Alkylation of 5-Substituted 1 H-Tetrazoles via the Diazotization of Aliphatic Amines

Article abstract of DOI:10.1021/acs.joc.1c01585

A new alkylation reaction of monosubstituted tetrazoles via the diazotization of aliphatic amines is reported. This method enables preferential formation of 2,5-disubstituted tetrazoles. A one-pot 1,3-dipolar cycloaddition/diazotization sequence starting from widely available nitriles is also described. Azide residues are quenched in the second step with the nitrite reagent, thus limiting the intrinsic risk associated with trimethylsilyl azide. The reaction conditions were compatible with several functional groups, including thiocyanates, which afford preferentially disubstituted 2-alkyl-5-(substituted-thio)tetrazoles.

Full text of DOI:10.1021/acs.joc.1c01585

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Alkylation of 5‑Substituted 1H‑Tetrazoles via the Diazotization of
Aliphatic Amines
̀
Guillaume Reynard and Hélene Lebel*
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ABSTRACT: A new alkylation reaction of monosubstituted tetrazoles via the
diazotization of aliphatic amines is reported. This method enables preferential
formation of 2,5-disubstituted tetrazoles. A one-pot 1,3-dipolar cycloaddition/
diazotization sequence starting from widely available nitriles is also described.
Azide residues are quenched in the second step with the nitrite reagent, thus
limiting the intrinsic risk associated with trimethylsilyl azide. The reaction
conditions were compatible with several functional groups, including
thiocyanates, which afford preferentially disubstituted 2-alkyl-5-(substituted-thio)tetrazoles.
etrazoles are an important class of 5-membered hetero-
cycles with a wide range of applications in medicinal
an organic nitrite reagent. In these processes, the intermediate
formed between the amine and the nitrite reagent is
protonated by the substrate, presumably affording the
diazonium ion pair that undergoes a substitution reaction
(Scheme 1). Since the pKa of tetrazoles is similar to that of
carboxylic acids, we hypothesized that it should be possible for
them to react in a similar process. Herein, we report the
alkylation of 1H-5-monosubstituted tetrazoles via diazotization
of alkylamines in the presence of an organic nitrite to afford
2,5-disubstituted tetrazoles in good to excellent yields. A
T
chemistry.1 1H-5-Monosubstituted tetrazoles (1H-Tz) (Figure
1) are commonly used as carboxylic acid isosteres in
Figure 1. Structures of 1H-Tz, 1,5-Tz, and 2,5-Tz.
Scheme 1. Alkylation Reactions via Amine Diazotization
biologically active compounds.2,3 Losartan, an FDA-approved
antihypertensive drug, is one of many examples of 5-
substituted tetrazole-containing pharmaceutical ingredients.4
Disubstituted tetrazoles, such as 1,5-disubstituted tetrazoles
(1,5-Tz), and 2,5-disubstituted tetrazoles (2,5-Tz) (Figure 1),
are used as amide isosteres5 found in various biologically active
compounds,6 in addition to being important synthetic
precursors.1
Numerous methods, mostly based on 1,3-dipolar cyclo-
additions with an azide reagent, are available to synthesize a
large variety of 1,5-Tz derivatives.7−14 Conversely, condensa-
tion reactions to synthesize 2,5-Tz compounds are
limited.15−17 Typically, 2,5-Tz are prepared from 1H-Tz via
substitution at the nitrogen.18−24 While a variety of substituted
2,5-Tz have been reported to be prepared in high yields and
selectivities, these methods were not suitable for the
preparation of 2,5-Tz products containing nucleophilic groups,
such as alcohols or amines. As a result, despite recent advances,
there remains a need for synthetic methods to afford diversely
substituted 2,5-Tz.
Received: July 5, 2021
Recently, we have reported esterification of carboxylic
acids25−27 and the etherification of phenols28 via the
diazotization of various aliphatic amines in the presence of
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multicomponent process combining the cycloaddition and
alkylation reactions is also described.
Scheme 2. Synthesis of 2,5-Disubstituted Tetrazoles via
Amine Diazotization
a
We first investigated the reaction of 5-(4-bromophenyl)-1H-
tetrazole and benzylamine in various solvents in the presence
of 1,3-(2,2-dimethyl)propanedinitrite27 at 80 °C (Figure 2).29
Figure 2. Optimization of the solvent. Yields of the 2,5-Tz and molar
ratios were determined by NMR using tetrachloroethane as a
standard.
a
Isolated yields using 0.5 mmol of tetrazole, 2.5 equiv of amine, and
b
1.6 equiv of dinitrite. Reaction was performed in CHCl3.
We are pleased to report that the corresponding 2,5-Tz
product 1 was the major isomer formed in good yield and ratio
with ethyl acetate as the solvent.30 Other reagent stoichiome-
tries, reaction times, and temperatures were tested; however,
no improvement for the synthesis of 2,5-Tz 1 was observed.
Commercially available nitrites such as tert-butyl nitrite and
isoamyl nitrite also afforded the desired 2,5-Tz with a similar
yield. 1,3-(2,2-Dimethyl)propanedinitrite, derived from readily
available neopentylglycol, was preferred over tert-butyl nitrite
and isoamyle nitrite since it displays a better atom-economy
profile.
The optimized reaction conditions were then used with a
variety of aryl-, heteroaryl-, and alkyltetrazoles and aliphatic
amines (Scheme 2). 2,5-Tz 1 could be easily separated from
minor isomer 1,5-Tz 2 and was isolated in 71% yield. Both
isomers were unambiguously established by X-ray crystal
structure resolution.31 Similar yields were obtained from other
aryl-substituted tetrazoles to afford 2,5-Tz 3 and 4. We were
pleased to find that an unprotected hydroxyalkyltetrazole could
be successfully reacted with benzylamine to furnish 2,5-Tz 5 in
74% yield. We next examine the reactivity of phenyltetrazole
with other aliphatic amines. Using the commercially available
2 M THF methylamine solution, 2,5-Tz 6 was isolated in 72%
yield. More sterically hindered amine, such as isopropylamine,
also afforded the desired 2,5-Tz 7 in good yields. With amine
substituted with a tertiary alkyl group, such as adamantly or
trityl, the minor isomer 1,5-Tz was not observed due to steric
hindrance. The overall reactivity was decreased, and the
desired 2,5-Tz 8-9 were isolated in, respectively, 59% and 65%
yields. The reaction conditions were compatible with amino
alcohols, affording 2,5-Tz 10−14 in good to excellent yields.
