Palladium-catalyzed N-Arylation of 1-substituted-1H-tetrazol-5-amines

Article abstract of DOI:10.1016/j.jorganchem.2018.11.007

A palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5-amines has been described for the first time. The reaction provides good yields of desired products with broad substrate scope and good functional group tolerance.

Full text of DOI:10.1016/j.jorganchem.2018.11.007

Accepted Manuscript
Palladium-catalyzed N-Arylation of 1-substituted-1H-tetrazol-5-amines
Andrea M. Nikolić, Vladimir Ajdačić, Igor M. Opsenica
PII:
S0022-328X(18)30840-4
DOI:
https://doi.org/10.1016/j.jorganchem.2018.11.007
JOM 20627
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 26 September 2018
Revised Date: 24 October 2018
Accepted Date: 2 November 2018
Please cite this article as: A.M. Nikolić, V. Ajdačić, I.M. Opsenica, Palladium-catalyzed N-Arylation
of 1-substituted-1H-tetrazol-5-amines, Journal of Organometallic Chemistry (2018), doi: https://
doi.org/10.1016/j.jorganchem.2018.11.007.
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ACCEPTED MANUSCRIPT
Palladium-Catalyzed N-Arylation of 1-Substituted-1H-tetrazol-5-amines
Andrea M. Nikolić, Vladimir Ajdačić, Igor M. Opsenica*
University of Belgrade – Faculty of Chemistry, PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia
ABSTRACT: A palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5-amines has been
described for the first time. The reaction provides good yields of desired products with broad substrate
scope and good functional group tolerance.
Key words: palladium, transition metal catalyst, C‒N cross coupling, arylation, heterocycles
AUTHOR INFORMATION
Corresponding Author
*E-mail: igorop@chem.bg.ac.rs
ORCID
Andrea M. Nikolić: 0000-0003-1907-1565
Vladimir Ajdačić: 0000-0002-3423-0862
Igor M. Opsenica: 0000-0003-4942-4042

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1. Introduction
Nitrogen-heterocyclic scaffolds are one of the most common structural motifs in pharmaceuticals.1 As
such 5-aminotetrazole is an important heterocyclic moiety of many bioactive compounds (Figure 1).
Substituted 5-aminotetrazoles exhibit versatile biological activities such as antiallergic,2
antiinflammatory,3 antidiabetic,4 antineoplastic5 and antibiotic activity.6 Moreover, 5-aminotetrazoles
provide excellent inhibition against the corrosion of stainless steel7 and are used as cholecystokinin B
(CCK-B) receptor antagonists8 and ligands in coordination chemistry.9 Recent studies have described
the use of 5-aminotetrazoles as photoprecursors of reactive intermediates.10
Figure 1. Important molecules containing 5-aminotetrazole moiety
Two main synthetic strategies for the synthesis of N5-substituted 5-aminotetrazoles are reported in the
literature. The classical approach utilizes the formation of the tetrazole ring from N-substituted acyclic
precursors (Figure 2),11,12 and converse approach involves N5-amino group functionalization of the
previously formed 5-aminotetrazoles.2,13,14 Recently, Bollikolla and co-workers developed copper-
catalyzed double arylation of 5-aminotetrazole for the synthesis of substituted 1-aryl-5-(N-arylamino)-
tetrazoles.15

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Previous works
N
C
R
S
N N
H H
N
NaN3
I2 or CuI
TMSN3
FeCl3
R
12a,b
12e
NaN3
PhI(OAc)2
NH
CN
Se
N N
H H
CuI
12d
NH
R
12c
R N3
R
N
N
N
N
I
NH2
Cu(OAc)2.H2O
1,10-Phen
H
NH
N
+
N
N
15
N
N
N
N
N
This work
NH2
Br
Pd2(dba)3, t-BuXPhos
NaOt-Bu
dioxane, 105 oC, Ar
R
NH
N
N
+
N
N
R
N
N
N
N
Figure 2. Synthetic methods for the preparation of N-aryl 1-substituted-1H-tetrazol-5-amines
Palladium-catalyzed arylation of amines has emerged as powerful tool in organic synthesis and
medicinal chemistry.16,17 Of particular interest is palladium catalyzed arylation of primary amine
derivatives of five- and six-membered heterocyclic compounds, which have been challenging
substrates.18,19 As we have recently demonstrated, electrostatic map potential of 5-aminotetrazoles
shows that most of the electron density is located in the tetrazole ring while the amino group is in the
blue region. This indicates that amino group is electron deficient and therefore less nucleophilic.20
Herein, we report the first example of a palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5-
amines.
2. Results and discussion
In order to optimize the reaction condition, we began our study by choosing readily available 1-benzyl-
1H-tetrazol-5-amine 1a and bromobenzene 2a as the model substrates with catalytic amount of
Pd2(dba)3 (10 mol % Pd with respect to 2a) as source of palladium and NaOt-Bu (1.2 equiv) as a base,
in toluene at 105 °C. An excess amount of the 5-aminotetrazole substrate was used in the reaction in

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order to prevent the formation of diarylated product. Using biaryl phosphane ligand JohnPhos (20 mol
% with respect to 2a) the desired product 3a was obtained in 8% isolated yield after 24 h reaction time
(Table 1, entry 1). Unfortunately, the reaction with SPhos was inefficient (Table 1, entry 2). When the
reaction was carried out in 1,4-dioxane as solvent using JohnPhos as ligand under the same conditions,
34% of 3a was isolated (Table 1, entry 3). To further improve the yield, different ligands were
evaluated (Table 1, entries 4-6). With BrettPhos and t-BuXPhos significantly improved yields were
observed (Table 1, entries 4 and 5). However, dppf was found to be unsuitable for the reaction (Table
1, entry 6). Moreover, shortening the reaction time from 24 h to 10 h was proven to be detrimental
(Table 1, entry 7 vs entry 5). Notably, screening of the base revealed that K2CO3 was also very
effective (Table 1, entry 8). On the other hand, Cs2CO3 was less effective in this reaction and resulted
in lower yield (Table 1, entry 9).

