbic acid in each system ranged between 20 and 25 equiv. relative to that of the copper(II) complex. For alkyne structures,
see Scheme 4. [b] mol-% relative to alkyne. [c] t1 = reaction time for azide–alkyne cycloaddition, t2 = reaction time for ATRA. For all
alkyl halides 2 equiv. were used relative to AzPM or AzMVB, except for CCl4 where only 1 equiv. was utilized. [d] The yield is based on
1
the formation of the product and was determined by H NMR spectroscopy by using p-dimethoxybenzene as internal standard (relative
errors are Ϯ15%). [e] Isolated yield for the large-scale reaction.
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One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and ATRA
7.26 ppm, CD2Cl2: δ = 5.32 ppm; 13C: CDCl3: δ = 77.2 ppm,
CD2Cl2: δ = 54.0 ppm).
Certainly, from the point of view of further synthetic modi-
fications of the resulting sequential product such as conver-
sion to a Grignard reagent, monohalogenated alkyl halides
are of particular interest. Future efforts in our laboratories
are directed towards optimizing reaction conditions for
such substrates and utilizing more active copper complexes.
Stock Solutions: [CuII(TPMA)Cl][Cl] solutions (0.04 m, 0.02 m and
0.01 m) were prepared by dissolving the corresponding copper(II)
complex in methanol using volumetric flasks to accommodate vari-
ous catalyst loadings. Azidopropyl methacrylate (320 μL,
2.0 mmol) was mixed with an equimolar amount of the alkyne
{2.0 mmol: 220 μL (phenylacetylene), 240 μL [(3,4-difluorophenyl)-
acetylene], 117 μL (propargyl alcohol), 194 μL (2-methyl-3-butyn-
2-ol), 179 μL (methyl propopiolate), 203 μL (ethyl propopiolate)}
and p-dimethoxybenzene added as internal standard (approxi-
mately 0.1 mol-% relative to azidopropyl methacrylate). Methanol
was then added in order to make each stock solution 3.3 m in azi-
dopropyl methacrylate.
General Procedure for Azide–Alkyne [3+2] Cycloaddition Catalyzed
by [CuII(TPMA)Cl][Cl] in the Presence of Ascorbic Acid: All reac-
tions were performed in disposable 5.0 mm NMR tubes equipped
with a plastic cap and Teflon tape. In a typical experiment, 60 μL
of the stock solution [0.2 mmol of azidopropyl methacrylate
(AzPM) and 0.2 mmol of alkyne] was added to the NMR tube,
followed by the desired amount of the copper(II) catalyst {from
Figure 2. Molecular structure of (S)-monoadduct 12a formed by
the sequential azide–alkyne [3+2] cycloaddition between azidopro-
pyl methacylate and methyl propiolate followed by ATRA of CBr4
at 296 K, shown with 30% probability displacement ellipsoids. H
atoms have been omitted for clarity.
0.04 m [CuII(TPMA)Cl][Cl] and for [AzPM]0/[CuII]0
(50 μL), from 0.02 m [CuII(TPMA)Cl][Cl] and for [AzPM]0/[CuII]0
200:1 (50 μL), from 0.01 m [CuII(TPMA)Cl][Cl] and for
= 100:1
=
[AzPM]0/[CuII]0 = 400:1 and 500:1 (50 μL and 40 μL, respectively)}
and 20–25 equiv. of 0.25 m ascorbic acid in methanol {relative to
[CuII(TPMA)Cl][Cl]}. Methanol was then added in order to main-
tain a constant volume and a total concentration of 0.50 m in azi-
dopropyl methacrylate. Each reaction mixture was immediately
flushed with argon for at least 30 s and immersed in an oil bath
Conclusions
We have reported the first examples of one-pot sequential
reactions involving azide–alkyne [3+2] cycloaddition and
atom transfer radical addition (ATRA). Both transforma- thermostatted at 60 °C. The percent yield of the expected triazole
was obtained by 1H NMR spectroscopy relative to the internal
standard. If necessary, solvent was partially evaporated prior to 1H
NMR analysis.
