Synthesis of functionalized polytriazoles via one-pot sequential copper-catalyzed azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA)

Article abstract of DOI:10.1002/ijch.201100111

As a continuing effort of expanding the scope of catalyst regeneration in the presence of environmentally benign reducing agents, one-pot sequential azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) reactions were performed via in situ reduction of copper(II) by ascorbic acid. The formation of functionalized triazoles was achieved utilizing a ligand-free catalytic system for the cycloaddition between tripropargylamine and vinylbenzyl azide and subsequent addition of tris(2-pyridyl)methylamine (TPMA) ligand in the ATRA step. With this strategy, reactions with carbon tetrachloride and carbon tetrabromide proceeded efficiently providing the desired triazoles in nearly quantitative yields (>90 %) using 10 mol % of copper. Sequential azide-alkyne [3+2] cycloaddition and ATRA reactions were also extended to less active alkyl halides such as methyl trichloroacetate, methyl dichloroacetate and dichloroacetonitrile. The corresponding products were obtained in modest yields (50-80 %). The presented methodology enables efficient synthesis of functionalized polytriazoles, which could have a potential use as chelating agents for a variety of transition metals. Copyright

Full text of DOI:10.1002/ijch.201100111

Full Paper
C. L. Ricardo and T. Pintauer
DOI: 10.1002/ijch.201100111
Synthesis of Functionalized Polytriazoles via One-Pot
Sequential Copper-Catalyzed Azide–Alkyne [3+2]
Cycloaddition and Atom Transfer Radical Addition
(ATRA)
Carolynne L. Ricardo[a] and Tomislav Pintauer*[b]
Dedicated to Prof. Krzysztof Matyjaszewski on occasion of receiving the 2011 Wolf Prize in Chemistry
Abstract: As a continuing effort of expanding the scope of
catalyst regeneration in the presence of environmentally
benign reducing agents, one-pot sequential azide–alkyne
[3+2] cycloaddition and atom transfer radical addition
(ATRA) reactions were performed via in situ reduction of
copper(II) by ascorbic acid. The formation of functionalized
triazoles was achieved utilizing a ligand-free catalytic system
for the cycloaddition between tripropargylamine and vinyl-
benzyl azide and subsequent addition of tris(2-pyridyl)me-
thylamine (TPMA) ligand in the ATRA step. With this strat-
egy, reactions with carbon tetrachloride and carbon tetrabro-
mide proceeded efficiently providing the desired triazoles in
nearly quantitative yields (>90%) using 10 mol% of
copper. Sequential azide–alkyne [3+2] cycloaddition and
ATRA reactions were also extended to less active alkyl hal-
ides such as methyl trichloroacetate, methyl dichloroacetate
and dichloroacetonitrile. The corresponding products were
obtained in modest yields (50–80%). The presented meth-
odology enables efficient synthesis of functionalized poly-
triazoles, which could have a potential use as chelating
agents for a variety of transition metals.
Keywords: atom transfer radical addition · catalyst regeneration · click chemistry · copper · polytriazoles
1. Introduction and Background
The term “click chemistry”, coined in 2001, serves as
a guiding principle in the synthesis of compounds with de-
sired functionality using “near perfect” reaction condi-
tions.[1] Typically, reactions classified under the click
chemistry umbrella are defined by a stringent set of crite-
ria and among them, copper-catalyzed Huisgen [3+2] cy-
cloaddition popularized by the Meldal[2] and Sharpless[3]
groups was the first to achieve the “click status”. To date,
this reaction has dominated this area of research and has
become synonymous with “click chemistry”, mainly due
to its reliability, robustness, functional group tolerance,
ability to withstand a wide spectrum of solvents, and de-
sirable properties of the resulting triazoles. Immense con-
tributions have been made and wide arrays of applica-
tions found in various disciplines such as biology,[4,5]
chemistry,[1,6–8] bioconjugation,[7,9] drug discovery[9–12] and
materials/polymer science.[8,13–16]
the copper(I) center, resulting in the formation of a p-
complex (Scheme 1). This step lowers the pKa of terminal
alkyne proton by approximately 10 units, enabling the
conversion of the p-complex to a s-acetylide copper(I) in-
termediate. Kinetic investigation[20] has revealed that the
reaction rate is second-order with respect to the metal,
suggesting the strong tendency of copper(I) acetylide spe-
cies to form m-coordinate bridged aggregates,[18,19] the for-
mation of which is highly dependent on the nature of the
complexing ligand. The next step in the catalytic cycle is
the coordination of the organic azide, which consequently
[a] C. L. Ricardo
Duquesne University, Department of Chemistry and Biochem-
istry
600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, PA 15282
(USA)
[b] T. Pintauer
The mechanism of copper-catalyzed azide–alkyne [3+2]
cycloaddition has been widely investigated using compu-
tational[17–19] and experimental[3,20,21] techniques. Regard-
less of the starting copper salt or complex (either CuI or
CuII), it has been established that CuI is the active catalyt-
ic species in the coupling of azide and alkyne.[6] The cata-
lytic cycle begins with the coordination of the alkyne to
Duquesne University, Department of Chemistry and Biochem-
istry
600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, PA 15282
(USA)
phone: (+1)412-396-1626
fax: (+1)412-396-5683
e-mail: pintauert@duq.edu
320
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Isr. J. Chem. 2012, 52, 320 – 327

Synthesis of Functionalized Polytriazoles
Scheme 1. Proposed mechanism for copper-catalyzed azide–
alkyne [3+2] cycloaddition.
activates the N-terminus for nucleophilic attack to the
acetylide. This results in the formation of vinylidine-like
structure, which subsequently converts to a more stable
copper(I) triazolide. Lastly the catalytic cycle is complet-
ed by protonolysis, which yields the desired 1,2,3-triazole
and regenerates the active copper(I) species.