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Table 1. Optimization of the palladium-catalyzed N-arylation reaction conditionsa
entry
ligand
JohnPhos
SPhos
base
solvent
PhMe
time (h)
24
yield (%)b
1
2
3
4
5
6
7
8
9
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
K2CO3
8
PhMe
24
-
JohnPhos
BrettPhos
t-BuXPhos
dppf
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
24
34
82
91
18
40
90
79
24
24
24
t-BuXPhos
t-BuXPhos
t-BuXPhos
10
24
Cs2CO3
24
aReactions were performed in a flame-dried closed reaction tube. Pd2(dba)3 (10 mol % Pd), ligand (20 mol %) and base (1.2
equiv) were added to the reaction tube followed by the solvent. The mixture was stirred under an inert atmosphere at room
temperature for 5 min, after which 2a (1.0 equiv) and 1a (1.2 equiv) were added. The tube was sealed and the mixture was
heated at 105 °C in an oil bath for the indicated reaction time. bIsolated yield.
With the optimized reaction conditions in hand, we examined the substrate scope with respect to
arylbromides.

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Table 2. Substrate scope for Pd-catalyzed N-arylation of 1-benzyl-1H-tetrazol-5-aminea
Ar
hetAr
NH2
Pd2(dba)3, t-BuXPhos
NaOt-Bu
dioxane, 105 oC, Ar
Br
NH
+
N
N
Ar
hetAr
N
N
N
N
N
N
1a
2
3
aReactions conditions: 1a (0.300 mmol, 1.2 equiv), 2 (0.250 mmol, 1.0 equiv), Pd2(dba)3 (0.012 mmol, 10 mol % Pd), t-
BuXPhos (0.050 mmol, 20 mol %), NaOt-Bu (0.300 mmol, 1.2 equiv), 1,4-dioxane (1 mL), 105 °C, 24 h, Ar. Isolated
yields are shown. bReaction performed on 1.0 mmol scale. cK2CO3 (0.300 mmol, 1.2 equiv) and 1,4-dioxane (3.2 mL) were
used. Isolated yields are shown.
As shown in Table 2, a series of arylbromides, including those with electron-donating group (‒OMe)
and others with electron-withdrawing groups (‒NO2, ‒CN, ‒CO2Me, ‒CHO, and ‒COCH3) were
transformed into the desired products in moderate to good yields (Table 2, 3b-3g), providing a potential
point for further functionalization of the coupling products. In the cases of substrates with sensitive

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functional groups, K2CO3 was used as base (Table 2, 3d-3g). In addition, with 1-bromo-4-
chlorobenzene and 1-bromo-3-chlorobenzene excellent selectivity was observed (Table 2, 3h and 3i).
Moreover, when sterically demanding 2-bromo-5-chlorotoluene was employed as substrate, the
reaction provided the corresponding product 3j in good yield. The scope of this method was further
investigated by utilizing heteroaryl bromides. The present method is also applicable to 3-
bromopyridine and corresponding product 3l was obtained in 51% yield, while there was no reaction
with 2-bromothiophene (Table 2, 3k). Notably, the reaction could be scaled up to 1 mmol scale,
yielding 3a in 91% isolated yield.
Next, we examined the substrate scope with respect to 1-substituted-1H-tetrazol-5-amines and
arylbromides. As shown in Table 3, 1-(4-methoxybenzyl)-1H-tetrazol-5-amine 1b reacted smoothly
with both electron-poor and electron-rich aryl bromides and afford the corresponding desired
substituted products 3m-3r in moderate to excellent yields (54-95%). In addition, 4-((5-amino-1H-
tetrazol-1-yl)methyl)benzonitrile 1c and 1-propyl-1H-tetrazol-5-amine 1d reacted with bromobenzene
2a affording 3s and 3t in moderate yields. Furthermore, 1-phenyl-1H-tetrazol-5-amine 1e was also
reacted with 2a and gave the desired product 3u in 71% yield.

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Table 3. Substrate scope for palladium catalyzed N-arylationa
MeO
O2N
NH
NH
NH
N
N
N
N
N
N
N
N
N
N
N
N
MeO
MeO
MeO
3m, 95%
3n, 70%
3o, 71%
Cl
Cl
Cl
NH
NH
NH
N
N
N
N
N
N
N
N
N
N
N
N
MeO
MeO
MeO
3p, 66%
3q, 54%
3r, 71%
HN
NH
NH
N
N
N
N
N
N
N
N
N
N
N
N
NC
3s, 52%b
3t, 61%
3u, 71%
aReactions conditions: 1 (0.300 mmol, 1.2 equiv), 2 (0.250 mmol, 1.0 equiv), Pd2(dba)3 (0.012 mmol, 10 mol % Pd), t-
BuXPhos (0.050 mmol, 20 mol %), NaOt-Bu (0.300 mmol, 1.2 equiv), 1,4-dioxane (1 mL), 105 °C, 24 h, Ar. Isolated
yields are shown. bReactions conditions: 1 (0.180 mmol, 1.2 equiv), 2 (0.150 mmol, 1.0 equiv), Pd2(dba)3 (0.008 mmol, 10
mol % Pd), t-BuXPhos (0.030 mmol, 20 mol %), K2CO3 (0.180 mmol, 1.2 equiv), 1,4-dioxane (1.9 mL), 105 °C, 24 h, Ar.
Isolated yields are shown.

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The reaction conditions also proved applicable to the coupling reaction of 1-benzyl-1H-tetrazol-5-
amine 1a with iodobenzene 4 and chlorobenzene 5, and to a lesser extent to the coupling reaction of 1a
and phenyl trifluoromethanesulfonate 6 (Scheme 1).
Scheme 1. Reaction of 1-benzyl-1H-tetrazol-5-amine 1a with iodobenzene 4, chlorobenzene 5 and
phenyl trifluoromethanesulfonate 6
Finally, as an expansion of this study, we explored the removal of benzyl group21 in order to obtain N-
phenyl-1H-tetrazol-5-amine. Under hydrogen atmosphere (1atm), 3a was converted into 7a in almost
quantitative yield, using Pd/C (5 mol % Pd) as a catalyst (Scheme 2).
Scheme 2. Removal of benzyl group
3. Conclusions
In conclusion, we have successfully developed an efficient palladium-catalyzed N-arylation of 1-
substituted-1H-tetrazol-5-amines. The reaction exhibits broad substrate scope and good functional
group compatibility. Considering the generality, this methodology could be of synthetic utility in the
industry and drug discovery and development process.
4. Experimental section
4.1. General Information.

