RETRACTED ARTICLE: Room-temperature Cu(II)-catalyzed chemo- and regioselective ortho-nitration of arenes via C-H functionalization

Article abstract of DOI:10.1021/jo501617g

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 has been described with good functional group compatibility. The procedure features the use of an 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/jo501617g

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Featured 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 • DOI: 10.1021/jo501617g • Publication Date (Web): 24 Aug 2014
Downloaded from http://pubs.acs.org on August 25, 2014
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Room Temperature Cu(II)-Catalyzed Chemo- and Regioselective
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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
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 CuCl2ꢁ2H2O as catalyst and Fe(NO3)3ꢁ9H2O as
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
carbonꢀheteroatom bonds.1 The second row transition metals, such as Ru,2 Rh,3 and Pd,4 have
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been considerably explored for this purpose. In contrast, the first row transition metals have
received less attention despite their high abundance in the earth crust.5 In particular, a few
studies are focused on the copper catalyzed aerobic CꢀH functionalization reactions.6 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(NO3)3ꢁ9H2O at room temperature. From an industrial point, this process would be useful due
to its mild conditions, good functional group compatibility and free from the use of nitric acid.
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Aromatic nitro compounds are versatile building blocks in organic, medicinal and
pharmaceutical sciences as well as in chemical industry.7 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
group tolerance under harsh conditions.8 To overcome these drawbacks, several approaches have
been explored including the ipsoꢀnitration by the nitrodemetalation of an aryl CꢀM bond (M=B,
Li),9 the ipsoꢀoxidation10 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
or Cu).11 Although these methods have led to overcome some of the above limitations, still they
suffer from the requirement of prefunctionalized substrate precursors.12 Attention has thus been
recently focused on the chelation assisted direct regioselective aromatic CꢀH nitrations using
Cu/AgNO2,13a,d Rh/NaNO213b and Pd/AgNO2/NO2.13c,e
RESULTS AND DISCUSSION
N,1ꢀDiarylꢀ5ꢀaminotetrazoles and N,4ꢀdiarylꢀ3ꢀaminoꢀ1,2,4ꢀtriazoles are structural motifs present
in many compounds that are important in biological and medicinal sciences.14,15 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 CuCl2∙2H2O (20 mol %)
and Fe(NO3)3∙9H2O (35 mol %) in 1,2ꢀdichloroethane (DCE) for 11 h at room temperature. In a
set of copper sources screened, CuCl2ꢁ2H2O exhibited superior results compared to
Cu(OAc)2ꢁH2O, Cu(OTf)2, CuSO4ꢁ5H2O, Cu(NO3)2ꢁ3H2O, CuI, CuBr2, CuBr and CuCl (entries
1ꢀ9). Among the nitro sources examined, Fe(NO3)3ꢁ9H2O gave the best results, whereas
Ca(NO3)2∙4H2O, AgNO3, Bi(NO3)3∙5H2O and NaNO2 afforded the target product in <26% yield
(entries 10ꢀ13). DCE was found to be the solvent of choice giving the highest yield, whereas
dichloromethane (DCM), toluene and CH3CN afforded 2a in 62ꢀ89% yields. In contrast, THF
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(NO3)2∙3H2O without
Fe(NO3)3∙9H2O afforded 2a in 50% yield (entry 21).
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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 72ꢀ94% 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 73ꢀ86% yields. Next, the
substrates having the unsymmetrical substituents in the aryl rings were subjected to the
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Table 1. Optimization of the Reaction Conditionsa
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entry Cu source (20 mol %)
[NO2] source (35 mol %)
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Ca(NO3)2·4H2O
Bi(NO3)3·5H2O
AgNO3
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
yield (%)
52
1
Cu(OAc)2·H2O
Cu(OTf)2
2
48
3
CuSO4·5H2O
CuI
trace
44
4
5
CuCl
84
6
CuBr2
86
7
Cu(NO3)2ꢁ3H2O
CuBr
10
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74
9
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
ꢀ
95
10b
11
12c
13d
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18
19e
20
21f
trace
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26
NaNO2
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Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
ꢀ
89
trace
74
toluene
DMF
CH3CN
DCE
DCE
DCE
n.d.
62
61
trace
50
Cu(NO3)2ꢁ3H2O
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a Reaction conditions: N,1ꢀdiphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1a (1 mmol), Cu source (20 mol %),
Fe(NO3)3.9H2O (35 mol %), solvent (3 mL), rt, 11 h. b Ca(NO3)3ꢁ4H2O (50 mol %) was used. c
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AgNO3 (1.1 equiv) was used. NaNO2 (1.1 equiv) was used. e CuCl2·2H2O (10 mol %) was
used. f Cu(NO3)2ꢁ3H2O (100 mol %) was used. n.d. = not detected.
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Scheme 1. Ortho-Nitration of Symmetrically Substituted N,1-Diaryl-5-aminotetrazolesa
N
N
N
N
N
N
N
.
