A Multicomponent Approach toward Angularly Fused/Linear Bitriazoles: A Cascade Cornforth Rearrangement and Triazolization

Article abstract of DOI:10.1021/acs.joc.0c03014

A multicomponent reaction of triazoloketones, primary amines, and 4-nitrophenyl azide was developed for the synthesis of hitherto unknown angularly fused/linear bitriazoles. The two-stage mechanism was well proven by the isolation of the intermediate. Thi

Full text of DOI:10.1021/acs.joc.0c03014

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A Multicomponent Approach toward Angularly Fused/Linear
Bitriazoles: A Cascade Cornforth Rearrangement and Triazolization
Santhini Pulikkal Veettil, Shandev Pookkandam Parambil, Max Van Hoof, and Wim Dehaen*
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ABSTRACT: A multicomponent reaction of triazoloketones, primary amines, and 4-nitrophenyl azide was developed for the
synthesis of hitherto unknown angularly fused/linear bitriazoles. The two-stage mechanism was well proven by the isolation of the
intermediate. This sequential reaction consists of Cornforth rearrangement and triazolization, which has also been demonstrated in a
one-pot manner.
rganic frameworks adorned with fused or linked
Opolyheterocycles have attracted much attention due to
their numerous applications in material and medicinal
chemistry.1 One of the privileged five membered hetero-
aromatic ring scaffolds, namely 1,2,3-triazoles, are extensively
used as synthetic building blocks in both simple and complex
molecular structures.2−4 Triazole-fused polycyclic heterocycles
have potential application as organometallic ligands, pharma-
ceuticals, and materials.5−7
The copper/ruthenium/iridium-catalyzed azide−alkyne cy-
cloadditions (AACs) have been widely applied for the selective
synthesis of 1,2,3-triazoles.8−10 However, considering that
these metal ions are toxic to living systems, the development of
efficient greener alternatives for their synthesis has received
significant attention over the last few decades. In this regard,
much effort has been devoted toward the organocatalyzed
synthesis of 1,2,3-triazoles.11−15 Surprisingly, among these
approaches, only limited reports dealt with azide-free syn-
thesis.16 The latter would undoubtedly provide a great
advantage because organic azides are highly explosive and
hazardous when used in large scale synthesis. Thus, we
developed a metal-free three-component reaction for the
synthesis of 1,5-di- and 1,4,5-trisubsituted 1,2,3-triazoles from
readily available enolizable ketones, primary alkylamines and
the 4-nitrophenyl azide (4-NPA).17 Later, we explored this so-
called “triazolization reaction” toward the synthesis of
triazapentalenes, various heterocycles, and post functionaliza-
tion and synthesis of natural products.18−22 In light of these
recent advances, we envisioned the possibility of making an
extension of this methodology toward bitriazole motifs.
Apart from the great variety of applications of 1,2,3-triazoles
in medicinal chemistry and other disciplines, suitably
substituted derivatives have been employed as outstanding
and attractive synthons due to their ability to ring open and
generate α-diazoimines. The formed diazoimines always exist
in equilibrium with their closed isomers, which may lead to
several heterocycles through rearrangements.23 It was also
found that the amount of open form becomes larger with an
increasingly electron-withdrawing character of the substituents
and with increasing temperatures. It is also worth noting that
the imino metallocarbene formed after the denitrogenative
decomposition of electron deficient triazoles in the presence of
transition metal catalysts has been well utilized for the
construction of heterocycles by various research groups, as
documented in recent reviews.24,25 Herein, we report the acid
catalyzed formation of an imine resulting from 1,2,3-triazolo
Received: December 23, 2020
Published: February 12, 2021
https://dx.doi.org/10.1021/acs.joc.0c03014
© 2021 American Chemical Society
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a
ketone 1 and the consecutive Cornforth rearrangement
followed by triazolization toward the angularly fused/linear
bitriazoles 4 (Scheme 1).26
Table 1. Optimization of the Reaction Conditions
Scheme 1. Triazolization and Bitriazolization Reactions
At present, the most reliable way of synthesizing 4−4′/5−5′-
linked symmetric bitriazoles and the bis-triazole is the classical
copper-catalyzed Huisgen cycloaddition of dialkynes.27−30
While there are some earlier reports from our laboratory for
the metal-free synthesis of bitriazole scaffolds.6,17 Despite these
advances, alternative and nonmetal catalyzed approaches are
still highly desirable and will lead to greater advancement in
the exploration of bitriazoles and their fused derivatives.
Building on our previous results on the triazolization
reactions, we envisioned an extension of our methodology
toward the synthesis of bitriazoles (4a′) by utilizing
triazoloketone 1a as an enolizable ketone (Scheme 2). The
Scheme 2. Multicomponent Reaction
a
Reaction conditions: triazoloketone 1a (0.20 mmol), p-methoxy
benzylamine 2a (0.50 mmol), p-nitrophenyl azide 3 (0.24 mmol),
b
c
additive (30 mol %), solvent (2.0 mL). Isolated yields. 1a (0.20
d
mmol), p-2a (0.24 mmol), 3 (0.20 mmol). 1a (0.20 mmol), 2a (0.40
mmol), 3 (0.20 mmol).
observed that acetic acid was optimal for the conversion, and
only traces of the product were detected without organic acid.
An increased reaction time for 24 h without the addition of
acid delivered the product 4a in only 20% yield, and further
increase of time did not much effect the conversion (Table 1,
entries 9−12). A temperature of 100 °C proved to be optimal,
and decreasing the temperature drastically reduced the yield of
the reaction (Table 1, entries 4, 13, and 14). Moreover, at 60
°C, no conversion of starting material was observed (Table 1,
entry 15). These observations clearly indicate that an organic
acid and an increased temperature are essential for complete
conversion. Finally, the optimized reaction conditions were
established to provide a maximum yield of 81%, which are
depicted in Table 1, entry 7.
With the optimized reaction conditions in hand, we
evaluated the substrate scope of this methodology (Table 2).
First, the multicomponent process was found to be general
with a diverse range of benzylamines substituted with both
electron-donating and withdrawing substituents, which fur-
nished the fused bitriazole 4a−4e in good yields ranging 65−
81%. Pleasingly, we also found that linear alkylamines were
well tolerated and gave the products in high yields of 85% (4f)
triazoloketone used for this reaction was obtained via the
organocatalytic azide/enolate cycloaddition reaction of 1,3-
diketones 5a and p-nitrophenyl azide 3 (see Experimental
Section, Procedure A).31−33 Thus, we initiated our experi-
ments by treating 1 equiv of triazoloketone 1a, 1.2 equiv of
amine 2a, and 1 equiv of 3 in toluene at 100 °C in the presence
of a catalytic amount of acetic acid for 12 h. The expected
product of triazolization would be 4a′. Surprisingly, the
formation of an angularly fused tetrahydrobenzo-bis([1,2,3]-
triazole) 4a was observed in 45% yield instead (Scheme 2).