Scheme 2. Proposed mechanism for copper-catalyzed atom trans-
fer radical addition (ATRA) in the presence of reducing agents.
Other CÀC forming reactions that are becoming more
synthetically useful are the transition-metal-catalyzed
atom transfer radical addition (ATRA) and the intramo-
lecular counterpart, atom transfer radical cyclization
(ATRC).[22–27] Traditionally, both were conducted in the
presence of high catalyst loadings, therefore facing issues
in product separation and catalyst recycling. A solution to
these problems was found for the mechanistically similar
atom transfer radical polymerization (ATRP)[28,29] in
which reducing agents were utilized to continuously re-
generate the activator or copper(I) complex (Scheme 2).
The catalyst regeneration technique has also been shown
to be highly efficient in ruthenium-[30] and copper-cata-
lyzed ATRA and ATRC reactions.[26,31–34] The presence of
the reducing agents (free-radical diazo initiators, magnesi-
um or ascorbic acid) successfully allowed the reduction in
the amount of transition-metal complex, and as a result,
these reactions can now be conducted using very low
amounts of the catalyst.[35–46] The synthetic usefulness of
the methodology has also been demonstrated in sequen-
tial organic transformations involving ATRA/ATRC.[47–49]
The proposed mechanism[26,34] for copper-catalyzed
ATRA in the presence of reducing agents is shown in
Scheme 2. The role of the reducing agent is to continu-
ously regenerate copper(I) from the copper(II) complex
that accumulates in the reaction mixture as a result of un-
avoidable and often diffusion controlled radical–radical
termination reactions. The catalytic cycle starts with a ho-
molytic cleavage of the alkyl halide bond by the cop-
per(I) complex to produce an alkyl radical, which subse-
quently adds across a carbon–carbon double bond of an
alkene. The generated secondary radical is then trapped
by irreversible abstraction of halogen atom from the cop-
per(II) complex to form the desired monoadduct. This
step regenerates the activator or copper(I) complex, com-
pleting the catalytic cycle. As indicated in Scheme 2, the
competing side reactions in this process besides radical
terminations by either coupling or disproportionation in-
clude repeating radical additions to alkene to form oligo-
mers/polymers.
A combination of copper-catalyzed azide–alkyne [3+2]
cycloaddition and mechanistically similar ATRP was first
explored by the group of Matyjaszewski in a two-pot,
two-step manner consisting of converting the halogen
end-groups in well-defined polymers to azides and then
subsequently triazoles.[50,51] The methodology was also
successfully extended to one-pot simultaneous reactions,
in which propargyl methacrylate and alkyl azides were re-
acted to yield highly functionalized and well-defined
polymeric materials.[52,53] Furthermore, our laboratory
also initiated the study on sequential reactions involving
copper(I)-catalyzed azide–alkyne [3+2] cycloaddition and
mechanistically similar ATRA.[54] A wide variety of small
organic molecules bearing triazole and halide functionali-
ties have been synthesized.
Since we have demonstrated the efficiency of our cata-
lytic system to mediate both organic transformations in
a one-pot, two-step process, our focus has shifted towards
functionalized polytriazoles. Such compounds are very ef-
Isr. J. Chem. 2012, 52, 320 – 327
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
321

Full Paper
C. L. Ricardo and T. Pintauer
fective chelating agents and have found use in many dif-
ferent areas of catalysis.[55] A recent study has shown that
the incorporation of polytriazole ligands enhanced the
photophysical and electron-transfer properties of tripodal
zinc porphyrins (TPZn3).[56] In DNA and RNA chemistry,
multiple alkynylation of nucleosides and oligonucleotides
followed by functionalization via the copper(I)-catalyzed
Huisgen cycloaddition with fluorophore-decorated organ-
ic azides resulted in the formation of modified DNA and
RNA molecules that are highly fluorescent.[57]
tions with azidopropyl methacrylate and 1-(azidomethyl)-
4-vinylbenzene in the presence of a variety of alkynes
and alkyl halides, catalyzed by as low as 0.5 mol% of
[CuII(TPMA)X][X] (X=BrÀ, ClÀ) complex, proceeded
efficiently to yield highly functionalized (poly)halogenat-
ed esters and aryl compounds containing triazolyl group
in almost quantitative yields (>90%, Scheme 3).
In this article, we report on the synthesis of halogenat-
ed polytriazole derivatives employing sequential copper-
catalyzed azide–alkyne [3+2] cycloaddition and atom
transfer radical addition (ATRA). The presence of the
halide functionality in the resulting molecule offers versa-
tility towards further organic transformations involving
reduction, elimination, conversion to a Grignard reagent,
and/or free radical chemistry.
2. Results and Discussion
The motivation for the study of one-pot sequential reac-
tions involving azide–alkyne [3+2] cycloaddition and
atom transfer radical addition[54] catalyzed by [CuII-
(TPMA)X][X] (TPMA=tris(2-pyridylmethyl)amine, X=
ClÀ, BrÀ) complexes in the presence of ascorbic acid as
a reducing agent was primarily to demonstrate the syn-
thetic usefulness of the catalyst regeneration technique
originally developed for mechanistically similar ATRP.
