An Azirine Strategy for the Synthesis of Alkyl 4-Amino-5-(trifluoromethyl)-1 H -pyrrole-2-carboxylates

Article abstract of DOI:10.1055/s-0037-1610840

1-(3,3,3-Trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide serves as a trifluoromethyl-containing building block for the preparation of trifluoromethyl-substituted aminopyrroles based on the 2 H -azirine ring expansion strategy. The primary products, 3-

Full text of DOI:10.1055/s-0037-1610840

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–N
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L. D. Funt et al.
Feature
Synthesis
An Azirine Strategy for the Synthesis of Alkyl 4-Amino-5-(trifluo-
romethyl)-1H-pyrrole-2-carboxylates
Liya D. Funt
Olesya A. Tomashenko
Mikhail S. Novikov
Alexander F. Khlebnikov*
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Saint Petersburg State University, Institute of Chemistry,
7/9 Universitetskaya nab., St. Petersburg, 199034,
Russian Federation
a.khlebnikov@spbu.ru
Received: 22.09.2018
Accepted after revision: 18.10.2018
Published online: 15.11.2018
We earlier discovered the reaction of 2H-azirines with
N-phenacylpyridinium ylides,8 leading to 1-(1H-pyrrol-3-
yl)pyridinium salts, which formed the basis of a new strate-
gy for the synthesis of heteryl- and amino-substituted pyr-
roles.9 The reaction was successfully extended to N-
DOI: 10.1055/s-0037-1610840; Art ID: ss-2018-z0644-fa
Abstract 1-(3,3,3-Trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bro-
mide serves as a trifluoromethyl-containing building block for the
preparation of trifluoromethyl-substituted aminopyrroles based on the
2H-azirine ring expansion strategy. The primary products, 3-aryl-2-(me-
thoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-(trifluoromethyl)pyrrol-1-ides,
can be hydrogenated by H2/PtO2 to form alkyl 3-aryl-4-(piperidin-1-yl)-
5-(trifluoromethyl)-1H-pyrrole-2-carboxylates and transformed into al-
kyl 4-amino-3-aryl-1-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carbox-
ylates via methylation/hydrazinolysis.
phenacylimidazolium,10
ylides11
and 2-methoxy-2-oxo-1-(pyridin-1-ium-1-
N-phenacyl-1,2,4-triazolium
yl)ethan-1-ides,12 to obtain a great variety of pyrrolyl-imid-
azole and pyrrolyl-triazole dyads, azole betaines, and NHCs.
Zincke cleavage13 of the pyridinium ring in 4-(pyridin-1-
ium-1-yl)pyrrol-1-ides and 1-(1H-pyrrol-3-yl)pyridinium
salts14 allowed us to synthesize 3-aminopyrrole derivatives.
Based on this background, we hypothesized that the reac-
tion of 2H-azirines 1 with trifluoromethylated ylide 2,
3,3,3-trifluoro-2-oxo-1-(pyridin-1-ium-1-yl)propan-1-ide,
as a trifluoromethyl-containing building block, could be po-
tentially used for the synthesis of trifluoromethylated pyr-
roles with N-heterocyclic and amino substituents 3–5
(Scheme 1).
Key words trifluoromethylpyrrole, aminopyrrole, trifluoromethylated
pyridinium ylide, pyridine, piperidine
Functionalized pyrroles are present as a structural motif
in a range of natural products and bioactive molecules.1
They are also versatile building blocks in heterocyclic syn-
thesis and have found applications in the development of
new progressive materials that are useful for bioimaging
applications and chemosensors.1,2 Therefore, many synthet-
ic methodologies have been developed for the construction
of a variety of substituted pyrroles.2 In particular, trifluoro-
methylated pyrroles are privileged structures in medicinal
chemistry research due to a remarkable influence of the tri-
fluoromethyl group on many important properties of po-
tential drugs, such as metabolic stability, lipophilicity, and
bioavailability.3,4 There are two main synthetic approaches
to trifluoromethylated pyrroles; namely, direct trifluoro-
methylation of the pyrrole ring4,5 and cyclizations involving
trifluoromethylated building blocks.5,6 Amino-substituted
pyrroles have a wide range of biological activities, and they
are also useful as precursors for the preparation of a variety
of valuable acyclic and heterocyclic derivatives.7 Substitut-
ed pyrroles containing both the trifluoromethyl and amino
groups have, to our knowledge, been previously unknown.
R1
N
R1
R2
N
R1
N
R2
CF3
N
H
1
4
R2
O
CF3
N
R1
NH2
N
CF3
3
R2
2
CF3
N
H
5
Scheme 1 Retrosynthetic scheme for the synthesis of trifluoromethyl-
ated pyrroles with N-heterocyclic and amino substituents
To start with, the simplest substrate 3-phenyl-2H-azir-
ine was reacted with 1-(3,3,3-trifluoro-2,2-dihydroxypro-
pyl)pyridin-1-ium bromide (6) under the reaction condi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
L. D. Funt et al.
Feature
Synthesis
tions that were successfully used for the preparation of 1-
(1H-pyrrol-3-yl)pyridinium salts by the reaction of 2H-azir-
ines with N-phenacylpyridinium ylides.9 The model reac-
tion was carried out in CH2Cl2 at room temperature with 1.1
equivalents of Et3N as a base and molecular sieves as a sup-
porting dehydrating agent. Monitoring the reaction mixture
Table 1 Optimization of Reaction Conditionsa
O
Br
N
Ph
N
F3C
HO
Ph
Et3N
O
MeO
+
OH
CF3
N
N
1
MeO
1a
by H NMR spectroscopy showed that, after 24 hours, the
6
3a
only result of the reaction was partial conversion of salt 6
into the enol form of ylide 2 (ca. 30%). Increasing the tem-
perature led to considerable tarring of the reaction mixture,
but still no trace of the target pyrrole was detected. Per-
forming the reaction in CH3CN, which was the solvent of
choice in the case of some substituted azirines,10–12 at either
room temperature of under heating, was also not success-
ful. Similarly, adding Cu(OAc)2 to activate azirine15 gave no
positive result. Thus, the reaction of 3-phenyl-2H-azirine
with trifluoromethylated ylide 2 did not lead to the target
pyrrole under any of the conditions. The reaction with 2,3-
diaryl-substituted azirine, 2,3-diphenyl-2H-azirine, also
failed. The electron-withdrawing character of the CF3-group
means that ylide 2 is less nucleophilic than N-phenacylpyri-
dinium ylide, which easily reacted with 3-phenyl-2H-azir-
ine and 2,3-diphenyl-2H-azirine. We therefore further test-
ed more electrophilic azirines containing an electron-ac-
ceptor substituent at the azirine ring. Furthermore, since
the preparation of pure ylide 2 from 6 gives 2 in only 22%
yield,16 optimization of the reaction conditions for the syn-
thesis of pyrrole 3a from azirine 1a was performed by gen-
eration of 2 in situ from 6 by reaction with triethylamine at
20–120 °C in MeCN, MeOH and 1,2-dichloroethane (DCE)
(Table 1). Salt 6 did not react with methyl 3-phenyl-2H-
azirine-2-carboxylate 1a in MeCN at room temperature, but
the reaction slowly proceeded at 80 °C to afford desired
pyrrole 3a in 31% yield (Table 1). The best yield of 3a could
be achieved with MeCN as solvent at 120 °C.
Entry
Solvent
Temp (°С)
Time (h)
Yield of 3a (%)b
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
DCE
r.t.
24
96
48
48
48
48
0
31
34
42
0
80
100
120
100
100
MeOH
0
a A solution of 1a (1.3 equiv), 6 (1 equiv) and Et3N (1.05 equiv) in solvent (2
mL) was heated under stirring at the indicated temperature in a screw-cap
thick-wall test tube for the period shown; the reaction mixture was cooled,
and the product was isolated by column chromatography on silica gel
(CH2Cl2/MeOH, 10:1), the resulting residue was suspended in water, fil-
tered off, and dried under vacuum.
b Isolated yields calculated based on bromide 6.
Table 2 Synthesis of Betaines 3
R1
N
N
R1
HO OH
Et3N
+
N
O
R2
CF3
O
CF3
N
Br
O
R2
O
6
3a–j
1a–j
Entry
1
R1
R2
Me
Yield of 3 (%)
1
2
1a
Ph
4-BrC6H4
42
50
22
45
26
32
28
33
35
32
1b
1c
1d
1e
1f
Me
Me
Me
t-Bu
Me
Me
Me
t-Bu
Me
3
4-MeOC6H4
4-NO2C6H4
2-BrC6H4
4-MeC6H4
3,4-Me2C6H3
4-FC6H4
The use of excess Et3N enhanced tar formation but, on
the other hand, with the amount of base less than 1.05
equivalents, full conversion of the starting material could
not be achieved.
To evaluate the scope of the reaction, we synthesized al-
kyl 2H-azirine-2-carboxylates 1a–j, containing various 3-
aryl/hetaryl-substituents, by Fe(II)-catalyzed isomerization
of the corresponding 5-alkoxyisoxazoles 7a–j (Scheme 2).
Azirines 1a–j were reacted with pyridinium bromide 6 un-
der the optimal conditions to obtain the corresponding be-
taines 3a–j in 22–50% yield (Table 2).
4
5
6
7
1g
1h
1i
8
9
Ph
10
1j
2-thienyl
Decrease of thermal stability (azirine 1c) and increase
of steric congestion (azirines 1e, 1g) of the azirine leads to
lower yield of the betaine. Compounds 3a–j were character-
ized by standard spectroscopic methods. The structure of
3a was also confirmed by single-crystal X-ray analysis (Fig-
ure 1).17
R1
R1
O
O
FeCl2•4H2O
MeCN
R2
N
N
O
O
R2
1a–j
7a–j
Piperidine is a privileged structural moiety, which is
ranked as the most frequently present in FDA-approved
drugs.18 The pyridine substituent in a molecular system can
Scheme 2 Synthesis of alkyl 2H-azirine-2-carboxylates 1a–j (Ri see Ta-
ble 2)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
L. D. Funt et al.
Feature
Synthesis
H2N
O2N
1) H2, cat. PtO2
MeOH, r.t., 12 h
N
N
2HCl
O
O
CF3
CF3
2) HCl, Et2O
N
N
H
O
O
3d
4d, 75%
Scheme 3 Reduction of betaine 3d
Then we tried to transform the pyridinium moiety in
compounds 3 to the amino group, but, unexpectedly, the
procedure,14 which was successfully used for the Zincke
cleavage of the pyridinio substituent in pyrroles containing
no CF3 group, failed. A complex mixture of unidentified
products formed in the reaction of compound 3a with hy-
drazine. Earlier we used (1H-pyrrol-3-yl)pyridin-1-ium
salts as starting materials for the preparation of 3-amino-
pyrroles by Zincke cleavage, even though this reaction is
most likely to proceed through the corresponding betaines
formed from the salts in the presence of excess of hydra-
zine.14 To check the use of salts for the synthesis of trifluo-
romethylated NH-pyrroles 5, we prepared 2-trifluorometh-
yl-(1H-pyrrol-3-yl)pyridin-1-ium bromide 8a in a nearly
quantitative yield by treatment of betaine 3a with aqueous
HBr (Scheme 4).
Figure 1 X-ray crystal structure of betaine 3a
serve as the synthetic equivalent of the piperidine moiety,
because it can be selectively hydrogenated when neces-
sary.9,12,14a It was found that betaines 3a, 3c, and 3f–i can be
hydrogenated at room temperature in MeOH under atmo-
spheric pressure of H2 in the presence of Adams’ catalyst to
give the corresponding alkyl 3-aryl-4-(piperidin-1-yl)-5-
Ph
N
(trifluoromethyl)-1H-pyrrole-2-carboxylates
4 in good
yields (Table 3). Hydrogenation of compounds 3b, 3d, and
3e under these conditions in addition to the reduction of
the pyridinium fragment, leads to substitution of bromine
for hydrogen in the 3-(2/4-bromophenyl) moieties (com-
pounds 3b and 3e) and reduction of the nitro group in the
3-(4-nitrophenyl) moiety (compound 3d) to the amino
group (Scheme 3).
