Chemoselectivity in the Synthesis of 1,2,3-Triazoles from Enolizable Ketones, Primary Alkylamines, and 4-Nitrophenyl Azide

Article abstract of DOI:10.1055/s-0036-1588856

In recent years, several organocatalytic/metal-free synthetic pathways towards 1,2,3-triazoles have been reported. One of them is a general metal-free route towards the synthesis of 1,5-di- or fully-substituted 1,2,3-triazoles, designed by our group and named the 'triazolization' reaction of ketones. Limitations of this route were encountered in reactions with more activated ketones, where the corresponding 1-(4-nitrophenyl)-1,2,3-triazole was found back as the major product. Interestingly, three different triazoles are formed when 1,3-diphenylacetone is used as the ketone. In the present work, 1,3-diphenylacetone was used as a model substrate to investigate the chemoselectivity of our metal-free route under different reaction circumstances. This led to the conclusion that the formation of the desired 1,2,3-triazole is favored in apolar solvents, at high temperatures, and in the presence of acetic acid. By using one equivalent of acetic acid, previously inaccessible fully decorated 1,2,3-triazoles can be synthesized from simple α-arylketones in moderate to high yields..

Full text of DOI:10.1055/s-0036-1588856

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
special topic
A
en
T. Opsomer et al.
Special Topic
Synthesis
Chemoselectivity in the Synthesis of 1,2,3-Triazoles from Enoliz-
able Ketones, Primary Alkylamines, and 4-Nitrophenyl Azide
Tomas Opsomer
Joice Thomas*1
Wim Dehaen*
Molecular Design and Synthesis, Department of Chemistry,
KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
wim.dehaen@chem.kuleuven.be
Published as part of the Special Topic Modern Cyclization
Strategies in Synthesis
Received: 30.03.2017
Accepted after revision: 08.05.2017
Published online: 07.06.2017
tions, for example, perturbation of naturally occurring pro-
cesses in biological systems.6 In addition, the alkyne moi-
eties are not always readily available and their introduction
often requires a difficult multistep synthesis. Hence, in re-
cent years, the search for metal-free and organocatalytic
routes toward 1,2,3-triazoles has become a thriving area.7
Various amines and organic bases have been successful-
ly applied as catalysts in reactions toward 1,2,3-triazole
heterocycles.8 Depending on the nature of the catalyst and
the reagents, either an enamine, iminium ion, or enolate
occurs as a dipolarophilic intermediate in the reaction
mechanism.7 The in situ formed dipolarophiles can then re-
act with an azido compound. Many of these routes are sim-
ilar to the previously reported Dimroth reaction, described
by L’abbé as ‘the condensation of organic azides with active
methylene compounds in the presence of an equimolar
amount of organic or inorganic base leading to highly sub-
stituted 1,2,3-triazoles in a regioselective manner’.9 The or-
ganocatalytic reactions leading to diversely functionalized
1,2,3-triazoles are of high synthetic importance due to their
advantages; they are metal-free, regioselective, and they
make use of cheap and readily available building blocks.
However, there are a number of weaknesses. First, the sub-
stituents at the N1 position are limited to aryl groups, as in
most cases only aryl azides can be applied. Second, a differ-
ent azide is needed for the synthesis of each analogue.
These azides are potentially hazardous and in many cases
commercially not available.10
DOI: 10.1055/s-0036-1588856; Art ID: ss-2017-c0209-st
Abstract In recent years, several organocatalytic/metal-free synthetic
pathways towards 1,2,3-triazoles have been reported. One of them is a
general metal-free route towards the synthesis of 1,5-di- or fully-substi-
tuted 1,2,3-triazoles, designed by our group and named the ‘triazoliza-
tion’ reaction of ketones. Limitations of this route were encountered in
reactions with more activated ketones, where the corresponding 1-(4-
nitrophenyl)-1,2,3-triazole was found back as the major product. Inter-
estingly, three different triazoles are formed when 1,3-diphenylacetone
is used as the ketone. In the present work, 1,3-diphenylacetone was
used as a model substrate to investigate the chemoselectivity of our
metal-free route under different reaction circumstances. This led to the
conclusion that the formation of the desired 1,2,3-triazole is favored in
apolar solvents, at high temperatures, and in the presence of acetic ac-
id. By using one equivalent of acetic acid, previously inaccessible fully
decorated 1,2,3-triazoles can be synthesized from simple α-arylketones
in moderate to high yields.
