Room-Temperature Cu(II)-Catalyzed Chemo- and Regioselective Ortho-Nitration of Arenes via C-H Functionalization

Article abstract of DOI:10.1021/acs.joc.5b01021

An efficient Cu-catalyzed chemo- and regioselective ortho-nitration of N,1-diaryl-5-aminotetrazoles and N,4-diaryl-3-amino-1,2,4-triazoles have been described with good functional group compatibility. The procedure features the use of operationally simple protocol utilizing the commercially available less toxic CuCl₂·2H₂O as catalyst and Fe(NO₃)₃·9H₂O as nitration source at room temperature. Removal of the 5-aminotetrazole directing group has been demonstrated using base hydrolysis to afford substituted 2-nitroanilines.

Full text of DOI:10.1021/acs.joc.5b01021

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Article
Room Temperature Cu(II)-Catalyzed Chemo- and Regioselective
Ortho-Nitration of Arenes via C-H Functionalization
Pradeep Sadhu, Santhosh Kumar Alla, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 10 Jul 2015
Downloaded from http://pubs.acs.org on July 11, 2015
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Room Temperature Cu(II)-Catalyzed Chemo- and Regioselective
†
Ortho-Nitration of Arenes via C-H Functionalization
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Pradeep Sadhu, Santhosh Kumar Alla and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India.
Eꢀmail: tpunni@iitg.ernet.in
(Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical Society)
ABSTRACT: An efficient Cuꢀcatalyzed chemoꢀ and regioselective orthoꢀnitration of N,1,ꢀ
diarylꢀ5ꢀaminotetrazoles and N,4,ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀtriazoles have been described with good
functional group compatibility. The procedure features the use of operationally simple protocol
utilizing the commercially available less toxic CuCl ꢁ2H O as catalyst and Fe(NO ) ꢁ9H O as
2
2
3 3
2
nitration source at room temperature. Removal of the 5ꢀaminotetrazole directing group has been
demonstrated using base hydrolysis to afford substituted 2ꢀnitroanilines.
INTRODUCTION
The chelation assisted direct CꢀH functionalization using transition metal catalysis has recently
emerged as a powerful synthetic tool for the regioselective formation of carbonꢀcarbon and
1
2
3
4
carbonꢀheteroatom bonds. The second row transition metals, such as Ru, Rh, and Pd, have
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been considerably explored for this purpose. In contrast, the first row transition metals have
5
received less attention despite their high abundance in the earth crust. In particular, a few
6
studies are focused on the copper catalyzed aerobic CꢀH functionalization reactions. Herein, we
wish to report an efficient copper(II)ꢀcatalyzed direct chemoꢀ and regioselective orthoꢀnitration
of N,1ꢀdiarylꢀ5ꢀaminotetrazoles and N,4ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀtriazoles in the presence of
Fe(NO ) ꢁ9H O at room temperature. From an industrial point, this process would be useful due
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to its mild conditions, good functional group compatibility and free from the use of nitric acid.
Aromatic nitro compounds are versatile building blocks in organic, medicinal and
7
pharmaceutical sciences as well as in chemical industry. The electrophilic nitration of arenes has
long been the classical synthetic approach for the preparation of the aromatic nitro compounds.
However, these traditional processes often suffer due to poor selectivity and imperfect functional
8
group tolerance under harsh conditions. To overcome these drawbacks, several approaches have
been explored including the ipsoꢀnitration by the nitrodemetalation of an aryl CꢀM bond (M=B,
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Li), the ipsoꢀoxidation of an amino or azide group to a nitro group and the crossꢀcoupling
protocols of aryl halides, triflates and nonaflates with nitrite using transition metal catalysis (Pd
11
or Cu). Although these methods have led to overcome some of the above limitations, still they
1
2
suffer from the requirement of prefunctionalized substrate precursors. Attention has thus been
recently focused on the chelation assisted direct regioselective aromatic CꢀH nitrations using
1
3a,d
13b
13c,e
Cu/AgNO2,
Rh/NaNO2 and Pd/AgNO /NO .
2 2
RESULTS AND DISCUSSION
N,1ꢀDiarylꢀ5ꢀaminotetrazoles and N,4ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀtriazoles are structural motifs present
14,15
in many compounds that are important in biological and medicinal sciences.
Their direct and
selective CꢀH functionalization will thus be relevant to drug discovery. First, we commenced the
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optimization studies with Nꢀarylꢀ1ꢀarylꢀ1Hꢀtetrazolꢀ5ꢀamine 1a as a model substrate using a
series of copper salts as catalyst with different nitro sources and solvents (Table 1). Gratifyingly,
the reaction occurred selectively at the orthoꢀposition of the Nꢀaryl ring without affecting the 1ꢀ
aryl ring to give 2a in 95% yield when the substrate 1a was stirred with CuCl ∙2H O (20 mol %)
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2
2
and Fe(NO ) ∙9H O (35 mol %) in 1,2ꢀdichloroethane (DCE) for 11 h at room temperature. In a
3
3
2
set of copper sources screened, CuCl ꢁ2H O exhibited superior results compared to
2
2
Cu(OAc) ꢁH O, Cu(OTf) , CuSO ꢁ5H O, Cu(NO ) ꢁ3H O, CuI, CuBr , CuBr and CuCl (entries
2
2
2
4
2
3 2
2
2
1
ꢀ9). Among the nitro sources examined, Fe(NO ) ꢁ9H O gave the best results, whereas
3 3 2
Ca(NO ) ∙4H O, AgNO , Bi(NO ) ∙5H O and NaNO afforded the target product in <26% yield
3
2
2
3
3 3
2
2
(entries 10ꢀ13). DCE was found to be the solvent of choice giving the highest yield, whereas
dichloromethane (DCM), toluene and CH CN afforded 2a in 62ꢀ89% yields. In contrast, THF
3
and DMF furnished inferior results (entries 14ꢀ18). Lowering the amount of the Cuꢀsource (10
mol %) led the formation of 2a in 61% yield (entry 19). Control experiment confirmed that
without the Cuꢀsource, no reaction was observed and starting material 1a was recovered intact
(
entry 20). In addition, the use of stoichiometric amount of Cu(NO ) ∙3H O without
3 2 2
Fe(NO ) ∙9H O afforded 2a in 50% yield (entry 21).
