Synthesis of 1-Tri(di)fluoromethyl 1,4-Diketones Enabled by Radical Brook Rearrangement

Article abstract of DOI:10.1002/ejoc.202100860

Herein, we disclose the first and simple one-pot-two-step process to the synthesis of 1-difluoromethyl 1,4-diketones, through Mn-catalyzed radical Brook rearrangement. The methodology is also amenable to the synthesis of 1-trifluoromethyl 1,4-diketones. T

Full text of DOI:10.1002/ejoc.202100860

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of 1-Tri(di)fluoromethyl 1,4-Diketones Enabled by
Radical Brook Rearrangement
Authors: Zhihong Zhu, Xiang Chen, Shanshan Liu, Jianjun Zhang, and
Xiao Shen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100860
Link to VoR: https://doi.org/10.1002/ejoc.202100860
01/2020

10.1002/ejoc.202100860
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of 1-Tri(di)fluorom ethyl 1,4-Diketones Enabled by
Radical Brook Rearrangem ent
Zhihong Zhu,[a] Xiang Chen,[a] Shanshan Liu,[a] Jianjun Zhang,[b] and Xiao Shen*[a,c]
Dedicated to Professor Martin Oestreich on the occasion of his 50th birthday and his receipt of the WACKER Silicone Award in 2021
[a]
Z. Zhu, Dr. X. Chen, Dr. S. Liu, and Prof. Dr. X. Shen
The Institute for Advanced Studies, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, Wuhan University,
Wuhan 430072, China. http://xiaoshen.whu.edu.cn/
E-mail: xiaoshen@whu.edu.cn
[b]
[c]
Prof. J. Zhang
State Key Laboratory of Fluorinated Greenhouse Gases Replacement and Control Treatment, Zhejiang Research Institute of Chemical Industry, Hangzhou
310023, China
Prof. Dr. X. Shen
Shenzhen Research Institute of Wuhan University, Wuhan University,
Shenzhen 518057, China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Herein, we disclose the first and simple one-pot-two-step
process to the synthesis of 1-difluoromethyl 1,4-diketones, through
Mn-catalyzed radical Brook rearrangement. The methodology is
also amenable to the synthesis of 1-trifluoromethyl 1,4-diketones.
The products are efficiently converted to fluoroalkyl substituted
furans, thiophenes, pyrroles and pyridazines which are important
structural motifs in natural products and pharmaceuticals.
1,4-diketones[1] are among the most useful precursors to
synthesize furans, thiophenes, pyrroles and pyridazines, which
are important structural motifs in natural products and
pharmaceuticals such as Lophotoxin,[2] non-natural amino
acid Fmoc-D-3-Ala(2-thienyl)-OH,[3] Minaprine[4] and Liptor
(Figure 1).[5] In this scenario, much effort has been devoted to
the synthesis of 1,4-diketones.[6] Among various 1,4-diketones,
fluorinated ones are attracting chemists’ more and more
attention, since fluorine incorporation has become a routine
strategy in drug development.[7] It is well known that the
introduction of fluorine or fluoroalkyl groups can often bring
beneficial effects to the parent molecules by changing the
physical, chemical and biological properties. Among various
fluoroalkyl groups, CF3 is of particular importance due to its
strong electron-withdrawing property and chemical stability.[8]
Schem e 1. Background and our strategy for the synthesis of 1-
tri(di)fluoromethyl 1,4-Diketone.
CF2H is also very valuable since it can not only mimic OH and
SH groups but also behaves as a hydrogen donor through
hydrogen bonding.[9] Therefore, 1-trifluoromethyl and 1-
difluoromethyl 1,4-diketones are desired compounds for the
synthesis of fluoroalkylated biological important furans,
thiophenes, pyrroles and pyridazines.
Traditional ways to prepare trifluoromethyl substituted 1,4-
diketones are based on the two electron processes.[10] For
example, Leadbeaters and coworkers reported the reaction with
3-benzoylpropionic acid as starting material and TMS-CF3 as
Figure 1. Representative examples of biologically active molecules with
hetero-aromatic rings.
1
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10.1002/ejoc.202100860
European Journal of Organic Chemistry
COMMUNICATION
trifluoromethyl source (Scheme 1a).[10a] Since there were two
reaction sites, it was essential to protect the benzyl carbonyl
group, and therefore the whole synthesis took seven steps in
total, including protection, nucleophilic reaction and deprotection
steps. Jiang and co-workers reported a copper-catalyzed cross-
dehydrogenative coupling reaction for the synthesis of 2-
(trifluoromethyl)dihydropyrrole, which could be hydrolyzed to
trifluoromethylated 1,4-diketones containing R substituents next
to the trifluoroacetyl group (Scheme 1b).[10b] Maekawa’s group
