Metal-Free Intermolecular Azide-Alkyne Cycloaddition Promoted by Glycerol

Article abstract of DOI:10.1002/chem.201503858

Metal-free intermolecular Huisgen cycloadditions using nonactivated internal alkynes have been successfully performed in neat glycerol, both under thermal and microwave dielectric heating. In sharp contrast, no reaction occurs in other protic solvents, su

Full text of DOI:10.1002/chem.201503858

DOI: 10.1002/chem.201503858
Full Paper
&
Synthetic Methods
Metal-Free Intermolecular Azide–Alkyne Cycloaddition Promoted
by Glycerol
Marta Rodríguez-Rodríguez,[a, b] Emmanuel Gras,[c] Miquel A. Pericàs,*[b] and
Montserrat Gómez*[a]
Abstract: Metal-free intermolecular Huisgen cycloadditions
using nonactivated internal alkynes have been successfully
performed in neat glycerol, both under thermal and micro-
wave dielectric heating. In sharp contrast, no reaction occurs
in other protic solvents, such as water, ethanol, or diols. DFT
calculations have shown that the BnN3/glycerol adduct pro-
motes a more important stabilization of the corresponding
LUMO than that produced in the analogous BnN3/alcohol
adducts, favoring the reactivity with the alkyne in the first
case. The presence of copper salts in the medium did not
change the reaction pathway (Cu(I) acts as spectator),
except for disubstituted silylalkynes, for which desilylation
takes place in contrast to the metal-free system.
Introduction
For biological and pharmacological applications, metal-free
AAC methodologies (back to the origins) still remain attractive
approaches.[9] Bertozzi and co-workers first used the strained-
promoted strategy involving substituted cycloalkynes for bio-
conjugation purposes.[10] Another elegant method is through
intramolecular AAC reactions by taking advantage of the favor-
able entropy effects.[11] However, to the best of our knowledge,
intermolecular cycloadditions between organic azides and non-
activated internal alkynes under metal-free conditions remain
an important challenge to be solved.
Azide–alkyne cycloadditions (AAC) represent a powerful tool
for the synthesis of 1,2,3-triazoles, valuable heterocycles in-
volved in diverse fields, such as biochemistry, organic synthe-
sis, or materials science.[1] Although this reaction was first re-
ported in 1893 by Michael[2] and in particular developed by
Huisgen in the 1960s,[3] it was not up to the beginning of the
21st century that the reaction found widespread practical in-
terest after overcoming kinetic and regioselective concerns by
transforming the thermally activated process into a catalytic re-
action, mainly by using copper-based systems.[1,4] Since then,
many catalytic systems have been described, also including
metals other than copper (such as Ag,[5] Ru,[6] Ir,[7] or Ni[8]),
which allow access to substituted-1,2,3-triazoles from organic
azides and alkynes. The use of internal alkynes leading to the
formation of 1,4,5-trisubstituted 1,2,3-triazoles generally re-
quires harsher conditions, and activated alkynes (either substi-
tuted by electron-withdrawing groups or strained).
In the last years, with the purpose of using ecofriendly sol-
vents, we have developed glycerol catalytic phases. They ex-
hibit appealing properties mainly regarding the immobilization
of the metal species, probably owing to the supramolecular ar-
rangement shown by glycerol.[12] In particular, Cu2O nanoparti-
cles prepared in neat glycerol led to the synthesis of 1,4-disub-
stituted-1,2,3-triazoles, permitting an easy recycling of the cat-
alytic phase.[13] With the assumption of glycerol having a nonin-
nocent role in this process, we decided to investigate the
metal-free AAC in glycerol for the synthesis of 1,4,5-trisubsti-
tuted 1,2,3-triazoles.