3 3
2
Having the optimal conditions in hand, we explored the scope of this procedure for the
substrates having symmetrical substituents on the aryl rings (Scheme 1). The substrates 1b-h
having 3ꢀmethyl, 4ꢀchloro, 4ꢀfluoro, 4ꢀmethyl, 4ꢀmethoxy, 4ꢀisopropyl and 4ꢀethyl substituents
on the aryl rings readily proceeded reaction to provide the corresponding nitration products 2b-h
in 77ꢀ95% yields. Likewise, the substrates 1i-k containing 2,4ꢀ, 3,4ꢀ and 3,5ꢀdimethyl
substituents could be nitrated to give the target products 2i-k in 77ꢀ84% yields. Next, the
substrates having the unsymmetrical substituents in the aryl rings were subjected to the
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a
Table 1. Optimization of the Reaction Conditions (Reproduced from J. Org. Chem. 2014, 79,
8541. Copyright 2015 American Chemical Society)
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entry Cu source (20 mol %)
[NO ] source (35 mol %)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
yield (%)
52
2
1
2
3
4
5
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8
9
1
Cu(OAc) ·H O
Fe(NO ) ·9H O
2
2
3 3
2
Cu(OTf)2
CuSO ·5H O
Fe(NO ) ·9H O
48
3 3
2
Fe(NO ) ·9H O
trace
44
4
2
3 3
2
CuI
Fe(NO ) ·9H O
3 3 2
CuCl
Fe(NO ) ·9H O
84
3 3
2
CuBr2
Cu(NO ) ꢁ3H O
Fe(NO ) ·9H O
86
3 3
2
Fe(NO ) ·9H O
10
3
2
2
3 3
2
CuBr
CuCl ·2H O
Fe(NO ) ·9H O
74
3
3
2
Fe(NO ) ·9H O
95
2
2
3 3
2
b
0
CuCl ·2H O
Ca(NO ) ·4H O
trace
21
2
2
3 2
2
11
CuCl ·2H O
Bi(NO ) ·5H O
3 3 2
2
2
c
12
13
14
CuCl ·2H O
AgNO3
NaNO2
Fe(NO ) ·9H O
26
2
2
d
CuCl ·2H O
24
2
2
CuCl ·2H O
89
2
2
3 3
2
15
16
CuCl ·2H O
Fe(NO ) ·9H O
trace
74
2
2
3 3
2
CuCl ·2H O
Fe(NO ) ·9H O
toluene
DMF
2
2
3 3
2
17
18
19
20
21
CuCl ·2H O
Fe(NO ) ·9H O
n.d.
62
2
2
3 3
2
CuCl ·2H O
Fe(NO ) ·9H O
CH CN
2
2
3 3
2
3
e
f
CuCl ·2H O
Fe(NO ) ·9H O
DCE
DCE
DCE
61
2
2
3 3
2
ꢀ
Fe(NO ) ·9H O
trace
50
3
3
2
Cu(NO ) ꢁ3H O
ꢀ
3
2
2
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a
Reaction conditions: N,1ꢀdiphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1a (1 mmol), Cu source (20 mol %),
b
c
Fe(NO ) .9H O (35 mol %), solvent (3 mL), rt, 11 h. Ca(NO ) ꢁ4H O (50 mol %) was used.
3
3
2
3 3
2
d
e
AgNO (1.1 equiv) was used. NaNO (1.1 equiv) was used. CuCl ·2H O (10 mol %) was
3
2
2
2
f
used. Cu(NO ) ꢁ3H O (100 mol %) was used. n.d. = not detected.
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a
Scheme 1. Ortho-Nitration of Symmetrically Substituted N,1-Diaryl-5-aminotetrazoles
(Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical Society)
N
N
N
N
N
N
N
.
0 mol % CuCl 2H O
2 2
2
3
N
.
NO2
5 mol % Fe(NO ) 9H O
3
3
2
HN
1b-k
HN
2b-k
DCE, rt
R'
R'
R"
R"
i
R', R" = H, Me, Et, Pr, F, Cl
N
N
N
N
N
N
N
Me
N
N
N
N
N
HN
F
HN
HN
Cl
NO2
NO2
NO2
Me
F
Cl
2b, 12 h, 77%
2d, 8 h, 91%
2
c, 8 h, 91%
N
N
N
N
N
N
N
N
N
N
N
N
Me
NO2
HN
HN
HN
Me
O
NO2
NO2
Me
Me
Me
e, 8 h, 95%
O
Me
Me
Me
2
2f, 8 h, 79%
2g, 8 h, 88%
N
Me
N
N
N
N
N
N
Me
Me
N
N
N
N
N
HN
HN
HN
NO Me
NO2
2
NO2
Me
Me
Me
Me
2j, 8 h, 84%
Me
Me
2i, 12 h, 77%
2h, 8 h, 91%
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a
Reaction conditions: Nꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1b-k (1 mmol), CuCl ꢁ2H O (20 mol %),
2
2
Fe(NO ) ꢁ9H O (35 mol %), DCE (3 mL), rt.
3
3
2
a
Scheme 2. Ortho-Nitration of Unsymmetrically Substituted N,1-Diaryl-5-aminotetrazoles
Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical Society)
(
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a
Reaction conditions: Nꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1l-v (1 mmol), CuCl ꢁ2H O (20 mol %),
2
2
Fe(NO ) ꢁ9H O (35 mol %), DCE (3 mL), rt.
3
3
2
a
Scheme 3. Ortho-Nitration of N,4-Diaryl-3-amino-1,2,4-triazoles (Reproduced from J. Org.
Chem. 2014, 79, 8541. Copyright 2015 American Chemical Society)
N
N
N
.
2
3
0 mol % CuCl 2H O
2
2
N
N
N
.
NO2
5 mol % Fe(NO ) 9H O
3
3
2
NH
NH
DCE, rt
R'
3a-c
R'
4a-c
R"
R"
R', R" = H, F, Me
N
N
N
N
N
N
N
N
N
NH
Me
NH
NH
F
NO2
NO2
NO2
Me
4c, 6 h, 87%
F
4
b, 6 h, 82%
4a, 6 h, 84%
a
Reaction conditions: N,4ꢀdiphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ3ꢀamine 3a-c (1 mmol), CuCl ꢁ2H O (20
2
2
mol %), Fe(NO ) ꢁ9H O (35 mol %), DCE (3 mL), rt.
3
3
2
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optimized reaction conditions (Scheme 2). As above, the reaction readily occurred to give the
target products in high yields. For examples, the substrates 1l-p with 2ꢀchloro, 4ꢀfluoro, 4ꢀ
isopropyl, naphthyl and 4ꢀnitro substituents proceeded reaction to produce the corresponding
nitration products 2l-p in 75ꢀ94% yields. Similarly, the substrates 1q having 2ꢀfluoro and 4ꢀethyl
substituents underwent reaction to furnish 2q in 86% yield. Furthermore, the substrates 1r-v
containing 2,6ꢀdimethyl, 4ꢀmethyl, 4ꢀnitro, 4ꢀacetanilide and 4ꢀcyano substituents were
proceeded reaction to give the respective nitration products 2r-v in 77ꢀ93% yields.
0
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The reaction conditions were also effective for the nitration of N,4ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀ
triazoles (Scheme 3). For examples, the unsubstituted substrate 3a proceeded reaction with
greater reactivity compared to the corresponding 5ꢀaminoꢀtetrazole derivative to yield the
nitration product 4a in 6 h with 84% yield. Similarly, the substrates having symmetrical
substituents such as 4ꢀfluoro and 4ꢀmethyl 3b and 3c groups readily underwent reaction to
furnish 4b and 4c in 6 h with 82% and 87% yields, respectively.
