Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of N,1-Diaryl-1 H-tetrazol-5-amines

Article abstract of DOI:10.1021/acs.joc.1c00282

The Pd-catalyzed N-arylation method for the synthesis of eighteen N,1-diaryl-1H-tetrazol-5-amine derivatives is reported. By running the reactions at 35 °C, compounds were isolated as single isomers since the undesired Dimroth rearrangement was completely

Full text of DOI:10.1021/acs.joc.1c00282

pubs.acs.org/joc
Article
Controlling Pd-Catalyzed N‑Arylation and Dimroth Rearrangement
in the Synthesis of N,1-Diaryl‑1H‑tetrazol-5-amines
̌
́ ́
Andrea M. Nikolic, Jelena Stanic, Matija Zlatar, Maja Gruden, Boban And̵elkovic, Zivota Selakovic,
́
́
̌
́
Vladimir Ajdacic, and Igor M. Opsenica*
Cite This: J. Org. Chem. 2021, 86, 4794−4803
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The Pd-catalyzed N-arylation method for the synthesis of
eighteen N,1-diaryl-1H-tetrazol-5-amine derivatives is reported. By
running the reactions at 35 °C, compounds were isolated as single
isomers since the undesired Dimroth rearrangement was completely
suppressed. Furthermore, the Dimroth rearrangement of N,1-diaryl-1H-
tetrazol-5-amines was rationalized by conducting comprehensive experi-
ments and NMR analysis as well as density functional theory (DFT)
calculations of thermodynamic stability of the compounds. It was
established that the Dimroth rearrangement is thermodynamically
controlled, and the equilibrium of the reaction is determined by the
stability of the corresponding isomers. The mechanism was investigated by
additional DFT calculations, and the opening of the tetrazole ring was
shown to be the rate-determining step. By maneuvering Pd-catalyzed N-
arylation and the subsequent Dimroth rearrangement, two more N,1-
diaryl-1H-tetrazol-5-amine derivatives were acquired, which otherwise cannot be synthesized by employing the C−N cross-coupling
reaction.
INTRODUCTION
■
The tetrazole scaffold is a well-known motif in bioactive
compounds. This heterocyclic moiety can be found in FDA
approved drugs, such as Losartan, an angiotensin II receptor
blocker used to treat high blood pressure,1 or cefonicid, an
antibiotic active against Gram-negative rods.2 As its derivative,
the 1H-tetrazol-5-amine scaffold is an important pharmaco-
phore in drug discovery and development. Recently, 1-aryl-5-
arylamino-1H-tetrazoles have been shown to possess anti-
tubercular potential (compound 1, Figure 1),3 while other 1-
aryl-5-alkylamino derivatives are proven to be active against
Gram-positive and Gram-negative strains (compound 2, Figure
1).4 There have also been reports on antiallergic5 and
antidiabetic6 activity of aminotetrazoles. Applications outside
medicinal chemistry include protection against steel corrosion
(compound 4, Figure 1)7 as well as uses in coordination
chemistry as ligands8 and in synthetic chemistry as reactive
intermediates.9 Additionally, Krishnan et al. demonstrated the
Figure 1. Selected molecules containing an aminotetrazole moiety.
utility of aminotetrazole-functionalized nanoparticle compo-
sites for the removal of dyes and detection of heavy metal
ions.10
Received: February 4, 2021
Published: March 8, 2021
The most common approach for the synthesis of the N,1-
diaryl-1H-tetrazol-5-amines is based on the formation of the
tetrazole ring from N-substituted acyclic precursors;11
however, this methodology usually provides the mixture of
isomeric compounds.9b,11d Having in mind the importance of
https://dx.doi.org/10.1021/acs.joc.1c00282
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 4794−4803
4794

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Temperature Controlled Outcome of Pd-Catalyzed N-Arylation
b
entry
temperature (°C)
yield (%)
isomer ratio
1
2
3
4
5
r.t.
35
80
105
130
33
98
86
95
88
1:0
1:0
1:3.5
1:3.5
1:3.0
c
c
c
a
Reactions conditions: 5a (1.05 equiv), 6a (1.0 equiv), Pd2(dba)3 (10 mol % Pd), t-BuXPhos (20 mol %), NaOt-Bu (1.05 equiv), 1,4-dioxane, 24
b
c
1
h, Ar. Isomer ratio by H NMR spectroscopy. Yield of a mixture of isomers.
this class of heterocycles and the aforementioned difficulties,
the development of a highly selective synthetic method
presents a challenge.
formed into the desired products in good to excellent yields
(Table 2, 7b−7h). Reactions of halogen substituted com-
pounds 5 and 6 also gave the corresponding products 7i−7n in
high yields, showing excellent selectivity toward the bromine
atom. When sterically demanding 2-bromo-1,3,5-trimethylben-
zene 6i was reacted with 5a, the desired product 7q was
obtained in 27% yield. The scope of this method was further
expanded by utilizing heteroaryl bromides or 1-heteroaryl-1H-
tetrazol-5-amines. The desired pyridine substituted tetrazoles
7o and 7p were obtained in 84 and 69% yield, respectively. By
reacting 2,4-dichloropyrimidine 6j with 1-phenyl-1H-tetrazol-
5-amine 5a in the presence of Pd2(dba)3, t-BuXPhos as a
ligand, and K2CO3 as a base in 1,4-dioxane, product 7r was
obtained in 44% yield. However, by changing the ligand to
XantPhos, the yield of the desired product 7r was raised to
63%. Unfortunately, there was no reaction when 3-bromo-1-
tosyl-1H-indole 6k was employed as a substrate (Table 2, 7s).
This indole derivative has been shown in the literature to be
problematic in this type of reactions. Notably, the reaction
scale could be increased to 1 mmol, shown on the example of
the compound 7h. It is worth mentioning that all the products
were isolated as single isomers, with no detection of side-
products, showcasing the selectivity of this method and the
hindering of the subsequent rearrangement reaction. This
method allows for the synthesis of any isomer as a single
compound as illustrated for 7b (Tables 1 and 2). As most of
the desired compounds were synthesized in good to excellent
yields, with a broad substrate scope, this method could be
utilized for further functionalization and the synthesis of more
complex compounds.
Since Dimroth rearrangement is successfully employed as a
method of attaining various heterocyclic structures, applied to
industrial processes and even observed in biological systems, as
a continuation of this research, we wanted to further study the
said transformation on this heterocyclic system.17 Dimroth
rearrangement of 1H-tetrazole-5-amine derivatives was first
observed in 1953,18,19 during heating of various monosub-
stituted 5-aminotetrazoles and some 5-alkyl-1-aryl-1H-tetra-
zole-5-amines. A similar transformation was noticed by
Dimroth in 1H-1,2,3-triazole-5-amine derivatives20 and later
recognized as a valuable method for acquiring some previously
unavailable aminotetrazoles.21 The occurrence of Dimroth
rearrangement of tetrazoles still seems to be somewhat
neglected in modern organic synthesis, appearing more often
RESULTS AND DISCUSSION
■
The palladium-catalyzed formation of the C−N bond between
aryl-halides and amines is one of the most important reactions
in modern organic chemistry and drug development
process12,13 and under classical Buchwald−Hartwig reaction
conditions, the reaction mixture is heated between 80 and 120
°C.14,15 As a continuation of our previous research in the
chemistry of tetrazoles, we sought to synthesize new 1-aryl-N-
aryl-1H-tetrazol-5-amines. Applying previously used reaction
conditions16 on 5a and 6a yielded a mixture of two
regioisomeric compounds 7a and 7b (Table 1, entry 4). It is
worth mentioning that compounds 7a and 7b could not be
separated by standard chromatographic techniques. In-depth
analysis showed that the mixture of compounds is a result of
N-arylation followed by Dimroth rearrangement. Therefore,
our next step was to optimize the reaction conditions to
suppress the rearrangement reaction. By lowering the reaction
temperature to 80 °C, the yield dropped and the rearrange-
ment product 7b was still the dominant one (Table 1, entry 3).
Running the reaction at room temperature yielded solely the
desired product 7a albeit in low yield, while starting compound
5a was recovered (Table 1, entry 1). Raising the temperature
to 35 °C resulted in the formation of the desired product 7a,
which was obtained in high yield, while the rearrangement
product 7b was not detected (Table 1, entry 2). Additionally,
we wanted to examine whether raising the reaction temper-
ature to 130 °C would impact the ratio of the products and
yield only one product (Table 1, entry 5). We concluded that
higher temperatures do not play a significant role in the
product distribution of the Dimroth rearrangement and that,
perhaps, structural parameters govern the outcome of the
reaction.
