5-Aryltetrazoles from Direct C-H Arylation with Aryl Bromides

Article abstract of DOI:10.1021/acs.joc.0c00085

A mild, direct C-H arylation of 1-substituted tetrazoles to 5-aryltetrazoles is developed using a Pd/Cu cocatalytic system with readily available aryl bromides. The methodology avoids late-stage usage of azides and tolerates a wide range of functionalities.

Full text of DOI:10.1021/acs.joc.0c00085

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Note
5-Aryl Tetrazoles from Direct C–H Arylation with Aryl Bromides
Yuan Zhang, Jack Chang Hung Lee, Matthew R Reese,
Brian P Boscoe, John M. Humphrey, and Christopher J Helal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00085 • Publication Date (Web): 25 Mar 2020
Downloaded from pubs.acs.org on March 27, 2020
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commercial copper reagents using conditions modified from
those of Pour and coworkers (Table 1).
5-Aryl Tetrazoles from Direct C–H Arylation with
Aryl Bromides
We opted to use 1-p-methoxybenzyl(PMB) tetrazole (1) as
the model substrate due to its ready availability, facile PMB
removal and importantly, its acceptable safety profile.10,11
While copper(I) iodide successfully promoted direct C–H
arylation of 4-tolyl iodide, it did not work for 4-tolyl bromide.
Among the selected commercial organocopper(I) species, only
Cu(XantPhos)I gave significant conversion at 20 mol%
loading. The much improved reactivity of Cu(XantPhos)I was
tentatively attributed to its efficient coordination to N4 of 1,
which enabled a facile deprotonation followed by a N4 to C5
Yuan Zhang*, Jack Chang Hung Lee, Matthew R. Reese,
Brian P. Boscoe, John M. Humphrey, Christopher J. Helal
Pfizer Worldwide Research and Development, Eastern Point
Road, Groton, Connecticut 06340, United States
yuan.zhang9@pfizer.com
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RECEIVED DATE (will be automatically inserted after
manuscript is accepted).
copper shift to provide
a ligand-stabilized tetrazolyl
organocopper species.12
Pd(OAc)2
PMB
DavePhos
PMB
Ar
N
N
N
N
NH
Cu(XantPhos)I
N
TABLE 1. Investigation of copper(I) reagentsa
MsOH
HFIP
+
Br Ar
N
N
N
N
N
Cs2CO3, MeCN
Ar
N
60 o
C
[Cu] (1 eq)
Pd(OAc)2 (5mol%)
PMB
PMB
P(2-furanyl)3 (10 mol%)
N
N
N
N
+
X
Me
N
A mild direct C–H arylation of 1-substituted tetrazoles to 5-
aryl tetrazoles is developed using a Pd/Cu co-catalytic
system with readily available aryl bromides. The
methodology avoids late stage usage of azides and tolerates
a wide range of functionalities.
N
N
Cs2CO3 (2.5 eq)
Me
N
MeCN (0.33 M), 60 o
C
1
2a
3a
Entry
X
[Cu]
CuI
CuI
Yieldb (%)
1
2
3
4
5
6
7
8
I
32
0
Br
Br
Br
Br
Br
Br
Br
c
Cu(MeCN)4PF6
0
Tetrazoles are important structural scaffolds that have found
broad applications in medicines, biochemistry, and material
science.1 As bioisosteres of carboxylic acids and amides,
tetrazoles have been widely used in medicinal chemistry to
modulate physicochemical properties and to lower drug-drug
interaction (DDI) risks.2,3 There are over twenty marketed drugs
that possess tetrazole motifs, spanning a variety of therapeutic
areas such as antimicrobial, oncology and cardiovascular.1,4
We recently found that certain 5-aryl tetrazoles exhibited
potent and selective activities towards the desired target in one
of our medicinal chemistry programs. Conventional synthesis
of such tetrazoles relies on 1,3-dipolar cycloaddition between
aryl nitriles and azides, which often suffers from the use of
toxic/explosive reagents, high temperatures, and low
yields.5Limited examples of Pd-catalyzed cross-coupling
approaches have also been reported, though functional handles
such as halogens or metallic species are generally required.6,7
Because of their wide applications in medicinal chemistry
including our recent program, we were interested in exploring
alternative access to aryl tetrazoles, ideally from a large, diverse
monomer class and without late stage usage of azides.
Pour and coworkers recently reported a direct C–H arylation
approach between 1-substituted tetrazoles and aryl iodides
using a Pd(OAc)2/P(2-furyl)3/CuI system.8 This strategy
aligned with our interest in utilizing readily available aryl
halides as building blocks towards aryl tetrazoles. The limited
diversity of aryl iodides however, prompted us to investigate
the possibility of exploring more accessible aryl bromides.9 We
reasoned that a ligand-stabilized tetrazolyl organocopper
species may improve the reactivity towards the aryl-Pd(II)-Br
species. To test this hypothesis, we surveyed several
CuTc c
[(iPr)CuCl] c
0
0
c
Cu(Phen)(PPh3)2NO3
<5
<5
72
Cu(PPh3)3Br c
Cu(XantPhos)I c
aReaction conditions: 1 (0.33 mmol, 1.0 equiv), 2a (1.5 equiv), Pd(OAc)2 (5
mol%), P(2-furyl)3 (10 mol%), [Cu] (1 equiv, unless otherwise noted), Cs2CO3
(2.5 equiv), MeCN (1 mL), 60 °C, 6 h. bThe yield was determined by 1H NMR
spectroscopy using dimethylsulfone as an internal standard. c20 mol% of [Cu]
was used.
We subsequently investigated the effects of phosphine
ligands and solvents in the Pd/Cu co-catalytic system (Table 2).
