Preparation of Acidic 5-Hydroxy-1,2,3-triazoles via the Cycloaddition of Aryl Azides with β-Ketoesters

Article abstract of DOI:10.1021/acs.joc.1c00778

Herein, a high-yielding cycloaddition reaction of β-ketoesters and azides to provide 1,2,3-triazoles is described. The reactions employing 2-unsubstituted β-ketoesters were found to provide 5-methyl-1,2,3-triazoles, whereas 2-alkyl-substituted β-ketoester

Full text of DOI:10.1021/acs.joc.1c00778

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Article
Preparation of Acidic 5‑Hydroxy-1,2,3-triazoles via the
Cycloaddition of Aryl Azides with β‑Ketoesters
Roberta Pacifico,∇ Dario Destro,∇ Malachi W. Gillick-Healy, Brian G. Kelly, and Mauro F. A. Adamo*
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ABSTRACT: Herein, a high-yielding cycloaddition reaction of β-
ketoesters and azides to provide 1,2,3-triazoles is described. The
reactions employing 2-unsubstituted β-ketoesters were found to
provide 5-methyl-1,2,3-triazoles, whereas 2-alkyl-substituted β-
ketoesters provided 5-hydroxy-1,2,3-triazoles (shown to be relatively
acidic) in high yields and as single regioisomers. Several novel
compounds were reported and characterized including long-chain 5-
hydroxy-1,2,3-triazoles potentially bioisosteric to hydroxamic acids.
INTRODUCTION
■
1,2,3Ttriazoles are important scaffolds employed in medicinal
chemistry,1 catalysis,2 materialscience,3 and biology.4 The
electronic and physicochemical properties of triazoles bear a
close similarity to those of the amide functionality and
therefore can be classified as amide bioisosteres.5,6 Copper-
catalyzed alkyne−azide cycloaddition is the most accredited
method to synthesize substituted 1,2,3-triazoles,7−11 while the
less well-known reactions of malonates or β-ketoesters with
aromatic azides have become attractive alternatives as they do
not require metal catalysts to proceed (Figure 1).12
β-Ketoesters react quickly with mild bases, providing highly
reactive enolates that have a myriad of reported applications in
organic chemistry.13,14 Dimroth reported a cycloaddition of β-
ketoesters and azides in 190215 where ethyl acetoacetate
reacted with azidobenzene in the presence of sodium ethoxide
to provide 5-hydroxytriazoles in poor yields. This material was
properly identified; however, it was not characterized beyond
the physical constants and, notably, their remarkable acidity
was overlooked. More recently, Wang and co-workers reported
the cycloaddition of β-ketoesters and azides, via organo-
catalysis, to yield 1,4-disubstituted 1,2,3-triazoles.16 Intrigued
by these reports15,16 where the same reagents gave rise to
different products under similar basic conditions, and in a
continuation of our studies on the reactivity of azides and
enolates (Figure 1),17 we decided to re-examine the cyclo-
addition of simple ketoesters and aromatic azides in the
presence of organic bases.
Figure 1. Historical and novel approaches for the synthesis of 1,2,3-
triazoles.
β-ketoester. These findings were subsequently exploited to
prepare a family of 5-hydroxytriazoles, whose acidity has been
shown to be even stronger (pKa = 4.20 for 5a) than those for
RESULTS AND DISCUSSION
Received: April 2, 2021
■
This work involved reacting a selection of pyridyl- or aryl-
azides and β-ketoesters and showed that distinct triazole
products could be obtained in high yields via a divergent
reaction pathway that led to either disubstituted 1,2,3-triazoles
or 5-hydroxy-1,2,3-triazoles depending upon the nature of the
© XXXX The Authors. Published by
https://doi.org/10.1021/acs.joc.1c00778
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American Chemical Society
A

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a
Table 1. Cycloaddition of β-Ketoester 1a with Aryl Azides 2
b
entry
keto ester
aryl azide
Py
product
catalyst
solvent
yield (%)
1
2
3
4
1a
1a
1a
1a
2a
2b
2c
2c
4-pyridyl
3-pyridyl
2-pyridyl
2-pyridyl
3a
3b
3c
3c
MeCN
MeCN
MeCN
DMSO
80
72
0
Cu(OTf)2·C6H5CH3
50
a
b
Reaction conditions are as follows: 1a (1.2 equiv), 2a−c (1 equiv), DBU (1.2 equiv), and solvent (0.2 M). Isolated yield.
analogous compounds (pKa = 5.14−6.21) reported by Sainas
and co-workers.18 Our observation of the relatively strong
acidity of 5-hydroxytriazoles has the potential to be applied
toward hydroxamic acid bioisosteres (Figure 1).
Our investigation began with the cycloaddition reaction of
pyridyl azides 2a−c with ethyl acetoacetate 1a in the presence
of organic soluble bases, from which 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) gave the best yield. The reactions of
pyridyl azides 2a and 2b with 1a furnished triazoles 3a and 3b
in 80% and 72% isolated yields, respectively, whereas the
reaction of pyridyl azide 2c, bearing an ortho-nitrogen, showed
no conversion to 3c (Table 1).