In order to investigate the scope of the palladium catalyzed
N-arylation reaction at 35 °C, we synthesized a series of 17
additional derivatives 7b−7r (Table 2). These compounds
would later be used as substrates for the rearrangement
reaction and the detailed analysis of the relationship between
the structural parameters and the isomer distribution. A series
of aryl bromides and 1-aryl-1H-tetrazol-5-amines, including
those with an electron-donating group (−OMe) and with
electron-withdrawing groups (−NO2, −CF3), were trans-
4795
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 2. Substrate Scope for Palladium Catalyzed N-Arylation
a
Reactions conditions: 5 (1.05 equiv), 6 (1.0 equiv), Pd2(dba)3 (10 mol % Pd), t-BuXPhos (20 mol %), NaOt-Bu (1.05 equiv), 1,4-dioxane, 35 °C,
b
c
24 h, Ar. Reaction performed on 1.1 mmol scale. K2CO3 (1.05 equiv) used as a base and XantPhos (20 mol %) used as a ligand.
as an unexpected22 or unwanted23 side reaction than as the
desired transformation.24
the ratio of the isomers, always giving 7a/7b = 1:3.5 ratio. This
strongly suggested that the solvent does not play an important
role in the outcome of the reaction. Next, in order to
investigate the influence of structural characteristics on the
ratio of the isomers, we subjected all compounds to Dimroth
rearrangement, by heating them at 105 °C for 24 h in either
1,4-dioxane or DMSO-d6 (Table 3). Based on the acquired
results, several conclusions could be made. Primarily, the
electronic effects of substituents play an important role.
Compounds containing a phenyl core with electron-donating
groups on the endocyclic nitrogen of the tetrazole ring will
always be in excess after the reaction. This means that electron-
With a set of N,1-diaryl-1H-tetrazol-5-amines shown in
Table 2, we sought to explore the outcome of Dimroth
rearrangement. First, the reaction conditions were studied.
When compound 7a was heated in 1,4-dioxane (105 °C, 24 h)
without a palladium source and a ligand either in the presence
of NaOt-Bu (1.05 equiv) or in the absence of the base, the
isomer ratio remained the same, meaning that neither the base
nor palladium play a role in the rearrangement. Changing the
solvent to CD3OD, CDCl3, C6D6, and DMSO-d6 and heating
7a in the corresponding solvent at 105 °C for 24 h did not alter
4796
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
isomer to another. It is important to outline that the isomer
ratio in the Dimroth reaction remained the same, regardless of
which single isomer was used as a starting compound. This
suggests that the ratio was dictated by the stability of the
compounds, implying a thermodynamic control of the
reaction. We next sought to determine the temperature at
which the reaction initiates. To achieve this, we chose a pair of
Table 3. Substrate Scope for Dimroth Rearrangement
b
ratio of
A/B
ratio of isomers
c
1
substrates 7m and 7n and we recorded the H NMR spectra
entry
R1
R2
(based on ΔrG)
while the sample was gradually heated (∼1 °C/min) inside the
NMR spectrometer (see the Supporting Information, Tables
S1 and S2). We observed that 7n begins to transform into 7m
at 80 °C, while for the corresponding 7m, we detected the
formation of 7n only at 99 °C. From the experimental data, we
concluded that the transformation of different starting isomers
proceeds at different rates at the same temperature presumably
due to the difference in the activation energies. The two
isomers exist in equilibrium, and the stability of the
compounds determines the position of the equilibrium
between the two regioisomers. This hypothesis was further
investigated and reinforced by in silico methods (Tables 3, S3).
Based on all the acquired dataexperimental results, density
functional theory (DFT) calculations, and NMR experiments,
we propose the mechanism of Dimroth rearrangement
(Scheme 1, Figures 2, S1). The transformation proceeds
through a thermally induced ring opening-ring closing process.
The conformational changes arising from the rotation of the
C5−N bond were chosen, for the sake of clarity, to represent
the first and the last step, although they can occur at any stage
of the reaction pathway. Temperature-induced opening of the
tetrazole ring leads to a substituted guanylazide II, which can
transform further to IV via bond rotation-proton transfer (via
intermediate III) or proton transfer (intermediate VI)
followed by bond rotation. The cyclization of guanylazide II
and IV to I and V, respectively, is thermodynamically
favorable. Notably, the compound with an electron-rich
aromatic ring in N1 position 7b is more stable than the
other isomer 7a (Figure 2). It is also worth mentioning that
the relative energies of II and IV are different and that the less
stable IV has lower activation energy for cyclization to 7b. This
is in agreement with the fact that the electron-donating
methoxy group destabilizes IV. Overall, it can be concluded
1
2
3
4
5
6
7
8
H
4-OMe
H
4-NO2
4-OMe
4-NO2
H
3-CF3
H
3-F
H
4-F
H
4-OMe
H
4-NO2
H
4-NO2
4-OMe
3-CF3
H
3-F
H
4-F
H
22:78
78:22
100:0
0:100
100:0
0:100
89:11
12:88
79:21
25:75
50:50
50:50
81:19
19:81
78:22
22:78
4:96
7a/7b = 13:87
7c/7d = 99:1
7e/7f = 100:0
7g/7h = 88:12
7i/7j = 80:20
9
10
11
12
13
14
15
16
17
18
7k/7l = 51:49
3-Cl
H
3-pyr
H
7m/7n = 85:15
7o/7p = 90:10
3-Cl
H
3-pyr
H
Mes
A/B = <1:>99
A/B = 76:24
H
4-2-Cl-pyrimidine
100:0
a
Reaction conditions: 7 (10 mg), 1,4-dioxane or DMSO-d6 (0.5 mL),
b
105 °C, 24 h. Isomer ratio by 1H NMR spectroscopy (see the
c
Supporting Information). Based on the difference in Gibbs free
energies of isomers (T = 378.15 K) calculated at the BLYP-D4/def2-
TZVP(-f)-SMD (dioxane) level of theory.
withdrawing substituents show a preference for the exocyclic
position. An additive effect could also be observed, when
comparing entry 1 and entry 6 as well as entry 15 and entry 18
(Table 3). Additionally, the position of the substituent (m-F vs
p-F) also impacts the outcome of the reaction (entries 10 and
12)the difference in the isomer ratio of this pair of
compounds can be attributed to the stronger influence of the
inductive effect. Three methyl groups (entry 17) greatly affect
the rearrangement with almost a complete conversion of one
Scheme 1. Proposed Mechanism for Dimroth Rearrangement
4797
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 2. Calculated reaction profile for the Dimroth rearrangement of 7a and 7b. Gibbs free energies (in kcal/mol relative to 7a) at 378.15 K,
obtained using the BLYP-D4/def2-TRVP(-f)-SMD(dioxane) level of theory.
that the reaction is thermodynamically controlled and that
ring-opening is the rate-determining step. To the best of our
knowledge, this is the first time that the mechanism has been
studied on N,1-diaryl-1H-tetrazol-5-amines.
In order to further demonstrate the control of the Dimroth
rearrangement and the applicability of the synthesized N,1-
diaryl-1H-tetrazol-5-amines, compounds 7t and 7u were
synthesized (Scheme 2). Compound 7d was converted into
free energies is 4:96 (calculated at the BLYP-D4/def2-TZVP(-
f)-SMD(dioxane) level of theory at T = 378.15 K). To further
confirm the structure of 7u, compound 7d was reacted with
hydrogen in the presence of Pd/C (5 mol % Pd) and 7u was
obtained in quantitative yield. It is important to outline that
compounds 7t and 7u cannot be efficiently synthesized
through Pd-catalyzed N-arylation of 1-phenyl-1H-tetrazol-5-
amine 5a or 1-(4-aminophenyl)-1H-tetrazol-5-amine, respec-
tively, as there is a competing effect between the amino-
tetrazole and aniline moiety. Additionally, the amino group
represents another possible point for further derivatization of
N,1-diaryl-1H-tetrazol-5-amines.
Scheme 2. Synthesis of 7t and 7u
CONCLUSIONS
■
In conclusion, we used Pd-catalyzed N-arylation to synthesize
a set of N,1-diaryl-1H-tetrazol-5-amines. By controlling the
reaction temperature, unwanted Dimroth rearrangement was
prevented and the desired compounds were isolated as single
isomers. A better insight into the Dimroth rearrangement was
gained by further studying the isomer distribution at elevated
temperatures. The equilibrium was found to be a function of
thermodynamic stability of the products. The thermodynamic
control of the reaction, as well as the distribution of isomers in
the Dimroth rearrangement, was confirmed by in silico
methods. Additionally, DFT calculations were used to propose
a reaction mechanism, elucidating the ring-opening as the rate-
limiting step. Finally, with the newly gained understanding of
the structural parameters that determine the rearrangement
outcome, we applied a sequence of reactions to synthesize
compounds that cannot otherwise be selectively obtained
through Pd-catalyzed reactions.
