Pd(II)-catalyzed aminotetrazole-directed ortho-selective halogenation of arenes

Article abstract of DOI:10.1021/jo400755q

A Pd(II)-catalyzed ortho-selective halogenation of N-aryl ring of N,1-diaryl-1H-tetrazol-5-amine has been described employing N-halosuccinimide as a halogen source via C-H bond activation. The present work features 5-aminotetrazole, as a directing group, for the chemo- and regioselective C-H halogenation of arenes. The kinetic isotope study (k_H/k_D = 2.9) suggests that the cleavage of the C-H bond takes place in the rate-determining step. The scope and mechanism of the protocol have been demonstrated.

Full text of DOI:10.1021/jo400755q

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Article
Pd(II)-Catalyzed Aminotetrazole Directed
Ortho-Selective Halogenation of Arenes
Pradeep Sadhu, Santhosh Kumar Alla, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400755q • Publication Date (Web): 28 May 2013
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Pd(II)-Catalyzed Aminotetrazole Directed Ortho-Selective
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Halogenation of Arenes
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Pradeep Sadhu, Santhosh Kumar Alla and Tharmalingam Punniyamurthy
*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Eꢀmail: tpunni@iitg.ernet.in
ABSTRACT: A Pd(II)ꢀcatalyzed orthoꢀselective halogenation of Nꢀaryl ring of N,1ꢀdiarylꢀ1Hꢀ
tetrazolꢀ5ꢀamine has been described employing Nꢀhalosuccinimide as a halogen source via CꢀH
bond activation. The present work features 5ꢀaminotetrazole, as a directing group, for the chemoꢀ
and regioselective CꢀH halogenation of arenes. The kinetic isotope study (kH/kD = 2.9) suggests
that the cleavage of the CꢀH bond takes place in the rate determining step. The scope and
mechanism of the protocol have been demonstrated.
INTRODUCTION
The recent advances in transitionꢀmetalꢀcatalysis have led to the development of effective
methods for the direct functionalization of CꢀH bonds.1 In these reactions, the incorporation of a
directing group in the substrate has been found to be effective for the selective activation of a
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particular CꢀH bond (Figure 1).2 In this context, considerable effort has been made on the search
of effective directing groups for the selective CꢀH functionalization processes.3ꢀ9
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NꢀArylꢀ5ꢀaminotetrazole is an essential structural motif in many compounds that are
important in biological and medicinal sciences. For example, the compounds having Nꢀarylꢀ5ꢀ
aminotetrazole core structure exhibit antiꢀinflammatory,10a antiꢀasthmatic,10bꢀc antiꢀviral,10d antiꢀ
neoplastic,10e cognition disorder10f and antibiotic10g properties. In particular, Nꢀ(2ꢀhalophenyl)ꢀ
1Hꢀtetrazolꢀ5ꢀamines are known to exhibit herbicidal and antiꢀallergic properties.11 However,
these compounds could not be obtained by desulfurization12 techniques as shown in Scheme 1. In
addition, the classical methods used for the synthesis of Nꢀ(2ꢀhalophenyl)ꢀ1ꢀphenylꢀ1Hꢀtetrazolꢀ
5ꢀamines often suffer due to limited substrate scope along with the requirement of harsh reaction
conditions.11 The development of a straightforward protocol for the direct orthoꢀhalogenation of
the Nꢀaryl ring of the Nꢀarylꢀ5ꢀaminotetrazole is thus highly desirable.
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Furthermore, aryl halides are extremely valuable starting materials for synthetic elaboration.
For example, they find widespread applications as precursors for the synthesis of organometallic
reagents.13a In recent decades, aryl halides are used as substrates to construct carbonꢀcarbon and
carbonꢀheteroatom bonds via transition metal catalyzed crossꢀcoupling reactions.13bꢀc In addition,
they serve as a prominent structural motif in biologically active molecules.14 However, the
classical methods used for the arene halogenation often suffer due to over halogenation and low
regioselectivity.15 Thus, considerable efforts have been recently made for the development of
new methods for the regioselective CꢀH halogenation of arenes employing directing groups in
the presence of transition metal catalysis.3 Palladium based catalytic systems have been studied
for the halogenation of arenes employing carboxylic acid, amide, nitrile and pyridine as the
directing groups,3aꢀf while the rhodium based systems have been demonstrated with amides and
esters.3g Herein, we report a Pdꢀcatalyzed 5ꢀaminotetrazole directed chemoꢀ and orthoꢀselective
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halogenation of arenes utilizing Nꢀhalosuccinimide as a halogen source. This protocol is simple,
general and effective at moderate temperature to afford the target products in moderate to high
yield.
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Figure 1. Examples of different diverse directing groups for CꢀH activation reactions.
Scheme 1.
RESULTS AND DISCUSSION
First, the optimization of the reaction conditions for bromination was carried out using 1ꢀ(2ꢀ
chlorophenyl)ꢀNꢀphenylꢀ1Hꢀtetrazolꢀ5ꢀamine 1a as a model substrate with Nꢀbromosuccinimide
(NBS) as a bromine source using different Pdꢀsources, solvents and additives at varied
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temperatures (Table 1). To our delight, the reaction proceeded selectively to brominate the orthoꢀ
position of the Nꢀaryl ring in high yield. Among the set of additives examined, CF3SO3H gave
the desired product 2a in 92% yield (entry 3), while CF3CO2H (TFA) and pꢀTsOH (PTSA) were
found to be less effective in affording the target product in 50ꢀ60% yield. In case of the solvents,
1,2ꢀdichloroethane (DCE) gave the best results, whereas 1,2ꢀdimethoxyethane (DME) and
CH3CO2H gave inferior results, while CH3CN and toluene were failed to produce the desired
product. The catalytic activity of different Pdꢀsources was evaluated, and Pd(OAc)2 was found to
be superior to PdCl2 and Pd(PPh3)2Cl2. Lowering the amount of the Pdꢀsource and the
temperature led to afford the target product 2a in <72% yield. Control experiments without the
Pdꢀsource gave 2a in 10% yield along with unreacted starting material 1a.