tions are catalyzed by [CuII(TPMA)X][X] (X = Br– or Cl–)
complexes in conjunction with ascorbic acid as the reducing
agent. Reactions with azidopropyl methacrylate and 1-(azi-
domethyl)-4-vinylbenzene in the presence of a variety of al-
kynes and alkyl halides proceeded efficiently to yield highly
functionalized (poly)halogenated esters and aryl com-
General Procedure for Sequential Azide–Alkyne [3+2] Cycload-
dition/Atom Transfer Radical Addition Catalyzed by [CuII(TPMA)
Cl][Cl] in the Presence of Ascorbic Acid: The first step was per-
pounds containing a triazolyl group in the presence of as formed as explained above. After completion of the azide–alkyne
[3+2] cycloaddition, the reaction mixture was taken into a dry box
(Ͻ 1.0 ppm O2 and Ͻ 0.5 ppm H2O), and carbon tetrachloride
(24 μL, 2.5 mmol, 1.25 equiv. relative to AzPM) or (poly)haloge-
nated alkyl halide (4.0 mmol, 2.0 equiv. relative to AzPM) was
added. The NMR tube was then capped and sealed with Teflon
tape and immersed in an oil bath thermostatted at 60 °C. The per-
cent yield of the expected triazolyl halogenated alkyl ester was ob-
low as 0.5 mol-% of the catalyst. It is envisioned that the
presented methodology could have further implications in
organic synthesis of functionalized triazoles. Such com-
pounds have recently been identified as the lead targets for
the screening of potential pharmaceutical drugs. Addition-
ally, our methodology incorporates a highly desirable halo-
gen functionality, which is very versatile towards further or-
ganic transformations.
1
tained by H NMR spectroscopy relative to the internal standard.
If necessary, solvent was partially evaporated prior to 1H NMR
analysis.
X-ray Crystal Structure Determination: The X-ray intensity data
were collected with a Bruker Smart Apex II CCD diffractometer
at 150 K by using graphite-monochromated Mo-Kα radiation (λ =
0.71073 Å). Data reduction included absorption corrections by the
multi-scan method using SADABS.[53] Structures were solved by
direct methods and refined by full-matrix least-squares using the
SHELXTL 6.1 bundled software package.[54] Hydrogen atoms were
positioned geometrically (aromatic C–H 0.93 Å, methylene C–H
0.97 Å, methyl C–H 0.96 Å) and treated as riding atoms during
Experimental Section
General Procedures: All alkynes [phenylacetylene, (3,4-difluo-
rophenyl)acetylene, propargyl alcohol, 2-methyl-3-butyn-2-ol,
methyl propiolate and ethyl propiolate], 3-bromopropanol, methac-
ryloyl chloride, and solvents (methanol, dichloromethane and pen-
tane) were purchased from commercial sources and used as re-
ceived. Tris(2-pyridylmethyl)amine,[51] azidopropyl methacrylate,[45]
1-(azidomethyl)-4-vinylbenzene,[52] and [CuII(TPMA)X][X] (X =
Br– or Cl–)[24,25] were synthesized according to literature pro-
subsequent refinement, with Uiso(H) = 1.2Uequiv(C) or 1.5Uequiv
-
1
cedures. H and 13C NMR spectra were obtained with Bruker Av-
(methyl C). The methyl groups were allowed to rotate about their
local threefold axes. ORTEP-3 for Windows[55] and Crys-
tal Maker 7.2 were used to generate molecular graphics. Further
ance 400 MHz and 500 MHz spectrometers. All chemical shifts are
given in ppm relative to residual solvent peaks (1H: CDCl3: δ =
Eur. J. Inorg. Chem. 2011, 1292–1301
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1297

C. L. Ricardo, T. Pintauer
FULL PAPER
details are given in Table 4. CCDC-805615 contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
3-[4-(2-Hydroxyprop-2-yl)-1H-1,2,3-triazol-1-yl]propyl Methacry-
late (4): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.49 (s, 1 H), 6.11
(s, 1 H), 5.60 (s, 1 H), 4.46 (t, J = 7.0 Hz, 2 H), 4.20 (t, J = 6.0 Hz,
2 H), 2.35–2.29 (m, 2 H), 1.95 (s, 3 H), 1.64 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 167.32, 15.79, 135.95, 127.79,
126.03, 119.59, 68.38, 61.41, 47.19, 30.57, 29.50, 18.23 ppm.
