Method for assigning structure of 1,2,3-triazoles

Article abstract of DOI:10.1021/jo301265t

1,4-Disubstituted-1H-1,2,3-triazoles 1 can easily be distinguished from the isomeric 1,5-disubstituted-1H-1,2,3-triazoles 2 by simple one-dimensional ¹³C NMR spectroscopy using gated decoupling. The C₅ signal of 1 appears at δ ～120 p

Full text of DOI:10.1021/jo301265t

Note
pubs.acs.org/joc
Method for Assigning Structure of 1,2,3-Triazoles
Xavier Creary,* Andrew Anderson, Carl Brophy, Frances Crowell, and Zachary Funk
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: 1,4-Disubstituted-1H-1,2,3-triazoles 1 can easily be distinguished from the isomeric 1,5-disubstituted-1H-1,2,3-
triazoles 2 by simple one-dimensional 13C NMR spectroscopy using gated decoupling. The C5 signal of 1 appears at δ ∼120 ppm,
while the C4 signal of 2 appears at δ ∼133 ppm. Computational studies also predict the upfield shift of C5 of 1 relative to C4 in 2.
riazoles are a class of compounds of much recent interest.
TThey are generally prepared by cycloaddition reactions of
azides with alkynes. The original thermal cycloaddition reaction
discovered by Huisgen1 has been largely supplanted by copper-
catalyzed reactions of azides with alkynes, which give 1,4-
disubstituted-1H-1,2,3-triazoles of general structure 1.2,3
References to this copper-catalyzed reaction, since Sharpless
first introduced the concept of the “Click Reaction” in 2001,4
are too numerous to list. Hence, a few general reviews are
given.5 The regioisomeric 1,5-disubstituted-1H-1,2,3-triazoles 2
can often be prepared by a ruthenium-catalyzed reaction,6 or by
addition of acetylide anions to azides.7 The structures of many
of these triazoles were proven by X-ray crystallographic
analysis2,6 or by more sophisticated NMR methods including
NOE,2,3 HMQC, HSQC, and HMBC8 studies. While structures
of triazoles in the Sharpless/Fokin studies and in certain other
studies have been rigorously demonstrated, in many subsequent
studies in the literature, the structures of triazoles are not
Figure 1. (A) Expanded 13C NMR of 1a. (B) 1H coupled 13C NMR of
“proven” but are simply assigned using the assumption that Cu
1a.
catalysis gives isomers of type 1, while Ru catalysis gives type 2
isomers. While these assumptions are most likely correct, a
simple method for verification of structure is desirable.
spectrum B uses the relatively old and simple gated decoupling
sequence (decoupler off during acquisition), where coupling to
neighboring hydrogens is observed. Identification of the C5
carbon signal of 1a is straightforward due to the relatively large
C−H coupling constant of 191 Hz. The corresponding C−H
coupling constants for aromatic carbons are much smaller
(∼155 Hz). The doublet of triplets (J = 191, 2.7 Hz) at δ 119.5
is due to the C5 carbon coupled to the directly bonded
hydrogen and 3-bond coupled to the two benzylic hydrogens.
X-ray, NOE, and multidimensional NMR techniques are
powerful methods for structure elucidation. However, they are
not always routine, rapid, simple, or inexpensive techniques. As
part of another investigation, we have generated a number of
isomeric triazoles for mechanistic studies. We therefore wanted
a simple protocol for rapidly distinguishing between the
isomeric triazoles 1 and 2. We now report that structures can
be easily assigned from simple 1-dimensional 13C NMR data.
Figure 1 shows an expanded region of the 13C NMR
spectrum of triazole 1a prepared by a Cu catalyzed reaction.
Spectrum A is the standard proton decoupled spectrum, while
Received: June 27, 2012
© XXXX American Chemical Society
A
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Table 1. 13C Shifts of C5 of Triazole 1 and C4 of Triazole 2
This rapid “low tech” experiment gives the same coupling
information as the more tedious HMQC and HMBC methods.
