Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids

Article abstract of DOI:10.1021/jacs.8b02650

Herein we disclose an efficient method for the conversion of carboxylic acids to trifluoromethyl groups via the combination of photoredox and copper catalysis. This transformation tolerates a wide range of functionality including heterocycles, olefins, al

Full text of DOI:10.1021/jacs.8b02650

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Communication
Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids
Jacob A. Kautzky, Tao Wang, Ryan W Evans, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02650 • Publication Date (Web): 14 May 2018
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Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids
Jacob A. Kautzky,‡ Tao Wang,‡ Ryan W. Evans, and David W. C. MacMillan*
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Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
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Supporting Information Placeholder
Impact of Trifluoromethyl Group in Drug Design
ABSTRACT: Herein we disclose an efficient method for the
conversion of carboxylic acids to trifluoromethyl groups via the
H
N
O
combination of photoredox and copper catalysis. This
transformation tolerates a wide range of functionality including
heterocycles, olefins, alcohols, and strained ring systems. To
demonstrate the broad potential of this new methodology for
late-stage functionalization, we successfully converted a
diverse array of carboxylic acid-bearing natural products and
medicinal agents to the corresponding trifluoromethyl
analogues.
ꢀ improved metabolic stability
ꢀ increased membrane permeance
ꢀ favorable protein-ligand interactions
O
Cl
CF3
efavirenz
Traditional Methods of Constructing Csp3–CF3 Bonds
CF3
X
• CF3
[CuCF3]
In drug discovery, a commonly used strategy to protect
against in vivo metabolism involves the incorporation of a tri-
fluoromethyl group (CF3) into medicinal candidates. Moreover,
a variety of studies have shown that CF3 groups can increase the
efficacy of a drug candidate by modulating protein-ligand inter-
actions and improving membrane permeance, among other ben-
efits.1 While significant advancements have been made in the
development of general, catalytic protocols that access aryl–
CF3 adducts, methods for the formation of aliphatic Csp3–CF3
unsaturated
substrates
alkyl–CF3
product
pre-activated
substrates
This Work: Trifluoromethylation of Aliphatic Carboxylic Acids
F3C
I
O
CO2H
CF3
Ir
Cu
Me
Me
N
N
bonds remain limited.2 Conventional approaches towards Csp3
–
Boc
Boc
CF3 installation include (i) difunctionalization of olefins via CF3
radical addition,3 (ii) nucleophilic substitution of alkyl halides
or triflates with stoichiometric [CuCF3] species,4 and (iii) oxi-
dative coupling of alkyl boronic acids with [CuCF3] reagents.5
These elegant methods nonetheless require the preactivation of
the coupling partner, a step that can often limit their potential
utility in late-stage functionalization and other diversification
steps. As such, the discovery of a catalytic trifluoromethylation
mechanism that allows the conversion of native, abundant func-
tional groups into Csp3–CF3 motifs should be of considerable
value to medicinal chemists and the synthetic community as a
whole.
carboxylic
acid
Togni’s
reagent I
alkyl–CF3
product
propensity to undergo facile reductive elimination from its high
valency oxidation state.9 At the same time, we hoped that Csp3
–
carboxylic acid bonds could be activated via photoredox to gen-
erate alkyl radicals that would rapidly engage in a copper cata-
lytic cycle. Indeed, it is well-established that aliphatic open-
shell intermediates will undergo capture by copper species at
rates that approach rates of diffusion.10 This concept was re-
cently employed by our laboratory in a C–N-heteroaryl bond-
forming reaction wherein aliphatic carboxylic acids underwent
decarboxylative coupling with many classes of N-nucleo-
philes.11 Herein, we report the successful translation of this new
strategy to C–C bond formation and describe the first copper-
catalyzed decarboxylative trifluoromethylation of aliphatic car-
boxylic acids.