7c using the conditions for Dimroth rearrangement (Table 3).
Compound 7t was obtained in quantitative yield by reducing
the nitro group of 7c, under a hydrogen atmosphere (1 atm)
using Pd/C (5 mol % Pd) as a catalyst. By exploiting the
selectivity of Dimroth rearrangement, compound 7t was
quantitatively converted into the compound 7u when it was
heated in 1,4-dioxane at 105 °C for 24 h (Scheme 2). This
result is in a good agreement with the results obtained by DFT
calculations, where the ratio of isomers for 7t/7u from Gibbs
EXPERIMENTAL SECTION
■
General Information. Unless stated otherwise, all solvents and
reagents were obtained from commercial sources and used without
further purification. Dry-flash chromatography was performed on
SiO2 (0.018−0.032 mm). Melting points were determined on a
4798
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Boetius PMHK apparatus and are not corrected. IR spectra were
1-(4-Fluorophenyl)-1H-tetrazol-5-amine (5f). Following the
procedure described for 5d, compound 5f was obtained as a pale
yellow solid (328 mg, 45%) starting from 4-fluoroaniline (448 mg,
4.03 mmol); mp 160−162 °C. IR (ATR): 3303, 3133, 2989, 1662,
recorded on a Thermo Scientific Nicolet 6700 FT-IR Diamond
1
Crystal instrument. H and 13C NMR spectra were recorded on a
Bruker Ultrashield Avance III spectrometer (at 500 and 125 MHz,
respectively) and Varian spectrometer (at 400 and 100 MHz,
respectively). Chemical shifts are expressed in parts per million
(ppm) on the (δ) scale. Chemical shifts were calibrated relative to
those of the solvent. All new compounds were analyzed by high
resolution tandem mass spectrometry using a LTQ Orbitrap XL
(Thermo Fisher Scientific Inc., USA) mass spectrometer. The sample
was dissolved in MeCN, and it was injected directly. Ionization was
done in the positive mode on a heated electrospray ionization (HESI)
probe. HESI parameters were spray voltage 4.7 kV, vaporizer
temperature 60 °C, sheath and auxiliary gas flow 24 and 10 (arbitrary
units), respectively, capillary voltage 49 V, capillary temperature 275
°C, tube lens voltage 80 V, and resolution (at m/z 400): 30,000.
Synthesis. Compounds 1-phenyl-1H-tetrazol-5-amine (5a),25a 1-
(4-methoxyphenyl)-1H-tetrazol-5-amine (5b),25b 1-(4-nitrophenyl)-
1H-tetrazol-5-amine (5c),25a 1-(3-chlorophenyl)-1H-tetrazol-5-amine
(5g),25c and 3-bromo-1-tosyl-1H-indole (6k)25d were synthesized
according to the previously reported procedures. Compounds 1-
bromo-4-methoxybenzene (6a), bromobenzene (6b), 1-bromo-4-
nitrobenzene (6c), 1-bromo-3-(trifluoromethyl)benzene (6d), 1-
bromo-3-fluorobenzene (6e), 1-bromo-4-fluorobenzene (6f), 1-
bromo-3-chlorobenzene (6g), 3-bromopyridine (6h), 2-bromo-
1,3,5-trimethylbenzene (6i), and 2,4-dichloropyrimidine (6j) are
commercially available.
1-(3-(Trifluoromethyl)phenyl)-1H-tetrazol-5-amine (5d). A
round-bottom reaction flask equipped with a reflux condenser was
charged with 3-(trifluoromethyl)aniline (772 μL, 6.20 mmol, 1.0
equiv), NaN3 (444 mg, 6.83 mmol, 1.1 equiv), triethyl orthoformate
(3.1 mL, 19 mmol, 3 equiv), and glacial AcOH (28.4 mL, 49.6 mmol,
8 equiv). The mixture was stirred and heated at 80 °C in an oil bath
for 4 h, after which it was cooled to room temperature and diluted
with brine (125 mL). Solid Na2CO3 was added to the stirring solution
until the gas evolution ceased. The formed precipitate was separated
by filtration, washed with H2O, and dried. The product, 1-(3-
(trifluoromethyl)phenyl)-1H-tetrazole, was used in the next step
without any additional purification.
1
1579, 1516, 1321, 1220, 1143, 1092, 843, 621 cm−1. H NMR (400
Hz, CD3OD): δ 7.65−7.55 (m, 2H), 7.39−7.31 (m, 2H) ppm.
13C{1H} NMR (100 Hz, CD3OD): δ 164.4 (d, J = 248 Hz), 156.6,
131.0 (d, J = 3 Hz), 128.0 (d, J = 9 Hz), 117.9 (d, J = 24 Hz) ppm.
+
HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for C7H7FN5 ,
180.0680; found, 180.0687.
1-(Pyridin-3-yl)-1H-tetrazol-5-amine (5h). Following the proce-
dure described for 5d, compound 5h was obtained as a pale pink solid
(230 mg, 27%) starting from 3-aminopyridine (500 mg, 5.31 mmol);
mp 145−146 °C. IR (ATR): 3108, 1672, 1584, 1491, 14, 1435, 1124,
1079, 806, 720 cm−1. 1H NMR (400 Hz, DMSO-d6): δ 8.85−8.77 (m,
1H), 8.77−8.71 (m, 1H), 8.08−8.02 (m, 1H), 7.69−7.62 (m, 1H),
7.05 (s, 2H) ppm. 13C{1H} NMR (100 Hz, DMSO-d6): δ 155.3,
150.3, 145.2, 132.4, 130.4, 124.6 ppm. HRMS (HESI/Orbitrap) m/z:
+
[M + H]+ calcd for C6H7N6 , 163.0727; found, 163.0728.
General Procedure for the Palladium Catalyzed N-Arylation
Reaction. General Procedure A. N-(4-Methoxyphenyl)-1-phenyl-
1H-tetrazol-5-amine (7a).9b The previously reported procedure16
was modified in a way that the reaction mixture was heated at 35 °C
in an oil bath for 24 h. Compounds 1-phenyl-1H-tetrazol-5-amine 5a
(41 mg, 0.25 mmol, 1.05 equiv) and 1-bromo-4-methoxybenzene 6a
(30 μL, 0.24 mmol, 1.0 equiv) were coupled in the presence of
Pd2(dba)3 (11 mg, 0.012 mmol, 10 mol % Pd), t-BuXPhos (20 mg,
0.048 mmol, 20 mol %) NaOt-Bu (24 mg, 0.25 mmol, 1.05 equiv),
and 1,4-dioxane (1 mL). Compound 7a was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 7/3) as a pale yellow
powder (63 mg, 98%); mp 132−133 °C. IR (ATR): 3239, 3197,
3004, 1609, 1572, 1508, 1491, 1456, 1268, 1233, 1177, 1030, 811,
1
771 cm−1. H NMR (400 Hz, CDCl3): δ 7.65−7.56 (m, 3H), 7.54−
7.49 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 6.40
(s, 1H), 3.79 (s, 3H) ppm. 13C{1H} NMR (100 Hz, CDCl3): δ 156.3,
152.3, 133.0, 131.3, 130.6, 130.5, 124.8, 120.7, 114.6, 55.7 ppm.
1-(4-Methoxyphenyl)-N-phenyl-1H-tetrazol-5-amine (7b).9b Fol-
lowing the general procedure A, compound 7b was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 7/3) as a pale
yellow powder (57 mg, 89%) from 5b (48 mg, 0.25 mmol) and 6b
(25 μL, 0.24 mmol); mp 166−169 °C. IR (ATR): 1612, 1574, 1497,
A round-bottom reaction flask was charged with 1-(3-
(trifluoromethyl)phenyl)-1H-tetrazole (1.000 g, 4.670 mmol, 1.0
equiv), NaN3 (455 mg, 7.00 mmol, 1.5 equiv), NaOH (280 mg, 7.00
mmol, 1.5 equiv), Et3N (1.3 mL, 9.3 mmol, 2 equiv), and i-PrOH
(1.57 mL, 18.7 mmol, 4 equiv) after which DMSO (3.3 mL, 46.7
mmol, 10 equiv) was added dropwise. The reaction mixture was
stirred at room temperature until the gas evolution ceased (2 h), and
then, it was treated with glacial AcOH (800 μL, 14.0 mmol, 3 equiv).