HO
Et3N
DCM, r.t.
24 h
CF3
R1
N
N
O
Br
HBr (48%)
R2O
3a,e,i
MeOH, r.t.
10 min
CF3
R1 = Ph
R2 = H
N
H
O
N
Ph
8a, R1 = Ph, R2 = Me; 97%
8e, R1 = 2-BrC6H4, R2 = H; 97%
8i, R1 = Ph, R2 = H; 89%
O
CF3
N
H
O
9, 92%
Table 3 Synthesis of 4-Piperidinopyrroles 4a, 4c, and 4f–i
Scheme 4 Synthesis of salts 8a, 8e, and 8i, and betaine 9
R1
N
R1
N
In the case of tert-butyl esters 3e and 3i, the formation
of pyridinium salts under these conditions was accompa-
nied by the HBr-catalyzed hydrolysis of the ester group to
give salts 8e and 8i. It is interesting that the neutralization
of salt 8i with Et3N afforded trifluoromethylated betaine 9
in high yield. According to the NMR spectra, the latter exists
as a mixture of rapidly interconverting OH and NH tautom-
ers.
However, like with betaine 3a, the reaction of hydrazine
with salt 8a gave a complex mixture of unidentified prod-
ucts, probably because of the instability of NH-aminopyr-
role 5 under the reaction conditions. Therefore, methyl pro-
tection of the pyrrole nitrogen was further tried. The start-
ing compounds 3a–j were N-methylated with methyl iodide
to give the corresponding 1-(5-(alkoxycarbonyl)-4-aryl-1-
H2, cat. PtO2
O
R2
O
R2
MeOH, r.t., 12 h
CF3
CF3
N
N
H
O
O
4a,c,f–i
3a,c,f–i
Entry
R1
R2
Yield of 4 (%)
1
2
3
4
5
6
Ph
Me
4a, 71
4c, 74
4f, 57
4g, 62
4h, 93
4i, 72
4-MeOC6H4
4-MeC6H4
3,4-Me2C6H3
4-FC6H4
Me
Me
Me
Me
t-Bu
Ph
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

D
L. D. Funt et al.
Feature
Synthesis
methyl-2-(trifluoromethyl)-1H-pyrrol-3-yl)pyridin-1-ium
iodides 10a–j in nearly quantitative yields. Hydrazinolysis
of the pyridinium moiety in compounds 10a–j provided the
target trifluoromethylated aminopyrroles 11a–j in good to
excellent yields (Table 4).
peak of CHCl3 (δ = 7.26 ppm) or DMSO-d6 (δ = 2.50 ppm). 13C{1H} and
13C DEPT135 were calibrated according to the peak of CDCl3 (δ =
77.00 ppm) or DMSO-d6 (δ = 39.51 ppm). 19F NMR spectra were cali-
brated according to a CFCl3 external standard (δ = 0 ppm). Mass spec-
tra were recorded with a Bruker maXis HRMS-ESI-QTOF, electrospray
ionization, in positive mode. Thin-layer chromatography (TLC) was
conducted on aluminum sheets with 0.2 mm silica gel (fluorescent in-
dicator, Macherey-Nagel) and Macherey-Nagel Silica 60 M was used
for column chromatography.
Table 4 Synthesis of Compounds 10 and 11
R1
NH2
R1
N
Synthesis of Starting Materials
R1
N
MeI
N2H4•H2O
O
I
O
O
CF3
MeCN
45 °C
2 h
MeCN
45 °C
3–6 h
N
CF3
Preparation of Azirines 1a–j; General Procedure
CF3
N
R2O
N
R2O
Me
R2O
Iron(II) chloride tetrahydrate (1 mmol, 10 mol%) was added to a
stirred solution of 3-aryl-5-alkoxyisoxazole 7a–j (10 mmol) in MeCN
(23 mL) and the resulting mixture was stirred for 2 h under an inert
atmosphere at r.t. (monitored by TLC, hexane/EtOAc, 4:1). After com-
pletion of the reaction, the solution was filtered through Celite, con-
centrated in vacuo and the product was purified by flash column
chromatography (hexane/EtOAc, 4:1) to give azirines 1a–j.
Me
3a–j
11a–j
10a–j
Entry R1
R2
Yield of 10 (%) Yield of 11 (%)
1
2
Ph
Me
10a, 90
10b, 98
10c, 92
10d, 98
10e, 97
10f, 91
10g, 96
10h, 96
10i, 88
10j, 92
11a, 75
11b, 97
11c, 81
11d, 90
11e, 78
11f, 93
11g, 89
11h, 94
11i, 76
11j, 89
4-BrC6H4
Me
Me
Me
t-Bu
Me
Me
Me
t-Bu
Me
3
4-MeOC6H4
4-O2NC6H4
2-BrC6H4
Methyl 3-Phenyl-2H-azirine-2-carboxylate (1a)
Azirine 1a was prepared from isoxazole 7a19 (1.15 g, 6.57 mmol) and
FeCl2·4H2O (131 mg, 0.66 mmol).
4
5
Yield: 1.09 g (95%); colorless solid; mp 76–78 °C (hexane/EtOAc)
(Lit.20 44–46 °C).
6
4-MeC6H4
7
3,4-Me2C6H3
4-FC6H4
Ph
8
Methyl 3-(4-Bromophenyl)-2H-azirine-2-carboxylate (1b)
Azirine 1b was prepared from isoxazole 7b19 (1.0 g, 3.93 mmol) and
FeCl2·4H2O (78 mg, 0.39 mmol).
9
10
2-thienyl
Yield: 1.0 g (100%); colorless solid; mp 74–75 °C (EtOAc) (Lit.21 68.2–
68.7 °C).
In
summary,
1-(3,3,3-trifluoro-2,2-dihydroxypro-
pyl)pyridin-1-ium bromide was used as a trifluoromethyl-
containing building block for the preparation of trifluoro-
methyl-substituted aminopyrroles using the 2H-azirine
ring expansion strategy. The primary products, 3-aryl-
2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-(trifluoro-
methyl)pyrrol-1-ides, were hydrogenated with hydrogen
on Adams’ catalyst to give the corresponding alkyl 3-aryl-4-
(piperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carbox-
ylates. Hydrogenation of the pyridinium ring in compound
3d, containing the nitro group in the aryl moiety, under
these conditions is accompanied by the reduction of the ni-
tro to amino group. 3-Aryl-2-(methoxycarbonyl)-4-(pyri-
Methyl 3-(4-Methoxyphenyl)-2H-azirine-2-carboxylate (1c)
Azirine 1c was prepared from isoxazole 7c19 (1.2 g, 5.85 mmol) and
FeCl2·4H2O (116 mg, 0.58 mmol).
Yield: 1.07 g (89%); colorless solid; mp 47–48 °C (hexane/EtOAc)
(Lit.22 colorless oil).
Methyl 3-(4-Nitrophenyl)-2H-azirine-2-carboxylate (1d)
Azirine 1d was prepared from isoxazole 7d23 (1.3 g, 5.88 mmol) and
FeCl2·4H2O (117 mg, 0.59 mmol).
Yield: 1.28 g (98%); yellow solid; mp 93–95 °C (hexane/EtOAc) (Lit.24
96–98 °C).
din-1-ium-1-yl)-5-(trifluoromethyl)pyrrol-1-ides
were
tert-Butyl 3-(2-Bromophenyl)-2H-azirine-2-carboxylate (1e)
transformed into alkyl 4-amino-3-aryl-1-methyl-5-(trifluo-
romethyl)-1H-pyrrole-2-carboxylates through methylation
of the pyrrole nitrogen with MeI followed by Zincke cleav-
age of the pyridinium moiety.
3-(2-Bromophenyl)-5-chloroisoxazole
2-Bromo-N-hydroxybenzimidoyl chloride25 (4 g, 0.017 mol, 1 equiv)
in 1,1-dichloroethylene (17 mL) and anhydrous 1,2-dichloroethane
(32 mL) was slowly added dropwise to a stirred solution of Et3N (4.31
g, 0.043 mol, 2.5 equiv) in 1,1-dichloroethylene (17 mL) cooled to 0 °C
with an ice bath. The reaction mixture was stirred at r.t. overnight
and then water (90 mL) was added and the solution was extracted
with benzene (2 × 40 mL). The combined organic phases were washed
with saturated NH4Cl (2 × 40 mL), water (2 × 40 mL), and brine (2 × 40
mL), dried over Na2SO4, filtered off, concentrated in vacuo and the res-
idue was purified by column chromatography (hexane/EtOAc, 12:1).
Melting points were determined with a Stuart SMP30 capillary melt-
ing-point apparatus. 1H (400 MHz) and 13C (100 or 125 MHz), 19F (376
or 470 MHz) NMR spectra of CDCl3 or DMSO-d6 solutions were re-
corded with Bruker Avance III 400 and 500 MHz spectrometers.
Chemical shifts (δ) are reported in ppm downfield from TMS (δ =
0.00 ppm). 1H NMR spectra were calibrated according to the residual
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
L. D. Funt et al.
Feature
Synthesis
Yield: 3.37 g (77%); pale-yellow solid; mp 44–45 °C (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 6.64 (s, 1 H), 7.30–7.38 (m, 1 H), 7.39–
7.45 (m, 1 H), 7.58–7.65 (m, 1 H), 7.66–7.73 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 103.1 (CH), 122.3 (C), 127.9 (CH),
129.8 (C), 131.3 (CH), 131.7 (CH), 133.9 (CH), 154.4 (C), 164.4 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C9H5BrClNNaO+: 279.9135; found:
279.9136.
1H NMR (400 MHz, DMSO-d6): δ = 2.27 (s, 10.40 H), 4.27 (s, 1.60 H),
5.65 (s, 1 H), 7.20–7.35 (m, 1.80 H), 7.38–7.47 (m, 1.80 H), 7.51 (s,
1.80 H), 12.83 (s, 0.80 H).
The 13С NMR spectrum consisted of very wide signals due to the tau-
tomeric equilibrium.
HRMS-ESI: m/z [M + H]+ calcd for C11H12NO2+: 190.0863; found:
190.0868.
3-(3,4-Dimethylphenyl)-5-methoxyisoxazole (7g)
3-(2-Bromophenyl)-5-(tert-butoxy)isoxazole (7e)
A solution of diazomethane [prepared from 1-methyl-1-nitrosourea
(9.17 g, 0.089 mol, 3 equiv), potassium hydroxide (17.27 g, 0.31 mol,
10 equiv), H2O (25 mL) and Et2O (100 mL)] was added dropwise under
stirring to a cold (ice bath) suspension of 3-(3,4-dimethylphenyl)isox-
azol-5(4H)-one (5.83 g, 0.031 mol, 1 equiv) in Et2O (30 mL). The re-
sulting mixture was stirred at r.t. for 1 h, unreacted diazomethane
was destroyed with AcOH, and the homogeneous solution was con-
centrated in vacuo. The solid product was recrystallized from MeOH.
tBuOK (1.04 g, 9.29 mmol, 1.2 equiv) was added to a stirred solution
of 3-(2-bromophenyl)-5-chloroisoxazole (1.93 g, 7.45 mmol, 1 equiv)
in anhydrous THF (25 mL) at r.t. After homogenization, the reaction
mixture was heated at reflux for 4 h. When the reaction was over
(monitored by TLC, hexane/EtOAc, 4:1) water (70 mL) was added and
the reaction mixture was extracted with Et2O (70 mL). The organic
phase was washed with water (2 × 50 mL), and saturated NH4Cl
(2 × 50 mL) and again with water (2 × 50 mL), dried over Na2SO4, fil-
tered off and concentrated in vacuo.
Yield: 2.78 g (44%); colorless solid; mp 100–102 °C (MeOH).
Yield: 1.84 g (83%); colorless solid; mp 37–38 °C (Et2O).