It also gives precise values of coupling constants, which are used
to readily assign the C5 signal. The single frequency decoupled
spectrum (not shown), where the benzylic hydrogens at δ =
substrates
R1
R2
C5 of 1 (ppm) C4 of 2 (ppm)
1a/2a
1b/2b
1c/2c
1d/2d
1e/2e
1f/2f
Ph
PhCH2
n-hexyl
PhCH2
n-hexyl
PhCH2
PhCH2
Ph
119.5
119.2
120.4
120.3
123.6
119.0
117.6
118.8
122.3
122.6
121.5
117.3
120.3
121.8
121.6
125.1
127.3
125.2
105.9
133.3
133.0
132.5
131.9
135.3
130.9
133.4
132.3
134.8
134.6
132.9
132.6
132.4
134.9
136.3
141.2
138.2
138.6
113.8
Ph
1
n-Bu
n-Bu
5.57 ppm in the H NMR spectrum are irradiated, confirms
that the triplet is due to long-range coupling to the benzylic
hydrogens. This verifies that the carbon signal at δ 119.5 is
indeed due to the C5 carbon of 1a.
CH2OAc
C(OH)Me2
Ph
1g/2g
1h/2h
1i/2i
n-Bu
Ph
C(OH)Ph2
CH2OPh
Ph
n-hexyl
PhCH2
PhCOCH2
cyclohexyl
cinnamyl
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
1j/2j
1k/2k
1l/2l
Ph
1m/2m
1n/2n
1o/2o
1p/2p
1q/2q
1r/2r
1s/2s
n-Bu
Figure 2 shows an expanded region of the 13C NMR
spectrum of the isomeric triazole 2a. The signal at δ = 133.3
CH(OEt)2
CH2OH
CHO
CO2Et
COCH3
OEt
Computational Studies. While 13C chemical shifts of the
C5 and C4 carbons of 1 and 2 appear to be a reliable empirical
method of assigning structure, we sought a theoretical basis for
these shifts. GIAO calculated shifts12 (B3LYP/6-31G* level) of
C5 and C4 for compounds 6 and 7 are δ = 114 and 127 ppm,
respectively. These calculated values are about 6 ppm upfield
from the experimental values for 1 and 2. However, there is still
a large difference (13 ppm) between C5 of 6 and C4 of 7. This
calculated difference is completely consistent with the
experimental findings.
Figure 2. (A) Expanded 13C NMR of 2a. (B) 1H coupled 13C NMR of
2a.
ppm is due to the C4 carbon, and this is confirmed by the gated
decoupling experiment that shows a doublet (J = 195 Hz) due
to the directly attached hydrogen. The 4-bond coupling to the
benzylic hydrogens is not observed. These 13C spectra are easy
to acquire and may be obtained in less that one hour using
routine techniques.
We have now prepared and analyzed the 19 pairs of triazoles
in Table 1 by these simple 13C NMR methods. In all of these
triazoles, the C5 carbon of 1 is always further upfield than the
C4 carbon of 2. The average chemical shift of C5 for triazoles
1a−1o is δ = 120 3 ppm, while the shift of C4 is δ = 133
3
ppm for 2a−2o. The previously reported triazoles 3,9 4,10 and
511 (whose structures were based solely on the copper-
catalyzed synthetic method) have also been analyzed, and the
C5 shifts also fall within the δ = 120 3 ppm range.
Why is the C5 carbon in isomer 1 further upfield than C4 in
isomer 2? A valence bond approach can rationalize this
observation. While there are a number of resonance
contributors in 1, consider the important form 1y (which
B
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Note
places formal negative charge on the more electronegative
nitrogen N3) and form 1z. The upfield position of the C5
carbon in 1 can be attributed to resonance donation from the
N1 nitrogen, which places formal negative charge on N3 and
consequently on C5 carbon. Analogous resonance donation
from N1 in isomer 2 does not place formal negative charge on
C4. Instead, the quarternary C5 of isomer 2 is predicted to be
shifted upfield (form 2z). This is indeed the case
experimentally, where C5 of isomers 2 are all upfield relative
to the analogous quaternary carbons C4 in isomers 1.
structure based on some experimental method, and not simply
to assign structure based on the catalyst used.