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Having these optimal conditions in hand, the scope of the protocol was studied for the
bromination of a wide range of N,1ꢀdiarylꢀ1Hꢀtetrazolꢀ5ꢀamine derivatives (Table 2). The
substrates 1c-f having 4ꢀCl, 4ꢀF, 4ꢀiPr and 4ꢀMe substituents on both the aryl rings readily
proceeded reaction to afford the target products 2c-f in 84%, 82%, 88% and 91% yields,
respectively. The substrate bearing 2,4ꢀdiMe substituents 1h required slightly longer reaction
time to give the desired product 2h in 63% yield. While the unsymmetrical substrates 1j-n
bearing electron donating and ꢀwithdrawing groups underwent reaction to produce the target
orthoꢀbrominated products 2j-n in 74ꢀ92% yields. In case of the substrates having 3ꢀMe and 3,4ꢀ
diMe groups on the aryl rings, a mixture of 2ꢀbromo and 2,6ꢀdibromo compounds 2b and 2b',
and 2i and 2i' was obtained in 78% and 90% yields, respectively. Likewise, the symmetrical
substrate bearing 4ꢀOMe group on the aryl rings 1g gave a mixture of orthoꢀbrominated products
2g and 2g' in 88% yield.
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Table 1. Optimization of the Reaction Conditionsa
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Entry
Catalyst
Additive
TFA
Solvent
DCE
Yield (2a) (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
60
50
92
0
2
PTSA
DCE
3
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
DCE
4
CH3CN
toluene
DME
CH3CO2H
DCE
5
0
6
40
60
47
55
72
43
10
7
8
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Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
ꢀ
DCE
10c
11d
DCE
DCE
12
DCE
a
Reaction conditions: substrate 1a (1 mmol), Pdꢀsource (10 mol %), NBS (1.2 mmol),
b
1
additive (0.5 mmol), solvent (2 mL), 60 °C, 6 h. Determined by 400 MHz H NMR.
c Temperature (40 °C) was used. d Pdꢀsource (5 mol %) was used.
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Table 2. Ortho-Bromination of N-Aryl Ring of N,1-Diaryl-1H-tetrazol-5-aminea
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9
N
N
N
N
N
N
N
10 mol% Pd(OAc)2
1.2 equiv NBS
N
R'
R'
HN
HN
R', R" = EDG, EWG
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Br
0.5 equiv CF3SO3H
DCE, 60 °C
R"
R"
2b-n
1b-n
N
N
N
N
N
N
N
N
N
N
N
Me
Me
N
N
N
HN
N
N
HN
HN
HN
Cl
F
Br
Br
Br
Br
Br
Me
6 h, 78%, 3.2:1
Me
Cl
F
2b
2b'
2c, 6 h, 84%
2d, 10 h, 82%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
HN
HN
HN
HN
MeO
MeO
Me
Br
Br
Br
Br
Me
Br
OMe
OMe
Me
Me
Me
2g
2e, 10 h, 88%
2g'
2f, 10 h, 91%
6 h, 88%, 1:1
Me
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
N
N
N
N
N
N
HN
HN
HN
HN
Me
Br
Br
Me
Br
Br
Br
Me
Me
Me
O2N
Me
Me
Me
2h, 8 h, 63%
2i
2i'
6 h, 90%, 2.5:1
2j, 8 h, 79%
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Table 2 Continues...
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N
Cl
N
Cl
F
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
9
HN
Me
HN
Br
HN
HN
Br
Br
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Me
Me
NO2
2l, 8 h, 74%
Me
2k, 6 h, 92%
2m, 8 h, 79%
2n, 8 h, 89%
a Substrate (1 mmol), Pd(OAc)2 (10 mol %), NBS (1.2 mmol), CF3SO3H (0.5 mmol), DCE (2
mL), 60 °C, 6ꢀ10 h.
Next, the chlorination of the substituted N-arylꢀ1ꢀarylꢀ1Hꢀtetrazolꢀ5ꢀamine derivatives was
studied employing Nꢀchlorosuccinimide (NCS) as a halogen source (Table 3). The symmetrically
substituted substrates with 4ꢀCl, 4ꢀF, 4ꢀiPr, 4ꢀMe and 2,4ꢀdiMe groups on the aryl rings
proceeded reaction to give the corresponding orthoꢀchlorinated products 3b-f in 68ꢀ88% yields.
Similarly, the unsymmetrical substrates 1a and 1l-n readily underwent reaction to afford the
target products 3a and 3h-j in 86% and 79ꢀ90% yields, respectively, while the substrate 1i led to
the formation of a mixture of 2ꢀchloroꢀ and 2,6ꢀdichlorinated products 3g and 3g' in 90% yield.
Finally, the iodination of N-arylꢀ1ꢀarylꢀ1Hꢀtetrazolꢀ5ꢀamines was investigated in the
presence of Nꢀiodosuccinimide (NIS) as a halogen source (Table 4). The reactions of N,1ꢀdiarylꢀ
1Hꢀtetrazolꢀ5ꢀamines having 4ꢀF, 4ꢀiPr, 4ꢀMe, 2,4 diMe and 3,4ꢀdiMe groups both on the aryl
rings were studied. As above, the reactions occurred to give the corresponding orthoꢀiodinated
products 4a-e in 73ꢀ93% yields, while the substrate 1k and 1n with unsymmetrical substituents
gave the target products 4f and 4g in 89% and 90% yields, respectively. In these substrates, the
reactions were selective affording mono iodinated compounds as the sole products.
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Table 3. Ortho-Chlorination of N-Aryl Ring of N,1-Diaryl-1H-tetrazol-5-aminea
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6
7
8
N
N
N
N
N
N
N
10 mol% Pd(OAc)2
1.2 equiv NCS
N
R', R" = EDG, EWG
R'
R'
HN
HN
9
Cl
0.5 equiv CF3SO3H
DCE, 60 °C
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R"
R"
1a, 1i, 1j-n
3a-j
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
HN
HN
HN
HN
Cl
Cl
F
Cl
Cl
Cl
Me
Cl
F
Me
Me
3a, 6 h, 86%
3b, 6 h, 83%
3c, 6 h, 88%
3d, 10 h, 82%
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
N
N
HN
HN
HN
HN
Cl
Me
Me
Cl
Cl
Cl
Cl
Me
Me
Me
Me
Me
3e, 6 h, 83%
Cl
Me
Me
3g
3g'
6 h, 90%, 2.4:1
3f, 10 h, 68%
F
N
N
N
N
N
N
N
Me
N
N
N
N
N
HN
HN
Cl
Cl
Cl
HN
Me
Me
NO2
3h, 8 h, 79%
Me
3j, 6 h, 90%
3i, 6 h,82 %
a
Substrate (1 mmol), Pd(OAc)2 (10 mol %), Nꢀchlorosuccinimide (NCS) (1.2 mmol),
CF3SO3H (0.5 mmol), DCE (2 mL), 60 °C, 6ꢀ10 h.
