Preparation of 2-(2H-Tetrazol-2-yl)benzoic Acids via Regioselective Cu(I) Catalyzed N2 Arylation of Tetrazole

Article abstract of DOI:10.1021/acs.oprd.9b00243

2-(2H-Tetrazol-2-yl)benzoic acid 1 and analogs were prepared via Cu(I) catalyzed C-N coupling of 2-iodo or 2-bromo benzoic acids with 5-(ethylthio)-1H- tetrazole followed by reductive cleavage of the thioether bond. The C-N coupling was regioselective toward the N2-position on tetrazole. The scope of this methodology was demonstrated on a series of 2-halobenzoic acid substrates in moderate yields.

Full text of DOI:10.1021/acs.oprd.9b00243

Subscriber access provided by Caltech Library
Full Paper
Preparation of 2-(2H-Tetrazol-2-yl)benzoic Acids via
Regioselective Cu(I) Catalyzed N2 Arylation of Tetrazole
Zhiguo Jake Song, Peter E. Maligres, Carmela Molinaro, Guy R.
Humphrey, Jeff Fritzen, Jonathan Wilson, and Yonggang Chen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00243 • Publication Date (Web): 30 Sep 2019
Downloaded from pubs.acs.org on October 7, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Preparation of 2-(2H-Tetrazol-2-yl)benzoic Acids
via Regioselective Cu(I) Catalyzed N2 Arylation of
Tetrazole
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zhiguo Jake Song*, Peter Maligres*, Carmela Molinaro, Guy Humphrey, Jeff Fritzen,
Jonathan Wilson, Yonggang Chen.
Process Research & Development, Merck & Co. Inc, P.O. Box 2000, Rahway, NJ
07065, USA.
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 38
1
2
3
4
5
Scheme for TOC
6
7
8
9
EtS
EtS
N
N
N
N
N
N
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H
I
Ra-Ni
N
N
CO2H
CO2H
CO2H
or
Cu(MeCN)4PF6
bipy/Base
Et3SiH/Pd
2
16
1
ABSTRACT 2-(2H-Tetrazol-2-yl)benzoic acid 1 and analogs were prepared via Cu(I)
catalyzed C-N coupling of 2-iodo or 2-bromo benzoic acids with 5-(ethylthio)-1H- tetrazole
followed by reductive cleavage of the thioether bond. The C-N coupling was
regioselective toward the N2-position on tetrazole. The scope of this methodology was
demonstrated on a series of 2-halobenzoic acid substrates in moderate yields.
KEYWORDS: Tetrazole benzoic acid, N-2 regioselective tetrazole arylation,
ACS Paragon Plus Environment
2

Page 3 of 38
Organic Process Research & Development
1
2
3
4
5
Introduction
6
7
8
9
Tetrazoles are important building blocks in organic synthesis. They play important roles
in materials, catalysis and biologically active compounds.1 Tetrazole structures have
been found in several important drugs.2 Depending on the substitution patterns on the
tetrazoles, their preparative methods, especially on scale, range from relatively well
established to rather specific. While 5-substituted (C-substituted) tetrazoles are readily
accessible from nitrile compounds and azides, 1-(N1-) and 2-(N2-) substituted
tetrazoles are much less accessible.3 In this paper, we report the development of a
scalable method for preparing N2 arylated tetrazole 1 (Figure 1) and analogs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
1
CO2H
Figure 1: 2-(2H-Tetrazol-2-yl)benzoic Acid
Results and Discussion
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 38
1
2
3
4
5
6
7
8
9
Arylation of Tetrazole The prior route to the substituted tetrazole 1 involved an Ullman
type4 copper (I) catalyzed, microwave-promoted N-arylation of tetrazole 3 with 2-
iodobenzoic acid (2) in DMAc at 100 °C. Unfortunately, this reaction gave a mixture of
the two regio isomers 1 and 1a in 1:4 ratio, favoring the undesired isomer. The isolated
yield of 1 after chromatography was ca. 20% (Scheme 1).5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1: Direct Arylation of Tetrazole
N
N
N N
3
2.5 eq.
HN
N
N
N
I
CO2H
0.1 eq. CuI
HO2C
CO2H
1
+
NMe2
0.2 eq.
1a
1.7 eq. Cs2CO3, DMAc
100 oC, microwave
2
Undesired
Major
Desired
Minor
20% yield
In an attempt to improve the yield of this reaction, high throughput screening of the
reaction variables including Cu and Pd catalysts, bases, solvents and aryl substrates 2,
2a, 4, 5 (aryl iodide, fluoride, boronic acid) was carried out. Most reactions gave no
product or proceeded with very low conversions. In all cases, where products were
formed, the major isomer was the undesired N1 substituted tetrazole product 1a or 1b
(Figure 2).
ACS Paragon Plus Environment
4