A comment on the structure of phenyl-1,2,3-triazole8a,13 is
appropriate. This triazole has been shown at various times as
tautomer 14, 15, or 16.14 What then is the correct structure?
The actual 13C NMR spectrum of phenyl-1,2,3-triazole in
CDCl3 shows a doublet (J = 190 Hz) at δ = 129.2 ppm and a
singlet at δ = 146.9 ppm. These values are not consistent with
either structure 14 or 15. Shown in Figure 3 are the B3LYP/6-
Exceptions. Carbonyl containing substrates 1p−1r give C5
shifts that are about 6 ppm downfield from the δ = 120
3
ppm range. The isomeric substrates 2p−2r follow a similar
trend, and shifts are also about 6 ppm downfield from the δ =
133
3 ppm range. Computational predictions agree with
these experimental findings and B3LYP/6-31G* GIAO
calculated shifts in aldehydes 8 and 9 are 5 and 7 ppm
downfield, respectively, from calculated shifts in 6 and 7.
Standard carbonyl group resonance effects, as in 8a, account for
the further downfield shifts of C5 in carbonyl containing
substrates 1p−1r, as well as the further downfield shifts of C4 in
2p−2r.
Figure 3. B3LYP/6-31G* GIAO calculated 13C shifts and relative
energies of tautomeric triazoles 14−16.
31G* GIAO calculated 13C shifts of the appropriate carbons of
14-16, as well as the relative energies. Since actual shifts are
about 6 ppm downfield from the GIAO calculated shifts, the
observed 13C shifts implicate tautomer 16 as the actual
structure. Further evidence for tautomer 16 as the actual
structure comes from the calculated energies of these
tautomers. The lowest energy tautomer is 16, which lies 4.3
and 5.0 kcal/mol lower than 14 and 15, respectively.
Consequently, one would expect 16 to predominate in any
equilibrium, while 14 and 15 should not be observable by
NMR.
In summary, 1,4-disubstituted-1H-1,2,3-triazoles 1 show a
characteristic 13C signal at δ ∼120 ppm for C5, while C4 in the
isomeric 1,5-disubstituted-1H-1,2,3-triazoles 2 appears at δ
∼133 ppm. These 13C signals are readily identified by the large
1-bond C−H coupling constant in the gated decoupled 13C
NMR spectrum. B3LYP/6-31G* GIAO computational studies
agree with this trend, although calculated shifts are consistently
about 6 ppm upfield from actual values. This combination of
13C NMR and computational observations offers a simple
method for distinguishing between triazoles 1 and 2.
Other triazoles, where chemical shifts of C5 and C4 lie
outside of the “expected” range, are the ethoxy-substituted
triazoles 1s and 2s, where the observed shifts are δ = 105.9 and
113.8 ppm, respectively. Computational studies on triazoles 10
and 11 predict that the C5 and C4 carbons of these triazoles will
be shifted upfield. Resonance interactions, as in 10a, account
for these upfield shifts.
Applications. During the attempted synthesis of 2r, we
carried out the Cp*RuCl(PPh3)2 catalyzed reaction of
PhCH2N3 with 1-propyn-3-one. This is a complex reaction,
where significant amounts of the alkyne trimers 12 and 13 were
formed. The major triazole isolated was 1r and not the
expected isomer 2r. This example illustrates the need to assign
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded on a Varian DirectDrive 600
MHz spectrometer. HRMS measurements were carried out using a
Bruker MicroTOF-II spectrometer (electrospray ionization source
with time-of-flight mass analyzer).
Preparation of Triazoles 1 by Cu(I)-Catalyzed Reactions.