1H NMR (400 MHz, CDCl3): δ = 2.30 (s, 3 H), 2.31 (s, 3 H), 4.03 (s, 3 H),
5.50 (s, 1 H), 7.15–7.23 (m, 1 H), 7.39–7.50 (m, 1 H), 7.55 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.54 (s, 9 H), 5.79 (s, 1 H), 7.26–7.31
(m, 1 H), 7.35–7.42 (m, 1 H), 7.61–7.72 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 28.4 (CH3), 85.2 (C), 86.3 (CH), 122.3
(C), 127.7 (CH), 131.0 (CH), 131.2 (CH), 131.4 (C), 133.7 (CH), 164.1
(C), 171.3 (C).
13С NMR (100 MHz, CDCl3): δ = 19.8 (CH3), 19.8 (CH3), 58.9 (CH3), 75.4
(CH), 124.1 (CH), 127.2 (C), 127.6 (CH), 130.1 (CH), 137.2 (C), 139.0
(C), 164.4 (C), 174.5 (C).
HRMS-ESI: m/z [M + H]+ calcd for C12H14NO2+: 204.1019; found:
204.1025.
HRMS-ESI: m/z [M + Na]+ calcd for C13H14BrNNaO2+: 318.0100; found:
318.0114
Azirine 1g was prepared from isoxazole 7g (2.68 g, 0.013 mol) and
FeCl2·4H2O (262 mg, 1.32 mmol).
Azirine 1e was prepared from isoxazole 7e (350 mg, 1.15 mmol) and
FeCl2·4H2O (23 mg, 0.12 mmol).
Yield: 2.50 g (93%); yellowish oil.
Yield: 319 mg (94%); colorless solid; mp 77–79 °C (hexane/EtOAc)
(Lit.26 80–86 °C).
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H), 2.35 (s, 3 H), 2.80 (s, 1 H),
3.72 (s, 3 H), 7.29–7.36 (m, 1 H), 7.55–7.61 (m, 1 H), 7.61–7.69 (m,
1 H).
13С NMR (100 MHz, CDCl3): δ = 19.7 (CH3), 20.4 (CH3), 29.4 (CH), 52.3
(CH3), 119.8 (C), 128.2 (CH), 130.7 (CH), 131.5 (CH), 138.1 (C), 143.9
(C), 158.1 (C), 172.4 (C).
Methyl 3-(4-Methylphenyl)-2H-azirine-2-carboxylate (1f)
Azirine 1f was prepared from isoxazole 7f20 (1.30 g, 6.88 mmol) and
FeCl2·4H2O (137 mg, 0.69 mmol).
HRMS-ESI: m/z [M + H]+ calcd for C12H14NO2+: 204.1019; found:
Yield: 1.26 g (97%); colorless oil.
204.1009.
1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 2.82 (s, 1 H), 3.73 (s, 3 H),
7.33–7.43 (m, 2 H), 7.72–7.83 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 22.0 (CH3), 29.4 (CH3), 52.3 (CH), 119.5
Methyl 3-(4-Fluorophenyl)-2H-azirine-2-carboxylate (1h)
(C), 130.2 (CH), 130.6 (CH), 145.1 (C), 158.1 (C), 172.3 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C11H11NNaO2+: 212.0682; found:
3-(4-Fluorophenyl)-5-methoxyisoxazole (7h)
A solution of diazomethane [prepared from 1-methyl-1-nitrosourea
(7.13 g, 0.069 mol, 4 equiv), potassium hydroxide (9.70 g, 0.17 mol, 10
equiv), H2O (20 mL) and Et2O (80 mL)] was added dropwise under
stirring to a cold (ice bath) suspension of 3-(4-fluorophenyl)isoxazol-
5(4H)-one (3.10 g, 0.017 mol, 1 equiv) in Et2O (20 mL). The resulting
mixture was stirred at r.t. for 1 h, unreacted diazomethane was de-
stroyed with AcOH, and the homogeneous solution was concentrated
in vacuo. The solid product was recrystallized from MeOH.
212.0682.
Methyl 3-(3,4-Dimethylphenyl)-2H-azirine-2-carboxylate (1g)
3-(3,4-Dimethylphenyl)isoxazol-5(4H)-one
Hydroxylamine hydrochloride (7.96 g, 0.11 mol, 3 equiv) was added
to a suspension of ethyl 3-(3,4-dimethylphenyl)-3-oxopropanoate
(8.40 g, 0.038 mol, 1 equiv) in water (25 mL) and the mixture was
heated at 100 °C for 5 min. EtOH (ca. 80 mL, to homogenization) was
added to the reaction mixture and the solution was heated at reflux
for 1 h, then cooled. The precipitate formed was filtered off, washed
with cold 50% EtOH and dried to obtain pure product.
Yield: 2.69 g (81%); colorless solid; mp 82–84 °C (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.05 (s, 3 H), 5.49 (s, 1 H), 7.06–7.19
(m, 2 H), 7.66–7.81 (m, 2 H).
19F NMR (470 MHz, CDCl3): δ = –110.53.
13С NMR {1H, 19F} (125 MHz, CDCl3): δ = 59.0 (CH3), 75.5 (CH), 116.0
Yield: 5.83 g (81%); colorless solid; mp 106–108 °C (hexane/EtOAc).
(CH), 125.9 (C), 128.5 (CH), 163.4 (C), 163.9 (C), 174.7 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C10H8FNNaO2+: 216.0431; found:
216.0424.
The compound in DMSO solution is a mixture of two tautomers: 3-
(3,4-dimethylphenyl)isoxazol-5(4H)-one and 3-(3,4-dimethylphe-
nyl)isoxazol-5-ol in 1:0.8 ratio.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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L. D. Funt et al.
Feature
Synthesis
Azirine 1h was prepared from isoxazole 7h (2.61 g, 0.014 mol) and
FeCl2·4H2O (270 mg, 1.35 mmol).
3-(4-Bromophenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-
5-(trifluoromethyl)pyrrol-1-ide (3b)
Compound 3b was prepared according to the typical procedure from
Yield: 2.39 g (92%); colorless solid; mp 47–49 °C (hexane/EtOAc).
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
(111 mg, 0.40 mmol), methyl 3-(4-bromophenyl)-2H-azirine-2-car-
boxylate 1b (135 mg, 0.53 mmol) and Et3N (43 mg, 0.42 mmol).
6
1H NMR (400 MHz, CDCl3): δ = 2.86 (s, 1 H), 3.75 (s, 3 H), 7.20–7.33
(m, 2 H), 7.87–7.96 (m, 2 H).
19F NMR (376 MHz, CDCl3): δ = –102.48.
13С NMR {1H, 19F} (125 MHz, CDCl3): δ = 29.7 (CH), 52.5 (CH3), 117.0
(CH), 118.7 (C), 133.0 (CH), 157.6 (C), 166.1 (C), 172.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C10H8FNNaO2+: 216.0431; found:
216.0431.
Yield: 86 mg (50%); beige solid; mp >240 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 3.57 (s, 3 H), 6.93–7.10 (m, 2 H),
7.28–7.44 (m, 2 H), 8.00–8.18 (m, 2 H), 8.52–8.71 (m, 1 H), 8.93–9.12
(m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.63.
13С NMR (100 MHz, DMSO-d6): δ = 50.0 (CH3), 119.6 (C), 123.0 (C, q,
J = 268.2 Hz), 123.7 (C, q, J = 34.8 Hz), 124.1 (C), 124.9 (C), 126.6 (C),
127.6 (CH), 130.4 (CH), 131.8 (CH), 132.9 (C), 146.3 (CH), 147.3 (CH),
164.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C18H13BrF3N2O2+: 425.0107; found:
425.0125.
tert-Butyl 3-Phenyl-2H-azirine-2-carboxylate (1i)
Azirine 1i was prepared from isoxazole 7i23 (3.43 g, 0.016 mol) and
FeCl2·4H2O (315 mg, 1.58 mmol).
Yield: 3.35 g (98%); colorless solid; mp 55–57 °C (hexane/EtOAc)
(Lit.27 71–72 °C).
Methyl 3-(Thiophen-2-yl)-2H-azirine-2-carboxylate (1j)
Azirine 1j was prepared from isoxazole 7j14b (1.24 g, 6.85 mmol) and
FeCl2·4H2O (136 mg, 0.69 mmol).
2-(Methoxycarbonyl)-3-(4-methoxyphenyl)-4-(pyridin-1-ium-1-
yl)-5-(trifluoromethyl)pyrrol-1-ide (3c)
Compound 3c was prepared according to the typical procedure from
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
Yield: 1.16 g (94%); yellow oil.
6
1H NMR (400 MHz, CDCl3): δ = 2.88 (s, 1 H), 3.75 (s, 3 H), 7.23–7.31
(m, 1 H), 7.71 (dd, J = 3.8, 1.2 Hz, 1 H), 7.88 (dd, J = 5.0, 1.2 Hz, 1 H).
(214 mg, 0.79 mmol), methyl 3-(4-methoxyphenyl)-2H-azirine-2-
carboxylate 1c (210 mg, 1.02 mmol) and Et3N (87 mg, 0.86 mmol).
13С NMR (100 MHz, CDCl3): δ = 30.4 (CH), 52.5 (CH3), 124.7 (C), 128.7
Yield: 65 mg (22%); beige solid; mp >220 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 3.56 (s, 3 H), 3.68 (s, 3 H), 6.68–
6.77 (m, 2 H), 6.94–7.04 (m, 2 H), 8.03–8.12 (m, 2 H), 8.54–8.65 (m,
1 H), 8.94–9.06 (m, 2 H).
(CH), 135.56 (CH), 135.64 (CH), 151.9 (C), 171.8 (C).
HRMS-ESI: m/z [M + H]+ calcd for C8H8NO2S+: 182.0270; found:
182.0275.
19F NMR (470 MHz, DMSO-d6): δ = –56.48.
Preparation of Betaines 3a–j; Typical Procedure
13С NMR (125 MHz, DMSO-d6): δ = 49.9 (CH3), 54.8 (CH3), 113.0 (CH),
123.16 (C, q, J = 268.2 Hz), 123.23 (C, q, J = 33.3 Hz), 124.3 (C), 125.6
(C), 126.0 (C), 126.5 (C), 127.4 (CH), 130.8 (CH), 146.0 (CH), 147.4
(CH), 157.7 (C), 164.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C19H16F3N2O3+: 377.1108; found:
377.1114.
Methyl 3-phenyl-2H-azirine-2-carboxylate 1a (83 mg, 0.48 mmol, 1.3
equiv) and Et3N (39 mg, 0.38 mmol, 1.05 equiv) were subsequently
added to a stirred suspension of 1-(3,3,3-trifluoro-2,2-dihydroxypro-
pyl)pyridin-1-ium bromide 6 (100 mg, 0.37 mmol) in anhydrous
MeCN (3 mL). The reaction mixture was heated in a sealed test-tube
for 48 h at 120 °C, then concentrated in vacuo and purified by column
chromatography on silica gel (CH2Cl2/MeOH, 10:1). The crude product
was suspended in water, filtered off and dried to give compound 3a.
2-(Methoxycarbonyl)-3-(4-nitrophenyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide (3d)
Compound 3d was prepared according to the typical procedure from
2-(Methoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluo-
romethyl)pyrrol-1-ide (3a)
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
(200 mg, 0.73 mmol), methyl 3-(4-nitrophenyl)-2H-azirine-2-carbox-
ylate 1d (209 mg, 0.95 mmol) and Et3N (78 mg, 0.77 mmol).
Compound 3a was prepared according to the typical procedure from
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
Yield: 128 mg (45%); beige solid; mp >200 °C (dec.).
(100 mg, 0.37 mmol), methyl 3-phenyl-2H-azirine-2-carboxylate 1a
(83 mg, 0.48 mmol) and Et3N (39 mg, 0.38 mmol) and additionally re-
crystallized from CHCl3.
1H NMR (400 MHz, DMSO-d6): δ = 3.60 (s, 3 H), 7.25–7.43 (m, 2 H),
7.98–8.07 (m, 2 H), 8.08–8.17 (m, 2 H), 8.55–8.74 (m, 1 H), 8.98–9.17
(m, 2 H).