Page 5 of 38
Organic Process Research & Development
1
2
3
4
5
6
N
N
X
N
N
CO2Y
CO2Y
7
8
9
2 (X = I, Y = H)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2a (X = I, Y = Me)
4 (X = F, Y = Me)
5 (X = B(OH)2, Y = Me)
1a (Y = H)
1b (Y= Me)
Figure 2
Although this approach did provide a few hundred milligrams of material to support the
initial SAR efforts, this route was not scalable due to low yield and poor selectivity.
Furthermore, handling of tetrazole poses serious safety challenges. We found that
unsubstituted tetrazole 3 has an energy release of 1000 cal/g as determined by DSC
with an initial decomposition temperature of 165 °C , and is difficult to obtain on scale. It
is presumed to be shock sensitive and spontaneously decomposes with nitrogen gas
release well below 100 °C in reaction mixtures. Therefore, a more practical synthesis of
1 was required.
The [3+2] Cycloaddition Approach: A de novo route to the tetrazole system was
devised to set the desired regiochemistry. This approach (Scheme 2) is based on
Kakehi’s synthesis of 5-phenyltetrazole.6 Thus, 2-(methoxycarbonyl)
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 38
1
2
3
4
5
6
7
8
9
benzenediazonium tetrafluoroborate salt (7) was prepared in quantitative yield from
aniline 6 using non-aqueous conditions described by Doyle6d and isolated as a white
powder. Compound 7 was tested and determined to be safe to prepare on >100g scale.
Hydrazone formation using glyoxylic acid mono hydrate (8) and p-tosyl hydrazide (9)
under acidic conditions followed by an esterification with TMS-Cl in MeOH provided an
E/Z mixture of methyl 2-(2-tosylhydrazono)acetate (10) as a white solid in 61% overall
yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2: [3+2] Cycloaddition Followed by Decarboxylation
BF4
N2
NH2
CO2Me
CO2Me
a
HO2C
MeO2C
N
N
N
N
N
N
f
d
e
N
N
6
1
7
CO2H
CO2Me
Ts
NH2
TsHN
HO
HO
OH
b, c
N
. HCl
+
NH2
11
12
O
CO2Me
10
9
8
(a) 1.5 eq. BF3OEt2, 1.2 eq. t-butyl nitrite, DCM, hept, quant ; (b) 1.2 eq. HCl, water, 55 oC, 81% (c) 2 eq. TMS-Cl,
o
o
slow addition,
MeOH, r.t., 75 C, 75% (d) 2 eq. TEA/ACN,
ACN, -10-0 C. (e) 1). Darco KB-G, THF 2). 2.5 eq.
19M NaOH, EtOH, r.t. 75% for 2 steps. (f) 4 eq. aq H2SO4, DMSO, 124 oC, 70%.
For the key [3+2] cycloaddition step,7 we found that slow addition of 2 eq. of
triethylamine7c to the mixture of 7 and 10 at -10 °C in acetonitrile resulted in clean
formation of tetrazole diester 11, none of the N1 substituted tetrazole was observed. A
ACS Paragon Plus Environment
6

Page 7 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Darco KB-G treatment at this stage followed by saponification provided diacid 12 in
75% yield for the two steps. Thermal decarboxylation of 12 provided the desired product
1, undesired isomer 13 and 2-phenyl-2H-tetrazole 14. 6g A screen of acids, bases and
polar/water miscible solvents was carried out for this step and H2SO4 in DMSO/water
mixture was identified to provide the best overall performance. With 4 eq. H2SO4 in
DMSO in the absence of water at 124 °C, the reaction gave 70% isolated yield of
desired compound 1 on 90g scale. But it was also observed that the assay yield
reached a maximum at ~8 hours and dropped drastically with longer reaction time (e.g.,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
assay yield was 80% at 8 hours but 55% at 25 hours).
HO2C
N
N
N
N
N
N
N
N
14
13
Figure 3
The [3+2] cycloaddition route employs readily available starting materials and
generated the desired N2- regio isomer. However, the long cumbersome sequence and
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 38
1
2
3
4
5
6
7
8
high energy intermediates in this route prompted us to explore more practical
alternatives for larger scale deliveries.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Arylation of Ethylthiotetrazole. For kilogram quantity preparations, we re-evaluated
the N-arylation of tetrazole. N2 selective arylations of 5-substituted tetrazoles have
been reported with very reactive diaryliodonium salts under the catalysis of Cu(I) salt or
palladium catalysts.8a,b It is also known that aryl boronic acids can undergo oxidative C-
N coupling with 5-substituted tetrazoles catalyzed by copper salts.8c,d Although SNAr
type displacement of activated aryl fluorides with 5-substituted tetrazoles is known, the
scope is very limited and the regio selectivities were poor 9 We reasoned that the low
yield of direct C-N coupling with tetrazole itself was the result of its low thermal stability
and weak nucleophilicity. Employing a 5-substituted tetrazole was expected to
increase both the thermal stability and the nucleophilicity. While a variety of 5-
substituted tetrazoles such as 5-methyl, 5-methylthio, 5-phenyl-, 5-ethylthio and 5-
benzylthio-1H-tetrazole are commercially available, only 5-ethylthio-1H-tetrazole (15) is
readily available, inexpensive, and stable with low molecular weight. Additionally,
conditions are known to cleave the alkylthio ether bonds on aromatic rings with Raney-
ACS Paragon Plus Environment
8

Page 9 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
Ni or Pd catalysts; therefore, we decided to focus our efforts on this reagent for the N2
arylation.10
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High throughput screening of the reaction between 5-ethylthio-1H-tetrazole (15) and
methyl 2-iodobenzoate (2a), in the presence of Cu(MeCN)4PF6, was carried out with 22
ligands and three carbonate bases (K2CO3, Na2CO3, Cs2CO3) in DMAc solvent at 120
°C.11 In most cases a 9:1 mixture of desired N2 and undesired N1 regio isomers of the
carboxylic acids 16 and 17 were observed, albeit in low yields.12 Using 2,2’-bipyridine
as ligand, K2CO3 as base, the desired isomer acid 16 was obtained in 30% HPLC assay
yield.
Scheme 3. N2-Arylation of 5-Ethylthiotetrazole (15)
EtS
EtS
N
N N
N
N
15
Ra-Ni
I
N
N
N
N
EtS
+
N
N
N
1
CO2R
H
CO2H
CO2H
10 mol% Cu(MeCN)4PF6
15 mol% bipy
Base
2 (R = H)
2a (R = Me)
17
16
Undesired
Minor
Desired
Major
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 38
1
2
3
4
5
6
7
8
9
In comparison, the C-N coupling of 5-ethylthio-1H-tetrazole (15) and 2-iodobenzoic
acid (2) was also screened under the similar conditions and found to be much more
facile and higher yielding.13 The formation of only the carboxylic acid product in the
original screen was likely because the ester was partially hydrolyzed before undergoing
C-N coupling. The same 2,2’-bipyridine in combination with the soluble Cu(MeCN)4PF6
was found to be the optimal catalyst. Potassium phosphate was found to be the best
base among the weak bases sceened.14 Reaction temperature was also optimized and
85 °C was found to be better than the original 120 °C. A by-product observed during this
screen was the formation of salicylic acid due to the C-O coupling of adventitious
moisture present in K3PO4 with aryliodide 2. After further exploration it was found that
the use of excess 2-ethylthiotetrazole (15) (2 equivalents) reduced the formation of
salicylic acid. An initial solvent screen showed the general trend observed was that the
reaction gave better conversion and yields in polar ether type solvents such as 1,4-
dioxane and DME. In order to rapidly deliver bulk material for subsequent studies
dioxane was chosen as the solvent for further scale up. Subsequently, a more
comprehensive solvent screen was conducted to avoid the use of the toxic 1,4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
10

Page 11 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
dioxane.15 The general trend observed was the same as before, better results were
obtained in polar ether type as well as in nitrile solvents such as 1,4-dioxane, 1,3-
dioxolane, DME, acetonitrile, benzonitrile, tetrahydropyran, and N-methylmorpholine.
The three most promising hits were scaled up on 5 mmol scale and the results are
shown on Table 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1 : N-Arylation in the Best Solventsa
Entry
Solvent
Ratioc
Assay Yield
Isolated
Yieldd
16 (%)
61
16 : 17
16 (%)
1
MeCN
Dioxolane
Dioxane
6.7 : 1
8.7 : 1
69
78
81
2
3b
66
10.8 : 1
66
aReaction conditions: 10 mol% Cu(MeCN)4PF6, 15 mol% bipy, 3 eq. K3PO4, solvent,
b
85 °C, 18 h on 5 mmol scale except entry 3. 20 mol run. cAt the end of reaction. dAfter
washing cake with water, desired isomer only.
Work-up of this reaction presented some challenges. Precipitation of insoluble,
difficult to filter copper salts was observed when aqueous acid was added to the
reaction mixture to convert the carboxylate salt to the organic soluble free acid. This
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 38
1
2
3
4
5
6
7
8
9
challenge was addressed by adding zinc dust to the mixture to reduce the copper
species to copper metal, which was easily filtered off from the reaction mixture. After
extraction with cyclopentylmethyl ether (CPME), the coupling product 16 was isolated
as the diisopropylamine salt in 66% isolated yield with 94% LC purity (6% of isomer 17,
yield corrected for purity).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The removal of the ethylthio group was screened under oxidative (H2O2/HOAc,
NaOCl/aq THF, NaNO2/HOAc) and reductive (hydrogenolysis in the presence of metal
catalysts, Et3SiH/PdCl2/TMSCl, Et3SiH/Pd-C) conditions. The oxidative reactions gave
complex reaction mixtures. The palladium catalyzed triethylsilane reduction gave
desired product but produced ethanethiol (stench). A screen of reductive cleavage
under hydrogenation conditions catalyzed by several commercially available Raney
nickel and palladium catalysts identified inexpensive Raney Nickel A-5B09 as a
convienent reagent.10 It was found that the Raney Nickel reduction could be performed
at 50-70 °C in water as solvent without hydrogen, which alleviate the safety concerns
related to filtration of the nickel in the presence of flammable solvents. The ethylthio
group was cleaved to generate ethane gas and the sulfur was bound to the nickel as an
ACS Paragon Plus Environment
12

Page 13 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
insoluble sulfide17. As a result, no appreciable stench was produced for this step. After
Raney Nickel removal by filtration, the product was extracted with EtOAc under acidic
conditions. The EtOAc extract was solvent switched to toluene from which 1 was
crystallized in 80% yield and 99.9% purity with complete rejection of the undesired
regioisomer. The structure of 1 was confirmed by NMR and by single crystal X-ray
crystallography (Figure 3).16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3 : X-Ray Structure Thermal Ellipsoid Representation of 1, with Thermal
Ellipsoids Set at the 50% Probability Level.
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 38
1
2
3
4
5
6
7
8
9
Scope of Methodology: Given the success of the synthesis of 1 on kilogram scale, we
evaluated the scope of this methodology. A series of 2-halo benzoic acid analogs were
subjected to the C-N coupling reaction with 5-ethylthio-1H-tetrazole. Table 2 shows the
substrates that gave useful yields of the desired N2 products. In general, bromo and
iodo substrates performed similarly in these reactions. Other substituents had
significant effects on the reactivities, e.g., the best performing substrates had electron
donating groups such as methoxy or methyl para to the halogens (Table 2, entries 3
and 11). A nitro group para to the halogen resulted in lower yields (Table 2, entry 12).
One interesting substrate is 2-bromo-6-iodo benzoic acid where the 6-iodo product was
isolated (Table 2, entry 7). Even though it appears that the bromide reacted more
readily than the iodide, a more likely explanation is that the iodide reacted first but the
bromide product underwent halogen exchange to give the iodide product as the major
product. Figure 4 shows the substrates that gave either messy profile or poor
conversions. We also evaluated a number of other directing groups such as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
trifluoroacetamido, benzoimidazole. But none of them proved to be effective. The
ACS Paragon Plus Environment
14

Page 15 of 38
Organic Process Research & Development
1
2
3
4
5
presence of pyridine in the substrate lead to failed reactions in all cases, presumably
6
7
8
caused by competing coordination of the basic nitrogen with Cu (I) catalyst.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
CO2H
CO2H
CO2H
X
R
+
R
R
4
N
N
N
N
SEt
N
2
N
N
N
EtS
N2 isomer
N1 isomer
products
products
16, 30-38
substrates
18-29
17, 30a-38a
Table 2: C-N Coupling of 5-Ethylthiotetrazole with 2-Halobenzoic Acids
entry Substrat Substrat
R-
Product Isomer
Isolated
N2 isomer
yield %
56
e
e
N2/N1
isomer
16/17
16/17
ratio
N2/N1
3.7
X-
Br
Cl
Br
Br
Br
1
2
3
4
5
18
19
20
21
22
H
H
7.2
31
5-methoxy 30/30a
3.8
66
5-bromo
4,5-
31/31a
32/32a
5.4
55
10
54
difluoro
5-nitro
6
7
23
24
25
26
27
28
29
Br
33/33a
34/34a
35/35a
36/36a
37/37a
38/38a
33/33a
-
20
26
44
54
62
73
22
Br
6-iodo
-
8
I
I
I
I
I
4-bromo
5-chloro
5-fluoro
5-methyl
5-nitro
8.4
27
6.9
5.7
-
9
10
11
12
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 38
1
2
3
4
5
6
7
8
F
Br
I
CO2H
Br
CO2H
Br
I
CO2H
I
N
NO2
9
39
40
41
HN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
CO2H
I
CO2H
I
N
N
N
N
Br
42
43
44
H
N
H
N
CF3
CF3
O
O
I
MeO2C
I
45
46
CO2H
Br
CO2H
Br
Br
N
N
N
47
48
49
Figure 4: Poor Substrates
Three of the C-N coupling products were subjected to reductive cleavage conditions
to remove the ethylthio group. In addition to the Raney nickel conditions, palladium
catalyzed reduction with triethylsilane was also demonstrated to be effective. Both
methods were applied to each of the 3 compounds 36, 37, 38, and the yields are listed
in Scheme 4. For reduction with triethylsilane, relatively high palladium loading (method
B) appeared to be needed for complete conversion and high yield. This is
ACS Paragon Plus Environment
16

Page 17 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
recommended for small scale reactions. Raney nickel maybe cost effective on larger
scale, but in case of compound 36, significant amount of compound 16 was formed as
side product in the Raney reduction step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4
R
CO2H
R
CO2H
Methods
N
N
N
N
A or B or C
SEt
N
N
N
N
Methods/Yields
A
B
(AY)
C
(AY)
(IY)
36
37
38
50
51
52
: R = Cl
: R = F
: R = Me
76%
39%
49%
91%
88%
87%
42%
75%
53%
: R = Cl
: R = F
: R = Me
Methods: (A) Et3SiH/10% Pd/C (10%wt loading)
(B) Et3SiH/10% Pd/C (100%wt loading)
(C) Ra Ni
IY = Isolated Yield, AY = Assay Yield
In summary, scalable regioselective N2 arylation of tetrazole was achieved by copper
(I) catalyzed C-N coupling of 2-iodo and 2-bromo benzoic acid with 5-ethylthio-1H-
tetrazole followed by thioether cleavage. This methodology was applied to several
analogs and compound 1 was scaled up to kilogram scale.
Experimental Section.
ACS Paragon Plus Environment
17

Organic Process Research & Development
Page 18 of 38
1
2
3
4
5
6
7
8
9
General Reagents and solvents were purchased from commercial suppliers and used
as received unless otherwise noted. Reaction conversion and assay yields were
calibrated against isolated pure standards by HPLC. Compound characterizations were
carried out on samples purified via standard silica gel columns and confirmed to be 95%
or higher purity by HPLC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(5-(Ethylthio)-2H-tetrazol-2-yl)benzoic acid from 2-iodobenzoic acid (16). To a 100-L
3-neck glass vessel equipped with a mechanical stirrer, nitrogen inlet and thermocouple
probe under nitrogen atmosphere, 5-(ethylthio)-1H-tetrazole 15 (5.21 kg, 40.0 mol), 2-
iodobenzoic acid 2 (4.96 kg, 20 mol), 2,2'-bipyridine (0.469 kg, 3.00 mol),
tetrakis(acetonitrile) copper(I) hexafluorophosphate (0.745 kg, 2.000 mol), potassium
phosphate (12.74 kg, 60.0 mol) and 1,4-dioxane (24.80 L) were added. The dark red
mixture was heated to 86-88 °C for 14 h. HPLC analysis after 14 h indicated product
(16) /isomer (17) /iodobenzoic acid (2) = 88.6/11.4/0.0. The mixture was cooled to 42
°C; then zinc dust (0.497 kg, 7.60 mol), 5M aq HCl (24 L, 120 mol, pre-cooled to 5 °C),
and water (9.92 L) were added sequentially maintaining the temperature below 63 °C.
ACS Paragon Plus Environment
18

Page 19 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Solka-Floc (500 g), Darco KB charcoal (0.500 kg, 41.6 mol) and CPME (12.40 L) were
added. The mixture was stirred for 45 min and filtered through Solka-Floc pad. The filter
cake was washed with CPME (37.2 L). The combined filtrate was transferred to a 100-L
extractor through an inline filter and heated to 40 °C. The phases were separated, and
the organic phase was washed with water (2 x 9.92 L). HPLC analysis of the final
organic phase indicated 6.23 kg, 88.6% assay yield of 16 and 17 (16/17 = 91.5/8.5).
The organic phase was concentrated to 37 L volume under vacuum (70-80 °C batch
temperature). Diisopropylamine (6.27 L, 44.0 mol) was added to the homogeneous
mixture over 30 min with stirring at 76-90 °C to give a tan slurry. The slurry was cooled
to 25 °C over 1 h and aged for an additional 1 h. The crystalline solid was collected by
filtration and washed with CPME (25 L). The filter-cake was slurry washed with water
twice (5 Lx2) to remove residue tetrazole 15. The off-white solid was dried on the filter
pot under nitrogen stream to give diisopropylamine salt of 16 (5.22 kg, 13.9 mol
total,16/17 = 93.91/6.09 with <0.3A% 15, 66.4 % yield for 16). A small sample of the
isolated solid diisopropylamine salt was converted to the free acid by partitioning
between 1M aq HCl and MTBE followed by separation of the isomers by preparative
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
19

Organic Process Research & Development
Page 20 of 38
1
2
3
4
5
6
7
8
9
TLC (silica gel, MTBE); Major isomer: 1H-NMR (500 MHz, CD3CN): δ 1.45 (t, J = 7.3 Hz,
3H), 3.29 (q, J = 7.3 Hz, 2H) , 7.77 (m, 2H), 7.84 (m, 1H), 8.05 (m, 1H). 13C-NMR (125
MHz, CD3CN): δ 14.4, 26.5, 126.3, 127.4, 131.0, 131.2, 133.1, 135.3, 164.2, 165.3. .
Minor isomer: 1H-NMR (500 MHz, CD3CN): δ 1.42 (t, J = 7.3 Hz, 3H), 3.30 (q, J = 7.3
Hz, 2H), 7.57 (dd, J = 7.7, 1.3 Hz, 1H), 7.80 (dd, J = 7.7, 1.3 Hz, 1H), 7.88 (dd, J = 7.7,
1.6 Hz, 1H), 8.05 (dd, J = 7.7, 1.6 Hz, 1H). 13C-NMR (125 MHz, CD3CN): δ 14.2, 27.5,
127.5, 128.5, 131.7, 132.1, 132.6, 134.0, 155.8, 164.3..
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2H-Tetrazol-2-yl)benzoic acid (1). To a 100-L glass vessel protected under nitrogen,
equipped with a mechanical stirrer, nitrogen inlet/outlet and thermocouple probe, Raney
nickel A-5B09 (Johnson-Matthey, ~19 kg Ni, ~330 mol, water slurry as supplied), water
(4 L) and diisopropylamine salt of 16 (4.00 kg, 11.4 mol, 94/6 isomer mixture from
previous step) were added. The mixture gradually evolved gas (believed to be ethane)17
which was swept out with nitrogen flow. The mixture was heated to 50 °C, stirred at 50
°C for 2 h then 60 °C for 4 h. The mixture was cooled to room temperature and filtered
through a Solka-Floc pad. The filter cake was washed with water (20 L, Caution: Cake
ACS Paragon Plus Environment
20

Page 21 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
must be kept water wet throughout the filtration). The filtrate was mixed with sodium
chloride (6 kg) and then 37% aq HCl (0.935 L, 11.38 mol), extracted twice with ethyl
acetate (8 Lx2) at 35-40 °C. The combined organic phase was washed with brine (25%
NaCl, 2 L) and dried over magnesium sulfate. After removal of magnesium sulfate by
filtration, the solution was concentrated under vacuum and solvent switched to toluene
by distillation with a final volume 24 L (<60 °C at 28” Hg vacuum). The mixture was
heated to 91 °C to give a homogeneous solution, cooled to 87 °C and seeded with 1 (5
g). The mixture was gradually cooled to 22 °C over 2h. The solid was collected by
filtration and the filter cake was washed with toluene (8 L), and dried under nitrogen
stream to give 1.732 kg of 1 (83% yield). HPLC analysis indicated the crystalline solid
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
product contained <0.05A% isomer 1a. H-NMR (400 MHz, DMSO-d6): δ 7.78-7.87 (m,
3H), 8.01 (m, 1H), 9.24 (s, 1H), 13.42 (br s, 1H) ; 13C-NMR (100 MHz, DMSO-d6): δ
126.9, 129.0, 131.1, 132.8, 134.2, 135.3, 154.0, 166.3..
General procedure for other analogs: A typical procedure is for the preparation of 2-(5-
(ethylthio)-2H-tetrazol-2-yl)benzoic acid (16) from 2-bromobenzoic acid (18) To a 25
ACS Paragon Plus Environment
21

