Sequential Pd(0)/Fe(III) Catalyzed Azide-Isocyanide Coupling/Cyclization Reaction: One-Pot Synthesis of Aminotetrazoles

Article abstract of DOI:10.1021/acs.joc.8b01261

A rapid and efficient synthesis of aminotetrazole from aryl azides, isocyanides, and TMSN₃ is developed. The reaction is promoted by sequential Pd(0)/Fe(III) catalysis. The reaction sequence utilizes the Pd-catalyzed azide-isocyanide denitrogenative coupling reaction to generate unsymmetric carbodiimide in situ, which reacts with TMSN₃ in the presence of FeCl₃ in a single pot. The methodology has distinct advantages over traditional synthetic approaches where toxic Hg and Pb salts are employed at stoichiometric scale.

Full text of DOI:10.1021/acs.joc.8b01261

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Note
Sequential Pd(0)/Fe(III) catalyzed azide-Isocyanide Coupling/
Cyclization Reaction: One-pot synthesis of Aminotetrazoles
RAMDAS S. PATHARE, Arshad J Ansari, Sarika Verma, Anand Maurya, Antim K
Maurya, Vijai K Agnihotri, Ashoke Sharon, Ram T. Pardasani, and Devesh M Sawant
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01261 • Publication Date (Web): 24 Jul 2018
Downloaded from http://pubs.acs.org on July 24, 2018
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Sequential
Coupling/Cyclization
Aminotetrazoles
Pd(0)/Fe(III)
catalyzed
azide-Isocyanide
synthesis of
Reaction: One-pot
9
Ramdas S. Pathare,a Arshad J. Ansari,a Sarika Verma,b Anand Maurya,a Antim K.
Maurya,c Vijai K. Agnihotri,c Ashoke Sharon,b Ram. T. Pardasania and Devesh M.
Sawant*a
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a
School of Chemical Sciences and Pharmacy, Central University of Rajasthan, NHꢀ8, Bandarsindri, Ajmerꢀ
305817, Rajasthan, India, email: dms@curaj.ac.in
Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhandꢀ835215
Natural Product Chemistry and Process Development division, CSIRꢀInstitute of Himalayan Bioresource
b
c
Technology, Palampur, Himachal Pradesh ꢀ176061. India
Abstract
A rapid and efficient synthesis of aminotetrazole from aryl azides, isocyanides and TMSN3 is
developed. The reaction is promoted by sequential Pd(0)/Fe(III) catalysis. The reaction sequence
utilizes the Pdꢀcatalyzed azideꢀisocyanide denitrogenative coupling reaction to generate
unsymmetric carbodiimide in situ, which reacts with TMSN3 in the presence of FeCl3 in a single
pot. The methodology has distinct advantages over traditional synthetic approaches where toxic
Hg and Pb salts are employed at stoichiometric scale.
Aminotetrazoles are an interesting class of fiveꢀmembered nitrogenꢀrich aromatic heterocycles1
with a wide range of applications such as nonꢀclassical bioisosters for the carboxylic acid,2 cisꢀ
amide surrogate,3 antifoggants in photographic materials,4 plasmaꢀpolymer films in biomedical
applications,5 propellants6 and explosives7 in materials science, and ligand in coordination
chemistry.8 Interestingly, aminotetrazoles exhibits antiꢀHIV9 and antiallergic activity,10 and
inhibits crucial protein drug targets such as glutamate receptor,11 P2X7 receptors,12 peptidyl
endothelin converting enzyme (ECE),13 fatty acid amide hydrolase (FAAH),14 mitochondrial
thymidine kinase (TK 2)15 and hyaluronidase.16
Traditionally, aminotetrazoles were synthesized by diazotization of aminoguanidines,17 azidation
of cyanamides,18 carbodiimides,19 aminoiminoꢀmethanesulfonic acids20 (X = SO3R) and α–
chloroformamidines21 (X = Cl), and the reaction of amines with cyanogen azides22 or 5ꢀchloroꢀ
and 5ꢀsulfonylꢀtetrazoles23 (Scheme 1a). During the last couple of decades, a twoꢀstep synthesis
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of aminotetrazole is reported based on the inꢀsitu generation of carbodiimide by either
desulfurization of thiourea using mercury,24 lead,17a Copper,25 iodine26 or IBX27 or
deselenylation of selenylurea by hypervalent iodine reagent28 followed by azidation (Scheme 1a).
Recently, Ponnuswamy and coworkers developed a threeꢀcomponent assembly of
aminotetrazoles from isothiocyanides, amines and sodium azides in the presence of toxic
mercury salts (Scheme 1b).29 Despite their utility, these methodologies possess serious
drawbacks such as use of expensive and toxic reagents (mercury, lead and iodine etc.), harsher
reaction conditions, longer reaction time and sensitivity towards moisture. In addition, these
synthetic strategies are either multistep linear processes or employ complex precursors30
generated in a multistep fashion. Therefore, the development of rapid, efficient and sustainable
synthetic methodologies from easily available starting materials in oneꢀpot promoted by catalysts
instead of toxic reagents at stoichiometric scale remains highly desirable.
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Combining two transition metals for catalyzing new and valuable reactions has recently emerged
as a powerful strategy in the field of organic synthesis. The presence of second transition metal
expands the scope of synthetic transformation that wouldn't have been achieved with either of
the catalysts alone. Had the combination of two metals been allowed in oneꢀpot, additional
purification of intermediates could have been avoided leading to minimization of waste.