Compound 3c, however, was obtained in average yields
(50%) when a copper trifluoromethanesulfonate toluene
complex (Cu(OTf)2·C6H5CH3) in dimethyl sulfoxide
(DMSO) was added to the reaction mixture. The reaction of
1a and phenyl azide 4a (Table 2, entry 1) gave the
disubstituted triazole ester 3d16 in an excellent isolated yield.
In summary, the reaction of unsubstituted 1a with azides 2a−c
(Table 1) or 4a (Table 2) under basic conditions provided 4,5-
disubstituted 1,2,3-triazoles of a similar type to those reported
by Wang.16 However, when 2-substituted β-ketoester 1b was
reacted with azide 4a (Table 2, entry 2), a sharp diversion of
the reaction course was observed, and 5-hydroxy-triazole 5a
was isolated as the sole product (Table 2 entry 2). We then
investigated the scope of the reaction, applying the same
reaction protocol to β-ketoesters 1b and 1c and aryl azides
(4a−j) (Table 2). Reactions of ketoester 1b with aryl azides
4h−j did not lead to the formation of any product, and only
starting materials were recovered after 18 h. Reactions of
ketoesters 1b and 1c with azides 4a−g and 4a under identical
conditions provided 5-hydroxytriazoles 5a−g and 5k, which
with the exception of 5a are reported here for the first time.
The chemical structure of 5a was confirmed by single-crystal
X-ray diffractometry (see Figure 2 and the Supporting
Information).
The reaction of ketoesters 1b and 1c with aryl azides 4a−j in
the presence of 1.2 equiv of DBU in acetonitrile at 50 °C for
18 h provided 5-hydroxytriazoles 5a−k in moderate to good
yields. The reaction was, however, sensitive to the electronic
effects of substituents of the azide, where electron-neutral
azides 4a, 4b, 4d, and 4e gave highest yields. The electron-rich
azide 4c reacted well, albeit the yields were lower. Aromatic
azides 4f−g bearing strong electron-withdrawing groups
provided the corresponding 5-hydroxytriazoles 5f−g in only
moderate yields. Steric hindrance from aryl substituents of aryl
azides 4 was not found to affect reaction yield. The potential
for the organo-catalytic activity of DBU in this reaction was
also investigated; however, no evidence to support this was
found. We then proceeded to optimize the reaction conditions
between 1b and 4a by varying the base, solvent, temperature,
and reaction times.
Table 2. Cycloaddition of β-Ketoesters and Aryl Azides to
a
Give 5-Hydroxytriazoles
aryl
azide
time
product (h)
yield
b
entry ketoester
R
Ar
(%)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1b
1b
1b
1b
1b
H
4a
4a
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
3d
5a
5a
5b
5c
5d
5e
5f
18
6
87
80
Me
Me
Me
Me
Me
Me
Me
Me
c
18
18
18
18
18
18
18
98
87
62
75
79
53
56
4-BrC6H4
4-OMeC6H4
2-PhC6H4
1-naphthyl
4-NO2C6H4
2-NO2-4-
MeC6H3
2-Br-C6H4
n-Bu
Bn
Figure 2. X-ray crystal structure of 5-hydroxytriazole 5a.27
The high yield obtained when reacting 1b with 4a in the
presence of solid KOH (potassium hydroxide) as a base and
TBAB (tetrabutylammonium bromide) as a PTC (phase-
transfer catalyst) encouraged us to study the scope of this
transformation (Table 3). Phase-transfer conditions were
found to be particularly effective with electron-poor and
electron-neutral azides, such as 4a, 4g, and 4h, with yields up
to 95%. However, when bulky azide substituents where
present, such as 4e, only the hydrolyzed product 6 was
favored over cyclization (Table 3). Since compound 5a
4g
5g
d
d
d
10
11
12
13
1b
1b
1b
1c
Me
Me
Me
Bn
4h
4i
4j
5h
5i
5j
18
18
18
18
n.r.
n.r.
n.r.
75
4a
Ph
5k
a
Reaction conditions are as follows: 1b or 1c (1.2 equiv), 4a−j (1
b
equiv), and DBU (1.2 equiv) in MeCN (0.2 M) at 50 °C. Isolated
c
d
yield. 1H-NMR spectroscopic yield. No reaction.
B
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Table 3. Synthesis of 5-Hydroxytriazoles: PTC-Mediated
a
Cycloaddition of β-Ketoester 1b and Aryl Azides 4
b
entry aryl azide
Ar
product time (h) yield (%)
1
2
3
4
4a
4e
4g
4h
Ph
1-naphthyl
4-NO2C6H4
2-NO2-4-MeC6H3
5a
5e
5f
4
18
4
95
n.r.
76
c
Figure 3. Structural similarities between HDAC inhibitor SAHA (9)
and long-chain 5-hydroxytriazoles (10a−c).
5g
4
83
a
Reaction conditions are as follows: 1b (1.2 equiv), 4 (1.2 equiv),
TBAB (0.1 equiv), and KOH (2.2 equiv) in Et2O (0.2 M) at 20 °C.