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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 Boetius PMHK apparatus and
are not corrected. IR spectra were 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) using DMSO-d6 (unless stated otherwise) as the
solvent. 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 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 positive mode
on 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, resolution (at m/z 400):
30000.
4.2. Synthesis
Compounds 1-benzyl-1H-tetrazol-5-amine (1a)22, 1-propyl-1H-tetrazol-5-amine (1d)23 and 1-phenyl-
1H-tetrazol-5-amine (1e)24 were synthesized according to the previously reported procedures.
1-(4-Methoxybenzyl)-1H-tetrazol-5-amine (1b).19 In a flame-dried flask, CNBr (811 mg, 7.7 mmol, 2
equiv) was dissolved in dry acetonitrile (13 mL) at 0 °C. NaN3 (2.373 g, 36.5 mmol, 9.5 equiv) was
added at the cooled solution and the resulting mixture was stirred at 0 °C for 4 h. The precipitate was
filtered on a Hirsch funnel and the filtrate was added dropwise to a stirred emulsion of (4-
methoxyphenyl)methanamine (500 ꢀL, 3.8 mmol) in water (4 mL) at 0 °C. The resulting mixture was
stirred at room temperature for 48 h. After the time has passed, the solvents were removed under the
reduced pressure. The remaining residue was filtered and washed with water and acetonitrile. The
product was dried under reduced pressure to afford 1-(4-methoxybenzyl)-1H-tetrazol-5-amine as a
white crystalline solid (571 mg, 73%); m.p. 183–185 °C. IR (ATR) = 3326, 3162, 3025, 2960, 2840,
1660, 1590, 1512, 1459, 1436, 1307, 1281, 1252, 1179, 1115, 1088, 1032, 792, 763, 676, 557 cm-1. 1H
NMR (500 Hz, DMSO-d6): δ 7.21 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.79 (s, 2H), 5.26 (s,
2H), 3.72 (s, 3H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 159.0, 155.3, 129.2, 127.3, 114.1, 55.1, 47.1.
HRMS (HESI/Orbitrap) m/z: [M + Na]+ Calcd for C9H11N5ONa 228.08613; Found 228.08524.

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4-((5-Amino-1H-tetrazol-1-yl)methyl)benzonitrile (1c). Following the procedure described for 1b,
compound 4-((5-amino-1H-tetrazol-1-yl)methyl)benzonitrile (1c) was obtained as a white powder (119
mg, 28%) starting from 283 mg (2.4 mmol) of 4-(aminomethyl)benzonitrile; m.p. 200–202 °C. IR
(ATR) = 3342, 3144, 2763, 2234, 1659, 1638, 1586, 1509, 1482, 1424, 1336, 1269, 1125, 1094, 820,
698, 549 cm-1. 1H NMR (500 Hz, DMSO-d6): δ 7.84 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.89
13
(s, 2H), 5.47 (s, 2H). C{1H} NMR (125 Hz, DMSO-d6): δ 155.7, 140.9, 132.7, 128.3, 118.5, 110.8,
47.1. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C9H9N6 201.08887; Found 201.08801.
General procedure A for palladium catalyzed arylation of 1-substituated-1H-tetrazol-5-amines
To a flame-dried reaction tube, Pd2(dba)3 (11 mg, 0.012 mmol, 10 mol % Pd), t-BuXPhos (21 mg,
0.050 mmol, 20 mol %) and NaOt-Bu (42 mg, 0.300 mmol, 1.2 equiv) were added followed by 1,4-
dioxane (1 mL). The mixture was stirred at room temperature under an inert atmosphere for 5 min,
after which the aryl-bromide (0.250 mmol, 1.0 equiv) and amine (0.300 mmol, 1.2 equiv) were added,
the tube 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 mixture was diluted with EtOAc (30 mL). The mixture was
washed with water (30 mL), brine (30 mL) and the organic solution was dried over anhydrous MgSO4.
The mixture was filtered and the solvents were removed under the reduced pressure. The crude product
was purified by dry-flash column chromatography on SiO2.
General procedure B for palladium catalyzed arylation of 1-substituated-1H-tetrazol-5-amines
To a flame-dried reaction tube, Pd2(dba)3 (11 mg, 0.012 mmol, 10 mol % Pd), t-BuXPhos (21 mg,
0.050 mmol, 20 mol %) and K2CO3 (29 mg, 0.300 mmol, 1.2 equiv) were added followed by 1,4-
dioxane (3.2 mL). The mixture was stirred at room temperature under an inert atmosphere for 5 min,
after which the aryl-bromide (0.250 mmol, 1.0 equiv) and amine (0.300 mmol, 1.2 equiv) were added,
the tube 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 mixture was diluted with EtOAc (30 mL). The mixture was
washed with water (30 mL), brine (30 mL) and the organic solution was dried over anhydrous MgSO4.
The mixture was filtered and the solvents were removed under the reduced pressure. The crude product
was purified by dry-flash column chromatography on SiO2.
1-Benzyl-N-phenyl-1H-tetrazol-5-amine (3a). Following the general procedure A for palladium
catalyzed arylation, compound 3a was obtained after dry-flash column chromatography (SiO2:
Hex/EtOAc = 7/3) as a pale yellow solid (228 mg, 91%) from 210 mg (1.2 mmol) of 1a; m.p. 165–168