Pyridine-derived tetrazole 15 was also produced in 84% yield.
Chlorothiophene tetrazoles 16 and 17 were equally synthe-
sized in good yields.
Only a few monosubstituted tetrazoles (1H-Tz) are
commercially available, and substrates were typically prepared
via a 1,3-dipolar cycloaddition between a nitrile and sodium
azide using Bronsted or Lewis acid catalysts or an organo-
metallic azide reagent.19 Among these methods, reaction
conditions using trimethylsilyl azide and a catalytic amount of
tin oxide were found to be highly efficient to synthesize a large
variety of tetrazoles.32−34 To streamline the synthesis of 2,5-
Tz, we devised a multicomponent one-pot process that
combines the cycloaddition and the alkylation step from the
corresponding nitrile. Not only the efficiency of the process
would be improved, but such a one-pot procedure would also
allow the use of 1H-Tz unsuitable for isolation.
After optimization of the reaction conditions, toluene was
identified as a suitable solvent to run the one-pot reaction. The
cycloaddition between the nitrile and the azide reagent was
first performed, and then the dinitrite and the amine were
added to perform the alkylation reaction.29 Another advantage
associated with the process was the quench by the nitrite
reagent of any remaining azide reagent, mitigating the risk
B
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associated with the later reagent. 2,5-Tz 1 and 3 were isolated
in 65% and 59% yield, respectively, from the corresponding
nitrile (Scheme 3). In comparison, a step-by-step procedure
compounds could be accessed either from 5-substituted 1H-
tetrazole, or from nitriles, with the development of a one-pot
1,3-dipolar cycloaddition−diazotization procedure, enabling
rapid construction of molecular complexity from simple widely
available building blocks. The reaction was compatible with a
variety of functional groups, including ones that would
normally react with electrophiles typically used in substitution
reactions (such as alkyl halides). In addition, amines are
generally less harmful than the corresponding alkyl halide
equivalents (for instance methylamine vs methyl iodide).
Further studies are in progress to establish the factors that
govern the selectivity of the reaction.
Scheme 3. Multicomponent Synthesis of 2,5-Disubstituted
a
Tetrazoles from Nitriles
EXPERIMENTAL SECTION
■
General Information. Analytical thin-layer chromatography was
performed using 0.25 mm silica gel 60-F plates. Visualization of the
developed chromatogram was performed by UV absorbance, cerium
ammonium molybdate, or aqueous potassium permanganate. Flash
chromatography was performed using silica gel (230−400 mesh) with
the indicated solvent system. Infrared spectra are reported in
reciprocal centimeters (cm−1). Only the most important and relevant
1
frequencies are reported. Chemical shifts for H NMR spectra were
recorded in parts per million with the solvent resonance as the
reference CDCl3 (δ = 7.26 ppm) unless otherwise indicated. Data are
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, qn = quintuplet, sx = sextet, sept =
septet, m = multiplet and br = broad), coupling constant (in hertz),
and integration. Chemical shifts for 13C{1H} NMR spectra are
recorded in parts per million using the central peak of CDCl3 (δ =
77.16 ppm) as the reference unless otherwise indicated. All 13C{1H}
NMR spectra were obtained with complete proton decoupling. All
1
NMR yields were determined using quantitative H NMR spectra
using tetrachloroethane as an internal standard with a 10 s relaxation
time. High-resolution mass spectra analysis was performed by the
a
́
́
Centre regional de spectroscopie de masse de l’Universite de
Isolated yields using 0.5 mmol of nitrile, 1.5 equiv of TMSN3, 2.5
́
Montreal. Dinitrite reagents were synthesized according to previously
equiv of amine, and 1.6 equiv of dinitrite.
reported methods.26,27 DSC-TGA spectra of dinitrite reagents in a sealed
stainless-steel crucible revealed an important, strong exothermic event from
∼120 to 175 °C, with an important loss of mass and a significant
modification of temperature set point, consistent with a decomposition.
Heating dinitrite reagents concentrated or neat is thus not recommended,
as autocatalytic decomposition may occur and overpressure might develop,
due to the formation of gases. Distillation should also be avoided.
General Procedure A for the Alkylation of 5-Monosub-
stituted Tetrazoles. In a round-bottom flask with a magnetic
stirring bar was suspended 5-monosubstituted tetrazole (0.500 mmol,
1.00 equiv) in EtOAc (4 mL). The resulting suspension was stirred at
room temperature. 1,3-(2,2-Dimethyl)propanedinitrite (0.093 mL,
0.800 mmol, 1.60 equiv) was added, followed by the amine (1.25
mmol, 2.50 equiv). The flask was placed in an oil bath, and the
mixture was heated at 80 °C for 16 h. The solvent was removed under
reduced pressure, and the crude mixture was purified by flash
chromatography.
General Procedure B for One-Pot Cycloaddition−Diazotiza-
tion Reaction. In a round-bottom flask with a magnetic stirring bar,
nitrile (0.500 mmol, 1.00 equiv) was diluted in toluene (1.5 mL). The
resulting mixture was stirred at room temperature. Dibutyltin oxide
(18.7 mg, 0.075 mmol, 0.150 equiv) was added, followed by
azidotrimethylsilane (0.099 mL, 0.750 mmol, 1.50 equiv). The flask
was placed in an oil bath, and the mixture was heated at 110 °C for 4
h (procedure B1) or 16 h (procedure B2). The mixture was cooled to
room temperature, and toluene (2.5 mL) was added, followed by 1,3-
(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv)
and the amine (1.25 mmol, 2.50 equiv). The flask was placed in an oil
bath, and the mixture was heated at 110 °C for 16 h. The mixture was
cooled to room temperature. The solvent was removed under reduced
pressure, and the crude mixture was purified by flash chromatography.
afforded phenyl 1H-Tz in 82% yield and 2,5-Tz 3 in 72% yield,
thus giving an overall yield of 59% for the two steps. Dialkyl
2,5-Tz 18 was synthesized in 54% yield from acetonitrile.