In general, monodentate biaryl phosphine ligands performed
well and gave good conversion, with DavePhos affording the
best results in 80% isolated yield (entries 1–8). Solvent effects
were less pronounced. All solvents tested provided significant
conversion to product, and MeCN was chosen as the optimal
solvent (entries 8-13). It is noteworthy that the loading of
Cu(XantPhos)I can be further lowered to 10 mol% with only a
slight reduction of the yield (entry 13).
TABLE 2. Investigation of ligands and solventsa
Ligand (10 mol%)
Pd(OAc)2 (5mol%)
PMB
PMB
N
N
Cu(XantPhos)I (20 mol%)
N
N
+
Br
Me
N
N
N
Cs2CO3 (2.5 eq)
Me
N
Solvent (0.33 M), 60 o
C
2a'
3a
1
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Entry
1
Ligand
PPh3
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
Yieldb (%)
methodology tolerated a wide variety of functional groups and
52
<5
aromatic rings, but was sensitive to both electronic and steric
effects on the aryl bromides. In general, electron-poor and -
neutral aryl bromides afforded better isolated yields than
electron-rich bromides (3a, 3b vs 3d). Ortho-substituted aryl
bromides gave significantly reduced yields compared to their
para- and meta-substituted counterparts (3d, 3k vs 3o). It is
noteworthy that free -OH and amide -NH are tolerated in the
transformations (3h and 3l). Heteroaromatics such as pyridyl
bromides were good substrates, giving excellent isolated yields
regardless of the electronic bias of the substituents (3q-s). Other
heteroaromatic systems such as quinoline, diazines, thiophene,
and thiazole were all amenable substrates, affording modest to
excellent yields (3t-x). As a proof of concept for alkenyl
bromide substrates, 2-bromonorbornene was successfully
converted to tetrazole 3y in moderate yield. The scalability of
this methodology was demonstrated in a gram-scale synthesis
of tetrazole 3r with good yields.
The resulting 1-PMB-5-aryl tetrazoles can be subsequently
converted to 5-aryl tetrazoles under acidic PMB-removal
conditions. While commonly used TFA-anisole-DCM system
worked well with 1-PMB-5-phenyl tetrazoles, deprotection of
1-PMB-5-heteroaryl tetrazoles can be sluggish.13 We have since
discovered a general N-PMB-deprotection protocol using
methanesulfonic acid (MsOH) in hexafluoro-2-propanol (HFIP,
Scheme 2).14 A detailed communication on this N-PMB-
removal protocol will be reported separately in due course.
2
CataCXium A
dppf
3
26
4
P[(2,6-(OMe)2Ph]3
JohnPhos
XPhos
28
5
68
10
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13
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22
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32
33
6
76
7
BINAP
22
86 (80) c
8
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
9
70
10
11
12
13d
Dioxane
DME
70
76
toluene
62
MeCN
78
aReaction conditions: 1 (0.33 mmol, 1.0 equiv), 2a’ (1.5 equiv), Pd(OAc)2 (5
mol%), Ligand (10 mol%), Cu(XantPhos)I (20 mol%), Cs2CO3 (2.5 equiv),
Solvent (1 mL), 60 °C, 6 h. bThe yield was determined by 1H NMR
spectroscopy using dimethylsulfone as an internal standard. cIsolated yield in
parenthesis. d10 mol% of Cu(XantPhos)I was used.
Scheme 1. Scope of the direct C–H arylation of 1a,b
aReaction conditions: 1 (0.50 mmol, 1.0 equiv), 2 (1.5 equiv), Pd(OAc)2 (5
mol%), DavePhos (10 mol%), Cu(XantPhos)I (20 mol%), Cs2CO3 (2.5 equiv),
MeCN (1.5 mL), 60 °C, 6 h. bAll yields are isolated yields.
Pd(OAc)2 (5mol%)
With the
optimized
DavePhos (10 mol%)
PMB
PMB
Scheme 2. Example of deprotection of 1-PMB-5-aryl tetrazoles
Cu(XantPhos)I (20 mol%)
Cs2CO3 (2.5 eq)
N
N
N
N
Br Ar
+
conditions
in hand, we
set out to
investigate
the scope of
aryl
bromides
(Scheme 1).
The
N
Ar
N
N
N
PMB
2
MeCN (0.33 M), 60 o
C
3
1
CO2Me
CO2Me
N
NH
N
N
MsOH (3 equiv)
N
N
Aryl bromides:
N
N
N
N
34
HFIP (0.1M), rt, 20 h
74%
PMB
PMB
N
N
PMB
PMB
N
N
35
N
N
N
N
N
N
N
N
N
3s
4s
N
N
N
36
37
3a
38, 80%
F
OMe
CN
Me
F
3c
, 93%
PMB
3d
, 48%
PMB
3b
, 73%
PMB
While our focus was on 5-aryl tetrazoles as carboxylic acid
39 PMB
N
N
N
N
N
N
N
N
N
N
N
N 40
isosteres and using 1-PMB as a removable handle in the direct
C–H arylation, other functional groups at N1 position were also
tolerated. 1-phenyl tetrazole 5 underwent C–H arylation with 4-
tolyl bromide smoothly under standard conditions, affording
1,5-diaryl tetrazole in good yield (Scheme 3). 1,5-disubstituted
tetrazoles are privileged motifs in medicinal chemistry and have
shown to display numerous biological activities. We believe
this current C–H arylation strategy represents a complementary
approach to existing methods.15
N
N
N
N
41
42
O
S
N
F
O
O
OH
3g
, 88%
PMB
3e
3f
3h
, 71%
, 80%
PMB
, 69%
PMB
43
PMB
N
N
N
N
44
N
N
N
N
N
N
N
N
N
N
H
N
N
N
45
46
OMe
CO2Me
CF3
O
3l
, 21%
3j
3k
, 94%
, 64%
PMB
3i
47
, 70%
48 PMB
PMB
PMB
N
N
N
N
N
N
N
N
N
N
N
N
49
Scheme 3. Direct C–H arylation of 1-phenyl tetrazole
N
N
N
N
50
F
MeO
3o
MOMO
Me
Ph
Ph
standard
conditions
51
N
N
3p
, 33%
3m
3n
52, 22%
, 59%
PMB
, 32%
PMB
N
N
+
Br
Me
N
N
N
He5ter3oaryl bromides:
55%
Me
N
2a'
5
PMB
N
N
PMB
6
N
N
N
N
N
N
N
54
N
N
N
In summary, we have developed a mild and efficient C–H
arylation methodology from 1-substituted tetrazoles and aryl
bromides to generate 1,5-disubstituted tetrazoles. The use of
Cu(XantPhos)I significantly improves reactivity and expands
the scope of aryl halides to much more accessible bromides. An
N
N
N
N
55
CO2Me
MeO
N
N
N
56
57
N
3q
, 87%
3s
3t
, 63%
3r
, 80%
, 90%
77% (1 gram scale)
58
Alkenyl bromide:
59PMB
PMB
N
PMB
S
N
PMB
PMB
N
N
N
N6N0
N
N
N
N
N
N
N
N
N
N
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N
N
N
N
N
S
N
N
N
3y
, 24%
3v
3w, 41%
3x
, 34%
3u
, 41%
, 81%
2

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improved PMB-removal protocol enables facile conversion to
5-aryl tetrazoles. We believe this robust methodology will be a
useful addition to the synthetic chemistry community.