Method 1. General Comments. Triazoles 1 were prepared by the
C
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copper(I)-catalyzed cycloaddition of the appropriate alkynes and
azides using a water/CH2Cl2 solvent system.15 The presence of traces
of copper in triazoles 1 prepared by this CuSO4/sodium ascorbate
method broadens C5 (as well as C4) and can make identification of
these 13C signals problematic. Hence it is necessary to remove traces of
copper impurities by passing the sample through a small amount of
silica gel. Alternatively, addition of a small amount of Et3N to the
sample sharpens the 13C signals. Triazoles 1a,16 1b,17 1c,18 1e,19 1f,20
1g,21 1h,22 1j,23 1k,24 1l,22 1n,25 1o,26 1p,27 1q,28 1r,29 and 1s,30 have
been previously reported. Triazoles 1d, 1i, and 1m have not been
previously reported. The following procedure for the preparation of 1d
is representative.
Preparation of Triazole 1d. Method 1. A solution of 209 mg (1.65
mmol) of n-hexyl azide and 175 mg (2.13 mmol) of 1-hexyne in 4 mL
of CH2Cl2 was stirred and 3 mL of water was added followed by 54 mg
of CuSO4·5H2O. Sodium ascorbate (150 mg) was then added in small
portions and the mixture was stirred for 24 h at room temperature.
The CH2Cl2 phase was then separated and dried over MgSO4. After
filtration, the solvent was removed using a rotary evaporator and the
residue was chromatographed on 3 g of silica gel. The column was
eluted with increasing amounts of ether in pentane. Triazole 1d (322
mg; 94% yield) eluted with 75% ether in pentane. 1H NMR (CDCl3) δ
7.24 (s, 1 H), 4.30 (t, J = 7.3 Hz, 2 H), 2.71 (t, J = 7.7 Hz, 2 H), 1.88
(m, 2 H), 1.65 (m, 2 H), 1.39 (m, 2 H), 1.31 (m, 6 H), 0.93 (t, J = 7.4
Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H). 13C NMR (CDCl3) δ 148.4, 120.3,
150.2, 31.6, 31.2, 30.3, 26.2, 25.4, 22.4, 22.3, 13.9, 13.8. HRMS (ESI)
(MH+) calcd for C12H24N3 210.1965, found 210.1994.
the C6H6 was the removed using a rotary evaporator and the residue
was chromatographed on 6 g of silica gel (column packed with 10%
ether in pentane). The column was eluted with increasing amounts of
ether in pentane. The triazole 2n (183 mg, 83% yield) eluted with 50%
ether in pentane. 1H NMR (CDCl3) δ 7.70 (s, 1 H), 7.36−7.27 (m, 3
H), 7.25−7.21 (m, 2 H), 5.63 (s, 2 H), 5.42 (d, J = 0.6 Hz, 1 H), 3.46
(m, 4 H), 1.15 (t, J = 7.0 Hz, 6 H). 13C NMR (CDCl3) δ 134.9, 134.8,
134.0, 128.8, 128.2, 127.5, 94.4, 61.3, 52.4, 14.9. HRMS (ESI) (MH+)
calcd for C14H20N3O2 262.1550, found 262.1559.
Triazole 2e. This triazole was prepared in 94% yield by Method 2.
1H NMR (CDCl3) δ 7.73 (s, 1 H), 7.38−7.29 (m, 3 H), 7.19−7.15
(m, 2 H), 5.63 (s, 2 H), 5.02 (s, 2 H), 1.93 (s, 3 H). 13C NMR
(CDCl3) δ 170.0, 135.3, 134.6, 131.6, 129.0, 128.4, 127.1, 53.4, 52.2,
20.4. HRMS (ESI) (MH+) calcd for C12H13N3O2 232.1086, found
232.1096.
Triazole 2j. This triazole was prepared in 67% yield by Method 2.