Alkylamines could also be used with aromatic nitriles, and
products 19−23 were prepared in good to excellent yields.35
Amines containing functional groups such as basic tertiary
amines and acetal were also successfully reacted with tetrazoles
derived from alkylnitriles to afford 2,5-Tz 24 and 25 in 64%
and 77% yield, respectively.
The reaction of ethyl thiocyanate with trimethylsilyl azide
afforded ethyl thiotetrazole, which was alkylated with benzyl-
amine to produce 2,5-Tz 26 in 71% yield on 0.5 mmol scale.
The one-pot reaction with ethyl thiotetrazole was also run on a
gram scale, and 2,5-Tz 26 was isolated in 57% together with
33% of 1,5-Tz 27 (eq 1). The ratio between the two isomers
was slightly lower when the reaction was run on a larger scale
and further studies will be necessary to establish exactly why.
In conclusion, the diazotization of amines proved to be an
efficient method to afford 2,5-Tz in good yields. These
C
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2-Benzyl-5-(4-bromophenyl)-2H-tetrazole (1) and 1-Benzyl-5-(4-
bromophenyl)-1H-tetrazole (2). The title compounds were prepared
according to general procedure A using 5-(4-bromophenyl)-1H-
tetrazole (113 mg, 0.500 mmol, 1.00 equiv), benzylamine (0.137 mL,
1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4 mL). The crude
mixture was purified by flash chromatography (10% EtOAc/hexanes
(300 mL), then 25% EtOAc/hexanes (300 mL)) to separate the two
tetrazole isomers. Tetrazole 1 (112 mg, 0.355 mmol, 71% yield) was
isolated as a white solid. Spectral data matched those reported in the
literature:16 Rf 0.53 (20% EtOAc/hexanes); mp 103−107 °C (lit.
2-(2-Phenethyl-2H-tetrazol-5-yl)ethan-1-ol (5). The title com-
pound was prepared according to general procedure A using 2-(1H-
tetrazol-5-yl)ethanol (57.1 mg, 0.500 mmol, 1.00 equiv), benzylamine
(0.147 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4
mL). The crude mixture was purified by flash chromatography (100%
EtOAc/hexanes). Tetrazole 5 (80.8 mg, 0.370 mmol, 74% yield) was
isolated as a pale-yellow oil: Rf 0.31 (100% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 7.38−7.31 (m, 5H), 5.70 (s, 2H), 4.00 (t,
J = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.83−2.68 (br s, 1H);
13C{1H} NMR (75 MHz, CDCl3) δ 165.0, 133.2, 129.1, 129.0, 128.5,
60.3, 56.8, 28.9; FTIR (cm−1) (neat) 3700−3300, 3200−2800, 1456,
1497, 1606, 1052; HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C10H13N4O 205.1084, found 205.1087.
1
105−107 °C); H NMR (400 MHz, CDCl3) δ 8.01 (dt, J = 8.7 Hz,
2.1 Hz, 2H), 7.60 (dt, J = 8.7 Hz, 2.0 Hz, 2H), 7.45−7.34 (m, 5H),
5.80 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.8, 133.3,
132.2, 129.2, 128.6, 128.5, 126.5, 124.8, 57.0. Tetrazole 2 (36.8 mg,
0.117 mmol, 23% yield) was isolated as a white solid. Spectral data
matched those reported in the literature:36 Rf 0.28 (20% EtOAc/
hexanes); mp 92−94 °C; 1H NMR (300 MHz, CDCl3) δ 87.64 (d, J
= 9 Hz, 2H), 7.45 (d, J = 9 Hz, 2H), 7.37−7.34 (m, 3H), 7.17−7.12
(m, 2H), 5.61 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ154.0,
133.8, 132.7, 130.4, 129.4, 129.1, 127.2, 126.3, 122.8, 51.6. The title
compounds were also prepared according to general procedure B1
using 4-bromobenzonitrile (91.0 mg, 0.500 mmol, 1.00 equiv),
dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrime-
thylsilane (0.986 mL, 0.750 mmol, 1.50 equiv), benzylamine (0.137
mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4 mL, 1.5 mL for the
first step + 2.5 mL for the second step) leading to tetrazole 1 (102
mg, 0.324 mmol, 65% yield) as a white solid and tetrazole 2 (37.8 mg,
0.120 mmol, 24% yield) as a white solid.
2-Methyl-5-phenyl-2H-tetrazole (6). The title compound was
prepared according to general procedure A using 5-phenyl-1H-
tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), methylamine (0.625 mL,
1.25 mmol, 2 M solution in THF, 2.50 equiv), and 1,3-(2,2-
dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in
EtOAc (3.35 mL). The crude mixture was purified by flash
chromatography (10% EtOAc/hexanes (300 mL), then 30%
EtOAc/hexanes (300 mL)) to separate the two tetrazole isomers.
Tetrazole 6 (57.6 mg, 0.360 mmol, 72% yield) was isolated as a white
solid. Spectral data matched those reported in the literature:24 Rf 0.53
1
(25% EtOAc/hexanes); mp 49−52 °C (lit. 50−52 °C); H NMR
(400 MHz, CDCl3) δ 8.16−8.10 (m, 2H), 7.51−7.44 (m, 3H), 4.39
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.39, 130.4, 129.0,
127.5, 126.9, 39.6.
2-Isopropyl-5-phenyl-2H-tetrazole (7). The title compound was
prepared according to general procedure A using 5-phenyl-1H-
tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), isopropylamine (0.107
mL, 1.25 mmol, 2.50 equiv) and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4 mL). The crude
mixture was purified by flash chromatography (10% EtOAc/hexanes
(300 mL), then 25% EtOAc/hexanes (300 mL)) to separate the two
tetrazole isomers. Tetrazole 7 (64.0 mg, 0.340 mmol, 68% yield) was
isolated as a pale-yellow oil. Spectral data matched those reported in
the literature.38 Rf 0.39 (10% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) δ 8.18−8.12 (m, 2H), 7.52−7.41 (m, 3H), 5.11 (hept, J = 6.7
Hz, 1H), 1.70 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 130.2, 128.9, 127.8, 126.9, 56.7, 22.3.
