N-heterocyclic carbene (NHC) catalyzed synthesis of α,α- difluoro esters

Article abstract of DOI:10.1055/s-0033-1338955

A process for the synthesis of α,α-difluoro esters by NHC-catalyzed fluorination is described. The internal redox process exhibits good efficiency, selectivity, and functional-group compatibility. It provides an alternative strategy for the formation of the useful gem-difluoromethylene unit in organic molecules. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338955

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▌1221
cluster
N-Heterocyclic Carbene (NHC) Catalyzed Synthesis of α,α-Difluoro Esters
gem-Difluorination
Xiuqin Dong, Yu-Ming Zhao, Jianwei Sun*
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax +852(2358)1549; E-mail: sunjw@ust.hk
Received: 02.05.2013; Accepted after revision: 09.05.2013
parameters (Table 1), we were pleased to identify that the
Abstract: A process for the synthesis of α,α-difluoro esters by
reaction between 1a and Selectfluor (3.5 equiv), in the
NHC-catalyzed fluorination is described. The internal redox pro-
presence of 20 mol% of triazolium salt A as the precata-
cess exhibits good efficiency, selectivity, and functional-group
lyst and K3PO4 (4.0 equiv) as the base, proceeds at 50 °C
to give the desired α,α-difluoro ester 2a in good yield
(77%, Table 1, entry 1). Other achiral precatalysts, such as
thiazolium salt B as well as triazolium salts C and D, give
compatibility. It provides an alternative strategy for the formation
of the useful gem-difluoromethylene unit in organic molecules.
Key words: carbenes, fluorine, umpolung, aldehydes, esterifica-
tion
Table 1 Optimization of Reaction Parameters
A (20 mol%)
K3PO4 (4.0 equiv)
O
Organofluorine compounds have found wide applications
in the areas of agrochemical, pharmaceutical, and materi-
als sciences.1 Incorporation of fluorine can result in dra-
matic influence in the physical and chemical properties of
organic compounds. Consequently, there has been signif-
icantly increasing attention to the development of new
methods for monofluorination and trifluoromethylation.2
In contrast, strategies for the introduction of gem-difluo-
romethylene (CF2) unit into organic molecules are much
less explored.3 Nevertheless, gem-difluoromethylene unit
exhibits unique and useful properties.4 For example, it has
been demonstrated to be a useful isopolar and isosteric re-
placement for oxygen as well as a surrogate for a carbonyl
group.4 In particular, α,α-difluoro carbonyl compounds
are a family of useful compounds in medicinal chemistry.5
Typical strategies for the synthesis of this class of com-
pounds include the Reformatsky reaction and coupling re-
actions from small halodifluoro compounds.3 Here we
report an alternative synthesis of α,α-difluoro esters with
a double fluorination strategy enabled by N-heterocyclic
carbene (NHC) redox catalysis.6–8
F
F
Ph
H
Ph
CO2Me
Selectfluor® (3.5 equiv)
CHCl3, 50 °C, 17 h
OCO2Me
2a
1a
'standard conditions'
Me
Me
Cl
N+
N+
–
N
N+
BF4
Ph
(Selectfluor®)
N
N+
S
Bn
–
F
2BF4
Cl–
B
A
(PhSO2)2NF (NFSI)
Ph
N
Cl–
N
N+
N
N
N+
Ph
Ph
(F-Py)
N+
F
–
Mes
BF4
OTf–
C
D
Entry
Variation from the ‘standard conditions’ Yield (%)a
1
2
none
77
12
precatalyst B instead of A
precatalyst C instead of A
precatalyst D instead of A
NFSI instead of Selectfluor
F-Py instead of Selectfluor
NaOAc instead of K3PO4
K2CO3 instead of K3PO4
NaOMe instead of K3PO4
KHMDS instead of K3PO4
CH2Cl2 instead of CHCl3
EtOAc instead of CHCl3
THF instead of CHCl3
with MeOH (5 equiv) additive
3
14
Recently, we have reported an NHC-catalyzed enantiose-
lective fluorination process for the synthesis of α-fluoro
esters.8 During the optimization of the reaction conditions
for the monofluorination process, we were able to observe
an α,α-difluoro ester generated as byproduct. We rea-
soned that the formation of the α,α-difluoro product may
result from the readily enolizable monofluorinated prod-
uct or intermediate. We hypothesized that the α,α-difluo-
rination can be a major pathway upon careful choice of the
reaction parameters, thereby representing a useful strate-
gy for the α,α-difluoro ester synthesis.
4
32
5
71
6
<10
61
7
8
24
9
<10
<10
42
10
11
12
13
14
We began the study with racemic enal 1a, which is known
to generate the corresponding NHC enolate for subse-
quent C–F bond formation with an electrophilic fluorina-
tion reagent. After rigorous evaluation of the reaction
36
<10
<10
SYNLETT 2013, 24, 1221–1224
Advanced online publication: 28.05.2013
DOI: 10.1055/s-0033-1338955; Art ID: ST-2013-R0410-C
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
a Determined by 1H NMR spectroscopy with CH2Br2 as an internal
standard.