Furthermore, the protocol can be utilized for gram scale synthesis (Scheme 4). For example,
the reaction of 1a was carried out in gram scale, and the reaction occurred to afford the target
molecule 2a in 89% yield. In addition, we attempted a removal of the tetrazole directing group
using the products 2a, 2g and 2l as representative examples (Table 2). The reaction readily
o
occurred with NaOH in 1,4ꢀdioxane at 110 C to give the corresponding 2ꢀnitroaniline
1
6
derivatives in good yields.
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a
Table 2. Removal of Directing Group (Reproduced from J. Org. Chem. 2014, 79, 8541.
Copyright 2015 American Chemical Society)
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entry
substrate
product
time (h) yield (%)
N
N
N
N
R'
HN
NO2
R"
1
2
3
R’, R” = H (2a)
R” = H (5a)
22
12
22
78
87
84
i
i
R’, R” = Pr (2g)
R” = Pr (5b)
R’ = 2ꢀCl, R” = H (2l)
R” = H (5a)
a
Reaction conditions: 2a, 2g and 2l (1 mmol), NaOH (7.0 equiv), 1,4ꢀdioxane (3 mL), 110 °C.
The proposed catalytic cycle is shown in Scheme 7. The intermolecular kinetic isotope
experiments of the substrates 1r and 1rꢀD3 gave P /P = 1.2 (21% conversion), while the
H
D
intramolecular kinetic isotope experiments of the substrate 1s-D afforded P /P = 3.5 (Scheme
H
D
17
18
5
). These results suggest that the substrate binding step is the product determining step. In
addition, TEMPO does not inhibit the rate of the reaction, which suggests that the reaction may
1
9
not involve a radical intermediate (Scheme 6). In addition, the ESIꢀMS studies of the crude
+
reaction mixture of 1a before work up revealed the presence of four major species: [2a + H] and
+
+
+
three copper complexes {[2aꢁCu] , [(2a) ꢁCu] and [(2a) ꢁCuCl] } (see supporting information)
2
2
6
f,20
(
Figure 1).
However, attempts to isolate the species as single crystals remained unsuccessful.
Furthermore, CuCl ꢁ2H O and Fe(NO ) ꢁ9H O are insoluble in 1,2ꢀdichloroethane, however,
2
2
3 3
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with substrate 1a they readily dissolve to give a yellow solution, which suggest that the substrate
1a may first bind with the hydrated CuCl to give a soluble intermediate a that may undergo
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reaction with Fe(NO ) ꢁ9H O to afford the intermediate b (Scheme 7). The subsequent
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intramolecular orthoꢀnitration via an aromatic electrophilic substitution can give the intermediate
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c, which can afford the target product 2, and the hydrated CuX to complete the catalytic cycle.
2
Scheme 4. Gram Scale Synthesis (Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright
2015 American Chemical Society)
Scheme 5. Kinetic Isotope Experiments (Reproduced from J. Org. Chem. 2014, 79, 8541.
Copyright 2015 American Chemical Society)
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Scheme 6. Radical Scavenger Experiment (Reproduced from J. Org. Chem. 2014, 79, 8541.
Copyright 2015 American Chemical Society)
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Figure 1. Major species identified using ESIꢀMS analysis of the reaction mixture of 1a.
(Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical Society)
Scheme 7. Proposed Catalytic Cycle (Reproduced from J. Org. Chem. 2014, 79, 8541.
Copyright 2015 American Chemical Society)
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CONCLUSION
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In summary, we have developed an efficient copper catalyzed orthoꢀselective nitration of
arenes using iron(III) nitrate as nitration source under mild reaction conditions. The use of
inexpensive Cu catalyst and the greener nitration source provides an attractive way for the
preparation of nitro arenes. The reaction demonstrates good functional group tolerance in
attaining the product with excellent selectivity. Further, the reaction protocol is successfully
extended to 3ꢀaminoꢀ1,2,4ꢀtriazoles. Due to the versatility of nitro group in organic synthesis
these studies can open new avenue for further development of 5ꢀaminotetrazole and 3ꢀaminoꢀ
1,2,4ꢀtriazole derivatives in the area of pharmaceutical and biological sciences.
EXPERIMENTAL SECTION
General Information: Cu(OTf) (98%), CuI (98%) and CuCl (90%) were purchased from
2
Aldrich. Cu(OAc) ꢁH O (98%), CuBr (98%), Cu(NO ) ꢁ3H O (99%), CuCl ꢁ2H O (99%) and
2
2
2
3 2
2
2
2
Fe(NO ) ꢁ9H O (98%) were purchased from Merck. CuSO ꢁ5H O (99%) was obtained from
3 3
2
4
2
Rankem. These chemicals were used as received without further purification. The solvents were
22a
purchased from commercial source and dried according to standard procedure prior to use. 3ꢀ
2
2c
22b,dꢀe
5ꢀAminotetrazoles
and aminoꢀ1,2,4ꢀtriazoles
were prepared according to reported
procedure. Purification of the reaction products was carried out by column chromatography
using silica gel (60ꢀ120 mesh). Analytical TLC was performed on silica gel G/GF 254 plate.
NMR spectra were recorded on 600, 400 and 300 MHz instruments using CDCl , CD OD and
3
3
DMSOꢀd as solvent and Me Si as internal standard. Chemical shifts (δ) were reported in ppm
6
4
and spinꢀspin coupling constants (J) were given in Hz. Melting points were determined using
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melting point apparatus and are uncorrected. FTꢀIR spectra were recorded using IR spectrometer.
High resolution mass spectra were recorded on a QꢀTof ESIꢀMS Instrument and mass spectra
were obtained from a ESIꢀMS instrument.
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General Procedure for the Cu(II)-Catalyzed C-H Ortho-Nitration of Arenes. To a stirred
solution of 1,Nꢀdiarylꢀ5ꢀaminotetrazole 1a-v or N,1,ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀtriazoles 3a-c (1
mmol) in DCE (3 mL), CuCl2
∙
2H O (20 mol %, 0.2 mmol, 34.6 mg) and Fe(NO ) 9H O (35 mol
∙
2
3 3 2
%, 0.35 mmol, 141 mg) were added at room temperature under air. The progress of the reaction
was monitored by TLC using ethyl acetate and hexane as eluent. After completion, saturated
NaHCO solution (5 mL) was added to the reaction mixture, and the resultant solution was
3
extracted with ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL). Drying (Na SO ) and
2
4
evaporation of the solvent gave a residue that was purified on silica gel column chromatography
using nꢀhexane and ethyl acetate as eluent to afford analytically pure products.