1H NMR (CDCl3) δ 7.72 (s, 1 H), 7.33−7.26 (m, 5 H), 7.23−7.15
(m, 2 H), 7.04−6.99 (m, 1 H), 6.85−6.81 (m, 2 H), 5.65 (s, 2 H), 4.90
(s, 2 H). 13C NMR (CDCl3) δ 157.5, 134.6, 134.4, 132.3, 129.7, 129.0,
128.5, 127.6, 122.0, 114.6, 58.3, 52.6. HRMS (ESI) (MH+) calcd for
C16H15N3O 266.1288, found 266.1301.
Triazole 2m. This triazole was prepared in 68% yield by Method 2.
1H NMR (CDCl3) δ 7.49 (s, 1 H), 7.36−7.24 (m, 5 H), 6.46 (d, J =
15.9 Hz, 1 H), 6.29 (d of t, J = 15.9, 6.0 Hz, 1 H), 5.08 (d of d, J = 6.0,
1.5 Hz, 2 H), 2.64 (t, J = 7.6 Hz, 2 H), 1.65 (m, 2 H), 1.40 (m, 2 H),
0.93 (t, J = 7.4 Hz, 3 H). 13C NMR (CDCl3) δ 137.4, 135.6, 133.6,
132.4, 128.7, 128.3, 126.5, 122.6, 49.8, 30.1, 22.8, 22.3, 13.7. HRMS
(ESI) (MH+) calcd for C15H20N3 242.1652, found 242.1665.
Preparation of Triazoles 2 by Reaction of Magnesium
Acetylides with Azides. Method 3. Triazoles 2d, 2g,7a and 2h were
prepared by the reaction of the appropriate magnesium acetylide and
azides.7a The following procedure for the preparation of 2d is
representative.
Triazole 1i. This triazole was prepared in 98% yield by Method 1.
1H NMR (CDCl3) δ 7.36−7.24 (m, 10 H), 7.07 (s, 1 H), 4.28 (t, J =
7.4 Hz, 2 H), 3.96 (bs, 1 H), 1.86 (m, 2 H), 1.34−1.26 (m, 6 H), 0.87
(t, J = 7 Hz, 3 H). Irradiation of the 2 H triplet at δ = 4.28 ppm gives a
7% NOE of the 1 H singlet at δ = 7.07 ppm. 13C NMR (CDCl3) δ
153.9, 145.8, 128.0, 127.4, 127.2, 122.3, 50.4, 31.0, 30.2, 26.1, 22.4,
13.9. HRMS (ESI) (MH+) calcd for C21H26N3O 336.2070, found
336.2098.
Ethylmagnesium bromide (1.50 mL of a 1.0 M solution in THF;
1.50 mmol) was placed in flask under argon and a solution of 122 mg
of 1-hexyne (1.49 mmol) in 0.5 mL THF was added dropwise at 0 °C.
The mixture was warmed to room temperature and after 1.5 h, 205 mg
of n-hexyl azide (1.61 mmol) in 0.5 mL THF was added dropwise.
After 7 h at room temperature, the mixture was cooled in ice and
quenched with aqueous ammonium bromide solution. The mixture
transferred to a separatory funnel using ether and the organic phase
was washed with saturated salt solution. After drying over a mixture of
Na2SO4 and MgSO4, the solution was filtered and the solvent was
removed using a rotary evaporator. The residue was chromatographed
on 2.5 g of silica gel and the column was eluted with increasing
amounts of ether in pentane. The triazole 2d (208 mg; 67% yield)
eluted with 70% ether in pentane. 1H NMR (CDCl3) δ 7.44 (s, 1 H),
4.24 (t, J = 7.4 Hz, 2 H), 2.62 (t, J = 7.6 Hz, 2 H), 1.88 (m, 2 H), 1.66
(m, 2 H), 1.43 (m, 2 H), 2.32 (m, 6 H), 0.97 (t, J = 7.3 Hz, 3 H), 0.89
(t, J = 7.2 Hz, 3 H). 13C NMR (CDCl3) δ 136.8, 132.0, 47.7, 31.2,
30.3, 30.1, 26.3, 22.9, 22.5, 22.3, 14.0, 13.7. HRMS (ESI) (MH+) calcd
for C12H24N3 210.1965, found 210.1990.