However, development of such processes is not a straightforward affair owing to redox
incompatibility issues among various transition metals. In such cases, however sequential
catalysis, an addition of catalysts in a stepwise manner, is employed as a strategy to exploit the
synthetic potential of both metals.
Scheme 1: Various strategies for the synthesis of aminotetrazoles
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Based on our previous report on Pdꢀcatalyzed nitrene transfer on isocyanide31 and one pot
catalyses,32 we report herein development of threeꢀcomponent reaction catalyzed by sequential
Pd(0)/Fe(III) catalytic system to generate aminotetrazole (Scheme 1c). Our methodology is based
on Pd(0)ꢀcatalyzed azideꢀisocyanide denitrogenative coupling reaction to generate
carbodiimide33 in-situ and subsequent Fe(III)ꢀcatalyzed cyclization with TMSꢀN3. The use of
FeCl3 allowed rapid and sustainable generation of aminotetrazoles in oneꢀpot with excellent
regioselectivity.
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To achieve our goal, we embarked the investigation by optimizing the azideꢀisocyanide
denitrogenative coupling reaction for the synthesis of carbodiimide 3 (Table 1). A mixture of
arylazide 1a and isocyanide 2a were reacted with a catalytic amount of Pd(PPh3)4 as a catalyst in
toluene at rt to furnish carbodiimide 3a in 90 % yield (entry 6). The reaction was completed in
0.5 h. Screening with other Pdꢀsources and solvents for azideꢀisocyanide denitrogentive coupling
reaction turned out to be inferior with the optimized reaction. Among various Pdꢀsources tried,
Pd(PPh3)4 produced the best yields and the reaction failed to initiate in the absence of a catalyst.
Table 1. Optimization of reaction conditions for azideꢀisocyanide denitrogentive coupling
reactiona
Sr.
No.
1
Catalyst
(5 mol %)
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
ꢀ
Solvent
Yieldb
(%)
25
THF
toluene
2
57
3
toluene
70
4
toluene
0
5
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
toluene
75
6
toluene
1,4ꢀdioxane
1,2ꢀDCE
90
7
45
8
30
a Reaction conditions: all reactions (0.3 mmol scale) were performed using 1:1.2 ratio of 1a:2a, 5 mol % Pd(PPh3)4,
0.5 mL of toluene, 0.5 h. b Isolated yield; c Starting material was recovered.
Then, we shifted our attention to the reaction of carbodiimide 3a and TMSN3 (Table 2). Pdꢀ
sources failed to drive this reaction. Pleasingly, screening of other metal sources such as Cu and
Fe and solvents has improved the overall conversion. Of these, FeCl3 furnished excellent yields
o
of title compound 4a in toluene at 100 C. With the successes of finding a common solvent, we
next directed our efforts to design a relay protocol, where both Palladium and iron catalysts
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present at outset. Regrettably, we failed to develop the relay protocol and the reaction didn’t
initiate due to redox incompatibilities of these metals. Thus, a sequential protocol is developed,
where 1a and 2a
Table 2: Optimization of reaction conditions for cyclizationa
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Sr.
No
Catalyst
(10 mol %)
Pd(PPh3)4
ZnCl2
CuI
Solvent
Time Temp. Yieldb
(h)
8
(o C)
100
100
100
100
85
(%)
1
2
Toluene
Toluene
DMF
15
12
5
15c
43
3
4
FeCl3
1,4ꢀdioxane
Ethanol
Toluene
Toluene
Toluene
Toluene
Toluene
5
15
5
FeCl3
3
70
6
FeCl3
FeCl3
2
100
rt
90
7
8
37
8
FeCl3
4
110
130
100
50
9
FeCl3
5
57
10
ꢀ
8
Tracec
a) Reaction conditions: all reactions (0.3 mmol scale) were performed using 3a, 1.5 equiv TMSN3, 10 mol% FeCl3,
100 C, 1ꢀ2 h. followed by aqueous workup. Isolated yields after chromatography; Starting material was
recovered.
o
b
c
were first reacted in presence of Pd(PPh3)4 with toluene as solvent at rt for 0.5 h, then TMSꢀN3
and FeCl3 were added and the reaction was refluxed to 100 oC to furnish the 5ꢀamino tetrazole 4a
in 90% isolated yield. With optimal reaction conditions for the transformation of arylazides 1 to
tetrazoles 4 in hand, we explored the generality of this reaction. As shown in scheme 2, a broad
range of differently substituted aryl azides, bearing both electron donating and electron
withdrawing substituents reacted efficiently with a range of isocyanides 2 and TMSN3 to access
the corresponding 5ꢀaminoꢀ1H-tetrazoles 4 (Scheme 2). Substituents at all three positions (orthoꢀ
, metaꢀ and paraꢀ) of aryl azides were well tolerated with no detrimental steric effect observed
for the orthoꢀsubstitutions. Various alkylꢀ, cycloalkylꢀ, and arylꢀsubstituted isocyanides reacted
well under the optimized reaction conditions to generate 5ꢀaminoꢀ1Hꢀtetrazoles in good to
excellent yields as shown in scheme 2. However, aryl isocyanides bearing electronꢀdonating
substituents and aliphatic azides failed to react under standard condition. Pleasingly, the
bimetallic sequential reaction exhibited excellent and unique regioselectivity, which is
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unambiguously confirmed by single crystal Xꢀray crystallographic studies. Interestingly, the
regiochemical outcome was reversed for 4o-4s.34
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Scheme 2: Substrate scope for the synthesis of 4a.
