Debenzylation of functionalized 4- and 5-substituted 1,2,3-triazoles

Article abstract of DOI:10.1055/s-0031-1291160

A range of 4- and 5-substituted N-benzyl-1,2,3-triazoles have been submitted to debenzylation using Pd/C and hydrogen in the presence of 1,1,2-trichloroethane. Triazoles with oxygen-containing substituents are efficiently debenzylated under these conditio

Full text of DOI:10.1055/s-0031-1291160

2070▌
PAPER
paper
Debenzylation of Functionalized 4- and 5-Substituted 1,2,3-Triazoles
Debenzylation of 4- and 5-Substituted N-Benzyl-1,2,3-triazoles
Tahir Farooq,a Leiv K. Sydnes,*a Karl W. Törnroos,a Bengt Erik Haug*a,b
a
Department of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen, Norway
E-mail: leiv.sydnes@kj.uib.no
b
Centre for Pharmacy, Department of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen, Norway
Fax +47(55)589490; E-mail: bengt-erik.haug@farm.uib.no
Received: 20.02.2012; Accepted after revision: 23.04.2012
and a number of examples can be found in the patent lit-
erature.
Abstract: A range of 4- and 5-substituted N-benzyl-1,2,3-triazoles
have been submitted to debenzylation using Pd/C and hydrogen in
the presence of 1,1,2-trichloroethane. Triazoles with oxygen-con-
taining substituents are efficiently debenzylated under these condi-
tions. Triazoles with a phenyl or benzyl substituent on C4 or C5 are
not debenzylated, whereas a pentyl-substituted derivative was read-
ily debenzylated.
During our studies of 1,4-disubstituted 1,2,3-triazoles pre-
pared from highly functionalized terminal alkynes,12 we
found that triazole 1a could be debenzylated by catalytic
hydrogenolysis at atmospheric hydrogen pressure over
10% Pd/C in methanol for 24 hours to provide NH-1,2,3-
triazole 2a in 95% yield (Scheme 1). According to the lit-
erature, hydrogenolysis of benzylamines can be facilitated
by protonation using hydrochloric acid.13 However, when
the above reaction was repeated under these conditions,
the ketal functionality was converted into the ketone, giv-
ing 1-(1-benzyl-1H-1,2,3-triazol-4-yl)-2,2-diethoxyeth-
anone (1b; see Scheme 3 below) in 64% in addition to a
red-brown polymeric material after 24 hours. No deben-
zylation was observed.
Key words: hydrogenolysis, triazoles, alkynes, debenzylation, de-
hydrochlorination
Substituted 1,2,3-triazoles have been targeted for numer-
ous different applications, particularly since the discovery
of selective methods for the synthesis of 1,4-disubstituted
1,2,3-triazoles1 and 1,5-disubstituted 1,2,3-triazoles.2,3 N-
Unsubstituted 1,2,3-triazoles (i.e. NH-1,2,3-triazoles)
have shown a broad range of possible applications,4 and
their synthesis has therefore been the topic of numerous
reports in the literature. Lu et al.5 have reported a cuprous
ion-mediated cycloaddition of azide to terminal alkynes to
produce such triazoles, but when substoichiometric
amounts of copper salt were used, low yields were ob-
tained. N-Unsubstituted 1,2,3-triazoles have also been
synthesized through Cu(I)-catalyzed cycloaddition be-
tween terminal alkynes and hydrazoic acid, which is gen-
erated in situ from trimethylsilylazide.6 Methods that do
not involve copper catalysis have also been reported.7 1H-
1,2,3-Triazoles can be prepared from 1,4-disubstituted
1,2,3-triazoles by removing a variety of nitrogen substitu-
ents,8 including the benzyl group, by hydrogenolysis of N-
benzyl-substituted derivatives in the presence of palladi-
um on carbon or by treatment with sodium in liquid am-
monia.9
Ph
N
N
N
HN
10% Pd/C, H2 (1 atm)
MeOH, r.t., 24 h
N
N
OEt
OEt
OEt
OEt
95%
EtO
EtO
OEt
OEt
1a
2a
Scheme 1 Debenzylation of triazole 1a
A novel procedure developed by Cheng et al. describes
the accelerated hydrogenolysis of benzylamines by HCl
released in situ in the dehydrochlorination of 1,1,2-tri-
chloroethane.14 Following this protocol, triazole 1a was
completely debenzylated after only two hours to give 2a
in 97% yield. This result prompted us to investigate
whether other substituted 1-benzyl-1,2,3-triazoles could
be debenzylated following the same protocol. Towards
this end, a number of 1,4- and 1,5-disubstituted 1,2,3-tri-
azoles were prepared (Scheme 2 and Table 1).
Early reports on the use of the benzyl group as an N-pro-
tecting group for the synthesis of 1,2,3-triazoles prescribe
high temperature and elevated hydrogen pressure for the
debenzylation of 1-benzyl-4,5-disubstituted-1,2,3-tri-
azoles.9,10 More recent reports detail reactions using ele-
vated hydrogen pressure at room temperature or the use of
atmospheric hydrogen pressure to facilitate removal of an
N-benzyl group from C4- or C5-monosubstituted or 4,5-
disubstituted 1,2,3-triazoles.11 The debenzylation reaction
apparently tolerates a variety of substituents on C4 and C5
Ph
N3
Ph
N3
Ph
Ph
N
N
N
N
Cu catalyst
Ru catalyst
R
N
N
R
R
3a–i
1a–i
Scheme 2 Synthesis of 1,4- and 1,5-disubstituted 1,2,3-triazoles
SYNTHESIS 2012, 44, 2070–2078
Advanced online publication: 14.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291160; Art ID: SS-2012-Z0181-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Debenzylation of 4- and 5-Substituted N-Benzyl-1,2,3-triazoles
2071
Table 1 Synthesis of 1,4- and 1,5-Disubstituted 1,2,3-Triazoles
Alkyne
1,4-Isomera
Triazole
1,5-Isomerb
Triazole
Yield (%)
55
Time (h)
48
Yield (%)
Time (h)
EtO
EtO
1a
1b
3a
3b
no reaction
EtO
OEt
OEt
O
70
48
no reaction
EtO
O
1c
99
99
12
12
3c
3
4
3
OMe
1d
3d
86
Ph
Ph
1e
1f
95
99
95
12
20
12
–
–
–
4
4
MeO
PhO
EtO
3f
3g
76
97
1g
1h
98
12
3h
79
4
OEt
HO
1i
1j
97
99
24
24
3i
42–70
–
3
–
–
a Reaction conditions: CuSO4, sodium ascorbate, CH2Cl2–H2O (3:1).
b Reaction conditions: [Cp*RuCl(PPh3)2], benzene, 80 °C
When these triazoles were subjected to hydrogenation,
differences in reactivity were found; all triazoles with an
oxygen-containing substituent at C4 or C5 were readily
debenzylated, whereas analogues with a hydrocarbon sub-
stituent in the same positions showed varying reactivity.