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°C. IR (ATR) = 3729, 3276, 3209, 3129, 3107, 3061, 2925, 2854, 1615, 1577, 1540, 1498, 1457, 1332,
1104, 748, 716, 692 cm-1. 1H NMR (500 Hz, DMSO-d6): δ 9.46 (s, 1H), 7.65–7.60 (m, 2H), 7.38–7.30
13
(m, 5H), 7.26–7.22 (m, 2H), 7.02–6.96 (m, 1H), 5.64 (s, 2H). C{1H} NMR (125 Hz, DMSO-d6): δ
152.5, 139.8, 135.2, 129.0, 128.9, 128.1, 127.4, 122.0, 117.6, 48.2 ppm. HRMS (HESI/Orbitrap) m/z:
[M + H]+ Calcd for C14H14N5 252.12492; Found 252.12377.
Reaction of 1-benzyl-1H-tetrazol-5-amine 1a and iodobenzene 4:
Following the general procedure A for palladium catalyzed arylation, compound 3a was obtained after
dry-flash column chromatography (SiO2: Hex/EtOAc = 7/3) as a pale yellow solid (12 mg, 68%) from
1a (15 mg, 0.086 mmol) and iodobenzene 4 (8 ꢀL, 0.071 mmol).
Reaction of 1-benzyl-1H-tetrazol-5-amine 1a and chlorobenzene 5:
Following the general procedure A for palladium catalyzed arylation, compound 3a was obtained after
dry-flash column chromatography (SiO2: Hex/EtOAc = 7/3) as a pale yellow solid (9 mg, 51%) from
1a (15 mg, 0.086 mmol) and chlorobenzene 5 (7 ꢀL, 0.071 mmol).
Reaction of 1-benzyl-1H-tetrazol-5-amine 1a and phenyl trifluoromethanesulfonate 6:
Following the general procedure A for palladium catalyzed arylation, compound 3a was obtained after
dry-flash column chromatography (SiO2: Hex/EtOAc = 7/3) as a pale yellow solid (5 mg, 28%) from
1a (15 mg, 0.086 mmol) and phenyl trifluoromethanesulfonate 6 (16 mg, 0.071 mmol).
1-Benzyl-N-(4-methoxyphenyl)-1H-tetrazol-5-amine (3b). Following the general procedure A for
palladium catalyzed arylation, compound 3b was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 7/3) as a pale orange solid ((50 mg, 71%); 137–139 °C. IR (ATR) = 3317, 3032,
1
2929, 1634, 1607, 1562, 1512, 1458, 1243, 1033 cm-1. H NMR (500 Hz, DMSO-d6): δ 9.26 (s, 1H),
7.54 (d, J = 9.0 Hz, 2H), 7.40–7.35 (m, 2H), 7.34–7.30 (m, 1H), 7.27–7.22 (m, 2H), 6.93 (d, J = 9.0
13
Hz, 2H), 5.60 (s, 2H), 3.72 (s, 3H). C{1H} NMR (125 Hz, DMSO-d6): δ 154.6, 152.8, 135.2, 132.9,
128.8, 128.0, 127.4, 119.5, 114.2, 55.2, 48.0. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for
C15H16N5O 282.13549; Found 282.13465.
1-Benzyl-N-(4-nitrophenyl)-1H-tetrazol-5-amine (3c). Following the general procedure A for
palladium catalyzed arylation, compound 3c was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 6/4) as a pale orange solid (57 mg, 77%); m.p. 245–246 °C. IR (ATR) = 3277,
3231, 3191, 3112, 3078, 2924, 1625, 1585, 1544, 1515, 1497, 1455, 1335, 1261, 1110, 856, 715 cm-1.
1H NMR (500 Hz, DMSO-d6): δ 10.30 (s, 1H), 8.30–8.20 (m, 2H), 7.95–7.85 (m, 2H), 7.41–7.35 (m,
2H), 7.34–7.31 (m, 1H), 7.29–7.24 (m, 2H), 5.69 (s, 2H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 151.7,

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146.0, 141.1, 134.8, 128.9, 128.2, 127.5, 125.4, 117.0, 48.6. HRMS (HESI/Orbitrap) m/z: [M + H]+
Calcd for C14H13N6O2 297.10999; Found 297.10881.
4-((1-Benzyl-1H-tetrazol-5-yl)amino)benzonitrile (3d). Following the general procedure B for
palladium catalyzed arylation, compound 3d was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 6/4) as a pale yellow solid (48 mg, 69%); m.p. 220–222 °C. IR (ATR) = 3270,
3192, 3108, 3065, 2956, 2923, 2227, 1611, 1566, 1509, 1334, 844 cm-1. 1H NMR (500 Hz, DMSO-d6):
δ 10.07 (s, 1H), 7.85–7.75 (m, 4H), 7.38–7.35 (m, 2H), 7.33–7.29 (m, 1H), 7.26–7.22 (m, 2H), 5.67 (s,
2H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 151.8, 144.0, 134.9, 133.6, 128.9, 128.2, 127.4, 119.2,
117.5, 103.4, 48.5. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C15H13N6 277.12017; Found
277.11924.
Methyl 3-((1-benzyl-1H-tetrazol-5-yl)amino)benzoate (3e). Following the general procedure B for
palladium catalyzed arylation, compound 3e was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 7/3) as a pale yellow solid (63 mg, 82%); m.p. 142–144 °C. IR (ATR) = 3297,
3062, 2959, 2927, 2869, 1723, 1617, 1581, 1537, 1461, 1298, 1234, 1112, 756 cm-1. 1H NMR (500 Hz,
DMSO-d6): δ 9.77 (s, 1H), 8.30 – 8.25 (m, 1H), 8.00 – 7.95 (m, 1H), 7.61 – 7.57 (m, 1H), 7.52 – 7.47
(m, 1H), 7.39 – 7.35 (m, 2H), 7.33 – 7.30 (m, 1H), 7.27 – 7.24 (m, 2H), 5.66 (s, 2H), 3.86 (s, 3H).
13C{1H} NMR (125 Hz, DMSO-d6): δ 166.1, 152.2, 140.2, 135.0, 130.4, 129.5, 128.8, 128.1, 127.4,
122.5, 121.9, 118.0, 52.2, 48.2. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C16H16N5O2
310.13040; Found 310.13040.
4-((1-Benzyl-1H-tetrazol-5-yl)amino)benzaldehyde (3f). Following the general procedure B for
palladium catalyzed arylation, compound 3f was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 6/4) as a yellow solid (36 mg, 51%); m.p. 192–194 °C. IR (ATR) = 3274, 3120,
1
3063, 2923, 2726, 1698, 1604, 1565, 1539, 1334, 1169, 834 cm-1. H NMR (500 Hz, DMSO-d6): δ
10.07 (s, 1H), 9.86 (s, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.39–7.35 (m, 2H), 7.34–
13
7.29 (m, 1H), 7.27–7.23 (m, 2H), 5.68 (s, 2H). C{1H} NMR (125 Hz, DMSO-d6): δ 191.3, 151.9,
145.4, 134.9, 131.2, 130.2, 128.9, 128.2, 127.5, 117.1, 48.5. HRMS (HESI/Orbitrap) m/z: [M + H]+
Calcd for C15H14N5O 280.11984; Found 280.11891.
1-(4-((1-Benzyl-1H-tetrazol-5-yl)amino)phenyl)ethan-1-one (3g). Following the general procedure
B for palladium catalyzed arylation, compound 3g was obtained after dry-flash column

