Decarboxylative Trifluoromethylating Reagent [Cu(O2CCF3)(phen)] and Difluorocarbene Precursor [Cu(phen)2][O2CCF2Cl]

Article abstract of DOI:10.1002/chem.201504306

This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O₂CCF₃)] (1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)₂][O₂CCF₂Cl] (2). Treatment of copper tert-butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH₃CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)₂]⁺ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to-excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state.

Full text of DOI:10.1002/chem.201504306

DOI: 10.1002/chem.201504306
Full Paper
&
Synthetic Methods |Hot Paper|
Decarboxylative Trifluoromethylating Reagent [Cu(O2CCF3)(phen)]
and Difluorocarbene Precursor [Cu(phen)2][O2CCF2Cl]
Xiaoxi Lin+, Chuanqi Hou+, Haohong Li, and Zhiqiang Weng*[a]
Abstract: This article describes the new economic decarbox-
ylative trifluoromethylating reagent [Cu(phen)(O2CCF3)] (1;
phen=1,10-phenanthroline) and the efficient difluorocar-
bene precursor [Cu(phen)2][O2CCF2Cl] (2). Treatment of
copper tert-butoxide with phen and subsequent addition of
trifluoroacetic acid or chlorodifluoroacetic acid afforded air-
stable complexes 1 and 2, respectively, which were charac-
terized by X-ray crystallography. The copper(I) ion in 1 is co-
ordinated by a bidentate phen ligand, a monodentate tri-
fluoroacetate group, and a molecule of CH3CN in a distorted
tetrahedral coordination geometry. The molecular structure
of 2 adopts an ionic form that consists of a [Cu(phen)2]+
cation and a chlorodifluoroacetate anion. Complex 1 reacted
with a variety of aryl and heteroaryl halides to form trifluoro-
methyl (hetero)arenes in good yields. The corresponding
Hammett plot exhibited a linear relationship and a reaction
parameter (1)= +0.56Æ0.02, which indicated that the tri-
fluoromethylation reaction proceeded via a nucleophilic re-
active species. Complex 2 reacts with phenols to produce
aryl difluoromethyl ethers in modest-to-excellent yields.
Mechanistic investigations revealed that the difluoromethyl-
ation reaction proceeds by initial copper-mediated forma-
tion of difluorocarbene and subsequent concerted addition
of difluorocarbene to the phenol to form a three-center tran-
sition state.
Introduction
The synthesis of trifluoromethyl-containing aromatic com-
pounds is of general interest because this motif is present in
many commercial agrochemicals, pharmaceuticals, and func-
tional materials.[1,2] It is well-recognized that the introduction
of trifluoromethyl groups into bioactive molecules frequently
has a dramatic impact on their physical and chemical proper-
ties, which leads to increased biological activity and significant-
ly improved lipophilicity and metabolic stability.[3] Consequent-
ly, the incorporation of a trifluoromethyl group into bioactive
molecules has become a powerful tool in drug design and dis-
covery. Well-known examples of commercially meaningful tri-
fluoromethyl arenes (Scheme 1) include the antidepressant
Fluoxetine, the arthritis drug Celecoxib, Sorafenib and Flut-
amide (used for the treatment of kidney and prostate cancer,
respectively), as well as a number of herbicides (e.g., fluazifop-
butyl (Fusilade)).
Scheme 1. Selected examples of trifluoromethylated phamaceutical and
agrochemical compounds.
romethylation strategies have been developed in recent de-
cades.[4,5]
Traditionally, ArCF3 compounds have been prepared by
Swarts-type reactions, which involve treatment of benzotri-
chloride or benzoic acid derivatives with anhydrous HF, SbF5,
or SF4.[6] However, such harsh conditions and limited substrate
scope have been the main limitations for Swarts-type reac-
tions. Recently, transition-metal-promoted trifluoromethylation
reactions of arenes have been demonstrated to provide con-
venient methods for the facile formation of trifluoromethylated
arenes (Scheme 2).[7–10] These include palladium- and copper-
catalyzed/mediated trifluoromethylation of aryl chlorides[12]/io-
dides[11] (Scheme 2a), copper-catalyzed/mediated trifluorome-
thylation of aryl boronic acids[13] and boronates[14] (Scheme 2b),
copper-[15] and silver-mediated[16] trifluoromethylation of aryl-
Given the prevalence of the trifluoromethyl group in biologi-
cally active compounds, designing efficient methods to access
trifluoromethylated arenes is of high value. A variety of trifluo-
[a] X. Lin,+ C. Hou,+ Dr. H. Li, Prof. Dr. Z. Weng
State Key Laboratory of Photocatalysis on Energy and
Environment College of Chemistry, Fuzhou University
Fuzhou, 350108 (China)
E-mail: zweng@fzu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504306.
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Despite these notable advances, most strategies rely upon
using the costly Me3SiCF3 reagent or gaseous HCF3, which is
hard to handle in most academic laboratories, and Et3N·3HF or
Et3N·HCl to stabilize the CuCF3 reagent.
The use of readily available, convenient, and inexpensive al-
ternatives, such as trifluoroacetic acid (TFA) and its deriva-
tives,[4b,30–32] as the trifluoromethyl source for the preparation
of trifluoromethylarenes is an attractive prospect. Trifluorome-
thylation of aryl iodides with CuCF3 formed by decarboxylation
of methyl trifluoroacetate has been reported.[12e,33] Vicic and
co-workers also reported the preparation of (NHC)–copper–tri-
fluoroacetate complexes for decarboxylative trifluoromethyl-
ation of aryl halides.[34] However, despite their economically
benign nature, the reaction suffers from some disadvantages,
such as high operating temperatures (160–1808C), lack of prac-
ticability, and poor substrate scope. Very recently, Zhang and
co-workers reported an Ag-catalyzed radical CÀH trifluorome-
thylation of arenes with TFA as the trifluoromethylating re-
agent.[35] This method avoids prefunctionalization of the sub-
strate, but has low regioselectivity and limited functional-
group compatibility. Therefore, to match the increasing scien-
tific and practical demands, it is still of continued interest and
great importance to develop convenient and efficient methods
for arene trifluoromethylation. In this context, our group re-
Scheme 2. Strategies for the synthesis of trifluoromethylarenes (pin=pina-
colato).
diazonium salts (Scheme 2c), and palladium-,[17] copper-,[18] and
silver-catalyzed[19]/mediated[20] trifluoromethylation of aromatic
CÀH bonds (Scheme 2d).
In addition, the use of copper reagents in trifluoromethyl-
ation reactions has attracted much interest due to their good
reactivity, low toxicity, and good regiospecificity.[21] Since the
pioneering work of McLoughlin and Thrower in 1969 related to
the reductive coupling of aryl halides with perfluoroalkyl io-
dides in the presence of copper metal,[22] CuCF3 reagents have
been extensively studied and applied in stoichiometric trifluo-
romethylation reactions of aryl halides.[23] For example, Vicic
and co-workers reported the first thermally stable and well-de-
fined complexes of the type [Cu(CF3)(NHC)] (NHC=N-heterocy-
clic carbene), which were obtained from the reaction of
[CuCl(NHC)] with KOtBu followed by treatment with Me3SiCF3
at room temperature (Scheme 3a).[24] Hartwig and co-workers
cently developed an efficient copper-catalyzed trifluoromethyl-
[36]
ation of aryl iodides by using Me3SiCF3
and related
copper reagents for the synthesis of fluorinated organic com-
pounds.[37] Herein, we report the synthesis of complexes
[Cu(O2CCF3)(phen)] and [Cu(phen)2][O2CCF2Cl] and their suc-
cessful application to the trifluoromethylation and difluorome-
thylation of (hetero)aryl halides and phenols to furnish trifluo-
romethylarenes and (hetero)aryl difluoromethyl ethers, respec-
tively, in good yields.
Results and Discussion
Synthesis and structural studies
The reactions of copper tert-butoxide (prepared in situ from
CuCl and NaOtBu) with diimine ligand (1–2 equiv) and subse-
quent addition of TFA or chlorodifluoroacetic acid in THF at
room temperature afforded neutral copper–trifluoroacetate
complex [Cu(O2CCF3)(phen)] (1a), ionic complex [Cu-
(Me2phen)2][(O2CCF3)] (1b), or chlorodifluoroacetate complexes
[Cu(L)2][O2CCF2Cl] (2a–c; L=bpy, Me2bpy, and phen, respec-
tively) (Scheme 4). All these complexes were air stable in solu-
tion and in the solid state for several hours. These complexes
are soluble in DMF, CH3CN, and CH2Cl2, but insoluble in ben-
zene and toluene. Furthermore, these new trifluoroacetato and
chlorodifluoroacetato complexes are amenable to large-scale
synthesis (ꢀ3 g).
Scheme 3. Methods for the synthesis of copper trifluoromethylating re-
agents.
prepared the 1,10-phenanthroline (phen) ligated complex
[Cu(CF3)(phen)] by the reaction of copper tert-butoxide and
phen with Me3SiCF3 in benzene (Scheme 3b).[25] Grushin and
co-workers obtained the triphenylphosphine-coordinated com-
plex [Cu(CF3)(Ph3P)3] by heating a solution of CuF2·3H2O and
Ph3P in methanol at reflux temperature, followed by reaction
with Me3SiCF3 in THF (Scheme 3c);[26] they subsequently re-
ported the synthesis of CuCF3 derivatives from the reaction of
CuCl and KOtBu with fluoroform (Scheme 3d).[27] Mikami and
Hu also independently reported direct synthesis of the CuCF3
reagent from cuprate and trifluoromethyl ketone derivatives[28]
or phenyl trifluoromethyl sulfones, respectively[29] (Scheme 3e).
These copper reagents reacted with aryl iodides, bromides,
boronic acids, and boronate esters to give benzotrifluorides.
1
Complexes 1a, 1b, and 2a–c were characterized by H, 13C,
and 19F NMR spectroscopy, IR spectroscopy, and elemental
analysis. The IR spectrum of the crystalline product 1a shows
intense bands at n˜ =1674 (C=O) and 1434 cmÀ1 (CÀO), which
indicates h1-O monodentate coordination to the copper center.
Complex 1a exhibits a diagnostic resonance in the 19F NMR
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roacetate)] (1.842(4) Š; SIMes=1,3-dimesitylimidazolin-2-yli-
dene),[34] which is probably due to the tetrahedral geometry in
1a. The two CuÀN(phen) bond lengths are almost identical
(2.048(6) and 2.073(6) Š), and they are comparable to the cor-
responding lengths in [Cu(bathophenanthroline)CF3] (2.024(8)
and 2.096(8) Š).[36] The CuÀN(CH3CN) bond length was
1.886(7) Š, which is slightly longer than in three-coordinate
copper(I) complexes [Cu(CH3CN)(Me2phen)][X] (X=ClO4, PF6,
and BF4; 1.850–1.856 Š).[38] The monodentate coordination
mode of the trifluoroacetate group is further characterized
by the different C(1)ÀO(1) (1.170(10) Š) and C(1)ÀO(2)
(1.226(10) Š) bond lengths.
Crystals of 1b (co-crystallizes with adventitious CF3CO2H)
suitable for X-ray diffraction were grown by recrystallization
from a solution in CH3CN layered with Et2O. In contrast to 1a,
the structure of 1b contains a cationic tetrahedral copper(I)
center ligated by two Me2phen ligands and a free, unligated
trifluoroacetate anion (Figure 2). The range of CuÀN bond
Scheme 4. Synthesis of copper–trifluoroacetate and copper–chlorodifluoro-
acetate complexes 1 and 2.
spectrum in CD3CN at d=À74.3 ppm. Complexes 2a–c show
signals in the 19F NMR spectra at dꢁÀ57 ppm (chlorodifluo-
roacetate groups).
To support the spectroscopic evidence, single crystals of 1a,
obtained by solvent diffusion (Et2O/CH3CN), were subjected to
X-ray structural analysis. As shown in Figure 1, the copper
Figure 2. ORTEP drawing of 1b·CF3CO2H. Thermal ellipsoids are drawn at
40% probability, CF3CO2H and hydrogen atoms are omitted for clarity.
lengths observed in the [Cu(Me2phen)2]+ portion are 2.017(3)–
2.050(3) Š, which are similar to those in neutral 1a. The O(1)-
C(1)-O(2) angle (124.3(6)8) of the uncoordinated trifluoroace-
tate anion is significantly smaller than the angle in 1a
(133.1(12)8).
The structures of 2b and 2c contain a tetrahedral copper(I)
cation ligated by two Me2bpy or phen ligands, respectively,
and a free, unligated anionic chlorodifluoroacetate group (see
the Supporting Information). This is in contrast to the X-ray
crystal structure of [Cu(O2CCF2Cl)(SIiPr)] (SIiPr=1,3-diisopropyl-
imidazolin-2-ylidene), in which the chlorodifluoroacetate ion is
monodentately coordinated to the copper center to form
a neutral molecule.[34] The CuÀN bond lengths observed in 2b
(1.9958–2.0521 Š) are similar to those found in 2c (1.9983–
2.0693 Š). The two CÀO bond lengths in the carboxylate group
are nearly identical (1.233(3) Š and 1.235(3) Š for 2b;
1.234(2) Š and 1.221(2) Š for 2c), which together with the
planar geometry of the O(1)-O(2)-C(1)-C(2) unit indicates a delo-
calized structure for the ÀCO2 moiety. The CÀCl bond lengths
in 2b and 2c (1.767(2) and 1.768(3) Š, respectively) fall in the
Figure 1. ORTEP drawing of complex 1a. Thermal ellipsoids are drawn at
40% probability, hydrogen atoms are omitted for clarity.
center is bound by two N atoms from phen, one O atom from
the trifluoroacetato ligand, and one N atom from CH3CN in
a distorted-tetrahedral geometry. An interesting feature is the
monodentate coordination of the trifluoroacetato ligand,
which confirms the indications of the IR spectrum.
The substantially different values of the Cu(1)ÀO(1)
(2.080(7) Š) and Cu(1)ÀO(2) (3.243(7) Š) bond lengths in 1a
clearly imply monodentate coordination of the trifluoroacetato
ligand to the central copper(I) ion. In addition, the Cu(1)ÀO(1)
bond length is significantly longer than in [Cu(SIMes)(trifluo-
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normal range of 1.755–1.849 Š,[39] and the average CÀF bond
length of 1.342(3) Š in both 2b and 2c lies within the normal
range of 1.319–1.431 Š.[39] Additionally, the O-C-O angles in 2b
and 2c are identical (130.5(2)8) and similar to that in
[Cu(O2CCF2Cl)(SIiPr)] (130.0(9)8).[34]
Table 2. Comparison of the copper-mediated trifluoromethylation reac-
tions of 1-iodo-4-methoxybenzene (3n).
Entry
Conditions
Yield [%]
1
2
3
1a (2.0 equiv), NaF (3.0 equiv), DMF, 1408C
[Cu(CF3)(phen)] (1.2–1.5 equiv), DMF, 508C
[Cu(CF3)(PPh3)3] (0.9 equiv), tBubpy[c] (1.0 equiv),
toluene, 808C
Na[O2CCF3] (4.0 equiv), CuI (2.0 equiv), NMP, 1608C
MeO2CCF3 (4 equiv), CuI (20 mol%), CsF (1.2 equiv),
DMF, 1608C
83[a]
Trifluoromethylation reactions
96[a,b]
70–75[a,d]
To assess the potential of trifluoroacetate complexes 1a and
1b as trifluomethylation reagents, we investigated their reac-
tivity with 4-iodotoluene (3a). The results are summarized in
Table 1.
4
5
59[e,f]
84[g,h]
[a] Yields were determined by 19F NMR spectroscopy. [b] See ref. [25a].
[c] tBubpy=4,4’-di-tert-butyl-2,2’-bipyridine. [d] See ref. [26]. [e] Yields
were determined by GLC. [f] See ref. [23c]. [g] Yields were determined by
GC. [h] See ref. [12e].
Table 1. Optimization of the trifluoromethylation reaction of 3a.[a]
peratures (typically above 1608C) to facilitate efficient reactions
of (hetero)aryl halides.[4b,30]
Entry
[Cu]
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
NaF
NaF
NaF
NaF
NaF
NaF
NaF
–
DMF
DMF
83
56
46
43
54
0
Subsequently, a comparison of the reactivity in the copper-
mediated trifluoromethylation reaction of 1-iodo-4-methoxy-
benzene (3n) with other trifluoromethylation reagents was
performed (Table 2). The results clearly demonstrate that the
reactivity of 1a is comparable to reported reagents. It is also
noteworthy that the new reagent 1a is prepared from readily
available and inexpensive starting materials.
DMAc
diglyme
NMP
xylene
DMSO
DMF
0
56
[a] Conditions: 1 (0.15 mmol), 3a (0.10 mmol), NaF (0.30 mmol), solvent
(1.5 mL), N2 atmosphere, 1408C, 8h. [b] Yields were determined by
19F NMR spectroscopic analysis of the crude reaction mixture with an in-
ternal standard.
Having identified optimal conditions for the trifluoromethyl-
ation of 3a, we explored the scope and generality of the pro-
cedure (Table 3). Aryl iodides 3a–r, with different electronic
properties, were investigated. Methyl-, tert-butyl-, or phenyl-
Table 3. Scope of the trifluoromethylation of aryl iodides by 1a.[a,b]
Treatment of 1a and 1b with 3a in the presence of NaF
(3 equiv) as an additive in DMF at 1408C for 8 h resulted in
clean formation of 4-methylbenzotrifluoride (4a) in modest-to-
good yields (Table 1, entries 1 and 2). The phen-ligated reagent
1a was particularly effective and afforded 4a in 83% yield
(Table 1, entry 1). DMF was found to be a more-effective sol-
vent than N,N-dimethylacetamide (DMAc), diglyme, or N-meth-
ylpyrrolidone (NMP) (Table 1, entries 3–5). Other solvents, such
as xylene and DMSO, were completely unsatisfactory (Table 1,
entries 6 and 7). The role of the additive was then investigated.
A moderate yield of 4a (56%) was obtained when the reaction
was conducted in the absence of NaF (Table 1, entry 8). A com-
parable yield of 4a (80%) was obtained when LiF was used as
the additive (see the Supporting Information). Other additives,
such as KF, AgF, nBu4NF, and (HF)3NEt3, were ineffective or far-
less effective (see the Supporting Information). Prolonging the
reaction time to 15 h did not affect the result severely. More-
over, performing the reaction at a lower temperature (1208C)
furnished a lower yield of 4a, thus the reaction temperature of
1408C was essential to overcome the energy barrier for decar-
boxylation of the copper trifluoroacetate reagent. It should be
noted that previous reports on copper-mediated decarboxyl-
ative trifluoromethylation with Na[O2CCF3] noted higher tem-
[a] Conditions: 1a (0.45 mmol), 3 (0.30 mmol), NaF (0.90 mmol), DMF
(4.0 mL), 1408C, 8 h, N2 atmosphere. [b] Yields were determined by
19F NMR spectroscopic analysis of the crude reaction mixture with an in-
ternal standard. [c] Aryl bromide (4k’) was used.
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substituted aryl iodides 3a–f, and 1-iodonaphthalene (3g) pro-
vided the desired products 4a–g in good yields (70–83%).
Moreover, aryl iodides 3h–m, which contained nitrile, ketone,
aldehyde, ester, or nitro functionalities, were successfully react-
ed with 1a to give the corresponding products 4h–m in ac-
ceptable yields (50–73%). Remarkably, aryl iodides 3n and 3o
substituted with a deactivating methoxy group provided the
desired products 4n and 4o in 85 and 79% yield, respectively.
Similarly, 3-iodo-N-phenylcarbazole (3p) also reacted under the
standard reaction conditions to give the desired product 4p in
81% yield. Furthermore, chloro-substituted aryl iodides 3q and
3r were trifluoromethylated with high efficiency and afforded
the corresponding products 4q and 4r in 77 and 70% yield,
respectively. When aryl bromide 3k’ was utilized the desired
product 4k was formed in 31% yield.
3-Bromoquinoline (5n) yielded 6n in 79% yield, whereas 5-
bromoisoquinoline (5o) afforded 6o in 38% yield. In addition,
the use of 2- and 5-bromopyrimidine (5p, 5q) was tolerated
under the optimized conditions, and the corresponding prod-
ucts 6p and 6q were obtained in 50 and 75% yield, respec-
tively. In comparison, the trifluoromethylation of 2-bromoqui-
noxaline (5r) and 6-bromoimidazo[1,2-a]pyrazine (5s) proved
more challenging and afforded corresponding products 6r and
6s in lower yields (21 and 25%, respectively).
To further test and refine this methodology, we performed
a late-stage trifluoromethylation of an estradiol derivative
(Scheme 5). The reaction of 3s with 1a provided a 47% isolat-
ed yield of 4s. This result demonstrates that our protocol can
be extended to other pharmaceutically relevant molecules.
The scope of the trifluoromethylation reaction was further
explored by using heteroaryl bromides (Table 4). A variety of
Table 4. Scope of the trifluoromethylation of heteroaryl bromides by
1a.[a,b]
Scheme 5. Late-stage trifluoromethylation of estradiol derivative 3s.
To demonstrate the scalability of the protocol, a gram-scale
reaction was performed with 5n and 1a under the standard
conditions. After 12 h in DMF at 1408C, the trifluoromethylated
product 6n was isolated in 61% yield (Scheme 6).
Scheme 6. Scalability of the trifluoromethylation reaction of 5n.
Radical-probe experiment
To probe for possible radical intermediates in this transforma-
tion, a series of experiments were rationally designed and per-
formed. Trifluoromethylation of 3a with 1a was carried out in
the presence of radical scavenger 2,2,6,6-tetramethylpiperidine
N-oxide (TEMPO). The trifluoromethylated product 4a was ob-
tained in 40% yield (determined by 19F NMR spectroscopic
analysis). The addition of TEMPO did not completely suppress
the reaction, and no TEMPO–CF3 adduct was formed (see the
Supporting Information). Therefore, it is unlikely that a CF3 rad-
ical is formed during the trifluoromethylation reaction.
[a] Conditions: 1a (0.45 mmol), 5 (0.30 mmol), NaF (0.90 mmol), DMF
(4.0 mL), 1408C, 8 h, N2 atmosphere. [b] Yields were determined by
19F NMR spectroscopic analysis of the crude reaction mixture with an in-
ternal standard.
Similarly, the reaction proceeds cleanly in the presence of
1,9-dihydroanthracene—a known radical scavenger—to afford
the desired product 4a in 76% yield (see the Supporting Infor-
mation). These results indicate that the trifluoromethylation re-
action does not involve a radical-mediated mechanism.
heteroaryl bromides were investigated and showed excellent
tolerance for nitrogen-containing aromatic compounds. For ex-
ample, 2-bromopyridines 5a–e were suitable substrates and
provided the corresponding products 6a–c and 6e in moder-
ate-to-good yields; 6d was obtained in a low yield. Likewise,
3-bromopyridines 5 f–k and 4-bromopyridine 5m afforded the
corresponding trifluoromethylated products 6 f–m in accept-
able yields. The scope of the reaction was extended to the tri-
fluoromethylation of other brominated nitrogen heterocycles.
Furthermore, the reaction of 1a with 1-(allyloxy)-2-iodoben-
zene (3t) was conducted. The corresponding aryl radical has
been reported to undergo rapid cyclization to form a [3-(2,3-di-
hydrobenzofuran)]-methyl radical with a rate constant of 9.6”
109 sÀ1 en route to 3-methyl-2,3-dihydrobenzofuran.[40] The re-
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Table 5. Optimization of the difluoromethylation of 7w.[a]
Scheme 7. Test for an aryl-radical intermediate.
Entry
DCF2 source
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
2a
2b
2c
DMF
DMF
DMF
DMF
CH3CN
DMSO
NMP
diglyme
dioxane
toluene
45
77
99
35
33
28
33
0
action of 3t in DMF at 1408C for 12 h gave the trifluoromethyl-
ated product 4t as the sole product in 61% yield (Scheme 7).
No cyclization product was detected, thus this result also sug-
gests that the trifluoromethylation reaction does not proceed
via a free aryl-radical pathway.
Na[ClCF2CO2]
2c
2c
2c
2c
2c
2c
0
0
Hammett plots
10
[a] Conditions: difluorocarbene source (0.15 mmol), 7w (0.10 mmol),
NaOH (0.45 mmol), solvent (1.5 mL), 758C, 4h, N2 atmosphere. [b] Yields
were determined by 19F NMR spectroscopic analysis of the crude reaction
mixture with an internal standard.
The electronics of the reactive species were investigated by
using a Hammett correlation plot. Competition experiments
between para-substituted iodobenzene derivatives and iodo-
benzene were examined by reacting both iodoarenes
(10 equiv each), 1a (1 equiv), and NaF (3 equiv) in DMF at
1408C for 6 h. The product ratios were determined by 19F NMR
spectroscopy. Using the relative rates determined from each
competition experiment, a Hammett plot of log(kR/kH) versus
s1 was constructed (R is the para substituent of the iodoarene
analogue (Figure 3). This plot gave a 1 value of +0.56 (R2 =
this target by the use of non-ODS-based difluorocarbene re-
agents (ODS=ozone-depleting substance).[42–44]
After isolation and full characterization of the copper–chlo-
rodifluoroacetate complexes 2a–c, we evaluated the potential
of these complexes to serve as difluorocarbene precursors in
copper-mediated difluoromethylation of phenolic substrates.
Methyl 4-hydroxy cinnamate (7w) was chosen as a model
substrate for the optimization process (Table 5). In the pres-
ence of NaOH (4.5 equiv) at 758C in DMF for 4 h, difluorome-
thylation of 7w with 2a–c gave the desired product methyl 3-
(4-(difluoromethoxy)phenyl)acrylate (8w) in moderate-to-excel-
lent yields (Table 5, entries 1–3). Interestingly, the reaction pro-
ceeds chemoselectively at the OÀH bond but not at the C=C
and C=O bonds, which indicates that the OÀH bond is more
reactive towards difluorocarbene under basic conditions. Addi-
tionally, the nitrogen ligands were found to significantly affect
the reaction efficiency. Treatment of 7 w with 2a or 2b—ligat-
ed by bpy and Me2bpy, respectively—afforded 8w in 45 or
77% yield, respectively (Table 5, entries 1 and 2), whereas com-
plex 1c, with a phen ligand, gave 8w in 99% yield (Table 5,
entry 3). Notably, difluoromethylation of 7w with Na[ClCF2CO2]
afforded the product in a lower yield (35%) under similar reac-
tion conditions (Table 5, entry 4), which highlights the synthet-
ic utility of this method.
Figure 3. Hammett plots for the reactions of p-RC6H4I with 1a in DMF. Con-
ditions: [1a]=0.033 mm, [PhI]=0.33 mm, [aryl iodide]=0.33 mm,
[NaF]=0.10 mm, DMF (1.5 mL), 1408C, 6 h. Each point is the average of two
experiments.
0.99). On the basis of these Hammett studies, we propose that
the reactive species involved in the trifluoromethylation reac-
tion is nucleophilic in character.[30]
Complex 2c was selected for further optimization studies
after considering the cost and the good yield obtained in the
difluoromethylation reaction. The choice of solvent significant-
ly influenced the difluoromethylation yield (Table 5, entries 3
and 5–10); DMF was the optimal reaction medium, presumably
due to the excellent solubility of the copper reagent and
NaOH. The role of the basic additive was also investigated, and
NaOH gave the best result (see the Supporting Information).
A reaction temperature of 758C was essential to achieve
a good yield of 8w; no reaction occurred when the reaction
was conducted at 408C in DMF (see the Supporting Informa-
tion). In addition, a reaction time of 4 h was necessary for com-
Difluoromethylation reactions
Aryl difluoromethyl ethers are important structural motifs in
a range of compounds with biological or medicinal rele-
vance.[2b] There is a continued strong demand for efficient and
selective synthetic routes to these versatile scaffolds.[4f,41] In
recent years, developments in methodology have achieved
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pletion of the reaction; reducing the reaction time to 1 h low-
ered the yield of 8w to 40% (see the Supporting Information).
Notably, under the current conditions, complex 2c appears
to have a lower barrier for decarboxylation of the copper
chlorodifluoroacetate reagent, which enables the reaction to
proceed at a reasonably practical reaction temperature of
758C. For comparison, previously reported copper-mediated
examined (Table 6). An assortment of electron-deficient and
electron-rich phenols, as well as sterically hindered aromatic
phenols were successfully difluoromethylated with 2c.
Electron-deficient phenols 7a–e (4-cyanophenol, 4-cyano-4’-
hydroxybiphenyl, 6-cyano-2-naphthol, methyl paraben, and 4-
nitrophenol) reacted with 2c to give the corresponding prod-
ucts 8a–e in good-to-excellent yields, whereas 4-formylphenol
(7 f), 2- and 3-cyanophenol (7g, 7h), and 2- and 3-nitrophenol
(7i, 7j) gave products 8 f–j in moderate yields. In addition,
phenols with electron-donating groups, such as 3-methoxy-
phenol (7k) reacted with 2c to furnish the corresponding
product 8k in 33% yield. 4-Phenylphenol (7l) reacted to afford
the corresponding product 8l in 58% yield. The reaction could
also be carried out with 1- and 2-naphthol (7m, 7n) to pro-
duce products 8m and 8n, respectively, in moderate yields.
Notably, the reaction was compatible with an unprotected NH2
functionality (8o). Similarly, aryl halides were well tolerated,
and the desired products 8p–t were obtained in moderate-to-
good yields. The ability to incorporate a halogen moiety into
the difluoromethylated products provides opportunities for
further functional group manipulation by palladium-mediated
transformations. Furthermore, 4-hydroxy-4’-nitrostilbene (7u),
pterostilbene (7v), and methyl 4-hydroxy cinnamate (7w) were
amenable to the reaction conditions and were difluoromethyl-
ated to produce 8u–w in 76, 72, and 90% yield, respectively.
Pleasingly, reaction of 2c with 6-hydroxy-1-tetralone (7x) and
sesamol (7y) gave the desired products 8x and 8y in 94 and
50% yield, respectively.
decarboxylative
trifluoromethylation
reactions
with
MeO2CCF2Cl[31] or TMSO2CCF2Cl[45] required higher temperatures
(typically above 1008C).
With these optimal reaction conditions in hand, the difluoro-
methylation reactions of a variety of substituted phenols were
Table 6. Difluoromethylation of phenols.[a,b]
To demonstrate the scalability of this process, the difluoro-
methylation of 7v with 1c was repeated on a 4 mmol scale
and delivered 0.91 g (74% yield) of the difluoromethylated
product 8v. These results clearly imply both the scalability and
reliability of the method.
This difluoromethylation reaction was also applicable to hy-
droxypyridines. Various 3-hydroxypyridines were applied in the
reaction and afforded the desired difluoromethylation products
in moderate-to-good yields. Furthermore, chloro-, bromo-,
nitro-, cyano-, and ester-groups in various positions on the
ring were tolerated under the standard conditions. It is note-
worthy that the pyridone N-difluoromethylation products were
never detected under our reaction conditions.
This facile method makes late-stage difluoromethylation fea-
sible for complex biologically active compounds that contain
hydroxyl groups. To this end, estrone (7ai), estradiol (7aj), and
formononetin (7ak) were subjected to the optimized difluoro-
[a] Conditions: 2c (1.5 mmol),
7 (1.0 mmol), NaOH (4.5 mmol), DMF
(15.0 mL), 758C, 4h, N2 atmosphere. [b] Isolated yields. [c] Yields were de-
termined by 19F NMR spectroscopic analysis of the crude reaction mixture
with an internal standard.
Scheme 8. Synthesis of roflumilast intermediate 8z.
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methylation reaction conditions. The targeted products 8ai–
8ak were isolated in moderate-to-good yields. These examples
show the high functional-group tolerance and the potential of
this protocol for use with complicated biologically active com-
pounds.
Subsequently, this difluoromethylation protocol was applied
to the synthesis of roflumilast, an orally available drug devel-
oped by Altana Pharma[46] (Scheme 8). Roflumilast, used for the
treatment of chronic obstructive pulmonary disease exacerba-
tions, received approval in 2010 in the European Union and in
2011 in the USA.[3] Difluoromethylation of bromophenol 7z
was successfully performed to provide difluoro derivative 8z in
an isolated yield of 32%. Compound 8z could be readily trans-
formed into roflumilast by following reported procedures.[47]
Scheme 11. Proposed mechanism for difluoromethylation of phenols with
2c; M=Na.
experimentally by chemically induced dynamic nuclear polari-
zation NMR spectroscopy.[50] Gordon and Gano conducted ab
initio calculations for the insertion of methylene/silylene into
methane/silane at the 3-21G level of theory,[51] and Houk and
co-workers investigated the cycloadditions of difluorocarbene
with ethylene by using ab initio methods.[52] All these calcula-
tions indicate that singlet difluorocarbene, which possesses
higher electronic stability, can insert into EÀH (E=Si, Ge)
bonds in a nucleophilic fashion.
