Synthesis of isomeric (3,3,3-trifluoropropyl)anilines

Article abstract of DOI:10.1016/j.jfluchem.2014.06.003

Ortho-, meta- and para-isomers of (3,3,3-trifluoropropyl)aniline have been prepared in 60-70 g amount from the corresponding nitrobenzaldehydes in three steps. The key synthesis step was a transformation of the carboxylic group of 3-(nitrophenyl)propanoic acids into the trifluoromethyl group by SF₄.

Full text of DOI:10.1016/j.jfluchem.2014.06.003

Accepted Manuscript
Title: Synthesis of isomeric (3,3,3-trifluoropropyl)anilines
Author: Sergii Trofymchuk Andrii Bezdudny Yurii Pustovit
Pavel K. Mykhailiuk
PII:
S0022-1139(14)00149-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.06.003
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2-6-2014
4-6-2014
Please cite this article as: S. Trofymchuk, A. Bezdudny, Y. Pustovit, P.K. Mykhailiuk,
Synthesis of isomeric (3,3,3-trifluoropropyl)anilines, Journal of Fluorine Chemistry
(2014), http://dx.doi.org/10.1016/j.jfluchem.2014.06.003
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Short Communication
Synthesis of isomeric (3,3,3-trifluoropropyl)anilines.
Sergii Trofymchuk,a Andrii Bezdudny,b Yurii Pustovit,bꢀ Pavel K. Mykhailiuka,cꢀ
aEnamine Ltd., Vul. Oleksandra Matrosova 23, 01103 Kyiv, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska St. 5,
02660 Kiev-94, Ukraine
сDepartment of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska
Street, 64, Kyiv 01033, Ukraine
Ypus@ukr.net
Pavel.Mykhailiuk@gmail.com; Pavel.Mykhailiuk@mail.enamine.com
Abstract
Ortho-, meta- and para-isomers of (3,3,3-trifluoropropyl)aniline have been prepared in
60-70 g amount from the corresponding nitrobenzaldehydes in three steps. The key synthesis
step was a transformation of the carboxylic group of 3-(nitrophenyl)propanoic acids into the
trifluoromethyl group by SF4.
CF3
CHO
NO2
CO2H
1. SF4
2. [H]
NH2
NO2
60-70 g
3 isomers
Key words
Anilines, Amines, Trifluoromethyl, Fluorine, Sulfur tetrafluoride.
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1. Introduction
The influence of fluorine atoms and fluoroalkyl groups on physicochemical and
pharmacokinetic properties of organic compounds is no doubt today [1].Up to 25% of all
pharmaceuticals and 40% of agrochemicals contain at least one fluorine atom. Huge fraction of
these compounds bears the trifluoromethyl-substituted aromatics, e.g. trifluoromethylanilines
[2].Although conceptually attractive, however, anilines bearing other fluoroalkyl groups attracted
almost no attention so far. Presumably, the absence of practical approaches towards these
compounds renders their subsequent practical application. To fill in this gap, previously we
described the synthesis of isometric (2,2,2-trifluoroethyl)anilines [3]. Herein, we report on the
multigram preparation of three isomers of (3,3,3-trifluoropropyl)aniline (1a-с).
2. Results and discussion
In 2010, the synthesis of the para-isomer 1a was described in two patents [4]. The
authors obtained amine 1a by hydrogenation of the corresponding (3,3,3-trifluoroprop-1-en-1-
yl)nitrobenzene in 47-83% yield. Although the reaction seems to be scalable, the practical
availability of the starting material is somewhat limited [4-13]. Therefore, we developed an
alternative three-step synthesis of compound 1a starting from commercially available para-
nitrobenzaldehyde 2a (Scheme 1). First, compound 2a was reacted with Meldrum acid in
HCO2H to give acid 3a in 60% yield according to the literature protocol [14]. Next, acid 3a
was treated with SF4 (3 equiv) for four days [15]. The obtained product 4a was isolated from
the reaction mixture in 72% yield by distillation. Finally, standard hydrogenation of the nitro
group in 4a by Pd/H2 afforded the target amine 1a in 91% yield. The overall synthesis yield
was 45% and included three steps from aldehyde 2a. Importantly, the developed protocol to 1a
was fully reproducible upon scaling up, and allowed to obtain 63 g of the product in one
synthetic run.
