Easy Synthesis of Two Positional Isomeric Tetrazole Libraries

Article abstract of DOI:10.1055/s-0035-1562435

A fast and efficient synthesis of libraries of positional isomeric 1H-tetrazoles and 5H-tetrazoles, for the purpose of testing binding hypothesis of isomeric tetrazoles in fragment-based drug discovery, is described.

Full text of DOI:10.1055/s-0035-1562435

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
Y. Wang et al.
Paper
Synthesis
Easy Synthesis of Two Positional Isomeric Tetrazole Libraries
Yuanze Wang1
Pravin Patil1
Alexander Dömling*
University of Groningen, Department of Drug Design,
A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
a.s.s.domling@rug.nl
Received: 04.04.2016
Accepted after revision: 03.05.2016
Published online: 21.06.2016
DOI: 10.1055/s-0035-1562435; Art ID: ss-2016-t0232-op
Abstract A fast and efficient synthesis of libraries of positional isomer-
ic 1H-tetrazoles and 5H-tetrazoles, for the purpose of testing binding
hypothesis of isomeric tetrazoles in fragment-based drug discovery, is
described.
Key words 1H-tetrazole, 5H-tetrazole, cyanoacetamide, isocyano-
acetamide, [2+3] cycloaddition, Oliveri-Mandala and Alagna reaction,
fragment-based drug discovery
Monosubstituted tetrazoles can exist as two isomers,
the 1- and the 5-substituted form. The 1-substituted form
has a mobile hydrogen and comprises a tetrazole acid with
similar pKa as the carboxylic acid. The 5-substituted form,
however, is charge neutral and has no mobile hydrogen. At
present, there are 3 neutral and 55 negatively charged
tetrazole structures in the protein data bank (PDB).2 Both
forms are expected to interact differentially with protein
receptors (Figure 1).3 To have a testable library of both iso-
mers we decided to synthesize a small library of com-
pounds of both isomers each based on some previously
published synthetic work of us. These libraries will be use-
ful in fragment-based drug discovery to test binding hy-
pothesis.4
We have recently described two complementary
straightforward ways for the diverse synthesis of libraries
of cyano- and isocyanoacetamides, by simply reacting the
corresponding cyano- and isocyanoacetyl methyl esters sol-
ventless with a primary or secondary amine.7 Advanta-
geously, the products in most cases precipitate and simple
filtration affords very pure products. Here we describe their
conversion into libraries of corresponding positional iso-
meric tetrazoles (Scheme 1).
Figure 1 Examples of characteristic receptor-tetrazole binding modes
found in the PDB. Above: Sterol 14α-demethylase (CYP51) from Try-
panosoma cruzi in complex with the 1-tetrazole derivative VT-1161 (PDB
ID 5AJR) exhibiting the metal ligand character of tetrazoles;5 Below:
CTX-M-9 class A β-lactamase complexed with NH′-tetrazole (PDB ID
3G34) exhibiting a hydrogen contact to water and one hydrogen con-
tact to Gln-188 side chain amide.6
5-Substituted 1H-tetrazoles can be synthesized by the
simple [2+3] cycloaddition of nitriles to an azide.8 Initially,
the formation of 1H-tetrazoles from the cyanoacetamides
was tested, using various metal catalyst along with the sol-
vents like DMF and DMSO under vigorous reaction condi-
tions.9 Unfortunately, multiple product formations was ob-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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Y. Wang et al.
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Synthesis
O
N
N
O
O
N
NaN3 (3 equiv)
N
O
O
R1
CN
N
ref. 7a
ref. 7b
NC
CN
R1
N
R2
NC
CN
COOMe
COOMe
N
N
R1
R1
N
R2
N
N
R2
Et3N⋅HCl (3 equiv)
N
N
R2
H
H
R
R
R
toluene, 90 °C, 20 h
R
R
1
2
O
N
N
N
Scheme 2 Optimized conditions for the synthesis of 5-substituted 1H-
R1
R1
N
tetrazoles
N
R2
R2
R
Scheme 1 Synthetic strategy towards otherwise identical positional li-
braries of 1H-tetrazoles (red) and 5H-tetrazoles (blue)
We observed that using the combination of trimethyl-
amine hydrochloride in toluene at 90 °C afforded the prod-
uct with best conversion and yield. Particularly, the reac-
tion of N-benzyl-2-cyanoactamide (1a) with sodium azide
(3 equiv) and triethylamine hydrochloride salt (3 equiv)
heated in toluene at 90 °C for 20 hours gave the product N-
benzyl-2-(1H-tetrazol-5-yl)acetamide (2a) in 67% yield. In
this method, the product could be isolated by simple aque-
ous workup followed by filtration, and tedious purifications
were not required. The optimized protocol was examined
for various N-alkyl-substituted 2-cyanoactamides to study
the scope and generality of the reaction condition to obtain
various 5-substituted 1H-tetrazoles (Table 1).
served and it was difficult to isolate the pure product. Fur-
thermore, under the microwave conditions9e we failed to
obtain pure products.
The use of solvents play an important role in such type
of reactions.10 First, the synthesis of tetrazole 2a was tested
in various solvents such as toluene, DMF, DMSO, and aceto-
nitrile at various reaction times (6 to 24 h) and tempera-
tures from 55 to 160 °C using sodium azide (1.3 equiv) and
ammonium chloride as well as trialkylamine hydrochloride
salt (Scheme 2).
Table 1 Synthesis of N-Substituted 2-(1H-Tetrazol-5-yl)acetamides
Entry
1
Product 2
Yield (%)a
67
Entry
12
Product 2
Yield (%)a
56
N
N
O
N
O
N
N
N
Ph
N
N
N
N
H
H
H
H
Ph
2l
2a
2b
2
3
74
79
13
14
89
21
O
N
N
N
O
N
N
N
N
N
N
N
H
H
H
H
2m
N
N
N
O
N
O
N
N
O
N
N
N
H
N
H
H
H
2n
2c
4
5
86
64
15
16
65
55
N
N
N
S
O
O
N
N
N
N
N
N
N
H
H
H
H
2o
2d
N
N
N
N
O
O
N
N
N
N
N
N
H
N
H
H
H
2p
2q
Cl
2e
6
70
17
77
N
N
O
N
O
N
N
N
N
N
H
N
H
H
H
2f
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
Y. Wang et al.
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Synthesis
Table 1 (continued)
Entry
7
Product 2
Yield (%)a
76
Entry
18
Product 2
Yield (%)a
98
N
N
N
O
N
O
O
O
N
N
N
N
C12H25
N
N
N
N
H
H
H
H
2r
2s
Cl
2g
8
70
19
25
N
N
N
O
N
N
N
N
H
N
N
H
H
H
F
2h
9
87
93
20
21
51
9
F
N
N
N
N
O
N
N
N
H
N
H
N
N
H
H
2t
2i
10
N
O
N
O
N
N
N
O
N
N
N
N
H
H
H
O
2u
2j
11
70
22
25
N
N
N
N
OH
O
O
N
N
N
N
N
N
H
H
H
O
2k
2v
a Isolated yield.
N
O
O
Tetrazole derived from N-phenethyl-2-cyanoacetamide
(1b) gave N-phenethyl-2-(1H-tetrazol-5-yl)acetamide (2b)
in even better yield (74%) than 2a (67%). A similar trend of
increasing yields were observed as the carbon chain length
of N-alkylphenyl in 2-cyanoacetamides increased from 3 to
4, for example, N-phenpropyl-2-(1H-tetrazol-5-yl)acet-
amide (2c) and N-phenbutyl-2-(1H-tetrazol-5-yl)acet-
amide (2d) were obtained in 79% and 86% yield, respective-
ly. When the N-benzyl group of 2-cyanoacetamide was re-
placed with various substituted N-benzyl groups 1e–h, the
yields of products 2e–h were similar. Remarkably, in the
case of the highly electron rich N-(3,4-dimethoxypheyl)-2-
cyanoacetamide (1j), N-(3,4-dimethoxyphenyl)-2-(1H-
tetrazol-5-yl)acetamide (2j) was obtained in excellent yield
(93%). Furthermore, simple N-alkyl-substituted 2-cyano-
acetamides 1q–r gave good yield of products 2q–r. Howev-
er, N-allyl-2-cyanoacetamide (1s) was found to be less reac-
tive and gave N-allyl-2-(1H-tetrazol-5-yl)acetamide (2s) in
only 25% yield. Unfortunately, N,N-disubstituted 2-cyano-
acetamides 1u,v in the same reaction conditions gave poor
yields of 2u,v as 9% and 25%, respectively.
