Ruthenium-Free Preparation of 1,5-Disubstituted Triazoles by Alkylative Debenzylation of 1,4-Disubstituted Triazoles

Article abstract of DOI:10.1055/s-0035-1562603

A method that cleanly converts the 1,4-disubstituted 1,2,3-triazole products of the copper-catalyzed ‘click’ dipolar cycloaddition reaction of benzyl azide with terminal alkynes into 1,5-disubstituted triazoles is described. Selective N-alkylation of 1,4-

Full text of DOI:10.1055/s-0035-1562603

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
P. C. Bulman Page et al.
Letter
Synlett
Ruthenium-Free Preparation of 1,5-Disubstituted Triazoles by
Alkylative Debenzylation of 1,4-Disubstituted Triazoles
Philip C. Bulman Page*a
G. Richard Stephenson*a
James Harveya
Alexandra M. Z. Slawinb
t-BuOK, THF
R-I (5 equiv)
HI
MeCN, microwave
100 °C, 3 h
40–93%
0 °C to r.t.
49–93%
+
N
N
N
N
N
N
R
R
N
N
N
a School of Chemistry, University of East Anglia, Norwich
Research Park, Norwich, Norfolk NR4 7TJ, UK
p.page@uea.ac.uk
b Molecular Structure Laboratory, School of Chemistry,
University of St Andrews, Purdie Building, St. Andrews,
Fife KY16 9ST, Scotland
R = Me, Et, n-Pr, n-Bu
Received: 15.05.2016
NaN3
Accepted after revision: 29.06.2016
Published online: 01.08.2016
DOI: 10.1055/s-0035-1562603; Art ID: st-2016-d0344-l
Na ascorbate
CuSO4⋅5H2O
H2O/t-BuOH (1:1)
N
N
Br
Abstract A method that cleanly converts the 1,4-disubstituted 1,2,3-
triazole products of the copper-catalyzed ‘click’ dipolar cycloaddition
reaction of benzyl azide with terminal alkynes into 1,5-disubstituted tri-
azoles is described. Selective N-alkylation of 1,4-disubstituted 1,2,3-tri-
azoles under microwave irradiation is followed by debenzylation of the
resulting 1,3,4-trisubstituted triazolium cations by treatment with po-
tassium tert-butoxide.
method A: 24 h at reflux
N
method B: 10 min, microwave
1
A: 86%, B: 91%
R-I (5 equiv)
MeCN, microwave
100 °C, 3 h
Key words 1,2,3-triazole, debenzylation, microwave, disubstituted,
rearrangement
2 (R = Me; 93%)
3 (R = Et; 86%)
4 (R = n-Pr; 44%)
5 (R = n-Bu; 40%)
In recent years the Huisgen 1,3-dipolar cycloaddition
reaction of organic azides to alkynes has gained a great deal
of interest following the introduction of transition-metal
catalysis by Meldal in 2001.1 The Sharpless and Meldal lab-
oratories independently reported that the use of a catalyst
vastly improved both the regioselectivity and rate of the re-
action, resulting in an extremely effective method for the
synthesis of disubstituted 1,2,3-triazoles (e.g., Scheme 1).2,3
Although relatively unreactive, substituted 1,2,3-tri-
azoles, available through inexpensive copper-catalyzed
‘click’ cycloaddition (CuAAC) reactions, are of value in a
wide variety of research fields, including materials science4
and synthetic chemistry,5 as a ligating moiety in organome-
tallic chemistry,6 for cyclopropanation chemistry,7 and as a
pharmacophore in medicinal chemistry;8 they possess a
range of biological activities, including antifungal,9 anti-
body,10 anticancer,11 anti-Alzheimer’s,12 and anti-HIV activ-
ities. When converted into triazolium salts, they provide an
important class of ionic liquids.13 1,2,3-Triazoles have also
been converted into a variety of other functionalities such
as pyrroles,14 imidazoles, and imidazolones.15
I
+
N
N
R
N
Scheme 1 Preparation of 1,3,4-trisubstituted 1,2,3-triazolium salts by
a microwave-assisted selective N-akylation reaction
While the CuAAC ‘click’ reaction is general, rapid, and
high yielding, it only takes place with terminal alkynes and
always introduces a 1,4-disubstituted 1,2,3-triazole; for the
introduction of greater structural diversity, there would be
substantial advantage if a wider range of substitution and
functionality were accessible by modification of the tri-
azole. While there have been many reported examples of
the synthesis of 1,4-disubstituted 1,2,3-triazoles, there are
far fewer of the 1,5-disubstituted regioisomer. The first se-
lective synthesis of the 1,5-disubstituted triazole was re-
ported by Fokin,16 which utilized ruthenium catalysts to
yield the selected regioisomer in up to quantitative yield.
