Organocatalytic Nucleophilic Substitution Reaction of gem-Difluoroalkenes with Ketene Silyl Acetals

Article abstract of DOI:10.1021/acs.orglett.9b00566

An organocatalytic nucleophilic substitution reaction of gem-difluoroalkenes with ketene silyl acetals was developed. Phosphazene P4-tBu effectively catalyzed the reaction under mild conditions to provide monofluoroalkenes possessing an alkoxycarbonylmethyl group in high yields with high Z selectivities.

Full text of DOI:10.1021/acs.orglett.9b00566

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Nucleophilic Substitution Reaction of gem-
Difluoroalkenes with Ketene Silyl Acetals
Azusa Kondoh,‡ Kazumi Koda,† and Masahiro Terada*,†
†Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578,
Japan
S
* Supporting Information
ABSTRACT: An organocatalytic nucleophilic substitution reaction of gem-difluoroalkenes with ketene silyl acetals was
developed. Phosphazene P4-tBu effectively catalyzed the reaction under mild conditions to provide monofluoroalkenes
possessing an alkoxycarbonylmethyl group in high yields with high Z selectivities.
rganofluorine molecules are one of the privileged classes
of molecules used in various research fields due to the
Scheme 1. Organocatalytic Nucleophilic Substitution
Reaction of gem-Difluoroalkenes with Ketene Silyl Acetals
O
distinctive properties of the fluorine atom.1 In particular,
monofluoroalkenes are valuable as peptide bond isosteres
possessing higher metabolic and conformational stability and
increased lipophilicity in medicinal chemistry.2 They can also
serve as fluorinated synthons in organic synthesis.3 Thus,
considerable effort has been devoted to the development of
efficient methods for the synthesis of monofluoroalkenes.4 One
of the most general methodologies is the C−F functionaliza-
tion of readily available gem-difluoroalkenes. A conventional
approach based on this methodology is the nucleophilic
substitution reaction using organometallic reagents, such as
organolithium reagents and Grignard reagents, or anionic
nucleophiles generated by using a stoichiometric amount of a
Brønsted base, which proceeds through an addition−β-
elimination mechanism.5,6 In addition, transition-metal catal-
ysis as well as photocatalysis have emerged as powerful tools
for the C−F functionalization of gem-difluoroalkenes, and
various types of reactions have been developed so far.7−9
Nevertheless, there still remains the issue of the limitation of
scope of functional groups that can be directly introduced to
the alkene moiety. Therefore, the development of a new
reaction system that enables the expansion of the scope of
introducible functional groups is highly anticipated. In this
context, we envisioned the development of a new nucleophilic
substitution reaction of gem-difluoroalkenes with silylated
pronucleophiles, particularly ketene silyl acetals, by use of an
organobase catalyst.
activates ketene silyl acetal 2, completing the catalytic cycle.
Whereas catalytic SNAr reactions of silylated pronucleophiles
with fluoroarenes, where the eliminated fluoride is utilized for
the catalyst turnover, have been reported,12 the related
catalytic substitution reaction of gem-difluoroalkenes is rare.13
Herein, we report that phosphazene P4-tBu effectively
catalyzes the reaction under mild conditions to provide
monofluoroalkenes possessing an alkoxycarbonylmethyl
group in high yields with high Z selectivities.
Our investigation commenced with a screening for the
reaction conditions using gem-difluoroalkene 1a having a 2-
naphthyl group as the substrate and ketene silyl acetal 2a
(Table 1). The initial experiment involved treatment of 1a
with 2a in the presence of 10 mol % P4-tBu, which was
previously utilized as an activator of silylated pronucleophiles
in a catalytic SNAr reaction,12c,13 in toluene. As a result, desired
product 3aa was obtained in high yield (entry 1).14 In addition,
the reaction proceeded in a highly stereoselective manner, and
Our reaction design is shown in Scheme 1. Ketene silyl
acetal 2 is activated with the aid of an organobase catalyst to
generate ester enolate A, which is the initiation step of the
reaction.10 Subsequently, nucleophilic addition of the resulting
enolate A to gem-difluoroalkene 1 followed by the β-
elimination of fluoride from B provides the desired product
3 along with a generated fluoride.11 The fluoride then directly
Received: February 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Screening for Reaction Conditions
Table 2. Scope of gem-Difluoroalkene 1
b
yield (%)
b
c
entry
1
R1, R2
3
yield (%)
Z/E
c
entry
base
solvent
3aa
Z/E
1a
1
2
3
4
5
1b
1c
1d
1e
1f
1g
1h
1i
4-Br-C6H4, H
4-F3C-C6H4, H
4-NC-C6H4, H
4-MeO2C-C6H4, H
4-MeO-C6H4, H
3-F-C6H4, H
2-Cl-C6H4, H
1-naphthyl, H
2-thienyl, H
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
84
81
80
72
99/1
99/1
1
2
3
4
5
6
7
8
9
P4-tBu
P2-tBu
P1-tBu
iBu-PAP
TBAF
P4-tBu
P4-tBu
P4-tBu
P4-tBu
toluene
toluene
toluene
toluene
toluene
Et2O
THF
CH3CN
DMF
96 (96)
98/2
0
76
86
38
36
0
0
27
7
3
0
>99/1
>99/1
83/17
98/2
d
42
57
78
72
40
60
95/5
94/6
98/2
98/2
98/2
97/3
89
e
6
83
91
87
84
83
95
87
e
7
8
97/3
96/4
95/5
99/1
e
e
9
1j
1k
1l
3ja
3ka
3la
10
11
12
2-benzofuryl, H
Ph, Ph
Ph, OP(O)(OMe)2
e
a
Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), base (0.010
mmol), solvent (1.0 mL), rt, 13 h. Yields were determined by H