Key words 1,2,3-triazole, triazolization, metal-free, multicomponent
reaction, α-arylketone, Dimroth
In the past decade, 1,2,3-triazole chemistry gained a lot
of attention in the field of synthetic, material, and medici-
nal chemistry.2–4 With regards to the latter, the 1,2,3-tri-
azole moiety is believed to be an effective amide isoster be-
cause of its large dipole moment, capability for H-bond for-
mation, and metabolic stability. As examples have shown
that functionalized triazoles often possess interesting bio-
logical properties, they can be seen as potential targets for
drug discovery.3e,4 The renewed interest in 1,2,3-triazoles
started with the discovery of the Cu-catalyzed azide-alkyne
cycloaddition (AAC) reaction towards 1,4-disubstituted
1,2,3-triazoles. The CuAAC, together with the Ru-catalyzed
AAC reaction, still remains the synthetic route with the
largest impact.5 However, the use of toxic heavy metals is a
limiting factor for some spectroscopy or medicinal applica-
In response to these shortcomings and the scarceness of
selective pathways toward the synthesis 1,5-disubstituted
1,2,3-triazoles,11 our group has recently developed a metal-
free and regioselective three-component reaction
(Scheme 1, Eq. 2).10 This reaction was named the ‘tri-
azolization’ reaction and provides synthetic access to 1,5-
di- and fully-substituted 1-alkyl-1,2,3-triazoles, some of
them being previously inaccessible. A major advantage is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
T. Opsomer et al.
Special Topic
Synthesis
So far, the scope of the triazolization reaction, under the
optimized conditions, has been limited to unactivated eno-
lizable ketones. Organocatalytic routes toward 1,2,3-tri-
azoles from different activated enolizable ketones have
been described in literature, mainly by the groups of Ram-
achary and Wang (Scheme 1, Eq. 1).8b,k However, the scope
of these reactions is mostly limited to 1-aryl-1,2,3-tri-
azoles, as previously stated. Aiming to synthesize 1-alkyl-
1,2,3-triazoles starting from activated methylene ketones,
one can think of the triazolization reaction as a possible
strategy. In this article, the relevance of this idea will be
proven via investigation of the triazolization reaction be-
tween 1,3-diphenylacetone (1,3-DPA, 1a), p-methoxyben-
zylamine (PMBA, 2a), and 4-NPA (3) as reactants, which in-
triguingly led to the formation of three different triazole
compounds (Table 1). In an acid-free reaction mixture, the
desired triazolization product 5aa represented only a minor
fraction of the 1,2,3-triazoles being formed. A 1-(4-nitro-
phenyl)-1,2,3-triazole (6a), in contrast, was found back as
the major product. As this triazole is formed via a Dimroth
type of reaction, it is referred to as the Dimroth product.
Based on known literature about azide-ketone [3+2] cyc-
loaddition reactions, it can be stated that the Dimroth prod-
uct 6a is formed via either an enolate- or an enamine-medi-
ated cycloaddition reaction.8a–i,8k Aromatization of the tri-
azoline intermediate 4aa occurs upon elimination of water
or the amine, respectively. As the α-protons of α-arylke-
tones are rather acidic, the C4 proton of the triazoline can
Ramachary, Wang, Bressy: enamine-/enolate-mediated azide–ketone cycloaddition
R1
R3
R1
amine or base
N
R3 N3
+
(1)
O
R2
N
R2
N
Dehaen et al.: triazolization reaction from unactivated enolizable ketones
N3
R1
R3
R1
CH3COOH (0.3 equiv)
N
+
(2)
+
R3 NH2
O
R2
4 Å MS, toluene
100 °C, 12 h
– PNA
N
R2
N
NO2
Scheme 1 Cyclization reactions with enolizable ketones for the syn-
thesis of highly functionalized 1,2,3-triazoles
the use of readily available primary alkylamines and enoliz-
able ketones as starting materials. In the triazolization reac-
tion, a triazoline intermediate is formed via regioselective
cycloaddition of 4-nitrophenyl azide (4-NPA) onto an
enamine, this latter being derived from the condensation
between the amine and ketone in situ. Subsequently, ring-
opening and alternative ring-closure of the intermediate
generates the desired triazole. Along with aromatization, a
molecule of p-nitroaniline (PNA) is eliminated. The use of
4-NPA as a renewable dinitrogen source can be seen as an-
other important feature.10
Table 1 Proportion of the 1,2,3-Triazole Products 5aa, 6a and 7aa, Relative to the Total Triazole Content
NO2
NO2
NO2
OMe
H2N
N3
Ph
OMe
Ph
+
+
O
+
+
Ph
N
N
Ph
HN
N
N
N
HN
N
N
Ph
N
N
NO2
OMe
N
N
N
Ph
Ph
Ph
Ph
MeO
1a
2a
3
4aa
triazolization product 5aa
Dimroth product 6a
5-anilino-1,2,3-triazole 7aa
Entry
Temp (°C)
AcOHa
PMBA (2a)a
4-NPA (3)a
Solvent
5aab
6ab
7aab
1
2
3
4
5
6
7
8
9c
100
100
100
50
–
1
3
1
1
1
1
1
3
1
2
2
2
2
2
2
2
3
2d
toluene
toluene
DMF
21
3
48
59
88
74
75
27
7
31
38
12
23
13
3
–
–
0
–
toluene
toluene
toluene
toluene
toluene
toluene
3
50
0.3
0.3
1
12
70
91
3
100
100
100
100
2
–
54
20d
43
0
–
61
a In equivalents with respect to the amount of 1,3-DPA (1a; 0.5 mmol).
b Percentage of the total triazole content in the crude mixture, determined from the 1H NMR spectra.
c Reaction performed with 4-azidobenzonitrile instead of 4-NPA.
d This concerns the 4-cyanophenyl analogue.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
T. Opsomer et al.
Special Topic
Synthesis
be more readily abstracted compared to unactivated ke-
tones. Therefore, it is not surprising that the Dimroth tri-
azole is obtained as the major compound in an acid-free re-
action where an amine, such as PMBA, can act as a base to
facilitate the abstraction of the α-proton (Table 1, entry 1).