The merger of transition metal and photoredox catalysis,
termed metallaphotoredox catalysis, has enabled the discovery
of a range of synthetically valuable and hitherto elusive trans-
formations.6 In particular, carboxylic acids, a naturally abun-
dant class of compounds, can efficiently undergo decarboxyla-
tive cross-coupling via this dual catalysis platform to install a
myriad of valuable functionalities including Csp3–aryl, –alkyl, –
vinyl, and –acyl groups.7 Indeed, the capacity of carboxylic ac-
ids to act as an adaptive functionality renders them ideal starting
materials for both early- and late-stage bond formation. More-
over, these methodologies generally employ mild conditions
(i.e., visible light, room temperature) and exhibit broad func-
tional group tolerance, features that allow for their use with a
diverse array of complex, biologically relevant molecules.8 Re-
cently, we questioned if a metallaphotoredox platform might
enable a catalytic decarboxylative trifluoromethylation. As a
key design element, we envisioned the use of copper as the key
cross-coupling catalyst, effectively taking advantage of CuIII’s
Details of the proposed dual copper-photoredox cycle are
outlined in Scheme 1. We envisioned that photoexcitation of the
IrIII photocatalyst Ir[dF(CF3)ppy]2(4,4¢-dCF3bpy)PF6 (1) with
visible light would generate the highly oxidizing excited-state
red
*IrIII 2 (E1/2 [*IrIII/IrII] = 1.65 V vs. SCE in MeCN).12 At the
same time, the carboxylate anion derived from carboxylic acid
3 and base would ligate the CuII catalyst. Single-electron trans-
fer (SET) from copper carboxylate 4 to highly oxidizing ex-
cited-state IrIII 2 would then deliver CuIII carboxylate 5, or in
*
the dissociated form, a carboxyl radical and CuII complex (6),
along with reduced IrII photocatalyst 7. The resulting carboxyl
radical would extrude CO2 to generate an alkyl radical and CuII
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Scheme 1. Pathway of Decarboxylative Trifluoromethylation
upon mixing with a ligated CuI species (See SI for details). It
1
2
3
4
5
6
7
8
should be noted that sub-stoichiometric base (0.5 equiv., cf. Ta-
ble 1, entry 6) is critical to the success of the reaction. Carbox-
ylates are prone to form chelates with copper and deactivate the
Cu catalyst.17 The tertiary alcohol byproduct originating from
Togni’s reagent I after transfer of the CF3 moiety ultimately
serves as stoichiometric base (cf. 13 to 4). Control experiments
revealed that photocatalyst, copper catalyst, and light were all
essential for the success of this new decarboxylative trifluoro-
methylation protocol (Table 1, entry 7–9). With respect to the
proposed mechanism, it is important to note that [CuCF3] was
not detected by 19F NMR analysis (< 1 mol%). This mechanism
contrasts with the recent studies of the Li group, whereby stoi-
chiometric Cu(CF3)x was used to capture alkyl radicals.18 More-
over, mechanistic experiments reveal a copper-mediated decar-
boxylation is likely operative (see SI for details).
O
–CO2
•alkyl
LnCuIIX
LnCuIIX
•O
alkyl
8
6
Copper Catalytic
O2C—alkyl
LnCuIII
alkyl
LnCuIII
Cycle
5
X
9
X
IrII (7)
9
Photoredox Catalytic
Cycle
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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44
45
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60
SET
SET
IrIII (1)
*IrIII (2)
O2C—alkyl
alkyl
X
LnCuII
LnCuII
10
4
Table 1. Decarboxylative Trifluoromethylation: Initial Studiesa
X
Togni’s I
(11)
O
Ir
Cu
CF3
OCuIILnX
I
OH
Me
Me
BzN
CF3 source
BTMG, EtOAc
rt, 6 h
O
BzN
F3C
3
12
alkyl–CF3
HO
carboxylic acid
NBz
13
NBz
alkyl–CF3
product (12)
entry
conditions
Cu source
CF3 source
yieldb
carboxylic acid (3)
1
2
3
4
5
6
7
8
9
as shownc
as shownc
CuCl2
CuCl2
CuCl2
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
14
15
11
11
11
11
11
11
11
0%
2%
(8) which would rapidly recombine to form CuIII species 9. At
this point, we hypothesize that a single-electron transfer would
then occur between 9 and the reduced IrII state of photocatalyst
as shownc
39%
as shownc
72%
red
7 (E1/2 [IrIII/IrII] = –0.79 V vs. SCE in MeCN) to close the
as shown
83% (78%)
48%
1 equiv. of base
no photocatalyst
no Cu catalyst
no light
photoredox catalytic cycle and produce an alkylcopper(II) spe-
cies (10). At this stage, we hoped that 10 would engage Togni’s
reagent I (11) to deliver alkyl–CF3 product 12, presumably via
reductive elimination from a transiently formed CuIII intermedi-
ate.13 This is in accord with previous stoichiometric studies in
which an arylcopper(II) intermediate was trifluoromethylated.14
The resulting complex 13 would then undergo ligand exchange
with substrate acid 3 to complete this dual-catalytic cycle.
1%
0%
0%
CF3 sources
F3C
I
O
F3C
I
O
Me
Me
O
S
TfO–
Our investigation into this new decarboxylative trifluoro-
methylation began with exposure of 1-benzoylpiperidine-4-car-
boxylic acid (3) to various electrophilic trifluoromethyl
sources15 in the presence of photocatalyst 1, CuCl2, 3,4,7,8-tet-
ramethyl-1,10-phenanthroline, and Barton’s base (2-tert-butyl-
1,1,3,3-tetramethylguanidine, BTMG) in ethyl acetate. To our
delight, product formation was observed in 39% yield when
Togni’s reagent I (11, Ep [11/11•–] = –1.51 V vs. SCE in
MeCN)16 was used (Table 1, entry 3). More oxidizing CF3
sources such as Umemoto reagent (14, Ep [14+/14•] = –0.32 V
vs. SCE in MeCN, entry 1)16 and Togni’s reagent II (15, Ep
[15/15•–] = –0.79 V vs. SCE in MeCN, entry 2)16 were not as
efficient, presumably due to their unproductive reduction by the
reduced photocatalyst (7, E1/2red[IrIII/IrII] = –0.79 V vs. SCE in
MeCN). Further evaluation revealed that the use of CuCN as
the copper source, bathophenanthroline as the ligand, and addi-
tion of 30 equivalents of water further improved the reaction
efficiency (entry 5, 78% isolated yield). It is worth noting that
both CuI and CuII salts are capable pre-catalysts for this trans-
formation. When CuI sources such as CuCN are used, a signifi-
cant change in color can be observed upon addition of Togni’s
reagent I, potentially due to a change in oxidation state of the
copper species. This hypothesis is supported by in situ 19F NMR
analysis, in which an equivalent of Togni’s reagent is consumed
CF3
Umemoto reagent
Togni’s reagent II
Togni’s reagent I
14
15
11
aPerformed with acid 3 (0.05 mmol), photocatalyst 1 (1 mol%), Cu
source (20 mol%), bathophenanthroline (30 mol%), 2-tert-butyl-
1,1,3,3-tetramethylguanidine (BTMG, 0.5 equiv.), CF3 source (1.25
equiv.), and H2O (30 equiv.) in EtOAc (0.025 M). bYields by 19F NMR
analysis. Yields in parentheses are isolated yields. cThe ligand 3,4,7,8-
tetramethyl-1,10-phenanthroline was used on the Cu catalyst.
With optimized conditions in hand, we sought to evaluate the
scope of the Csp3–CF3 bond-forming reaction. As shown in Ta-
ble 2, a myriad of primary carboxylic acids are successful sub-
strates, providing the corresponding CF3 analogue in good to
excellent yield. Phenylacetic acids are generally competent,
with a diverse range of electron-withdrawing (16–19, 70–80%
yield), electron-donating (20, 74% yield), and electron-neutral
substituents (21 and 22, 60 and 66% yield, respectively) toler-
ated on the aryl ring. Notably, the efficacy of the reaction was
not hindered by ortho substitution (20, 74% yield), and useful
levels of efficiency were observed for an ortho, ortho-disubsti-
tuted heterocycle (26, 30% yield). Notably, boronic esters and
aryl bromides were also tolerated using this mild copper-
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Table 2. Scope of Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids via Copper and Photoredox Catalysisa
1
2
3
4
F3C
PF6
F
Ir[dF(CF3)ppy](4,4’-dCF3bpy)PF6 (1 mol%)
CuCN (20 mol%), bathophen (30 mol%)
O
F3C
I
O
N
Ir
F3C
F3C
CF3
N
N
Me
Me
F
F
OH
Ir
BTMG (0.5 equiv.), EtOAc, H2O
blue LEDs, fan, 6 h
5
N
6
alkyl–CF3 product
carboxylic acid
Togni’s reagent I
F
1
F3C
7
8
Primary Carboxylic Acid
Secondary Carboxylic Acid
9
CF3
CF3
CF3
Br
NC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
CF3
CF3
O
N
N
Boc
F
NHBoc
p-CF3Ph
16, 78% yieldb
17, 80% (63%) yieldb
18, 72% (53%) yieldb
34, 75% (70%) yield
35, 80% (80%) yield
36, 78% (76%) yield
> 20:1 dr
CF3
Boc
N
CF3
CF3
CF3
CF3
OMe
O2S
BocN
F3C
19, 70% yieldb
pinB
CF3
20, 74% (62%) yieldb
21, 60% (48%) yieldb
37, 82% (79%) yield
38, 67% yieldb
39, 83% (82%) yieldb
> 20:1 dr
CF3
CF3
CF3
N
CF3
CF3
N
CF3
N
N
Boc
BnO
BocN
22, 70% (66%) yieldb
23, 55% yieldb
24, 55% yieldb
40, 82% yieldb
41, 83% (75%) yieldb
42, 74% (65%) yieldb
2:1 dr
Me
H
CF3
N
N
CF3
CF3
CF3
N
CF3
CF3
BocN
H
S
N
Me
Ph
25, 70% (68%) yieldb
26, 30% yieldb
27, 77% yieldb
43, 58% yieldb
44, 59% yieldb, > 20:1 dr
45, 45% (42%) yieldb
> 20:1 dr
O
NH
Me
O
N
H
H
CF3
Me
CF3
TBSO
CF3
BnO
CF3
N
CF3
N
N
N
H
CF3
Me
Me
Me
N
N
46, 53% (50%) yieldb
47, 56% yieldb
48, 50% (45%) yieldb
28, 60% yieldb
29, 52% yieldb
30, 31% yieldb
9:1 dr
Tertiary Carboxylic Acid
CF3
O
CF3
CF3
CF3
F
F
CF3
NHBoc
CF3
BocN
MeO
Br
O
31, 63% (61%) yieldb
32, 71% (65%) yieldb
33, 82% (73%) yieldb
49, 87% (82%) yield
50, 89% (76%) yield
51, 93% (82%) yield
aPerformed on a 0.5 mmol scale. Due to volatility of products, yields were obtained by 19F NMR analysis of the crude reaction mixtures using an
internal standard. Isolated yields were provided in brackets See Supporting Information for isolation conditions and yields. Reaction performed
b
under modified conditions. See SI for details.