Triazole 1m. This triazole was prepared in 90% yield by Method 1.
1H NMR (CDCl3) δ 7.40−7.25 (m, 5 H), 7.32 (s, 1 H), 6.63 (d, J =
15.8 Hz, 1 H), 6.33 (d of t, J = 15.8, 6.6 Hz, 1 H), 5.08 (d of d, J = 6.7,
1.4 Hz, 2 H), 2.71 (t, J = 7.5 Hz, 2H), 1.64 (m, 2 H), 1.37 (m, 2 H),
0.92 (t, J = 7 Hz, 3 H). 13C NMR (CDCl3) δ 148.8, 135.6, 135.0,
128.7, 128.5, 126.7, 122.3, 120.3, 52.2, 31.6, 25.4, 22.3, 13.8. HRMS
(ESI) (MH+) calcd for C15H20N3 242.1652, found 242.1678.
Preparation of Triazoles 2 by Cp*RuCl(PPh3)2-Catalyzed
Reactions. Method 2. Triazoles 2a,6a 2b,31 2c,6a 2e, 2f,6a 2i, 2j, 2l,7a
2m, 2n, 2q,32 and 2s33 were prepared by the Cp*RuCl(PPh3)2-
catalyzed cycloaddition of the appropriate alkynes and azides.6 The
following procedures for the preparation of 2i and 2n are
representative.
Preparation of Triazole 2i. Method 2. n-Hexylazide (73 mg; 0.57
mmol) and 1,1-diphenylprop-2-yn-1-ol (101 mg; 0.49 mmol) were
placed in a 10 mL flask under argon and 2.5 mL of C6H6 was added.
The mixture was stirred as 8 mg of Cp*RuCl(PPh3)2 was added and
the flask was heated to reflux under argon. After 100 min, 0.75 g of
silica gel was added to the mixture and the C6H6 was the removed
using a rotary evaporator. The solid residue was added to a
chromatography column prepared from 4 g of silica gel. The column
was eluted with increasing amounts of ether in pentane. The triazole 2i
(126 mg, 77% yield) eluted with 50% ether in pentane as a white solid,
mp 125−126 °C. 1H NMR (CDCl3) δ 7.37−7.30 (m, 3 H), 7.26−7.20
(m, 2 H), 6.88 (s, 1 H), 4.12 (m, 2 H), 3.83 (s, 1 H), 1.65 (m, 2 H),
1.19 (m, 2 H), 1.12 (m, 4 H), 0.82 (t, J = 7.2 Hz, 3 H). Irradiation of
the 2 H multiplet at δ = 4.12 ppm gives no NOE of the 1 H singlet at δ
= 6.88 ppm. 13C NMR (CDCl3) δ 143.8, 141.6, 134.8, 128.4, 128.2,
126.9, 76.3, 49.7, 31.2, 29.5, 26.3, 22.4, 14.0. HRMS (ESI) (MH+)
calcd for C21H26N3O 336.2070, found 336.2065.
Triazole 2h. This triazole was prepared in 70% yield by Method 3.
1H NMR (CDCl3) δ 7.59 (s, 1 H), 7.57−7.48 (m, 3 H), 7.46−7.42
(m, 2 H), 2.66 (t, J = 7.5 Hz, 2 H), 1.58 (m, 2 H), 1.33 (m, 2 H), 0.88
(t, J = 7.5 Hz, 3 H). 13C NMR (CDCl3) δ 138.2, 136.4, 132.3, 129.42,
129.41, 125.2, 30.3, 23.3, 22.1, 13.6. HRMS (ESI) (MH+) calcd for
C12H16N3 202.1339, found 202.1362.
Preparation of Triazole 2k. Triazole 2k was prepared by the
Cp*Ru(PPh3)2Cl catalyzed cycloaddition of phenylacetylene with the
dimethylacetal of PhCOCH2N3, followed by hydrolysis of the resultant
triazole acetal. α-Azidoacetophenone dimethyl acetal (174 mg; 0.84
mmol) was placed in a flask under argon and 2 mL of C6H6 was added.