Table 4. Crystal structure analysis data for methyl 1-[3-(2,4,4,4-
tetrabromo-2-methylbutanoyloxy)propyl]-1H-1,2,3-triazole-4-carb-
oxylate (12a).
Methyl 1-[3-(Methacryloyloxy)propyl]-1H-1,2,3-triazole-4-carboxyl-
ate (5): 1H NMR (500 MHz, CDCl3, 25 °C): δ = 8.11 (s, 1 H), 6.08
(s, 1 H), 5.60 (s, 1 H), 4.52 (t, J = 7.0 Hz, 2 H), 4.20 (t, J = 6.0 Hz,
2 H), 3.95 (s, 3 H), 2.37–2.31 (m, 2 H), 1.93 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 173.03, 167.22, 147.64,
136.26, 126.21, 121.97, 61.38, 56.62, 47.36, 29.63, 18.26 ppm.
Empirical formula
Formula mass
Temperature
C12H15Br4N3O4
584.91
296(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions:
a
monoclinic, P21/n
Ethyl 1-[3-(Methacryloyloxy)propyl]-1H-1,2,3-triazole-4-carboxyl-
ate (6): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.11 (s, 1 H), 6.07
(s, 1 H), 5.59 (s, 1 H), 4.52 (t, J = 7.0 Hz, 2 H), 4.41 (q, J = 7.1 Hz,
3 H), 4.20 (t, J = 6.0 Hz, 2 H), 2.37–2.31 (m, 2 H), 1.92 (s, 3 H),
1.39 (t, J = 7.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 167.01 160.68, 140.36, 135.84, 127.65, 126.17, 61.35, 60.96,
47.71, 29.42, 18.29, 14.32 ppm.
11.6637(4) Å
6.0493(2) Å
b
c
β
26.2815(9) Å
98.406(2)°
Volume
1834.43(11) Å3
4, 2.118 Mg/m3
8.795 mm–1
Z, calculated density
Absorption coefficient
F(000)
1120
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-Tetrachloro-2-meth-
ylbutanoate (1a): Isolated yield = 620 mg (91 %). 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.82–7.80 (m, 2 H), 7.77 (s, 1 H),
δ7.43–7.40 (m, 2 H), 7.34–7.31 (m, 1 H), 4.53 (t, J = 7.0 Hz, 2 H),
4.36–4.32 (m, 1 H), 4.27–4.22 (m, 1 H), 4.02 (d, J = 15 Hz, 1 H),
3.50 (d, J = 15 Hz, 1 H), 2.36 (quint, J = 6.5 Hz, 2 H), 1.94 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.33, 130.44,
128.92, 128.32, 125.81, 119.99, 94.59, 64.76, 63.10, 62.18, 46.90,
29.17, 26.13 ppm.
Crystal size
0.32ϫ 0.09ϫ 0.05 mm
1.57–26.19°
θ range for data collection
Limiting indices:
h
–14 to 14
k
l
–7 to 7
–32 to 32
Reflections collected/unique
Completeness to θ
Absorption correction
Max./min. transmission
Refinement method
Data/restraints/parameters
Goodness of fit on F2
Final R indices [IϾ2σ(I)]
R indices (all data)
Largest difference peak/hole
21440/3654 [R(int) = 0.0426]
99.0%
semi-empirical from equivalents
0.6930/0.1676
full-matrix least squares on F2
3654/0/210
3-[4-(3,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]propyl-2,4,4,4-tetra-
chloro-2-methylbutanoate (2a): 1H NMR (500 MHz, CD2Cl2,
25 °C): δ = 7.80 (s, 1 H), 7.69 (ddd, J = 11.5, 7.7, 2.1 Hz, 1 H),
7.56–7.53 (m, 1 H), 7.25 (dt, J = 10.3, 8.4 Hz, 1 H), 4.53 (t, J =
6.9 Hz, 2 H), 4.30 (m, 1 H), 4.24 (m, 1 H), 3.99 (d, J = 15.4 Hz, 1
H), 3.53 (d, J = 15.4 Hz, 1 H), 2.39 (quint, J = 6.5 Hz, 2 H), 2.02
(s, 3 H) ppm. 13C NMR (100 MHz, CD2Cl2, 25 °C): δ = 169.33,
121.83, 121.76, 121.71, 117.82, 117.63, 114.66, 114.47, 94.67, 64.82,
63.24, 61.91, 47.10, 26.10, 26.19 ppm.