also disclosed a Mg-mediated reductive trifluoroacetylation of
α,β-unsaturated ketones in the synthesis of 1-trifluoromethyl 1,4-
diketones in two steps and the R substituent was next to the
trifluoroacetyl group (Scheme 1c).[10c] However, all of these
studies are limited to the synthesis of 1-trifluoromethyl 1,4-
diketones, and there have been no practical method for the
synthesis of 1-difluoromethyl 1,4-diketones, which might
because the acidic C-H bond of CF2H group would cause
problem in the synthesis via ionic reaction conditions. To the
best of our knowledge, there was only one patent mentioned the
synthesis and application of 1-difluoromethyl 1,4-diketones.[11]
Table 1. Optimization of reaction conditions.
[a] The yield of the product 3a was determined by 19F NMR with PhCF3 as an
internal standard. [b] equiv. of TEMPO was added. TEMPO: 2,2,6,6-
3
tetramethyl-1-piperidinyloxy. TBPB: tert-buty peroxybenzoate.
Herein, We disclosed
a
simple synthesis of both 1-
trifluoromethyl 1,4-diketones and 1-difluoromethyl 1,4-diketones
based on an single electron reaction process, in which radical
Brook rearrangement[12,13] was one of the key steps (Scheme
1d). The potential of this advance was highlighted by the
synthesis of fluoroalkyl substituted heterocycles such as furans,
thiophenes, pyrroles and pyridazine.
We have reported two fluorinated organosilicon reagents as
trifluoroethanol and difluoroethanol transferring reagents for the
synthesis of tri- and di-fluorinated alcohols that proceeds via a
Mn catalyzed radical Brook rearrangement.[13a] We envisioned
that the ketyl radicals generated through Brook rearrangement
could add to the double bond of an allylic alcohol, and then new
ketyl radical could be formed via
a neophyl-type radical
rearrangement, which could be further oxidized and
deprotonated to generate ketone-containing silyl ether
product.[14] After suitable desilylation and oxidation conditions,
the final fluoroalkyl 1,4-diketone compound could be prepared
(Scheme 1d).
With this idea in mind, we first tested the radical reaction
between β-fluorinated organosilicon reagent 1a and α, α-
diphenyl allylic alcohol 2a. We used 20 mol% of Mn(OAc)2•2H2O
as catalyst and 2.5 equivalent of TBPB as oxidant to explore the
influence of solvent on the efficiency of the reaction (Table 1,
entry 1~6). It was found that DCM was the best solvent (65%
yield, Table 1, entry 6), while hexane afforded similar yield
(Table 1, entry 5) and MTBE, THF, dioxane and toluene afforded
much lower yield (Table 1, entries 1~4). Next, we explored the
ratio of reagents to get a better yield (Table 1, entries 7~9).
When the amount of 1a was increased to 3 equivalents, the yield
improved to 72% (Table 1, entry 7). We got better yield when
excess of 2a was employed, and when 1a/2a is 1/3, a yield of
81% was obtained for 3a (Table 1, entry 9). Decreasing the
amount of TBPB to 2 equivalent would reduce the yield (Table 1,
entry 10). It was found that Mn(OAc)3•2H2O can also be used as
catalyst, and 78% yield of 3a was obtained (Table 1, entry 11).
The addition of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)
completely inhibited the formation of product 3a (Table 1, entry
12), supporting that the reaction might proceed through a radical
mechanism.[13a]
Schem e 2. Substrate scope of the synthesis of 1-trifluoromethyl 1,4-diketones.
The reactions were carried out on 0.2 mmol scale and the yield referred to
isolated yield. TBAF: tetra-n-butylammonium fluoride. DMP: Dess-Martin
periodinane.
Further investigation revealed that 1-trifluoromethyl 1,4-
diketone 4a could be easily obtained, when the coupling reaction
between 1a and 2a was quenched by tetra-n-butylammonium
fluoride (TBAF) followed by Dess-Martin oxidation (61% isolated
yield, Scheme 2). Aryl with halogen or alkyl substitution could be
used as migrating groups to obtain the target products in
moderate yields (4a-4g, 48%-61% yield). In addition, the
biphenyl group could also be tolerated (4h, 64% yield). We then
found that heteroaryl had better migratory aptitude, and only the
product derived of benzofuran migration was obtained (4i, 58%
yield). This migration order is constant to the previous report,
2
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10.1002/ejoc.202100860
European Journal of Organic Chemistry
COMMUNICATION
and it was proposed that the radicals might prefer to attack the
heteroaryl group with lower energy level of LUMO in the
intramolecular radical cyclization process.[15] Unfortunately, when
