The trifluoromethylation of iminium salts by the addition of trifluoromethyltrimethylsilane

Article abstract of DOI:10.3184/174751916X14636698285461

Eleven trifluoromethylated amines were synthesised in high yield (up to 98%) under metal-free and oxidant-free conditions using iminium salts as starting material and the addition of trifluoromethyltrimethylsilane in dimethylformide containing potassium f

Full text of DOI:10.3184/174751916X14636698285461

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 JUNE, 379–381
RESEARCH PAPER 379
The trifluoromethylation of iminium salts by the addition of
trifluoromethyltrimethylsilane
Haidong Liua,c, Bo Chena, Jin Caib, Junqing Chenb and Min Jia,c*
aSchool of Biological Science and Medical Engineering, Southeast University, Si Pai Lou 2#, Nanjing City 210096, P.R. China
bSchool of Chemistry and Chemical Engineering, Southeast University Si Pai Lou 2#, Nanjing City 210096, P.R. China
cSuzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou, 215123, P.R. China
Eleven trifluoromethylated amines were synthesised in high yield (up to 98%) under metal-free and oxidant-free conditions using iminium
salts as starting material and the addition of trifluoromethyltrimethylsilane in dimethylformide containing potassium fluoride.
Keywords: trifluoromethylation, trifluoromethylated amines, iminium salts, cyanation, Ruppert–Prakash reagent, metal-free, oxidant-free
1
Fluorine-containing compounds play a significant role in
modern pharmaceutical and agrochemistry. Approximately
20–25% of all drugs available in the market contains at least
one fluorine substituent.1–3 The unique nature of fluorine imparts
many desirable physicochemical properties to therapeutic and
diagnostic small molecule drugs that possess an appropriately
positioned fluorine substituent. These include enhanced
metabolic stability, better binding affinity for target biomolecules,
higher lipophilicity, and stronger dipole moments compared
to their non-fluorinated analogs.4–6 Celecoxib and fluoxetine
are both examples of top-selling pharmaceuticals containing
trifluoromethyl groups (Scheme 1).7,8 The trifluoromethyl group
can have dramatic effects on the bioavailability and efficacy of
organic molecules, and therefore, there has been considerable
interest in the development of synthetic methodologies for
the direct and selective introduction of the trifluoromethyl
moiety into industrially important molecules. Recently, amines
with a trifluoromethyl substituent at the alpha position have
attracted considerable attention as synthetic building blocks for
pharmaceutical products and agrochemicals.9–14
by HRMS, H NMR, and 13C NMR. In order to improve the
yield, various ratios of iminium salts, CF3TMS and KF were
examined. Increasing the amount of CF3TMS and KF increased
the yield of the product (entries 2–4). When the ratio of iminium
salts/CF3TMS/KF was 1:3:3, an excellent yield (92%) of the
desired product was obtained (entry 3). Any further increase
in the ratio proved to be detrimental to the reaction (entry 4).
Screening the solvent for the reaction indicated that MeCN,
toluene, THF, and 1,4-dioxane were not suitable because of the
poor solubility of 1a in these solvents (entries 5–8). DMF gave
the desired product in moderate yield (entry 9). An excellent
yield (96%) was obtained when the reaction was performed at
low temperature in DMF (entry 10).
With the optimised reaction conditions in hand (3 equiv. of
CF3TMS, 3 equiv. of KF in DMF under –20 °C), we examined
the scope of the reaction with a variety of iminium salts.
Representative examples are listed in Table 2. For aromatic
iminium salts, the reaction often provided good to excellent
yields of the desired products. For aliphatic iminium salts,
the corresponding product was also formed in good yield
(3d). The reaction conditions also tolerated the presence of an
alcohol functional group in the starting materials (3i and 3j).
Cyclic aromatic iminium salts such as 1e, 1h, and 1i can be
smoothly converted into the corresponding trifluoromethylated
derivatives in 93%, 95% and 71% isolated yield, respectively.
In general, iminium salts bearing electron-rich aryl substituents
(4-(N,N-dimethylamino)phenyl) afforded better yields than
Preformed iminium salts are of great theoretical and practical
interest. Nevertheless, there are only a few examples in the
literature concerning the synthesis and applications of these
compounds.15–22 In this paper, we describe an efficient synthesis
of trifluoromethylated amines through trifluoromethylation
of iminium salts with trimethyl(trifluoromethyl)silane under
metal-free and oxidant-free reaction conditions.