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aReaction conditions: All reactions (0.3 mmol scale) were performed using 1:1.2 ratio of 1a:2a, 5 mol% Pd(PPh3)4,
0.5 mL of toluene, 0.5 h, rt; after completion of reaction, addition of 1.5 equiv TMSN3, 10 mol% FeCl3, 100 oC, 1ꢀ2
h followed by aqueous workup, isolated yields after chromatography. bStarting material recovered.
In order to gain insight into the reaction mechanism, control experiments were carried out as
depicted in scheme 3. Azideꢀisocyanide denitrogenative coupling was a Pdꢀdependent process
(Scheme 3A), whereas azideꢀcarbodiimide cyclization was promoted by FeCl3 (Scheme 3B).
Radical scavengers did not alter the reaction pathway suggesting the involvement of a nonꢀ
radical pathway (Scheme 3C).
Scheme 3: Control Experiments
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On the basis of experimental findings and literature precedence,25,31,33 the plausible mechanism
was proposed as shown in scheme 4. The reaction begins with the coordination of Pd(PPh3)4 with
azidobenzene 1a and isocyanide 2 to generate 5, which on extrusion of dinitrogen gives nitrene
6. This is followed by intramolecular transfer of nitrene in a concerted manner31 to furnish
carbodiimide 3. Upon entering the Feꢀcycle, carbodiimide 3 first coordinates with iron metal
along with azide to produce complex 9. Azide nucleophile then attacks carbodiimide 3 to
generate guanidyl intermediate 10, which undergoes electrocyclization to furnish 4.
Scheme 4: Plausible reaction mechanism
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In conclusion, we have developed a rapid, efficient and atomꢀeconomical strategy for the
synthesis of tetrazole derivatives by employing Pd and Fe as a dual catalyst system. Robust
nature of each catalytic cycle of transition metals allowed development of the sequential oneꢀpot
protocol, which is evident by the failure of reaction in the absence of either of the catalyst. The
reaction involves the formation of three new chemical bonds. The salient features of the
methodology are shorter reaction times, broad substrate scope, milder reaction condition and use
of cheaper iron salts. The method underscores applicability of Pd(0)/Fe(III) promoted sequential
catalysis as an alternative for the synthesis of aminotetrazole form toxic Hg and Pb salts. The
detailed study of the regiochemical outcome of bimetallic sequential catalysis is under progress.
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Experimental Section
General Information: All the reactions were carried out under Ar atmosphere using
standard Schlenk techniques. DMF was purchased from Spectrochem. Isocyanides were
purchased from SigmaꢀAldrich. All other reagents were purchased from Aldrich or
Spectrochem used as such without purification. Analytical TLC was performed using 2.5 x
5cm plated coated with a 0.25mm thickness of silica gel (60Fꢀ254 Merck) and visualization
1
was accomplished with UV light or I2/ KMnO4 staining. H and 13C NMR spectra were
1
obtained from Bruker’s Ascend 500MHz spectrophotometer operating at 500.3 MHz for H
and 125.8 MHz for 13C experiments. The chemical shifts are reported in ppm scale with
1
respect to CDCl3 (7.269ppm) for H and (77.00ppm) for 13C NMR as an internal standard.
The abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double
doublet, m = multiplet, br.s = broad singlet & br = broad signal. Highꢀresolution mass
spectra (HRMS) were taken in the ESI positive ion mode.
General Procedure for the synthesis of 1:
The compound 1 was synthesized using the procedure reported in the literature.35 the
1
intermediates 1 were obtained and confirmed by recording their H NMR, which matched peak
by peak with the reported 1H NMR data.
CAUTION: It is known that azides are potential explosives and must be therefore handled with
care and stored at low temperature. It is also recommended to prepare azides at a maximum of
10 mmol scales to avoid risks.
General procedure for the synthesis of 4:
A 10 mL schlenk tube equipped with a stirꢀbar was charged with azido benzene (0.05 g, 0.42
mmol), tertꢀbutyl isocyanide (0.041 g, 0.50 mmol) in toluene (0.5 mL) as a solvent. The reaction
tube was purged with argon. Then after 5ꢀ10 min. Pd(PPh3)4 (0.004 g, 0.021 mmol) was added to
the reaction mixture followed by argon purging. The mixture was stirred at room temperature for
30 min. under an inert atmosphere. After completion of the reaction, TMSN3 (0.05 g, 0.84 mmol)
o
and iron chloride (0.007 g, 0.042 mmol) was added and stirred it at 100 C for 1 h. After
completion of the reaction, the reaction mixture was passed through celite bed and washed with
EtOAc. The reaction mixture was diluted with EtOAc, which was washed with water and brine
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successively, dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo.
Purification by silica gel (100ꢀ200 mesh) chromatography (EtOAc: Hexane) to yield the desired
product 4.