CF3
CO2H
CF3
O
i
ii
iii
a: 60%
b: 72%
c: 68%
72%
78%
80%
91%
95%
94%
NO2
4a-c
NO2
2a-c
NO2
3a-c
NH2
1a-c
a: para-, b: meta-, c: ortho-
i, Meldrum's acid, Et3N, formic acid, DMF, reflux
ii, SF4 (3 equiv), autoclave, from RT to 35 °C
iii, H2, Pd/C, MeOH, RT.
Scheme 1. Synthesis of (3,3,3-trifluoropropyl)anilines 1a-c.
Having the developed and scalable protocol in hand, we used it to prepare the
previously unknown isomers of amine 1a - compounds 1b and 1c. The same synthetic strategy
was successfully realized to afford amine 1b in 47% overall yield from aldehyde 2b [14] and
isomer 1c in 55% overall yield from aldehyde 2c [16]. 69 g of 1b and 67 g of 1c were obtained
in each synthetic run.
3. Conclusion
We developed a practical general approach to isomeric novel (1a) and known (1b, 1c)
(3,3,3-trifluoropropyl)anilines (1a-c). The syntheses commenced from the corresponding
nitrobenzaldehydes 2a-c and included three steps. The key reaction was the conversion the
aliphatic carboxylic group into the trifluoromethyl group by SF4. 63-69 g of the target amines 1a-
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c were obtained in one synthetic run. Given the scalability of the developed protocols, we believe
that the synthesized anilines will find true practical application in the field of both the drug
discovery and agrochemistry as the valuable building blocks.
4. Experimental
Solvents were purified according to the standard procedures. All reactions were
performed in argon atmosphere. All the other reagents were provided by Enamine LTD. Column
chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as the stationary
1
19
13
phase. H-, F-, C-NMR spectra were recorded on Bruker Avance 500 spectrometer (at 499.9
MHz, 470.3 MHz and 124.9 MHz). Chemical shifts are reported in ppm downfield from TMS
13
(1H, C) or CFCl3 (19F) as internal standards. MS analyses were done on an LCMS instrument
with chemical ionization (CI) or GCMS instrument with electron impact ionization (EI).
4.1. General procedure for the synthesis of nitro-3-phenylpropanoic acids 3a-c [14]:
NEt3 (56.6 g, 0.56 mol) was added dropwise to stirred formic acid (64.4g, 1.4 mol) at 5
°C. To the resulting reagent were added DMF (150 ml), Meldrum’s acid (57.6 g, 0.4 mol) and
aldehyde 2a-c (60.4 g, 0.4 mol). The reaction mixture was heated at reflux for 4 h. The solvent
was evaporated under vacuum.
The residue was triturated with water (1000 ml) and acidified with 12N HCl to pH = 2.
The formed product was filtered off, dried on air, and crystallized from EtOAc (3a) or CCl4
(3b,c) to obtain the pure material.
4.1.1. 4-Nitro-benzenepropanoic acid (3a)
Yield = 60% (46.8 g); m.p. 166 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.61 (t, J = 8.5 Hz, 2 H), 2.93 (t, J = 8.5 Hz, 2 H), 7.51 (d,
J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 8.12 (d, 3JHH = 8.7 Hz, 2 H), 12.25 (broad s).
13C NMR (125 MHz, DMSO-d6): δ = 30.2 (s), 34.4 (s), 123.4 (s), 129.7 (s), 146.0 (s), 148.4 (s),
173.4 (s).
LCMS: m/z = 194 (M-H+).
Anal. calcd for C9H9NO4: C, 55.39; H, 4.65; N, 7.18. Found: C, 55.22; H, 4.37; N, 7.48.
4.1.2. 3-Nitro-benzenepropanoic acid (3b)
Yield = 72% (56.2 g); m.p. 112 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.67 (t, J = 9.0 Hz, 2 H), 2.96 (t, J = 9.0 Hz, 2 H), 7.59 (t,
J = 9.5 Hz, 1 H), 7.73 (d, J = 9.5 Hz, 1 H), 8.07 (d, J = 9.5 Hz, 1 H), 8.13 (s, 1 H), 12.25 (broad
s).
13C NMR (125 MHz, DMSO-d6): δ = 29.9 (s), 34.7 (s), 121.2 (s), 123.0 (s), 129.8 (s), 135.4 (s),
143.4 (s), 147.9 (s), 173.5 (s).
LCMS: m/z = 194 (M-H+).
Anal. calcd for C9H9NO4: C, 55.39; H, 4.65; N, 7.18. Found: C, 55.25; H, 4.42; N, 7.39.
