Regioselective Approach to 5-Carboxy-1,2,3-triazoles Based on Palladium-Catalyzed Carbonylation

Article abstract of DOI:10.1055/s-0036-1591896

A regioselective two-step approach to 5-carboxy-1,2,3-triazoles based on palladium-catalyzed carbonylation has been developed. The protocol utilizes readily available 5-iodotriazoles as starting materials. The obtained products were used in the syntheses

Full text of DOI:10.1055/s-0036-1591896

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
Y. N. Kotovshchikov et al.
Paper
Synthesis
Regioselective Approach to 5-Carboxy-1,2,3-triazoles Based on
Palladium-Catalyzed Carbonylation
Yury N. Kotovshchikov
Gennadij V. Latyshev*
Irina P. Beletskaya
X
O
two-step regioselective approach
R
N
X = NH, O
N
N
2
1
Nikolay V. Lukashev
R2
R2
N
N
N
Pd(OAc)2
CuI, TTTA
50 °C, THF
N
Chemistry Department, M. V. Lomonosov Moscow State University,
1/3 Leninskiye Gory, Moscow 119991, Russian Federation
latyshev@org.chem.msu.ru
R1
R2
R1N3
N
+
N
R1
CO, ROH
Et3N, 50 °C
I
CO2R
N
N
I
N
up to 94%
20 examples
up to 96%
R
OH
CO2Me
Received: 27.10.2017
Accepted after revision: 26.12.2017
Published online: 31.01.2018
separation of the regioisomeric adducts is problematic and
can be achieved only by tedious column chromatography or
preparative HPLC.
DOI: 10.1055/s-0036-1591896; Art ID: ss-2017-z0696-op
R2
Abstract A regioselective two-step approach to 5-carboxy-1,2,3-tri-
azoles based on palladium-catalyzed carbonylation has been devel-
oped. The protocol utilizes readily available 5-iodotriazoles as starting
materials. The obtained products were used in the syntheses of fused
heterocycles as well as derivatization of the steroidal hormone
cortexolone.
R2
RO2C
4
N
N
heat
Traditional
approach:
R1N3
+
N
N
+
N1
R1
N 1
R1
R2
5
RO2C
low
CO2R
regioselectivity
minor product
H
N
O
N
Key words 1,2,3-triazole, carbonylation, catalysis, palladium, copper
O2N
N
N
5
1
N
N
N
OMe
Cl
N
Various compounds containing the 1,2,3-triazole moi-
ety are of importance in coordination and supramolecular
chemistry and polymer and materials sciences.1 This type
of nitrogen heterocycle has also been shown to be a phar-
macophore, and is now intensively studied in medicinal
chemistry.2 In particular, some 5-carboxy-1,2,3-triazoles
have been shown to be kinase inhibitors, PPARα/γ and TGR5
agonists, and also exhibit antiviral and antibacterial ef-
fects.3
N
Me2N
anti-influenza A
N
1
5
(25–43%)
Bn
O
kinase inhibitor
N
N
N
CO2Et
N
N
1
N
5
N1
N
Ph
5
O
NC
TGR5 agonist
(22%)
O
EtO
antibacterial
(33%)
MeO
OMe
R2
So far, the major synthetic route to 5-carboxy-1,2,3-tri-
azoles has been thermal 1,3-dipolar cycloaddition of organ-
ic azides to propiolic acid derivatives (Scheme 1). This
method suffers from rather harsh conditions, low to moder-
ate yields, and low regioselectivity.3,4 In the absence of
bulky R groups both in the ester and azide, the major prod-
uct of this reaction is the undesired 4-carboxytriazole iso-
mer. Nevertheless, this approach has traditionally been
used as a preparative method to access various biologically
active 5-carboxytriazoles. For instance, the yields of the de-
sired regioisomers at the cycloaddition step in the synthe-
ses of a number of triazole-based drugs are in the range of
22–43% and, in some cases, even less than 10%. Moreover,
R2
R2
N
N
R1N3
CuIAAC
[Pd], CO
our
approach:
N
N
ROH, base
carbonylation
N 1
R1
5
N 1
R1
5
RO2C
I
I
single isomer
Scheme 1 Synthetic routes to biologically active 5-carboxy-1,2,3-tri-
azoles (yields at cycloaddition step are presented in parentheses)
Since 5-iodo-1,2,3-triazoles are readily accessible via
Cu(I) catalysis,5 the subsequent carbonylation reaction
could become a new regioselective approach to 5-carboxy-
1,2,3-triazoles. To the best of our knowledge, there have
been no reports on the carbonylation of 5-iodo-1,2,3-tri-
azoles, although these substrates have been successfully
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
Y. N. Kotovshchikov et al.
Paper
Synthesis
involved in a number of Pd-catalyzed transformations,6
such as Suzuki, Stille, and Sonogashira cross-couplings and
the Heck reaction.
Nevertheless, Pd-catalyzed carbonylation of vinyl, aryl,
or hetaryl halides is a powerful methodology, which can be
used as a straightforward, efficient, and convenient route to
various derivatives of carboxylic acids.7 Herein, we report a
regioselective approach to 5-carboxy-1,2,3-triazoles based
on Cu-catalyzed synthesis of 5-iodo-1,2,3-triazoles fol-
lowed by Pd-catalyzed carbonylation.
A number of 5-iodo-1,2,3-triazoles 1a–q were prepared
according to a slightly modified reported procedure5a from
azides and 1-iodoalkynes in the presence of 5 mol% CuI and
5 mol% of the auxiliary ligand tris[(1-tert-butyl-1H-1,2,3-
triazolyl)methyl]amine (TTTA) in THF at 50 °C (Scheme 2).
High yields of up to 94% were observed for both aliphat-
ic and aromatic R substituents (1a–f), including some bulky
ones (1e and 1f), although only 20% conversion was reached
in the reaction of tert-butyl azide and (iodoethynyl)-
benzene. The protocol tolerates the presence of various
functional groups, such as hydroxyl (1j, 1k), ester (1g, 1l,
1m, 1q), ketone (1h), tertiary amine (1i), and nitro (1k, 1p);
however, the presence of free phenol inhibited the reaction.
Preliminary acylation of the OH group allowed us to achieve
a good yield of iodotriazole 1o (74%). Excellent yields (90–
91%) were achieved for compounds bearing an additional
heterocyclic moiety, such as indole (1m) and 1,3,4-oxadi-
azole (1n) (Scheme 2).
Iodotriazole 1a was chosen as a model substrate for
Pd-catalyzed methoxycarbonylation (Scheme 3). The for-
mation of target methyl ester 2a was accompanied by unde-
sirable reduction of the starting iodotriazole 1a affording 3
as a byproduct (Table 1, entry 1). To find appropriate reac-
tion conditions providing sufficient efficiency and selectivi-
ty, we have optimized a number of parameters, such as cat-
alyst, base, and solvent.