Increasing the equivalents of primary amine 2a from 1.2 to 2
equiv concomitantly increased the yield up to 62% (Table 1,
entry 2), which is due to the requirement of two equivalents of
primary amine for the complete conversion of 1a to bitriazole
4a. Further increasing the equivalents of primary amine 2a and
nitrophenyl azide 3 from 2:1 to 2.5:1.2 resulted in a rise in
yield up to 65% (Table 1, entry 3). Next, various solvents were
screened, including acetonitrile, toluene, DMF, DMSO, THF,
and dioxane (Table 1, entries 3−8), and dioxane proved to be
superior. After investigating the effect of various acids, we
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a
product with aliphatic (4p), benzyl (4q), and heteroaryl (4r)
substituents in excellent yields ranging 75−87%.
Table 2. Multicomponent Reaction
To our delight, reducing the reaction time to 1 h followed by
immediate purification afforded N-(4-methoxybenzyl) sub-
stituted triazoloketone 6a in 52% yield. This indicates that this
compound is an intermediate on the way from the reaction of
N-nitrophenyl triazolo ketone 1a to compounds 4a. The
formation of 6a could be referred to as a result of the well-
known Cornforth rearrangement of the imine resulting from
condensation of amine 2a with 1a, followed by hydrolysis of
the rearranged product under the reaction circumstances.27 To
further confirm this, we performed a control experiment in the
absence of 4-nitrophenyl azide 3, and the compound 6a was
isolated in 85% yield (Scheme 3).
Scheme 3. Control Experiments
To further demonstrate the value of this methodology, we
also tested the probability of formation of unsymmetrically
substituted fused bitriazole by making use of the isolated
triazolo ketone 6a. Pleasingly, triazolization reaction of 6a with
hexyl amine resulted the formation of an unsymmetrically
substituted fused bitriazole 7a in 82% yield (Scheme 4).
Scheme 4. Synthesis of Unsymmetrically Substituted Fused
Bitriazoles
a
Reaction conditions: 1 (0.20 mmol), 2 (0.50 mmol), 3 (0.24 mmol,
acetic acid (30 mol %), 1,4-dioxane (2.0 mL), 100 °C, 12 h.
and 81% (4g). Moreover, the bitriazole 4g formed from 2-
hydroxyethylamine was found to be water-soluble. The
aromatic amine p-anisidine reacted smoothly and led to 4h
in 75% yield. Next, allyl (4i) and heteroaryl groups (4j and 4k)
were efficiently incorporated in the bitriazole product.
Additionally, the tryptamine was successfully converted into
the fused bitriazole 4l in 60% yield, showing that natural
product derivatives can be obtained with this methodology.
Further studies were performed to evaluate the reactivity of
different cyclic ketones. Gratifyingly, fused triazoloketones 1b
and 1c derived from 1,3-cyclohexanediones substituted with
methyl and phenyl at the C5 position were well tolerated
under the reaction conditions, giving the corresponding
products 4m and 4n in high yield of 78 (4m) and 75%
(4n). Additionally, from the reaction of triazolodimedone 1d,
the desired product 4o was obtained in 84% yield. Finally, we
turned our attention toward acyclic triazoloketone 1e derived
from acyclic 1,3-diketone for the synthesis of linear bitriazoles.
To our delight, the reaction afforded the corresponding
Several insights from our synthetic work are mechanistically
relevant. First, intermediate 6a was isolated from the reaction
mixture. Second, 6a smoothly underwent triazolization toward
7a. Thus, based on this experimental evidence and the
mechanism reported in the previous work,17 we propose a
plausible mechanism which is depicted in Scheme 5. The
bitriazole synthesis consists of two individual steps involving a
Cornforth rearrangement and the triazolization reaction.26,34
In the first step, the keto triazole I reacts with an equimolar
amount of amine, resulting in the imine intermediate II.
Subsequent ring opening of triazole furnishes the diazo
intermediate III, which immediately cyclizes to the more
stable triazole intermediate IV. Then, hydrolysis of the imine
to ketone V completes the first stage of the reaction (Scheme
5a). The final product was formed by the reaction of V with
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Scheme 5. Plausible Mechanism of the Reaction
Scheme 7. Aromatization and Scale-Up
zoles have not previously been obtainable via other methods as
far as we could ascertain. Further studies to broaden the scope
and applications of these molecules are currently ongoing in
our laboratory.
another equivalent of primary amine and 4-nitrophenyl azide
in the presence of acetic acid (Scheme 5b, named
“triazolization”17). This reaction also involves the formation
of an imine, which via its equilibration with enamine reacts
with the 4-nitrophenyl azide and gives further ring opening,
recyclization, and elimination of 4-nitroaniline, giving 1,2,3-
triazoles as described earlier.17
Next, our success in the bitriazole synthesis from
triazoloketone prompted us to explore the same reaction in a
one-pot two-step reaction starting from readily available 1,3-
diketone. Thus, we treated equimolar amounts of 5a and 3 in 1
mL of DMSO at room temperature in the presence of 5 mol %
DBU. After complete consumption of diketone 5a, 2 equiv of
2a, an additional equivalent of 3, and 30 mol % AcOH were
added along with 1 mL of dioxane, and the mixture was left to
stir at 100 °C for 12 h. Pleasingly, the expected bitriazole 4a
was isolated in 73% yield (Scheme 6).
EXPERIMENTAL SECTION
■
Chemicals received from commercial sources were used without
further purification. Reaction solvents were used as received from
commercial sources. TLC was carried out on Kieselgel 60 F254 plates
(Merck) and visualized with a UV lamp at 254 nm. For column
chromatography, 70-230 mesh silica 60 (E. M. Merck) was used as
the stationary phase. NMR spectra were recorded on a Bruker
Advance III HD 400 (400 MHz) or a Bruker Advance 300 (300
1
MHz) instrument. Chemical shifts for H NMR spectra are reported
as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0)
and relative to the signal of chloroform-d (δ 7.26 ppm) or MeOD
(3.31 ppm). Multiplicities were given as s (singlet), d (doublet), t
(triplet), q (quartet), dd (double doublet), and m (multiplet).
Coupling constants are reported as J values in Hz. Carbon nuclear
magnetic resonance spectra (13C{1H} NMR) are reported as δ in
units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and
relative to the signal of chloroform-d (δ 77.16 ppm) or MeOD (49.0
ppm). Melting points were determined using a Reichert thermovar
apparatus and are uncorrected. Exact mass spectra were acquired with
a quadrupole orthogonal acceleration time-of-flight mass spectrometer
(Synapt G2 HDMS, Waters, Milford, MA). Samples were infused at
3uL/min, and spectra were obtained in positive (or negative)
ionization mode with a resolution of 15 000 (fwhm) using leucine
enkephalin as lock mass.