2-Benzyl-5-phenyl-2H-tetrazole (3). The title compound was
prepared according to general procedure A using 5-phenyl-1H-
tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), benzylamine (0.137 mL,
1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4 mL). The crude
mixture was purified by flash chromatography (10% EtOAc/hexanes
(300 mL), then 25% EtOAc/hexanes (300 mL)) to separate the two
tetrazole isomers. Tetrazole 3 (85.1 mg, 0.360 mmol, 72% yield) was
isolated as a white solid. Spectral data matched those reported in the
literature:37 Rf 0.57 (20% EtOAc/hexanes); mp 88−90 °C (lit. 90−92
1
°C); H NMR (400 MHz, CDCl3) δ 8.19−8.11 (m, 2H), 7.51−7.44
2-Adamantan-1-yl-5-phenyl-2H-tetrazole (8). The title com-
pound was prepared according to general procedure A using 5-
phenyl-1H-tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), adamantyl-
amine (189 mg, 1.25 mmol, 2.50 equiv) and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4
mL). The crude mixture was purified by flash chromatography (5%
EtOAc/hexanes (300 mL), then 10% EtOAc/hexanes (300 mL)).
Tetrazole 8 (106 mg, 0.295 mmol, 59% yield) was isolated as a white
solid. Spectral data matched those reported in the literature.24 Rf 0.47
(m, 3H), 7.44−7.32 (m, 5H), 5.80 (s, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 165.5, 133.5, 130.4, 129.1, 129.0, 128.9, 128.5, 127.5,
127.0, 56.9. The title compound was also prepared according to
general procedure B1 using benzonitrile (0.516 mL, 0.500 mmol, 1.00
equiv), dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv),
azidotrimethylsilane (0.986 mL, 0.750 mmol, 1.50 equiv), benzyl-
amine (0.137 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4
mL, 1.5 mL for the first step + 2.5 mL for the second step) leading to
tetrazole 3 (70.0 mg, 0.295 mmol, 59% yield) as a white solid.
2-Benzyl-5-(3-(trifluoromethyl)phenyl)-2H-tetrazole (4). The title
compound was prepared according to general procedure A using 5-(3-
(trifluoromethyl)phenyl)-1H-tetrazole (107 mg, 0.500 mmol, 1.00
equiv), benzylamine (0.137 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-
dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in
EtOAc (4 mL). The crude mixture was purified by flash
chromatography (10% EtOAc/hexanes (300 mL), then 25%
EtOAc/hexanes (300 mL)) to separate the two tetrazole isomers.
Tetrazole 4 (85.1 mg, 0.360 mmol, 72% yield) was isolated as a white
1
(10% EtOAc/hexanes); mp 85−88 °C (lit. 87−89 °C); H NMR
(500 MHz, CDCl3) δ 8.17−8.14 (m, 2H), 7.50−7.43 (m, 3H), 2.40
(d, J = 3.1 Hz, 6H), 2.31 (s, 3H), 1.83 (t, J = 3.1 Hz, 6H); 13C{1H}
NMR (125 MHz, CDCl3) δ 164.3, 130.1, 128.9, 128.1, 127.0, 64.0,
42.4, 36.0, 29.6.
5-Phenyl-2-triphenylmethyl-2H-tetrazole (9). The title compound
was prepared according to general procedure A using 5-phenyl-1H-
tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), triphenylmethylamine
(491 mg, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4
mL). The crude mixture was purified by flash chromatography (3%
EtOAc/hexanes). Tetrazole 9 (126 mg, 0.324 mmol, 65% yield) was
isolated as a white solid. Spectral data matched those reported in the
literature:37 Rf 0.47 (10% EtOAc/hexanes); mp 148−152 °C (lit.
1
solid: Rf 0.54 (20% EtOAc/hexanes); mp 69−74 °C; H NMR (400
MHz, CDCl3) δ 8.42 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.71 (d, J =
7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.46−7.33 (m, 5H), 5.82 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.2, 131.5 (q, J = 32.8
Hz), 130.1 (d, J = 0.8 Hz), 129.6, 129.2, 128.6, 128.4, 128.0, 127.0 (q,
J = 3.7 Hz), 123.9 (q, J = 3.9 Hz), 123.9 (d, J = 272.4 Hz), 57.1; 19F
NMR (375 MH, CDCl3) δ 62.82 (s); FTIR (cm−1) (neat) 3200−
2800, 1455, 1323, 1312, 1120; HRMS (ESI-TOF) m/z [M + Na]+
Calcd for C15H11F3N4Na 327.0828, found 327.0825.
1
154−155 °C); H NMR (400 MHz, CDCl3) δ 8.19−8.14 (m, 2H),
7.50−7.43 (m, 3H), 7.401−7.32 (m, 9H), 7.22−7.16 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.2, 141.5, 130.5, 130.4,
128.9, 128.5, 127.9, 127.7, 127.2, 83.2.
3-(5-Phenyl-2H-tetrazol-2-yl)propan-1-ol (10). The title com-
pound was prepared according to general procedure A using 5-phenyl-
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1H-tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), 3-amino-1-propanol
(0.101 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4
mL). The crude mixture was purified by flash chromatography (50%
EtOAc/hexanes (300 mL), then 75% EtOAc/hexanes (300 mL)) to
separate the two tetrazole isomers. Tetrazole 10 (74.5 mg, 0.365
mmol, 73% yield) was isolated as a clear oil: Rf 0.56 (75% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 8.10−8.05 (m, 2H), 7.46−
7.39 (m, 3H), 4.78 (t, J = 6.9 Hz, 2H), 3.70 (t, J = 5.9 HZ, 2H),
3.31−3.25 (br.s., 1H), 2.25 (qn, J = 6.4 Hz, 2H); 13C{1H} NMR (125
MHz, CDCl3) δ 165.0, 130.4, 128.9, 127.2, 126.7, 58.7, 50.1, 31.9;
FTIR (cm−1) (neat) 3600−3200, 3200−2800, 1611, 1530, 1450,
1044; HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H13N4O
205.1084, found 205.1082.