Ph
N
Ph
N
N
N
NaBH4
THF–H2O, 0 °C
N
N
83%
EtO
EtO
O
OH
OEt
OEt
While 1a was cleanly debenzylated to give 2a (Table 2),
the keto triazole 1b, in addition to the debenzylation, un-
derwent reduction to give 2k in high yield (Table 2). Di-
rect debenzylation of 1-(1-benzyl-1H-1,2,3-triazol-4-yl)-
2,2-diethoxyethanol (1k), prepared by NaBH4-mediated
reduction of 1b (see Scheme 3), afforded 2k in 97% iso-
lated yield after nine hours reaction time. Deketalization
of 2a following a published procedure gave ketone 2b in
high yield (Scheme 4).12,15 Furthermore, hydrogenolysis
of analogue 1c, containing a methoxy carbonyl substitu-
ent, gave 97% of the debenzylated product in 36 hours.
1b
1k
Scheme 3 Reduction of triazole 1b
HN
N
HN N
N
N
Dowex 50 W
acetone, reflux
EtO
OEt
OEt
EtO
93%
O
OEt
OEt
2a
2b
As was found for the triazoles containing an acetal, alco-
hol or ester group, triazoles 1f, 3f and 3g which contain
ether groups, were all readily debenzylated to give the
corresponding NH-1,2,3-triazoles in excellent yield (Ta-
ble 2). The conversion of 1g was found to be quite low,
most likely due to its poor solubility in methanol. Interest-
ingly, the C5-substituted isomer 3g was fully converted
into 2g under identical conditions and reaction time.
Scheme 4 Deketalization to provide triazole 2b
Changing the solvent to ethanol resulted in 39% conver-
sion of 1g into 2g after 48 hours (confirmed by GC-MS).
We were also able to obtain a single crystal X-ray struc-
ture from 2g (Figure 1). In the solid state an intermolecu-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2070–2078

2072
T. Farooq et al.
PAPER
Table 2 Debenzylation of 1,2,3-Triazolesa
Triazole
Time (h)
Yield (%)
97
Product
N
N
OEt
EtO
EtO
NH
1a
2
OEt
2a
N
N
1b
1k
24
9
85
97
HO
NH
EtO
OEt
Figure 1 Single-crystal X-ray structure of 2g with intermolecular hy-
2k
drogen bonding17
N
N
MeO
NH
H
N
N
N
1c
36
96
H
H
O
N
N
N
N
N
N
2c
R
R
R
1d
3d
1e
1f
no reaction
no reaction
no reaction
28
N3-H-C5
N1-H-C4
N2-H
Scheme 5 Tautomers of C-monosubstituted NH-1,2,3-triazoles
N
N
N
N
tomer being the most stable of the three possible tauto-
mers.18
95
94
30
94
94
MeO
NH
3f
21
24
24
24
In line with the reactivity described so far, the C4-alkoxy-
substituted triazole 1h and C5-alkoxysubstituted triazole
3h were efficiently debenzylated to the corresponding
NH-1,2,3-triazole in excellent yield, however, the ethoxy
groups were replaced by methoxy groups, giving 4-(di-
methoxymethyl)-1H-1,2,3-triazole (2l) instead of 2h as
the product. When the reaction was monitored by GC-MS
analysis, only two peaks were found in the chromatogram;
one reactant peak with ethoxy groups and one product
peak with methoxy groups. Furthermore, 2l was found to
be unstable, and decomposed to give aldehyde 2m upon
standing in the fume hood (see the experimental section).
X-ray analysis of a single crystal of 2m (Figure 2), re-
vealed that the N1-H-C4 tautomer is also the most stable
in the solid phase. The N1–N2–N3 bond angle was, in this
case, found to be 106.9°, which is consistent with the geo-
metry of this tautomeric form. Moreover, for this crystal
structure, intermolecular hydrogen bonding was evident.
In this case, the triazole NH forms hydrogen bonds, with
both the N3 and the carbonyl oxygen atom acting as hy-
2f
N
1g
3g
1h
PhO
NH
2g
N
MeO
NH
MeO
3h
24
94
2l
N
N
1i
3i
24
24
96
94
HO
NH
2i
N
N
NH
1j
24
98
2j
a Reaction conditions: H2 (1 atm), 10% Pd/C, ClCH2CHCl2, MeOH, r.t.
lar hydrogen bond with the triazole NH as the donor and drogen bond acceptors. The bond lengths were measured
a triazole N2 as the acceptor was observed. The hydrogen as 2.2 and 2.3 Å for the N–H and O–H bonds, respective-
bond length was measured as 2.1 Å with an N–H–N angle ly, with N–H–N and N–H–O bond angles of 141.8° and
of 148.4°. From the X-ray crystal structure it is clear that, 139.3°, respectively.
in the present case, the N1-H-C4 tautomer (Scheme 5) is
the preferred tautomer in the solid phase. The N1–N2–N3
When the debenzylation reaction of 1h was repeated using
ethanol as solvent, a clean conversion into 2h was ob-
served in 12 hours (Scheme 6).
bond angle was found to be 107.8°, which is typical for
this tautomeric form.16 For the N2-H tautomer, this bond
In contrast to what was observed for triazoles with an ox-
angle is typically found to be around 116°.16
ygen-containing substituent at C4 or C5, triazoles 1d, 1e,
For C-monosubstituted NH-1,2,3-triazoles, the N1-H-C4
1j and 3d, which contain only hydrocarbon substituents,
tautomer (Scheme 5) is generally described as being more
showed mixed reactivity. Thus, whereas 1-benzyl-4-pen-
tyl-1H-1,2,3-triazole (1j) suffered debenzylation and gave
stable than the N3-H-C5 tautomer,18,19 with the N2-H tau-
Synthesis 2012, 44, 2070–2078
© Georg Thieme Verlag Stuttgart · New York

PAPER
Debenzylation of 4- and 5-Substituted N-Benzyl-1,2,3-triazoles
2073
Kalisiak et al.21 previously found that triazole 5 can be
converted into the corresponding NH-1,2,3-triazole
through simple hydrogenation using 10% Pd/C in MeOH,
however, the reaction required seven days to reach com-
pletion. We envisioned that the chloroalkane could have
an accelerating effect also for this reaction; thus triazoles
5, 6 and 7 were prepared (Figure 3) to study this further.