1222
X. Dong et al.
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significantly lower yields (Table 1, entries 2–4). The use With ethyl carbonate and tert-butyl carbonate as the γ
of NFSI as the fluorination reagent results in slightly de- leaving group, the corresponding ethyl and tert-butyl ester
creased yield, but the fluoropyridium reagent (F-Py) is es- products can also be obtained, respectively (Equation 1).
sentially ineffective (Table 1, entries 5 and 6). The However, since the nucleophile is generated in situ from
reaction is quite sensitive to base and solvent (Table 1, en- the γ leaving group, and the addition of an external alco-
tries 7–13). For example, the use of relative strong bases, hol nucleophile is not effective to enhance the reaction ef-
such as K2CO3, NaOMe, and KHMDS, is detrimental to ficiency or outcompete the in situ generated nucleophile,
the formation of the desired product. Other commonly the reaction exhibits a limitation of nucleophiles.
used solvents, for example, dichloromethane, ethyl ace-
tate, and tetrahydrofuran, slow down the reaction and give
O
F
F
standard
conditions
inferior results. The use of methanol (5 equiv) as additive
leads to exclusive formation of the monofluoro ester prod-
uct (Table 1, entry 14), which is consistent with our previ-
ous study.8 Finally, it is worth noting that the use of 10
mol% of the precatalyst A could cause yield decrease, but
the Selectfluor loading can be reduced to 2.2 equivalents
with comparable efficiency.
Ph
H
Ph
CO2R
OCO2R
1j (R = Et)
1k (R = t-Bu)
2j 64% (41 h)
2k 40% (65 h)
Equation 1
In order to gain insight into the reaction mechanism, we
have done control experiments. As shown in Equation 2,
subjection of nonfluoro ester 3a or monofluoro ester 3b to
our standard reaction protocol does not give a trace of the
desired difluoro ester 2a. Thus, this observation rules out
the possibility of initial redox ester formation followed by
fluorination of the corresponding ester enolate or the
monofluoro ester enolate.
With the standard conditions, we next evaluated the reac-
tion scope. As depicted in Table 2, a range of β,γ-unsatu-
rated α,α-difluoro esters can be synthesized in moderate to
good yields.9 The process is compatible with a diverse set
of functional groups, such as esters, ethers, silyl ethers, al-
kenes, aryl halides, and even aryl aldehydes. The alkene
configuration in the products is exclusively E. In most
cases, a small amount of monofluoro ester could be ob-
served, but the major mass balance is an unknown mix-
ture. While γ-aryl-substituted enals (R = aryl) participate
smoothly in the difluorination reaction, γ-alkyl-substitut-
ed enals (R = alkyl) give the corresponding monofluoro
esters as the major products.
We have proposed a mechanism (Scheme 1). The reaction
begins with the formation of free NHC from the precata-
lyst and base. Addition of the free NHC to aldehyde 1 fol-
lowed by elimination of the carbonate leaving group
Table 2 Reaction Scopea
O
A (20 mol%)
K3PO4 (4.0 equiv)
F
F
R
H
Selectfluor® (3.5 equiv)
CHCl3, 50 °C
R
CO2Me
OCO2Me
1
2
F
F
F
F
F
F
F
CO2Me
CO2Me
CO2Me
2b
2a
2c
OMe
OAc
68% (17 h)
57% (41 h)
66% (17 h)
F
F
F
CO2Me
F
F
CO2Me
CO2Me
OTIPS
F
2f
2d
2e
56% (17 h)b
63% (17 h)
57% (17 h)
F
F
CO2Me
F
F
F
F
CO2Me
CO2Me
2h
2g
Br
2i
CHO
71% (41 h)
63% (41 h)
42% (17 h)
a Yield of purified product.
b TIPS = triisopropylsilyl.
Synlett 2013, 24, 1221–1224
© Georg Thieme Verlag Stuttgart · New York