Yield: 53 mg (42%); beige solid; mp >240 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 3.56 (s, 3 H), 7.00–7.23 (m, 5 H),
19F NMR (376 MHz, DMSO-d6): δ = –52.07.
7.96–8.16 (m, 2 H), 8.50–8.68 (m, 1 H), 8.91–9.11 (m, 2 H).
19F NMR (470 MHz, DMSO-d6): δ = –56.54.
13С NMR (125 MHz, DMSO-d6): δ = 50.0 (CH3), 123.1 (C, q, J =
262.5 Hz), 123.3 (C, q, J = 33.3 Hz), 124.3 (C), 126.2 (CH), 126.3 (C),
126.4 (C), 127.4 (CH), 127.5 (CH), 129.7 (CH), 133.5 (C), 146.2 (CH),
147.4 (CH), 164.3 (C).
13С NMR (100 MHz, DMSO-d6): δ = 50.2 (CH3), 122.7 (CH), 122.9 (C, q,
J = 266.7 Hz), 124.0 (C), 124.2 (C), 124.3 (C, q, J = 35.2 Hz), 127.2 (C),
127.7 (CH), 130.8 (CH), 141.1 (C), 145.6 (C), 146.5 (CH), 147.3 (CH, m),
164.2 (C).
HRMS-ESI: m/z [M + H]+ calcd for C18H13F3N3O4+: 392.0853; found:
392.0859.
HRMS-ESI: m/z [M + H]+ calcd for C18H14F3N2O2+: 347.1002; found:
347.1005.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
L. D. Funt et al.
Feature
Synthesis
3-(2-Bromophenyl)-2-(tert-butoxycarbonyl)-4-(pyridin-1-ium-1-
yl)-5-(trifluoromethyl)pyrrol-1-ide (3e)
3-(4-Fluorophenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-
5-(trifluoromethyl)pyrrol-1-ide (3h)
Compound 3e was prepared according to the typical procedure from
Compound 3h was prepared according to the typical procedure from
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
(250 mg, 0.92 mmol), tert-butyl 3-(2-bromophenyl)-2H-azirine-2-
carboxylate 1e (352 mg, 1.19 mmol) and Et3N (97 mg, 0.96 mmol).
(400 mg, 1.47 mmol), methyl 3-(4-fluorophenyl)-2H-azirine-2-car-
boxylate 1h (368 mg, 1.90 mmol) and Et3N (155 mg, 1.54 mmol).
Yield: 111 mg (26%); beige solid; mp 208–210 °C (dec.).
Yield: 175 mg (33%); beige solid; mp >210 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 1.14 (s, 9 H), 7.07–7.14 (m, 1 H),
7.19–7.25 (m, 1 H), 7.26–7.31 (m, 1 H), 7.45–7.54 (m, 1 H), 8.02–8.12
(m, 2 H), 8.52–8.61 (m, 1 H), 8.82–9.00 (m, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 3.56 (s, 3 H), 6.90–7.04 (m, 2 H),
7.06–7.16 (m, 2 H), 8.02–8.14 (m, 2 H), 8.51–8.68 (m, 1 H), 8.94–9.10
(m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.29.
19F NMR (376 MHz, DMSO-d6): δ = –116.42, 56.60.
13С NMR (100 MHz, DMSO-d6): δ = 27.6 (CH3), 77.3 (C), 122.6 (C, q, J =
30.0 Hz), 123.1 (C, q, J = 265.4 Hz), 123.6 (C), 124.2 (C), 124.9 (C),
126.8 (CH), 127.5 (CH), 128.6 (CH), 128.9 (C), 131.6 (CH), 132.2 (CH),
135.8 (C), 146.2 (CH), 146.8 (CH), 162.7 (C).
13С NMR (100 MHz, DMSO-d6): δ = 50.0 (CH3), 114.3 (CH, d, J =
21.2 Hz), 121.1 (C, q, J = 266.6 Hz), 123.3 (C, q, J = 33.8 Hz), 124.4 (C),
125.2 (C), 126.6 (C), 127.5 (CH), 129.9 (C, d, J = 2.8 Hz), 131.6 (CH, d,
J = 8.0 Hz), 146.2 (CH), 147.3 (CH), 160.9 (C, d, J = 242.9 Hz), 164.2 (C).
HRMS-ESI: m/z [M + H]+ calcd for C21H19BrF3N2O2+: 467.0577; found:
HRMS-ESI: m/z [M + H]+ calcd for C18H13F4N2O2+: 365.0908; found:
467.0596.
365.0924.
2-(Methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-3-(p-tolyl)-5-(triflu-
2-(tert-Butoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(tri-
oromethyl)pyrrol-1-ide (3f)
fluoromethyl)pyrrol-1-ide (3i)
Compound 3f was prepared according to the typical procedure from
Compound 3i was prepared according to the typical procedure from
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
(300 mg, 1.10 mmol), methyl 3-(p-tolyl)-2H-azirine-2-carboxylate 1f
(270 mg, 1.43 mmol) and Et3N (117 mg, 1.15 mmol).
(590 mg, 2.16 mmol), tert-butyl 3-phenyl-2H-azirine-2-carboxylate
1i (610 mg, 2.81 mmol) and Et3N (229 mg, 2.27 mmol).
Yield: 126 mg (32%); beige solid; mp >260 °C (dec.).
Yield: 293 mg (35%); beige solid; mp 241–243 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 2.21 (s, 3 H), 3.55 (s, 3 H), 6.83–
7.07 (m, 4 H), 7.98–8.19 (m, 2 H), 8.48–8.69 (m, 1 H), 8.88–9.12 (m,
2 H).
1H NMR (400 MHz, DMSO-d6): δ = 1.22 (s, 9 H), 7.02–7.20 (m, 5 H),
7.98–8.12 (m, 2 H), 8.46–8.66 (m, 1 H), 8.82–9.12 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.30.
13С NMR (100 MHz, DMSO-d6): δ = 27.8 (CH3), 77.4 (C), 122.9 (C, q, J =
35.0 Hz), 123.3 (C, q, J = 266.3 Hz), 124.0 (C), 125.7 (C), 125.9 (CH),
127.3 (CH), 127.4 (CH), 128.6 (C), 129.8 (CH), 134.5 (C), 145.9 (CH),
147.3 (CH), 165.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C21H20F3N2O2+: 389.1471; found:
389.1475.
19F NMR (470 MHz, DMSO-d6): δ = –56.49.
13С NMR (125 MHz, DMSO-d6): δ = 20.6 (CH3), 49.9 (CH3), 123.2 (C, q,
J = 266.6 Hz), 123.4 (C, q, J = 34.8 Hz), 124.4 (C), 126.2 (C), 126.6 (C),
127.4 (CH), 128.2 (CH), 129.5 (CH), 130.6 (C), 135.2 (C), 146.1 (CH),
147.4 (CH), 164.4 (C).
HRMS-ESI: m/z [M + H]+ calcd for C19H16F3N2O2+: 361.1158; found:
361.1155.
2-(Methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-3-(thiophen-2-yl)-5-
(trifluoromethyl)pyrrol-1-ide (3j)
3-(3,4-Dimethylphenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-
1-yl)-5-(trifluoromethyl)pyrrol-1-ide (3g)
Compound 3j was prepared according to the typical procedure from
Compound 3g was prepared according to the typical procedure from
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide
6
(300 mg, 1.10 mmol), methyl 3-(thiophen-2-yl)-2H-azirine-2-carbox-
ylate 1j (259 mg, 1.43 mmol) and Et3N (116 mg, 1.15 mmol).
(300 mg, 1.10 mmol), methyl 3-(3,4-dimethylphenyl)-2H-azirine-2-
carboxylate 3g (290 mg, 1.43 mmol) and Et3N (117 mg, 1.15 mmol)
and additionally recrystallized from CHCl3.
Yield: 125 mg (32%); beige solid; mp > 220 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 3.61 (s, 3 H), 6.75–6.84 (m, 1 H),
6.85–6.93 (m, 1 H), 7.27–7.41 (m, 1 H), 8.06–8.20 (m, 2 H), 8.58–8.72
(m, 1 H), 8.92–9.22 (m, 2 H).
Yield: 115 mg (28%); beige solid; mp >230 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 2.07 (s, 3 H), 2.12 (s, 3 H), 3.56 (s,
3 H), 6.67–7.77 (m, 1 H), 6.84–6.93 (m, 2 H), 8.00–8.15 (m, 2 H), 8.49–
8.70 (m, 1 H), 8.82–9.11 (m, 2 H).
19F NMR (470 MHz, DMSO-d6): δ = –56.93.
13С NMR (125 MHz, DMSO-d6): δ = 50.2 (CH3), 118.0 (C), 122.9 (C, q,
J = 268.4 Hz), 123.8 (C, q, J = 35.3 Hz), 124.7 (C), 125.7 (CH), 126.6
(CH), 127.0 (CH), 127.5 (C), 127.6 (CH), 133.9 (C), 146.6 (CH), 147.6
(CH), 164.1 (C).
HRMS-ESI: m/z [M + H]+ calcd for C16H12F3N2O2S+: 353.0566; found:
353.0582.
19F NMR (470 MHz, DMSO-d6): δ = –56.49.
13С NMR (125 MHz, DMSO-d6): δ = 18.9 (CH3), 19.3 (CH3), 50.0 (CH3),
123.1 (C, q, J = 266.6 Hz), 123.2 (C, q, J = 35.8 Hz), 124.3 (C), 126.3 (C),
126.4 (C), 126.8 (CH), 127.4 (CH), 128.7 (CH), 130.8 (C), 131.0 (CH),
134.0 (C), 135.0 (C), 146.1 (CH), 147.4 (CH), 164.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C20H18F3N2O2+: 375.1315; found:
375.1329.
Catalytic Hydrogenation of Betaines 3; Typical Procedure
A suspension of 2-(methoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-
yl)-5-(trifluoromethyl)pyrrol-1-ide 3a (51 mg, 0.15 mmol) and PtO2
(3 mg, 10 mol%) in MeOH (2 mL) was stirred at r.t. in a hydrogen at-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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L. D. Funt et al.
Feature
Synthesis
mosphere overnight (monitored by TLC). The resulting solution was
filtered from PtO2, concentrated in vacuo and purified by column
chromatography on silica gel (CH2Cl2).
Methyl 4-(Piperidin-1-yl)-3-(p-tolyl)-5-(trifluoromethyl)-1H-pyr-
role-2-carboxylate (4f)
Compound 4f was prepared according to the typical procedure from
2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-3-(p-tolyl)-5-(trifluo-
romethyl)pyrrol-1-ide 3f (91 mg, 0.25 mmol) and PtO2 (6 mg, 10
mol%).
Methyl 3-Phenyl-4-(piperidin-1-yl)-5-(trifluoromethyl)-1H-pyr-
role-2-carboxylate (4a)
Compound 4a was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluoro-
methyl)pyrrol-1-ide 3a (51 mg, 0.15 mmol) and PtO2 (3 mg, 10 mol%).
Yield: 53 mg (57%); colorless solid; mp 172–173 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.25–1.39 (m, 6 H), 2.35 (s, 3 H),
2.61–2.69 (m, 4 H), 3.60 (s, 3 H), 7.14–7.22 (m, 4 H), 12.47 (s, 1 H).
Yield: 37 mg (71%); colorless solid; mp 182–184 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.23–1.37 (m, 6 H), 2.60–2.71 (m,
4 H), 3.59 (s, 3 H), 7.14–7.46 (m, 5 H), 12.52 (s, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.08.
13С NMR (100 MHz, DMSO-d6): δ = 23.5 (CH2), 26.0 (CH2), 51.2 (CH3),
53.0 (CH2), 116.0 (C, q, J = 37.5 Hz), 119.0 (C, q, J = 1.8 Hz), 121.0 (C, q,
J = 268.4 Hz), 126.9 (CH), 127.2 (CH), 127.9 (C), 130.5 (CH), 133.7 (C),
138.2 (C, q, J = 2.2 Hz), 160.2 (C).