While this method was effective, the high cost of the ruthe-
nium catalyst makes this procedure less desirable. Other
methods have been reported, but still have the disadvan-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
P. C. Bulman Page et al.
Letter
Synlett
tage of requiring expensive transition-metal catalysts or
starting materials or are carried out under unattractive
conditions.17
of the triazolium ring in all four alkylation products,24 the
entire series is assigned as the 1-benzyl-3-alkyl-4-phenyl-
1,2,3-triazolium regioisomers. By varying temperature and
reaction time, an efficient and general microwave-mediat-
ed regioselective N-methylation procedure was developed,
involving four to five equivalents of methyl iodide, acetoni-
trile as solvent, a temperature of 100 °C, and irradiation in
sealed microwave vials over a period of three hours.
We have been addressing this issue through a study of
procedures for the modification of 1,4-substituted 1,2,3-tri-
azoles. Our approach has involved initial N-alkylation to
form a more reactive triazolium salt. We describe herein an
effective procedure for the N-alkylation step mediated by
microwave irradiation, and an investigation of reductive,
nucleophilic, and base-promoted transformations of the re-
sulting 1,3,4-trisubstituted 1,2,3-triazolium cations. The
single-crystal X-ray structure of 1-benzyl-3-ethyl-4-phe-
nyl-1,2,3-triazolium iodide is also reported to confirm the
regioselectivity of the N-alkylation reaction.
We chose the simple, readily available 1,2,3-triazole 1 as
a test system (Scheme 1).18 A convenient in situ method for
the CuAAC reaction was employed with phenylethyne, ben-
zyl bromide, and sodium azide using a sodium ascor-
bate/copper(II) sulfate protocol in tert-butanol/water (1:1)
under both standard thermal and microwave-irradiation
conditions. The product 1-benzyl-4-phenyl-1,2,3-triazole
(1) was obtained in 86% yield by heating at reflux for 24
hours.19 The microwave alternative proved far more conve-
nient, requiring only 10 minutes at 125 °C, and gave a
slightly improved yield (91%) of the product, as described
by Fokin.18 In practice. both were convenient routes to
make the required starting material.
Triazolium salts were prepared through N-alkylation,
first with methyl iodide in acetonitrile. Originally, we used
the methodology described by Hanelt,20 but due to low
yields or long reaction times we again utilized microwave
irradiation, which gave a much greater yield of salts with
much lower reaction times. The most efficient reaction
conditions (180 min at 100 °C) gave the expected 1-benzyl-
3-methyl-4-phenyl-1,2,3-triazolium iodide (2) in 93%
yield.21 The salt 2 has been prepared previously by Albrecht,
and the 1,3,4-substitution pattern was proven by single-
crystal X-ray structure determination of a derived palladi-
um complex.22 Using these irradiation conditions (Scheme
1), ethyl iodide proved similarly efficient, affording 1-ben-
zyl-3-ethyl-4-phenyl-1,2,3-triazolium iodide (3) in 86%
yield. The more hindered alkylating agents n-propyl iodide
and n-butyl iodide gave the corresponding triazolium salts
4 and 5 in rather lower yields (44% and 40%, respectively),
but in sufficient quantities for our intended study of the re-
activity of the triazolium cations. The ethylated triazolium
iodide 3 is highly crystalline, and recrystallization from di-
chloromethane/petroleum ether gave high quality crystals.