The required azide was prepared from benzyl chlorometh-
yl ether,21 and was reacted with terminal alkynes under ei-
ther copper or ruthenium catalysis to give 1,4-
disubstituted 1,2,3-triazoles 5 and 7 and the 1,5-disubsti-
tuted 1,2,3-triazole 6 respectively.
Figure 2 Single crystal X-ray structure of 2m with intermolecular hy-
drogen bonding20
HN
N
O
O
O
10% Pd/C, ClCH2CHCl2
EtOH, r.t.
Ph
Ph
Ph
Ph
N
Ph
N
N
N
1h
97%
N
N
N
EtO
N
OEt
N
N
Ph
5
6
7
2h
Figure 3 N-Alkoxy-substituted 1,2,3-triazoles used in this study
Scheme 6 Debenzylation using ethanol as solvent
It turned out that the N1-benzyloxymethyl (BOM) substi-
tuted triazoles 5, 6 and 7 were not converted into NH-
1,2,3-triazoles after being subjected to the debenzylation
conditions for 24 hours; in all cases the starting materials
recovered in near quantitative yield. Since this low reac-
tivity is consistent with that observed for 1d, 1e and 3d, it
thus seems that HCl accelerated hydrogenolysis is not
general. It should be noted that it is quite possible that the
removal of the BOM group from C4- and C5-substituted
1,2,3-triazoles could be achieved within a reasonable re-
action time. This has, however, not yet been investigated.
4-pentyl-1H-1,2,3-triazole (2j) in 98% yield after 24
hours, triazoles 1d, 1e and 3d were completely unreactive
and the starting materials were recovered almost quantita-
tively. This difference in reactivity is puzzling. Conceiv-
ably, the phenyl substituent of 1d and 3d interacts with the
triazole ring through resonance. Such interaction is im-
possible in 1e and 1j. On the other hand, the benzyl and
pentyl groups are sterically more demanding than the phe-
nyl substituent. If the lack of reactivity for 1d, 1e and 3d
is due to steric effects, 1j should not react either. This
might indicate that the reactivity is predominantly gov-
erned by electronic effects, however, this still does not ex-
plain the reactivity of 1j.
In conclusion, we have found that C-monosubstituted NH-
1,2,3-triazoles can be prepared by debenzylation of the
corresponding N-benzyl triazoles in excellent yields by
hydrogenation over 10% Pd/C and 1,1,2-trichloroethane
in methanol, provided that the substituent on the triazole
C-atom contains at least one oxygen atom. For hydrocar-
bon-substituted N-benzyl-1,2,3-triazoles, the reactivity
pattern is less general.
Since all 1,4- and 1,5-disubstituted 1,2,3-triazoles were
found to be susceptible to the debenzylation reaction, as
long as the C4/C5-substituent contained oxygen, we want-
ed to see if this was also the case for 4,5-disubstituted 1-
benzyl-1,2,3-triazoles. Thus, 1-benzyl-4,5-bis(methoxy-
methyl)-1H-1,2,3-triazole (4), which has the same C4/C5-
substituent as 1f and 3f, was prepared from 1,4-dimeth-
oxybut-2-yne and benzyl azide using [Cp*RuCl(PPh3)2]
as the catalyst benzene at reflux (Scheme 7).
IR spectra were recorded (neat) with a Nicolet 380 spectrometer
from Thermo Electron, and the intensities are given as weak (w),
medium (m), or strong (s). NMR spectra were recorded with Bruker
Spectrospin DPX-400 MHz and AV 500 MHz spectrometers;
chemical shifts (δ) are reported in ppm relative to Me4Si, coupling
constants (J) are given in Hz, and the multiplicity as singlet (s), dou-
blet (d), triplet (t) quartet (q), pentet (pent), or multiplet (m). Purifi-
cation by flash column chromatography was performed using silica
gel (230–400 mesh) as the stationary phase and mixtures of hexanes
and EtOAc as the mobile phase. TLC analyses were carried out us-
ing silica gel (60 F254) on aluminum sheets with mixtures of hex-
anes and EtOAc as the mobile phase. The progress of the reactions
was followed by GC-MS analysis. HRMS (ESI) spectra were ob-
tained with a Thermo electron LTQ Orbitrap MS at the University
of Tromsø.
Ph
N
N
PhCH2N3, Ru catalyst
C6H6, 80 °C
MeO
MeO
N
OMe
MeO
82%
4
Scheme 7 Synthesis of a 4,5-disubstituted 1-benzyl-1,2,3-triazole
Interestingly, 4 did not undergo a debenzylation reaction
during 24 hours, and the starting material could be recov-
ered in near quantitative yield. The reason for the lack of
reactivity of 4 compared to 1f and 3f is still not clear.
Cu-Catalyzed Cycloaddition Reactions; General Procedure
Terminal alkyne (1.0 mmol), benzyl azide (1.1 mmol),
CuSO4·5H2O (9.3 mg, 0.04 mmol) and sodium ascorbate (22 mg,
0.11 mmol) were suspended in a mixture of H2O–CH2Cl2 (1:3, 4
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2070–2078

2074
T. Farooq et al.
PAPER
mL). The reaction mixture was stirred vigorously at r.t. for 12–48 h
(Table 1). After extraction with CH2Cl2 (3 × 10 mL), the combined
organic layers were dried over MgSO4, the drying agent was re-
moved by filtration, and the filtrate was concentrated under vacu-
um. Purification of the crude product using flash column
chromatography (hexanes–EtOAc) provided 1,4-disubstituted
1,2,3-triazoles.
1-Benzyl-4-(phenoxymethyl)-1H-1,2,3-triazole (1g)
The title compound was prepared from phenyl propargyl ether
(0.145 g, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) accord-
ing to the general procedure for Cu-catalyzed cycloadditions. Ana-
lytical data are in accordance with those reported in the literature.26
Yield: 0.251 g (95%); colorless crystals.
1H NMR (400 MHz, CDCl3): δ = 5.19 (s, 2 H), 5.54 (s, 2 H), 6.95–
6.98 (m, 3 H), 7.28–7.30 (m, 5 H), 7.37–7.39 (m, 2 H), 7.53 (s,
1 H).
1-Benzyl-4-(1,1,2,2-tetraethoxyethyl)-1H-1,2,3-triazole (1a)
The title compound was prepared from 3,3,4,4-tetraethoxybut-1-
yne (0.230 g, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) ac-
cording to the general procedure for Cu-catalyzed cycloadditions.
Analytical data are in accordance with those reported earlier.12
1-Benzyl-4-(diethoxymethyl)-1H-1,2,3-triazole (1h)
The title compound was prepared from 3,3-diethoxy-1-propyne
(0.128 g, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) accord-
ing to the general procedure for Cu-catalyzed cycloadditions. Ana-
lytical data are in accordance with those reported in the literature.26
Yield: 0.199 g (55%); colorless crystals.