114.6, 55.4, 51.1, 21.6. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H17N4O 281.1397; found 281.1391.
4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)benzonitrile (3b).
Eluent: 0–50% EtOAc in heptane. Light yellow solid (106 mg,
73%). mp 101.9–102.3 °C. 1H NMR (400 MHz, Chloroform-
d) δ 7.80 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.06 (d,
J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.58 (s, 2H), 3.79 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 153.1, 133.0,
129.7, 128.7, 128.5, 125.3, 117.7, 115.4, 114.8, 55.5, 51.6.
HRMS (ESI) m/z: [M+H]+ Calcd for C16H14N5O 292.1193;
found 292.1187.
5-(4-(Difluoromethyl)phenyl)-1-(4-methoxybenzyl)-1H-
tetrazole (3c). Eluent: 0–30% EtOAc in heptane. White solid
(147 mg, 93%). mp 82.3–82.8 °C. 1H NMR (400 MHz,
Chloroform-d) δ 7.70 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz,
2H), 7.10 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.73 (t,
J = 56.0 Hz, 1H), 5.57 (s, 2H), 3.80 (s, 3H). 19F NMR (376
MHz, Chloroform-d) δ -112.15 (d, J = 57.7 Hz). 13C{1H} NMR
(101 MHz, Chloroform-d) δ 160.1, 153.8, 137.3 (t, J = 22.7 Hz),
129.5, 128.8, 126.5 (t, J = 6.1 Hz), 125.7, 114.7, 113.9 (t, J =
240.1Hz), 55.5, 51.3. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H15F2N4O 317.1208; found 317.1201.
EXPERIMENTAL SECTION
General Methods. Chemicals and solvents were purchased
from commercial sources when available and used without
further purification. Reactions were monitored by standard
thin-layer chromatography (TLC) and LC-MS techniques. TLC
analyses were performed using EMD silica gel 60F254 pre-
coated plates (0.25 mm thickness) and UV light (λ 254 nm or
365 nm) and potassium permanganate stain for visualization.
LC-MS were acquired using Waters Acquity UPLC equipped
with a Waters Acquity HSS T3 column, water/MeCN gradient
and 0.1% v/v formic acid as modifier. Chromatographic
separations were performed using ISCO Combiflash Rf using
pre-packed RediSep Gold silica-gel cartridges. Proton (1H),
carbon (13C), and fluorine (19F) nuclear magnetic resonance
(NMR) spectroscopy data were recorded on 400 MHz Bruker
or Varian spectrometers respectively. All 1H NMR spectra are
reported in parts per million (ppm) and were measured relative
to the solvent signals at 7.26 ppm (CHCl3). All 13C NMR
spectra were also reported in parts per million (ppm) and
measured relative to the solvent signals at 77.1 ppm (CHCl3).
Data for 1H NMR are described as follow: chemical shift (δ in
ppm), multiplicity (s: singlet; d: doublet; t: triplet; q: quartet;
quint: quintuplet; m: multiplet; br: broad signal), integration,
coupling constant J (Hz). Data for 13C NMR spectra are
described in terms of chemical shift (δ in ppm). HRMS was
conducted on an Agilent 6220 TOF mass spectrometer in
positive electrospray mode. Samples were separated by UPLC
on an Agilent 1200 system prior to mass spectrometric analysis.
Melting points were measured on OptiMelt MPA100 automated
melting point system from Stanford Research Systems. While
all procedures reported herein were conducted without incident,
appropriate laboratory safety precautions are recommended
when handling tetrazole compounds in general.
General Procedure for C–H Arylation of 1-PMB
Tetrazole. To a 2 dram vial with red pressure relief cap were
added 1-substituted tetrazole (0.50 mmol, 1 equiv), Pd(OAc)2
(5.61 mg, 5 mol%), DavePhos (19.7 mg, 10 mol%),
Cu(XantPhos)I (76.9 mg, 20 mol%), Cs2CO3 (407 mg, 2.5
equiv). For solid aryl bromide, it was added directly into the
mixture at this stage (1.5 equiv). The vial was sealed and purged
with N2 before MeCN (1.5 mL) was added. For liquid aryl
bromide, it was added at this stage via a syringe (1.5 equiv).
