Is Fe-catalyzed ortho C-H Arylation of Benzamides Sensitive to Steric Hindrance and Directing Group?

Article abstract of DOI:10.1021/acs.orglett.9b02359

The previously reported Fe-catalyzed ortho C-H arylation of benzamides relied on bi- or tridentate amide groups and specific iron ligands and was sensitive to steric hindrance. By using new mixed titanates, our present protocol accommodates various weakly coordinating benzamides and tolerates high steric hindrance and sensitive functional groups only under the catalysis of FeCl₃ and TMEDA. A wide range of privileged condensed ring compounds can thus be facilely accessed.

Full text of DOI:10.1021/acs.orglett.9b02359

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Is Fe-catalyzed ortho C−H Arylation of Benzamides Sensitive to
Steric Hindrance and Directing Group?
Yi-Ming Wei,† Meng-Fei Wang,† and Xin-Fang Duan*
College of Chemistry, Beijing Normal University, Beijing 100875, China
S
* Supporting Information
ABSTRACT: The previously reported Fe-catalyzed ortho C−
H arylation of benzamides relied on bi- or tridentate amide
groups and specific iron ligands and was sensitive to steric
hindrance. By using new mixed titanates, our present protocol
accommodates various weakly coordinating benzamides and
tolerates high steric hindrance and sensitive functional groups
only under the catalysis of FeCl3 and TMEDA. A wide range
of privileged condensed ring compounds can thus be facilely
accessed.
Scheme 1. Fe-Catalyzed ortho C−H Arylation of
ransition-metal-catalyzed directing-group-assisted ortho
TC−H functionalization has become an increasingly useful
tool for the direct and site-controlled transformation of C−H
bonds.1 The amide group (CONHR) is one of most
commonly used directing groups by virtue of two outstanding
advantages:1d,2 (a) It is compatible with a wide range of
transition-metal catalysts; and (b) the R group can be well
modified to improve the coordination (e.g., bidentate or
tridentate amides) with a catalyst. Because of its high
abundance, low toxicity, and biocompatibility, the correspond-
ing iron-catalyzed C−H activation has aroused extensive
attention.3 The implant of a 2-substituted aryl group through
such ortho C−H arylation is highly desired because the
arylated products can access a wide range of important
condensed-ring compounds (Scheme 1A).4−7 As with other
metal catalysts, such Fe-catalyzed arylations are often
facilitated by bi- or tridentate amide directing groups and
specific catalyst ligands (Scheme 1B).8 Although the Fe-
catalyzed arylations with aryl groups without 2-substituents
have been achieved, the arylation with 2-substituted aryl
groups remains challenging and elusive so far.9 To the best of
our knowledge, the syntheses of those compounds in Scheme
1A via Fe-catalyzed C−H arylation with 2-substituted aryl
groups have not been reported so far.10 These facts suggest
that the Fe-catalyzed C−H arylation of benzamides is sensitive
to steric hindrance and the types of amide groups and iron
ligands.
Benzamides
group (CONHMe) and the most common Fe catalyst (FeCl3/
TMEDA) without NHC or phosphine ligands (Scheme 1C).
We expect that these findings should provide inspiration for
developing new Fe-catalyzed C−H activation reactions.
Our study is based on the assumption that the difficulty of
the Fe-catalyzed ortho C−H arylation of benzamides should lie
not in the steric hindrance but in the ortho C−H deprotonative
ferration of the amides because our previous findings indicated
that two 2-substituted aryl Grignard reagents, after being
mediated by Ti(OR)4, could be facilely assembled into biaryls
We herein report an ortho C−H arylation of benzamides,
where various 2-substituted aryl groups could be facilely
introduced, and thus a series of condensed ring compounds
could be conveniently synthesized (Scheme 1A). In contrast
with the previous impression that this Fe-catalyzed C−H
arylation mainly relies on specific bi- or tridentate amide
groups and iron ligands,8 our present reaction can tolerate the
high steric hindrance using a simple weakly coordinating amide
Received: July 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02359
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
via a Fe-catalyzed oxidative coupling.11 After a series of
attempts (see Table S1), we found that an unprecedented
mixed titanate obtained by mixing 0.6 equiv of Ti-1, 1.2 equiv
TMPMgCl·LiCl, and 1.2 equiv ArMgX enabled the expected
arylation in high yield (Scheme 2). The present arylation was
Scheme 3. Fe-Catalyzed C−H Arylation Using Various 2-
a
Substituted Aryl Grignard Reagents
Scheme 2. Mixed Titanate Enabled a Facile Fe-Catalyzed
ortho C−H Arylation of Benzamides
not observed in the absence of titanate and TMPM (Table
S1), and thus the presence of both titanate and TMPM was
important to the success of this arylation. The combinations of
Ti-1 with TMPM and ArMgX have never been reported;
therefore, the structure of this new mixed titanate is unclear at
present.12 However, its reaction performance is intriguing: (a)
Only slightly excessive amounts of the two reagents (1.2 equiv
of ArMgX and TMPMgCl·LiCl) were required, and (b) the
two reagents in the mixed titanate could effectively implement
deprotonation and oxidative arylation, respectively, without
interfering with each other because the concomitant TMPH
formed after the deprotonation of TMPMgCl·LiCl did not
neutralize ArMgX, which would quench the oxidative arylation.