Experimental procedure for the radical trap experiment:
9
A 10 mL schlenk tube equipped with a stirꢀbar was charged with azido benzene (0.05 g, 0.42
mmol), tertꢀbutyl isocyanide (0.041 g, 0.50 mmol) in toluene (0.5 mL) as a solvent. The reaction
tube was purged with argon. Then after 5ꢀ10 min. Pd(PPh3)4 (0.004 g, 0.021 mmol) was added to
the reaction mixture followed by argon purging. The mixture was stirred at room temperature for
30 min. under an inert atmosphere. After completion of the reaction, trimethylsilylazide (0.05 g,
0.84 mmol), iron chloride (0.007 g, 0.042 mmol) and additives were added and stirred it at 100
oC for 1 h. After completion of the reaction, the reaction mixture was passed through celite bed
and washed with EtOAc. The reaction mixture was diluted with EtOAc, which was washed with
water and brine successively, dried over anhydrous sodium sulphate, filtered, and concentrated in
vacuo. Purification by silica gel (100ꢀ200 mesh) chromatography (EtOAc: Hexane) to get the
desired product with 82% yield.
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Experimental procedure for the one pot relay process:
A 10 mL schlenk tube equipped with a stirꢀbar was charged with azido benzene (0.05 g, 0.42
mmol), tertꢀbutyl isocyanide (0.041 g, 0.50 mmol), TMSN3 in toluene (0.5 mL) as a solvent. The
reaction tube was purged with argon. Then after 5ꢀ10 min. Pd(PPh3)4 (0.004 g, 0.021 mmol) and
o
iron chloride (0.007 g, 0.042 mmol) were added and stirred it at 100 C for 1ꢀ12 h. Monitored
this reaction by TLC. TLC shows only 15ꢀ20% 3, with remaining starting material as such.
4a: 1-(tert-butyl)-N-phenyl-1H-tetrazol-5-amine
o
1
White solid, Yield: 0.08 g (88%); m.p.: 148ꢀ150 C; Rf = 0.3 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500 MHz,
CDCl3): 7.45 (d, 2H, aromatic C-H, J = 7.6 Hz), 7.36 (t, 2H, aromatic C-H, J = 7.5 Hz), 7.09 (t, 1H, aromatic C-H, J
= 7.35 Hz), 6.13 (br s, 1H, NꢀH), 1.78 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 151.9, 139.2, 129.4,
123.2, 118.3, 59.5, 29.1. IR ν (cmꢀ1): 3313, 2962, 2925, 2854, 1733, 1601, 1564, 1499, 1455, 1372, 1261, 1098,
1024, 803, 746, 687, 498. HRMS (ESI): calcd for C11H16N5 [M+H]+ 218.1400, found 218.1388.
4b: 1-(tert-butyl)-N-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-amine
o
1
White solid, Yield: 0.059 g (78%); m.p.: 152ꢀ155 C; Rf = 0.2 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500 MHz,
CDCl3): 7.61 (d, 2H, aromatic C-H, J = 8.7 Hz), 7.55 (d, 2H, aromatic C-H, J = 8.65 Hz), 6.31 (br s, 1H, NꢀH), 1.80
(s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 151.2, 149.5, 142.3, 126.7 (JCF = 15.0 Hz), 125.0 (JCF
=
19
15.0 Hz), 123.0, 117.5, 116.2, 60.0, 29.2. F NMR: ꢀ61.93. IR ν (cmꢀ1): 3446, 3279, 2925, 2854, 1229, 1558, 1458,
1373, 1327, 1229, 1164, 1121, 1067, 830, 801, 585. HRMS (ESI): calcd for C12H15F3N5 [M+H]+ 286.1274, found
286.1270.
4c: N-(4-bromophenyl)-1-(tert-butyl)-1H-tetrazol-5-amine
o
1
White solid, Yield: 0.06 g (81%); m.p.: 137ꢀ138 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500 MHz,
CDCl3): 7.44 (d, 2H, aromatic C-H, J = 5.2 Hz), 7.36 (d, 2H, aromatic C-H, J = 8.5 Hz), 6.18 (br s, 1H, NꢀH), 1.77
13
(s, 9H, Sp3 CꢀH). C NMR (δ ppm): (125 MHz, CDCl3): 151.6, 138.3, 132.3, 119.9, 115.7, 59.7, 29.2. IR ν (cmꢀ1):
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3278, 3186, 3101, 2926, 2855, 1884, 1599, 1555, 1489, 1359, 1225, 1145, 1113, 1072, 819, 795, 574, 495. HRMS
(ESI): calcd for C11H15BrN5 [M+H]+ 296.0506, found 296.0498.
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4d: 4-((1-(tert-butyl)-1H-tetrazol-5-yl)amino)benzonitrile
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9
o
1
OffꢀWhite solid, Yield: 0.070 g (83%); m.p.: 143ꢀ145 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3):7.62 (d, 2H, aromatic C-H, J = 8.5 Hz), 7.54 (d, 2H, aromatic C-H, J = 8.5 Hz), 6.58 (br s, 1H, NꢀH),
1.79 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 150.8, 143.4, 133.7, 118.9, 117.7, 105.7, 60.3, 29.3.
IR ν (cmꢀ1): 3316, 3105, 2994, 2940, 2223, 1597, 1549, 1513, 1459, 1426, 1377, 1313, 1224, 1179, 1146, 1109,
1030, 835, 802, 728, 580, 544. HRMS (ESI): calcd for C12H15N6 [M+H]+ 243.1353, found 243.1355.