4.1.3. 2-Nitro-benzenepropanoic acid (3c)
Yield = 67% (52.2 g); m.p. 111 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.60 (d, J = 9.0 Hz, 2 H), 3.05 (d, J = 9.0 Hz, 2 H), 7.55
(t, J = 10.0 Hz, 1 H), 7.50 (d, J = 10.0 Hz, 1 H), 7.67 (t, J = 10.0 Hz, 1 H), 7.93 (d, J = 10.0 Hz,
1 H), 12.28 (broad s).
13C NMR (125 MHz, DMSO-d6): δ = 27.2 (s), 34.3 (s), 121.2 (s), 124.4 (s), 127.7 (s), 131.8 (s),
133.4 (s), 135.1 (s), 148.3 (s), 173.4 (s).
LCMS: m/z = 194 (M-H+).
Anal. calcd for C9H9NO4: C, 55.39; H, 4.65; N, 7.18. Found: C, 55.12; H, 4.38; N, 7.31.
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4.2. General procedure for fluorination of acids 3a-c:
Acid 3a-c (97.5 g, 0.5 mol) was placed in a 500-ml stainless steel autoclave which was
then evacuated, cooled with liquid nitrogen and charged with SF4 (162 g, 1.5 mol). The
autoclave was kept at RT for 4 days (3c) or at RT for 2 days and 2 days at 35 °C (3a-b). The
gaseous products were vented off, and the residue was dissolved in CH2Cl2, poured onto ice and
triturated with conc. NH4OH (200 ml). After 2 h the mixture was filtered, the organic phase was
separated, dried over Na2SO4 and concentrated. The residue was subjected to vacuum
distillation.
4.2.1. 1-Nitro-4-(3,3,3-trifluoropropyl)benzene (4a)
Yield = 72%; m.p. 32-33 °C; b.p. 101-103 °C /0.15 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.42-2.51 (m, 2 H), 3.01 (t, 3JHH = 8.3 Hz, 2 H), 7.40 (d, 3JHH
= 8.7 Hz, 2 H), 8.19 (d, 3JHH = 8.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 28.0 (q, 3JCF = 3.3 Hz), 34.8 (q, 2JCF = 29 Hz), 123.8, 126.2
(q, 1JCF = 276.7 Hz), 129.0, 146.3, 146.8.
19F NMR (188 MHz, CDCl3): δ = -66.96 (s).
GCMS: m/z = 219 (M+).
Anal. calcd for C9H8F3NO2: C, 49.32; H, 3.68; N, 6.39. Found: C, 49.20; H, 3.45; N, 6.67.
4.2.2. 1-Nitro-3-(3,3,3-trifluoropropyl)benzene (4b)
Yield = 78%; oil; b.p. 95-97 °C /0.15 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.42-2.52 (m, 2 H), 3.02 (t, 3JHH = 8.2 Hz, 2 H), 7.51 (t, 3JHH
= 7.9 Hz, 1 H), 7.57 (d, 3JHH = 7.9 Hz, 1 H), 8.09 (s, 1 H), 8.11 (d, 3JHH = 7.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 27.8 (q, 3JCF = 3.3 Hz), 34.9 (q, 2JCF = 29 Hz), 121.7, 123.0,
126.2 (q, 1JCF = 276 Hz), 129.6, 134.4, 140.7, 148.4.
19F NMR (188 MHz, CDCl3): δ = - 67.04 (s).
GCMS: m/z = 219 (M+).
Anal. calcd for C9H8F3NO2: C, 49.32; H, 3.68; N, 6.39. Found: C, 49.51; H, 3.72; N, 6.59.
4.2.3. 1-Nitro-2-(3,3,3-trifluoropropyl)benzene (4c)
Yield = 80% oil; b.p. 80-81 °C / 0.1 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.46-2.56 (m, 2 H), 3.15 (t, 3JHH = 8.1 Hz, 2 H), 7.4 (d, 3JHH
= 7.5 Hz, 1 H), 7.44 (t, 3JHH = 7.9 Hz, 1 H), 7.6 (t, 3JHH = 7.5 Hz, 1 H), 7.99 (d, 3JHH = 7.9 Hz,
1 H).
13C NMR (125 MHz, CDCl3): δ = 26.1 (q, 3JCF = 3.3 Hz), 34.5 (q, 2JCF = 28.7 Hz), 125.0, 126.4
(q, 1JCF = 276.7 Hz), 128.0, 132.1, 133.4, 134.0, 148.9.