TMSN3 (1.2 equiv)
N
R1
N
R1
NC
N
N
R2
N
R2
MeOH–H2O (3:1)
25 °C, 20 h
4
3
Scheme 3 Optimized conditions for the synthesis of 1-substituted 5H-
tetrazoles
Table 2 Optimization of N-Benzyl-2-(1H-tetrazol-1-yl)acetamide
Azide
Solvent
Temp (°C) Time (h) Yield (%)a
NaN3
MeOH
25
25
40
40
25
25
55
25
25
20
20
20
20
20
20
20
20
20
11
TMSN3
NaN3
CH2Cl2
traces
traces
traces
traces
27
MeCN
TMSN3
NaN3
CH2Cl2
CH2Cl2
TMSN3
TMSN3
NaN3
MeOH
MeOH
45
Noteworthy, the herein described method does not re-
quire any expensive organometallic reagents as well as
harsh reaction conditions such as very high reaction tem-
perature or microwave irradiation.
MeOH–H2O (3:1)
MeOH–H2O (3:1)
35
TMSN3
a Isolated yield.
97
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Synthesis
After successfully synthesizing the N-substituted-2-
(1H-tetrazol-5-yl)acetamides, the synthesis of N-alkyl-2-
(1H-tetrazol-1-yl)acetamide was examined by using the N-
alkyl-2-isocyanoacetamides (Scheme 3).
Isocyanide to tetrazole conversion is also known as the
Oliveri-Mandala and Alagna reaction.11 The freshly pre-
pared N-substituted 2-isocyanoacetamides were used as
they are easily synthesized by the neat reaction of 1° or 2°
alkylamines with methyl isocyanoacetate.7b
and Alagna reaction.11 Unfortunately, poor yield (11%) was
observed (Table 2). Then various solvents and azide sources
were tested. By using dichloromethane as the solvent, only
traces of the product formation was observed. When sodi-
um azide was changed to trimethylsilyl azide in methanol,
27% yield was obtained at room temperature. However, the
yield could be increased to 45% when the reaction was heat-
ed at 55 °C in methanol. Using 25% water in methanol as a
solvent with sodium azide at room temperature gave only
35% yield of the product.
Initially, the formation of the tetrazole 4a was tested by
reacting the N-phenethyl-2-isocyanoacetamide (3a) with
sodium azide in methanol, as in the general Oliveri-Mandala
Table 3 Synthesis of N-Substituted 2-(1H-Tetrazol-1-yl)acetamides
Entry
1
Reactant 3
Yield (%)a
85
Product 4
Yield (%)a
97
N
N
O
O
O
N
CN
N
N
H
N
H
3a
4a
2
3
87
85
95
98
O
N
N
N
N
CN
N
H
N
H
F
F
3b
4b
O
N
O
O
N
N
N
CN
N
H
N
H
Cl
Cl
3c
4c
4
5
83
86
97
98
N
N
O
N
CN
N
N
H
N
H
3d
4d
N
O
O
O
N
N
N
CN
S
S
N
H
N
H
3e
4e
6
7
89
90
86
95
N
O
N
N
N
CN
N
H
N
H
3f
4f
O
O
O
O
N
O
O
O
N
N
N
CN
N
H
N
H
3g
4g
8
86
86
O
N
N
N
N
CN
N
H
N
H
3h
4h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
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Synthesis
Table 3 (continued)
Entry
9
Reactant 3
Yield (%)a
75
Product 4
Yield (%)a
90
N
O
O
O
O
O
N
O
N
N
N
N
CN
N
H
N
H
3i
4i
10
11
12
13
88
92
86
89
92
78
74
84
N
O
N
N
N
CN
N
H
N
H
3j
4j
N
O
N
N
N
CN
N
H
N
H
3k
4k
N
O
O
O
O
N
N
N
CN
N
N
N
H
N
H
3l
4l
N
N
N
N
CN
N
N
N
N
3m
4m
14
15
16
17
87
81
78
83
87
86
72
74
O
O
O
N
O
O
O
N
N
N
CN
3n
4n
N
N
N
N
CN
N
N
N
N
O
O
N
3o
4o
N
N
N
N
CN
N
3p
4p
Cl
Cl
N
O
O
N
N
N
CN
N
N
H
H
3q
4q
18
82
69
O
N
O
N
N
N
CN
S
S
N
H
N
H
3r
4r
a Isolated yield.
Surprisingly, when sodium azide was replaced by
trimethylsilyl azide with 25% co-solvent water in methanol
at room temperature, the yield was dramatically increased
to 97% (Table 2). With this optimized conditions, substrate
scope of this method was investigated for various N-alkyl-
2-isocyanoacetamides to form N-alkyl-2-(1H-tetrazol-1-
yl)acetamides (Table 3). In all cases, excellent yield of prod-
ucts 4a–n (70–97%) were obtained. This method is very ef-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

F
Y. Wang et al.
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Synthesis
ficient, as we observed that all N-alkyl-2-(1H-tetrazol-1-
yl)acetamides were precipitated during the aqueous work-
up followed by simple filtration to afford the pure product.
In few cases 4l and 4o, precipitation from water did not oc-
cur; in such cases, the products were obtained by ex-
traction using a saturated solution of sodium chloride and
dichloromethane. Noteworthy, with this method all the
products 4a–q were obtained in good to excellent yields. To
support the fragment likeliness of our scaffolds and synthe-
sized compounds the chemical properties MW and clogP
were calculated, which are plotted in Figure 2.
peak. TLC was performed on Fluka precoated silica gel plates (0.20
mm thick, particle size 25 μm). Flash chromatography was performed
on a Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase Sil-
ica Flash Columns (Silica Gel 60 Å, 230–400 mesh) and on a Reveleris®
X2 Flash Chromatography, using Grace® Reveleris Silica flash car-
tridges (12 g). Reagents were available from commercial suppliers
(Sigma Aldrich, ABCR, Acros and AK Scientific) and used without any
purification, unless otherwise noted. Electrospray ionization mass
spectra (ESI-MS) were recorded on a Waters Investigator Semi-prep
15 SFC-MS instrument.
5-Substitubed Tetrazoles 2; General Procedure A (GP A)
To a stirred solution of N-alkyl-substituted 2-cyanoacetamide 1 (5
mmol) in toluene (10 mL) was added NaN3 (3 equiv) and triethyl-
amine hydrochloride salt (3 equiv). The reaction mixture was heated
to 90 °C for 20 h. Ice-cold H2O (25 mL) was added to the reaction mix-
ture and acidified with aq HCl and stirred at 0 °C for 30 min. The pre-
cipitated product was collected by filtration, washed with cold H2O
(25 mL), and dried in vacuum (Table 1).
2-Isocyanoacetamides 3; General Procedure B (GP B)
To the appropriate amine (10 mmol) was added methyl isocyanoace-
tate (1 g, 10 mmol), and the mixture was stirred overnight at r.t. If the
product precipitated during the reaction, it was collected by filtra-
tion, washed with cold Et2O (3 ×), and dried under vacuum overnight.
If no precipitation was observable, cold Et2O was added to the reac-
tion mixture, and the product was allowed to crystallize in the freezer
at –20 °C.
1-Substitubed Tetrazoles 4; General Procedure C (GP C)
To the N-alkyl-2-isocyanoacetamide (1.0 mmol) in a mixture of sol-
vents MeOH–H2O (3:1, 1 M) was added trimethylsilyl azide (138 mg,
1.2 mmol) and the resulting mixture was stirred overnight at r.t. The
reaction, which precipitated out was filtered and washed with cold
H2O (3 × 5 mL). The reactions which do not precipitate, were diluted
with brine (1 mL) and extracted with CH2Cl2 (3 × 10 mL). The solvents
were removed under reduced pressure to afford the pure product (Ta-
ble 3).
Figure 2 cLogP vs Mol. weight of virtual libraries of 500 randomly gen-
erated molecules of 1H-tetrazoles (violet) and 5H-tetrazoles (blue)
along with our synthesized library 1H-tetrazoles (green) and 5H-tetra-
zoles (red)
N-Benzyl-2-(1H-tetrazol-5-yl)acetamide (2a)
In conclusion, we have prepared two positional isomer-
ic monosubstituted tetrazole libraries by a convenient and
fast procedure. With mild reaction conditions, our new
methods provide significant advantages such as easy work-
up, short reaction time, and broad substrate scope. With
more and more drug candidates originating from fragment-
based lead discovery having been progressed into clinical
trials, the efficient build-up of fragment libraries containing
‘drug-like’ fragments like tetrazole is of great importance.
Further investigation of our herein-described positional
isomeric tetrazole libraries in different protein targets is
currently ongoing and will be reported in due course.
The product was obtained using GP A, 8 mmol scale; yield: 1.16 g
(67%); white solid; mp 166–168 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.83 (t, J = 5.9 Hz, 1 H), 7.40–7.19
(m, 5 H), 4.32 (d, J = 5.9 Hz, 2 H), 3.96 (s, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.1, 151.2, 138.9, 128.3, 127.4,
126.9, 42.5, 30.5.
SFC-MS (ESI): m/z [M]+ calcd for C10H11N5O: 217.10; found [M + H]+:
218.09.
N-Phenethyl-2-(1H-tetrazol-5-yl)acetamide (2b)
The product was obtained using GP A, 8 mmol scale; yield: 1.37 g
(74%); white solid; mp 170–171 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.43 (t, J = 5.5 Hz, 1 H), 7.38–7.11
(m, 5 H), 3.87 (s, 2 H), 3.39–3.25 (m, 2 H), 2.73 (t, J = 7.4 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.0, 151.2, 139.2, 128.6, 128.4,
126.2, 40.6, 35.0, 30.5.
SFC-MS (ESI): m/z [M]+ calcd for C11H13N5O: 231.11; found [M + H]+:
232.08.
NMR spectra were recorded on a Bruker Avance 500 spectrometer [1H
NMR (500 MHz), 13C NMR (126 MHz)]. Chemical shifts for 1H NMR
were reported as δ values and coupling constants were in hertz (Hz).
Standard abbreviations were used for defining spin multiplicity.
Chemical shifts for 13C NMR reported in ppm relative to the solvent
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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Synthesis
N-(3-Phenylpropyl)-2-(1H-tetrazol-5-yl)acetamide (2c)
N-(4-Fluorobenzyl)-2-(1H-tetrazol-5-yl)acetamide (2h)
The product was obtained using GP A, 8 mmol scale; yield: 1.58 g
(79%); white solid; mp 104–106 °C.
The product was obtained using GP A, 8 mmol scale; yield: 1.32 g
(70%); white solid; mp 171–173 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.37 (t, J = 5.5 Hz, 1 H), 7.27 (t, J =
7.5 Hz, 2 H), 7.23–7.12 (m, 3 H), 3.88 (s, 2 H), 3.10 (q, J = 6.6 Hz, 2 H),
2.59 (t, J = 7.7 Hz, 2 H), 1.72 (quint, J = 7.2 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.0, 151.3, 141.6, 128.3, 125.8,
38.5, 32.4, 30.7, 30.6.
1H NMR (500 MHz, DMSO-d6): δ = 8.85 (t, J = 5.9 Hz, 1 H), 7.48–7.25
(m, 2 H), 7.17 (t, J = 8.7 Hz, 2 H), 4.31 (d, J = 5.8 Hz, 2 H), 3.97 (s, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.2, 161.31 (d, J = 242.6 Hz),
151.2, 135.14 (d, J = 2.9 Hz), 129.39 (d, J = 8.2 Hz), 115.11 (d, J = 21.2
Hz), 41.8, 30.6.
SFC-MS (ESI): m/z [M]+ calcd for C12H15N5O: 245.13; found [M – H]+:
SFC-MS (ESI): m/z [M]+ calcd for C10H10FN5O: 235.09; found [M – H]+:
244.11.
233.97.
N-(4-Phenylbutyl)-2-(1H-tetrazol-5-yl)acetamide (2d)
N-(4-Fluorophenethyl)-2-(1H-tetrazol-5-yl)acetamide (2i)
The product was obtained using GP A, 8 mmol scale; yield: 1.78 g
(86%); white solid; mp 122–124 °C.
The product was obtained using GP A, 8 mmol scale; yield: 1.74 g
(87%); white solid; mp 159–161 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.31 (t, J = 5.7 Hz, 1 H), 7.27 (t, J =
7.7 Hz, 2 H), 7.23–7.12 (m, 3 H), 3.86 (s, 2 H), 3.11 (q, J = 6.7 Hz, 2 H),
2.57 (t, J = 7.7 Hz, 2 H), 1.62–1.51 (m, 2 H), 1.48–1.38 (m, 2 H).
1H NMR (500 MHz, DMSO-d6): δ = 8.41 (s, 1 H), 7.31–7.19 (m, 2 H),
7.17–7.01 (m, 2 H), 3.85 (s, 2 H), 3.30 (q, J = 6.8 Hz, 2 H), 2.72 (t, J = 7.3
Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.9, 151.2, 142.1, 128.3, 128.2,
125.7, 38.7, 34.8, 30.5, 28.6, 28.3.
SFC-MS (ESI): m/z [M]+ calcd for C13H17N5O: 259.14; found [M – H]+:
258.16.
13C NMR (126 MHz, DMSO-d6): δ = 166.1, 160.90 (d, J = 241.5 Hz),
151.2, 135.41 (d, J = 3.0 Hz), 130.45 (d, J = 7.9 Hz), 115.01 (d, J = 21.0
Hz), 40.6, 34.1, 30.6.
SFC-MS (ESI): m/z [M]+ calcd for C11H12FN5O: 249.10; found [M – H]+:
248.08.
N-[1-(4-Chlorophenyl)ethyl]-2-(1H-tetrazol-5-yl)acetamide (2e)
N-(3,4-Dimethoxybenzyl)-2-(1H-tetrazol-5-yl)acetamide (2j)
The product was obtained using GP A, 8 mmol scale; yield: 1.37 g
(64%); white solid; mp 182–184 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.84 (d, J = 7.8 Hz, 1 H), 7.51–7.26
(m, 4 H), 5.00–4.83 (m, 1 H), 3.95 (s, 2 H), 1.38 (d, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.3, 151.1, 143.3, 131.3, 128.3,
127.9, 47.9, 30.5, 22.3, 22.2.
The product was obtained using GP A, 8 mmol scale; yield: 1.03 g
(93%); white solid; mp 156–158 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.78 (s, 1 H), 6.92–6.85 (m, 2 H),
6.80 (d, J = 8.1 Hz, 1 H), 4.24 (d, J = 5.6 Hz, 2 H), 3.94 (s, 2 H), 3.73 (s, 3
H), 3.72 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.1, 151.4, 148.7, 147.9, 131.3,
119.5, 111.8, 111.5, 55.6, 45.7, 42.3, 30.6.
SFC-MS (ESI): m/z [M]+ calcd for C11H12ClN5O: 265.07; found [M – H]+:
263.90.
SFC-MS (ESI): m/z [M]+ calcd for C12H15N5O3: 277.12; found [M – H]+:
276.06.
2-(1H-Tetrazol-5-yl)-N-[1-(p-tolyl)ethyl]acetamide (2f)
The product was obtained using GP A, 4 mmol scale; yield: 0.69 g
(70%); white solid; mp 187–189 °C.