[a] M. Rodríguez-Rodríguez, Prof. M. Gómez
Laboratoire HØtØrochimie Fondamentale et AppliquØe (LHFA)
UniversitØ de Toulouse, UPS and CNRS UMR 5069
118, route de Narbonne, 31062 Toulouse cedex 9 (France)
E-mail: gomez@chimie.ups-tlse.fr
Results and Discussion
As a benchmark reaction, the intermolecular azide–alkyne cy-
cloaddition (AAC) between diphenylacetylene (1) and benzyl
azide (a) in neat glycerol under microwave dielectric heating
for 30 minutes was chosen, affording 1-benzyl-4,5-diphenyl-
1,2,3-triazole (1a; Table 1).[14] The organic products were isolat-
ed by a biphasic liquid–liquid extraction after adding dichloro-
methane to the reaction mixture. The triazole 1a was exclu-
sively obtained in a high yield of 85% (Table 1, entry 1). With
the aim of investigating the effect of copper in this reaction,[15]
we carried out the synthesis in the presence of a copper salt
(2.5 mol% of CuCl), obtaining 1a in almost the same isolated
[b] M. Rodríguez-Rodríguez, Prof. M. A. Pericàs
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Avda. Pa¨ısos Catalans, 16, 43007 Tarragona (Spain)
E-mail: mapericas@iciq.es
[c] Dr. E. Gras
Laboratoire de Chimie de Coordination (LCC)
Centre National de la Recherche Scientifique (CNRS)
205, route de Narbonne, 31077 Toulouse cedex 4 (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503858.
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yield (Table 1, entry 2). This evidences the spectator role of
copper (see Table S1 in the Supporting Information).[16] A simi-
lar trend was observed under classical thermal-promoted con-
ditions (Table 1, entries 3 and 4), albeit in lower yields (<35%)
after 20 h. In the absence of glycerol (i.e., under solvent-free
conditions), the product was obtained in only 18% yield
(Table 1, entry 5). No copper was detected by ICP-AES analysis
of neat glycerol (<3 ppm).
Table 1. Azide–alkyne cycloaddition of diphenylacetylene and benzyl
azide in neat glycerol.[a]
Entry
Solvent
Conversion [%][b][c]
Isolated yield [%][d]
1
glycerol
glycerol
glycerol
glycerol
–
protic solvent
H2O
1,4-dioxane
fluorobenzene
85
86
37
42
20
n.r.
13
n.r.
n.r.
85 (85)
82 (80)
33 (33)
28 (27)
18[g]
–
n.d.
–
–
To better control the temperature (the reaction conditions
were set at a targeted temperature, controlled by an external
infrared temperature sensor),[17] we employed a MW instru-
ment combining both internal optical fiber and external infra-
red temperature sensors (Figure S1 in the Supporting Informa-
tion). We carried out the cycloaddition at different tempera-
tures (100, 140, and 1808C, according to the internal optical
fiber sensor) and observed that the yield obtained at 1808C
was comparable to that obtained working with the instrument
equipped only with an infrared sensor (Table S2 in the Sup-
porting Information). Under classical heating conditions (oil
bath), only 65% yield was achieved at 1808C in the same reac-
tion time, which is consistent with a less efficient heat transfer.
Then, we decided to study the influence of the solvent
under metal-free conditions. Surprisingly, no reaction took
place when using other alcohol-based solvents, including etha-
nol and diols, such as ethylene glycol, propane-1,2-diol, and
propane-1,3-diol (Table 1, entry 6). Water gave a very low con-
version of benzyl azide of 13% (Table 1, entry 7). Aprotic polar
solvents, such as 1,4-dioxane and fluorobenzene, also disfa-
vored the cycloaddition (Table 1, entries 8 and 9). The varying
reactivity observed by using different protic solvents can be
explained by the solvent interaction with an external electric
field. Alcohols, in particular polyols, form extensive hydrogen
bonds, which in turn correlate with long relaxation times (the
time taken to achieve the random state after being submitted
to an external electric field).[18] Therefore, water (9.2 ps), etha-
nol (170 s), ethylene glycol (170 ps), or propane-1,3-diol
(340 ps) exhibit shorter relaxation times than glycerol
(1,215 ps), making it more relevant than other protic solvents
for synthetic purposes under microwave conditions, as illustrat-
ed here for the AAC reaction.