4-(5-Phenyl-2H-tetrazol-2-yl)butan-1-ol (11). The title compound
was prepared according to general procedure A using 5-phenyl-1H-
tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), 4-amino-1-butanol
(0.115 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in CHCl3 (4
mL). The crude mixture was purified by flash chromatography (50%
EtOAc/hexanes (300 mL), then 80% EtOAc/hexanes (300 mL)) to
separate the two tetrazole isomers. Tetrazole 11 (78.6 mg, 0.360
mmol, 72% yield) was isolated as a clear oil: Rf 0.46 (80% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 8.15−8.11 (m, 2H), 7.51−
7.43 (m, 3H), 4.70 (t, J = 7.0 Hz, 2H), 3.71 (t, J = 6.2 Hz, 2H), 2.17
(quint., J = 7.3 Hz, 2H), 1.84−1.76 (br.s., 1H), 1.68−1.60 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 165.2, 130.4, 129.0, 127.5,
126.9, 61.9, 53.1, 29.4, 26.1; FTIR (cm−1) (neat) 3600−3200, 3100−
2800, 1469, 1536, 1609, 1062; HRMS (ESI-TOF) m/z [M + H]+
calcd for C11H15N4O 219.1240, found 219.1238.
sticky oil: Rf 0.37 (75% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) δ 8.37 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz,
1H), 7.58 (t, J = 7.8 Hz, 1H), 7.84 (t, J = 5.3 Hz, 2H), 4.08 (t, J = 5.3
Hz, 2H), 3.69−3.63 (m, 2H), 3.60−3.55 (m, 2H), 2.64 (t, J = 5.9 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 131.5 (q, J = 32.8
Hz), 130.0 (d, J = 0.9 Hz), 129.6, 128.2, 127.0 (q, J = 3.7 Hz), 123.8
(q, J = 3.9 Hz), 123.9 (q, J = 272.4 Hz), 72.6, 68.2, 61.6, 53.2; 19F
NMR (375 MHz, CDCl3) δ −62.85 FTIR (cm−1) (neat) 3600−3200,
3200−2800, 1599, 1526, 1449, 1168, 1120, 1069; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C12H13F3N4O2 303.1063, found 303.1070.
4-(2-Phenethyl-2H-tetrazol-5-yl)pyridine (15). The title com-
pound was prepared according to general procedure A using 5-(4-
pyridyl)-1H-tetrazole (73.6 mg, 0.500 mmol, 1.00 equiv), phenethyl-
amine (0.157 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4
mL). The crude mixture was purified by flash chromatography (50%
EtOAc/hexanes (300 mL), then 80% EtOAc/hexanes (300 mL)) to
separate the two tetrazole isomers. Tetrazole 15 (106 mg, 0.422
mmol, 84% yield) was isolated as an off-white solid: Rf 0.38 (50%
EtOAc/hexanes); mp 60−69 °C; 1H NMR (400 MHz, CDCl3) δ 8.75
(d, J = 5.6 Hz, 2H), 7.99 (d, J = 5.6 Hz, 2H), 7.33−7.21 (m, 3H),
7.18 (d, J = 7.2 Hz, 2H), 4.90 (t, J = 7.6 Hz, 2H), 3.37 (t, J = 7.6 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 150.7, 136.2, 134.8,
129.0, 128.7, 127.3, 120.8, 54.5, 35.7; FTIR (cm−1) (neat) 3200−
2800, 1611, 1497, 1457; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C14H14N5 252.1244, found 252.1237.
3-(5-(5-Chlorothiophene-2-yl)-2H-tetrazol-2-yl)propan-1-ol (16).
The title compound was prepared according to general procedure A
using 5-(5-chloro-2-thienyl)-1H-tetrazole (93.3 mg, 0.500 mmol, 1.00
equiv), 3-amino-1-propanol (0.101 mL, 1.25 mmol, 2.50 equiv), and
1,3-(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60
equiv) in EtOAc (4 mL). The crude mixture was purified by flash
chromatography (50% EtOAc/hexanes (300 mL), then 75% EtOAc/
hexanes (300 mL)) to separate the two tetrazole isomers. Tetrazole
16 (93.0 mg, 0.380 mmol, 76% yield) was isolated as a pale-yellow oil:
2-(2-(5-Phenyl-2H-tetrazol-2-yl)ethoxy)ethan-1-ol (12). The title
compound was prepared according to general procedure A using 5-
phenyl-1H-tetrazole (73.1 mg, 0.500 mmol, 1.00 equiv), 2-(2-
aminoethoxy)ethanol (0.120 mL, 1.25 mmol, 2.50 equiv), and 1,3-
(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv)
in EtOAc (4 mL). The crude mixture was purified by flash
chromatography (80% EtOAc/hexanes). Tetrazole 12 (98.4 mg,
0.420 mmol, 84% yield) was isolated as a clear oil: Rf 0.53 (100%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.11−8.06 (m,
2H), 7.46−7.39 (m, 3H), 4.79 (t, J = 5.4 Hz, 2H), 4.02 (t, J = 5.4 Hz,
2H), 3.66−3.61 (m, 2H), 3.56−3.52 (m, 2H), 3.02−2.96 (br.s., 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 165.1, 130.4, 128.9, 127.2,
1
Rf 0.52 (75% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.49
(d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 4.75 (t, J = 6.9 Hz, 2H),
3.69 (t, J = 5.7 Hz, 2H), 3.02 (br s, 1H), 2.23 (qn, J = 6.4 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 160.2, 132.9, 127.4, 127.2,
127.1, 58.6, 50.2, 31.8; FTIR (cm−1) (neat) 3600−3200, 3200−2800,
1575, 1485, 1415, 1058, 1032, 1007; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C8H10ClN4OS 245.0258, found 245.0262.