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Table 4. Ortho-Iodination of N-Aryl Ring of N,1-Diaryl-1H-tetrazol-5-aminea
5
6
7
8
N
N
N
N
N
N
10 mol% Pd(OAc)2
1.2 equiv NIS
N
N
R'
R'
R', R" = Cl, F, iPr, Me
HN
HN
9
0. 5 equiv CF3SO3H
DCE, 60 °C
I
10
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R"
R"
4a-g
1d-f, h, i, k
a
Substrate (1 mmol), Pd(OAc)2 (10 mol %), Nꢀiodosuccinimide (NIS) (1.2 mmol),
CF3SO3H (0.5 mmol), DCE (2 mL), 60 °C, 6ꢀ10 h.
Recrystallization of 4b in CH3CN gave a single crystal whose structure was confirmed by
Xꢀray analysis (see Supporting Information). These results suggest that protocol is general and
can be used for the orthoꢀselective bromination, chlorination and iodination of arenes employing
Nꢀhalosuccinimide as a halogen source. It is noteworthy that the halogenation selectively takes
place on the Nꢀaryl ring without affecting the 1ꢀaryl system.
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5
N
N
N
Me
N
N
Me
N
N
10 mol% Pd(OAc)2
1.2 equiv NCS
N
D
Cl
6
7
8
0.5 equiv CF3SO3H
DCE, 60 °C
HN
Me
HN
Me
Me
Me
H/D
9
1o
3k
kH/kD = 2.9
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Scheme 2. Kinetic Isotope Study.
Scheme 3. Plausible Catalytic Cycle.
To reveal the nature of the CꢀH bond cleavage, the kinetic isotope effect was investigated for
the halogenation of Nꢀ(2ꢀdeuteroꢀ4ꢀmethylphenyl)ꢀ1ꢀ(2,6ꢀdimethylphenyl)ꢀ1Hꢀtetrazolꢀ5ꢀamine
1o (Scheme 2). The observed results (kH/kD = 2.9) indicate that the cleavage of ortho CꢀH bond
is involved in the rate determining step (see the Supporting Information).16e Thus, the reaction of
5ꢀaminotetrazole with Pd(OAc)2 may give a six membered cyclopalladated intermediate I via
aminoꢀtetrazole chelation assisted CꢀH bond activation (Scheme 3).16,3d The intermediate I may
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then undergo oxidative addition with NXS to yield Pd(IV)16d,e complex II, which may complete
the catalytic cycle via reductive elimination16,3d of the halogenated products and regeneration of
the Pd(II) species. The function of the CF3SO3H may be presumably to protonate the carbonyl of
the NXS that could lead to more effective Xꢀ source.3c,f In addition, CF3SOH may tune the
electrophilicity of Pd(II) that could improve the CꢀH activation process.16d
3
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CONCLUSIONS
In summary, Pd(II)ꢀcatalyzed 5ꢀaminotetrazole assisted orthoꢀselective direct halogenation
of Nꢀaryl ring of N,1ꢀdiarylꢀ1Hꢀtetrazolꢀ5ꢀamine derivatives has been described utilizing Nꢀ
halosuccinimide as a halogenating agent via CꢀH bond activation at moderate temperature. The
reaction is chemoꢀ and regioselective and the halogenated products can be obtained in moderate
to high yield.
EXPERIMENTAL SECTION
General Procedure for the Pd(II)-Catalyzed Halogenation of Aminotetrazoles. CF3SO3H
(0.5 mmol) was added to a stirred solution of aminotetrazole 1 (1 mmol), Pd(OAc)2 (10 mol %)
and NXS (1.2 mmol) in DCE (2 mL) under air. The mixture was stirred at 60 °C for the
appropriate time and the progress of the reaction was monitored by TLC using ethyl acetate and
hexane as eluent. After completion, the reaction mixture was cooled to room temperature and
treaed with saturated NaHCO3 (5 mL). The resulting 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 hexane and ethyl
acetate as eluent to afford analytically pure substituted Nꢀ(2ꢀhaloaryl)aminotetrazoles.
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N-(2-Bromophenyl)-1-(2-chlorophenyl)-1H-tetrazol-5-amine 2a. Analytical TLC on silica
gel, 1:4 ethyl acetate/hexane Rf = 0.71; 294 mg, 84% yield; white solid; mp 96ꢀ97 °C; 1H NMR
(400 MHz, CDCl3) δ 8.46 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 6.8 Hz, 2H), 7.50ꢀ7.47 (m, 2H), 7.37ꢀ
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7.33 (m, 2H), 7.13 (s, 1H), 7.04ꢀ7.00 (m, 1H); C NMR (100 MHz, CDCl3) δ 150.9, 134.6,
134.1, 131.7, 129.2, 128.4, 125.9, 124.9, 124.4, 124.1, 121.7, 120.2, 119.2; FTꢀIR (KBr) 3445,
3387, 2956, 2926, 1714, 1603, 1567, 1517, 1487, 1380, 1111, 1072, 827, 751 cmꢀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C13H9ClBrN5H 351.9781, found 351.9789.
