Iron-Catalyzed Highly para-Selective Difluoromethylation of Arenes

Article abstract of DOI:10.1021/jacs.0c09545

Direct functionalization of a C-H bond at either the meta or para position by only changing the catalyst system poses a significant challenge. We herein report the [Fe(TPP)Cl]-enabled, selective, C-H difluoromethylation of arenes using BrCF2CO2Et as the difluoromethylation source, which successfully altered the selectivity from the meta to the para position. A preliminary mechanistic study revealed the iron porphyrin complex not only activated the aromatic ring but also induced para selectivity due to the influence of ligand sterics.

Full text of DOI:10.1021/jacs.0c09545

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Iron-Catalyzed Highly para-Selective Difluoromethylation of Arenes
Wei-Tai Fan, Yuting Li, Dongjie Wang, Shun-Jun Ji,* and Yingsheng Zhao*
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ABSTRACT: Direct functionalization of a C−H bond at either the meta or para position by only changing the catalyst system poses
a significant challenge. We herein report the [Fe(TPP)Cl]-enabled, selective, C−H difluoromethylation of arenes using
BrCF2CO2Et as the difluoromethylation source, which successfully altered the selectivity from the meta to the para position. A
preliminary mechanistic study revealed the iron porphyrin complex not only activated the aromatic ring but also induced para
selectivity due to the influence of ligand sterics.
he efficient and selective transformation of a C−H bond
Tinto a carbon−carbon or carbon−heteroatom bond has
always attracted attention in synthetic chemistry.1 To control
the site-selective functionalization of a C−H bond on an
aromatic ring at a remote position is a key challenge. Various
directing groups have provided straightforward ways to access
ortho,2 meta,3 or para3e,4 position C−H-functionalized
products. However, these directing group (template) strategies
usually required additional synthetic steps to complete the
desired transformations. Recently, noncovalent interaction
strategies reported by the Nako,5 Chattopadhyay,6 Kuninobu,7
and Kanai8 groups offered direct and efficient approaches
toward aromatic ring functionalization at the meta or para
position. The Phipps9 group disclosed an ion-pair-directed
regioselective C−H borylation using an iridium catalyst in
which the interaction between anionic ligand and ammonium
salt substrates afforded meta selectivity. The Yu10 group also
smartly designed a bifunctional nitrile template that binds
heterocyclic substrates through reversible coordination to
achieve meta-selective C−H olefination. A ruthenium catalyst
Figure 1. Site-selective C−H activation reactions. (a) Current para-
C−H functionalization techniques. (b) Ruthenium(II)-catalyzed
meta-C−H difluoromethylation. (c) Our work on Fe(III)-enabled
para-selective difluoromethylation.
showed promising catalytic ability in promoting the remote
selective C−H functionalization. A cyclometalated ruthenium
complex not only provided ortho-selective C−H-function-
alized products with an electrophilic reagent but also acted as a
strong bulk-electronic-transient-metal functional group to
realize meta- or para-selective C−H transformations11 (Figure
1a). Although these methods greatly enriched approaches to
meta- or para-selective C−H functionalization, a highly
selective installation of a functional group at either the meta
or para position to one substrate by only changing the catalyst
system remains a significant challenge. Herein we report a
[Fe(TPP)Cl]-enabled, selective C−H difluoromethylation of
arenes using BrCF2CO2Et as the difluoromethylation source,
which successfully transformed selectivity from the meta to
para position in contrast to previously reported ruthenium
catalytic systems (Figure 1c).
complex pathway (Figure 1b). The difluoromethylene (CF2)
group is quite important in the agrochemical, pharmaceutical,
and life science industries.16 So the development of new
methods to realize para-selective difluoromethylation of
heteroaromatic compounds is not only important in synthetic
chemistry but also deepens the understanding of site-selective
C−H functionalization. Regarding previous reports,17 steric
hindrance usually impacts site selectivity during free radical
Received: September 4, 2020
Recently, the Ackermann,12 and Wang13 groups as well as
our group14 and others11e,15 have demonstrated that C−H
difluormethylation selectively occurs at the meta position of
heterocyclic compounds via a cyclometalated ruthenium
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difluoromethyl reactions with aromatic rings; therefore, a
transition metal complex with bulky ligands may enable para-
selective C−H difluoromethylations.
was not obtained using iron chloride or Fe(OTs)3 as the
catalyst (Table 1, entries 12, 13). The control experiment
showed that Fe(TPP)Cl is indispensable for this trans-
formation (Table 1, entry 14).