The pioneering work in our laboratory on copper-cata-
lyzed ATRA in the presence of free-radical diazo initia-
tor AIBN showed a significant reduction in the required
catalyst loading with high turnover numbers (TONs).[31,32]
Improved selectivity towards the desired monoadduct for-
mation for alkenes that are prone to free-radical polymer-
ization was demonstrated through the use of radical ini-
tiator that decomposes at ambient temperature (such as
V-70)[58] or photoinitiated ATRA.[59] Very recently,
copper-catalyzed ATRA and ATRC reactions have also
been conducted in the presence of a more environmental-
ly benign reducing agent such as ascorbic acid.[46] This re-
ducing agent enabled not only high product yields and
TONs, but also more superior selectivity towards mono-
adduct formation (particularly in the case of highly active
acrylonitrile).
Based on literature reports, triazole formation via cop-
per(I)-catalyzed [3+2] azide–alkyne cycloaddition is com-
monly conducted via in situ reduction of CuII to CuI com-
plex by either sodium ascorbate or ascorbic acid.[3,6,21]
Similarly, ATRA,[46] ATRC[46] and ATRP[60,61] reactions
also utilize the same reducing agent to regenerate the
copper(I) complex, which is needed to start the catalytic
cycle by homolytically cleaving the carbon–halogen bond.
Therefore, a logical step was taken in combining the two
reactions in a one-pot sequential manner.[54] Indeed, reac-
Scheme 3. Sequential copper-catalyzed azide–alkyne [3+2] cyclo-
addition and atom transfer radical addition (ATRA).[54]
Encouraged by these results, we then applied the same
methodology to azide–alkyne [3+2] cycloaddition be-
tween tripropargylamine and vinyl benzyl azide (VBA),
followed by sequential ATRA of carbon tetrachloride.
Surprisingly, reactions conducted in the presence of
1 mol% of [CuII(TPMA)Cl][Cl] complex and 20 mol% of
ascorbic acid (relative to CuII) for 24 h at 608C yielded
less than 10% of the desired product. Conducting reac-
tions at elevated temperatures (808C) for longer reaction
times (48 h) did not result in significant improvements.
At the present time, it is unclear why the same catalytic
system does not work efficiently for tripropargylamine.
On the one hand, this substrate could inherently be less
active in azide–alkyne cycloaddition. On the other, if the
reaction requires multiple coordinations to the copper(I)
center, such interactions will be efficiently blocked be-
cause of the tetradentate nature of TPMA ligand. We are
presently exploring both possibilities.
Since one-pot sequential reactions catalyzed by [CuII-
(TPMA)Cl][Cl] complex were not successful, we reverted
322
www.ijc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Isr. J. Chem. 2012, 52, 320 – 327

Synthesis of Functionalized Polytriazoles
Table 1. Copper-catalyzed ATRA of alkyl halides to TVBTA in the
presence of ascorbic acid.
to carrying out two-step, two-pot reactions. The first step
involved the reaction between vinylbenzyl azide (VBA)
and tripropargylamine at 608C in the presence of
10 mol% of CuIISO4 and sodium ascorbate (1:10 molar
ratio) in methylene chloride/water (50:50 by volume).
After heating for 24 h, the desired tris(2-vinylbenzyl)tria-
zole was isolated in 74% yield. Even better results were
obtained when the solvent was changed to methanol and
ascorbic acid utilized as a reducing agent (91% isolated
yield). The resulting triazole was characterized using
1H NMR and high resolution mass spectroscopy (HRMS).
The corresponding spectra are shown in Figure 1. Positive
ion mass spectrum indicates the presence of two molecu-
lar ion peaks, namely the protonated triazole (MH+) and
sodium ion (MNa+).
For the second step, ATRA reactions of various alkyl
halides were conducted in the presence of [CuII-
(TPMA)X][X] (X=BrÀ or ClÀ) and ascorbic acid. The re-
sults are summarized in Table 1. The addition of poly-
halogenated methanes such as CCl4 and CBr4 provided
nearly quantitative yields of TBTA(CCl4)3 (95%) and
RÀX[a]
[CuII][b]
T [8C]
Time [h]
Yield [%][c]
CCl4
CCl4
CCl4
CBr4
CBr4
CBr4
CCl3CO2Me
CCl3CO2Me
CCl2HCN
CCl2HCO2Me
CCl2HCO2Me
1.0
60
60
60
60
60
60
80
80
80
80
80
24
24
24
24
24
24
27
27
27
27
27
95
0.40
0.20
1.0
0.40
0.20
2.0
1.0
2.0
2.0
1.0
60(64)[d]
62
98(92)[d]
86
84
78(77)[d]
76
70(67)[d]
70(55)[d]
64
[a] All reactions were performed in MeOH using [TVBTA]0/[CCl4 or
CBr4]0 =1:3.75, or TVBTA]0/[CCl3CO2Me, CHCl2CN, or
CCl2HCO2Me]0 =1:6, [TVBTA]0 =0.08m. The amount of ascorbic
acid in each system ranged between 20 and 25 equiv relative to the
copper(II) complex. [b] Mol% relative to [TVBTA]. [c] The yield is
based on the formation of the triazole and was determined by
1H NMR spectroscopy using p-dimethoxybenzene as internal stan-
dard (relative errors are Æ15%). [d] Isolated yield after column
chromatography.
TBTA(CBr4)3 (98%) in the presence of as low as
1.0 mol% of the catalyst. Decreasing catalyst loadings to
0.4 and 0.2 mol% still resulted in reasonably high yields
of the desired polytriazole monoadducts. The scope of
ATRA was also extended to include trihalogenated
(methyl trichloroacetate) and dihalogenated (methyl di-
chloroacetate and dichloroacetonitrile) alkyl halides.