The vial was put on a preheated 60 °C metal heating block and
stirred for 6 h. After cooling to room temperature, the mixture
was filtered through celite and washed with ethyl acetate. The
filtrate was concentrated in vacuo and purified through column
chromatography.
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1-(4-Methoxybenzyl)-5-(4-methoxyphenyl)-1H-tetrazole
(3d). Eluent: 0–10% EtOAc in dichloromethane. Light tan solid
1
(71 mg, 48%). mp 117.2–119.3 °C (lit.16 mp 122–123 °C). H
NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.5 Hz, 2H),
7.11 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.86 (d, J
= 8.3 Hz, 2H), 5.54 (s, 2H), 3.87 (s, 3H), 3.79 (s, 3H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 162.0, 159.9,
154.4, 130.5, 128.8, 126.1, 116.0, 114.7, 114.6, 55.6, 55.4,
51.1. HRMS (ESI) m/z: [M+H]+ Calcd for C16H17N4O2
297.1346; found 297.1340.
5-(4-Fluorophenyl)-1-(4-methoxybenzyl)-1H-tetrazole (3e).
Eluent: 0–70% EtOAc in heptane. Light brown oil (114 mg,
80%). 1H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 8.5,
4.8 Hz, 2H), 7.20 (t, J = 8.5 Hz, 2H), 7.08 (d, J = 8.2 Hz,
2H), 6.86 (d, J = 8.2 Hz, 2H), 5.54 (s, 2H), 3.79 (s, 3H). 19F
NMR (376 MHz, Chloroform-d) δ -107.47. 13C{1H} NMR (101
MHz, Chloroform-d) δ 165.5 (d, J = 253 Hz), 160.0, 153.8,
131.2 (d, J = 9.0 Hz), 128.8, 125.8, 120.1 (d, J = 3.4 Hz),
116.6 (d, J = 22.2 Hz), 114.7, 55.4, 51.1. HRMS (ESI) m/z:
[M+H]+ Calcd for C15H14FN4O 285.1146; found 285.1138.
1-(4-Methoxybenzyl)-5-(4-(methylsulfonyl)phenyl)-1H-
tetrazole (3f). Eluent: 0–100% EtOAc in heptane. Light yellow
solid (119 mg, 69%). mp 133.9–134.6 °C. 1H NMR (400 MHz,
Chloroform-d) δ 8.06 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz,
1H), 7.07 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.58 (s,
1H), 3.77 (s, 2H), 3.09 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.2, 153.1, 143.2, 130.1, 129.3, 128.8, 128.3, 125.3,
114.8, 55.5, 51.5, 44.4. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H17N4O3S 345.1016; found 345.1012.
1-(4-Methoxybenzyl)-5-(p-tolyl)-1H-tetrazole (3a). Eluent:
0–50% EtOAc in heptane. Light yellow solid (112 mg, 80%).
4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-N,N-
dimethylbenzamide (3g). Eluent: 0–20% MeOH in EtOAc.
1
mp 78.4–81.8 °C (lit.16 mp 75–76 °C). H NMR (400 MHz,
1
White solid (148 mg, 88%). mp 105.8–107.2 °C. H NMR (400
Chloroform-d) δ 7.48 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz,
2H), 7.10 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.53 (s,
2H), 3.78 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.9, 154.6, 141.8, 130.0, 128.9, 128.8, 126.1, 121.0,
MHz, Chloroform-d) δ 7.63 (d, J = 8.0 Hz, 2H), 7.55 (d, J =
8.2 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz,
2H), 5.54 (s, 2H), 3.78 (s, 3H), 3.13 (s, 3H), 2.98 (s, 3H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 170.3, 160.0,
154.0, 139.4, 129.2, 128.9, 127.9, 125.8, 125.1, 114.7, 55.4,
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51.2, 39.5, 35.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C18H19N5O2 338.1611; found 338.1600.
55.4, 50.9, 19.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H17N4O 281.1397; found 281.1393.
2-(4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)phenyl)ethan-1-
ol (3h). Eluent: 0–100% EtOAc in dichloromethane. White
solid (110 mg, 71%). mp 93.2–93.7 °C. 1H NMR (400 MHz,
Chloroform-d) δ 7.51 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.9 Hz,
2H), 7.08 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.52
(s, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 2.93 (t, J = 6.6
Hz, 2H), 2.27 (s, 1H). 13C{1H} NMR (101 MHz, Chloroform-
d) δ 159.9, 154.6, 142.9, 130.0, 129.0, 128.8, 126.0, 121.8,
114.6, 63.1, 55.4, 51.1, 39.1. HRMS (ESI) m/z: [M+H]+ Calcd
for C17H19N4O2 311.1502; found 311.1496.
Methyl 3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzoate
(3i). Eluent: 0–50% EtOAc in heptane. Light yellow oil (113
mg, 70%). 1H NMR (400 MHz, Chloroform-d) δ 8.27 (t, J = 1.9
Hz, 1H), 8.22 (dt, J = 7.9, 1.4 Hz, 1H), 7.84 (dt, J = 7.8, 1.9 Hz,
1H), 7.61 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.86 (d,
J = 8.7 Hz, 2H), 5.58 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H).13C{1H}
NMR (101 MHz, CDCl3) δ 165.9, 160.1, 153.8, 133.4, 132.4,
131.3, 129.9, 129.6, 129.1, 125.6, 124.5, 114.7, 55.5, 52.6, 51.4.
HRMS (ESI) m/z: [M+H]+ Calcd for C17H17N4O3 325.1295;
found 325.1289.
