Economical and practical strategies for synthesis of α-trifluoromethylated amines

Article abstract of DOI:10.14233/ajchem.2015.17863

A powerful approach to synthesize α-trifluoromethylated amines has been developed. The method is operationally simple, broad in substrate scope and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile approach to synthesize α-trifluoromethylated amines but also provides a new method for exploring the new reactivity of trifluoroacetic anhydride.

Full text of DOI:10.14233/ajchem.2015.17863

Asian Journal of Chemistry; Vol. 27, No. 7 (2015), 2406-2408
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17863
Economical and Practical Strategies for Synthesis of α-Trifluoromethylated Amines
2
1
C.J. JIANG1,2,*, C.L. CHENG and S.F. YUAN
1School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, P.R. China
2Department of Chemical Engineering, Zhejiang University, Hangzhou, P.R. China
*Corresponding author: Tel./Fax: +86 571 85070370; E-mail: jcj312@zust.edu.cn
Received: 21 April 2014;
Accepted: 7 July 2014;
Published online: 30 March 2015;
AJC-17044
A powerful approach to synthesize α-trifluoromethylated amines has been developed. The method is operationally simple, broad in substrate
scope and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile approach to synthesize
α-trifluoromethylated amines but also provides a new method for exploring the new reactivity of trifluoroacetic anhydride.
Keywords: Trifluoromethylated amines, Trifluoroacetic anhydride, α-Trifluoromethylated amines, Grignard reagents.
reaction temperature (-78 °C) starting from ethyl trifluoro-
INTRODUCTION
acetate and the separation with the unreacted raw material13,14
.
Compounds related to α-trifluoromethylated amines have
attracted considerable attention due to the special chemical,
physical and biological properties conferred by the intro-
duction of trifluoromethyl group1-5. The available synthetic
methods for α-trifluoromethylated amines mainly involve the
direct transformation of CF3 with nucleophilic or electrophilic
trifluoromethylating reagents and the use of trifluoromethyl-
substituent imines6-9. However, trifluoromethylating reagents
such as C6H5SCF310, CF3CH(NMe2)211 and Me3SiCF312 are often
very expensive or difficult to be prepared. And trifluoro-
methyl-substituent imines are not easily available and unstable.
Therefore, the synthetic processes mentioned above are not
suitable for large-scale production and industrialization. Here,
we wish to describe the economical and practical methods for
the preparation of α-trifluoromethylated amines.
EXPERIMENTAL
All the reagents and solvents were industrial grade and
used without further purification. NMR spectra were recorded
on a BrukerAvance DPX-250. The purity of both starting mate-
rials as well as the reaction products were checked by TLC on
silica-gel polygram SILG/ UV254 plates or by a Shimadzu
Gas Chromatograph GC-10A instrument with a flame-ioniza-
tion detector using a 15 % carbowax 20 M chromosorb-w acid
washed 60-80 mesh column.
General procedure: To a suspension of N,O-dimethyl-
hydroxylamine hydrochloride (107.2 Kg, 1.1 kmol) in dichloro-
methane (400 L) were added trifluoroacetic anhydride (210
Kg, 1 kmol) and pyridine (174 Kg, 2.2 kmol) sequentially at
0 °C. The mixture was stirred at 0°C for 1 h and then diluted
with ice water (300 L) and washed with 2 M HCl (300 L). The
aqueous solution was extracted twice with dichloromethane
and dried under MgSO4. The crude Weinreb amide was
obtained after concentration without further purification (90 %
purity, 95 % yield). A mixture of the above 2,2,2-trifluoro-N-
As shown in Scheme-I, α-trifluoromethylated ketones
were the crucial intermediates which were formed by the
reaction of Weinreb amide with Grignard reagents. Weinreb
amide can be easily synthesized from trifluoroacetic anhydride
at room temperature with high yield, which avoided very low
O
OH
F3C
O
CF3
O
NH2
N
O
F3C
N
ii
iv
i
ii
+
NH
F3C
R
O
O
F3C
R
F3C
R
O
1
4
2
5
3
Scheme-I:Processes for synthesis of α-trifluoromethylated amines starting from trifluoroacetic anhydride and conditions: (i) CH2Cl2, rt, 95 %; (ii) RMgBr, THF,
0 °C, 76-90 %; (iii) NH2OH.HCl, CH3COONa, rt, 90-99 %; (iv) H2, Raney nickel, 90 °C, 98 %

Vol. 27, No. 7 (2015)
Economical and Practical Strategies for Synthesis of α-Trifluoromethylated Amines 2407
methoxy-N-methylacetamide (3 Kg, 90 % purity, 0.017 kmol)
in anhydrous THF (30 L) was cooled to 0 °C and treated with
0.5 M Grignard reagent in THF (42 L). The reaction mixture
was stirred at 0 °C for 0.5 h and allowed to warm to room
temperature. The resulting mixture was stirred at room tempe-
rature overnight. The reaction was quenched with saturated
aqueous ammonium chloride and extracted with ethyl acetate
three times. The organic layers were combined and washed
with water and brine, dried over MgSO4 and filtered. After
rectification, the resulting α-trifluoromethylated ketones were
obtained (95 % purity, 90 % yield).