Results and discussion
Table 1 Effect of variation of solvent-, base- and CF3TMS-loading on the
yield of trifluoromethylated amine (3a) formed by the trifluoromethylation
of iminium salt (1a)a
Based on Qing’s work on benzoyl peroxide (BPO)-promoted
oxidative trifluoromethylation of tertiary amines with the
Ruppert–Prakash reagent,23,24 we examined the synthesis of
trifluoromethylated amines by reacting CF3TMS with iminium
salts 1a in the presence of KF in DCM at 50 °C. The reaction
proceeded smoothly giving a novel product 3a in 37% yield,
(Table 1, entry 1) which was unambiguously characterised
F
3C
ClO4
KF
CF3TMS,
N
N
N
N
solvent, temp
Entry
CF3TMS
KF
Solvent
Yield/%b
1
2
3
4
5
6
7
8
9
1.0
2.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
2.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
DCM
DCM
DCM
DCM
MeCN
Toluene
THF
1,4-Dioxane
DMF
37
81
92
78
39
32
27
29
67
96c
O
NH2
S
F3C
O
N
O
N
N
H
F
3C
fluoxetine
celecoxib
1
0
DMF
Scheme 1
aThe reaction was carried out with 0.5 mmol of 1a, 1.5 mmol of CF3TMS, 1.5 mmol of KF,
in solvents (0.2 M).
b
Isolated yield.
cThe reaction was performed under –20 °C.
* Correspondent. E-mail: 101010516@seu.edu.cn

380 JOURNAL OF CHEMICAL RESEARCH 2016
Table 2 Yields of trifluoromethylated amines 3a–k formed by the
trifluoromethylation of iminium salts 1a–k with CF3TMS under optimised
reaction conditionsa
N
N
N
O
N
O
F
3C
ClO4
R3
CF3TMS, KF
R3
NC
N
O
N
R1
N
R2
R1
N
R2
DMF, –20 o
C
O
HN
a
4e
98%
a,b
5b
a,b
0%
6b
0%
Entry
1
1
R1
R2
Me
1b 4-MeC6H4 Me
R3
3
3a
Yield/% of 3b
96
N
N
1a Ph
4-Me2NC6H4
2
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
3b
3c
3d
3e
3e
3g
3h
3i
95
95
83
97
97
97
98
81
78
75
3
1c Ph
1d Bn
1e Bn
Et
N
N
N
4
Me
-CH2-
a,b
7b
0%
a,b,c
5
8b
trace
6
1f 3-Me C6H4 Et
1g 3-Me C6H4 Me
Scheme 2
7
presence of catalytic amounts of DBU and aluminium chloride (or in
the presence P2O5) was refluxed for 16 h under an argon atmosphere.
The solvent was removed under reduced pressure and the residual
oil was dissolved in DCM. Dry THF was added to the DCM solution
and the crystalline product was precipitated from the solution. The
resulting solid was dried under high vacuum to give the corresponding
iminium salts 1a–1k.
8
1h Bn
1i Bn
-(CH2)2- 4-Me2NC6H4
9
-CH2-
4-HOC6H4
4-HOC6H4
furan-2-yl
10
1j 4-MeC6H4 Me
3j
11
1k Ph Me
3k
aThe reaction was carried out with 0.5 mmol of 1, 1.5 mmol of CF3TMS, 1.5 mmol of KF, in
DMF (0.2 M) under –20 °C.
bIsolated yield after chromatography.
Synthesis of α-trifluoromethylated amines (3a–3k); general procedure
DMF (2.5 mL) was added to a flask (10 mL) containing an iminium
salt (0.5 mmol) and anhydrous potassium fluoride (87 mg, 1.5 mmol).
The reaction mixture was cooled to –20 °C. Ruppert’s reagent (213 mg,
1.5 mmol) was then slowly added to the reaction mixture which was
then stirred at this temperature for 2–10 h and the formation of the
product was monitored by TLC. After completion of the reaction, the
mixture was cooled to room temperature and the crude product was
purified by column chromatography using DCM and hexane to afford
corresponding pure products.