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4e: 1-(tert-butyl)-N-(3-chlorophenyl)-1H-tetrazol-5-amine
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OffꢀWhite solid, Yield: 0.063 g (77%); m.p.: 137ꢀ139 C; Rf = 0.2 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.43 (s, 1H, aromatic C-H), 7.25 (m, 1H, aromatic C-H), 6.98 (d, 1H, aromatic C-H, J = 5.1 Hz),
6.65 (s, 1H, aromatic C-H), 6.10 (br s, 1H, NꢀH), 1.71 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3):
151.4, 140.4, 135.1, 130.4, 123.2, 118.2, 116.2, 59.8, 29.2. IR ν (cmꢀ1): 3380, 3287, 2963, 2922, 2852, 1724, 1592,
1553, 1474, 1374, 1259, 1228, 1098, 1026, 906, 871, 804, 770, 680, 521. HRMS (ESI): calcd for C11H15ClN5
[M+H]+ 252.1011, found 252.1001.
4f: 1-(tert-butyl)-N-(3-methoxyphenyl)-1H-tetrazol-5-amine
o
1
OffꢀWhite solid, Yield: 0.059 g (71%); m.p.: 137ꢀ138 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.22 (t, 1H, aromatic C-H, J = 8.1 Hz), 7.14 (t, 1H, aromatic C-H, J = 2.1 Hz ), 6.91 (dd, 1H,
aromatic C-H, J = 1.5, 8.0 Hz), 6.61 (dd, 1H, aromatic C-H, J = 1.9, 8.2 Hz), 6.19 (br s, 1H, NꢀH), 3.82 (s, 3H, Sp3
CꢀH), 1.77 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 160.6, 151.8, 140.6, 130.1, 110.5, 108.9, 104.1,
59.6, 55.4, 29.1. IR ν (cmꢀ1): 3356, 3071, 2979, 2923, 2851, 1733, 1609, 1562, 1506, 1458, 1349, 1215, 1171, 1036,
951, 842, 770, 684, 511, 461.
4g: 4-bromo-2-((1-(tert-butyl)-1H-tetrazol-5-yl)amino)benzonitrile
1
Yellow oil, Yield: 0.057 g (70%); Rf = 0.2 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500 MHz, CDCl3): 8.39ꢀ8.37
(m, 1H, aromatic C-H), 7.74 (d, 1H, aromatic C-H, J = 9.0 Hz), 7.70 (s, 1H, aromatic CꢀH), 7.11 (br s, 1H, NꢀH),
1.83 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 150.2, 141.2, 137.9, 134.1, 119.9, 115.7, 114.5,
101.6, 60.3, 29.2. IR ν (cmꢀ1): 3433, 3304, 3060, 2977, 2927, 1934, 1722, 1666, 1608, 1460, 1399, 1375, 1320, 1234,
1148, 1099, 1068, 1024, 893, 816, 752, 609, 544, 428. HRMS (ESI): calcd for C12H14BrN6 [M+H]+ 321.0458, found
321.0455.
4h: N-phenyl-1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-amine
o
1
OffꢀWhite solid, Yield: 0.093 g (81%); m.p.: 137ꢀ138 C; Rf = 0.4 (4:6 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.49 (d, 2H, aromatic C-H, J = 7.9 Hz), 7.39 (t, 2H, aromatic C-H, J = 7.7 Hz), 7.12 (t, 1H, aromatic
C-H, J = 7.3 Hz), 6.13 (br s, 1H, NꢀH), 2.00 (s, 2H, Sp3 CꢀH), 1.89 (s, 6H, Sp3 CꢀH), 0.87 (s, 9H, Sp3 CꢀH). 13C
NMR (δ ppm): (125 MHz, CDCl3): 152.3, 139.1, 129.4, 123.3, 118.5, 62.9, 52.4, 31.8, 30.7, 29.8. IR ν (cmꢀ1): 3312,
2924, 2854, 1736, 1601, 1564, 1499, 1455, 1373, 1312, 1227, 1106, 1028, 802, 746, 687, 497. HRMS (ESI): calcd
for C15H24N5 [M+H]+ 274.2026, found 274.2025.
4i: 2-((1-cyclohexyl-1H-tetrazol-5-yl)amino)benzonitrile
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OffꢀWhite solid, Yield: 0.075 g (81%); m.p.: 141ꢀ143 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 8.32 (d, 1H, aromatic C-H, J = 8.55 Hz), 7.65 (td, 1H, aromatic C-H, J = 1.2, 8.6 Hz), 7.61 (dd, 1H,
aromatic CꢀH, J = 1.05, 7.8 Hz), 7.15 (t, 1H, aromatic CꢀH, J = 7.4 Hz), 6.84 (br s, 1H, NꢀH), 4.18ꢀ4.12 (m, 1H, Sp3
CꢀH), 2.17ꢀ2.14 (m, 2H, Sp3 CꢀH), 2.06ꢀ1.99 (m, 4H, Sp3 CꢀH), 1.53ꢀ1.46 (m, 2H, Sp3 CꢀH), 1.42ꢀ1.34 (m, 2H, Sp3
CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 150.1, 141.7, 134.9, 132.3, 122.8, 118.2, 116.7, 100.1, 57.4, 32.1,
25.1, 24.8. IR ν (cmꢀ1): 3451, 3164, 2924, 2856, 2225, 1609, 1560, 1488, 1248, 1078, 852, 761. HRMS (ESI): calcd
for C14H17N6 [M+H]+ 269.1509, found 269.1502.