1.363
R1 = 0.0587, wR2 = 0.1796
R1 = 0.0785, wR2 = 0.1947
2.685/–1.162 eÅ–3
Product Characterization
For detailed 1H and 13C NMR assignments, see the Supporting
Information.
3-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]propyl 2,4,4,4-Tetra-
chloro-2-methylbutanoate (3a): Isolated yield 550 mg (86%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.59 (s, 1 H), 4.82 (s, 2 H),
4.50 (t, J = 7.0 Hz, 2 H), 4.32 (dt, J = 11.6, 5.9 Hz, 1 H), 4.23 (dt,
J = 11.6, 5.8 Hz, 1 H), 4.34–4.3 (m, 1 H), 4.25–4.2 (m, 1 H), 4.02
(d, J = 15.4 Hz, 1 H), 3.52 (d, J = 15.4 Hz, 1 H), 2.39 (quint, J =
6.4 Hz, 2 H), 2.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 169.60, 148.17, 121.20, 94.72, 64.82, 62.97, 47.10, 29.37,
26.46 ppm.
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl Methacrylate (1): 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.82–7.80 (m, 2 H), 7.77 (s,
1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 1 H), 6.10 (s, 1
H), 5.60 (s, 1 H), 4.53 (t, J = 7.0 Hz, 2 H), 4.24 (t, J = 7.0 Hz, 2
H), 4.02 (d, J = 15 Hz, 1 H), 3.50 (d, J = 15 Hz, 1 H), 2.36 (quint,
J = 6.0 Hz, 2 H), 1.94 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 167.19, 147.94, 135.95, 130.52, 128.87, 128.23, 126.10,
125.75, 119.79, 61.25, 47.39, 29.58, 18.33 ppm.
3-[4-(2-Hydroxyprop-2-yl)-1H-1,2,3-triazol-1-yl]propyl 2,4,4,4-Tet-
rachloro-2-methylbutanoate (4a): 1H NMR (500 MHz, CDCl3,
25 °C): δ = 8.11 (s, 1 H), 4.56 (t, J = 7.0 Hz, 2 H), 4.35–4.31 (m, 1
H), 4.26–4.22 (m, 1 H), 4.02 (d, J = 15.4 Hz, 1 H), 3.12 (d, J =
15.4 Hz, 1 H), 2.72 (s, 3 H), 2.41 (quint, J = 6.4 Hz, 2 H), 2.05 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.47, 148.29,
125.76, 94.39, 64.62, 62.75, 62.75, 47.20, 28.96, 27.35, 26.28 ppm.
3-[4-(3,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]propyl Methacrylate
1
(2): H NMR (500 MHz, CDCl3, 25 °C): δ = 7.75 (s, 1 H), 7.67–
7.62 (m, 1 H), 7.52–7.49 (m, 1 H), 7.19 (q, J = 10 Hz, 1 H), 6.10
(s, 1 H), 5.60 (s, 1 H), 4.51 (t, J = 7.0 Hz, 2 H), 4.23 (t, J = 6.0 Hz,
1 H), 2.38–2.30 (m, 2 H), 1.93 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 167.18, 151.74, 149.27, 146.08, 135.92, 126.13,
121.78, 119.98, 117.79, 114.48, 61.16, 47.5, 29.34, 18.32 ppm.
Methyl-1-[3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl]-1H-
3-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]propyl
(3): H NMR (500 MHz. CDCl3): δ = 7.58 (s, 1 H), 6.13 (s, 1 H),
Methacrylate 1,2,3-triazole-4-carboxylate (5a): 1H NMR (500 MHz, CDCl3,
1
25 °C): δ = 8.15 (s, 1 H), 4.57 (t, J = 7.0 Hz, 2 H), 4.36–4.3 (m, 1
5.63 (s, 1 H), 4.83 (s, 2 H), 4.50 (t, J = 7.0 Hz, 2 H), 4.20 (t, J = H), 4.26–4.20 (m, 1 H), 4.01 (d, J = 15.4 Hz, 1 H), 3.98 (s, 3 H),
6.0 Hz, 2 H), 2.38–2.32 (m, 2 H), 1.97 (s, 3 H) ppm. 13C NMR 3.52 (d, J = 15.4 Hz, 1 H), 2.43 (quint, J = 6.4 Hz, 2 H), 2.05 (s, 3
(100 MHz, CDCl3, 25 °C): δ = 161.13, 140.23, 136.00, 127.79, H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.33, 161.13,
126.21, 60.85, 52.39, 47.63, 29.10, 18.26 ppm.