Mechanistic observations
To gain some insight into the reaction mechanism, a series of
experiments were designed and performed. To trap difluoro-
carbene, the reaction of 2c with tetramethylethylene or 1,1-di-
phenylethylene—conventional difluorocarbene scavengers—
and NaOH was carried out in DMF at 758C for 4 h. No difluoro-
cyclopropane products were detected by 19F NMR spectrosco-
py (Scheme 9). The difluorocarbene intermediate formed un-
dergoes decomposition to an unidentified species. This experi-
ment indicates that difluorocarbene reacts with phenol faster
than with tetramethylethylene or 1,1-diphenylethylene.[12i]
We carried out higher-level calculations to support this
mechanism. Geometry optimizations for all compounds with-
out symmetry constraints were performed by using DFT calcu-
lations at the B3LYP level.[53] The 6-31G(d) basis set was used
for C, H, O, and F atoms. Frequency calculations at the same
level of theory were also performed to identify all stationary
points as minima (zero imaginary frequency). Intrinsic reaction
coordinates (IRC) were also calculated to verify the transition
states. All calculations were performed by using the Gauss-
Scheme 9. Mechanistic experiments with difluorocarbene scavengers.
The reaction of sodium phenolate 7a’ with 2c and subse-
quent addition of H2O (1 equiv) under similar reaction condi-
tions did not produce the difluoromethylated product 8a
(Scheme 10). These results suggest that these difluoromethyl-
ation reactions with 2c are unlikely to proceed by an anionic
chain reaction[48] that involves addition of difluorocarbene to
the phenolate to form a carbanion intermediate (Scheme 11a).
For the reaction of an optically active silane with difluorocar-
bene, Sommer and co-workers proposed a concerted mecha-
nism with a three-center transition state, in which difluorocar-
bene inserted into SiÀH bonds.[49] This mechanism was proved
Figure 4. Top: Geometry of three-center transition state of CF2 carbene inser-
tion reaction (bond lengths in Š). Bottom: HOMO of three-center transition
state showing the bonding nature.
Scheme 10. Difluoromethylation of sodium phenolate 7a’.
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ian 03 software package.[54] According to the calculations, the
insertion reaction of difluorocarbene into phenol has an
energy barrier of 21.52 kcalmolÀ1, which is comparable to the
known activation energy (23.6 kcalmolÀ1, MP2/3-21G) for addi-
tion of difluorocarbene to propene.[48] This result also agrees
with experimental observations. The geometry of the three-
center transition state for this insertion reaction is shown in
Figure 4 (see the Supporting Information for the IRC data). The
lower energy barrier can be attributed to the higher electronic
stability of difluorocarbene, and bonding between the
s HOMO of difluorocarbene and the s* LUMO located at the
oxygen center is observed (Figure 4). In this transition, the s or-
bitals of the two fragments distort greatly to facilitate the
bonding process.
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Based on the results above, a concerted mechanism involv-
ing a three-center transition state is proposed (Scheme 11b).
Initially, the decarboxylative reaction of 2c with NaOH gener-
ates difluorocarbene with byproducts CO2 and [Cu(phen)2]Cl
byproducts. Electrophilic hydrogen-atom abstraction forms the
three-center transition state, which leads to the formation of
desired product.
Conclusions
We have synthesized new economic copper reagents
[Cu(O2CCF3)(phen)] (1a) and [Cu(phen)2][O2CCF2Cl] (2c) from
readily available and inexpensive starting materials. The struc-
tures of these compounds were elucidated by X-ray crystallog-
raphy. Air-stable complexes 1a and 2c serve as an efficient tri-
fluoromethylating reagent for decarboxylative trifluoromethyl-
ation of (hetero)aryl halides to form trifluoromethyl (hetero)ar-
enes or as a difluorocarbene precursor for difluoromethylation
of phenols and hydroxypyridines to form (hetero)aryl difluoro-
methyl ethers, respectively. Preliminary mechanistic investiga-
tions indicated that radical intermediates are unlikely to be in-
volved in the trifluoromethylation reaction. Hammett studies
revealed that the copper-mediated decarboxylative trifluoro-
methylation involves a reactive species with nucleophilic char-
acter. A concerted addition of difluorocarbene to phenol to
form a three-center transition state is proposed for the difluo-
romethylation reaction.
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (NSFC) (grant number 21372044), the Research
Fund for the Doctoral Program of Higher Education of China
(grant number 20123514110003), and Fuzhou University (grant
number 022494) is gratefully acknowledged.
Keywords: aryl difluoromethyl ethers · carbenes · copper ·
decarboxylation · trifluoromethylation
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Received: October 27, 2015
Published online on January 12, 2016
Chem. Eur. J. 2016, 22, 2075 – 2084
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2084
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