Taking 1,1,1-trifluoro-2-propylamine as an example.
Hydroxylamine hydrochloride (3.7 Kg, 53 mol) was added to
a solution of sodium acetate (5.3 Kg, 64 mol) in 20 L water.
Subsequently, 1,1,1-trifluoroacetone (3 Kg, 26.8 mol) was
dosed within 0.5 h at a temperature range of -5 to + 10 °C. The
reaction mixture was stirred at room temperature overnight.
The crude oxime was diluted with a solution of sodium carbo-
nate (0.7 Kg) in 5 L water and then separated. The low-boiling-
point substances were then removed under reduced pressure
to yield a pale yellow solid which was used for the next step
without further purification. An autoclave was charged with
3 Kg of the oxime obtained above, 0.1 Kg of Raney nickel
(moisturized with methanol) and 30 L of methanol. The
autoclave was pressurized with hydrogen at a pressure of 0.2
MPa and heated to 90 °C. After hydrogen was consumed
completely, the reaction mixture was cooled to room tempe-
rature and filtered. The filtrate was cooled down and acidified
with diluted hydrochloric acid. The acidified solution was
evaporated and the obtained solid was washed with diethyl
ether and dried to yield 2-amino-1,1,1-trifluoropropane
hydrochloride. Hydrochloride obtained above was placed in a
three necked flask with stirrer, dropping funnel and condenser.
The oil bath was heated up to 90 °C and an aqueous sodium
hydroxide solution was slowly added to the flask. The liberated
amine was collected by distillation with a boiling point of 46-
47 °C (98 % yield).
Compound 3h: 1H NMR (400 MHz, CDCl3): δ 8.03 (2H,
aromatic protons, d), 7.55 (2H, aromatic protons, d); 13C NMR
(100 MHz, CDCl3): δ 179.45, 142.48, 131.42, 129.57, 128.22,
116.52.
Compound 3i: 1H NMR (400 MHz, CDCl3): δ 7.37-7.09
(5H, aromatic protons, m), 3.94 (2H, CH2Ph, s); 13C NMR
(100 MHz, CDCl3): δ 188.68, 131.26, 130.31, 129.62, 128.93,
127.94, 43.02.
Compound 5a: 1H NMR (400 MHz, CDCl3): δ 3.44-3.17
(1H, CHCF3, m), 1.38 (2H, NH2, s), 1.25 (3H, CH3, d); 13C
NMR (100 MHz, CDCl3): δ 126.83, 49.46, 15.66.
Compound 5b: 1H NMR (400 MHz, CDCl3): δ 3.04 (1H,
NH, s), 1.77 (1H, CHCF3, m), 1.36 (3H, NHCH2, m), 1.05 (3H,
CH3, t); 13C NMR (100 MHz, CDCl3): δ 126.80, 55.13, 23.02,
10.18.
Compound 5c: 1H NMR (400 MHz, CDCl3): δ 3.00 (1H,
CHCF3, m), 2.15-1.93 (1H, CH(CH3)2, m), 1.32 (2H, NH2, s),
1.06 (3H, CH3, d), 0.98 (3H, CH3, d); 13C NMR (100 MHz,
CDCl3): δ 126.94, 58.10, 27.79, 20.32, 16.31.
Compound 5d: 1H NMR (400 MHz, CDCl3): δ 7.43 (5H,
aromatic protons, m), 4.41 (1H, CHCF3, m), 2.05 (2H, NH2,
s); 13C NMR (100 MHz, CDCl3): δ 135.52, 128.95, 128.67,
127.83, 124.34, 57.95.