NMR analysis of the crude mixture. Dibenzyl ether was used as the
b
1
f
g
1m
3ma
1/>99
a
Reaction conditions: 1 (0.10 mmol), 2a (0.11 mmol), P4-tBu (0.010
c
b
internal standard. Isolated yield is shown in parentheses. Determined
mmol), toluene (1.0 mL), rt, 13 h. Isolated yield of major isomer
1
c
unless otherwise noted. Determined by 1H NMR analysis of the
by H NMR analysis of the crude mixture.
d
e
crude mixture. Isolated yield of a mixture of isomers. 2.0 equiv of 2a
(0.20 mmol) was used. Reaction was performed with 2.0 equiv of 2a
(0.20 mmol) at −40 °C. Estimated on the basis of experimental
evidence and DFT calculations. See the SI for details.
f
Z-isomer was obtained as the major isomer.15 Other
phosphazenes, such as P2-tBu and P1-tBu, did not catalyze
the reaction, suggesting the basicity of phosphazenes was
important (entries 2 and 3). Proazaphosphatrane (iBu-PAP),
which was also utilized in the catalytic SNAr reaction12d and
the catalytic Mukaiyama aldol reaction with ketene silyl
acetal,16 was then tested (entry 4). In this case, the reaction
proceeded, but the yield of the product was moderate.
Furthermore, the Z selectivity was slightly decreased.
Tetrabutylammonium fluoride (TBAF) was also examined
and found to be less effective than P4-tBu (entry 5). These
results imply that a countercation of anionic species formed in
situ, such as an enolate, a benzyl anion, and a fluoride, is
influential on both catalyst turnover and stereoselectivity. The
solvent effect was then investigated (entries 1 and 6−9). As a
result, less polar solvents were suitable for this reaction, and
toluene was the solvent of choice (entry 1).
g
were not suitable for this reaction, and a complex mixture was
obtained. In this reaction, diphenyl-substituted 1l was also
applicable, and corresponding 3la was obtained in high yield
(entry 11). Furthermore, alkenylphosphate 1m provided
corresponding 3ma in high yield as a single isomer (entry 12).
Next, the scope of ketene silyl acetals was examined
(Scheme 2). Dialkyl-substituted 2b provided 3ab in moderate
Scheme 2. Scope of Ketene Silyl Acetals 2
With the optimized reaction conditions in hand, the scope of
gem-difluoroalkenes was investigated (Table 2). In this
reaction, a variety of monoaryl-substituted substrates were
applicable. In the case of substrates having an electron-
withdrawing group at the para-position of the aryl group, the
reaction proceeded smoothly to provide the corresponding
products in good yields with almost perfect Z selectivities
(entries 1−4). In contrast, in the case of 1f having an electron-
donating methoxy group at the para-position, the Z selectivity
was decreased (entry 5). We assume that generation of more
stabilized benzyl anion intermediate (B in Scheme 1) would
facilitate the β-elimination of fluoride to provide thermody-
namically favorable (Z)-product with higher selectivity. 3-
Fluorophenyl- and 2-chlorophenyl-substituted 1g and 1h
underwent the reaction without any problem to provide the
corresponding 3ga and 3ha in good yields with high Z
selectivities (entries 6 and 7). Owing to the mildness of the
reaction conditions, a wide range of functional groups on the
aryl group, such as halo, trifluoromethyl, methoxycarbonyl, and
cyano groups, were compatible. The reaction of heteroaryl-
substituted 1j and 1k also proceeded smoothly to afford 3ja
and 3ka, respectively. However, alkyl-substituted substrates
yield with high Z selectivity. The reaction of phenoxy-
substituted 2c also proceeded to provide 3ac. Monosubstituted
2d was also tested, but the desired product was formed only in
low yield (<5%).
In this reaction, silyl ketene imine 4 was also applicable as a
pronucleophile, and corresponding monofluoroalkene 5 was
obtained in good yield with almost perfect Z selectivity
(Scheme 3a). Furthermore, trimethylsilyl cyanide (6) under-
went the substitution reaction by using acetonitrile as solvent
to provide fluorinated acrylonitrile derivative 7 in good yield
(Scheme 3b). In this case, the E-isomer was the major isomer.
This reaction was sufficiently reliable to permit the synthesis
of 3 on gram scale, and 3.9 g of 3aa was isolated as a pure Z-
isomer after silica gel column chromatography (Scheme 4). It
B
DOI: 10.1021/acs.orglett.9b00566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Reaction with Other Silylated Pronucleophiles
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00566.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1890181 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
is worth noting that, in this case, the catalyst loading could be
reduced to 4 mol % without affecting yield and Z selectivity.
Scheme 4. Gram-Scale Synthesis of gem-Difluoroalkene 3aa
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mterada@m.tohoku.ac.jp.
ORCID
Azusa Kondoh: 0000-0001-7227-8579
Masahiro Terada: 0000-0002-0554-8652
Notes
Finally, the transformation of the products was examined
(Scheme 5). Reduction of the ester moiety of (Z)-3aa by
The authors declare no competing financial interest.
Scheme 5. Transformation of Products
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research (S) (JP16H06354) and a Grant-in-Aid for Scientific
Research (C) (JP16K05680) from the Japan Society for the
Promotion of Science (JSPS).
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Organic Letters
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