19F NMR (470 MHz, DMSO-d6): δ = –56.09.
13С NMR (125 MHz, DMSO-d6): δ = 20.9 (CH3), 23.6 (CH2), 26.1 (CH2),
51.2 (CH3), 53.0 (CH2), 116.0 (C, q, J = 37.3 Hz), 119.0 (C, q, J = 1.9 Hz),
121.0 (C, q, J = 268.2 Hz), 127.8 (CH), 127.8 (C), 130.4 (CH), 130.7 (C),
135.9 (C), 138.2 (C, q, J = 2.4 Hz), 160.2 (C).
HRMS-ESI: m/z [M + H]+ calcd for C19H22F3N2O2+: 367.1628; found:
367.1618.
HRMS-ESI: m/z [M + H]+ calcd for C18H20F3N2O2+: 353.1471; found:
Methyl 3-(3,4-Dimethylphenyl)-4-(piperidin-1-yl)-5-(trifluoro-
353.1483.
methyl)-1H-pyrrole-2-carboxylate (4g)
Compound 4g was prepared according to the typical procedure from
3-(3,4-dimethylphenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-
yl)-5-(trifluoromethyl)pyrrol-1-ide 3g (76 mg, 0.20 mmol) and PtO2
(5 mg, 10 mol%).
Methyl 3-(4-Methoxyphenyl)-4-(piperidin-1-yl)-5-(trifluoro-
methyl)-1H-pyrrole-2-carboxylate (4c)
Compound 4c was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-(4-methoxyphenyl)-4-(pyridin-1-ium-1-yl)-
5-(trifluoromethyl)pyrrol-1-ide 3c (57 mg, 0.15 mmol) and PtO2 (3
mg, 10 mol%).
Yield: 48 mg (62%); colorless solid; mp 181–183 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.24–1.40 (m, 6 H), 2.23 (s, 3 H),
2.25 (s, 3 H), 2.62–2.70 (m, 4 H), 3.60 (s, 3 H), 6.98–7.05 (m, 1 H),
7.06–7.14 (m, 2 H), 12.43 (s, 1 H).
Yield: 42 mg (73%); colorless solid; mp 144–146 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.26–1.39 (m, 6 H), 2.62–2.69 (m,
4 H), 3.60 (s, 3 H), 3.78 (s, 3 H), 6.86–6.96 (m, 2 H), 7.18–7.26 (m, 2 H),
12.43 (s, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.09.
13С NMR (100 MHz, DMSO-d6): δ = 19.1 (CH3), 19.3 (CH3), 23.6 (CH2),
26.1 (CH2), 51.1 (CH3), 52.9 (CH2), 115.9 (C, q, J = 37.4 Hz), 118.9 (C, q,
J = 1.5 Hz), 121.0 (C, q, J = 268.5 Hz), 127.88 (CH), 127.92 (C), 128.4
(CH), 130.9 (C), 131.6 (CH), 134.57 (C), 134.62 (C), 131.2 (C, q, J =
2.1 Hz), 160.2 (C).
HRMS-ESI: m/z [M + H]+ calcd for C20H24F3N2O2+: 381.1784; found:
381.1797.
19F NMR (376 MHz, DMSO-d6): δ = –56.03.
13С NMR (100 MHz, DMSO-d6): δ = 23.6 (CH2), 26.1 (CH2), 51.2 (CH3),
52.9 (CH2), 54.9 (CH3), 112.7 (CH), 116.0 (C, q, J = 37.4 Hz), 119.0 (C, q,
J = 1.7 Hz), 121.1 (C, q, J = 268.3 Hz), 125.7 (C), 127.6 (C), 131.6 (CH),
138.2 (C, q, J = 2.2 Hz), 158.2 (C), 160.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C19H22F3N2O3+: 383.1577; found:
383.1586.
Methyl 3-(4-Fluorophenyl)-4-(piperidin-1-yl)-5-(trifluorometh-
yl)-1H-pyrrole-2-carboxylate (4h)
Methyl 3-(4-Aminophenyl)-4-(piperidin-1-yl)-5-(trifluorometh-
yl)-1H-pyrrole-2-carboxylate dihydrochloride (4d)
Compound 4h was prepared according to the typical procedure from
3-(4-fluorophenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3h (40 mg, 0.11 mmol) and PtO2 (2 mg,
10 mol%).
Compound 4d was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-(4-nitrophenyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3d (50 mg, 0.13 mmol) and PtO2 (3 mg,
10 mol%). Due to low stability of the resulting amine it was dissolved
in EtOAc, treated with sat. HCl solution in Et2O, and the precipitate
formed was filtered off, washed and dried.
Yield: 38 mg (93%); colorless solid; mp 192–194 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.23–1.40 (m, 6 H), 2.62–2.71 (m,
4 H), 3.60 (s, 3 H), 7.06–7.29 (m, 2 H), 7.30–7.42 (m, 2 H), 12.57 (s,
1 H).
Yield: 42 mg (75%); colorless solid; mp >210 °C (dec.).
19F NMR (376 MHz, DMSO-d6): δ = –115.68, –55.99.
1H NMR (400 MHz, DMSO-d6): δ = 1.25–1.39 (m, 6 H), 2.63–2.70 (m,
4 H), 3.61 (s, 3 H), 7.33–7.39 (m, 2 H), 7.40–7.47 (m, 2 H), 10.19 (s,
1 H), 12.63 (s, 1 H).
13С NMR (100 MHz, DMSO-d6): δ = 23.5 (CH2), 26.0 (CH2), 51.2 (CH3),
52.9 (CH2), 114.1 (CH, d, J = 21.3 Hz), 166.0 (C, q, J = 37.6 Hz), 119.1
(C), 121.0 (C, q, J = 268.4 Hz), 126.7 (C), 129.9 (C, d, J = 3.2 Hz), 132.5
(CH, d, J = 8.0 Hz), 138.1 (C, q, J = 2.1 Hz), 160.1 (C), 161.4 (C, d, J =
243.4 Hz).
HRMS-ESI: m/z [M + H]+ calcd for C18H19F4N2O2+: 371.1377; found:
371.1383.
19F NMR (376 MHz, DMSO-d6): δ = –55.97.
13С NMR (100 MHz, DMSO-d6): δ = 23.5 (CH2), 26.1 (CH2), 51.3 (CH3),
52.9 (CH2), 116.2 (C, q, J = 37.8 Hz), 119.1 (C, q, J = 1.7 Hz), 121.0 (C, q,
J = 268.6 Hz), 122.2 (CH), 126.6 (C), 130.6 (C), 131.8 (CH), 133.6 (C),
138.1 (C, q, J = 2.0 Hz), 160.0 (C).
HRMS-ESI: m/z [M – 2HCl + H]+ calcd for C18H21F3N3O2+: 368.1580;
found: 368.1594.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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L. D. Funt et al.
Feature
Synthesis
tert-Butyl 3-Phenyl-4-(piperidin-1-yl)-5-(trifluoromethyl)-1H-
1-(5-Carboxy-4-phenyl-2-(trifluoromethyl)-1H-pyrrol-3-yl)pyri-
pyrrole-2-carboxylate (4i)
din-1-ium Bromide (8i)
Compound 4i was prepared according to the typical procedure from
2-(tert-butoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluo-
romethyl)pyrrol-1-ide 3i (60 mg, 0.15 mmol) and PtO2 (4 mg, 10
mol%).
HBr (48%, 1 mL) was added to a solution of 2-(tert-butoxycarbonyl)-3-
phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluoromethyl)pyrrol-1-ide
3i
(67 mg, 0.17 mmol) in MeOH (2 mL). The reaction mixture was stirred
for 10 minutes, concentrated in vacuo, washed with CH2Cl2 and dried.
Yield: 44 mg (72%); colorless solid; mp 151–153 °C (CH2Cl2).
Yield: 63 mg (89%); gray solid; mp 259–261 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 1.18 (s, 9 H), 1.22–1.28 (m, 2 H),
1.29–1.37 (m, 4 H), 2.60–2.69 (m, 4 H), 7.23–7.40 (m, 5 H), 12.36 (s,
1 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.17–7.23 (m, 2 H), 7.24–7.32 (m,
3 H), 8.20–8.31 (m, 2 H), 8.72–8.82 (m, 1 H), 9.24–9.35 (m, 2 H), 13.52
(s, 1 H), 14.38 (s, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.20.
19F NMR (376 MHz, DMSO-d6): δ = –57.00.
13С NMR (100 MHz, DMSO-d6): δ = 23.5 (CH2), 26.1 (CH2), 27.4 (CH3),
53.2 (CH2), 80.3 (C), 115.6 (C, q, J = 37.1 Hz), 121.0 (C, q, J = 1.8 Hz),
121.1 (C, q, J = 268.3 Hz), 126.6 (CH), 127.1 (CH), 127.3 (C), 130.5 (CH),
134.6 (H), 138.1 (C, q, J = 2.1 Hz), 159.6 (C).
13С NMR (100 MHz, DMSO-d6): δ = 116.9 (C, q, J = 39.6 Hz), 119.5 (C, q,
J = 269.2 Hz), 122.0 (C), 125.9 (C), 126.0 (C, q, J = 1.7 Hz), 128.1 (CH),
128.3 (CH), 128.3 (CH), 129.0 (C), 129.8 (CH), 147.5 (CH), 148.7 (CH),
160.6 (C).
HRMS-ESI: m/z [M + H]+ calcd for C21H26F3N2O2+: 395.1941; found:
HRMS-ESI: m/z [M – Br]+ calcd for C17H12F3N2O2+: 333.0845; found:
395.1938.
333.0862.
1-(5-(Methoxycarbonyl)-4-phenyl-2-(trifluoromethyl)-1H-pyrrol-
3-Phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluoromethyl)-1H-pyrrole-
3-yl)pyridin-1-ium Bromide (8a)
2-carboxylate (9)
HBr (48%, 1 mL) was added to a solution of 2-(methoxycarbonyl)-3-
Et3N (28 mg, 0.28 mmol, 2 equiv) was added to a solution of 1-(5-car-
boxy-4-phenyl-2-(trifluoromethyl)-1H-pyrrol-3-yl)pyridin-1-ium
bromide 7i (57 mg, 0.14 mmol) in CH2Cl2 (2 mL). The reaction mixture
was stirred for 24 h, filtered off, washed with CH2Cl2 and dried.
phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluoromethyl)pyrrol-1-ide
3a
(30 mg, 0.087 mmol) in MeOH (2 mL). The reaction mixture was
stirred for 10 minutes, concentrated in vacuo, washed with Et2O and
dried.
Yield: 42 mg (92%); colorless solid; mp 221–223 °C (CH2Cl2).
Yield: 37 mg (97%); gray solid; mp 200–202 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 7.04–7.20 (m, 5 H), 7.99–8.17 (m,
2 H), 8.54–8.67 (m, 1 H), 8.95–9.11 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.36.
13С NMR (100 MHz, DMSO-d6): δ = 122.1 (C, q, J = 35.4 Hz), 123.0 (C, q,
J = 268.1 Hz), 124.7 (C, q, J = 1.5 Hz), 125.2 (C), 126.2 (CH), 127.4 (C),
127.5 (CH), 127.5 (CH), 129.7 (CH), 133.5 (C), 146.3 (CH), 147.4 (CH),
164.5 (C).
HRMS-ESI: m/z [M – Br]+ calcd for C17H12F3N2O2+: 333.0845; found:
333.0831.
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 7.16–7.23 (m, 2 H),
7.25–7.32 (m, 3 H), 8.20–8.32 (m, 2 H), 8.74–8.83 (m, 1 H), 9.23–9.35
(m, 2 H), 14.56 (s, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –57.07.
13С NMR (100 MHz, DMSO-d6): δ = 52.2 (CH3), 117.5 (C, q, J = 39.8 Hz),
119.34 (C, q, J = 269.5 Hz), 120.7 (C, q, J = 1.0 Hz), 126.0 (C, q, J =
2.2 Hz), 126.4 (C), 128.1 (CH), 128.3 (CH), 128.5 (CH), 128.6 (C), 129.6
(CH), 147.4 (CH), 148.8 (CH), 159.6 (C).