Scheme 6. One-Pot Synthesis
Synthetic Procedure for the Multicomponent Reaction
toward Bitriazoles. Procedure A: Synthesis of Triazoloketone
(1a−1e).31 1,3-Diketone (1.0 mmol), a mixture of 4-nitrophenyl
azide 3 (1.0 mmol), DBU (5 mol %), and DMF (1.5 mL) were added
to a 25 mL round-bottomed flask and stirred at room temperature for
3 h. After completion of the reaction, the reaction mixture was
quenched with water (5 mL). The precipitate formed was collected by
filtration and further purified by silica gel column chromatography
using ethyl acetate/petroleum ether as eluent.
To highlight the versatility of this methodology, further
oxidative aromatization was executed in a one-pot strategy on
triazoloketone 1a and n-hexylamine 2f. After complete
conversion of 1a to bitriazole 4f, DDQ was added to the
same reaction tube, and this was then left to stir at 80 °C for 12
h. As expected, the benzofused heteroarene 8a was obtained in
70% yield. Additionally, the outlined methodology (Scheme 7)
was applied in the gram scale synthesis of 4f in good yield of
72% by utilizing 1.5 g of 1a.
In conclusion, we have reported herein the synthesis of
angularly fused/linear bitriazoles via the multicomponent
reaction of triazoloketones, primary amines, and 4-nitrophenyl
azide. This methodology was also successfully applied to one-
pot two-step synthesis of bitriazole starting from readily
available 1,3-diketones. Our bitriazolization strategy showed
broad substrate scope and good functional group tolerance.
The proposed two-stage mechanism was successfully proven
by the isolation of the intermediate. The synthesized angularly
fused symmetrically and unsymmetrically substituted bitria-
Procedure B: Synthesis of Bitriazoles (4a−4r).31 The triazolo
ketone (0.2 mmol), primary amine (0.50 mmol), and 4-nitrophenyl
azide (0.24 mmol) were weighed into a reaction tube. 1,4-Dioxane (2
mL) was added along with the addition of 30 mol % acetic acid and
allowed to stir at 100 °C using oil bath for 12 h. Upon completion of
the reaction, the solvent was evaporated in vacuo. The crude reaction
mixture was then directly purified by column chromatography (silica
gel) at first with CH2Cl2 as the eluent to remove all of the 4-
nitroaniline formed during the reaction followed by using a mixture of
petroleum ether and ethyl acetate as eluent.
1-(4-Nitrophenyl)-5,6,7,7a-tetrahydro-1H-benzo[d][1,2,3]triazol-
4(3aH)-one (1a). The reaction was performed according to procedure
A with 1,3-cyclohexanedione 5a (1.12 g, 10.0 mmol) and 4-
nitrophenylazide 3 (1.64 g, 10.0 mmol). The crude product was
purified by silica gel column chromatography (60% ethyl acetate in
hexane) to afford the product 1a as a pale yellow solid (1.87 g, 72%).
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mp: 192−194 °C. Analytical data of 1a: 1H NMR (300 MHz, CDCl3)
δ 8.47 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 3.14 (t, J = 6.3
Hz, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.35−2.27 (m, 2H). 13C{1H} (75
MHz, CDCl3) δ 189.8, 148.0, 144.5, 143.0, 140.5, 125.6, 123.8, 38.2,
23.3, 22.3. HRMS (ESI-HRMS) (m/z): Calcd for C12H11N4O3, (M
+H)+: 259.0826; found: 259.0833. Spectroscopic data for 1a are
consistent with previously reported data.31
134.0, 130.4, 129.3, 127.5, 126.4, 125.9, 114.6, 114.1, 55.4, 55.3, 52.8,
52.4, 20.2, 19.5. HRMS (ESI-HRMS) (m/z): Calcd for C22H23N6O2,
(M+H)+: 403.1877; found: 403.1873.
1,6-Dibenzyl-1,4,5,6-tetrahydrobenzo[1,2-d,3,4-d′]bis([1,2,3]-
triazole) (4b). The reaction was performed according to procedure B
with triazoloketone 1a (52 mg, 0.2 mmol), benzylamine 2b (54 mg,
0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24 mmol). The
crude reaction mixture was then directly purified by silica gel column
chromatography (CH2Cl2 followed by petroleum ether/EtOAc = 3:7)
to afford the product 4b as a white semisolid (53 mg, 78%). Analytical
6-Methyl-1-(4-nitrophenyl)-5,6,7,7a-tetrahydro-1H-benzo[d]-
[1,2,3]triazol-4(3aH)-one (1b). The reaction was performed accord-
ing to procedure A with 5-methyl-1,3-cyclohexanedione 5b (252 mg,
2.0 mmol) and 4-nitrophenylazide 3 (328 mg, 2.0 mmol). The crude
product was purified by silica gel column chromatography (60% ethyl
acetate in hexane) to afford the product 1b as a pale yellow solid (381
1
data of 4b: H NMR (400 MHz, CDCl3): δ 7.59−7.57 (m, 2H),
7.36−7.28 (m, 6H), 7.23−7.21 (m, 2H), 5.85 (s, 2H), 5.52 (s, 2H),
3.10 (t, J = 8.4 Hz, 2H), 2.86 (t, J = 8.4 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 142.0, 135.9, 135.3, 134.3, 134.0, 129.3, 129.0, 128.9,
128.8, 128.5, 127.7, 53.3, 52.8, 20.2, 19.5. HRMS (ESI-HRMS) (m/
z): Calcd for C20H19N6, (M+H)+: 343.1666; found: 343.1664.
1,6-Bis(4-fluorobenzyl)-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis-
([1,2,3]triazole) (4c). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), 4-fluoro
benzylamine 2c (63 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 3:7) to afford the product 4c as a white
solid (57 mg, 75%). mp: 175−177 °C. Analytical data of 4c: 1H NMR
(400 MHz, CDCl3): δ 7.60−7.57 (m, 2H), 7.25−7.22 (m, 2H),
7.08−6.98 (m, 4H), 5.81 (s, 2H), 5.49 (s, 2H), 3.13 (t, J = 8.0 Hz,
2H), 2.88 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
164.2, 164.1, 161.8, 161.7, 142.2, 136.0, 134.1, 131.1, 131.1, 130.9,
130.8, 129.7, 129.6, 126.5, 116.6, 116.3, 115.9, 115.7, 52.6, 52.1, 20.2,
19.5. HRMS (ESI-HRMS) (m/z): Calcd for C20H17F2N6, (M+H)+:
379.1478; found: 379.1482.
