Temperature dependent regioselective synthesis of aryl tetrazole amines using copper source

Article abstract of DOI:10.1016/j.jorganchem.2018.04.027

One pot highly efficient and simple protocol for the construction of aryl tetrazole amines via desulphurization/substitution/electro cyclization/C-N cross coupling reactions from thiourea with the use of cheap, readily available and air stable copper sour

Full text of DOI:10.1016/j.jorganchem.2018.04.027

Accepted Manuscript
Temperature dependent regioselective synthesis of aryl tetrazole amines using
copper source
S.N. Murthy Boddapati, A. Emmanuel Kola, Surendra Babu Kesana, Hari Babu
Bollikolla
PII:
S0022-328X(18)30279-1
10.1016/j.jorganchem.2018.04.027
JOM 20419
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 1 February 2018
Revised Date: 2 April 2018
Accepted Date: 20 April 2018
Please cite this article as: S.N. Murthy Boddapati, A. Emmanuel Kola, S.B. Kesana, H.B. Bollikolla,
Temperature dependent regioselective synthesis of aryl tetrazole amines using copper source, Journal
of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.04.027.
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ACCEPTED MANUSCRIPT
Temperature dependent regioselective synthesis of aryl
tetrazole amines using copper source
S N Murthy Boddapati,a,bA Emmanuel Kola,b Surendra Babu Kesana,c Hari Babu
Bollikollaa*
a Dept. of Chemistry, Acharya Nagarjuna University, Guntur, Andhar Pradesh, India-522510.
b Dept. Of Chemstry, Sir C. R. Reddy UG and PG College, Eluru, Andhra Pradesh, India-534002.
c Dept. Of Chemstry, SVRM College, Nagaram, Andhra Pradesh, India-522268
.
ABSTRACT
One pot highly efficient and simple protocol for the construction of aryl tetrazole amines via
desulphurization/substitution/electro cyclization/C-N cross coupling reactions from thiourea
with the use of cheap, readily available and air stable copper source as catalyst has been
described. The reaction proceeds through the in situ formation of amino tetrazole followed by
successive C-N cross-coupling reaction with aryl iodide. Further the temperature dependent
regioselectivity in N-arylation of tetrazole amines has been described.
KEYWORDS
‹ Aryl tetrazole amines
‹ Regioselective synthesis
‹ Copper catalyst
‹ Desulphurization
‹ C-N Cross-Coupling Reaction
- -- - - -- -----------------------
*Corresponding author information: Dr. B. Hari Babu, Email: dr.b.haribabu@gmail.com; ph: +91-
8632346575

ACCEPTED MANUSCRIPT
1. Introduction
Tandem reactions have gained vital role in the construction of small molecule
libraries [1]. Generally, in case of tandem reactions the intermediate need not be stable
enough to be isolated that follows further reaction to provide multiple organic compounds. In
recent times, various organic molecules which contain biological and pharmalogical activities
were constructed via tandem reaction and carbon-heteroatom cross coupling reaction using
transition metal [2]. In this connection we are also interested to make hetero cyclic
compounds such as substituted aryl tetrazole amines through tandem reaction.
Tetrazole is found in compounds having anti-allergic/anti-asthmatic [3],antiviral and
anti-inflammatory [4], anti-neoplastic [5] activities (Figure 1). In addition tetrazoles are also
used as ligands in coordination chemistry and they were shown in medicinal applications [6].
Therefore, synthetic organic chemists have drawn immense attention for the preparation of
substituted tetrazoles. In this connection, researchers have developed traditional methods for
the construction of tetrazoles. Especially, the preparation of tetrazoles is achieved by addition
of NaNO2 to aminoguanidine [7c], addition of NaN3 to carbodiimides or cyanamides [8],
reaction of amines with a leaving group in tetrazoles 5thposition[9], nucelophilic substitution
-
by N3 of (a) chlorine in α-chloroformamidines [10] and (b) sulfur from thioureas in presence
of mercury [11] or lead salts [7c] or iodine [12]. 5-Substituted-1H-tetrazoles have also
prepared from the reaction between corresponding nitriles and NaN3 via [3+2] cycloaddition
using Zn (II) salts [13] and ZnO nanocrystal [14]. Later, substituted tetrazole have been
prepared from the reaction between substituted nitriles and TMSN3 using TBAF [15] and
copper catalyst [16].
Fig 1: Some of the biologically important aminotetrazoles