The third compound, isolated from the reaction with 1,3-
DPA, was a 5-anilino-1,2,3-triazole (5-AT) 7aa. This type of
product was previously not observed in any triazolization
reaction and has, to this date, not been synthesized by oth-
er means.
explanation for the observed enhancement of the tri-
azolization reaction in the presence of acetic acid still re-
mains uncertain. However, the current findings support the
idea that the N3 nitrogen of the triazoline has to be proton-
ated in order for ring-opening to occur, an idea which was
postulated earlier by our group as being part of the tri-
azolization mechanism.10 Another observation underpin-
ning this hypothesis was the outcome of an acid-free reac-
tion between 1,3-DPA, PMBA, and 4-azidobenzonitrile. The
triazolization product to Dimroth triazole ratio was found
to be 3, where this was 0.44 for the reaction with 4-NPA un-
der the same conditions (Table 1, entries 1 and 9). A plausi-
ble explanation may be an increase in basicity of the
N3 nitrogen of the triazoline intermediate, as a result of the
less electron-withdrawing nature of the nitrile substituent,
allowing protonation and subsequent ring-opening to be
faster. Although the triazolization reaction is favored when
using 4-azidobenzonitrile, the total yield of all triazoles
combined is not higher compared to the reaction with 4-
The remarkable reaction between 1,3-DPA (1a), PMBA
(2a), and 4-NPA (3) was studied more in detail by repeating
the reaction under modified conditions. For each of the re-
actions, the contribution of the different triazole com-
pounds, relative to the total triazole content in the reaction
1
mixture, was roughly determined from the crude H NMR
spectra after a reaction time of 15 hours (Table 1). Interest-
ingly, when the reaction was performed with a large excess
of amine, the triazolization product 5aa lost ground both in
favor of the Dimroth product 6a and 5-AT 7aa (Table 1,
entry 2). This indicates that the formation of the 5-AT is fa-
vored in acid-free/basic medium. Next, few experiments
were carried out to check the influence of solvent polarity
and temperature. According to the observations, the use of
a polar solvent and performing the reaction at lower tem-
peratures increases the amount of Dimroth triazole (entries
3–5). One experiment was carried out to check the influ-
ence of solvent polarity. DMF was chosen as a high boiling
polar solvent in which the acid-free reaction was repeated.
Both the relative amount of triazolization product and the
5-AT are lower compared to the reaction in toluene. In fact,
the triazolization product is not detected in the reaction
mixture with DMF. The conditions that favor formation of
the Dimroth product are combined in the azide-ketone cyc-
loaddition reaction developed by Ramachary et al., who
were able to synthesize fully substituted triazoles in DMSO
at room temperature and in the presence of a catalytic
amount of DBU.8k Applying the procedure of Ramachary et
al. on 1,3-DPA, using 4-NPA, compound 6a could be synthe-
sized in 83% isolated yield. This result showed that 1,3-DPA
can be added to the scope of ketones, which already includ-
ed phenylacetone, deoxybenzoin, and various derivatives of
these α-arylketones.
N3
CH3COOH (1 equiv)
toluene, 100 °C, 15 h
R1
R1
R2
R2 NH2
+
O
N
+
Ph
– PNA
N
Ph
N
NO2
1, 0.5 mmol
2, 0.5 mmol
3, 1 mmol
5aa–ca
Various amines:
OMe
N
N
N
N
N
N
N
N
N
5aa, 75%
5ab, 80%
5ac, 84%
NH
H
N
N
N
N
N
N
Given that the formation of the Dimroth product and
the 5-AT is base-/amine-catalyzed, it was surmised that
acidifying the reaction medium would change the reaction
outcome. Indeed, in the presence of one equivalent of acetic
acid, the triazolization product was almost exclusively
formed (Table 1, entry 7). Comparing the reactions at 50 °C
and 100 °C (Table 1, entries 5–6), one can conclude that the
triazolization reaction is favored at higher temperatures.
