TCDA: Practical Synthesis and Application in the Trifluoromethylation of Arenes and Heteroarenes

Article abstract of DOI:10.1021/acs.oprd.6b00079

A practical synthesis of the reagent trimethylsilyl chlorodifluoroacetate (TCDA) is reported on 50 g scale. The trifluoromethylation with TCDA was optimized, and the reaction shows very broad scope with respect to electron-deficient, -neutral, -rich aryl/heteroaryl iodides, as well as excellent functional group tolerability, such as ester, amide, aldehyde, hydroxyl, and carboxylic acid. The reagent was also applied to the late-stage trifluoromethylation of three medicinally relevant compounds. Additionally, the building block trifluoromethylpyridine and one drug related molecule Boc-Fluoxetin were synthesized in 10 g scale by this method, demonstrating its practical applications in process chemistry.

Full text of DOI:10.1021/acs.oprd.6b00079

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Communication
TCDA: practical synthesis and application in
trifluoromethylation of arenes and heteroarenes
Jian Wang, Xiaomin Zhang, Zehong Wan, and Feng Ren
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00079 • Publication Date (Web): 29 Mar 2016
Downloaded from http://pubs.acs.org on March 29, 2016
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TCDA: practical synthesis and application in
trifluoromethylation of arenes and heteroarenes
Jian Wang, Xiaomin Zhang*, Zehong Wan, Feng Ren
Neurodegeneration DPU, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong,
Shanghai, 201203, China
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Table of contents graphic
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Abstract
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A practical synthesis of the reagent trimethylsilyl chloro-difluoroacetate (TCDA) is
reported on 50 g scale. The trifluoromethylation with TCDA was optimized and
the reaction shows very broad scope with respect to electron-deficient, -neutral, -
rich aryl / heteroaryl iodides, as well as excellent functional group tolerability,
such as ester, amide, aldehyde, hydroxyl, and carboxylic acid. The reagent was
also applied to the late-stage trifluoromethylation of three medicinally relevant
compounds. Additionally, the building block trifluoromethyl pyridine and one drug
related molecule Boc-Fluoxetin were synthesized in 10 g scale by this method,
demonstrating its practical applications in process chemistry.
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Key word: TCDA, trifluoromethylation, aryl iodide, process chemistry
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Introduction
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Trifluoromethylation is a hot topic in recent years due to its wide applications in
pharmaceutics, agrochemicals and material science. 1,2 The introduction of a CF3
group to a molecule can often improve its bioactivity, permeability, and metabolic
stability. Therefore, many CF3 transformations have been reported, basically via
electrophilic (+CF3), nucleophilic (-CF3), and radical (·CF3) reactions. 3 A novel
reagent, TCDA designed by our group, was demonstrated to efficiently introduce
a CF3 group via cooperative interaction of AgF and CuI. 4,5,6 The reaction was
proposed to form difluoro-carbene intermediate then CF3 anion, which has been
well described by Burton and Chen’s group. 7 Although the reaction of TCDA has
shown very good functional group tolerance, the drawback for the reaction is also
obvious due to the high loading of expensive AgF, which could limit its practical
application. Additionally, the synthesis of TCDA especially in large scale is yet to
be improved, and its trifluoromethylation reaction in gram scale needs to be
evaluated from process chemistry aspect. Herein, we report the practical
synthesis of TCDA in 50 g scale, as well as further optimization of the reaction
condition either reducing equivalent of AgF or replacing it with KF to introduce the
trifluoromethyl group. The scope of this transformation and its application to
make drug molecule and building block in decagram scale are also explored.
Scheme 1. Synthesis of TCDA
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As shown in Scheme 1, TCDA is prepared in a one-step process by mixing
sodium chlorodifluoroacetate and chlorotrimethylsilane without solvent.