Isolated yield. Only the hydrolysis product 2-methyl-3-oxobutanoic
The preparation of 10a−c (n = 1−3, respectively) is
reported in the Experimental section. The structural and
functional similarities between hydroxamic acid 9 and 5-
hydroxytriazoles 10 are highlighted in Figure 3 and include the
following: (i) nominally similar scaffolds and chemical
functionalities; (ii) analogous lone pairs (circled in red) of
the carbonyl oxygen of the hydroxamic acid and the pyridyl-
like N of the triazole system;24 (iii) hydrophobic backbones
(circled in green), which are essential for interaction with
active sites of HDAC isoforms, e.g., zinc-binding groups; and
(iv) aromatic rings (in pink), which are essential for the correct
positioning in the enzyme active site via π−π stacking.25
Based on the reactivity observed, two reaction mechanisms
have been proposed (Scheme 1), which lead to distinct
b
c
acid (6) was formed.
behaved as a relatively strong Brønsted acid, we decided to
carry out a titration experiment to better characterize its
properties. The pKa of 5a was found to be 4.2, which is
comparable to that of a carboxylic acid (see the Supporting
Information).19 This result was very unexpected compared to
the pKa values of the related 4-hydroxy-1,2,3-triazoles, which
were found to be significantly less acidic than those reported
by Pippione and co-workers.20 Moreover, we found 5-
hydroxytriazoles to be highly soluble in water when
accompanied by both organic and inorganic bases, thus
justifying their attractiveness as candidates for drug discovery.
We further expanded the scope of the cyclization reaction to
include cyclic β-ketoesters 7a−c to provide novel long-chain 5-
hydroxytriaxoles 8. Interestingly, poor conversion was
observed when the reaction was performed in solvent, while
we saw a notable improvement when the cyclization was
performed solvent-free with yields up to 79% (Table 4).
Scheme 1. Proposed Distinct Mechanistic Pathways for the
Formation of 5-Hydroxytriazoles 5 (Pathway a) versus 5-
Methyl-triazoles 3 (Pathway b)
a
Table 4. Synthesis of Long-Chain 5-Hydroxytriazoles
b
entry
ketoester
R
n
solvent
product
yield (%)
1
2
3
4
7a
7a
7b
7c
Et
Et
Me
Et
1
1
2
3
MeCN
none
none
8a
8a
8b
8c
29
44
79
38
none
a
Reaction conditions are as follows: 7 (1.2 equiv), 4a (1 equiv), and
b
DBU (1.2 equiv) at 50 °C for 18 h. Isolated yield.
products via analogous intermediates 12a and 12b. Inter-
mediates 12a and 12b arise from reaction of enolate 11 with
aryl azides (pathway a or pathway b), respectively. In pathway
a, species 12a is formed and will evolve toward cyclic amide
13a, which contains no enolizable proton, and the concomitant
elimination of ethoxide. A subsequent attack of ethoxide to the
acetoxy group in 13a will lead to the elimination of ethyl
acetate and the formation of 5. Conversely, in the presence of
an enolizable proton such as in 12b (pathway b), the following
cyclization to 13b and its subsequent protonation will generate
14b, which will provide compounds 3 after dehydration. A
rationale similar to ours used to explain the mechanism in
Scheme 1 has been reported by Pedersen and Begtrup for the
reaction between phenyl azides and amides of malonic acids.26
A literature search highlighted the structural similarity of 5-
hydroxytriazoles and hydroxamic acids.21 Hydroxamic acids
and 5-hydroxytriazoles share similar pKa valuesand amide-like
bioisosterism, which makes them excellent ligands for enzyme-
bound metals. Compounds 5a−g and 8 reacted with Fe2+ and
Cu2+ salts to provide blue-violet and red-colored solutions,
indicating a ligand-like behavior similar to that of hydroxamic
acids. Suberanilohydroxamic acid 9 (SAHA) is a hydroxamic
acid that is active as a histone deacetylase (HDAC)
inhibitor.22,23 To exemplify the potential of the 5-hydroxy-
triazole nucleus in medicinal chemistry, we set out to convert
long-chain 5-hydroxytriazoles 8a−c into terminal N-phenyl-
amide-substituted triazoles 10a−c, which bear a close
structural relationship to hydroxamic acid 9 (Figure 3).
C
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purified via flash column chromatography (MeOH/DCM/AcOH
90:10:0.1) to afford title compounds 3a and 3b as solids.
CONCLUSION
■
In conclusion, we have demonstrated that aryl azides undergo
two distinct cycloaddition reactions with enolizable β-
ketoesters depending on the substitution pattern on the β-
ketoester, leading to different products. The cycloaddition of 2-
unsubstituted β-ketoester with pyridyl azides and phenyl azide
was found to lead to 5-methyl-triazoles, whereas the cyclo-
addition of 2-alkyl-substituted β-ketoesters with phenyl azide
and substituted aryl azides was found to lead to 5-
hydroxytriazoles, where the structure of one of the products
has been confirmed via X-ray diffractometry (see Figure 2 and
the Supporting Information).27 The reaction of phenyl azide
and substituted aryl azides with 2-alkyl-substituted β-ketoesters
has been shown to be a fast, mild, and high-yielding method
for the synthesis of 5-hydroxy-1,2,3-triazoles. The relatively
acidic nature we observed for the 5-hydroxytriazoles has led us
propose the study of 5-hydroxytriazole analogues as a new class
of bioisosteres of hydroxamic acids. Future work will involve
an investigation of this novel class of compounds as potential
biological targets and their potential as a bioisosteric relative of
biologically active hydroxamic acids.
Ethyl 5-Methyl-1-(pyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate
3a. Yellow solid (93 mg, 80% yield). 1H NMR (400 MHz,
CDCl3): δ 8.88 (d, J = 6.1 Hz, 2H), 7.51 (d, J = 6.1 Hz, 2H), 4.48
(q, J = 7.1 Hz, 2H), 2.72 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 161.4, 151.7, 142.5, 138.7, 118.7, 61.4,
14.4, 10.3. IR (KBr, cm−1): 3278, 3132, 3100, 1748, 1560, 1480. mp
120−120.7 °C. HRMS (ESI) m/z: [M + H]+ calcd for C11H12N4O2
232.0960, found 232.0948.
Ethyl 5-Methyl-1-(pyridin-3-yl)-1H-1,2,3-triazole-4-carboxylate
3b. Yellow solid (84 mg, 72% yield). 1H NMR (400 MHz,
CDCl3): δ 8.83 (d, J = 4.8 Hz, 1H), 8.78 (s, 1H), 7.89 (d, J = 8.1
Hz, 1H), 7.58 (dd, J = 8.1, 4.8 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.65
(s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 161.5, 151.2, 145.9, 139.1, 137.2, 132.9, 132.4, 124.3, 77.1, 77.1,
76.8, 61.3, 14.4, 9.9. All analytical data are consistent with those
reported in the literature.31
Synthesis of Ethyl 5-Methyl-1-(pyridin-2-yl)-1H-1,2,3-tria-
zole-4-carboxylate 3c. To a solution of 2c (100 mg, 0.83 mmol, 1
equiv) in DMSO (1.4 mL, 0.6M) were added 1a (141 ul, 1 mmol, 1.2
equiv), DBU (150 ul, 1 mmol, 1.2 equiv), and Cu(OTf)2·C6H5CH3
(43 mg, 0.083 mmol, 0.1 equiv). The reaction mixture turned from
light brown to black upon the addition of the catalyst and was stirred
for 8 h at reflux in an oil bath. After 8 h, TLC showed the complete
consumption of 2c, and the mix was cooled to room temperature and
extracted with DCM/H2O three times. The collected organic phases
were filtered through a Celite pad and concentrated in vacuo. The
crude product was purified by flash column chromatography (DCM/
AcOEt 90:10) to afford the product 3c in a modest yield (58 mg, 50%
yield) as a yellow oil. TLC showed the product to be visible as a
brilliant purple spot under an UV lamp at a short wavelength. All
analytical data are consistent with those reported in the literature. 1H
NMR (400 MHz, CDCl3): δ 8.58 (d, J = 4.6 Hz, 1H), 7.95 (m, 2H),
7.42 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.91 (s, 3H), 1.44 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.7, 149.2, 147.5,
138.7, 138.1, 136.3, 123.1, 117.34, 60.1, 13.4, 10.0.
General Procedure for the DBU-Promoted Synthesis of 5-
Hydroxy-1,2,3-triazoles 5a−k (GP2). To a solution of aryl azides 4
(0.5 mmol, 1 equiv) and β-ketoester 1 (0.6 mmol, 1.2 equiv) in
MeCN (0.2M) was added DBU (0.6 mmol, 1.2 equiv), and the
reaction mixture was stirred at 50 °C in an oil bath overnight. The
crude mixture was evaporated under vacuum and purified via flash
column chromatography (MeOH/DCM/AcOH 90:10:0.1) to afford
title compounds 5a−k as solids. In some cases after chromatography,
products 5a−k still contained traces of the DBU salt, which were
easily removed by the trituration of the solid with a minimum
quantity of water.
EXPERIMENTAL SECTION
■
1H and 13C{1H} NMR spectra were recorded on a Bruker 400
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm) relative to residual solvent signals (1H NMR, 7.26 ppm for
CDCl3, 2.50 ppm for DMSO-d6, and 3.31 ppm for CD3OD; 13C{1H}
NMR, 77.16 ppm for CDCl3, 39.53 ppm for DMSO-d6, and 49.03 for
CD3OD). 13C{1H} NMR spectra were acquired with the H broad
1
band decoupled mode. Coupling constants (J) are in hertz (Hz).
Melting points were measured using a Stuart scientific melting point
apparatus and were uncorrected. Infrared spectra (IR) were recorded
with KBr discs using a Bruker Tensor27 FT-IR instrument. High-
resolution mass spectra were obtained on a Waters Micromass GCT
PremierMS spectrometer or on a Bruker microTOF-Q III LC-MS
spectrometer (APCI method). Optical rotations were measured on a
PerkinElmer 343 polarimeter. HPLC chromatograms was recorded on
a YMC-Triart Phenyl 150 × 4.6 mm column using a 5 μL injection
volume (60:40 MeCN/H2O) at two different wavelengths of 190 and
254 nm, respectively. The purity of the final products was verified by
1
HPLC analysis and H and 13C{1H} NMR spectroscopy. Analytical-
grade solvents and commercially available reagents were used as
received. Dry DCM was purchased from Sigma-Aldrich. Reactions
were monitored by TLC (Merck, silica gel 60 F254). Flash column
chromatography was performed using silica gel 60 (0.040−0.063 mm,
230−400 mesh). Substituted arylazides 4a−j28 and pyridyl azides 2a−
c were prepared according to reported procedures.29,30 β-Ketoesters
1a−c and modified ketoesters 7a−c were purchased from Sigma-
Aldrich and used without further purification. 5-Hydroxy-1,2,3-
triazoles 5a, 5e, 5f, and 5g were synthesized via phase-transfer
catalysis according to GP3 and via DBU-promoted synthesis
according to GP2, while 5-hydroxy-1,2,3-triazoles 5b, 5c, 5d, and
5k were synthesized according to GP2 via a DBU-promoted synthesis.
5-Methyl-1,2,3-triazoles 3a−b were synthesized according to the GP1
procedure. 5-Methyl-1,2,3-triazole 3c was synthesized according to a
modified version of GP1. Long-chained 5-hydroxy-1,2,3-triazoles
based SAHA analogs 10b−c were synthesized according to GP6 via
long-chained 5-hydroxy-1,2,3-triazole precursors 8a−c, which were
synthesized according to GP4. The long-chained 5-hydroxy-1,2,3-
triazole-based SAHA analog 10a was synthesized according to a
modified version of GP4.
General Procedure for the Synthesis of 5-Hydroxy-1,2,3-
triazoles 5a and 5e−g via Phase-Transfer Catalysis (GP3). To a
solution of aryl azides 4a, 4e−g (1.2 mmol, 1 equiv), and β-ketoester
1 (1.2 mmol,1 equiv) in diethyl ether (0.2M) were added
tetrabutylammonium bromide (0.11 mmol, 10 mol %) and finely
ground KOH (2.4 mmol, 2 equiv) at room temperature. After 4 h of
vigorous stirring, the white precipitate was collected by vacuum
filtration. The solid, a potassium salt of 5, was dispersed in 1 mL of
MeCN, and acetic acid was added until dissolution. The mixture was
evaporated and purified via flash column chromatography (MeOH/
DCM 1:9) to afford the products 5a and 5e−g.
5-Hydroxy-4-methyl-1-phenyl-1,2,3-triazole 5a. Prepared accord-
ing both GP2 and GP3 to provide 5a as a white solid (70 mg, 80%
1
yield and 201 mg, 95% yield, respectively). H NMR (400 MHz,
CDCl3): δ 12.82 (bs, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.7
Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 2.25 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 152.2, 135.8, 129.1, 128.4, 122.4, 119.6, 8.3. IR
(KBr, cm−1): 1852, 1493, 759. mp 140−140.1 °C. HRMS (ESI) m/z:
[M + H]+ calcd for C9H10N3O 176.0824, found 176.0819.
General Procedure for the DBU-Promoted Synthesis of 5-
Methyl-1,2,3-triazoles 3a and 3b (GP1). To a solution of pyridyl
azides 2a or 2b (0.5 mmol, 1 equiv) and β-ketoester 1a (0.6 mmol,
1.2 equiv) in MeCN (2.5 mL, 0.2M) was added DBU (0.6 mmol, 1.2
equiv), and the reaction mixture was stirred at 50 °C in an oil bath
overnight. The crude mixture was evaporated under vacuum and
5-Hydroxy-4-methyl-1-(4-bromophenyl)-1,2,3-triazole 5b. Pre-
1
pared according to GP2. Off-white solid (110 mg, 87% yield). H
NMR (400 MHz, DMSO-d6): δ 11.76 (bs, 1H), 7.70−7.74 (m, 4H),
D
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2.18 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 147.2, 135.5,
132.8, 124.2, 123.2, 121.0, 9.6. IR (KBr, cm−1): 2389, 1991, 1493. mp
154−154.4 °C. HRMS (ESI) m/z: [M + H]+ calcd for C9H9BrN3O
253.9929, found 253.9935.
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 173.9, 152.0,
135.7, 129.1, 128.4, 123.3, 122.4, 60.4, 33.8, 27.8, 24.1, 22.4, 14.2. IR
(KBr, cm−1): 2507, 1734, 1604, 1570. mp 98−99.1 °C. HRMS (ESI)
m/z: [M + H]+ calcd for C15H20N3O3290.1505, found 290.1502.
Methyl 6-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)hexanoic Ester
8b. Off-white solid (275 mg, 79% yield in solvent-free conditions). 1H
NMR (400 MHz, CDCl3): δ 10.61 (bs, 1H), 7.87 (d, J = 7.7 Hz, 2H),
7.49−7.40 (m, 2H), 7.38−7.33 (m, 1H), 3.61 (s, 3H), 2.65 (t, J = 7.6
Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1.69−1.61 (m, 2H), 1.60−1.51 (m,
2H), 1.34−1.24 (m, 2H). 13C{1H}NMR (101 MHz, CDCl3): δ 174.5,
151.5, 136.0, 129.0, 128.2, 124.3, 122.2, 51.6, 33.8, 28.5, 28.2, 24.3,
22.7. IR (KBr, cm−1): 2857, 2512, 1744, 1606. mp 112−112.6 °C.
HRMS (ESI) m/z: [M + H]+ calcd for C15H20N3O3 290.1505, found
290.1492.
Ethyl 7-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)heptanoic ester
8c. Off-white solid (145 mg, 38% yield in solvent-free conditions).
1H NMR (400 MHz, CDCl3): δ 13.43 (bs, 1H), 7.90 (d, J = 7.6 Hz,
2H), 7.50−7.42 (m, 2H), 7.40−7.32 (m, 1H), 4.08 (q, J = 7.1 Hz,
2H), 2.64 (t, J = 7.6 Hz, 2H), 2.18 (t, J = 7.5 Hz, 2H), 1.71−1.58 (m,
2H), 1.55−1.45 (m, 2H), 1.33−1.10 (m, 7H). 13C{1H} NMR (101
MHz, CDCl3): δ 174.0, 151.9, 136.1, 129.0, 128.1, 124.1, 122.2, 60.3,
34.2, 28.8, 28.7, 28.5, 24.8, 23.0, 14.2. IR (KBr, cm−1): 2869, 2524,
1732, 1599. mp 100−101.3 °C. HRMS (ESI) m/z: [M + H]+ calcd
for C17H24N3O3 318.1818, found 318.1816.
5-Hydroxy-4-methyl-1-(4-methoxyphenyl)-1,2,3-triazole 5c. Pre-
1
pared according to GP2. White solid (64 mg, 62% yield). H NMR
(400 MHz, DMSO-d6): δ 9.67 (bs, 1H), 7.57 (d, J = 9.0 Hz, 1H),
7.09 (d, J = 9.0 Hz, 1H), 3.82 (s, 1H), 2.17 (s, 1H). 13C{1H}NMR
(101 MHz, DMSO-d6): δ 159.3, 146.8, 129.2, 124.5, 123.2, 114.9,
55.9, 9.7. IR (KBr, cm−1): 2616, 1522, 1257. mp 153−154 °C. HRMS
(ESI) m/z: [M + H]+ calcd for C10H12N3O2 206.0930, found
206.0928.
5-Hydroxy-4-methyl-1-(2-phenylphenyl)-1,2,3-triazole 5d. Pre-
pared according to GP2. Off-white solid (95 mg, 75% yield). 1H
NMR (400 MHz, DMSO-d6): δ 9.87 (bs, 1H), 7.70−7.62 (m, 1H),
7.61−7.52 (m, 2H), 7.49−7.41 (m, 1H), 7.36−7.25 (m, 3H), 7.18−
7.05 (m, 2H), 2.05 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
158.9, 147.9, 139.2, 138.3, 133.1, 131.2, 130.7, 128.9, 128.8, 128.5,
127.9, 122.0, 9.6. IR (KBr, cm−1): 2315, 1597, 1478, 1271, 1232. mp
143−143.7 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H14N3O
252.1137, found 252.1129.
5-Hydroxy-4-methyl-1-(1-naphtyl)-1,2,3-triazole 5e. Prepared
1
according to GP2. White solid (89 mg, 79% yield). H NMR (400
MHz, DMSO-d6): δ 8.16 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.8 Hz,
1H), 7.73−7.56 (m, 4H), 7.36 (d, J = 8.2 Hz, 1H), 2.28 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 148.3, 134.1, 131.9, 130.4,
General Procedure for the Synthesis of Long-Chained 5-
Hydroxy-1,2,3-triazolecarboxylic acids 11a−c (GP5). To a
dispersion of 1,2,3-triazole esters 8a−c (0.5 mmol, 1 equiv) in
water (0.1M) at 0 °C was added KOH pellets (5.0 mmol, 10 equiv).
Upon the complete dissolution of KOH and the ester, the ice bath
was removed, and the reaction mixture was vigorously stirred for 2 h
at room temperature. The reaction mixture was again cooled to 0 °C,
and HCl (37% aq.) was added dropwise to reach pH 1 and precipitate
out the free form of the desired compound. The latter was collected
by vacuum filtration and dried under vacuum to afford 5-hydroxy-
1,2,3-triazolecarboxylic acids 11a−c in their pure form.
129.4, 128.6, 128.0, 127.3, 125.9, 125.6, 123.1, 122.4, 9.8. IR (KBr,
cm−1): 3236, 2980, 2867, 2167. mp 119−119.3 °C. HRMS (ESI) m/
z: [M + H]+ calcd for C13H12N3O 226.0980, found 226.0972.
5-Hydroxy-4-methyl-1-(4-nitrophenyl)-1,2,3-triazole 5f. Prepared
according both GP2 and GP3. Yellow solid (59 mg, 53% yield and 202
mg, 76% yield, respectively). 1H NMR (400 MHz, DMSO-d6): δ
12.45 (bs, 1H), 8.42 (d, J = 9.1 Hz, 2H), 8.13(d, J = 9.1 Hz, 2H), 2.19
(s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 146.3, 141.3, 125.6,
125.2, 121.9, 120.6, 9.51. IR (KBr, cm−1): 3350, 2350, 1517, 1330.
mp 156−157.2 °C. HRMS (ESI) m/z: [M + H]+ calcd for C9H9N4O3
221.0675, found 221.0679.
5-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)pentanoic Acid 11a.
1
White solid (79 mg, 60% yield). H NMR (400 MHz, DMSO-d6):
δ 11.95 (bs, 1H), 11.38 (bs, 1H), 7.65 (d, J = 7.3 Hz, 2H), 7.56−7.45
(m, 2H), 7.44−7.34 (m, 1H), 2.51 (t, J = 6.8 Hz, 2H), 2.19 (t, J = 6.8
Hz, 2H), 1.65−1.42 (m, 4H). 13C{1H}NMR (101 MHz, DMSO-d6):
δ 174.5, 135.8, 129.4, 128.0, 122.2, 33.5, 28.4, 24.2, 23.1. IR (KBr,
cm−1): 3340, 2350, 1700, 1601, 1562. mp 122−122.8 °C. HRMS
(ESI) m/z: [M + H]+ calcd for C13H16N3O3 262.1192, found
262.1184.
5-Hydroxy-4-methyl-1-(4-methyl-2-nitrophenyl)-1,2,3-triazole
5g. Prepared according both GP2 and GP3. Yellow solid (66 mg, 56%
1
yield and 234 mg, 83% yield, respectively). H NMR (400 MHz,
CD3OD): δ 8.00 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0
Hz, 1H), 2.54 (s, 3H), 2.22 (s, 3H). 13C{1H} NMR (101 MHz,
CD3OD): δ 145.8, 143.4, 137.0, 135.7, 129.6, 126.7, 126.6, 123.9,
21.0, 8.4. IR (KBr, cm−1): 3088, 2921, 1183, 759. mp 112−112.9 °C.
HRMS (ESI) m/z: [M + H]+ calcd for C10H11N4O3 235.0831, found
235.0822.
6-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)hexanoic Acid 11b.
1
White solid (122 mg, 88% yield). H NMR (400 MHz, DMSO-d6):
δ 11.80 (s, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.53−7.46 (m, 2H), 7.44−
7.36 (m, 1H), 2.51 (t, J = 7.6 Hz, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.61−
1.44 (m, 4H), 1.35−1.23 (m, 2H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 174.6, 135.9, 129.3, 127.9, 122.2, 33.7, 28.6, 28.3, 24.4,
23.2. IR (KBr, cm−1): 3395, 2938, 1724, 1629, 1599. mp 115−115.3
°C. HRMS (ESI) m/z: [M + H]+ calcd for C14H18N3O3 276.1348,
found 276.1333.
5-Hydroxy-4-benzyl-1-phenyl-1,2,3-triazole 5k. Prepared accord-
ing to GP2. White solid (95 mg, 75% yield). H NMR (400 MHz,
1
DMSO-d6): δ 12.30 (bs, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.57−7.50 (m,
2H), 7.46−7.40 (m, 1H), 7.29−7.24 (m, 4H), 7.22−7.15 (m, 1H),
3.96 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 147.5, 140.2,
136.0, 129.3, 128.3, 128.2, 127.7, 126.2, 125.9, 122.0, 29.3. IR (KBr,
cm−1): 2783, 1596, 1493. mp 146−146.5 °C. HRMS (ESI) m/z: [M
+ H]+ calcd for C15H14N3O 252.1137, found 252.1130.
General Procedure for the Synthesis of Long-Chained 5-
Hydroxy-1,2,3-triazole Esters 8a−c (GP4). To a mixture of
commercially available cyclic ketoesters 7a−c (2.4 mmol, 1.2 equiv)
and azidobenzene 4a (2.0 mmol, 1 equiv) in MeCN (0.2M) was
added DBU (2.4 mmol, 1.2 equiv), and the reaction mixture was
stirred at 60 °C in an oil bath overnight. The crude mixture was
purified by silica flash chromatography (AcOEt/petroleum ether
gradient from 1:2 to 1:0) to afford 1,2,3-triazole esters 8a−c as solids.
Better yields were obtained when using the same protocol in solvent-
free conditions.
7-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)heptanoic Acid 11c.
1
White solid (118 mg, 81% yield). H NMR (400 MHz, DMSO-d6):
δ 11.89 (bs, 2H), 7.71 (d, J = 7.7 Hz, 2H), 7.58−7.50 (m, 2H), 7.48−
7.39 (m, 1H), 2.58−2.52 (m, 2H), 2.20 (t, J = 7.3 Hz, 2H), 1.63−
1.54 (m, 2H), 1.54−1.44 (m, 2H), 1.38−1.27 (m, 4H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 174.6, 135.8, 129.3, 128.0, 122.2,
33.7, 28.7, 28.5, 28.4, 24.5, 23.3. IR (KBr, cm−1): 3223, 2948, 1717,
1599. mp 117−117.4 °C. HRMS (ESI) m/z: [M + H]+ calcd for
C15H20N3O3 290.1505, found 290.1518.