Complementing this with the need for an apolar solvent, a
reaction in toluene at 100 °C with acetic acid can be put for-
ward as the method of choice for the synthesis of 1-alkyl-
1,2,3-triazoles from 1,3-DPA (Scheme 2). At this point, the
5ad, 72%
5ae, 57%
Other ketones:
OMe
OMe
N
N
N
N
N
N
5ba, 73%
5ca, 52%
Scheme 2 Synthesis of fully substituted 1,2,3-triazoles from α-aryl-
ketones 1, primary amines 2, and 4-NPA (3). Scope with respect to
amines and ketones.
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D
T. Opsomer et al.
Special Topic
Synthesis
Table 2 Influence of Substrates in Acid-Free Three-Component Reactionsa
NO2
R1
N3
toluene
100 °C, 15 h
N
O
R2NH2
N
+
+
R2
N
O2N
N
Ph
1H
R
Ph
4
1
2
3
l
l
l
l
l
R1 = benzyl
NO2
R2
R2
NO2
N
N
N
N
N
N
N
N
N
R1
N
H
Ph
R1
Ph
Ph
5
6
7
Entry
1
Ketone
Amine
Product, Yield (%)b
Ph
Ph
H2N
O
1a
2a
5aa, 20
6a, 45
7aa, 29
OMe
2
3
1a
1a
2b
2c
5ab, n.d.
5ac, 50
6a, 58
6a, 6
7ab, 34
7ac, 16
H2N
H2N
NH
4
5
1a
1a
2d
2e
5ad, 9
6a, 44
7ad, 35
7ae, 23
H2N
H2N
H
5ae, 38
6a, 9
O
6
1b
1b
2a
2a
5ba, 21
5ba, 73
6b, 60
6b, 15
n.a.
n.a.
Ph
7c
Ph
O
8
1c
2a
5ca, 12
6c, 74
n.a.
Ph
9c
1c
2a
5ca, 52
6c, 20
n.a.
a Unless indicated, all reactions were performed under the following conditions: 1 (0.5 mmol), 2 (1 equiv), 3 (2 equiv), toluene (0.5 mL), 100 °C, 15 h.
b Isolated yield. n.d.: Not detected; n.a.: Not applicable.
c CH3COOH (1 equiv).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
T. Opsomer et al.
Special Topic
Synthesis
1
NPA (acid-free conditions). In the presence of one equiva-
lent of acetic acid, the reaction with 1,3-DPA, PMBA, and 4-
azidobenzonitrile furnished the triazolization product with
a comparable yield of 72%.
is released. By analyzing the H NMR spectra of the crude
reaction mixtures, it could be noticed that distinctly more
azide was consumed compared to the amount of PNA
formed. Of course, it was taken into account that azide is
also consumed in the formation of the Dimroth product,
without release of PNA.
Under the optimized conditions for the triazolization
reaction, 1,2,3-triazole compounds 5aa–ae from 1,3-DPA
and various amines were synthesized in moderate to high
yields (Scheme 2). The scope of ketones was also explored
to some extent. An obvious example was the triazolization
product 5ba from phenylacetone, which could be isolated in
73% yield with complete regioselectivity (Table 2, entry 7).
For the slightly more activated deoxybenzoin, the opti-
mized reaction afforded the triazolization product 5ca with
an isolated yield of 52% (Table 2, entry 9). Again, the yield
could not be increased by using 4-azidobenzonitrile (43%).
When applying stronger acids such as p-toluenesulfonic
acid and trifluoroacetic acid, the triazolization reaction did
not proceed. This was also the case for reactions with ethyl
benzoylacetate. Some attempts were made to synthesize 1-
alkyl-1,2,3-triazoles from this highly activated β-keto ester.
Even in the presence of one equivalent of acetic acid, only
the Dimroth product was formed. Note that the aimed tri-
azoles are accessible in another way via a method devel-
oped in our laboratory.12
When performing the triazolization reactions from 1,3-
DPA (1a) and various amines 2a–e without acetic acid, a
correlation between steric hindrance of the amine and the
mutual ratio of triazole compounds was observed (Table 2).
In general, using less sterically hindered amines such as
hexylamine (2b) and tryptamine (2d) leads to higher yields
of both the Dimroth triazole and 5-AT (Table 2, entries 2
and 4). In contrast, a reaction with the more sterically hin-
dered (R)-(+)-α-methylbenzylamine (2c) clearly generates
the triazolization product 5ac as the major product
(entry 3). A similar result was obtained in the case of (+)-
dehydroabietylamine (2e) (entry 5). From the acid-free re-
actions, different 5-ATs 7aa–ae were obtained. It is worth
mentioning that these remarkable compounds were only
generated as a side product in reactions with 1,3-DPA,
NO2
NO2
NO2
4-NPA
N
N
HN
N
N
N
R
NH
R
Ph
R
N
N
H
Ph
N2
Ph
N
Ph
Ph
4a
8
7a
Scheme 3 Cycloreversion step in the postulated mechanism for the
formation of the 5-ATs 7aa–ac
In conclusion, we can state that both solvent, tempera-
ture, and presence of acid or base influence the chemose-
lectivity in triazolization reactions. The results of experi-
ments with different ketones revealed a trend of decreasing
efficiency of the triazolization reaction with the acidity of
the enolizable ketones. This is a valuable information in the
framework of the exploration of the triazolization reaction,
of which the limitations are now more specified.