N
N
t-Bu
N
t-Bu
N
N
N
R1N3
+
5 mol% CuI
5 mol% TTTA
N
N
N
R1
R2
N
THF, 50 °C
I
I
R2
N
N
TTTA
N
1a–q, 46–94%
t-Bu
N
N
N N
N
N
N
Ph
Ph
Ph
N
N
N
N
N
[Pd], CO (1 atm)
Bn
Bn
Bn
Ph
N
N
N
+
MeOH, cosolvent
base
N
N
N
I
I
1c, 83%
I
MeO2C
I
Bn
Bn
Bn
1a, 93%
1b, 94%
OMe
1a
2a
carbonylation
3
N
N
N
N
N
N
reduction
N
N
N
Ph
Ph
Ph
7
Scheme 3 Model reaction for Pd-catalyzed carbonylation of 5-iodo-
1,2,3-triazoles
I
I
I
1d, 74%
1e, 86%
1f, 75%
N
N
N
N
N
N
MeO2C
NEt2
N
N
N
Table 1 Ligand and Solvent Effect on Methoxycarbonylation of 1aa
Ph
Ph
Bn
Ph
I
I
I
O
1g, 68%
1h, 70%
1i, 46%
Entry Catalyst
Additive
Solvent
Yield (%)b
2a
O
N
N
N
N
N
N
N
N
3
OH
OH
N
N
Bn
O
N
Ph
1
2
Pd(OAc)2
–
THF–MeOH (1:1)
THF–MeOH (1:1)
THF–MeOH (1:1)
THF–MeOH (1:1)
THF–MeOH (1:1)
THF–MeOH (1:1)
THF–MeOH (1:1)
MeCN–MeOH (1:1)
DMF–MeOH (1:1)
MeOH
23
4
6
O2N
I
I
I
Pd(PPh3)4
–
21
10
6
1j, 69%
1l, 50%
1k, 88%
3
Pd(PPh3)2Cl2
–
14
7
CO2Et
c
Ph
4
Pd(dppf)Cl2
–
N
N
N
N
O
O
c
N
N
5
Pd(dppb)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
0
19
2
Bn
Ph
N
6
40% PVIc
0
I
I
1m, 91%
1n, 90%
n-Bu
N
7
40% PVPc
40
35
35
63
51
2
n-Bu
n-Bu
N
N
N
N
N
8
–
7
N
N
9
–
5
N
I
I
I
AcO
O2N
MeO2C
10
11
–
5
40% PVPc
MeOH
1
a Reaction conditions: 1a (0.1 mmol), cat. (5 mol%), Et3N (20 equiv), sol-
vent (0.1 M solution), CO (1 atm), r.t., 17 h.
1o, 74%
1p, 87%
1q, 51%
Scheme 2 Preparation of 5-iodo-1,2,3-triazoles
b Yield determined by 1H NMR.
c dppf = 1,1′-bis(diphenylphosphino)ferrocene; dppb = 1,4-bis(diphenyl-
phosphino)butane; PVI = polyvinylimidazole; PVP = polyvinylpyrrolidone.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
Y. N. Kotovshchikov et al.
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Synthesis
Screening of Pd catalysts under 1 atm of CO at ambient
temperature (Table 1) in a MeOH–THF mixture has shown
that Pd(OAc)2 and Pd(PPh3)4 were the most efficient. Other
phosphine complexes such as Pd(dppb)Cl2 and Pd(dppf)Cl2,
which are known to produce highly active catalysts in the
carbonylation of hetaryl chlorides,8 gave lower yields and
selectivity in comparison with Pd(OAc)2 and Pd(PPh3)4 (cf.
entries 1, 2 and 4, 5).
During the initial stage of the reaction we observed rap-
id formation of Pd black. In order to prevent aggregation of
Pd nanoparticles, believed to play a crucial role in phos-
phine-free catalysis,9 several soluble polymers capable of
retarding the Ostwald ripening were examined. While the
reaction was inhibited by polyvinylimidazole, the yield of
2a was enhanced by addition of polyvinylpyrrolidone (PVP)
(entries 6 and 7). The change of THF for other cosolvents,
such as MeCN and DMF, slightly increased the yield of 2a
(entries 8 and 9), but the best results were obtained in neat
MeOH (entry 10). It should be noted that the beneficial ef-
fect of PVP was reversed when the THF–MeOH solvent mix-
ture was changed to MeOH (entry 1 vs 7 and entry 10 vs
11).
1,2,3-triazole-5-carboxylates 2 were obtained in good
yields (up to 96%). Substrates with both aliphatic and aro-
matic substituents afforded the corresponding products
2a–d in high yields (84–91%). However, the carbonylation
proved to be rather sensitive to steric hindrance. 1,4-Diaryl-
5-iodotriazoles were much less reactive and gave incom-
plete conversions of 1 with significant amounts of reduc-
tion byproducts (40–50%). For instance, the yield of ester 2e
bearing the 3,5-dimethylphenyl group was only 45%. More-
over, in the case of the even more sterically demanding
2,6-dimethylphenyl substituent, only trace amounts of
product 2f were observed (6%).
N
N
N
N
5 mol% Pd(OAc)2, CO (1 atm)
ROH, Et3N, 50 °C, 17 h
N
N
R1
R2
R1
R2
I
CO2R
1a–n
2a–p
N
N
N
N
N
N
N
N
N
Bn
Bn
Bn
Ph
CO2Me
CO2Me
2c, 90%
CO2Me
2a, 91%
OMe
2b, 84%
N
N
N
N
N N
Triethylamine was found to be the best base for the re-
action (Table 2). Interestingly, the use of a large excess of
base (20 equiv instead of 5) increased the yield of 2a from
49 to 63% (entries 1 and 2). A complete conversion of 1a
and high yield of 2a were achieved by raising the tempera-
ture to 50 °C (entry 7). Thus, it was established that Pd-cat-
alyzed alkoxycarbonylation of 5-iodo-1,2,3-triazoles could
be carried out efficiently under very mild conditions, em-
ploying only 1 atm of CO at 50 °C in the presence of 5 mol%
Pd(OAc)2 and Et3N in MeOH.
N
N
N
Ph
CO2Me
Ph
CO2Me
2e, (45%)
Ph
CO2Me
2f, (6%)
7
2d, 88%
O
N
N
N
N
N
N
MeO2C
NEt2
Ph
N
N
N
Ph
Ph
CO2Me
Bn
CO2R
CO2Me
2i, (25%)
2h, 96% (R = Me)
2o, 82% (R = Et)
2p, 36% (R = CH2CF3)
2g, 82%
O
N
N
N
N
N
N
OH
OH
N
N
N
Bn
Table 2 Effect of Base and Temperaturea
O
Ph
CO2Me
2l, 61%
O2N
CO2Me
2j, 93%
CO2Me
Entry
Base
Temp
Yield (%)b
2k, 65%
CO2Et
2a
3
N
N
Ph
N
N
N N
1
2
3
4
5
6c
7
Et3N (5 equiv)
r.t.