126.8, 72.5, 68.2, 61.4, 52.9; FTIR (cm−1) (neat) 3600−3200, 3200−
2800, 1611, 1530, 1450, 1175, 1124, 1046; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C11H15N4O2 235.1190, found 235.1185.
2-(5-(4-Bromophenyl)-2H-tetrazol-2-yl)ethan-1-ol (13). The title
compound was prepared according to general procedure A using 5-(4-
bromophenyl)-1H-tetrazole (113 mg, 0.500 mmol, 1.00 equiv),
ethanolamine (0.081 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-
dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in
EtOAc (4 mL). The crude mixture was purified by flash
chromatography (50% EtOAc/hexanes (300 mL), then 75%
EtOAc/hexanes (300 mL)) to separate the two tetrazole isomers.
Tetrazole 13 (109 mg, 0.405 mmol, 81% yield) was isolated as a white
crystalline solid: Rf 0.64 (75% EtOAc/hexanes); mp 125−127 °C; 1H
NMR (500 MHz, CDCl3) δ 7.95 (dt, J = 8.5 Hz, 2.1 Hz, 2H), 7.60
(dt, J = 8.4 Hz, 2.0 Hz, 2H), 4.79 (t, J = 5.0 Hz, 2H), 4.26−4.21 (m,
2H), 2.78 (t, J = 6.4 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
164.5, 132.3, 128.4, 126.1, 125.0, 60.5, 55.7; FTIR (cm−1) (neat)
3600−3200, 3200−2800, 1601, 1449, 1419, 1048, 1004; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C9H10BrN4O 269.0033, found
269.0036.
8-(5-(5-Chlorothiophene-2-yl)-2H-tetrazol-2-yl)octan-1-ol (17).
The title compound was prepared according to general procedure A
using 5-(4-bromophenyl)-1H-tetrazole (113 mg, 0.500 mmol, 1.00
equiv), 8-amino-1-octanol (189 mg, 1.25 mmol, 2.50 equiv), and 1,3-
(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv)
in EtOAc (4 mL). The crude mixture was purified by flash
chromatography (40% EtOAc/hexanes (300 mL), then 50%
EtOAc/hexanes (300 mL)) to separate the two tetrazole isomers.
Tetrazole 17 (120 mg, 0.381 mmol, 76% yield) was isolated as a pale-
yellow oil: Rf 0.48 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.50 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 4.54 (t, J
= 7.2 Hz, 2H), 3.55 (t, J = 6.7 Hz, 2H), 2.38 (br.s., 1H), 1.96 (qn, J =
6.9 Hz, 2H), 1.53−1.44 (m, 2H), 1.34−1.21 (m, 8H); 13C{1H} NMR
(125 MHz, CDCl3) δ 160.1, 132.6, 127.6, 127.1, 126.9, 62.6, 53.3,
32.6, 29.2, 29.1, 28.8, 26.2, 25.6; FTIR (cm−1) (neat) 3600−3200,
3200−2800, 1576, 1486, 1034, 1007; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C13H20ClN4OS 315.1041, found 315.1046.
2-Benzyl-5-methyl-2H-tetrazole (18). The title compound was
prepared according to general procedure B2 using acetonitrile (0.261
mL, 0.500 mmol, 1.00 equiv), dibutyltin oxide (18.7 mg, 0.075 mmol,
0.150 equiv), azidotrimethylsilane (0.986 mL, 0.750 mmol, 1.50
equiv), benzylamine (0.137 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-
dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in
toluene (4 mL, 1.5 mL for the first step + 2.5 mL for the second step).
The crude mixture was purified by flash chromatography (25%
EtOAc/hexanes (300 mL), then 60% EtOAc/hexanes (300 mL)) to
separate the two tetrazole isomers. Tetrazole 18 (47.0 mg, 0.270
mmol, 54% yield) was isolated as a clear oil: Rf 0.39 (25% EtOAc/
2-(2-(5-(3-(Trifluoromethyl)phenyl)-2H-tetrazol-2-yl)ethoxy)-
ethan-1-ol (14). The title compound was prepared according to
general procedure A using 5-(3-(trifluoromethyl)phenyl)-1H-tetrazole
(107 mg, 0.500 mmol, 1.00 equiv), 2-(2-aminoethoxy)ethanol (0.120
mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4 mL). The crude
mixture was purified by flash chromatography (75% EtOAc/hexanes).
Tetrazole 14 (125 mg, 0.414 mmol, 83% yield) was isolated as a clear
E
https://doi.org/10.1021/acs.joc.1c01585
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 5H), 5.69 (s, 2H),
2.51 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 133.5,
129.1, 129.0, 128.5, 56.6, 11.0; FTIR (cm−1) (neat) 3200−2800,
1606, 1498, 1456; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C9H10N4Na 197.0798, found 197.0793.
7.60 (d, J = 8.0 Hz, 1H), 7.40−7.25 (m, 4H), 7.20 (d, J = 7.3 Hz,
2H), 4.88 (t, J = 7.7 Hz, 2H), 3.38 (t, J = 7.6 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 163.9, 136.4, 133.4, 130.6, 129.9, 129.5, 129.0,
128.8, 127.4, 125.5, 123.1, 54.5, 35.8; FTIR (cm−1) (neat) 3200−
2800, 1604, 1517, 1439; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C15H14BrN4 329.0396, found 329.0397.
2-Methyl-5-(3,5-dinitrophenyl)-2H-tetrazole (19). The title com-
pound was prepared according to general procedure B1 using 3,5-
dinitrobenzonitrile (96.6 mg, 0.500 mmol, 1.00 equiv), dibutyltin
oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane
(0.986 mL, 0.750 mmol, 1.50 equiv), methylamine (0.625 mL, 1.25
mmol, 2.50 equiv, 2 M solution in THF), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4
mL, 1.5 mL for the first step + 2.5 mL for the second step). The crude
mixture was purified by flash chromatography (25% EtOAc/hexanes
(300 mL), then 50% EtOAc/hexanes (300 mL)) to separate the two
tetrazole isomers. Tetrazole 19 (108 mg, 0.432 mmol, 86% yield) was
isolated as a white flaky solid. Spectral data matched those reported in
the literature:39 Rf 0.69 (50% EtOAc/hexanes); mp 141−142 °C; 1H
NMR (500 MHz, CDCl3) δ 9.28 (d, J = 2.1 Hz, 2H), 9.10 (t, J = 2.1
Hz, 1H), 4.50 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9,
149.2, 131.1, 126.7, 119.9, 40.1.
