Palladium-Catalyzed Cross-Coupling of Ethyl Bromodifluoroacetate with Aryl Bromides or Triflates and Cross-Coupling of Ethyl Bromofluoroacetate with Aryl Iodides

Article abstract of DOI:10.1021/acs.orglett.7b00938

A palladium-catalyzed Negishi cross-coupling reaction of ethyl bromodifluoroacetate with aryl bromides or aryl triflates to construct C(sp²)-CF₂ bonds is described. The reaction was conducted under mild reaction conditions, and no preparation of organozinc reagents is required. This is the first report encompassing the conversion of aryl triflates into products containing C-CF₂ bonds. In addition, the construction of C(sp²)-CHF bonds was achieved under mild conditions via a cross-coupling of aryl iodides with ethyl bromofluoroacetate.

Full text of DOI:10.1021/acs.orglett.7b00938

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Cross-Coupling of Ethyl Bromodifluoroacetate
with Aryl Bromides or Triflates and Cross-Coupling of Ethyl
Bromofluoroacetate with Aryl Iodides
Tingting Xia,† Lei He,† Yahu A. Liu,‡ John F. Hartwig,*,§ and Xuebin Liao*,†
†School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua
University, Beijing 100084, China
‡Medicinal Chemistry, Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, United States
§Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed Negishi cross-coupling reaction of ethyl bromodifluoroacetate with aryl bromides or aryl
triflates to construct C(sp2)−CF2 bonds is described. The reaction was conducted under mild reaction conditions, and no
preparation of organozinc reagents is required. This is the first report encompassing the conversion of aryl triflates into products
containing C−CF2 bonds. In addition, the construction of C(sp2)−CHF bonds was achieved under mild conditions via a cross-
coupling of aryl iodides with ethyl bromofluoroacetate.
The cross-couplings of aryl iodides with halodifluoroacetates
were first described by Kobayashi et al. and later by Kumadaki et
al.15 under reaction conditions comprising superstoichiometric
copper in DMSO solvent. This method has been used to prepare
fluorinated arenes, and the yields are generally modest.
Unfortunately, aryl bromides do not react with halodifluoroace-
tates under these conditions.15d,e Thus, we sought a method to
couple the low-cost ethyl bromodifluoroacetate with common
reagents, such as aryl bromides and aryl triflates. In addition, only
one example of the cross-coupling of ethyl bromofluoroacetate
with an aryl iodide was recently reported by analogous copper-
mediated methods ina 23% yield.16 Herein, we report apalladium
catalyzed Negishi cross-coupling of ethyl bromodifluoroacetate
with aryl bromides and, for the first time, aryl triflates. We also
report the cross-coupling of ethyl bromofluoroacetate with aryl
iodides under similarly mild conditions to form the α-aryl
monofluoro esters in good yield. These results show that the
coupling can be conducted with catalytic amounts of metal
complexes.
luorinated molecules are of increasing significance as
1
Fmaterials, agrochemicals, and pharmaceuticals.
In the
pharmaceutical sciences, fluorinated molecules are often enlisted
to modulate the lipophilicity or the metabolic stability of
biologically active scaffolds.2 They also change the noncovalent
interactions of aryl groups, providing a method to alter binding
affinity and binding selectivity.3 Difluoromethylene (CF2) groups
are considered to be especially desirable structures because they
are bioisosteres of carbonyl groups or ethers.4
Aryldifluorocarboxylic acid derivatives are particularly valuable
in pharmaceutical sciences because they contain two fluorine
atoms at a metabolically labile benzylic position.4c,5 Moreover,
aryldifluorocarboxylic acid derivatives are valuable synthetic
precursors because their carbonyl unit can be transformed into
a wide range of functional groups. Although aryl difluoromethyl
ketones6 and aryl difluoroacetamides7 have been prepared from
aryl halides by catalytic methods, the synthesis of aryldifluor-
oacetates from aryl halides is limited.