N-(2-Bromo-5-methylphenyl)-1-m-tolyl-1H-tetrazol-5-amine 2b and
N-(2,6-dibromo-3-methylphenyl)-1-m-tolyl-1H-tetrazol-5-amine 2b'. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.68; white solid; 283 mg, 78% yield; mp 101ꢀ102 °C;
both isomers are reported together (ratio: 3.2:1 as determined by NMR);1H NMR (400 MHz,
CDCl3) δ 8.42 (s, 1H, major isomer), 8.30 (d, J = 9.2 Hz, 1H, minor isomer), 7.64 (s, 1H, major
isomer), 7.57ꢀ7.50 (m, 4H, 2H major + 2H minor isomers ), 7.41ꢀ7.36 (m, 6H, 3H major + 3H
minor isomers), 7.16 (br s, 1H), 2.56 (s, 3H, minor isomer), 2.47 (s, 6H, 3H major + 3H minor
isomers), 2.40 (s, 3H, major isomer);13C NMR (75 MHz, CDCl3) δ 150.8, 150.7, 141.3, 139.2,
137.7, 135.4, 134.8, 134.7, 132.3, 132.2, 131.5, 130.5, 125.0, 124.9, 121.2, 121.1, 120.3, 118.0,
117.2, 114.9, 108.9, 24.6, 23.0, 21.4; FTꢀIR (KBr) 3365, 3086, 2918, 2857, 1958, 1598, 1559,
1522, 1493, 1449, 1385, 1313, 1124, 1089, 1046, 875, 795, 692 cmꢀ1; HRMS (ESI) m/z: [M+H]+
calcd for C15H14BrN5H 344.0505, found 344.0504; HRMS (ESI) m/z: [M+H]+ calcd for
C15H13Br2N5H 423.9689, found 423.9685.
N-(2-Bromo-4-chlorophenyl)-1-(4-chlorophenyl)-1H-tetrazol-5-amine 2c. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; white solid; 320 mg, 84% yield; mp 175ꢀ176 °C;
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.57ꢀ7.53 (m,
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3H), 7.39 (dd, J = 8.8, 2.4 Hz. 1H), 7.13 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 150.8, 137.3,
133.4, 131.3, 131.0, 129.5, 129.2, 129.0, 128.7, 125.8, 122.2, 120.0; FTꢀIR (KBr) 3434, 3364,
2923, 2846, 1733, 1602, 1561, 1399, 1259, 1086, 1034, 814, 735 cmꢀ1; HRMS (ESI) m/z:
[M+H]+ calcd for C13H8BrCl2N5H 383.9413, found 383.9427.
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N-(2-Bromo-4-fluorophenyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine 2d. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.62; white solid; 287 mg, 82% yield; mp 171ꢀ172 °C;
1H NMR (400 MHz, CDCl3) δ 8.47ꢀ8.44 (m, 1H), 7.61ꢀ7.57 (m, 2H), 7.39ꢀ7.33 (m, 2H), 7.30ꢀ
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7.27 (m, 1H), 7.16ꢀ7.11 (m, 1H), 6.97 (br s, 1H); C NMR (100 MHz, CDCl3 + DMSOꢀd6) δ
164.1, 161.6, 159.4, 156.9, 153.1, 151.7, 132.6, 128.5, 126.6, 126.5, 122.4, 122.3, 119.5, 119.2,
117.2, 117.0, 115.3, 115.1, 114.6, 114.5; FTꢀIR (KBr) 3423, 3385, 2961, 2926, 2254, 1618,
1578, 1508, 1260, 1237, 1157, 1024, 809, 760 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C13H8F2BrN5H 352.0004, found 352.0000.
N-(2-Bromo-4-isopropylphenyl)-1-(4-isopropylphenyl)-1H-tetrazol-5-amine 2e. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.64; thick colorless liquid; 352 mg, 88% yield;
1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.4 Hz, 1H), 7.50ꢀ7.45 (m, 4H), 7.35ꢀ7.34 (d, J = 2.0
Hz, 1H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (br s, 1H), 3.03ꢀ2.99 (m, 1H), 2.85ꢀ2.82 (m, 1H),
1.30 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 151.5, 151.0,
145.1, 133.5, 130.2, 130.0, 128.5, 126.8, 124.1, 119.2, 112.1, 33.9, 33.2, 23.8, 23.7; FTꢀIR (KBr)
3372, 2961, 2928, 2870, 1598, 1556, 1523, 1460, 1388, 1364, 1316, 1238, 1117, 1084, 1058,
1013, 838, 710 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C19H22BrN5H 402.1113, found
402.1119.
N-(2-Bromo-4-methylphenyl)-1-p-tolyl-1H-tetrazol-5-amine 2f. Analytical TLC on silica gel,
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1:4 ethyl acetate/hexane Rf = 0.72; white solid; 313 mg, 91% yield; mp 152ꢀ153 °C; H NMR
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(400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1H), 7.47ꢀ7.42 (m, 4H), 7.32 (s, 1H), 7.19 (dd, J = 8.4,
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1.6 Hz, 1H), 7.09 (br s, 1H), 2.47 (s, 3H), 2.29 (s, 3H); C NMR (100 MHz, CDCl3) δ 151.2,
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141.1, 134.2, 133.4, 132.6, 131.3, 130.1, 129.6, 124.3, 119.0, 112.0, 21.4, 20.5; FTꢀIR (KBr)
3381, 3085, 2917, 1599, 1566, 1525, 1318, 1235, 1179, 1083, 1038, 816, 720 cmꢀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C15H14BrN5H 344.0505, found 344.0504.
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N-(2-Bromo-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-tetrazol-5-amine 2g and
N-(2,6-dibromo-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-tetrazol-5-amine
2g'.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.48; white solid; 366 mg, 88% yield;
mp 147ꢀ148 °C; both isomers are reported together (ratio: 1:1 as determined by NMR); 1H NMR
(400 MHz, CDCl3) δ 8.68 (s, 1H), 8.32 (d, J = 9.2 Hz, 1H ), 7.49ꢀ7.46 (m, 5H), 7.13ꢀ7.06 (m,
4H), 7.02 (s, 1H), 6.95 (dd, J = 9.2, 2.8 Hz, 1H), 6.80 (br s, 1H), 3.89 (s, 6H), 3.84 (s, 3H), 3.77
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(s, 3H); C NMR (75 MHz, CDCl3) δ 161.2, 161.1, 155.6, 151.6, 151.1, 151.0, 128.5, 128.2,
126.2, 124.9, 124.7, 122.6, 120.9, 120.4, 120.2, 115.7, 115.6, 114.8, 113.6, 112.7, 56.7, 55.8;
FTꢀIR (KBr) 3434, 3393, 2925, 2851, 1603, 1523, 1486, 1263, 1209, 1086, 1021, 824, 801, 746
cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd C15H14BrN5O2H 376.0404, found 376.0404; [M+H]+
calcd for C15H13Br2N5O2H 455.9416, found 455.9420.