1-(4-Methoxybenzyl)-5-(3-(trifluoromethyl)phenyl)-1H-
tetrazole (3j). Eluent: 0–50% EtOAc in heptane. Dark yellow
solid (158 mg, 94%). mp 94.3–102.8 °C. 1H NMR (400 MHz,
Chloroform-d) δ 7.85–7.75 (m, 3H), 7.70–7.62 (m, 1H), 7.10
(d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.56 (s, 2H), 3.78
(s, 3H). 19F NMR (376 MHz, Chloroform-d) δ -62.90. 13C{1H}
NMR (101 MHz, Chloroform-d) δ 160.2, 153.4, 132.4, 131.8
(q, J = 33.2 Hz), 130.0, 128.9, 128.1 (q, J = 3.7 Hz), 126.0 (q,
J = 3.8 Hz), 125.5, 125.0, 123.5 (q, J = 273.7 Hz), 114.8, 55.5,
51.5. HRMS (ESI) m/z: [M+H]+ Calcd for C16H14F3N4O
335.1114; found 335.1107.
1-(4-Methoxybenzyl)-5-(3-methoxyphenyl)-1H-tetrazole (3k).
Eluent: 0–10% EtOAc in dichloromethane. Light yellow oil (95
mg, 64%). 1H NMR (400 MHz, Chloroform-d) δ 7.42 (t, J = 7.9
Hz, 1H), 7.16–7.08 (m, 5H), 6.86 (d, J = 8.2 Hz, 2H), 5.56 (s,
2H), 3.80 (s, 3H), 3.79 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 160.1, 160.0, 154.5, 130.4, 128.9, 126.0, 125.1,
121.1, 117.6, 114.6, 114.2, 55.6, 55.4, 51.1. HRMS (ESI) m/z:
[M+H]+ Calcd for C16H17N4O2 297.1346; found 297.1342.
N-(3-(1-(4-Methoxybenzyl)-1H-tetrazol-5-
yl)phenyl)acetamide (3l). Eluent: 0–100% EtOAc in heptane.
Colorless oil (34 mg, 21%). 1H NMR (400 MHz, Chloroform-
d) δ 8.44 (s, 1H), 7.97–7.73 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H),
7.24 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J =
8.4 Hz, 2H), 5.58 (s, 2H), 3.77 (s, 3H), 2.23 (s, 3H). 13C{1H}
NMR (101 MHz, Chloroform-d) δ 169.2, 160.0, 154.3, 139.3,
130.0, 129.3, 125.7, 124.2, 124.0, 122.7, 120.3, 114.5, 55.4,
51.3, 24.6. HRMS (ESI) m/z: [M+H]+ Calcd for C17H18N5O2
324.1455; found 324.1449.
1-(4-Methoxybenzyl)-5-(o-tolyl)-1H-tetrazole (3m). Eluent:
0–50% EtOAc in heptane. Colorless oil (31 mg, 22%). 1H NMR
(400 MHz, Chloroform-d) δ 7.44 (t, J = 7.6 Hz, 1H), 7.34–
7.22 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.3 Hz,
2H), 6.75 (d, J = 8.3 Hz, 2H), 5.30 (s, 2H), 3.75 (s, 3H), 1.96
(s, 3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 160.0,
154.1, 138.6, 131.2, 131.0, 129.7, 1262, 125.6, 123.8, 114.3,
5-(2-Fluorophenyl)-1-(4-methoxybenzyl)-1H-tetrazole (3n).
Eluent: 0–50% EtOAc in heptane. Colorless oil (84 mg, 59%).
1H NMR (400 MHz, Chloroform-d) δ 7.61–7.50 (m, 1H),
7.49–7.36 (m, 1H), 7.35–7.19 (m, 2H), 6.98 (d, J = 8.3 Hz,
2H), 6.73 (d, J = 8.4 Hz, 2H), 5.45 (s, 2H), 3.72 (s, 3H). 19F
NMR (376 MHz, Chloroform-d) δ -111.81. 13C{1H} NMR
(101 MHz, Chloroform-d) δ 160.0, 159.7, 133.7, 131.8, 129.6,
125.3, 125.2, 116.4, 114.3, 112.7, 55.4, 51.6. HRMS (ESI)
m/z: [M+H]+ Calcd for C15H14FN4O 285.1146; found 285.1142.
1-(4-Methoxybenzyl)-5-(2-methoxyphenyl)-1H-tetrazole
(3o). Eluent: 0–50% EtOAc in heptane. Colorless oil (47 mg,
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32%). H NMR (400 MHz, Chloroform-d) δ 7.54 (td, J = 7.8,
1.8 Hz, 1H), 7.32(dt, J = 7.6, 1.7 Hz, 1H), 7.08–6.98 (m, 2H),
6.97 (dt, J = 9.4, 2.4 Hz, 2H), 6.77–6.69 (m, 2H), 5.38 (s, 2H),
3.76 (s, 3H), 3.75 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 159.8, 157.0, 152.7, 133.0, 131.9, 129.5,
126.0, 121.3, 114.2, 113.4, 111.4, 55.7, 55.4, 51.3. HRMS
(ESI) m/z: [M+H]+ Calcd for C16H17N4O2 297.1346; found
297.1333.
1-(4-Methoxybenzyl)-5-(2-(methoxymethoxy)phenyl)-1H-
tetrazole (3p). Eluent: 0–100% EtOAc in heptane. Colorless oil
(54 mg, 33%). 1H NMR (400 MHz, Chloroform-d) δ 7.50 (ddd,
J = 8.4, 7.4, 1.8 Hz, 1H), 7.29–7.24 (m, 2H), 7.11 (td, J =
7.5, 1.0 Hz, 1H), 7.01–6.91 (m, 2H), 6.78–6.68 (m, 2H), 5.40
(s, 2H), 5.06 (s, 2H), 3.73 (s, 3H), 3.31 (s, 3H). 13C{1H} NMR
(101 MHz, Chloroform-d) δ 159.8, 155.0, 152.6, 133.0, 131.7,
129.5, 125.9, 122.5, 115.3, 114.4, 114.2, 95.1, 56.5, 55.4,
51.2. HRMS (ESI) m/z: [M+H]+ Calcd for C17H19N4O3
327.1452; found 327.1436.