With the optimized conditions, we investigated the scope of
this facile Fe-catalyzed arylation reaction. Initially, the
arylations of various 2-substituted aryl Grignard reagents
with different benzamides were carried out, and the results are
outlined in Scheme 3. It can be seen that various 2-substituted
aryl groups could be facilely incorporated through the present
ortho C−H arylation. Using 2-MeC6H4MgBr, various benza-
mides could be arylated, with F and Cl being tolerated (2b−e).
As for 2f and 2g, the arylations selectively occurred at the less
congested ortho position of the amide, although the MeO
group is also a common directing group for ortho metalation.
The arylation of 2-substituted amides, which led to 1,2,3-
trisubstituted benzamides, was highly difficult to achieve using
previously reported Fe-catalyzed protocols;8 in contrast, the
present protocol could smoothly achieve this type of arylation
(2h and 2i). Likewise, disubstituted aryl Grignard reagents
could also facilely participate in the C−H arylation (2j−l).
Noticeably, highly hindered mesitylmagnesium bromide could
also undergo the present coupling, providing the desired
product (2m) in a satisfactory yield. It should be noted that
even in the Pd- or Ni-catalyzed Kumada, Negishi, and Stille
couplings of mesityl metal reagents with aryl bromides, specific
phosphine or NHC ligands were usually required.13 In contrast
the present C−H arylation of mesitylmagnesium bromide
could facilely occur under Fe catalysis without phosphine or
NHC ligands, demonstrating that the present reaction proves
to be a highly powerful method for Fe-catalyzed C−H
arylation. Similarly, 2-Et and 2-Priphenyl and naphthalen-1-yl
magnesium bromides could all undergo the arylation in high
yield (2n−q). Whereas the introduction of 1-naphthyl via Fe-
catalyzed ortho C−H arylation has never been reported, our
protocol achieved this arylation in high yield (2p and 2q), and
these products can be facilely transformed into benzo[c]-
a
Reactions were carried out on a 2 mmol scale under the same
conditions as in Scheme 2.
fluorenones, a skeleton frequently found in pharmaceutical
compounds and optoelectronical materials.6 2-Alkoxyphenyl-
magnesium bromides, especially the hindered 2-
PriOC6H4MgBr, were also well suited for the present arylation
(2r and 2s). To the best of our knowledge, the arylation via
Fe-catalyzed ortho C−H activation of benzamides using
Knochel-type 2-functionalized aryl Grignard reagents14 has
never been documented. Nevertheless, our present reaction
accommodates this type of magnesium reagent and smoothly
afforded the desired products (2t−v), fully demonstrating the
broad scope and high functional group tolerance of this Fe-
catalyzed C−H functionalization.
Next, we explored the arylation of 3- or 4-substituted
Grignard reagents. Meanwhile, the arylation using the amides
with different N substituents was also investigated. These
results are outlined in Scheme 4. It can be seen that the
arylation still proceeded facilely, as expected. Various 3- or 4-
substituted Grignard reagents smoothly underwent the
arylation (3a−f), where 2-substituted benzamides were also
arylated to yield 1,2,3-trisubstituted products (3f). Also, a
heterocyclic Grignard reagent such as thiophen-2-ylmagnesium
bromide was also competent (3d). It is noteworthy that 3- or
4-functionalized Grignard reagents participated in the coupling
B
DOI: 10.1021/acs.orglett.9b02359
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Arylation Using Various 3- or 4-Substituted Aryl
Scheme 5. Facile Syntheses of Privileged Compounds Using
Fe-Catalyzed C−H Arylation as the Key Step
Grignard Reagents and Different N-Substituted
a
Benzamides
available reagents and simple FeCl3/TMEDA catalysts, which
makes these preparations really straightforward and conven-
ient. As far as we know, these syntheses of fused heterocycles
and diarylation represent the first examples for the applications
of Fe-catalyzed ortho C−H arylation of benzamides.