N-(2-Nitrophenyl)-1-phenyl-1H-tetrazol-5-amine 2a. Analytical TLC on silica gel, 1:4 ethyl
1
acetate/hexane R = 0.61; yellow solid; 268 mg, yield 95%; mp 186ꢀ187 °C; H NMR (400 MHz,
f
CDCl ) δ 10.79 (br s, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 8.4, 1.2 Hz, 1H), 7.77ꢀ7.59 (m,
3
1
3
6
1
1
H), 7.16ꢀ7.12 (m, 1H); C{H} NMR (100 MHz, CDCl + DMSOꢀd ) δ 150.8, 137.1, 135.9,
3 6
35.0, 132.4, 131.2, 130.9, 126.4, 124.8, 122.4, 120.2; FTꢀIR (KBr) 3228, 2854, 1598, 1564,
ꢀ1
+
538, 1525, 1381, 1336, 1280, 1121, 1092, 1019 cm . HRMS (ESI) m/z: [M+H] calcd for
C H N O 283.0938, found 283.0948.
13
10
6
2
N-(5-Methyl-2-nitrophenyl)-1-(m-tolyl)-1H-tetrazol-5-amine 2b. Analytical TLC on silica
1
gel, 1:4 ethyl acetate/hexane R = 0.66; yellow solid; 239 mg, yield 77%; mp 188ꢀ189 °C; H
f
NMR (400 MHz, CDCl ) δ 10.84 (br s, 1H), 8.72 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.54 (t, J =
3
1
3
7.6 Hz, 1H), 7.43ꢀ7.37 (m, 3H), 6.93 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H), 2.48 (s, 3H); C{H}
NMR (150 MHz, CDCl ) δ 150.8, 149.4, 141.4, 135.9, 133.0, 132.3, 131.9, 130.6, 126.4, 125.2,
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23.5, 121.7, 120.0, 22.5, 21.6; FTꢀIR (KBr) 3095, 2923, 1592, 1534, 1489, 1324, 1281, 1161,
ꢀ1
+
1091, 870, 846 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 311.1251, found
15
14
6
2
3
11.1251.
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N-(4-Chloro-2-nitrophenyl)-1-(4-chlorophenyl)-1H-tetrazol-5-amine 2c. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane R = 0.69; yellow solid; 318 mg, yield 91%; mp 187ꢀ188 °C;
f
1
H NMR ( 600 MHz, CDCl ) δ 10.72 (br s, 1H), 8.96 (d, J = 9.6 Hz, 1H), 8.27 (d, J = 1.8 Hz,
3
13
1
H), 7.73 (dd, J = 9.0, 1.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H) ; C{H}
NMR (150 MHz, CDCl ) δ 150.5, 137.6, 137.2, 135.1, 134.4, 131.3, 130.7, 127.8, 126.0, 125.9,
3
ꢀ
121.7; FTꢀIR (KBr) 3259, 2921, 1639, 1538, 1499, 1341, 1275, 1245, 1154, 1091, 903, 838 cm
1
+
.
HRMS (ESI) m/z: [M+H] calcd for C H Cl N O 351.0167, found 351.0163.
1
3
8
2
6
2
N-(4-Fluoro-2-nitrophenyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine 2d. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane R = 0.62; yellow solid; 289 mg, yield 91%; mp 170ꢀ171 °C;
f
1
H NMR (600 MHz, CDCl ) δ 10.59 (br s, 1H), 9.00ꢀ8.98 (m, 1H), 7.99 (dd, J = 8.4, 3.0 Hz,1H),
3
1
3
7.62ꢀ7.59 (m, 2H), 7.55ꢀ7.52 (m, 1H), 7.41ꢀ7.38 (m, 2H); C{H} NMR (150 MHz, CDCl ) δ
3
1
64.7 (d, J = 252.0 Hz), 157.4 (d, J = 244.5 Hz), 150.8, 134.8 , 132.4 , 128.2 , 127.2 (d, J = 9.0
Hz), 125.0 (d, J = 22.5 Hz), 122.0 (d, J = 7.5 Hz), 118.3 (d, J = 22.5 Hz), 112.8 (d, J = 27.0 Hz);
FTꢀIR (KBr) 3260, 3091, 2923, 1598, 1576, 1537, 1513, 1468, 1384, 1336, 1284, 1161, 1137,
ꢀ1
+
1090, 949, 843 cm . HRMS (ESI) m/z: [M+H] calcd for C H F N O 319.0750, found
13 8 2 6 2
3
19.0748.
N-(4-Methyl-2-nitrophenyl)-1-(p-tolyl)-1H-tetrazol-5-amine 2e. Analytical TLC on silica gel,
1
1:4 ethyl acetate/hexane R = 0.73; yellow solid; 295 mg, yield 95%; mp 192ꢀ193 °C; H NMR
f
(400 MHz, CDCl ) δ 10.63 (br s, 1H), 8.83 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.56 (dd, J = 8.4,
3
1
3
1
.6 Hz, 1H), 7.45 (s, 4H), 2.48 (s, 3H), 2.38 (s, 3H); C{H} NMR (100 MHz, CDCl ) δ 150.9,
3
1
41.6, 138.1, 134.7, 133.7, 132.5, 131.4, 129.8, 126.0, 124.6, 120.1, 21.6, 20.6; FTꢀIR (KBr)
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ꢀ
1
3
083, 2922, 2852, 1594, 1524, 1463, 1333, 1303, 1247, 1116, 927, 811 cm . HRMS (ESI) m/z:
+
[M+H] calcd for C H N O 311.1251, found 311.1251.
1
5
14
6
2
N-(4-Methoxy-2-nitrophenyl)-1-(4-methoxyphenyl)-1H-tetrazol-5-amine 2f. Analytical TLC
10
11
12
13
14
15
16
17
18
19
20
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22
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on silica gel, 1:4 ethyl acetate/hexane R = 0.36; brown solid; 270 mg, yield 79%; mp 166ꢀ167
f
1
°
C; H NMR (400 MHz, CDCl ) δ 10.45 (br s, 1H), 8.87 (d, J = 9.6 Hz, 1H), 7.69 (d, J = 2.8 Hz,
3
1H), 7.48ꢀ7.45 (m, 2H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.15ꢀ7.11 (m, 2H), 3.90 (s, 3H), 3.85 (s,
13
3
H); C{H} NMR (100 MHz, CDCl ) δ 161.6, 154.3, 151.2, 135.2, 130.1, 126.5, 125.3, 124.8,
3
121.6, 115.9, 108.6, 56.2, 55.9; FTꢀIR (KBr) 3259, 2924, 2852, 1599, 1562, 1534, 1384, 1348,
ꢀ1
+
1
268, 1245, 1024, 998, 830 cm HRMS (ESI) m/z: [M+H] calcd for C H N O 343.1149,
15 14 6 4
found 343.1153.