1H NMR (400 MHz, MeOD): δ = 1.08 (t, J = 7.0 Hz, 6 H), 1.16 (t,
J = 7.0 Hz, 6 H), 3.41–3.71 (m, 8 H), 4.72 (s, 1 H), 5.57 (s, 2 H),
7.29–7.36 (m, 5 H), 7.82 (s, 1 H).
Yield: 0.255 g (98%); crystalline colorless solid.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 6 H), 3.54–3.70
(m, 4 H), 5.51 (s, 2 H), 5.59 (s, 1 H), 7.26–7.36 (m, 5 H), 7.49 (s,
1 H).
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2,2-diethoxyethanone (1b)
The title compound was prepared from 1,1-diethoxybut-3-yn-2-one
(0.156 g, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) accord-
ing to the general procedure for Cu-catalyzed cycloadditions. Ana-
lytical data are in accordance with those reported previously.12
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethanol (1i)
The title compound was prepared from 3-butyn-2-ol (70 mg, 1.00
mmol) and benzyl azide (0.146 g, 1.10 mmol) according to the gen-
eral procedure for Cu-catalyzed cycloadditions. Analytical data are
in accordance with those reported in the literature.27
Yield: 0.201 g (70%); light-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 6 H), 3.65–3.81
(m, 4 H), 5.45 (s, 1 H), 5.57 (s, 2 H), 7.29–7.40 (m, 5 H), 8.12 (s,
1 H).
Yield: 0.197 g (97%); crystalline colorless solid.
1H MNR (400 MHZ, CDCl3): δ = 1.50 (d, J = 6.4 Hz, 3 H), 4.93–
4.97 (q, J = 7.2 Hz, 1 H), 5.57 (s, 2 H), 7.31–7.36 (m, 5 H), 7.83 (s,
1 H).
Methyl 1-Benzyl-1H-1,2,3-triazol-4-carboxylate (1c)
The title compound was prepared from methyl propiolate (84 mg
1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) according to the
general procedure for Cu-catalyzed cycloadditions. Analytical data
are in accordance with those reported in the literature.22
1-Benzyl-4-pentyl-1H-1,2,3-triazole (1j)
The title compound was prepared from 1-heptyne (0.192 g 2.00
mmol) and benzyl azide (0.294 g, 2.20 mmol) according to the gen-
eral procedure for Cu-catalyzed cycloadditions. Analytical data are
in accordance with those reported in the literature.28
Yield: 0.215 g (99%); crystalline colorless solid.
1H NMR (400 MHz, CDCl3): δ = 3.93 (s, 3 H), 5.58 (s, 2 H), 7.69–
7.26 (m, 5 H), 7.97 (s, 1 H).
Yield: 0.455 g (99%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 0.79 (t, J = 7.2 Hz, 3 H), 1.21–
1.24 (m, 4 H), 1.53–1.57 (m, 2 H), 2.59 (t, J = 7.6 Hz, 2 H), 5.39 (s,
2 H), 7.12 (s, 1 H), 7.15–7.17 (m, 2 H), 7.24–7.29 (m, 3 H).
1-Benzyl-4-phenyl-1H-1,2,3-triazole (1d)
The title compound was prepared from phenyl acetylene (0.102 g,
1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) according to the
general procedure for Cu-catalyzed cycloadditions. Analytical data
are in accordance with those reported in the literature.23
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2,2-diethoxy-ethanol (1k)
To a solution of ketone 1b (0.396 g, 1.37 mmol) in THF–H2O (9:1,
10 mL) at 0 °C was added NaBH4 (26 mg, 0.69 mmol) in one por-
tion. After 30 min, the starting material had been consumed and 0.1
M HCl (3 mL) was added. The aqueous layer was extracted with
CH2Cl2 (3 × 15 mL) and the combined organic layers were dried
over MgSO4. The drying agent was removed by filtration and the
filtrate was concentrated. Purification of the crude product flash
column chromatography (hexanes–EtOAc, 1:1) provided the title
compound.
Yield: 0.233 g (99%); crystalline colorless solid.
1H MNR (400 MHz, CDCl3): δ = 5.58 (s, 2 H), 7.30–7.42 (m, 8 H),
7.67 (s, 1 H), 7.81 (d, J = 8.7 Hz, 2 H).
1,4-Dibenzyl-1H-1,2,3-triazole (1e)
The title compound was prepared from prop-2-ynylbenzene (0.116
g, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) according to
the general procedure for Cu-catalyzed cycloadditions. Analytical
data are in accordance with those reported in the literature.24
Yield: 0.340 g (85%); colorless oil; Rf = 0.14 (hexanes–EtOAc,
1:1).
Yield: 0.237 g (95%); light-yellow crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 4.07 (s, 2 H), 5.46 (s, 2 H), 7.16–
7. 53 (m, 11 H).
IR: 3388 (br), 2975 (m), 2882 (w), 1737 (s), 1497 (w), 1455 (w),
1333 (w), 1221 (w), 1119 (s), 1050 (s), 804 (w), 713 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.17 (t,
J = 7.2 Hz, 3 H), 2.88 (d, J = 4.4 Hz, 1 H), 3.52–3.56 (m, 2 H),
3.69–3.81 (m, 2 H), 4.72 (d, J = 4.8 Hz, 1 H), 4.86 (t, J = 4.4 Hz,
1 H), 5.52 (s, 2 H), 7.25–7.27 (m, 2 H), 7.35–7.37 (m, 3 H), 7.48 (s,
1 H).
1-Benzyl-4-(methoxymethyl)-1H-1,2,3-triazole (1f)
The title compound was prepared from methyl propargyl ether (70
mg, 1.00 mmol) and benzyl azide (0.146 mg, 1.10 mmol) according
to the general procedure for Cu-catalyzed cycloadditions. Analyti-
cal data are in accordance with those reported in the literature.25
13C NMR (101 MHz, CDCl3): δ = 15.4, 15.5, 54.4, 64.2, 64.3, 104.1,
128.3, 128.9, 129.3, 134.8, 147.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H22N3O3: 292.1656; found:
292.1658.
Yield: 0.201 g (99%); light-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 3.39 (s, 3 H), 4.55 (s, 2 H), 5.52
(s, 2 H), 7.26–7.37 (m, 5 H), 7.46 (s, 1 H).