Comparing with our previous report, the reaction time was reduced from 6 h to 2
h with decreased temperature from 60 to 50 °C, and the yield was increased from
43% to 58%. The reaction was executed on 50 g scale, followed by one
distillation to afford TCDA with purity above 95%. In addition, the starting
materials are commercially available and inexpensive. As such, TCDA is very
convenient to scale up, and no obvious decomposition was observed when
storing under nitrogen at 5 °C for two weeks.
Table 1. Optimization of the molar ratio of reagents.
yield [%]
ClF2CO2TMS/ KF/
CuI/TMEDA
entry
product
temp
2h
22
34
4h
1
1.5: 3: 1.5: 1.5
2: 4: 1.5: 1.5
100 oC
90 o
C
2
3
2: 4: 1.5: 1.5
100 oC
90 oC
37
52
4
2: 4: 1.5: (TEA)
53
5
2: 5: 1.5: 1.5
90 oC
43
50
6
2: 5: 1.5: (TEA)
90 o
C
64
ClF2CO2TMS/ KF [a] (AgF
yield [%]
entry
product
temp
[b])/CuI/TMEDA
4h
24
6h
30
7
8
9
2: 5: 1.5: 1.5 [a] (TEA)
2: 4: 1.5: 1.5 [b]
2: 4: 1.5: 1.5 [b]
90 o
90 o
C
C
37
43
53
100 oC
46
Reaction conditions: [a] 1a-1b (1 mmol), CuI, KF and 2 in DMF (1 mL) and TEA (1 mL); [b] 1a-1b (1 mmol), CuI, AgF,
TMEDA and 2 in DMF (2 mL) were stirred at 100 oC under nitrogen in a sealed vial for 1 h. Yields were determined by 19
F
NMR spetroscopy using PhCF3 as an internal standard.
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In order to make the trifluromethylation more practical for process chemistry, the
expensive AgF should be replaced by other fluoride reagent, or at least its equiv
needs to be reduced. This time, 1.5 equiv CuI was used instead of 2.5 equiv
comparing with our previous condition. We firstly tried KF to replace AgF for the
trifluoromethylation. The optimization was started with 1.5 equiv TCDA to react
with eletron-poor 4-iodobenzoate and the yield was only 22% (entry 1, Table 1)
after 2 h at 100 °C. Then the TCDA was increased to 2 equiv, similar yields were
obtained for the reaction either at 90 or 100 °C (entries 2, 3, Table 1). As the
temperature has marginal influence on the reaction yield, the lower temperature
90 °C was selected for further optimization. The yield was increased to 52%
when 5 equiv KF was used (entry 4, Table 1). To our surprise, the higher yield 64%
was observed in 4 h when TMEDA was replaced by TEA (entry 6, Table 1).
However, the same reaction condition worked much slower and gave poor yield
of 24% in 4 h and 30% in 6 h for electron-rich 4-methoxybenzene iodide (entry 7,
Table 1). We subsquently chose AgF to optimize the trifluoromethylation of
electron-rich substrate. In our earlier report, 2.5 equiv TCDA and 5 equiv AgF
were found to be optimal conditions. Here, AgF was reduced to 4 equiv to obtain
the higher yield at 100 °C than 90 °C. In addition, longer reaction time gave
better yields (entries 7, 8, 9, Table 1). Based on the optimized results, the molar
ratios of TCDA/CuI/KF 2:1.5:5 together with TEA and TCDA/CuI/AgF/TMEDA
2:1.5:4:1.5 were used for electron-poor and -rich substrates, respectively.
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Table 2. Substrate scope of the trifluoromethylation.
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entry
product
yield [%]
entry
product
yield [%]
entry
product
yield [%]
1
64 [a]
8
50 [a]
15
26 [b] 12 [c]
2
99 [a]
9
60 [b]
16
68 [b] 25 [c]
Cl
N
3
4
42 [b]
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11
25 [b]
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75 [a] 38 [c]
3q
CF3
75 [b]
27 [b]
92 [a]
5
6
87 [a]
12
13
53 [b]
19
20
52 [a]
48 [a]
34 [b]
100 [a] 72 [c]
7
46 [a]
14
72 [b] 42 [c]
[a] Reaction conditions: 1a-t (1.0 mmol), CuI (1.5 mmol), KF (5.0 mmol) and 2 (2.0 mmol) in DMF (1 mL) and
Triethylamine (1 mL) were stirred at 90 °C for 4 h unless specifized, under nitrogen in a sealed tube. Yields were
determined by 19F NMR spetroscopy using PhCF3 as an internal standard. [b] 1a-t (1.0 mmol), CuI (1.5 mmol), AgF (4.0
mmol), TMEDA (1.5 mmol) and 2 (2.0 mmol) in DMF (2 mL) were stirred at 100 °C for 6 h. [c] Isolated yields.
Having the two sets of optimal reaction conditions, we switched our effort to
explore the scope of this transformation. A broad range of aryl iodides were
selected based on the electron density, substituted functional group diversity, and
some commonly used heterocycles. The condition of KF and TEA combination
was applied for electron-deficient aryl, heteroaryl and brominated aryl iodides.
The optimized reaction conditions with AgF was used for the trifluoromethylation
of aldyhyde/ketone, electron-rich aryl iodides, and aryl iodides having protic
functional groups. The reactions were analyzed at different time points at 4 h or 6
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h depending on the reaction conditions. As shown in Table 2, it is clear to see
that ring electronics has no obvious effect on the reaction yield. In most cases we
found it was difficult to isolate the trifluoromethylated products either in high yield
or in pure form, due to their high volatility or similar polarity to the iodoarene
starting materials. All the yields in Table 2 were determined by 19F NMR
spectroscopy with an internal standard. The isolated yields were also obtained
for 3n, 3o, 3p, 3q and 3t.
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The reaction was well tolerated with different functional groups, such as ester,
formyl, nitro, cyano, amide groups (42-99% yield, entries 1-7, Table 2). However,
the observed low yield with 4-iodophenyl acetate (25%, entry 10, Table 2) is likely
due to its decomposition during reaction. The trifluoromethylation of electron-rich
aryl iodides gave good yields (34-60%, entries 9, 12 and 13, Table 2). Remarkbly,
the iodoarenes containing carboxylic acid, hydroxyl groups (3n, 3o, and 3p)
could also be efficiently trifluoromethylated, demonstrating excellent tolerance of
protic functionality. As expected, the isolated yields of 3n 3o, and 3p were lower
than the yield determined by 19F NMR spectroscopy due to difficult separation.
The moderate to high yield (52-100%) for reactions with quinoline, pyridazine,
and pyridine, is very encouraging (entries 17-20, Table 2). Moreover, it is
noteworthy to see that trifluoromethylation of bromo- and chloro-substituted
iodoarenes 3h and 3q selectively took place at the iodide selectively.
Additionally, we also compared the reactivity of TCDA with ClCF2CO2Na under
the two sets of optimized conditions. The condition of KF and TEA combination
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was applied to the reaction of 1a and 1t with ClCF2CO2Na. Unfortunately, both
reaction didn’t afford any desired trifluoromethylated compound 3a and 3t. Then
we tested the reaction using the optimized reaction condition of AgF/TMEDA,
moderate yields were obtained for 3a (45%) and 3t (40%) after 4 h, which is still
much lower than the optimal condition of KF/TEA (64% for 3a, 100% for 3t, Table
2). The new reagent TCDA shows superior reactivity to that of ClCF2CO2Na for
trifluoromethylation reaction.
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Given the simplicity and efficiency of this method, we expect the incorporation of
a CF3 group at the late stage of a multi-step synthesis should be possible, even
with highly functionalized molecules. To further demonstrate the practical
applications of TCDA, the reagent was subsequently evaluated for late-stage
trifluoromethylation to make pharmaceutically relevant molecules. As shown in
Scheme 2, Boc-Fluoxetin, Fluvoxamine, and Flutamide were prepared in
moderate to high yields (35%, 55%, 99%, respectively) by introducing a CF3
group with TCDA in the last step. In addition, the methyl 6-
(trifluoromethyl)nicotinate and Boc-Fluoxetin were prepared in 10 g scale with
isolated yields of 71.9% and 35.6%, demonstrating its practical applications in
process chemistry.
Scheme 2. Trifluoromethylation to make medicinal relevant molecules
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Reaction conditions: aryl iodide(1.0 mmol), CuI (1.5 mmol), AgF (4.0 mmol), TMEDA (1.5 mmol) and 2 (2.0 mmol) in DMF
(2 mL) were stirred at 100 °C for 6 - 8 h.
Conclusions
We have developed the improved synthesis of a readily accessible and relatively
inexpensive reagent TCDA and its applications to introduce the trifluoromethyl
group to arenes and heteroarenes, including complicated drug molecules at the
last step. The reagent provides good conversion for electron-deficient, electron-
neutral and electron–rich substrates, and its application to process chemistry is
also demonstrated through making the pyridine building block and drug related
molecule in decagram scale.
Experimental details
1
General. H NMR and 19F NMR spectrums were recorded on Bruker AM400 and
Varian Mercury Plus 300 MHz spectrometer. Chemical shifts (δ) are reported in
ppm, and coupling constants (J) are in Hertz (Hz). The following abbreviations
were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad.
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Materials: All reagents were used as received from commercial sources, unless
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specified otherwise, or prepared as described in the literature.
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Trimethylsilyl 2-chloro-2,2-difluoroacetate (TCDA). A mixture of sodium 2-
chloro-2,2-difluoroacetate (50 g, 0.33 mol) and TMSCl (39 g, 0.36 mol) was
o
stirred for 2 h at 50 C (oil bath temperature) under N2. After cooled to rt, the
mixture was distilled under reduced pressure using water pump (0.95 MPa) to
afford the title compound (BP: 97-98 oC) as a colorless liquid (38.8 g, yield: 58%).
1
Since TCDA is water sensitive, it should be kept under N2. H NMR (300 MHz,
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CDCl3): 0.35 (s, 9H). F NMR (377MHz, CDCl3) δ (ppm): -64.74. 13C NMR (101
Hz, CDCl3) δ (ppm): 0.3, 117.8 (t, J=302.2 Hz), 159.1 (t, J= 34.3 Hz).
Ethyl 4-(trifluoromethyl)-benzoate (3a). To a mixture of 4-Iodo-benzoic acid
ethyl ester (276 mg, 1 mmol) in anhydrous triethylamine (1 mL) and anhydrous
DMF (1 mL) in a 5 mL vial were added trifluoromethylbenzene (160 mg, 1 mmol),
CuI (286 mg, 1.5 mmol), KF (290 mg, 5.0 mmol), and TCDA (373 mg, 2.0 mmol),
then sealed. The mixture was stirred for 4 h under N2 at 90 oC. After cooled to rt,
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the yield was monitored by 19F NMR spectroscopy. F NMR (377MHz, CDCl3) δ
(ppm): -63.05.
Procedure for the synthesis of 3b, 3e, 3f, 3g, 3h, 3q, 3r, 3s, 3t is similar to 3a.
1-Methoxy-4-(trifluoromethyl)benzene (3l). To a mixture of 1-iodo-4-
methoxybenzene (234 mg, 1 mmol) in anhydrous DMF (2 mL) in a 5 mL vial were
added trifluoromethylbenzene (160 mg, 1 mmol), CuI (286 mg, 1.5 mmol), AgF
(508 mg, 4.0 mmol), TMEDA (174 mg, 1.5 mmol), and TCDA (373 mg, 2.0 mmol),
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then sealed. The mixture was stirred for 6 h under N2 at 100 oC. After cooled to rt,
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the yield was monitored by 19F NMR spectroscopy. F NMR (377MHz, CDCl3) δ
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(ppm): -61.44.