ACCEPTED MANUSCRIPT
chromatography (SiO2: Hex/EtOAc = 6/4) as a pale yellow solid (41 mg, 56%); m.p. 222–223 °C. IR
1
(ATR) = 3278, 3194, 3119, 3061, 1678, 1603, 1563, 1538, 1455, 1270, 841 cm-1. H NMR (500 Hz,
DMSO-d6): δ 9.94 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.39 – 7.35 (m, 2H), 7.34
13
– 7.30 (m, 1H), 7.27 – 7.23 (m, 2H), 5.68 (s, 2H), 2.52 (s, 3H). C{1H} NMR (125 Hz, DMSO-d6): δ
196.3, 152.0, 144.1, 135.0, 130.5, 129.9, 128.9, 128.1, 127.4, 116.7, 48.4, 26.4. HRMS
(HESI/Orbitrap) m/z: [M + H]+ Calcd for C16H16N5O 294.13549; Found 294.13406.
1-Benzyl-N-(4-chlorophenyl)-1H-tetrazol-5-amine (3h). Following the general procedure A for
palladium catalyzed arylation, compound 3h was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 7/3) as a dark yellow solid (57 mg, 80%); m.p. 202–204 °C. IR (ATR) = 3268,
1
3200, 3121, 3062, 1615, 1571, 1540, 1492, 1331, 829 cm-1. H NMR (500 Hz, DMSO-d6): δ 9.71 (s,
1H), 7.70–7.65 (m, 2H), 7.40–7.38 (m, 2H), 7.37–7.34 (m, 2H), 7.33–7.30 (m, 1H), 7.27–7.22 (m, 2H),
13
5.65 (s, 2H). C{1H} NMR (125 Hz, DMSO-d6): δ 152.6, 139.2, 135.4, 129.2, 128.5, 127.8, 125.9,
119.6, 48.6. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C14H13ClN5 286.08595; Found
286.08469.
1-benzyl-N-(3-chlorophenyl)-1H-tetrazol-5-amine (3i). Following the general procedure A for
palladium catalyzed arylation, compound 3i was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 7/3) as a yellow solid (42 mg, 58%); m.p. 173–176 °C. IR (ATR) = 3256, 3189,
1
3105, 3059, 1618, 1571, 1541, 1477, 1455, 1389, 1329, 1112, 785, 723 cm-1. H NMR (500 Hz,
DMSO-d6): δ 9.72 (s, 1H), 7.85–7.80 (m, 1H), 7.57–7.54 (m, 1H), 7.39–7.35 (m, 3H), 7.35–7.30 (m,
1H), 7.26–7.23 (m, 2H), 7.03–7.06 (m, 1H), 5.64 (s, 2H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 152.1,
141.2, 135.0, 133.4, 130.7, 128.8, 128.1, 127.4, 121.6, 116.9, 116.1, 48.3. HRMS (HESI/Orbitrap) m/z:
[M + H]+ Calcd for C14H13ClN5 286.08595; Found 286.08541.
1-Benzyl-N-(4-chloro-2-methylphenyl)-1H-tetrazol-5-amine (3j). Following the general procedure
A for palladium catalyzed arylation, compound 3j was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 85/15) as an orange viscous oil (53 mg, 70%); IR (ATR) = 3269, 3031, 2926,
1
1611, 1492, 1452, 1095, 700 cm-1. H NMR (500 Hz, DMSO-d6): δ 8.66 (s,1H), 7.46–7.42 (m, 1H),
7.40–7.36 (m, 2H), 7.34–7.31 (m, 1H), 7.30–7.29 (m, 1H), 7.26–7.22 (m, 3H), 5.59 (s, 2H), 2.07 (s,
3H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 153.5, 136.7, 134.8, 133.5, 130.2, 128.8, 128.5, 128.2,
127.6, 126.3, 124.7, 48.4, 17.4. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C15H15ClN5
300.10160; Found 300.10036.

ACCEPTED MANUSCRIPT
N-(1-benzyl-1H-tetrazol-5-yl)pyridin-3-amine (3l). Following the general procedure A for palladium
catalyzed arylation, compound 3l was obtained after dry-flash column chromatography (SiO2:
Hex/EtOAc = 3/7) as a pink solid (32 mg, 51%); m.p. 156–158 °C. IR (ATR) = 3271, 3198, 3061,
1
2924, 1620, 1574, 1538 cm-1. H NMR (500 Hz, DMSO-d6): δ 9.74 (s, 1H), 8.85–8.80 (m, 1H), 8.25–
8.19 (m, 1H), 8.14–8.10 (m, 1H), 7.40–7.36 (m, 3H), 7.34–7.31 (m, 1H), 7.28–7.25 (m, 2H), 5.65 (s,
2H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 152.3, 143.0, 139.6, 136.6, 135.0, 128.9, 128.1, 127.4,
124.4, 123.8, 48.3. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C13H13N6 253.12017; Found
253.11951.
1-(4-Methoxybenzyl)-N-phenyl-1H-tetrazol-5-amine (3m). Following the general procedure A for
palladium catalyzed arylation, compound 3m was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 7/3) as a pale orange solid (67 mg, 95%); m.p. 152–155 °C. IR (ATR) = 3268,
3210, 3112, 3063, 2932, 1615, 1578, 1542, 1438, 1246, 1180, 735 cm-1. 1H NMR (500 Hz, DMSO-d6):
δ 9.42 (s, 1H), 7.65–7.60 (m, 2H), 7.36–7.31 (m, 2H), 7.25–7.22 (m, 2H), 7.01–6.97 (m, 1H), 6.94–
13
6.90 (m, 2H), 5.55 (s, 2H), 3.71 (s, 3H). C{1H} NMR (125 Hz, DMSO-d6): δ 159.1, 152.2, 139.8,
129.2, 129.0, 127.0, 121.9, 117.6, 114.2, 55.1, 47.8. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for
C15H16N5O 282.13549; Found 282.13544.
1-(4-Methoxybenzyl)-N-(4-methoxyphenyl)-1H-tetrazol-5-amine (3n). Following the general
procedure A for palladium catalyzed arylation, compound 3n was obtained after dry-flash column
chromatography (SiO2: Hex/EtOAc = 6/4) as a pale yellow solid (54 mg, 70%); m.p. 123 – 125 °C. IR
1
(ATR) = 3286, 2956, 2930, 1612, 1582, 1535, 1513, 1462, 1249, 1179, 1034 cm-1. H NMR (500 Hz,
DMSO-d6): δ 9.22 (s, 1H), 7.60–7.50 (m, 2H), 7.25–7.20 (m, 2H), 6.95–6.90 (m, 4H), 5.50 (s, 2H),
13
3.72 (s, 3H), 3.71 (s, 3H). C{1H} NMR (125 Hz, DMSO-d6): δ 159.0, 154.6, 152.6, 133.0, 129.1,
127.0, 119.5, 114.2, 55.2, 55.1, 47.6. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C16N18N5O2
312.14605; Found 312.14465.
1-(4-methoxybenzyl)-N-(4-nitrophenyl)-1H-tetrazol-5-amine (3o). Following the general procedure
A for palladium catalyzed arylation, compound 3o was obtained after dry-flash column
chromatography (SiO2: Hex/EtOAc = 6/4) as a yellow solid (58 mg, 71%); m.p. 171–173 °C. IR (ATR)
1
= 3264, 3102, 3072, 2960, 1620, 1583, 1542, 1517, 1339, 1262, 1111, 821 cm-1. H NMR (500 Hz,
DMSO-d6): δ 10.27 (s, 1H), 8.26 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H),