20 mol % CuCl2 2H2O
N
.
NO2
35 mol % Fe(NO3)3 9H2O
HN
1b-k
HN
2b-k
DCE, rt
R'
R'
R"
R"
R', R" = H, Me, Et, iPr, F, Cl
N
N
N
N
N
N
N
Me
N
N
N
N
N
HN
HN
HN
F
Cl
NO2
NO2
NO2
Me
F
Cl
2d, 8 h, 91%
2b, 12 h, 72%
2c, 8 h, 89%
N
N
N
N
N
N
N
N
N
N
N
N
Me
NO2
HN
HN
HN
Me
O
NO2
NO2
Me
Me
Me
2e, 8 h, 94%
O
Me
Me
Me
2g, 8 h, 92%
2f, 8 h, 83%
Me
N
N
N
N
N
N
N
Me
Me
N
N
N
N
N
HN
HN
HN
NO
2 Me
NO2
NO2
Me
Me
Me
Me
2j, 8 h, 86%
Me
Me
2i, 12 h, 73%
2h, 8 h, 90%
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N
N
Me
N
N
HN
6
NO2
Me
7
8
9
Me
Me
2k, 12 h, 75%
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a Reaction conditions: Nꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1b-k (1 mmol), CuCl2ꢁ2H2O (20 mol %),
Fe(NO3)3ꢁ9H2O (35 mol %), DCE (3 mL), rt.
Scheme 2. Ortho-Nitration of Unsymmetrically Substituted N,1-Diaryl-5-aminotetrazolesa
N
N
N
N
N
N
N
N
.
20 mol % CuCl2 2H2O
.
NO2
35 mol % Fe(NO3)3 9H2O
NH
NH
DCE, rt
R'
R'
Cl
2l-w
1l-w
R"
R"
R', R" = EDG, EWG
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NO2
NO2
NO2
F
Me
Me
2n, 8 h, 93%
2l, 12 h, 84%
2m, 8 h, 87%
Cl
N
N
Cl
F
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NO2
NO2
O2N
NO2
2p, 12 h, 81%
Me
2q, 8 h, 89%
2o, 12 h, 74%
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a
Reaction conditions: Nꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1l-v (1 mmol), CuCl2ꢁ2H2O (20 mol %),
Fe(NO3)3ꢁ9H2O (35 mol %), DCE (3 mL), rt.
Scheme 3. Ortho-Nitration of N,4-Diaryl-3-amino-1,2,4-triazolesa
N
N
.
20 mol % CuCl2 2H2O
N
N
N
N
.
NO2
35 mol % Fe(NO3)3 9H2O
NH
NH
DCE, rt
R'
R'
4a-c
3a-c
R"
R"
R', R" = H, F, Me
N
N
N
N
N
N
N
N
N
NH
NH
Me
F
NH
NO2
NO2
NO2
Me
4c, 6 h, 87%
F
4b, 6 h, 82%
4a, 6 h, 84%
a
Reaction conditions: N,4ꢀdiphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ3ꢀamine 3a-c (1 mmol), CuCl2ꢁ2H2O (20
mol %), Fe(NO3)3ꢁ9H2O (35 mol %), DCE (3 mL), rt.
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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 74ꢀ93% yields. Similarly, the substrates 1q having 2ꢀfluoro and 4ꢀethyl
substituents underwent reaction to furnish 2q in 89% 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 77ꢀ96% yields.
Recrystallization of 2c in CH3CN gave single crystals whose structure was confirmed by Xꢀray
analysis (See supporting information).
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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
derivatives in good yields.16
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Table 2. Removal of Directing Groupa
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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)
R” = iPr (5b)
R” = H (5a)
22
12
22
78
87
84
R’, R” = iPr (2g)
R’ = 2ꢀCl, R” = H (2l)
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 PH/PD = 1.2 (21% conversion), while the
intramolecular kinetic isotope experiments of the substrate 1s-D afforded PH/PD = 3.5 (Scheme
5).17 These results suggest that the substrate binding step is the product determining step.18 In
addition, TEMPO does not inhibit the rate of the reaction, which suggests that the reaction may
not involve a radical intermediate (Scheme 6).19 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)2ꢁCu]+ and [(2a)2ꢁCuCl]+} (see supporting information)
(Figure 1).6f,20 However, attempts to isolate the species as single crystals remained unsuccessful.
Furthermore, CuCl2ꢁ2H2O and Fe(NO3)3ꢁ9H2O are insoluble in 1,2ꢀdichloroethane, however,
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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 CuCl2 to give a soluble intermediate a that may undergo
reaction with Fe(NO3)3ꢁ9H2O to afford the intermediate b (Scheme 7).21 The subsequent
intramolecular orthoꢀnitration via an aromatic electrophilic substitution can give the intermediate
c, which can afford the target product 2, and the hydrated CuX2 to complete the catalytic cycle.