Phenylacetylene (94 mg; 0.92 mmol) in 1 mL of C6H6 was then added
followed by 9.5 mg of Cp*RuCl(PPh3)2. The mixture was then
refluxed under argon for 5.5 h. About 1 g of silica gel was added to the
mixture and the C6H6 was the removed using a rotary evaporator. The
residue was chromatographed on 4 g of silica gel. The column was
eluted with increasing amounts of ether in pentane. The
dimethylacetal derivative of triazole 2k (179 mg, 69% yield) eluted
Preparation of Triazole 2n. Method 2. Benzyl azide (113 mg; 0.85
mmol) was placed in a 10 mL flask under argon and 2 mL of C6H6 was
added. Propiolaldehyde diethyl acetal (128 mg; 1.00 mmol) in 0.5 mL
of C6H6 was then added followed by 8.8 mg of Cp*RuCl(PPh3)2 . The
mixture was then heated to reflux under argon for 4 h. About half of
D
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Note
1
with 50% ether in pentane. H NMR (CDCl3) δ 7.40 (s, 1 H), 7.31
2s, and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
(m, 1 H), 7.23 (m, 2 H), 7.14 (m, 2 H), 7.01 (m, 2 H), 6.89 (m, 2 H),
6.66 (m, 2 H), 4.72 (s, 2 H), 3.33 (s, 6 H). 13C NMR (CDCl3) δ
138.9, 137.2, 132.4, 128.7, 128.6, 128.5, 128.3, 128.0, 126.7, 101.7,
51.1, 49.3.
AUTHOR INFORMATION
■
A solution of 170 mg (0.55 mmol) of the acetal prepared above in 5
mL of THF was stirred as 2.0 g of 3% H2SO4 in water was added
dropwise. The mixture was then heated at reflux for 20 h and then
solid NaHCO3 was then added to neutralize the H2SO4. The organic
phase was then decanted and dried over a mixture of Na2SO4 and
MgSO4. After filtration the solvent was removed using a rotary
evaporator. This residue was dissolved in CH2Cl2 and filtered through
1.8 g of silica gel in a column. The triazole 2k (110 mg; 76% yield)
eluted with CH2Cl2. 1H NMR (CDCl3) δ 7.92 (m, 2 H), 7.79 (s, 1 H),
7.64 (m, 1 H), 7.51 (m, 2 H), 7.44−7.39 (m, 3 H), 7.37−7.32 (m, 2
H), 5.81 (s, 2 H). 13C NMR (CDCl3) δ 190.8, 139.2, 134.4, 134.0,
133.1, 129.7, 129.11, 129.07, 128.6, 128.1, 126.7, 54.0. HRMS (ESI)
(MH+) calcd for C16H14N3O 264.1131, found 264.1152.
Corresponding Author
*creary.1@nd.edu
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Huisgen, R. P. Chem. Soc. London 1961, 357. (b) Huisgen, R.
Pure Appl. Chem. 1989, 61, 613.
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Preparation of Triazole 2p. Triazole 2p34 was prepared by
hydrolysis of 2n. A solution of 154 mg (0.59 mmol) of the acetal
2n in 10 mL of THF was stirred as 2.7 g of 3% H2SO4 in water was
added dropwise. The stirred solution was heated for 41 h at 50−52 °C
and the mixture was then neutralized with NaHCO3. Most of the THF
was removed using a rotary evaporator and 4 mL of water and 7 mL of
CH2Cl2 was added. The CH2Cl2 phase was dried over Na2SO4,
filtered, and the solvent was removed using a rotary evaporator to give
111 mg (100% yield) of aldehyde 2p.34 1H NMR (CDCl3) δ 9.95 (s, 1
H), 8.25 (s, 1 H), 7.37−7.28 (m, 5 H), 5.90 (s, 2 H). 13C NMR
(CDCl3) δ 178.2, 141.2, 134.4, 133.4, 128.9, 128.7, 128.2, 53.8.