Since they are generally less active compared to CCl4 and
CBr4, reactions were performed utilizing an excess of
Figure 1. 1H NMR (a) and HRMS (b) spectra of tris((1-(4-vinylben-
zyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA).
Isr. J. Chem. 2012, 52, 320 – 327
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
323

Full Paper
C. L. Ricardo and T. Pintauer
Table 2. One-pot sequential copper-catalyzed [3+2] azide–alkyne cy-
cloaddition and ATRA in the presence of ascorbic acid.
alkyl halides (6.0 equivalents relative to TVBTA), elevat-
ed temperatures (808C), prolonged reaction times (27 h),
and higher catalyst loadings (1.0–2.0 mol%). As indicated
in Table 1, the results were clearly inferior to those of
CCl4 and CBr4. Modest yield (78%) was obtained in the
addition of CCl3CO2Me in the presence of 2.0 mol% of
[CuII(TPMA)Cl][Cl] and ascorbic acid. For the case of
CCl2HCN and CCl2HCO2Me, the yields of the halogenat-
ed polytriazoles were approximately 70% using the same
catalyst loading (2.0 mol%). Further decrease in the
amount of copper catalyst resulted in a decrease in the
yield of the desired monoadduct.
We have already demonstrated that copper-catalyzed
[3+2] azide–alkyne cycloaddition between vinylbenzyl
azide and tripropargylamine in the presence of TPMA
ligand can be problematic. However, TPMA is necessary
for the ATRA step, and it is currently among the most
active nitrogen-based ligands for such copper-catalyzed
organic transformations.[26,33,34] With a strong determina-
tion to fulfill a one-pot synthesis of halogenated polytria-
zoles, a new strategy was devised. In the first step, [3+2]
azide–alkyne cycloaddition between vinylbenzyl azide
and tripropargylamine was conducted in a ligand-free cat-
alytic system containing ascorbic acid. After completion
of the reaction, free TPMA and alkyl halide were then
added to the same reaction mixture and ATRA allowed
to proceed. Indeed, with this protocol, the monoadduct in
the case of CCl4 was obtained in 91% yield using
10 mol% of copper (Table 2, entry 1). Increasing the re-
action time for ATRA from 8 to 19 h did not result in sig-
nificant increase in the product yield (90%, entry 2). Fur-
thermore, decreasing catalyst loading to 1.0 mol% result-
ed in a significant decrease in the yield of the monoad-
duct (entry 3). The same trend was also observed in the
case of CBr4 (entries 4–6). As indicated in Table 2, se-
quential [3+2] azide–alkyne cycloaddition and ATRA
proceeded reasonably well with less active methyl tri-
chloroacetate (entry 7 and 8) and methyl dichloroacetate
(entry 9 and 10). For both reactions, a large excess of
alkyl halide was used (6.0 equivalents relative to vinyl
benzyl azide).
Entry[a]
RÀX
CCl4
CCl4
CCl4
CBr4
CBr4
CBr4
CCl3CO2Me
CCl3CO2Me
CCl2HCO2Me
CCl2HCO2Me
[CuII][b]
t1 [h]/t2 [h][c]
Yield [%][d]
91(80)[e]
90
1
2
3
4
5
6
7
8
10
10
1.0
10
10
1.0
10
1.0
10
1.0
1/8
1/19
1/19
1/8
1/19
1/19
1/24
1/24
1/24
1/24
56
92(86)[e]
99
60
75(78)[e]
43
9
10
66(43)[e]
50
[a] All reactions were performed at 608C in MeOH using
[VBA]0:[tripropargylamine]0 =3:1, [VBA]0 =0.1m. The amount of as-
corbic acid was 20 equiv relative to CuIISO4. In the second step,
1.0 equiv of TPMA relative to CuIISO4 and RX (CCl4 or CBr4 =
3.75 equiv, CCl3CO2Me or CCl2HCO2Me=6.0 equiv relative to VBA)
were added. [b] Mol% of CuIISO4 relative to VBA. [c] t1 =time for
click reaction, t2 =time for ATRA. [d] The yield is based on the for-
1
mation of the triazole and was determined by H NMR spectrosco-
py using p-dimethoxybenzene as internal standard (relative errors
are Æ15%). [e] Isolated yield after column chromatography.
Product characterization via spectroscopic techniques
(1H and 13C NMR) and high resolution mass spectroscopy
(HRMS) were carried out for all substrates to verify the
formation of the monoadducts. Shown in Figure 2 are the
1H NMR and HRMS spectra of the addition product in-
volving CCl4. In the HRMS spectrum, there are two ob-
servable molecular ion peaks corresponding to the pro-
tonated triazole (MH+) and sodium ion (MNa+).
tion and atom transfer radical addition (ATRA). In the
first step, reactions were performed in a ligand-free cata-
lytic system, composed of anhydrous CuIISO4 and ascor-
bic acid. After completion of the click reaction, free
TPMA and alkyl halide were then added to the same re-
action mixture and ATRA allowed to proceed. It was ob-
served that the reaction between vinyl benzyl azide, tri-
propargylamine and tetrahalogenated methanes (CCl4
and CBr4), proceeded efficiently in the presence of as low
as 10.0 mol% of copper. Reactions with trihalogenated
(methyl trichloroacetate) and dihalogenated (methyl di-
chloroacetate and dichloroacetonitrile) substrates were
also successful, although the products were isolated in
modest yields (50–80%). The presented methodology en-
ables efficient synthesis of functionalized polytriazoles,
3. Conclusions
In summary, we reported an efficient synthesis of func-
tionalized polytriazoles via one-pot sequential reactions
involving copper-catalyzed [3+2] azide–alkyne cycloaddi-
324
www.ijc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Isr. J. Chem. 2012, 52, 320 – 327

Synthesis of Functionalized Polytriazoles
nol were purchased from commercial sources and used without
further purification. Tris(2-pyridylmethyl)amine (TPMA)[62] and
4-vinylbenzyl azide (VBA)[63] were synthesized according to liter-
1
ature procedures. H NMR and 13C NMR spectra were obtained
using Bruker Avance 400 MHz operating at room temperature.