2[e]
3[f]
4[e][f]
5
6[h]
7
8
9
[a] Results from duplicate experiments. Reaction conditions: benzyl azide
(0.4 mmol) and diphenylacetylene (0.6 mmol) in solvent (1 mL) under mi-
crowaves activation (250 W) at 1008C for 30 minutes (temperature con-
trolled by external infrared sensor). [b] Based on benzyl azide. [c] Deter-
1
mined by H NMR spectroscopy using 2-methoxynaphthalene as an inter-
nal standard. [d] In brackets: yields determined by 1H NMR spectroscopy
using 2-methoxynaphthalene as an internal standard. [e] In the presence
of 2.5 mol% of CuCl. [f] Reaction in a sealed tube under thermal activa-
tion at 1008C for 20 h. [g] Determined by 1H NMR spectroscopy using 2-
methoxynaphthalene as an internal standard. [h] Results obtained with
the following alcohols as solvents: ethanol, ethylene glycol, propane-1,2-
diol, and propane-1,3-diol.
lated yield (after 1 h under microwave irradiation; Table 2,
entry 4).
Unsymmetrically substituted alkynes 6 and 7 led to an
almost equimolar mixture of both regioisomers (Table 2, en-
tries 5 and 6). In view of synthetic applications and to explore
the role of the silyl group as a directing group during the cy-
cloaddition,[19] we carried out the synthesis of triazoles 8–10
from the corresponding alkynes containing silyl-based groups,
such as SiMe3 (alkynes 8 and 9; Table 2, entries 7 and 8) and
Si(tBu)Me2 (10; Table 2, entry 9). As expected, the 4-silyl-substi-
tuted heterocycle was obtained as the major regioisomer[20]
and as the sole product for the bulky tert-butyldimethylsilyl
(TBDMS) derivative (Table 2, entry 9).
Under thermal conditions (Table S3 in the Supporting Infor-
mation), the reactivity in the different solvents follows the
same trend, except for ethylene glycol and water for which 1a
was obtained in 25 and 31% yield, respectively (33% yield in
glycerol; Table 1, entry 3), after 20 h at 1008C. This clearly con-
trasts with the lack of reactivity observed under microwave
heating (Table 1, entries 6 and 7), despite the high internal
temperature achieved under MW activation (see above).
Phenyl (b) and n-octyl (c) azides also gave the expected tria-
zoles; conversions and yields were lower than those obtained
when using benzyl azide (Figure 1).[21] In contrast to benzyl
and n-octyl azides, PhN3 tends to decompose under the reac-
tion conditions employed.[22]
We studied the effect of Cu(I) in the synthesis of silyl-based
triazoles 8a–10a. For the synthesis of 10a, bearing a TBDMS
group, the reactivity was similar to the one observed in the ab-
sence of Cu(I). However, for the TMS-substituted ones (8a, 9a),
a mixture of two triazoles was obtained: the expected 8a or
9a and the desilylated 1-benzyl-4R-1,2,3-triazole (R=Me (11 a),
Ph (12a)), which was obtained as a single regioisomer
(Scheme 1). Under the classical thermal conditions, the same
behavior was observed (Scheme S1 in the Supporting Informa-
tion).
With these results in hand, we decided to study the scope
of the process by using other internal alkynes (Table 2). For the
symmetrical disubstituted alkynes 2–5 (Table 2, entries 1–4),
moderate to high yields were obtained (32–90%). No transes-
terification reaction between the alkyne 2 or the triazole 2a
and glycerol was observed, in contrast to the reaction in etha-
nol (see Tables S4 and S5 in the Supporting Information). It is
important to note that the nonactivated 4-octyne reacted with
BnN3 to give 1-benzyl-4,5-dipropyl-1,2,3-triazole 5a in 71% iso-
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Table 2. Azide–alkyne cycloaddition of internal alkynes and benzyl azide
in neat glycerol.[a]
Entry
1[d]
Alkyne
(R, R’)
Product
Conv.
Yield
[%][c]
[%][b][c]
Scheme 1. Reactivity of silyl-based alkynes in the presence of CuCl under mi-
crowave activation. Data from NMR analysis.