Organic Process Research & Development
Page 22 of 38
1
2
3
4
5
6
7
8
9
mL 2-neck flask were charged with 2-bromobenzoic acid 18 (200 mg, 1.0 mmol), 5-
(ethylthio)-1H-tetrazole 15 (260 mg, 1.99 mmol), 2,2'-bipyridine (23.4 mg, 0.15 mmol),
tetrakis(acetonitrile) copper(I) hexafluorophosphate (37.1 mg, 0.1 mmol), potassium
phosphate (0.63 g, 2.98 mmol) and degassed 1,4-dioxane (2 mL). The mixture was
heated to 86-88 °C overnight and cooled to room temperature. LCMS analysis showed
desired product 16/isomer 17/18 = 78.6/21.4/0.0. The mixture was poured into 50 mL
water. The mixture was neutralized with AcOH to pH = 5 and extracted with EtOAc (50
mL x 3). The organic phase was concentrated and purified by Combi-Flash (ACN:H2O
with 0.05% TFA 30%-60%, 30min ). 140 mg 2-(5-(ethylthio)-2H-tetrazol-2-yl)benzoic
acid 16 (56%) was obtained as white solid. The assay yield was 69% which was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
determined by HPLC using a purified sample as standard. H-NMR (400 MHz, CDCl3):
δ 1.43 (t, J = 7.3 Hz, 3H), 3.24 (q, J = 7.3 Hz, 2H), 7.64–7.80 (m, 3H), 8.08 (d, J = 7.5
Hz, 1H), 11.60 (br s, 1H). 13C-NMR (101 MHz, CDCl3): δ 14.83, 26.73, 126.27, 126.32,
130.83, 131.63, 133.43, 135.78, 164.79, 169.77. HRMS (ESI): calcd for C10H10N4O2S
[M+H]+ : 251.05972; found 251.05919.
ACS Paragon Plus Environment
22

Page 23 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-5-methoxybenzoic acid (30) From 2-bromo-5-
methoxybenzoic acid (20, 200 mg, 0.87 mmol), 2-(5-(ethylthio)-2H-tetrazol-2-yl)-5-
methoxybenzoic acid (66%) was obtained as yellow solid. The assay yield was 74%.
1H-NMR (400 MHz, CDCl3): δ 1.43 (t, J = 7.3 Hz, 3H), 3.23 (q, J = 7.3 Hz, 2H), 3.93 (s,
3H), 7.22 (dd, J = 8.8, 2.7 Hz, 1H), 7.54-7.57 (m, 2H), 11.40 (br s, 1H) ppm. 13C-NMR
(101 MHz, CDCl3): δ 14.83, 26.74, 56.05, 116.36, 118.84, 127.52, 128.03, 128.90,
160.98, 164.36, 169.25 ppm. HRMS (ESI): calcd for C11H12N4O3S [M+H]+ : 281.07029;
found 281.06967.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Bromo-2-(5-(ethylthio)-2H-tetrazol-2-yl)benzoic acid (31) From 2,5-dibromobenzoic
acid (21, 200 mg, 0.72 mmol), 130 mg 5-bromo-2-(5-(ethylthio)-2H-tetrazol-2-yl)benzoic
1
acid (55%) was obtained as light-yellow solid. The assay yield was 68%. H-NMR (400
MHz, CDCl3): δ 1.44 (t, J = 7.3 Hz, 3H), 3.24 (q, J = 7.3 Hz, 2H), 7.61 (d, J = 2.1 Hz, 1H),
7.88 (d, J = 8.5, 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 11.22 (br s, 1H) ppm 13C-NMR
(101 MHz, CDCl3): δ 14.79, 26.69, 124.81, 127.37, 127.68, 134.42, 134.44, 136.29,
165.18, 168.26 ppm. HRMS (ESI): calcd for C10H9BrN4O2S [M+H]+ : 330.96874; found
330.96725.
ACS Paragon Plus Environment
23

Organic Process Research & Development
Page 24 of 38
1
2
3
4
5
6
7
8
9
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-4,5-difluorobenzoic acid (32) From 2-bromo-4,5-
difluorobenzoic acid (22, 200 mg, 0.84 mmol), 130 mg 2-(5-(ethylthio)-2H-tetrazol-2-yl)-
4,5-difluorobenzoic acid (54%) was obtained as yellow solid. The assay yield was 66%.
1H-NMR (400 MHz, CDCl3): δ 1.44 (t, J = 7.3 Hz, 3H), 3.25 (q, J = 7.3 Hz, 2H), 7.59 (dd,
J = 9.3, 6.5 Hz, 1H), 7.96 (t, J = 8.7 Hz, 1H), 11.34 (br s, 1H) ppm. 19F-NMR (376 MHz,
CDCl3): δ -130.74 (d, J = 21.3 Hz), -125.87 (d, J = 21.3 Hz) ppm. 13C-NMR (101 MHz,
CDCl3): δ 14.75, 26.63, 116.63 (d, J = 21.2 Hz), 120.99 (d, J = 20.3 Hz), 123.43, 132.46
(dd, J = 8.2, 3.7 Hz), 150.42 (dd, J = 148.3, 13.0 Hz), 152.99 (dd, J = 152.2, 13.0 Hz),
165.36, 167.39 ppm. HRMS (ESI): calcd for C10H8F2N4O2S [M+H]+ : 287.04088; found
287.04013.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-5-nitrobenzoic acid (33) From 2-bromo-5-nitrobenzoic
acid (23, 500 mg, 2.03 mmol), 120 mg 2-(5-(ethylthio)-2H-tetrazol-2-yl)-5-nitrobenzoic
acid (20%) was obtained as light brown solid. The assay yield was 20%. Conversion
was about 48% based on HPLC with UV detector set at 210 nm. The reaction of 2-iodo-
5-nitrobenzoic acid (29, 500 mg, 1.7 mmol) gave 110 mg 33 (22%) as yellow solid. The
assay yield was 26%, LCMS indicated about 55% conversion. 1H-NMR (400 MHz,
ACS Paragon Plus Environment
24