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Often thesemethods useeither toxic reagents or harsh reaction conditions such as high
temperature, using toxic reagents, unavailable starting precursors and lack of regioselectivity
[17]. Hence to overcome the above mentioned draw backs we wish to develop an efficient
methodology for the synthesis of substituted tetrazoles from thiourea using copper via
desulphurization/substitution/electro cyclization/C-N cross-coupling reaction. To the best of
our knowledge no report is available for the synthesis of aryl tetrazole amines from thiourea
using copper.
2. Materials and methods
2.1 General information: Thiourea, DMSO, EtOH, EtOAC, n-Hexane, n-Heptane,
1,10-Phenanthroline, CuSO4·5H2O (98%), CuI (98%), CuBr (98%), Cu2O (97%),
CuCl(99%), and Cu(OAc)2·H2O (98%), Et3N, sodium azide, K3PO4·3H2O, KOH, K2CO3,
Cs2CO3 were purchased from Aldrich and used without further purification. The solvents
were purchased and dried according to standard procedure prior to use. 1H NMR (400MHz)
spectra were recorded with a Varian 400 spectrometer. Infrared (IR) spectra recorded on a
Perkin Elmer Spectrum one FT-IR spectrometer. VKSI Medico centrifuge machine was used
for our experimental procedure for the synthesis of resulting compounds
2.2. Representative experimental procedure for the synthesis of Phenyl tetrazole amine 1a:
To a stirred solution of DMSO (2-3 mL), thiourea (1 mmol, 76 mg) was added in slowly and
followed by Et3N (1 mmol, 101 mg) and Cu(OAc)2.H2O (50 mol %, 100 mg) were added at
room temperature. The whole reaction mixture stirred for one hour (until get the black color)
at room temperature. The reaction was monitored by TLC. After completion of the reaction
(monitored by TLC), to this, NaN3 (2 mmol, 130 mg) was added. Then, the reaction mixture
stirred for 1 h. Later, iodobenzene (1 mmol, 204 mg), Cs2CO3 (1 mmol, 325 mg),
Cu(OAc)2.H2O (10 mol %, 19.9 mg) and 1,10-phenanthroline (20 mol %, 36 mg) were added
consecutively for several min and the reaction mixture was stirred for 18 h at 85 °C. The
progress of the reaction was investigated by TLC (5% ethylacetate in hexane). After
completion of the reaction, the reaction mixture was transferred into centrifuged tubes and the
mixture was centrifuged for 10 min by using centrifugation machine. Black color solid was
settled in the bottom of centrifuged tubes. The clear solution was concentrated by using
rotary evaporator and the crude mixture was purified by silica gel (60-120 mesh) column
chromatography using 20% ethylacetate in hexane as eluent to obtain a phenyl tetrazole
amine 1a as a white solid.

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2.3 General Procedure for the Synthesis of Diphenyl Tetrazole amine 2a: To a stirred
solution of DMSO (2-3 ml), thiourea (1 mmol, 76 mg) was added in slowly and followed by
Et3N (1 mmol, 101 mg) and Cu(OAc)2.H2O (50 mol %, 100 mg) were added at room
temperature. The whole reaction mixture stirred for one hour (until get the black color) at
room temperature. The reaction was monitored by TLC. After completion of the reaction
(monitored by TLC), to this, NaN3 (2 mmol, 130 mg) was added. Then, the reaction mixture
stirred for 1 h. Later, iodobenzene (2 mmol, 408 mg), Cs2CO3 (1.5 mmol, 485 mg),
Cu(OAc)2.H2O (10 mol %, 19.9 mg) and 1,10-phenanthroline (20 mol %, 36 mg) were added
consecutively for several min and the reaction mixture was stirred for 24 h at 115 °C. The
progress of the reaction was investigated by TLC (5% ethylacetate in hexane). After
completion of the reaction, the reaction mixture was transferred into centrifuged tubes and the
mixture was centrifuged for 10 min by using centrifugation machine. Black color solid was
settled in the bottom of centrifuged tubes. The clear solution was concentrated by using
rotary evaporator and the crude mixture was purified by silica gel (60-120 mesh) column
chromatography using 30% ethylacetate in hexane as eluent to obtain thediphenyl tetrazole
amine 2a as a white solid.
3. Results and discussions
Thiourea gave 1H-tetrazol-5-amine via desulfurization using copper source fallowed
by substitution and electro cyclizationreactions with NaN3. Further, 1H-tetrazol-5-amine
reacts with iodobenzene using a copper source as catalyst under moderate reaction conditions
to afford the target products phenyltetrazolamine and 1-phenyl-5-(N-phenyl amino) tetrazole
(Scheme 1).
Scheme 1. Synthetic route for aryltetrazolamine and 1-aryl-5-(N-aryl amino) tetrazole.