With these conditions in mind, a sterically hindered
porphyrin was selected as the ligand and ruthenium as the
catalyst precursor. Initially, 9-benzyl-6-phenylpurine (1a) was
treated with bromodifluoroacetate (2) in the presence of
[RuCl2(p-cymene)]2 (5 mol %), L1 (10 mol %), and K2CO3
(3 equiv) in DCE at 140 °C for 24 h. Mixed meta- and para-
difluoromethylated products were obtained in 51% yield
(para:meta = 2.7:1; Table 1, entry 1). When PivOH was
a
Scheme 1. Scope of N-Substituted Purines
a
Table 1. Optimized Reaction Conditions
(3a+3a′) yield (3a/3a′) (p/
a
b
c
entry
1
catalyst (x mol %)
ligand
(%)
51
m)
[RuCl2(p-cymene)]2
(5)
[RuCl2(p-cymene)]2
(5)
[RuCl2(p-cymene)]2
(5)
[RuCl2(p-cymene)]2
(5)
L1
2.7:1
1:1.5
1:1.5
1:3.9
d
2
PivOH
L2
22
38
42
d
3
a
4
5
L3
Reactions were performed in 0.2 mmol scale with 2 (1.2 mmol) in a
b
sealed tube; isolated yields. K2CO3 (2 equiv) was added for 48 h.
[RuCl2(p-cymene)]2
(5)
L4
trace
With the optimized reaction conditions established, we next
explored the substrate scope of this reaction. Various N-
substituted purines were subjected to the standard reaction
conditions; phenemyl, 4-methylbenzyl, methyl, isopropyl, and
n-pentyl substrates were all well tolerated and afforded para-
selective difluoromethylated products in good to excellent
yields (3b−h). More appealingly, we found that highly reactive
nucleosides were all well-tolerated, even those bearing sensitive
protecting groups, which led to the para-difluoromethylated
products in moderate to good yields (3i−k). These results are
complementary to the ruthenium-catalyzed meta-difluoroalky-
lation reaction reported by the Ackermann12 group and also
have potential use for antiviral or anticancer drug screenings.
We expanded this strategy to substrates with strongly
coordinating heteroaromatic compounds. For example, various
5-position-substituted 2-phenylpyridines were well tolerated
and yielded para-difluoromethylated products in moderate to
good yields (5a and 5g). Functional groups (methyl, methoxy,
fluoro, chloro, and cyano) were fully compatible with this
transformation (5b−f). Several 2-arylpyrimidines provided
para-selective difluoromethylated products in moderate to
good yields, highlighting the importance of this synthetic
method (5i−n). Interestingly, substrate 4h yielded product 5h
in good yield with high para selectivity, while 2-fluoro-6-
phenylpyridine and 2-methoxy-6-phenylpyridine all gave
difluoromethylated products with poor site selectivity.
Although the reason is unclear, it might be due to a weak
interaction between the chlorine atom in 4h with the iron
6
7
8
9
10
11
12
13
14
hemin (5)
Fe(TPP)Cl (2.5)
CoTPP (5)
NiTPP (5)
CuTPP (5)
Mn(TPP)Cl (2.5)
FeCl3 (10)
Fe(OTs)3 (10)
41
78
25:1
20:1
trace
trace
trace
50
trace
trace
nr
17:1
a
Reactions were performed with 1a (0.2 mmol), 2 (1.2 mmol, 160
uL), cat. (x mol %), and K2CO3 (0.6 mmol, 3 equiv) in DCE (0.5
mL), Ar, 140 °C, 24 h. Yields of product after silica gel
chromatography. The ratio of selectivity determined by H NMR
b
c
1
d
spectroscopy. K2CO3 (0.4 mmol, 2 equiv) was added at 120 °C.
used instead of L1, the meta-difluoromethylated product 3a′
was obtained as the major product (Table 1, entry 2). Various
porphyrins were tested; however, neither the yield nor
selectivity was improved (Table 1, entries 4, 5). To our great
delight, when the hemin was used instead of the ruthenium
catalyst, C−H difluoromethylated product 3a was obtained in
41% yield with high para selectivity (Table 1, entry 6).