N-(2-Bromo-4,6-dimethylphenyl)-1-(2,4-dimethylphenyl)-1H-tetrazol-5-amine
2h.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 234 mg, 63% yield;
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mp 98ꢀ99 °C; H NMR (400 MHz, CDCl3) δ 7.29ꢀ7.20 (m, 4H), 7.02 (s, 1H), 5.73 (br s, 1H),
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2.43 (s, 3H), 2.29 (s, 6H), 2.20 (s, 3H); C NMR (100 MHz, CDCl3) δ 153.8, 141.6, 138.8,
137.6, 135.9, 132.5, 132.0, 131.2, 130.7, 128.6, 128.2, 126.9, 122.0, 21.2, 20.6, 18.9, 17.3; FTꢀ
IR (KBr) 3370, 3247, 2959, 2923, 1714, 1587, 1515, 1476, 1381, 1293, 1227, 1102, 1087, 1027,
818, 734 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C17H18BrN5H 372.0818, found 372.0820.
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N-(2-Bromo-4,5-dimethylphenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine 2i and
N-(2,6-dibromo-3,4-dimethylphenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine
2i'.
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Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.71; white solid; 354 mg, 90% yield;
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mp 116ꢀ117 °C; both isomers are reported together (ratio: 2.5:1 as determined by NMR); H
NMR (400 MHz, CDCl3)δ 8.26 (s, 1H, major isomer), 8.24 (s, 1H, minor isomer), 7.40 (s, 1H,
minor isomer), 7.38ꢀ7.37 (m, 2H, major isomer ), 7.34ꢀ7.30 (m, 2H, 1H major + 1H minor
isomers), 7.27 (s, 1H, major isomer), 7.19 (d, J = 8.4 Hz, 1H, minor isomer), 7.09 (br s, 1H),
2.38 (s, 15H, 6H major + 9H minor isomers), 2.32 (s, 3H minor isomer), 2.29 (s, 3H major
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isomer), 2.21 (s, 3H, major isomer); C NMR (75 MHz, CDCl3) δ 151.2, 151.0, 139.5, 137.7,
136.6, 133.8, 133.3, 132.8, 132.6, 132.4, 131.5, 130.2, 130.1, 129.4, 125.1, 121.3, 120.0, 116.0,
115.6, 108.6, 20.8, 20.3, 19.9, 19.87, 19.7, 19.0; FTꢀIR (KBr) 3376, 2971, 2920, 1594, 1558,
1518, 1451, 1396, 1245, 1114, 1087, 1026, 874, 832, 723cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd
for C17H18BrN5H 372.0818, found 372.0807; [M+H]+ calcd for C17H17Br2N5H 453.9866, found
453.9862.
N-(2-Bromo-5-nitrophenyl)-1-p-tolyl-1H-tetrazol-5-amine 2j. Analytical TLC on silica gel,
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1:4 ethyl acetate/hexane Rf = 0.54; 295 mg, 79% yield; thick yellow liquid; H NMR (400 MHz,
CDCl3) δ 8.51 (d, J = 8.4 Hz, 1H), 7.56ꢀ7.47 (m, 6H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3 +
DMSOꢀd6) δ 150.8, 150.6, 141.5, 137.9, 131.3, 129.5, 129.2, 124.2, 121.9, 119.0, 103.9, 21.4;
FTꢀIR (KBr) 3427, 2912, 2247, 1635, 1605, 1525, 1344, 1116, 1024, 998, 823, 764 cmꢀ1. HRMS
(ESI) m/z: [M+Na]+ calcd for C14H11BrN6O2Na 397.0030, found 397.0025.
N-(2-Bromo-4-methylphenyl)-1-(2-chlorophenyl)-1H-tetrazol-5-amine 2k. Analytical TLC
on silica gel, 1:4 ethyl acetate/ hexane Rf = 0.70; white solid; 337 mg, 92% yield; mp 158ꢀ159
°C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.4, 0.8 Hz, 1H), 7.42
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(s, 1H), 7.30ꢀ7.22 (m, 3H), 7.12 (br s, 1H), 6.97ꢀ6.93 (m, 1H), 2.44 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 150.8, 141.3, 134.6, 131.5, 129.1, 128.4, 127.1, 126.3, 123.8, 122.6, 121.5, 119.0, 23.6;
FTꢀIR (KBr) 3381, 3104, 2921, 1898, 1605, 1567, 1515, 1314, 1093, 1034, 823, 736 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C14H11BrClN5H 363.9959, found 363.9957.
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N-(2-Bromo-4-nitrophenyl)-1-(2-chlorophenyl)-1H-tetrazol-5-amine 2l. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.42; white solid; 293 mg, 74% yield; mp 116ꢀ117 °C;
1H NMR (400 MHz, CDCl3 + DMSOꢀd6) δ 8.36 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H),
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8.19ꢀ8.16 (m, 2H), 7.67ꢀ 7.61 (m, 3H), 7.56 (dd, J = 7.6, 1.6 Hz, 1H); C NMR (75 MHz,
CDCl3 + DMSOꢀd6) δ 150.6, 141.8, 141.2, 132.4, 130.5, 130.4, 128.8, 128.7, 128.1, 127.5,
123.7, 117.8, 111.1; FTꢀIR (KBr) 3445, 3109, 2928, 2258, 1605, 1520, 1412, 1339, 1283, 1115,
1025, 1001, 827, 742 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C13H8BrClN6O2H 394.9653,
found 394.9658.
N-(2-Bromo-4-ethylphenyl)-1-(2-fluorophenyl)-1H-tetrazol-5-amine 2m. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 285 mg, 79% yield; mp 106ꢀ107 °C;
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.64ꢀ7.56 (m, 2H), 7.43ꢀ7.35 (m, 2H),
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7.32 (s, 1H), 6.93 (br s, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); C NMR (100
MHz, CDCl3) δ 157.4, 154.8, 152.0, 141.0, 133.8, 133.4, 133.23, 133.2, 131.6, 129.4, 129.0,
128.4, 128.3, 126.09, 126.1, 125.0, 122.9, 120.3, 120.2, 120.0, 119.4, 117.8, 117.6, 112.4, 28.6,
15.5; FTꢀIR (KBr) 3383, 3074, 2966, 2931, 2863, 1599, 1563, 1522, 1461, 1390, 1316, 1258,
1228, 1085, 1041, 979, 877, 824, 757, 663 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C15H13BrFN5H 362.0411, found 362.0413.