5-(4-Nitrophenyl)-2-phenethyl-2H-tetrazole (23). The title com-
pound was prepared according to general procedure B1 using 4-
nitrobenzonitrile (74.1 mg, 0.500 mmol, 1.00 equiv), dibutyltin oxide
(18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane (0.986 mL,
0.750 mmol, 1.50 equiv), phenethylamine (0.157 mL, 1.25 mmol,
2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800
mmol, 1.60 equiv) in toluene (4 mL, 1.5 mL for the first step + 2.5
mL for the second step). The crude mixture was purified by flash
chromatography (10% EtOAc/hexanes (300 mL), then 25% EtOAc/
hexanes (300 mL)) to separate the two tetrazole isomers. Tetrazole
23 (118 mg, 0.400 mmol, 80% yield) was isolated as a white
crystalline solid: Rf 0.55 (25% EtOAc/hexanes); mp 143−146 °C; 1H
NMR (500 MHz, CDCl3) δ 8.37−8.30 (m, 4H), 7.34−7.29 (m, 2H),
7.26 (tt, J = 7.3 Hz, 1.3 Hz, 1H), 7.22−7.18 (m, 2H), 4.92 (t, J = 7.7
Hz, 2H), 3.40 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3)
δ 163.3, 149.0, 136.2, 133.4, 129.0, 128.7, 127.7, 127.4, 124.3, 54.6,
35.8; FTIR (cm−1) (neat) 3200−2800, 1604, 1515, 1454, 1334, 1046;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H14N5O2 296.1142,
found 296.1152.
2-Butyl-5-(3,5-dinitrophenyl)-2H-tetrazole (20). The title com-
pound was prepared according to general procedure B1 using 3,5-
dinitrobenzonitrile (96.6 mg, 0.500 mmol, 1.00 equiv), dibutyltin
oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane
(0.986 mL, 0.750 mmol, 1.50 equiv), n-butylamine (0.124 mL, 1.25
mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite (0.093
mL, 0.800 mmol, 1.60 equiv) in toluene (4 mL, 1.5 mL for the first
step + 2.5 mL for the second step). The crude mixture was purified by
flash chromatography (10% EtOAc/hexanes (300 mL), then 25%
EtOAc/hexanes (300 mL)) to separate the two tetrazole isomers.
Tetrazole 20 (113 mg, 0.387 mmol, 77% yield) was isolated as a white
2-(5-Benzyl-2H-tetrazol-2-yl)-N,N-diethylethan-1-amine (24).
The title compound was prepared according to general procedure
B2 using benzyl cyanide (58.6 mg, 0.500 mmol, 1.00 equiv),
dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrime-
thylsilane (0.986 mL, 0.750 mmol, 1.50 equiv), 2-diethylaminoethyl-
amine (145 mg, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4
mL, 1.5 mL for the first step + 2.5 mL for the second step). The crude
mixture was purified by flash chromatography (75% EtOAc/hexanes
(300 mL), then 100% EtOAc (300 mL)) to separate the two tetrazole
isomers. Tetrazole 24 (83.0 mg, 0.320 mmol, 64% yield) was isolated
1
solid: Rf 0.62 (25% EtOAc/hexanes); mp 88−89 °C; H NMR (500
MHz, CDCl3) δ 9.34−9.31 (m, 2H), 9.13 (t, J = 2.1 Hz, 1H), 4.74 (t,
J = 7.1 Hz, 2H), 2.01 (qn, J = 7.4 Hz, 2H), 1.43 (sx, J = 7.5 Hz, 2H),
1.01 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.7,
149.2, 131.4, 127.8, 119.8, 53.7, 31.4, 19.7, 13.5; FTIR (cm−1) (neat)
3200−2800, 1552, 1539, 1515, 1344, 1074; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C11H12N6O4 293.0993, found 293.0993.
1
as a clear oil. Rf 0.37 (75% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) δ 7.32−7.25 (m, 4H), 7.24−7.18 (m, 1H), 4.59 (t, J = 6.9
Hz, 2H), 4.23 (s, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.52 (q, J = 7.1 Hz,
4H), 0.95 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.4, 136.9, 128.8, 128.7, 126.9, 51.8, 51.5, 47.4, 31.9, 12.1; FTIR
(cm−1) (neat) 3200−2800, 1604, 1495, 1454, 1137, 1073, 1028;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H22N5 260.1870,
found 260.1879.
2-(4-Bromophenethyl)-5-(3,5-dinitrophenyl)-2H-tetrazole (21).
The title compound was prepared according to general procedure
B1 using 2,4-dinitrobenzonitrile (96.6 mg, 0.500 mmol, 1.00 equiv),
dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrime-
thylsilane (0.986 mL, 0.750 mmol, 1.50 equiv), 4-bromophenethyl-
amine (250 mg, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4
mL, 1.5 mL for the first step + 2.5 mL for the second step). The crude
mixture was purified by flash chromatography (20% EtOAc/hexanes).