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Firstly, the optimization was started for the synthesis of tetrazole amine using thiourea
as a model substrate with various solvents and copper sources at room temperature. Among
the solvents protic polar solvents like EtOH and EtOAc (Table 1, entries 1-2), aprotic
solvents DMSO and DMF (Table 1, entries 6-7) gave final product A in complete
conversion. The reaction didn’t provide the target product in the presence of nonpolar
solvents n-hexane and n-heptane (Table 1, entries 3-4). The reaction using both copper (I)
and (II) sources to afford final product A in complete conversion. The reaction using the
lower amount of catalyst 50 mol % and 25 mol % to give final product in 100% and 65%
conversion, respectively (Table 1, entries13-14). Control experiment confirmed that the
reaction did not provide target product in the absence of catalyst (Table 1, entry 15).
Table 1: Optimization for the synthesis of tetrazole aminea
S
I. Solvent, Et3N (1 eq)
Copper source (100 mol %)
H
N
H2N
H2N
NH2
N
RT, 1 h
II. NaN3, RT, 1 h
N
N
A
Entry
Solvent
Copper source
Conversion(%)b
A
1
2
3
4
EtOH
EtOAc
n-Hexane
n-Heptane
CuI
CuI
CuI
CuI
100
100
n.d
n.d
5
6
7
8
9
H2O
DMF
DMSO
DMSO
DMSO
DMSO
CuI
CuI
CuI
CuCl
CuBr
Cu2O
56
100
100
100
100
100
10
11
DMSO
CuSO4.5H2O
100
12
13c
14d
15
DMSO
DMSO
DMSO
DMSO
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
-
100
100
65
n.d
aReaction conditions: Thiourea (1 mmol), solvent (2 mL), Et3N (1 eq),Copper source (100 mol %), 1 h, room
temperature, then, NaN3 (2 mmol) room temperature, 1h. bConversion based on diagnostic peaks
integration in 1H NMR of crude reaction mixture. c Copper source (50 mol %) wasused. d Copper source (25 mol
%) was used. n.d. = not detected.
Later, the optimization reaction conditions were performed for the synthesis of
phenyltetrazole amine using tetrazole amine and iodobenzene as model substrates with
various bases, ligands and copper sources. We were glad to observe that the reaction could
give target product 1a incomplete conversion using 10 mol % copper source, 20 mol %
ligand (1,10-phenanthroline)and 1 equiv. Cs2CO3 at 85 °C temperature in the presence of
DMSO solvent (Table2, entry 4)

ACCEPTED MANUSCRIPT
Table 2:Optimization for the synthesis of phenyltetrazole aminea
H
H2N
N
III. PhI (1 eq), DMSO, Copper source (10 mol %)
base (1 eq), ligand (20 mol %), 85 °C, 18 h
H2N
HN
N
N
N
N
+
N
N
N
N
N
N
N
A
1a
2a
H2N
NH2
HO
OH
N
N
L1
L2
L3
Entry
Copper source
Base
Ligand
Conversionb
1a
2a
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
K3PO4·3H2O
KOH
K2CO3
68
72
62
100
100
100
100
100
70
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
L3
L3
L3
L3
L3
L3
L3
L3
L1
L2
L3
L3
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuBr
CuCl
CuSO4·5H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
-
9
10
11c
12d
13
14
15e
16f
17g
55
40
35
20
n.d.
100
85
-
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
L3
L3
L3
L3
15
50
n.d
50
100
18h
a
Reaction conditions: Amino tetrazole (1 mmol), DMSO (2 mL), iodo benzene (1 mmol), catalyst (10 mol %),
ligand
(20
mol
%),
base
(1
mmol),
18
h,
85
°C.
c
bConversion based on diagnostic peaks integration in1H NMR ofcrude reaction mixture. Copper source (5 mol
%) used. d Cs2CO3 (0.5 equiv) used. e Iodobenzene (2 eq) was used. f Iodobenzene (2 eq) and temp 100 °C were
g
h
used. Iodobenzene (2 eq), temp 100 °C, 24h and Cs2CO3(1.5 eq) were used. Iodobenzene (2 eq), temp 115
°C, 24h and Cs2CO3 (1.5 eq) were used. n.d. = not detected.
The reaction using Cs2CO3 exhibited greater reactivity compared to that of K3PO4·3H2O,
K2CO3 and KOH. In a set of ligands L1-L3 screened, L3 (Table 2, entry 4) was found to be
the most effective in comparison to L1-L2 (Table 2, entries 9-10). Both copper (I) and (II)
sources (CuI, CuBr, CuCl, Cu(OAc)2.H2O and CuSO4.5H2O) exhibited a similar
catalyticactivity (Table 2, entries 4-8). Lowering the amount of base (0.5 equiv) or the
copper source (5 mol %) led to the N-arylation to afford target product in less conversion
(Table 2, entries 11 and 12).