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4j: N,1-diphenyl-1H-tetrazol-5-amine36
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OffꢀWhite solid, Yield: 0.077 g (77%); m.p.: 165ꢀ167 C; Rf = 0.4 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.63ꢀ7.59 (m, 3H, aromatic C-H), 7.54 (t, 4H, aromatic C-H, J = 8.6 Hz), 7.34 (t, 2H, aromatic C-H,
J = 7.4 Hz), 7.08 (t, 1H, aromatic C-H, J = 7.1 Hz), 6.59 (br s, 1H, NꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3):
151.7, 138.0, 132.7, 130.6, 130.5, 129.4, 124.8, 123.5, 118.3. IR ν (cmꢀ1): 3434, 3192, 2924, 1609, 1569, 1529, 1495,
1453, 1405, 1324, 1243, 1121, 1087, 1020, 825, 749, 690. HRMS (ESI): calcd for C13H12N5 [M+H]+ 238.1087,
found 238.1080.
4k: 4-((1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)amino)benzonitrile
o
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OffꢀWhite solid, Yield: 0.088 g (85%); m.p.: 174ꢀ176 C; Rf = 0.2 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.63 (d, 2H, aromatic C-H, J = 8.5 Hz), 7.58 (d, 2H, aromatic C-H, J = 8.6 Hz), 6.55 (br s, 1H, Nꢀ
H), 1.99 (s, 2H, Sp3 CꢀH), 1.88 (s, 6H, Sp3 CꢀH), 0.82 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3):
151.2, 143.1, 133.7, 118.9, 117.9, 105.9, 63.7, 52.6, 31.8, 30.7, 29.9. IR ν (cmꢀ1): 3341, 3183, 3110, 3055, 2951,
2907, 2224, 1599, 1550, 1515, 1474, 1365, 1228, 1179, 1093, 1027, 839, 732, 547. HRMS (ESI): calcd for C16H23N6
[M+H]+ 299.1979, found 299.1982.
4l: N-(4-methoxyphenyl)-1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-amine
o
1
OffꢀWhite solid, Yield: 0.077 g (76%); m.p.: 137ꢀ138 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.37 (d, 2H, aromatic C-H, J = 7.9 Hz), 6.90 (d, 2H, aromatic C-H, J = 7.9 Hz), 6.0 (br s, 1H, NꢀH),
3.80 (s, 3H, Sp3 CꢀH), 1.96 (s, 2H, Sp3 CꢀH), 1.84 (s, 6H, Sp3 CꢀH), 0.84 (s, 9H, tBu). 13C NMR (δ ppm): (125 MHz,
CDCl3): 156.2, 153.1, 132.2, 121.3, 114.6, 62.6, 55.6, 52.0, 30.7, 29.8. IR ν (cmꢀ1): 3297, 2954, 2925, 2856, 1732,
1603, 1570, 1512, 1467, 1363, 1259, 1228, 1179, 1095, 1037, 823, 807, 595, 513. HRMS (ESI): calcd for
C16H25N5O [M+H]+ 304.2132, found 304.2115.
4m: 2-((1-(tert-butyl)-1H-tetrazol-5-yl)amino)benzonitrile
o
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OffꢀWhite solid, Yield: 0.071 g (85%); m.p.: 137ꢀ139 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 8.44 (d, 1H, aromatic C-H, J = 8.6 Hz), 7.65 (t, 1H, aromatic C-H, J = 7.5 Hz), 7.60 (d, 1H, aromatic
CꢀH, J = 7.0 Hz) 7.13 (t, 1H, aromatic CꢀH, J = 7.5 Hz), 7.09 (br s, 1H, NꢀH), 1.84 (s, 9H, Sp3 CꢀH). 13C NMR (δ
ppm): (125 MHz, CDCl3): 150.5, 142.1, 134.9, 132.0, 122.6, 118.2, 116.9, 100.0, 60.1, 29.1. IR ν (cmꢀ1): 3440, 3278,
2925, 2856, 1713, 1657, 1603, 1463, 1371, 1229, 1147, 760. HRMS (ESI): calcd for C12H15N6 [M+H]+ 243.1353,
found 243.1350.
4n: 2-((1-(p-tolyl)-1H-tetrazol-5-yl)amino)benzonitrile:
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OffꢀWhite solid, Yield: 0.068 g (71%); m.p.: 178ꢀ180 C; Rf = 0.3 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 8.57 (d, 1H, aromatic C-H, J = 8.5 Hz), 7.67 (t, 1H, aromatic C-H, J = 8.4 Hz), 7.57 (d, 1H, aromatic
CꢀH, J = 7.7 Hz), 7.47 (s, 4H, aromatic CꢀH), 7.16 (br s, 1H, NꢀH), 7.14 (d, 1H, aromatic CꢀH, J = 7.5 Hz), 2.48 (s,
3H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 150.5, 141.6, 140.9, 134.8, 132.3, 131.4, 129.5, 124.2, 123.1,
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118.5, 116.2, 100.5, 21.4. IR ν (cmꢀ1): 3384, 3078, 2923, 2220, 1609, 1594, 1571, 1526, 1458, 1314, 1291, 1091,
824, 759, 720, 543, 484, 424. HRMS (ESI): calcd for C15H13N6 [M+H]+ 277.1196, found 277.1190.