Tetrazole 21 (178 mg, 0.425 mmol, 85% yield) was isolated as a white
5-Benzhydryl-2-(2,2-dimethoxyethyl)-2H-tetrazole (25). The title
compound was prepared according to general procedure B2 using
diphenylacetonitrile (96.6 mg, 0.500 mmol, 1.00 equiv), dibutyltin
oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane
(0.986 mL, 0.750 mmol, 1.50 equiv), aminoacetaldehyde dimethyl
acetal (131 mg, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)-
propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4
mL, 1.5 mL for the first step + 2.5 mL for the second step). The crude
mixture was purified by flash chromatography (10% EtOAc/hexanes
(300 mL), then 25% EtOAc/hexanes (300 mL)). Tetrazole 25 (125
mg, 0.385 mmol, 77% yield) was isolated as a clear oil: Rf 0.17 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.36−7.29 (m,
8H), 7.25 (tt, J = 6.8 Hz, 1.8 Hz, 2H), 5.81 (s, 1H), 4.95 (t, J = 5.8
Hz, 1H), 4.72 (d, J = 5.8 Hz, 2H), 3.38 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 168.0, 140.8, 128.8, 128.6, 127.1, 101.2, 54.0, 53.7,
48.6; FTIR (cm−1) (neat) 3200−2800, 1600, 1493, 1450, 1070;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H21N4O2 325.1659,
found 325.1652.
2-Benzyl-5-(ethylthio)-2H-tetrazole (26) and 1-Benzyl-5-(ethyl-
thio)-1H-tetrazole (27). The title compounds were prepared
according to general procedure B2 using ethyl thiocyanate (43.6
mg, 0.500 mmol, 1.00 equiv), dibutyltin oxide (18.7 mg, 0.075 mmol,
0.150 equiv), azidotrimethylsilane (0.986 mL, 0.750 mmol, 1.50
equiv), benzylamine (0.137 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-
dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in
toluene (4 mL, 1.5 mL for the first step + 2.5 mL for the second step).
1
solid: Rf 0.50 (25% EtOAc/hexanes); mp 142−147 °C; H NMR
(500 MHz, CDCl3) δ 9.30 (d, J = 2.1 Hz, 2H), 9.13 (t, J = 2.1 Hz,
1H), 7.43 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.95 (t, J = 7.4
Hz, 2H), 3.40 (t, J = 7.4 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3)
δ 161.8, 149.2, 134.9, 132.3, 131.1, 130.4, 126.8, 121.6, 120.0, 54.6,
35.1; FTIR (cm−1) (neat) 3200−2800, 1594, 1554, 1542, 1518, 1456,
1342; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H11BrN6O4Na
440.9917, found 440.9919.
5-(3-Bromophenyl)-2-phenethyl-2H-tetrazole (22). The title
compound was prepared according to general procedure B1 using
3-bromobenzonitrile (91.0 mg, 0.500 mmol, 1.00 equiv), dibutyltin
oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane
(0.986 mL, 0.750 mmol, 1.50 equiv), phenethylamine (0.157 mL,
1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite
(0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4 mL, 1.5 mL for
the first step + 2.5 mL for the second step). The crude mixture was
purified by flash chromatography (10% EtOAc/hexanes (300 mL),
then 25% EtOAc/hexanes (300 mL)) to separate the two tetrazole
isomers. Tetrazole 22 (127 mg, 0.386 mmol, 77% yield) was isolated
1
as a white solid: Rf 0.50 (25% EtOAc/hexanes); mp 84−86 °C; H
NMR (400 MHz, CDCl3) δ8.31 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H),
F
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The crude mixture was purified by flash chromatography (10%
EtOAc/hexanes (300 mL), then 25% EtOAc/hexanes (300 mL)) to
separate the two tetrazole isomers. Tetrazole 26 (78.2 mg, 0.355
mmol, 71% yield) was isolated as a clear oil: Rf 0.37 (10% EtOAc/
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1
hexanes); H NMR (500 MHz, CDCl3) δ 7.41−7.32 (m, 5H), 5.70
(s, 2H), 3.19 (qd, J = 7.4 Hz, 0.3 Hz, 2H), 1.40 (td, J = 7.5 Hz, 0.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ164.7, 133.2, 129.12,
129.11, 128.5, 57.1, 26.6, 15.0; FTIR (cm−1) (neat) 3200−2800,
1606, 1497, 1456; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C10H13N4S 221.0855, found 221.0847. Tetrazole 27 (25.3 mg, 0.115
mmol, 23% yield) was isolated as a white crystalline solid: Rf 0.41
(25% EtOAc/hexanes); mp 48−51 °C; 1H NMR (400 MHz, CDCl3)
δ 7.38−7.33 (m, 3H), 7.30−7.24 (m, 2H), 5.40 (s, 2H), 3.31 (q, J =
7.4 Hz, 2H), 1.42 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 154.1, 133.1, 129.2, 129.1, 128.2, 51.0, 28.0, 14.8; FTIR
(cm−1) (neat) 3200−2800, 1586, 1496, 1446; HRMS (ESI-TOF) m/
z [M + Na]+ calcd for C10H12N4SNa 243.0675, found 243.0670.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01585.
Additional optimization tables, NMR spectra for all
synthesized compounds, X-ray structure data, and DSC-
TGA spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1−27 (ZIP)
Accession Codes
CCDC 2087914−2087915 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
̀
Hélene Lebel − Département de Chimie, Center for Green
Chemistry and Catalysis, Université de Montréal, Montréal,
Québec, Canada H3C 3J7; orcid.org/0000-0001-8835-
5786; Email: helene.lebel@umontreal.ca
Author
Guillaume Reynard − Département de Chimie, Center for
Green Chemistry and Catalysis, Université de Montréal,
Montréal, Québec, Canada H3C 3J7
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01585
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Natural Science and
Engineering Research Council of Canada (NSERC-discovery
grant), the Centre in Green Chemistry and Catalysis (CGCC),
and the Université de Montréal. We thank Prof. Shawn Collins
and Dr. James J. Mousseau for fruitful discussions.
(21) Wang, L.; Zhu, K.; Chen, Q.; He, M. Transition-Metal-Free
Direct Alkylation of Aryl Tetrazoles via Intermolecular Oxidative C-N
Formation. J. Org. Chem. 2014, 79, 11780−11786.
(22) Lisakova, A. D.; Ryabukhin, D. S.; Trifonov, R. E.; Ostrovskii,
V. A.; Vasilyev, A. V. Alkylation of 5-substituted NH-tetrazoles by
alcohols in the superacid CF3SO3H. Tetrahedron Lett. 2015, 56,
7020−7023.
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