The coupling of difluoroacetates with heteroarenes or alkenes
has been achieved only in the presence of stoichiometric amounts
ofcopperpowder8 orbyradicaladditions.9 Classicpreparationsof
aryldifluoroacetates rely on deoxyfluorination of hydroxyl or
carbonylgroups withdeoxo-fluor, DAST, ortheirderivatives,10 or
difluorination of enolates.11 Other methods for installation of
ethyl aryldifluoroacetates required arylboronic acids,12 aryl
Grignard reagents,13 arylzinc13 reagents, or α-silyldifluoroace-
tates14 as coupling partners, but these reagents are not as widely
available as are aryl halides and bromodifluoroacetate.
Christman and co-workers showed that the organozinc reagent
BrZnCF2COOEt can be prepared in situ via oxidative addition of
activated Zn(0) to BrCF2COOEt.17 Aryl bromides are known to
undergo oxidative addition to Pd(0).18 We envisioned that,
provided the transmetalation of BrZnCF2COOEt to palladium-
(II) complex [ArPdLnBr] occurs, the desired ethyl aryldifluor-
Received: March 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oacetates could be formed via the reductive elimination of the
palladium(II) complex [ArPdLn(CF2COOEt)]. Although the
Reformatsky−Negishi type coupling of aryl halides with
BrZnCH2COOR is well established by Hartwig in 200317c and
recently reported by Zhang,17d the related coupling of
BrZnCF2COOEt was reported by Zhang to proceed to low
conversion.17d In light of these studies, we initiated our
investigation to identify a catalyst that would lead to the
construction of C(sp2)−CF2 bonds via Negishi cross-coupling
of the zinc enolates of difluoro esters.
The cross-coupling of 4-bromo-1,1′-biphenyl 1a and
BrCF2COOEt 1 in the presence of zinc powder and the
combination of a Pd precursor and ligand was chosen as a
model system to determine conditions that would lead to the
coupled product. Initial experiments with a series of ligands
occurred in modest yields. For example, those conducted with Q-
phos as a ligand gave the desired product 2a in a 17% yield (Table
1, entry 1), those with Amphos did not form 2a (Table 1, entry 2),
forming a “Reformasky reagent” with the dimeric structure
(BrZnCF2COOEt−THF)2.19
To improve the yields further, we focused on the trans-
metalation step, which we expected to be the rate-limiting step.20
Alkylzinc species were shown recently to form a higher-order
zincate species prior to transmetalation,21 but the mechanism of
transmetalation of fluoroalkylzinc species has not yet been
reported. Organ et al. previously proposed that halide ions can
assist transmetalation by forming “fluoroalkylzincate” species.21b
Although addition of n-Bu4NI had little influence on the reaction
(Table 1, entry 7), and addition of n-Bu4NCl completely
suppressed the reaction (Table 1, entry 8), the addition of n-
Bu4NBr (TBAB) increased the yield of cross-coupling to 94%
(Table 1, entry 9). The yield of 2a was a lower 77% when the
amount of TBAB was 2.0 equiv (Table 1, entry 10), instead of 1.5
equiv. Reducing the amount of activated zinc powder to 2.0 equiv
resulted in a dramatic decrease in the yield of 2a to 10% (Table 1,
entry 11). A series of Pd sources were evaluated under conditions
with THF as solvent and TBAB as additive. [Pd(π-cinnamyl)-
Cl]2was the most active catalyst precursor of the ones tested
(Table 1, entries 9, 13−16). In the presence of 5 mol % [Pd(π-
cinnamyl)Cl]2 and 15 mol % Xantphos the desired product was
obtained in 94% yield. At a lower [Pd(π-cinnamyl)Cl]2 loading of
2.5 mol %, the yield of 2a was only 67% (Table 1, entry 12).