The resulting solution was stirred and heated at 80 °C in an oil bath
for 2 h, cooled to room temperature, and diluted with brine (60 mL).
The formed precipitate was separated by filtration, washed with H2O,
and dried. Compound 5d was obtained as a pale yellow powder (865
mg, 81%); mp 129−130 °C. IR (ATR): 3317, 3142, 1658, 1582,
1505, 1477, 1347, 1322, 1308, 1277, 164, 1144, 1086, 1056, 903, 806,
702 cm−1. 1H NMR (400 Hz, DMSO-d6): δ 7.97−7.81 (m, 4H), 7.05
(s, 2H) ppm. 13C{1H} NMR (100 Hz, DMSO-d6): δ 155.1, 134.1,
131.2, 130.5 (q, J = 33 Hz), 128.4, 126.1 (q, J = 4 Hz), 123.6 (q, J =
272 Hz), 121.2 (q, J = 4 Hz) ppm. HRMS (HESI/Orbitrap) m/z: [M
1
1250, 1104, 838, 747 cm−1. H NMR (400 MHz, CDCl3): δ 7.50−
7.45 (m, 2H), 7.41−7.37 (m, 2H), 7.32−7.26 (m, 2H), 7.07−7.00
(m, 3H), 3.85 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3 +
CD3OD): δ 161.1, 152.2, 138.3, 129.3, 126.9, 125.2, 123.3, 118.2,
115.5, 55.8 ppm.
N-(4-Nitrophenyl)-1-phenyl-1H-tetrazol-5-amine (7c). Following
the general procedure A, compound 7c was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 8/2) as a yellow
powder (94 mg, 88%) from 5a (64 mg, 0.40 mmol) and 6c (77 mg,
0.38 mmol); mp 185−186 °C. IR (ATR): 3266, 3098, 1623, 1582,
1534, 1493, 1333, 1255, 1109, 851 cm−1. 1H NMR (400 MHz,
DMSO-d6): δ 10.18 (s, 1H), 8.25 (d, J = 9.1 Hz, 2H), 7.86 (d, J = 9.1
Hz, 2H), 7.74−7.64 (m, 5H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6): δ 151.5, 146.3, 141.1, 132.8, 130.4, 130.0, 125.8, 125.2,
117.5 ppm. HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for
+
C13H11N6O2 , 283.0938; found, 283.0943.
+
+ H]+ calcd for C8H7F3N5 , 230.0648; found, 230.0654.
1-(4-Nitrophenyl)-N-phenyl-1H-tetrazol-5-amine (7d). Following
the general procedure A, compound 7d was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 8/2) as a red powder
(113 mg, 84%) from 5c (103 mg, 0.500 mmol) and 6b (50 μL mg,
0.48 mmol); mp 177−178 °C. IR (ATR): 3233, 3192, 3115, 1599,
1-(3-Fluorophenyl)-1H-tetrazol-5-amine (5e). Following the
procedure described for 5d, compound 5e was obtained as a pale
yellow solid (369 mg, 46%) starting from 3-fluoroaniline (498 mg,
4.48 mmol); mp 146−147 °C. IR (ATR): 3313, 3125, 1660, 1607,
1577, 1502, 1471, 1312, 1200, 1140, 1093, 875, 792, 677 cm−1. H
1588, 1521, 1497, 1455, 1340, 1313, 1241, 1104, 855, 752 cm−1. H
1
1
NMR (400 Hz, CD3OD): δ 7.69−7.59 (m, 1H), 7.48−7.37 (m, 2H),
7.36−7.28 (m, 1H) ppm. 13C{1H} NMR (100 Hz, CD3OD): δ 164.4
(d, J = 247 Hz), 156.4, 136.2 (d, J = 10 Hz), 132.8 (d, J = 9 Hz),
121.0 (d, J = 4 Hz), 117.6 (d, J = 22 Hz), 112.7 (d, J = 25 Hz) ppm.
NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.49 (d, J = 9.0 Hz,
2H), 8.02 (d, J = 9.0 Hz, 2H), 7.63−7.58 (m, 2H), 7.37−7.32 (m,
2H), 7.06−7.01 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-
d6): δ 152.4, 147.8, 139.6, 138.2, 128.9, 126.6, 125.2, 122.4, 118.4
ppm. HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for
+
HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for C7H7FN5 ,
+
180.0680; found, 180.0687.
C13H11N6O2 , 283.0938; found, 283.0945.
4799
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1-(4-Methoxyphenyl)-N-(4-nitrophenyl)-1H-tetrazol-5-amine
(7e). Following the general procedure A, compound 7e was obtained
after dry-flash column chromatography (SiO2: Hex/EtOAc = 7/3) as
a yellow powder (47 mg, 60%) from 5b (50 mg, 0.26 mmol) and 6c
(50 mg, 0.25 mmol); mp 237 °C. IR (ATR): 3071, 3935, 1620, 1584,
1535, 1512, 1334, 1258, 1108, 749 cm−1. 1H NMR (400 MHz,
DMSO-d6): δ 10.06 (s, 1H), 8.24 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 9.2
Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 3.87 (s,
3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 160.6, 151.8,
146.4, 141.0, 127.7, 125.3, 125.2, 117.4, 115.0, 55.7 ppm. HRMS
(55 μL, 0.53 mmol); mp 109−110 °C. IR (ATR) 3429, 3201, 3085,
3044, 2993, 2925, 1604, 1571, 1534, 1494, 1466, 1451, 1401, 1321,
1268, 1243, 1198, 1153, 1084, 1034, 1006, 984, 890, 865, 795, 747,
1
688, 523 cm−1. H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H),
7.74−7.60 (m, 4H), 7.57−7.47 (m, 2H), 7.37−7.29 (m, 2H), 7.05−
6.99 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 162.2
(d, J = 244 Hz), 152.4, 139.7, 134.2 (d, J = 11 Hz), 131.7 (d, J = 9
Hz), 128.8, 122.2, 122.1 (d, J = 4 Hz), 118.4, 117.1 (d, J = 21 Hz),
113.5 (d, J = 25 Hz) ppm. HRMS (HESI/Orbitrap) m/z: [M + H]+
+
calcd for C13H11FN5 , 256.0993; found, 256.0996.
+
(HESI/Orbitrap) m/z: [M + H]+ calcd for C14H13N6O3 , 313.1044;
N-(4-Fluorophenyl)-1-phenyl-1H-tetrazol-5-amine (7k). Follow-
ing the general procedure A, compound 7k was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
white powder (110 mg, 81%) from 5a (100 mg, 0.559 mmol) and 6f
(55 μL, 0.53 mmol); mp 165−167 °C. IR (ATR): 3244, 3213, 3178,
3126, 3069, 3038, 3001, 2961, 2912, 2826, 2773, 1620, 1575, 1502,
1456, 1439, 1393, 1325, 1211, 1158, 1125, 1094, 1070, 1045, 1019,
992, 847, 814, 790, 770, 729, 692, 643, 621, 585, 506 cm−1. 1H NMR
(400 MHz, DMSO-d6): δ 9.35 (s, 1H), 7.84−7.44 (m, 7H), 7.24−
7.10 (m, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 157.5
(d, J = 237 Hz), 152.4, 136.2 (d, J = 2 Hz), 133.0, 130.1, 129.9, 125.6,
120.2 (d, J = 8 Hz), 115.3 (d, J = 23 Hz) ppm. HRMS (HESI/
found, 313.1051.
N-(4-Methoxyphenyl)-1-(4-nitrophenyl)-1H-tetrazol-5-amine
(7f). Following the general procedure A, compound 7f was obtained
after dry-flash column chromatography (SiO2: Hex/EtOAc = 7/3) as
an orange powder (58 mg, 74%) from 5c (54 mg, 0.26 mmol) and 6a
(31 μL, 0.25 mmol); mp 98−99 °C. IR (ATR): 3278, 3086, 2959,
2927, 2856, 1727, 1616, 1577, 1511, 1463, 1340, 1295, 1257, 1113,
1
1077, 1032, 854, 746 cm−1. H NMR (400 MHz, DMSO-d6): δ 9.34
(s, 1H), 8.48 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.50 (d, J =
9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.73 (s, 3H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6): δ 155.0, 152.8, 147.6, 138.3, 132.6,
126.5, 125.2, 120.6, 114.1, 55.2 ppm. HRMS (HESI/Orbitrap) m/z:
+
Orbitrap) m/z: [M + H]+ calcd for C13H11FN5 , 256.0993; found,
+
[M + H]+ calcd for C14H13N6O3 , 313.1044; found, 313.1057.
256.0993.