1
mg, 70%). mp: 232−234 °C. Analytical data of 1b: H NMR (400
MHz, CDCl3): δ 8.48 (d, J = 9.2 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H),
3.17−3.11 (m, 1H), 2.87−2.75 (m, 2H), 2.56−2.44 (m, 2H), 1.26 (d,
J = 6.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 189.3, 148.0,
144.1, 143.0, 140.5, 125.6, 123.8, 46.6, 31.6, 30.1, 21.0. HRMS (ESI-
HRMS) (m/z): Calcd for C13H13N4O3, (M+H)+: 273.0982; found:
273.0995. Spectroscopic data for 1b are consistent with previously
reported data.31
1-(4-Nitrophenyl)-6-phenyl-5,6,7,7a-tetrahydro-1H-benzo[d]-
[1,2,3]triazol-4(3aH)-one (1c). The reaction was performed accord-
ing to procedure A with 5-phenyl-1,3-cyclohexanedione 5c (376 mg,
2.0 mmol) and 4-nitrophenylazide 3 (328 mg, 2.0 mmol). The crude
product was purified by silica gel column chromatography (60% ethyl
acetate in hexane) to afford the product 1c as a pale yellow solid (434
1
mg, 65%). mp: 172−174 °C. Analytical data of 1c: H NMR (400
MHz, CDCl3): δ 8.46−8.44 (m, 2H), 7.86−7.83 (m, 2H), 7.42−7.29
(m, 5H), 3.66−3.61 (m, 1H), 3.35−3.25 (m, 2H), 3.07−2.86 (m,
2H). 13C{1H} NMR (75 MHz, CDCl3): δ 188.6, 148.0, 143.8, 143.0,
141.1, 140.3, 129.4, 128.1, 126.8, 125.6, 123.8, 45.26, 42.0, 30.3.
HRMS (ESI-HRMS) (m/z): Calcd for C18H15N4O3, (M+H)+:
335.1539; found: 335.1533.
1,6-Bis(4-chlorobenzyl)-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis-
([1,2,3]triazole) (4d). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), 4-chloro
benzylamine 2d (71 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 3:7) to afford the product 4d as a white
solid (64 mg, 78%). mp: 98−100 °C. Analytical data of 4d: 1H NMR
(400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 2H), 7.36−7.34 (m, 2H),
7.30−7.28 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H), 5.81 (s, 2H), 5.49 (s,
2H), 3.13 (t, J = 8.4 Hz, 2H), 2.88 (t, J = 8.4 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3): δ 142.2, 135.9, 135.1, 134.6, 134.2, 133.6, 132.4,
130.3, 129.6, 129.1, 129.1, 126.5, 52.6, 52.1, 20.2, 19.5. HRMS (ESI-
HRMS) (m/z): Calcd for C20H17Cl2N6, (M+H)+: 411.0916; found:
411.0880.
6,6-Dimethyl-1-(4-nitrophenyl)-5,6,7,7a-tetrahydro-1H-benzo-
[d][1,2,3]triazol-4(3aH)-one (1d). The reaction was performed
according to procedure A with 5,5-dimethyl-cyclohexane 1,3-dione
5d (280 mg, 2.0 mmol) and 4-nitrophenylazide 3 (328 mg, 2 mmol).
The crude product was purified by silica gel column chromatography
(60% ethyl acetate in hexane) to afford the product 1d as a pale
yellow solid (400 mg, 70%). mp: 204−206 °C. Analytical data of 1d:
1H NMR (300 MHz, CDCl3): δ 8.48 (d, J = 9.0 Hz, 2H), 7.85 (d, J =
9.0 Hz, 2H), 2.97 (s, 2H), 2.59 (s, 2H), 1.19 (s, 6H). 13C{1H} NMR
(100 MHz, CDCl3) δ 189.3, 148.0, 143.6, 142.3, 140.4, 125.6, 123.8,
52.3, 36.3, 35.9, 28.5. HRMS (ESI-HRMS) (m/z): Calcd for
C14H14N4NaO3, (M+Na)+: 309.0958; Found: 309.0958. Spectro-
scopic data for 1d are consistent with previously reported data.31
1-(5-Methyl-1-(4-nitrophenyl)-4,5-dihydro-1H-1,2,3-triazol-4-yl)-
ethenone (1e). The reaction was performed according to procedure A
with pentane-2,4-dione 5e (252 mg, 2.0 mmol) and 4-nitro-
phenylazide (1.64 g, 2 mmol). The crude product was purified by
silica gel column chromatography (40% ethyl acetate in hexane) to
afford the product 1e as a pale yellow solid (398 mg, 81%). mp: 142−
144 °C. Analytical data of 1e: 1H NMR (400 MHz, CDCl3) δ 8.47 (d,
J = 8.4 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 2.77 (s, 3H), 2.69 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 194.3, 148.4, 144.2, 140.3, 137.5,
1,6-Bis(3,4,5-trimethoxybenzyl)-1,4,5,6-tetrahydrobenzo[1,2-
d:3,4-d′]bis([1,2,3]triazole) (4e). The reaction was performed
according to procedure B with triazoloketone 1a (52 mg, 0.2
mmol), 3,4,5 trimethoxy benylamine 2e (99 mg, 0.50 mmol), and 4-
nitrophenylazide 3 (39 mg, 0.24 mmol). The crude reaction mixture
was then directly purified by silica gel column chromatography
(CH2Cl2 followed by petroleum ether/EtOAc = 1:9) to afford the
product 4e as a white solid (68 mg, 65%). mp: 115−117 °C.
1
Analytical data of 4e: H NMR (400 MHz, CDCl3): δ 6.96 (s, 2H),
6.44 (s, 2H), 5.75 (s, 2H), 5.44 (s, 2H), 3.84−3.79 (m, 18H), 3.14 (t,
J = 8.0 Hz, 2H). 2.92 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 153.9, 153.4, 142.2, 138.5, 138.1, 136.0, 134.3, 130.7, 129.4,
126.5, 106.3, 104.9, 61.0, 60.9, 56.4, 56.3, 53.8, 53.0, 20.3, 19.5.
HRMS (ESI-HRMS) (m/z): Calcd for C26H31N6O6, (M+H)+:
523.2300; found: 523.2306.
1,6-Dihexyl-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis([1,2,3]-
triazole) (4f). The reaction was performed according to procedure B
with triazoloketone 1a (52 mg, 0.2 mmol), n-hexylamine 2f (51 mg,
0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24 mmol). The
crude reaction mixture was then directly purified by silica gel column
chromatography (CH2Cl2 followed by petroleum ether/EtOAc = 1:1)
to afford the product 4f as a colorless viscous liquid (56 mg, 85%).
Analytical data of 4f: 1H NMR (400 MHz, CDCl3): δ 4.68 (t, J = 7.2
Hz, 2H), 4.31 (t, J = 7.2 Hz, 2H), 3.24−3.20 (m, 2H), 3.08−3.04 (m,
125.9, 125.3, 28.1, 10.49. HRMS (ESI-HRMS) (m/z): Calcd for
C11H10N4NaO3, (M+Na)+: 269.0645; Found: 269.0605.