N,N-Dimethyl-4-(2,2,2-trifluoro-1-(methyl(phenyl)amino)ethyl)
aniline (3a): Colourless oil; 1H NMR: δ 7.12–7.24 (m, 4H), 6.84 (d, 2H,
J = 8.1 Hz), 6.77 (t, 1H, J = 7.2, 14.4 Hz), 6.60 (d, 2H, J = 9.0 Hz),
5.35 (dd, 1H, J = 8.4, 17 Hz), 2.89 (s, 3H), 2.64 (s, 3H); 13C NMR: δ
150.22, 131.98, 129.25, 128.95, 128.17, 124.38, 122.62, 119.69, 118.46,
113.98, 112.10, 64.78, 64.39, 64.01, 63.63, 40.30, 33.27; HRMS (ESI)
for C17H20F3N2 [M + H]+ calcd 309.1579; found: 309.1588.
those containing electron-poor substituents (4-hydroxl-phenyl
and 2-furanyl). This result was expected since electron-rich aryl
substituents would increase the carbonium ion character of the
iminium carbon due to the diminished ability of the nitrogen to
contribute its lone pair to the C–N bond. Overall, these results
demonstrate the versatility of the present methodology.
We also examined the direct functionalisation of iminium
salts with other nucleophiles. We were delighted when
TMSCN afforded the desired cyanide product 4e in 98%
yields. However, nucleophiles derived from dimethylmalonate,
indole, N-methylindole, N-methylpyrrole, and phenylethynyl
groups did not react with iminium salts 1b to afford the desired
products. Moreover, (phenylethynyl) copper also failed to react
with iminium salts 1b to afford the desired product in solvents
such as MeCN, MeOH, and DMF at temperatures ranging from
–20 °C to 90 °C (Scheme 2).
N-(1-(4-(Dimethylamino)phenyl)-2,2,2-trifluoroethyl)-N,4-
dimethylaniline (3b): Colourless oil; 1H NMR: δ 7.08 (m, 2H, J = 8.4,
9.1 Hz), 6.97 (d, 2H, J = 8.4), 6.72 (d, 2H, J = 8.4), 6.56 (d, 2H, J = 9.0),
5.19 (dd, 1H, J = 8.4, 17 Hz), 2.85 (s, 6H), 2.58 (s, 3H), 2.18 (s, 3H);
13C NMR: δ 150.25, 148.29, 132.08, 129.77, 129.01, 128.28, 127.87,
124.49, 120.68, 119.88, 114.42, 112.13, 65.39, 65.01, 64.63, 64.25,
40.30, 33.43, 20.29; HRMS (ESI) for C18H22F3N2 [M + H]+ calcd
323.1735; found: 323.1745.
4-(1-(Ethyl(phenyl)amino)-2,2,2-trifluoroethyl)-N,N-dimethyl-
aniline (3c): Colourless oil; 1H NMR: δ 7.10–7.20 (m, 4H), 6.83 (d, 2H,
J = 8.1), 6.72 (t, 1H, J = 7.2), 6.56 (d, 2H, J = 9.0), 5.25 (dd, 1H, J = 8.4,
17 Hz), 3.05 (m, 2H), 2.85 (s, 6H), 0.88 (t, 3H, J = 6.9); 13C NMR: δ
150.18, 148.23, 132.07, 129.23, 129.11, 129.09, 128.28, 124.50, 120.47,
118.54, 115.37, 112.10, 40.29, 39.85, 12.71; HRMS (ESI) for C18H22F3N2
[M + H]+ calcd 323.1735; found: 323.1751.
Experimental
All reagents including analytical-grade solvents were purchased from
Sigma-Aldrich (USA), Aladdin (P.R. China), or Sinopharm Chemical
Reagent (P.R. China) and were used without further purification.
Melting points are uncorrected. NMR spectra were obtained on a
Bruker 300 MHz spectrometer (1H NMR at 300 Hz, 13C NMR at
75 Hz) in CDCl3 using TMS as internal standard. Chemical shifts (δ)
are given in ppm and coupling constants (J) in Hz. Mass spectra (MS)
were obtained from Finnigan (USA) MAT-95 Spectrometry Services.
The synthesised compounds were obtained as detailed below. Silica gel
(200–300 µm) for flash chromatography was purchased from Qingdao
Haiyang Chemical (P.R. China).