49
63
60
35
0
1
5
O
O
N
N
Bn
Ph
N
Et3N (20 equiv)
DIPEA (20 equiv)
DABCO (20 equiv)
DMAP (20 equiv)
K2CO3 (2 equiv)
Et3N (20 equiv)
r.t.
CO2Me
CO2Me
2n, 70%a
r.t.
3
2m, 83%
r.t.
6
Scheme 4 Pd-catalyzed alkoxycarbonylation of 5-iodo-1,2,3-triazoles
1 (yields determined by 1H NMR are presented in parentheses). a
MeOH–DMF (4:1) as solvent.
r.t.
0
r.t.
8
54
6
50 °C
94
a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol%), base, MeOH (2
mL), CO (1 atm), 17 h.
Various functional groups, such as ester (2g, 2l), ketone
(2h), hydroxyl (2j, 2k), and nitro (2k), were tolerated by the
developed carbonylation protocol, and the corresponding
products were isolated in good to excellent yields (61–96%)
(Scheme 4). The combination of steric hindrance and com-
peting cleavage of γ-butyrolactone moiety by methanol led
to a somewhat diminished yield of 2l (61%). High yields
were achieved for heterocyclic derivatives 2m (83%) and 2n
(70%). The poor yield (25%) for 2i bearing a tertiary amine
b Yield determined by 1H NMR.
c MeCN–MeOH (1:1) mixture used as solvent.
With the optimized conditions for carbonylation in
hand, we investigated the scope of the protocol employing
5-iodotriazoles 1a–n (Scheme 4). In most cases, the devel-
oped procedure was quite efficient and the target methyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
Y. N. Kotovshchikov et al.
Paper
Synthesis
substituent is likely to be associated with the involvement
of amine in intramolecular coordination with the Pd center,
hindering the binding of a CO molecule.
Bn
Bn
Bn
N
N
N
N
N
N
5 mol% Pd(OAc)2
CO (1 atm)
N
N
N
O
O
Et3N
I
CO2Me
MeOH, Et3N
50 °C, 17 h
toluene
heat
Carbonylation of iodotriazole 1h in other alcohols al-
lowed the formation of ethyl and trifluoroethyl esters 2o
and 2p (Scheme 4). High yields were achieved by carrying
out the reaction in MeOH and EtOH (96 and 82%, respec-
tively). The use of the much less nucleophilic СF3CH2OH led
to the predominant formation of deiodinated triazole.
Therefore, the corresponding ester 2p was obtained in rath-
er low yield (36%).
The introduction of the ester moiety to the 1,2,3-tri-
azole ring can be used to obtain substrates that serve as
valuable precursors of various fused heterocyclic systems.
For instance, Pd-catalyzed carbonylation of 1o, bearing the
easily cleavable phenyl ester moiety, as well as its deacetyl-
ated analog 1r led to an approximately equimolar mixture
of methyl ester 2q and lactone 4 (Scheme 5). Complete
cyclization to 4 was achieved by heating the crude mixture
in refluxing toluene in the presence of Et3N. Similarly, re-
duction of the nitro group10 in 1p and the subsequent car-
bonylation of aniline 1s furnished lactam 5 in high yield
(77%) (Scheme 5).
OH
OH
1t
2r, 70%
6, 92%
Scheme 6 Synthesis of triazolocoumarin 6
sure led to a sharp decrease in the yield of 2s, which is
probably attributed to the accelerated reduction of the pre-
catalyst and aggregation of the formed Pd(0) complexes to
give catalytically inactive Pd black. Gratifyingly, the yield of
the desired diester 2s was improved to 78% by carrying out
the reaction under an increased pressure of CO (5 atm) in
the presence of 5 mol% Pd(PPh3)4 as the catalyst (Scheme 7).
The subsequent Dieckmann condensation of 2s was per-
formed by addition of potassium tert-butoxide, smoothly
affording [1,2,3]triazolo[1,5-a]quinoline 7 in excellent yield
(93%).
MeO2C
MeO2C
5 mol% Pd(PPh3)4
N
N
N N
CO (5 atm)
N
N
n-Bu
n-Bu
n-Bu
n-Bu
CO2Me
n-Bu
MeOH, Et3N
50 °C, 17 h
N
N
N
5 mol% Pd(OAc)2
CO (1 atm)
I
N
N
N
O
I
CO2Me
OH
N
N
N
+
1q
2s, 78%
N
N
MeOH, Et3N
50 °C, 17 h
O
OR
N
n-Bu
t-BuOK
THF, 0 °C
Et3N, toluene, heat
K2CO3
MeOH–H2O, r.t.
100%
OH
CO2Me
1o, R = Ac
1r, R = H
2q
4, 78%
7, 93%
Scheme 7 Synthesis of [1,2,3]triazolo[1,5-a]quinoline 7
n-Bu
n-Bu
n-Bu
N
N
N
5 mol% Pd(OAc)2
CO (1 atm)
N
N
N
O
Fe, CaCl2
To demonstrate the applicability of our protocol for the
derivatization of complex natural products, we followed a
previously reported procedure12 to introduce an azido
group to cortexolone 8, an important steroidal hormone
(Scheme 8). Azide 9 was subsequently transformed into
iodotriazole 10 and the corresponding methyl ester 11, in
high yields for both steps (91 and 84%, respectively).
I
I
N
N
N
EtOH–H2O
60 °C
MeOH, Et3N
50 °C, 17 h
NH
NO2
NH2
1p
1s, 51%
5, 77%
Scheme 5 Routes to triazole-fused benzoxazinone 4 and quinoxalinone 5
A similar approach was utilized for the preparation of
fused heterocycle 6 comprising 1,2,3-triazole and coumarin
(Scheme 6). Iodotriazole 1t was prepared from 1a by
Pd-catalyzed acetoxylation followed by hydrolysis accord-
ing to a previously reported procedure.11 In contrast to the
carbonylation of 1o and 1r (Scheme 5), the same reaction in
the case of 1t afforded methyl ester 2r with only trace
amounts of cyclized product 6. Nevertheless, complete lac-
tonization was achieved after heating 2r in refluxing tolu-
ene for several hours, furnishing 6 in excellent yield (92%).
Iodotriazole 1q bearing an enolizable ester group in the
ortho position was found to be rather unreactive in Pd-cata-
lyzed carbonylation, and the use of the standard reaction
conditions was complicated by low conversion (less than
50%) and deiodination. Surprisingly, increasing the CO pres-
In conclusion, we have developed a regioselective ap-
proach to 5-carboxy-1,2,3-triazoles based on Cu-catalyzed
synthesis of 5-iodo-1,2,3-triazoles and subsequent Pd-cata-
lyzed carbonylation. We have shown that alkoxycarbonyla-
tion of iodotriazoles can be performed efficiently under
mild conditions (1 atm CO, 50 °C) employing a simple palla-
dium catalyst Pd(OAc)2. The method featured very good
functional group tolerance, furnishing the target com-
pounds in high yields (up to 96%). The obtained 5-carboxy-
1,2,3-triazoles were shown to be valuable precursors in the
preparation of diverse fused heterocyclic scaffolds combin-
ing 1,2,3-triazole with benzoxazinone, quinoxalinone,
quinoline, and coumarin. Synthetic utility of the protocol
was also demonstrated in derivatization of the steroidal
hormone cortexolone.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
Y. N. Kotovshchikov et al.
Paper
Synthesis
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C17H16N3O2: 294.1237;
found: 294.1247.