The conversion of a variety of aryl bromides to the
corresponding ArCF2COOEt was investigated under the
optimized reaction conditions (Scheme 1). Aryl bromides
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
additive
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
9
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd 1
−
−
−
−
−
−
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
THF
THF
THF
dioxane
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
17
0
23
14
0
Scheme 1. Cross-Coupling of Ethyl Bromodifluoroacetate
a
with Aryl Bromides
Pd 1
Pd 1
68
65
0
Pd 1
n-Bu4NI
n-Bu4NCl
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
Pd 1
Pd 1
94
77
10
67
63
83
80
68
b
10
Pd 1
c
11
Pd 1
d
12
Pd 1
13
14
15
16
Pd(OAc)2
Pd(dba)2
Pd(COD)Cl2
Pd(CH3CN)2Cl2
a
Reactions performed on a 0.50 mmol scale. Yield is that of the
isolated product. Pd 1: [Pd(π-cinnamyl)Cl]2. Reaction conditions: 1a
(1.0 equiv), BrCF2COOEt (3.0 equiv), palladium catalyst (10 mol %),
ligand (30 mol % for L1 or L2, or 15 mol % for L3), Zn (3.0 equiv),
and additive (1.5 equiv) in solvent (5.0 mL) under N2 at 60 °C for 24
b
c
d
h. TBAB (2.0 equiv). Zn (2.0 equiv). [Pd(π-cinnamyl)Cl]2 (0.025
a
Yield is that of the isolated product. Conditions: aryl bromides 1
(0.50 mmol), BrCF2COOEt (1.5 mmol), [Pd(π-Cinnamyl)Cl]2 (5.0
equiv, Pd catalyst 5 mol %), and Xantphos (7.5 mol %).
mol %), Xantphos (15 mol %), Zn (1.5 mmol), and TBAB (0.75
b
mmol) in THF (5.0 mL) under N2 at 60 °C for 24 h. Conducted at
1.2 mmol scale.
containing either electron-donating or -withdrawing groups
coupled with BrCF2COOEt in moderate to excellent yields
within 24 h. Ether (2g, 2h, 2i), ester (2c, 2d, 2f), and nitrile (2e)
functional groups were well tolerated under the reaction
conditions. Aldehydes and ketones were found to be incompat-
ible with the reaction, probably due to nucleophilic attack of the
organozinc reagents on the carbonyl groups. Reactions with
substrates containing dibenzofuryl (2j) or carbazolyl (2k)
moieties proceeded smoothly under the standard reaction
conditions, affording the desired products in high yields. In
addition, aryl iodides coupled with BrCF2CO2Et under the same
and those conducted with Xantphos gave 2a in an only slightly
higher 23% yield (Table 1, entry 3). The identity of the solvent
also strongly influenced the yield. No desired product was
obtained from reactions catalyzed by [Pd(π-cinnamyl)Cl]2 and
Xantphos, even at 80 °C, in DMF (Table 1, entry 5), acetonitrile,
toluene, or dichloroethane, and the yield in dioxane was only 14%
(Table 1, entry 4). However, the yield was much higher (68%) for
analogous reactions in THF (Table 1, entry 6), which could result
from the ability of THF to stabilize the organozinc reagent by
B
DOI: 10.1021/acs.orglett.7b00938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions within 12 h, affording the desired products in good to
excellent yields (see details in Supporting Information Part V).
Unfortunately, the reaction with aryl bromides bearing an ortho
substituted group resulted in poor yields or no reaction. Aryl
chlorides also did not react with BrCF2COOEt under these
conditions.
Scheme 3. Cross-Coupling of Ethyl Bromofluoroacetate with
Aryl Iodides
a
Aryl triflates can be readily prepared from phenols and are used
extensively as synthetic precursors in cross-coupling reactions.
However, thetransformation ofC−ObondstoC−CF2 bondshas
not been reported. We found that aryl triflates 3 couple with
BrCF2COOEt under our reaction conditions to afford the
corresponding products 2 (Scheme 2). The yields were slightly
Scheme 2. Cross-Coupling of Ethyl Bromodifluoroacetate
a
with Aryl Triflates
a
Yield is that of the isolated product. Conditions: aryl iodides (0.50
mmol), BrCFHCOOEt (1.5 mmol), [Pd(π-Cinnamyl)Cl]2 (5 mol %),
Xantphos (15 mol %), Zn (1.5 mmol), and TBAB (0.38 mmol) in
b
THF (5.0 mL) under N2 at 60 °C for 24 h. Conducted at 1.2 mmol
scale.
a
Yield is that of the isolated product. Conditions: aryl triflates 3 (0.50
mmol), BrCF2COOEt (1.5 mmol), Zn (1.5 mmol), [Pd(π-Cinnamyl)-
Cl]2 (5 mol %), Xantphos(15 mol %), and TBAB (0.75 mmol) in
b
THF (5.0 mL) under N2 at 60 °C for 48 h. Conducted at 2.0 mmol
scale.