Synthesis of iminium salts; general procedure
4- (1- (Benzyl (methyl) amino) -2,2,2-trifluoroethyl) -N,N-
dimethylaniline (3d): Colourless oil; 1H NMR: δ 7.12 (m, 2H), 6.93 (m,
2H), 6.49–6.58 (m, 4H), 4.95 (dd, 1H, J = 9.0, 18 Hz), 3.43 (m, 1H),
3.09 (m, 1H), 2.85(m, 8H); 13C NMR: δ 150.62, 150.48, 131.85, 129.85,
129.83, 129.18, 128.06, 127.29, 124.72, 124.28, 120.50, 118.61, 117.90,
112.05, 106.25, 61.96, 61.56, 61.17, 60.77, 48.36, 40.24, 28.28; HRMS
(ESI) for C18H22F3N2 [M + H]+ calcd 323.1735; found: 323.1744.
N,N-Dimethyl-4-(2,2,2-trifluoro-1-(indolin-1-yl)ethyl)aniline (3e):
The amine (10 mmol) in ethanol (10 mL) was added to a round-bottom
flask and was cooled to 0–5 °C. Whilst stirring, perchloric acid
(10 mmol) (aqueous solution, 70% by weight) was added dropwise.
Stirring was continued for an additional 20 min at 0–5 °C, and then the
pH value was measured and corrected to 4–5 by the dropwise addition
of amine. The solvent was evaporated and the residue was dried in
vacuo. The crude crystalline product was purified by recrystallisation
from dichloromethane and isopropyl alcohol.
1
Colourless oil; H NMR: δ 7.15–7.26 (m, 6H), 6.63 (d, 2H, J = 8.7),
A mixture of 4 mmol of N-alkylanilinium perchlorate and the
respective aldehyde (5 mmol) in dry chloroform (10 mL) in the
4.01 (dd, 1H, J = 8.8, 17.7 Hz), 3.67 (d, 1H, J = 13.8), 3.40 (d, 1H,
J = 13.5), 2.89 (s, 6H), 2.23 (s, 3H); 13C NMR: δ 150.34, 139.10, 132.25,

JOURNAL OF CHEMICAL RESEARCH 2016 381
130.35, 128.73, 128.47, 128.34, 127.12, 124.69, 120.93, 119.18, 111.91,
67.81, 67.45, 67.09, 66.72, 59.37, 40.32, 38.80, 38.78; HRMS (ESI) for
C18H20F3N2 [M + H]+ calcd 321.1579; found: 321.1594.
(s, 1H), 3.25 (m, 2H), 3.01 (m, 8H); 13C NMR: δ 150.84, 149.32, 130.79,
128.43, 127.41, 124.98, 120.24, 119.61, 116.43, 112.29, 108.54, 53.79,
53.69, 50.01, 40.37, 28.07; HRMS (ESI) for C17H19N2+ [M – CN]+ calcd
251.1543; found: 251.1547.
N-(1-(4-(Dimethylamino)phenyl)-2,2,2-trifluoroethyl)-N-ethyl-
1
3-methylaniline (3f): Colourless oil; H NMR: δ 7.18–7.28 (m, 3H),
6.69–6.80 (m, 5H), 5.41 (dd, 1H, J = 8.8, 17.2 Hz), 3.24 (m, 2H), 2.99
(s, 6H), 2.38 (s, 3H), 1.02 (t, J = 6.8, 3H); 13C NMR: δ 150.22, 148.37,
138.91, 129.13, 129.11, 129.09, 127.85, 125.01, 120.69, 119.56, 116.28,
112.65, 112.14, 109.98, 65.04, 64.76, 64.47, 64.19, 40.27, 40.26, 39.85,
21.86, 12.79; HRMS (ESI) for C19H24F3N2 [M + H]+ calcd 337.1892;
found: 337.1904.
We are grateful for financial support from the National Basic
Research Program of China (no. 2013AA032205).
Received 19 February 2016; accepted 8 April 2016
Paper 1603929 doi: 10.3184/174751916X14636698285461
Published online: 25 May 2016
N-(1-(4-(Dimethylamino)phenyl)-2,2,2-trifluoroethyl)-N,3-
1
dimethylaniline (3g): Colourless oil; H NMR: δ 7.04–7.14 (m, 4H),
References
6.55–6.64 (m, 4H), 5.27 (dd, 1H, J = 8.5, 17.0 Hz), 2.85 (s, 6H), 2.60 (s,
3H), 2.24 (s, 3H); 13C NMR: δ 150.37, 150.23, 138.97, 132.00, 129.08,
128.94, 128.21, 124.42, 120.63, 119.89, 119.42, 114.78, 112.14, 111.19,
64.77, 64.39, 64.01, 63.63, 40.29, 33.29, 29.68, 21.86; HRMS (ESI) for
C18H22F3N2 [M + H]+ calcd 323.1735; found: 323.1750.