we used α-alkyl-α-aryl alcohol as the substrate, we did not get
withdrawing CF3 group was favored, giving product 5o in 60%
yield.
To show the general applicability of this protocol, the
reaction was carried out at 10 mmol scale and we successfully
prepared 2.1 grams of 5a in 71% yield (Scheme 4a). The
obtained tri(di)fluoromethyl substituted 1,4-diketones 4a and 5a
are ideal precursors for the synthesis of fluoroalkyl substituted
heterocycles (Scheme 4b). Under the catalysis of p-TsOH,
compound 4a has been converted to trifluoromethylated furan
derivative 6 in 77% yield. When 1,4-diketone 4a was treated with
aniline in the presence of BINOL hydrogenphosphate in toluene
at 100 oC for 24 h, trifluoromethylated pyrrole derivative 7 was
obtained in 81% yield. The reaction between 1,4-diketone 5a
with Lawesson’s reagent performed well in pyridine, and
difluoromethylated thiophene derivative 8 has been made in
78% yield. Last but not least, the condensation reaction of 5a
with hydrazine hydrate efficiently afforded difluoromethyl
containing dihydropyridazine compound 9 in 78% yield.
the target product 4j. 9-Vinyl-9H-fluoren-9-ol was
a more
challenging substrate because of the difficulty in the opening of
the stable five-member ring, and no desired 4k was obtained.
There was no product 4l formed when the methyl group was at
the β-position of the alkene, which might be resulted from the
steric hindrance.
Schem e 4. Gram-scale reaction and the application of fluoroalkyl substituted
1,4-diketones in the synthesis of fluoroalkyl heterocycles.
Schem e 3. Substrate scope of the synthesis of 1-difluoromethyl 1,4-diketones.
The reactions were carried out on 0.2 mmol scale and the yield referred to
isolated yield.
In summary, we have developed a practical reaction for the
synthesis of 1-trifluoromethyl and 1-difluoromethyl 1,4-diketones
enabled by radical Brook rearrangement and Dess-Martin
oxidation. The synthetic potential of this advance has been
highlighted by the facile conversion of these products to
fluoroalkylated furans, thiophenes, pyrroles and pyridazines.
Because of the importance of heterocycles and fluorine
incorporation in drug development, we believe our methodology
will attract interests not only from synthesis field but also from
medicinal and agrochemical fields. Further studies on the
application of radical Brook rearrangement of organosilicon
reagents in the synthesis of important organofluorine
compounds are underway in our laboratory.
Considering the importance of difluoromethyl group in
pharmaceutical chemistry and the fact that there has been no
general methodology reported in the synthesis of 1-
difluoromethyl 1,4-diketones,[9,11] we decided to test whether our
strategy could be applied in the preparation of this kind of
compounds. Delightedly, the reaction between reagent 1b and
various vinyl diaryl alcohols proceeded well, affording the
desired products 5a-5l in 42%-69% yield (Scheme 3). The large
naphthyl group could also function as a migration group to
produce corresponding product 5k in 58% yield. Alcohols which
contain heteroaryl groups, such as benzofuryl, benzothienyl, and
thienyl groups could also be employed as the substrates,
affording the heterocyclic group migrated products 5l, 5m and
5n in 53%, 56% and 54% yield, respectively. Then, the allyl
alcohol with different aryl groups (2o) was tested, and we found
that the migration of the aryl group which contain electron
3
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We are grateful to the National Natural Science Foundation of
China (21901191), Guangdong Basic and Applied Basic
Research Foundation (2021A1515010105), the Fundamental
Research Funds for the Central Universities and Wuhan
University for financial support.
Keyw ords: Difluoromethyl • Fluorine • Ketones • Radical Brook
rearrangement • Trifluoromethyl
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Difluoromethylation and Difluoroalkylation of (Hetero) Arenes. Emerging
4
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Entry for the Table of Contents
I
The application of Mn-catalyzed radical Brook rearrangement of fluorinated organosilicon reagents in the synthesis of 1-
trifluoromethyl and 1-difluoromethyl 1,4-diktones have been disclosed for the first time. The potential of this advance have been
highlighted by the transformation of the products to biologically important fluoroalkylated heterocycles.
Institute and/or researcher Twitter usernames: (XiaoShe57346111)
5
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