ACCEPTED MANUSCRIPT
6.92 (d, J = 8.5 Hz, 2H), 5.60 (s, 2H), 3.71 (s, 3H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 159.2, 151.4,
146.0, 141.1, 129.2, 126.6, 125.4, 117.0, 114.2, 55.1, 48.2. HRMS (HESI/Orbitrap) m/z: [M + Na]+
Calcd for C15H14N6O3Na 349.10251; Found 349.10096.
N-(4-chlorophenyl)-1-(4-methoxybenzyl)-1H-tetrazol-5-amine (3p). Following the general
procedure A for palladium catalyzed arylation, compound 3p was obtained after dry-flash column
chromatography (SiO2: Hex/EtOAc = 7/3) as an orange solid (52 mg, 66%); m.p. 198–200 °C. IR
(ATR) = 3265, 3198, 3119, 3060, 1614, 1570, 1514, 1490, 1458, 1263, 1252, 821 cm-1. 1H NMR (500
Hz, DMSO-d6): δ 9.60 (s, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 8.5 Hz,
13
2H), 6.92 (d, J = 8.5 Hz, 2H), 5.54 (s, 2H), 3.71 (s, 3H). C{1H} NMR (125 Hz, DMSO-d6): δ 159.1,
152.0, 138.8, 129.2, 128.8, 126.9, 125.5, 119.1, 114.2, 55.1, 47.8. HRMS (HESI/Orbitrap) m/z: [M +
Na]+ Calcd for C15H14ClN5ONa 338.07846; Found 338.07687.
N-(3-chlorophenyl)-1-(4-methoxybenzyl)-1H-tetrazol-5-amine (3q). Following the general
procedure A for palladium catalyzed arylation, compound 3q was obtained after dry-flash column
chromatography (SiO2: Hex/EtOAc = 7/3) as a yellow solid (43 mg, 54%); m.p 173–174 °C. IR (ATR)
= 3266, 3195, 3116, 3063, 2997, 2927, 1617, 1568, 1540, 1514, 1459, 1310, 1261, 780 cm-1. 1H NMR
(500 Hz, DMSO-d6): δ 9.68 (s, 1H), 7.79 – 7.78 (m, 1H), 7.60 – 7.50 (m, 1H), 7.40 – 7.35 (m, 1H),
7.24 (d, J = 8.5 Hz, 2H), 7.05 – 7.00 (m, 1H), 6.92 (d, J = 8.5 Hz, 2H), 5.55 (s, 2H), 3.71 (s, 3H).
13C{1H} NMR (125 Hz, DMSO-d6): δ 159.1, 151.8, 141.2, 133.4, 130.7, 129.2, 126.8, 121.5, 116.9,
116.0, 114.2, 55.1, 47.9. HRMS (HESI/Orbitrap) m/z: [M + Na]+ Calcd for C15H14ClN5ONa
338.07846; Found 338.07730.
N-(4-chloro-2-methylphenyl)-1-(4-methoxybenzyl)-1H-tetrazol-5-amine (3r). Following the general
procedure A for palladium catalyzed arylation, compound 3r was obtained after dry-flash column
chromatography (SiO2: Hex/EtOAc = 8/2) as a yellow viscous oil (58 mg, 71%); IR (ATR) = 3237,
1
2962, 1612, 1590, 1516, 1488, 1253, 1162, 819 cm-1. H NMR (500 Hz, DMSO-d6): δ 8.61 (s, 1H),
7.47–7.41 (m, 1H), 7.33–7.28 (m, 1H), 7.26–7.20 (m, 3H), 6.90–6.95 (m, 2H), 5.50 (s, 2H), 3.72 (s,
3H), 2.09 (s, 3H). 13C{1H} NMR (125 Hz, DMSO-d6): δ 159.1, 153.3, 136.8, 133.3, 130.2, 129.2,
128.4, 126.7, 126.3, 124.6, 114.2, 55.1, 48.0, 17.4. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for
C16H17ClN5O 330.11216; Found 330.11145.