19F NMR (188 MHz, CDCl3): δ = - 66.98 (s).
GCMS: m/z = 219 (M+).
Anal. calcd for C9H8F3NO2: C, 49.32; H, 3.68; N, 6.39. Found: C, 49.12; H, 3.86; N, 6.23.
4.3. General procedure for hydrogenation of (3,3,3-trifluoropropyl)nitrobenzenes 4a-c:
A solution of nitro compound (82.4 g, 0.376 mol) in MeOH (500ml) was stirred under an
atmosphere of hydrogen at ambient temperature and pressure in the presence of Pd/C (12 g, 5%)
until consumption of hydrogen ceased. The catalyst was filtered off, and the filtrate was
evaporated and vacuum distilled.
4.3.1. 4-(3,3,3-Trifluoropropyl)aniline (1a)
Yield = 91%; oil; b.p. 103-104 °C /11 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.26-2.36 (m, 2 H), 2.74 (t, 3JHH = 8.3 Hz, 2 H), 3.55 (br s, 2
4
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H), 6.62 (d, 3JHH = 8.2 Hz, 2 H), 6.96 (d, 3JHH = 8.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 27.1 (q, 3JCF = 3 Hz), 35.8 (q, 2JCF = 28 Hz), 115.2, 126.7 (q,
1JCF = 277 Hz), 128.7, 128.8, 144.7.
19F NMR (188 MHz, CDCl3): δ = -67.15 (s).
HPLC: m/z = 190 (M + H+).
Anal. calcd for C9H10F3N: C, 57.14; H, 5.33; N, 7.40. Found: C, 57.45; H, 5.64; N, 7.12.
4.3.2. 3-(3,3,3-Trifluoropropyl)aniline (1b)
Yield = 95%; oil; b.p. 105-107 °C /12 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.28-2.38 (m, 2 H), 2.74 (t, 3JHH = 8.4 Hz, 2 H), 3.57 (br s, 1
H), 6.47 (s, 1 H), 6.52 (d, 3JHH = 7.8 Hz, 1 H), 6.56 (d, 3JHH = 7.8 Hz, 1 H), 7.07 (t, 3JHH = 7.8
Hz, 1 H).
13C NMR (125 MHz): δ = 27.9 (q, 3JCF = 3 Hz), 35.3 (q, 2JCF = 28.3 Hz), 113.2, 114.7, 118.1,
126.6 (q, 1JCF = 276.7 Hz, CDCl3), 129.4, 140.1, 146.6.
19F NMR (188 MHz, CDCl3): δ = - 67.25 (s).
HPLC: m/z = 190 (M + H+).
Anal. calcd for C9H10F3N: C, 57.14; H, 5.33; N, 7.40. Found: C, 56.96; H, 5.12; N, 7.72.
4.3.3. 2-(3,3,3-Trifluoropropyl)aniline (1c)
Yield = 94%; oil; b.p. 108-109 °C /14 mm Hg.
1H NMR (500 MHz, CDCl3): δ = 2.33-2.43 (m, 2 H), 2.71 (t, 3JHH = 8.4 Hz, 2 H), 3.49 (br s,
1H), 6.67 (d, 3JHH = 7.9 Hz, 1 H), 6.74 (t, 3JHH = 7.5 Hz, 1 H), 7.01 (d, 3JHH = 7.5 Hz, 1 H),
7.06 (t, 3JHH = 7.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 23.7 (q, 3JCF = 3.3 Hz), 32.7 (q, 2JCF = 28.3 Hz), 115.8,
118.9, 122.9, 126.8 (q, 1JCF = 277 Hz), 127.7, 129.1, 143.9.
19F NMR (188 MHz, CDCl3): δ = -66.97 (s).
HPLC: m/z = 190 (M + H+).
Anal. calcd for C9H10F3N: C, 57.14; H, 5.33; N, 7.40. Found: C, 57.02; H, 5.35; N, 7.17.
Supporting Information
Copies of NMR spectra for all new compounds.
Acknowledgement
All authors are grateful to Prof. Dr. Yurii L.Yagupolskii for helpful discussions on the
manuscript; and to Prof. Dr. Andrei Tolmachev for the financial support of the project.
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Three isomeric (3,3,3-trifluoropropyl)anilines are synthesized.
The compounds are obtained in a multigram scale.
SF4 is used to convert COOH group into the CF3 one.
8
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