1
2
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4
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4-(1-(3,4-Dihydroquinolin-1(2H)-yl)-2,2,2-trifluoroethyl)-N,N-
dimethylaniline (3h): Colourless oil; 1H NMR: δ 7.13 (m, 2H), 7.0 (m,
1H), 6.85 (m, 1H), 6.76 (m, 1H), 6.56 (m, 3H), 5.39 (dd, 1H, J = 8.6,
17.2 Hz), 2.90–3.12 (m, 2H), 2.85 (s, 6H), 2.50–2.72 (m, 2H), 1.55 (m,
1H), 1.75 (m, 1H); 13C NMR: δ 150.23, 145.22, 132.07, 129.75, 129.22,
129.20, 128.27, 127.15, 124.47, 123.42, 119.87, 117.19, 112.11, 111.61,
62.57, 62.18, 61.80, 61.41, 44.10, 40.29, 29.70, 28.26, 21.74; HRMS
(ESI) for C19H22F3N2 [M + H]+ calcd 335.1735; found: 335.1745.
4-(2,2,2-Trifluoro-1-(indolin-1-yl)ethyl)phenol (3i): Colourless oil;
1H NMR: δ 7.17 (d, 2H, J = 7.5 Hz), 7.0 (m, 2H), 6.71 (d, 2H, J = 8.7),
6.58 (m, 1H), 6.49 (d, 1H, J = 7.8), 5.00 (dd, 1H, J = 8.7, 17.5 Hz), 3.45
(m, 1H), 3.08 (m, 1H), 2.83 (m, 2H); 13C NMR: δ 156.00, 150.32,
131.57, 130.33, 130.31, 129.12, 127.79, 127.33, 124.82, 124.02, 123.65,
120.25, 118.16, 115.58, 106.23, 61.74, 61.34, 60.95, 60.55, 48.32, 29.69,
28.27; HRMS (ESI) for C16H15F3NO [M + H]+ calcd 294.1106; found:
294.1117.
5
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4-(2,2,2-Trifluoro-1-(methyl(p-tolyl)amino)ethyl)phenol (3j): Colourless
1
oil; H NMR: δ 7.34 (s, 1H), 7.01 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H,
J = 8.4 Hz), 6.31–6.39 (m, 2H), 5.27 (dd, 1H, J = 7.7, 15.5 Hz), 2.70 (s, 3H),
2.21 (s, 3H); 13C NMR: δ 147.77, 146.41, 143.00, 130.72, 129.79, 128.81,
126.94, 123.16, 119.42, 115.05, 110.27, 110.19, 110.17, 61.57, 61.16, 60.75,
60.34, 33.65, 33.63, 20.31; HRMS (ESI) for C16H17F3NO [M + H]+ calcd
296.1262; found: 296.1271.
N-Methyl-N-(2,2,2-trifluoro-1-(furan-2-yl)ethyl)aniline (3k): Colourless
1
oil; H NMR: δ 7.29 (d, 1H, J = 1.2 Hz), 7.12 (m, 2H), 6.77 (d, 2H,
J = 8.4 Hz), 6.72 (m, 3H), 6.3 (m, 2H), 5.3 (dd, 1H, J = 7.7, 15.3 Hz), 2.68 (s,
3H); 13C NMR: δ 149.78, 146.29, 143.08, 129.29, 126.89, 119.34, 114.60,
61.01, 60.59, 60.18, 59.79, 33.44, 29.69; HRMS (ESI) for C13H13F3NO [M +
H]+ calcd 256.0949; found: 256.0957.
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25.
2-(4-(Dimethylamino)phenyl)-2-(indolin-1-yl)acetonitrile
(4e):
Colourless oil; IR (KBr, νmax/cm−1): 2151 (CN). 1H NMR: δ 7.43 (d, 2H,
J = 8.4 Hz), 7.15 (m, 2H), 6.84 (m, 2H), 6.75 (m, 2H), 6.75 (m, 2H), 5.69