All chemical shifts are given in ppm relative to residual solvent
peaks (CDCl3, 1H: d=7.26 ppm and 13C: d=77.2 ppm). Mass
spectroscopic analyses were performed using electrospray ioniza-
tion time of flight mass spectrometry on a Bruker microTOF in-
strument. Simulated data for the molecular ion peaks and isotop-
ic distributions were obtained using an Isotopic Distribution Sim-
ulator (IsoPro) v. 3.0.
Stock solutions: 0.01m [CuII(TPMA)X][X] (X=ClÀ or BrÀ) and
anhydrous CuIISO4 solutions were prepared in methanol. Ascor-
bic acid solution (0.25m) was prepared in methanol immediately
before use.
Copper-catalyzed [3+2] azide–alkyne cycloaddition between 4-
vinylbenzyl azide and tripropargylamine: Into a 100 mL Schlenk
flask equipped with a stirring bar were added 4-vinylbenzyl azide
(VBA) (12.0 mmol, 1.8 mL), tripropargylamine (4.0 mmol,
564 mL), CH2Cl2/H2O (50 mL, 1:1 mixture by volume),
CuSO4·5H2O (0.30 g, 1.2 mmol) and sodium ascorbate
(12.0 mmol, 2.377 g). The reaction flask was then capped with
a rubber septum and stirred overnight at room temperature. The
reaction was quenched by adding H2O and ethylenediamine tet-
raacetic acid sodium salt dihydrate (Na4EDTA·2H2O, 1.2 mmol,
0.499 g), stirred for approximately 1 h and poured into a separato-
ry funnel. The product was extracted with CH2Cl2 (2ꢀ10 mL).
The collected organic extract was dried over MgSO4 and solvent
was removed in vacuo to give yellow solid in 74% yield
(2.98 mmol, 1.813 g). In another reaction flask, VBA (3.0 mmol,
450 mL), tripropargylamine (1.0 mmol, 141 mL), anhydrous
CuSO4 (0.3 mmol, 0.0479 g) and ascorbic acid (6.0 mmol,
1.0578 g dissolved in 24 mL MeOH) were mixed together. Afore-
mentioned procedure was followed and after aqueous work-up
and solvent removal, product was isolated in 91% yield
(0.0913 mmol, 0.556 g).
General procedure for the ATRA of alkyl halides to TVBTA
catalyzed by [CuII(TPMA)X][X] (X=ClÀ or BrÀ) and ascorbic
acid: TVBTA (0.1 mmol, 0.0609 g), alkyl halide (CCl4 =
0.375 mmol, 36 mL; CBr4 =0.375 mmol, 0.1244 g; Cl3CO2Me=
0.6 mmol,
72 mL;
Cl2HCO2Me=0.6 mmol,
62 mL
and
CHCl2CN=0.6 mmol, 48 mL), p-dimethoxybenzene, and the cor-
responding amount of [CuII(TPMA)X][X] were added into
a 5 mL Schlenk flask equipped with micro stirring bar. Methanol
was then added in order to maintain constant volume and con-
centration of 0.08m for TVBTA. Ascorbic acid solution was then
added and immediately each reaction flask was secured with an
airtight Teflon cap. The resulting reaction mixtures were im-
mersed in an oil bath thermostated at 608C/808C for 24/27 h.
The percent yield of the expected functionalized polytriazole
Figure 2. 1H NMR (a) and experimental (b) and simulated (c) mass
spectra of tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-tria-
zol-4-yl)methyl)amine.
1
(TBTA(RX)3) was obtained using H NMR spectroscopy relative
to the internal standard. If necessary, the solvent was partially
which could have a potential use as chelating agents for
a variety of transition metals.
evaporated prior to 1H NMR analysis.
General procedure for sequential copper-catalyzed [3+2] cyclo-
addition and atom transfer radical addition in the presence of as-
corbic acid: In a typical experiment, a stock solution containing
VBA (3.0 mmol, 450 mL), tripropargylamine (1.0 mmol, 141 mL),
p-dimethoxybenzene and 2.4 mL MeOH was prepared to give
a 1.0m solution in VBA. Aliquots of the solution (0.5 mmol in
VBA, 500 mL) were distributed into 5 mL Schlenk flasks contain-
ing a micro stirring bar. For each reaction mixture with [VBA]0:-
4. Experimental Section
General
procedures:
Copper(II)
sulfate
(anhydrous),
CuSO4·5H2O, ascorbic acid, tripropargylamine, alkyl halides
(carbon tetrachloride, carbon tetrabromide, methyl trichloroace-
tate, methyl dichloroacetate and dichloroacetonitrile) and metha-
Isr. J. Chem. 2012, 52, 320 – 327
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
325

Full Paper
C. L. Ricardo and T. Pintauer
[CuII]0 ratio of 10:1, anhydrous CuIISO4 (0.05 mmol, 0.0080 g)
and ascorbic acid solution (1.0 mmol, 4.0 mL from 0.25m solu-
tion) were added. For reactions utilizing [VBA]0:[CuII]0 ratio of
100:1, anhydrous CuIISO4 (0.005 mmol, 500 mL from 0.01m
CuSO4 solution) and ascorbic acid solution (0.1 mmol, 400 mL)
were added. The volume of each reaction mixture was adjusted
by adding MeOH in order to maintain constant concentration of
VBA (0.10m). Schlenk flasks were secured with an airtight
Teflon cap and immersed in an oil bath thermostated at 608C for
1 h (10.0 mol% of CuIISO4) or 20 h (1.0 mol% of CuIISO4).