Page 25 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
CDCl3): δ 1.47 (t, J = 7.3 Hz, 3H), 3.29 (q, J = 7.3 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 8.60
(dd, J = 8.8, 2.4 Hz, 1H), 8.85 (d, J = 2.3 Hz, 1H), 9.82 (br s, 1H) ppm. 13C-NMR (101
MHz, DMSO-d6): δ 15.30, 26.62, 125.96, 127.97, 128.03, 130.09, 138.43, 148.79,
164.91, 164.99 ppm. HRMS (ESI): calcd for C10H9N5O4S [M+H]+ : 296.04480; found
296.04410.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-6-iodobenzoic acid (34) From 2-bromo-6-iodobenzoic
acid (24, 200 mg, 0.6 mmol), 60 mg 2-(5-(ethylthio)-2H-tetrazol-2-yl)-6-iodobenzoic acid
1
(26%) was obtained as yellow solid. H-NMR (400 MHz, CDCl3): δ 1.47 (t, J = 7.3 Hz,
3H), 3.27 (q, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 8.02–8.06 (m, 2H), 8.60 (s, 1H)
ppm. 13C-NMR (101 MHz, CDCl3): δ 14.83, 26.66, 93.83, 122.12, 131.59, 132.54,
133.44, 140.92, 165.54, 170.32 ppm. HRMS (ESI): calcd for C10H9IN4O2S [M+H]+ :
376.95637; found 376.95538.
4-Bromo-2-(5-(Ethylthio)-2H-tetrazol-2-yl) benzoic acid (35) From 4-bromo-2-
iodobenzoic acid 25 (200 mg, 0.6 mmol), 88 mg 4-bromo-2-(5-(ethylthio)-2H-tetrazol-2-
1
yl) benzoic acid (44%) was obtained as yellow solid. The assay yield was 52%. H-
NMR (400 MHz, CDCl3): δ 1.44 (t, J = 7.3 Hz, 3H), 3.25 (q, J = 7.3 Hz, 2H), 7.81 (dd, J =
ACS Paragon Plus Environment
25

Organic Process Research & Development
Page 26 of 38
1
2
3
4
5
6
7
8
9
8.4, 1.6 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 11.19 (s, 1H) ppm.
13C-NMR (101 MHz, CDCl3): δ 14.80, 26.67, 124.94, 127.61, 129.31, 132.79, 133.95,
136.35, 165.25, 169.25 ppm. HRMS (ESI): calcd for C10H9BrN4O2S [M+H]+ :
330.96874; found 330.96719.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Chloro-2-(5-(ethylthio)-2H-tetrazol-2-yl)benzoic acid (36)18 From 5-chloro-2-
iodobenzoic acid (26, 1 g, 3.54mmol), 0.54 g 5-chloro-2-(5-(ethylthio)-2H-tetrazol-2-
yl)benzoic acid (54%) was obtained as off-white solid. 1H-NMR (400 MHz, CDCl3): δ
1.44 (t, J = 7.3 Hz, 3H), 3.25 (q, J = 7.3 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.73 (dd, J =
8.5, 2.3 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 10.13 (s, 1H) ppm. 13C-NMR (101 MHz,
DMSO-d6): δ 15.38, 26.58, 127.90, 128.87, 129.75, 130.03, 133.41, 135.45, 162.93,
166.29 ppm. HRMS (ESI): calcd for C10H9ClN4O2S [M+H]+ : 285.02075; found
285.02014.
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-5-fluorobenzoic acid (37)18 From 5-fluoro-2-
iodobenzoic acid (27, 1 g, 3.76 mmol), 0.63 g 2-(5-(ethylthio)-2H-tetrazol-2-yl)-5-
fluorobenzoic acid (62%) was obtained as light-yellow solid. The assay yield was 71%.
1H-NMR (400 MHz, CDCl3): δ 1.43 (t, J = 7.3 Hz, 3H), 3.24 (q, J = 7.3 Hz, 2H), 7.50-
ACS Paragon Plus Environment
26

Page 27 of 38
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
7.42 (m, 1H), 7.70 (dd, J = 8.8, 4.6 Hz, 1H), 7.79 (dd, J = 8.1, 2.6 Hz, 1H), 11.53 (s, 1H)
ppm. 19F-NMR (376 MHz, CDCl3): δ -106.7 ppm. 13C-NMR (101 MHz, CDCl3): δ 14.78,
26.68, 118.85 (d, J = 25.3 Hz), 120.41 (d, J = 23.0 Hz), 128.60 (d, J = 8.7 Hz, 2C),
131.96 (d, J = 3.5 Hz), 162.99 (d, J = 254.5 Hz), 164.94, 168.04 ppm. HRMS (ESI):
calcd for C10H9FN4O2S [M+H]+ : 269.05030; found 269.04971.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(5-(Ethylthio)-2H-tetrazol-2-yl)-5-methylbenzoic acid (38) From 2-iodo-5-
methylbenzoic acid (28, 1 g, 3.82 mmol), 0.76 g 2-(5-(ethylthio)-2H-tetrazol-2-yl)-5-
methylbenzoic acid (73%) was obtained as white solid. 1H-NMR (400 MHz, CDCl3): δ
1.44 (t, J = 7.3 Hz, 3H), 2.51 (s, 3H), 3.24 (q, J = 7.3 Hz, 2H), 7.51-7.59 (m, 2H), 7.89
(s, 1H), 9.71 (s, 1H) ppm. 13C-NMR (101 MHz, CDCl3): δ 14.68, 21.21, 26.82, 125.59,
126.41, 132.32, 133.45, 134.32, 142.01, 164.61, 170.08 ppm. HRMS (ESI): calcd for
C11H12N4O2S [M+H]+ : 265.07537; found 265.07483.
5-Chloro-2-(2H-tetrazol-2-yl)benzoic acid (50)
Method A To a 10 mL flask were charged with 10% Pd/C (20 mg), 5-chloro-2-(5-
(ethylthio)-2H-tetrazol-2-yl)benzoic acid (36, 200 mg, 0.70 mmol), and THF (1.0 mL)
under nitrogen. The mixture was placed in a 0 ºC bath, treated with triethylsilane (490
ACS Paragon Plus Environment
27

Organic Process Research & Development
Page 28 of 38
1
2
3
4
5
6
7
8
9
mg, 4.22 mmol) and warmed to room temperature slowly. After stirred for overnight the
mixture was filtered and the filtrate was purified by Combi-flash (ACN:H2O with 0.05%
TFA 30%-60%, 30 min ). Compound 50 (120 mg, 76%) was obtained as white solid.
Method B To a 10 mL 2-neck RB flask was charged with 10% Pd/C (100 mg) and 36
(100 mg, 0.35 mmol) in THF (1.0 mL). The mixture was placed in a 0 ºC bath, treated
with triethylsilane (245 mg, 2.11 mmol) and warmed to room temperature slowly. After
agitation overnight, the mixture was filtered. The assay yield of 50 was 91% by HPLC.
Method C A solution of 5-chloro-2-(5-(ethylthio)-2H-tetrazol-2-yl)benzoic acid (36, 100
mg, 0.35 mmol) was dissolved in 1 mL water with 2 eq iPr2NH. The solution was added
dropwise to 350 mg Raney Ni in 1 mL water. The mixture was warmed to 50 °C slowly
and agitated for 4 h. LCMS showed complete reaction. The mixture was filtered and the
assay yield for 50 was 42%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H-NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.5 Hz, 1H), 7.75 (dd, J = 8.5, 2.3 Hz, 1H),
8.08 (d, J = 2.3 Hz, 1H), 8.72 (s, 1H), 9.81 (s, 1H) ppm. 13C-NMR (101 MHz, DMSO-
d6): δ 128.65, 130.66, 130.91, 132.98, 133.82, 136.30, 154.05, 165.23 ppm. HRMS
(ESI): calcd for C8H5ClN4O2 [M+H]+ : 225.01738; found 225.01685
ACS Paragon Plus Environment
28

Page 29 of 38
Organic Process Research & Development
1
2
3
4
5
5-Fluoro-2-(2H-tetrazol-2-yl)benzoic acid (51)
6
7
1
White solid (method A, 39%; method B, 88%; method C, 75%) H-NMR (400 MHz,
CDCl3): δ 7.48 (ddd, J = 8.8, 7.2, 2.9 Hz, 1H), 7.70 (dd, J = 8.8, 4.7 Hz, 1H), 7.82 (dd, J
= 8.2, 2.9 Hz, 1H), 8.72 (s, 1H), 9.12 (s, 1H) ppm. 19F-NMR (376 MHz, CDCl3): δ -
106.55 ppm. 13C-NMR (101 MHz, DMSO-d6): δ 118.02 (d, J = 25.0 Hz), 120.02 (d, J =
23.2 Hz), 129.61 (d, J = 9.2 Hz), 131.65 (d, J = 3.0 Hz), 131.94 (d, J = 8.0 Hz), 153.90,
163.03 (d, J = 250.8 Hz), 165.21 ppm. HRMS (ESI): calcd for C8H5FN4O2 [M+H]+ :
209.04693; found 209.04652.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Methyl-2-(2H-tetrazol-2-yl)benzoic acid (52)
1
White solid (method A, 49%; method B, 87%; method C, 53%) H-NMR (400 MHz,
CDCl3) : δ 2.53 (s, 3H), 7.56 (s, 2H), 7.92 (s, 1H), 8.69 (s, 1H) ppm. 13C-NMR (101
MHz, DMSO-d6): δ 21.08, 126.80, 128.85, 131.44, 133.04, 133.47, 141.99, 153.77,
166.43 ppm. HRMS (ESI): calcd for C9H8N4O2 [M+H]+: 205.07200; found 205.07161.
ACS Paragon Plus Environment
29