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Scheme 4. Gram Scale Synthesis
Scheme 5. Kinetic Isotope Experiments
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Scheme 6. Radical Scavenger Experiment
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Figure 1. Major species identified using ESIꢀMS analysis of the reaction mixture of 1a.
Scheme 7. Proposed Catalytic Cycle
CONCLUSION
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
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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.
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EXPERIMENTAL SECTION
General Information: Cu(OTf)2 (98%), CuI (98%) and CuCl (90%) were purchased from
Aldrich. Cu(OAc)2ꢁH2O (98%), CuBr2 (98%), Cu(NO3)2ꢁ3H2O (99%), CuCl2ꢁ2H2O (99%) and
Fe(NO3)3ꢁ9H2O (98%) were purchased from Merck. CuSO4ꢁ5H2O (99%) was obtained from
Rankem. These chemicals were used as received without further purification. The solvents were
purchased from commercial source and dried according to standard procedure prior to use.22a 3ꢀ
5ꢀAminotetrazoles22c and aminoꢀ1,2,4ꢀtriazoles22b,dꢀe 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 CDCl3, CD3OD and
DMSOꢀd6 as solvent and Me4Si as internal standard. Chemical shifts (δ) were reported in ppm
and spinꢀspin coupling constants (J) were given in Hz. Melting points were determined using
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. Single crystal was measured on a Xꢀray
diffractometer. Using Olex2, the structure was solved with the superflip structure solution
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program using charge flipping and refined with the Olex2 refine refinement package using
Gauss−Newton minimisation.
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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
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mmol) in DCE (3 mL), CuCl
∙
2 2H2O (20 mol %, 0.2 mmol, 34.6 mg) and Fe(NO3)3 9H2O (35 mol
∙
%, 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
NaHCO3 solution (5 mL) was added to the reaction mixture, and the resultant solution was
extracted with ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL). Drying (Na2SO4) and
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
acetate/hexane Rf = 0.61; yellow solid; 268 mg, yield 95%; mp 187ꢀ188 °C; 1H NMR (300 MHz,
CDCl3) δ 10.82 (br s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.80ꢀ7.61 (m, 6H),
13
7.19ꢀ7.14 (m, 1H); C{H} NMR (100 MHz, CDCl3 + DMSOꢀd6 ) δ 150.6, 136.9, 135.6, 134.8,
132.1, 131.0, 130.6, 126.1, 124.6, 122.2, 119.9; FTꢀIR (KBr) 3345, 1602, 1589, 1569, 1527,
1498, 1384, 1339, 1279, 1145, 1113, 1078, 1025, 996, 758, 739 cmꢀ1. HRMS (ESI) m/z: [M+H]+
calcd for C13H10N6O2 283.0938, found 283.0937.
N-(5-Methyl-2-nitrophenyl)-1-(m-tolyl)-1H-tetrazol-5-amine 2b. Analytical TLC on silica
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gel, 1:4 ethyl acetate/hexane Rf = 0.68; yellow solid; 223 mg, yield 72%; mp 188ꢀ189 °C; H
NMR (300 MHz, CDCl3) δ 10.86 (br s, 1H), 8.74 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.58ꢀ7.38 (m,
13
4H), 6.94 (d, J = 8.4 Hz, 1H), 2.50 (s, 6H); C{H} NMR (100 MHz, CDCl3) δ 150.7, 149.4,
141.4, 135.8, 132.9, 132.2, 131.8, 130.6, 126.4, 125.2, 123.4, 121.6, 119.9, 22.5, 21.5; FTꢀIR
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(KBr) 3095, 2921, 1608, 1541, 1493, 1450, 1378, 1340, 1293, 1125, 1094, 1055, 1033, 850, 768
cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C15H14N6O2 311.1251, found 311.1255.
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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 Rf = 0.70; yellow solid; 312 mg, yield 89%; mp 187ꢀ188 °C;
1H NMR (400 MHz, CDCl3) δ 10.70 (br s, 1H), 8.93 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 2.4 Hz,
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1H), 7.71ꢀ7.64 (m, 3H), 7.56ꢀ7.53 (m, 2H); C{H} NMR (100 MHz, CDCl3) δ 150.5, 137.6,
137.1, 135.1, 134.3, 131.3, 130.6, 127.8, 126.0, 125.9, 121.6; FTꢀIR (KBr) 3259, 3108, 1604,
1556, 1542, 1502, 1417, 1338, 1275, 1247, 1094, 1006, 843, 820, 752 cmꢀ1. HRMS (ESI) m/z:
[M+H]+ calcd for C13H8Cl2N6O2 351.0167, found 351.0161.
N-(4-Fluoro-2-nitrophenyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine 2d. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.62; yellow solid; 289 mg, yield 91%; mp 171ꢀ172 °C;
1H NMR (300 MHz, CDCl3) δ 10.62 (br s, 1H), 9.02ꢀ8.97 (m, 1H), 8.01 (dd, J = 8.1, 2.7 Hz.