Upon completion, each reaction mixture was taken inside the
glovebox and uncapped. The corresponding amounts of TPMA
(1.0 equiv relative to CuIISO4) and alkyl halide (CCl4 =
1.875 mmol, 181 mL; CBr4 =1.875 mmol, 0.622 g; Cl3CO2Me=
43.6. HR-ESI-TOF for C46H50N10Cl12O6 [M+H+]: simulated:
1157.1051, experimental: 1160.9780.
4,4’,4’’-(((4,4’,4’’-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1-
diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobuta-
nenitrile)) (TBTA(CHCl2CN)3): 1H NMR (400 MHz; CDCl3):
mixture of diastereomers d=7.76 (s, 3H), 7.75 (s, 3H), 7.42 (d,
J=8.4 Hz, 6H), 7.31 (d, J=8.4 Hz, 6H), 5.54 (s, 6H), 5.13–5.05
(m, 3H), 4.79–4.75 (m, 3H), 4.55–4.51 (m, 3H), 3.72 (s, 6H),
2.85–2.77 (m, 3H), 2.73–2.66 (m, 3H), 2.66–2.56 (m, 3H).
13C NMR (100 MHz; CDCl3): d=144.15, 144.06; 139.40, 139.10;
136.09, 135.98; 128.79, 128.75; 127.77, 127.75; 124.10, 124.05;
116.29, 116.04; 57.85, 57.70; 53.54; 46.98, 46.96; 45.73, 45.40;
40.20, 39.91. HR-ESI-TOF for C42H40Cl6N13 [M+H+]: simulated:
938.16275,
experimental:
938.2882.
HR-ESI-TOF
for
3.0 mmol,
360 mL;
Cl2HCO2Me=3.0 mmol,
310 mL
or
C42H39Cl6N13Na [M+Na+]: simulated: 960.1459, experimental:
CHCl2CN=3.0 mmol, 240 mL) were added. The resulting mix-
tures were then heated in an oil bath at 608C for 8 h (10.0 mol%
of CuIISO4) or 24 h (1.0 mol% of CuIISO4). The percent yield of
the expected functionalized polytriazole (TBTA(RX)3) was ob-
960.2722.
Trimethyl 4,4’,4’’-(((4,4’,4’’-(nitrilotris(methylene))tris(1H-1,2,3-
triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-
1
tained using H NMR spectroscopy relative to the internal stan-
dichlorobutanoate)
(TBTA(Cl2HCCO2Me)3):
1H NMR
dard. If necessary, the solvent was partially evaporated prior to
(400 MHz; CDCl3): mixture of diastereomers d=7.73 (s, 3H),
7.72 (s, 3H), 7.39 (d, J=8.0 Hz, 6H), 7.29 (d, J=8.4 Hz, 6H),
5.49 (s, 6H), 5.14 (dd, J=5.9, 2.9 Hz, 3H), 5.12–5.02 (m, 3H),
4.71–4.62 (m, 6H), 3.77 (s, 9H), 3.67 (s, 6H), 3.66 (s, 6H), 2.76–
2.61 (m, 6H), 2.43–2.31(m, 6H). 13C NMR (100 MHz; CDCl3):
d=169.28, 168.99, 144.11, 144.03, 140.79, 135.45, 128.57, 127.84,
124.03, 124.0, 59.11, 57.1, 56.94, 54.84, 53.31, 46.97, 44.1. HR-
ESI-TOF for C46H53N10Cl6O6 [M+H+]: simulated: 1053.2217, ex-
perimental: 1053.2524.
1H NMR analysis.
Product Characterization
Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine
1
(TVBTA): H NMR (400 MHz; CDCl3): d=7.69 (s, 3H), 7.41(d,
J=8.4 Hz, 6H), 7.24 (d, J=8 Hz, 6H), 6.71 (dd, J=17.6, 10.9 Hz,
3H), 5.77 (d, J=17.6 Hz, 3H), 5.50 (s, 6H), 5.30 (d, J=10.9 Hz,
3H), 3.73 (s, 6H). 13C NMR (100 MHz; CDCl3): d=144.5, 138.0,
136.0, 134.1, 128.3, 126.8, 124.0, 114.9, 53.9, 47.1. HR-ESI-TOF
for C36H37N10 [M+H+]: simulated: 609.3202, experimental:
609.3952. HR-ESI-TOF for C36H36N10Na [M+Na+]: simulated:
631.3022, experimental: 631.3791.