ACCEPTED MANUSCRIPT
Table 3: Substrate scope for the synthesis of substituted aryltetrazole aminesa
R
H
N
ArI (1 eq), Cu(OAc)2.H2O (50 mol %)
H2N
H2N
N
N
N
Cs2CO3 (1 eq), 1,10-Phen (20 mol %)
85 °C, 18 h
N
N
N
N
R = EDG, EWG
Entry
1
Substrate
I
Product
NH2
Yieldb
N
N
N
96
(1a)
N
NH2
I
N
N
N
OMe
2
98
(1b)
(1c)
(1d)
N
MeO
NH2
I
I
N
N
3
4
97
87
N
Me
Cl
Me
Cl
N
N
NH2
N
N
N
NH2
N
I
N
N
5
6
80
(1e)
(1f)
F
F
N
N
NH2
N
I
N
N
47
46
CN
NC
NH2
N
I
7
N
N
COOMe
MeOOC
N
(1g)
NH2
I
N
NO2
Me
N
8
9
52
87
N
(1h)
(1i)
(1j)
N
O2N
NH2
I
N
N
N
N
Me
NH2
I
N
N
10
90
87
N
N
Me
Me
Me
I
NH2
N
N
11
Me
(1k)
N
N
Me
Me
a Reaction conditions: Tetrazole amine (1 mmol), DMSO (2 mL), Cu(OAc)2.H2O (10 mol %), ArI (1 mmol), ligand(20 mol
%), Cs2CO3 (1 mmol), 18 h, 85 °C. b Isolated yield.
Table 4: Substrate scope for the synthesis of substituted 1-aryl-5-(N-arylamino) tetrazolea

ACCEPTED MANUSCRIPT
R
H
H
N
ArI (2 eq), Cu(OAc)2.H2O (10 mol %)
N
H2N
N
N
N
N
Cs2CO3 (1.5 eq), 1,10-Phen (20 mol %)
115 °C, 24 h
N
N
N
R = EDG, EWG
Entry
1
Substrate
I
Product
Yieldb
H
(2a)
95
97
N
N
N
N
N
OMe
I
H
N
N
(2b)
2
N
Cl
MeO
MeO
N
N
H
I
I
N
N
3
(2c)
(2d)
78
43
N
CN
Cl
N
Cl
N
H
N
N
N
4
5
N
NC
N
NC
I
Me
Me
H
N
Me
76
80
(2e)
N
N
N
N
Me
I
H
N
Me
Me
6
N
N
(2f)
N
N
a Reaction conditions: Tetrazole amine (1 mmol), DMSO (2 mL), Aryl iodide (2 mmol), Cu(OAc)2.H2O (10 mol %),
ligand(20 mol %), Cs2CO3 (1.5 mmol), 24 h, 115 °C. b Isolated yield.
In order to know the role of ligand, the reaction was also performed without ligand
(Table 2, entry 13) and it gave the target product in very less yield even for prolonged

ACCEPTED MANUSCRIPT
reaction times. Control experiments without ligand and the copper source confirmed that the
formation of final product was not observed (Table 2, entry 14).
In order to optimize for another target product 2a, addition experiments were
conducted with high amount of iodobenzene and base at 100 °C and 115 °C. The results
shown in Table 2 clearly suggest that increasing temperature, base and iodobenzene
increases the yield of target product 2a (Table 2, entry 18).
Having the optimal conditions in hand, the scope of the protocol was next explored to
substituted phenyltetrazoleamines (Table 3). The substrates having both electron donating
and electron with drawing groups on the aryl rings could give their respective target products
1a-1k in moderate to high yield. Aryl iodide having electron donating substituents (4-Me,
2-Me, 4-OMe and 2,4-dimethyl) showed greater reactivity compared to that bearing electron
withdrawing substituent’s (4-Cl, 4-F, 4-CN and 4-COOMe groups). The phenyl ring having
electron donating groups such as 4-methoxy, 4-methyl could give their respective aromatic
cyanamides 1b and 1c in 98 and 97 % yield (Table 3, entries 2 and 3). The unsubstited
phenyl ring also gave target product 1a in excellent yield. Electron withdrawing groups such
as 4-chloro and 4-fluoro substituents provide their target products 1d and 1e in 87% and 80%
yields, (Table 3, entries 4 and 5) respectively. Aryl ring bearing other strong electron
withdrawing substituents such as nitrile, ester and nitro could give target products 1f-1h in
moderate yield (Table 3, entries 6-8). Aryl iodides bearing ortho and meta substituted methyl
groups readily underwent the reaction to give final products 1i-1j in 87 and 90% yields
respectively (Table 3, entries 9 and 10). 2,4-Di-Methyl substituents on aryl ring gave
targetproduct 1k in 87% yield (Table 3, entry 11).
Further, we have also explored for the construction of substituted 1-aryl-5-(N-
arylamino) tetrazole under optimized reaction conditions (Table 4). The reaction of
tetrazoleamine with aryl iodides containing both electron donating, electron withdrawing
groups were investigated. Aryl iodide having electron donating substituents (4-OMe, 3-Me
and 2-Me) showed greater reactivity compared to that bearing electron withdrawing
substituent’s (4-Cl and 4-CN groups). The phenyl ring having electron donating groups such
as 4-methoxy, 3-methyl and 2-methyl could give their respective 1-aryl-5-(N-aryl amino)
tetrazole 2b-2d in 97-78% yield (Table 4, entries 2-4). The unsubstituted phenyl ring also
gave target product 2a in excellent yield (Table 4, entry 1). Electron withdrawing groups
such as 4-chloro and 4-cyano substituents provide their target products 2e and 2f in 76% and
43% yields, respectively (Table 4, entries 5 and 6).