Synthesis 2012, 44, 2070–2078
© Georg Thieme Verlag Stuttgart · New York

PAPER
Debenzylation of 4- and 5-Substituted N-Benzyl-1,2,3-triazoles
2075
1-(Benzyloxymethyl)-4-phenyl-1H-1,2,3-triazole (5)
The title compound was prepared from phenyl acetylene (0.102 g,
1.00 mmol) and [(azidomethoxy)methyl]benzene (0.179 g, 1.10
mmol) according to the general procedure for Cu-catalyzed cyclo-
additions. Analytical data are in accordance with those reported in
the literature.21
general procedure for Ru-catalyzed cycloadditions using THF at
65 °C. Analytical data are in accordance with those reported in the
literature.3
Yield: 0.303 g (86%); yellowish white crystals.
1H NMR (400 MHz, CDCl3): δ = 5.54 (s, 2 H), 7.05–7.07 (m, 2 H),
7.23–7.28 (m, 5 H), 7.38–7.45 (m, 3 H), 7.73 (s, 1 H).
Yield: 0.203 g (77%); colorless crystals.
1H NMR (400 MHz, CDCl3): δ = 4.58 (s, 2 H), 5.79 (s, 2 H), 7.32–
7.39 (m, 6 H), 7.45 (t, J = 7.2 Hz, 2 H), 7.86 (d, J = 7.6 Hz, 2 H),
7.95 (s, 1 H).
1-Benzyl-5-(methoxymethyl)-1H-1,2,3-triazole (3f)
The title compound was prepared from methyl propargyl ether (70
mg, 1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) according
to the general procedure for Ru-catalyzed cycloadditions using ben-
zene at 80 °C.
1-(Benzyloxymethyl)-5-phenyl-1H-1,2,3-triazole (6)
The title compound was prepared from phenyl acetylene (0.102 g,
1.00 mmol) and [(azidomethoxy)methyl]benzene (0.179 g, 1.10
mmol) according to the general procedure for Ru-catalyzed cyclo-
additions using THF at 65 °C. Analytical data are in accordance
with those reported in the literature.2
Yield: 0.154 g (76%); red-brown oil; Rf = 0.22 (hexanes–EtOAc,
7:3).
IR: 3032 (w), 2930 (w), 2825 (w), 1605 (w), 1593 (w), 1497 (m),
1455 (s), 1331 (m), 1220 (m), 1190 (m), 1103 (s), 1084 (s), 1029
(m), 980 (m), 954 (m), 906 (m), 836 (m), 755 (m), 717 (s), 694 (s)
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.27 (s, 3 H), 4.34 (s, 2 H), 5.62
(s, 2 H), 7.22–7.35 (m, 5 H), 7.65 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 52.6, 58.3, 62.6, 127.8, 128.6,
129.1, 133.3, 134.8, 134.9
HRMS (ESI): m/z [M + H]+ calcd for C11H14N3O: 204.1131; found:
204.1132.
Yield: 90 mg (34%); red-brown oil; Rf = 0.50 (hexanes–EtOAc,
7:3).
1H NMR (400 MHz, CDCl3): δ = 4.75 (s, 2 H), 5.73 (s, 2 H), 7.33–
7.37 (m, 5 H), 7.48–7.51 (m, 3 H), 7.64–7.66 (m, 2 H), 7.83 (s,
1 H).
4-Benzyl-1-(benzyloxymethyl)-1H-1,2,3-triazole (7)
The title compound was prepared from prop-2-ynylbenzene (0.116
g, 1.00 mmol) and [(azidomethoxy)methyl]benzene (0.179 g, 1.10
mmol) according to the general procedure for Cu-catalyzed cyclo-
additions. Purification by flash column chromatography (hexanes–
EtOAc, 8:2) afforded the title compound.
1-Benzyl-5-(phenoxymethyl)-1H-1,2,3-triazole (3g)
The title compound was prepared from phenyl propargyl ether
(0.145 g, 1.10 mmol) and benzyl azide (0.133 g, 1.00 mmol) accord-
ing to the general procedure for Ru-catalyzed cycloadditions using
benzene at 80 °C.
Yield: 0.253 g (91%); very viscous yellow semisolid; Rf = 0.11
(hexanes–EtOAc, 8:2).
Yield: 0.257 g (97%); crystalline colorless solid; Rf = 0.24 (hex-
anes–EtOAc, 7:3); mp 121.0–122.4 °C.
IR: 3062 (w), 3028 (w), 2872 (w), 1602 (w), 1548 (w), 1493 (m),
1454 (m), 1434 (w), 1379 (m), 1346 (w), 1302 (w), 1222 (m), 1096
(s), 1048 (s), 1026 (s), 797 (w), 755 (s), 737 (m), 725 (s), 694 (s)
cm–1.
1H NMR (400 MHz, MeOD): δ = 4.06 (s, 2 H), 4.54 (s, 2 H), 5.73
(s, 2 H), 7.19–7.31 (m, 10 H), 7.79 (s, 1 H).
IR: 3132 (w), 2921 (w), 2871 (w), 1737 (w), 1712 (w), 1598 (m),
1584 (m), 1494 (s), 1486 (s), 1428 (m), 1382 (m), 1330 (m), 1237
(s), 1218 (s), 1177 (m), 1119 (m), 1053 (s), 1029 (s), 1005 (s), 987
(m), 855 (m), 753 (s), 690 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.90 (s, 2 H), 5.69 (s, 2 H), 6.83
(d, J = 7.6 Hz, 2 H), 7.02 (t, J = 7.2 Hz, 1 H), 7.17–7.19 (m, 2 H),
7.27–7.31 (m, 5 H), 7.73 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 52.8, 58.5, 114.8, 122.2, 127.8,
128.7, 129.1, 129.9, 132.4, 134.6, 134.8, 157.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O: 266.1288; found:
266.1290.
13C NMR (101 MHz, MeOD): δ = 32.5, 72.4, 79.2, 123.9, 127.5,
129.1, 129.4, 129.6, 138.0, 140.3, 149.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17N3ONa: 302.1264;
found: 302.1269.
Ru-Catalyzed Cycloaddition; General Procedure
Alkyne (1–1.8 mmol), organic azide (0.99–1.1 mmol) and [Cp*Ru-
Cl(PPh3)2] (1 mol%) were dissolved in anhydrous benzene (or an-
hydrous THF) (8–10 mL). The resulting mixture was heated to
80 °C (or 65 °C for THF) and stirred vigorously for 3–4 h (Table 1).
After cooling to r.t., the solvent was removed under vacuum. Puri-
fication flash column chromatography (hexanes–EtOAc) provided
1,5-disubstituted 1,2,3-triazoles (Table 1).
1-Benzyl-5-(diethoxymethyl)-1H-1,2,3-triazole (3h)
The title compound was prepared from 3,3-diethoxy-1-propyne
(0.230 g, 1.80 mmol) and benzyl azide (0.132 g, 0.99 mmol) accord-
ing to the general procedure for Ru-catalyzed cycloadditions using
benzene at 80 °C.