Acknowledgements
Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4-
yl)methyl)amine (TBTA(CCl4)3): 1H NMR (400 MHz; CDCl3):
d=7.76 (s, 3H), 7.46 (d, J=8.4 Hz, 6H), 7.29 (d, J=8.4 Hz, 6H),
5.54 (s, 6H), 5.32–5.29 (m, 3H), 3.74 (s, 6H), 3.59 (dd, J=15.4,
5.4 Hz, 3H), 3.49 (dd, J=15.4, 6.4 Hz, 3H). 13C NMR (100 MHz;
CDCl3): d=149.40, 141.24, 135.79, 128.53, 128.19, 124.68, 96.02,
62.57, 57.61, 53.68, 46.02, 62.57, 57.61, 53.68, 46.81. HR-ESI-TOF
for C36H37Cl12N10 [M+H+]: simulated: 1070.9358, experimental:
1071.0706. HR-ESI-TOF for C36H36Cl12N10Na [M+Na+]: simu-
lated: 1092.9186, experimental: 1093.0548.
Financial support from NSF CAREER Award (CHE-
0844131) is greatly acknowledged. Dr. Stephanie Wetzel
and Rebecca Wagner are acknowledged for the assistance
in ESITOF measurements.
References
[1] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001,
113, 2056–2075; Angew. Chem. Int. Ed. 2001, 40, 2004–
2021.
Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4-
yl)methyl)amine (TBTA(CBr4)3): 1H NMR (400 MHz; CDCl3):
d=7.78 (s, 3H), 7.51 (d, J=8.4 Hz, 6H), 7.27 (d, J=8.4 Hz, 6H),
5.53 (s, 6H), 5.32 (dd, J=7.6, 4.0 Hz, 3H), 4.12 (dd, J=15.4,
4.0 Hz, 3H), 4.03 (dd, J=15.4, 7.8 Hz, 3H), 3.75 (s, 6H).
13C NMR (100 MHz; CDCl3): d=143.35, 141.36, 135.48, 128.94,
128.45, 124.47, 82.90, 66.27, 56.90, 53.65, 49.14, 46.89. HR-ESI-
TOF for C36H37Br12N10 [M+H+]: simulated: 1604.3242, experi-
mental: 1604.5386. HR-ESI-TOF for C36H36Br12N10Na [M+Na+
]: simulated: 1626.3115, experimental: 1626.5079.
[2] C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057–3064.
[3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708–2711; Angew. Chem. Int. Ed.
2002, 41, 2596–2599.
[4] N. J. Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem.
Soc. 2004, 126, 15046–15047.
[5] A. J. Dirks, S. S. van Berkel, N. S. Hatzakis, J. A. Opsteen,
F. L. van Delft, J. J. L. M. Cornelissen, A. E. Rowan, J. C. M.
van Hest, F. P. J. T. Rutjes, R. J. M. Nolte, Chem. Commun.
2005, 4172–4174.
[6] M. Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952–3015.
[7] J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007, 36,
1249–1262.
[8] W. H. Binder, C. Kluger, Curr. Org. Chem. 2006, 10, 1791–
1815.
[9] H. C. Kolb, K. B. Sharpless, Drug Discov. Today 2003, 8,
1128–1137.
Trimethyl 4,4’,4’’-(((4,4’,4’’-(nitrilotris(methylene))tris(1H-1,2,3-
triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,2,4-
1
trichlorobutanoate) (TBTA(Cl3CCO2Me)3): H NMR (400 MHz;
CDCl3): d=8.10 (s, 3H), 7.44 (d, J=8.4 Hz, 6H), 7.00 (d, J=
8.4 Hz, 6H), 5.56 (s, 6H), 5.24 (dd, J=7.6, 5.8 Hz, 3H), 3.93 (s,
9H), 3.71 (s, 6H), 3.42 (dd, J=15.0, 7.6 Hz, 3H), 3.18 (dd, J=
15.0, 5.8 Hz, 3H). 13C NMR (101 MHz; CDCl3): d=165.6, 143.8,
140.3, 135.6, 128.4, 128.1, 124.2, 81.9, 57.8, 54.5, 53.9, 53.6, 46.8,
326
www.ijc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Isr. J. Chem. 2012, 52, 320 – 327

Synthesis of Functionalized Polytriazoles
[10] F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 2009, 109,
4207–4220.
[11] C. Hein, X.-M. Liu, D. Wang, Pharm. Res. 2008, 25, 2216–
2230.
[40] J. M. Munoz-Molina, A. Caballero, M. M. Diaz-Requejo, S.
Trofimenko, T. R. Belderrain, P. J. Perez, Inorg. Chem. 2007,
46, 7725–7730.
[41] J. M. Munoz-Molina, T. R. Belderrain, P. J. Perez, Inorg.
[12] C. Najera, J. M. Sansano, Org. Biomol. Chem. 2009, 7,
4567–4581.
[13] W. H. Binder, R. Sachsenhofer, Macromol. Rapid Commun.
Chem. 2010, 49, 642–645.
[42] A. J. Clark, P. Wilson, Tetrahedron Lett. 2008, 49, 4848–
4850.
2007, 28, 15–54.
[43] M. A. Fernandez-Zumel, K. Thommes, G. Kiefer, A. Sien-
kiewicz, K. Pierzchala, K. Severin, Chem. Eur. J. 2009, 15,
11601–11607.
[14] H. Nandivada, X. Jiang, J. Lahann, Adv. Mater. 2007, 19,
2197–2208.
[15] P. L. Golas, K. Matyjaszewski, QSAR Comb. Sci. 2007, 26,
1116–1134.
[44] R. J. Lundgren, M. A. Rankin, R. McDonald, M. Stradiotto,
Organometallics 2008, 27, 254–258.
[16] P. L. Golas, K. Matyjaszewski, Chem. Soc. Rev. 2010, 39,
1338–1354.
[45] R. P. Nair, T. H. Kim, B. J. Frost, Organometallics 2009, 28,
4681–4688.