ACCEPTED MANUSCRIPT
H
N
H2N
H2N
N
ArBr (1 eq), Cu(OAc)2.H20 (10 mol %)
N
N
N
N
DMSO, Cs2CO3 (1 eq), 1,10-Phen (20 mol %),
85 °C, 18 h
N
N
1a
A
Yield 26%
Scheme 2. Reaction with aryl bromide
Moreover, we also check the employability of the reaction with aryl bromide instead
of aryl iodide under optimized reaction conditions (Scheme 2). Very unfortunately, the
reaction gave target product in fewer yields. It might be occurred due to very hard to
formation of aryl bromide and copper complex [18].
The mechanism of formation for substituted aryltetrazole amine from thiourea is
shown in below Scheme 3. The experimental evidence and from the literature reports the
mechanism is proposed. Copper can co-ordinate with thiourea and followed by removal of
protons to afford intermediate R via intermediates P and Q. The intermediate R may provide
tetrazole amine A along with by-products CuS and poly sulphide [19] via
desulphurization/substitu-tion/electrocyclization [20]. On the other hand, oxidative addition
of aryl iodide with copper (I) species (it could be formed from copper (II) species) [21]
can lead to the formation of a which can undergo intermolecular C-N cross-coupling reaction
[22] with tetrazole amine using base to give the intermediate b that can complete the catalytic
cycle by reductive elimination to get target product aryltetarzole amine 1a.
[Cu]
[Cu]
[Cu]
S
S
CuII
+e
CuI
S
NaN3
NH
H
NH2
HN
NH2
H2N
NH2
Q
R
P
S
H:B
B
H2N
NH2
NH2
N
N3
[CuS]
+ poly sulfide
Electrocyclization
HN
HN
NH2
CuLnI
N
N
S
I
A
:B
oxidative
addition
a
+ I-
H:B
CuII
+e
CuI
NH2
Cu
Ln
reductive
N
N
elimination
N
N
b
NH2
N
N
N
N
1a
Scheme 3: Proposed mechanism for aryl tetrazolamine
.

ACCEPTED MANUSCRIPT
4. Conclusion
In conclusion, we have developed methodology for the regioselective synthesis of
aryltetrazoleamines from thiourea in one pot multistep reaction. It is a general, efficient and
easy method. Although the overall isolated yields look moderate, considering that the
reactions are multiprocesses, the yields are in fact good to excellent. Many reports are
available for the preparation of aminotetrazoles, however, the simplicity, environmental
acceptability and cost effectiveness of the copper makes this method more practical. The
reactions were involved desulphurization/substitution/electrocyclization followed by inter
molecular C-N cross-coupling reaction.
Acknowledgments
The authors thankful to Department of Chemistry, Acharya Nagarjuna University,
Nagarjuna Nagar, Guntur for providing work space and the authors are greatful to
Management Committee, Sir C R Reddy College, Eluru for Financial Support.
Conflicts of interest
The authors declare there are no conflicts of interest
.
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Highlights
‹ An efficient methodology for the synthesis of substituted tetrazoles
has been described.
‹ The reactions are general, clean and efficient.
‹ Desulfurization is developed by cheap, available and air stable
copper catalyst.
‹ All the substrates could obtain their target products in good to
excellent yields.