Deoxofluorination of (Hetero)aromatic Acids

Article abstract of DOI:10.1021/acs.joc.9b03011

Diverse trifluoromethyl-substituted compounds were synthesized by deoxofluorination of cinnamic and (hetero)aromatic carboxylic acids with sulfur tetrafluoride. The obtained products were used as starting materials in the preparation of novel fluorinated amino acids, anilines, and aliphatic amines - valuable building blocks for medicinal chemistry and agrochemistry.

Full text of DOI:10.1021/acs.joc.9b03011

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Article
Deoxofluorination of (Hetero)aromatic Acids
Serhii Trofymchuk, Maksym Bugera, Anton A. Klipkov, Bohdan Razhyk, Sergey Semenov, Karen
Tarasenko, Viktoriia S. Starova, Olga A. Zaporozhets, Oksana Y. Tananaiko, Anatoliy N. Alekseenko,
Yurii Pustovit, Oleksandr Kiriakov, Igor I. Gerus, Andrei A. Tolmachev, and Pavel K. Mykhailiuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03011 • Publication Date (Web): 13 Jan 2020
Downloaded from pubs.acs.org on January 15, 2020
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The Journal of Organic Chemistry
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Deoxofluorination of (Hetero)aromatic Acids
Serhii Trofymchuk,1 Maksym Bugera,1,2 Anton A. Klipkov,1,2 Bohdan Razhyk,1 Sergey Semenov,1 Karen
Tarasenko,2,3 Viktoriia S. Starova,4 Olga A. Zaporozhets,4 Oksana Y. Tananaiko,4 Anatoliy N. Alekseenko,5
Yurii Pustovit,5 Oleksandr Kiriakov,1 Igor I. Gerus,3 Andrei A. Tolmachev1,4 Pavel K. Mykhailiuk1,4*
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1 Enamine Ltd.; Chervonotkatska 78, 02094 Kyiv (Ukraine), www.enamine.net; www.mykhailiukchem.org
2 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry NAS of Ukraine; Murmanskaya 1, 02094 Kyiv (Ukraine)
3 UkrOrgSyntez Ltd. (UORSY), 29 Schorsa Str., 01133 Kyiv (Ukraine)
4 Taras Shevchenko National University of Kyiv; Chemistry Department; Volodymyrska 64, 01601 Kyiv (Ukraine).
5 Institute of Organic Chemistry NAS of Ukraine, Murmanskaya 5, 02094 Kyiv (Ukraine)
Carboxylic acids are amongst the most available chemical
compounds classes, and it would have been desirable to have a
practical method to converting them into the trifluoromethyl-
substituted derivatives. Indeed, in 1960, Engelhardt developed
deoxofluorination of aromatic acids with sulfur tetrafluoride to
obtain the corresponding trifluoromethylated products (Scheme
1).5 Subsequently, this approach was used by other groups for the
synthesis of trifluoromethyl-substituted pyridines,6 furans,7
thiazoles, uracils,8 pyrazoles,9 quinolones,10 etc.11 One of the
biggest contributions to the field came from the school of Soviet
Union chemists led by Yagupolskii.12 Later, two other methods
that proceed via different mechanisms appeared. In particular, in
2017, Sandford developed a decarbonylation of aromatic acyl
chlorides with Pd(dba)2/Brettphos.13 Subsequent coupling of the
obtained aryl chlorides with CF3SiEt314 allowed for the direct one-
pot conversion of aromatic acyl chlorides into the
trifluoromethylated derivatives. In 2018, Schoenebeck performed
a [Pd]-catalyzed decarbonylative coupling of aromatic acyl
ABSTRACT: Diverse trifluoromethyl-substituted compounds
were synthesized by deoxofluorination of cinnamic and
(hetero)aromatic carboxylic acids with sulfur tetrafluoride. The
obtained products can be used as starting materials in the
preparation of novel fluorinated amino acids, anilines and
aliphatic amines – valuable building blocks for medicinal
chemistry and agrochemistry.
INTRODUCTION
Modern medicinal chemistry and agrochemistry are tightly
bound to organofluorine chemistry, because around 20% of all
pharmaceuticals and up to 30% of agrochemicals are organic
compounds that contain at least one fluorine atom.1,2 For example,
trifluoromethyl-substituted (hetero)aromatic derivatives, that
usually posess higher metabolic stability over the non-fluorinated
counteparts, comprise to a structure of more than seventy drugs
and one hundred agrochemicals (Figure 1).3 It is no surprise that
over the past decade a number of synthetic methods to practically
access the trifluoromethyl-substituted organic molecules appeared
in the literature.4
Previous work
>75 drugs
>100 agrochemicals
SF4, HF
CF3
Cl
Ar-CO2H
t
Me
NH
Engelhardt (1960)7
HO
N
H
O
N
NH
1. Pd(dba)2
Brettphos
O2N
NO2
Cl
CF3
Ar, dioxane
130 oC, 16h
N
CF3
CF3
Ar-COCl
Ar-COF
Ar-CF3
CF3
Fluazinam
fungicide
2. TESCF3, KF
130 oC, 16h
Sandford (2017)7
Fluoxetine
Mefloquine
antimalarial drug
(Prozak)
(Lariam)
antidepressant
CF3
[Pd]/Xantphos
TESCF3, K3PO4
toluene, 170 oC, 16h
N
O
N
N
H
N
Me
Schoenebeck (2018)7
Me
O
CF3
This work
SO2NH2
CF3-amino acids
CF3-piperidines
CF3-anilines
SF4
(Het)
HF, 85 o
45-93%
[65 examples]
C
(Het)
Celecoxib
Leflunomide
(Avara)
antirheumatic drug
(Celebrex)
CF3
CO2H
Ar
Ar
antiinflammatory drug
Figure 1. Selected drugs and agrochemicals with the trifluoromethyl-
substituted (hetero)aromatic motif.
Scheme 1. Conversion of (hetero)aromatic carboxylic acids or its
derivatives into the trifluoromethyl-substituted compounds.
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fluorides with CF3SiEt3 to obtain the CF3-substituted products.15,16
CF3
CO2H
CF3
CO2H
SF4, HF
1
2
3
4
A work of Umemoto, who developed Fluolead reagent for the
fluorination of hydroxyl and carbonyl groups, should also be
noticed.17 The authors showed one example of deoxofluorination
of benzoic acid into trifluorotoluene. Unfortunately, the scope of
this transformation was not further elaborated.
Ar
Ar
or
or
85 oC, 24 h
52-93%
25 examples
Ar
Ar
2 26
2a 26a
-
-
5
Aromatic acids
6
7
8
9
In spite of wide application of the method of Englelhardt
during the last century,18 these days it has become very rare.19 On
the other hand, our research group has been involved in this
chemistry for more than a decade already. As a chemical supplier
of building blocks, we often receive requests from pharmaceutical
and agrochemicals companies for the synthesis of trifluoromethyl-
substituted (hetero)aromatic products. From our experience, the
deoxofluorination of carboxylic acids with sulfur tetrafluoride is
one of the most effective and practical methods to access these
compounds on a gram scale. It is undeservedly one of the most
underrated reactions today.
Previously, we reported on the deoxofluorination of aliphatic
acids with sulfur tetrafluoride.20 In this manuscript, therefore, we
would like to disclose our results on deoxofluorination of
(hetero)aromatic and cinnamic acids into the trifluoromethyl-
substituted products. This is the first comprehensive study on that
transformation in the open literature. In particular, sixty five
trifluoromethyl-substituted (hetero)aromatic derivatives were
obtained, none of them being synthesized by this method before.
We also show here, how the obtained compounds could be used in
the preparation of interesting trifluoromethyl-substituted amino
acids, anilines and aliphatic amines.
Me
CF3
F
CF3
Br
CF3
Br
F
Cl
2a
5a
8a
3a
6a
9a
4a
7a
(93%)
(88%)
(64%)
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F
Me
Br
CF3
Me
I
CF3
CF3
Br
Br
Cl
F
(87%)
(61%)
(61%)
F
F
Me
F
F
CF3
CF3
CF3
F
10a
(82%)
Br
(72%)
Cl
(75%)
NO2
CF3
CF3
CF3
I
I
11a
12a
13a
(73%)
Br
(71%)
(67%)
OMe
F
CF3
CF3
CF3
RESULTS AND DISCUSSION
In 2012, we performed deoxofluorination of pyrazole
O2N
14a
O2N
15a
O2N
16a
(74%)
NO2
(78%)
F
(65%)
carboxylic acid
1
with sulfur tetrafluoride to obtain
tris(trifluoromethyl)pyrazole 1a (Scheme 2).9a Later, compound
1a was used by Diaz and coworkers as a unique ligand for
transition metals.21 The product was easily obtained on a gram
scale, and we became intrigued if we could use the same method
for the preparation of other trifluoromethyl-substituted
(hetero)aromatic derivatives. As already mentioned before, we
often received requests from commercial companies for those
molecules, and we needed to elaborate a robust procedure to
access them.
O S O
O2N
F
CF3
CF3
CF3
Hal
Me
O2N
18a
19a
20a
(Br, 74%)
(Cl, 90%)
17a
(77%)
(54%)
from Ar-SO3H
O2N
Cl
CF3
Me
O2N
Me
22a
CF3
F
F
CF3
F
Me
Previous contribution (2012):
21a
23a
(65%)
(63%)
Cinnamic acids
CF3
(93%)
CF3
N
CO2H
CF3
CF3
N
CF3
CF3
SF4, HF
CF3
100 oC, 80%
CF3
N
N
H
H
NO2
O2N
1
1a
NO2
25a
24a
26a
(63%)
(52%)
(57%)
Scheme 2. Synthesis of pyrazole 1a – a ligand for transition metals.9a
Scheme 3. Scope of deoxofluorination of aromatic and cinnamic acids
with SF4. Reaction conditions: (i) carboxylic acid (1.0 equiv), SF4 (3.0
equiv), hydrogen fluoride, 85 °C, 24 h; (ii) work up; (iii) distillation.
Scope. After some experimentation, we found that for
aromatic substrates, the reaction temperature could be safely
reduced to 85-90 °C. Luckily, we could deoxofluorinate diverse
aromatic acids 2-23 into the needed trifluoromethyl-substituted
products 2a-23a in 54-93% yield after a distillation (Scheme 3).
The reaction had a good functional group tolerance: aromatic
fluorine (3a, 7a-9a, etc), chlorine (4a, 12a, 13a, etc), bromine (2a,
4a, 5a, etc) and iodine atoms (6a, 11a, 12a), ether (16a) and nitro
(13a-17a etc) groups were compatible with the reaction
conditions. Three peculiarities are additionally worth mentioning.
First, deoxofluorination of the carboxylic acid with a sulfonic
group (18) afforded the trifluoromethyl-substituted sulfonyl
fluoride 18a in 54% yield – a class of building blocks especially
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· 40 examples
· metal-free
· FGs compatibility
(Br, Cl, NH)
· available SMs
· 5-/6-memb. Het
· gram-scale
1
2
3
4
SF4, HF
Het
Het
CF3
CO2H
85 oC, 24 h
45-91%
27 66
-
27a 66a
-
5
6
5-Membered Heterocycles
Br
Br
CF3
N
N
7
8
9
Cl
27a
CF3
Br
CF3
CF3
S
Br
CF3
S
S
S
CF3
S
S
a
a
a
a
b
28a
29a
30a
31a
32a
(56%)
(61%)
(48%)
(63%)
(61%)
Br
(45%)
CF3
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59
60
CF3
Me
CF3
N
N
N
S
N
N
N
N
CF3
33a
CF3
Br
CF3
Br
N
N
S
N
H
N
H
Me
Me
38a
(88%)
c
b
34a
35a
36a
37a
(50%)
(85%)
(87%)
(73%)
(62%)
Me
6-Membered Heterocycles
Me
Me
Br
F
Cl
F
N
CF3
N
CF3
N
CF3
N
CF3
N
CF3
N
CF3
39a
40a
41a
42a
43a
44a
(69%)
(78%)
(54%)
(76%)
(71%)
(75%)
Me
CF3
O
CF3
CF3
O
Br
Br
CF3
47a
CF3
O
N
CF3
N
H
N
F
N
CF3
N
CF3
O
N
H
H
H
45a
46a
52a
48a
49a
50a
(69%)
(81%)
(73%)
(89%)
(79%)
(71%)
CF3
Cl
Me
CF3
CF3
(66%)
Cl
CF3
Cl
(72%)
Br
CF3
CF3
CF3
Cl
Cl
F
N
N
N
F
N
H
O
N
Me
N
51a
53a
54a
55a
56a
(87%)
(56%)
(77%)
(63%)
CF3
CF3
CF3
CF3
F
N
N
O
N
F
N
Cl
Me
N
Cl
H
57a
58a
59a
60a
(79%)
(73%)
(68%)
(75%)
Quinolines, Isoquinolines
CF3
CF3
CF3
CF3
CF3
N
N
(77%)
N
CF3
N
N
N
63a
64a
65a
66a
(79%)
(84%)
(81%)
61a
62a
(86%)
(89%)
Scheme 4. Scope of fluorination of heterocyclic acids with sulfur tetrafluoride. Reaction conditions: (i) heterocyclic acid (1.0 equiv), sulfur tetrafluoride
(3.0 equiv), hydrogen fluoride, 85 °C, 24 h; (ii) work up; (iii) distillation. aThe reaction was performed at 115 °C for three days. bThe reaction was
performed at 45 °C for two days. cThe reaction was performed at 75 °C for four days.
popular these days in medicinal chemistry.22 Second,
deoxofluorination of nitro cinnamic acids 24-26 was also
accomplished to obtain the trifluoromethylated styrenes 24a-26a
in 52-63% yield. Previously this transformation was reported via
radical processes only.23 Third, the method was efficient for
converting the hindered 1,1'-disubstituted benzoic acids 4, 7 into
the corresponding trifluoromethyl-substituted derivatives 4a, 7a.
Next, we studied a scope of heterocyclic acids (Scheme 4).
(38), - gave the needed trifluoromethylated products 27a-38a in
45-88% yield after a distillation. Notably, deoxofluorination of
thiophenes 27-30 under the standard conditions (85 °C, 24 h)
afforded products 27a-30a in only 5-10% yield. However,
performing the reaction at higher temperature (115 °C) without
hydrogen fluoride gave the needed products in 48-63% yield.