All chemicals were purchased from Acros Organics, Sigma Aldrich,
Alfa Aesar, and TCI Europe and used as received. Azides were pre-
pared according to literature procedures.10,14 All reactions were car-
ried out in oven dried glassware, but no special precautions were tak-
en for the exclusion of moisture. Reaction solvents (toluene) were
dried using a M-Braun SPS-800 system. For column chromatography,
60–200 mesh silica gel 60 (Acros) was used as the stationary phase.
NMR spectra were recorded on commercial instruments (Bruker
Avance 300 MHz, Bruker AMX 400 MHz, or Bruker Avance II+ 600
MHz) and chemical shifts (δ) are reported in parts per million (ppm)
referenced to TMS (1H), or the internal (NMR) solvent signal (13C).
High-resolution mass spectra were acquired on a quadrupole orthog-
onal acceleration time-of-flight mass spectrometer (Synapt G2
HDMS, Waters, Milford, MA, USA). Samples were infused at 3 μL/min
and spectra were obtained in positive (or negative) ionization mode
with a resolution of 15 000 (FWHM) using leucine enkephalin as lock
mass. Melting points were determined on a Mettler-Toledo DSC 1 in-
strument, using a heating rate of 10 °C min–1 and under a He atmo-
sphere.
which
may
be
explained
via
the
proposed
mechanism (Scheme 3). Just as for the Dimroth and tri-
azolization products, the 5-AT 7a is expected to be formed
from the triazoline intermediate 4a. Triazolines bearing an
electron-withdrawing substituent at the N1 position are
known to be more labile. Therefore, 4a may, to a limited ex-
tent, undergo a [3+2] cycloreversion process, generating
phenyldiazomethane and the corresponding N′-(4-nitro-
phenyl)-2-phenylacetamidine (8) (Scheme 3).13 Subsequent
diazotransfer onto the amidine would then generate the 5-
AT. The postulated mechanism is based on the report of Ugo
et al., who observed cycloreversion of triazolines from tosyl
azide at low temperatures.13a According to the postulated
mechanism, two equivalents of azide are consumed in the
reaction toward the 5-AT, while only one equivalent of PNA
1-Alkyl-1,2,3-triazoles 5aa–ca,7aa–ae; Modified Triazolization
Procedure
To an oven-dried screw-capped reaction tube equipped with a mag-
netic stirring bar was added the ketone 1 (0.5 mmol) and AcOH
(0.5 mmol). The mixture was dissolved in toluene (0.3 mL), after
which the amine 2 (0.5 mmol) and azide 3 (1 mmol) were added in
the respective order. The walls of the reaction tube were then rinsed
with toluene (0.2 mL). The reaction mixture was heated immediately
after addition of the reagents and left stirring for 15 h at 100 °C. The
crude reaction mixtures were directly purified by column chromatog-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
T. Opsomer et al.
Special Topic
Synthesis
raphy after cooling down to r.t. CH2Cl2 was used at first as the eluent
to remove PNA, followed by a heptane–EtOAc or CH2Cl2–EtOAc gradi-
ent to afford the corresponding 1,2,3-triazoles.
1H NMR (CDCl3, 300 MHz): δ = 8.52 (s, 1 H, indole NH), 7.64–7.58 (m,
2 H), 7.39–7.29 (m, 4 H), 7.28–7.13 (m, 5 H), 7.09–7.03 (m, 1 H), 6.90–
6.84 (m, 2 H), 6.78 (d, J = 2.3 Hz, 1 H), 4.34 (t, J = 7.3 Hz, 2 H), 3.80 (s, 2
H), 3.24 (t, J = 7.2 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 145.53, 136.26, 136.19, 131.48, 131.34,
128.97, 128.75, 127.89, 127.73, 127.27, 127.05, 126.91, 122.71,
122.13, 119.51, 118.14, 111.43, 111.11, 48.89, 28.12, 26.39.
Note: The reactions to obtain compounds 7aa–ae were performed
without AcOH.
5-Benzyl-1-(4-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (5aa)
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C25H22N4: 379.1917; found:
379.1923.
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), PMBA (2a; 68.6 mg, 0.5 mmol), 4-
NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg, 0.5 mmol); yellow sol-
id; yield: 133.5 mg (75%); mp 104 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.68–7.65 (m, 2 H), 7.41–7.23 (m, 6 H),
7.02 (d, J = 8.7 Hz, 2 H), 6.98 (d, J = 6.5 Hz, 2 H), 6.80 (d, J = 8.7 Hz, 2 H),
5.26 (s, 2 H), 4.09 (s, 2 H), 3.76 (s, 3 H).
13C NMR (CDCl3, 101 MHz): δ = 159.54, 146.42, 136.01, 131.28,
130.84, 129.02, 128.74, 127.92, 127.78, 127.18, 127.08, 126.64,
114.23, 55.28, 51.75, 28.58.