Single-crystal X-ray structural determination of 3 (Figure 1)
confirmed that ethylation had taken place at N3.23 In this
series of compounds, the expected selectivity for N-alkyl-
ation at N3 is thus unambiguously known for structures 2
and 3 and can be reliably extrapolated for the whole series
by comparison of NMR spectra: on the basis of consistent
chemical shifts observed for the C5 methine hydrogen atom
Figure 1 X-ray crystal structure of 1-benzyl-3-ethyl-4-phenyl-1,2,3-tri-
azolium iodide (3, cation shown)
The reactivity of the substituted triazolium cations was
first investigated under various reductive conditions. We
initially examined the Birch reduction of 1-benzyl-3-meth-
yl-4-phenyl-1,2,3-triazolium iodide (4) in the hope of re-
ducing the level of unsaturation of the cationic aromatic
five-membered ring, thus obtaining products that would be
susceptible to hydrolysis, but without success. The alterna-
tive of hydride reduction was examined next, and because
of the expected low reactivity of the aromatic cationic π-
system as a hydride acceptor, we choose the highly reactive
lithium aluminium hydride as the reducing agent. The tri-
azolium salt was indeed slowly reduced to form a neutral
product, but we were surprised to find that this proved to
be a debenzylated 1,5-disubstituted 1,2,3-triazole (24%
yield), rather than
a
reduced dihydro-1,2,3-triazole
(Scheme 2). The unexpected formation of the 1,5-regioiso-
mer, however, is itself an important result, since it opens
the way for an inexpensive copper-mediated ‘click’ reaction
to access the 1,5-disubstituted products, which normally
require ruthenium catalysis.16
A recent report has pointed out the strategic advantages
of the availability of both the 1,3- and 1,5-disubstituted
1,2,3-triazole regioisomers.25 In that work, Koguchi and
Izawa developed a specialized azide (3,4-dimethoxybenzyl
azide) cycloaddition partner for the CuAAC step. After in-
stalling a selection of alkyl groups at N3, the 3,4-dime-
thoxybenzyl protecting group was removed using either
ammonium nitrate (presumably acting as a mild acid) to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
P. C. Bulman Page et al.
Letter
Synlett
was obtained upon application of the 1,3- to 1,5-disubstitu-
tion conversion methodology to monotriazole 10, which we
had previously synthesized.26 We were successful in chang-
ing the regiochemistry of the triazole, but the methyl ester
group was also lost (Scheme 3). Analysis of the N-alkylation
step showed a mixture of two products, which after being
exposed to the tert-butoxide-mediated debenzylation reac-
tion, gave a single product, identified as 1-(2-cyano-pent-
4-ynyl)-substituted 1,5 triazole (11). These results can be
accounted for if the mixture of products observed following
the methylation step consisted of the expected malononi-
trile 12 and the decarboxylated nitrile 13.
LiAlH4, THF
0 °C to r.t.
I –
overnight
+
or t-BuOK, THF
0 °C to r.t.
N
N
N
N
R
R
N
N
overnight
2 (R = Me)
3 (R = Et)
6 (R = Me; 24%, using LiAlH4)
6 (R = Me; 93%)
R = Me
1
4 (R = n-Pr)
5 (R = n-Bu)
7 (R = Et; 90%)
NaOMe or NaOEt
THF, 0 °C to r.t.
overnight
8 (R = n-Pr; 88%)
9 (R = n-Bu; 49%)
Scheme 2 Debenzylation reactions of 1-benzyl-3-alkyl-triazolium salts
promote an SN1 process suited to the powerful stabilization
of the benzylic cation by the dimethoxy substitution of the
arene) or through an oxidative procedure using ceric am-
monium nitrate (the electron-rich arene is easily oxidized).
We reasoned that our alkylative debenzylation of 2
could provide a more general and more easily executed
solution to the 1,3- to 1,5-disubstitution interconversion
problem. We were encouraged by the fact that, although
the LiAlH4 reaction was low yielding, the main problem
seemed to be lack of reactivity (the starting material was
recovered in 66% yield). In search of a more effective deben-
zylation reaction, we switched from hydride donors to oth-
er nucleophile types (NaOMe in methanol and NaOEt in
ethanol) but in this case it was the methyl group, not the
benzyl group, that was removed, reforming 1 in 96% yield.