140.23, 94.19, 64.56, 62.71, 62.13, 52.39, 47.36, 29.10, 26.19 ppm.
1298
www.eurjic.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2011, 1292–1301

One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and ATRA
Ethyl 1-[3-(2,4,4,4-Tetrachloro-2-methylbutanoyloxy)propyl]-1H-
1,2,3-triazole-4-carboxylate (6a): Isolated yield 610 mg (89%). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 8.11 (s, 1 H), 4.55 (t, J =
6.9 Hz, 2 H), 4.43 (q, J = 7.1 Hz, 3 H), 4.33–4.3 (m, 1 H), 4.26–
4.17 (m, 1 H), 3.99 (d, J = 15.4 Hz, 1 H), 3.49 (d, J = 15.4 Hz, 1
H), 2.43–2.37 (m, 2 H), 2.02 (s, 3 H), 1.41 (t, J = 7.1 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.38, 160.63, 140.46,
127.77, 94.48, 64.70, 62.74, 62.14, 61.41, 47.28, 29.01, 26.19,
14.34 ppm.
25 °C): δ = 169.84, 161.06, 127.92, 65.79, 62.59, 57.69, 52.33. 47.40,
31.06, 29.00, 25.99 ppm.
1-Ethyl 5-{3-[4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl]propyl}
2,2,4-Trichloro-4-methylpentanedioate (13a): 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 8.18 (s, 1 H), 4.58 (t, J = 6.9 Hz, 2 H), 4.38 (q,
J = 7.1 Hz, 2 H), 4.29–4.21 (m, 2 H), 3.97 (s, 3 H), 3.61 (d, J =
15.2 Hz, 1 H), 3.47 (d, J = 15.2 Hz, 1 H), 2.45–2.38 (quint, J =
6.2 Hz, 2 H), 1.86 (s, 3 H), 1.39 (t, J = 15.2 Hz, 1 H) ppm. 13C
NMR (101 MHz, CDCl3, 25 °C): δ = 170.1, 165.3, 161.2, 140.12,
127.8, 80.7, 65.4, 64.3, 62.6, 53.3, 52.3, 47.3, 29.1, 27.6, 13.3 ppm.
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-Tetrabromo-2-
methylbutanoate (7a): Isolated yield 870 mg (90 %). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.84 (s, 1
H), 7.45 (t, J = 7.4 Hz, 3 H), 7.36 (t, J = 7.4 Hz, 1 H), 4.73 (d, J
= 15.6 Hz, 1 H), 4.59 (t, J = 6.8 Hz, 3 H), 4.42–4.36 (m, 1 H),
4.30–4.24 (s, 1 H), 3.99 (d, J = 15.6 Hz, 1 H), 2.45 (quint, J =
6.4 Hz, 3 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 169.8, 147.9, 130.4, 128.9, 128.3, 125.8, 65.8, 62.9, 57.8,
47.0, 31.2, 29.1, 26.0 ppm.
5-{3-[4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl]propyl} 1-Methyl
2,2,4-Trichloro-4-methylpentanedioate (14a): 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 8.20 (s, 1 H), 4.57 (t, J = 6.9 Hz, 2 H), 4.28–
4.22 (m, 2 H), 3.95 (s, 3 H), 3.56 (d, J = 15.0 Hz, 1 H), 3.44 (d, J
= 15.0 Hz, 1 H), 2.39 (quint, J = 6.2 Hz, 2 H), 1.82 (s, 3 H) ppm.
