Oxidative 3,3,3-trifluoropropylation of arylaldehydes

Article abstract of DOI:10.3762/bjoc.9.279

A reaction between (E)-trimethyl(3,3,3-trifluoroprop-1-en-1-yl)silane (1) and arylaldehydes 2 was triggered by fluoride anions to afford aryl 3,3,3-trifluoropropyl ketones 3 in moderate to good yield. A mechanistic study of this reaction indicated that it occurred via an allyl alkoxide (4). A subsequent 1,3-proton shift of the benzylic proton of 4 forms 3. This reaction involves oxidative 3,3,3-trifluoropropylation of an arylaldehyde to afford 4,4,4-trifluoro-1-arylbutan-1-one.

Full text of DOI:10.3762/bjoc.9.279

Oxidative 3,3,3-trifluoropropylation of arylaldehydes
Akari Ikeda, Masaaki Omote, Shiho Nomura, Miyuu Tanaka, Atsushi Tarui,
Kazuyuki Sato and Akira Ando*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2417–2421.
Faculty of Pharmaceutical Sciences, Setsunan University, 45–1,
Nagaotoge-cho, Hirakata, Osaka 573–0101, Japan
doi:10.3762/bjoc.9.279
Received: 27 August 2013
Accepted: 10 October 2013
Published: 11 November 2013
Email:
Akira Ando* - aando@pharm.setsunan.ac.jp
* Corresponding author
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Keywords:
cesium fluoride; organo-fluorine; 1,3-proton shift; trifluoromethyl;
3,3,3-trifluoropropenyl
© 2013 Ikeda et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A reaction between (E)-trimethyl(3,3,3-trifluoroprop-1-en-1-yl)silane (1) and arylaldehydes 2 was triggered by fluoride anions to
afford aryl 3,3,3-trifluoropropyl ketones 3 in moderate to good yield. A mechanistic study of this reaction indicated that it occurred
via an allyl alkoxide (4). A subsequent 1,3-proton shift of the benzylic proton of 4 forms 3. This reaction involves oxidative 3,3,3-
trifluoropropylation of an arylaldehyde to afford 4,4,4-trifluoro-1-arylbutan-1-one.
Introduction
Trifluoromethyl groups are an essential motif in pharmaceut- sulfenyl)vinyltrimethylsilane for the addition to aldehydes in
icals, agricultural chemicals, and functional materials because the presence of fluoride anion [29]. Recently, Prakash et al. [30]
trifluoromethylation of such chemicals often significantly reported the synthesis of β-trifluoromethylstyrenes through a
improves their performance [1-6]. To date, the trifluoromethyla- Heck coupling reaction of aryl iodides with 1-iodo-3,3,3-trifluo-
tion of carbonyl compounds [7-10] and aryl halides [11-13] has ropropane, allowing a direct introduction of 3,3,3-trifluoro-
been extensively explored. On the other hand, the 2,2,2-trifluo- propenyl groups to aromatic rings. Approximately at the same
roethylation and the 3,3,3-trifluoropropylation, which elongate time, our research group demonstrated that (E)-trimethyl(3,3,3-
the product by two and three carbon atoms, respectively, have trifluoroprop-1-en-1-yl)silane (1) effectively participated in a
not been explored yet. 2-Bromo-3,3,3-trifluoropropene [14-26] Hiyama cross-coupling reaction with aryl iodide to construct
and 1,1,1,3,3-pentafluoropropane [27,28] have been used in β-trifluoromethylstyrenes in good to excellent yield [31,32]. In
place of (3,3,3-trifluoropropynyl)lithium, which can add to car- the course of this study, we found that the reaction of 1 with
bonyl compounds and couple with aryl halides through a zinc benzaldehyde in the presence of fluoride anions afforded an
intermediate. For the 3,3,3-trifluoropropenyl synthon Yamazaki allyl alcohol, which spontaneously isomerized to phenyl 3,3,3-
et al. reported the use of 2-(trifluoromethyl)-1-(phenyl- trifluoropropyl ketone (3a). This reaction involves a one-pot
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Beilstein J. Org. Chem. 2013, 9, 2417–2421.