N-Phenyl-1-(3-(trifluoromethyl)phenyl)-1H-tetrazol-5-amine
(7g). Following the general procedure A, compound 7g was obtained
after dry-flash column chromatography (SiO2: Hex/EtOAc = 9/1) as
a pale yellow powder (155 mg, 86%) from 5a (100 mg, 0.620 mmol)
and 6d (82 μL, 0.59 mmol); mp 103−106 °C. IR (ATR): 3254, 3101,
3058, 1620, 1591, 1533, 486, 1463, 1339, 1320, 1292, 1150, 1112,
1-(4-Fluorophenyl)-N-phenyl-1H-tetrazol-5-amine (7l). Follow-
ing the general procedure A, compound 7l was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
white powder (118 mg, 87%) from 5f (100 mg, 0.559 mmol) and 6b
(55 μL, 0.53 mmol); mp 145−147 °C. IR (ATR): 3260, 3207, 3125,
3095, 3060, 3010, 2940, 2866, 1620, 1575, 1539, 1508, 1462, 1422,
1322, 1228, 1184, 1157, 1127, 1094, 1039, 1014, 994, 889, 841, 807,
751, 693, 632, 597, 536, 501 cm−1. 1H NMR (400 MHz, DMSO-d6):
δ 9.29 (s, 1H), 7.80−7.70 (m, 2H), 7.66−7.58 (m, 2H), 7.55−7.47
(m, 2H), 7.36−7.28 (m, 2H), 7.03−6.97 (m, 1H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6): δ 162.7 (d, J = 246 Hz), 152.5, 139.8,
129.4 (d, J = 3 Hz), 128.8, 128.6 (d, J = 9 Hz), 122.1, 118.2, 116.9 (d,
J = 23 Hz) ppm. HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for
1
1094, 1068, 805, 766, 697 cm−1. H NMR (400 MHz, DMSO-d6): δ
9.68 (s, 1H), 8.05 (s, 1H), 7.96−7.92 (m, 1H), 7.73−7.61 (m, 5H),
7.59−7.54 (m, 1H), 7.36−7.32 (m, 1H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6): δ 152.0, 140.7, 132.9, 130.3, 130.1, 130.0, 129.6 (q,
J = 31 Hz), 125.8, 124.2 (q, J = 270 Hz), 121.8 (q, J = 1 Hz), 118.3
(q, J = 4 Hz), 114.4 (q, J = 4 Hz) ppm. HRMS (HESI/Orbitrap) m/
+
z: [M + H]+ calcd for C14H11F3N5 , 306.0961; found, 306.0976.
+
N-Phenyl-1-(3-(trifluoromethyl)phenyl)-1H-tetrazol-5-amine
(7h). Following the general procedure A, compound 7h was obtained
after dry-flash column chromatography (SiO2: Hex/EtOAc = 9/1) as
an orange powder (211 mg, 63%) from 5d (250 mg, 1.17 mmol) and
6b (115 μL, 1.10 mmol); mp 79−81 °C. IR (ATR): 3192, 3081,
3038, 2997, 1613, 1572, 1532, 1495, 1470, 1451, 1334, 1313, 1250,
C13H11FN5 , 256.0993; found, 256.0994.
N-(3-Chlorophenyl)-1-phenyl-1H-tetrazol-5-amine (7m). Follow-
ing the general procedure A, compound 7m was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
yellow powder (60 mg, 88%) from 5a (42 mg, 0.26 mmol) and 6g (29
μL, 0.25 mmol); mp 114−117 °C. IR (ATR): 3233, 3160, 3072,
3033, 2974, 1612, 1595, 1566, 1527, 1496, 1479, 1455, 1091, 1072,
1020, 909, 872, 772, 766, 687 cm−1. 1H NMR (400 MHz, DMSO-d6):
δ 9.56 (s, 1H), 7.83−7.78 (m, 1H), 7.71−7.61 (m, 5H), 7.60−7.55
(m, 1H), 7.38−7.32 (m, 1H), 7.08−7.03 (m, 1H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6): δ 151.9, 141.4, 133.2, 132.9, 130.5,
130.2, 130.0, 125.7, 121.6, 117.6, 116.6 ppm. HRMS (HESI/
1
1161, 1135, 1098, 1073, 85, 749, 699 cm−1. H NMR (400 MHz,
DMSO-d6): δ 9.45 (s, 1H), 8.13 (s, 1H), 8.04−7.98 (m, 2H), 7.92−
7.87 (m, 1H), 7.63−7.58 (m, 2H), 7.36−7.30 (m, 2H), 7.04−6.99
(m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 152.5, 139.7,
133.8, 131.3, 130.5 (q, J = 32 Hz), 130.1, 128.9, 126.9 (q, J = 4 Hz),
123.6 (q, J = 217 Hz), 123.1 (q, J = 4 Hz), 122.3, 118.4 ppm. HRMS
+
(HESI/Orbitrap) m/z: [M + H]+ calcd for C14H11F3N5 , 306.0961;
+
Orbitrap) m/z: [M + H]+ calcd for C13H11ClN5 , 272.0698; found,
found, 306.0974.
272.0706.
N-(3-Fluorophenyl)-1-phenyl-1H-tetrazol-5-amine (7i). Follow-
ing the general procedure A, compound 7i was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
white powder (121 mg, 91%) from 5a (90 mg, 0.56 mmol) and 6e
(58 μL, 0.52 mmol); mp 152−154 °C. IR (ATR): 3169, 3075, 2999,
2922, 1610, 1573, 1530, 1492, 1453, 1402, 1326, 1269, 1248, 1171,
1148, 1121, 1092, 1073, 1046, 1021, 992, 963, 924, 864, 824, 768,
727, 686, 631, 535 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 9.59 (s,
1H), 7.76−7.61 (m, 5H), 7.61−7.52 (m, 1H), 7.48−7.40 (m, 1H),
7.39−7.30 (m, 1H), 6.89−6.77 (m, 1H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6): δ 162.4 (d, J = 240 Hz), 152.0, 141.7 (d, J = 11
Hz), 132.9, 130.4 (d, J = 10 Hz), 130.2, 130.0, 125.7, 114.1 (d, J = 2
Hz), 108.4 (d, J = 21 Hz), 105.0 (d, J = 27 Hz) ppm. HRMS (HESI/
1-(3-Chlorophenyl)-N-phenyl-1H-tetrazol-5-amine (7n). Follow-
ing the general procedure A, compound 7n was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
yellow powder (58 mg, 85%) from 5g (51 mg, 0.26 mmol) and 6b
(26 μL, 0.25 mmol); mp 96−98 °C. IR (ATR): 3192, 3114, 3078,
3035, 2992, 2919, 1615, 1572, 1531, 1499, 1482, 1436, 1253, 1100,
1
1086, 787, 768, 749, 693 cm−1. H NMR (400 MHz, DMSO-d6): δ
9.39 (s, 1H), 7.86 (s, 1H), 7.75−7.65 (m, 3H), 7.65−7.59 (m, 2H),
7.37−7.29 (m, 2H), 7.05−6.99 (m, 1H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6): δ 152.4, 139.7, 134.2, 134.0, 131.5, 130.2, 128.8,
126.0, 124.8, 122.2, 118.4 ppm. HRMS (HESI/Orbitrap) m/z: [M +
+
H]+ calcd for C13H11ClN5 , 272.0698; found, 272.0709.
N-(1-Phenyl-1H-tetrazol-5-yl)pyridin-3-amine (7o). Following the
general procedure A, compound 7o was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 6/4) as a pale yellow
powder (50 mg, 84%) from 5a (42 mg, 0.26 mmol) and 6h (24 μL,
0.25 mmol); mp 125−126 °C. IR (ATR): 3258, 3051, 2962, 1611,
+
Orbitrap) m/z: [M + H]+ calcd for C13H11FN5 , 256.0993; found,
256.0993.
1-(3-Fluorophenyl)-N-phenyl-1H-tetrazol-5-amine (7j). Follow-
ing the general procedure A, compound 7j was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as an off-
white powder (130 mg, 96%) from 5e (100 mg, 0.560 mmol) and 6b
1
1570, 1532, 1499, 1486 cm−1. H NMR (400 MHz, DMSO-d6): δ
9.58 (s, 1H), 8.82−8.78 (m, 1H), 8.25−8.20 (m, 1H), 8.13−8.08 (m,
4800
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 7.73−7.63 (m, 5H), 7.40−7.35 (m, 1H) ppm. 13C{1H} NMR
(100 MHz, DMSO-d6): δ 152.1, 143.1, 140.4, 136.7, 132.9, 130.2,
130.0, 125.6, 125.1, 123.5 ppm. HRMS (HESI/Orbitrap) m/z: [M +
13C{1H} NMR (125 MHz, CD3OD): δ 155.1, 145.4, 134.7, 131.4,
131.2, 131.1, 126.3, 123.5, 117.0 ppm. HRMS (HESI/Orbitrap) m/z:
+
[M + H]+ calcd for C13H13N6 , 253.1196; found, 253.1208.