OH
O
N3
O
OH
5 mol% CuI
5 mol% TTTA
OH
H
Methyl 1-Benzyl-4-(3-methoxyphenyl)-1H-1,2,3-triazole-5-car-
boxylate (2b)
THF, 50 °C
H
H
I
H
Prepared from 1b (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
O
OH
cortexolone
8
9
N
N
N
N
OH
OH
N
Yellowish oil; yield: 67.8 mg (84%).
N
I
CO2Me
O
O
1H NMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 8 H, 5 H Ph + 3 H Ar),
6.94 [ddd, J = 7.8, 2.7, 1.3 Hz, 1 H, 4-CH(Ar)], 5.89 (s, 2 H, CH2), 3.80 (s,
3 H, CH3), 3.75 (s, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 159.5 [C=O or 3-C(Ar)], 159.2 [C=O
or 3-C(Ar)], 150.2 [4-C(triazole)], 135.0 [1-C(Ph)], 131.3 [1-C(Ar)],
129.0 [5-CH(Ar)], 128.7 [2 C, CH(Ph)], 128.3 [4-CH(Ph)], 127.8 [2 C,
CH(Ph)], 123.8 [5-C(triazole)], 121.7 [6-CH(Ar)], 115.1 [2- or 4-
CH(Ar)], 114.3 [2- or 4-CH(Ar)], 55.3 (CH3OAr), 54.2 (CH2), 52.3
(CO2CH3).
5 mol% Pd(OAc)2
CO (1 atm)
OH
OH
MeOH, Et3N
50 °C, 17 h
H
H
10, 91%
11, 84%
Scheme 8 Modification of cortexolone
HRMS (MALDI-TOF): m/z [M + Na]+ calcd for C18H17N3NaO3: 346.1162;
found: 346.1166.
NMR spectra were recorded on Bruker Avance 400, Agilent 400MR
(1H, 400 MHz; 13C, 100.6 MHz; 19F, 376 MHz) and Bruker Avance 600
(1H, 600 MHz; 13C, 150 MHz) spectrometers at ambient temperature.
Chemical shifts in ppm are referenced to hexamethyldisiloxane (δ =
0.05 ppm) or tetramethylsilane (δ = 0 ppm) in the 1H NMR spectra
and to the solvent signal in the 13C NMR spectra. MALDI-TOF spectra
were recorded with a Bruker Daltonics UltraFlex instrument in a dith-
ranol matrix using PEG 400 or PEG 600 as the internal standard. ESI-
TOF spectra were recorded with a Thermo Scientific Orbitrap Elite in-
strument. Elemental analyses were performed with an Elementar
Vario MICRO cube apparatus. Column chromatography was carried
out on Macherey–Nagel silica gel 60 (0.040–0.063 mm).
Anal. Calcd for C18H17N3O3: C, 66.86; H, 5.30; N, 13.00. Found: C,
66.69; H, 5.28; N, 12.89.
Methyl 1-Benzyl-4-butyl-1H-1,2,3-triazole-5-carboxylate (2c)
Prepared from 1c (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
Yellowish oil; yield: 61.3 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.21 (m, 5 H, Ph), 5.84 (s, 2 H,
CH2N), 3.85 (s, 3 H, CH3O), 2.92–2.87 (m, 2 H, CH2Pr), 1.67 (m, 2 H,
CH2Et), 1.37 (sext, J = 7.3 Hz, 2 H, CH2CH3), 0.91 (t, J = 7.3 Hz, 3 H,
CH2CH3).
13C NMR (100.6 MHz, CDCl3): δ = 159.5 (C=O), 152.9 [4-C(triazole)],
135.3 [1-C(Ph)], 128.6 [2 C, CH(Ph)], 128.1 [4-CH(Ph)], 127.7 [2 C,
CH(Ph)], 123.6 [5-C(triazole)], 53.8 (CH2N), 52.0 (CH3O), 31.2 (CH2Pr),
26.1 (CH2Et), 22.4 (CH2CH3), 13.7 (CH2CH3).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C15H20N3O2: 274.1550;
found: 274.1559.
Palladium-Catalyzed Carbonylation of 5-Iodo-1H-1,2,3-triazoles 1;
General Procedure
In a flask, equipped with a condenser, the appropriate 5-iodo-1H-
1,2,3-triazole 1 (0.25 mmol), Pd(OAc)2 (2.8 mg, 12.5 μmol, 5 mol%),
and Et3N (0.70 mL, 5 mmol, 20 equiv) were mixed under a CO atmo-
sphere in the appropriate alcohol (MeOH, EtOH, or CF3CH2OH) as a
solvent (5 mL). The reaction mixture was stirred at 50 °C for 17 h,
then diluted with CH2Cl2 (25 mL), washed with 10% aq HCl (25 mL)
and H2O (25 mL). The organic layer was dried with anhydrous Na2SO4,
and the solvents were evaporated in vacuo. The residue was purified
by column chromatography.
Anal. Calcd for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37. Found: C,
65.90; H, 7.08; N, 15.03.
Methyl 1-Octyl-4-phenyl-1H-1,2,3-triazole-5-carboxylate (2d)
Prepared from 1d (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
CH2Cl2).
Methyl 1-Benzyl-4-phenyl-1H-1,2,3-triazole-5-carboxylate (2a)
Prepared from 1a (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1). Spectral data are in accordance with the litera-
ture.13
Yellowish oil; yield: 69.6 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 7.72–7.65 [m, 2 H, 2,6-CH(Ph)], 7.46–
7.36 [m, 3 H, 3,4,5-CH(Ph)], 4.69 (t, J = 7.3 Hz, 2 H, CH2N), 3.82 (s, 3 H,
CH3O), 1.91 (quin, J = 7.3 Hz, 2 H, CH2CH2N), 1.43–1.17 (m, 10 H), 0.86
(t, J = 7.0 Hz, 3 H, CH2CH3).
13C NMR (100.6 MHz, CDCl3): δ = 159.7 (C=O), 150.2 [4-C(triazole)],
130.4 [1-C(Ph)], 129.2 [2 C, CH(Ph)], 128.8 [4-CH(Ph)], 128.0 [2 C,
CH(Ph)], 123.7 [5-C(triazole)], 52.2 (CH3O), 51.1 (CH2N), 31.6, 30.3,
29.0, 28.9, 26.4, 22.5, 14.0 (CH2CH3).