Compound 5e: 1H NMR (400 MHz, CDCl3): δ 7.25 (1H,
aromatic protons, t), 6.88 (3H, aromatic protons, m), 6.21 (1H,
NH, d), 5.75-5.46 (1H, CHCF3, m), 3.75 (3H, OCH3, s), 2.01
(3H, COCH3, s); 13C NMR (100 MHz, CDCl3): δ 169.49, 159.90,
134.25, 130.10, 124.47, 120.02, 114.43, 114.08, 55.34, 54.04,
23.13.
Compound 5f: 1H NMR (400 MHz, CDCl3): δ 7.53 (4H,
aromatic protons, m), 6.19 (1H, NH, d), 5.73 (1H, CHCF3,
m), 2.04 (3H, COCH3, s); 13C NMR (100 MHz, CDCl3): δ
169.41, 140.66, 133.94, 131.54, 129.60, 128.30, 126.26,
124.36, 122.07, 53.88, 23.12.
Compound 5g: 1H NMR (400 MHz, CDCl3): δ 7.42-6.93
(4H, aromatic protons, m), 6.17 (1H, NH, d), 5.66 (1H, CHCF3,
m), 2.03 (3H, COCH3, s); 13C NMR (100 MHz, CDCl3): δ169.49,
162.83, 135.06, 130.64, 129.03, 124.09, 116.38, 114.98, 53.89,
23.09.
NMR data of compound 3 and 5
Compound 3a: 1H NMR (400 MHz, CDCl3): δ 2.42 (3H,
CH3, s); 13C NMR (100 MHz, CDCl3): δ 188.66, 115.38, 23.65.
Compound 3b: 1H NMR (400 MHz, CDCl3): δ 2.77 (2H,
CH2, m), 1.18 (3H, CH3, t); 13C NMR (100 MHz, CDCl3): δ
192.14, 115.63, 29.87, 6.27.
Compound 5h: 1H NMR (400 MHz, CDCl3): δ 7.36-7.25
(4H, aromatic protons, m), 6.34-5.92 (1H, NH, m), 5.65 (1H,
CHCF3, m), 2.01 (3H, COCH3, s); 13C NMR (100 MHz,
CDCl3): δ 169.38, 132.85, 129.29, 129.03, 127.89, 123.08,
54.24, 23.19.
Compound 3d: 1H NMR (400 MHz, CDCl3): δ 8.05-7.42
(5H, aromatic protons, m); 13C NMR (100 MHz, CDCl3): δ
180.35, 135.53, 130.11, 129.92, 129.10, 116.68.
Compound 5i: 1H NMR (400 MHz, CDCl3): δ 7.43-7.25
(5H, aromatic protons, m), 3.49 (1H, CHCF3, m), 3.16 (1H,
CH2Ph, dd), 2.65 (1H, CH2Ph, dd), 1.55 (2H, NH2, s); 13C NMR
(100 MHz, CDCl3): δ 136.67, 129.27, 128.76, 127.06, 55.15,
36.31.
Compound 3e: 1H NMR (400 MHz, CDCl3):δ 7.49 (4H,
aromatic protons, m), 3.90 (3H, OCH3, s); 13C NMR (100 MHz,
CDCl3): δ 180.30, 159.97, 131.01, 130.07, 122.63, 122.14,
118.10, 113.84, 55.37.
RESULTS AND DISCUSSION
Compound 3f: 1H NMR (400 MHz, CDCl3): δ 8.35 (1H,
aromatic protons, s), 8.28 (1H, aromatic protons, d), 8.00 (1H,
aromatic protons, d), 7.75 (1H, aromatic protons, t); 13C NMR
(100 MHz, CDCl3): δ 179.53, 133.10, 131.87, 130.46, 129.92,
126.84, 124.54, 121.84, 114.92.
As shown in Scheme-I, α-trifluoromethylated ketones
were the crucial intermediates which were formed by the reac-
tion of Weinreb amide with Grignard reagents. Weinreb amide
can be easily synthesized from trifluoroacetic anhydride at
room temperature with high yield, which avoided very low
reaction temperature (-78 °C) starting from ethyl trifluoro-
acetate and the separation with the unreacted raw material.
Compound 3g: 1H NMR (400 MHz, CDCl3): δ 7.90-7.45
(4H, aromatic protons, m); 13C NMR (100 MHz, CDCl3): δ
179.69, 163.97, 131.73, 130.95, 125.94, 122.88, 122.67, 116.60.