Figure 1. Transformation of ethyl aryldifluoroacetates.
lower and the reaction time longer (48 h) than those of reactions
ofarylbromides, butsynthetically usefulamountsofproductwere
formed. Thereaction conditions werefound to tolerate ether (2p,
2g), tertiary amino (2q), chloro (2m), and cyano (2l, 2e) groups.
In addition to aryldifluoroacetates, α-aryl-α-fluoroacetates
have attracted increasing attention in recent years as useful
structures for medicinal chemistry.11a,22 However, prior to our
work, only one example of the cross-coupling of ethyl
bromofluoroacetate with aryl iodide was reported; this reaction
was conducted as a copper-mediated process in 23% yield.16
Thus, we assessed whether the conditions for reactions of
bromofluoroacetates would also lead to coupling of ethyl
bromofluoroacetate (BrCHFCO2Et) to prepare α-aryl-α-fluo-
roacetates.
nucleophilic acyl substitution with amines to form aryldifluor-
oamides24 (Figure 1, f).
Insummary, wehavedevelopedaversatile, palladium-catalyzed
systemforconstructingarylC(sp2)−CF2 bondsfromaryliodides,
bromides, or triflates and for constructing C(sp2)−CHF bonds
from aryl iodides. A broad range of aryl bromides, iodides, and
triflates were coupled with ethyl bromodifluoroacetate in
moderate to excellent yields. Under similarly mild reaction
conditions, aryl iodides were coupled with ethyl bromofluoro-
acetate to afford α-aryl-α-fluoroacetates efficiently.
Indeed, the cross-coupling occurred smoothly when 0.75 equiv
of TBAB was used, resulting in the desired products 4 in good to
excellent yield in most cases. The scope of the coupling of
BrCHFCO2Et is summarized in Scheme 3. The reaction
conditions were found to tolerate ester (4a, 4g), ether (4b),
bromo (4e, 4j), and nitrile (4f) groups. Neither aryl bromides nor
aryl chlorides reacted with BrCHFCO2Et under these conditions.
Ethyl aryldifluoroacetates can serve as precursors to prepare a
wide range of compounds containing a CF2 unit. For example,
ethyl aryldifluoroacetates can be hydrolyzed to aryl difluoroacetic
acids14 (Figure 1, a), decarboxylated to difluoroarenes14 (Figure
1, b), transformed to trifluoromethylarenes by Selectfluor in the
presence of silver salts (Figure 1, c),23 or reduced to the
corresponding alcohol (Figure 1, d).24 Grignard reactions with
ethyl aryldifluoroacetates afforded the corresponding secondary
alcohols24 (Figure 1, e), and the aryldifluoroamides underwent
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00938.
■
S
Detailed experimental procedure, characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jhartwig@berkeley.edu.
*E-mail: liaoxuebin@mail.tsinghua.edu.cn.
ORCID
John F. Hartwig: 0000-0002-4157-468X
Xuebin Liao: 0000-0002-0290-894X
C
DOI: 10.1021/acs.orglett.7b00938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Org. Chem. 2010, 75, 3401. (e) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Work by X.L. was supported by the Collaborative Innovation
Centre for the Diagnosis and Treatment of Infectious Diseases,
the Tsinghua-Peking Centre for Life Sciences, and the “1000
Talents Recruitment Program”. Work by J.F.H. was supported by
the NSF (CHD-1565886) and the 111 program at Tsinghua
University.
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(14) (a) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560. (b) Li, J.; Wan, W.; Ma, G.; Chen, Y.; Hu, Q.; Kang, K.;
Jiang, H.; Hao, J. Eur. J. Org. Chem. 2016, 2016, 4916.
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