5-Ethyl 1-{3-[4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl]propyl}
2,4-Dichloro-2-methylpentanedioate (15a): Isolated yield 670 mg
1
(73%). H NMR (500 MHz, CDCl3, 25 °C; approx. 50:50 mixture
1-Ethyl 5-[3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl] 2,2,4-Trichloro-
of diastereomers): δ = 8.02 (s, 1 H), 8.16 (s, 1 H), 4.86–4.79 (m, 1
H), 4.57–4.54 (m, 1 H), 4.58 (t, J = 7.0 Hz, 2 H), 4.27–4.16 (m, 2
H), 3.95 (s, 3 H), 2.96 (dd, J = 15.1, 6.9 Hz, 1 H), 2.78 (qd, J =
16.4, 6.6 Hz, 1 H), 2.65 (dd, J = 15.1, 6.2 Hz, 1 H), 2.41–2.35 (m,
2 H), 1.84 (s, 3 H), 1.81 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3, 25 °C): δ = 170.0, 168.9, 161.1, 140.0,
128.0, 66.7, 66.1, 62.6, 52.6, 52.3, 47.3, 45.8, 29.0, 27.7, 13.9 ppm.
1
4-methylpentanedioate (8a): H NMR (400 MHz, CDCl3, 25 °C): δ
= 7.85 (d, J = 8.2 Hz, 2 H), 7.84 (s, 1 H), 7.45 (t, J = 7.4 Hz, 3 H),
7.36 (t, J = 7.4 Hz, 1 H), 4.56 (t, J = 7 Hz, 2 H), 4.36 (q, J = 7 Hz,
2 H), 4.29–4.23 (m, 2 H), 3.61 (d, J = 15.2 Hz, 1 H), 3.47 (d, J =
15.2 Hz, 1 H), 2.45–2.35 (m, 2 H), 1.86 (s, 3 H), 1.41 (t, J = 15.2 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.0, 165.3,
147.8, 130.5, 128.9, 128.2, 125.7, 120.2 80.9, 65.3, 64.4, 63.3, 53.8,
53.3, 48.0, 29.1, 27.8, 13.7 ppm.
1-{3-[4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl]propyl} 5-Methyl
2,4-Dichloro-2-methylpentanedioate (16a): 1H NMR (500 MHz,
CDCl3, 25 °C; approx. 50:50 mixture of diastereomers): δ = 8.20
(s, 1 H), 8.19 (s, 1 H), 4.54–4.61 (m, 2 H), 4.25–4.18 (m, 1 H), 4.27–
4.16 (m, 2 H), 3.95 (s, 3 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 2.99 (dd,
J = 15.1, 7.0 Hz, 1 H), 2.80 (qd, J = 13.8, 6.6 Hz, 2 H), 2.65 (dd,
J = 15.1, 6.1 Hz, 1 H), 2.43–2.36 (m, 2 H), 1.85 (s, 3 H), 1.83 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 169.9, 169.4,
161.1, 140.0 128.1, 66.7, 66.1, 62.8, 62.7, 53.4, 52.9, 52.3, 47.3, 46.2,
46.0, 29.4, 28.9, 27.8 ppm.
5-Ethyl 1-[3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl] 2,4-Dichloro-2-
1
methylpentanedioate (9a): H NMR (400 MHz, CDCl3, 25 °C; ap-
prox. 50:50 mixture of diastereomers): δ = 7.85 (d, J = 8.2 Hz, 2
H), 7.84 (s, 1 H), 7.42 (t, J = 7.4 Hz, 3 H), 7.33 (t, J = 7.4 Hz, 1
H), 4.57–4.51 (m, 1 H), 4.54 (t, J = 7 Hz, 2 H), 4.33 (q, J = 7.2 Hz,
2 H), 4.26–4.19 (m, 2 H), 3.01–2.96 (m, 1 H), 2.85–2.74 (m, 1 H),
2.68–2.63 (m, 1 H), 2.40–2.33 (m, 2 H), 1.84 (s, 3 H), 1.82 (s, 3 H),
1.30 (t, J = 15.2 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3,
25 °C): δ = 169.9, 169.3, 147.7, 130.5, 128.8, 128.2, 125.7, 120.1,
66.7, 63.5, 53.3, 52.5, 48.0, 45.8, 29.3, 29.1, 13.9 ppm.