5-Benzyl-1-{[(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-
1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]methyl}-4-phe-
nyl-1H-1,2,3-triazole (5ae)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), (+)-dehydroabietylamine (2e; 143 mg,
0.5 mmol), 4-NPA (3; 164.1 mg, 1 mmol,), and AcOH (30 mg,
0.5 mmol); yellow semi-solid; yield: 143.5 mg (57%).
1H NMR (CDCl3, 300 MHz): δ = 7.67–7.62 (m, 2 H), 7.41–7.23 (m, 6 H),
7.13 (d, J = 8.2 Hz, 1 H), 7.02–6.94 (m, 3 H), 6.91–6.88 (m, 1 H), 4.36
(d, J = 17.3 Hz, 1 H), 4.22 (d, J = 17.4 Hz, 1 H), 4.16 (d, J = 14.3 Hz, 1 H),
3.80 (d, J = 14.3 Hz, 1 H), 3.14–2.74 (m, 3 H), 2.29–2.20 (m, 1 H), 2.08–
1.96 (m, 1 H), 1.90–1.55 (m, 4 H), 1.50–1.42 (m, 1 H), 1.35–1.18 (m, 11
H), 1.06 (s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 146.84, 145.69, 145.00, 136.27, 134.87,
132.12, 131.46, 129.09, 128.71, 127.80, 127.27, 127.16, 126.99,
124.10, 123.80, 58.19, 45.43, 39.29, 38.03, 37.63, 36.78, 33.46, 29.91,
29.07, 25.68, 24.05, 23.97, 19.40, 18.92, 18.54.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C23H21N3O: 356.1757;
found: 356.1761.
5-Benzyl-1-hexyl-4-phenyl-1H-1,2,3-triazole (5ab)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), hexylamine (2b; 50.6 mg, 0.5 mmol),
4-NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg, 0.5 mmol); yellow
viscous oil; yield: 128.4 mg (80%).
1H NMR (CDCl3, 400 MHz): δ = 7.70–7.66 (m, 2 H), 7.41–7.36 (m, 2 H),
7.34–7.22 (m, 4 H), 7.06 (d, J = 7.1 Hz, 2 H), 4.24 (s, 2 H), 4.10 (t, J = 7.4
Hz, 2 H), 1.72 (pent, J = 7.4 Hz, 2 H), 1.28–1.15 (m, 6 H), 0.84 (t, J = 6.9
Hz, 3 H).
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C35H41N3: 504.3373; found:
504.3371.
13C NMR (CDCl3, 101 MHz): δ = 145.63, 136.40, 131.49, 130.66,
129.04, 128.74, 127.83, 127.78, 127.20, 127.15, 48.32, 31.12, 29.77,
28.74, 26.19, 22.35, 13.93.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C21H25N3: 320.2121; found:
320.2118.
1-(4-Methoxybenzyl)-5-methyl-4-phenyl-1H-1,2,3-triazole (5ba)
Prepared according to the triazolization procedure, using
phenylacetone (1b; 67.1 mg, 0.5 mmol), PMBA (2a; 68.6 mg,
0.5 mmol), 4-NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg,
0.5 mmol); yellow viscous oil; yield: 102.0 mg (73%).
1H NMR (CDCl3, 400 MHz): δ = 7.68 (d, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5
Hz, 2 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.16 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.4
Hz, 2 H), 5.47 (s, 2 H), 3.78 (s, 3 H), 2.33 (s, 3 H).
13C NMR (CDCl3, 101 MHz): δ = 159.55, 144.98, 131.66, 129.02,
128.66, 128.64, 127.59, 127.11, 126.84, 114.35, 55.30, 51.59, 9.22.
(R)-5-Benzyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole (5ac)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), (R)-(+)-α-methylbenzylamine (2c;
60.6 mg, 0.5 mmol), 4-NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg,
0.5 mmol); off-white solid; yield: 142.8 mg (84%); mp 123 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.68–7.64 (m, 2 H), 7.40–7.34 (m, 2 H),
7.33–7.20 (m, 7 H), 7.12–7.08 (m, 2 H), 7.00–6.96 (m, 2 H), 5.26 (q, J =
7.0 Hz, 1 H), 4.23 (d, J = 17.3 Hz, 1 H), 3.91 (d, J = 17.3 Hz, 1 H), 1.94 (d,
J = 7.1 Hz, 3 H).
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C17H17N3O: 280.1444;
found: 280.1449.
1-(4-Methoxybenzyl)-4,5-diphenyl-1H-1,2,3-triazole (5ca)
Prepared according to the triazolization procedure, using
deoxybenzoin (1c; 98.1 mg, 0.5 mmol), PMBA (2a; 68.6 mg,
0.5 mmol), 4-NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg,
0.5 mmol); off-white solid; yield: 89.0 mg (52%); mp 88 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.57–7.52 (m, 2 H), 7.51–7.40 (m, 3 H),
7.28–7.19 (m, 3 H), 7.18–7.13 (m, 2 H), 6.96 (d, J = 8.6 Hz, 2 H), 6.76
(d, J = 8.6 Hz, 2 H), 5.34 (s, 2 H), 3.76 (s, 3 H).