synthesis of aryl 3,3,3-trifluoropropyl ketones from the corres- A variety of arylaldehydes participated in the reaction to give
ponding arylaldehyde, representing the oxidative 3,3,3-propeny- products in moderate to good yields (Table 2). The reactions
lation of the arylaldehyde. Here, we report our study of this with benzaldehyde derivatives with an electron-withdrawing
unusual reaction.
group, such as chloro-, bromo-, fluoro- or trifluoromethyl, at the
para-position proceeded to give 3b–e in moderate to good
yields (Table 2, entries 1 to 4). The substitution with other elec-
Results and Discussion
At the outset of our study, we attempted selective C–Si bond tron-withdrawing groups such as methoxycarbonyl and cyano
dissociation of 1 with several fluoride anion sources. The subse- decreased the yield of the product, 3f and 3g were obtained in
quently generated carbanion was trapped with benzaldehyde to 38% and 46% yield, respectively (Table 2, entries 5 and 6). In
generate 4,4,4-trifluoromethylallyl alcohol 4 (Table 1). We contrast, the substitution of benzaldehyde with an electron-
found that this reaction did not take place when either TiF4 in donating group slowed down the reaction substantially.
THF or CuF2/dppp in DMF was used (Table 1, entries 1 and 2). p-Methyl and p-methoxybenzaldehydes gave 3h and 3i in 26%
However, the reaction proceeded when two equivalents of CsF and 17% yield, respectively (Table 2, entries 7 and 8). meta-
to arylaldehyde 2 were used in DMA at a temperature of 55 °C, Substitution of benzaldehyde with a methoxy group gave 3j in
affording 3a and 4a in 15% and 16% yield, respectively 58% yield (Table 2, entry 9). These results are in accordance
(Table 1, entry 3). In contrast, the reaction did not proceed in with the Hammett equation. ortho-Substitution of substrates
THF (Table 1, entry 4). The yield increased as the temperature decreased the yield of the products substantially, probably
was raised to 80 °C, but a further increase to 100 °C did not because of the steric hindrance introduced by the substituent
improve the yield of the reaction (Table 1, entries 5 and 6). (Table 2, entries 10 and 11). While the reaction could be
Changing the solvent to DMF considerably shortened the reac- applied to polycyclic and heterocyclic compounds, 3m and 3n
tion time. The added amount of CsF also influenced this reac- were only obtained in low yield (Table 2, entries 12 and 13). An
tion. The reaction conducted with four equivalents of CsF aliphatic aldehyde did not participate in the reaction (Table 2,
afforded 3a and 4a in 52% and 27% yield, respectively entry 14).
(Table 1, entry 8). However, a further increase of the amount of
CsF did not improve the reaction yield (Table 1, entry 9). We During the course of this study, it became obvious that the reac-
thus determined that the conditions used in entry 8 of Table 1 tion gave allyl alcohol 4 first, and then subsequent transforma-
were optimal. We explored the scope and limitation of this reac- tion of 4 into 3 occurred during the reaction process. Recently,
tion by using these optimal conditions.
both Cahard et al. [33,34] and Qing et al. [35] independently
Table 1: Reaction of 1 with benzaldehyde in the presence of fluoride anions.a
entry
F anion (equiv)b
1 (equiv)b
solvent
temp (°C)
time (h)
yield (%)c,d
3a
4a
1
2
3
4
5
6
7
8
9
TiF4 (2)
CuF2 (1)/dppp (2)
CsF (2)
2
2
THF
DMF
DMA
THF
60
80
55
55
80
100
80
80
80
24
26
24
24
4
–
–
–
–
1.5
1.5
2
15
–
16
–
CsF (2)
CsF (2)
DMA
DMA
DMF
DMF
DMF
53
47
49
–
CsF (2)
2
4
–
CsF (2)
2
1
10
27
5
CsF (4)
2
1
52 (43)
38
CsF (6)
2
1
aThe reaction was carried out with 2a (0.2 mmol) and a solvent (2.0 mL). bThe value in parentheses indicates equiv with respect to benzaldehyde (0.2
mmol). cNMR yields, which were calculated by integration of the 19F NMR signals of 3a and 4a relative to that of the internal standard of 1,4-bis(triflu-
oromethyl)benzene. dThe value in parentheses indicates isolated yield (%).