1H), 7.63ꢀ7.51 (m, 3H), 7.43 (t, J = 8.4 Hz, 2H); 13C{H} NMR (75 MHz, CDCl3) δ 165.3, (d, J =
252.0 Hz), 157.9 (d, J = 245.3 Hz), 150.6, 134.6 (d, J = 8.3 Hz), 132.2 (d, J = 2.3 Hz), 127.9 (d,
J = 3.8 Hz), 127.0 (d, J = 9.0 Hz), 124.9 (d, J = 22.5 Hz), 121.8 (d, J = 6.8 Hz), 118.1 (d, J =
24.0 Hz), 112.7 (d, J = 27.0 Hz); FTꢀIR (KBr) 3260, 3091, 1615, 1598, 1537, 1513, 1428, 1337,
1249, 1161, 1090, 949, 843, 819, 758 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C13H8F2N6O2
319.075, found 319.0758.
N-(4-Methyl-2-nitrophenyl)-1-(p-tolyl)-1H-tetrazol-5-amine 2e. Analytical TLC on silica gel,
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1:4 ethyl acetate/hexane Rf = 0.71; yellow solid; 291 mg, yield 94%; mp 193ꢀ194 °C; H NMR
(600 MHz, CDCl3) δ 10.64 (br s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.59 (dd, J = 9.0,
13
1.8 Hz. 1H), 7.48 (s, 4H), 2.50 (s, 3H), 2.41 (s, 3H); C{H} NMR (150 MHz, CDCl3) δ 150.9,
141.6, 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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3083, 2922, 1656, 1604, 1562, 1526, 1489, 1334, 1281, 1109, 1093, 1015, 883, 812, 766 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C15H14N6O2 311.1251, found 311.1255.
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N-(4-Methoxy-2-nitrophenyl)-1-(4-methoxyphenyl)-1H-tetrazol-5-amine 2f. Analytical TLC
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on silica gel, 1:4 ethyl acetate/hexane Rf = 0.38; brown solid; 283 mg, yield 83%; mp 166ꢀ167
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°C; H NMR (300 MHz, CDCl3) δ 10.48 (br s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.51
(d, J = 6.9 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 6.6 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H);
13C{H} NMR (75 MHz, CDCl3) δ 161.2, 154.0, 150.9, 134.8, 129.9, 126.3, 125.1, 124.4, 121.3,
115.6, 108.2, 55.9, 55.7; FTꢀIR (KBr) 3259, 2845, 1637, 1598, 1563, 1533, 1348, 1285, 1268,
1110, 1040, 924, 831, 799 cmꢀ1 HRMS (ESI) m/z: [M+H]+ calcd for C15H14N6O4 343.1149,
found 343.1151.
N-(4-Isopropyl-2-nitrophenyl)-1-(4-isopropylphenyl)-1H-tetrazol-5-amine 2g. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; yellow solid; 336 mg, yield 92%; mp 116ꢀ
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117 °C; H NMR (400 MHz, CDCl3) δ 10.62 (br s, 1H), 8.81 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H),
7.61ꢀ7.47 (m, 5H), 3.10ꢀ3.01 (m, 1H), 3.00ꢀ2.93 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H), 1.28 (d, J =
7.2 Hz, 6H); 13C{H} NMR (100 MHz, CDCl3) δ 152.0, 150.6, 143.1, 135.5, 134.6, 133.7, 129.8,
128.6, 124.4, 123.2, 119.9, 34.0, 33.1, 23.8, 23.6; FTꢀIR (KBr) 3258, 2963, 1628, 1596, 1560,
1537, 1519, 1460, 1341, 1277, 1252, 1153, 1088, 838 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for
C19H22N6O2 367.1877, found 367.1878.
N-(4-Ethyl-2-nitrophenyl)-1-(4-ethylphenyl)-1H-tetrazol-5-amine 2h. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.69; yellow solid; 304 mg, yield 90%; mp 115ꢀ116 °C;
1H NMR (600 MHz, CDCl3) δ 10.65 (br s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.8 Hz,
1H), 7.61 (dd, J = 9.0, 1.8 Hz. 1H), 7.50 (s, 4H), 2.82 (q, J = 7.8 Hz, 2H), 2.72 (q, J = 7.8 Hz,
2H), 1.34 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C{H} NMR (150 MHz, CDCl3) δ 150.8,
147.7, 138.7, 136.9, 134.8, 133.8, 130.1, 129.9, 124.8, 124.6, 120.1, 28.8, 27.9, 15.3, 15.2; FTꢀ
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IR (KBr) 3471, 2962, 1626, 1595, 1516, 1463, 1335, 1296, 1182, 1086, 915, 834, 741 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C17H18N6O2 339.1564, found 339.1568.
