p-Toluenesulfonic acid catalysed fluorination of α-branched ketones for the construction of fluorinated quaternary carbon centres

Article abstract of DOI:10.1039/c8cc06643d

A p-toluenesulfonic acid catalyzed fluorination of α-branched ketones for the construction of fluorinated quaternary carbon centers has been developed, featuring a broad substrate scope, environmentally benign reaction conditions, and operational simplicity.

Full text of DOI:10.1039/c8cc06643d

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p-Toluenesulfonic acid catalysed fluorination of
a-branched ketones for the construction of
fluorinated quaternary carbon centres†
Cite this: Chem. Commun., 2018,
54, 12377
Received 15th August 2018,
Accepted 9th October 2018
Shi-Zhong Tang,a Hong-Li Bian,a Zong-Song Zhan,a Meng-En Chen,a Jian-Wei Lv,a
ab
Shaolei Xiea and Fu-Min Zhang
*
DOI: 10.1039/c8cc06643d
rsc.li/chemcomm
A p-toluenesulfonic acid catalyzed fluorination of a-branched ketones
for the construction of fluorinated quaternary carbon centers has
been developed, featuring a broad substrate scope, environmentally
benign reaction conditions, and operational simplicity.
The structural motif bearing a quaternary C–F centre is seldom
found in natural products but widely present in clinical drugs,
agrochemicals, organocatalysts, and functional materials.1,2
For example, nucleocidin (1a)1r is one of the five fluorine-
containing natural products that have been isolated to date, while
fluticasone (1b)2b has been used for the treatment of asthma as
a clinical drug. Other representative compounds containing a
quaternary C–F center include the insecticide flubendiamide (1c),1n
maxipost (1d), which is used as a potent opener of maxi-K channels
and an activator of KCNQ4 potassium channels,1n,p compound 1e
Fig. 1 The representative functional molecules bearing a C–F quaternary
stereogenic centre.
and its analogues with potential neuroprotective activity,1h and groups have been used to address this problem.4 Among them,
organocatalysts 1f and 1g (Fig. 1).1o,q Because of the dramatic the carbonyl group is usually used for this propose because of not
change in the physical, chemical, biological, and structural only its wide presence in many functional organic molecules but
properties of the parent compounds by fluorine substitution, also its diverse transformations into other functionalities. Although
the introduction of a fluorine atom to organic molecules is of its enolized intermediate has usually been applied to introduce the
great importance in modern medical chemistry, pharmaceutical quaternary C–F bond,2 from the synthetic viewpoint, the direct
industry, chemical biology, and materials science.1,2 However, fluorination of ketones is much more efficient and should receive
due to the rather limited presence of fluorine-containing organic the attention from synthetic chemists. Despite the extensive inves-
molecules in nature, achieving these fluorine-containing func- tigation of the fluorination, even the asymmetric fluorination of the
tional molecules relies mainly on various fluorination reactions. 1,3-dicarbonyl compound and its variants (Scheme 1a),2b the
Consequently, diverse fluorinating reagents and fluorinating a-fluorination of a-branched ketones remained underexplored.5
methodologies for the construction of various C–F bonds have Very recently, Toste and coworkers have developed an efficient
been discovered and developed.3
asymmetric approach for the construction an a-fluorinated
Compared with other classic C–F bonds, the construction of a-branched ketone scaffold, but some shortcomings still existed in
quaternary C–F carbon centres is a more challenging topic in their procedure, such as moderate to good chemical yields, the use
modern fluorination chemistry, therefore certain functional of 2.0 equiv. of ketones, and the relatively narrow substrate scope
(alkyl substituted substrates are not compatible) (Scheme 1b).5a
Therefore, the development of new synthetic approaches toward
this valuable scaffold is still in high demand. In continuation of
a State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou University, Lanzhou, 730000, P. R. China. E-mail: zhangfm@lzu.edu.cn
b Key Laboratory of Drug-Targeting of Education Ministry and Department of
our research interest for the construction of aza-quaternary
carbon centres,6 herein, we reported an efficient approach for
Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
the preparation of a-fluorinated a-branched ketones through a
Chengdu, 610041, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc06643d p-toluenesulfonic acid (PTSA) catalysed fluorination.
