Copper-catalyzed decarboxylative trifluoromethylation of allylic bromodifluoroacetates

Article abstract of DOI:10.1021/ol402780k

The development of new synthetic fluorination reactions has important implications in medicinal, agricultural, and materials chemistries. Given the prevalence and accessibility of alcohols, methods to convert alcohols to trifluoromethanes are desirable. However, this transformation typically requires four-step processes, specialty chemicals, and/or stoichiometric metals to access the trifluoromethyl-containing product. A two-step copper-catalyzed decarboxylative protocol for converting allylic alcohols to trifluoromethanes is reported. Preliminary mechanistic studies distinguish this reaction from previously reported Cu-mediated reactions.

Full text of DOI:10.1021/ol402780k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Decarboxylative
Trifluoromethylation of Allylic
Bromodifluoroacetates
Brett R. Ambler and Ryan A. Altman*
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive,
Lawrence, Kansas 66045, United States
raaltman@ku.edu
Received September 25, 2013
ABSTRACT
The development of new synthetic fluorination reactions has important implications in medicinal, agricultural, and materials chemistries. Given
the prevalence and accessibility of alcohols, methods to convert alcohols to trifluoromethanes are desirable. However, this transformation
typically requires four-step processes, specialty chemicals, and/or stoichiometric metals to access the trifluoromethyl-containing product. A two-
step copper-catalyzed decarboxylative protocol for converting allylic alcohols to trifluoromethanes is reported. Preliminary mechanistic studies
distinguish this reaction from previously reported Cu-mediated reactions.
New synthetic methods for the efficient incorporation
of trifluoromethanes into organic molecules are important
for the fields of agricultural chemistry,1 medicinal chemis-
try,2 chemical biology,2a,b and materials science.3 As a
result, many elegant and important preparations of tri-
fluoromethanes have emerged in recent years.4 However,
many simple, useful, and important transformations have
not been achieved.
The ability to convert alcohols into trifluoromethanes
using a simple, mild, and robust catalytic system represents
a desirable transformation. Alcohols are found in materi-
als, bioactive molecules, and many chemical libraries,
are readily accessed by many synthetic methods, and
provide a wide variety of substrates for synthetic transfor-
mations. However, alcohols rarely serve as precursors to
trifluoromethanes. Most commonly, the conversion of
alcohols into trifluoromethanes requires four-step se-
quences that (1) involve undesirable manipulation of
oxidation states; (2) require excess time and labor to
conduct; (3) generate excess waste; and (4) lead to dimin-
ished overall yields (Scheme 1, eq 1).5 Alternatively, alco-
hols can be converted to halides,6 trifluoroacetates,6b
halodifluoroacetates,7 fluorosulfonyldifluoroacetates,6f,7a
or xanthates,8 which can be trifluoromethylated in the
ꢀ
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(5) (a) Fustero, S.; Roman, R.; Sanz-Cervera, J. F.; Simon-Fuentes,
A.; Bueno, J.; Villanova, S. J. Org. Chem. 2008, 73, 8545. (b) Del Valle,
J. R.; Goodman, M. Angew. Chem., Int. Ed. 2002, 41, 1600. (c) Jeannot,
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X.-L.; Qing, F.-L. J. Org. Chem. 2002, 67, 7162. (e) Serafinowski, P. J.;
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Wang, Y.; Wei, Z.; Zhou, Y.; Zhu, Y. (Alectos Therapeutics Inc., Can.;
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Tam, T. F.; Leung-Toung, R.; Wang, Y.; Zhao, Y. (Apotex Technologies Inc.,
Can.) WO 2008116301 A1 October 2, 2008.
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2013, 19, 12800.
r
10.1021/ol402780k
XXXX American Chemical Society

the heating of the catalyst and reagents in DMF at 50 °C
prior to addition of the substrate (vide infra).
Scheme 1. An Economical Approach for the Conversion of
Allylic Alcohols to Trifluoromethanes
Three parameters, including reaction concentration,
ligand, and activation of the catalyst, proved most critical
for obtaining a high yield of product (Table 1). Compared
with the optimized reaction conditions (entry 1), reactions
run at lower concentration (entry 2) or without employing
the activation procedure (entry 3) provided less efficient
catalyst systems as defined by the ratio of yield/conversion.