N-(2-Hydroxy-2-phenylethyl)-2-(1H-tetrazol-5-yl)acetamide (2k)
The product was obtained using GP A, 8 mmol scale; yield: 1.39 g
(70%); white solid; mp 162–164 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.47 (t, J = 5.7 Hz, 1 H), 7.36–7.29
(m, 4 H), 7.28–7.21 (m, 1 H), 5.53 (s, 1 H), 4.62 (dd, J = 8.1, 4.4 Hz, 1 H),
3.91 (s, 2 H), 3.34 (dt, J = 13.4, 6.2, 4.4 Hz, 1 H), 3.15 (ddd, J = 13.4, 8.1,
5.2 Hz, 1 H).
1H NMR (500 MHz, DMSO-d6): δ = 8.75 (d, J = 7.9 Hz, 1 H), 7.20 (d, J =
7.8 Hz, 2 H), 7.13 (d, J = 7.8 Hz, 2 H), 4.95–4.81 (m, 1 H), 3.92 (s, 2 H),
2.26 (s, 3 H), 1.35 (d, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.1, 151.1, 141.1, 135.9, 128.8,
125.9, 48.1, 30.5, 22.4, 20.6.
SFC-MS (ESI): m/z [M]+ calcd for C12H15N5O: 245.13; found [M – H]+:
244.05.
13C NMR (126 MHz, DMSO-d6): δ = 166.3, 151.2, 143.5, 128.1, 127.2,
126.0, 71.2, 47.2, 30.5.
SFC-MS (ESI): m/z [M]+ calcd for C11H13N5O2: 247.11; found [M – H]+:
246.19.
N-(4-Chlorobenzyl)-2-(1H-tetrazol-5-yl)acetamide (2g)
The product was obtained using GP A, 3.6 mmol scale; yield: 0.57 g
(76%); white solid; mp 189–191 °C.
1H NMR (500 MHz, DMSO-d6): δ = 7.36 (d, J = 8.2 Hz, 2 H), 7.26 (d, J =
8.2 Hz, 2 H), 6.46 (t, J = 6.2 Hz, 1 H), 5.57 (s, 2 H), 4.08 (d, J = 6.2 Hz, 2
H).
13C NMR (126 MHz, DMSO-d6): δ = 158.7, 140.1, 131.0, 128.8, 128.1,
42.2, 42.1.
N-(2,2-Diphenylethyl)-2-(1H-tetrazol-5-yl)acetamide (2l)
The product was obtained using GP A, 4 mmol scale; yield: 0.69 g
(56%); white solid; mp 181–183 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.42 (s, 1 H), 7.38–7.25 (m, 8 H),
7.23–7.13 (m, 2 H), 4.18 (td, J = 7.8, 2.2 Hz, 1 H), 3.84–3.68 (m, 4 H).
13C NMR (126 MHz, DMSO-d6): δ = 166.2, 151.1, 142.7, 128.5, 127.9,
126.4, 50.0, 43.5, 30.4.
SFC-MS (ESI): m/z [M]+ calcd for C10H10ClN5O: 251.06; found [M + Na]
+: 274.17.
SFC-MS (ESI): m/z [M]+ calcd for C17H17N5O: 307.14; found [M – H]+:
306.18.
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N-(Naphthalen-2-ylmethyl)-2-(1H-tetrazol-5-yl)acetamide (2m)
1H NMR (500 MHz, DMSO-d6): δ = 8.28 (d, J = 7.4 Hz, 1 H), 3.84 (s, 2
H), 1.45–1.15 (m, 22 H), 0.85 (t, J = 6.8 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.8, 151.2, 38.9, 31.3, 30.5, 29.1,
The product was obtained using GP A, 8 mmol scale; yield: 1.90 g
(89%); white solid; mp 213–215 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.89 (d, J = 5.6 Hz, 1 H), 8.15–8.01
(m, 1 H), 8.01–7.91 (m, 1 H), 7.87 (dd, J = 7.0, 2.4 Hz, 1 H), 7.65–7.35
(m, 4 H), 4.79 (d, J = 5.6 Hz, 2 H), 3.98 (s, 2 H).
28.9, 28.8, 26.4, 22.1, 13.9.
SFC-MS (ESI): m/z [M]+ calcd for C15H29N5O: 295.24; found [M – H]+:
294.27.
13C NMR (126 MHz, DMSO-d6): δ = 166.1, 151.3, 134.0, 133.4, 130.9,
128.6, 127.8, 126.4, 125.9, 125.8, 125.5, 123.5, 40.7, 30.5.
N-Allyl-2-(1H-tetrazol-5-yl)acetamide (2s)
SFC-MS (ESI): m/z [M]+ calcd for C14H13N5O: 267.11; found [M – H]+:
266.04.
The product was obtained using GP A, 8 mmol scale; yield: 0.34 g
(25%); white solid; mp 140–142 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.49 (d, J = 6.0 Hz, 1 H), 5.87–5.69
(m, 1 H), 5.17 (dq, J = 17.2, 1.8 Hz, 1 H), 5.11–5.03 (m, 1 H), 3.91 (s, 2
H), 3.76–3.68 (m, 2 H).
N-(Furan-2-ylmethyl)-2-(1H-tetrazol-5-yl)acetamide (2n)
The product was obtained using GP A, 8 mmol scale; yield: 0.35 g
(21%); white solid; mp 166–168 °C.
13C NMR (126 MHz, DMSO-d6): δ = 165.9, 151.2, 134.8, 115.5, 41.2,
1H NMR (500 MHz, DMSO-d6): δ = 8.81 (t, J = 5.5 Hz, 1 H), 7.59 (s, 1 H),
6.40 (d, J = 3.0 Hz, 1 H), 6.28 (d, J = 3.0 Hz, 1 H), 4.29 (d, J = 5.5 Hz, 2 H),
3.93 (s, 2 H).
30.4.
SFC-MS (ESI): m/z [M]+ calcd for C6H9N5O: 167.08; found [M – H]+:
165.98.
13C NMR (126 MHz, DMSO-d6): δ = 166.0, 151.7, 151.1, 142.3, 110.5,
107.3, 35.8, 30.4.
N-Cyclohexyl-2-(1H-tetrazol-5-yl)acetamide (2t)
SFC-MS (ESI): m/z [M]+ calcd for C8H9N5O2: 207.08; found [M + Na]+:
230.12.
The product was obtained using GP A, 8 mmol scale; yield: 0.85 g
(51%); white solid; mp 215–217 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.21 (d, J = 7.9 Hz, 1 H), 3.84 (s, 2
H), 3.59–3.39 (m, 1 H), 1.82–1.62 (m, 4 H), 1.53 (dt, J = 12.3, 3.9 Hz, 1
H), 1.37–1.00 (m, 5 H).
2-(1H-Tetrazol-5-yl)-N-[2-(thiophen-2-yl)ethyl]acetamide (2o)
The product was obtained using GP A, 8 mmol scale; yield: 1.24 g
(65%); white solid; mp 150–152 °C.
13C NMR (126 MHz, DMSO-d6): δ = 164.9, 151.2, 47.9, 32.3, 30.6, 25.2,
1H NMR (500 MHz, DMSO-d6): δ = 8.50 (t, J = 5.7 Hz, 1 H), 7.33 (d, J =
5.1 Hz, 1 H), 7.00–6.79 (m, 2 H), 3.88 (s, 2 H), 3.41–3.25 (m, 2 H), 2.95
(t, J = 7.1 Hz, 2 H).
24.4.
SFC-MS (ESI): m/z [M]+ calcd for C9H15N5O: 209.13; found [M – H]+:
208.01.
13C NMR (126 MHz, DMSO-d6): δ = 166.2, 151.2, 141.3, 127.0, 125.3,
124.1, 40.7, 30.6, 29.1.
1-(Pyrrolidin-1-yl)-2-(1H-tetrazol-5-yl)ethan-1-one (2u)
SFC-MS (ESI): m/z [M]+ calcd for C9H11N5OS: 237.07; found [M – H]+:
236.05.
The product was obtained using GP A, 8 mmol scale; yield: 0.13 g
(9%); white solid; mp 137–139 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.10 (s, 2 H), 3.55 (t, J = 6.8 Hz, 2 H),
3.31 (t, J = 6.8 Hz, 2 H), 1.91 (quint, J = 6.8 Hz, 2 H), 1.80 (quint, J = 6.8
Hz, 2 H).