Preparation of Triazole 2o. Triazole 2o35 was prepared by NaBH4
reduction of 2p. A solution of 17 mg (0.091 mmol) of aldehyde 2p in
1 mL of methanol was cooled in a water bath to 15 °C as 15 mg of
solid NaBH4 (0.41 mmol) was added in small portions. After stirring
for 4 h at room temperature, the methanol was removed using a rotary
evaporator. A few drops of 10% HCl in water were added followed by
1 mL of water and the mixture was extracted with 3 mL of CH2Cl2.
The CH2Cl2 extract was dried over Na2SO4 and the solvent was
removed using a rotary evaporator to give 15 mg (87% yield) of
triazole 2o.35 1H NMR (CDCl3) δ 7.52 (s, 1 H), 7.35−7.28 (m, 3 H),
7.25−7.21 (m, 2 H), 5.63 (s, 2 H), 4.58 (s, 2 H). 13C NMR (CDCl3) δ
136.3, 134.8, 133.2, 129.0, 128.4, 127.6, 53.1, 46.0.
2007, 9, 5337. (c) Johansson, J. R.; Lincoln, P.; Norden
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A. Zh. Org. Khim. 1967, 3, 2241. (d) Akimova, G. S.; Chistokletov, V.
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Cuberes, R.; Dordal, A. ARKIVOC 2010, 127.
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Mobashery, S. ARKIVOC 2011, 221.
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E.; Smith, B. D. J. Fluoresc. 2012, 22, 93.
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Wallingford, CT, 2009.
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50, 8944.
(14) Tautomers 14 (1680-44-0) and 16 (112614-96-7) even have
different CAS registry numbers, while commercial sources of phenyl-
1,2,3-triazole show the structure as 14 or 15.
(15) Lee, B.-Y.; Park, S. R.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett.
2006, 47, 5105.
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47, 8881.
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Org. Lett. 2004, 6, 4223.
Preparation of Triazole 2r. Triazole 2r36 was prepared by addition
of CH3MgBr to 2p followed by PCC oxidation of the resultant alcohol.
Tetrahydrofuran (2 mL) was placed in a flask under argon and 1.4 mL
of 0.75 M CH3MgI in ether (1.05 mmol) was added. A solution of 105
mg of triazole 2p (0.56 mmol) in 2 mL of THF was added dropwise to
the stirred solution. The mixture was then warmed at 35 °C for 10
min, cooled in a water bath, and then quenched with aqueous
ammonium bromide solution. The organic phase was separated, dried
using Na2SO4, and the solvent was removed using a rotary evaporator.
The residue was dissolved in CH2Cl2 and redried using Na2SO4.
Solvent removal using a rotary evaporator gave 93 mg of crude alcohol
product that was used directly in the next step.
A solution of the alcohol prepared above (84 mg; 0.46 mmol) in 2
mL of CH2Cl2 was stirred as 103 mg of pyridinium chlorochromate
(0.48 mmol) was added in small portions. After stirring for 6 h at
room temperature, 5 mL of ether was added to the dark mixture and
the organic phase was filtered through a small amount of silica gel in a
pipet. The solvent was then removed using a rotary evaporator to give
40 mg (48% yield) of triazole 2r.36 1H NMR (CDCl3) δ 8.16, 7.38−
7.27 (m, 5 H), 5.90 (s, 2 H), 2.53 (s, 3 H). 13C NMR (CDCl3) δ
187.1, 136.6, 134.9, 133.1, 128.7, 128.4, 128.2, 53.6, 28.8.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Complete ref 12, the B3LYP/6-31G* calculated structures,
energies, and Cartesian coordinates of 6, 7, 8, 9, 10, 11, 14, 15,
(24) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith,
S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559.
1
and 16, and H and 13C NMR spectra of triazoles 1a−1s, 2a−
E
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The Journal of Organic Chemistry
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