ACCEPTED MANUSCRIPT
4-((5-(Phenylamino)-1H-tetrazol-1-yl)methyl)benzonitrile (3s). Following the general procedure B
for palladium catalyzed arylation, compound 3s was obtained after dry-flash column chromatography
(SiO2: Hex/EtOAc = 6/4) as a pale yellow solid (21 mg, 52%) from 36 mg (0.180 mmol) of 1c and the
reaction was performed in 1.9 mL of dioxane; m.p. 212–215 °C. IR (ATR) = 3266, 3208, 3107, 3067,
2928, 2234, 1616, 1577, 1540, 1499, 756 cm-1. 1H NMR (500 Hz, DMSO-d6): δ 9.48 (s, 1H), 7.90–7.84
(m, 2H), 7.64–7.61 (m, 2H), 7.41–7.38 (m, 2H), 7.36–7.32 (m, 2H), 7.01–6.95 (m, 1H), 5.75 (s, 2H).
13C{1H} NMR (125 Hz, DMSO-d6): δ 152.6, 140.6, 139.6, 132.8, 129.0, 128.2, 122.0, 118.5, 117.6,
110.8, 47.8. HRMS (HESI/Orbitrap) m/z: [M + H]+ Calcd for C15H13N6 277.12017; Found 277.11983.
N-phenyl-1-propyl-1H-tetrazol-5-amine (3t).25 Following the general procedure A for palladium
catalyzed arylation, compound 3t was obtained after dry-flash column chromatography (SiO2:
Hex/EtOAc = 8/2) as a yellow solid (31 mg, 61%); IR (ATR) = 3288, 3208, 3124, 3055, 2963, 2927,
1
2874, 1611, 1574, 1532, 1501, 1457, 744, 686 cm-1. H NMR (500 Hz, DMSO-d6): δ 9.21 (s, 1H),
7.65–7.60 (m, 2H), 7.35–7.30 (m, 2H), 7.05–6.95 (m, 1H), 4.29 (t, J = 7.0 Hz, 2H), 1.80 (sx, J = 7.0
Hz, 2H), 0.88 (t, J = 7.0 Hz, 3H).
N,1-diphenyl-1H-tetrazol-5-amine (3u).26 Following the general procedure A for palladium catalyzed
arylation, compound 3u was obtained after dry-flash column chromatography (SiO2: Hex/EtOAc = 9/1)
as a colorless solid (34 mg, 71%) from 39 mg (0.242 mmol) of 1e; IR (ATR) = 3239, 3195, 3076,
3043, 3000, 1606, 1572, 1532, 1498, 1454, 748, 692 cm-1. 1H NMR (500 Hz, CDCl3): δ 7.68–7.60 (m,
3H), 7.58–7.50 (m, 4H), 7.38–7.34 (m, 2H), 7.10–7.05 (m ,1H), 6.34 (s, 1H).
N-phenyl-1H-tetrazol-5-amine (7a).27 In a flame-dried flask, 3a (23 mg, 0.092 mmol) was dissolved
in deoxygenated methanol (1 mL) and Pd/C (5 mg, 0.005 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 72 h. The reaction mixture was filtered through a pad of Celite and washed
with EtOAc (25 mL). The solvents were removed under the reduced pressure to afford the pure 7a as a
colorless solid (15 mg, 99%). IC (ATR) = 3271, 3135, 3075, 1629, 1583, 1545, 1498, 1245, 1065, 742
cm-1. 1H NMR (500 Hz, CDCl3): δ 9.76 (s, 1H), 7.55–7.40 (m, 2H), 7.35–7.25 (m, 2H), 7.05–6.90 (m,
1H).
ACKNOWLEDGMENT

ACCEPTED MANUSCRIPT
This research was financially supported by the Ministry of Education, Science and Technological
Development of Serbia (Grant No. 172008).
The authors acknowledge the support of the FP7 RegPot project FCUB ERA GA No. 256716. The EC
does not share responsability for the content of the article.
Appendix A. Supplementary data
Supplementary data related to this article can be found at https://doi.org/10.1016/
Notes
The authors declare no competing financial interest.
REFERENCES
1
E. Vitaku, D. T. Smith, J. T. Njardarson, Analysis of the structural diversity, substitution patterns,
and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals, J. Med. Chem. 57
(2014) 10257‒10274.
2 R. E. Ford, P. Knowles, E. Lunt, S. M. Marshall, A. J. Penrose, C. A. Ramsden, A. J. H. Summers, J.
L. Walker, D. E. Wright, Synthesis and Quantitative Structure-Activity Relationships of Antiallergic 2-
Hydroxy-N-1H-tetrazol-5-ylbenzamides and N-(2-Hydroxypheny1)-1H-tetrazole-5-carboxamides, J.
Med. Chem. 29 (1986) 538‒549.
3
V. M. Girijavallabhan, P. A. Pinto, A. K. Genguly, R. W. Versace, Eur. Patent EP274867, 1988,
Chem. Abstr. 110 (1989) 23890.
4
D. Edmont, R. Rocher, C. Plisson, J. Chenault, Synthesis and evaluation of quinolone
carboxyguanidines as antidiabetic agents, Bioorg. Med. Chem. Lett. 10 (2000) 1831‒1834.
5 H. Akimoto, K. Ootsuand, F. Itoh, Eur. Patent EP530537, 1993, Chem. Abstr. 119 (1993) 226417.
6
A. Andrus, B. Partridge, J. V. Heck, B. G. Christensen, The synthesis of N-(tetrazol-5-yl)azetidin-2-
ones, Tetrahedron Lett. 25 (1984) 911‒914.
7
A. Ehsani, M. G. Mahjani, R. Moshre, H. Mostaanzadeh, J. Shabani Shayeh, 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. 4 (2014) 20031‒20037.
8 J. L. Castro, R. G. Ball, H. B. Broughton, M. G. N. Russell, D. Rathbone, A. P. Watt, R. Baker, K. L.
Chapman, A. E. Fletcher, S. Patel, A. J. Smith, G. R. Marshall, W. Ryecroft, V. G. Matassa, Controlled