HRMS-ESI: m/z [M – Br]+ calcd for C18H14F3N2O2+: 347.1002; found:
347.1017.
N-Methylation of Betaines 3a–j; Typical Procedure
MeI (156 mg, 1.09 mmol, 10 equiv) was added to a solution of 2-(me-
thoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluorometh-
yl)pyrrol-1-ide 3a (38 mg, 0.11 mmol) in MeCN (3 mL) and the reac-
tion mixture was stirred for 2 h at 45 °C. The resulting mixture was
concentrated in vacuo to obtain pure solid product 10a.
1-(4-(2-Bromophenyl)-5-carboxy-2-(trifluoromethyl)-1H-pyrrol-
3-yl)pyridin-1-ium Bromide (8e)
HBr (48%, 1 mL) was added to a solution of 3-(2-bromophenyl)-2-
(tert-butoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-(trifluorometh-
yl)pyrrol-1-ide 3e (80 mg, 0.17 mmol) in MeOH (2 mL). The reaction
mixture was stirred for 10 minutes, concentrated in vacuo, washed
with Et2O and dried.
1-(5-(Methoxycarbonyl)-1-methyl-4-phenyl-2-(trifluoromethyl)-
1H-pyrrol-3-yl)pyridin-1-ium Iodide (10a)
Yield: 83 mg (99%); gray solid; mp 274–276 °C (MeOH).
Compound 9a was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluoro-
methyl)pyrrol-1-ide 3a (38 mg, 0.11 mmol) and MeI (156 mg, 1.09
mmol).
1H NMR (400 MHz, DMSO-d6): δ = 7.21–7.29 (m, 1 H), 7.31–7.38 (m,
1 H), 7.40–7.48 (m, 1 H), 7.54–7.63 (m, 1 H), 8.19–8.34 (m, 2 H), 8.67–
8.86 (m, 1 H), 9.06–9.42 (m, 2 H), 13.59 (s, 1 H), 14.62 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): δ = –56.90.
Yield: 48 mg (90%); orange solid; mp 151–153 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 3.63 (s, 3 H), 4.11 (s, 3 H), 7.06–
7.18 (m, 2 H), 7.25–7.34 (m, 3 H), 8.20–8.32 (m, 2 H), 8.72–8.85 (m,
1 H), 9.23–9.41 (m, 2 H).
13С NMR (125 MHz, DMSO-d6): δ = 116.9 (C, q, J = 39.9 Hz), 119.4 (C, q,
J = 269.5 Hz), 123.1 (C), 123.8 (C), 124.3 (C), 125.7 (C, q, J = 1.5 Hz),
127.6 (CH), 128.3 (CH), 130.2 (C), 130.8 (CH), 132.2 (CH), 132.3 (CH),
147.2 (CH), 149.0 (CH), 160.3 (C).
19F NMR (470 MHz, DMSO-d6): δ = –56.70.
HRMS-ESI: m/z [M – Br]+ calcd for C17H11BrF3N2O2+: 410.9951; found:
410.9968.
13С NMR (125 MHz, DMSO-d6): δ = 36.0 (CH3, q, J = 1.6 Hz), 52.3 (CH3),
118.4 (C, q, J = 37.5 Hz), 119.5 (C, q, J = 270.0 Hz), 123.3 (C, q, J =
1.6 Hz), 126.0 (C, q, J = 1.4 Hz), 126.4 (C), 128.3 (CH), 128.3 (CH), 128.5
(CH), 128.8 (C), 129.3 (CH), 147.4 (CH), 148.9 (CH), 159.8 (C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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L. D. Funt et al.
Feature
Synthesis
HRMS-ESI: m/z [M – I]+ calcd for C19H16F3N2O2+: 361.1158; found:
361.1171.
1-(4-(2-Bromophenyl)-5-(tert-butoxycarbonyl)-1-methyl-2-(tri-
fluoromethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10e)
Compound 10e was prepared according to the typical procedure from
3-(2-bromophenyl)-2-(tert-butoxycarbonyl)-4-(pyridin-1-ium-1-yl)-
5-(trifluoromethyl)pyrrol-1-ide 3e (27 mg, 0.058 mmol) and MeI (82
mg, 0.58 mmol).
1-(4-(4-Bromophenyl)-5-(methoxycarbonyl)-1-methyl-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10b)
Compound 10b was prepared according to the typical procedure from
3-(4-bromophenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3b (49 mg, 0.12 mmol) and MeI (164
mg, 1.15 mmol).
Yield: 34 mg (97%); ochre solid; mp 178–180 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 1.14 (s, 9 H), 4.16 (s, 3 H), 7.23–
7.32 (m, 1 H), 7.33–7.44 (m, 2 H), 7.58–7.66 (m, 1 H), 8.17–8.36 (m,
2 H), 8.70–8.86 (m, 1 H), 9.07–9.22 (m, 1 H), 9.25–9.47 (m, 1 H).
Yield: 64 mg (98%); orange solid; mp 100–102 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 3.66 (s, 3 H), 4.11 (s, 3 H), 7.07–
7.15 (m, 2 H), 7.47–7.54 (m, 2 H), 8.23–8.32 (m, 2 H), 8.74–8.90 (m,
1 H), 9.23–9.35 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.65.
13С NMR (100 MHz, DMSO-d6): δ = 27.0 (CH3), 34.9 (C, q, J = 2.0 Hz),
82.5 (C), 118.4 (C, q, J = 37.8 Hz), 119.4 (C, q, J = 270.2 Hz), 123.7 (C),
124.4 (C, q, J = 1.9 Hz), 125.0 (C), 125.6 (C, q, J = 1.7 Hz), 127.6 (CH),
128.3 (CH), 128.4 (CH), 130.7 (C), 130.8 (CH), 131.8 (CH), 132.2 (CH),
147.08 (CH), 147.10 (CH), 149.2 (CH), 158.0 (C).
HRMS-ESI: m/z [M – I]+ calcd for C22H21BrF3N2O2+: 481.0733; found:
481.0750.
19F NMR (376 MHz, DMSO-d6): δ = –56.73.
13С NMR (100 MHz, DMSO-d6): δ = 35.1 (CH3, q, J = 2.4 Hz), 52.4 (CH3),
118.6 (C, q, J = 37.3 Hz), 119.4 (C, q, J = 268.4 Hz), 122.1 (C), 123.3 (C,
q, J = 1.7 Hz), 125.2 (C), 125.8 (C, q, J = 2.3 Hz), 128.1 (C), 128.4 (CH),
131.3 (CH), 131.5 (CH), 147.4 (CH), 149.0 (CH), 159.7 (C).
HRMS-ESI: m/z [M – I]+ calcd for C19H15BrF3N2O2+: 439.0264; found:
439.0264.
1-(5-(Methoxycarbonyl)-1-methyl-4-(p-tolyl)-2-(trifluorometh-
yl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10f)
1-(5-(Methoxycarbonyl)-4-(4-methoxyphenyl)-1-methyl-2-(tri-
fluoromethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10c)
Compound 10f was prepared according to the typical procedure from
2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-3-(p-tolyl)-5-(trifluo-
romethyl)pyrrol-1-ide 3f (40 mg, 0.11 mmol) and MeI (162 mg, 1.14
mmol).
Compound 10c was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-(4-methoxyphenyl)-4-(pyridin-1-ium-1-yl)-
5-(trifluoromethyl)pyrrol-1-ide 3c (38 mg, 0.10 mmol) and MeI (142
mg, 1.00 mmol).
Yield: 51 mg (91%); yellow solid; mp 63–65 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 2.23 (s, 3 H), 3.64 (s, 3 H), 4.09 (s,
3 H), 6.95–7.05 (m, 2 H), 7.05–7.15 (m, 2 H), 8.19–8.34 (m, 2 H), 8.72–
8.89 (m, 1 H), 9.20–9.39 (m, 2 H).
Yield: 47 mg (92%); orange solid; mp 85–87 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 3.65 (s, 3 H), 3.70 (s, 3 H), 4.09 (s,
3 H), 6.79–6.86 (m, 2 H), 7.01–7.09 (m, 2 H), 8.22–8.31 (m, 2 H), 8.75–
8.83 (m, 1 H), 9.24–9.32 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –56.68.
13С NMR (100 MHz, DMSO-d6): δ = 20.7 (CH3), 35.0 (CH3, q, J = 2.1 Hz),
52.3 (CH3), 118.4 (C, q, J = 37.2 Hz), 119.5 (C, q, J = 268.4 Hz), 123.3 (C,
q, J = 1.9 Hz), 125.7 (C), 126.0 (C, q, J = 1.7 Hz), 126.3 (C), 128.3 (CH),
128.9 (CH), 129.1 (CH), 137.8 (C), 147.5 (CH), 148.9 (CH), 159.9 (C).
HRMS-ESI: m/z [M – I]+ calcd for C20H18F3N2O2+: 375.1315; found:
375.1332.
19F NMR (376 MHz, DMSO-d6): δ = –56.67.
13С NMR (100 MHz, DMSO-d6): δ = 35.0 (CH3, q, J = 2.2 Hz), 52.3 (CH3),
55.0 (CH3), 113.7 (CH), 118.3 (C, q, J = 37.5 Hz), 119.5 (C, q, J =
270.0 Hz), 120.5 (C), 123.3 (C, q, J = 2.4 Hz), 126.1 (C, q, J = 1.9 Hz),
126.2 (C), 128.3 (CH), 130.6 (CH), 147.5 (CH), 148.8 (CH), 159.1 (C),
159.9 (C).
HRMS-ESI: m/z [M – I]+ calcd for C20H18F3N2O3+: 391.1264; found:
1-(4-(3,4-Dimethylphenyl)-5-(methoxycarbonyl)-1-methyl-2-(tri-
391.1258.
fluoromethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10g)
Compound 10g was prepared according to the typical procedure from
3-(3,4-dimethylphenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-
yl)-5-(trifluoromethyl)pyrrol-1-ide 3g (52 mg, 0.14 mmol) and MeI
(197 mg, 1.39 mmol).
1-(5-(Methoxycarbonyl)-1-methyl-4-(4-nitrophenyl)-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10d)
Compound 10d was prepared according to the typical procedure from
2-(methoxycarbonyl)-3-(4-nitrophenyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3d (33 mg, 0.084 mmol) and MeI (120
mg, 0.84 mmol).
Yield: 69 mg (96%); yellow solid; mp 191–193 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3 H), 2.14 (s, 3 H), 3.65 (s,
3 H), 4.08 (s, 3 H), 6.76–6.84 (m, 1 H), 6.85–6.94 (m, 1 H), 6.97–7.06
(m, 1 H), 8.21–8.32 (m, 2 H), 8.73–8.84 (m, 1 H), 9.23–9.35 (m, 2 H).
Yield: 44 mg (98%); orange solid; mp 84–86 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 3.65 (s, 3 H), 4.14 (s, 3 H), 7.40–
7.51 (m, 2 H), 8.09–8.20 (m, 2 H), 8.23–8.33 (m, 2 H), 8.74–8.96 (m,
1 H), 9.25–9.39 (m, 2 H).
19F NMR (470 MHz, DMSO-d6): δ = –56.67.
13С NMR (125 MHz, DMSO-d6): δ = 19.0 (CH3), 19.2 (CH3), 35.0 (CH3, q,
J = 2.3 Hz), 52.3 (CH3), 118.3 (C, q, J = 37.2 Hz), 119.5 (C, q, J =
270.1 Hz), 123.3 (C, q, J = 1.6 Hz), 125.9 (C, q, J = 1.2 Hz), 126.0 (C),
126.2 (C), 126.5 (CH), 128.3 (CH), 129.4 (CH), 130.1 (CH), 136.1 (C),
136.6 (C), 147.5 (CH), 148.9 (CH), 160.0 (C).
HRMS-ESI: m/z [M – I]+ calcd for C21H20F3N2O2+: 389.1471; found:
389.1489.