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gem-Difluorination
1223
Acknowledgment
standard
conditions
X
R
F
F
Financial support was provided by Hong Kong RGC (ECS605812).
Ph
CO2Me
Ph
CO2Me
3a (R = H)
3b (R = F)
no reaction
0%
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Equation 2
References and Notes
forms NHC enolate F. Subsequent C–F bond formation
with Selectfluor gives G. With a relatively low concentra-
tion of nucleophile (methoxide ion), the monofluoro acyl
NHC species G is readily enolized to give NHC enolate
H. A second fluorination step to form I followed by acyl
substitution with methoxide furnishes the desired product
2 and regenerates the NHC catalyst. The mechanism is
consistent with our control experiments in Equation 2 as
well as the observation of exclusive formation of mono-
fluoro ester with five equivalents of methanol additive.
The added methanol can facilitate the monofluoro ester
formation by trapping of the monofluoro acyl NHC spe-
cies G and thus outcompete the desired enolization
towards H.
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In summary, we have developed a new strategy for the
synthesis of α,α-difluoro esters by NHC catalysis. With
proper choice of the precatalyst, base, solvent, and fluori-
nation reagent, the internal redox fluorination process ex-
hibits good efficiency, selectivity, and functional-group
compatibility. It represents a new addition to the strategies
for efficient formation of the useful gem-difluorometh-
ylene unit in organic molecules. Control experiments pro-
vided insight into the reaction mechanism.
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N
R
CHO
O
N
N
R
Ph
OCO2Me
OMe
F
F
NHC
1
2
MeO–
OH
Ph
O
N
O
Ph
MeO
O
N
NHC+
I
N
F
F
E
K3PO4
O
R
CO2, MeO–
OMe
Selectfluor
Ph
F
O–
O–
NHC+
with MeOH
additive
Ph
NHC+
F
F
H
O
Selectfluor
Ph
NHC+
G
K3PO4
F
Scheme 1 Plausible mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1221–1224

1224
X. Dong et al.
CLUSTER
(5) (a) Moore, C. L.; Leatherwood, D. D.; Diehl, T. S.; Selkoe,
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(9) Typical Procedure
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In a glove box, an oven-dried 4 mL vial was charged with
triazolium salt A (10.9 mg, 0.04 mmol), anhyd CHCl3 (2
mL), K3PO4 (169.8 mg, 0.8 mmol), and enal 1a (0.2 mmol).
Selectfluor (248 mg, 0.7 mmol) was then added, and the vial
was capped and removed from the glove box. The reaction
mixture was stirred at 50 °C for 17 h. The solvent was
removed in vacuo, and the product 2a was purified by silica
gel chromatography (10% EtOAc in hexanes) as colorless
oil (68%). 1H NMR (400 MHz, CDCl3): δ = 7.44–7.40 (m, 2
H), 7.39–7.35 (m, 3 H), 7.11–7.06 (dt, J1 = 16.0 Hz, J2 = 2.4
Hz, 1 H), 6.35–6.26 (dt, J1 = 16.4 Hz, J2 = 11.6 Hz, 1 H),
3.91 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 164.4 (t,
J = 35.0 Hz), 136.9 (t, J = 9.0 Hz), 134.0, 129.7, 128.8,
127.4, 118.7 (t, J = 25.0 Hz), 112.8 (t, J = 244.0 Hz), 53.5.
Synlett 2013, 24, 1221–1224
© Georg Thieme Verlag Stuttgart · New York