The Procedure for the synthesis of 3c, 3d, 3i, 3j, 3k, 3m, 3n, 30, 3p, Flutamide,
Boc-Fluoxectin, N-Acetyl Fluvoxamine is similar to 3l.
Methyl 6-(trifluoromethyl)nicotinate.
To a mixture of (trifluoromethyl)benzene (4.67 ml, 38.0 mmol), methyl 6-
iodonicotinate (10 g, 38.0 mmol), TCDA (15.41 g, 76 mmol), CuI (10.86 g, 57.0
mmol) and KF (11.04 g, 190 mmol) in N,N-Dimethylformamide (DMF) (40 mL)
and TEA (40ml, 287 mmol), was added trifluoromethylbenzene (4.67 ml, 38.0
mmol). The reaction mixture was stirred and heated under N2 at 90 °C for 8 h,
then cooled to rt and diluted with 500 mL ethyl acetate, filtrated and concentrated.
Purification via silica column (PE:EA=4:1), afforded the title compound as a white
1
solid (5.7 g, 27.3 mmol, 71.9 % yield). H NMR (400 MHz, CDCl3) δ (ppm): d
4.01 (s, 3H), 7.79 (d, J=8.19 Hz, 1H), 8.50 (d, J=8.07 Hz, 1H), 9.31 (s, 1H). 19F
13
NMR (377MHz, CDCl3) (ppm): -68.3. C NMR (101MHz, CDCl3) δ (ppm):52.9,
120.2 (q, J=3.03 Hz), 121.1 (q, J=275.7 Hz), 128.5, 138.8, 151.0, 151.3 (q,
J=35.4 Hz),164.5.
Tert-butylmethyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl) carbamate
(Boc-Fluoxetin).
To
a
mixture
of
tert-butyl
(3-(4-iodophenoxy)-3-
phenylpropyl)(methyl) carbamate (10.0 g, 21.40 mmol), TCDA (8.67 g, 42.8
mmol), AgF (10.86 g, 86 mmol), CuI (6.11 g, 32.1 mmol) and TMEDA (4.84 mL,
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32.1 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added
trifluoromethylbenzene (2.63 mL, 21.40 mmol). The reaction mixture was stirred
and heated under N2 at 100 °C for 8 h, then cooled to rt, diluted with 500 mL
ethyl acetate, filtrated, and concentrated. Purification via short silica column (PE:
EA= 4:1) then Pre-HPLC, afforded the title compound as a clear oil (3.15 g, 7.62
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mmol, 35.6 % yield). H NMR (400 MHz, DMSO-d6) δ (ppm): 1.26 (br. s., 5H),
1.34 (br. s., 4H), 2.02 (br. s., 1H), 2.11 (dt, J=13.54 Hz, 6.74 Hz, 1H), 2.78 (s, 3H),
3.28 (br. s., 1H), 3.32-3.58 (m, 1H), 5.42 (d, J=3.79 Hz, 1H), 7.06 (d, J=8.31 Hz,
2H), 7.22-7.31 (m, 1H), 7.36 (t, J=7.52 Hz, 2H), 7.39-7.45 (m, 2H), 7.55 (br. s.,
1H), 7.57 (br. s., 1H). 19F NMR (377MHz, DMSO-d6) (ppm): -59.97. 13C NMR
(101MHz, DMSO-d6) δ (ppm):28.3, 34.1, 36.5, 45.3, 77.4, 78.8, 116.5, 121.7 ( q,
J=32.3 Hz), 124.9 (q, J=272.7 Hz), 126.4, 127.2 (d, J=3.03 Hz), 128.2, 129.1,
141.2, 155.1, 160.9.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
xiaomin.m.zhang@gsk.com
Notes
The authors declare no competing financial interest.
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