2-Methoxy-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-
yl)pyridine (3q). Eluent: 0–50% EtOAc in heptane. White solid
(129 mg, 87%). mp 103.6–104.0 °C. 1H NMR (400 MHz,
Chloroform-d) δ 8.36 (dd, J = 4.9, 1.9 Hz, 1H), 7.65 (dd, J =
7.3, 1.9 Hz, 1H), 7.02–6.93 (dd, J = 7.3, 4.9 Hz, 1H), 6.97 (d,
J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H), 5.47 (s, 2H), 3.96 (s,
3H), 3.75 (s, 3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ
160.6, 159.9, 150.4, 140.9, 129.5, 125.6, 117.1, 114.3, 108.2,
55.4, 54.0, 51.7. HRMS (ESI) m/z: [M+H]+ Calcd for
C15H16N5O2 298.1298; found 298.1293.
4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-2,6-
dimethylpyridine (3r). Eluent: 0–100% EtOAc in heptane. Light
yellow oil (133 mg, 90%). 1H NMR (400 MHz, Chloroform-d)
δ 7.13 (s, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H),
5.55 (s, 2H), 3.78 (s, 3H), 2.56 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 160.1, 159.3, 153.0, 132.3, 128.9, 125.6, 119.5,
114.7, 55.5, 51.5, 24.7. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H18N5O 296.1506; found 296.1502.
Methyl 4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)picolinate
(3s). Eluent: 0–100% EtOAc in heptane. Light yellow oil (130
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mg, 80%). H NMR (400 MHz, Chloroform-d) δ 8.89 (d, J =
5.0 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 5.0, 1.7 Hz,
1H), 7.11 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.64 (s,
2H), 4.02 (s, 3H), 3.76 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 164.7, 160.3, 151.8, 151.0, 149.1, 133.3, 129.0, 126.0,
124.9, 124.0, 114.9, 55.5, 53.4, 51.9. HRMS (ESI) m/z: [M+H]+
Calcd for C16H16N5O3 326.1248; found 326.1243.
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6-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)quinoline
(3t).
Eluent: 0–100% EtOAc in heptane. Colorless oil (100 mg, 63%).
1H NMR (400 MHz, Chloroform-d) δ 9.05 (d, J = 4.0 Hz, 1H),
8.25 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.10 (d, J =
1.9 Hz, 1H), 7.90 (dd, J = 8.7, 2.0 Hz, 1H), 7.52 (dd, J = 8.3,
4.1 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H),
5.64 (s, 2H), 3.79 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 160.1, 154.1, 152.6, 148.9, 136.7, 130.9, 129.7,
128.9, 128.7, 127.9, 125.8, 122.5, 122.1, 114.7, 55.4, 51.4.
HRMS (ESI) m/z: [M+H]+ Calcd for C18H16N5O 318.1349;
found 318.1343
mg, 0.75 mmol) as a white solid (97 mg, 55%). Eluent: 0–10%
EtOAc in dichloromethane. mp 134.3–134.7 °C (lit.8 mp 136–
137 °C). 1H NMR (400 MHz, Chloroform-d) δ 7.58–7.46 (m,
3H), 7.45–7.34 (m, 4H), 7.20 (d, J = 7.8 Hz, 2H), 2.38 (s,
3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 153.8, 141.9,
134.8, 130.4, 130.0, 129.8, 128.9, 125.4, 120.7, 21.6. HRMS
(ESI) m/z: [M+H]+ Calcd for C14H13N4 237.1135; found
237.1130.
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Procedure for Gram-Scale Preparation of 3r. To a 50 mL
round bottom flask fitted with a reflux condenser were added 1-
PMB tetrazole (1, 1.00 g, 1 equiv), 4-bromo-2,6-dimethyl
pyridine (2r, 1.47 g, 1.5 equiv), Pd(OAc)2 (59 mg, 5 mol%),
DavePhos (207 mg, 10 mol%), Cu(XantPhos)I (809 mg, 20
mol%) and Cs2CO3 (4.28 g, 2.5 equiv). The flask was evacuated
and refilled with N2 three times before MeCN (15.9 mL, 0.33
M) was added. The mixture was allowed to stir at 60 °C in an
oil bath for 6 h. After cooling to room temperature, the reaction
mixture was filtered through celite and washed with ethyl
acetate. The filtrate was concentrated in vacuo and purified
through column chromatography with 0–100% EtOAc in
heptane. Product 4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-
2,6-dimethylpyridine (3r) was obtained as a light yellow oil
(1.20 g, 77%).
2-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)pyrazine
(3u).
Eluent: 0–100% EtOAc in heptane. Light tan solid (109 mg,
81%). mp 106.2–106.6 °C. 1H NMR (400 MHz, Chloroform-
d) δ 9.59 (d, J = 1.5 Hz, 1H), 8.78–8.71 (m, 2H), 7.30 (d, J
= 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.12 (s, 2H), 3.77 (s,
3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 159.9, 149.7,
146.3, 145.7, 143.6, 140.9, 129.9, 126.3, 114.3, 55.4, 52.4.
HRMS (ESI) m/z: [M+H]+ Calcd for C13H13N6O 269.1145;
found 269.1138.
5-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)pyrimidine (3v).
Eluent: 0–100% EtOAc in heptane. Light yellow oil (55 mg,
41%). 1H NMR (400 MHz, Chloroform-d) δ 9.36 (s, 1H), 8.95
(s, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.63
(s, 2H), 3.78 (s, 3H). 13C{1H} NMR (101 MHz, Chloroform-d)
δ 160.5, 160.3, 156.4, 149.8, 128.7, 124.9, 119.7, 115.0, 55.5,
51.8. HRMS (ESI) m/z: [M+H]+ Calcd for C13H13N6O
Procedure for N-PMB deprotection. To a solution of
methyl
4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)picolinate
(3s) (89 mg, 0.273 mmol, 1 equiv) in HFIP (2.73 mL, 0.1M)
was added MsOH (78.7 mg, 53.2 L, 3 equiv) at room
temperature. The mixture was allowed to stir at room
temperature for 20 h before volatiles were removed in vacuo.