Employing the activation procedure, the use of CuI/
DMEDA seemed to provide a less active catalyst than
that derived from CuI alone at the 1.5 h time point
(entries 1, 4); however, when the reactions were allowed
to proceed to full conversion, a higher yield of product was
reproducibly obtained using CuI/DMEDA (entries 5ꢀ6).
Thus, DMEDA could serve to stabilize the active catalyst
against decomposition near the end of the reaction.
Table 1. Sensitivity of Cu-Catalyzed Trifluoromethylation to
Concentration, Ligand, and Activation of Catalysta
presence of stoichiometric quantities of transition metals
(eq 2). However, for economic and environmental con-
siderations, catalytic methods are desirable. To this end,
a Cu-based catalyst recently converted allylic bromides or
chlorides (one step from allylic alcohols) to trifluoro-
methanes using the RuppertꢀPrakash reagent (eq 3).9
In contrast, we envisioned an attractive approach might
involve the conversion of an alcohol to a halodifluoroacetic
ester, followed by a catalytic decarboxylative trifluoro-
methylation (eq 4). Although trifluoromethylation reactions
of halodifluoroacetic esters have been conducted using
stoichiometric CuI,6d,e,7,10 catalytic reactions have proven
elusive over many years. Herein, we report a Cu-catalyzed
conversion of allyl bromodifluoroacetic ester into trifluor-
omethanes and preliminary mechanistic findings that distin-
guish this reaction from analogous Cu-mediated reactions.
Initial screening ofcatalysts and conditions revealedthat
the Cu-mediated reaction of cinnamyl bromodifluoroace-
tate (1A) could be adapted to provide a Cu-catalyzed
procedure. Several CuI salts and ligands provided catalytic
activity, and CuI and N,N0-dimethylethylenediamine
(DMEDA) were selected as an inexpensive and efficient
system that is already available in many synthetic chem-
istry laboratories and stockrooms worldwide.11 The opti-
mized catalyst included the use of 10 mol % CuI, 10 mol %
DMEDA as a ligand, 25 mol % NaO2CCF2Br, KF
(2 equiv), in DMF (1.0 M) at 50 °C. Importantly, a
beneficial activation procedure was identified that involved
[1A] DMEDA yieldb convb
entry activation (M)
(mol %)
(%)
(%)
yield/conv
√
1
1.0
0.33
1.0
1.0
1.0
1.0
1.0
0.33
10
10
10
0
52
63
26
66
83
72
50
52
64
0.82
0.74
0.49
0.83
0.83
0.72
0.76
0.67
√
2
85
3
ꢀ
54
√
4
79
√
5c
6c
7
10
0
100
100
66
√
ꢀ
ꢀ
0
8
0
78
a Reactions were performed with 0.20 mmol of substrate, 0.050 mmol
of NaO2CCF2Br, and 0.40 mmol of KF in 0.20 mL of DMF at 50 °C for
1.5 h. b Conversion and yield data were determined by GC/FID analysis
using dodecane as an internal standard. Each data point represents
an average of 2ꢀ4 experiments. c The reactions were run for 8 h instead
of 1.5 h.
A variety of 2-, 3-, and 4-substituted cinnamyl bromodi-
fluoroacetates (2A) were compatible with the present
reaction (Table 2). Electron-deficient (entries 1ꢀ5) and
electron-neutral cinnamyl systems (entries 7ꢀ8) reacted in
good yields, although an electron-rich substrate provided
the product in slightly lower yield (entry 9). In general,
substrates capable of affording resonance stabilized allyl
cations (e.g., 4-NMe2) were unstable to both acidic
and basic conditions, which limited purification and sto-
rage of this class of substrates. Aryl (pseudo)halides
were well tolerated and did not undergo aromatic
(9) Miyake, Y.; Ota, S.-i.; Nishibayashi, Y. Chem.;Eur. J. 2012, 18,
13255.
(10) (a) MacNeil, J. G., Jr.; Burton, D. J. J. Fluorine Chem. 1991, 55,
225. (b) Duan, J.-X.; Su, D.-B.; Wu, J.-P.; Chen, Q.-Y. J. Fluorine Chem.