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Table 1 The screening of optimal conditionsa
Entry
F reagent
Acid
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.5)
Selectfluor (1.5)
Selectfluor (1.0)
Selectfluor-II (2.0)
NFSI (2.0)
PTSA
PTSA
—
DCE
23c
82d
NRe
79
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/DCM
CH3CN/DMSO
CH3CN/THF
CH3CN/hexane
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
HCl
H2SO4
H3PO4
HBF4
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
78d
37d
77d
84
9
0e
Scheme 1 An overview of construction of the quaternary C–F bond from
ketone derivatives.
10
11
12
13
14
15
16
17
82d
80d
85
78
74
80
23
0e
Initially, we selected 2-phenylcyclohexanone (2a) as a model
substrate and Selectfluor as the fluoride source to investigate
the fluorination reaction. When PTSA was used as the catalyst
to promote the fluorination in 1,2-dichloroethane (DCE) at
room temperature for 48 hours, the desired product 3a was
isolated in 23% yield with the recovery of 66% starting material
2a (entry 1, Table 1). Further solvent screening showed that
CH3CN was the most suitable solvent for the reaction, but trace
unknown by-products was observed.7 In order to reduce these
undesired by-products, the replacement of PTSA with other
protonic acids was then evaluated, albeit with only inferior
results obtained (entries 3–7, Table 1). Next, some mixed
solvents were further tested, and CH3CN/DCM (v/v = 4/1) was
found to be the best choice, which reduced the undesired side-
NFPY (2.0)
a
Reactions were performed using 2-phenylcyclohexanone (2a, 0.20 mmol)
and fluorinating reagents (0.40 mmol) in 1.0 mL solvent at room
temperature under an argon atmosphere. Isolated yield. Recovery
of 66% starting material. Trace impurity was observed in the isolated
product 3a. Recovery of the starting material.
b
c
d
e
reactions and increased the isolated yield of product 3a to 84% product 3q was obtained in 69% yield without the isolation of the
(entries 8–11, Table 1). Subsequently, the screening of the disubstituted product. Then, substrates with different ring sizes were
amount of Selectfluor revealed that increasing the Selectfluor investigated. Cyclopentanone, cycloheptanone, oxa-cyclohexanone,
content to 2.5 equivalents slightly improved the yield of product and benzocyclic ketones were all tolerated in the current fluorina-
3a (entries 12–14, Table 1), while decreasing the amount of tion, affording the corresponding products 3r–3u in acceptable to
catalyst PTSA led to the observation of unknown by-products good yields. Finally, in contrast to Toste’s procedure, which is not
and the need of a relatively longer reaction time.7 Finally, other compatible with linear substrates, when linear substrate 2v was
fluorinating reagents were evaluated; however, no better results subjected to the optimal conditions, the reaction performed well
were obtained (entries 15–17, Table 1). Therefore, 1.0 equiv. of and generated 3v in 91% yield with excellent selectivity. These results
ketone, 2.0 equiv. of Selectfluor, and 0.2 equiv. of PTSA in 1 mL demonstrated that the current fluorination is a complementary
CH3CN/DCM at room temperature were selected as the optimal fluorination methodology to Toste’s procedure. Notably, the sub-
reaction conditions for the next investigation.
stituents (Cl, Br, OMe, Me, and NO2 groups) on arene could be
We then investigated the substrate scope of this fluorination further transformed into other functionalities and thus afford more
reaction under the optimal conditions. As summarized in Table 2, sophisticated fluorine-containing molecules.