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4o: N-(tert-butyl)-1-(p-tolyl)-1H-tetrazol-5-amine
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White solid, Yield: 0.071 g (83%); m.p.: 133ꢀ135 C; Rf = 0.4 (4:6 EtOAc/hexane). H NMR, (δ ppm): (500 MHz,
CDCl3): 7.38 (d, 2H, aromatic C-H, J = 8.1 Hz), 7.33 (d, 2H, aromatic C-H, J = 8.2 Hz), 4.16 (br s, 1H, NꢀH), 2.45
(s, 3H, Sp3 C-H), 1.47 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 153.3, 140.3, 130.9, 130.7, 124.3,
53.1, 28.9, 21.3. IR ν (cmꢀ1): 3418, 3337, 2970, 2925, 2871, 1563, 1517, 1457, 1393, 1218, 1082, 813, 508. HRMS
(ESI): calcd for C12H18N5 [M+H]+ 232.1557, found 232.1548.
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4p: N-(tert-butyl)-1-(4-fluorophenyl)-1H-tetrazol-5-amine
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OffꢀWhite solid, Yield: 0.066 g (77%); m.p.: 150ꢀ152 C; Rf = 0.2 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.48ꢀ7.45 (m, 2H, aromatic C-H), 7.30ꢀ7.27 (m, 2H, aromatic C-H), 4.15 (br s, 1H, NꢀH), 1.48 (s,
9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 163.0 (JCF = 249.9 Hz), 153.3, 129.3, 126.7 (JCF = 8.9 Hz),
117.5 (JCF = 23.1 Hz), 53.3, 28.9. F NMR: ꢀ109.5. IR ν (cmꢀ1): 3434, 3317, 3088, 2971, 2926, 2873, 1575, 1515,
1283, 1221, 1130, 1081, 841, 808, 613, 517. HRMS (ESI): calcd for C11H15FN5 [M+H]+ 236.1306, found 236.1299.
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4q: N-(tert-butyl)-1-(3,4-dichlorophenyl)-1H-tetrazol-5-amine
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OffꢀWhite solid, Yield: 0.054 g (72%); m.p.: 163ꢀ165 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3):7.67 (d, 1H, aromatic C-H, J = 13.5 Hz), 7.64 (d, 1H, aromatic C-H, J = 2.3 Hz), 7.36 (dd, 1H,
aromatic C-H, J = 2.3, 8.5 Hz), 4.20 (br s, 1H, NꢀH), 1.49 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3):
153.0, 134.7, 134.5, 132.5, 132.0, 126.4, 123.2, 53.6, 28.9. IR ν (cmꢀ1): 3400, 3107, 2991, 2929, 1595, 1555, 1473,
1414, 1342, 1221, 1131, 1098, 1025, 867, 818, 671, 584, 437. HRMS (ESI): calcd for C11H14Cl2N5 [M+H]+
286.0621, found 286.0614.
4r: N-(tert-butyl)-1-(naphthalen-1-yl)-1H-tetrazol-5-amine
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OffꢀWhite solid, Yield: 0.065 g (83%); m.p.: 137ꢀ138 C; Rf = 0.3 (2:8 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 8.08 (d, 1H, aromatic C-H, J = 8.3 Hz), 7.99 (d, 1H, aromatic C-H, J = 8.0 Hz), 7.64ꢀ7.60 (m, 2H,
aromatic C-H), 7.57 (t, 1H, aromatic C-H , J = 7.4 Hz), 7.52 (d, 1H, aromatic C-H, J = 7.0 Hz), 7.37 (d, 1H,
aromatic C-H, J = 8.3 Hz), 3.90 (br s, 1H, NꢀH), 1.42 (s, 9H, Sp3 CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3):
154.5, 134.6, 131.4, 128.9, 128.8, 128.6, 128.2, 127.5, 125.5, 125.4, 122.0, 53.1, 28.9. IR ν (cmꢀ1): 3342, 3053, 2979,
2927, 2869, 1579, 1508, 1411, 1215, 1080, 990, 793, 770, 733, 659, 578, 530, 434. HRMS (ESI): calcd for C15H18N5
[M+H]+ 268.1557, found 268.1545.
4s: N-(tert-butyl)-1-(2-chlorophenyl)-1H-tetrazol-5-amine
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OffꢀWhite solid, Yield: 0.057 g (70%); m.p.: 125ꢀ128 C; Rf = 0.3 (3:7 EtOAc/hexane). H NMR, (δ ppm): (500
MHz, CDCl3): 7.63 (d, 1H, aromatic C-H, J = 7.9 Hz), 7.56 (td, 1H, aromatic C-H, J = 1.4, 7.5 Hz), 7.50 (td, 1H,
aromatic CꢀH, J = 0.8, 7.9 Hz), 7.46 (dd, 1H, aromatic CꢀH, J = 1.4, 7.7 Hz), 3.91 (br s, 1H, NꢀH), 1.46 (s, 9H, Sp3
CꢀH). 13C NMR (δ ppm): (125 MHz, CDCl3): 153.8, 132.3, 131.6, 131.2, 130.5, 129.7, 128.6, 53.3, 28.9. IR ν (cmꢀ1):
3285, 2973, 2922, 1733, 1574, 1519, 1485, 1393, 1216, 1095, 1037, 756, 718, 656, 584, 502, 456. HRMS (ESI):
calcd for C11H15ClN5 [M+H]+ 252.1011, found 252.1009.