2
100
78
(CO2Me)
Control experiments proved that the desilylation neither
took place on the alkyne 8 or 9 nor on the triazole 8a or 9a
(Scheme S2 in the Supporting Information). In addition, when
the AAC reaction was carried out in dioxane, no corresponding
desilylation occurred. Monitoring the reaction by GC-MS dem-
onstrated that the formation of 9a is faster than that corre-
sponding to 12a (after 5 min, the ratio 9a/12a was approxi-
mately 3.4:1; after 15 min, the ratio was approximately 1.2:1,
with full conversion of BnN3). Once BnN3 was consumed com-
pletely, desilylation of the alkyne 9 could be observed (Fig-
ure S4 in the Supporting Information). These facts led us to
propose that the desilylation giving 12a (and 11 a) occurs
upon coordination of the alkyne to copper (intermediate I in
Scheme 2), which is promoted by glycerol that is undoubtedly
3
2
96
56
73
91
49
65
92
85
90
(CH2OMe)
4
3
32
(CH2OH)
5
(Pr)
4[e]
71
6
5
83[f]
(Ph, CO2Me)
7
6
49[f]
(Ph, Me)
8
7
62 (9:1)[g]
85 (9:1)[g]
84[h]
(Me, TMS)
9
8
(Ph, TMS)
10
9
(Ph, TBDMS)
[a] Results from duplicate experiments. Reaction conditions: benzyl azide
(0.4 mmol) and the corresponding alkyne (0.6 mmol) in solvent (1 mL)
under microwaves activation (250 W) at 1008C for 30 min (temperature
controlled by external infrared sensor). [b] Based on benzyl azide. [c] De-
Scheme 2. Plausible Cu-mediated desilylation of SiMe3-based alkynes pro-
moted by glycerol.
1
termined by H NMR spectroscopy using 2-methoxynaphthalene as an in-
ternal standard. [d] Reaction time: 15 min. [e] Reaction time: 60 min.
[f] Regioisomer ratio: 1:1. [g] In brackets: regioisomer ratio (major isomer:
1-benzyl-4-trimethylsilyl-5R-1,2,3-triazole (for R=Me: maj-8a; for R=Ph:
maj-9a); minor isomer: 1-benzyl-5-trimethylsilyl-4R-1,2,3-triazole (for R=
Me: min-8a; for R=Ph: min-9a). [h] Only one isomer was obtained (1-
benzyl-4-tert-butyldimethylsilyl-5-phenyl-1,2,3-triazole); see ref. [20].
close to the coordination sphere owing to its interaction with
BnN3 through hydrogen bonds (see below). Intermediate II
then evolves to give the favored regioisomer 1-benzyl-4R-1,2,3-
triazole, according to the accepted Cu-catalyzed mecha-
nisms.[4b,23] The formation of the corresponding silyl derivative
of glycerol was proven by NMR spectroscopy (see Figures S5
and S6 in the Supporting Information).[24] Alkyne 10 did not
give the corresponding desilylated triazole, probably as a con-
sequence of the steric hindrance triggered by the TBDMS
group around the metal center.
To rationalize the effect of glycerol in AAC reactions, we
studied the interaction of glycerol with benzyl azide by theo-
retical calculations (DFT B3LYP, 6-31G*), taking into account the
ability of glycerol to form hydrogen bonds.[25,26] For compara-
tive purposes, we also analyzed this effect with ethanol and
several diols (ethylene glycol, 1,2-, and 1,3-propanediol). The
resulting BnN3/alcohol adducts increase the dipolar character
of BnN3 in relation to neat benzyl azide (see calculated charges
Figure 1. 1,4,5-Trisubstituted 1,2,3-triazoles from phenyl (1b) and n-octyl
azides (1c, 5c, 9c). Isolated yields are given (conversions are given in brack-
ets).
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in Figure S7 in the Supporting Information). It is important to
note that in the case of polyols (ethylene glycol, 1,2-propane-
diol, and glycerol) the intramolecular hydrogen bonds trigger
an additional stabilization of the corresponding BnN3/alcohol
adduct (see Figure S8 in the Supporting Information). The anal-
ysis of the relative energies of frontier orbitals for the different
BnN3/alcohol adducts (see Figure S9 in the Supporting Infor-
mation) showed that the BnN3/glycerol LUMO, which overlaps
with the dipolarophile HOMO (diphenylacetylene was chosen
for the calculations), is more stable than the ones obtained for
the other adducts (see Table S6 in the Supporting Information).
In consequence, the reactivity should be enhanced, as ob-
served in this work for a range of alkynes.
General AAC procedure in glycerol under microwave activa-
tion
A sealed tube equipped with a stirring bar was successively
charged with the corresponding alkyne (0.6 mmol) and glycerol
(1 mL); the mixture was stirred at room temperature for 5 min.