Methyl 1-[3-(2,4-Dichloro-4-cyano-2-methylbutanoyloxy)propyl]-
1H-1,2,3-triazole-4-carboxylate (17a): 1H NMR (400 MHz. CDCl3,
25 °C; approx. 50:50 mixture of diastereomers): δ = 8.18 (s, 1 H),
8.16 (s, 1 H), 4.87–4.79 (m, 1 H), 4.58 (t, J = 7.0 Hz, 2 H), 4.30–
4.23 (m, 2 H), 3.97 (s, 3 H), 3.83 (s, 3 H), 3.07–3.01 (m, 1 H), 2.94–
2.88 (m, 1 H), 2.83–2.78 (m, 1 H), 2.70–2.63 (m, 1 H), 2.48–2.39
(m, 2 H), 1.90 (s, 3 H), 1.89 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3, 25 °C): δ = 169.5, 140.2, 127.6, 116.1, 66.0, 63.7, 58.6, 52.2,
47.2, 38.3, 32.3, 29.3, 28.9 ppm.
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4-Dichloro-4-cyano-2-
methylbutanoate (10a): 1H NMR (400 MHz, CDCl3, 25 °C; approx.
50:50 mixture of diastereomers): δ = 7.84 (d, J = 6.0 Hz, 2 H), 7.82
(s, 1 H), 7.47–7.43 (m, 2 H), 7.39–7.34 (m, 1 H), 4.86–4.79 (m, 1
H), 4.62–4.55 (m, 1 H), 4.38–4.28 (m, 1 H), 3.04 (ddd, J = 14.8,
8.8, 0.6 Hz), 2.95–2.89 (m, 1 H), 2.83–2.78 (m, 1 H), 2.68–2.63 (m,
1 H), 2.46–2.39 (m, 2 H), 1.90 (s, 3 H), 1.89 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3, 25 °C): δ = 169.5, 148, 130.4, 128.9,
128.3, 125.7, 120, 116.6, 65.9, 63.8, 47.6, 38.7, 29, 28.8 ppm.
Methyl 1-[3-(2-Bromo-4-cyano-2-methylpentanoyloxy)propyl]-1H-
1
1,2,3-triazole-4-carboxylate (18a): H NMR (400 MHz, CDCl3,
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propyl 2-Bromo-4-cyano-2-meth-
ylpentanoate (11a): 1H NMR (400 MHz, CDCl3, mixture of dia-
stereomers): δ = 7.88 (s, 1 H), 7.86 (d, J = 6.8 Hz, 2 H), 7.47–7.44
(m, 2 H), 7.38–7.35 (m, 1 H), 4.59 (t, J = 6.8 Hz, 2 H), 4.38–4.29
(m, 2 H), 2.99–2.82 (m, 1 H), 2.64–2.53 (m, 1 H), 2.49–2.41 (m, 1
H), 2.31–2.32 (m, 1 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.45 (d, J =
7.2 Hz, 3 H), 1.42 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 170.2, 161.3, 140.0, 130.5, 128.9, 128.2, 125.7, 120.2,
118.2, 63.4, 57.9, 48.0, 45.2, 29.1, 27.8, 22.7, 19.5 ppm.
25 °C; approx. 50:50 mixture of diastereomers): δ = 8.19 (s, 1 H),
8.12 (s, 1 H), 4.60 (t, J = 7.0 Hz, 2 H), 4.34–4.21 (m, 2 H), 3.97 (s,
3 H), 3.83 (s, 3 H), 2.95–2.88 (m, 1 H), 2.65–2.55 (m, 1 H), 2.59–
2.55 (m, 1 H), 2.70–2.63 (m, 1 H), 2.61–2.54 (m, 1 H), 2.45–2.39
(m, 1 H), 2.07 (s, 3 H), 2.04 (s, 3 H), 1.46 (d, J = 7.1 Hz, 3 H), 1.43
(d, J = 7.1 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ
= 170.3, 161.3, 140.0, 128.1, 114.7, 63.0, 55.8, 46.5, 45.3, 29.7, 27.2,
21.0, 19.5 ppm.
