Modular synthesis of α-aryl β-perfluoroalkyl ketones: Via N-heterocyclic carbene catalysis

Article abstract of DOI:10.1039/d0cc00293c

A new general de novo synthesis of pharmaceutically important α-aryl β-perfluoroalkyl ketones has been disclosed. Compared with trifluoromethylation-initiated radical 1,2-aryl migration of α,α-diaryl allylic alcohols, this protocol employs a new strategy of biomimetic carbene catalysis to assemble alkene, aldehyde and perfluoroalkyl reagents, providing access to products with excellent flexibility of the aryl unit and perfluoroalkyl group. This method also demonstrates excellent functional group compatibility, including some Grignard reagent sensitive groups.

Full text of DOI:10.1039/d0cc00293c

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A modular synthesis of α-aryl β-perfluoroalkyl ketones via N‑
heterocyclic carbene catalysis
Hai-Bin Yang,*a Zhi-Hou Wang,a Jin-Mei Lia and Chuande Wu*ab
A new general de novo synthesis of pharmaceutically important α- and Sodeoka4c independently reported that these fascinating
aryl β-perfluoroalkyl ketones has been disclosed. Compared with molecules could be accessed via trifluoromethylation-initiated
trifluoromethylation-initiated radical 1,2-aryl migration of α, α- radical 1,2-aryl migration of α, α-diaryl allylic alcohol in 2013
diaryl allylic alcohol, this protocol employs a new strategy of (Fig. 1b). After that, great endeavors toward improving the
biomimetic carbene catalysis to assemble alkene, aldehyde and original protocols were made, including cheaper
perfluoroalkyl reagent, providing access to products with excellent trifluoromethylation reagent and milder reaction condition
flexibility of aryl unit and perfluoroalkyl group. This method also through light or electricity as the driving force of reaction, but
demonstrates excellent functional group compatibility, including several limitations still exist.4-5 Firstly, migration is an electrically
some Grignard reagent sensitive groups.
controlled process and electron-deficient aryl group migrates
preferentially when R1 (R2 ) is meta or para substituent.
However, ortho-substituted aryl ring migrates less effectively,
regardless of whether R1 (R2) is electron-donating or electron-
α-Aryl ketone is an important motif which is found in a lot of
biological active compounds.1 As shown in Fig. 1, compound 1
is a selective endothelin A receptor antagonist having a IC50
value of 0.72 μmol1a and compound 2 was identified as
potential small-molecule mediator of Foxm-DNA interaction
which is relevant to human colorectal cancer.1b Replacing C-H
bond with C-F bond is a common strategy in drug design and
optimization, because this substitution will not markedly alter
three-dimensional conformation of apparent molecule due to
the very close volume between hydrogen and fluorine.2
However, C-F bond is stronger and more lipophilic, and so the
replacement will improve the stability of anti-metabolism and
the ability of permeating biomembrane.3 Hence, the
development of new method for synthesizing fluorinated
analogue of α-aryl ketone (for example, compound 3) has
significant meaning. It remains very diffcult to synthesize
compound 3 incorporating partially fluorinated aliphatic moiety
via direct fluorination.
withdrawing group. Therefore, isomer of anti-migration rule is
a. The application of -aryl ketone in medicinal chemistry

O
O
O
O
FG
F F
COOH
COOH
O
O
Bn
3
2
1
b. Previous work_Trifluoromethylation-initiated radical 1,2-aryl migration (Ref. 4-5)
O
CF3
HO
CF3
aryl migration
HO
F3C
R1
R2
R1
R2
R1
R2
c. N-heterocyclic carbene-catalyzed alkylacylation of alkenes (Ref. 11)
O
NHC
O
O
O
R4
+
+
R5
R3
N
R5
O
R3
H
R4
O
d. This work- A modular synthesis of -aryl -perfluoroalkyl ketones
The synthesis of α-aryl β-perfluoroalkyl ketones has
attracted much attention over the past few years. Wu,4a Tu4b
Ar2
Ar1
NHC
O
CF2R
+
+
H
Ar1
XCF2R
(X = I or Br)
Ar2
O
Feedstocks
thiazolium/base
a. School of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, P. R. China. Email: Haibiny@gdut.edu.cn,
cdwu@zju.edu.cn.
M+
O
O
S
Ar2
S
XCF2R
CF2R
Ar1
Ar1
CF2R
Ar2
SET
N
N
b. State Key Laboratory of Silicon Materials, Department of Chemistry, Zhejiang
University, Hangzhou 310027, P. R. China
electrophilic radical
Ar
Ar
C
D
B
A
Fig. 1 The application of α-aryl ketone and synthetic strategies
of α-aryl β-perfluoroalkyl Ketones
†Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available.
See
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Journal Name
Table 1 Optimization studies on acylperfluoroVaielkwyAlartitciloe nOnlionef
alkenea
DOI: 10.1039/D0CC00293C
unattainable and the reaction has low selectivity for substrate
with two electrically similar aryl groups. Secondly, these
protocols can only introduce trifluoromethyl (CF3) group with
only one exception where difluoroalkyl group (CF2CO2R moiety)
can be incorporated.5b At last, it takes three steps to synthesize
α, α-diaryl allylic alcohol from aldehyde and the usage of
Grignard reagent during the preparation of starting material
also limits the available pattern of substituent in aryl motif of α
-aryl β-perfluoroalkyl ketones. Therefore, it is highly desirable
to develop new method for accessing this structural array with
excellent flexibility of aryl unit and perfluoroalkyl group from
readily available starting materials.
Ph
O
O
C1 (25 mol%)
Cs2CO3 (1.0 equiv)
H
+ C4F9I
DMSO (0.5 M)
60 oC, 2 h
C4F9
4a
5a
6a
7a
(1.0 equiv)
(1.5 equiv)
(2.0 equiv)
Conv. (4a, %)
Entry
1
Variation from "standard" conditions
none
Yield (7a, %)
80 (78)
97
2
3
45
41
0.5 eq base
K2CO3
C2
63
77
4
53
98
98
5
6
7
70
44
27
C3
10% of C1
CH3CN
65
69
We envisaged
a modular synthesis of α-aryl β-
Me
Me
perfluoroalkyl ketone from alkene, aldehyde and perfluoroalkyl
reagent that may address the synthetic issues (Fig. 1d).6 In
contrast to previous strategy which provides carbonyl group via
intramolecular aryl group migration, aldehyde is directly
employed as carbonyl source. This should be a great challenge,
because aldehyde is neither a nucleophile nor a good
SOMOphile due to the difficulty of forming energy-uphill oxygen
radical.7 However, the participation of carbene catalyst will
enable this unconventional disconnection. The Breslow
intermediate A formed from aldehyde and carbene precusor in
the presence of base should be a strong reductant (Fig. 1d).8 The
fast SET process between the Breslow intermediate A and
ClO4
ClO4
iPr
N
iPr
ClO4
iPr
N
iPr
iPr
S
N
iPr
S
S
C1
C2
C3
aReaction performed on 0.2 mmol scale. Yield of 7a determined by 1H NMR
spectroscopy using CH2Br2 as an internal standard. The isolated yield is given
in parenthesis.
With the optimized condition in hand, we investigated the
scope of acylperfluoroalkylation of alkene (Table 2). A number
of perfluoroalkyl reagents were effective partners, delivering
compounds 7a-7d in 40-81% yields. This demonstrates the
versatility of our protocol in terms of introducing perfluoroalkyl
group. We also investigated the reaction employing various
aldehydes. A range of benzaldehydes which bear substituents
at the para or meta position including acetyl, methoxy, ester,
and nitrile were well tolerated, affording compounds 7e-7h in
39-71% yields. For heteroaryl aldehydes, the reaction
proceeded well to provide compounds 7i-7l in 43-75% yields.
Ortho-substituted aromatic aldehyde such as 2-
bromobenzaldehyde was not a suitable subtrate and we could
only detect a trace of product under the optimized condition.
Next, we focused on investigating the scope of alkenes. Various
styrenes incorporating electron-withdrawing or electron-
donating substituents at the aryl motif were found to
participate in the reaction, giving the corresponding products
7m-7r in 55-84% yields. Employing alkenes substituted
heteroaryl groups as substrates, the reaction proceeded well to
provide compounds 7s-7u in 58-91% yields. The reaction
afforded compound 7w and 7x in 63 and 68% yields by flexibly
choosing suitable aldehyde and alkene as reaction partners,
which were obtained as a 1.8: 1 inseparable mixture of
regioisomers according to previous report.5f It is noteworthy
that the method is compatible with some Grignard reagent
sensitive groups (7e, 7j, 7l and 7u). The result is very meaningful
because it would take additional protection/deprotection steps
to prepare α, α-diaryl allylic alcohol employed as starting
material in the aryl migration strategy. However, this protocol
is ineffective for simple aliphatic alkene.
perfluoroalkyl halide will yield the intermediate
C and
electrophilic radical B which can be fastly added to electron-rich
alkene to produce nucleophilic radical D.9 The C-C bond is
formed through the recombination of the resulting radicals C
and D. Like the terminating step of most N-heterocyclic carbene
catalyzed reactions, the acyl group is introduced along with the
regeneration of carbene catalyst.10
We began our studies by examining the reaction of
benzaldehyde 4a, 2-vinylnaphthalene 5a with perfluorobutyl
iodide 6a. Inspired by N-heterocyclic carbene catalyzed
alkylacylation of alkenes reported by Ohmiya and coworkers
(Fig. 1c),11 we examined the use of thiazolium as carbene
precursor. Thiamine diphosphate acts as a coenzyme to catalyze
the decarboxylation of pyruvate in nature, 12 which enables the
application of thiazolium-based carbene catalyst to organic
synthesis. Although the reductive potential of the
corresponding Breslow intermediate A (-0.7 to -1.0 V vs SCE)13a-b
is higher than that of perfluorobutyl iodide (-1.27 V vs SCE),14
a
fast electron transfer will be feasible because the cation motif
of the intermediate A may activate the carbon iodine bond of
perfluorobutyl iodide to overcome this endergonic event.15
After a careful screening, we identified optimal conditions using
25 mol% of carbene precusor C116 and 1.0 equivalent of Cs2CO3
as base in DMSO to provide product 7a in 80% yield by 1H NMR
(Table 1, entry 1). Lowering the Cs2CO3 loading or using other
base instead of Cs2CO3 led to decreased yields (entries 2 and 3).
Thiazoliums C2 and C3 are not as effective as C1 albeit with
similar conversion (entries 4 and 5). Compound 7a was obtained
in lower yield when reducing the C1 loading to 10 mol% (entry
6). Carrying out the reaction in less polar CH3CN, the reaction
delivered compound 7a in 27% yield (entry 7).
To demonstrate the synthetic utility of our protocol, we
targeted the synthesis of difluorinated analogue of compound
1 which is a selective endothelin A receptor antagonist.
Performing with 3-(benzyloxy)benzaldehyde, styrene and ethyl
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC00293C
COMMUNICATION
Table 2 Scope for carbene catalyzed three component reaction of alkene, aldehyde and perfluoroalkyl reagentsa
NHC
O
Ar2
Ar1
RF2C
Grignard reagent sensitive functional group
ClO4
+
XCF2R
H
Ar1
Ar2
S
N
(X = I or Br)
O
R
4
5
6
7
R = 2,6-diisopropylphenyl
feedstocks
Perfluoroalkyl group
O
Aldehydes
O
MeO2C
NC
O
O
O
O
MeO
O
C4F9
CF3
CF3
CF3
CF3
CF3
7a: 78%
7b: 81%
7e: 55%
7f: 54%
7g: 39%
7h: 71% (62%b)
N
N
O
O
O
O
O
O
O
O
N
HO
H
CF3
CF3
CF3
CF2Br
CF2CO2Et
CF3
7c: 40% (X = Br)
7d: 62% (X = Br)
7i: 60%
7j: 64%
7k: 75%
7l: 43%
Regiodivergent synthesis
Me
Olefins
Ph
O
Ph
O
Ph
O
Ph
O
Ph
O
O
CF3
CF3
CF3
CF3
CF3
MeO2C
MeO
Br
CF3
Me
7q: 74%
7m: 83%
7n: 84%
7o: 82%
7p: 55%
7w: 63%
O
Ph
O
Ph
O
Ph
O
O
BnO
O
CF2CO2Et
CF3
N
CF3
N
CF3
CF3
Br
7r: 74%
CF3
HN 7u: 58%
Me
7s: 91%
7t: 66%
7v: 67% (X = Br)
7x: 68%
aThe reaction was performed with carbene catalyst precursor C1 (25 mol%), aryl aldehyde (0.2 mmol, 1.0 equiv),aryl alkene (1.5 equiv), perfluoroalkyl reagent
(2.0 equiv) and cesium carbonate (1.0 equiv) in DMSO at 60 oC. All yields are isolated yields. b1.84 mmol of 3-methoxybenzaldehyde was used.
The major limitation of our protocol is high catalyst loading
bromodifluoroacetate under standard condition, the which is an issue for a lot of carbene-catalyzed reactions (～20
corresponding product 7v was obtained in 67% yield (Table 2). mol%).10 When a lower catalyst loading was used, the reaction
Hydrolysis of ester group afforded the target compound 8. For stoped at a lower conversion even if prolonging reaction time
compound 1, the introduction of two fluorine didn’t notably or increasing reaction temperature, which indicates catalyst
affect the volume of molecule but modify the pka value of deactivation during reaction.17 However, effort of separating
carboxyl group.
byproduct to probe the mechanism of catalyst deactivation was
In order to shed light on this new three component unfruitful.
reaction， we performed some mechanistic experiments. The
In summary, we have reported a new strategy of preparing
reaction was inhibited by the radical scavengers BHT and α-aryl β-perfluoroalkyl ketones in moderate to good yields. The
TEMPO，which demonstrates radical intermediate is involved striking feature of our protocol is that flexibile construction of
in mechanistic pathway. Combing with previous studies on aryl unit and perfluoroalkyl group from simple precursors which
redox potential of the Breslow intermediate A, we tend to free the synthesis from the intrinsic dilemma in
believe the above mentioned mechanism in Fig. 1 is reasonable. trifluoromethylation-initiated radical 1,2-aryl migration of α, α-
diaryl allylic alcohol. Seeking robust catalyst and strategy of
Scheme 1 The synthesis of difluorinated analogue of compound controlling entioselectivity for the reaction are underway in our
1
lab.
O
O
Financial support from the 100 Young Talents Programme
CO2Et
HOOC
F
LiOH, THF/H2O
0 oC, 1 h
of Guangdong University of Technology (No. 220413292) is
gratefully acknowledged.
F
F
F
O
O
Bn
Bn
8, 89%
7v
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Journal Name
2019, 84, 12925-12932; e) E. Valverde, S. KVaiewwaAmrticuleraO,nliDne.
Conflicts of interest
There are no conflicts to declare.
Sekine, M. Sodeoka, Chem. Sci. 2018, 9, 7115-7121.
DOI: 10.1039/D0CC00293C
10 For selected reviews on N-Heterocyclic carbene catalysis, see:
a) A. Grossmann and D. Enders, Angew. Chem. Int. Ed. 2012,
51, 314-325; b) X. Bugaut and F. Glorius, Chem. Soc. Rev. 2012,
41, 3511-3522; c) M. N. Hopkinson, C. Richter, M. Schedler
and F. Glorius. Nature 2014, 510, 485-496; d) S. R. Yetra, A.
Patra and A. T. Biju, Synthesis 2015, 47, 1357; e) D. M. Flanigan,
F. Romanov-Michailidis, N. A. White and T. Rovis, Chem. Rev.
2015, 115, 9307-9387; f) X.-Y. Chen, Q. Liu, P. Chauhan and D.
Enders, Angew. Chem. Int. Ed. 2018, 57, 3862-3873; g) K. J. R.
Murauski, A. A. Jaworski and K. A. Scheidt, Chem. Soc. Rev.
2018, 47, 1773-1782; h) S. Mukherjee and A. T. Biju, Chem.
Asian J. 2018, 13, 2333-2349; i) S. Mondal, S. R. Yetra, S.
Mukherjee and A. T. Biju, Acc. Chem. Res. 2019, 52, 425-436.
11 a) T. Ishii, K. Ota, K. Nagao and H. Ohmiya, J. Am. Chem. Soc.
2019, 141, 14073-14077; b) T. Ishii, Y. Kakeno, K. Nagao and
H. Ohmiya, J. Am. Chem. Soc. 2019, 141, 3854-3858.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC00293C
Ar2
Ar1
NHC
O
CF2R
XCF2R
+
+
Ar2
H
Ar1
O
(X = I or Br)
flexibile introduction of aryl unit and perfluoroalkyl group
A new strategy of assembling alkene, aldehyde and perfluoroalkyl reagent under the catalysis of
N-heterocyclic carbene afforded valuable α-aryl β-perfluoroalkyl ketone.