N-(4-Isopropyl-2-nitrophenyl)-1-(4-isopropylphenyl)-1H-tetrazol-5-amine 2g. Analytical
TLC on silica gel, 1:5 ethyl acetate/hexane R = 0.57; yellow solid; 322 mg, yield 88%; mp 116ꢀ
f
1
1
7
6
1
17 °C; H NMR (400 MHz, CDCl ) δ 10.63 (br s, 1H), 8.83 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H),
3
.62 (d, J = 8.4 Hz, 1H), 7.51 (s, 4H), 3.06ꢀ2.99 (m, 1H), 2.97ꢀ2.92 (m, 1H), 1.32 (d, J = 7.2 Hz,
1
3
H), 1.27 (d, J = 6.8 Hz, 6H); C{H} NMR (100 MHz, CDCl ) δ 152.3, 150.9, 143.4, 135.7,
3
34.8, 133.9, 130.0, 128.8, 124.5, 123.5, 120.2, 34.2, 33.4, 23.9, 23.8; FTꢀIR (KBr) 2963, 1627,
ꢀ1
+
1596, 1535, 1518, 1425, 1338, 1283, 1252, 1087, 1013, 841 cm . HRMS (ESI) m/z: [M+H]
calcd for C H N O 367.1877, found 367.1884.
1
9
22
6
2
N-(4-Ethyl-2-nitrophenyl)-1-(4-ethylphenyl)-1H-tetrazol-5-amine 2h. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane R = 0.69; yellow solid; 308 mg, yield 91%; mp 114ꢀ115 °C;
f
1
H NMR (400 MHz, CDCl ) δ 10.61 (br s, 1H), 8.80 (dd, J = 8.8, 0.8 Hz, 1H), 8.03 (s, 1H), 7.56
3
(d, J = 8.4 Hz, 1H), 7.47 (s, 4H), 2.77 (q, J = 8.0 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.29 (t, J =
1
3
7
.6 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); C{H} NMR (100 MHz, CDCl ) δ 150.8, 147.6, 138.7,
3
136.9, 134.7, 133.8, 130.1, 129.9, 124.8, 124.6, 120.1, 28.8, 27.9, 15.4, 15.2; FTꢀIR (KBr) 3245,
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ꢀ
1
2
960, 2926, 1596, 1559, 1531, 1516, 1384, 1335, 1251, 1183, 1086, 915, 843 cm . HRMS (ESI)
+
m/z: [M+H] calcd for C H N O 339.1564, found 339.1564.
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N-(2,4-Dimethyl-6-nitrophenyl)-1-(2,4-dimethylphenyl)-1H-tetrazol-5-amine 2i. Analytical
0
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9
0
TLC on silica gel, 1:4 ethyl acetate/hexane R = 0.51; yellow solid; 260 mg, yield 77%; mp 188ꢀ
f
1
1
6
1
89 °C; H NMR (400 MHz, CDCl ) δ 9.33 (br s, 1H), 8.34 (s, 1H), 7.20 (s, 1H), 7.14 (s, 2H),
3
1
3
.79 (s, 1H), 2.45 (s, 3H), 2.42 (s, 6H), 2.40 (s, 3H); C{H} NMR (100 MHz, CDCl ) δ 150.9,
3
45.3, 141.1, 136.7, 135.3, 133.9, 132.5, 132.3, 127.4, 121.9, 118.4, 22.1, 21.4, 21.2; FTꢀIR
ꢀ1
(KBr) 2922, 1615, 1544, 1493, 1377, 1344, 1294, 1249, 1091, 851 cm . HRMS (ESI) m/z:
+
[
M+H] calcd for C H N O 339.1564, found 339.1565.
1
7
18
6
2
N-(4,5-Dimethyl-2-nitrophenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine 2j. Analytical
TLC on silica gel, 1:5 ethyl acetate/ hexane R = 0.52; yellow solid; 284 mg, yield 84%; mp 158ꢀ
f
1
159 °C; H NMR (400 MHz, CDCl ) δ 10.66 (br s, 1H), 8.63 (s, 1H), 7.93 (s, 1H), 7.38ꢀ7.26 (m,
3
13
3
H), 2.36 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H); C{H} NMR (100 MHz, CDCl ) δ
3
1
50.7, 148.3, 140.0, 139.7, 133.8, 132.6, 131.6, 131.3, 129.9, 126.3, 125.5, 121.7, 120.3, 20.8,
1
9.9, 19.8, 19.1; FTꢀIR (KBr) 3266, 2921, 2852, 1593, 1529, 1504, 1406, 1323, 1298, 1259,
ꢀ1
+
1
135, 1092, 905, 892 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 339.1564, found
17 18 6 2
339.1563.
N-(3,5-Dimethyl-2-nitrophenyl)-1-(3,5-dimethylphenyl)-1H-tetrazol-5-amine 2k. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane R = 0.60; yellow solid; 267 mg, yield 79%; mp 180ꢀ
f
1
1
81 °C; H NMR (400 MHz, CDCl ) δ 9.32 (br s, 1H), 8.30 (s, 1H), 7.18 (s, 1H), 7.12 (s, 2H),
3
1
3
6.76 (s, 1H), 2.40 (s, 9H), 2.37 (s, 3H); C{H} NMR (100 MHz, CDCl ) δ 150.8, 145.2, 140.9,
3
1
36.5, 135.2, 133.8, 132.3, 132.2, 127.2, 121.7, 118.2, 22.0, 21.3, 21.1; FTꢀIR (KBr) 3094, 2922,
ꢀ1
2
844, 1606, 1539, 1491, 1339, 1293, 1249, 1093, 1033, 871, 850 cm . HRMS (ESI) m/z:
+
[
M+H] calcd for C H N O 339.1564, found 339.1566.
1
7
18
6
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-(2-Chlorophenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine 2l. Analytical TLC on silica gel,
1
1:4 ethyl acetate/ hexane R = 0.71; yellow solid; 256 mg, yield 81%; mp 135ꢀ136 °C; H NMR
f
(400 MHz, CDCl ) δ 10.38 (br s, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.72ꢀ
3
1
3
7
.67 (m, 2H), 7.65ꢀ7.58 (m, 1H), 7.56 (d, J = 3.6 Hz, 2H), 7.09 (t, J = 8.8 Hz, 1H); C{H} NMR
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60
(
100 MHz, CDCl ) δ 151.4, 136.9, 135.6, 134.7, 133.3, 131.8, 131.5, 129.4, 129.3, 128.9, 126.2,
3
1
22.3, 119.8; FTꢀIR (KBr) 3290, 3090, 2923, 1600, 1570, 1537, 1503, 1394, 1342, 1321, 1265,
ꢀ
1
+
1087, 887, 767, 739 cm . HRMS (ESI) m/z: [M+H] calcd for C H ClN O 317.0548, found
1
3
9
6
2
3
17.0547.