1,6-Bis(4-methoxybenzyl)-1,4,5,6-tetrahydrobenzo[1,2-d,3,4-d′]-
bis([1,2,3]triazole) (4a). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), 4-methoxy
benzylamine 2a (69 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 3:7) to afford the product 4a as a white
1
semisolid (66 mg, 81%). Analytical data of 4a: H NMR (400 MHz,
CDCl3): δ 7.54 (d, J = 8 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 6.84 (dd, J1
= 8 Hz, J2 = 16.4 Hz, 4H), 5.77 (s, 2H), 5.44 (s, 2H), 3.78 (s, 3H),
3.74 (s, 3H), 3.08 (t, J = 8.4 Hz, 2H), 2.85 (t, J = 8.4 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 160.0, 159.7, 142.0, 135.9,
4350
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Note
2H), 2.08−2.00 (m, 2H), 1.94−1.87 (m, 2H), 1.33−1.25 (m, 12H),
0.90−0.84 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 141.9,
135.5, 133.8, 126.8, 50.1, 48.8, 31.4, 31.3, 30.1, 30.0, 26.3, 26.2, 22.6,
20.5, 19.6, 14.1, 14.1. HRMS (ESI-HRMS) (m/z): Calcd for
C18H31N6, (M+H)+: 331.2605; found: 331.2605.
1H), 7.09−7.07 (m, 1H), 7.00−6.98 (m, 1H), 6.93−6.91 (m, 1H),
6.02 (s, 2H), 5.70 (s, 2H), 3.17−3.13 (m, 2H), 3.01−2.97 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 142.1, 136.9, 135.8, 134.1,
128.6, 127.9, 127.5, 127.2, 127.1, 126.9, 47.7, 47.4, 20.3, 19.6. HRMS
(ESI-HRMS) (m/z): Calcd for C16H15N6S2,(M+H)+: 355.0794;
found: 355.0794
2,2′-(4,5-Dihydrobenzo[1,2-d:3,4-d′]bis([1,2,3]triazole)-1,6-diyl)-
diethanol (4g). The reaction was performed according to procedure
B with triazoloketone 1a (52 mg, 0.2 mmol), 2-aminoethanol 2g (31
mg, 0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24 mmol). The
crude reaction mixture was then directly purified by silica gel column
chromatography (CH2Cl2 followed by petroleum ether/EtOAc = 2:8)
to afford the product 4g as a colorless viscous liquid (40 mg, 81%).
Analytical data of 4g: 1H NMR (400 MHz, MeOD) δ 4.78 (t, J = 5.6
Hz, 2H), 4.49 (t, J = 4.8 Hz, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.96 (t, J =
4.8 Hz, 2H), 3.25−3.21 (m, 2H), 3.18−3.14 (m, 2H). 13C{1H} NMR
(101 MHz, MeOD) δ 143.6, 137.8, 135.7, 128.8, 61.9, 61.3, 53.3,
52.3, 20.9, 20.5. HRMS (ESI-HRMS) (m/z): Calcd for C10H15N6O2,
(M+H)+: 251.1251; Found: 251.1256.
1,6-Bis(2-(1H-indol-3-yl)ethyl)-1,4,5,6-tetrahydrobenzo[1,2-
d:3,4-d′]bis([1,2,3]triazole) (4l). The reaction was performed
according to procedure B with triazoloketone 1a (52 mg, 0.2
mmol), 2-(1H-indol-3-yl)ethanamine 2l (80 mg, 0.50 mmol), and 4-
nitrophenylazide 3 (39 mg, 0.24 mmol). The crude reaction mixture
was then directly purified by silica gel column chromatography
(CH2Cl2 followed by petroleum ether/EtOAc = 1:4) to afford the
product 4l as a white semisolid (54 mg, 60%). Analytical data of 4l:
1H NMR (300 MHz, CDCl3) δ 8.09−8.07 (m, 2H), 7.66 (d, J = 7.5
Hz, 1H), 7.40−7.28 (m, 3H), 7.20−7.04 (m, 5H), 6.71 (d, J = 2.0 Hz,
1H), 4.97 (t, J = 7.6 Hz, 2H), 4.55 (t, J = 6.5 Hz, 2H), 3.50 (t, J = 7.5
Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 8.1 Hz, 2H), 2.15 (t, J =
8.1 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.1, 142.1,
136.3, 136.2, 135.1, 134.8, 127.6, 127.0, 126.9, 122.8, 122.7, 122.1,
120.0, 119.7, 111.7, 111.6, 111.2, 111.1, 50.6, 49.5, 26.7, 26.3, 20.1,
19.1. HRMS (ESI-HRMS) (m/z): Calcd for C26H25N8, (M+H)+:
449.2197; found: 449.2193.
1,6-Dihexyl-4-methyl-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis-
([1,2,3]triazole) (4m). The reaction was performed according to
procedure B with triazoloketone 1b (54 mg, 0.2 mmol), n-hexylamine
2f (51 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24
mmol). The crude reaction mixture was then directly purified by silica
gel column chromatography (CH2Cl2 followed by petroleum ether/
EtOAc = 3:7) to afford the product 4m as a colorless viscous liquid
(54 mg, 78%). Analytical data of 4m: 1H NMR (400 MHz, CDCl3) δ
4.67 (t, J = 7.2 Hz, 2H), 4.35−4.27 (m, 2H), 3.52−3.42 (m, 1H),
3.15 (dd, J1 = 16.4 Hz, J2 = 7.6 Hz, 1H), 2.70 (dd, J1 = 16.4, J2 = 8.4
Hz, 1H), 2.07−2.00 (m, 2H), 1.91−1.86 (m, 2H), 1.47 (d, J = 6.8 Hz,
3H), 1.35−1.28 (m, 12H), 0.89−0.83 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 146.4, 135.2, 133.6, 125.9, 50.0, 48.8, 31.3, 30.1, 28.3,
27.9, 26.2, 22.6, 19.8, 14.1. HRMS (ESI-HRMS) (m/z): Calcd for
C19H33N6, (M+H)+: 345.2761; found: 345.2761.
1,6-Bis(4-methoxyphenyl)-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]-
bis([1,2,3]triazole) (4h). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), 4-methoxy
aniline 2h (62 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39 mg,
0.24 mmol). The crude reaction mixture was then directly purified by
silica gel column chromatography (CH2Cl2 followed by petroleum
ether/EtOAc = 2:8) to afford the product 4h as a white solid (56 mg,
1
75%). mp: 182−184 °C. Analytical data of 4h: H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 9.2 Hz, 2H), 7.46−7.44 (m,2H), 7.10−7.05 (m,
4H), 3.89 (s, 6H), 3.30−3.25 (m, 2H), 3.19−3.15 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 160.6, 160.2, 143.0, 135.9, 134.8, 130.2,
129.1, 125.3, 124.9, 115.0, 114.6, 55.8, 55.7, 20.9, 20.5. HRMS (ESI-
HRMS) (m/z): Calcd for C20H19N6O2, (M+H)+: 375.1564; found:
375.1567.
