Copper-Mediated Synthesis of Monofluoro Aryl Acetates via Decarboxylative Cross-Coupling

Article abstract of DOI:10.1055/s-0036-1588516

We report the Cu-promoted oxidative cross-coupling of α-fluoromalonate half-esters and aryl boron reagents to deliver mono-fluoro α-aryl acetates under mild conditions (in air at room temperature). The reaction uses a simple, readily available monofluorinated building block to generate arylated compounds with functional groups that are not easily tolerated by existing methods, such as aryl bromides, iodides, pyridines, and pyrimidines.

Full text of DOI:10.1055/s-0036-1588516

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
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en
A. Fahandej-Sadi, R. J. Lundgren
Letter
Synlett
Copper-Mediated Synthesis of Monofluoro Aryl Acetates via
Decarboxylative Cross-Coupling
Anis Fahandej-Sadi
X
O
X
O
50 mol% Cu(OTf)2
r.t., air
R'
Rylan J. Lundgren*
0
0
0
0
0-
0
0
2
7-
7
6
0
6-
9
4
6
R'
CO2H
RO
RO
[B]
Department of Chemistry, University of Alberta,
Edmonton, Alberta, T6G 2G2, Canada
rylan.lundgren@ualberta.ca
F
F
mild decarboxylative arylation
readily available monofluoro building block
76–43% yield
22 examples
Dedicated to Victor Snieckus on the occasion of his
80th birthday.
Received: 27.05.2017
Accepted after revision: 03.07.2017
Published online: 08.08.2017
highly reactive fluorinating agents (Scheme 1A). Alterna-
tively, the ability to arylate simple, readily available mono-
fluoro acetate derivatives presents an attractive alternative
route to polyfunctionalized fluorinated derivatives (Scheme
1B).8 In this regard, the Pd- or Ni-catalyzed cross-coupling
of α-bromo-α-fluoroacetates with aryl nucleophiles pro-
vides direct access to monofluoro aryl acetates.9,10 Although
these reports provide a useful strategy for preparing in-
creasingly complex benzyl fluoride compounds, relatively
high reaction temperatures (80–100 °C), the requirement
DOI: 10.1055/s-0036-1588516; Art ID: st-2017-r0405-l
Abstract We report the Cu-promoted oxidative cross-coupling of α-
fluoromalonate half-esters and aryl boron reagents to deliver mono-
fluoro α-aryl acetates under mild conditions (in air at room tempera-
ture). The reaction uses a simple, readily available monofluorinated
building block to generate arylated compounds with functional groups
that are not easily tolerated by existing methods, such as aryl bromides,
iodides, pyridines, and pyrimidines.
Key words arylation, cross-coupling, copper, aerobic catalysis, fluo-
rine
A. Aryl Acetate Fluorination
base
anodic ox.
O
O
O
O
Ar
Ar
Ar
Ar
The installation of fluorine atoms into bioactive mole-
cules can have a profound impact on the physical and bio-
chemical properties of the target compound. The ability to
selectively incorporate fluorine into complex molecules or
rapidly build structural complexity from available fluori-
nated chemical feedstocks is a wide spanning goal in syn-
thetic methodology development because a strong need for
such technology exists in the drug discovery and agrochem-
ical sectors.1 Challenges associated with enabling mild and
general synthetic routes to prepare polyfunctionalized or-
ganofluorine compounds has motivated the development of
new fluorination reactions and fluorinating reagents, and
has led to increased availability of fluorine-containing syn-
thetic building blocks.2
The preparation of α-fluoro aryl acetate derivatives typ-
ify the evolution of the field, whereby modern metal-cata-
lyzed strategies and the use of novel fluorinating agents
have emerged,2b,3 offering the potential to supplant tradi-
tional methodologies such as electrophilic fluorination of
enolates generated under strongly basic conditions,4 elec-
trochemical routes,5 or the deoxyfluorination of α-hydroxy
esters,6,7 which require forcing reaction conditions with
"F+"
F–
RO
RO
RO
RO
O
Ar
RO
F
"F"
[Cu]
F–
N2
OH
B. Established Fluoro Acetate Arylation Methods
Ar–H
or
Ar–X
Ar–[M]
[Pd] or [Ni]
O
O
O
Br
Ar
CO2R
RO
RO
RO
F
F
F
C. This Work: Oxidatively Driven Decarboxylative Cross-Coupling