Yellowish oil; yield: 66.8 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.71–7.66 [m, 2 H, 2,6-CH(4-Ph)],
7.43–7.36 [m, 3 H, CH(Ph)], 7.34–7.25 [m, 5 H, CH(Ph)], 5.90 (s, 2 H,
CH2), 3.73 (s, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 159.5 (C=O), 150.5 [4-C(triazole)],
135.1 [1-C(1-CH2Ph)], 130.2 [1-C(4-Ph)], 129.2 [2 C, CH(Ph)], 128.9
[4-CH(Ph)], 128.7 [2 C, CH(Ph)], 128.3 [4-CH(Ph)], 128.0 [2 C, CH(Ph)],
127.8 [2 C, CH(Ph)], 123.7 [5-C(triazole)], 54.2 (CH2), 52.2 (CH3).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C18H26N3O2: 316.2020;
found: 316.2023.
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Y. N. Kotovshchikov et al.
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Anal. Calcd for C18H25N3O2: C, 68.54; H, 8.01; N, 13.32. Found: C,
68.66; H, 8.01; N, 13.20.
Methyl 4-(Hydroxymethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole-5-
carboxylate (2k)
Prepared from 1k (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
CH2Cl2–MeOH, 30:1).
Methyl 1-(2-Methoxy-2-oxoethyl)-4-phenyl-1H-1,2,3-triazole-5-
carboxylate (2g)
Prepared from 1g (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
Off-white solid; yield: 45.3 mg (65%); mp 150–151 °C.
1H NMR (400 MHz, DMSO-d6–CCl4): δ = 8.42–8.36 [m, 2 H, 3,5-
CH(Ar)], 7.87–7.82 [m, 2 H, 2,6-CH(Ar)], 5.08 (br s, 1 H, OH), 4.76 (s, 2
H, CH2), 3.83 (s, 3 H, CH3).
Yellowish oil; yield: 56.6 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 7.77–7.72 [m, 2 H, 2,6-CH(Ph)], 7.46–
7.39 [m, 3 H, 3,4,5-CH(Ph)], 5.49 (s, 2 H, CH2), 3.81 (s, 3 H, CH3), 3.79
(s, 3 H, CH3).
13C NMR (100.6 MHz, DMSO-d6–CCl4): δ = 157.8 (C=O), 151.1 [4-C(tri-
azole)], 147.6 [4-C(Ar)], 141.2 [1-C(Ar)], 126.7 [2 C, CH(Ar)], 125.7 [2
C, CH(Ar)], 123.9 [5-C(triazole)], 54.4 (CH2), 52.3 (CH3).
13C NMR (100.6 MHz, CDCl3): δ = 166.8 (CH2CO2Me), 159.5 (CCO2Me),
150.2 [4-C(triazole)], 129.8 [1-C(Ph)], 129.4 [2 C, CH(Ph)], 129.1 [4-
CH(Ph)], 128.0 [2 C, CH(Ph)], 124.3 [5-C(triazole)], 52.9, 52.4, 52.0.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C11H11N4O5: 279.0724;
found: 279.0720.
HRMS (MALDI-TOF): m/z [M + Na]+ calcd for C13H13N3NaO3: 298.0798;
Methyl 1-(2-Oxotetrahydrofuran-3-yl)-4-phenyl-1H-1,2,3-tri-
found: 298.0811.
azole-5-carboxylate (2l)
Prepared from 1l (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 1:1).
Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C,
56.76; H, 4.86; N, 15.09.
Methyl 1-(2-Oxo-2-phenylethyl)-4-phenyl-1H-1,2,3-triazole-5-
Yellowish oil; yield: 43.6 mg (61%).
carboxylate (2h)
1H NMR (400 MHz, CDCl3): δ = 7.71–7.65 [m, 2 H, 2,6-CH(Ph)], 7.46–
7.40 [m, 3 H, 3,4,5-CH(Ph)], 6.17 (dd, J = 10.2, 9.3 Hz, 1 H, CHN), 4.71
(td, J = 9.3, 2.6 Hz, 1 H, CH2O), 4.50 (td, J = 9.3, 7.0 Hz, 1 H, CH2O), 3.82
(s, 3 H, CH3), 3.13 (dq, J = 12.7, 9.3 Hz, 1 H, CH2CH), 2.92 (dddd, J =
12.7, 10.2, 7.0, 2.6 Hz, 1 H, CH2CH).
Prepared from 1h (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
CH2Cl2–MeOH, 100:1).
Yellow oil; yield: 77.0 mg (96%).
13C NMR (100.6 MHz, CDCl3): δ = 170.8 (CHCO2), 159.7 (CO2Me), 150.5
[4-C(triazole)], 129.7 [1-C(Ph)], 129.4 [2 C, CH(Ph)], 129.2 [4-CH(Ph)],
128.1 [2 C, CH(Ph)], 124.1 [5-C(triazole)], 66.0 (CH2O), 58.3 (CHN),
52.7 (CH3), 28.6 (CH2CH).
HRMS (MALDI-TOF): m/z [M + Na]+ calcd for C14H13N3NaO4: 310.0798;
found: 310.0802.
1H NMR (400 MHz, CDCl3): δ = 8.03–7.97 [m, 2 H, 2,6-CH(Bz)], 7.80–
7.75 [m, 2 H, 2,6-CH(4-Ph)], 7.68–7.62 [m, 1 H, 4-CH(Bz)], 7.56–7.50
[m, 2 H, 3,5-CH(Bz)], 7.47–7.39 [m, 3 H, 3,4,5-CH(Ph)], 6.20 (s, 2 H,
CH2), 3.72 (s, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 190.2 [C=O(ketone)], 159.6 [C=O(es-
ter)], 150.1 [4-C(triazole)], 134.3 [4-CH(Bz)], 134.1 [1-C(Bz)], 130.1
[1-C(4-Ph)], 129.5 [2 C, CH(Ph)], 129.1 [2 C, CH(Ph)], 129.0 [4-CH(4-
Ph)], 128.0 [4 C, CH(Ph)], 124.8 [5-C(triazole)], 57.0 (CH2), 52.3 (CH3).
Anal. Calcd for C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C,
58.35; H, 4.55; N, 14.32.
HRMS (MALDI-TOF): m/z [M + K]+ calcd for C18H15KN3O3: 360.0745;
found: 360.0752.
Ethyl 5-{[1-Benzyl-5-(methoxycarbonyl)-1H-1,2,3-triazol-4-
yl]methoxy}-1,2-dimethyl-1H-indole-3-carboxylate (2m)
Methyl 1-Benzyl-4-(hydroxymethyl)-1H-1,2,3-triazole-5-
carboxylate (2j)
Prepared from 1m (0.15 mmol) according to the general procedure
for carbonylation; purification by column chromatography (silica gel,
CH2Cl2–MeOH, 50:1).
Prepared from 1j (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
CH2Cl2–MeOH, 30:1).
Off-white solid; yield: 66.1 mg (83%); mp 99–101 °C.