1994, 66, 167. (c) Langlois, B. R.; Roques, N. J. Fluorine Chem. 2007,
128, 1318. (d) McReynolds, K. A.; Lewis, R. S.; Ackerman, L. K. G.;
Dubinina, G. G.; Brennessel, W. W.; Vicic, D. A. J. Fluorine Chem. 2010,
131, 1108. (e) Li, Y.; Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.;
Duan, C. Synlett 2011, 12, 1713. (f) Schareina, T.; Wu, X.-F.; Zapf, A.;
ꢀ
Cotte, A.; Gotta, M.; Beller, M. Top. Catal. 2012, 55, 426.
(11) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13–31.
B
Org. Lett., Vol. XX, No. XX, XXXX

trifluoromethylation (entries 1ꢀ3, 6). In addition, com-
pounds bearing heterocycles were tolerated (entries 9ꢀ10).
Finally, on an 8 mmol scale, over 1.9 g of material was
obtained in high yield (entry 2), which suggests that the
present reaction could be amenable to larger scale
processes.
Table 3. Disubstituted and Nonconjugated Allylic Bromodi-
fluoroacetates Undergo Decarboxylative Trifluoromethylationa
Table 2. Substituted Cinnamyl Bromodifluoroacetates Under-
go Decarboxylative Trifluoromethylationa
a Reactions were performed with 0.20 mmol of substrate, 0.020 mmol
of CuI, 0.020 mmol of DMEDA, 0.050 mmol of NaO2CCF2Br, 0.40
mmol of KF in 0.20 mL of DMF at 50 °C for 8 h following 10 min
activation. b Determined by 1H NMR. c Determined by 19F NMR.
d Isolated yield; number in parentheses indicates 19F NMR yield using
R,R,R-trifluorotoluene as an internal standard. e 18 h.
a Reactions were performed with 0.20 mmol substrate, 0.020 mmol
CuI, 0.020 mmol DMEDA, 0.050 mmol NaO2CCF2Br, 0.40 mmol KF
in 0.20 mL DMF at 50 °C for 8 h following 10 min activation. b Isolated
yield; number in parentheses indicates 19F NMR yield using R,R,R-
trifluorotoluene as an internal standard. c Reaction conducted on an
8 mmol scale.
explanations for this isomerization phenomenon cannot be
excluded.
Using the Cu/DMEDA-based catalyst system, bromo-
difluoroacetic esters provided unique reactivity (Table 4).
A trend of increasing reactivity was observed for cinnamyl
trifluoroacetate < chlorodifluoroacetate < bromodi-
fluoroacetate (entries 1ꢀ3);12 however, the reaction of
cinnamyl difluoroiodoacetate provided a low yield of
product (entry 4). It was hypothesized that Iꢀ, generated
as a byproduct of the reaction, inhibited catalysis. In
support of this theory, the addition of exogenous KI to
the reaction of cinnamyl bromodifluoroacetate decreased
the yield of product (entry 5). Combined, these two find-
ings suggest that Iꢀ does not participate in the catalytic
reaction. In fact, the Cu-catalyzed reaction could be con-
ductedinthe complete absenceofIꢀ (entry 6), a key feature
that distinguishes the present Cu-catalyzed reaction from
previously reported Cu-mediated reactions.7
Disubstituted and nonconjugated allylic esters (3A)
containing a diverse array of functional groups provided
moderate to good yields of E alkene products (3B, Table 3).