Yield: 0.206 g (79%); red-brown oil; Rf = 0.50 (hexanes–EtOAc,
7:3).
Methyl 1-Benzyl-1H-1,2,3-triazol-5-carboxylate (3c)
The title compound was prepared from methyl propiolate (84 mg,
1.00 mmol) and benzyl azide (0.146 g, 1.10 mmol) according to the
general procedure for Ru-catalyzed cycloadditions using benzene at
80 °C. Analytical data are in accordance with those reported in the
literature.29
IR: 2975 (m), 2930 (w), 2883 (w), 1606 (w), 1552 (w), 1497 (w),
1455 (m), 1370 (w), 1231 (w), 1185 (w), 1109 (s), 1048 (s), 983
(m), 915 (m), 842 (m), 720 (s), 694 (s), 577 (w) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.2 Hz, 6 H), 3.41–3.50
(m, 4 H), 5.41 (s, 1 H), 5.62 (s, 2 H), 7.21–7.30 (m, 5 H), 7.69 (s,
1 H).
Yield: 7 mg (3%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 3.93 (s, 3 H), 5.58 (s, 2 H), 7.30–
7.40 (m, 5 H), 7.97 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 15.0, 52.6, 61.5, 94.6, 127.7,
128.4, 128.9, 134.2, 135.0, 135.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H20N3O2: 262.1550; found:
262.1552.
1-Benzyl-5-phenyl-1H-1,2,3-triazole (3d)
The title compound was prepared from phenyl acetylene (0.30 mL,
2.73 mmol) and benzyl azide (0.200 g, 1.50 mmol) according to the
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2070–2078

2076
T. Farooq et al.
PAPER
1-(1-Benzyl-1H-1,2,3-triazol-5-yl)ethanol (3i)
The title compound was prepared from 3-butyn-2-ol (70 mg, 1.25
mmol) and benzyl azide (0.133 g, 1.00 mmol) according to the gen-
eral procedure for Ru-catalyzed cycloadditions using benzene at
80 °C.
and the combined organic layers were dried over MgSO4. The dry-
ing agent was removed by filtration and the filtrate was concentrat-
ed. The crude product was purified flash column chromatography
(hexanes–EtOAc, 7:3) to give the title compound.
Yield: 79 mg (93%); yellow oil; Rf = 0.22 (hexane–EtOAc 7:3).
Yield: 0.143 g (70%); yellowish oil; Rf = 0.22 (hexanes–EtOAc,
1:1).
IR: 3145 (br), 2977 (m), 2930 (w), 1697 (s), 1536 (w), 1479 (w),
1370 (w), 1325 (w), 1234 (w), 1051 (s), 965 (w), 925 (w), 827 (m),
681 (m) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6 H), 3.68–3.81
(m, 4 H), 5.38 (s, 1 H), 8.49 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 15.3, 63.8, 101.3, 133.0, 142.3,
IR: 3263 (br), 2976 (m), 2931 (w), 1496 (m), 1455 (s), 1373 (w),
1294 (w), 1233 (m), 1181 (w), 1113 (s), 1076 (s), 1027 (s), 984 (m),
889 (m), 833 (m), 715 (s), 693 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.50 (d, J = 6.8 Hz, 3 H), 2.02 (d,
J = 6.4 Hz, 1 H), 4.72–4.79 (pent, J = 6.4 Hz, 1 H), 5.66 (q, J =
6.4 Hz, 2 H), 7.19–7.32 (m, 5 H), 7.53 (s, 1 H).
187.8.
HRMS (ESI): m/z [M + H]+ calcd for C8H14N3O3: 200.1030; found:
200.1033.
13C NMR (101 MHz, CDCl3): δ = 22.5, 52.4, 60.3, 127.6, 128.5,
129.1, 131.7, 135.2, 140.2.
HRMS (ESI): m/z [M + H]+ calcd for C11H14N3O: 204.1131; found:
204.1133.
Methyl 1H-1,2,3-Triazole-4-carboxylate (2c)
The title compound was prepared from 1c (0.200 g, 0.92 mmol) ac-
cording to the general protocol for debenzylation.
1-Benzyl-4,5-bis(methoxymethyl)-1H-1,2,3-triazole (4)
The title compound was prepared from 1,4-dimethoxybut-2-yne
(0.114 g, 1.00 mmol) and benzyl azide (0.160 g, 1.20 mmol) accord-
ing to the general procedure for Ru-catalyzed cycloadditions using
benzene at 80 °C.
Yield: 0.112 g (96%); crystalline colorless solid; mp 142.6–
143.2 °C; Rf = 0.18 (hexanes–EtOAc, 7:3).
IR: 3135 (m), 2935 (m), 1727 (s), 1499 (m), 1431 (m), 1356 (s),
1242 (m), 1207 (s), 1019 (s), 864 (m), 778 (s), 762 (w) cm–1.
1H NMR (400 MHz, OD): δ = 3.89 (s, 3 H), 8.33 (s, 1 H).
13C NMR (101 MHz, ): δ = 51.4, 130.8, 138.6, 161.6.
Yield: 0.202 g (82%); red-brown oil; Rf = 0.26 (hexanes–EtOAc,
1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C4H5O2N3Na: 150.0274;
found: 150.0270.
IR: 2927 (w), 2820 (w), 1589 (w), 1497 (m), 1455 (m), 1436 (m),
1329 (w), 1191 (s), 1116 (s), 1080 (s), 1028 (w), 996 (m), 950 (m),
905 (m), 825 (w), 719 (s), 694 (s), 583 (w), 538 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.24 (s, 3 H), 3.35 (s, 3 H), 4.35
(s, 2 H), 4.55 (s, 2 H), 5.58 (s, 2 H), 7.21–7.32 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = 52.7, 58.1, 58.2, 61.6, 65.4, 127.7,
128.4, 128.9, 131.6, 134.8, 143.8.
HRMS (ESI): m/z [M + H]+ calcd for C13H18N3O2: 248.1394; found:
248.1396.
4-(Methoxymethyl)-1H-1,2,3-triazole (2f)
The title compound was prepared from 1f (0.175 g, 0.86 mmol) us-
ing the general protocol for debenzylation.
Yield: 92 mg (95%); light-yellow oil; Rf = 0.20 (hexanes–EtOAc,
7:3).