Encouraged by this result, several metal porphyrin complexes,
such as Fe(TPP)Cl, CoTPP, NiTPP, CuTPP, and Mn(TPP)-
Cl, were examined (Table 1, entries 7−11). Those results
clearly showed that Fe(TPP)Cl was the most effective catalyst
and afforded product 3a in a 78% yield with high para-
selectivity (Table 1, entry 7). The difluoromethylated product
B
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a
A mixture of meta- and para-difluoromethylated mixed
products was observed when substrate 6a was subjected to
standard reaction conditions. To further expand the substrate
scope, various iron complexes were further explored. We
determined that on using hemin as the catalyst instead of
Fe(TPP)Cl, para-selective difluoromethylated product 7a
occurred in a synthetically acceptable yield. The scope of
substrates was expanded to oxadiazoles and aryltetrazoles,
leading to para-selective difluoromethylated products in
moderate yields (7a−7h). It should be noted that mono-
fluoromethylation failed using ethyl bromofluoroacetate as the
fluorine source under the optimized standard conditions.
This reaction system also tolerated aniline derivatives, and
difluoromethyl products were obtained in excellent yields with
only para selectivity (Scheme 4).
Scheme 2. Arene Substrate Scope
Scheme 4. Para-Selective C−H Difluoromethylation of
a
Anilides
a
Reactions performed in 0.2 mmol scale with 2 (1.2 mmol) in a
a
sealed tube; isolated yields.
Reactions performed in 0.2 mmol scale with 2 (1.2 mmol) in a
b
c
sealed tube; isolated yields. Two equiv of K2CO3. 2 (0.8 mmol) and
d
e
f
The synthetic utility of this system was further demonstrated
by the synthesis of fluorinated fenclorim analogues (Scheme
5a), which are used to protect wet-sown rice from
K2CO3 (0.4 mmol, 2 euqiv) were added. 24 h. 48 h. 4 (0.2 mmol),
2 (0.6 mmol, 3 equiv), hemin (0.01 mmol, 5 mol %), and K2CO3 (0.6
mmol, 3 equiv) in DCE (0.8 M), under Ar, 140 °C for 24 h.
Scheme 5. Derivation Experiments
center to form a stable key iron complex and preferentially
yield the high para selectivity of 5h. When 2-phenylpyridine
was used, slightly lower selectivity for the difluoromethylated
product 5o was observed, along with side product 5o′.
a
Scheme 3. Arene Substrate Scope
pretilachlor.18 Standard reaction conditions were readily scaled
to 1 mmol, yielding the corresponding product 5i in 62% yield.
Interestingly, the meta-difluoromethylated product 5r was
obtained in 70% yield when using a ruthenium catalyst13
(Scheme 5b).
Several experiments were carried out to explore the reaction
pathway of this catalytic system (Scheme 6). The difluor-
omethylated product was not obtained when the reaction was
performed in the presence of the radical scavenger
TEMPO.11c,12a The radical scavenger 1,1-diphenylethylene
trapped •CF2CO2Et directly to generate 11 in 65% yield using
an iron catalyst. In contrast, product 11 was obtained in less
than 5% yield when the reaction took place without Fe(TPP)
a
Reactions performed in 0.2 mmol scale with 2 (0.6 mmol) in a
b
c
sealed tube; isolated yields. 48 h. 36 h.
C
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Scheme 6. Preliminary Mechanistic Study
Scheme 7. Additional Mechanistic Study Experiments
supported the notion that a cyclized iron intermediate was not
formed (Scheme 7c and d). Several control reactions were
performed, and the catalyst residue was further analyzed by
XPS spectroscopy and cyclic voltammetry, which suggested the
iron(II) complex might be formed during the catalytic cycle22
(for details see the Supporting Information).
Based on these results and previous reports,17,20d,23
a
Cl (Scheme 6a). These results indicated the reaction
proceeded via a free radical pathway and Fe(TPP)Cl played
an important role in generating the CF2CO2Et free radical.
plausible reaction pathway is proposed. The Fe(TPP)Cl
cyclized iron coordinated to the substrate led to the formation
of intermediate I. The free radical •CF2CO2Et, generated using
an iron porphyrin, reacts directly with I at the less sterically
hindered para position to form intermediate II, followed by
deprotonation and aromatization to provide the para-
difluoromethylated product and an iron complex (Scheme 8).