[17] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodle-
man, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005,
127, 210–216.
[18] M. Ahlquist, V. V. Fokin, Organometallics 2007, 26, 4389–
4391.
[19] B. F. Straub, Chem. Commun. 2007, 3868–3870.
[20] V. O. Rodionov, V. V. Fokin, M. G. Finn, Angew. Chem.
2005, 117, 2250–2255; Angew. Chem. Int. Ed. 2005, 44,
2210–2215.
[46] M. J. W. Taylor, W. T. Eckenhoff, T. Pintauer, Dalton Trans.
2010, 39, 11475–11482.
[47] C. Ricardo, T. Pintauer, Chem. Commun. 2009, 3029–3031.
[48] K. Thommes, G. Kiefer, R. Scopelliti, K. Severin, Angew.
Chem. 2009, 121, 8259–8263; Angew. Chem. Int. Ed. 2009,
48, 8115–8119.
[49] J. M. Munoz-Molina, T. R. Belderrain, P. J. Perez, Adv.
Synth. Catal. 2008, 350, 2365–2372.
[50] B. S. Sumerlin, N. V. Tsarevsky, G. Louche, R. Y. Lee, K.
Matyjaszewski, Macromolecules 2005, 38, 7540–7545.
[51] N. V. Tsarevsky, K. V. Bernaerts, B. Dufour, F. E. Du Prez,
K. Matyjaszewski, Macromolecules 2004, 37, 9308–9313.
[52] J. Geng, J. Lindqvist, G. Mantovani, D. M. Haddleton,
Angew. Chem. 2008, 120, 4248–4251; Angew. Chem. Int. Ed.
2008, 47, 4180–4183.
[21] V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51–68.
[22] D. P. Curran, Synthesis 1988, 417–439.
[23] D. P. Curran, Synthesis 1988, 489–513.
[24] D. P. Curran, Comprehensive Organic Synthesis Pergamon,
New York, 1992.
[25] J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519–
564.
[53] B. Grignard, C. Calberg, C. Jerome, C. Detrembleur, J. Su-
percrit. Fluids 2010, 53, 151–155.
[26] W. T. Eckenhoff, T. Pintauer, Cat. Rev.–Sci. Eng. 2010, 51,
1–59.
[54] C. L. Ricardo, T. Pintauer, Eur. J. Inorg. Chem. 2011, 1292–
1301.
[27] K. Severin, Curr. Org. Chem. 2006, 10, 217–224.
[28] J.-S. Wang, K. Matyjaszewski, J. Am. Chem. Soc. 1995, 117,
5614–5615.
[29] K. Matyjaszewski, J. Xia, Chem. Rev. 2001, 101, 2921–2990.
[30] L. Quebatte, K. Thommes, K. Severin, J. Am. Chem. Soc.
2006, 128, 7440–7441.
[31] W. T. Eckenhoff, T. Pintauer, Inorg. Chem. 2007, 46, 5844–
5846.
[32] W. T. Eckenhoff, S. T. Garrity, T. Pintauer, Eur. J. Inorg.
[55] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org.
Lett. 2004, 6, 2853–2855.
[56] A. Takai, M. Chkounda, A. Eggenspiller, C. P. Gros, M.
Lachkar, J. M. Barbe, S. Fukuzumi, J. Am. Chem. Soc. 2010,
132, 4477–4489.
[57] F. Seela, S. A. Ingale, J. Org. Chem. 2010, 75, 284–295.
[58] T. Pintauer, W. T. Eckenhoff, C. Ricardo, M. N. C. Balili,
A. B. Biernesser, S. T. Noonan, M. T. Taylor, Chem. Eur. J.
2009, 15, 38–41.
Chem. 2008, 2008, 563–571.
[59] M. N. C. Balili, T. Pintauer, Dalton Trans. 2011, 40, 3060–
3066.
[60] K. Min, H. Gao, K. Matyjaszewski, J. Am. Chem. Soc. 2005,
127, 3825–3830.
[61] K. Min, H. Gao, K. Matyjaszewski, Macromolecules 2007,
40, 1789–1791.
[62] Z. Tyeklar, R. R. Jacobson, N. Wei, N. N. Murthy, J. Zubieta,
K. D. Karlin, J. Am. Chem. Soc. 1993, 115, 2677–2689.
[63] L. Q. Xu, F. Yao, G.-D. Fu, L. Shen, Macromolecules 2009,
42, 6385–6392.
[33] T. Pintauer, ACS Symp. Ser. 2009, 1023, 63–84.
[34] T. Pintauer, Eur. J. Inorg. Chem. 2010, 2449–2460.
[35] M. N. C. Balili, T. Pintauer, Inorg. Chem. 2009, 48, 9018–
9026.
[36] M. N. C. Balili, T. Pintauer, Inorg. Chem. 2010, 49, 5642–
5649.
[37] T. Pintauer, W. T. Eckenhoff, C. Ricardo, M. N. C. Balili,
A. B. Biernesser, S. T. Noonan, M. T. Taylor, Chem. Eur. J.
2009, 15, 38–41.
[38] K. Thommes, B. Icli, R. Scopelliti, K. Severin, Chem. Eur. J.
2007, 13, 6899–6907.
[39] J. Wolf, K. Thommes, O. Briel, R. Scopelliti, K. Severin, Or-
ganometallics 2008, 27, 4464–4474.
Received: September 20, 2011
Accepted: October 9, 2011
Published online: March 1, 2012
Isr. J. Chem. 2012, 52, 320 – 327
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
327