The LiAlH4 reagent thus appeared to have a special role
in the debenzylation reaction. We reasoned that the reagent
might be acting as a base, rather than as a nucleophile in-
ducing direct displacement of the triazole; in place of the
nucleophilic bases methoxide and ethoxide, we therefore
chose the stronger non-nucleophilic base potassium tert-
butoxide. When this was employed, we were immediately
rewarded with excellent results in the debenzylation step
(Scheme 2). The expected 1,5-disubstited 1,2,3-trazoles 6–
9 were isolated in 49–93% yields.
We reasoned that the decarboxylation may result from
Krapcho decarboxylation in the presence of the nucleophil-
ic iodide counterion.27 In order to avoid the presence of io-
dide in both the methylation and debenzylation steps, the
microwave-mediated methylation of 10 was repeated using
methyl triflate, which produced only the trisubstituted
1,2,3-triazolium triflate salt 14 in 96% yield. Attempted de-
benzylation of 14 by treatment with potassium tert-butox-
ide then, however, proved unsuccessful, only starting mate-
rial being recovered, supporting the contention that iodide
also plays an important role in the debenzylation process.
Attempted debenzylation of the simpler triazolium io-
dide salt 2 was therefore carried out with the potassium
tert-butoxide omitted from the reaction. No reaction was
observed, suggesting that both iodide and potassium tert-
butoxide are indeed required for successful debenzylation.
In summary, we have developed an efficient generally
applicable microwave-mediated method to convert 1-ben-
zyl-4-phenyl-1,2,3-triazoles, available through inexpensive
copper-catalyzed ‘click’ cycloaddition reactions, into 1-al-
kyl-5-phenyl 1,2,3-triazoles,28 without the need to re-engi-
neer the chiral-ligand-controlled cyclization for the rather
different organoruthenium catalysts, normally required for
selective preparation of 1,5-disubstituted 1,2,3-triazoles by
‘click’ chemistry. The process is especially effective for
methyl and ethyl alkyl groups. While ruthenium-catalyzed
synthesis of 1,5-disubstituted 1,2,3-triazoles remains an
important process, the results described here provide a
low-cost alternative by a simple, high-yielding selective al-
kylative debenzylation process.
We conjectured that the base induces deprotonation at
the iminium nitrogen substituent, to produce a nitrogen
ylid. The iodide counterion, freed from any ion pairing, can
then cause debenzylation by nucleophilic attack at the ben-
zylic carbon atom. Additional support for this mechanism
O
O
N
N
N
N
b
O
O
a
N
+
N
N
N
N
N
N
N
N
N
N
X
N
I
10
12, X = I
13
11
14, X = OTf
Scheme 3 Conversion of the 1,4-disubstituted triazole 10 into the 1,5-disubstituted triazole 11. Reagents and conditions: (a) MeI or MeOTf (5 equiv),
MeCN, microwave; (b) t-BuOK, THF, 0 °C to r.t.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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P. C. Bulman Page et al.
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Acknowledgment
This investigation has enjoyed the support of EU Interreg IVA (project
4061). We are indebted to the EPSRC UK National Mass Spectrometry
Facility at the University of Wales, Swansea.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562603.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(20) Hanelt, S.; Liebscher, J. Synlett 2008, 1058.
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Diego, 2001, 263–264.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596.
(21) N-Alkylation of 1,4-substituted 1,2,3-triazoles with alkyl
halides always occurs on N-3: Gompper, R. Chem. Ber. 1957, 90,
374.
(22) Mathew, P.; Neels, A.; Albrecht, N. J. Am. Chem. Soc. 2008, 130,
13534.
(3) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(23) C17H18IN3, M = 391.25, monoclinic, space group P21/c, a =
17.436(4), b = 7.723(2), c = 12.207(3) Å, V = 1628.2(6) Å3, Z = 4, μ
(Mo Kα) = 0.71075, 9847 independent reflections, (Rint =
0.0594), R1[I > 2σ(I)] = 0.0376, wR2 (all reflections) = 0.0874.
CCDC 1479260 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(4) (a) Such, G. K.; Johnston, A. P. R.; Liang, K.; Caruso, F. Prog.
Polym. Sci. 2012, 37, 985. (b) Binder, W. H.; Sachsenhofer, R.
Macromol. Rapid Commun. 2007, 28, 15.
(5) See, for example: (a) Bock, V. D.; Hiemstra, H.; Van Maarseveen,
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Q. Synth. Met. 2011, 161, 330. (c) Johansson, H.; Pedersen, D. S.