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N-(2,4-Dimethyl-6-nitrophenyl)-1-(2,4-dimethylphenyl)-1H-tetrazol-5-amine 2i. Analytical
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TLC on silica gel, 1:4 ethyl acetate/ hexane Rf = 0.52; yellow solid; 246 mg, yield 73%; mp 187ꢀ
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188 °C; H NMR (600 MHz, CDCl3) δ 9.36 (br s, 1H), 8.38 (s, 1H), 7.23 (s, 1H), 7.17 (s, 2H),
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6.82 (s, 1H), 2.48 (s, 3H), 2.46 (s, 6H), 2.44 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ 150.7,
145.1, 140.9, 136.4, 135.1, 133.8, 132.2, 132.1, 127.2, 121.7, 118.1, 21.9, 21.2, 21.1; FTꢀIR
(KBr) 3095, 2772, 1608, 1540, 1493, 1377, 1340, 1294, 1248, 1125, 1093, 850, 785, 723 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C17H18N6O2 339.1564, found 339.1574.
N-(4,5-Dimethyl-2-nitrophenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine 2j. Analytical
TLC on silica gel, 1:4 ethyl acetate/ hexane Rf = 0.68; yellow solid; 290 mg, yield 86%; mp 158ꢀ
159 °C; 1H NMR (400 MHz, CDCl3) δ 10.55 (br s, 1H), 8.53 (s, 1H), 7.82 (s, 1H), 7.32ꢀ7.19 (m,
13
3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.12 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ
150.6, 148.2, 139.9, 139.6, 133.7, 132.5, 131.5, 131.2, 129.9, 126.1, 125.3, 121.7, 120.2, 20.7,
19.9, 19.8, 19.0; FTꢀIR (KBr) 3266, 2921, 1624, 1594, 1561, 1529, 1449, 1375, 1324, 1259,
1093, 1015, 879, 821, 756 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C17H18N6O2 339.1564,
found 339.1571.
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 Rf = 0.59; yellow solid; 253 mg, yield 75%; mp 181ꢀ
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182 °C; H NMR (400 MHz, CDCl3) δ 9.26 (br s, 1H), 8.25 (s, 1H), 7.13 (s, 1H), 7.07 (s, 2H),
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6.71 (s, 1H), 2.35 (s, 9H), 2.31 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ 150.8, 145.2, 140.9,
136.5, 135.2, 133.8, 132.3, 132.2, 127.2, 121.7, 118.2, 22.0, 21.3, 21.1; FTꢀIR (KBr) 3162, 2829,
1634, 1571, 1504, 1481, 1393, 1338, 1294, 1229, 1197, 1099, 894, 785, cmꢀ1. HRMS (ESI) m/z:
[M+H]+ calcd for C17H18N6O2 339.1564, found 339.1572.
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1-(2-Chlorophenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine 2l. Analytical TLC on silica gel,
1:4 ethyl acetate/ hexane Rf = 0.71; yellow solid; 266 mg, yield 84%; mp 135ꢀ136 °C; 1H NMR
(400 MHz, CDCl3) δ 10.39 (br s, 1H), 8.84 (d, J = 8.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.2 Hz, 1H),
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7.73ꢀ7.54 (m, 5H), 7.13 (t, J = 7.6 Hz, 1H); C{H} NMR (100 MHz, CDCl3) δ 151.4, 137.0,
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135.6, 134.8, 133.3, 131.8, 131.6, 129.4, 129.3, 129.0, 126.2, 122.3, 119.8; FTꢀIR (KBr) 3288,
2964, 1598, 1564, 1533, 1501, 1441, 1342, 1287, 1137, 1096, 769, 739 cmꢀ1. HRMS (ESI) m/z:
[M+H]+ calcd for C13H9ClN6O2 317.0548, found 317.0558.
1-(2-Chlorophenyl)-N-(4-fluoro-2-nitrophenyl)-1H-tetrazol-5-amine 2m. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.69; yellow solid; 289 mg, yield 87%; mp 142ꢀ143 °C;
1H NMR (600 MHz, CDCl3) δ 10.26 (br s, 1H), 8.96ꢀ8.94 (m, 1H), 7.96ꢀ7.94 (m, 1H), 7.73 (d, J
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= 7.8 Hz, 1H), 7.67ꢀ7.64 (m, 1H), 7.59ꢀ7.50 (m, 3H); C{H} NMR (150 MHz, CDCl3) δ 157.1
(d, J = 247.5 Hz), 151.3, 134.6, 133.3, 132.2, 131.7, 131.5, 129.3, 129.2, 128.9, 124.7 (d, J =
22.5 Hz), 121.7, 112.5 (d, J = 28.5 Hz); FTꢀIR (KBr) 278, 3088, 1596, 1575, 1533, 1516, 1340,
1248, 1135, 1095, 946, 825, 777 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C13H8ClFN6O2
335.0454, found 335.0457.
1-(2-Chlorophenyl)-N-(4-isopropyl-2-nitrophenyl)-1H-tetrazol-5-amine 2n. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; yellow solid; 337 mg, yield 93%; mp 157ꢀ158
°C; 1H NMR (400 MHz, CDCl3) δ 10.30 (br s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 2.0 Hz,
1H), 7.71 (d, J = 8.0 Hz, 1H), 7.65ꢀ7.53 (m, 4H), 2.95ꢀ2.90 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H);
13C{H} NMR (100 MHz, CDCl3) δ 151.7, 143.6, 135.7, 134.8, 133.6, 133.3, 131.9, 131.6, 129.5,
129.0, 123.5, 120.1, 33.4, 23.8; FTꢀIR (KBr) 3291, 2891, 1591, 1572, 1528, 1497, 1441, 1349,
1291, 1137, 1085, 757, 727 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C16H15ClN6O2 359.1018,
found 359.1015.
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1-(2-Chlorophenyl)-N-(2-nitronaphthalen-1-yl)-1H-tetrazol-5-amine 2o. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; reddish yellow gummy liquid; 271 mg, yield 74%;
1H NMR (600 MHz, CDCl3) δ 8.56 (dd, J = 8.4, 0.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.05 (d, J
= 8.4 Hz, 1H), 7.72ꢀ7.61 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (td, J = 8.4, 1.2 Hz, 1H), 7.29
(dd, J = 8.4, 1.2 Hz, 1H), 7.01 (td, J = 8.4, 1.2 Hz, 1H), 6.84 (br s, 1H); 13C{H} NMR (150 MHz,
CDCl3) δ 152.4, 134.7, 132.2, 129.2, 128.9, 128.8, 128.4, 128.1, 127.9, 125.6, 125.3, 123.8,
121.9, 121.6, 119.1; FTꢀIR (neat) 3256, 3113, 2925, 1585, 1549, 1511, 1350, 1289, 1170, 842,
775 cmꢀ1 HRMS (ESI) m/z: [M+H]+ calcd for C17H11ClN6O2 367.0710, found 367.0708.
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1-(2-Chlorophenyl)-N-(2,4-dinitrophenyl)-1H-tetrazol-5-amine 2p. Analytical TLC on silica
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gel, 1:4 ethyl acetate/hexane Rf = 0.42; orange solid; 292 mg, yield 81%; mp 189ꢀ190 °C; H
NMR (400 MHz, CDCl3) δ 9.105 (br s, 1H), 9.10 (d, J = 6.4 Hz, 1H), 8.55 (dd, J = 9.2, 2.4 Hz,
13
1H), 7.75 (m, 3H), 7.63 (m, 2H); C{H} NMR (75 MHz, CDCl3) δ 150.6, 141.0, 139.9, 133.6,
133.5, 131.6, 131.4, 130.9, 129.3, 129.0, 128.8, 122.6, 120.5; FTꢀIR (KBr) 3253, 3104, 1609,
1549, 1488, 1421, 1351, 1141, 1113, 912, 855, 841, 764, 726 cmꢀ1. HRMS (ESI) m/z: [M+H]+
calcd for C13H8ClN7O4 362.0399, found 362.0390.
N-(4-Ethyl-2-nitrophenyl)-1-(2-fluorophenyl)-1H-tetrazol-5-amine 2q. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; yellow solid; 292 mg, yield 89%; mp 139ꢀ140 °C;
1H NMR (400 MHz, CDCl3) δ 10.42 (br s, 1H), 8.70 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 1.6 Hz,
1H), 7.65ꢀ7.51 (m, 3H), 7.44ꢀ7.38 (m, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 157.5 (d, J = 253.2 Hz), 151.5, 138.8, 136.8, 134.7, 133.6,
133.53, 133.5, 128.4, 126.1 (d, J = 3.8 Hz), 124.7, 119.9 (d, J = 9.9 Hz), 117.9 (d, J = 18.3 Hz),
27.8, 15.1; FTꢀIR (KBr) 3286, 2977, 1630, 1618, 1563, 1506, 1339, 1265, 1118, 1085, 891, 842,
763 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C15H13FN6O2 329.1157, found 329.1152.
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1-(2,6-Dimethylphenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine 2r. Analytical TLC on silica
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gel, 1:4 ethyl acetate/hexane Rf = 0.69; yellow solid; 283 mg, yield 91%; mp 195ꢀ196 °C; H
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8
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NMR (400 MHz, CDCl3) δ 10.21 (br s, 1H), 8.94 (dd, J = 8.8, 0.8 Hz, 1H), 8.22 (dd, J = 8.4, 1.6
Hz, 1H), 7.76 (td, J = 8.4, 1.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.14
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(td, J = 8.4, 1.6 Hz, 1H), 2.03 (s, 6H); C{H} NMR (100 MHz, CDCl3) δ 151.4, 137.1, 136.6,
135.7, 132.0, 129.7, 129.4, 126.3, 122.2, 119.9, 17.6; FTꢀIR (KBr) 3230, 2926, 1626, 1598,
1538, 1524, 1410, 1380, 1337, 1281, 1241, 1122, 1092, 926, 831, 772, 759 cmꢀ1. HRMS (ESI)
m/z: [M+H]+ calcd for C15H14N6O2 311.1256, found 311.1248.