The residue was washed with heptane and recrystallized from
ethanol and heptane to give methyl 4-(1H-tetrazol-5-
yl)picolinate (4s) as a white solid (42 mg, 74%). mp 228.0–
229.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 5.0
Hz, 1H), 8.63 (d, J = 1.7 Hz, 1H), 8.24 (dd, J = 5.0, 1.7 Hz,
1H), 3.95 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
165.1, 155.5, 151.7, 149.1, 134.0, 124.6, 122.2, 53.2. HRMS
(ESI) m/z: [M+H]+ Calcd for C8H8N5O2 206.0673; found
206.0676.
269.1145; found 269.1138.
1-(4-Methoxybenzyl)-5-(5-methylthiophen-2-yl)-1H-
tetrazole (3w). Eluent: 0–50% EtOAc in heptane. white solid
(59 mg, 41%). mp 94.5–95.5 °C. 1H NMR (400 MHz,
Chloroform-d) δ 7.32 (d, J = 3.7 Hz, 1H), 7.14 (d, J = 8.4 Hz,
2H), 6.88 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 3.6 Hz, 1H), 5.67
(s, 2H), 3.80 (s, 3H), 2.56 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 159.9, 149.8, 145.9, 130.6, 128.6, 126.8,
125.7, 121.5, 114.6, 55.4, 51.0, 15.5. HRMS (ESI) m/z:
[M+H]+ Calcd for C14H15N4OS 287.0961; found 287.0955.
4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-2-methylthiazole
(3x). Eluent: 0–100% EtOAc in heptane. Light yellow oil (49
mg, 34%). 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H),
7.34 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.07 (s,
2H), 3.77 (s, 3H), 2.85 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 167.5, 159.8, 148.6, 139.8, 130.0, 127.0,
123.1, 114.2, 55.4, 51.6, 19.4. HRMS (ESI) m/z: [M+H]+
Calcd for C13H14N5OS 288.0914; found 288.0908.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at
http://pubs.acs.org.
NMR spectra of new and known compounds
Single crystal X-ray data for compound 6 (CIF)
5-(Bicyclo[2.2.1]hept-2-en-2-yl)-1-(4-methoxybenzyl)-1H-
ACKNOWLEDGMENTS
We thank Kevin Filipski, Bethany L. Kormos, Neal Sach, Louise
Bernier for helpful discussions, Jacob Belval for purification
assistance, Ivan Samardjiev for generation of single crystal x-ray
structures, and Jamison B. Tuttle, Lei Zhang, Patrick R. Verhoest, and
Christopher R. Butler for support.
tetrazole (3y). Eluent: 0–35% EtOAc in heptane. Light yellow
1
oil (34 mg, 24%). mp 78.4–81.8 °C. H NMR (400 MHz,
Chloroform-d) δ 7.05 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz,
2H), 6.51 (d, J = 3.2 Hz, 1H), 5.61 (d, J = 15.6 Hz, 1H), 5.44
(d, J = 15.6 Hz, 1H), 3.79 (s, 3H), 3.54 (br s, 1H), 3.08 (br s,
1H), 1.85–1.74 (m, 2H), 1.57–1.52 (m, 1H), 1.28 (d, J = 6.6
Hz, 1H), 1.21–1.13 (m, 1H), 1.08–0.99 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 159.8, 150.5, 141.3, 132.3,
128.3, 125.9, 114.5, 55.4, 50.9, 48.2, 45.2, 44.0, 25.2, 24.7.
HRMS (ESI) m/z: [M+H]+ Calcd for C16H19N4O 283.1554;
found 283.1563.
(1) For a recent review on tetrazoles, see: Neochoritis, C. G.; Zhao, T.;
Doemling, A. Tetrazoles via Multicomponent Reactions. Chem. Rev. 2019, 119,
1970–2042. For a recent review on tetrazoles as biomedicines, see: Popova, E.
A.; Trifonov, R. E.; Ostrovskii, V. A. Tetrazoles for Biomedicine. Russ. Chem.
Rev. 2019, 88, 644–676.
(2) Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Medicinal Chemistry of
Tetrazoles. Russ. Chem. Bull. 2012, 61, 768–780.
(3) (a) Herr, R. J. 5-Substituted-1H-Tetrazoles as Carboxylic Acid Isosteres:
Medicinal Chemistry and Synthetic Methods. Bioorg. Med. Chem. 2002, 10,
1-Phenyl-5-(p-tolyl)-1H-tetrazole (6). 6 was synthesized
according to the general procedure with 1-phenyl tetrazole (110
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3379–3393. (b) May, B. C. H.; Abell, A. D. The Synthesis and Crystal Structure
of Alpha-Keto Tetrazole-Based Dipeptide Mimics. Tetrahedron Lett. 2001, 42,
5641–5644.
(4) (a) Arulmozhi, R.; Abirami, N.; Helen, K. P. A Pharmacological Expedition
of Tetrazole Compounds towards Medical Field – An Overview. Int. J. Pharm.
Sci. Rev. Res. 2017, 46, 110–114. (b) Gao, C.; Chang, L.; Xu, Z.; Yan, X.-F.;
Ding, C.; Zhao, F.; Wu, X.; Feng, L.-S. Recent Advances of Tetrazole
Derivatives as Potential Anti-Tubercular and Anti-Malarial Agents. Eur. J. Med.
Chem. 2019, 163, 404–412.