In conclusion, we developed an [Fe(TPP)Cl]-enabled, para-
selective C−H difluoromethylation of arenes using
BrCF2CO2Et as the difluoromethylation source. A wide variety
of heteroaromatic compounds were all compatible, leading to
•
Substrate 12, with two potential reaction sites, was subjected to
standard reaction conditions and gave only product 13 in 52%
yield (trace amounts of product 14 were obtained; Scheme
6b). Substrate 15 failed to provide the difluoromethylated
product under standard reaction conditions, and 2-benzylpyr-
idine was recovered (Scheme 6c). These results indicated the
benzene ring adjacent to the nitrogen atom in the
heteroaromatic compound was activated by the iron complex.
•
The CF2CO2Et radical forms from 2-bromo-2,2-difluoroace-
tates and has been reported by the Ackermann,12 Wang,13 and
Kondratov19 groups as well as our group.14 Thus, we directly
subjected substrates 4a and 2 to these reported catalytic
systems (Scheme 6d). Unfortunately, 5a′ was not obtained in
yields above 5%. These results further suggested the Lewis acid
iron complex may coordinate to the nitrogen, which results in
an electron-deficient (hence more active) arene core.20
Meanwhile, the steric hindrance brought by the TPP blocked
ortho- and meta-difluoromethylation on the aromatic ring and
resulted in high para selectivity.5a,17,21
Scheme 8. Plausible Mechanism
Finally, compared with substrate 4a, product 5s was
obtained in 32% yield with high para selectivity when fluorine
was in the ortho position. Methyl, methoxy, and other
functional groups in the ortho position did not yield para-
difluoromethylated products, and the only material obtained
was the recovered starting material (Scheme 7a). These results
suggested that the key intermediate may not be formed with a
sterically hindered functional group. Isotopic-labeling experi-
ments indicated that ortho-C−H activation did not occur
(Scheme 7b), and a kinetic isotope effect of 1.0 further
D
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̈
12138−12204. (e) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-
the corresponding products in moderate to good yields. A
preliminary mechanistic study revealed the iron complex not
only activates the aromatic ring but also affords the para
selectivity by utilizing the steric effect of TPP.
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̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09545.
■
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1H, 13C, and 19F NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Shun-Jun Ji − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science Soochow University, Suzhou 215123,
China; orcid.org/0000-0002-4299-3528;
Email: shunjun@suda.edu.cn
Yingsheng Zhao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science Soochow University, Suzhou 215123,
China; School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007,
China; orcid.org/0000-0002-6142-7839;
Email: yszhao@suda.edu.cn
Authors
̈
(d) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Farooq Zia, M.; Wencel-
̈
Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A comprehensive
Wei-Tai Fan − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science Soochow University, Suzhou 215123,
China
Yuting Li − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science Soochow University, Suzhou 215123,
China
Dongjie Wang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science Soochow University, Suzhou 215123,
China
overview of directing groups applied in metal-catalysed C−H
functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603−6743.
(e) Roy, P.; Bour, J. R.; Kampf, J. W.; Sanford, M. S. Catalytically
Relevant Intermediates in the Ni-Catalyzed C(sp2)−H and C(sp3)−H
Functionalization of Aminoquinoline Substrates. J. Am. Chem. Soc.
2019, 141, 17382−17387. (f) Lee, S. J.; Makaravage, K. J.; Brooks, A.
F.; Scott, P. J. H.; Sanford, M. S. Copper-Mediated Aminoquinoline-
Directed Radiofluorination of Aromatic C−H Bonds with K18F.
Angew. Chem., Int. Ed. 2019, 58, 3119−3122. (g) Rej, S.; Ano, Y.;
Chatani, N. Bidentate Directing Groups: An Efficient Tool in C−H
Bond Functionalization Chemistry for the Expedient Construction of
C−C Bonds. Chem. Rev. 2020, 120, 1788−1887.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09545
(3) (a) Mihai, M. T.; Genov, G. R.; Phipps, R. J. Access to the meta
Position of Arenes through Transition Metal Catalysed C−H Bond
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Chem. - Eur. J. 2019, 25, 9433−9437. (c) Porey, S.; Zhang, X.;
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Linchpin Strategy for Drug:Pharmacophore Conjugation: Exper-
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (No. 21772139), the Jiangsu Province Natural
Science Found for Distinguished Young Scholars
(BK20180041), and the PAPD Project.
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