IR: 3132 (br), 2929 (m), 2825 (w), 1450 (m), 1385 (m), 1192 (m),
1087 (s), 1022 (w), 952 (w), 802 (m), 767 (m) cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.39 (s, 3 H), 4.61 (s, 2 H), 8.71
Debenzylation; General Procedure
To a solution of the 1,2,3-triazole (0.88 mmol) in MeOH (25 mL)
was added 10% Pd/C (36 mg) and the reaction mixture was affixed
with hydrogen balloon (1 atm). Air was removed and ClCH2CHCl2
(0.128 g, 0.96 mmol) was added. The solution was vigorously
stirred at r.t. for 24 h, after which it was filtered through a pad of
Celite. The filtrate was concentrated to produce the title compound.
(s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 58.5, 65.5, 131.2, 143.8.
HRMS (ESI): m/z [M + H]+ calcd for C4H8N3O: 114.0662; found:
114.0658.
4-(Phenoxymethyl)-1H-1,2,3-triazole (2g)
4-(1,1,2,2-Tetraethoxyethyl)-1H-1,2,3-triazole (2a)
The title compound was prepared from 1a (0.181 g, 0.50 mmol) ac-
cording to the general protocol for debenzylation.
The title compound was prepared from 1,5-disubstituted 1,2,3-tri-
azole 3g (0.232 g, 0.88 mmol) according to the general procedure
for debenzylation. The analytical data are in accordance with those
reported in the literature.30
Yield: 0.132 g (97%); viscous colorless oil; Rf = 0.15 (hexanes–
EtOAc, 7:3).
Yield: 0.145 g (94%); colorless crystals; Rf = 0.50 (hexanes–
EtOAc, 7:3).
IR: 3217 (br), 2975 (m), 2930 (w), 2890 (w), 1444 (w), 1373 (w),
1197 (w), 1117 (m), 1080 (s), 961 (m), 924 (w), 861 (w), 808 (w),
762 (w) cm–1.
1H NMR (500 MHz, ): δ = 5.19 (s, 2 H), 6.95–6.99 (m, 3 H), 7.27–
7.31 (m, 2 H), 7.78 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.2 Hz, 12 H), 3.27–
3.73 (m, 8 H), 4.68 (s, 1 H), 7.76 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 15.4, 57.8, 65.3, 99.5, 103.2,
4-(Diethoxymethyl)-1H-1,2,3-triazole (2h)
The title compound was prepared from 1h (0.248 g, 0.95 mmol) us-
ing the general protocol for debenzylation with EtOH as the solvent.
133.1, 135.7.
Yield0.157 g (97%); viscous colorless oil; Rf = 0.19 (hexanes–
EtOAc, 7:3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H23N3ONa: 296.1581;
found: 296.1584.
IR: 3134 (br), 2976 (w), 2884 (w), 1445 (w), 1340 (w), 1103 (m),
1053 (s), 974 (w), 805 (w) cm–1.
1H NMR (CDCl3): δ = 1.25 (t, J = 6.8 Hz, 3 H), 3.60–3.69 (m, 4 H),
5.76 (s, 1 H), 7.76 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 22.6, 62.1, 126.7, 149.9.
2,2-Diethoxy-1-(1H-1,2,3-triazol-4-yl)ethanone (2b)
To a solution of NH-1,2,3-triazole 2a (0.119 g, 0.43 mmol) in a mix-
ture of acetone (9 mL) and H2O (0.5 mL), was added Dowex 50 W
(16–40 mesh, 0.170 g). The mixture was heated at reflux for 6 h
then the Dowex resin was removed by filtration and acetone was re-
moved The aqueous layer was extracted with CH2Cl2 (3 × 5 mL)
Synthesis 2012, 44, 2070–2078
© Georg Thieme Verlag Stuttgart · New York

PAPER
Debenzylation of 4- and 5-Substituted N-Benzyl-1,2,3-triazoles
2077
HRMS (ESI): m/z [M + Na]+ calcd for C7H13N3O2Na: 194.0900;
found: 194.0905.
HRMS (ESI): m/z [M + Na]+ calcd for C3H3N3ONa: 120.0163;
found: 120.0168.
1-(1H-1,2,3-riazol-4-yl)ethanol (2i)
The title compound was prepared from 1i (0.190 g, 0.94 mmol) ac-
cording to the general protocol for debenzylation.
Acknowledgment
The authors thank the Higher Education Commission (HEC) of
Pakistan and the Norwegian State Educational Loan Fund Quota
Scheme for financing a PhD fellowship for T.F.
Yield: 0.102 g (96%); yellow oil; Rf = 0. 22 (hexanes–EtOAc, 1:1).
IR: 3145 (br), 2977 (m), 2930 (w), 1697 (s), 1536 (w), 1479 (w),
1370 (w), 1325 (w), 1234 (w), 1051 (s), 965 (w), 925 (w), 827 (m),
681 (m) cm–1.
References
1H NMR (400 MHz, CDCl3): δ = 1.47 (d, J = 6.4 Hz, 3 H), 4.93–
4.98 (q, J = 6.4 Hz, 1 H), 7.65 (s, 1 H).
(1) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596.
(2) Krasiński, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004,
6, 1237.
(3) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc.
2005, 127, 15998.
13C NMR (101 MHz, CDCl3): δ = 22.6, 62.6, 126.6, 149.9.
HRMS (ESI): m/z [M + H]+ calcd for C4H8N3O: 114.0666; found:
114.0659.
4-Pentyl-1H-1,2,3-triazole (2j)
The title compound was prepared from 1j (0.452 g, 1.97 mmol) ac-
cording to the general protocol for debenzylation. Analytical data
are in accordance with those reported in the litterature.31
(4) (a) Dabak, K.; Sezer, Ö.; Akar, A.; Anaç, O. Eur. J. Med.
Chem. 2003, 38, 215. (b) Baures, P. W. Org. Lett. 1999, 1,
249. (c) Komeda, S.; Lutz, M.; Spek, A. L.; Yamanaka, Y.;
Sato, T.; Chikuma, M.; Reedijk, J. J. Am. Chem. Soc. 2002,
124, 4738. (d) Fan, W. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1996, 1-126.
(5) Lu, L.-H.; Wu, J.-H.; Yang, C.-H. J. Chin. Chem. Soc
(Taipei, Taiwan) 2008, 55, 414.
(6) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004,
3789.
(7) (a) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.;
Zunino, E.; Vaccaro, L. J. Org. Chem. 2005, 70, 6526.
(b) Barluenga, J.; Valdés, C.; Beltrán, G.; Escribano, M.;
Aznar, F. Angew. Chem. Int. Ed. 2006, 45, 6893. (c) Zhang,
W.; Kuang, C.; Yang, Q. Synthesis 2010, 283.
(8) (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 7786. (b) Looker, J. J. J. Org. Chem. 1965,
30, 638. (c) Loren, J. C.; Krasiński, A.; Fokin, V. V.;
Sharpless, K. B. Synlett 2005, 2847.