2-arylcyclohexanones with a range of arene substituents were first
Next, we turned our attention to a-alkyl substituted ketones,
evaluated, and substrates with either aryl electron-withdrawing which are not compatible under Toste’s fluorination conditions
groups (such as F, Cl, and Br, and even NO2 and CF3) or electron- and thus more challenging to fluorinate. To our pleasure, these
t
donating groups (such as Me, Bu, and OMe) all performed well, ketones are viable substrates under the current fluorination
producing the desired products 3a–3n in good to excellent yields. conditions (Table 3). For example, either linear n-hexyl-, benzyl-
Moreover, the position of the substituent could slightly affect the or cyclohexyl-substituted substrates performed well, producing
yields of the products (3b–3d), and the bis-substituted aryl ring the corresponding products 3w–3y in good to excellent yields.
product 3o could be isolated in 81% yield. These results indicated Moreover, an alkyl group bearing other terminal functionalities
that the substituents on arene had a slight influence on the such as ether or nitrile also reacted smoothly, and the expected
reaction outcomes. 2-(2-Naphthyl)cyclohexanone was also proved products 3z and 3aa could be obtained in 67% and 82% yields,
to be a viable substrate, providing the corresponding product 3p respectively. Specifically, symmetric dialkylketones could be mono-
in satisfactory yield. It should be noted that the mono-fluorinated fluorinated in high chemoselectivity, affording the expected
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Table 2 The scope of a-aryl substituted ketonesa
Table 3 The scope of a-alkyl and a-alkynyl substituted ketonesa
a
Reactions were performed using substrates (0.20 mmol) and Select-
fluor (0.40 mmol) in 1.0 mL CH3CN/DCM (4/1) at noted temperature
under an argon atmosphere, and the isolated yields are listed.
functional molecules.8 Therefore, some natural monoterpenes
were subjected to the optimal conditions, and the expected
products were isolated in acceptable yields (Scheme 2b). For
(+)-methone (4), two diastereoisomers (À)-(2S,5R)-2-fluoro-2-
isopropyl-5-methylcyclohexanone (4a) and (+)-(2R,5R)-2-fluoro-2-
isopropyl-5-methylcyclohexanone (4b) could be isolated in 57%
and 31% yields, respectively.7,9 In comparison, (À)-isopinocam-
phone (5) would produce a single diastereoisomer 5a under the
optimal conditions but in a relatively low yield (41%) presumably
due to the volatility of product 5a.7 These chiral products possess
the similar skeleton to the organocatalyst 1g.
a
Reactions were performed using substrates (0.20 mmol) and Select-
fluor (0.40 mmol) in 1.0 mL CH3CN/DCM (4/1) at noted temperature
under an argon atmosphere, and the isolated yields are listed.
products 3ab–3ad in good yields without isolation of difluorination
products.7 Finally, other types of alkyl substituted ketones were
further evaluated. Benzocyclic ketones could provide products 3ae
and 3af in 72% and 88% yields, respectively. Remarkably, similar
to the aryl substituted linear substrate 2v, alkyl substituted linear
ketones were also amenable to the fluorination, and the desired
products 3ag–3ah could be obtained after a prolonged reaction
time at higher temperature. These reaction results again indicated
that our fluorination methodology provided an alternative
approach for the synthesis of challenging a-alkyl substituted
ketones, either cyclic or linear.
In conclusion, an efficient fluorination of ketones for the
construction of the challenging quaternary C–F bond has been
achieved. The current catalytic transformation features a broad
substrate scope, good to excellent yields, and environmentally
The current fluorination was further expanded to a-alkynyl
and a-alkenyl substituted ketones (Table 3). The expected
alkynyl ketones 3ai–3ak could be isolated in moderated yields,
while 2-(1-cyclohexenyl)cyclohexanone gave complex mixtures.
A practical application of this fluorination was next studied.
The gram-scale reactions of 2a and 2y were conducted, which
produced the expected products 3a and 3y in 91% and 81%
yields, respectively. These results demonstrated that the
current fluorination procedure could be applied for the gram-
scale synthesis of either aryl substituted or alkyl substituted
fluorine-containing ketones (Scheme 2a).
Late-stage fluorination of small molecules, especially
natural products, is one of the valuable synthetic strategies for
the design, preparation, and discovery of fluoride-containing
Scheme 2 Some synthetic applications of fluorination.
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We are grateful to the NSFC (No. 21772076 and 21502080)
and PCSIRT of MOE (No. IRT-15R28) for supporting this work.
We also thank Prof. Z. L. Liu and Prof. Q. X. Wu for the
discussion of chemical structures of products 4a, 4b, and 5a.
Conflicts of interest
There are no conflicts to declare.
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