Ar–[B]
O
O
[Cu]
CO2H
Ar
RO
RO
r.t., air
F
F
Scheme 1 Synthetic methods used for the preparation of monofluoro
aryl acetates; (A) Fluorination of aryl acetates, α-hydroxy aryl acetates, or
α-diazo esters; (B) Arylation of fluoroacetate and malonate derivatives;
(C) Cu-promoted decarboxylative arylation of fluoromalonic half-esters
with aryl boron reagents reported herein
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
A. Fahandej-Sadi, R. J. Lundgren
Letter
Synlett
for substrate bromination as a prefunctionalization step,
and the lack of tolerance to reactive electrophilic function-
ality or substrates bearing basic nitrogen heterocycles re-
main a challenge for the general application of these ap-
proaches. Dialkyl fluoromalonate derivatives can be arylat-
ed via SNAr11 or metal-catalyzed cross-coupling methods;12
however, these reactions proceed with limited substrate
scope and with the requirement for subsequent dealkoxy-
carbonylation steps to generate the aryl acetate product
(Scheme 1B).
The amount of aryl boron could be reduced to 1.2 equiva-
lents with a minor decrease in yield (58%; entry 10), and
the corresponding potassium carboxylate of 1 could be used
instead of the acid with only a slight reduction in product
formation (62%; entry 11). The aryl boroxine can be used as
the limiting reagent upon minor modifications to the reac-
tion conditions (Scheme 2). Highlighting the importance of
the half-ester structure to reactivity, diethyl fluorom-
alonate, fluoromalonic acid, and ethyl fluoroacetate failed
to give more than 10% product under the standard reaction
conditions (Figure 1).
We have recently developed Cu-mediated oxidative
cross-coupling reactions to enable the functionalization of
malonate derivatives with aryl boron reagents.13,14 This re-
action manifold provides an alternative to traditional orga-
no(pseudo)halide / nucleophile carbon–carbon bond form-
ing arylation processes, tolerating electrophilic functional
groups that are reactive under typical coupling conditions.
We report herein that fluorinated malonic acid derivatives
can be employed as substrates in decarboxylative arylation
processes promoted by Cu to enable an exceptionally mild
route to high-value fluorinated compounds (Scheme 1C).
Monofluoro malonate half-esters present potentially
confounding chemical properties for cross-coupling cataly-
sis. The carboxylic acid moiety is rendered more acidic in
comparison to the unsubstituted derivative via inductive
effects; however, the malonyl C–H group is considerably
less acidic due to fluorine’s anion destabilizing α-effect,
thus resulting in a more nucleophilic enolate species upon
formation of a putative dianion.15 Perhaps unsurprisingly,
use of conditions established for the cross-coupling of mon-
oethyl malonate13b resulted in a poor yield of the desired
monofluoro aryl acetate product when using the fluorinat-
ed acid 1 (34% yield; Table 1, entry 1). In competition stud-
ies between protio- and fluoromalonic half-esters, the un-
substituted half-ester was seen to dramatically out-com-
pete the fluorinated derivative, suggesting that the fluorine
group induces a significant reduction in decarboxylative
cross-coupling reactivity (see the Supporting Information
for details). Undeterred, a range of experimental parame-
ters were explored, ultimately resulting in the identifica-
tion of mild conditions that resulted in good yields of prod-
uct (50 mol% Cu(OTf)2, 2.5 equiv aryl boroxine, room tem-
perature in air: 78% yield; entry 2). Selected reaction
parameters that are important for a productive process are
outlined in Table 1. Cu(OAc)2 was completely ineffective as a
catalyst (<2% yield); however, Cu(I) species with noncoordi-
nating counter anions, such as Cu(MeCN)4PF6 provided
good yields of product (74%), presumably due to rapid oxi-
dation under the reaction conditions. Ambient air provided
the best conditions for reoxidation of copper; a pure O2 en-
vironment resulted in 30% product yield, whereas reactions
conducted under N2 resulted at 14% yield (entries 5 and 6).
Aryl boroxines were superior boron reagents; the use
B(neop) derivatives resulted in acceptable yields (64%), but
B(pin) or B(OH)2 reagents performed poorly (entries 7–9).
Table 1 Effect of Reaction Parameters on the Cu-Promoted Oxidative
Cross-Coupling of α-Fluoromalonic Half Esters and Aryl Boron Reagents
250 mol% (Ar–BO)3
50 mol% Cu(OTf)2
O
O
CO2H
EtO
EtO
Br
300 mol% NEt3
DMA, r.t. in air
F
F
1
2a
standard conditions
Entry
Variation from standard conditionsa
Conv.
(%)b
Yield
(%)b
1
2
from ref.13b (malonate half ester conditions)
none
68
>95
50
34
78
<2
74
30
14
64
14
<2
58
62
3
Cu(OAc)2 instead of Cu(OTf)2
Cu(MeCN)4PF6 instead of Cu(OTf)2
O2 atmosphere instead of air
N2 instead of air
4
>95
65
5
6
55
7
Ar–B(neop) instead of boroxine
Ar–B(pin) instead of boroxine
Ar–B(OH)2 instead of boroxine
1.2 equiv boroxine
88
8
70
9
20
10
11
82
K-carboxylate instead of free acid
>95
a 0.2 M in DMA, 48 hours.
b Conversions and yields determined by calibrated 1H NMR.
unproductive substrates (<10% yield of product)
O
O
O
CO2Et
CO2H
EtO
HO
EtO
F
F
F
Figure 1 Unproductive substrates (<10% yield of product)
200 mol% 1
O
100 mol% Cu(OTf)2
EtO
Br
[B]
Br
600 mol% NEt3
DMA, r.t. in air
F
boroxine
limiting reagent
2a 60%
Scheme 2 Preparation of a monofluoro aryl acetate using the arylating
species as the limiting reagent
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
A. Fahandej-Sadi, R. J. Lundgren
Letter
Synlett
The scope of the oxidative cross-coupling reaction be-
tween monofluoromalonate half ester 1 and a structurally
diverse series of aryl boron substrates was explored
(Scheme 3). The reaction proceeds with synthetically useful
yields under the standard conditions for aryl boroxines con-
taining halogens (2a, 2e–i), including an aryl iodide (2g),
trifluoromethoxy (2b), nitro (2d), methoxy (2c), trifluoro-
methyl (2l), cyano (2j), and ester groups (2r), including sub-
strates with polysubstitution (2e, 2j–l). Pyridine and py-
rimidine heterocycles can be alkylated in moderate yields
(2j, 2k). For more complex substrates in which boroxine
generation is less convenient (such as heteroaryl sub-
strates), the corresponding aryl B(neop) reagent could be
employed (2j–n). The use of highly electron-deficient cou-
pling partners such as 4-NO2 aryl boroxine (2o) led to lower
yields owing to the formation of diarylated product; this
was presumably because of the high acidity of the monoflu-
oro aryl acetate product. The electron-rich substrate 4-OMe
aryl boroxine delivered the product in modest yield due to
sluggish reactivity (2p; 37%). The reaction was not compat-
ible with NH amides, aldehydes or bulkier ortho-substitut-
ed boroxines (2-tolyl). Whereas the scope of the reactivity
is not universal with respect to the arylating reagent, the
tolerance to potentially reactive aryl iodides and bromides
and ability to generate electron-poor heterocyclic monofluo-
ro aryl acetates addresses reactivity problems found when
using α-bromo-α-fluoroacetates under Ni or Pd catalysis or
Cu-catalyzed fluorination reactions of α-diazo esters.3a,9,16
The scope of reactivity with alternative α-fluoro car-
boxylic acids was also briefly explored. Isopropyl, benzyl,
α,α,α-trifluoroethyl, and allyl half-esters could be arylated
under the standard conditions with acceptable yields (3a–
d, 56–74%; Scheme 4). An α-fluoro-α-keto acid substrate
was not a productive reaction partner, forming less than
10% product (3e). In a competition study between the Et-(1)
and CF3CH2-(3c) substituted malonate half-esters, the
α,α,α-trifluoroethyl derived substrate was observed to form
the product at approximately twice the rate of the ethyl
substrate (see the Supporting Information for a plot). These
results confirm the empirical trend that increasing the C–H
acidity of the malonic half-ester results in an increased rate
of reaction, and suggest that the generation of a Cu/malonic
dianion intermediate is a key step in the reaction.
1
Y
Y
O
cat. Cu(OTf)2
FG
FG
OEt
NEt3, DMA
r.t., air
[B]
F
2
Br
[B]
F3CO
[B]
[B]
MeO
[B]
2a: 73%
2b: 70%
2c: 55%
F
Cl
O2N
[B]
[B]
F
2d: 56% (66%)a
2e: 59%
2f: 58%
Br
I
Cl
[B]
[B]
[B]
2g: 59%
2h: 65%
2i: 69%
CF3
OMe
MeO
Br
F
NC
[B]
MeO
[B]
[B]
2j: 49%b
2k: 76%b
2l: 67%c
N
F
MeO
N
N
O2N
[B]
2m: 51%b
[B]
[B]
2o: 26%a
2n: 43%b
MeO
EtO2C
[B]
2q: 59%a
[B]
[B]
2p: 37%a
2r: 50%a
Scheme 3 Aryl boron substrate scope for the Cu-mediated oxidative
coupling of fluoromalonate half esters. Reagents and conditions: aryl
boroxine (250 mol%), Cu(OTf)2 (50 mol%), NEt3 (300 mol%), 0.2 M; a Yield
based on 1H/19F NMR spectroscopic analysis; b Obtained using ArB(neop);
c Aryl[B] (200 mol%) was used.
in ambient air then reoxidizes the two equivalents of Cu(I)
generated in the reaction back to Cu(II). Given that α-fluoro
ethyl acetate is not observed as a side product in the reac-
tion, we favor a process in which carbon–carbon bond for-
mation precedes decarboxylation;19 however, additional
studies are required to provide a more accurate mechanistic
description of the reaction.
In summary, we have reported a mild and efficient
route to monofluoro aryl acetates by the oxidative cross-
coupling of fluoromalonic acid derivatives and aryl boron
reagents.20 The reaction serves as a useful complement to
both aryl acetate fluorination protocols and cross-coupling
reactions that use halogenated fluoroacetates. The demon-
strated tolerance towards electrophilic aryl halide function-
ality and nitrogen-containing heterocycles aids in address-
ing challenges associated with traditional cross-coupling
methods. Future efforts will focus on developing a clear
A potential series of mechanistic steps for the cross-
coupling reaction is given in Scheme 5. Transmetalation of
the substrates and disproportion between two Cu(II) spe-
cies would generate a Cu(III) aryl malonate intermediate.
These steps are similar to those proposed for related Cu-cat-
alyzed oxidative coupling reactions of aryl boron reagents
(the Chan–Evans–Lam reaction).17 The Cu(III) species, simi-
lar to those postulated in Hurtley-type cross-couplings of
aryl electrophiles and malonates,18 would be capable of un-
dergoing facile carbon–carbon bond-forming reductive
elimination to form an aryl carboxylate. Molecular oxygen
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
A. Fahandej-Sadi, R. J. Lundgren
Letter
Synlett
58, 8315. (e) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena,
J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116,
422.
O
[B]
Br
O
F
(2) (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed.
2013, 52, 8214. (b) Champagne, P. A.; Desroches, J.; Hamel, J. D.;
Vandamme, M.; Paquin, J. F. Chem. Rev. 2015, 115, 9073.
(c) Yang, X. Y.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015,
115, 826.
50 mol% Cu(OTf)2
R
F
R
NEt3, DMA
r.t., air
CO2H
Br
O
O
O
Me
(3) (a) Gray, E. E.; Nielsen, M. K.; Choquette, K. A.; Kalow, J. A.;
Graham, T. J.; Doyle, A. G. J. Am. Chem. Soc. 2016, 138, 10802.
(b) Lee, S. Y.; Neufeind, S.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
8899. (c) Li, F. Y.; Wu, Z. J.; Wang, J. Angew. Chem. Int. Ed. 2015,
54, 656. (d) Paull, D. H.; Scerba, M. T.; Alden-Danforth, E.;
Widger, L. R.; Lectka, T. J. Am. Chem. Soc. 2008, 130, 17260.
(4) For example, see the supporting information section of:
Verhoog, S.; Pfeifer, L.; Khotavivattana, T.; Calderwood, S.;
Collier, T. L.; Wheelhouse, K.; Tredwell, M.; Gouverneur, V.
Synlett 2016, 27, 25.
F
F
F
Me
O
BnO
F3C
O
CO2H
CO2H
CO2H
3a: 69%
3b: 59%
3c: 56%
O
O
F
F
O
Me
CO2H
CO2H
3d: 74%
3e: <10%
(5) Kabore, L.; Chebli, S.; Faure, R.; Laurent, E.; Marquet, B. Tetrahe-
dron Lett. 1990, 31, 3137.
(6) For a representative example, see: Audia, J. E.; Thompson, R. C.;
Wilkie, S. C.; Britton, T. C.; Porter, W. J.; Huffman, G. W.;
Latimer, L. H. Elan Pharmaceuticals, Inc., Eli Lilly and Company
Patent US6509331 B1, 2003.
(7) For an improved protocol achieved by reagent development,
see: Goldberg, N. W.; Shen, X.; Li, J.; Ritter, T. Org. Lett. 2016, 18,
6102.
(8) The direct use of fluoroacetic acid is not advisable because of its
high toxicity, see: Goncharov, N. V.; Jenkins, R. O.; Radilov, A. S.
J. Appl. Toxicol. 2006, 26, 148.
Scheme 4 Scope of alternative α-fluoro carboxylic acid derivatives in
the Cu-mediated decarboxylative cross-coupling reaction with aryl bo-
ron reagents
Ar
1
– CuI
– CO2
Ar–[B]
CuII
CuIII
O
CuII
O
O
Ar
RO
– CuI
F
RO
O
transmetalation
disproportionation
reductive elimination
decarboxylation
F
(9) (a) Qing, F.-L.; Guo, C.; Yue, X. Synthesis 2010, 1837. (b) Su, Y.
M.; Feng, G. S.; Wang, Z. Y.; Lan, Q.; Wang, X. S. Angew. Chem. Int.
Ed. 2015, 54, 6003. (c) Wu, Y.; Zhang, H. R.; Cao, Y. X.; Lan, Q.;
Wang, X. S. Org. Lett. 2016, 18, 5564.
Scheme 5 Potential mechanistic steps in the Cu-mediated cross-cou-
pling of α-fluoromalonic half esters and aryl boron reagents
(10) For the Ir-catalyzed coupling with electron-rich heteroarenes,
see: Yu, W.; Xu, X.-H.; Qing, F.-L. New J. Chem. 2016, 40, 6564.
(11) Harsanyi, A.; Sandford, G.; Yufit, D. S.; Howard, J. A. Beilstein J.
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(13) (a) Moon, P. J.; Halperin, H. M.; Lundgren, R. J. Angew. Chem. Int.
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Chem. Soc. 2016, 138, 13826. (c) Moon, P. J.; Lundgren, R. J.
Synlett 2017, 28, 515.
(14) For a review of decarboxylative carbon–carbon bond-forming
processes, see: Patra, T.; Maiti, D. Chem. Eur. J. 2017, 23, 7382.
(15) (a) Hine, J.; Mahone, L. G.; Liotta, C. L. J. Am. Chem. Soc. 1967, 89,
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(16) Xia, T.; He, L.; Liu, Y. A.; Hartwig, J. F.; Liao, X. Org. Lett. 2017, 19,
2610.
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tallics 2012, 31, 7948. (b) Lam, P. Y. S. Chan–Lam Coupling Reac-
tion: Copper-promoted C–Element Bond Oxidative Coupling Reac-
mechanistic understanding of the process and expanding
the diversity of α-fluorinated acids that can be used a cou-
pling partners.
Acknowledgment
We thank NSERC (Discovery Grant to R.J.L., PGS-D fellowship to A.F.S)
and the University of Alberta for support. Patrick J. Moon is thanked
for late-stage experimental contribution and for helpful discussions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588516.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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References and Notes
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Chem. 2014, 167, 16. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J.
L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.;
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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A. Fahandej-Sadi, R. J. Lundgren
Letter
Synlett
(20) General Procedure for the Copper-Mediated Synthesis of
Monofluoro Aryl Acetates via Decarboxylative Cross-Cou-
pling; Procedure A (0.50 mmol scale): In an atmosphere con-
trolled glovebox, Cu(OTf)2 (90.4 mg, 0.250 mmol, 0.50 equiv)
and aryl boronic ester (1.25 mmol, 2.5 equiv) or aryl boroxine
(0.42 mmol, 2.5 equiv Ar-B) were added sequentially to a 1
dram screw-top vial containing a stir bar. The fluoromalonic
half ester (0.50 mmol, 1.0 equiv) was added as a solution in
anhydrous DMA (1.0 mL). Additional DMA (2 × 0.6 mL) was
used to quantitatively transfer the solution to the reaction mix-
ture. The solution was stirred until the majority of the solid had
dissolved, followed by the addition of NEt3 (0.2 mL, 1.5 mmol,
3.0 equiv). The vial was sealed with a PTFE-lined cap, removed
from the glovebox, and the PTFE septum was pierced with an 18
gauge needle. The reaction mixture was gently stirred at room
temperature. Upon reaction completion (24 to 72 h), the reac-
tion mixture was diluted with EtOAc (60 mL), and washed
sequentially with NH4Cl (60 mL), 0.5 M NaOH (2 × 60 mL), and
brine (60 mL). The organic layer was dried with Na2SO4, concen-
trated in vacuo, and purified by silica gel chromatography. Note,
the needle gauge and vial size can influence the reaction rates
and overall efficiency, see the Supporting Information for more
detail. Reactions conducted without the use of a glovebox gave
similar results. Cu(OTf)2 and aryl boroxines are hydroscopic and
should be stored under inert gas.
Synthesis of 2b: Prepared according to Procedure A from
the corresponding aryl boroxine (229 mg, 0.42 mmol, 2.5 equiv
Ar–B) and fluoromalonic half ester (75 mg, 0.50 mmol, 1.0
equiv), 49 h. Isolated in 73% yield after purification by column
chromatography (10:1, Hex/EtOAc) as a light-yellow oil. 1H NMR
(CDCl3, 700 MHz): δ = 7.63–7.61 (m, 1 H), 7.54–7.51 (m, 1 H),
7.41–7.38 (m, 1 H), 7.29–7.26 (m, 1 H), 5.72 (d, J = 47.4 Hz, 1 H),
4.30–4.20 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H); 13C NMR (CDCl3, 176
MHz): δ = 167.9 (d, J = 27.1 Hz), 136.3 (d, J = 21.3 Hz), 132.6,
130.3, 129.5 (d, J = 6.7 Hz), 125.0 (d, J = 6.2 Hz), 122.8, 88.4 (d, J
= 187.6 Hz), 62.1, 14.0; 19F NMR (CDCl3, 377 MHz): δ = –182.3
(d, J = 47.4 Hz); HRMS (EI): m/z [M]+ calcd for C10H10BrFO4:
259.9848; found: 259.9846
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E