2408 Jiang et al.
Asian J. Chem.
With regards to ketones, which could be directly obtained only
by distillation in vacuum. In general, oximes exist as solid
and can be synthesized by condensation of a ketone with
hydroxylamine. In our method, it was used for the nex step
without further purification. The oxime were subjected to
hydrogenation to produce corresponding α-trifluoromethylated
amines with high yield. Under the optimal reaction conditions,
the scope of the cascade reaction was then investigated by
using a variety of substrates to establish the generality of the
process (Table-1).
suitable to be scaled up and kilogram amounts of the target
amines had been prepared successfully.
Conclusion
In summary, we have developed a time and energy econo-
mical method for the synthesis of drug-related trifluoro-
methylated amines. This cascade approach is extremely
efficient since the reaction was afforded the desired products
with good to excellent yields. Furthermore, this method is
operationally simple with wide substrate generality and
amenable to scale-up.Notably, the simple and commonly
available CF3 source trifluoro acetic anhydride was employed
in trifluoromethylated amines. Therefore, this strategy provides
a new general approach for activation and application of
trifluoro acetic anhydride. We expect this novel method to be
of broad utility in the synthesis of biologically active medicinal
agents. We are continuing to explore the mechanism of this
reaction with various anhydrides and study the bioactivities
of these trifluoromethylated derivatives. The results of these
investigations will be reported elsewhere.
TABLE-1
SYNTHESIS OF α-TRIFLUOROMETHYLATED AMINES
Entry
R
Me
Et
Yield (%)
a
b
c
83
80
86
d
e
86
82
O
ACKNOWLEDGEMENTS
f
75
80
The authors thank for the financial support from Postdoctor
Fund Program of China.
CF3
g
REFERENCES
F
h
i
81
85
1. S. Purser, P.R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev.,
37, 320 (2008).
2. Y. Gong, K. Kato and H. Kimoto, Bull. Chem. Soc. Jpn., 75, 2637
(2002).
Cl
3. G.L. Grunewald, J. Lu, K.R. Criscione and C.O. Okoro, Bioorg. Med.
Chem. Lett., 15, 5319 (2005).
4. Z.J. Liu and J.T. Liu, Chem. Commun., 41, 5233 (2008).
5. C. Philippe, T. Milcent, T. Nguyen Thi Ngoc, B. Crousse and D. Bonnet-
Delpon, Eur. J. Org. Chem., 5215 (2009).
6. K. Funabiki, M. Nagamori, M. Matsui and D. Enders, Synthesis, 2585
(2002).
7. F. Gosselin, P.D. O'Shea, S. Roy, R.A. Reamer, C. Chen and R.P.
Volante, Org. Lett., 7, 355 (2005).
8. A. Deutsch, H. Glas, A. Hoffmann-Röder and C. Deutsch, RSC Adv.,
4, 9288 (2014).
9. M. Liu, J. Li, X. Xiao, Y. Xie and Y. Shi, Chem. Commun., 49, 1404
(2013).
10. Y. Yokoyama and K. Mochida, Tetrahedron Lett., 38, 3443 (1997).
11. Y. Xu and W.R. Dolbier, J. Org. Chem., 65, 2134 (2000).
12. G.K.S. Prakash and M. Mandal, J. Fluor. Chem., 112, 123 (2001).
13. I. Durán, A. Parrilla, J. Feixas and A. Guerrero, Bioorg. Med. Chem.
Lett., 3, 2593 (1993).
The cascade process was found to be broad in scope, with
good to excellent yields obtained for all the products (75-86 %).
The reaction allowed incorporation of a wide range of func-
tional groups in the α-trifluoromethylated products. The aro-
matic groups bearing electron-withdrawing or donating groups
were both well tolerated, as were substituted aromatic rings.
Sterically demanding substrates (Table-1, entry f) and hetero-
aromatic groups (Table-1, entry g and entry h), were also
successfully converted into the corresponding products with
excellent yields. More importantly, this cascade protocol is
also amenable to scale-up. It was satisfactory that the inter-
mediates ketones and the products amines were easily purified
by distillation or crystallization from n-hexane/EtOH without
requiring chromatographic purification. Therefore, the process
for the synthesis of α-trifluoromethylated amines were most
14. G.L. Grunewald, T.M. Caldwell, Q. Li and K.R. Criscione, J. Med.
Chem., 42, 3315 (1999).