Copper-Catalyzed Synthesis of α-Trifluoromethylacrylates from Trifluoroborylacrylates via Stereoretentive Radical Trifluoromethylation

Article abstract of DOI:10.1002/adsc.202000937

We report the synthesis of α-trifluoromethylacrylates from α-trifluoroborylacrylates via a stereoretentive radical trifluoromethylation with inexpensive reagents NaSO₂CF₃ and TBHP at room temperature. Under these conditions, a wide substrate scope afforded the (E)-diastereomer exclusively in moderate to good yield. The utility of the reaction products is demonstrated in the synthesis of phenyl-4H-pyran, a potent and selective class of IKCa channel blockers. (Figure presented.).

Full text of DOI:10.1002/adsc.202000937

Title: Copper-catalyzed Synthesis of α-Trifluoromethylacrylates
from Trifluoroborylacrylates via Stereoretentive Radical
Trifluoromethylation
Authors: Swetha Jos and Webster Santos
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000937
Link to VoR: https://doi.org/10.1002/adsc.202000937

10.1002/adsc.202000937
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Copper-Catalyzed Synthesis of α-Trifluoromethylacrylates
from Trifluoroborylacrylates via Stereoretentive Radical
Trifluoromethylation
Swetha Jos and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, USA. Email: santosw@vt.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. We report the synthesis of α-
trifluoromethylacrylates from α-trifluoroborylacrylates
via a stereoretentive radical trifluoromethylation with
inexpensive reagents NaSO2CF3 and TBHP at room
temperature. Under these conditions, a wide substrate
scope afforded the (E)-diastereomer exclusively in
moderate to good yield. The utility of the reaction
products is demonstrated in the synthesis of phenyl-4H-
pyran, a potent and selective class of IKCa channel
blockers.
Keywords: α-trifluoroborylacrylates; α-
trifluoromethylacrylates; trifluoromethylation; copper;
phenyl-4H-pyran
The introduction of a trifluoromethyl functional group (CF3)
is a common strategy in medicinal chemistry to impart
favorable changes in reactivity, metabolic stability, and
solubility.[1] Moreover, the CF3 group is receiving increased
attention due to its role as a synthetic intermediate.[2]
Trifluoromethylalkene derivatives containing C(sp2)-CF3
bonds are particularly attractive and versatile intermediates
in medicinal and materials chemistry.[3] However, synthetic
routes to such molecules are limited in diastereoselectivity
and substrate scope.[4] Methods to install the CF3 group
include the use of Togni’s reagent,[5] Umemoto’s reagent,[6]
Ruppert-Prakash reagents,[7] Langlois reagent,[8] and
photoredox conditions.[9] Among others, one particularly
attractive route to trifluoromethylalkenes is with the use of
copper reagents.[10] Cu-catalyzed methods are user-friendly
and low cost. Boronic acids and their derivatives, which are
commercially available building blocks in organic synthesis,
are readily converted into CF3 groups under copper-
catalyzed conditions.[11] More recently, trifluoroboryl
derivatives have emerged as an excellent alternative due to
their superior shelf stability.[12] Trifluoromethylalkenes such
as α-trifluoromethyl acrylates are useful synthetic
intermediates for the synthesis of trifluoromethyl bearing
nucleosides or peptides.[13] However, methods to prepare
such derivatives are scarce and suffer narrow substrate scope,
lack of diastereoselectivity, use costly reagents, and lack
user-friendliness due to harsh conditions like high
temperature and use of moisture sensitive reagents.[10b, 10c, 14]
Beller and co-workers described a method to convert aryl
and vinyl boronic acids to a CF3 group via radical process
Scheme 1. Strategies for the synthesis of trifluoromethyl
alkenes.
using copper (Scheme 1a).[11c] More recently, Molander and
co-workers reported examples where trifluoroboryl alkenes
were converted to CF3 under similar conditions (Scheme
1b).[12a] Our laboratories have a long standing interest in the
borylation of α,β-unsaturated carbonyl group, their
transformation, and their biological applications.[15] In
particular, access to α-trifluoromethyl acrylates is hampered
by the presence of an electron withdrawing carbonyl moiety
and methods for their synthesis remains a challange.[14i, 16]
For example, 3-substituted-α-trifluoromethyl acrylates can
be generated from α-trifluoromethyl acrylates via a
palladium-catalyzed Mizoroki-Heck reaction. However, the
1
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10.1002/adsc.202000937
Advanced Synthesis & Catalysis
resulting products are afforded as a mixture of E and Z precursor.[17] Thus, we initiated our study (Table 1) using
isomers and limited to aryl cross-coupling partners. Inspired previously reported conditions for the trifluoromethylation