1,6-Diallyl-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis([1,2,3]-
triazole) (4i). The reaction was performed according to procedure B
with triazoloketone 1a (52 mg, 0.2 mmol), allylamine 2i (26 mg, 0.50
mmol), and 4-nitrophenylazide 3 (39 mg, 0.24 mmol). The crude
reaction mixture was then directly purified by silica gel column
chromatography (CH2Cl2 followed by petroleum ether/EtOAc = 2:8)
to afford the product 4i as a brown viscous liquid (33 mg, 68%).
1
1,6-Dihexyl-4-phenyl-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis-
([1,2,3]triazole) (4n). The reaction was performed according to
procedure B with triazoloketone 1c (67 mg, 0.2 mmol), n-hexylamine
2f (51 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24
mmol). The crude reaction mixture was then directly purified by silica
gel column chromatography (CH2Cl2 followed by petroleum ether/
EtOAc = 3:7) to afford the product 4n as a brown viscous liquid (61
Analytical data of 4i: H NMR (400 MHz, CDCl3) δ 6.20−6.10 (m,
1H), 6.03−5.93 (m, 1H), 5.40−5.33 (m, 2H), 5.34−5.28 (m, 3H),
5.24−5.18 (m, 1H), 4.99−4.97 (m, 2H), 3.21 (t, J = 7.6 Hz, 2H),
3.05 (t, J = 8.8 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.1,
135.7, 134.4, 131.5, 130.8, 126.8, 119.8, 52.1, 51.3, 20.4, 19.5. HRMS
(ESI-HRMS) (m/z): Calcd for C12H15N6, (M+H)+: 243.1353;
Found: 243.1350.
1
mg, 75%). Analytical data of 4n: H NMR (300 MHz, CDCl3) δ
1,6-Bis(pyridin-2-ylmethyl)-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-
d′]bis([1,2,3]triazole) (4j). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), pyridin-2-
ylmethanamine 2j (54 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 1:9) to afford the product 4j as a brown
7.30−7.23 (m, 4H), 7.16−7.13 (m, 2H), 4.74 (t, J = 7.5 Hz, 2H),
4.68−4.63 (m, 1H), 4.26 (t, J = 6.9 Hz, 2H), 3.48−3.40 (m, 1H),
3.19−3.11 (m, 1H), 2.11−2.04 (m, 2H), 1.84−1.75 (m, 2H), 1.39−
1.24 (m, 12H), 0.89−0.85 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 144.4, 142.0, 135.3, 133.1, 129.0, 127.5, 127.4, 50.2, 48.9,
38.7, 31.3, 31.2, 30.1, 30.0, 29.6, 26.3, 26.2, 22.6, 22.5, 14.1. HRMS
(ESI-HRMS) (m/z): Calcd for C24H35N6, (M+H)+: 407.2918; found:
407.2915.
1
viscous liquid (45 mg, 65%). Analytical data of 4j: H NMR (400
MHz, CDCl3) δ 8.58−8.55 (m, 2H), 7.69−7.67 (m, 1H), 7.62−7.60
(m, 2H), 7.28−7.24 (m, 2H), 7.21−7.18 (m, 2H), 6.02 (s, 2H), 5.62
(s, 2H), 3.22−3.18 (m, 2H), 3.11−3.06 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 154.8, 154.0, 149.9, 149.9, 142.2, 137.5, 137.1,
135.7, 135.2, 127.4, 123.6, 123.1, 122.4, 122.3, 54.7, 54.2, 20.3, 19.7.
HRMS (ESI-HRMS) (m/z): Calcd for C18H17N8, (M+H)+:
345.1571; Found: 345.1580.
1,6-Dihexyl-4,4-dimethyl-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]-
bis([1,2,3]triazole) (4o). The reaction was performed according to
procedure B with triazoloketone 1d (58 mg, 0.2 mmol), 4-methoxy
benzylamine 2a (69 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 3:7) to afford the product 4o as a white
1,6-Bis(thiophen-2-ylmethyl)-1,4,5,6-tetrahydrobenzo[1,2-d:3,4-
d′]bis([1,2,3]triazole)(4k). The reaction was performed according to
procedure B with triazoloketone 1a (52 mg, 0.2 mmol), thiophen-2-
ylmethanamine 2k (57 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39
mg, 0.24 mmol). The crude reaction mixture was then directly
purified by silica gel column chromatography (CH2Cl2 followed by
petroleum ether/EtOAc = 1:9) to afford the product 4k as a brown
1
semisolid (72 mg, 84%). Analytical data of 4o: H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.84 (dd,
J1 = 16.6, J2 = 8.8 Hz, 4H), 5.78 (s, 2H), 5.46 (s, 2H), 3.78 (s, 3H),
3.74 (s, 3H), 2.64 (s, 2H), 1.29 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.9, 159.7, 150.1, 135.4, 133.9, 130.4, 129.1, 127.5, 126.2,
124.5, 114.6, 114.1, 55.4, 55.3, 52.8, 52.3, 35.5, 33.6, 28.1. HRMS
(ESI-HRMS) (m/z): Calcd for C24H27N6O2, (M+H)+: 431.2190;
found: 431.2189.
1
semisolid (51 mg, 72%). Analytical data of 4j: H NMR (400 MHz,
CDCl3) δ 7.36−7.35 (m, 1H), 7.32−7.30 (m, 1H), 7.24−7.23 (m,
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Note
1,3′-Bis(4-methoxybenzyl)-5-methyl-1H,3′H-4,4′-bi(1,2,3-tria-
zole) (4p). The reaction was performed according to procedure B
with triazoloketone 1e (49 mg, 0.2 mmol), 4-methoxy benzylamine
(69 mg, 0.50 mmol), and 4-nitrophenylazide 3 (39 mg, 0.24 mmol).
The crude reaction mixture was then directly purified by silica gel
column chromatography (CH2Cl2 followed by petroleum ether/
EtOAc = 2:8) to afford the product 4p as a semi white solid (62 mg,
eluent to afford the product 7a as a white semisolid (60 mg, 82%).
Analytical data of 7a: 1H NMR (400 MHz, CDCl3) δ 7.19−7.17 (m,
2H), 6.88−6.85 (m, 2H), 5.46 (s, 2H), 4.65 (t, J = 7.3 Hz, 2H), 3.78
(s, 3H), 3.13−3.09 (m, 2H), 2.89−2.85 (m, 2H), 2.04−1.98 (m, 2H),
1.37−1.24 (m, 6H), 0.86−0.83 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.0, 141.8, 136.0, 133.9, 129.2, 126.6, 126.0, 114.6, 55.4,
52.4, 50.0, 31.3, 30.0, 26.2, 22.5, 20.3, 19.6, 14.1. HRMS (ESI-
HRMS) (m/z): Calcd for C20H27N6O, (M+H)+: 367.2241; found:
367.2239.
Synthesis and Characterization of 1,6-Dihexyl-1,6-
dihydrobenzo[1,2-d:3,4-d′]bis([1,2,3]triazole) (8a). The triazolo
ketone 1a (52 mg, 0.2 mmol), n-hexylamine 2f (20 mg, 0.20
mmol), and 4-nitrophenyl azide (33 mg, 0.20 mmol) were weighed
into a reaction tube, and 1,4-dioxane (2 mL) and 30 mol % acetic acid
were added and allowed to stir at 100 °C for 12 h. Upon completion
of the reaction, the solvent was evaporated in vacuo. One milliliter of
dioxane and DDQ were added to the same reaction tube, and this was
then left to stir at 80 °C using an oil bath for 12 h. The crude reaction
mixture was then directly purified by column chromatography (silica
gel) at first with CH2Cl2 as the eluent to remove all the 4-nitroaniline
formed during the reaction followed by using a mixture of petroleum
ether and ethyl acetate (60% ethyl acetate in hexane) to afford the
product 8a as a colorless viscous liquid (46 mg, 70%). Analytical data
of 8a: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 1H), 7.44
(d, J = 9.2 Hz, 1H), 5.08 (t, J = 7.2 Hz, 2H), 4.71 (t, J = 7.2 Hz, 2H),
2.25−2.16 (m, 2H), 2.09−2.02 (m, 2H), 1.43−1.23 (m, 12H), 0.89−
0.83 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.9, 133.1,
132.4, 125.0, 120.1, 106.9, 50.6, 49.0, 31.3, 30.0, 29.8, 26.5, 26.3, 22.6,
22.5, 14.1, 14.0. HRMS (ESI-HRMS) (m/z): Calcd for C18H29N6, (M
+H)+: 329.2448; found: 329.2448.
Procedure for One-Pot Reaction. 1,3-Cyclohexanedione 5a (112
mg, 1.0 mmol), 4-nitrophenylazide 3 (164 mg, 1.0 mmol), DBU (5
mol %), and DMSO (1.0 mL) were added to a reaction tube and
stirred at room temperature for 1 h. After completion of the reaction,
n-hexylamine 2f (202 mg, 2 mmol) and 4-nitrophenyl azide 3 (164
mg, 1.0 mmol) were weighed into the same reaction tube, and 1,4-
dioxane (1 mL) was added along with 30 mol % acetic acid and
allowed to stir at 100 °C using oil bath for 12 h. Upon completion of
the reaction, the solvent was evaporated in vacuo. To the reaction
mixture, water was added and then extracted with ethyl acetate. The
combined organic layers were thoroughly washed with water and
dried over MgSO4, and the solvent was removed under vacuo. The
crude reaction mixture was then directly purified by column
chromatography (silica gel) at first with CH2Cl2 as the eluent to
remove all the 4-nitroaniline formed during the reaction followed by
using a mixture of petroleum ether and ethyl acetate as eluent to
afford the product 4f as a viscous liquid (241 mg, 73%).
Gram Scale Synthesis. The triazolo ketone 6a (1.5 g, 5.8 mmol),
n-hexylamine 2f (1.5 g, 14.5 mmol), and 4-nitrophenyl azide 3 (1.1 g,
6.96 mmol) were weighed into a 100 mL round-bottom flask, and 1,4-
dioxane (30 mL) was added along with 30 mol % acetic acid and
allowed to stir at 100 °C using oil bath for 12 h. Upon completion of
the reaction, the solvent was evaporated in vacuo. The crude reaction
mixture was then directly purified by column chromatography (silica
gel) at first with CH2Cl2 as the eluent to remove all the 4-nitroaniline
formed during the reaction followed by using a mixture of petroleum
ether and ethyl acetate as eluent to afford the product 4f as a viscous
solid (1.4 g, 72%).
1
80%). Analytical data of 4p: H NMR (400 MHz, CDCl3) δ 7.70 (s,
1H), 7.12 (dd, J1 = 16.8, J2 = 8.8 Hz, 4H), 6.88 (d, J = 8.4 Hz, 2H),
6.70 (d, J = 8.8 Hz, 2H), 5.87 (s, 2H), 5.45 (s, 2H), 3.80 (s, 3H), 3.72
(s, 3H), 2.08 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.9,
159.4, 133.7, 132.7, 132.1, 129.7, 128.9, 127.9, 127.7, 126.2, 114.6,
114.0, 55.5, 55.3, 52.4, 52.0, 8.6. HRMS (ESI-HRMS) (m/z): Calcd
for C21H23N6O2, (M+H)+: 391.1877; found: 391.1873.
1,3′-Dihexyl-5-methyl-1H,3′H-4,4′-bi(1,2,3-triazole) (4q). The
reaction was performed according to procedure B with triazoloketone
1e (52 mg, 0.2 mmol), n-hexylamine 2f (69 mg, 0.50 mmol), and 4-
nitrophenylazide (39 mg, 0.24 mmol). The crude reaction mixture
was then directly purified by silica gel column chromatography
(CH2Cl2 followed by petroleum ether/EtOAc = 1:1) to afford the
product 4q as a colorless viscous liquid (55 mg, 87%). Analytical data
1
of 4q: H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 4.72−4.68 (m,
2H), 4.33−4.29 (m, 2H), 2.40 (s, 3H), 1.93−1.88(m, 4H), 1.34−1.25
(m, 12H), 0.90−0.81 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
133.4, 132.0, 131.4, 128.1, 49.7, 48.5, 31.3, 31.3, 30.3, 29.9, 26.3, 26.2,
22.6, 22.5, 14.1, 8.8. HRMS (ESI-HRMS) (m/z): Calcd for
C17H31N6, (M+H)+: 319.2605; found: 319.2598.
5-Methyl-1,3′-bis(thiophen-2-ylmethyl)-1H,3′H-4,4′-bi(1,2,3-tria-
zole) (4r). The reaction was performed according to procedure B with
triazoloketone 1a (52 mg, 0.2 mmol), benzylamine (69 mg, 0.50
mmol), and 4-nitrophenylazide (39 mg, 0.24 mmol). The crude
reaction mixture was then directly purified by silica gel column
chromatography (CH2Cl2 followed by petroleum ether/EtOAc = 3:7)
to afford the product 4r as a brown semisolid (51 mg, 75%).
1
Analytical data of 4r: H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H),
7.32 (dd, J = 5.1, 1.3 Hz, 1H), 7.13 (dd, J 1= 5.1, J 2= 1.2 Hz, 1H),
7.04−6.94 (m, 3H), 6.80 (dd, J = 5.1, 3.5 Hz, 1H), 6.14 (s, 2H), 5.71
(s, 2H), 2.27 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 137.2,
136.1, 133.5, 132.4, 132.2, 127.9, 127.6, 127.4, 126.9, 126.8, 126.5,
47.6, 47.3, 8.9. HRMS (ESI-HRMS) (m/z): Calcd for C15H14N6NaS2,
(M+Na)+: 365.0614; found: 365.0611.