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Beilstein J. Org. Chem. 2013, 9, 2417–2421.
Table 2: Investigation of reaction scope with optimal conditions.a
entry
Ar–CHO
3
yield (%)b
4
yield (%)b
1
2
p-Cl-C6H4
p-Br-C6H4
3b
3c
3d
3e
3f
72
79
55
59
38
46
26
17
58
12
16
41
31
–
4b
4c
4d
4e
4f
8
6
3
p-F-C6H4
4
4
p-CF3-C6H4
p-CH3OC(O)-C6H4
p-CN-C6H4
p-CH3-C6H4
p-CH3O-C6H4
m-CH3O-C6H4
o-CH3O-C6H4
o-Cl-C6H4
6
5
6
6
3g
3h
3i
4g
4h
4i
10
8
7
8
16
10
35
16
5
9
3j
4j
10
11
12
13
14
3k
3l
4k
4l
2-naphthyl
3m
3n
3o
4m
4n
3o
3-pyridyl
12
–
C6H5(CH2)2
aReactions were carried out with 1 (0.4 mmol), 2 (0.2 mmol) and CsF (0.8 mmol) in DMF (2.0 mL) at 80 °C. bNMR yields, which were calculated by
integration of the 19F NMR signals 3 and 4 relative to that of the internal standard of 1,4-bis(trifluoromethyl)benzene.
reported that the isomerization of a 4,4,4-trifluoromethylallyl further investigate the reaction mechanism, 4a was exposed to
alcohol substructure was promoted by a ruthenium catalyst to basic conditions to observe whether or not the isomerization of
form a 3,3,3-trifluoropropylcarbonyl unit. We hypothesized that 4a to 3a would occur. Indeed, the treatment of 4a with a stoi-
the formation of 3 would be promoted by inter- or intramolec- chiometric amount of DBU resulted in an almost quantitative
ular migration of the benzylic proton of 4 in the basic medium. conversion to 3a (Scheme 1, (2)).
To confirm the hypothesis, we conducted the reaction by using
benzaldehyde-d to clarify whether or not proton migration was This suggests that the reaction provides 4 first. 4 subsequently
involved in the reaction sequence. When benzaldehyde-d was isomerizes to form 3, which is an oxidative 3,3,3-trifluoro-
treated with 1 and CsF in DMF at 80 °C, the reaction gave a propylation of the arylaldehyde. These results allowed us to
product in which deuterium was inserted on the α- and propose the reaction mechanism shown in Scheme 2, which
β-carbons of the carbonyl group with rates of 22% and 53%, includes the isomerization of 5 to 6 in the formation of 3. To
respectively (Scheme 1, (1)). This result suggests that deuterium support our proposed mechanism, a computational calculation
on the β-carbon should be incorporated by a 1,3-proton shift. In was performed with Gaussian 03W at the B3LYP/6-31+G*
contrast, deuterium on the α-carbon should be inserted when the level of theory to confirm that key intermediate 7 was involved
enolate intermediate, which is generated during the reaction, in the isomerization process. The calculation indicated that
intermolecularly extracted the benzylic deuterium of 4. To intermediate 5 generated in the first step of the reaction was
Scheme 1: Experiments to elucidate the reaction mechanism.
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Beilstein J. Org. Chem. 2013, 9, 2417–2421.
Scheme 2: The proposed reaction mechanism.
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We reacted 1 with benzaldehyde in the presence of CsF to
provide 3. We demonstrated that 4 was generated in the first
step of the reaction, and then subsequently isomerized to 3
under basic conditions. This sequential reaction involves an
oxidative 3,3,3-trifluoropropylation of the arylaldehyde to form
a 3,3,3-trifluoropropylcarbonyl unit. A further refinement of the
reaction conditions to enhance the compatibility of the reaction
with substrates such as aliphatic aldehydes is in progress in our
group.
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Supporting Information File 1
Experimental details and characterization data for all new
compounds.
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