Benzyl azide (0.4 mmol, 53.2 mg) was then added and the sealed
tube was placed into the microwave reactor (1008C, 250 W) for
30 min (or the appropriate time). It is important to note that at
room temperature the reaction mixture gave a kind of emulsion
but that at 1008C a homogeneous solution was obtained (i.e., re-
agents and products were soluble in glycerol).[27] The organic prod-
ucts were extracted with dichloromethane (6”2 mL). The com-
bined chlorinated organic layers were filtered through a Celite pad
and the resulting filtrate was concentrated under reduced pres-
sure. The products were purified by chromatography (silica short
column, eluent: cyclohexane/ethyl acetate 1:1) to determine the
isolated yields of the corresponding triazoles.
Compound maj-8a: Yellow oil; IR (neat): n˜ =1606, 1497, 1416,
1
1248 cmÀ1; H NMR (500 MHz, CDCl3): d=0.35 (s, 9H), 2.22 (s, 3H),
Conclusion
5.51 (s, 2H), 7.15–7.20 (m, 2H), 7.27–7.39 ppm (m, 3H); 13C{1H} NMR
(125 MHz, CDCl3): d=À0.9, 9.3, 51.2, 127.2, 128.1, 128.9, 135.1,
138.1, 143.8 ppm; HRMS (ESI+): m/z [M+H]+ calcd for C13H20N3Si:
246.1412; found: 246.1421; elemental analysis calcd (%) for
C13H19N3Si: C 63.63, H 7.80, N 17.11; found: C 63.22, H 7.88, N
16.94.
We have shown that glycerol acts as a noninnocent solvent for
metal-free azide–alkyne cycloadditions, promoting the reaction
between internal alkynes and organic azides in contrast to
other protic solvents, both under classical and dielectric heat-
ing. Moreover, the reactivity in glycerol was particularly en-
hanced by microwave heating, probably owing to the long re-
laxation time of glycerol in comparison with other protic sol-
vents, which is related to its supramolecular arrangement
through intermolecular hydrogen bonds. At a molecular level,
analysis of the frontier orbitals for the BnN3/glycerol adduct
pointed to a higher stabilization of the corresponding LUMO
than that for comparable adducts involving ethanol and diols.
This trend justifies the increase of the reaction rate according
to a concerted pathway for the metal-free cycloaddition.
These results permit us to envisage the formation of fully
substituted 1,2,3-triazoles by using a metal-free methodology,
which is particularly interesting for the synthesis of drugs and
natural products.
Compound 10a: Yellow oil; IR (neat): n˜ =1606, 1497, 1456, 1249
1
cmÀ1; H NMR (500 MHz, CDCl3): d=0.05 (s, 6H), 0.90 (s, 9H), 5.35
(s, 2H), 6.94–7.00 (m, 2H), 7.05–7.10 (m, 2H), 7.21–7.28 (m, 3H),
7.35–7.40 (m, 2H), 7.43–7.48 (m, 1H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) d=5.3, 26.6, 51.4, 127.6, 127.9, 128.2, 128.5, 128.8, 129.3,
130.4, 135.6, 142.8, 144.1, 173.4 ppm; HRMS (ESI+): m/z [M+H]+
calcd for C21H28N3Si: 350.2050; found: 350.2047; elemental analysis
calcd (%) for C21H27N3Si: C 72.16, H 7.79, N 12.02; found: C 72.24, H
8.27, N 11.87.
Compound 5c: Yellow oil; IR (neat): n˜ =1611, 1570, 1544,
;
1247 cmÀ1 1H NMR (500 MHz, CDCl3): d=0.89 (t, J=7.0 Hz, 3H),
0.98 (t, J=7.4 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H), 1.20–1.40 (m, 10H),
1.53–1.62 (m, 2H), 1.68–1.77 (m, 2H), 1.83–1.96 (m, 2H), 2.55–2.61
(m, 4H), 4.16–4.20 (m, 2H) ppm; 13C{1H} NMR (125 MHz, CDCl3): d=
13.85, 13.98, 14.05, 22.58, 22.60, 22.94, 24.49, 26.69, 27.23, 29.06,
29.70, 30.35, 31.71, 47.89, 132.44, 144.71 ppm; HRMS (ESI+): m/z
[M+H]+ calcd for C16H32N3: 266.2591; found: 266.2594; elemental
analysis calcd (%) for C16H31N3: C 72.40, H 11.77, N 15.83; found: C
72.13, H 12.28, N 15.53.