1-(2,6-Dimethylphenyl)-N-(4-methyl-2-nitrophenyl)-1H-tetrazol-5-amine 2s. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane Rf = 0.72; yellow solid; 305 mg, yield 96%; mp 192ꢀ193
°C; 1H NMR (400 MHz, CDCl3) δ 10.05 (br s, 1H), 8.78 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 1.2 Hz,
1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 2.34 (s,
13
3H), 2.00 (s, 6H); C{H} NMR (100 MHz, CDCl3) δ 151.5, 138.0, 136.6, 134.5, 133.5, 132.4,
131.9, 129.6, 129.4, 125.9, 119.8, 20.5. 17.5; FTꢀIR (KBr) 3230, 2926, 1626, 1598, 1538, 1524,
1410, 1380, 1337, 1281, 1241, 1122, 1092, 926, 831, 772, 759 cmꢀ1. HRMS (ESI) m/z: [M+H]+
calcd for C16H16N6O2 325.1408, found 325.1409.
1-(2,6-Dimethylphenyl)-N-(2,4-dinitrophenyl)-1H-tetrazol-5-amine 2t. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.41; yellow solid; 280 mg, yield 79%; mp 189ꢀ190 °C;
1H NMR (600 MHz, CDCl3) δ 10.55 (br s, 1H), 9.23 (d, J = 9.6 Hz, 1H), 9.13 (d, J = 2.4 Hz,
1H), 8.59 (dd, J = 9.6, 2.4 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 2.02 (s,
13
6H); C{H} NMR (150 MHz, CDCl3) δ 150.7, 141.2, 140.0, 136.5, 133.4, 132.4, 131.1, 129.9,
129.0, 122.7, 120.7, 17.54; FTꢀIR (KBr) 3471, 1626, 1595, 1516, 1463, 1335, 1296, 1182, 1149,
1086, 915, 834, 741 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C15H13N7O4 356.1107, found
356.1100.
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N-(4-((1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)amino)-3-nitrophenyl)acetamide
2u.
4
5
6
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.48; yellow solid; 283 mg, yield
1
7
8
77%; mp 262ꢀ263 °C; H NMR (400 MHz, CDCl3) δ 10.05 (br s, 1H), 8.90 (d, J = 9.2 Hz, 1H),
9
8.68 (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),
7.34 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H), 2.06 (s, 6H); 13C{H} NMR (150 MHz, CDCl3 + DMSOꢀd6
+ CD3OD) 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,
22.8, 16.2; FTꢀIR (KBr) 3334, 3238, 1674, 1611, 1546, 1360, 1296, 1273, 1260, 1091, 1016,
886, 773 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C17H18N7O3 368.1471, found 368.1480.
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4-((1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)amino)-3-nitrobenzonitrile 2v. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane Rf = 0.30; yellow solid; 275 mg, yield 82%; mp 205ꢀ206
°C; 1H NMR (400 MHz, CDCl3) δ 10.42 (br s, 1H), 9.15 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 2.0 Hz,
1H), 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,
13
6H); C{H} NMR (100 MHz, CDCl3) δ 150.8, 139.2, 138.8, 136.5, 134.1, 132.3, 130.8, 129.8,
129.0, 121.1, 116.7, 105.8, 17.5; FTꢀIR (KBr) 3504, 2922, 2852, 2237, 1629, 1557, 1519, 1383,
1283, 1194, 1092, 852, 775, 674 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C16H13N7O2
336.1209, found 336.1206.
N-(2-Nitrophenyl)-4-phenyl-4H-1,2,4-triazol-3-amine 4a. Analytical TLC on silica gel, 1:1
ethyl acetate/hexane Rf = 0.40; yellow solid; 236 mg, yield 84%; mp 176ꢀ177 °C; 1H NMR (400
MHz, CDCl3) 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),
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,
CDCl3) 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
IR (KBr) 3451, 3053, 2923, 2852, 1617, 1564, 1553, 1507, 1444, 1384, 1272, 1193, 1145, 1023,
841, 736, 609 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H11N5O2 282.0991, found 282.0991.
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N-(4-Fluoro-2-nitrophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-amine 4b. Analytical TLC
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on silica gel, 1:1 ethyl acetate/hexane Rf = 0.42; reddish yellow solid; 260 mg, yield 82%; mp
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7
8
189ꢀ190 °C; H NMR (400 MHz, CDCl3) δ 10.25 (br s, 1H), 9.08ꢀ9.04 (m, 1H), 8.12 (s, 1H),
9
13
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
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MHz, CDCl3) 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
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,
1337, 1236, 1162, 1131, 1001, 944, 878, 837, 760, 704 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd
for C14H9F2N5O2 318.0803, found 318.0802.