N-(2-Bromo-4-methylphenyl)-1-(2,6-dimethylphenyl)-1H-tetrazol-5-amine 2n. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.55; white solid; 318 mg, 89% yield; mp 134ꢀ
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135 °C; H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz, 1H), 7.32ꢀ7.28 (m, 1H), 7.18ꢀ7.16
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(m, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.47 (br s, 1H), 2.16 (s, 3H), 1.95 (s, 6H); C NMR (100
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MHz, CDCl3) δ 151.9, 136.6, 134.3, 133.1, 132.4, 131.5, 129.4, 129.3, 119.2, 112.1, 20.3, 17.4;
FTꢀIR (KBr) 3483, 3367, 3137, 3953, 2921, 2863, 2754, 2360, 1590, 1566, 1493, 1404, 1310,
1243, 1170, 1119, 1144, 1043, 891, 814, 775, 596 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C16H16BrN5H 360.0643, found 360.0644
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N,1-Bis(2-chlorophenyl)-1H-tetrazol-5-amine 3a. Analytical TLC on silica gel, 1:4 ethyl
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acetate/hexane Rf = 0.66; white solid; 264 mg, 86% yield; mp 81ꢀ82 °C; H NMR (400 MHz,
CDCl3) δ 8.44 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.63ꢀ7.59 (m, 1H), 7.57ꢀ7.53 (m,
2H), 7.35ꢀ7.31(m, 2H), 7.01ꢀ6.97 (m, 1H), 6.82 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 151.8,
134.6, 133.0, 131.4, 131.3, 129.6, 129.4, 129.1, 128.9, 128.2, 124.0, 121.8, 119.2; FTꢀIR (KBr)
3433, 2925, 2857, 2318, 1742, 1603, 1568, 1465, 1448, 1265, 1089, 1028, 795, 744 cmꢀ1; HRMS
(ESI) m/z: [M+H]+ calcd for C13H9Cl2N5H 306.0308, found 306.0307.
1-(4-Chlorophenyl)-N-(2,4-dichlorophenyl)-1H-tetrazol-5-amine 3b. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 212 mg, 63% yield; mp 180ꢀ181 °C;
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.4 Hz, 1H), 7.68ꢀ7.66 (m, 2H), 7.59ꢀ7.55 (m, 2H),
7.47ꢀ7.40 (m, 1H), 7.35ꢀ7.27 (m, 1H), 7.10 (br s, 1H); 13C NMR (100 MHz, CDCl3 + DMSOꢀd6)
δ 151.1, 135.9, 133.8, 131.0, 130.5, 130.2, 128.7, 128.5, 127.7, 125.4, 121.3; FTꢀIR (KBr) 3459,
3375, 3096, 2915, 1652, 1652, 1599, 1559, 1511, 1491, 1467, 1275, 1260, 1093, 1048, 859, 831,
764, 749 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C13H8Cl3N5H 339.9918, found 339.9907.
N-(2-Chloro-4-fluorophenyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine 3c. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.61; white solid; 270 mg, 88% yield; mp 101ꢀ102 °C;
1H NMR (400 MHz, CDCl3) δ 8.46ꢀ8.41 (m, 1H), 7.60ꢀ7.56 (m, 2H), 7.38ꢀ7.33 (m, 2H), 7.15ꢀ
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7.06 (m, 2H), 6.92 (br s, 1H); C NMR (100 MHz, CDCl3 + DMSOꢀd6) δ 164.0, 161.4, 159.3,
156.8, 153.0, 151.7, 131.4, 128.5, 126.5, 126.4, 125.0, 124.8, 122.62, 122.6, 117.0, 116.8, 116.4,
116.2, 114.8, 114.5, 114.3; FTꢀIR (KBr) 3398, 3325, 2981, 2394, 1685, 1612, 1578, 1502, 1365,
1260, 1242, 1162, 1023, 826, 793 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C13H8F2ClN5H
308.0509, found 308.0509.
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N-(2-Chloro-4-isopropylphenyl)-1-(4-isopropylphenyl)-1H-tetrazol-5-amine 3d. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.60; thick colorless liquid; 291 mg, 82% yield;
1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.0 Hz, 1H), 7.50ꢀ7.45 (m, 4H), 7.19ꢀ7.16 (m, 2H),
7.06 (br s, 1H), 3.05ꢀ2.98 (m, 1H), 2.87ꢀ2.80 (m, 1H), 1.30 (d, J = 7.2 Hz, 6H), 1.21 (d, J = 6.8
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Hz, 6H); C NMR (100 MHz, CDCl3) δ 151.7, 151.1, 144.8, 132.4, 130.2, 128.6, 126.8, 126.2,
124.1, 119.1, 33.9, 33.3, 23.8, 23.7; FTꢀIR (KBr) 3388, 3043, 2961, 2928, 2870, 1908, 1599,
1556, 1523, 1461, 1416, 1390, 1317, 1240, 1117, 1143, 1085, 1051, 1013, 980, 909, 837, 780,
723, 676 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C19H22ClN5H 356.1636, found 356.1637.
N-(2-Chloro-4-methylphenyl)-1-p-tolyl-1H-tetrazol-5-amine 3e. Analytical TLC on silica gel,
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1:4 ethyl acetate/hexane Rf = 0.70; white solid; 249 mg, 83% yield; mp 137ꢀ138 °C; H NMR
(400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 7.46ꢀ7.41 (m, 4H), 7.16ꢀ7.13 (m, 2H), 7.04 (br s,
1H), 2.47 (s, 3H), 2.29 (s, 3H);13C NMR (100 MHz, CDCl3) δ 151.2, 141.2, 133.8, 132.3, 131.3,
130.1, 129.5, 129.0, 124.3, 121.4, 119.0, 21.5, 20.7; FTꢀIR (KBr) 3397, 3085, 2922, 2851, 1619,
1604, 1561, 1525, 1380, 1316, 1234, 1087, 1046, 817 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C15H14ClN5H 300.1010; found 300.1007.