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(5) For a recent review on tetrazole synthesis, see: Ostrovskii, V. A.; Popova, E.
A.; Trifonov, R. E. Developments in Tetrazole Chemistry (2009-2016); Elsevier
Ltd, 2017.
(6) For representative cross-coupling reactions with 5-halo-tetrazoles or
equivalents, see: (a) Yi, K. Y.; Yoo, S.-E. Synthesis of 5-Aryl and Vinyl
Tetrazoles by the Palladium-Catalyzed Cross-Coupling Reaction. Tetrahedron
Lett. 1995, 36, 1679–1682. (b) Walker, S. D.; Barder, T. E.; Marinelli, J. R.;
Buchwald, S. L. A Rationally Designed Universal Catalyst for Suzuki-Miyaura
Coupling Processes. Angew. Chem. Int. Ed. 2004, 43, 1871–1876. (c) Tang, Q.;
Gianatassio, R. Synthesis of 1,5-Disubstituted Tetrazoles via Suzuki-Miyaura
Cross-Coupling of 5-Chloro-1-Phenyltetrazole. Tetrahedron Lett. 2010, 51,
3473–3476. (d) Hennessy, E. J.; Cornebise, M; Gingipalli, L.; Grebe, T.; Hande,
S.; Hoesch, V.; Huynh, H.; Throner, S.; Varnes, J. Wu, Y. Preparation of Highly
Functionalized 1,5-Disubstituted Tetrazoles via Palladium-Catalyzed Suzuki
Coupling. Tetrahedron Lett. 2017, 58, 1709–1713.
(7) For representative cross-coupling reactions with 5-metallo-tetrazoles, see: (a)
Wiedemann, S. H.; Bio, M. M.; Brown, L. M.; Hansen, K. B.; Langille, N. F.
Some Practical Methods for the Application of 5-Metallo-1-Benzyl-1H-
Tetrazoles in Synthesis. Synlett 2012, 23, 2231–2236. (b) Bookser, B. C. 2-
Benzyloxymethyl-5-(tributylstannyl)tetrazole. A Reagent for the Preparation of
5-Aryl- and 5-Heteroaryl-1H-Tetrazoles via the Stille Reaction. Tetrahedron
Lett. 2000, 41, 2805–2809.
(8) Špulák, M.; Lubojacký, R.; Šenel, P.; Kuneš, J.; Pour, M. Direct C–H
Arylation and Alkenylation of 1-Substituted Tetrazoles: Phosphine as
Stabilizing Factor. J. Org. Chem. 2010, 75, 241–244.
(9) To the best of our knowledge, the only example of direct C–H arylation
between 1-substituted tetrazole and aryl bromide is on 1-Methyl tetrazole with
3-bromo-5-nitrotolune in 21% yield, see: Singh, R.; Li, H.; Zhao, H.; Kolluri,
R.; Tso, K.; Ramphal, J.; Gu, S.; Valdez, C.; Zhang, J.; Stauffer, E.; Duncton,
M.; Al-Varez, S. Derivatives of N2-(3-Pyridil or Phenyl)-N4-(4-Piperidyl)-2,4-
Pyrimidinediamine Useful in the Treatment of Inflammatory, Autoimmune or
Proliferative Diseases. WO 2010/090875A1, 12 Aug 2010.
(10) For synthesis of 1-PMB tetrazole, see: Yang, H.; Ouyang, Y.; Ma, H.;
Cong, H.; Zhuang, C.; Lok, W.-T.; Wang, Z.; Zhu, X.; Sun, Y.; Hong, W., Wang,
H. Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their
Binding Preferences Using Molecular Modelling. Bioorg. & Med. Chem. Lett.
2017, 27, 4635–3642.
(11) Onset temperature of 1-PMB tetrazole in Differential Scanning Calorimetry
(DSC) is 173 °C. Pfizer internal safety protocol requires a minimum 100 °C
window between DSC onset temperature and reaction temperature.
(12) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.;
Faul, M. M. A Highly Efficient Palladium/Copper Cocatalytic System for Direct
Arylation of Heteroarenes: An Unexpected Effect of Cu(Xantphos)I. J. Am.
Chem. Soc. 2010, 132, 3674–3675.
(13) For PMB-deprotection with TFA-anisole-DCM system, see: Yoshida, K.-
I.; Nakayama, K.; Ohtsuka, M.; Kuru, N.; Yokomizo, Y.; Sakamoto, A.;
Takemura, M.; Hoshino, K.; Kanda, H.; Nitanai, H.; Namaba, K.; Yoshida, K.;
Imamura, Y.; Zhang, J. Z.; Lee, V. J.; Watkins, W. MexAB-OprM Specific
Efflux Pump Inhibitors in Pseudomonas aeruginosa. Part 7: Highly Soluble and
in vivo Active Quaternary Ammonium Analogue D13-9001, a Potential
Preclinical Candidate. Bioorg. Med. Chem. 2007, 15, 7087–7097.
(14) For a related O-PMB deprotection, see: Volbeda, A. G.; Kistemaker, H. A.
V.; Overkleeft, H. S.; van der Marel, G. A.; Filippov, D. V.; Godée, J. D. C.
Chemoselective Cleavage of p-Methoxybenzyl and 2-Naphthylmethyl Ethers
Using a Catalytic Amount of HCl in Hexafluoro-2-propanol. J. Org. Chem. 2015,
80, 8796–8806. (15) For a review of synthesis of 1,5-disubstituted tetrazoles,
see: Sarvary, A.; Maleki, A. A Review of Syntheses of 1,5-Disubstituted
Tetrazole Derivatives. Mol. Divers. 2015, 19, 189–212.
(16) El Kaim, L.; Grimaud, L; Patil, P. Three-Component Strategy toward 5-
Membered Heterocycles from Isocyanide Dibromides. Org. Lett. 2011, 13,
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