catalyzed protocol, with no chemoselectivity issues (17 and 21,
80 and 60% yield, respectively). The reaction is also amenable
to a range of non-benzylic primary acids (27–33, 31–77% yield).
Moreover, substrates incorporating b,b-branching afforded the
desired product in good yields (31 and 32, 63 and 71% yield
respectively) revealing that steric constraints can be overcome.
Gratifyingly, an array of heterocycles, many of which include
basic nitrogens, can be utilized in this transformation (23–26
and 28–30, 30–68% yield).
formed the desired bond with good efficiency. This is a signifi-
cant finding given that many of these bicyclic systems serve as
aryl ring bioisosteres in drug design.19 Moreover, acyclic sys-
tems also produced the desired CF3 product in good efficiency
(46–48, 50–56% yield). Notably, the compatibility of this reac-
tion with medicinally relevant structures was demonstrated with
a b-lactam (46, 53% yield). Last, a number of tertiary carbox-
ylic acids were also successfully converted to Csp3–CF3 bonds
in excellent yield (49–51, 87–93% yield).
We next turned our attention to secondary and tertiary car-
boxylic acids (34–51, 45–93% yield). We were pleased to find
that cyclic carboxylic acids, including strained 3- and 4-mem-
bered rings, participate in this trifluoromethylation in moderate
to excellent yield (39–45, 45–82% yield). Several bicyclic and
spirocyclic compounds (38, 39, 42, and 45, 45–78% yield)
To further demonstrate the utility of this decarboxylative tri-
fluoromethylation protocol, we performed a series of late-stage
modifications on medicinal agents and natural products (Table
3). To our delight, a large variety of biologically relevant sys-
tems that incorporate olefins, carbonyls, alcohols, and hetero-
cycles underwent chemoselective installation of a CF3
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Table 3. Late-Stage Decarboxylative Trifluoromethylation of Natural Products and Medicinal Agents Containing Carboxylic Acidsa
1
2
3
4
H
CF3
CF3
CF3
CF3
Me
Me
Me
NHBoc
O
5
6
from stearic acid
from oleic acid
from jasmonic acid
54, 46% yieldc
from gabapentin
55, 69% yieldc
52, 67% yield
53, 70% yield
7
8
9
CF3
O
Me
O
CF3
N
S
Ph
N
N
N
CF3
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
O
Cl
Cl
from lonazolac
56, 63% yieldb
from isoxepac
57, 52% yieldb
from tolmetin
58, 43% yieldb
from fenclozic acid
59, 40% yieldb
Me
O
O
Me
Me
O
(
)
6
OAc
Me
O
CF3
O
CF3
H
HO
HO
CF3
CF3
Me
H
H
O
OMe
Me
H
H
O
Me
Me
HO
O
OH
from fenbufen
from mycophenolic acid
from nutriacholic acid
from mupirocin
60, 32% yield
61, 30% yield
62, 71% yield
63, 45% yield
aAll yields are isolated. Performed with acid (0.5 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%), CuCl2 (20 mol%), 3,4,7,8-tetramethyl-1,10-phenan-
throline (Me4phen, 25 mol%), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.5 equiv.), Togni’s reagent I (1.25 equiv.), and H2O (30 equiv.) in
EtOAc (0.025 M). bPerformed with di(2-pyridyl) ketone and 1,1,3,3-tetramethylguanidine (TMG) in lieu of Me4phen and BTMG, and no water was
added.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: (link to DOI)
Corresponding Author
*dmacmill@princeton.edu
Author Contributions: ‡Authors contributed equally.
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
Financial support provided by the NIHGMS (RO1
GM103558-05), and kind gifts from Merck, BMS, Pfizer,
Janssen, and Eli Lilly. J.A.K. thanks the NSF GRFP (DGE
1656466) for funding.
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TOC
CO2H
CF3
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Ir Cu
N
alkyl–CF3
product
CO2H
CO2H
Ph
BzN
48 examples
catalytic copper
catalyst
Late-stage functionalization
1°, 2°, and 3° alkyl acids
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