-(2-Chlorophenyl)-N-(4-fluoro-2-nitrophenyl)-1H-tetrazol-5-amine 2m. Analytical TLC on
1
silica gel, 1:4 ethyl acetate/hexane R = 0.70; yellow solid; 281 mg, yield 84%; mp 142ꢀ143 °C;
f
1
H NMR (400 MHz, CDCl ) δ 10.27 (br s, 1H), 8.96ꢀ8.92 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.73
3
13
(d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.59ꢀ7.49 (m, 3H); C{H} NMR (100 MHz,
CDCl ) δ 157.7 (d, J = 245.5 Hz), 151.5, 133.5, 132.4, 131.9, 131.7, 129.5, 129.4, 129.0, 124.9
3
(d, J = 22.1 Hz), 121.9 (d, J = 7.6 Hz), 112.8 (d, J = 27.5 Hz); FTꢀIR (KBr) 2923, 2857, 1631,
ꢀ1
+
1
541, 1521, 1338, 1247, 1067, 947, 759 cm . HRMS (ESI) m/z: [M+H] calcd for
C H ClFN O 335.0454, found 335.0462.
13
8
6
2
1-(2-Chlorophenyl)-N-(4-isopropyl-2-nitrophenyl)-1H-tetrazol-5-amine 2n. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane R = 0.69; yellow solid; 337 mg, yield 94%; mp 156ꢀ157
f
1
°
C; H NMR (600 MHz, CDCl ) δ 10.33 (br s, 1H), 8.81 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 2.4 Hz,
3
1H), 7.74 (dd, J = 7.8, 1.2 Hz, 1H), 7.67ꢀ7.63 (m, 2H), 7.60ꢀ7.55 (m, 2H), 2.99ꢀ2.94 (m, 1H),
13
1
.28 (d, J = 7.2 Hz, 6H); C{H} NMR (150 MHz, CDCl ) δ 151.8, 143.7, 135.8, 134.9, 133.7,
3
1
33.4, 132.1, 131.7, 129.64, 129.60, 129.0, 123.6, 120.2, 33.5, 23.8; FTꢀIR (KBr) 2963, 2926,
ꢀ1
1627, 1601, 1562, 1536, 1519, 1461, 1336, 1265, 1208, 1160, 1037, 928, 839 cm . HRMS (ESI)
+
m/z: [M+H] calcd for C H ClN O 359.1018, found 359.1021.
1
6
15
6
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-(2-Chlorophenyl)-N-(2-nitronaphthalen-1-yl)-1H-tetrazol-5-amine 2o. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane R = 0.52; reddish yellow gummy liquid; 275 mg, yield 75%;
f
1
H NMR (400 MHz, CDCl ) δ 8.56 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6
3
Hz, 1H), 7.72ꢀ7.59 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 7.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.84 (br s, 1H); C{H} NMR (100 MHz, CDCl ) δ 152.4,
3
134.8, 134.7, 132.2, 129.2, 128.94, 128.90, 128.8, 128.4, 128.1, 127.9, 125.6, 125.3, 123.8,
121.9, 121.5, 119.1; FTꢀIR (neat) 3113, 2925, 1603, 1567, 1520, 1452, 1312, 1232, 1087, 1053,
ꢀ1
+
1034, 802, 772, 750 cm . HRMS (ESI) m/z: [M+H] calcd for C H ClN O 367.0710, found
17 11 6 2
367.0710.
1-(2-Chlorophenyl)-N-(2,4-dinitrophenyl)-1H-tetrazol-5-amine 2p. Analytical TLC on silica
1
gel, 1:4 ethyl acetate/hexane R = 0.42; orange solid; 311 mg, yield 86%; mp 189ꢀ190 °C; H
f
NMR (400 MHz, CDCl +DMSOꢀd ) δ 10.37 (br s, 1H), 8.86ꢀ8.85 (m, 1H), 8.81ꢀ8.78 (m, 1H),
3
6
1
3
8.34ꢀ8.31 (m, 1H), 7.54ꢀ7.46 (m, 2H), 7.43ꢀ7.38 (m, 2H); C{H} NMR (100 MHz, CDCl +
3
DMSOꢀd ) δ 150.4, 140.6, 139.7, 133.4, 133.2, 131.1, 130.9, 130.4, 129.1, 128.7, 128.5, 122.1,
6
1
1
3
20.1; FTꢀIR (KBr) 3260, 3105, 2855, 1604, 1588, 1543, 1510, 1424, 1342, 1312, 1251, 1142,
ꢀ1
+
039, 912, 846, 772 cm . HRMS (ESI) m/z: [M+H] calcd for C H ClN O 362.0399, found
13
8
7
4
62.0398.
N-(4-Ethyl-2-nitrophenyl)-1-(2-fluorophenyl)-1H-tetrazol-5-amine 2q. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane R = 0.72; yellow solid; 282 mg, yield 86%; mp 139ꢀ140 °C;
f
1
H NMR (400 MHz, CDCl ) δ 10.43 (br s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.67ꢀ7.51
3
13
(m, 3H), 7.44ꢀ7.39 (m, 2H), 2.64 (q, J = 8.0 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); C{H} NMR (100
MHz, CDCl ) δ 157.5 (d, J = 253.2 Hz), 151.4, 138.8, 136.9, 134.7, 133.63, 133.60, 133.5,
3
128.4, 126.1 (d, J = 3.8 Hz), 124.7, 119.9 (d, J = 11.4 Hz), 117.9 (d, J = 19.0 Hz), 27.8, 15.1;
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ꢀ
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FTꢀIR (KBr) 3276, 2964, 2926, 1597, 1536, 1505, 1416, 1343, 1300, 1110, 1088, 889, 760 cm .
+
HRMS (ESI) m/z: [M+H] calcd for C H FN O 329.1157, found 329.1155.
1
5
13
6
2
1-(2,6-Dimethylphenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine 2r. Analytical TLC on silica
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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49
50
51
52
53
54
55
56
57
58
59
60
1
gel, 1:4 ethyl acetate/hexane R = 0.70; yellow solid; 288 mg, yield 93%; mp 196ꢀ197 °C; H
f
NMR (400 MHz, CDCl ) δ 10.21 (br s, 1H), 8.94 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H),
3
7
.75 (t, J = 8.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 7.2 Hz,
13
1
H), 2.03 (s, 6H); C{H} NMR (100 MHz, CDCl ) δ 151.5, 137.1, 136.7, 135.8, 134.7, 132.0,
3
129.7, 129.4, 126.3, 122.2, 120.0, 17.60, 17.56; FTꢀIR (KBr) 3089, 2928, 2855, 1598, 1568,
ꢀ1
1
538, 1503, 1380, 1340, 1321, 1282, 1240, 1146, 1034, 910, 842, 740 cm . HRMS (ESI) m/z:
+
[
M+H] calcd for C H N O 311.1256, found 311.1264.
1
5
14
6
2
1
-(2,6-Dimethylphenyl)-N-(4-methyl-2-nitrophenyl)-1H-tetrazol-5-amine 2s. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane R = 0.72; yellow solid; 295 mg, yield 91%; mp 192ꢀ193
f
1
°
C; H NMR (400 MHz, CDCl ) δ 10.06 (br s, 1H), 8.78 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.54
3
(
d, J = 8.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H), 2.00 (s, 6H);
1
3
C{H} NMR (100 MHz, CDCl ) δ 151.5, 138.0, 136.6, 134.4, 133.4, 132.3, 131.8, 129.5, 129.3,
3
1
25.8, 119.7, 20.4. 17.5; FTꢀIR (KBr) 3230, 3062, 2960, 2923, 1600, 1563, 1522, 1408, 1375,
ꢀ1
+
1334, 1264, 1113, 1092, 1027, 924, 830 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O
2
1
6
16
6
3
25.1408, found 325.1416.