ACCEPTED MANUSCRIPT
modification of acidity in cholecystokinin B receptor antagonists:ꢁ N-(1,4-benzodiazepin-3-yl)-N‘-[3-
(tetrazol-5-ylamino)phenyl]ureas, J. Med. Chem. 39 (1996) 842‒849.
9
T. V. Serebryanskaya, T. Yung, A. A. Bogdanov, A. Shchebet, S. A. Johnsen, A. S. Lyakhov, L. S.
Ivashkevich, Z. A. Ibrahimava, T. S. Garbuzenco, T. S. Kolesnikova, N. I. Melnova, P. N. Gaponik, O.
A. Ivashkevich, 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. 120 (2013) 44‒53.
10
A. Ismael, R. Fausto, M. L. S. Cristiano, Photochemistry of 1- and 2-Methyl-5-aminotetrazoles:
Structural Effects on Reaction Pathways, J. Org. Chem. 81 (2016) 11656‒11663.
11 a) A. R. Katritzky, B. V. Rogovoy, K. V. Kovalenko, A General Route to 5-Aminotetrazoles, J. Org.
Chem. 68 (2003) 4941‒4943. b) K. Ishihara, M. Kawashima, T. Matsumoto, T. Shioiri, M. Matsugi, A
practical synthesis of 5-substituted 1H-tetrazoles from aldoximes employing the azide anion from
diphenyl phosphorazidate, Synthesis 50 (2018) 1293‒1300.
12
a) R. Yella, N. Khatun, S. K. Rout, B. K. Patel, Tandem regioselective synthesis of tetrazoles and
related heterocycles using iodine, Org. Biomol. Chem. 9 (2011) 3235‒3245; b) S. Guin, S. K. Rout, A.
Gogoi, S. Nandi, K. K. Ghara, B. K. Patel, Desulfurization Strategy in the Construction of azoles
possessing additional nitrogen, oxygen or sulfur using a copper(I) catalyst, Adv. Synth. Catal. 354
(2012) 2757‒2770. c) Y. Xie, D. Guo, X. Jiang, H. Pan, W. Wang, T. Jin, Z. Mi, An efficient method
for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2, Tetrahedron Lett.
56 (2015) 2533‒2536. d) S. N. M. Boddapati, N. Polam, B. R. Mutchu, H. B. Bollikolla, The synthesis
of arylcyanamides: a copper-catalyzed consecutive desulfurizati on and C–N cross-coupling strategy,
New J. Chem. 42 (2018) 918‒922. e) R. S. Pathare, A. J. Ansari, S. Verma, A. Maurya, A. K. Maurya,
V. K. Agnihotri, A. Sharon, R. T. Pardasani, D. M. Sawant, Sequential Pd(0)/Fe(III) catalyzed
azide‒isocyanide coupling/cyclization reaction: One-pot synthesis of aminotetrazoles, J. Org. Chem. 83
(2018) 9530‒9537; and references cited therein.
13
N. P. Peet, Reactions of 2‐isocyanatobenzoyl chloride and 2‐carbomethoxyphenyl isocyanate with
5‐aminotetrazole, J. Heterocycl. Chem. 24 (1987) 223‒225.
14 J. Sun, Q. Tan, W. Yang, B. Liu, B. Xu, Copper-catalyzed aerobic oxidative annulation and carbon-
carbon bond cleavage of arylacetamides: Domino synthesis of fused quinazolinones, Adv. Synth. Catal.
356 (2014) 388‒394.
15 S.N. M. Boddapati, A. E. Kola, S. B. Kesana, H. B. Bollikolla, Temperature dependent regioselective
synthesis of aryl tetrazole amines using copper source, J. Organomet. Chem. 866 (2018) 177‒183.

ACCEPTED MANUSCRIPT
16
J. Bariwal, E. Van der Eycken, C‒N bond forming cross-coupling reactions: an overview, Chem.
Soc. Rev. 42 (2013) 9283‒9303.
17
a) P. Ruiz-Castillo, S. L. Buchwald, Applications of palladium-catalyzed C‒N cross-coupling
reactions, Chem. Rev. 116 (2016) 12564‒12649. b) M. M. Heravi, Z. Kheilkordi, V. Zadsirjan, M.
Heydari, M. Malmir, Buchwald-Hartwig reaction: An overview, J. Organomet. Chem. 861 (2018)
17‒104.
18
J. Yin, M. M. Zhao, M. A. Huffman, J. M. McNamara, Pd-Catalyzed N-arylation of
heteroarylamines, Org. Lett. 4 (2002) 3481–3484.
19
M. A. McGowan, J. L. Henderson, S. L. Buchwald, Palladium-catalyzed N-arylation of 2-
aminothiazoles, Org. Lett. 14 (2012) 1432–1435.
20 T. P. Andrejević, A. M. Nikolić, B. Đ. Glišić, H. Wadepohl, S. Vojnovic, M. Zlatović, M. Petković,
J. Nikodinovic-Runic, I. M. Opsenica, M. I. Djuran, Synthesis, structural characterization and
antimicrobial activity of silver(I) complexes with 1-benzyl-1H-tetrazoles, Polyhedron 154 (2018) 325–
333.
21 C. Behloul, M. Benlahrech, F. Foubelo, C. Nájera, M. Yus, Indium-, magnesium-, and zinc-mediated
debenzylation of protected 1H-tetrazoles: A comparative study, Synthesis 50 (2018) 3430‒3435.
22
Y-H. Joo, J. M. Shreeve, 1-Substituted 5-aminotetrazoles: syntheses from CNN3 with primary
amines, Org. Lett. 10 (2008) 4665–4667.
23
E. Vieira, J. Huwyler, S. Jolidon, F. Knoflach, V. Mutel, J. Wichmann, 9H-Xanthene-9-carboxylic
acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides as potent, orally available
mGlu1 receptor enhancers, Bioorg. Med. Chem. Lett. 15 (2005) 4628–4631.
24
A. N. Vorobiov, P. N. Gaponik, P. T. Petrov, O. A. Ivashkevich, One-pot syntheses of 5-amino-1-
aryltetrazole derivatives, Synthesis 8 (2006) 1307–1312.
25
I. Goljer, J. Svetlik, I. Hrusovsky, Carbon-13 NMR of substituted tetrazoles, Monatsh. Chem. 114
(1983) 65–70.
26
P. S. Chaudhari, S. P. Pathare, K. G. Akamanchi, o-Iodoxybenzoic acid mediated oxidative
desulfurization initiated domino reactions for synthesis of azoles, J. Org. Chem. 77 (2012) 3716–3723.
27 S. B. Bhagat, V. N. Telvekar, L-Proline: An efficient organocatalyst for the synthesis of 5-substituted
1H-tetrazoles via [3+2] cycloaddition of nitriles and sodium azide, Synlett 29 (2018) 874–879.

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The first palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5-amines.
The reaction provides good yields of desired products.
Broad substrate scope and good functional group compatibility.
This methodology could be of synthetic utility in the industry and drug discovery.