19F NMR (376 MHz, DMSO-d6): δ = –56.80.
13С NMR (100 MHz, DMSO-d6): δ = 35.2 (CH3, q, J = 2.3 Hz), 52.5 (CH3),
119.0 (C, q, J = 37.4 Hz), 119.3 (C, q, J = 268.5 Hz), 123.3 (CH), 123.5
(C), 124.5 (C), 125.7 (C, q, J = 1.9 Hz), 128.5 (CH), 131.0 (CH), 135.9 (C),
147.29 (C), 147.33 (CH), 149.1 (CH), 159.4 (C).
HRMS-ESI: m/z [M – I]+ calcd for C19H15F3N3O4+: 406.1009; found:
406.0995.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

K
L. D. Funt et al.
Feature
Synthesis
1-(4-(4-Fluorophenyl)-5-(methoxycarbonyl)-1-methyl-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10h)
Synthesis of 3-Amino-2-trifluoromethyl-pyrroles 11a–j; Typical
Procedure
Compound 10h was prepared according to the typical procedure from
3-(4-fluorophenyl)-2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3h (81 mg, 0.22 mmol) and MeI (316
mg, 2.22 mmol).
Hydrazine hydrate (38 mg, 0.76 mmol, 10 equiv) was added to a solu-
tion of 1-(5-(methoxycarbonyl)-1-methyl-4-phenyl-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10a (37 mg, 0.076
mmol) in MeCN (2 mL) and the reaction mixture was stirred for 3–6 h
at 45 °C (monitored by TLC). After completion of the reaction the sol-
vent was removed in vacuo and the residue was purified by column
chromatography on silica gel (CH2Cl2) to give 11a.
Yield: 108 mg (96%); yellow solid; mp 46–48 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 3.64 (s, 3 H), 4.12 (s, 3 H), 7.07–
7.16 (m, 2 H), 7.17–7.27 (m, 2 H), 8.21–8.33 (m, 2 H), 8.73–8.87 (m,
1 H), 9.22–9.35 (m, 2 H).
Methyl 4-Amino-1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyr-
role-2-carboxylate (11a)
19F NMR (376 MHz, DMSO-d6): δ = –112.96, –56.71.
13С NMR (100 MHz, DMSO-d6): δ = 35.1 (CH3, q, J = 2.3 Hz), 52.3 (CH3),
115.2 (CH, d, J = 21.8 Hz), 118.5 (C, q, J = 37.5 Hz), 119.4 (C, q, J =
268.5 Hz), 123.3 (C, q, J = 1.7 Hz), 125.1 (C, d, J = 3.1 Hz), 125.6 (C),
126.0 (C, q, J = 2.1 Hz), 128.3 (CH), 131.6 (CH, d, J = 8.5 Hz), 147.4 (CH),
148.9 (CH), 159.7 (C), 161.9 (C, d, J = 245.9 Hz).
HRMS-ESI: m/z [M – I]+ calcd for C19H15F4N2O2+: 379.1064; found:
379.1059.
Compound 11a was prepared according to the typical procedure from
1-(5-(methoxycarbonyl)-1-methyl-4-phenyl-2-(trifluoromethyl)-1H-
pyrrol-3-yl)pyridin-1-ium iodide 10a (37 mg, 0.076 mmol) and
N2H4·H2O (38 mg, 0.76 mmol).
Yield: 17 mg (75%); colorless solid; mp 46–48 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.51 (s, 3 H), 3.77 (s, 3 H), 4.01 (s,
2 H), 7.17–7.24 (m, 2 H), 7.30–7.36 (m, 1 H), 7.37–7.43 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.66.
1-(5-(tert-Butoxycarbonyl)-1-methyl-4-phenyl-2-(trifluorometh-
yl)-1H-pyrrol-3-yl)pyridin-1-ium Iodide (10i)
13С NMR (100 MHZ, DMSO-d6): δ = 33.20 (CH3, q, J = 2.4 Hz), 51.3
(CH3), 106.7 (C, q, J = 35.8 Hz), 118.6 (C), 122.6 (C, q, J = 2.3 Hz), 122.6
(C, q, J = 267.3 Hz), 127.0 (CH), 128.2 (CH), 129.7 (CH), 132.5 (C), 133.2
(C, q, J = 2.1 Hz), 161.0 (C).
Compound 10i was prepared according to the typical procedure from
2-(tert-butoxycarbonyl)-3-phenyl-4-(pyridin-1-ium-1-yl)-5-(trifluo-
romethyl)pyrrol-1-ide 3i (54 mg, 0.14 mmol) and MeI (198 mg, 1.40
mmol).
HRMS-ESI: m/z [M + H]+ calcd for C14H14F3N2O2+: 299.1002; found:
299.1016.
Yield: 65 mg (88%); ochre solid; mp 174–176 °C (MeCN).
1H NMR (400 MHz, DMSO-d6): δ = 1.17 (s, 9 H), 4.10 (s, 3 H), 7.14–
7.21 (m, 2 H), 7.27–7.35 (m, 3 H), 8.20–8.30 (m, 2 H), 8.71–8.82 (m,
1 H), 9.22–9.37 (m, 2 H).
Methyl 4-Amino-3-(4-bromophenyl)-1-methyl-5-(trifluorometh-
yl)-1H-pyrrole-2-carboxylate (11b)
Compound 11b was prepared according to the typical procedure from
1-(4-(4-bromophenyl)-5-(methoxycarbonyl)-1-methyl-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10b (55 mg, 0.097
mmol) and N2H4·H2O (49 mg, 0.97 mmol).
19F NMR (470 MHz, DMSO-d6): δ = –56.70.
13С NMR (125 MHz, DMSO-d6): δ = 27.1 (CH3), 34.7 (CH3, q, J = 1.6 Hz),
82.7 (C), 118.0 (C, q, J = 37.5 Hz), 119.5 (C, q, J = 269.9 Hz), 124.4 (C, q,
J = 2.2 Hz), 125.9 (C, q, J = 1.6 Hz), 126.3 (C), 128.21 (CH), 128.25 (CH),
128.3 (CH), 129.37 (C), 129.43 (CH), 147.3 (CH), 148.8 (CH), 158.5 (C).
HRMS-ESI: m/z [M – I]+ calcd for C22H22F3N2O2+: 403.1628; found:
403.1636.
Yield: 35 mg (97%); colorless solid; mp 101–103 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.54 (s, 3 H), 3.77 (s, 3 H), 4.10 (s,
2 H), 7.11–7.22 (m, 2 H), 7.52–7.63 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.66.
13С NMR (100 MHz, DMSO-d6): δ = 33.3 (CH3, q, J = 2.4 Hz), 51.4 (CH3),
106.7 (C, q, J = 35.8 Hz), 117.3 (C), 120.3 (C), 122.5 (C, q, J = 2.4 Hz),
122.5 (C, q, J = 267.2 Hz), 131.1 (CH), 131.9 (C), 132.1 (CH), 133.2 (C, q,
J = 1.9 Hz), 160.8 (C).
1-(5-(Methoxycarbonyl)-1-methyl-4-(thiophen-2-yl)-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide (10j)
Compound 10j was prepared according to the typical procedure from
2-(methoxycarbonyl)-4-(pyridin-1-ium-1-yl)-3-(thiophen-2-yl)-5-
(trifluoromethyl)pyrrol-1-ide 3j (38 mg, 0.11 mmol) and MeI (152
mg, 1.07 mmol).
+
HRMS-ESI: m/z [M
+
H]+ 377.0107 calcd for C14H13BrF3N2O2
:
377.0107; found: 377.0121.
Yield: 49 mg (92%); brown solid; mp 58–60 °C (MeCN).
Methyl 4-Amino-3-(4-methoxyphenyl)-1-methyl-5-(trifluoro-
methyl)-1H-pyrrole-2-carboxylate (11c)
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 4.08 (s, 3 H), 6.82–
7.06 (m, 2 H), 7.46–7.67 (m, 1 H), 8.18–8.45 (m, 2 H), 8.70–8.96 (m,
1 H), 9.21–9.48 (m, 2 H).
Compound 11c was prepared according to the typical procedure from
1-(5-(methoxycarbonyl)-4-(4-methoxyphenyl)-1-methyl-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10c (36 mg, 0.069
mmol) and N2H4·H2O (35 mg, 0.69 mmol).
19F NMR (376 MHz, DMSO-d6): δ = –56.89.
13С NMR (100 MHz, DMSO-d6): δ = 35.1 (CH3), 52.6 (CH3), 118.7 (C, q,
J = 37.2 Hz), 118.8 (C), 119.3 (C, q, J = 270.1 Hz), 124.3 (C), 126.2 (C),
127.3 (CH), 127.7 (C), 128.4 (CH), 128.7 (CH), 129.4 (CH), 147.6 (CH),
149.1 (CH), 159.6 (C).
HRMS-ESI: m/z [M – I]+ calcd for C17H14F3N2O2S+: 367.0723; found:
367.0723.
Yield: 18 mg (81%); colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 3.53 (s, 3 H), 3.76 (s, 3 H), 3.78 (s,
3 H), 3.97 (s, 2 H), 6.89–7.03 (m, 2 H), 7.07–7.22 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.64.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

L
L. D. Funt et al.
Feature
Synthesis
13С NMR (100 MHz, DMSO-d6): δ = 33.2 (CH3, q, J = 2.3 Hz), 51.3 (CH3),
55.0 (CH3), 106.6 (C, q, J = 36.0 Hz), 113.7 (CH), 118.4 (C), 122.6 (C, q,
J = 2.3 Hz), 122.6 (C, q, J = 267.2 Hz), 124.4 (C), 131.0 (CH), 133.3 (C, q,
J = 2.2 Hz), 158.2 (C), 161.0 (C).
HRMS-ESI: m/z [M + H]+ calcd for C15H16F3N2O2+: 313.1158; found:
313.1150.
Methyl 4-Amino-3-(3,4-dimethylphenyl)-1-methyl-5-(trifluoro-
methyl)-1H-pyrrole-2-carboxylate (11g)
HRMS-ESI: m/z [M + H]+ calcd for C15H16F3N2O3+: 329.1108; found:
329.1116.
Compound 11g was prepared according to the typical procedure from
1-(4-(3,4-dimethylphenyl)-5-(methoxycarbonyl)-1-methyl-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10g (45 mg, 0.087
mmol) and N2H4·H2O (44 mg, 0.87 mmol).
Methyl 4-Amino-1-methyl-3-(4-nitrophenyl)-5-(trifluorometh-
yl)-1H-pyrrole-2-carboxylate (11d)
Compound 11d was prepared according to the typical procedure from
1-(5-(methoxycarbonyl)-1-methyl-4-(4-nitrophenyl)-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10d (38 mg, 0.071
mmol) and N2H4·H2O (35 mg, 0.71 mmol).
Yield: 25 mg (89%); colorless solid; mp 79–81 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 2.23 (s, 3 H), 2.24 (s, 3 H), 3.52 (s,
3 H), 3.75 (s, 3 H), 3.97 (s, 2 H), 6.86–6.93 (m, 1 H), 6.95–7.01 (m, 1 H),
7.11–7.20 (m, 1 H).
Yield: 22 mg (90%); yellow solid; mp 128–130 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.54 (s, 3 H), 3.80 (s, 3 H), 4.27 (s,
2 H), 7.48–7.55 (m, 2 H), 8.19–8.29 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.70.
13С NMR (100 MHz, DMSO-d6): δ = 33.4 (CH3, q, J = 2.4 Hz), 51.5 (CH3),
106.9 (C, q, J = 35.9 Hz), 116.4 (C), 122.5 (C, q, J = 267.4 Hz), 122.7 (C,
q, J = 2.3 Hz), 123.2 (CH), 131.2 (CH), 133.4 (C, q, J = 2.2 Hz), 140.2 (C),
146.1 (C), 160.5 (C).
19F NMR (376 MHz, DMSO-d6): δ = –53.63.