13C NMR (CDCl3, 101 MHz): δ = 159.43, 144.51, 133.68, 130.97,
130.16, 129.64, 129.15, 129.04, 128.41, 128.00, 127.64, 127.41,
126.70, 114.01, 55.26, 51.59.
13C NMR (CDCl3, 101 MHz): δ = 146.16, 140.71, 136.27, 131.38,
130.75, 129.02, 128.84, 128.70, 127.99, 127.85, 127.68, 127.24,
127.06, 126.12, 58.76, 28.62, 22.45.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C23H21N3: 340.1808; found:
340.1815.
3-[2-(5-Benzyl-4-phenyl-1H-1,2,3-triazol-1-yl)ethyl]-1H-indole
(5ad)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), tryptamine (2d; 80.1 mg, 0.5 mmol),
4-NPA (3; 164.1 mg, 1 mmol), and AcOH (30 mg, 0.5 mmol); off-
white solid; yield: 136.5 mg (72%); mp 151 °C.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C22H19N3O: 342.1601;
found: 342.1609.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
T. Opsomer et al.
Special Topic
Synthesis
5-Benzyl-1-(4-nitrophenyl)-4-phenyl-1H-1,2,3-triazole (6a)
1H NMR (CDCl3, 400 MHz): δ = 8.00 (d, J = 9.2 Hz, 2 H), 7.74–7.70 (m, 2
H), 7.32–7.24 (m, 6 H), 7.19–7.15 (m, 2 H), 6.44 (d, J = 9.1 Hz, 2 H),
5.86 (s, 1 H, NH), 5.51 (q, J = 7.1 Hz, 1 H), 2.01 (d, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 101 MHz): δ = 149.25, 141.86, 140.98, 139.81,
129.51, 129.11, 129.04, 128.82, 128.52, 128.51, 126.22, 126.19,
125.86, 113.13, 58.44, 21.44.
To an oven-dried screw-capped reaction tube equipped with a mag-
netic stirring bar was added 1,3-DPA (1a; 105.1 mg, 0.5 mmol) and 4-
NPA (3; 123.1 mg, 0.75 mmol). The mixture was dissolved in
DMSO (1 mL), after which DBU (0.05 mmol, 7.6 mg) was added. The
reaction mixture was left stirring for 2 h at 25 °C and subsequently
worked up with aq NH4Cl. The aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The product was purified by column chro-
matography using a heptane–EtOAc gradient: white solid; yield:
147.4 mg (83%); mp 156 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.28 (d, J = 9.0 Hz, 2 H), 7.77–7.73 (m, 2
H), 7.56 (d, J = 9.0 Hz, 2 H), 7.46–7.36 (m, 3 H), 7.32–7.23 (m, 3 H),
7.02–6.97 (m, 2 H), 4.32 (s, 2 H).
13C NMR (CDCl3, 101 MHz): δ = 147.84, 146.80, 141.19, 136.21,
131.64, 130.38, 129.28, 128.96, 128.50, 127.71, 127.41, 127.24,
125.63, 124.87, 29.33.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C22H19N5O2: 386.1611;
found: 386.1610.
1-[2-(1H-Indol-3-yl)ethyl]-N-(4-nitrophenyl)-4-phenyl-1H-1,2,3-
triazol-5-amine (7ad)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), tryptamine (2d; 80.1 mg, 0.5 mmol),
and 4-NPA (3; 164.1 mg, 1 mmol); brown semi-solid; yield: 73.4 mg
(35%).
1H NMR (CDCl3, 300 MHz): δ = 8.42 (s, 1 H, indole NH), 7.81 (d, J = 9.1
Hz, 2 H), 7.58–7.53 (m, 2 H), 7.48–7.43 (m, J = 8.1, 3.1 Hz, 2 H), 7.33–
7.11 (m, 5 H), 6.74 (d, J = 2.3 Hz, 1 H), 5.86 (d, J = 9.2 Hz, 2 H), 4.90 (s,
1 H, NH), 4.50 (t, J = 6.1 Hz, 2 H), 3.33 (t, J = 6.1 Hz, 2 H).
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C21H16N4O2: 357.1346;
found: 357.1348.
13C NMR (CDCl3, 75 MHz): δ = 148.42, 140.54, 139.93, 136.21, 130.22,
129.55, 128.71, 128.31, 126.23, 125.90, 125.72, 123.50, 122.96,
120.41, 118.22, 112.92, 112.12, 110.80, 47.44, 26.72.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C24H20N6O2: 425.1720;
found: 425.1718.