Reaction of thiazole 33 with hydrogen fluoride at high
temperature led to partial decarboxylation. Therefore, we
Various five-membered heterocycles
-
thiophenes (27-30),
thiazoles (31-34), pyrazoles (35, 36), imidazoles (37) and triazoles
performed
a two-step sequence: first, we added sulfur
tetrafluoride to thiazole 33 at room temperature, to generate the
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SF4, HF
t
corresponding acyl fluoride, and then performed the
(Het)
(Het)
CF3
CO2H
Ar
Ar
1
2
3
4
5
6
7
8
deoxofluorination at lower temperature (75 °C) to obtain the
needed product 33a in 50% yield. Pyridines and pyridones 39-59
as well as diazinone 60 were also transformed into the
trifluoromethyl-substituted compounds 39a-60a in 54-89% yield.
Finally, quinolines and isoquinolines 61-66 also provided the
needed CF3-substituted derivatives 61a-66a in 77-89% yield.
It is important to mention that in spite of previous literature
precedents on deoxofluorination of (hetero)aromatic acids,5-12
none of products 2a-65a synthesized here, was ever obtained by
this method before. It seems that even today, after almost sixty
years since the discovery, this powerful synthetic strategy has not
realized its full potential yet.
Practical aspects. From the practical standpoint, the reaction
was performed in a Hastelloy autoclave using hydrogen fluoride
as a solvent. After heating the reaction mixture at 85 °C for one
day, the reaction was cooled to a room temperature, and the
gaseous products were vented off into an aqueous solution of
sodium hydroxide. The reaction mixture was then poured into an
ice followed by a standard work up. We purified all crude
products by simple distillation. The reaction also produced ca.
10% of the dimeric side product RCF2OCF2R that remained in the
residue after distillation, and we did not isolate it in the pure
state.24 Most of syntheses were performed on a gram scale, but
also can be realized on a milligram amount. For example, the
synthesis of compound 35a was performed on 600 mg (81%
yield) and 30 g scale (87% yield). On a large scale the yields were
higher, because the distillation procedure was technically easier to
do (Scheme 5).
Mechanism
SF4 + HF
+
-
SF3 + HF2
F
F
+
F
F
SF4
rt
SF3
O S
F
F
t
R-CO2H
R
R-COF
R
-SOF2
A
B
9
A
F-
10
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13
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16
17
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20
21
22
23
24
25
26
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35
36
37
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53
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57
58
59
60
F
R-CF2-O-CF2-R
F-
(Het)
R-CF2-O
CF3
side product
(ca. 10%)
Ar
R
C
Scheme 6. Mechanism of fluorination of (hetero)aromatic acids with
sulfur tetrafluoride in hydrogen fluoride.
additionally wanted to demonstrate their high utility as starting
materials for further synthesis of trifluoromethyl-substituted
aliphatic and aromatic derivatives.
NO2
CF3
NH2
CF3
Fe/NH4Cl
Ar
Ar
iPrOH/H2O
55-84%
13a 17a
13b 17b
- ,
-
,
,
20a 22a 24a-26a
20b 22b 24b-26b
,
, ,
Anilines
NH2
NH2
CF3
NH2
NH2
CF3
Caution! Sulfur tetrafluoride (SF4) and hydrogen fluoride
(HF) are toxic. Special care and an additional technical training
must be taken before working with them.
Br
F
OMe
Cl
CF3
14b
CF3
16b
13b
15b
(73%)
NH2
(77%)
NH2
(84%)
(78%)
NH2
CO2H
CF3
1) SF4, HF
F
Me
CF3
N
N
85 oC, 24 h
2) distillation
N
N
CF3
CF3
Me
Me
Me
Cl
20b
F
600 mg scale: 81%
30 g scale: 87%
17b
22b
(69%)
(65%)
(76%)
35
35a
NH2
NH2
NH2
Scheme 5. Synthesis of pyrazole 35a on different scale.
CF3
Mechanism. Mechanistically, hydrogen fluoride plays two
roles in the reaction: as a solvent and as an “activator” for sulfur
tetrafluoride.25 First, sulfur tetrafluoride reacts with a carboxylic
acid to rapidly give acyl fluoride A (Scheme 6). This step is fast
and already proceeds at 0 °C or below. The next step is rate-
limiting and requires a heating. Sulfur tetrafluoride reversibly
reacts with hydrogen fluoride to give an active SF3+ intermediate.
CF3
(58%)
CF3
24b
25b
26b
(61%)
(55%)
F
Me
H
H
H
N
N
CF3
CF3
N
NMe2
O
O
F
+
O
Next, SF3 cation reacts with acyl fluoride (A) to form the
CF3
difluoromethyl cation (B). The latter either reacts with
hydrodifluoride anion to give the target CF3-substituted product;
or with another molecule of acyl fluoride to form the side dimeric
product (RCF2)2O via intermediate C (Scheme 6).
Practical application. Many trifluoromethyl-substituted
products highlighted at Schemes 3 and 4 contain bromine/iodine
or activated chlorine/fluorine atoms, and therefore are of practical
interest for both metal-mediated cross-coupling reactions (Br, I)
and SNAr2 nucleophilic substitutions (Cl, F). But we also
Bistrifluron
insecticide
Fluometuron
herbicide
Scheme 7. Synthesis of trifluoromethyl-substituted anilines 13b-17b, 20b,
22b and 24b-26b. Bistrifluron, Fluometuron: derivatives of
trifluoromethyl-substituted anilines in argochemistry.
In particular, reduction of the nitro group in aromatic
compounds 13a-17a, 20a, 22a and 24a-26a with iron dust,
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ammonium chloride in isopropanol/water mixture gave unique
We studied also an influence of the trifluoromethyl moiety on
1
2
3
4
5
6
7
8
trifluoromethyl-substituted anilines 13b-17b, 20b, 22b and 24b-
26b in 55-84% yield – molecules with high potential for
agrochemistry (Figure 1, Scheme 7).
Selective hydrogenation of pyridine ring in quinolines and
isoquinolines 61a-66a at 150 bar using 10% Pd/C as a catalyst in
methanol gave the benzo-annulated trifluoromethyl-substituted
pyperidines 61b-66b in 66-82% yield – interesting building
blocks for medicinal chemistry (Scheme 8).26
the acidity/basicity of functional groups, and the conformation of
homo-GABA.27 pKa values of the functional groups in compounds
68-72 were determined by potentiometric titration (please, see SI
for details). Indeed, placing the trifluoromethyl substituent at the
α-position to the carboxylic group in 68 - compound 69, -
increased its acidity by almost two orders of magnitude: pKa
(CO2H) = 2.5 (69) vs 4.2 (68). As expected the trifluoromethyl
substituents at β-position of homo-GABA - amino acid 70, - had
much lower effect on the acidity of the carboxylic group: pKa
(CO2H) = 3.6 (70) vs 4.2 (68). The trifluoromethyl group at the
γ-(71) and δ-(72) positions of homo-GABA had a minor effect on
the acidity of the carboxyl group: pKa (CO2H) = 4.0 (71) vs 4.1
(72) vs 4.2 (68) (Table 1).
9
10
11
12
13
14
15
16
17
18
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23
24
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54
55
56
57
58
59
60
R
R
CF3
CF3
H2/Pd/C
N
N
MeOH, rt
66-82%
H
61a 66a
61b 66b
-
-
The trifluoromethyl substituent had also a dramatic effect on
the basicity of the amino function in compound 68. Amino acid
72 was almost four magnitudes of order less basic than homo-
Piperidines
CF3
CF3
+
GABA: pKa (NH3 ): = 6.7 (72) vs 10.8 (68).28Amino group in 71
CF3
was ca. one magnitude of order less basic than that in homo-
N
H
N
+
N
GABA: pKa (NH3 ): = 9.5 (71) vs 10.8 (68). The trifluoromethyl
H
H
substituent in amino acids 69 and 70 only slightly decreased the
61b
(68%)
62b
63b
(72%)
(82%)
CF3
+
basicity of the amino group: pKa (NH3 ): = 10.4 (70) vs 10.5 (69)
CF3
CF3
vs 10.8 (68) (Table 1).
Table 1. Experimental pKa values for amino acids 68-72.
+
Amino acid
pKa(CO2H) pKa(NH3 )
N
H
N
H
N
H
68
CO2H
CO2H
4.2
2.5
3.6
4.0
4.1
10.8
10.5
10.4
9.5
64b
(66%)
65b
66b
(74%)
(78%)
H2N
(homo-GABA)
Scheme 8. Synthesis of trifluoromethyl-substituted benzo-annulated
piperidines 61b-66b.
H2N
69*HCl
70*HCl
71*HCl
72*HCl
CF3
CF3
Finally, we synthesized and characterized all four
regioisomers of trifluoromethyl-substituted 5-aminovaleric acid
(homo-GABA, 68) analogues 69-72 (Scheme 9). Hydrogenation
of pyridones 45a, 48a, 56a and 67a in trifluoroacetic acid at room
temperature using PtO2 as a catalyst gave piperidones 45b, 48b,
56b, 67b. Hydrolysis of latters in aqueous hydrochloric acid under
a prolonged heating provided four fluorinated acids 69*HCl-
72*HCl.
CO2H
H2N
H2N
CO2H
CF3
CF3
6.7
CO2H
H2N
To study an effect of the trifluoromethyl group on the
conformation of homo-GABA, we obtained single crystals of
amino acids 69*HCl-72*HCl suitable for X-Ray analysis.29
X-Ray structure of homo-GABA (68) was already reported in the
literature so that we could use this data.30 In the crystal state,
compound 68 adopted an extended linear conformation, with the
distance, d = 6.23 Å between amino and carboxyl groups (Table
2). Intriguingly, all four amino acids 69*HCl-72*HCl possessed
different conformations (Table 2). In molecules 69 and 72, for
CF3
CF3
H2/PtO2
HCl aq.
CF3
CO2H
TFA, rt
73-91%
reflux
79-92%
H2N
N
O
N
O
*HCl
H
H
45b 48b
,
,
45a 48a
,
,
69-72
56b 67b
,
56a 67a
,
homo-GABAs
CF3
CO2H
*HCl
H2N
*HCl
CO2H
H2N
CF3
X-Ray
69
(92%)
X-Ray
example, the bulky trifluoromethyl group acted as
a
70
(91%)
conformational “anchor” – it occupied the terminus of the
extended conformation, pushing the carboxyl (69) or the amino
group (72) away from the zig-zag chain. Similar effect was
observed in molecules 70 and 71, where the trifluoromethyl
substituent also occupied the terminus of the zig-zag
conformation. Not surprisingly, that in all four molecules
69*HCl-72*HCl the distance (d) was different: 5.25 Å (69); 4.23
Å (70); 5.12 Å (71) and 5.38 Å (72). Moreover, it significantly
CF3
CO2H
*HCl
H2N
*HCl
CO2H
H2N
CF3
X-Ray
71
X-Ray
72
(81%)
(79%)
Scheme 9. Synthesis of trifluoromethyl-substituted amino acids 69-72
(substituted analogues of homo-GABA).
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deviated from d = 6.23 Å in the parent amino acid homo-GABA
(68).
As a brief summary, in isomeric amino acids 69*HCl-
CONCLUSIONS
1
2
3
4
5
6
7
8
In 1960, Engelhardt developed deoxofluorination of aromatic
acids with sulfur tetrafluoride.5 Even though many research
groups subsequently extended this approach onto heterocyclic
acids,6-12 these days it remains mostly in the shadow. In this work,
therefore, we disclosed our results over the past ten years on the
deoxofluorination of cinnamic and (hetero)aromatic carboxylic
acids with sulfur tetrafluoride. In particular, the synthesis of sixty
five trifluoromethyl-substituted products is described here on a
gram scale. These compounds were further used as starting
materials to obtain unique building blocks for medicinal
72*HCl, the trifluoromethyl group tuned both the electronic
properties and the molecular conformation of compounds. First,
due to (–I)-inductive effect, it altered the acidity/basicity of amino
and carboxyl groups. Second, as a bulky substituent - “anchor,” -
it defined the conformation of all four molecules, occurring at the
terminus of the zig-zag chain. As a result all five compounds, -
homo-GABA (68) and its isomeric trifluoromethyl-substituted
analogues 69-72, - have completely different acidity/basicity of
functional groups and the conformation in the crystal phase. It is
beyond the scope of this work, but we expect that five amino
acids 69-72 will have different affinity to GABA receptors.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
chemistry and agrochemistry
- trifluoromethylated anilines,
piperidines and amino acids.31,32 We hope that after the current
study, chemists will keep in mind this approach when planning
the synthesis of trifluoromethyl-substituted molecules.
Table 2. X-Ray crystal structure, and the representative conformation of
amino acids 68-72. Distance, d (Å) between amino and carboxyl groups in
the crystal state is shown. The N, C, F, O-atoms are shown at 30% thermal
ellipsoid % probability. Distance (d) between carboxyl and amino groups
is shown.
EXPERIMENTAL SECTION
General. All chemicals were provided by Enamine Ltd.
(www.enamine.net). Autoclaves were provided by UOSLab
(en.uoslab.com). All solvents were treated according standard
methods. Product purification was performed using distillation.
TLC-characterization was performed with pre-coated silica gel
GF254 (0.2 mm), while column chromatography characterization
was performed with silica gel (100-200 mesh).1H-NMR, 19F-
NMR, 13C-NMR spectra were recorded with tetramethylsilane
-
CO2
H3N
d = 6.23 A
68
1
(homo-GABA)
(TMS, δ = 0.00 ppm) as the internal standard. H-NMR spectra
were recorded at 400 or 500 MHz (Varian); 19F-NMR spectra
were recorded at 376 MHz (Varian) and 13C NMR spectra were
Conformation,
distance (d, Å)
X-Ray
1
recorded at 100, 126 or 151 MHz (Varian). H-NMR chemical
shifts are reported downfield from CDCl3 (δ = 7.26 ppm), D2O (δ
= 4.79 ppm) or DMSO-d6 (δ = 2.50 ppm). 13C-NMR chemical
shifts for 13C-NMR are reported relative to the central CDCl3 (δ =
77.16 ppm) or DMSO-d6 (δ = 39.52 ppm). Coupling constants are
given in Hz. MS analysis was performed on an LCMS instrument
with chemical ionization or GCMS with electrospray ionization.