N-(2-Chloro-4,6-dimethylphenyl)-1-(2,4-dimethylphenyl)-1H-tetrazol-5-amine 3f. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.48; white solid; 222 mg, 68% yield; mp 102ꢀ
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103 °C; H NMR (400 MHz, CDCl3) δ 7.28ꢀ7.26 (m, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 6.98 (s,
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1H), 5.72 (br s, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.9,
141.7, 138.4, 137.5, 136.0, 132.6, 130.9, 130.6, 128.6, 128.3, 127.7, 126.9, 21.3, 20.9, 18.7,
17.4; FTꢀIR (KBr) 3158, 3065, 2968, 2923, 1587, 1512, 1478, 1312, 1285, 1227, 1114, 1085,
1027, 850, 816 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C17H18ClN5H 328.1323, found
328.1323.
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N-(2-Chloro-4,5-dimethylphenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine 3g and
N-(2,6-dichloro-3,4-dimethylphenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine
3g'.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; white solid; 304 mg, 90% yield;
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mp 130ꢀ131 °C; both isomers are reported together (ratio: 2.4:1 as determined by NMR); H
NMR (400 MHz, CDCl3) δ 8.24 (s, 1H, major isomer), 8.21 (s, 1H, minor isomer), 7.38 (s, 1H,
minor isomer), 7.36 (d, J = 11.6 Hz, 1H, major isomer), 7.29 (dd, J = 8.0, 2.4 Hz, 2H, major
isomer), 7.20 (s, 1H, minor isomer), 7.14 (d, J = 8.4 Hz, 1H, minor isomer), 7.10 (s, 1H, major
isomer), 7.02 (br s, 1H), 2.36 (s, 12H, 6H major + 6H minor isomers), 2.30 (3H, minor isomer),
2.28 (3H, major isomer), 2.27 (3H, minor isomer), 2.19 (3H, major isomer); 13C NMR (75 MHz,
CDCl3) δ 151.1, 151.0, 139.6, 137.0, 134.8, 132.6, 132.3, 132.2, 132.1, 131.5, 130.2, 130.15,
129.5, 128.7, 125.2, 122.1, 121.2, 120.0, 118.3, 115.8, 20.4, 19.9, 19.8, 19.7, 19.0, 16.9; FTꢀIR
(KBr) 3158, 3065, 2968, 2923, 1587, 1512, 1478, 1312, 1285, 1227, 1114, 1085, 1027, 850, 816,
732 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C17H18ClN5H 328.1323; found 328.1318; [M+H]+
calcd for C17H17Cl2N5H 362.0934; found 362.0927.
N-(2-Chloro-4-nitrophenyl)-1-(2-chlorophenyl)-1H-tetrazol-5-amine 3h. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.20; white solid; 276 mg, 79% yield; mp 135ꢀ136 °C;
1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 9.2 Hz, 1H), 8.29ꢀ8.24 (m, 2H), 7.75ꢀ7.56 (m, 4H),
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7.19 (br s, 1H); C NMR (100 MHz, CDCl3 + DMSOꢀd6) δ 151.0, 142.3, 140.4, 133.0, 131.2,
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130.9, 129.3, 128.8, 124.8, 124.0, 121.5, 118.0; FTꢀIR (KBr) 3439, 3112, 2932, 2249, 1624,
1524, 1409, 1337, 1279, 1125, 1045, 1003, 810, 725, 649 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd
for C13H8Cl2N6O2H 351.0159, found 351.0157.
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N-(2-chloro-4-ethylphenyl)-1-(2-fluorophenyl)-1H-tetrazol-5-amine 3i. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 259 mg, 82% yield; mp 113ꢀ114 °C;
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 7.61ꢀ7.55 (m, 2H), 7.46ꢀ7.36 (m, 2H),
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7.15ꢀ7.12 (m, 2H), 6.91 (br s, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 157.3, 154.8, 152.0, 140.6, 133.2, 133.1, 132.3, 128.4, 128.3, 127.7,
126.13, 126.1, 121.9, 120.4, 120.3, 119.4, 117.8, 117.6, 28.1, 15.5; FTꢀIR (KBr) 3444, 3066,
2970, 2871, 1602, 1522, 1503, 1464, 1390, 1318, 1257, 1230, 1131, 1021, 874, 755, 708 cmꢀ1;
HRMS (ESI) m/z: [M+H]+ calcd for C15H13ClFN5H 318.0916, found 318.0912.
N-(2-Chloro-4-methylphenyl)-1-(2,6-dimethylphenyl)-1H-tetrazol-5-amine 3j. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 281 mg, 90% yield; mp 130ꢀ
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131 °C; H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 7.46ꢀ7.42 (m, 1H), 7.31ꢀ7.28
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(m, 2H), 7.18ꢀ7.16 (m, 2H), 6.49 (br s, 1H), 2.30 (s, 3H), 2.08 (s, 6H); C NMR (100 MHz,
CDCl3) δ 151.9, 136.8, 134.0, 132.1, 131.6, 129.5, 129.4, 128.8, 121.6, 119.4, 20.5, 17.4; FTꢀIR
(KBr) 3141, 3056, 2924, 2886, 1701, 1657, 1611, 1556, 1501, 1478, 1445, 1379, 1305, 1263,
1242, 1208, 1161, 785 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C16H16ClN5H 314.1167, found
314.1168.
N-(4-Fluoro-2-iodophenyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine 4a. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.66; white solid; 360 mg, 90% yield; mp 173ꢀ174 °C;
1H NMR (400 MHz, CDCl3 + DMSO) δ 8.35ꢀ8.31 (m, 1H), 7.63ꢀ7.59 (m, 2H), 7.48 (dd, J = 8.0,
3.2 Hz, 1H), 7.37ꢀ7.33 (m, 2H), 7.17ꢀ7.12 (m, 1H), 6.83 (br s, 1H); 13C NMR (100 MHz, CDCl3
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+ DMSOꢀd6) δ 163.3, 160.8, 159.4, 156.9, 152.1, 135.7, 128.3, 126.3, 126.2, 125.0, 124.8, 123.8,
116.3, 116.1, 115.3, 115.1, 93.0; FTꢀIR (KBr) 3427, 2255, 2128, 1645, 1578, 1522, 1509, 1234,
1048, 1025, 103, 825, 764, 632 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C13H8F2IN5H
399.9865, found 399.9856.