Synthesis of N-Phenyl-5-(5-hydroxy-1-phenyl-1,2,3-triazol-
4-yl)pentanamide 10a. Carboxylic acid 11a (0.49 mmol, 1 equiv)
was dissolved in thionyl chloride (0.49 M). The reaction mixture was
refluxed at 60 °C for 2 h in an oil bath. The reaction mixture was
evaporated under vacuum to remove the excess thionyl chloride. The
crude acyl chloride was dissolved in dry DCM (1 mL), and to the
solution were added aniline (0.54 mmol, 1.1 equiv) and triethylamine
(0.54 mmol, 1.1 equiv). The reaction mixture was stirred at room
Ethyl 5-(5-Hydroxy-1-phenyl-1,2,3-triazol-4-yl)pentanoic Ester
8a. Off-white solid (153 mg, 44% yield in solvent-free conditions
versus 101 mg, 29% yield with solvent present). 1H NMR (400 MHz,
CDCl3): δ 13.50 (bs, 1H), 7.85 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 6.9
Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 2.70 (t, J =
7.1 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.75−1.53 (m, 4H), 1.19 (t, J =
E
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Article
temperature under nitrogen overnight. The crude was diluted in
AcOEt (20 mL) and washed with saturated sodium bicarbonate (5
mL) and HCl (5 mL of 1 M aq.). The organic phase was dried over
sodium sulfate and evaporated under vacuum. The crude amide was
purified by flash column chromatography (AcOEt/petroleum ether
1:1 to 1:0) to yield the target compound 10a in a 61% yield (101 mg)
as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 7.72
(d, J = 7.8 Hz, 2H), 7.64−7.51 (m, 4H), 7.48−7.39 (m, 1H), 7.32−
7.23 (m, 2H), 7.06−6.97 (m, 1H), 2.67−2.58 (m, 2H), 2.42−2.31
(m, 2H), 1.75−1.60 (m, 4H). 13C{1H} NMR (101 MHz, DMSO-d6):
δ 171.3, 139.4, 135.8, 129.3, 128.7, 128.0, 123.0, 122.2, 119.1, 36.4,
28.6, 24.9, 23.2. IR (KBr, cm−1): 2372, 1649, 1590. mp 152−153 °C.
HRMS (ESI) m/z: [M + H]+ calcd for C19H21N4O2 337.1665, found
337.1676.
General Procedure for the Synthesis of Long-Chained N-
Phenyl-5-hydroxy-1,2,3-triazoleamides 10b and 10c (GP6). To
a solution of carboxylic acid 11b or 11c (0.40 mmol, 1 equiv) in dry
DCM (0.2M) in a round-bottom flask was added triethylamine (0.48
mmol, 1.2 equiv) and aniline (0.48 mmol, 1.2 equiv). The solution
was added with carbonyldiimidazole (CDI) (0.48 mmol, 1.2 equiv)
and stirred overnight at room temperature. The crude mixture was
diluted with AcOEt (20 mL), washed with HCl (5 mL of 0.5 M aq.),
dried over sodium sulfate, and evaporated under vacuum. The crude
amide was purified by flash column chromatography (AcOEt/
petroleum ether 1:1 to 1:0) to yield the title compounds 10b and
10c as white solids.
Surgeons in Ireland, Dublin 2, Ireland; orcid.org/0000-
0001-9072-3648; Phone: (+353) 1 4022208;
Email: madamo@rcsi.ie
Authors
Roberta Pacifico − Centre for Synthesis and Chemical Biology
(CSCB), Department of Chemistry, Royal College of
Surgeons in Ireland, Dublin 2, Ireland
Dario Destro − Centre for Synthesis and Chemical Biology
(CSCB), Department of Chemistry, Royal College of
Surgeons in Ireland, Dublin 2, Ireland
Malachi W. Gillick-Healy − Centre for Synthesis and
Chemical Biology (CSCB), Department of Chemistry, Royal
College of Surgeons in Ireland, Dublin 2, Ireland; KelAda
Pharmachem Ltd., Belfield, Dublin 4, Ireland
Brian G. Kelly − KelAda Pharmachem Ltd., Belfield, Dublin 4,
Ireland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00778
Author Contributions
∇R.P. and D.D. contributed equally.
Notes
N-Phenyl-6-(5-hydroxy-1-phenyl-1,2,3-triazol-4-yl)hexanamide
The authors declare no competing financial interest.
1
10b. White solid (49 mg, 35% yield). H NMR (400 MHz, DMSO-
d6): δ 11.36 (bs, 1H), 9.86 (s, 1H), 7.71 (d, J = 6.7 Hz, 2H), 7.62−
7.50 (m, 4H), 7.48−7.40 (m, 1H), 7.32−7.22 (m, 2H), 7.05−6.96
(m, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.72−1.55
(m, 4H), 1.45−1.33 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6):
δ 171.3, 139.4, 135.9, 129.3, 128.7, 127.9, 122.9, 122.2, 119.0, 36.4,
28.7, 28.4, 25.0, 23.2. IR (KBr, cm−1): 2387, 1654, 1599. mp 148−
149.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C20H23N4O2
351.1821, found 351.1815.
ACKNOWLEDGMENTS
■
We acknowledge IRC GOIPG/2018/3165 for support to R.P.
and IRC EPSPD/2019/184 for a grant to M.G.H.
REFERENCES
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■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00778.
1
Copies of the H- and 13C{1H}-NMR spectra of the
synthesized compounds, HPLC data of 5a, potentio-
metric titration procedure for triazole 5a, and crystallo-
graphic data of 5a (PDF)
Accession Codes
CCDC 2051417 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
Corresponding Author
Mauro F. A. Adamo − Centre for Synthesis and Chemical
Biology (CSCB), Department of Chemistry, Royal College of
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