High-resolution mass spectra (HRMS) were recorded on an
Agilent LC/MSD TOF mass spectrometer by electrospray
ionization time of flight reflectron experiments.
CF3
H3N
CO2H
d = 5.25 A
69
NH3
CO2H
CF3
Caution! Sulfur tetrafluoride (SF4) and hydrogen fluoride (HF)
are highly toxic. Special care and an additional technical training
must be taken before working with them.33,34
d = 4.23 A
70
General procedure A (2a as an example)
1-Bromo-3-methyl-5-(trifluoromethyl)benzene (2a). Compound
2 (21.5 g, 0.1 mol, 1 equiv) was placed in 500 mL autoclave made
of Hastelloy nickel alloy. The reaction vessel was cooled down by
liquid nitrogen and anhydrous HF (17.2 mL, 0.8 mL for 1 g of
acid) was added. Then SF4 (32.4 g, 0.3 mol, 3 equiv) was
condensed into a reaction vessel. Cooling bath was removed, and
the mixture was allowed to warm up to a room temperature. It was
then heated at 85 °C in oil bath for 24 h. The autoclave was
allowed to cool down to a room temperature, and the gaseous
products were vented off into a trap with aqueous solution of
NaOH (1M). The residue was poured onto a suspension of
NaHCO3 and ice (500 g) (for products with no basic centers, just
ice can be used) extracted with MTBE, and an organic extract was
washed with saturated aq. NaHCO3 (500 mL). The organic layer
was separated, dried over Na2SO4, filtered and concentrated under
NH3
CO2H
CF3
H
d = 5.12 A
71
NH3
CO2H
CF3
d = 5.38 A
72
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The Journal of Organic Chemistry
reduced pressure to afford the desired product. The final product
(t, J = 20.7 Hz, 1F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
2
3
4
5
6
7
8
was purified by distillation. Yield: 22.2 g, 93%, yellow oil, b.p. 85
°C, 15 mmHg. H NMR (400 MHz, СDCl3) δ 7.57 (s, 1H), 7.51
C7H3F6, 201.0139; found 201.0139.
2,4-Difluoro-1-(trifluoromethyl)benzene (9a): yield: 13.1 g,
72%, colorless oil, b.p. 85 °C, 760 mmHg. H NMR (400 MHz,
CDCl3) δ 7.62 (dd, J = 14.7, 8.1 Hz, 1H), 7.03 – 6.89 (m, 2H). 13
{1H} NMR (126 MHz, CDCl3) δ 165.4 (dd, J = 254.8, 11.4 Hz),
160.7 (ddd, J = 259.2, 12.7, 1.8 Hz), 129.2 – 128.5 (m), 122.5 (q,
J = 271.5 Hz), 115.8 – 114.3 (m), 111.7 (dd, J = 22.0, 3.8 Hz),
105.7 (dd, J = 25.6, 24.4 Hz). 19F NMR (376 MHz, CDCl3) δ -
61.5 (d, J = 13.2 Hz, 3F), -103.4 (d, J = 11.7 Hz, 1F), -110.0 (dt, J
= 25.8, 12.8 Hz, 1F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H4F5, 183.0233; found 183.0235.
1
(s, 1H), 7.36 (s, 1H), 2.40 (s, 3H). 13C {1H} NMR (126 MHz,
CDCl3) δ 141.1, 135.6, 132.3 (q, J = 32.6 Hz), 125.7 (q, J = 3.8
Hz), 124.8 (q, J = 3.6 Hz), 123.4 (q, J = 272.9 Hz), 122.6, 21.2.
19F NMR (376 MHz, CDCl3) δ -63.3 (s). GCMS (m/z): 239 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H7BrF3, 238.9683;
found 238.9680.
1
C
9
1,3-Difluoro-5-(trifluoromethyl)benzene (3a): yield: 16 g, 88%,
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
colorless oil, b.p. 75 °C, 15 mmHg. H NMR (400 MHz, CDCl3)
δ 7.17 (d, J = 5.2 Hz, 2H), 7.01 (t, J = 8.6 Hz, 1H). 13C {1H}
NMR (126 MHz, CDCl3) δ 163.1 (dd, J = 251.7, 12.2 Hz), 134.2
– 133.3 (m), 126.2 – 119.4, 109.6 – 109.2 (m), 109.2 – 108.9 (m),
107.7 (t, J = 24.9 Hz). 19F NMR (376 MHz, CDCl3) δ -63.6 (s,
3F), -107.7 (s, 2F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H4F5, 183.0233; found 183.0230.
4-Bromo-2-methyl-1-(trifluoromethyl)benzene (10a): yield
17.85 g, 75%, colorless oil, b.p. 95 °C, 15 mmHg. H NMR (400
1
MHz, CDCl3) δ 7.52 – 7.36 (m, 3H), 2.46 (s, 3H). 13C {1H} NMR
(126 MHz, CDCl3) δ 139.0 (d, J = 1.6 Hz), 134.9, 129.1, 128.1 (q,
J = 30.5 Hz), 127.5 (q, J = 5.6 Hz), 126.2, 124.4 (q, J = 273.5
Hz), 19.3 (d, J = 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ -62.2 (s).
GCMS (m/z): 239 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H7BrF3, 238.9683; found 238.9688.
1-Bromo-3-chloro-2-(trifluoromethyl)benzene (4a): yield:
1
16.45 g, 64%, yellow oil, b.p. 82 °C, 15 mmHg. H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H),
7.24 (t, J = 8.1 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ
134.8, 134.5, 132.7, 131.5, 127.8 (q, J = 30.6 Hz), 122.5 (q, J =
276.5 Hz), 121.8 (d, J = 1.5 Hz). 19F NMR (376 MHz, CDCl3) δ -
56.4 (s). GCMS (m/z): 259 (M). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C7H4BrClF3, 258.9137; found 258.9139.
2-Bromo-4-iodo-1-(trifluoromethyl)benzene (11a): yield: 18.25
g, 73%, olive oil, b.p. 36 °C, 0.1 mmHg. H NMR (400 MHz,
1
CDCl3) δ 8.04-8.14 (m, 1H), 7.69-7.82 (m, 1H), 7.31-7.45 (m,
1H). 13C {1H} NMR (126 MHz, CDCl3) δ 143.2, 136.7, 130.1 (q,
J = 31.8 Hz), 129.0 (q, J = 5.2 Hz), 123.0 (q, J = 273.3 Hz),
121.0, 98.9. 19F NMR (376 MHz, CDCl3) δ -63.4 (s). GCMS
(m/z): 250 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H4BrF3I, 350.8493; found 350.8495.
1-Bromo-2-methyl-4-(trifluoromethyl)benzene (5a): yield: 20.8
1
g, 87%, colorless oil, b.p. 67 °C, 15 mmHg. H NMR (400 MHz,
CDCl3) δ 7.65 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.30 (d, J = 8.2
Hz, 1H), 2.46 (s, 3H). 13C {1H} NMR (126 MHz, CDCl3) δ 139.1,
133.0, 129.9 (q, J = 32.6 Hz), 128.9, 127.6 (q, J = 3.5 Hz), 124.2
(q, J = 3.6 Hz), 124.0 (q, J = 272.3 Hz), 23.1. GCMS (m/z): 239
(M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H7BrF3,
238.9683; found 238.9681.
2-Chloro-4-iodo-1-(trifluoromethyl)benzene (12a): yield: 21.7
g, 71%, yellow oil, b.p. 56 °C, 1 mmHg. H NMR (400 MHz,
1
CDCl3) δ 7.89 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.2
Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 140.0, 136.2,
133.3, 128.7 (q, J = 5.3 Hz), 128.3 (q, J = 31.8 Hz), 122.9 (q, J =
273.2 Hz), 98.6. 19F NMR (376 MHz, CDCl3) δ -63.4 (s). GCMS
(m/z): 306 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H4ClF3I, 306.8998; found 306.8994.
1-Iodo-2-methyl-4-(trifluoromethyl)benzene (6a): yield: 17.4 g,
61%, pink oil, b.p. 90 °C, 15 mmHg. 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H),
2.49 (s, 3H). 13C {1H} NMR (126 MHz, CDCl3) δ 142.6, 139.6,
130.8 (q, J = 32.6 Hz), 126.2 (q, J = 3.7 Hz), 124.1 (q, J = 272.2
Hz), 124.1 (q, J = 3.7 Hz), 105.4, 28.33 (s). 19F NMR (376 MHz,
CDCl3) δ -63.4 (s). GCMS (m/z): 286 (M). HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C8H7F3I, 286.9545; found 286.9541.
5-Bromo-1,3-difluoro-2-(trifluoromethyl)benzene (7a): yield:
4-Chloro-2-nitro-1-(trifluoromethyl)benzene (13a): yield: 15.1
g, 67%, yellow oil, b.p. 72 °C, 1 mmHg. H NMR (400 MHz,
1
CDCl3) δ 7.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4
Hz, 1H). 13C {1H} NMR (101 MHz, DMSO-d6) δ 148.0, 138.8,
133.4, 130.3 – 129.4 (m), 125.4, 120.9 – 119.3 (m). 19F NMR
(376 MHz, DMSO-d6) δ -59.5 (s). GCMS (m/z): 225 (M). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C7H4ClF3NO2, 225.9883;
found 225.9888.
2-Bromo-4-nitro-1-(trifluoromethyl)benzene (14a): yield: 20 g,
74%, orange oil, b.p. 91 °C, 1 mmHg. 1H NMR (400 MHz,
CDCl3) δ 8.6 (s, 1H), 8.3 (d, J = 8.4 Hz, 1H), 7.9 (d, J = 8.6 Hz,
1H). 13C {1H} NMR (126 MHz, CDCl3) δ 150.0, 135.8 (q, J =
32.2 Hz), 130.1, 129.1 (q, J = 5.4 Hz), 122.3, 122.1 (q, J = 274.5
Hz), 121.4. 19F NMR (376 MHz, CDCl3) δ -63.7 (s). GCMS
(m/z): 270 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H4BrF3NO2, 269.9378; found 269.9378.
2-Fluoro-4-nitro-1-(trifluoromethyl)benzene (15a): yield: 16.3
g, 78%, yellow oil, b.p. 64 °C, 1 mmHg. H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 9.7 Hz, 1H), 7.86
(t, J = 7.7 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 159.8 (d,
J = 262.2 Hz), 151.3, 128.7 (d, J = 4.5 Hz), 124.7 – 124.1 (m),
121.6 (q, J = 273.6 Hz), 119.4 (d, J = 4.2 Hz), 113.1 (d, J = 25.7
1
15.9 g, 61%, colorless oil, , b.p. 60 °C, 15 mmHg. H NMR (400
MHz, CDCl3) δ 7.21 (s, 1H), 7.19 (s, 1H). 13C {1H} NMR (126
MHz, CDCl3) δ 160.0 (d, J = 263.5 Hz), 160.0 (d, J = 263.9 Hz),
127.1 (t, J = 12.2 Hz), 121.5 (q, J = 273.4 Hz), 117.0 (d, J = 3.7
Hz), 116.8 (d, J = 3.7 Hz), 107.7 – 107.3 (m). 19F NMR (376
MHz, CDCl3) δ -57.0 (t, J = 22.6 Hz, 3F), -109.5 (dd, J = 45.6,
23.0 Hz, 2F). GCMS (m/z): 261 (M). HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C7H3BrF5, 260.9338; found 260.9342.
1,2,3-Trifluoro-4-(trifluoromethyl)benzene (8a): yield: 16.4 g,
1
82%, colorless oil, b.p. 77 °C, 760 mmHg. H NMR (400 MHz,
CDCl3) δ 7.43 – 7.34 (m, 1H), 7.14 – 7.05 (m, 1H). 13C {1H}
NMR (151 MHz, CDCl3) δ 153.8 (dd, J = 257.2, 13.7 Hz), 149.7
(dd, J = 262.0, 17.0 Hz), 140.6 (dt, J = 254.6, 14.9 Hz), 121.9 (q,
J = 272.5 Hz), 121.7 – 121.1 (m), 117.1 – 115.8 (m), 112.5 (dd, J
= 18.4, 4.4 Hz). 19F NMR (376 MHz, CDCl3) δ -61.4 (d, J = 13.2
Hz, 3F), -127.2 – -127.4 (m, 1F), -134.5 – -135.0 (m, 1F), -157.9
1
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Hz). 19F NMR (376 MHz, CDCl3) δ -62.5 (d, J = 13.2 Hz, 3F), -
(400 MHz, CDCl3) δ 8.34 (d, J = 6.5 Hz, 1H), 7.22 (d, J = 10.2
Hz, 1H), 2.70 (s, 3H). 13C {1H} NMR (126 MHz, CDCl3) δ 161.3
(d, J = 265.6 Hz), 141.8 (d, J = 9.8 Hz), 125.3 – 125.0 (m), 121.5
(q, J = 272.4 Hz), 121.4, 121.3, 117.9 – 117.2 (m), 21.2. 19F NMR
(376 MHz, CDCl3) δ -62.2 (d, J = 11.7 Hz, 3F), -106.7 (q, J =
14.4 Hz, 1F). GCMS (m/z): 223 (M). HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C8H6F4NO2, 224.0335; found 224.0337.
1
2
3
4
5
6
7
8
109.2 (dd, J = 26.9, 13.7 Hz, 1F). GCMS (m/z): 209 (M). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C7H4F4NO2, 210.0178; found
210.0174.
2-Methoxy-4-nitro-1-(trifluoromethyl)benzene (16a): yield:
14.35 g, 65%, yellow solid, m.p. 35 °C, b.p. 68 °C, 0.1 mmHg. 1H
NMR (400 MHz, СDCl3) δ 7.88 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H),
7.76 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H). 13C {1H} NMR (126 MHz,
CDCl3) δ 158.4, 151.4, 128.3 (q, J = 5.2 Hz), 124.5 (q, J = 31.8
Hz), 122.6 (q, J = 273.3 Hz), 115.1, 107.2, 56.8. 19F NMR (376
MHz, CDCl3) δ -63.8 (s). GCMS (m/z): 221 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C8H7F3NO3, 222.0378; found
222.0382.
1,4-Difluoro-2-methyl-5-(trifluoromethyl)benzene (23a): yield:
1
12.7 g, 65%, colorless oil, b.p. 71 °C, 15 mmHg. H NMR (400
9
MHz, CDCl3) δ 7.23 (dd, J = 8.5, 6.1 Hz, 1H), 7.03 (dd, J = 9.9,
6.0 Hz, 1H), 2.32 (s, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ
156.6 (d, J = 240.3 Hz), 156.4 – 154.4 (m), 131.7 (dd, J = 20.1,
9.1 Hz), 122.1 (q, J = 271.9 Hz), 119.6 (d, J = 5.5 Hz), 119.5 (d, J
= 5.5 Hz), 114.1 – 113.1 (m), 14.9 (d, J = 3.4 Hz). 19F NMR (376
MHz, CDCl3) δ -61.9 (d, J = 14.8 Hz, 3F), -121.5 – -121.9 (m,
2F). GCMS (m/z): 196 (M). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C8H6F5, 197.0390; found 197.0398.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methyl-2-nitro-1-(trifluoromethyl)benzene (17a): yield: 15.8
1
g, 77%, yellow oil, b.p. 58 °C, 0.1 mmHg. H NMR (400 MHz,
CDCl3) δ 7.75 – 7.65 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 2.51 (s,
3H). 13C {1H} NMR (126 MHz, CDCl3) δ 148.2, 144.6, 133.1,
127.9 (q, J = 5.1 Hz), 125.5, 122.3 (q, J = 272.6 Hz), 120.8 (q, J =
34.2 Hz), 21.3. 19F NMR (376 MHz, CDCl3) δ -60.3 (s). GCMS
(m/z): 205 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H7F3NO2, 206.0429; found 206.0425.
1-Nitro-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (24a): yield:
1
11.3 g, 52%, yellow solid, b.p. 98 °C, 0.1 mmHg. H NMR (400
MHz, CDCl3) δ 8.10 (d, J = 7.9 Hz, 1H), 7.76 – 7.65 (m, 2H),
7.63 – 7.53 (m, 2H), 6.23 – 6.08 (m, 1H). 13C {1H} NMR (101
MHz, CDCl3) δ 148.1, 134.4 (q, J = 7.0 Hz), 134.0, 130.5, 129.9,
129.4, 125.2, 122.8 (q, J = 269.6 Hz), 120.7 (q, J = 34.5 Hz). 19F
NMR (376 MHz, CDCl3) δ -65.1 (s). GCMS (m/z): 217 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C9H7F3NO2, 218.0429;
found 218.0430.
5-Nitro-2-(trifluoromethyl)benzenesulfonyl fluoride (18a):
yield: 14.74 g, 54%, grey solid, m.p. 56-58 °C, b.p. 91 °C, 0.1
1
mmHg. H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.74 (d, J =
8.4 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H). 13C {1H} NMR (126 MHz,
CDCl3) δ 149.8, 134.6 (q, J = 35.5 Hz), 134.0 (d, J = 30.8 Hz),
131.1 (q, J = 5.8 Hz), 130.1, 127.8, 121.1 (q, J = 275.4 Hz). 19F
NMR (376 MHz, CDCl3) δ 65.71 (q, J = 13.4 Hz, 1F), -59.45 (d,
J = 13.4 Hz, 3F). GCMS (m/z): 273 (M). HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C7H4F4NO4S, 273.9797; found 273.9791.
1-Bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (19a):
yield: 21.2 g, 74%, yellow solid, 82-84 °C, b.p. 82 °C, 1 mmHg.
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.1 Hz, 1H), 7.74 (d, J
= 9.4 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 156.5 (d, J =
275.4 Hz), 136.0 – 135.8 (m), 128.0 – 127.5 (m), 126.3 – 126.0
(m), 125.9, 125.7, 121.6 (q, J = 273.9 Hz). 19F NMR (376 MHz,
CDCl3) δ -63.2 (s, 3F), -110.0 (s, 1F). GCMS (m/z): 287 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H3BrF4NO2,
287.9283; found 287.9289.
1-Nitro-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (25a): yield:
1
12.4 g, 57%, brown solid, m.p. 40 °C, b.p. 65 °C, 0.1 mmHg. H
NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H),
7.78 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.23 (dd, J =
16.2, 1.8 Hz, 1H), 6.37 (dq, J = 16.1, 6.3 Hz, 1H). 13C {1H} (126
MHz, CDCl3) δ 148.9, 135.6 (q, J = 6.7 Hz), 135.3, 133.4, 130.2,
124.6, 123.1 (q, J = 269.4 Hz), 122.3, 119.2 (q, J = 34.4 Hz). 19F
NMR (376 MHz, CDCl3) δ -64.35 (s), -64.36 (s). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C9H7F3NO2, 218.0429; found
218.0437.
1-Nitro-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (26a): yield:
13.7 g, 63%, yellow solid, m.p. 98 °C, b.p. 50 °C, 0.1 mmHg. 1H
NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.6 Hz, 2H), 7.63 (d, J =
8.5 Hz, 2H), 7.23 (d, J = 16.3 Hz, 1H), 6.42 – 6.30 (m, 1H). 13C
{1H} NMR (126 MHz, CDCl3) δ 148.7, 139.6, 135.6 (q, J = 6.7
Hz), 128.5, 124.4, 123.0 (q, J = 269.5 Hz), 120.2 (q, J = 34.4 Hz).
19F NMR (376 MHz, CDCl3) δ -64.5 (s). HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C9H7F3NO2, 218.0429; found 218.0432.
General procedure B for the synthesis of 27a-30a (27a as an
1-Chloro-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (20a):
yield: 21.9 g, 90%, yellow solid, m.p. 46 °C, b.p. 93 °C, 1 mmHg.
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 7.4 Hz, 1H), 7.54 (d, J
= 9.8 Hz, 1H). 13C {1H} NMR (151 MHz, CDCl3) δ 158.5 – 155.3
(m), 140.1 (d, J = 10.5 Hz), 135.5, 126.2 – 126.1 (m), 122.4,
122.3, 121.4 (q, J = 273.8 Hz). 19F NMR (376 MHz, CDCl3) δ -
63.1 (s, 3F), -109.4 (s, 1F). GCMS (m/z): 243 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C7H3ClF4NO2, 243.9788; found
243.9788.
example)
2-Chloro-5-(trifluoromethyl)thiophene (27a). Compound 27
(16.25 g, 0.1 mol, 1 equiv) was placed in 280 mL autoclave made
of Hastelloy nickel alloy. The reaction vessel was cooled down by
liquid nitrogen, and then SF4 (32.4 g, 0.3 mol, 3 equiv) was
condensed into a reaction vessel. Cooling bath was removed, and
the mixture was allowed to warm up to a room temperature. It was
then heated at 115 °C in oil bath for 3 d. The autoclave was
allowed to cool down to a room temperature, and the gaseous
products were vented off into a trap with aqueous solution of
NaOH (1M). The residue was poured onto aq NH4OH (25%) and
extracted with CH2Cl2, dried over Na2SO4, filtered and
concentrated under a reduced pressure to afford the desired
product. The final product was purified by distillation. Yield: 10.4
1-Chloro-5-methyl-2-nitro-4-(trifluoromethyl)benzene (21a):
1
yield: 15 g, 63%, yellow oil, b.p. 69 °C, 0.1 mmHg. H NMR
(500 MHz, CDCl3) δ 8.20 (s, 1H), 7.52 (s, 1H), 2.56 (s, 3H). 13C
{1H} NMR (151 MHz, CDCl3) δ 145.3, 143.5, 135.5, 130.9,
128.8 (q, J = 32.6 Hz), 124.0 (q, J = 6.2 Hz), 122.9 (q, J = 273.7
Hz), 19.4. 19F NMR (376 MHz, CDCl3) δ -62.8 (s). GCMS (m/z):
239 (M). HRMS (ESI-TOF) m/z: [M
+
H]+ calcd for
C8H6ClF3NO2, 240.0039; found 240.0043.
1-Fluoro-5-methyl-4-nitro-2-(trifluoromethyl)benzene (22a):
1
g, 56%, colorless oil, b.p. 52 °C, 15 mmHg. H NMR (400 MHz,
1
yield: 20.7 g, 93%, yellow oil, b.p. 58 °C, 1 mmHg. H NMR
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The Journal of Organic Chemistry
CDCl3) δ 7.23 (d, J = 2.9 Hz, 1H), 6.91 (d, J = 3.6 Hz, 1H). 13C
TOF) m/z: [M + H]+ calcd for C4H2BrF3NS, 231.9043; found
{1H} NMR (126 MHz, CDCl3) δ 137.5 – 131.2 (m), 129.7 (q, J =
39.3 Hz), 128.3 (dd, J = 8.1, 4.0 Hz), 126.2, 121.8 (q, J = 269.0
Hz). 19F NMR (376 MHz, CDCl3) δ -56.4 (s). GCMS (m/z): 186
(M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C5H3ClF3S,
186.9596; found 186.9599.
231.9045.
1
2
3
4
2-(Trifluoromethyl)thiazole (33a). Compound 33 (12.9 g, 0.1
mol, 1 equiv) was placed in 280 mL autoclave made of Hastelloy
nickel alloy. The reaction vessel was cooled down by liquid
nitrogen and SF4 (16.2 g, 0.15 mol, 1.5 equiv) was condensed into
a reaction vessel. Cooling bath was removed, and the mixture was
allowed to warm up to a room temperature. The gaseous products
were vented off into a trap with aqueous solution of NaOH (1M)
and anhydrous HF (2.1 mL, 0.1 mol, 1 equiv) was added. Then
SF4 (21.6 g, 0.2 mol, 2 equiv) was condensed into a reaction
vessel. It was then heated at 75 °C in oil bath for 4 d. The
autoclave was allowed to cool down to a room temperature, and
the gaseous products were vented off into a trap with aqueous
solution of NaOH (1M). The residue was poured onto aq. NH4OH
(25%) and extracted with Et2O, dried over Na2SO4, filtered and
concentrated under a reduced pressure to afford the desired
product. The final product was purified by distillation. Yield: 7.65
g, 50%, colorless oil, b.p. 88 °C, 760 mmHg. 1H NMR (400 MHz,
CDCl3) δ 7.99 (s, 1H), 7.61 (d, J = 2.9 Hz, 1H). 13C {1H} NMR
(126 MHz, CDCl3) δ 156.1 (q, J = 40.7 Hz), 144.2, 122.8, 120.0
(q, J = 271.8 Hz). 19F NMR (376 MHz, CDCl3) δ -61.3 (s).
GCMS (m/z): 153 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C4H3F3NS, 153.9938; found 153.9938.
5
6
7
8
9
2-Bromo-5-(trifluoromethyl)thiophene (28a): yield: 14.1 g,
61%, colorless oil, b.p. 48 °C, 15 mmHg. H NMR (400 MHz,
1
CDCl3) δ 7.22 – 7.19 (m, 1H), 7.04 (d, J = 3.5 Hz, 1H). 13C {1H}
NMR (126 MHz, CDCl3) δ 132.7 (q, J = 39.2 Hz), 130.0, 129.1
(q, J = 3.9 Hz), 121.8 (q, J = 269.0 Hz), 117.2. 19F NMR (376
MHz, CDCl3) δ -56.3 (s). GCMS (m/z): 231 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C5H3BrF3S, 230.9091; found
230.9092.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Bromo-2-(trifluoromethyl)thiophene (29a): yield: 11.1 g,
1
48%, colorless oil, b.p. 63 °C, 15 mmHg. H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 1.4 Hz, 1H), 7.38 (s, 1H). 13C {1H} NMR
(126 MHz, CDCl3) δ 132.8 (q, J = 39.6 Hz), 131.4 (q, J = 3.7 Hz),
126.3, 121.7 (q, J = 269.3 Hz), 110.2. 19F NMR (376 MHz,
CDCl3) δ -56.6 (s). GCMS (m/z): 231 (M). HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C5H3BrF3S, 230.9091; found 230.9093.
3-Bromo-4-(trifluoromethyl)thiophene (30a): yield: 14.6 g,
1
63%, colorless oil, b.p. 84 °C, 15 mmHg. H NMR (400 MHz,
CDCl3) δ 7.76 (d, J = 3.0 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H). 13C
{1H} NMR (151 MHz, CDCl3) δ 131.1 (q, J = 35.2 Hz), 128.9 (q,
J = 5.2 Hz), 126.6, 121.3 (q, J = 270.5 Hz), 107.6 (d, J = 1.7 Hz).
19F NMR (376 MHz, CDCl3) δ -61.2 (s). GCMS (m/z): 231 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C5H3BrF3S, 230.9091;
found 230.9089.
5-Bromo-2-(trifluoromethyl)thiazole (34a): yield: 19.7 g, 85%,
1
colorless oil, b.p. 55 °C, 15 mmHg. H NMR (400 MHz, CDCl3)
δ 7.87 (s, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 157.7 – 156.1
(m), 145.3, 119.2 (q, J = 272.4 Hz), 114.0. 19F NMR (376 MHz,
CDCl3) δ -62.1 (s). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C4H2BrF3NS, 231.9043; found 231.9046.
5-(Trifluoromethyl)thiazole (31a): yield: 9.3 g, 61%, colorless
1
oil, b.p. 55 °C, 15 mmHg H NMR (400 MHz, CDCl3) δ 8.97 (s,
1-Methyl-4-(trifluoromethyl)-1H-pyrazole (35a): yield: 13.1 g,
1H), 8.23 (s, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 156.1,
144.7, 127.6 – 127.0 (m), 122.2 (q, J = 268.8 Hz). 19F NMR (376
MHz, CDCl3) δ -54.6 (s). GCMS (m/z): 153 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C4H3F3NS, 153.9938; found
153.9936.
87%, colorless oil, b.p. 42 °C, 15 mmHg. H NMR (400 MHz,
1
CDCl3) δ 7.67 (s, 1H), 7.63 (s, 1H), 3.92 (s, 3H). 13C {1H} NMR
(101 MHz, CDCl3) δ 137.1 (d, J = 2.7 Hz), 129.3 (d, J = 3.2 Hz),
122.7 (q, J = 265.6 Hz), 113.9 (q, J = 38.4 Hz), 39.4. 19F NMR
(376 MHz, CDCl3) δ -56.9 (s). LCMS (m/z): 151 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C5H6F3N2, 151.0483; found
151.0489.
General procedure C for the synthesis of 32a and 34a (32a as
an example).
2-Bromo-5-(trifluoromethyl)thiazole (32a). Compound 32 (20.8
g, 0.1 mol, 1 equiv) was placed in 500 mL autoclave made of
Hastelloy nickel alloy. The reaction vessel was cooled down by
liquid nitrogen and anhydrous HF (16.6 mL, 1 mol, 10 equiv) was
added. Then SF4 (32.4 g, 0.3 mol, 3 equiv) was condensed into a
reaction vessel. Cooling bath was removed, and the mixture was
allowed to warm up to a room temperature. It was then heated at
45 °C in oil bath for 48 h. The autoclave was allowed to cool
down to a room temperature, and the gaseous products were
vented off into a trap with aqueous solution of NaOH (1M). The
residue was poured onto ice, dissolved in CH2Cl2, and washed
with saturated aq. NaHCO3 (500 mL). The organic layer was
separated, dried over Na2SO4, filtered and concentrated under a
reduced pressure to afford the desired product. The final product
was purified by distillation. Yield: 10.4 g, 45%, colorless oil, b.p.
3-Methyl-4-(trifluoromethyl)-1H-pyrazole (36a): yield: 13.05
g, 87%, white solid, m.p. 97-99 °C, b.p. 51 °C, 1 mmHg. 1H NMR
(400 MHz, CDCl3) δ 11.43 (br s, 1H), 7.75 (s, 1H), 2.44 (s, 3H).
13C {1H} NMR (151 MHz, CDCl3) δ 142.3, 134.5 (d, J = 3.2 Hz),
123.3 (q, J = 266.0 Hz), 111.2 (q, J = 37.7 Hz), 10.8. 19F NMR
(376 MHz, CDCl3) δ -57.4 (s). LCMS (m/z): 151 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C5H6F3N2, 151.0483; found
151.0478.
4,5-Dibromo-2-(trifluoromethyl)-1H-imidazole (37a): yield:
18.1 g, 62%, brown solid, m.p. 127-129 °C, b.p. 92 °C, 0.1
1
mmHg. H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 5.42 (br s,
1H). 13C {1H} NMR (126 MHz, CDCl3) δ 128.3 (q, J = 41.1 Hz),
120.2(q, J = 268.7 Hz), 118.7 (d, J = 8.9 Hz), 106.6. 19F NMR
(376 MHz, CDCl3) δ -62.9 (s). LCMS (m/z): 295 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C4H2Br2F3N2, 292.8537;
found 292.8530.
84 °C, 15 mmHg. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H). 13
C
{1H} NMR (126 MHz, CDCl3) δ 143.8 (q, J = 4.0 Hz), 140.4,
130.6 (q, J = 39.2 Hz), 121.1 (q, J = 269.8 Hz). 19F NMR (376
MHz, CDCl3) δ -55.5 (s). GCMS (m/z): 232 (M). HRMS (ESI-
1-Methyl-4-(trifluoromethyl)-1H-1,2,3-triazole (38a): yield:
13.29 g, 88%, yellow solid, m.p. 77-79 °C, b.p. 74 °C, 15 mmHg.
1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 4.13 (s, 3H). 13C
{1H} NMR (101 MHz, DMSO-d6) δ 136.7 (q, J = 38.2 Hz), 126.3,
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120.9 (q, J = 266.9 Hz), 36.9. 19F NMR (376 MHz, DMSO-d6) δ -
60.2 (s). LCMS (m/z): 152 (M+H)+. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C4H5F3N3, 152.0436; found 152.0431.
Hz), 119.4, 109.8 (q, J = 4.2 Hz). 19F NMR (376 MHz, CDCl3) δ -
68.0 (s). LCMS (m/z): 162 (M-H)-. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C6H5F3NO, 164.0323; found 164.0325.
1
2
3
4
3-Bromo-2-(trifluoromethyl)pyridine (39a): yield: 17.66 g,
69%, beige solid, m.p. 41-43 °C, b.p. 81 °C, 15 mmHg H NMR
3-Bromo-6-fluoro-2-(trifluoromethyl)pyridine (46a): yield:
17.74 g, 73%, colorless oil, b.p. 76 °C, 15 mmHg. H NMR (400
1
1
5
6
7
8
(400 MHz, CDCl3) δ 8.63 (d, J = 3.5 Hz, 1H), 8.07 (d, J = 8.0 Hz,
1H), 7.37 (dd, J = 7.4, 4.6 Hz, 1H). 13C {1H} NMR (151 MHz,
CDCl3) δ 147.3, 146.3 (q, J = 34.2 Hz), 143.2, 127.5, 121.2 (q, J
= 275.1 Hz), 118.4. 19F NMR (376 MHz, CDCl3) δ -66.7 (s).
GCMS (m/z): 256 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C6H4BrF3N, 225.9479; found 225.9472.
MHz, CDCl3) δ 8.14 (t, J = 7.2 Hz, 1H), 7.07 (dd, J = 8.5, 3.5 Hz,
1H). 13C {1H} NMR (151 MHz, CDCl3) δ 161.1 (d, J = 245.6 Hz),
148.2 (d, J = 7.5 Hz), 144.56– 143.8 (m), 120.3 (q, J = 275.6 Hz),
114.6 (d, J = 37.8 Hz), 114.1 (d, J = 4.8 Hz). 19F NMR (376 MHz,
CDCl3) δ -66.9 (s, 3F), -68.0 (s, 1F). GCMS (m/z): 243 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H2BrF5N, 261.9291;
found 261.9293.
9
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Fluoro-2-(trifluoromethyl)pyridine (40a): yield: 12.87 g,
1
78%, colorless oil, b.p. 122 °C, 760 mmHg. H NMR (400 MHz,
3-Bromo-2,6-bis(trifluoromethyl)pyridine (47a): yield: 26.17 g,
CDCl3) δ 8.52 (d, J = 4.0 Hz, 1H), 7.65 – 7.51 (m, 2H). 13C {1H}
NMR (126 MHz, CDCl3) δ 157.3 (d, J = 268.3 Hz), 145.1 (d, J =
5.3 Hz), 136.3 (dd, J = 35.7, 11.3 Hz), 128.6 (d, J = 4.2 Hz),
125.7, 125.6, 120.9 (qd, J = 274.3, 4.5 Hz). 19F NMR (376 MHz,
CDCl3) δ -66.2 (d, J = 15.4 Hz, 3F), -122.16 (q, 1F). GCMS
(m/z): 165 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C6H4F4N, 166.0280; found 166.0282.
89%, yellow oil, b.p. 59 °C, 15 mmHg. H NMR (400 MHz,
1
CDCl3) δ 8.28 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H). 13C
{1H} NMR (151 MHz, CDCl3) δ 146.8 (q, J = 35.6 Hz), 146.3 (q,
J = 37.1 Hz), 144.9, 124.2, 121.6, 120.8 (q, J = 274.5 Hz), 120.5
(q, J = 276.0 Hz). 19F NMR (376 MHz, CDCl3) δ -67.0 (s, 3F), -
68.4 (s, 3F). GCMS (m/z): 294 (M). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C6H2BrF5N, 261.9291; found 261.9289.
3-Chloro-2-(trifluoromethyl)pyridine (41a): yield: 9.77 g, 54%,
3-(Trifluoromethyl)pyridin-2(1H)-one (48a): yield: 12.88 g,
1
1
beige solid, m.p. 55-56 °C, b.p. 79 °C, 15 mmHg. H NMR (400
79%, yellow solid, b.p. 64 °C, 1 mmHg. H NMR (400 MHz,
MHz, CDCl3) δ 8.59 (d, J = 4.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H),
7.47 (dd, J = 8.1, 4.6 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3)
δ 146.9, 144.9 (q), 139.8, 130.7, 127.4, 121.1 (q, J = 275.2 Hz).
19F NMR (376 MHz, CDCl3) δ -66.8 (s). GCMS (m/z): 181 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H4ClF3N, 181.9984;
found 181.9987.
4-Methyl-2-(trifluoromethyl)pyridine (42a): yield: 12.24 g,
76%, brown oil, b.p. 48 °C, 15 mmHg. 1H NMR (400 MHz,
CDCl3) δ 8.56 (d, J = 4.8 Hz, 1H), 7.49 (s, 1H), 7.29 (d, J = 4.6
Hz, 1H), 2.44 (s, 3H). 13C {1H} NMR (126 MHz, CDCl3) δ 149.9,
149.2, 148.3 (q, J = 34.2 Hz), 127.3, 121.8 (q, J = 274.1 Hz),
121.4 (q, J = 2.6 Hz), 21.3. 19F NMR (376 MHz, CDCl3) δ -68.6
(s). LCMS (m/z): 162 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C7H7F3N, 162.0531; found 162.0531.
CDCl3) δ 13.42 (br s, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.66 (d, J =
6.0 Hz, 1H), 6.39 (t, J = 6.7 Hz, 1H). 13C {1H} NMR (151 MHz,
CDCl3) δ 161.6, 140.8 (q, J = 5.4 Hz), 139.3, 122.8 (q, J = 271.4
Hz), 120.4 (q, J = 31.5 Hz), 105.7. 19F NMR (376 MHz, CDCl3) δ
-66.2 (s). LCMS (m/z): 162 (M-H)-. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C6H5F3NO, 164.0323; found 164.0328.
3,5-Bis(trifluoromethyl)pyridin-2(1H)-one (49a): yield: 16.4 g,
1
71%, white solid, m.p. 145-147 °C, b.p. 79 °C, 15 mmHg. H
NMR (400 MHz, DMSO-d6) δ 13.03 (br s, 1H), 8.29 (s, 1H), 8.11
(s, 1H). 13C {1H} NMR (126 MHz, DMSO-d6) δ 158.0, 141.0 (d,
J = 4.5 Hz), 136.2, 123.2 (q, J = 269.7 Hz), 122.3 (q, J = 271.5
Hz), 119.0 (q, J = 31.0 Hz), 105.9 (q, J = 35.9 Hz). 19F NMR (376
MHz, DMSO-d6) δ -60.5 (s, 3F), -65.2 (s, 3F). LCMS (m/z): 232
(M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H4F6NO,
232.0197; found 232.0199.
3,4-Dimethyl-2-(trifluoromethyl)pyridine (43a): yield: 12.43 g,
1
71%, grey solid, m.p. 51-52 °C, b.p. 71 °C, 15 mmHg. H NMR
4-Methyl-5-(trifluoromethyl)pyridin-2(1H)-one (50a): yield:
12.21 g, 69%, yellow solid, m.p. 182-183 °C, b.p. 65 °C, 1
(400 MHz, CDCl3) δ 8.36 (d, J = 4.5 Hz, 1H), 7.24 (d, J = 4.5 Hz,
1H), 2.37 (s, 3H), 2.35 (s, 3H). 13C {1H} NMR (126 MHz, CDCl3)
δ 148.8, 146.0 (q, J = 31.8 Hz), 145.9, 131.7, 127.8, 122.7 (q, J =
275.6 Hz), 19.9, 13.9. 19F NMR (376 MHz, CDCl3) δ -64.6 (s).
GCMS (m/z): 175 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H9F3N, 176.0687; found 176.0687.
1
mmHg. H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.77 (s,
1H), 6.34 (s, 1H), 2.20 (s, 3H). 13C {1H} NMR (151 MHz,
DMSO-d6) δ 161.9, 147.6, 135.9 (q, J = 6.9 Hz), 124.2 (q, J =
270.2 Hz), 120.8, 107.1 (q, J = 31.6 Hz), 18.6 (d, J = 1.4 Hz). 19
F
NMR (376 MHz, DMSO-d6) δ -59.7 (s). LCMS (m/z): 178
(M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H7F3NO,
178.0480; found 178.0483.
5-Fluoro-2-(trifluoromethyl)pyridine (44a): yield: 12.37 g,
1
75%, colorless oil, b.p. 105 °C, 760 mmHg. H NMR (400 MHz,
CDCl3) δ 8.57 (d, J = 2.2 Hz, 1H), 7.73 (dd, J = 8.6, 4.1 Hz, 1H),
7.57 (td, J = 8.4, 2.4 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3)
δ 160.8 (d, J = 262.2 Hz), 144.5 (qd, J = 35.5, 4.0 Hz), 139.0 (d, J
= 25.1 Hz), 124.0 (d, J = 19.1 Hz), 122.3 (q, J = 2.7 Hz), 121.3 (q,
J = 273.8 Hz). 19F NMR (376 MHz, CDCl3) δ -67.8 (s, 3F), -
121.5 (s, 1F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C6H4F4N, 166.0280; found 166.0285.
6-(Trifluoromethyl)pyridin-2(1H)-one (45a): yield: 13.20 g,
81%, white solid, b.p. 61 °C, 1 mmHg. 1H NMR (400 MHz,
CDCl3) δ 11.80 (br s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 6.99 (d, J =
7.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H). 13C {1H} NMR (151 MHz,
CDCl3) δ 164.8, 140.9, 140.6 (q, J = 35.5 Hz), 120.6 (q, J = 274.0
4-Chloro-3-(trifluoromethyl)pyridine (51a): yield: 10.14 g,
56%, yellow oil, b.p. 68 °C, 15 mmHg. 1H NMR (400 MHz,
CDCl3) δ 8.88 (s, 1H), 8.68 (d, J = 4.7 Hz, 1H), 7.48 (d, J = 5.1
Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 153.8, 148.4 (q, J =
5.7 Hz), 142.9, 126.0, 122.5 (q, J = 273.7 Hz). 19F NMR (376
MHz, CDCl3) δ -63.1 (s). GCMS (m/z): 181 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C6H4ClF3N, 181.9984; found
181.9984.
6-Chloro-2,3-bis(trifluoromethyl)pyridine (52a): yield: 16.43 g,
1
66%, colorless oil, b.p. 58 °C, 15 mmHg. H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H). 13C
{1H} NMR (151 MHz, CDCl3) δ 154.2, 146.0 (q, J = 37.9 Hz),
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139.0 (q, J = 5.4 Hz), 127.6, 124.4 (q, J = 35.7 Hz), 122.0 (q, J =
2-Chloro-6-methyl-4-(trifluoromethyl)pyridine (59a): yield:
14.63 g, 75%, colorless oil, b.p. 72 °C, 15 mmHg. H NMR (400
273.8 Hz), 119.9 (q, J = 275.7 Hz). 19F NMR (376 MHz, CDCl3)
δ -60.0 (q, J = 12.2 Hz, 3F), -65.1 (q, J = 12.2 Hz. 3F). GCMS
(m/z): 249 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H3ClF6N, 249.9858; found 249.9861.
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7
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MHz, CDCl3) δ 7.37 (s, 1H), 7.29 (s, 1H), 2.62 (s, 3H). 13C {1H}
NMR (126 MHz, CDCl3) δ 161.3, 151.7, 141.3 (q, J = 34.2 Hz),
122.3 (q, J = 273.6 Hz), 117.8 (q, J = 3.2 Hz), 117.6 (q, J = 3.6
Hz), 24.5. 19F NMR (376 MHz, CDCl3) δ -65.3 (s). GCMS (m/z):
195 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H6ClF3N,
196.0141; found 196.0139.
5-(Trifluoromethyl)pyridazin-3(2H)-one (60a): yield: 12.96 g,
79%, beige solid, m.p. 108-109 °C, b.p. 59 °C, 1 mmHg. 1H NMR
(400 MHz, DMSO-d6) δ 13.64 (br s, 1H), 8.21 (d, J = 1.4 Hz,
1H), 7.39 (s, 1H). 13C {1H} NMR (151 MHz, DMSO-d6) δ 159.4,
133.1 (q, J = 33.5 Hz), 131.6 (d, J = 2.6 Hz), 128.1 (q, J = 4.2
Hz), 122.3 (t, J = 274.4 Hz). 19F NMR (376 MHz, DMSO-d6) δ -
65.2 (s). LCMS (m/z): 165 (M+H)+. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C5H4F3N2O, 165.0276; found 165.0273.
5-(Trifluoromethyl)quinolone (61a): yield: 17.53 g, 89%,
colorless oil, b.p. 74 °C, 5 mmHg. 1H NMR (400 MHz, CDCl3) δ
9.00 (d, J = 3.4 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 8.5
Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.53
(dd, J = 8.7, 4.2 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ
151.15 (s), 148.47 (s), 134.42 (s), 132.72 (s), 127.95 (s), 126.50
(q, J = 30.8 Hz), 125.30 (q, J = 5.6 Hz), 124.58 (s), 122.44 (s),
122.08 (d, J = 273.5 Hz). 19F NMR (376 MHz, CDCl3) δ -59.7 (s).
GCMS (m/z): 197 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C10H7F3N, 198.0531; found 198.0533.
2,5-Dichloro-3-(trifluoromethyl)pyridine (53a): yield: 15.48 g,
1
72%, colorless oil, b.p. 84 °C, 15 mmHg. H NMR (400 MHz,
CDCl3) δ 8.54 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H). 13C
{1H} NMR (126 MHz, CDCl3) δ 151.2, 147.0, 136.5 (q, J = 5.0
Hz), 131.0, 126.4 (q, J = 33.9 Hz), 121.5 (q, J = 273.5 Hz). 19F
NMR (376 MHz, CDCl3) δ -64.5 (s). GCMS (m/z): 215 (M).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H3Cl2F3N,
215.9595; found 215.9591.
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5-Bromo-2-fluoro-3-(trifluoromethyl)pyridine (54a): yield:
1
18.71 g, 77%, colorless oil, b.p. 66 °C, 15 mmHg. H NMR (400
MHz, CDCl3) δ 8.47 (s, 1H), 8.15 (dd, J = 7.8, 1.9 Hz, 1H). 13C
{1H} NMR (126 MHz, CDCl3) δ 158.8 (d, J = 247.1 Hz), 152.3
(d, J = 15.3 Hz), 140.9, 121.0 (dq, J = 272.8, 6.1 Hz), 116.4 (d, J
= 5.2 Hz), 115.9 – 114.4 (m). 19F NMR (376 MHz, CDCl3) δ -
63.3 (d, J = 11.4 Hz, 3F), -69.1 (d, J = 10.8 Hz, 1F). GCMS (m/z):
243 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H3BrF4N,
243.9385; found 243.9387.
2-Chloro-4,6-dimethyl-3-(trifluoromethyl)pyridine
(55a):
1
yield: 13.17 g, 63%, yellow solid, b.p. 62 °C, 1 mmHg. H NMR
(400 MHz, CDCl3) δ 6.98 (s, 1H), 2.53 – 2.44 (m, 6H). 13C {1H}
NMR (126 MHz, CDCl3) δ 161.3, 150.2, 149.2 (d, J = 1.6 Hz),
125.8, 123.9 (q, J = 274.7 Hz), 121.3 (q, J = 31.4 Hz), 23.9, 21.6
(q, J = 4.3 Hz). 19F NMR (376 MHz, CDCl3) δ -55.9 (s). GCMS
(m/z): 209 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H8ClF3N, 210.0297; found 210.0297.
6-(Trifluoromethyl)quinolone (62a): yield: 16.94 g, 86%, white
1
solid, m.p. 39-41 °C, b.p. 69 °C, 1 mmHg. H NMR (400 MHz,
CDCl3) δ 9.03 (d, J = 3.1 Hz, 1H), 8.23 (t, J = 9.3 Hz, 2H), 8.14
(s, 1H), 7.88 (dd, J = 8.7, 1.2 Hz, 1H), 7.50 (dd, J = 8.3, 4.2 Hz,
1H). 13C {1H} NMR (126 MHz, CDCl3) δ 152.6, 149.3, 137.0,
130.9, 128.7 (q, J = 32.6 Hz), 127.4, 125.9 (q, J = 4.3 Hz), 125.3
(q, J = 2.9 Hz), 124.1 (q, J = 272.2 Hz), 122.4. 19F NMR (376
MHz, CDCl3) δ -62.9 (s). GCMS (m/z): 197 (M). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C10H7F3N, 198.0531; found
198.0535.
4-(Trifluoromethyl)pyridin-2(1H)-one (56a): yield: 14.18 g,
1
87%, yellow solid, m.p. 160-161 °C, b.p. 62 °C, 1 mmHg. H
NMR (400 MHz, DMSO-d6) δ 12.18 (br s, 1H), 7.64 (d, J = 6.7
Hz, 1H), 6.68 (s, 1H), 6.37 (d, J = 6.7 Hz, 1H). 13C {1H} NMR
(151 MHz, DMSO-d6) δ 161.5, 140.8 (q, J = 32.6 Hz), 138.5,
122.4 (q, J = 274.0 Hz), 117.2 (q, J = 4.3 Hz), 99.8 (d, J = 2.6
Hz). 19F NMR (376 MHz, DMSO-d6) δ -66.0 (s). LCMS (m/z):
164 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C6H5F3NO, 164.0323; found 164.0325.
4-(Trifluoromethyl)isoquinoline (63a): yield: 16.55 g, 84%,
colorless oil, b.p. 62 °C, 0.1 mmHg. 1H NMR (400 MHz, CDCl3)
δ 9.39 (s, 1H), 8.86 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.07 (d, J =
2,5-Difluoro-4-(trifluoromethyl)pyridine (57a): yield: 13.36 g,
8.2 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H). 13
C
1
73%, colorless oil, b.p. 48 °C, 15 mmHg. H NMR (400 MHz,
{1H} NMR (101 MHz, CDCl3) δ 157.1, 141.2 (q, J = 6.5 Hz),
132.3, 131.6, 128.6, 128.5, 128.3, 124.5 (q, J = 273.5 Hz), 123.5,
120.4 (q, J = 30.5 Hz). 19F NMR (376 MHz, CDCl3) δ -60.7 (s).
LCMS (m/z): 198 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C10H7F3N, 198.0531; found 198.0529.
CDCl3) δ 8.25 (s, 1H), 7.19 (t, J = 3.8 Hz, 1H). 13C {1H} NMR
(151 MHz, CDCl3) δ 159.0 (d, J = 239.5 Hz), 153.7 (d, J = 261.5
Hz), 137.3 (dd, J = 26.8, 15.8 Hz), 131.0 – 130.5 (m), 120.6 (q, J
= 272.8 Hz), 107.8 (dq, J = 44.2, 4.4 Hz). 19F NMR (376 MHz,
CDCl3) δ -64.0 (d, J = 12.9 Hz, 3F), -69.3(d, J = 29.5 Hz, 1F), -
134.8 (dt, J = 27.1, 13.1 Hz 1F). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C6H3F5N, 184.0186; found 184.0189.
5-(Trifluoromethyl)isoquinoline (64a): yield: 15.96 g, 81%,
white solid, b.p. 65 °C, 0.1 mmHg. 1H NMR (400 MHz, CDCl3) δ
9.34 (s, 1H), 8.66 (d, J = 6.1 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H),
8.06 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 4.9 Hz, 1H), 7.66 (t, J = 7.8
Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 153.3, 144.8,
132.4, 132.0, 128.9 (q, J = 5.4 Hz), 125.9, 125.7 (q, J = 31.0 Hz),
124.2 (q, J = 273.4 Hz), 117.0 (d, J = 1.8 Hz). 19F NMR (376
MHz, CDCl3) δ -60.8 (s). LCMS (m/z): 198 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C10H7F3N, 198.0531; found
198.0528.
2-Chloro-5-fluoro-4-(trifluoromethyl)pyridine (58a): yield:
1
13.52 g, 68%, colorless oil, b.p. 79 °C, 15 mmHg. H NMR (400
MHz, CDCl3) δ 8.45 (s, 1H), 7.56 (d, J = 4.8 Hz, 1H). 13C {1H}
NMR (151 MHz, CDCl3) δ 154.9 (d, J = 264.4 Hz), 147.1 (d, J =
3.9 Hz), 139.8 (d, J = 25.3 Hz), 128.6 (qd, J = 35.3, 12.2 Hz),
121.8 (q, J = 4.3 Hz), 120.7 (q, J = 274.0 Hz). 19F NMR (376
MHz, CDCl3) δ -63.7 (d, J = 12.3 Hz, 3F), -132.3 (q, J = 12.3 Hz,
1F). GCMS (m/z): 199 (M). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C6H3ClF4N, 199.9890; found 199.9892.
6-(Trifluoromethyl)isoquinoline (65a): yield: 15.17 g, 77%,
white solid, m.p. 35-36 °C, b.p. 53 °C, 0.1 mmHg. 1H NMR (400
MHz, CDCl3) δ 9.35 (s, 1H), 8.65 (d, J = 5.7 Hz, 1H), 8.14 (s,
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1H), 8.10 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.75 (d, J
J = 5.2 Hz), 124.5 (q, J = 270.5 Hz), 108.7 (q, J = 31.5 Hz),
= 5.7 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 152.7, 144.5,
135.0, 132.2 (q, J = 32.6 Hz), 129.5, 129.0, 124.5 (q, J = 4.4 Hz),
123.8 (d, J = 272.7 Hz), 123.2 (q, J = 2.9 Hz), 121.1. 19F NMR
(376 MHz, CDCl3) δ -63.5 (s). LCMS (m/z): 198 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C10H7F3N, 198.0531; found
198.0534.
105.8, 98.4, 55.8. 19F NMR (376 MHz, CDCl3) δ -61.1 (s). LCMS
(m/z): 192 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H9F3NO, 192.0636; found 192.0632.
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5-Methyl-2-(trifluoromethyl)aniline (17b): yield: 5.3 g, 69%,
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz,
1H), 6.60 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 3.97 (br s, 2H), 2.29
(s, 3H). 13C {1H} NMR (126 MHz, CDCl3) δ 144.5, 143.5, 126.6
(q, J = 5.1 Hz), 125.4 (d, J = 271.6 Hz), 118.9, 117.7, 111.5 (q, J
= 30.1 Hz), 21.4. 19F NMR (376 MHz, CDCl3) δ -62.6 (s). LCMS
(m/z): 176 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C8H9F3N, 176.0687; found 176.0684.
7-(Trifluoromethyl)isoquinoline (66a): yield: 15.56 g, 79%,
beige solid, m.p. 38-39 °C, b.p. 49 °C, 0.1 mmHg. 1H NMR (400
MHz, CDCl3) δ 9.35 (s, 1H), 8.66 (d, J = 5.7 Hz, 1H), 8.28 (s,
1H), 7.94 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.71 (d, J
= 5.7 Hz, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 153.4, 145.2,
137.2, 129.4 (q, J = 32.7 Hz), 128.0, 127.5, 126.1 (q, J = 2.8 Hz),
125.7 (q, J = 4.4 Hz), 123.9 (q, J = 272.4 Hz), 120.4. 19F NMR
(376 MHz, CDCl3) δ -63.2 (s). LCMS (m/z): 198 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C10H7F3N, 198.0531; found
198.0531.
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4-Chloro-2-fluoro-5-(trifluoromethyl)aniline (20b): yield: 6.1
1
g, 65%, yellow oil. H NMR (400 MHz, CDCl3) δ 7.13 (d, J =
10.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.89 (br s, 2H). 13C {1H}
NMR (126 MHz, CDCl3) δ 152.3 (d, J = 248.2 Hz), 133.6 (d, J =
13.2 Hz), 124.9 (qd, J = 31.4, 3.5 Hz), 122.8 (q, J = 272.9 Hz),
120.6 (d, J = 9.2 Hz), 118.7 (d, J = 22.7 Hz), 115.34 (p, J = 5.5
Hz). 19F NMR (376 MHz, CDCl3) δ -62.5 (s, 3F), -128.8 (s, 1F).
GCMS (m/z): 213 (M). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C7H5ClF4N, 214.0047; found 214.0045.
General procedure for reduction for the synthesis of 13b-17b,
20b, 22b and 24b-26b (13b as an example).
5-Chloro-2-(trifluoromethyl)aniline (13b). To a 500 mL three
necked flask carrying a mechanical stirrer, thermometer pocket
was charged i-PrOH (200 mL) followed by 13a (10 g, 0.044 mol,
1 equiv), ammonium chloride (0.89 g, 0.016 mol), water (8.9 mL)
and con. HCl (0.9 mL). The mixture was heated at reflux and
carefully iron powder (8.9 g, 0.159 mol, 3.6 equiv) was added in
portions. TLC shows completion of the reaction, the reaction
mixture was filtered throught celite. The filtrate was concentrated,
diluted with EtOAc and a solution of NaHCO3. The organic layer
was separated and addionally washed with brine, dried over
Na2SO4, filtered and concentrated under a reduced pressure to
4-Fluoro-2-methyl-5-(trifluoromethyl)aniline hydrochloride
(22b): yield: 6.45 g, 76%, beige solid, m.p. 218-219 °C. 1H NMR
(400 MHz, DMSO-d6) δ 8.87 (br s, 3H), 7.76 (d, J = 6.6 Hz, 1H),
7.50 (s, 1H), 2.40 (s, 3H). 13C {1H} NMR (151 MHz, DMSO-d6)
δ 156.1 (d, J = 252.7 Hz), 138.7, 130.9, 122.3 (q, J = 271.6 Hz),
119.8, 119.6 (d, J = 21.8 Hz), 114.4 (qd, J = 34.0, 13.5 Hz), 17.5.
19F NMR (376 MHz, DMSO-d6) δ -60.54 (d, J = 13.5 Hz), -
120.77 (s). LCMS (m/z): 194 (M+H)+. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C8H8F4N, 194.0593; found 194.0598.
1
afford the desired product. Yield: 6.26 g, 73%, colorless oil. H
2-(3,3,3-Trifluoroprop-1-en-1-yl)aniline (24b): yield: 4.5 g,
1
NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.9 Hz, 1H), 6.77 – 6.69
(m, 2H), 2.41 (br s, 2H). 13C {1H} NMR (126 MHz, CDCl3) δ
145.7, 138.9, 128.1 (q, J = 5.2 Hz), 124.8 (q, J = 271.8 Hz),
117.9, 116.8, 112.4 (q, J = 30.4 Hz). 19F NMR (376 MHz, CDCl3)
δ -63.1 (s). GCMS (m/z): 195 (M). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C7H6ClF3N, 196.0141; found 196.0143.
3-Bromo-4-(trifluoromethyl)aniline (14b): yield: 8.1 g, 77%,
brown oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 1H),
6.95 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.00 (br s, 2H).
13C {1H} NMR (126 MHz, CDCl3) δ 150.2, 129.0 (q, J = 5.4 Hz),
123.7 (q, J = 271.3 Hz), 121.1, 120.1, 119.5 (q, J = 31.6 Hz),
112.6. 19F NMR (376 MHz, CDCl3) δ -61.2 (s). LCMS (m/z): 240
(M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H6BrF3N,
239.9636; found 239.9639.
3-Fluoro-4-(trifluoromethyl)aniline (15b): yield: 6.6 g, 84%,
white solid, m.p. 55-56 °C. 1H NMR (400 MHz, CDCl3) δ 7.32 (t,
J = 8.4 Hz, 1H), 6.45 – 6.37 (m, 2H), 4.06 (br s, 2H). 13C {1H}
NMR (126 MHz, CDCl3) δ 161.3 (d, J = 252.7 Hz), 151.7 (d, J =
11.2 Hz), 128.4– 128.2 (m), 123.5 (q, J = 270.3 Hz), 109.7 (d, J =
2.4 Hz), 108.2 – 107.2 (m), 102.1 (d, J = 23.8 Hz). 19F NMR (376
MHz, DMSO-d6) δ -65.1 (d, J = 12.3 Hz, 3F), -119.6 (q, J = 12.3
Hz, 1F). GCMS (m/z): 179 (M). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C7H6F4N, 180.0436; found 180.0432.
55%, white solid, m.p. 52-54 °C. H NMR (400 MHz, CDCl3) δ
7.33 – 7.14 (m, 3H), 6.80 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.0 Hz,
1H), 6.27 – 5.91 (m, 1H), 3.85 (br s, 2H). 13C {1H} NMR (126
MHz, CDCl3) δ 144.9, 133.5 (q, J = 6.8 Hz), 131.1, 128.1, 123.8
(q, J = 269.1 Hz), 119.6, 119.4, 117.0, 116.8 (q, J = 33.6 Hz). 19
F
NMR (376 MHz, CDCl3) δ -63.7 (s). LCMS (m/z): 188 (M+H)+.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C9H9F3N, 188.0687;
found 188.0687.
3-(3,3,3-Trifluoroprop-1-en-1-yl)aniline (25b): yield: 4.77 g,
1
58%, yellow oil. H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.8
Hz, 1H), 7.06 (dd, J = 16.1, 1.7 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H),
6.75 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.25 – 6.07 (m, 1H), 3.71
(br s, 2H). 13C {1H} NMR (126 MHz, CDCl3) δ 147.0, 138.0 (q, J
= 6.8 Hz), 134.6, 130.0, 123.8 (q, J = 268.8 Hz), 118.2, 116.9,
115.8 (q, J = 33.7 Hz), 113.7. 19F NMR (376 MHz, CDCl3) δ -
63.8 (s). LCMS (m/z): 188 (M+H)+. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C9H9F3N, 188.0687; found 188.0689.
4-(3,3,3-Trifluoroprop-1-en-1-yl)aniline (26b): yield: 5.02 g,
61%, yellow solid, m.p. 84-85 °C. 1H NMR (400 MHz, CDCl3) δ
7.24 (d, J = 8.3 Hz, 2H), 7.01 (dd, J = 16.1, 1.5 Hz, 1H), 6.64 (d,
J = 8.4 Hz, 2H), 6.05 – 5.87 (m, J = 13.3, 6.6 Hz, 1H), 3.82 (br s,
2H). 13C {1H} NMR (151 MHz, CDCl3) δ 148.3, 137.6 (q, J = 6.9
Hz), 129.2, 124.4 (q, J = 268.3 Hz), 123.8, 115.0, 111.7 (q, J =
33.5 Hz). 19F NMR (376 MHz, CDCl3) δ -63.0 (s). LCMS (m/z):
188 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C9H9F3N, 188.0687; found 188.0685.
3-Methoxy-4-(trifluoromethyl)aniline (16b): yield: 6.56 g, 78%,
1
yellow solid, m.p. 46-48 °C. H NMR (400 MHz, CDCl3) δ 7.31
(d, J = 8.5 Hz, 1H), 6.27 – 6.18 (m, 2H), 3.96 (br s, 2H), 3.83 (s,
2H). 13C {1H} NMR (126 MHz, CDCl3) δ 159.1, 151.3, 128.5 (q,
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General procedure for reduction for the synthesis of 61b-66b
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H11F3N, 202.0844;
1
(61b as an example)
found 202.0840.
2
5-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline
(61b).
7-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
(66b):
3
4
5
6
7
8
9
Compound 61a (10 g, 0.05 mol, 1 equiv) was dissolved in 150 mL
of MeOH and 1 g of 10%-Pd/C was added to the mixture. The
mixture was hydrogenated under 150 bar during 24 h. Then Pd/C
was filtered out, and the reaction mixture was concentrated under
reduced pressure. The crude residue was purified by distillation
under high vacuum to afford the final pure compound. Yield: 6.84
yield: 7.44 g, 74%, yellow solid, m.p. 35-37 °C, b.p. 67 °C, 1
mmHg. H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.9 Hz, 1H),
1
7.24 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.02 (s, 2H), 3.13 (t, J = 5.9
Hz, 2H), 2.82 (t, J = 5.6 Hz, 2H), 1.85 (s, 1H). 19F NMR (376
MHz, CDCl3) δ -62.9 (s). 13C {1H} NMR (126 MHz, CDCl3) δ
139.1, 136.7, 129.9, 128.2 (q, J = 32.2 Hz), 126.6 (q, J = 272.0
Hz), 123.3 (q, J = 3.8 Hz), 122.8 (q, J = 3.7 Hz), 48.3, 43.7, 29.3.
LCMS (m/z): 202 (M+H)+. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C10H11F3N, 202.0844; found 202.0839.
1
g, 68%, colorless oil, b.p. 66 °C, 1 mmHg. H NMR (400 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMSO-d6) δ 6.99 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H),
6.69 (d, J = 8.1 Hz, 1H), 6.13 (br s, 1H), 3.26 – 3.13 (m, 2H), 2.75
(t, J = 6.0 Hz, 2H), 1.87 – 1.72 (m, 2H). 13C {1H} NMR (151
MHz, DMSO-d6) δ 146.5, 127.4 (q, J = 28.2 Hz), 126.4, 124.9 (q,
General procedure for pyridine hydrogenation. Synthesis of
compounds 45b, 48b, 56b, 67b.
J = 274.0 Hz), 117.5, 116.9, 111.8 (q, J = 6.1 Hz), 23.2, 20.6. 19
F
Corresponding pyridine (0.01 mol) was dissolved in 10 mL of
TFA and mixed with PtO2 (83 mg, 5 wt%) and was hydrogenated
under 1 atm at ambient temperature until the calculated amount of
hydrogen was consumed. Reaction mixture was filtered, and the
filtrate was concentrated under reduced pressure, treated with a
10% K2CO3 (100 mL) solution and filtered. Solid residue was
washed with water (3 × 100 mL) and dried at ambient temperature
to yield: crude product which was further crystallized from
benzene.
NMR (376 MHz, DMSO-d6) δ -60.1 (s). LCMS (m/z): 202
(M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H11F3N,
202.0844; found 202.0844.
6-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (62b): yield:
8.24 g, 82%, yellow oil, b.p. 72 °C, 1 mmHg. 1H NMR (400
MHz, CDCl3) δ 7.21 – 7.13 (m, 2H), 6.45 (d, J = 8.8 Hz, 1H),
3.91 (br s, 1H), 3.34 (t, J = 5.5 Hz, 1H), 2.77 (t, J = 6.3 Hz, 2H),
1.94 (dt, J = 12.0, 6.1 Hz, 2H). 13C {1H} NMR (126 MHz, CDCl3)
δ 147.4, 127.4 (q, J = 270.1 Hz), 126.6 (q, J = 3.7 Hz), 124.2 (q, J
= 3.6 Hz), 120.7, 118.2 (q, J = 32.5 Hz), 113.2, 41.8, 27.1, 21.6.
19F NMR (376 MHz, CDCl3) δ -61.4 (s). LCMS (m/z): 202
(M+H)+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H11F3N,
202.0844; found 202.0841.
6-(Trifluoromethyl)piperidin-2-one (45b): yield: 1.64 g, 98%,
1
white solid, m.p. 123-124 °C. H NMR (400 MHz, DMSO-d6)
δ 1.68-1.96 (m, 4H), 2.14-2.24 (m, 2H), 4.08 (m, 1H), 8.07 (br. s,
1H). 13C {1H} NMR (100 MHz, DMSO-d6) δ 18.1, 20.9, 31.4,
52.6 (q, J = 27 Hz), 125.9 (q, J = 299 Hz), 171.6. 19F NMR
(376 MHz, DMSO-d6) δ -76.1 (s). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C6H9F3NO, 168.0636; found 168.0631.
3-(Trifluoromethyl)piperidin-2-one (48b): yield: 1.52 g, 91%,
white solid, m.p. 108-109 °C. 1H NMR (400 MHz, DMSO-d6) δ
1.68-1.74 (m, 2H), 1.78-2.10 (m, 2H), 3.14 (br. s, 2H), 3.31-3.40
(m, 1H), 7.87 (br. s, 1H). 13C {1H} NMR (100 MHz, DMSO-d6)
δ 20.3, 21.4 (q, J = 2 Hz), 41.0, 44.4 (q, J = 25 Hz), 126.0 (q, J =
278 Hz), 164.1 (q, J = 2 Hz). 19F NMR (376 MHz, DMSO-d6): δ
-66.4 (s). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H9F3NO,
168.0636; found 168.0638.
4-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
(63b):
1
yield: 7.23 g, 72%, colorless oil, b.p. 64 °C, 1 mmHg. H NMR
(400 MHz, CDCl3) δ 7.32 (d, J = 7.5 Hz, 1H), 7.25 (t, J = 7.7 Hz,
1H), 7.20 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 4.08 – 3.93
(m, 2H), 3.55 (dd, J = 14.2, 2.2 Hz, 1H), 3.38 – 3.25 (m, 1H),
3.24 – 3.11 (m, 1H), 1.87 (s, 2H). 13C {1H} NMR (126 MHz,
CDCl3) δ 137.6, 131.0, 128.2, 127.6, 126.50, 126.47, 124.9 (q, J =
280.9 Hz), 47.8, 43.2 (q, J = 2.7 Hz), 40.4 (q, J = 24.6 Hz). 19F
NMR (376 MHz, CDCl3) δ -68.1 (s). LCMS (m/z): 202 (M+H)+.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H11F3N, 202.0844;
found 202.0840.
4-(Trifluoromethyl)piperidin-2-one (56b): yield: 1.2 g, 72%,
1
5-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
(64b):
white solid, m.p. 118-119 °C. H NMR (400 MHz, DMSO-d6)
yield: 6.63 g, 66%, white solid, m.p. 31-32 °C, b.p. 55 °C, 1
δ 1.55-1.97 (m, 2H), 2.10-2.37 (m, 2H), 2.62-2.99 (m, 1H), 3.11-
3.20 (m, 2H), 7.73 (br. s, 1H). 13C {1H} NMR (100 MHz, DMSO-
d6) δ 21.2 (q, J = 2 Hz), 30.0 (q, J = 2 Hz), 36.4 (q, J = 28 Hz),
39.2, 127.3 (q, J = 278 Hz), 167.7. 19F NMR (376 MHz, DMSO-
d6) δ -73.2 (s). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C6H9F3NO, 168.0636; found 168.0640.
5-(Trifluoromethyl)piperidin-2-one (67b): yield: 1.49 g, 89%,
white solid, m.p. 142-143 °C. 1H NMR (400 MHz, DMSO-d6) δ
1.70-1.99 (m, 2H), 2.24-2.32 (m, 2H), 2.84 (br. s, 1H), 3.14-3.32
(m, 2H), 7.62 (br. s, 1H). 13C {1H} NMR (100 MHz, DMSO-d6)
δ 19.8, 29.3, 36.6 (q, J = 27 Hz), 39.4 (q, J = 27 Hz), 127.3 (q, J =
298 Hz), 169.7. 19F NMR (376 MHz, DMSO-d6) δ -71.4 (s).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H9F3NO, 168.0636;
found 168.0632.
1
mmHg. H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.1 Hz, 1H),
7.24 – 7.13 (m, 2H), 4.07 (s, 2H), 3.15 (t, J = 5.9 Hz, 2H), 2.95 (t,
J = 5.5 Hz, 2H), 1.79 (s, 1H). 13C {1H} NMR (126 MHz, CDCl3)
δ 137.6, 133.8, 130.2, 129.1 (q, J = 29.2 Hz), 125.5, 124.7 (q, J =
274.1 Hz), 124.0 (q, J = 5.9 Hz), 48.9, 43.5, 26.1. 19F NMR (376
MHz, CDCl3) δ -61.9 (s). LCMS (m/z): 202 (M+H)+. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C10H11F3N, 202.0844; found
202.0844.