N-Cyclopropyl-2-(1H-tetrazol-5-yl)acetamide (2p)
The product was obtained using GP A, 8 mmol scale; yield: 0.74 g
(55%); white solid; mp 173–175 °C.
13C NMR (126 MHz, DMSO-d6): δ = 164.6, 151.1, 46.2, 45.7, 29.9, 25.5,
1H NMR (500 MHz, DMSO-d6): δ = 8.41 (s, 1 H), 3.81 (s, 2 H), 2.68–
24.0.
SFC-MS (ESI): m/z [M]+ calcd for C7H11N5O: 181.10; found [M + H]+:
2.60 (m, 1 H), 0.66–0.60 (m, 2 H), 0.45–0.38 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 167.1, 151.1, 30.4, 22.5, 5.6.
182.11.
SFC-MS (ESI): m/z [M]+ calcd for C6H9N5O: 167.08; found [M + Na]+:
190.05.
1-Morpholino-2-(1H-tetrazol-5-yl)ethan-1-one (2v)
The product was obtained using GP A, 8 mmol scale; yield: 0.40 g
(25%); white solid; mp 196–198 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.21 (s, 2 H), 3.65–3.59 (m, 2 H),
3.59–3.52 (m, 4 H), 3.50–3.43 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.4, 151.3, 66.0, 66.0, 45.7, 41.9,
N-Butyl-2-(1H-tetrazol-5-yl)acetamide (2q)
The product was obtained using GP A, 8 mmol scale; yield: 1.14 g
(77%); white solid; mp 82–84 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.28 (s, 1 H), 3.85 (s, 2 H), 3.12–
3.02 (m, 2 H), 1.46–1.34 (m, 2 H), 1.33–1.22 (m, 2 H), 0.86 (t, J = 7.3
Hz, 3 H).
28.6.
SFC-MS (ESI): m/z [M]+ calcd for C7H11N5O2: 197.09; found [M + H]+:
13C NMR (126 MHz, DMSO-d6): δ = 166.0, 151.2, 38.7, 31.1, 30.6, 19.6,
198.12.
13.7.
N-Benzyl-2-isocyanoacetamide (3a)
SFC-MS (ESI): m/z [M]+ calcd for C7H13N5O: 183.11; found [M – H]+:
The product was obtained using GP B, 10 mmol scale; yield: 1.48 g
(85%), white solid; mp 125–127 °C.
182.11.
N-Dodecyl-2-(1H-tetrazol-5-yl)acetamide (2r)
1H NMR (500 MHz, DMSO-d6): δ = 8.66 (s, 1 H), 7.35–7.24 (m, 5 H),
4.42 (s, 2 H), 4.32 (d, J = 5.9 Hz, 2 H).
The product was obtained using GP A, 4 mmol scale; yield: 1.03 g
(98%); white solid; mp 152–154 °C.
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13C NMR (126 MHz, DMSO-d6): δ = 163.0, 158.2, 138.6, 128.3, 127.4,
1H NMR (500 MHz, CDCl3): δ = 6.52 (s, 1 H), 4.14 (s, 2 H), 2.78–2.73
127.0, 44.8, 42.5.
(m, 1 H), 0.87–0.83 (m, 2 H), 0.62–0.59 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 163.7, 161.9, 45.2, 22.9, 8.3, 6.4.
N-(4-Fluorobenzyl)-2-isocyanoacetamide (3b)
The product was obtained using GP B, 10 mmol scale; yield: 1.68 g
(87%); white solid; mp 135–137 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.66 (s, 1 H), 7.31 (dd, J = 8.5, 5.9
Hz, 2 H), 7.15 (t, J = 8.9 Hz, 2 H), 4.40 (s, 2 H), 4.28 (d, J = 5.9 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ =163.1, 162.3, 160.3, 158.2, 134.9,
134.9, 129.5, 129.4, 115.2, 115.0, 44.8, 41.8.
N-(1-Benzylpiperidin-4-yl)-2-isocyanoacetamide (3i)
The product was obtained using GP B, 10 mmol scale, yield: 1.94 g
(75%); white solid; mp 135–137 °C.
1H NMR (500 MHz, CDCl3): δ = 7.32–7.26 (m, 5 H), 6.26 (d, J = 6.1 Hz, 1
H), 4.14 (s, 2 H), 3.87–3.81 (m, 1 H), 3.52 (s, 2 H), 2.84 (d, J = 11.6 Hz, 2
H), 2.15 (t, J = 11.1 Hz, 2 H), 1.92 (d, J = 12.6 Hz, 2 H), 1.60–1.52 (m, 2
H).
13C NMR (126 MHz, CDCl3): δ = 162.4, 161.6, 138.2, 129.2, 128.4,
N-(4-Chlorobenzyl)-2-isocyanoacetamide (3c)
127.2, 63.0, 52.1, 47.4, 45.4, 32.0.
The product was obtained using GP B, 10 mmol scale; yield: 1.79 g
(85%); white solid; mp 122–124 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.69 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2
H), 7.29 (d, J = 8.4 Hz, 2 H), 4.42 (s, 2 H), 4.29 (d, J = 5.9 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 163.2, 158.3, 137.8, 131.6, 129.3,
N-Butyl-2-isocyanoacetamide (3j)
The product was obtained using GP B, 10 mmol scale; yield: 1.24 g
(88%); white solid; mp 53–55 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.11 (s, 1 H), 4.30 (s, 2 H), 3.08 (q,
J = 6.9 Hz, 2 H), 1.39 (quint, J = 6.9 Hz, 2 H), 1.27 (sext, J = 7.7 Hz, 2 H),
0.87 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.4, 162.2, 45.4, 39.9, 31.4, 20.1,
13.8.
128.3, 44.8, 41.8.
2-Isocyano-N-(1-phenylethyl)acetamide (3d)
The product was obtained using GP B, 10 mmol scale; yield: 1.57 g
(83%); white solid; mp 128–130 °C.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.29 (m, 5 H), 6.60 (s, 1 H), 5.14
(quint, J = 7.1 Hz, 1 H), 4.15 (d, J = 8.5 Hz, 2 H), 1.56 (d, J = 6.9 Hz, 3 H).
2-Isocyano-N-(prop-2-yn-1-yl)acetamide (3k)
The product was obtained using GP B, 10 mmol scale; yield: 1.13 g
(92%); white solid; mp 108–110 °C.
1H NMR (500 MHz, CDCl3): δ = 6.66 (s, 1 H), 4.21 (s, 2 H), 4.13–4.12
13C NMR (126 MHz, DMSO-d6): δ = 163.2, 158.3, 137.8, 131.6, 129.2,
128.3, 44.8, 41.8.
(m, 2 H), 2.32–2.30 (m, 1 H).
2-Isocyano-N-(thiophen-2-ylmethyl)acetamide (3e)
13C NMR (126 MHz, CDCl3): δ = 162.9, 162.2, 78.2, 72.7, 45.3, 29.8.
The product was obtained using GP B, 10 mmol scale; yield: 1.55 g
(86%); white solid; mp 97–99 °C.
1H NMR (500 MHz, CDCl3): δ = 7.27 (s, 1 H), 7.02 (d, J = 3.5 Hz, 1 H),
7.01 (m, 2 H), 6.80 (s, 2 H), 4.67 (d, J = 5.7 Hz, 2 H), 4.19 (s, 2 H).
13C NMR (126 MHz, CDCl3): δ = 162.5, 162.2, 139.3, 127.2, 126.9,
2-Isocyano-N-(2-morpholinoethyl)acetamide (3l)
The product was obtained using GP B, 10 mmol scale, yield: 1.70 g
(86%); white solid; mp 80–81 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.09 (s, 1 H), 4.33 (s, 2 H), 3.56 (t,
J = 4.5 Hz, 4 H), 3.21 (q, J = 6.4 Hz, 2 H), 2.34 (t, J = 6.8 Hz, 6 H).