a
In conclusion, we uncovered an unexpectedly facile Fe-
catalyzed ortho C−H arylation of benzamides. This protocol
could accommodate various weakly coordinating amide
groups16 and exhibit high tolerance for steric hindrance in
the absence of phosphine or NHC ligands. For the first time,
highly hindered and Knochel-type functionalized aryl Grignard
reagents have been successfully used for C−H arylation,
allowing for the facile syntheses of a series of privileged
compounds such as urolithin B and crinasiadine. Moreover,
highly hindered diarylation leading to fully substituted
thiophene has been unprecedentedly accomplished. Thus we
expect that the present reaction should provide a mild yet
powerful steric-hindrance- and functional-group-tolerant pro-
tocol for Fe-catalyzed C−H arylation. Whereas the optimiza-
tion of directing groups and catalyst ligands has been an
important task in this field,1d,15 our experiments suggest that
these two factors seemed to not play a key role under our
reaction conditions. Instead, a titanate-mediated deprotonating
reagent (Ti-1·ArMgX·TMPMgCl·LiCl) significantly facilitated
this Fe-catalyzed C−H arylation. We expect that these findings
should provide inspiration for developing new Fe-catalyzed C−
H activation reactions.
Reactions were carried out on a 2 mmol scale under the same
conditions as in Scheme 2.
to give the products (3g−k), where the arylation still occurred
selectively at the less congested ortho position of the amide
(3k). In the previous reports, the Fe-catalyzed C−H arylation
was quite sensitive to the type of directing amide group:
Bidentate or tridentate amides (Scheme 1B) were suitable
substrates, whereas N-phenyl amide was completely inert to
the arylation.8 Our results clearly indicated that the present
reaction could accommodate various amide groups (3l−n),
where N-phenyl amide could be arylated with a 2-substituted
aryl Grignard reagent in a slightly lower yield (3m) compared
with N-(8-quinolinyl)benzamide (3n).15 These findings
indicated that our present reaction was insensitive to the
type of amide directing groups.
To illustrate the synthetic potential of our Fe-catalyzed C−
H arylation, facile syntheses of a series of privileged
compounds using the present reaction as the pivotal step are
outlined in Scheme 5. Simple N-methyl (dimethoxy)-
benzamides were arylated using 2-methoxylaryl Grignard
reagents, conveniently affording dihydroxybenzocoumarin
4a4a and urolithin B (4b)4b,e after demethylation. Besides, a
Knochel-type Grignard reagent (2-PhCHNC6H4MgCl·
LiCl)14 was coupled to produce crinasiadine (4c) in 68%
yield after hydrolytic cyclization. It should be noted that the
diarylation of thiophene-2,5-dicarboxamide is highly challeng-
ing because it will yield a highly hindered fully substituted
thiophene derivative. Despite this, we achieved such diary-
lation using the present reaction and smoothly obtained 4d,
which could be conveniently converted to diindenothiophenes
(Scheme 1A), an important class of structural cores for organic
materials.7 It can be seen that all aforementioned syntheses
start with simple N-methyl benzamides and only use readily
Although the combination of Ti-1, ArMgX, and TMPMgCl·
LiCl to form a new mixed titanate enabled a facile
deprotonation and oxidative arylation in slight excess (1.2
equiv) under mild conditions, its structure and reaction mode
are not clear at present. We will focus on this subject in the
future.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02359.
C
DOI: 10.1021/acs.orglett.9b02359
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, additional tables, character-
Letter
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ization data, and NMR spectra for products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xinfangduan@vip.163.com.
ORCID
Xin-Fang Duan: 0000-0003-1480-853X
Author Contributions
†Y.-M.W. and M.-F.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the National Science Foundation of China
(21372031 and 21572022).
■
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DOI: 10.1021/acs.orglett.9b02359
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