-(2,6-Dimethylphenyl)-N-(2,4-dinitrophenyl)-1H-tetrazol-5-amine 2t. Analytical TLC on
1
silica gel, 1:4 ethyl acetate/hexane R = 0.45; yellow solid; 298 mg, yield 84%; mp 188ꢀ189 °C;
f
1
H NMR (400 MHz, CDCl ) δ 10.54 (br s, 1H), 9.21 (d, J = 9.6 Hz, 1H), 9.11 (s, 1H), 8.56 (d, J
3
13
=
9.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.03 (s, 6H); C{H} NMR (150
MHz, CDCl ) δ 150.7, 141.1, 140.0, 136.5, 133.5, 132.4, 131.1, 129.9, 128.9, 122.7, 120.7, 17.6;
3
FTꢀIR (KBr) 3251, 3113, 2924, 2854, 1606, 1586, 1548, 1511, 1424, 1345, 1310, 1264, 1144,
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+
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116, 1019, 909, 842 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 356.1107, found
1
5
13
7
4
356.1097.
N-(4-((1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)amino)-3-nitrophenyl)acetamide
2u.
0
1
2
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9
0
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane R = 0.48; yellow solid; 283 mg, yield
f
1
7
8
7
7%; mp 262ꢀ263 °C; H NMR (400 MHz, CDCl ) δ 10.05 (br s, 1H), 8.90 (d, J = 9.2 Hz, 1H),
3
.68 (d, J = 2.4 Hz, 1H), 7.98 (br s, 1H), 7.93 (dd, J = 9.2, 2.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H),
13
.34 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H), 2.06 (s, 6H); C{H} NMR (150 MHz, CDCl + DMSOꢀd
3
6
+ CD OD) δ 168.3, 150.6, 135.4, 134.4, 133.3, 130.8, 129.4, 128.45, 128.4, 126.7, 119.6, 114.7,
3
2
2.8, 16.2; FTꢀIR (KBr) 3334, 3238, 1674, 1611, 1546, 1360, 1296, 1273, 1260, 1091, 1016,
ꢀ1
+
8
86, 773 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 368.1471, found 368.1480.
1
7
18
7
3
4
-((1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)amino)-3-nitrobenzonitrile 2v. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane R = 0.30; yellow solid; 275 mg, yield 82%; mp 205ꢀ206
f
1
°
C; H NMR (400 MHz, CDCl ) δ 10.42 (br s, 1H), 9.15 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 2.0 Hz,
3
1
6
1
H), 7.97 (dd, J = 9.2, 2.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 2.01 (s,
1
3
H); C{H} NMR (100 MHz, CDCl ) δ 150.8, 139.2, 138.8, 136.5, 134.1, 132.3, 130.8, 129.8,
3
29.0, 121.1, 116.7, 105.8, 17.5; FTꢀIR (KBr) 3504, 2922, 2852, 2237, 1629, 1557, 1519, 1383,
ꢀ1
+
1283, 1194, 1092, 852, 775, 674 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O
2
1
6
13
7
3
36.1209, found 336.1206.
N-(2-Nitrophenyl)-4-phenyl-4H-1,2,4-triazol-3-amine 4a. Analytical TLC on silica gel, 1:1
1
ethyl acetate/hexane R = 0.40; yellow solid; 236 mg, yield 84%; mp 176ꢀ177 °C; H NMR (400
f
MHz, CDCl ) δ 10.39 (br s, 1H), 8.97 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H),
3
13
7
.67ꢀ7.58 (m, 4H), 7.43 (d, J = 7.6 Hz, 2H), 7.02 (t, J = 8.0 Hz, 1H); C{H} NMR (100 MHz,
CDCl ) δ 149.2, 140.6, 137.2, 136.9, 134.1, 132.1, 131.0, 130.6, 126.2, 125.8, 121.0, 119.9; FTꢀ
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IR (KBr) 3451, 3053, 2923, 2852, 1617, 1564, 1553, 1507, 1444, 1384, 1272, 1193, 1145, 1023,
ꢀ1
+
841, 736, 609 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 282.0991, found 282.0991.
1
4
11
5
2
N-(4-Fluoro-2-nitrophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-amine 4b. Analytical TLC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
on silica gel, 1:1 ethyl acetate/hexane R = 0.42; reddish yellow solid; 260 mg, yield 82%; mp
f
1
1
89ꢀ190 °C; H NMR (400 MHz, CDCl ) δ 10.25 (br s, 1H), 9.08ꢀ9.04 (m, 1H), 8.12 (s, 1H),
3
1
3
7
.93 (dd, J = 8.4, 2.8 Hz, 1H), 7.50ꢀ7.43 (m, 3H), 7.39 (t, J = 8.0 Hz, 2H); C{H} NMR (100
MHz, CDCl ) δ 164.8 (d, J = 251.7 Hz), 156.9 (d, J = 244.0 Hz), 149.3, 140.7, 133.84 (d, J = 4.6
3
Hz), 133.8, 128.2 (d, J = 8.4 Hz), 127.9 (d, J = 3.0 Hz), 125.0 (d, J = 22.9 Hz), 121.7 (d, J = 7.6
Hz), 118.3 (d, J = 22.9 Hz), 112.3 (d, J = 26.7 Hz); FTꢀIR (KBr) 1629, 1599, 1557, 1514, 1384,
ꢀ1
+
1
337, 1236, 1162, 1131, 1001, 944, 878, 837, 760, 704 cm . HRMS (ESI) m/z: [M+H] calcd
for C H F N O 318.0803, found 318.0802.
1
4
9
2
5
2
N-(4-Methyl-2-nitrophenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-amine 4c. Analytical TLC on silica
gel, 1:1 ethyl acetate/hexane R = 0.45; reddish yellow solid; 269 mg, yield 87%; mp 176ꢀ177
f
1
°
C; H NMR (400 MHz, CDCl ) δ 10.31 (br s, 1H), 8.90 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 8.0 (s,
3
1
3
1
H), 7.50 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H); C{H} NMR
(
100 MHz, CDCl ) δ 149.5, 141.0, 140.7, 138.1, 135.1, 133.9, 131.5, 131.0, 129.5, 125.8, 125.6,
3
120.0, 21.5, 20.5; FTꢀIR (KBr) 3471, 1731, 1632, 1598, 1514, 1449, 1386, 1238, 1163, 946, 837,
ꢀ1
+
7
82 cm . HRMS (ESI) m/z: [M+H] calcd for C H N O 310.1306, found 310.1306.