+
H]+ calcd for C12H11N6 , 239.1040; found, 239.1044.
1-(4-Aminophenyl)-N-phenyl-1H-tetrazol-5-amine (7u). Follow-
ing the procedure described for 7t, compound 7u was obtained as a
yellow solid (10 mg, quant) starting from 7d (12 mg, 0.041 mmol, 1
equiv); mp 138−140 °C. IR (ATR): 3640, 3476, 3063, 3254, 3236,
1610, 1576, 1528, 1501, 1319, 836 cm−1. 1H NMR (500 MHz,
CD3OD): δ 7.54−7.50 (m, 2H), 7.32−7.27 (m, 2H), 7.23 (d, J = 8.7
Hz, 2H), 7.05−7.00 (m, 1H), 6.84 (d, J = 8.7 Hz, 2H) ppm. 13C{1H}
NMR (125 MHz, CD3OD): δ 154.4, 151.8, 140.9, 130.0, 127.9,
123.9, 123.0, 120.0, 116.1 ppm. HRMS (HESI/Orbitrap) m/z: [M +
N-Phenyl-1-(pyridin-3-yl)-1H-tetrazol-5-amine (7p). Following
the general procedure A, compound 7p was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 6/4) as a pale yellow
powder (41 mg, 69%) from 5h (43 mg, 0.26 mmol) and 6b (26 μL,
0.25 mmol); mp 115−117 °C. IR (ATR): 3263, 3205, 3121, 3090,
1
3044, 2924, 2853, 1611, 1571, 1533, 1501, 1434, 756, 696 cm−1. H
NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.94−8.88 (m, 1H),
8.86−8.79 (m, 1H), 8.20−8.14 (m, 1H), 7.74−7.69 (m, 1H), 7.66−
7.59 (m, 2H), 7.37−7.30 (m, 2H), 7.05−6.99 (m, 1H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6): δ 152.7, 151.0, 146.7, 139.6, 134.0,
130.2, 128.8, 124.7, 122.2, 118.3 ppm. HRMS (HESI/Orbitrap) m/z:
+
H]+ calcd for C13H13N6 , 253.1196; found, 253.1206.
Dimroth-like Rearrangement of 7t to 7u. A flame-dried
reaction tube charged with compound 7t (13 mg, 0.053 mmol) and
1,4-dioxane (0.5 mL) was sealed, and the mixture was heated at 105
°C in an oil bath for 24 h. The reaction mixture was cooled to room
temperature, and the solvent was removed under the reduced
pressure. NMR spectroscopy analysis showed a complete conversion
of 7t to 7u.
+
[M + H]+ calcd for C12H11N6 , 239.1040; found, 239.1050.
N-Mesityl-1-phenyl-1H-tetrazol-5-amine (7q). Following the
general procedure A, compound 7q was obtained after dry-flash
column chromatography (SiO2: Hex/EtOAc = 8/2) as a pale yellow
powder (18 mg, 27%) from 5a (41 mg, 0.25 mmol) and 6i (37 μL,
0.24 mmol); mp 90−97 °C. IR (ATR): 3172, 3059, 2961, 2918, 2858,
1
1599, 1564, 1506, 1458, 1125, 1065, 760, 694 cm−1. H NMR (400
COMPUTATIONAL METHODS
■
MHz, CDCl3): δ 7.62−7.49 (m, 5H), 6.88 (s, 2H), 5.86 (s, 1H), 2.25
(s, 3H), 2.17 (s, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
153.7, 137.6, 135.2, 133.3, 131.9, 130.4, 130.2, 129.5, 124.4, 21.0, 18.4
All DFT calculations were done with the Orca program package
(version 4.1.2).26 The def2-TZVP(-f) basis set was used for all atoms.
The SMD solvation model (with dioxane as a solvent)27 was used in
all calculations. Geometry optimizations were performed using
general gradient functional consisting of Becke’s exchange28 and
LYP correlation,29 with Grimme’s fourth-generation dispersion energy
corrections,30 that is, BLYP-D4 functional. The resolution-of-the-
identity approximation in the Split-RI-J variant and def2/J auxiliary
basis sets was used. Numerical harmonic frequencies were calculated
at the same level of theory to ascertain the nature of stationary points
(minima or transition states). Vibrational analysis in quasi-harmonic
approximation as proposed by Truhlar,31 with frequency cutoff 100
cm−1, has been used to evaluate zero-point effects and entropic and
thermal corrections to the Gibbs free energy. To assess the impact of
the hybrid functional, single-point energies were computed with
B3LYP-D4,32 with the chain-of-sphere approximation to the exact
exchange, on the optimized BLYP-D4/def2-TZVP(-f) geometries
(see the Supporting Information, Table S3).
+
ppm. HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for C16H18N5 ,
280.1557; found, 280.1567.
2-Chloro-N-(1-phenyl-1H-tetrazol-5-yl)pyrimidin-4-amine (7r).
Following the general procedure A, compound 7r was obtained
after dry-flash column chromatography (SiO2: Hex/EtOAc = 8/2) as
colorless powder (30 mg, 44%) from 5a (42 mg, 0.26 mmol) and 6j
(37 mg, 0.25 mmol).
Compounds 1-phenyl-1H-tetrazol-5-amine 5a (42 mg, 0.26 mmol,
1.05 equiv) and 2,4-dichloropyrimidine 6j (37 mg, 0.25 mmol, 1.0
equiv) were coupled in the presence of Pd2(dba)3 (11 mg, 0.012
mmol, 10 mol % Pd), XantPhos (29 mg, 0.050 mmol, 20 mol %),
K2CO3 (36 mg, 0.26 mmol, 1.05 equiv), and 1,4-dioxane (3.2 mL) at
35 °C in an oil bath for 24 h. Compound 7r was obtained after dry-
flash column chromatography (SiO2: Hex/EtOAc = 8/2) as a
colorless powder (43 mg, 63%); mp 140−141 °C. IR (ATR): 3228,
3134, 3045, 2980, 2917, 1613, 1589, 1523, 1506, 1486, 1456, 1413,
1356, 1333, 1212, 988, 830, 769, 699, 682, 546 cm−1. 1H NMR (400
MHz, CDCl3): δ 8.56 (d, J = 4 Hz), 8.31 (d, J = 4 Hz), 7.71−7.64 (m,
3H), 7.56−7.49 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
161.0, 158.8, 149.6, 149.6, 131.8, 131.6, 131.0, 125.3, 106.8 ppm.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00282.
+
HRMS (HESI/Orbitrap) m/z: [M + H]+ calcd for C11H9ClN7 ,
274.0602; found, 274.0616.
1
Copies of H and 13C NMR spectra for the synthesized
General Procedure for Dimroth-like Rearrangement. Gen-
eral Procedure B. A flame-dried reaction tube charged with
compound 7 (10 mg) and 1,4-dioxane (0.5 mL) was sealed, and
the mixture was heated at 105 °C in an oil bath for 24 h. The reaction
mixture was cooled to room temperature, and the solvent was
removed under the reduced pressure. The isomer ratio was
determined by NMR spectroscopy (Table 3).
NMR Spectroscopic Analysis in DMSO-d6. A flame-dried
reaction tube charged with compound 7 (10 mg) and DMSO-d6
(0.5 mL) was sealed, and the mixture was heated at 105 °C in an oil
bath for 24 h. The reaction mixture was cooled to room temperature.
The isomer ratio was determined by NMR spectroscopy (Table 3).