1H NMR (400 MHz, CDCl3): δ = 7.76 [d, J = 2.5 Hz, 1 H, 4-CH(indole)],
7.34–7.25 (m, 5 H, Ph), 7.13 [d, J = 8.8 Hz, 1 H, 7-CH(indole)], 6.91 [dd,
J = 8.8, 2.5 Hz, 1 H, 6-CH(indole)], 5.89 (s, 2 H, PhCH2), 5.15 [s, 2 H,
CH2C(triazole)], 5.36 [s, 2 H, CH2C(triazole)], 4.36 (q, J = 7.1 Hz, 2 H,
CH2CH3), 3.82 (s, 3 H, OCH3), 3.60 (s, 3 H, NCH3), 2.70 (s, 3 H, 2-CH3),
1.41 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (100.6 MHz, CDCl3): δ = 166.0 (CO2Et), 158.8 (CO2Me), 154.5
[5-C(indole)], 147.3 [4-C(triazole)], 145.4 [2-C(indole)], 134.8 [1-
C(Ph)], 131.9 [7a-C(indole)], 128.7 [2 C, CH(Ph)], 128.3 [4-CH(Ph)],
128.0 [2 C, CH(Ph)], 127.2 [3a-C(indole)], 125.6 [5-C(triazole)], 112.5
[6- or 7-CH(indole)], 109.6 [6- or 7-CH(indole)], 105.6 [4-CH(indole)],
103.6 [3-C(indole)], 62.6 [CH2C(triazole)], 59.2 (CH2CH3), 53.8
(PhCH2), 52.5 (OCH3), 29.6 (NCH3), 14.6 (2-CH3), 11.9 (CH2CH3).
Yellow oil; yield: 57.3 mg (93%).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 5 H, Ph), 5.85 (s, 2 H,
CH2N), 4.90 (s, 2 H, CH2OH), 3.89 (s, 3 H, CH3), 3.29 (br s, 1 H, OH).
13C NMR (100.6 MHz, CDCl3): δ = 158.9 (C=O), 151.5 [4-C(triazole)],
134.8 [1-C(Ph)], 128.7 [2 C, CH(Ph)], 128.3 [4-CH(Ph)], 127.8 [2 C,
CH(Ph)], 124.1 [5-C(triazole)], 56.7 (CH2O), 54.0 (CH2N), 52.6 (CH3).
HRMS (MALDI-TOF): m/z [M + K]+ calcd for C12H13KN3O3: 286.0588;
found: 286.0590.
Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 17.00. Found: C,
58.47; H, 5.58; N, 16.63.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C25H27N4O5: 463.1976;
found: 463.1991.
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Y. N. Kotovshchikov et al.
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Anal. Calcd for C25H26N4O5: C, 64.92; H, 5.67; N, 12.11. Found: C,
65.13; H, 5.88; N, 11.86.
19F NMR (376 MHz, CDCl3): δ = –73.1 (t, JHF = 8.2 Hz, 3 F).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C19H15F3N3O3: 390.1060;
found: 390.1073.
Methyl 4-Phenyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1H-
1,2,3-triazole-5-carboxylate (2n)
Anal. Calcd for C19H14F3N3O3: C, 58.62; H, 3.62; N, 10.79. Found: C,
58.65; H, 3.80; N, 10.47.
Prepared from 1n (0.2 mmol) according to the general procedure for
carbonylation using MeOH–DMF (4:1) mixture as a solvent to in-
crease the substrate solubility; purification by column chromatogra-
phy (silica gel, hexanes–EtOAc, 4:1).
Methyl 1-Benzyl-4-(2-hydroxyphenyl)-1H-1,2,3-triazole-5-carbox-
ylate (2r)
Prepared from 1t (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
CH2Cl2 CH2Cl2–MeOH, 100:1).
White solid; yield 50.5 mg (70%); mp 96–98 °C.
1H NMR (400 MHz, CDCl3): δ = 8.02–7.97 [m, 2 H, 2,6-CH(5-Ph)],
7.79–7.73 [m, 2 H, 2,6-CH(4-Ph)], 7.55–7.41 [m, 6 H, CH(Ph)], 6.25 (s,
2 H, CH2), 3.86 (s, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 165.7 [5-C(oxadiazole)], 160.3 [2-
C(oxadiazole) or C=O], 159.2 [2-C(oxadiazole) or C=O], 150.7 [4-C(tri-
azole)], 132.1 [4-CH(5-Ph)], 129.5 [1-C(4-Ph)], 129.4 [2 C, CH(Ph)],
129.3 [4-CH(4-Ph)], 129.1 [2 C, CH(Ph)], 128.1 [2 C, CH(Ph)], 127.0 [2
C, CH(Ph)], 124.3 [5-C(triazole)], 123.2 [1-C(5-Ph)], 52.7 (CH3), 45.5
(CH2).
White solid; yield: 54.0 mg (70%); mp 154–156 °C.
1H NMR (400 MHz, CDCl3–CD3OD): δ = 7.57 [d, J = 7.6 Hz, 1 H, 6-
CH(Ar)], 7.38–7.20 [m, 6 H, 5 H Ph + 1 H 4-CH(Ar)], 6.99–6.89 [m, 2 H,
3,5-CH(Ar)], 5.89 (s, 2 H, CH2), 3.77 (s, 3 H, CH3), 3.74 (br s, 1 H, OH).
13C NMR (100.6 MHz, CDCl3–CD3OD): δ = 159.8 (CO2), 155.0 [4-C(tri-
azole) or 2-C(Ar)], 147.2 [4-C(triazole) or 2-C(Ar)], 134.4 [1-C(Ph)],
130.5 [4- or 6-CH(Ar)], 129.6 [4- or 6-CH(Ar)], 128.6 [2 C, CH(Ph)],
128.3 [4-CH(Ph)], 127.6 [2 C, CH(Ph)], 124.9 [5-C(triazole)], 119.3 [3-
or 5-CH(Ar)], 116.2 [3- or 5-CH(Ar)], 115.4 [1-C(Ar)], 54.0 (CH2), 52.3
(OCH3).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C19H16N5O3: 362.1248;
found: 362.1247.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C17H16N3O3: 310.1186;
found: 310.1179.
Ethyl 1-(2-Oxo-2-phenylethyl)-4-phenyl-1H-1,2,3-triazole-5-car-
boxylate (2o)
Prepared from 1h (0.15 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
Methyl 4-Butyl-1-[2-(2-methoxy-2-oxoethyl)phenyl]-1H-1,2,3-tri-
azole-5-carboxylate (2s)
Carbonylation of 1q was performed in a 25 mL capacity glass low
pressure reactor RLP25ML (www.openscience.ru) equipped with gas
feeding system, magnetic stirrer and manometer. In a pressure vessel,
1q (0.5 mmol), Pd(PPh3)4 (29.0 mg, 25 μmol, 5 mol%), and Et3N (1.40
mL, 10 mmol, 20 equiv) were mixed in MeOH (5 mL). The reaction
mixture was stirred under a CO atmosphere (5 atm) at 50 °C for 18 h,
then diluted with CH2Cl2 (25 mL) and washed with 10% aq HCl (25
mL) and H2O (25 mL). The organic layer was dried with anhydrous
Na2SO4, and the solvents were evaporated in vacuo. The residue was
purified by column chromatography (silica gel, hexanes–EtOAc, 4:1).