Yield: 0.268 g (98%); yellow oil.
1H NMR (400 MHz, DMSO-d6): δ = 0.80–0.89 (m, 3 H), 1.20–1.35
(m, 4 H), 1.53–1.64 (m, 2 H), 2.60–2.69 (m, 2 H), 7.67 (s, 1 H).
2,2-Diethoxy-1-(1H-1,2,3-triazol-4-yl)ethanol (2k)
The title compound was prepared from 1k (0.158 g, 0.54 mmol) ac-
cording to the general protocol for debenzylation.
Yield: 0.105 g (97%); colorless oil; Rf = 0.21 (hexanes–EtOAc,
7:3).
IR: 3147 (br), 2975 (m), 2930 (w), 2895 (w), 1444 (w), 1373 (w),
1117 (m), 1050 (s), 981 (m), 782 (w) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.2 Hz, 3 H), 1.22 (t,
J = 7.2 Hz, 3 H), 3.48–3.83 (m, 4 H), 4.65 (d, J = 5.6 Hz, 1 H), 4.94
(d, J = 6 Hz, 1 H), 7.73 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 15.3, 15.4, 64.1, 64.5, 67.8, 104.1,
133.8, 148.2.
HRMS (ESI): m/z [M + H]+ calcd for C8H16N3O3: 202.1186; found:
202.1185.
(9) Wiley, R. H.; Hussung, K. F.; Moffat, J. J. Org. Chem. 1956,
21, 190.
(10) Buckle, D. R.; Rockell, C. J. M.; Oliver, R. S. J. Heterocycl.
Chem. 1982, 19, 1147.
4-(Dimethoxymethyl)-1H-1,2,3-triazole (2l)
The title compound was prepared from 3h (0.232 g, 0.89 mmol) ac-
cording to the general protocol for debenzylation.
(11) (a) Boechat, N.; Ferreira, M. de L. G.; Bastos, M. M.;
Camilo, A. L. S.; Wardell, S. M. S. V.; Wardell, J. L.;
Tiekink, E. R. T. J. Chem. Crystallogr. 2010, 40, 1137.
(b) Pati, H. N.; Wicks, M.; Holt, H. L. Jr.; LeBlanc, R.;
Weisbruch, P.; Forrest, L.; Lee, M. Heterocycl. Commun.
2005, 11, 117. (c) Youcef, R. A.; Dos Santos, M.; Roussel,
S.; Baltaze, J.-P.; Lubin-Germain, N.; Uziel, J. J. Org.
Chem. 2009, 74, 4318.
Yield: 0.120 g (94%); viscous yellow oil; Rf = 0.40 (hexanes–
EtOAc, 7:3).
IR: 3137 (br), 2937 (w), 2833 (w), 1447 (w), 1320 (w), 1192 (m),
1100 (s), 1046 (s), 970 (s), 799 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.30 (s, 6 H), 5.59 (s, 1 H), 7.73
(s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 52.9, 97.9, 130.5, 144.7.
(12) Farooq, T.; Sydnes, L. K.; Törnroos, K. W.; Haug, B. E.
Monatsh. Chem. 2012, 143, 505.
(13) Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.;
Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948.
(14) Cheng, C.; Sun, J.; Xing, L.; Xu, J.; Wang, X.; Hu, Y. J. Org.
Chem. 2009, 74, 5671.
HRMS (ESI): m/z [M + H]+ calcd for C5H9N3O2Na: 166.0587;
found: 166.0588.
1H-1,2,3-riazole-4-carbaldehyde (2m)
While sitting in open air, 2l (0.120 g, 0.84 mmol) decomposed to
give the title compound.
(15) Sydnes, L. K.; Holmelid, B.; Sengee, M.; Hanstein, M.
J. Org. Chem. 2009, 74, 3430.
(16) Abboud, J.-L. M.; Foces-Foces, C.; Notario, R.; Trifonov, R.
E.; Volovodenko, A. P.; Ostrovskii, V. A.; Alkorta, I.;
Elguero, J. Eur. J. Org. Chem. 2001, 3013.
(17) CCDC860712 contains the supplementary crystallographic
data for 2g. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Yield: 94 mg (97%); yellow crystalline solid; mp 135.8–136.5 °C.
IR: 3170 (br), 3126 (m), 2889 (w), 1693 (m), 1668 (s), 1530 (w),
1454 (w), 1399 (m), 1322 (s), 1237 (s), 1108 (m), 1028 (m), 829 (s),
764 (s), 636 (s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.17, 11.58.
13C NMR (101 MHz, CDCl3): δ = 127.8, 139.4, 194.75.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2070–2078

2078
T. Farooq et al.
PAPER
(25) Asano, K.; Matsubara, S. Org. Lett. 2010, 12, 4988.
(26) Jlalia, I.; Beauvineau, C.; Beauvière, S.; Önen, E.; Aufort,
M.; Beauvineau, A.; Khaba, E.; Herscovici, J.; Meganem, F.;
Girard, C. Molecules 2010, 15, 3087.
(27) Martina, K.; Leonhardt, S. E. S.; Ondruschka, B.; Curini, M.;
Binello, A.; Cravotto, G. J. Mol. Catal. A: Chem. 2011, 334,
60.
(28) Jin, T.; Yan, M.; Menggenbateer; Minato, T.; Bao, M.;
Yamamoto, Y. Adv. Synth. Catal. 2011, 353, 3095.
(29) Margetic, D.; Butler, D. N.; Warrener, R. N. Aust. J. Chem.
2000, 53, 959.
(18) Dabbagh, H. A.; Rasti, E.; Najafi, Chermahini. A.
THEOCHEM 2010, 947, 92.
(19) Ozimiński, W. P.; Dobrowolski, J. C.; Mazurek, A. P.
J. Mol. Struct. 2003, 651-653, 697–704.
(20) CCDC 860711 contains the supplementary crystallographic
data for 2m. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(21) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008,
10, 3171.
(22) Nakamura, T.; Terashima, T.; Ogata, K.; Fukuzawa, S.-i.
Org. Lett. 2011, 13, 620.
(30) Yap, A. H.; Weinreb, S. M. Tetrahedron Lett. 2006, 47,
3035.
(31) Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Org. Lett. 2010, 12,
5414.
(23) Raghavendra, M. S.; Lam, Y. Tetrahedron Lett. 2004, 45,
6129.
(24) Leeb, L.; Gmeiner, P.; Löber, S. QSAR Comb. Sci. 2007, 26,
1145.
Synthesis 2012, 44, 2070–2078
© Georg Thieme Verlag Stuttgart · New York