1-(4-Methoxybenzyl)-N-(4-nitrophenyl)-4-phenyl-1H-1,2,3-tri-
azol-5-amine (7aa)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), PMBA (2a; 68.6 mg, 0.5 mmol), and 4-
NPA (3; 164.1 mg, 1 mmol); brown semi-solid; yield: 59.1 mg (29%).
1H NMR (CDCl3, 400 MHz): δ = 8.01 (d, J = 8.9 Hz, 2 H), 7.74–7.69 (m, 2
H), 7.30–7.25 (m, 3 H), 7.08 (d, J = 8.5 Hz, 2 H), 6.73 (d, J = 8.5 Hz, 2 H),
6.48 (d, J = 8.9 Hz, 2 H), 6.24 (s, 1 H, NH), 5.32 (s, 2 H), 3.72 (s, 3 H).
13C NMR (CDCl3, 101 MHz): δ = 159.88, 149.34, 141.77, 140.95,
129.48, 129.36, 129.26, 128.84, 128.55, 126.17, 125.87, 125.81,
114.35, 113.23, 55.33, 51.43.
1-{[(1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-1-yl]methyl}-N-(4-nitrophenyl)-4-phe-
nyl-1H-1,2,3-triazol-5-amine (7ae)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), (+)-dehydroabietylamine (2e; 143 mg,
0.5 mmol), and 4-NPA (3; 164.1 mg, 1 mmol); yellow semi-solid;
yield: 63.1 mg (23%).
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C22H19N5O3: 402.1561;
1H NMR (CDCl3, 600 MHz): δ = 8.09 (d, J = 8.9 Hz, 2 H), 7.69 (d, J = 7.0
Hz, 2 H), 7.30–7.23 (m, 3 H), 7.10 (d, J = 8.2 Hz, 1 H), 6.97 (d, J = 8.1 Hz,
1 H), 6.88 (s, 1 H), 6.60 (d, J = 8.7 Hz, 2 H), 6.28 (s, 1 H, NH), 4.15 (d, J =
14.0 Hz, 1 H), 3.92 (d, J = 14.0 Hz, 1 H), 3.04–2.90 (m, 2 H), 2.85–2.77
(m, 1 H), 2.23 (d, J = 12.8 Hz, 1 H), 2.05–1.99 (m, 1 H), 1.87–1.78 (m, 1
H), 1.74–1.65 (m, 1 H), 1.57–1.48 (m, 2 H), 1.40–1.34 (m, 1 H), 1.28–
1.18 (m, 11 H), 1.08 (s, 3 H).
13C NMR (CDCl3, 151 MHz): δ = 149.24, 146.61, 145.87, 141.15,
140.24, 134.51, 130.40, 129.50, 128.82, 128.46, 126.96, 126.43,
125.89, 124.03, 123.92, 113.25, 57.54, 45.49, 39.18, 38.00, 37.57,
36.74, 33.43, 29.80, 25.51, 23.99, 23.95, 19.33, 18.83, 18.44.
found: 402.1552.
1-Hexyl-N-(4-nitrophenyl)-4-phenyl-1H-1,2,3-triazol-5-amine
(7ab)
Prepared according to the triazolization procedure, using 1,3-
DPA (1a; 105.1 mg, 0.5 mmol), hexylamine (2b; 50.6 mg, 0.5 mmol),
and 4-NPA (3; 164.1 mg, 1 mmol); brown semi-solid; yield: 62.9 mg
(34%).
1H NMR (CDCl3, 400 MHz): δ = 8.11 (d, J = 9.1 Hz, 2 H), 7.73–7.68 (m, 2
H), 7.32–7.27 (m, 3 H), 6.69–6.63 (m, 3 H), 4.15 (t, J = 7.4 Hz, 2 H), 1.84
(pent, J = 7.3 Hz, 2 H), 1.33–1.17 (m, 6 H), 0.83 (t, J = 6.9 Hz, 3 H). NH
could not be assigned unambiguously.
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C34H39N5O2: 550.3176;
13C NMR (CDCl3, 101 MHz): δ = 149.78, 141.09, 141.05, 129.55,
129.39, 128.87, 128.51, 126.43, 125.85, 113.22, 47.55, 31.07, 29.66,
26.23, 22.36, 13.91.
found: 550.3178.
Funding Information
HRMS (ESI-Q-TOF): m/z [M + H]+ calcd for C20H23N5O2: 366.1924;
found: 366.1924.
Tomas Opsomer is a doctoral fellow of FWO Vlaanderen (1154417N).
Mass spectrometry was made possible by the support of the Hercules
(R)-N-(4-Nitrophenyl)-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-tri-
azol-5-amine (7ac)
Foundation of the Flemish Government (grant 20100225–7).
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Prepared according to the triazolization procedure, using 1,3-
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60.6 mg, 0.5 mmol), and 4-NPA (3; 164.1 mg, 1 mmol); brown semi-
solid; yield: 30.5 mg (16%).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588856.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
T. Opsomer et al.
Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H