Synthesis and Characterization of 1-(4-Methoxybenzyl)-6,7-
dihydro-1H-benzo[d][1,2,3]triazol-4(5H)-one (6a). The triazolo
ketone 1a (52 mg, 0.2 mmol) and 4-methoxy benzylamine 2a (27
mg, 0.20 mmol) were weighed into a reaction tube. After that, 30 mol
% acetic acid and 1,4-dioxane (2 mL) were added and allowed to stir
at 100 °C using oil bath for 3 h. Upon completion of the reaction, the
solvent was evaporated in vacuo. The crude reaction mixture was then
directly purified by column chromatography (silica gel) at first with
CH2Cl2 as the eluent to remove all the 4-nitroaniline formed during
the reaction followed by using a mixture of petroleum ether and ethyl
acetate as eluent to afford the product 6a as a white solid (44 mg,
1
85%). mp: 140−142 °C. Analytical data of 6a: H NMR (400 MHz,
CDCl3): δ 7.18 (d, J = 8.8 Hz, 2H), 6.89−6.87(m, 2H), 5.47 (s, 2H),
3.79 (s, 3H), 2.72−2.69 (m, 2H), 2.55−2.52 (m, 2H), 2.16−2.13 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 190.2, 160.0, 144.5, 142.5,
129.3, 125.8, 114.6, 55.4, 52.1, 38.2, 23.0, 20.5. HRMS (ESI-HRMS)
(m/z): Calcd for C14H15N3NaO2, (M+Na)+: 280.1056; found:
280.1059.
Synthesis and Characterization of 1-Hexyl-6-(4-methoxybenzyl)-
1,4,5,6-tetrahydrobenzo[1,2-d:3,4-d′]bis([1,2,3]triazole) (7a). The
triazolo ketone 6a (56 mg, 0.2 mmol), n-hexylamine 2f (20 mg,
0.20 mmol), and 4-nitrophenyl azide 3 (33 mg, 0.20 mmol) were
weighed into a reaction tube, and 1,4-dioxane (2 mL) was added
along with 30 mol % acetic acid and allowed to stir at 100 °C using oil
bath for 12 h. Upon completion of the reaction, the solvent was
evaporated in vacuo. The crude reaction mixture was then directly
purified by column chromatography (silica gel) at first with CH2Cl2 as
the eluent to remove all the 4-nitroaniline formed during the reaction
followed by using a mixture of petroleum ether and ethyl acetate as
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03014.
NMR spectra of all of the synthesized compounds (1a−
1e, 4a−4r, 6a, 7a, and 8a) (PDF)
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J. Org. Chem. 2021, 86, 4346−4354

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Functionalized NH-1,2,3-Triazoles. Chem. - Eur. J. 2008, 14 (30),
9143−9147.
AUTHOR INFORMATION
■
Corresponding Author
(12) Belkheira, M.; El Abed, D.; Pons, J. M.; Bressy, C.
Organocatalytic Synthesis of 1,2,3-Triazoles from Unactivated
Ketones and Arylazides. Chem. - Eur. J. 2011, 17 (46), 12917−12921.
(13) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J.
Organocatalytic Enamide-Azide Cycloaddition Reactions: Regiospe-
cific Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles. Chem. - Eur. J.
2011, 17 (13), 3584−3587.
Wim Dehaen − Molecular Design and Synthesis, Department
of Chemistry, KU Leuven, Leuven B-3001, Belgium;
orcid.org/0000-0002-9597-0629; Email: wim.dehaen@
kuleuven.be
Authors
(14) John, J.; Thomas, J.; Dehaen, W. Organocatalytic Routes
toward Substituted 1,2,3-Triazoles. Chem. Commun. 2015, 51 (54),
10797−10806.
Santhini Pulikkal Veettil − Molecular Design and Synthesis,
Department of Chemistry, KU Leuven, Leuven B-3001,
Belgium; orcid.org/0000-0003-2244-9741
Shandev Pookkandam Parambil − Molecular Design and
Synthesis, Department of Chemistry, KU Leuven, Leuven B-
3001, Belgium; orcid.org/0000-0001-8996-2772
Max Van Hoof − Molecular Design and Synthesis, Department
of Chemistry, KU Leuven, Leuven B-3001, Belgium;
orcid.org/0000-0001-5396-9892
(15) Ramachary, D. B.; Shashank, A. B.; Karthik, S. An Organo-
catalytic Azide-Aldehyde [3 + 2] Cycloaddition: High-Yielding
Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles. Angew.
Chem. Int. Ed. 2014, 53 (39), 10420−10424.
(16) Chen, Z.; Cao, G.; Song, J.; Ren, H. Recent Developments in
Azide-Free Synthesis of 1,2,3-Triazoles. Chin. J. Chem. 2017, 35 (12),
1797−1807.
(17) Thomas, J.; Jana, S.; John, J.; Liekens, S.; Dehaen, W. A General
Metal-Free Route towards the Synthesis of 1,2,3-Triazoles from
Readily Available Primary Amines and Ketones. Chem. Commun.
2016, 52 (14), 2885−2888.
(18) Silveira-Dorta, G.; Jana, S.; Borkova, L.; Thomas, J.; Dehaen,
W. Straightforward Synthesis of Enantiomerically Pure 1,2,3-Triazoles
Derived from Amino Esters. Org. Biomol. Chem. 2018, 16 (17), 3168−
3176.
(19) Karypidou, K.; Ribone, S. R.; Quevedo, M. A.; Persoons, L.;
Pannecouque, C.; Helsen, C.; Claessens, F.; Dehaen, W. Synthesis,
Biological Evaluation and Molecular Modeling of a Novel Series of
Fused 1,2,3-Triazoles as Potential Anti-Coronavirus Agents. Bioorg.
Med. Chem. Lett. 2018, 28 (21), 3472−3476.
(20) Krasniqi, B.; Dehaen, W. Synthesis of 1,2,3-Triazolo-Fused
Allocolchicine Analogs via Intramolecular Oxidative Biaryl Coupling.
Org. Lett. 2019, 21 (13), 5002−5005.
(21) Wang, R.; Li, Y.; Dehaen, W. Antiproliferative Effect of
Mitochondria-Targeting Allobetulin 1,2,3-Triazolium Salt Derivatives
and Their Mechanism of Inducing Apoptosis of Cancer Cells. Eur. J.
Med. Chem. 2020, 207, 112737.
(22) Wang, Y.; Opsomer, T.; Van Meervelt, L.; Dehaen, W. Ring-
Degenerate Rearrangement Resulting from the Azo Coupling
Reaction of a 3-Aryl-1,3a,6a-Triazapentalene. J. Org. Chem. 2020, 85
(14), 9434−9439.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03014
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
W.D. acknowledges financial support from KU Leuven (grant
C14/19/78). P.V.S. acknowledges KU Leuven Internal Funds
for PDM fellowship (PDM/18/128). Mass spectrometry was
made possible by the support of the Hercules Foundation of
the Flemish Government (grant 20100225-7).
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