125.9, 45.3, 38.6.
13C NMR (126 MHz, CDCl3): δ = 162.4, 162.31, 67.1, 56.3, 53.3, 45.5,
2-Isocyano-N-phenethylacetamide (3f)
35.9.
The product was obtained using GP B, 10 mmol scale; yield: 1.68 g
(89%); white solid; mp 94–96 °C.
1H NMR (500 MHz, CDCl3): δ = 7.35–7.20 (s, 5 H), 6.44 (s, 1 H), 4.12 (s,
2 H), 3.59 (q, J = 6.9 Hz, 2 H), 2.87 (t, J = 7.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 162.4, 161.9, 138.1, 128.8, 128.7,
2-Isocyano-1-(pyrrolidin-1-yl)ethan-1-one (3m)
The product was obtained using GP B, 10 mmol scale; yield: 1.24 g
(89%); white solid; mp 71–73 °C.
1H NMR (500 MHz, CDCl3): δ = 4.21 (s, 2 H), 3.51 (t, J = 7.0 Hz, 2 H),
3.39 (t, J = 6.8 Hz, 2 H), 2.00 (quint, J = 6.8 Hz, 2 H), 1.90 (quint, J = 6.8
Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 160.7, 160.1, 46.6, 46.2, 45.0, 26.1,
24.0.
126.8, 45.2, 41.0, 35.3.
N-(3,4-Dimethoxyphenethyl)-2-isocyanoacetamide (3g)
The product was obtained using GP B, 10 mmol scale; yield: 2.23 g
(90%); white solid; mp 95–97 °C.
1H NMR (500 MHz, CDCl3): δ = 6.82 (d, J = 8.1 Hz, 1 H), 6.74 (dd, J = 8.2,
1.7 Hz, 1 H), 6.71 (d, J = 1.4 Hz, 1 H), 6.46 (s, 1 H), 4.12 (s, 2 H), 3.88 (s,
3 H), 3.86 (s, 3 H), 3.56 (q, J = 6.8 Hz, 2 H), 2.81 (t, J = 7.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 162.3, 162.2, 149.2, 148.0, 130.6,
120.7, 111.8, 111.6, 56.5, 55.9, 45.3, 41.2, 35.0.
2-Isocyano-1-(piperidin-1-yl)ethan-1-one (3n)
The product was obtained using GP B, 10 mmol scale; yield: 1.33 g
(87%); white solid; mp 84–86 °C.
1H NMR (500 MHz, CDCl3): δ = 4.27 (s, 2 H), 3.56 (t, J = 5.6 Hz, 2 H),
3.31 (t, J = 5.5 Hz, 2 H), 1.68–1.55 (m, 6 H).
13C NMR (126 MHz, CDCl3): δ = 160.6, 160.5, 46.5, 44.5, 43.6, 26.0,
N-(Cyclopropylmethyl)-2-isocyanoacetamide (3h)
25.2, 24.1.
The product was obtained using GP B, 10 mmol scale; yield: 1.08 g
(86%); white solid; mp 89–91 °C.
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2-Isocyano-1-morpholinoethan-1-one (3o)
N-(4-Chlorobenzyl)-2-(1H-tetrazol-1-yl)acetamide (4c)
The product was obtained using GP B, 10 mmol scale; yield: 1.26 g
(81%); brown solid; mp 69–71 °C.
The product was obtained using GP C, 1 mmol scale; yield: 0.247 g
(98%); white solid; mp 160–162 °C.
1H NMR (500 MHz, CDCl3): δ = 4.30 (s, 2 H), 3.70–3.66 (m, 4 H), 3.61
(t, J = 4.9 Hz, 2 H), 3.37 (t, J = 4.8 Hz, 2 H).
1H NMR (500 MHz, DMSO-d6): δ = 9.39 (s, 1 H), 8.96 (t, J = 5.5 Hz, 1 H),
7.41 (dd, J = 45.4, 5.5 Hz, 4 H), 5.33 (s, 2 H), 4.34 (d, J = 5.9 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 161.4, 161.2, 66.6, 66.2, 45.9, 44.4,
13C NMR (126 MHz, DMSO-d6): δ = 165.3, 145.6, 138.2, 132.1, 129.7,
42.8.
128.8, 49.9, 42.2.
SFC-MS (ESI): m/z [M]+ calcd for C10H10ClN5O: 251.06; found [M – H]+:
249.94.
1-(4-Benzylpiperazin-1-yl)-2-isocyanoethan-1-one (3p)
The product was obtained using GP B, 10 mmol scale; yield: 1.91 g
(78%); white solid; mp 80–82 °C.
N-(1-Phenylethyl)-2-(1H-tetrazol-1-yl)acetamide (4d)
1H NMR (500 MHz, CDCl3): δ = 7.30 (m, 5 H), 4.27 (s, 2 H), 3.65 (t, J =
4.8 Hz, 2 H), 3.53 (s, 2 H), 3.40 (t, J = 4.7 Hz, 2 H), 2.49–2.46 (m, 4 H).
The product was obtained using GP C, 1 mmol scale; yield: 0.216 g
(97%); white solid; mp 143–144 °C.
13C NMR (126 MHz, CDCl3): δ = 161.3, 160.8, 137.3, 129.1, 128.4,
127.4, 62.7, 52.5, 52.4, 45.7, 44.4, 42.6.
1H NMR (500 MHz, DMSO-d6): δ = 9.35 (s, 1 H), 8.93 (d, J = 7.7 Hz, 1
H), 7.38–7.25 (m, 5 H), 5.29 (s, 2 H), 4.92 (t, J = 7.3 Hz, 1 H), 1.41 (d, J =
7.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 163.7, 145.1, 143.8, 128.4, 126.9,
N-(4-Chlorobenzyl)-2-isocyano-4-methylpentanamide (3q)
126.0, 49.4, 48.5, 22.4.
SFC-MS (ESI): m/z calcd for C11H13N5O [M]+: 231.11; found [M + Na]+:
The product was obtained using GP B, 5 mmol scale; yield: 1.09 g
(83%); white solid; mp 82–84 °C.
1H NMR (500 MHz, CDCl3): δ = 7.33 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4
Hz, 2 H), 6.78 (s, 1 H), 4.44 (d, J = 5.9 Hz, 2 H), 4.27–4.22 (m, 1 H),
1.94–1.75 (m, 3 H), 1.00 (d, J = 6.4 Hz, 3 H), 0.97 (d, J = 6.4 Hz, 3 H).
254.16.
2-(1H-Tetrazol-1-yl)-N-(thiophen-2-ylmethyl)acetamide (4e)
13C NMR (126 MHz, CDCl3): δ = 166.1, 162.0, 135.8, 133.9, 129.3,
129.2, 57.3, 43.4, 41.6, 25.0, 22.9, 20.8.
The product was obtained using GP C, 1 mmol scale; yield: 0.218 g
(98%); white solid; mp 153–154 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.38 (s, 1 H), 9.04 (t, J = 5.4 Hz, 1 H),
7.44 (dd, J = 5.1, 1.1 Hz, 1 H), 7.02–6.97 (m, 2 H), 5.29 (s, 2 H), 4.50 (d,
J = 5.8 Hz, 2 H).
2-Isocyano-4-methyl-N-(thiophen-2-ylmethyl)pentanamide (3r)
The product was obtained using GP B, 5 mmol scale; yield: 0.96 g
(82%); white solid; mp 70–72 °C.
13C NMR (126 MHz, DMSO-d6): δ = 164.5, 145.2, 141.2, 126.8, 126.0,
1H NMR (500 MHz, CDCl3): δ = 7.27–7.25 (m, 1 H), 7.01–6.99 (m, 1 H),
6.98–6.94 (m, 1 H), 6.79 (s, 1 H), 4.67–4.63 (m, 2 H), 4.25–4.21 (m, 1
H), 1.94–1.86 (m, 1 H), 1.78 (dd, J = 13.8, 5.1 Hz, 2 H), 0.99 (d, J = 6.5
Hz, 3 H), 0.96 (d, J = 6.5 Hz, 3 H).
125.4, 49.3, 37.4.
SFC-MS (ESI): m/z calcd for C8H9N5OS [M]+: 223.05; found [M – H]+:
222.00.
13C NMR (126 MHz, CDCl3): δ = 165.9, 162.0, 139.6, 127.2, 126.7,
N-Phenethyl-2-(1H-tetrazol-1-yl)acetamide (4f)
125.9, 57.2, 41.5, 38.8, 25.0, 22.9, 20.9.
The product was obtained using GP C, 1 mmol scale; yield: 0.198 g
(86%); white solid; mp 144–145 °C.
N-Benzyl-2-(1H-tetrazol-1-yl)acetamide (4a)
1H NMR (500 MHz, DMSO-d6): δ = 9.36 (s, 1 H), 8.56 (t, J = 5.2 Hz, 1 H),
7.33–7.21 (m, 5 H), 5.23 (s, 2 H), 3.37 (q, J = 6.9 Hz, 2 H), 2.77 (t, J = 7.4
Hz, 2 H).
The product was obtained using GP C, 1 mmol scale; yield: 0.211 g
(97%); white solid; mp 135–137 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.39 (s, 1 H), 8.93 (t, J = 5.4 Hz, 1 H),
7.36–7.26 (m, 5 H), 5.32 (s, 2 H), 4.34 (t, J = 5.8 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.7, 145.2, 138.7, 128.4, 127.4,
13C NMR (126 MHz, DMSO-d6): δ = 164.6, 145.2, 145.1, 139.2, 128.7,
128.43, 126.3, 49.4, 40.6, 34.9.
SFC-MS (ESI): m/z calcd for C11H13N5O [M]+: 231.11; found [M + H]+:
232.20.
127.1, 49.4, 42.5.
SFC-MS (ESI): m/z [M]+ calcd for C10H11N5O: 217.10; found [M + Na]+:
240.14.
N-(3,4-Dimethoxyphenethyl)-2-(1H-tetrazol-1-yl)acetamide (4g)
The product was obtained using GP C, 1 mmol scale; yield: 0.276 g
(95%); white solid; mp 137–139 °C.
N-(4-Fluorobenzyl)-2-(1H-tetrazol-1-yl)acetamide (4b)
1H NMR (500 MHz, DMSO-d6): δ = 9.34 (s, 1 H), 8.50 (t, J = 5.3 Hz, 1 H),
6.88 (d, J = 8.2 Hz, 1 H), 6.82 (d, J = 1.9 Hz, 1 H), 6.73 (dd, J = 8.1, 1.9 Hz,
1 H), 5.21 (s, 2 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.31 (t, J = 6.3 Hz, 2 H),
2.67 (t, J = 7.4 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.5, 148.6, 147.3, 145.1, 131.5,
120.4, 112.5, 111.9, 55.5, 55.4, 55.4, 49.4, 40.7, 34.5.
The product was obtained using GP C, 1 mmol scale; yield: 0.224 g
(95%); white solid; mp 164–166 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.38 (s, 1 H), 8.93 (s, 1 H), 7.33 (dd,
J = 8.5, 5.9 Hz, 2 H), 7.17 (t, J = 8.9 Hz, 2 H), 5.32 (s, 2 H), 4.32 (d, J = 5.8
Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.7, 162.3, 160.4, 145.2, 134.8,
SFC-MS (ESI): m/z [M]+ calcd for C13H17N5O3: 291.13; found [M – H]+:
290.16.
134.8, 129.5, 129.4, 115.2, 115.1, 49.4, 41.8.
SFC-MS (ESI): m/z [M]+ calcd for C10H10FN5O: 235.09; found [M – H]+:
234.13.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
Y. Wang et al.
Paper
Synthesis
N-(Cyclopropylmethyl)-2-(1H-tetrazol-1-yl)acetamide (4h)
1-(Pyrrolidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (4m)
The product was obtained using GP C, 1 mmol scale; yield: 0.155 g
(86%); white solid; mp 149–150 °C.
The product was obtained using GP C, 1 mmol scale; yield: 0.151 g
(84%); white solid; mp 161–163 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.35 (s, 1 H), 8.53 (s, 1 H), 5.17 (s, 2
H), 2.68–2.63 (m, 1 H), 0.68–0.64 (m, 2 H), 0.46–0.43 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 165.6, 145.1, 49.3, 22.4, 5.6.
SFC-MS (ESI): m/z [M]+ calcd for C8H9N5O: 167.08; found [M + H]+:
1H NMR (500 MHz, DMSO-d6): δ = 9.31(s, 1 H), 5.52 (s, 2 H), 3.54 (t, J =
6.8 Hz, 2 H), 3.34 (t, J = 6.8 Hz, 2 H), 1.99–1.91 (m, 2 H), 1.87–1.79 (m,
2 H).
13C NMR (126 MHz, DMSO-d6): δ = 162.9, 145.2, 49.2, 45.9, 45.1, 25.6,
23.7.
167.93.
SFC-MS (ESI): m/z [M]+ calcd for C7H11N5O: 181.10; found [M + H]+:
182.11.
N-(1-Benzylpiperidin-4-yl)-2-(1H-tetrazol-1-yl)acetamide (4i)
The product was obtained using GP C, 1 mmol scale, yield: 0.269 g
(90%); white solid; mp 126–128 °C.
1-(Piperidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (4n)
The product was obtained using GP C, 1 mmol scale; yield: 0.169 g
(87%); white solid; mp 189–190 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.29 (s, 1 H), 5.62 (s, 2 H), 3.45 (q,
J = 5.5 Hz, 4 H), 1.60 (t, J = 7.7 Hz, 4 H), 1.47 (q, J = 5.5 Hz, 2 H).
1H NMR (500 MHz, DMSO-d6): δ = 9.36 (s, 1 H), 8.79 (d, J = 6.1 Hz, 1
H), 7.54–7.39 (m, 5 H), 5.25 (s, 2 H), 4.01 (s, 2 H), 3.74 (s, 1 H), 3.16 (d,
J = 14.9 Hz, 2 H), 2.74 (s, 2 H), 1.90 (d, J = 11.4 Hz, 2 H), 1.77 (d, J = 11.7
Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 163.9, 145.1, 129.6, 128.4, 127.7,
13C NMR (126 MHz, DMSO-d6): δ = 163.0, 145.3, 48.8, 45.2, 42.6, 25.7,
61.0, 51.0, 49.4, 45.7, 30.2.
25.1, 23.8.
SFC-MS (ESI): m/z [M]+ calcd for C15H20N6O: 300.17; found [M + H]+:
SFC-MS (ESI): m/z [M]+ calcd for C8H13N5O: 195.11; found [M – H]+:
301.25.
194.08.
N-Butyl-2-(1H-tetrazol-1-yl)acetamide (4j)
1-Morpholino-2-(1H-tetrazol-1-yl)ethan-1-one (4o)
The product was obtained using GP C, 1 mmol scale; yield: 0.168 g
(92%); white solid; mp 132–134 °C.
The product was obtained using GP C, 1 mmol scale; yield: 0.169 g
(86%); white solid; mp 133–135 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.35 (s, 1 H), 8.40 (s, 1 H), 5.22 (s, 2
H), 3.11 (q, J = 6.8 Hz, 2 H), 1.41 (quint, J = 7.4 Hz, 2 H), 1.30 (sext, J =
7.5 Hz, 2 H), 0.87 (t, J = 7.3 Hz, 3 H).
1H NMR (500 MHz, DMSO-d6): δ = 9.30 (s, 1 H), 5.65 (s, 2 H), 3.66 (t,
J = 4.6 Hz, 2 H), 3.59 (t, J = 4.7 Hz, 2 H), 3.52 (t, J = 4.9 Hz, 2 H), 3.46 (t,
J = 5.0 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.4, 145.1, 145.1, 49.4, 31.0,
13C NMR (126 MHz, DMSO-d6): δ = 163.7, 145.3, 145.3, 65.9, 65.8,
19.5, 13.6.
48.7, 44.7, 42.0.