by previous reports, we envisioned that a copper-catalyzed of a trifluoroboryl group.[12a] Treatment of methyl (Z)-3-
reaction utilizing inexpensive radical trifluoromethylating phenyl-2-(trifluoroboryl)acrylate (3a) with CuCl (1.0 equiv),
reagents, such as NaSO2CF3, would convert shelf-stable NaSO2CF3
(3.0
equiv),
TBHP
(5.0
equiv),
vinyl BF3 substrates into the corresponding α- DCM/MeOH/H2O (1:1:0.8) afforded methyl (E)-3-phenyl-
trifluoromethylated derivatives and overcome the 2-(trifluoromethyl)acrylate 4a in a 4% yield (entry 1).
limitations of other methods (Scheme 1d). Addressing these Screening equivalencies[11c] of TBHP and NaSO2CF3 in the
challenging aspects, we report
a
method for presence of imidazole as base suggested that 16.0 equiv of
trifluoromethylation at the α carbon of trifluoroboryl TBHP and 7.0 equiv of NaSO2CF3 was beneficial (entry 2,
acrylate substrates with exclusive (E)-selectivity, moderate for details see the supplemental information). We then
to good yields, and a diverse substrate scope.
investigated a variety of Cu reagents (entries 3-9). While
The α-trifluoroboryl acrylate starting materials were copper (I) sources such as CuBr and CuI afforded 4a, the
prepared from potassium bifluoride and pinacolboronate yields were reduced in comparison to that obtained with
Table 1. Optimization of reaction conditions[a]
entry Cu source
(equiv)
solvent
base (equiv)
yield (%)[b]
1[c]
CuCl (1.0)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
MeCN
THF
--
4
2
CuCl (1.0)
imidazole
31
27
13
25
26
43
46
42
17
34
14
17
5
3
CuBr (1.0)
imidazole
4
CuI (1.0)
imidazole
5
CuCl2 (1.0)
imidazole
6
Cu(NO3)2 (1.0)
CuSO4(1.0)
imidazole
7
imidazole
8
Cu(CF3SO3)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.5)
Cu(OAc)2 (2.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
--
imidazole
9
imidazole
10
12
13
14
15
16
17
18
19[d]
20[e]
21
22[f]
2,4,6-Collidine (2.0)
methyl 1H-imidazole-5-carboxylate
2-ethyl-5-methyl-1H-imidazole
imidazole
imidazole
imidazole
28
10
9
imidazole
imidazole
H2O
imidazole
30
10
0
DCM
DCM
DCM
imidazole
imidazole
Cu(OAc)2 (1.0)
imidazole
10
[a] Reaction conditions: 3a (1.0 equiv), imidazole (1.5 equiv) NaSO2CF3 (7.0 equiv), TBHP (16.0 equiv), Cu (1.0
equiv), solvent (0.3 mL), H2O (0.1 mL)
[b] Yields based on 19F NMR spectroscopy using 4-fluoronitrobenzene as a reference.
[c] TBHP (5.0 equiv), NaSO2CF3 (3.0 equiv), MeOH (0.1 mL) and H2O (0.08 mL).
[d] without DCM
[e] without H2O
[f] boron pinacolate ester was used instead of 3a
2
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10.1002/adsc.202000937
Advanced Synthesis & Catalysis
readily available. A survey of other bases such as 2,4,6-
collidine, methyl 1H-imidazole-5-carboxylate, and 2-ethyl-
5-methyl-1H-imidazole did not improve the yield (entries
10-13). Decreasing or increasing the equivalency of
Cu(OAc)2 to 0.5 or 2.0 equiv reduced the overall yield of 4a
(entries 10-11). To determine the effect of solvent, toluene,
acetonitrile and THF were investigated (entries 16-18). Our
observations suggest that a biphasic system is required as
either water or DCM alone resulted in a drastic decrease in
yield (entries 19-20). Finally, removal of copper did not
afford product 4a suggesting its critical role in the
transformation (entry 21). Thus, our study indicate that
Cu(OAc)2 (1.0 equiv), NaSO2CF3 (7 equiv), TBHP (16
equiv), and imidazole (1.5 equiv) in DCM/H2O (3:1) as
optimal conditions (entry 9). Importantly, all reaction
conditions resulted in complete stereoretention yielding
exclusively the (E)-product. To compare the efficiency of
the borylacrylate substrate, we ran a control reaction with
the corresponding pinacol ester substrate and obtained 10%
NMR yield (entry 22).
With the optimized conditions in hand, we proceeded to
evaluate the substrate scope and limitations of this
transformation. As shown in Scheme 2, model substrate
methyl (Z)-3-phenyl-2-(trifluoroboryl)acrylate (3a) was
converted
to
methyl
(E)-3-phenyl-2-
(trifluoromethyl)acrylate 4a in 40% isolated yield. A variety
of substituted phenyl trifluoroborylacrylates including small
to larger alkyl groups on the para position were well
tolerated and afforded the corresponding products in
moderate to good yield (4b-4d). Electron-donating
substituents improved the yield with the para-propoxy (4e)
substrate affording product in the highest yield among all
substrates tested. The substitution pattern on the aryl ring
was also well tolerated as para (3f), meta (3g) and ortho (3h)
methoxy ether derivatives gave the corresponding
trifluoromethylated products 4f-4h in good to high yields.
Electron-withdrawing substituents such as halogens gave
lower yields. However, chlorine substitution at the meta (4k)
and ortho (4l) positions was more tolerated than the para
position (4j). A heteroaromatic ring such as benzofuran 4m
or a biphenyl group (4n) did not adversely affect the reaction.
With alkyl substituents on the 3-position of the acrylate, we
observed a slight reduction in yield with cyclohexyl
derivative (4o) and further reduction with an n-nonyl
derivative
(4p).
The
stereochemistry
of
the
trifluoromethylation products were consistent with the
literature.[14i]
We next investigated the effect of the ester substituent
on the outcome of the reaction ( Scheme 3). In the presence
of allyl ester 5a, the corresponding trifluoromethyl
derivative 6a was formed in 55% in a chemoselective
fashion. Furthermore, methoxyethyl 6b and phenyl 6c
trifluoromethylacrylate esters are achieved in modest yields.
With the trifluoromethylation protocol established, we
set out to demonstrate the application of the products
(Scheme 4). In particular, phenyl-4H-pyrans are potent and
selective IKCa channel blockers that can be accessed
through this methodology.[18] Thus, treatment of 4f with
acetylacetone in the presence of K2CO3 in DMF afforded 2-
fluoropyran derivative 7 in 65% yield.
Scheme 2. Substrate scope for the trifluoromethylation.
Isolated yields.
CuCl. Copper (II) reagents, however, proved more
productive. CuSO4, Cu(CF3SO3)2 and Cu(OAc)2 catalyzed
the transformation of 3a to 4a in modest yields (42-46%).
We chose Cu(OAc)2 in future studies because it is cheap and
3
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10.1002/adsc.202000937
Advanced Synthesis & Catalysis
adds to Cu(II) species producing 8 (path a). Transmetallation
with 3a generates alkenylCuIIICF3 intermediate 9 that
undergoes reductive elemination to provide the desired
trifluoromethylated product 4a. Alternatively, Cu(II) can
transmetallate with 3a to afford alkenylCuIILn 10 (path b).
Addition of a trifluoromethyl radical generates key
intermediate 9 that reductively eliminates to provided 4a. To
provide evidence whether the reaction proceeds to either
path a or b, we performed a time-course 19F NMR study (Fig.
2). As the reaction proceeds, a peak at -17.5 ppm that is
indicative of 8 appears immediately after the addition of
TBHP, which increases and decays over time. We
concomitantly observe the formation and eventual decay of
a secondary peak at -26.5 ppm, which does not completely
vanish even after 20 h. We suspect that the peak at -26.5 ppm
is alkenylCuIIICF3 intermediate 9.[20] The reductive
elimination of 9 is the rate-limiting step in the conversion to
4a.[20b]
Scheme 3. Substrate scope for the trifluoromethylation.
Isolated yields.
Scheme 4. Synthesis of fluorinated pyran derivative 7.
Figure 1. 19F NMR for the formation and the decay of
intermediates 8 and 9 to generate 4a.
In summary, we developed a Cu-catalyzed method for
synthesis of α-trifluoromethyl acrylates by the reaction of α-
trifluoroborylacrylates with inexpensive NaSO2CF3, and
TBHP under open-to-air conditions. This method proceeds
with complete stereoretention in moderate to good yield. A
wide variety of aryl and aliphatic substituted acrylates were
efficiently trifluoromethylated. In addition, a possible
mechanism was proposed based on 19F NMR studies. The
synthetic utility of the trifluoromethylated products was
demonstrated on the synthesis of a fluorinated phenyl-4H-
pyran.
Experimental Section
Scheme 5. Proposed mechanism.
Synthesis of α-Trifluoromethylacrylates from
Trifluoroborylacrylates
A proposed mechanistic pathway for the copper-
catalyzed trifluoromethylation of 2-trifluoroborylacrylates
is shown in Scheme 5.[11c] Previous work has shown that
TBHP initiates the reaction forming t-BOO•, which reacts
with NaSO2CF3 to produce a CF3 radical[19] that oxidatively
To a 1-dram fixed with a septum and stir-bar was added
trifluoroborylacrylate (1.0 equiv), imidazole (1.5 equiv),
Cu(OAc)2 (1.0 equiv), NaSO2CF3 (7.0 equiv) at room
temperature. To the resulting mixture, 3:1 DCM/H2O was
4
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10.1002/adsc.202000937
Advanced Synthesis & Catalysis
added. The reaction was stirred for 1-2 min prior to the
addition of TBHP (16.0 equiv) in portions. The reaction
mixture turns from blue to greenish and then to yellow. The
septum was pierced with a small-tip needle and the reaction
mixture was stirred for 20 h at room temperature and
quenched with a saturated solution of NaHCO3. The mixture
was extracted with DCM. The combined organic layers were
washed with a saturated solution of Na2S2O3 then
concentrated in vacuo to afford a liquid that was purified by
column chromatography (silica gel, 40 % DCM/Hexanes).
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6
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COMMUNICATION
Copper-catalyzed Synthesis of α-
Trifluoromethylacrylates from Trifluoroborylacrylates
via Stereoretentive Radical Trifluoromethylation
Adv. Synth. Catal. Year, Volume, Page – Page
Swetha Jos and Webster L. Santos*
7
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