N1-(1-Phenyl-1H-tetrazol-5-yl)benzene-1,4-diamine (7t). A
flame-dried round-bottom reaction flask was charged with compound
7c (15 mg, 0.053 mmol, 1 equiv) and deoxygenated methanol (1 mL)
after which Pd/C (3 mg, 0.003 mmol, 5 mol % Pd) was added. The
flask was closed with a rubber septum, and the reaction mixture,
connected to a balloon of hydrogen, was stirred at room temperature
for 2 h. The reaction mixture was filtered, and the solvent was
removed under the reduced pressure to afford pure 7t as an orange
powder (13 mg, quant.); mp 93−94 °C. IR (ATR): 3344, 1609, 1575,
1517, 1497, 1458, 763 cm−1. 1H NMR (500 MHz, CD3OD): δ 7.65−
7.58 (m, 5H), 7.20 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H) ppm.
compounds; Extended computational results; and total
electronic energies, number of imaginary frequencies;
and Cartesian coordinates of all structures (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Igor M. Opsenica − Faculty of Chemistry, University of
Belgrade, 11158 Belgrade, Serbia; orcid.org/0000-0003-
4942-4042; Email: igorop@chem.bg.ac.rs
Authors
́
Andrea M. Nikolic − Faculty of Chemistry, University of
Belgrade, 11158 Belgrade, Serbia; orcid.org/0000-0003-
1907-1565
́
Jelena Stanic − Faculty of Chemistry, University of Belgrade,
11158 Belgrade, Serbia
Matija Zlatar − Institute of Chemistry, Technology and
Metallurgy, National Institute of the Republic of Serbia,
University of Belgrade, 11000 Belgrade, Serbia; orcid.org/
0000-0002-3809-0940
4801
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(9) (a) Bégué, D.; Dargelos, A.; Wentrup, C. Aryl nitrile imines and
diazo compounds. Formation of indazole, pyridine N-Imine, and 2-
pyridyldiazomethane from tetrazoles. J. Org. Chem. 2020, 85, 7952−
7958. (b) Nimnual, P.; Tummatorn, J.; Boekfa, B.; Thongsornkleeb,
C.; Ruchirawat, S.; Piyachat, P.; Punjajom, K. Construction of 5-
aminotetrazoles via in situ generation of carbodiimidium ions from
ketones promoted by TMSN3/TfOH. J. Org. Chem. 2019, 84, 5603−
5613.
(10) Krishnan, S.; Chatterjee, S.; Solanki, A.; Guha, N.; Singh, M. K.;
Gupta, A. K.; Rai, D. K. Aminotetrazole-functionalized SiO2 coated
MgO nanoparticle composites for removal of acid fuchsin dye and
detection of heavy metal ions. ACS Appl. Nano Mater. 2020, 3,
11203−11216.
Maja Gruden − Faculty of Chemistry, University of Belgrade,
11158 Belgrade, Serbia; orcid.org/0000-0002-0746-
5754
́
̵elkovic − Faculty of Chemistry, University of
Boban And
Belgrade, 11158 Belgrade, Serbia
̌
́
Zivota Selakovic − Faculty of Chemistry, University of
Belgrade, 11158 Belgrade, Serbia
̌
́
Vladimir Ajdacic − Innovative Centre, Faculty of Chemistry,
Ltd., 11158 Belgrade, Serbia; orcid.org/0000-0002-
3423-0862
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00282
(11) (a) Katritzky, A. R.; Rogovoy, B. V.; Kovalenko, K. V. A general
route to 5-aminotetrazoles. J. Org. Chem. 2003, 68, 4941−4943.
(b) Yella, R.; Khatun, N.; Rout, S. K.; Patel, B. K. Tandem
regioselective synthesis of tetrazoles and related heterocycles using
iodine. Org. Biomol. Chem. 2011, 9, 3235−3245. (c) Guin, S.; Rout, S.
K.; Gogoi, A.; Nandi, S.; Ghara, K. K.; Patel, B. K. Desulfurization
Strategy in the Construction of azoles possessing additional nitrogen,
oxygen or sulfur using a copper(I) catalyst. Adv. Synth. Catal. 2012,
354, 2757−2770. (d) Xie, Y.; Guo, D.; Jiang, X.; Pan, H.; Wang, W.;
Jin, T.; Mi, Z. An efficient method for the synthesis of substituted 5-
aminotetrazoles from selenoureas using PhI(OAc)2. Tetrahedron Lett.
2015, 56, 2533−2536. (e) Pathare, R. S.; Ansari, A. J.; Verma, S.;
Maurya, A.; Maurya, A. K.; Agnihotri, V. K.; Sharon, A.; Pardasani, R.
T.; Sawant, D. M. Sequential Pd(0)/Fe(III) Catalyzed Azide-
Isocyanide Coupling/Cyclization Reaction: One-Pot Synthesis of
Aminotetrazoles. J. Org. Chem. 2018, 83, 9530−9537.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the Ministry of
Education, Science, and Technological Development of
Republic of Serbia (contract numbers: 451-03-9/2021-14/
200168, 451-03-9/2021-14/200288, and 451-03-9/2021-14/
200026) and Serbian Academy of Sciences and Arts under
strategic projects programme-grant agreement no. 01-2019-
F65. The authors acknowledge the support of the FP7 RegPot
project FCUB ERA GA no. 256716. The EC does not share
responsibility for the content of the article.
(12) Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in
palladium-catalyzed amination. Angew. Chem., Int. Ed. 2008, 47,
6338−6361.
REFERENCES
■
(1) Aulakh, G. K.; Sodhi, R. K.; Singh, M. An update on non-peptide
angiotensin receptor antagonists and related RAAS modulators. Life
Sci. 2007, 81, 615−639.
(2) Saltiel, E.; Brogden, R. N. Cefonicid. Drugs 1986, 32, 222−259.
(3) Szulczyk, D.; Bielenica, A.; Głogowska, A.; Augustynowicz-
(13) Ruiz-Castillo, P.; Buchwald, S. L. Applications of palladium-
catalyzed C−N cross-coupling reactions. Chem. Rev. 2016, 116,
12564−12649.
(14) Heravi, M. M.; Kheilkordi, Z.; Zadsirjan, V.; Heydari, M.;
Malmir, M. Buchwald-Hartwig reaction: An overview. J. Organomet.
Chem. 2018, 861, 17−104.
́
́
Kopec, E.; Dobrowolski, M.; Roszkowski, P.; Stępien, K.;
Chrzanowska, A.; Struga, M. Development of (4-methoxyphenyl)-
1H-tetrazol-5-amine regioisomers as a new class of selective
antitubercular agents. Eur. J. Med. Chem. 2020, 186, 111882.
(4) Szulczyk, D.; Dobrowolski, M. A.; Roszkowski, P.; Bielenica, A.;
(15) Charles, M. D.; Schultz, P.; Buchwald, S. L. Efficient Pd-
catalyzed amination of heteroaryl halides. Org. Lett. 2005, 7, 3965−
3968.
́
́
́
Stefanska, J.; Kolinski, M.; Kmiecik, S.; Józwiak, M.; Wrzosek, M.;
Olejarz, W.; Struga, M. Design and synthesis of novel 1H-tetrazol-5-
amine based potent antimicrobial agents: DNA topoisomerase IV and
gyrase affinity evaluation supported by molecular docking studies. Eur.
J. Med. Chem. 2018, 156, 631−640.
́
̌
́
(16) Nikolic, A. M.; Ajdacic, V.; Opsenica, I. M. Palladium-catalyzed
N-arylation of 1-substituted-1H-tetrazol-5-amines. J. Organomet.
Chem. 2019, 880, 134−142.
(17) (a) El Ashry, E. S. H.; Nadeem, S.; Shah, M. R.; El Kilany, Y.
Recent advances in the Dimroth rearrangement: A valuable tool for
the synthesis of heterocycles. Adv. Heterocycl. Chem. 2010, 101, 161−
228. (b) Krajczyk, A.; Boryski, J. Dimroth rearrangement-Old but not
outdated. Curr. Org. Chem. 2017, 21, 2515−2529. (c) Ferreira, V. F.;
da Silva, T. d. B.; Pauli, F. P.; Ferreira, P. G.; Forezi, L. d. S. M.; Lima,
C. G. d. S.; da Silva, F. d. C. Dimroth’s Rearrangement as a synthetic
strategy towards new heterocyclic compounds. Curr. Org. Chem. 2020,
24, 1999−2018. (d) El Ashry, E. S. H.; El Kilany, Y.; Rashed, N.;
Assafir, H. Dimroth rearrangement: Translocation of heteroatoms in
heterocyclic rings and its role in ring transformations of heterocycles.
Adv. Heterocycl. Chem. 1999, 75, 79−165. (e) L’abbé, G. Molecular
rearrangements of five-membered ring heteromonocycles. J. Hetero-
cycl. Chem. 1984, 21, 627−638.
(5) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.; Penrose, A. J.;
Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.; Wright, D. E.
Synthesis and quantitative structure-activity relationships of anti-
allergic 2-hydroxy-N-(1H-tetrazol-5-yl)benzamides and N-(2-hydrox-
yphenyl)-1H-tetrazole-5-carboxamides. J. Med. Chem. 1986, 29, 538−
549.
(6) Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Synthesis and
evaluation of quinoline carboxyguanidines as antidiabetic agents.
Bioorg. Med. Chem. Lett. 2000, 10, 1831−1834.