13С NMR (100 MHz, DMSO-d6): δ = 19.1 (CH3), 19.3 (CH3), 33.2 (CH3, q,
J = 2.3 Hz), 51.3 (CH3), 106.5 (C, q, J = 36.0 Hz), 118.6 (C), 122.6 (C, q,
J = 267.3 Hz), 122.6 (C, q, J = 2.2 Hz), 121.7 (CH), 129.3 (CH), 129.8 (C),
130.6 (CH), 133.2 (C, q, J = 1.9 Hz), 134.8 (C), 135.9 (C), 161.1 (C).
HRMS-ESI: m/z [M + H]+ calcd for C16H18F3N2O2+: 327.1315; found:
327.1329.
HRMS-ESI: m/z [M + H]+ calcd for C14H13F3N3O4+: 344.0853; found:
Methyl 4-Amino-3-(4-fluorophenyl)-1-methyl-5-(trifluorometh-
yl)-1H-pyrrole-2-carboxylate (11h)
344.0860.
Compound 11h was prepared according to the typical procedure from
1-(4-(4-fluorophenyl)-5-(methoxycarbonyl)-1-methyl-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10h (67 mg, 0.13
mmol) and N2H4·H2O (66 mg, 1.32 mmol).
tert-Butyl 4-Amino-3-(2-bromophenyl)-1-methyl-5-(trifluoro-
methyl)-1H-pyrrole-2-carboxylate (11e)
Compound 11e was prepared according to the typical procedure from
1-(4-(2-bromophenyl)-5-(tert-butoxycarbonyl)-1-methyl-2-(trifluo-
romethyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10e (40 mg, 0.066
mmol) and N2H4·H2O (33 mg, 0.66 mmol).
Yield: 39 mg (94%); colorless solid; mp 99–101 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.52 (s, 3 H), 3.78 (s, 3 H), 4.05 (s,
2 H), 7.10–7.37 (m, 4 H).
Yield: 21 mg (78%); colorless solid; mp 103–105 °C (CH2Cl2).
19F NMR (376 MHz, DMSO-d6): δ = –115.53, –53.67.
1H NMR (400 MHz, DMSO-d6): δ = 1.09 (s, 9 H), 3.81 (s, 3 H), 3.89 (s,
2 H), 7.21–7.26 (m, 1 H), 7.27–7.33 (m, 1 H), 7.39–7.45 (m, 1 H), 7.66–
7.73 (m, 1 H).
13С NMR (100 MHz, DMSO-d6): δ = 33.3 (CH3, q, J = 2.4 Hz), 51.3 (CH3),
106.7 (C, q, J = 35.9 Hz), 115.0 (CH, d, J = 21.3 Hz), 117.6 (C), 122.6 (C,
q, J = 267.2 Hz), 122.6 (C, q, J = 2.3 Hz), 128.8 (C, d, J = 3.2 Hz), 131.9
(CH, d, J = 8.3 Hz), 133.4 (C, q, J = 1.5 Hz), 160.8 (C), 161.3 (C, d, J =
243.4 Hz).
HRMS-ESI: m/z [M + H]+ calcd for C14H13F4N2O2+: 317.0908; found:
317.0922.
19F NMR (376 MHz, DMSO-d6): δ = –53.51.
13С NMR (100 MHz, DMSO-d6): δ = 27.2 (CH3), 32.9 (CH3, q, J = 2.3 Hz),
80.5 (C), 106.3 (C, q, J = 36.0 Hz), 117.8 (C), 122.6 (C, q, J = 267.2 Hz),
123.5 (C, q, J = 2.2 Hz), 125.1 (C), 127.6 (CH), 129.2 (CH), 132.2 (CH),
132.3 (CH), 133.2 (C, q, J = 1.8 Hz), 134.7 (C), 159.3 (C).
HRMS-ESI: m/z [M + H]+ calcd for C17H19BrF3N2O2+: 419.0577; found:
tert-Butyl 4-Amino-1-methyl-3-phenyl-5-(trifluoromethyl)-1H-
pyrrole-2-carboxylate (11i)
419.0561.
Compound 11i was prepared according to the typical procedure from
1-(5-(tert-butoxycarbonyl)-1-methyl-4-phenyl-2-(trifluoromethyl)-
1H-pyrrol-3-yl)pyridin-1-ium iodide 10i (39 mg, 0.074 mmol) and
N2H4·H2O (37 mg, 0.74 mmol).
Methyl 4-Amino-1-methyl-3-(p-tolyl)-5-(trifluoromethyl)-1H-
pyrrole-2-carboxylate (11f)
Compound 11f was prepared according to the typical procedure from
1-(5-(methoxycarbonyl)-1-methyl-4-(p-tolyl)-2-(trifluoromethyl)-
1H-pyrrol-3-yl)pyridin-1-ium iodide 10f (37 mg, 0.074 mmol) and
N2H4·H2O (37 mg, 0.74 mmol).
Yield: 19 mg (76%): colorless solid; mp 52–54 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.14 (s, 9 H), 3.75 (s, 3 H), 3.93 (s,
2 H), 7.15–7.22 (m, 2 H), 7.31–7.37 (m, 1 H), 7.38–7.45 (m, 2 H).
Yield: 21 mg (93%); colorless solid; mp 70–71 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 2.33 (s, 3 H), 3.52 (s, 3 H), 3.76 (s,
3 H), 3.98 (s, 2 H), 7.04–7.14 (m, 2 H), 7.16–7.26 (m, 2 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.64.
13С NMR (100 MHz, DMSO-d6): δ = 20.8 (CH3), 33.2 (CH3, q, J = 2.4 Hz),
51.3 (CH3), 106.6 (C, q, J = 36.0 Hz), 118.5 (C), 122.6 (C, q, J = 267.1 Hz),
122.6 (C, q, J = 2.4 Hz), 128.8 (CH), 129.4 (C), 129.6 (CH), 133.2 (C, q,
J = 2.0 Hz), 136.1 (C), 161.0 (C).
19F NMR (376 MHz, DMSO-d6): δ = –53.55.
13С NMR (100 MHz, DMSO-d6): δ = 27.4 (CH3), 33.1 (CH3, q, J = 2.5 Hz),
81.1 (C), 106.2 (C, q, J = 35.9 Hz), 118.6 (C), 122.9 (C, q, J = 267.1 Hz),
124.2 (C, q, J = 2.5 Hz), 127.1 (CH), 128.4 (CH), 130.2 (CH), 133.3 (C, q,
J = 1.6 Hz), 133.3 (C), 160.0 (C).
HRMS-ESI: m/z [M + H]+ calcd for C17H20F3N2O2+: 341.1471; found:
341.1481.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

M
L. D. Funt et al.
Feature
Synthesis
Methyl 4-Amino-1-methyl-3-(thiophen-2-yl)-5-(trifluorometh-
(5) Nenajdenko, V.; Muzalevskiy, V. M.; Serdyuk, O. V. Chemistry of
yl)-1H-pyrrole-2-carboxylate (11j)
Fluorinated Pyrroles, In Fluorine in Heterocyclic Chemistry;
V
o
l.
1
Nenajdenko, V., Ed.; Springer: Switzerland, 2014, 55–116.
Compound 11j was prepared according to the typical procedure from
1-(5-(methoxycarbonyl)-1-methyl-4-(thiophen-2-yl)-2-(trifluoro-
methyl)-1H-pyrrol-3-yl)pyridin-1-ium iodide 10j (30 mg, 0.061
mmol) and N2H4·H2O (30 mg, 0.61 mmol).
(6) For recent examples, see: (a) Sommer, H.; Braun, M.; Schröder,
B.; Kirschning, A. Synlett 2018, 29, 121. (b) Rahmani, F.;
Darehkordi, A. Synlett 2017, 28, 1224. (c) Huang, C.; Zeng, Y.;
Cheng, H.; Hu, A.; Liu, L.; Xiao, Y.; Zhang, J. Org. Lett. 2017, 19,
4968.
Yield: 16 mg (89%); colorless solid; mp 63–65 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.60 (s, 3 H), 3.75 (s, 3 H), 4.18 (s,
2 H), 6.97–7.02 (m, 1 H), 7.09–7.14 (m, 1 H), 7.51–7.54 (m, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –53.77.
13С NMR (100 MHz, DMSO-d6): δ = 33.4 (CH3, q, J = 2.7 Hz), 51.6 (CH3),
106.3 (C, q, J = 36.3 Hz), 110.3 (C), 122.4 (C, q, J = 267.1 Hz), 123.6 (C,
q, J = 2.6 Hz), 126.6 (CH), 127.2 (CH), 127.7 (CH), 132.5 (C), 134.1 (C, q,
J = 1.8 Hz), 160.7 (C).
HRMS-ESI: m/z [M + H]+ calcd for C12H12F3N2O2S+: 305.0566; found:
305.0575.
(7) Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G. Aminopyr-
roles, In Chemistry of Heterocyclic Compounds, Pyrroles, Pt. 2;
Jones, R. A., Ed.; John Wiley & Sons, Inc: Chichester, 1992, 299–
523.
V
o
l.
4
8
(8) Jacobs, J.; Van Hende, E.; Claessens, S.; De Kimpe, N. Curr. Org.
Chem. 2011, 15, 1340.
(9) Khlebnikov, A. F.; Golovkina, M. V.; Novikov, M. S.; Yufit, D. S.
Org. Lett. 2012, 14, 3768.
(10) (a) Khlebnikov, A. F.; Tomashenko, O. A.; Funt, L. D.; Novikov, M.
S. Org. Biomol. Chem. 2014, 12, 6598. (b) Galenko, E. E.;
Tomashenko, O. A.; Khlebnikov, A. F.; Novikov, M. S. Beilstein J.
Org. Chem. 2015, 11, 1732. (c) Tomashenko, O. A.; Novikov, M.
S.; Khlebnikov, A. F. J. Org. Chem. 2017, 82, 616.
Funding Information
(11) (a) Funt, L. D.; Tomashenko, O. A.; Khlebnikov, A. F.; Novikov, M.
S.; Ivanov, Yu. A. J. Org. Chem. 2016, 81, 11210. (b) Funt, L. D.;
Tomashenko, O. A.; Mosiagin, I. P.; Novikov, M. S.; Khlebnikov, A.
F. J. Org. Chem. 2017, 82, 7583.
We gratefully acknowledge the financial support of the Russian Sci-
ence Foundation (Grant no. 16-13-10036).
R
u
si
a
n
S
c
i
e
n
c
e
F
o
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n
d
ati
o
n
(16-13-1
0
0
3
6)
(12) Funt, L. D.; Novikov, M. S.; Starova, G. L.; Khlebnikov, A. F. Tetra-
hedron 2018, 74, 2466.
Acknowledgment
(13) (a) Zincke, T.; Heuser, G.; Möller, W. Justus Liebigs Ann. Chem.
1904, 333, 296. (b) Zincke, T. Justus Liebigs Ann. Chem. 1904,
330, 361. (c) Zincke, T.; Wurker, W. Justus Liebigs Ann. Chem.
1905, 338, 107.
This research was carried out using the resources of the X-ray Diffrac-
tion Centre, the Centre for Magnetic Resonance, and the Centre for
Chemical Analysis and Materials of St. Petersburg State University.
(14) (a) Galenko, E. E.; Tomashenko, O. A.; Khlebnikov, A. F.; Novikov,
M. S. Org. Biomol. Chem. 2015, 13, 9825. (b) Galenko, E. E.;
Galenko, A. V.; Khlebnikov, A. F.; Novikov, M. S.; Shakirova, J. R.
J. Org. Chem. 2016, 81, 8495. (c) Galenko, E. E.; Galenko, A. V.;
Novikov, M. S.; Khlebnikov, A. F.; Kudryavtsev, I. V.; Terpilowski,
M. A.; Serebriakova, M. K.; Trulioff, A. S.; Goncharov, N. V. Chem-
istrySelect 2017, 2, 7508.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610840.
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(15) Galenko, A. V.; Khlebnikov, A. F.; Novikov, M. S.; Avdontseva, M.
S. Tetrahedron 2015, 71, 1940.
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