Experimental Section
General
Acknowledgements
All manipulations were performed by using standard Schlenk tech-
niques under argon atmosphere. Unless stated otherwise, commer-
cially available compounds were used without further purification.
Glycerol was treated under vacuum at 808C overnight prior to use.
NMR spectra were recorded on Bruker Avance 300, 400, and 500
spectrometers at 293 K. GC analyses were carried out on an Agilent
GC6890 with a flame ionization detector using a SGE BPX5 column
composed of 5% of phenylmethylsiloxane. Reactions under micro-
wave activation were carried out on single-mode microwave CEM
Explorer SP 48, 2.45 GHz, Max Power 300 W Synthesis System, CEM
Focused MicrowaveTM Synthesis System Model Discover, and
Anton Paar Monowave 300 instruments. Theoretical studies were
carried out by using the following software: SPARTAN’14 for Win-
dows and Linux, Wavefunction, InC. 18401 Von Karmaan Avenue,
suite 307, Irvine, CA 92612, USA. Calculations were carried out with
Density Functional B3LYP by using the basis set 6-31G*.
Financial support from the Centre National de la Recherche
Scientifique (CNRS), the UniversitØ de Toulouse 3 – Paul Sabati-
er, and MINECO (grant CTQ2012-38594-C02-01) are gratefully
acknowledged. The authors thank Pierre Lavedan and StØ-
phane Massou for NMR discussions and DOSY experiments.
M.R. thanks the CNRS for a PhD grant.
Keywords: azide–alkyne cycloaddition
· density functional
calculations · glycerol · metal-free reactions · microwave
activation
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[20] For 8a, the assignment of both regioisomers was carried out by NOESY
NMR correlations (see Figure S2 in the Supporting Information). For 9a
and 10a, desilylation reactions with tetrabutylammonium fluoride
(TBAF) were carried out to unambiguously determine the major isomer
(see Figure S3 in the Supporting Information).
[21] Reaction conditions: azide (0.4 mmol) and the corresponding alkyne
(0.6 mmol) in solvent (1 mL) under microwave activation (250 W) at
1008C for 1 h (1c), 2 h (5c), or 30 min (9c). For 1b, similar conditions
were used but with applying a power of 150 W for 1 h. Reactions in-
volving PhN3 were protected from light.
[22] 70 and 56% of PhN3 were recovered from a glycerol solution of PhN3
after 30 min under MW activation at 150 and 250 W, respectively. Under
classical heating, 95% of PhN3 was recovered after 20 h at 1008C.
[23] B. T. Worrell, J. A. Malik, V. V. Fokin, Science 2013, 340, 457–460.
[24] A control experiment between glycerol and TMSCl was carried out to
identify the major concomitant silylglycerol derivative observed (see Ex-
perimental part of the Supporting Information, Scheme S3 and Figures
S5 and S6).
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Chem. Soc. Jpn. 2013, 86, 351–353.
[26] DOSY NMR experiments were inconclusive on the effect of different sol-
vents on the interaction with reagents involved in azide–alkyne cyclo-
additions (see Table S7 in the Supporting Information).
[27] When using other solvents instead of glycerol (water, ethanol, ethylene
glycol, propane-1,2-diol, propane-1,3-diol, dioxane, fluorobenzene), the
reagents and products were soluble, even at room temperature for eth-
anol, dioxane and fluorobenzene.
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[15] For the Cu-catalyzed synthesis of 1-benzyl-4,5-diphenyl-1,2,3-triazole by
using preformed well-defined complexes (15a: 72% yield after 48 h at
808C; 15b: 68% yield after 12 h at 1208C in DMF) and heterogeneous
catalyst (15c: 54% yield after 24 h at 808C), see: a) S. Hohloch, D.
Received: September 25, 2015
Published online on November 6, 2015
Chem. Eur. J. 2015, 21, 18706 – 18710
www.chemeurj.org
18710
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