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 Rf = 0.45; reddish yellow solid; 269 mg, yield 87%; mp 176ꢀ177
°C; 1H NMR (400 MHz, CDCl3) δ 10.31 (br s, 1H), 8.90 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 8.0 (s,
13
1H), 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, CDCl3) δ 149.5, 141.0, 140.7, 138.1, 135.1, 133.9, 131.5, 131.0, 129.5, 125.8, 125.6,
120.0, 21.5, 20.5; FTꢀIR (KBr) 3471, 1731, 1632, 1598, 1514, 1449, 1386, 1238, 1163, 946, 837,
782 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C16H15N5O2 310.1306, found 310.1306.
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 (Na2SO4) and
evaporation of the solvent gave a residue that was purified on silica gel column chromatography
using nꢀhexane and ethyl acetate as eluent.
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2-Nitroaniline 5a.23 Analytical TLC on silica gel, 1:10 ethyl acetate/hexane Rf = 0.40; yellow
solid; mp 71ꢀ72 °C; 1H NMR (600 MHz, CDCl3) δ 8.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.36 (td, J =
6.6, 1.2 Hz, 1H), 6.81 (dd, J = 9.0, 1.2 Hz, 1H), 6.71 (td, J = 7.8 Hz, 1.2, 1H), 6.07 (br s, 2H);
13C{H} NMR (150 MHz, CDCl3) δ 144.9, 135.8, 132.5, 126.4, 118.9, 117.1; FTꢀIR (KBr) 3479,
3352, 1630, 1593, 1507, 1433, 1347, 1253, 1093, 995, 745 cmꢀ1.
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4-Isopropyl-2-nitroaniline 5b. Analytical TLC on silica gel, 1:10 ethyl acetate/hexane Rf =
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0.40; thick yellow liquid; 157 mg, yield 87%; H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 1.6
13
Hz, 1H), 7.28 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.96 (br s, 2H); C{H} NMR (100 MHz,
CDCl3) δ 143.1, 138.1, 135.0, 127.3, 123.1, 119.0, 33.1, 23.9; FTꢀIR (neat) 3483, 3364, 2954,
2917, 1638, 1561, 1520, 1466, 1409, 1335, 1249, 1167, 1085, 952, 818 cmꢀ1.
Preparation of Aniline-d3 (Scheme 8). The titled compound was prepared according to the
1
reported procedure17a 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, Rf =
0.32; pale brown solid; yield 85%; 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H), 3.62 (bs, 2H).
Scheme 8
Preparation of 1-(2,6-dimethylphenyl)-N-(2-nitrophenyl)-1H-tetrazol-5-amine-d3 1r-d3
(Scheme 9). The titled compound was prepared according to the reported procedure.22c 3:7 ethyl
acetate/ hexane; Rf = 0.25; white solid; yield 74%; 1H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 8.0
Hz, 1H), 7.35 (s, 2H), 7.29 (d, J = 7.6 Hz, 2H), 6.10 (bs, 1H), 2.06 (s, 6H).
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Scheme 9
Intramolecular Kinetic Isotope Effect Study (Scheme 10). To a stirred solution of Nꢀ(2ꢀ
deuterioꢀ4ꢀmethylphenyl)ꢀ1ꢀ(2,6ꢀdimethylphenyl)ꢀ1Hꢀtetrazolꢀ5ꢀamine4c 1s-d (0.5 mmol, 140
mg) in DCE (2 mL), CuCl
∙
2 2H2O (20 mol %, 0.1 mmol, 17 mg) and Fe(NO3)3 9H2O (35 mol %,
∙
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 (Na2SO4) and evaporation
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
83% (138 mg) yield. The ratio of deuterium to hydrogen was determined from the H NMR
relative integration values of Ha (8.84 ppm) based on Hb (7.58 ppm).
Scheme 10
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-d3) (0.42 mmol, 111 mg) in
DCE (2 mL), CuCl2
∙
2H2O (20 mol %, 0.2 mmol, 34 mg) and Fe(NO3)3 9H2O (35 mol %, 0.35
∙
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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 (Na2SO4) and evaporation
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-d2 and 2r as a yellow solid in 18%
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(56 mg) yield. The ratio of deuterium to hydrogen was determined by the H NMR relative
integration values of Ha (8.96 ppm) based on Hb (8.24 ppm).
Scheme 11
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
Crystal structure and data, mass spectra of reaction of 1a and NMR (1H and 13C) spectra of 2a-v,
4a-c, anilineꢀd3,1r-d3, 2s-d, 2r-d2, 5a and 5b. This material is available free of charge via the
internet at http://pubs.acs.org.
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Miura, M. J. Org. Chem. 2014, 79, 7649.
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Q. J. Am. Chem. Soc. 2012, 134, 11948. (b) Kuninobu, Y.; Iwanaga, T.; Omura, T.; Takai, K.
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(5) For some examples on first row metal catalyzed reactions, see: (a) Gao, K.; Lee, P.ꢀS.;
Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010, 132, 12249. (b) Shiota, H.; Ano, Y.; Aihara,
Y.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 14952. (c) Asako, S.; Ilies, L.;
Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755.
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