(7) Ehsani, A.; Mahjani, M. G.; Moshrefi, R.; Mostaanzadeh, H.;
Shayeh, J. S. Electrochemical and DFT study on the inhibition of
316L stainless steel corrosion in acidic medium by 1-(4-nitrophenyl)-
5-amino-1H-tetrazole. RSC Adv. 2014, 4, 20031−20037.
(8) (a) Serebryanskaya, T. V.; Yung, T.; Bogdanov, A. A.; Shchebet,
A.; Johnsen, S. A.; Lyakhov, A. S.; Ivashkevich, L. S.; Ibrahimava, Z.
A.; Garbuzenco, T. S.; Kolesnikova, T. S.; Melnova, N. I.; Gaponik, P.
N.; Ivashkevich, O. A. Synthesis, characterization, and biological
evaluation of new tetrazole-based platinum(II) and palladium(II)
chlorido complexesPotent cisplatin analogues and their trans
isomers. J. Inorg. Biochem. 2013, 120, 44−53. (b) Tang, H.; Zhou,
Z.; Li, Z.; Chen, S.; Wang, L.; Zhang, T. Copper (II) complexes of 1-
methyl-5-aminotetrazole with different energetic anions: syntheses,
crystal structures and properties. J. Energ. Mater. 2021, 39, 23−32.
(18) Finnegan, W. G.; Henry, R. A.; Lieber, E. Preparation and
isomerization of 5-alkylaminotetrazoles. J. Org. Chem. 1953, 18, 779−
791.
(19) Garbrecht, W. L.; Herbst, R. M. The synthesis of certain 5-
aminotetrazole derivatives. IV. The rearrangement of certain
monosubstituted 5-aminotetrazole derivatives. J. Org. Chem. 1953,
18, 1269−1282.
(20) Dimroth, O. Ueber intramolekulare Umlagerungen. Umlager-
ungen in der Reihe des 1, 2, 3-Triazols. Justus Liebigs Ann. Chem.
1909, 364, 183−226.
4802
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(21) (a) Henry, R. A.; Finnegan, W. G.; Lieber, E. Thermal
Isomerization of Substituted 5-Aminotetrazoles. J. Am. Chem. Soc.
1954, 76, 88−93. (b) Henry, R. A.; Finnegan, W. G.; Lieber, E.
Kinetics of the isomerization of substituted 5-aminotetrazoles. J. Am.
Chem. Soc. 1955, 77, 2264−2270. (c) Nguyen, M. T.; Leroy, G.; Sana,
Calculations on First-Row Transition Metals. J. Chem. Phys. 1994,
101, 7729.
(30) Caldeweyher, E.; Ehlert, S.; Hansen, A.; Neugebauer, H.;
Spicher, S.; Bannwarth, C.; Grimme, S. A Generally Applicable
Atomic-Charge Dependent London Dispersion Correction. J. Chem.
Phys. 2019, 150, 154122.
́
M.; Elguero, J. Note sur le mecanisme reactionnel de la transposition
(31) (a) Zhao, Y.; Truhlar, D. G. Computational characterization
and modeling of buckyball tweezers: Density functional study of
concave-convex π···π Interactions. Phys. Chem. Chem. Phys. 2008, 10,
2813−2818. (b) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.;
Truhlar, D. G. Use of solution-phase vibrational frequencies in
continuum models for the free energy of solvation. J. Phys. Chem. B
2011, 115, 14556−14562.
́
de Dimroth. Une etude ab initio. J. Heterocycl. Chem. 1982, 19, 943−
944. (d) Hegarty, A. F.; Tynan, N. M.; Fergus, S. Rate-determining
nitrogen inversion in the isomerisation of isoimides to imides and
azides to tetrazoles: direct observation of intermediates stabilized by
trifluoroethyl groups. J. Chem. Soc., Perkin Trans. 2 2002, 1328−1334.
(22) (a) Kolos, N. N.; Paponov, B. V.; Orlov, V. D.; Lvovskaya, M.
I.; Doroshenko, A. O.; Shishkin, O. V. Derivatives of Δ2-pyrazoline-
products of 1,5-diaminotetrazole interaction with chalcone: Molecular
structure and spectral properties. J. Mol. Struct. 2006, 785, 114−122.
(b) Brigas, A. F.; Clegg, W.; Dillon, C. J.; Fonseca, C. F. C.;
Johnstone, R. A. W. Metal-assisted reactions. Part 29. Structure and
hydrogenolysis of C−N bonds in derivatives of aromatic amines.
Bond length and electronegativity changes from X-ray crystallographic
data. J. Chem. Soc., Perkin Trans. 2 2001, 1315−1324. (c) Li, Q.; Yu,
M.-H.; Xu, J.; Li, A.-L.; Hu, T.-L.; Bu, X.-H. Two new metal-organic
frameworks based on tetrazole-heterocyclic ligands accompanied by
in-situ ligand formation. Dalton Trans. 2017, 46, 3223−3228.
(23) (a) Vorobiov, A.; Gaponik, P.; Petrov, P.; Ivashkevich, O. One-
pot syntheses of 5-amino-1-aryltetrazole derivatives. Synthesis 2006,
1307−1312. (b) Van Poecke, S.; Negri, A.; Janssens, J.; Solaroli, N.;
Karlsson, A.; Gago, F.; Balzarini, J.; Van Calenbergh, S. Synthesis,
modeling and evaluation of 3′-(1-aryl-1H-tetrazol-5-ylamino)-sub-
stituted 3′-deoxythymidine derivatives as potent and selective human
mitochondrial thymidine kinase inhibitors. Org. Biomol. Chem. 2011,
9, 892−901.
(32) Becke, A. D. Density-Functional Thermochemistry. III. The
Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652.
(24) (a) Moderhack, D.; Goos, K.-H.; Preu, L. Dimroth-umlagerung
von iminen des 1,5-diaminotetrazols. Chem. Ber. 1990, 123, 1575−
1578. (b) Vasil’kova, N. O.; Filimonova, V. N.; Kriven’ko, V. P. One-
pot synthesis of isomeric 2-hydroxyphenyl-substituted cycloalkate-
trazolopyrimidines. Russ. J. Org. Chem. 2017, 53, 639−641.
(c) L’abbé, G.; Vandendriessche, A.; Van Essche, G.; Toppet, S.
Dimroth rearrangement of 5-hydrazino-1,2,3-triazoles and 5-hydrazi-
notetrazoles. Bull. Soc. Chim. Belg. 1988, 97, 543−544.
(25) (a) Vorobiov, A.; Gaponik, P.; Petrov, P.; Ivashkevich, O. One-
pot syntheses of 5-amino-1-aryltetrazole derivatives. Synthesis 2006,
̌
̌
̌
̌
̌
1307−1312. (b) Skoch, K.; Císarová, I.; Stepnicka, P. Selective gold-
catalysed synthesis of cyanamides and 1-substituted 1H-tetrazol-5-
amines from isocyanides. Chem.Eur. J. 2018, 24, 13788−13791.
(c) Yella, R.; Khatun, N.; Rout, S. K.; Patel, B. K. Tandem
regioselective synthesis of tetrazoles and related heterocycles using
iodine. Org. Biomol. Chem. 2011, 9, 3235−3245. (d) Yao, C.-H.; Song,
J.-S.; Chen, C.-T.; Yeh, T.-K.; Hsieh, T.-C.; Wu, S.-H.; Huang, C.-Y.;
Huang, Y.-L.; Wang, M.-H.; Liu, Y.-W.; Tsai, C.-H.; Kumar, C. R.;
Lee, J.-C. Synthesis and biological evaluation of novel C-indolylxylo-
sides as sodium-dependent glucose Co-transporter 2 inhibitors. Eur. J.
Med. Chem. 2012, 55, 32−38.
(26) Neese, F. Software Update: The ORCA Program System,
Version 4.0. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2018, 8,
No. e1327.
(27) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal
Solvation Model Based on Solute Electron Density and on a
Continuum Model of the Solvent Defined by the Bulk Dielectric
Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113,
6378−6396.
(28) Becke, A. D. Density-Functional Exchange-Energy Approx-
imation with Correct Asymptotic Behavior. Phys. Rev. A 1988, 38,
3098−3100.
(29) (a) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-
Salvetti Correlation-Energy Formula into a Functional of the Electron
Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−
789. (b) Johnson, B. G.; Gill, P. M. W.; Pople, J. A. The Performance
of a Family of Density Functional Methods. J. Chem. Phys. 1993, 98,
5612. (c) Russo, T. V.; Martin, R. L.; Hay, P. J. Density Functional
4803
https://dx.doi.org/10.1021/acs.joc.1c00282
J. Org. Chem. 2021, 86, 4794−4803