SFC-MS (ESI): m/z [M]+ calcd for C7H13N5O: 183.11; found [M – H]+:
SFC-MS (ESI): m/z [M]+ calcd for C7H11N5O: 197.09; found [M – H]+:
182.11.
196.31.
N-(Prop-2-yn-1-yl)-2-(1H-tetrazol-1-yl)acetamide (4k)
1-(4-Benzylpiperazin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (4p)
The product was obtained using GP C, 1 mmol scale; yield: 0.129 g
(78%); white solid; mp 117–119 °C.
The product was obtained using GP C, 1 mmol scale; yield: 0.207 g
(72%); white solid; mp 92–94 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.37 (s, 1 H), 8.92 (s, 1 H), 5.28 (s, 2
H), 3.95–3.94 (m, 2 H), 3.21 (t, J = 2.5 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.5, 145.1, 80.3, 73.7, 49.2, 28.3.
SFC-MS (ESI): m/z [M]+ calcd for C6H7N5O: 165.07; found [M – H]+:
163.90.
1H NMR (500 MHz, DMSO-d6): δ = 9.30 (s, 1 H), 7.36–7.26 (m, 5 H),
5.63 (s, 2 H), 3.52 (t, J = 8.4 Hz, 4 H), 3.47 (s, 2 H), 2.46 (s, 2 H), 2.36 (s,
2 H).
13C NMR (126 MHz, DMSO-d6): δ = 163.3, 145.3, 128.9, 128.3, 127.1,
61.8, 52.4, 51.9, 48.7, 44.2, 41.7.
SFC-MS (ESI): m/z [M]+ calcd for C14H18N6O: 286.15; found [M + H]+:
287.16.
N-(2-Morpholinoethyl)-2-(1H-tetrazol-1-yl)acetamide (4l)
The product was obtained using GP C, 1 mmol scale; yield: 0.177 g
(74%); white solid; mp 99–101 °C.
1H NMR (500 MHz, CDCl3): δ = 8.87 (s, 1 H), 6.61 (s, 1 H), 5.15 (s, 2 H),
3.69 (t, J = 4.6 Hz, 4 H), 3.39 (q, J = 5.5 Hz, 2 H), 2.49 (t, J = 6.0 Hz, 2 H),
2.43 (t, J = 4.2 Hz, 4 H).
N-(4-Chlorobenzyl)-4-methyl-2-(1H-tetrazol-1-yl)pentanamide
(4q)
The product was obtained using GP C, 1 mmol scale; yield: 0.228 g
(74%); clear liquid.
1H NMR (500 MHz, DMSO-d6): δ = 9.63 (s, 1 H), 9.10 (t, J = 5.7 Hz, 1 H),
7.39 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H), 5.58–5.54 (m, 1 H),
4.30 (s, 2 H), 2.19–2.12 (m, 1 H), 1.99–1.92 (m, 1 H), 1.25–1.15 (m, 1
H), 0.88 (d, J = 5.2 Hz, 3 H), 0.86 (d, J = 5.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 163.4, 143.8, 67.0, 56.4, 53.3, 50.7,
36.1.
SFC-MS (ESI): m/z [M]+ calcd for C9H16N6O2: 240.13; found [M + H]+:
241.09.
13C NMR (126 MHz, DMSO-d6): δ = 167.9, 144.1, 144.1, 138.0, 132.1,
129.7, 128.8, 60.4, 55.4, 42.4, 24.9, 22.8, 21.7.
SFC-MS (ESI): m/z [M]+ calcd for C14H18ClN5O: 307.12; found [M – H]+:
305.92.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

L
Y. Wang et al.
Paper
Synthesis
4-Methyl-2-(1H-tetrazol-1-yl)-N-(thiophen-2-ylmethyl)pentan-
amide (4r)
(2) Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.;
Weissig, H.; Shindyalov, I. N.; Bourne, P. E. Nucleic Acids Res.
2000, 28, 235.
(3) (a) Herr, R. J. Bioorg. Med. Chem. 2002, 23, 2699. (b) Matta, C. F.;
Arabi, A. A.; Weaver, D. F. Eur. J. Med. Chem. 2010, 45, 1868.
(4) Murray, C. W.; Rees, D. C. Angew. Chem. Int. Ed. 2016, 55, 488.
(5) Hoekstra, W. J.; Hargrove, T. Y.; Wawrzak, Z.; da Gama Jaen
Batista, D.; da Silva Cristiane, F.; Nefertiti, A. S. G.; Rachakonda,
G.; Schotzinger, R. J.; Villalta, F.; Soeiro, M. C.; Lepesheva, G. I.
Antimicrob. Agents Chemother. 2016, 60, 1058.
The product was obtained using GP C, 1 mmol scale; yield: 0.193 g
(69%); clear liquid.
1H NMR (500 MHz, CDCl3): δ = 8.94 (s, 1 H), 7.58 (t, J = 5.7 Hz, 1 H),
7.21–7.15 (m, 1 H), 6.96–6.86 (m, 2 H), 5.48 (t, J = 7.9 Hz, 1 H), 4.68–
4.51 (m, 2 H), 2.05 (t, J = 7.5 Hz, 2 H), 1.37–1.28 (m, 1 H), 0.89 (d, J =
4.2 Hz, 3 H), 0.87 (d, J = 4.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 167.2, 142.2, 139.6, 127.1, 126.5,
125.6, 61.3, 42.1, 38.8, 24.7, 22.5, 21.6.
SFC-MS (ESI): m/z [M]+ calcd for C12H17N5OS: 279.12; found [M – H]+:
278.33.
(6) Chen, Y.; Shoichet, B. K. Nat. Chem. Biol. 2009, 5, 158.
(7) (a) Wang, K.; Nguyen, K.; Huang, Y.; Dömling, A. ACS. Comb. Sci.
2009, 11, 920. (b) Dömling, A.; Beck, B.; Fuchs, T.; Yazbak, A. ACS
Comb. Sci. 2006, 8, 872.
(8) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc. 1958,
80, 3908.
Acknowledgment
(9) (a) Mani, P.; Singh, A. K.; Awasthi, S. K. Tetrahedron Lett. 2014,
55, 1879. (b) Gawande, S. D.; Raihan, M. J.; Zanwar, M.; Kavala,
V.; Janreddy, D.; Kuo, C. W.; Chen, M. L.; Kuo, T. S.; Yao, C. F. Tet-
rahedron 2013, 69, 1841. (c) Gawande, S. D.; Raihan, M. J.;
Zanwar, M. R.; Kavala, V.; Janreddy, D.; Kuo, C. W.; Chen, M. L.;
Kuo, T. S.; Yao, C. F. Tetrahedron 2013, 69, 1841. (d) Das, B.;
Reddy, C. R.; Kumar, D. N.; Krishnaiah, M.; Narender, R. Synlett
2010, 391. (e) Yoneyama, H.; Usami, Y.; Komeda, S.; Harusawa,
S. Synthesis 2013, 45, 1051. (f) Roh, J.; Artamonova, T. V.;
Vávrová, K.; Koldobskii, G. I.; Hrabálek, A. Synthesis 2009, 2175.
(g) Vorona, S.; Artamonova, T.; Zevatskii, Y.; Myznikov, L. Syn-
thesis 2014, 46, 781. (h) Cantillo, D.; Gutmann, B.; Kappe, C. O.
J. Am. Chem. Soc. 2011, 133, 4465.
The research leading to these results has received support from the
NIH (1R01GM097082) and from the Innovative Medicines Initiative
Joint Undertaking under grant agreement no. 115489. These resourc-
es are composed of financial contribution from the European Union’s
Seventh
Framework
Programme (FP7/2007-2013)
and EFPIA
companies’ in-kind contribution. Y.W. acknowledges a CSC stipend-
ship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562435.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(10) Kappe, C. O.; Stadler, A.; Dallinger, D. Microwaves in Organic and
Medicinal Chemistry, In Methods and Principles in Medicinal
Chemistry; Vol. 52; Mannhold, R.; Kubinyi, H.; Folkers, G., Eds.;
Wiley-VCH: Weinheim, 2012, 487.
References
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(1) These authors contributed equally to this article.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L