Eur. J. Org. Chem. 2012, 4267.
(6) Crowley, J. D.; McMorran, D. A. Top. Heterocycl. Chem. 2012, 28,
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(9) Lima-Neto, R. G.; Cavalcante, N. N. M.; Srivastava, R. M.;
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V. Molecules 2012, 17, 5882.
(10) Millward, S. W.; Agnew, H. D.; Lai, B.; Lee, S. S.; Lim, J.; Nag, A.;
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The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(24) For 1, the triazole proton is at δ = 7.66 ppm in the 1H NMR spec-
trum, and moves to δ = 9.33 ppm in the triazolium salt 2.
Similar chemical shift changes have been previously observed
in related structures; see for example: Saravanakumar, R.;
Ramkumar, V.; Sankararaman, S. Organometallics 2011, 30,
1689.
(25) Koguchi, S.; Izawa, K. Synthesis 2012, 44, 3603.
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(28) General Procedure for the Formation of the Triazolium Salts
from 1-Benzyl-4-phenyl 1,2,3-Triazoles
1-Benzyl-4-phenyl 1,2,3-triazole was dissolved in MeCN in a
microwave vial, and the alkyl halide (5 equiv) was added. The
reaction was irradiated in the microwave instrument for 3 h at
100 °C. Solvents were removed under reduced pressure to yield
the triazolium salt.
1-Benzyl-3-methyl-4-phenyl-1H-1,2,3-triazolium Iodide (2)
Prepared according to the general procedure from 1 (1.66 g,
7.07 mmol) and MeI (1.73 mL, 4.98 g, 35.10 mmol). Compound
2 was isolated as a pale yellow solid (2.79 g, 93%), mp 133–135
°C. IR (neat): 3467, 3040, 1611, 1493, 1455, 1155, 768, 746, 699
cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.33 (s, 1 H), 7.69–7.60 (m,
4 H), 7.54–7.40 (m, 3 H), 7.37–7.33 (m, 3 H), 5.97 (s, 2 H), 4.26
(s, 3 H).13C NMR (126 MHz, CDCl3): δ = 143.2, 132.2, 131.4,
130.1, 130.1, 129.8, 129.7, 129.6, 129.4, 121.7, 57.6, 39.6.
General Procedure for the Debenzylation of Triazolium Salts
Using t-BuOK
(15) (a) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.;
Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. (b) Chuprakov,
S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc. 2013, 135, 4652.
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Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998. (b) Johansson, J.; Lincoln, P.; Nordén, B.; Kann, N. J. Org.
Chem. 2011, 76, 2355.
(17) The 1,5 regioisomer can also be accessed from alkynyl Grignard
reagents: (a) Krasiński, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett.
2004, 6, 1237. Under base-catalyzed conditions: (b) Kwok, S. K.;
Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V. Org. Lett.
2010, 12, 4217. Using sulfonyl azides: (c) Meza-Aviña, M. E.;
1-Benzyl-3-alkyl-4-phenyl triazolium iodide was dissolved in
THF, and the solution cooled to 0 °C. t-BuOK (2.5 equiv) was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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P. C. Bulman Page et al.
Letter
Synlett
added, and the reaction stirred overnight. H2O was added, and
the mixture was stirred for 30 min and filtered through Celite.
The solution was extracted using EtOAc, and the solvents were
removed under reduced pressure to give the desired 1,5-disub-
stituted triazole.
1-Methyl-5-phenyl-1H-1,2,3-triazole (6)
Prepared according to the general procedure from 2 (0.78 g,
2.05 mmol), and t-BuOK (0.61 g, 5.46 mmol) was dissolved in
THF (45 mL). The crude product was purified by column chro-
matography, eluting with EtOAC–petroleum ether (1:1), yield-
ing the titled compound 6 as an orange oil (0.31 g, 93%). IR
(neat): 3060, 3030, 2953, 1732, 1484, 1454, 1245, 767 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 7.73 (s, 1 H), 7.57–7.45 (m, 3 H),
7.45–7.35 (m, 2 H), 4.08 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ =
129.3, 128.7, 127.1, 35.7, 14.3 (quaternary signals not
observed).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E