White solid; yield: 41.0 mg (82%); mp 101–103 °C.
1H NMR (400 MHz, CDCl3): δ = 8.01–7.97 [m, 2 H, 2,6-CH(Bz)], 7.80–
7.75 [m, 2 H, 2,6-CH(4-Ph)], 7.66–7.61 [m, 1 H, 4-CH(Bz)], 7.55–7.49
[m, 2 H, 3,5-CH(Bz)], 7.45–7.37 [m, 3 H, 3,4,5-CH(Ph)], 6.19 (s, 2 H,
CH2N), 4.19 (q, J = 7.1 Hz, 2 H, CH2O), 1.12 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 190.2 [C=O(ketone)], 159.2 [C=O(es-
ter)], 150.2 [4-C(triazole)], 134.3 [4-CH(Bz)], 134.2 [1-C(Bz)], 130.2
[1-C(4-Ph)], 129.6 [2 C, CH(Ph)], 129.1 [2 C, CH(Ph)], 129.0 [4-CH(4-
Ph)], 128.0 [2 C, CH(Ph)], 127.9 [2 C, CH(Ph)], 125.2 [5-C(triazole)],
61.9 (CH2O), 57.0 (CH2N), 13.6 (CH3).
Brown oil; yield: 129.4 mg (78%).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C19H18N3O3: 336.1343;
found: 336.1341.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.47 [m, 2 H, CH(Ar)], 7.46–7.40
[m, 1 H, 4- or 5-CH(Ar)], 7.29 [d, J = 7.8 Hz, 1 H, 3- or 6-CH(Ar)], 3.73
[s, 3 H, C(triazole)CO2CH3], 3.55 (s, 3 H, CH2CO2CH3), 3.35 (s, 2 H,
CH2CO2), 3.03 (t, J = 7.7 Hz, 2 H, CH2Pr), 1.84–1.75 (m, 2 H, CH2Et), 1.45
(sext, J = 7.4 Hz, 2 H, CH2Me), 0.98 (t, J = 7.4 Hz, 3 H, CH2CH3).
Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C,
68.39; H, 5.37; N, 12.45.
13C NMR (100.6 MHz, CDCl3): δ = 170.1 (CH2CO2Me), 158.7 [C(tri-
azole)CO2Me], 152.1 [4-C(triazole)], 136.5 [1-C(Ar)], 131.2 [2-C(Ar)],
131.1 [CH(Ar)], 130.3 [CH(Ar)], 127.7 [CH(Ar)], 127.5 [CH(Ar)], 126.3
[5-C(triazole)], 52.0 (CH3O), 51.9 (CH3O), 36.5 (CH2CO2), 31.1 (CH2Pr),
25.7 (CH2Et), 22.2 (CH2Me), 13.7 (CH2CH3).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C17H22N3O4: 332.1605;
found: 332.1615.
2,2,2-Trifluoroethyl 1-(2-Oxo-2-phenylethyl)-4-phenyl-1H-1,2,3-
triazole-5-carboxylate (2p)
Prepared from 1h (0.2 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
Off-white solid; yield: 27.9 mg (36%); mp 85–87 °C.
1H NMR (400 MHz, CDCl3): δ = 8.03–7.98 [m, 2 H, 2,6-CH(Bz)], 7.78–
7.72 [m, 2 H, 2,6-CH(4-Ph)], 7.71–7.65 [m, 1 H, 4-CH(Bz)], 7.58–7.52
[m, 2 H, 3,5-CH(Bz)], 7.48–7.42 [m, 3 H, 3,4,5-CH(Ph)], 6.22 (s, 2 H,
CH2N), 4.50 (q, JHF = 8.2 Hz, 2 H, CH2O).
13C NMR (100.6 MHz, CDCl3): δ = 189.9 [C=O(ketone)], 157.6 [C=O(es-
ter)], 151.3 [4-C(triazole)], 134.6 [4-CH(Bz)], 133.9 [1-C(Bz)], 129.6 [2
C, CH(Ph)], 129.5 [1-C(4-Ph)], 129.4 [4-CH(4-Ph)], 129.1 [2 C, CH(Ph)],
128.1 [2 C, CH(Ph)], 128.0 [2 C, CH(Ph)], 123.7 [5-C(triazole)], 122.3
(q, JCF = 277.5 Hz, CF3), 60.9 (q, JCF = 37.4 Hz, CH2O), 57.2 (CH2N).
3-Butyl-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin-4-one (4)
In a flask, equipped with a condenser, 1o (0.25 mmol), Pd(OAc)2 (2.8
mg, 12.5 μmol, 5 mol%), and Et3N (0.70 mL, 5 mmol, 20 equiv) were
mixed under a CO atmosphere in MeOH (5 mL). The reaction mixture
was stirred at 50 °C for 17 h, then diluted with CH2Cl2 (25 mL), and
washed with 10% aq HCl (25 mL) and H2O (25 mL). The organic layer
was dried with anhydrous Na2SO4, and the solvents were evaporated
in vacuo. The residue was dissolved in a mixture of toluene (3 mL)
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Y. N. Kotovshchikov et al.
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and Et3N (0.1 mL) and refluxed for 1 h. The solvents were evaporated
in vacuo and the residue was purified by column chromatography
(silica gel, CH2Cl2).
hydrous Na2SO4, the solvents were evaporated in vacuo, and the resi-
due was purified by column chromatography (silica gel, CH2Cl2–
MeOH, 100:1).
White solid; yield: 47.5 mg (78%); mp 130–131 °C.
White solid; yield: 64.6 mg (93%); mp 120–122 °C.
1H NMR (400 MHz, CDCl3): δ = 8.31 [dd, J = 8.0, 1.4 Hz, 1 H, 9-CH(Ar)],
7.52 [ddd, J = 8.6, 7.0, 1.4 Hz, 1 H, 7-CH(Ar)], 7.47–7.41 [m, 2 H, 6,8-
CH(Ar)], 3.13 (t, J = 7.6 Hz, 2 H, CH2Pr), 1.85–1.76 (m, 2 H, CH2Et), 1.43
(sext, J = 7.4 Hz, 2 H, CH2Me), 0.95 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 153.7 [3- or 4-C], 152.3 [3- or 4-C],
142.8 [5a-C], 129.8 [CH(Ar)], 125.8 [CH(Ar)], 121.2 [3a- or 9a-C], 118.2
[3a- or 9a-C], 117.9 [CH(Ar)], 116.2 [CH(Ar)], 30.9 (CH2Pr), 25.3
(CH2Et), 22.2 (CH2Me), 13.7 (CH3).
1H NMR (400 MHz, CDCl3): δ = 13.39 (s, 1 H, OH), 8.63–8.59 [m, 1 H,
6- or 9-CH(Ar)], 8.51–8.47 [m, 1 H, 6- or 9-CH(Ar)], 7.49–7.40 [m, 2 H,
7,8-CH(Ar)], 4.10 (s, 3 H, OCH3), 3.19 (t, J = 7.7 Hz, 2 H, CH2Pr), 1.88–
1.79 (m, 2 H, CH2Et), 1.46 (sext, J = 7.4 Hz, 2 H, CH2Me), 0.98 (t, J = 7.4
Hz, 3 H, CH2CH3).