Substituents at the R and β positions of the styrene were
tolerated (entries 1ꢀ3), and nonconjugated allylic systems
displayed good reactivity (entries 4ꢀ7). Several aliphatic
functional groups were compatible with the reaction, in-
cluding esters, imides, and benzyl ethers (entries 5ꢀ7). In
entries5ꢀ6, diastereomeric mixturesof substrates (3A, E/Z
= 4:1) provided thermodynamically stable E-allyl trifluor-
omethane products 3B in excellent selectivities (E/Z >
19:1). Further, the reaction of a pure Z-alkene substrate
afforded the E product in excellent diastereoselectivity
(entry 7). When monitoring the reaction by both GC/
FID and 19F NMR, slow isomerization of the substrate
was observed, while the E-product was formed in greater
than 15:1 dr throughout the course of the reaction. In
control reactions, the Z-substrate was stable when treated
with KF in DMF at 50 °C. These data could implicate the
existence of a π-allyl intermediate that reacts to generate
the more stable E-product.6b,9 However at present, other
Although thorough mechanistic studies have not been
conducted, the present Cu-catalyzed reaction likely involves
a mechanism distinct from CuI-mediated reactions of allyl
halodifluoroacetates. For the Cu-catalyzed reaction, the
activation procedure presumably serves to convert the pre-
catalytic combination of CuI/DMEDA/NaO2CCF2Br/KF
(12) At higher temperatures, the chlorodifluoroacetic ester provided
mild activity, while the trifluoroacetic ester provided no reactivity.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Unique Reactivity of Allyl Bromodifluoroacetesa
Scheme 2. Proposed Catalytic Cycle Involving a Reactive
CuꢀCF3 Species
entry X
Y
other
conv (%)b yield (%)b yield/conv
1
2
3
4
5
6
F
I
ꢀ
ꢀ
ꢀ
ꢀ
26
31
52
53
68
>99
0
0
Cl I
Br I
1
0.03
0.88
0.47
0.56
0.79
46
25
38
79
I
I
Br I
þ100% KI
Br (MeCN)4PF6 8 h
a Reactions were performed with 0.20 mmol of substrate, 0.050 mmol
of NaO2CCF2Br, 0.40 mmol of KF in 0.20 mL of DMF at 50 °C for
1.5 h. b Conversion and yield data were determined by GC/FID analysis
using dodecane as an internal standard.
into the active catalyst, LnCuꢀCF3 (Scheme 2A). LnCuꢀ
CF3 can then promote direct trifluoromethylation of the
substrate without participation of Iꢀ. The substitution reac-
tion potentially involves a π-allyl intermediate, which has
been proposed in other allylic substitution reactions using
LnCuꢀCF3 in both stoichiometric6b and catalytic9 systems.
In contrast, the Cu-mediated reaction invokes Iꢀ as a key
feature of the mechanism (Scheme 2B).7a In this case, Iꢀ
participated by converting the bromodifluoroacetic ester
to an allyl iodide, which then reacted with CuꢀCF3. Studies
to thoroughly explore the mechanism of the present trans-
formation, including the activation procedure, are ongoing,
and results will be presented in due time. Further, ongoing
work aimed to expand the scope of this process to alternate
classes of substrates is currently underway.
In conclusion, a catalytic method for the conversion of
allylic alcohols to trifluoromethanes via bromodifluoroa-
cetic esters has been developed. Conjugated and noncon-
jugated substrates bearing a variety of functional groups
afford R-substituted trifluoromethylated products in mod-
erate to good yield and excellent diastereoselectivity for the
E-stereoisomer. Beneficial aspects of this transformation
include (1) employment of a mild, inexpensive, and atom-
economical source of CF3 in near-stoichiometric quantity;
(2) development of a shortened strategy for converting
readily available allylic alcohols into trifluoromethyl ana-
logs; and (3) the ability to conduct trifluoromethylation
reactions using only a catalytic quantity of metal. Finally,
functionalization of the allyl trifluoromethane-based pro-
duct should be useful for accessing more complex fluori-
nated compounds.7b,13
Acknowledgment. We thank the donors of the Herman
Frasch Foundation for Chemical Research (701-HF12)
for support of this project and the NIGMS Training Grant
on Dynamic Aspects of Chemical Biology (T32 GM08545)
for a graduate traineeship (B.R.A.). We also gratefully
acknowledge support of from the University of Kansas
Office of the Provost, Department of Medicinal Chemis-
try, and New Faculty General Research Fund (2302264).
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(13) (a) Shimizu, R.; Egami, H.; Hamashima, Y.; Sodeoka, M.
Angew. Chem., Int. Ed. 2012, 51, 4577. (b) Wang, C.-J.; Sun, X.; Zhang,
X. Angew. Chem., Int. Ed. 2005, 44, 4933.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX