Photocatalytic site-selective C-H difluoroalkylation of aromatic aldehydes

Article abstract of DOI:10.1039/c9cc09586a

The direct photocatalyzed para-selective C_Ar-H difluoroalkylation of aromatic aldehyde derivatives has been accomplished using a newly explored catalytic system. In addition, when using para-substituted benzaldehydes as substrates, ortho-selective C_Ar-H difluoroalkylation was also accomplished. It is worth noting that all the above site-selectivity is opposite to traditional Friedel-Crafts reactions of aromatic aldehydes. The preliminary mechanistic investigations indicate that an electrophilic difluoroalkyl radical is involved in the catalytic cycle.

Full text of DOI:10.1039/c9cc09586a

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DOI: 10.1039/C9CC09586A
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Photocatalytic Site-Selective C−H Difluoroalkylation of Aromatic
Aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
Wei-Ke Tang,a Fei Tang,a Jun Xu,*a Qi Zhang,a Jian-Jun Dai,a Yi-Si Feng,*a,b & Hua-Jian Xu*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
(a)
Site-selective C-H activation
The direct photocatalyzed para-selective CAr−H difluoroalkylation
of aromatic aldehyde derivatives has been accomplished using a
newly explored catalytic system. In additional, when using para-
substituted benzaldehydes as substrates, ortho-selective CAr–H
difluoroalkylation was also accomplished. It is worth noting that
all the above site-selectivity is opposite to traditional Friedel–
Crafts reactions of aromatic aldehydes. The preliminary
mechanistic investigations indicate that an electrophilic
difluoroalkyl radical is involved in the catalytic cycle.
CHO
CHO
CHO
FG
[M]
[M] or Friedel-Crafts
Ar
H
Ar
Ar
H
H
H
H
H
H
M = Pd, Ir
M = Pd, Ir, Ru
FG
(b)
This work:
CHO
R = H
p/(o+m) = 7/1
high-para selectivity
Rf
CHO
3
Rf
A
R
Ir
X-
+
f
R
X = Br, I
Rf = CF2CO2Et
CHO
Rf
R = H
Aromatic aldehydes are important, readily available reagents
in synthetic organic chemistry. However, their susceptibility
toward oxidation, high reactivity and weak coordinating ability
have rendered them recalcitrant directing groups in the direct
CAr−H functionalization of aromatic aldehydes.1 Thus, the
catalytic and site-selective CAr−H functionalization of readily
available aromatic aldehydes is highly desirable and attractive
in the modern chemical society.
To overcome the weak coordinating ability, , susceptibility
toward oxidation and undesired metal insertion into acyl C−H
bond,2 great process has been made in transition-metal-
catalyzed ortho- and meta-selective functionalization reactions
of aromatic aldehydes by using either preinstalled3 or transient
directing groups (Figure 1a).4 However, the para-selective C–H
functionalization of aromatic aldehydes is less explored,5 which
is possibly due to the long distance between the para-C−H
bond and (transient) directing groups. Recently, the radical
substitution reaction is now one of the most important tools
for achieve directly para-selective C–H functionalization of
arenes without (transient) directing groups.5d,6 For example,
para-selective functionalization of aromatic ketones by
employing palladium as the catalyst were developed by the
o/m = 8/1
high-ortho selective
R
6
Figure 1 C–H activation of aromatic aldehydes.
Xu6c and Zhao6d groups. However, the Pd-catalyzed para-
selective functionalization of benzaldehyde is still impeded by
the aldehyde’s undesired metal insertion into acyl C−H bond.6c
In view of photo-induced C-H functionalization has emerged as
a powerful tool for molecular synthesis, because the process
serves as an environmentally friendly method for promoting
selective radical reactions.7 Whether we can design a novel
visible-light-induced site-selective C−H functionalization of
aromatic aldehydes by using suitable photocatalyst to avoid
undesired metal insertion into acyl C−H bond.
Besides, the difluoroalkyl group is a ubiquitous fluorine-
containing functional group in various bioactive compounds,
agrochemicals, and life sciences,8 which can significantly affect
their properties, and thus enhances bioavailability, solubility,
and metabolic stability.8b,9 Although the site selective C-H
difluoromethylation of arenes have been well studied,6b,10 the
direct site-selective difluoroalkylation of aromatic aldehydes
still remains undeveloped and requires an urgent solution.
Herein, we reported a general photocatalytic para-selective
CAr−H difluoroalkylation of aromatic aldehydes in alcohol
solvent, avoiding the aldehyde’s undesired metal insertion into
acyl C−H bond. The reaction occurs under far mild conditions
and displays good para selectivity. Moreover, unusual ortho
selectivity was also achieved, when using a series of para-
substituted aromatic aldehydes derivatives as substrates in
DMSO/DMF. It is worth noting that all the above site-
a. School of Chemistry and Chemical Engineering, School of Food and Biological
Engineering, Institute of Industry & Equipment Technology, Hefei University of
Technology, Hefei 230009, P. R. China
E-mail: junxu@hfut.edu.cn, fengyisi@hfut.edu.cn, hjxu@hfut.edu.cn.
b. Anhui Province Key Laboratory of Advance Catalytic Materials and Reaction
Engineering, Hefei 230009, P. R. China
c. †Electronic Supplementary Information (ESI) available: Experimental procedures,
NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Optimization of para-C-H difluoroalkylation of 1aa
Table 2 para-C–H difluoroalkylation of 1a-ta
View Article Online
fac-Ir(ppy)3
DOI: 10.1039/C9CC09586A
PC (3 mol %)
base (6 equiv)
CHO
CHO
CHO
CHO
CHO
KOAc or K2CO3
R1
R2O2C
3
R1
CF
Br 2CO2Et
+
CF
Br 2CO2Et
F
+
+
MeOH/TFE or tBuOH
18 W blue LED, Ar, rt
R
2 = Et
R
F
solvent
Ar, rt, 18 h
18 W blue LED
F
2 = Me
H
H
3'
1
2
F
CF2CO2R
H
CO2R
2
5
CHO
CHO
Me
CHO
MeO
CHO
4
F3CO
1a
2
3a,
3a',
R = Et
3
o and m-selective
MeO2C
R = Me
MeO2C
2
6
R2O2C
4
4
MeO2C
3
F
F
F
F
ratioc
p/(o+m)
F
yield (%)b
F
3a',
F
entry
cat.
base
solvent
F
2 = Me, 80%[c] (C4/C6 > 25:1)
3d'
[d]
63%
3c',
R
, 30%
3b'
, 49%
, R2 = Et, 78%[f] (C4/C6 = 13:1)
[C4/(C2+C3) = 7:1]
(C4/C6 = 12:1.8) 3c
(C4/C6 = 14:1)
1
2
3
4
5
PC-1
PC-2
PC-3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
TFE
TFE
-
-
-
< 8
trace
0
CHO
F
CHO
CHO
OHC
EtO2C
Cl
CHO
Br
R2O2C
MeO2C
MeO2C
p
TFE
m
F
F
F
F
F
F
F
F
3g'
PC-4
PC-4
PC-4
0.9/1.0
4.3/1.0
TFE
30
64
40
18
2 = Me,34%[d] (C4/C6 = 9:1)
2 = Et, 50%[f] (C4/C6 = 7:1) (C4/C6 > 25:1)
, 40%
[d]
[d]
3e',
3f'
R
[e]
, 39%
3h
, 38%
t-BuOH
3e,
R
(C4/C6 > 25:1)
6
CHO
5
6d
7
7.0/1.0
0.7/1.0
1.0/1.0
1.5/1.0
7.0/1.0
MeOH/TFE
n-hexane
CHO
NC
CHO
CHO
PC-4
EtO2C
EtO2C
EtO2C
EtO2C
2
4
3
8
9e
10d
11d
12d
13d,f
DCM
37
65
PC-4
PC-4
Me
OMe
OCF3
F
F
F
F
F
F
F
F
t-BuOH/TFE
MeOH/TFE
MeOH/TFE
[f]
70%[f] (C4/C6 = 11:2)
3l
, 50%[f] (C4/C6 = 10:1)
CHO
Me
68%[f](C4/C6 = 6/1.5)
3i,
15%
3j,
3k,
63
0
PC-4
-
CHO
-
-
CHO
CHO
KOAc
-
MeOH/TFE
MeOH/TFE
trace
0
PC-4
PC-4
MeO2C
EtO2C
2
EtO2C
EtO2C
4
Cl
[f]
F
Br
[f]
F
F
F
-
F
KOAc
F
F
Me
F
F
[f]
a
3p',
51% (C4/C2 = 16:1)
3m,
3o,
59%
38%
3n,
3r',
Reaction conditions: 1a (0.1 mmol), BrCF2CO2Et 2 (1 mmol), K2CO3 (6 equiv),
photoredox catalyst (PC, 3 mol %) in solvent (2 mL) at room temperature under
an argon atmosphere and a 18 W blue light bulb, unless otherwise noted. PC-1:
57%
CHO
CHO
HOOC
MeO2C
F
F
O2N
MeO2C
CHO
Cl
MeO2C
b
MeO2C
2
Ru(bpy)3(PF6)2. PC-2: [Ru(bpy)3]Cl2·6H2O. PC-3: Eosin Y. PC-4: fac-Ir(ppy)3.
4
F
F
F
Isolated yields. c The ratio of isomers was determined by 1H NMR. d MeOH/TFE (2
F
F
CHO
3t', 60%
MeO
N
F
Cl
29%d (C4/C2 = 15:1)
3s', 0%
0%
mL, 17/3). e t-BuOH/TFE (2 mL, 17/3). fReaction was carried out in the dark.
3q',
a
A mixture of 1 (0.1 mmol), BrCF2CO2Et 2 (1 mmol), KOAc (6 equiv) and fac-
Ir(ppy)3 (3 mol %), at room temperature in MeOH/TFE (2 mL, 17/3), under a 18
selectivity is in contrast to classical Friedel–Crafts reactions of
electron-deficient aromatics.
b
W blue LED, 18 h. Yield of the isolated product; the ratio of selectivity
c
d
determined by 1H NMR. Fe(OAc)2 (1.2 equiv). BrCF2CO2Et 2 (1.5 mmol) in
MeOH/TFE (2 mL, 17/3). e t-BuOH/acetone (0.5 mL, 4/1). f K2CO3 (4 equiv) and t-
BuOH (0.5 mL), 40 h.
At the outset, we investigated the model reaction of
benzaldehyde 1a with BrCF2CO2Et 2 (Table 1). At the very
beginning, Various commonly used photocatalysts were
screened with TFE as a solvent. The initial result was obtained
when using fac-Ir(ppy)3 as catalyst in the para-selective C–H
bond difluoroalkylation of 1a (entry 4). Even though iridium
Suprisingly, 1,3-benzenedicarboxaldehyde (1h) was primarily
transformed into para-difluoroalkylated product (3h), and
without the formation of meta-difluoroalkylated product.
Subsequently, a series of ortho-substituted benzaldehydes (1j-
photocatalyst gave the difluoroalkylated product 3a in 30% 1o) were also performed well in present catalyst systems, and
the corresponding para-difluoroalkylated products 3j-3o were
obtained in satisfactory yields (38-70%). Interestingly, when
the electron donating ortho-methoxy-substituted benzalde-
hyde (1k) was tested, the corresponding difluoroalkylated
product (3k) was still selectively formed at para-position of
aldehyde group, which in contrast to the traditional Friedel-
Crafts electrophilic reaction. Importantly, substrates bearing
chloro and bromo groups can also be tolerated, and the
products (3f′, 3g′, 3n and 3o) can be utilized for the synthesis
of complex organofluoro compounds via cross-coupling.
Further study revealed that the disubstituted aromatic
aldehydes were also compatible in these reactions, gaving the
excellently para-selective difluoroalkylated products (3p′ and
3q′). However, the strong electron-withdrawing group -COOH
and -NO2 substituted aromatic aldehydes did not give the
target products (3r′and 3s′). Further investigation showed that
yield, the site selectivity was very poor. To our delight, when t-
BuOH was used as the solvent, it dramatically increased the
yield (64%) and para-selectivity of 3a (entry 5). Encouraged by
this result, we decided to further optimize the conditions by
screening various solvents. Surprisingly, when a mixed solvent
of MeOH/TFE was used, para-selectivity product 3a′ was
obtained in moderate yield with excellent para-selectivity
(entry 6). In the reaction, the group of CF2CO2Et was converted
to CF2CO2Me by transesterification with MeOH. Thus, 3a’ was
obtained. Conventionally used DCM or n-hexane as a reaction
solvent gave an unsatisfactory yield with decreased selectivity
(entry 7 and 8). Subsequently, various inorganic and organic
bases were tested (see the ESI†). Delightfully, when KOAc was
used as the base, the product 3a′ was obtained in 63% yield
with high para-selectivity (entry 10). Besides, the importance
of the photocatalyst, base and irradiation was also established
by control experiments (entries 11-13).
Having identified the optimal reaction conditions, we then
investigated the diversity of the aromatic aldehyde substrates
to explore the versatility of this para-selective difluoro-
alkylation protocol (Table 2). First, aromatic aldehydes with
various meta substituted functional groups in the aryl rings
were well tolerated, thus affording the corresponding in situ
transesterification difluoroalkylated products (3b′-3g′, and 3i)
in moderate to good yields with excellent regioselectivity.
heterocyclic
aldehyde,
such
as
6-methoxy-2-
pyridinecarboxaldehyde, was also well tolerated in this
transformation and gave the corresponding desire product in
60% yield (3t′).
We have also examined the substrates of para-substitued
benzaldehyde (para-position blocked) to assess whether its C–
H activation proceeds smoothly. To our surprise, when a mixed
solvent of DMSO/DMF were used, the ortho-difluoroalkylated
product 6 were obtained in moderate to good yields with
2 | J. Name., 2012, 00, 1-3
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Scheme 1 Diverse transformations of 3c. All the reactions were performed in 0.2
satisfactory regioselectivity (Table 3). A set of functional
groups, such Me, MeS, tBu, F, I, CO2Et and CHO were all
Table 3 ortho-C–H difluoroalkylation of 5a-la
View Article Online
mmol scale. Isolated yields. a 1-aminopiperidine, MgSO4, rt. b Eosin Y, MeOH, 36
DOI: 10.1039/C9CC09586A
W Green LED. c (NH4)2S2O8, MeOH, 60 oC.
Scheme 2 Intermolecular competition experiments.
CHO
CHO
fac-Ir(ppy)3 (3 mol %)
fac-Ir(ppy)3, KOAc
KOAc (6 equiv)
MeOH/TFE
F
CHO
CF
MeO
CHO
Br 2CO2Et
+
DMSO/DMF
18 W blue LED, Ar, rt, 30 h
R
CF
R
2CO2Et
a)
+
3c'
3c'
+
+
/ = /
3e' 3c' 3e' 7 1
2
5
6
2
(1 mmol)
(1H NMR)
1c (0.1 mmol each)
1e
Ar, rt, 18 h
18 W blue LED
O
Me
CHO
CHO
CF
2CO2Et
CF
2CO2Et
MeO
MeO
CHO
Me
CHO
OMe
CF
2CO2Et
Condition as above
Condition as above
b)
c)
+
3b'
3c' 3b' 5 1
/ = /
(1H NMR)
1c
1c
NO2
(0.1 mmol each)
R
1b
Me
CHO
6a
6b
6c
6d
6e
, R = Me, 58% (o/m = 8:1)
, R = Et, 60% (o/m = 13:1)
, R = tBu, 70% (o/m = 25:1)
, R = SMe, 32% (o/m = 3:1)
, R = F, 45% (o/m = 11:1)
, R = I,18% (o/m = 33:1)
6i
6j,
, 0%
31% (o/m = 4:1)
Rf
+
3c'
+
trace
O
CHO
CF
OMe
10
(0.1 mmol each)
11', major products
Me
O
Determined by GC-MS
2CO2Et
S
6f
S
CF
2CO2Et
6l
, 43%
6g
, R = CO2Me, 43% (o/m = 2:1)
c
In order to understand these unusual selectivity, preliminary
6k
, 46%
6h
, R = CHO, 29%
a A mixture of 5 (0.1 mmol), BrCF2CO2Et 2 (1.5 mmol), KOAc (4 equiv) and fac-
Ir(ppy)3 (3 mol %) in DMSO/DMF (2 mL, 19/1), at room temperature, under a 18
W blue LED. b Yield of the isolated product; the ratio of selectivity determined by
1H NMR spectroscopy of the crude product mixture. c acetone (2 mL).
DFT calculations were carried out to model the key step of
·CF2CO2Et radical addition to benzaldehyde. The corresponding
transition states of the radical attacking different positions of
benzaldehyde (see the ESI† for more details). We found that
the relative free energy of 3a_meta site TS is higher compared
to that of 3a_para site TS or 3a_ortho site TS (the energy is
calculated relative to 1a and ·CF2R radical), which is consistent
with the experimentally observation. Besides, previous
literature reports revealed that alcohol solvents with a high
capacity for donating hydrogen bonds would generate solvates
that enhance or alter the selectivity of a number of
synthetically important reaction.12 Based on these literature
precedents, we speculated that the solvate produced by the
hydrogen bond interaction between the substrate and the
alcohol solvent, which may be the physical origin that favours
para-selective difluoroalkylation.13
According to the above investigations and previous studies,
a proposed mechanism involving the radical process is
depicted in Scheme 3. Initially, photoexcitation of fac-Ir(ppy)3
upon blue irradiation results in a metal-to-ligand charge
transfer excited state fac-[Ir3+(ppy)3]*.14 Then the reaction
proceeded via the generation of the key intermediate
difluoroacetate radical A, which was formed by transfer of a
single electron from fac-[Ir3+(ppy)3]* to 2.15 Next, a radical
adduct B or C might be formed by the interaction of the
electrophilic ·CF2CO2R radical with aromatic aldehyde
substrates.16 Then, the base removes a proton from the radical
adduct B (C) to produce an arene radical anion D (E), which is
stabilized by the electron-withdrawing group.5a,17 Finally, the
desired product 3 (6) is formed by single electron transfer
tolerated by this procedure (6a-6h). However, no reaction
occurred with strongly electron-withdrawing groups (NO2) on
the aromatic ring (6i). Further investigation showed that
aromatic ketones, such as 4-methylacetophenone, were also
compatible with the reaction, delivering the desired ortho-
difluoroalkylated product in moderate yield (6j). In additional,
this photoredox protocol can also be applied to the
intermolecular ortho-C-H difluoro-alkylation of thiophene
derivatives (6k and 6l).
To further evaluate the applications of this method, further
transformations of the difluoromethylated product 3c were
carried out (Scheme 1). For example, a variety of difluoroalkyl-
containing organic molecules such as imine (Scheme 1, 7c),
acetal (Scheme 1, 8c), and bezoates (Scheme 1, 9c) can be
derivatized in high yields through different known procedures,
as illustrated in Scheme 1. The variant late-stage
transformations of the aldehyde group further showcased the
potential of the present protocol in drug modification.
To gain preliminary information about the reaction
mechanism, several control experiments were conducted
(Scheme 2). The substrates of different substituted
benzaldehydes were subjected to the standard reaction
conditions, which indicated the electron-rich methoxy-
substituted benzaldehyde 1c to react preferentially, thereby
being suggestive of an electrophilic-type activation. Moreover,
when a radical scavenger TEMPO or 1,1-diphenylethylene11
was added (see Scheme S4 in the ESI† for more details), only a
trace amount of the difluoroalkylated products was observed. (SET) with strong oxidant fac-Ir(ppy)3]+.
In this case, a TEMPO−CF2R adduct or the by-product 12 were
detected by GC−MS. These results suggested that a ·CF2R
radical was involved in the reaction pathway.
CHO
3
or
6
CHO
para
ortho
R
H
H
R
Ir3+
R = H
5
or
1
MeO
N
Rf
A
*Ir3+
Br Rf
N
radical
addition
F C
2
EtO2C
Ir4+
7c
, 80%
2
Rf
A
a
O
OMe
OMe
MeO
CHO
CHO
Rf
CHO
MeO
F C
c
b
CHO
or
MeO
F C
CHO
Rf
-H+
OMe
or
H
F C
EtO2C
2
R
Rf
EtO2C
EtO2C
Rf
2
2
R
E
D
9c
, 83%
B
8c,
3c
78%
C
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Scheme 3 Proposed mechanism.
54, 8889; (j) X.-Y. Chen and E. J. Sorensen, Chem. Sci., 2018, 9,
View Article Online
8951.
DOI: 10.1039/C9CC09586A
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and B. Yu, Chem. Commun., 2019, 55, 5408.
In conclusion, we have developed a photocatalytic method
for the site-selective CAr–H difluoroalkylation of the aromatic
aldehydes using iridium catalyst. Unusual para-selectivity is
achieved from various substrates that exhibit broad functional
group tolerance across a wide range of aromatic aldehydes
containing electronically diverse functional groups, regardless
of the substitu- tion pattern on the aromatic ring. Additionally,
when using para-substituted benzaldehydes, as a substrate,
the ortho-preferred difluoroalkylated products can also be
synthesized by our protocol. Overall, it provides a rare instance
of site-selective CAr–H functionalization of electron-deficient
arenes through photocatalytic method and opens a new
avenue in using photocatalytic method in remote CAr–H
functionalization.
We gratefully acknowledge financial support from the
National Natural Science Foundation of China (21571047,
21971051, 21871074, 21472033), the Key Research and
Development Program Projects in Anhui Province
(201904a07020069) and the Fundamental Research Funds for
the Central Universities. This article is dedicated to Professor
Qing-Xiang Guo, an outstanding organic chemist, on the
occasion of his 70th birthday.
7
Conflicts of interest
There are no conflicts to declare.
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