Methyl 1-[3-(2,4,4,4-Tetrabromo-2-methylbutanoyloxy)propyl]-1H-
1,2,3-triazole-4-carboxylate (12a): Isolated yield 850 mg (86%). H
4-Phenyl-1-[4-(1,3,3,3-tetrachloropropyl)benzyl]-1H-1,2,3-triazole
(19a): Isolated yield 600 mg (86%). 1H NMR (400 MHz, CDCl3,
1
NMR (400 MHz, CDCl3, 25 °C): δ = 8.18 (s, 1 H), 4.68 (d, J = 25 °C): δ = 7.83 (d, J = 7.2 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H),
15.5 Hz, 1 H), 4.59 (t, J = 6.9 Hz, 2 H), 4.37–4.31 (m, 1 H), 4.25–
4.19 (m, 1 H), 3.97 (d, J = 15.6 Hz, 1 H), 3.96 (s, 3 H), 2.43 (quint,
7.44–7.41 (m, 2 H), 7.36–7.32 (m, 1 H), 7.33 (d, J = 8.0 Hz, 2 H),
5.59 (s, 2 H), 5.31 (dd, J = 6.3, 5.6 Hz, 1 H), 3.63 (dd, J = 15.3,
J = 6.4 Hz, 2 H), 2.30 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3, 5.3 Hz, 1 H), 3.52 (dd, J = 15.3, 6.5 Hz, 1 H) ppm. 13C NMR
Eur. J. Inorg. Chem. 2011, 1292–1301
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1299

C. L. Ricardo, T. Pintauer
FULL PAPER
(101 MHz, CDCl3, 25 °C): δ = 148.3, 140.9, 135.6, 130.5, 128.9,
128.50, 128.31, 128.25, 125.7, 119.8, 96.1, 62.5, 57.7, 53.6 ppm.
Methyl 1-[4-(1,3,3-Trichloropropyl)benzyl]-1H-1,2,3-triazole-4-carb-
oxylate (28a): 1H NMR (400 MHz, CDCl3, 25 °C; approx. 50:50
mixture of enantiomers): δ = 8.04 (s, 1 H), 8.00 (s, 1 H), 7.46 (d, J
= 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 6.72 (dd, J = 17.6,
10.9 Hz, 1 H), 5.84–5.81 (m, 1 H), 5.61 (s, 2 H), 5.58 (s, 2 H), 5.09
(dd, J = 9.6, 4.8 Hz, 1 H), 3.95 (s, 3 H), 3.94 (s, 3 H), 2.96 (ddd, J
= 14.6, 9.7, 4.8 Hz, 1 H), 2.76 (ddd, J = 14.7, 8.5, 4.8 Hz, 1 H)
ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 161.2, 140.5, 135.8,
134.7, 128.9, 128.0, 127.1, 70.1, 58.6, 57.0, 54.3, 52.3 ppm.
Ethyl 2,2,4-Trichloro-4-{4-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-
phenyl}butanoate (20a): 1H NMR (400 MHz, CDCl3, 25 °C): δ =
8.05 (s, 1 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H),
5.60 (d, J = 4.2 Hz, 2 H), 5.26–5.22 (m, 1 H), 4.35 (q, J = 7.2 Hz,
2 H), 3.44 (dd, J = 15.0, 7.2 Hz, 1 H), 3.20 (dd, J = 15.0, 6.0 Hz,
1 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3,
25 °C): δ = 165.5, 148.3, 140.2, 135.7, 130.4, 128.9, 128.7, 128.4,
128.2, 125.6, 81.9, 64.1, 57.8, 54.5, 53.7, 13.8 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Details of spectroscopic data for isolated compounds.
Methyl 2,2,4-Trichloro-4-{4-[(4-phenyl-1H-1,2,3-triazol-1-yl)meth-
yl]phenyl}butanoate (21a): 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 7.81 (d, J = 7.2 Hz, 2 H), 7.79 (s, 1 H), 7.42–7.38 (m, 4 H), 7.35–
7.28 (m, 3 H), 5.55 (s, 2 H), 5.22 (dd, J = 7.5, 6.0 Hz, 1 H), 3.87
(s, 3 H), 3.42 (dd, J = 15.0, 7.6 Hz, 1 H), 3.17 (dd, J = 15.0, 5.9 Hz,
1 H) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 165.5, 148.3,
140.2, 135.7, 130.4, 128.4, 128.3, 128.2, 125.7, 81.9, 57.8, 54.5, 53.9,
53.8 ppm.
Acknowledgments
Financial support from a National Science Foundation CAREER
Award (CHE-0844131) is greatly acknowledged.
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Published Online: February 4, 2011
Eur. J. Inorg. Chem. 2011, 1292–1301
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
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