ASSOCIATED CONTENT
Supporting Information
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The Supporting information is available free of charge on the ACS Publication website at DOI:
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10.1021/acs.joc.XXXXXXX.
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Details on mechanistic experiments, optimization studies, and the copies of 1H and 13C NMR spectra for
9
all new compounds 4a-4s (PDF)
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Xꢀray structure and crystallographic data for compound 4m with CCDC 1573778 and 4s with CCDC
1843251 (CIF).
AUTHOR INFORMATION
Corresponding Authors
*Email: dms@curaj.ac.in
Notes
The authors declare no competing financial interest.
Acknowledgements
DMS and RTP are grateful to Central University of Rajasthan, DST [EMR/2016/003969 and
EMR/2016/008016] and CSIR [02(0201)/14/EMRꢀII] for funds
References:
(1) For reviews of tetrazole chemistry see: (a) Sarvary, A.; Maleki, A. A review of syntheses of 1, 5ꢀdisubstituted
tetrazole derivatives. Mol Divers, 2015, 19, 189ꢀ212. (b) Moderhack, D. Ring transformations in tetrazole
chemistry. J. Prakt. Chem. 1998, 340, 687ꢀ709. (c) Wittenberger, S. J. Recent developments in tetrazole
chemistry. A review. Org. Prep. Proced. Int. 1994, 26, 499ꢀ531. (d) Butler, R. N. Recent advances in tetrazole
chemistry. Adv. Heterocycl. Chem., 1977, 21, 323ꢀ435
(2) (a) Herr, R. J. 5ꢀSubstitutedꢀ1Hꢀtetrazoles as Carboxylic Acid Isosteres: Medicinal Chemistry and Synthetic
Methods. Bioorg. Med. Chem., 2002, 10, 3379ꢀ3393. (b) Thornber, C. W. Isosterism and molecular
modification in drug design. Chem. Soc. Rev., 1979, 8, 563ꢀ580. (c) Burger, A. Isosterism and bioisosterism in
drug design. Prog. Drug. Res., 1991, 37, 287ꢀ371. (d) Lipinski, C. A. Chapter 27. Bioisosterlsm in Drug
Design. Annu. Rep. Med. Chem., 1986, 2721, 283ꢀ291.
(3) (a) Zabrocki, J.; Smith, G. D.; Dunbar, J. B. Jr.; Iijima, H.; Marshall, G. R. Conformational Mimicry. 1. 1,5ꢀ
Disubstituted Tetrazole Ring as a Surrogate for the Cis Amide Bond. J. Am. Chem. Soc. 1988, 110, 5875ꢀ5880.
(b) Zabrocki, J.; Marshall, G. R. The 1,5ꢀDisubstituted Tetrazole Ring as a cisꢀAmide Bond Surrogate.
Methods Mol. Med. 1999, 23, 417ꢀ436. (c) Yu, K.ꢀL.; Johnson, R. L. Synthesis and Chemical Properties of
Tetrazole Peptide Analogues. J. Org. Chem. 1987, 52, 2051ꢀ2059.
(4) Tuites, R. C.; Whiteley, T. E.; Minsk, L. M. High molecular weight, long chain tetrazoleꢀcontaining polymers for
antifogging use in photographic elements. US Patent 1 245 614, 1971.
(5) Marasescu, F. T.; Wertheimer, M. R. NitrogenꢀRich PlasmaꢀPolymer Films for Biomedical Applications. Plasma
Process. Polym. 2008, 5, 44–57.
(6) Cao, C.ꢀY.; Lu, S.; Zhang, D.; Gong, L.ꢀL.; Zhang, H.ꢀP. Effects of nitroguanidine on the thermal behavior and
burning characteristics of 5ꢀaminoꢀ1H tetrazoleꢀbased propellants. RSC Adv., 2017, 7, 13808ꢀ13816.
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(7) (a) Fischer, N.; Klapötke, T.M.; Stierstorfer, K. J.; Wiedemann, C. 1ꢀNitratoethylꢀ5ꢀnitriminotetrazole derivatives
– Shaping future high explosives. Polyhedron, 2011, 30, 2374ꢀ2386. (b) Joo, Y. ꢀH.; Twamley, B.; Garg, S.;
Shreeve, J. M. Energetic NitrogenꢀRich Derivatives of 1,5ꢀDiaminotetrazole. Angew. Chem. Int. Ed. 2008, 47,
6236ꢀ6239.
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(8) (a) Popova, E. A.; Trifonov, R. E.; Ostrovskii, V. A. Advances in the synthesis of tetrazoles coordinated to metal
ions. ARKIVOC 2012, 45ꢀ65. (b) Aromí, G.; Barrios, L. A.; Roubeau, O.; Gamez, P. Triazoles and tetrazoles:
Prime ligands to generate remarkable coordination materials. Coord. Chem. Rev. 2011, 255, 485ꢀ546. (c)
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