16 15 5 2
General Procedure for the Removal of Directing Group. To a stirred solution of 2a, 2g and 2l
1 mmol) in 1,4ꢀdioxane (3 mL), NaOH (7.0 mmol, 280 mg) was added at room temperature, and
(
the mixture was stirred at 110 °C for 12ꢀ22 h. The progress of the reaction was monitored by
TLC using ethyl acetate and hexane as eluent. After completion, the resultant mixture was
extracted with ethyl acetate (3 x 10 mL) and washed with brine (3 x 5 mL). Drying (Na SO ) and
2
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evaporation of the solvent gave a residue that was purified on silica gel column chromatography
using nꢀhexane and ethyl acetate as eluent.
23
2
-Nitroaniline 5a. Analytical TLC on silica gel, 1:10 ethyl acetate/hexane R = 0.40; yellow
f
1
solid; mp 71ꢀ72 °C; H NMR (600 MHz, CDCl ) δ 8.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.36 (td, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
6.6, 1.2 Hz, 1H), 6.81 (dd, J = 9.0, 1.2 Hz, 1H), 6.71 (td, J = 7.8, 1.2 Hz, 1H), 6.07 (br s, 2H);
13
C{H} NMR (150 MHz, CDCl ) δ 144.9, 135.8, 132.5, 126.4, 118.9, 117.1; FTꢀIR (KBr) 3479,
3
ꢀ1
3352, 1630, 1593, 1507, 1433, 1347, 1253, 1093, 995, 745 cm .
4-Isopropyl-2-nitroaniline 5b. Analytical TLC on silica gel, 1:10 ethyl acetate/hexane R =
f
1
0
.40; thick yellow liquid; 157 mg, yield 87%; H NMR (400 MHz, CDCl ) δ 7.95 (dd, J = 1.6
3
Hz, 1H), 7.28 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.96 (br s, 2H), 2.86ꢀ2.83 (m, 1H), 1.23 (d, J =
1
3
6.8 Hz, 6H); C{H} NMR (100 MHz, CDCl ) δ 143.1, 138.1, 135.0, 127.3, 123.1, 119.0, 33.1,
3
23.9; FTꢀIR (neat) 3483, 3364, 2954, 2917, 1638, 1561, 1520, 1466, 1409, 1335, 1249, 1167,
ꢀ1
1
085, 952, 818 cm .
Preparation of Aniline-d (Scheme 8). The titled compound was prepared according to the
3
1
7a
1
reported procedure and the deuterium incorporation was determined by H NMR analysis of
the mixture. Characterization data for the deuterated product only. 1;4 ethyl acetate/ hexane, R =
f
1
0.32; pale brown solid; yield 85%; H NMR (400 MHz, CDCl ) δ 7.23 (s, 2H), 3.62 (bs, 2H).
3
Scheme 8 (Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical
Society)
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Preparation of 1-(2,6-dimethylphenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine-d3 1r-d3
2
2c
(Scheme 9). The titled compound was prepared according to the reported procedure. 3:7 ethyl
1
acetate/ hexane; R = 0.25; white solid; yield 74%; H NMR (400 MHz, CDCl ) δ 7.44 (t, J = 8.0
f
3
Hz, 1H), 7.35 (s, 2H), 7.29 (d, J = 7.6 Hz, 2H), 6.10 (bs, 1H), 2.06 (s, 6H).
10
11
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Scheme 9 (Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American Chemical
Society)
Intramolecular Kinetic Isotope Effect Study (Scheme 10). To a stirred solution of Nꢀ(2ꢀ
4c
deuterioꢀ4ꢀmethylphenyl)ꢀ1ꢀ(2,6ꢀdimethylphenyl)ꢀ1Hꢀtetrazolꢀ5ꢀamine 1s-d (0.5 mmol, 140
mg) in DCE (2 mL), CuCl2
∙
2H O (20 mol %, 0.1 mmol, 17 mg) and Fe(NO ) 9H O (35 mol %,
∙
2
3 3 2
0.175 mmol, 71 mg) were added at room temperature under air. The progress of the reaction was
monitored by TLC using ethyl acetate and hexane as eluent. After 8 h, saturated NaHCO3
solution (5 mL) was added to the reaction mixture and the resultant mixture was extracted with
ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL). Drying (Na SO ) and evaporation
2
4
of the solvent gave a residue that was purified on silica gel column chromatography using
hexane and ethyl acetate as eluent to afford a 22:78 mixture of 2s and 2s-d as a yellow solid in
1
8
3% (138 mg) yield. The ratio of deuterium to hydrogen was determined from the H NMR
relative integration values of H (8.84 ppm) based on H (7.58 ppm).
a
b
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Scheme 10 (Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American
Chemical Society)
Intermolecular Kinetic Isotope Effect Study (Scheme 11). To a stirred solution of 1ꢀ(2,6ꢀ
dimethylphenyl)ꢀNꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine (1r) (0.58 mmol, 156 mg) and 1ꢀ(2,6ꢀ
dimethylphenyl)ꢀNꢀ(2,4,6ꢀtrideuteriophenyl)ꢀ1Hꢀtetrazolꢀ5ꢀamine(1r-d ) (0.42 mmol, 111 mg) in
3
DCE (2 mL), CuCl2
∙
2H O (20 mol %, 0.2 mmol, 34 mg) and Fe(NO ) 9H O (35 mol %, 0.35
∙
2
3 3 2
mmol, 141 mg) were added at room temperature under air. The progress of the reaction was
monitored by TLC using ethyl acetate and hexane as eluent. After 1.5 h, saturated NaHCO3
solution (5 mL) was added to the reaction mixture and the resultant mixture was extracted with
ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL). Drying (Na SO ) and evaporation
2
4
of the solvent gave a residue that was purified on silica gel column chromatography using
hexane and ethyl acetate as eluent to afford a mixture of 2r-d and 2r as a yellow solid in 18%
2
1
(56 mg) yield. The ratio of deuterium to hydrogen was determined by the H NMR relative
integration values of H (8.96 ppm) based on H (8.24 ppm).
a
b
Scheme 11 (Reproduced from J. Org. Chem. 2014, 79, 8541. Copyright 2015 American
Chemical Society)
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ASSOCIATED CONTENT
ACKNOWLEDGMENTS
We gratefully acknowledge Department of Science and Technology, New Delhi, and Council of
Scientific and Industrial Research, New Delhi, for financial support. P. S. thanks UGC for SRF
Fellowship. We also thank Central Instrumental Facility, IIT Guwahati for NMR facilities. We
thank Prof. V Manivannan for discussion of the ESIꢀMS analysis for the reaction mixture.
Supporting Information
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Mass spectra of reaction of 1a and NMR ( H and C) spectra of 2a-v, 4a-c, anilineꢀd ,1r-d , 2s-
3
3
d, 2r-d , 5a and 5b. This material is available free of charge via the internet at
2
http://pubs.acs.org.
Notes
†
Revised manuscript of Sadhu, P.; Alla, S. K.; Punniyamurthy, T. J. Org. Chem. 2014, 79, 8541;
J. Org. Chem. 2015, 80, 3358
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