6-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
(65b):
1
yield: 7.84 g, 78%, colorless oil, b.p. 58 °C, 1 mmHg. H NMR
(400 MHz, CDCl3) δ 7.40 – 7.31 (m, 2H), 7.10 (d, J = 7.7 Hz,
1H), 4.04 (s, 2H), 3.15 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.8 Hz,
2H), 1.83 (s, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 140.1,
135.7, 128.5 (q, J = 32.2 Hz), 126.8, 126.3 (q, J = 3.8 Hz), 124.4
(q, J = 271.8 Hz), 122.6 (q, J = 3.7 Hz), 48.4, 43.7, 29.3. 19F
NMR (376 MHz, CDCl3) δ -62.9 (s). LCMS (m/z): 202 (M+H)+.
General procedure for piperidone hydrolysis: Synthesis of
amino acids 69-71. Corresponding piperidone (0.01 mol) was
dissolved in 10 mL of concentrated HCl and was heated at reflux
for 16 h. The reaction mixture was concentrated under reduced
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(1) (a) Bioorganic and medicinal chemistry of fluorine (Eds.: Bégué,
pressure and the solid residue was crystallized from
acetone/benzene.
J.-P.; Bonnet-Delpon, D.), John Wiley & Sons, New Jersey, 2008.
(b) Fluorine in medicinal chemistry and chemical biology (Ed.:
Ojima, I.), Blackwell Publishing, 2009. (c) Fluorine in
pharmaceutical and medicinal chemistry: from biophysical
aspects to clinical applications (Eds.: Gouverneur, V.; Müller, K.),
Imperial College Press, London, 2012.
1
2
3
4
5
6
7
8
5-Amino-2-(trifluoromethyl)pentanoic acid hydrochloride
(69): yield: 2.11 g, 95%, white solid, m.p. 153-155 °C. 1H NMR
(400 MHz, D2O) δ 1.72-2.00 (m, 4H), 2.39-2.44 (m, 2H), 4.06 (m,
1H). 13C {1H} NMR (100 MHz, D2O) δ 19.4, 25.5, 32.7, 52.2 (q, J
= 31 Hz), 123.7 (q, J = 284 Hz), 177.4. 19F NMR (376 MHz, D2O)
(2) Selected reviews: (a) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy,
M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in
medicinal chemistry. ChemBioChem 2004, 5, 637-643. (b) Kirk,
K. L. Fluorination in medicinal chemistry: methods, strategies, and
recent developments. Org. Process Res. Dev. 2008, 12, 305-321.
(c) Hagmann, W. K. The many roles for fluorine in medicinal
chemistry. J. Med. Chem. 2008, 51, 4359-4369. (d) Wang, J.;
Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A.
E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
pharmaceutical industry: fluorine-containing drugs introduced to
the market in the last decade (2001–2011). Chem. Rev. 2014, 114,
2432-2506.
3
3
δ -77.7 (d, JHF = 7 Hz, CF3), -75.0 (d, JHF = 7 Hz, CF3). Anal.
calcd for C6H11ClF3NO2: C, 32.52; H, 5.00; Cl, 16.00; N, 6.32.
Found: C, 32.38; H, 5.17; Cl, 16.17; N, 6.05.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Amino-3-(trifluoromethyl)pentanoic acid hydrochloride
(70): yield: 2.11 g, 95%, white solid, m.p. 144-146 °C. 1H NMR
(400 MHz, D2O) δ 1.76-2.04 (m, 2H), 2.55 (t, J = 7.53 Hz, 2H,),
2.65-2.70 (m, 1H), 3.10-3.17 (m, 2H). 13C {1H} NMR (100 MHz,
D2O) δ 20.7, 30.4, 37.4, 40.1 (q, J = 28 Hz), 126.9 (q, J = 271
Hz), 176.8. 19F NMR (376 MHz, D2O) δ -70.5 (d, J = 8 Hz). Anal.
calcd for C6H11ClF3NO2: C, 32.52; H, 5.00; Cl, 16.00; N, 6.32.
Found: C, 32.41; H, 4.85; Cl, 15.90; N, 6.59.
5-Amino-4-(trifluoromethyl)pentanoic acid hydrochloride
(71): yield: 1.82 g, 82%, white solid, m.p. 151-152 °C. 1H NMR
(400 MHz, D2O) δ 1.63-1.84 (m, 2H), 2.31-2.53 (m, 2H), 2.63 (br.
s, 1H), 2.87 (br. s, 2H). 13C {1H} NMR (100 MHz, D2O): δ 25.6,
32.5, 36.8 (m), 37.0, 127.1 (q, J= 284 Hz), 174.7. 19F NMR
(376 MHz, D2O): δ = -71.7 (d, J = 8 Hz). Anal. calcd for
C6H11ClF3NO2: C, 32.52; H, 5.00; Cl, 16.00; N, 6.32. Found: C,
32.67; H, 4.87; Cl, 15.88; N, 6.22.
(3) The search was performed at www.drugbank.ca in November
2019.
(4) (a) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Innate C-H
trifluoromethylation of heterocycles. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411-14415. (b) Novák, P.; Lishchynskyi, A.;
Grushin, V. V. Trifluoromethylation of α-haloketones. J. Am.
Chem. Soc. 2012, 134, 16167-16170. (c) Grygorenko, O. O.;
Artamonov, O. S.; Komarov, I. V.; Mykhailiuk, P. K.
Trifluoromethyl-substituted cyclopropanes. Tetrahedron 2011, 67,
803-823. (d) Charpentier, J.; Früh, N.; Togni, A. Electrophilic
trifluoromethylation by use of hypervalent iodine reagents. Chem.
Rev. 2015, 115, 2, 650-682. (e) Pan, X.; Xia, H.; Wu, J. Recent
advances
in
photoinduced
trifluoromethylation
and
difluoroalkylation. Org. Chem. Front. 2016, 3, 1163-1185.
5-Amino-5-(trifluoromethyl)pentanoic acid hydrochloride
(5) (a) Smith, W. C.; Tullock, C. W.; Muetterties, E. L.; Hasek, W. R.;
Fawcett, F. S.; Engelhardt, W. A.; Coffman, D. D. Fluorination
reactions of sulfur tetrafluoride. J. Am. Chem. Soc. 1959, 3165-
3166. (b) Hasek, W. R.; Smith, W. C.; Engelhardt, W. A. The
chemistry of sulfur tetrafluoride. II. The fluorination of organic
carbonyl compounds. J. Am. Chem. Soc. 1960, 543-551.
(6) (a) Raasch, M. S. The chemistry of sulfur tetrafluoride. IX.
Reaction with amino acids in hydrogen fluoride. J. Org. Chem.
1962, 27, 1406-1409. (b) Kobayashi, Y.; Chinenm E. Studies on
organic fluorine compounds. Syntheses and infrared absorption of
bis(trifluoromethyl)pyridines. Chem. Pharm. Bull. 1967, 15, 1896-
1900. (c) Sipyagin, A. M.; Kunchenko, B. V. Reactions of
1
(72): yield: 1.84 g, 83%, white solid, m.p. 78-80 °C. H NMR
(400 MHz, D2O) δ 1.73-1.91 (m, 4H), 2.98 (br. s, 2H), 3.38 (q, J
3
= 7 Hz, 1H). C {1H} NMR (100 MHz, D2O) δ 22.6, 24.0, 38.9,
49.0 (q, J = 27 Hz), 124.7 (q, J = 239 Hz), 171.1. 19F NMR
(376 MHz, D2O) δ -69.0 (d, J = 8 Hz). Anal. calcd for
C6H11ClF3NO2: C, 32.52; H, 5.00; Cl, 16.00; N, 6.32. Found: C,
32.37; H, 5.15; Cl, 15.79; N, 6.45.
ASSOCIATED CONTENT
polyhalopyridines.
Synthesis
of
the
isomeric
trifluoromethyltetrachloropyridines. Chem. Het. Comp. 1994, 30,
576-577. (d) Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M.
Recommendable routes to trifluoromethyl-substituted pyridine-
and quinolinecarboxylic acids. Eur. J. Org. Chem. 2003, 1559-
1568.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra of new and known compounds, pKa and pI
determination, CIF files and photos.
(7) (a) Sherman, W. R., Freifelder, M.; Stone, G. R. Three 2-
fluoroalkyl-5-nitrofurans. J. Org. Chem. 1960, 25, 2048-2049. (b)
Nishida, M.; Fujii, S.; Aoki, T.; Hayakawa, Y. Synthesis and
polymerization of ethynylthiophenes and ethynylfurans containing
trifluoromethyl groups J. Fluor. Chem. 1990, 46, 445-459.
(8) (a) Mertes, M. P.; Saheb, S. E. Use of sulfur tetrafluoride in
syntheses of potential anticancer agents. J. Pharm. Sci. 1963, 508-
509. (b) Mertes, M. P.; Saheb, S. E. 5-Trifluoromethyl-6-azauracil.
J. Het. Chem. 1965, 4, 491.
AUTHOR INFORMATION
Corresponding Author
E-mail: Pavel.Mykhailiuk@gmail.com
www.mykhailiuk.org, www.enamine.net
Notes
Conflict of interests: PM is an employee of a chemical supplier
Enamine.
(9) (a) Gerus, I. I.; Mironetz, R. X.; Kondratov, I. S.; Bezdudny, A.
V., Dmytriv, Y. V.; Shishkin, O. V.; Starova, V. S.; Zaporozhets,
O. A.; Tolmachev, A. A. Mykhailiuk, P. K. “Reported, but still
ACKNOWLEDGMENT
unknown.”
A
closer look into 3,4-bis- and 3,4,5-
Authors are grateful to Prof. A. A. Tolmachev (Enamine Ltd.) for
financial support; to Dr. S. Shishkina (ISC, Kharkiv, Ukraine) for
X-ray studies; to Mrs. I. Sadkova (Enamine Ltd., Kyiv, Ukraine)
and Dr. V. O. Iaroshenko (CMMS, Łódź, Poland) for the helpful
suggestions on the manuscript.
tris(trifluoromethyl)pyrazoles. J. Org. Chem. 2012, 77, 47−56. (b)
Mykhailiuk, P. K. Three-component synthesis of C2F5-substituted
pyrazoles from C2F5CH2NH2·HCl, NaNO2 and electron-deficient
alkynes. Beilstein J. Org. Chem. 2015, 11, 16-24. (c) Ivonin, S. P.;
Kurpil,’ B. B.; Bezdudny, A. V.; Volochnyuk, D. M.; Grygorenko,
O. O. An approach to (4-fluoroalkyl-1-alkyl-1H-pyrazol-3-
yl)methylamines. J. Fluor. Chem. 2015, 176, 78-81.
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chetyrekhftoristoy
aromaticheskikh
seroy.
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tris(pyrazolyl)borate decorated with nine
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1
2
3
4
5
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(26) Our previous interest in fluorinated amines: (a) Artamonov, O. S.;
Slobodyanyuk, E. Y.; Volochnyuk, D. M.; Komarov, I. V.;
Tolmachev, A. A.; Mykhailiuk, P. K. Synthesis of trifluoromethyl-
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Artamonov, O. S.; Slobodyanyuk, E. Y.; Shishkin, O. V.;
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Ulrich,
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Incorporation
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difluoromethanoproline into a peptide as a stable label for 19F
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difluoromethanoprolines into polypeptides. Org. Lett. 2012, 14,
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evaluation as a structural substitute of proline for solid state 19F-
NMR peptide studies. Org. Biomol. Chem. 2015, 13, 3171-3181.
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A.; Iaroshenko, V. O.; Mykhailiuk, P. K. Copper-Catalyzed O-
Difluoromethylation of Functionalized Aliphatic Alcohols: Access
to Complex Organic Molecules with an OCF2H Group J. Org.
Chem. 2016, 81, 5803-5813. (e) Mykhailiuk, P. K.; Voievoda, N.
M.; Afonin, S.; Ulrich, A. S.; Komarov, I. V. An optimized
9
trifluoromethyl-3-azabicyclo[3.1.0]hexanes:
conformationally
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restricted analogues of 4-trifluoromethylpiperidine. Synthesis
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I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Synthesis of
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drug discovery. Chem. Eur. J. 2018, 24, 12291-12297.
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protocol
for
the
multigram
synthesis
of
3-
(28) For an influence of the trifluoromethyl froup on the basicity of
aliphatic amines, see: (a) Shcherbatiuk, A. V.; Shyshlyk, O. S.;
Yarmoliuk, D. V.; Shishkin, O. V.; Shishkina, S. V.; Starova, V.
S.; Zaporozhets, O. A.; Zozulya, S.; Moriev, R.; Kravchuk, O.;
Manoilenko, O.; Tolmachev, A. A.; Mykhailiuk, P. K. Synthesis
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drug discovery. Tetrahedron 2013, 69, 3796-3804. (b)
Yarmolchuk, V. S.; Shishkin, O. V.; Starova, V. S.; Zaporozhets,
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K. Synthesis and Characterization of β-Trifluoromethyl-
Substituted Pyrrolidines. Eur. J. Org. Chem. 2013, 15, 3086-3093.
(29) CCDC numbers: 1847305 (73*HCl), 1847360 (74*HCl), 1847364
(75*HCl), 1847365 (76*HCl).
(trifluoromethyl)bicyclo[1.1.1]pent-1-ylglycine (CF3-Bpg). J.
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2019, 119, 10718-10801.
(33) Sulfur tetrafluoride (SF4), safety issues:
https://pubchem.ncbi.nlm.nih.gov/compound/Sulfur-tetrafluoride
(34) Hydrogen fluoride (HF), safety issues:
https://pubchem.ncbi.nlm.nih.gov/compound/hydrogen%20fluoride
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Insert Table of Contents artwork here
1
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CF3
CF3
5
6
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8
CF3
CO2H
SF4
HF, 85 oC
(Het)
Ar
(Het)
Ar
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N
[65 examples]
[gram-scale, fast, metal-free]
NO2
CF3
Cl
N
N
CF3
Me
N
S
Br
CF3
S
N
CF3
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