13C NMR (100.6 MHz, CDCl3): δ = 171.9 (CO2), 158.4 (quat.), 146.2
(quat.), 127.9 (quat.), 127.5 [CH(Ar)], 126.5 [CH(Ar)], 126.2 [CH(Ar)],
123.1 [3a- or 5a-C(Ar)], 121.1 [3a- or 5a-C(Ar)], 116.1 [9-CH(Ar)], 99.0
[5-C(Ar)], 52.9 (OCH3), 31.9 (CH2Pr), 25.9 (CH2Et), 22.3 (CH2Me), 13.8
(CH2CH3).
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C13H14N3O2: 244.1081;
found: 244.1087.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N3O3: 300.1343; found:
300.1343.
Anal. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C,
64.32; H, 5.42; N, 16.82.
Methyl 1-(17-Hydroxy-3,20-dioxopregn-4-en-21-yl)-4-(hy-
droxymethyl)-1H-1,2,3-triazole-5-carboxylate (11)
3-Butyl-[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-one (5)
Prepared from 1s (0.25 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 4:1).
Prepared from 10 (0.15 mmol) according to the general procedure for
carbonylation; purification by column chromatography (silica gel,
hexanes–EtOAc, 1:3).
White solid; yield: 46.5 mg (77%); mp 234–235 °C.
Off-white solid; yield: 61.4 mg (84%); mp 230–231 °C.
1H NMR (400 MHz, CDCl3–CD3OD): δ = 8.38 [d, J = 8.1 Hz, 1 H, 9-
CH(Ar)], 7.51–7.45 [m, 1 H, 7-CH(Ar)], 7.42–7.32 [m, 2 H, 6,8-CH(Ar)],
3.19 (t, J = 7.6 Hz, 2 H, CH2Pr), 1.88–1.78 (m, 2 H, CH2Et), 1.45 (sext, J =
7.4 Hz, 2 H, CH2Me), 0.97 (t, J = 7.4 Hz, 3 H, CH3), NH proton was not
assigned.
13C NMR (100.6 MHz, CDCl3–CD3OD): δ = 155.4 [3- or 4-C], 150.0 [3-
or 4-C], 129.0 [CH(Ar)], 128.4 [5a-C], 124.0 [CH(Ar)], 122.8 [3a- or 9a-
C], 121.5 [3a- or 9a-C], 116.6 [CH(Ar)], 116.0 [CH(Ar)], 31.2 (CH2Pr),
25.1 (CH2Et), 22.1 (CH2Me), 13.5 (CH3).
1H NMR (400 MHz, CDCl3–CD3OD): δ = 6.12 (d, J = 18.3 Hz, 1 H, 21-
CH2), 5.73 (br s, 1 H, 4-CH), 5.57 (d, J = 18.3 Hz, 1 H, 21-CH2), 4.89 (s, 2
H, CH2OH), 3.90 (s, 3 H, OCH3), 3.49 (br s, 2 H, OH), 2.66–2.58 (m, 1 H),
2.47–2.25 (m, 4 H), 2.07–2.01 (m, 1 H), 1.97 (td, J = 12.8, 3.8 Hz, 1 H),
1.89–1.54 (m, 6 H), 1.48 (qd, J = 13.1, 3.8 Hz, 1 H), 1.36–1.21 (m, 3 H),
1.19 (s, 3 H, 19-CH3), 1.15–1.06 (m, 1 H), 1.04–0.98 (m, 1 H), 0.66 (s, 3
H, 18-CH3).
13C NMR (100.6 MHz, CDCl3–CD3OD): δ = 204.1 [C(20)=O], 200.5
[C(3)=O], 172.4 (5-C), 159.0 (CO2Me), 150.0 [4-C(triazole)], 125.6 [5-
C(triazole)], 123.4 (4-CH), 89.4 (17-COH), 58.0 (21-CH2 or CH2OH),
55.7 (21-CH2 or CH2OH), 53.0, 52.6, 50.4, 48.2 (quat.), 38.5 (quat.),
35.4, 35.3, 34.4, 33.6, 32.7, 31.8, 29.9, 23.4, 20.6, 17.1, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H15N4O: 243.1240; found:
243.1241.
3-Benzylchromeno[3,4-d][1,2,3]triazol-4(3H)-one (6)
HRMS (ESI): m/z [M + H]+ calcd for C26H36N3O6: 486.2599; found:
486.2601.
In a flask, equipped with a condenser, 2r (0.15 mmol) and Et3N (0.1
mL) were mixed in toluene (3 mL). After reflux of the mixture for 5 h,
the solvents were evaporated in vacuo and the residue was purified
by column chromatography (silica gel, CH2Cl2).
Funding Information
White solid; yield: 38.3 mg (92%); mp 197–198 °C.
1H NMR (600 MHz, CDCl3): δ = 8.24 [dd, J = 7.7, 0.9 Hz, 1 H, 9-CH(Ar)],
7.55–7.50 [m, 3 H, 2 H 2,6-CH(Ph) + 1 H CH(Ar)], 7.45–7.39 [m, 2 H,
CH(Ar)], 7.37–7.30 [m, 3 H, CH(Ar)], 6.00 (s, 2 H, CH2).
13C NMR (151 MHz, CDCl3): δ = 153.0 (quat.), 152.3 (quat.), 148.3
(quat.), 134.1 [1-C(Ph)], 130.7 [CH(Ar)], 129.0 [2 C, CH(Ph)], 128.9 [4-
CH(Ph)], 128.7 [2 C, CH(Ph)], 125.4 [CH(Ar)], 123.0 [CH(Ar)], 119.8
[3a- or 9a-C], 117.3 [6-CH], 114.1 [3a- or 9a-C], 53.8 (CH2).
This work was supported by the Russian Foundation for Basic Re-
search (grant number 16-33-00801-mol_a) and M. V. Lomonosov
Moscow State University Program of Development. I. P. Beletskaya is
grateful to the Russian Science Foundation (grant number 14-23-
00186).
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Acknowledgment
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3O2: 278.0924; found:
The authors would like to acknowledge Thermo Fisher Scientific Inc.,
MS Analytica (Moscow, Russia) and Prof. A. Makarov personally for
providing mass spectrometry equipment for this work.
278.0913.
Methyl 3-Butyl-4-hydroxy-[1,2,3]triazolo[1,5-a]quinoline-5-car-
boxylate (7)
In a flask, 2s (0.231 mmol) was dissolved in THF (3 mL). The solution
was cooled in an ice–water bath and t-BuOK (31.1 mg, 0.277 mmol,
1.2 equiv) was added under an argon atmosphere. After stirring for 30
min, the reaction mixture was diluted with 10% aq HCl (25 mL) and
extracted with CH2Cl2 (25 mL). The organic layer was dried with an-
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591896.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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Y. N. Kotovshchikov et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I