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N-(2-Iodo-4-isopropylphenyl)-1-(4-isopropylphenyl)-1H-tetrazol-5-amine 4b. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 388 mg, 87% yield; mp 109ꢀ
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110 °C; H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H),7.47ꢀ
7.37 (m, 4H), 7.17 (dd, J = 8.4, 1.4 Hz, 1H), 6.87 (br s, 1H), 2.95ꢀ2.90 (m, 1H), 2.74ꢀ2.69 (m,
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1H), 1.21 (d, J = 6.8 Hz, 6H), 1.12 (d, J = 6.8 Hz, 6H); C NMR (100 MHz, CDCl3) δ 151.8,
151.6, 145.9, 136.7, 136.3, 130.2, 128.6, 127.9, 124.6, 119.1, 88.6, 34.0, 33.2, 23.92, 23.9; FTꢀ
IR (KBr) 3492, 337, 2960, 2868, 1593, 1557, 1523, 1483, 1460, 1410, 1388, 1314, 1261,1084,
1058, 1031, 1013, 837, 749 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for C19H22IN5H 448.0993,
found 448.0997.
N-(2-Iodo-4-methylphenyl)-1-p-tolyl-1H-tetrazol-5-amine 4c. Analytical TLC on silica gel,
1:4 ethyl acetate/hexane Rf = 0.73; white solid; 364 mg, 93% yield; 1H NMR (400 MHz, CDCl3)
δ 8.27 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.49ꢀ7.42 (m, 4H), 7.21 (d, J = 8.4 Hz, 1H), 6.92 (br s,
1H), 2.47 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)δ 151.5, 141.1, 139.1, 136.0, 134.8,
131.2, 130.5, 130.0, 124.5, 118.7, 88.3, 21.4, 20.3; FTꢀIR (KBr) 3456, 3352, 2922, 2846, 1722,
1594, 1559, 1523, 1478, 1380, 1305, 1085, 1035, 818, 740 cmꢀ1; HRMS (ESI) m/z: [M+H]+
calcd for C15H14IN5H 392.0367, found 392.0368.
N-(2-Iodo-4,6-dimethylphenyl)-1-(2,4-dimethylphenyl)-1H-tetrazol-5-amine 4d. Analytical
TLC on silica gel,1:4 ethyl acetate/hexane Rf = 0.53; brown liquid; 307 mg, 73% yield; 1H NMR
(400 MHz, CDCl3) δ 7.48 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 6.4 Hz,
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1H), 7.04 (s, 1H), 5.55 (br s, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H); 13C NMR
( 75 MHz, CDCl3) δ 153.6, 141.8, 139.5, 137.3, 136.9, 136.1, 134.8, 132.7, 132.4, 128.5, 128.3,
127.0, 99.7, 21.4, 20.5, 19.5, 17.7; FTꢀIR (KBr) 3389, 3054, 2922, 2851, 1599, 1565, 1520,
1453, 1386, 1245, 1113, 1087, 1022, 877, 819, 639 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C17H18IN5H 420.0680, found 420.0682.
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N-(2-Iodo-4,5-dimethylphenyl)-1-(3,4-dimethylphenyl)-1H-tetrazol-5-amine 4e. Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.71; white solid; 362 mg, 86% yield; mp 153ꢀ
154 °C;1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.47 (s, 1H), 7.37ꢀ7.33 (m, 3H), 6.91 (br s,
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1H), 2.36 (s, 6H), 2.27 (s, 3H), 2.16 (s, 3H); C NMR (75 MHz, CDCl3) δ 151.3, 139.6, 139.0,
138.8, 136.1, 133.7, 131.5, 130.1, 125.3, 121.8, 120.0, 84.1, 20.0, 19.9, 19.8, 18.8; FTꢀIR (KBr)
3359, 3054, 2950, 2919, 2851, 1589, 1557, 1518, 1450, 1393, 1245, 1084, 873, 831 cmꢀ1; HRMS
(ESI) m/z: [M+H]+ calcd for C17H18IN5H 420.0680, found 420.0685.
1-(2-Chlorophenyl)-N-(2-iodo-4-methylphenyl)-1H-tetrazol-5-amine 4f. Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.72; white solid; 364 mg, 89% yield; mp 108ꢀ109 °C;
1H NMR (400 MHz, CDCl3) δ 8.44ꢀ8.42 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.4 Hz,
1H), 7.35ꢀ7.30 (m, 2H), 7.18 (br s, 1H), 7.12 (dd, J = 8.4, 2.4 Hz, 1H), 7.02 (td, J = 8.0, 1.6 Hz,
1H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.6, 144.9, 141.0, 134.5, 132.5, 129.1, 128.3,
125.0, 123.9, 122.5, 121.5, 119.0, 103.2, 28.4; FTꢀIR (KBr) 3467, 3387, 2922, 2840, 1603, 1566,
1520, 1470, 1374, 1317, 1088, 1017, 576 cmꢀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C14H11ClIN5H 411.9820, found 411.9831.
1-(2,6-Dimethylphenyl)-N-(2-iodo-4-methylphenyl)-1H-tetrazol-5-amine 4g: Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; white solid; 364 mg, 90% yield; mp 156ꢀ157 °C;
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 1.2 Hz, 1H), 7.34ꢀ7.30 (m,
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(s, 6H); C NMR (100 MHz, CDCl3) δ 152.1, 138.9, 136.8, 135.7, 134.8, 131.6, 130.4, 129.5,
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129.4, 118.7, 88.3, 20.2, 17.5; FTꢀIR (KBr) 3343, 3201, 2920, 2858, 1596, 1588, 1561, 1525,
1486, 1473, 1445, 1376, 1308, 1236, 1169, 1087, 984, 868, 811, 777, 730 cmꢀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C16H16IN5H 406.0523, found 406.0524.
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ASSOCIATED CONTENT
Supporting Information
General information, procedure for the preparation of deuterated aniline, isotopic kinetic study,
13
crystal structure and data, and NMR (1H and C) spectra of 2a-n, 3a-j, 4a-g, 1o and 3o. This
material is available free of charge via the internet at http://pubs.acs.org.
ACKNOWLEDGMENTS
We gratefully acknowledge Department of Science and Technology, New Delhi, and Council of
Scientific and Industrial Research, New Delhi, for financial support.
REFERENCES
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