Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group

Article abstract of DOI:10.1021/acs.joc.9b01563

Biologically relevant N-arylisoindolinones efficiently underwent arylation reactions under ruthenium catalysis via C-H bond functionalization. The reactions exclusively led to monoarylated products, and only ortho selectivity was observed in the aromatic ring connected to the nitrogen atom. Interestingly, no C-H bond functionalization was observed in the other benzene ring in the ortho position with respect to the carbonyl group. This ruthenium-catalyzed reaction displayed a high functional group tolerance, and it employed readily available and benchmark stable boronic acid and potassium aryltrifluoroborate derivatives as coupling partners. An appealing late-stage functionalization of indoprofen applying this methodology is showcased.

Full text of DOI:10.1021/acs.joc.9b01563

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Article
Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with
Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group
Yu-Chao Yuan, Christian Bruneau, Thierry Roisnel, and Rafael Gramage-Doria
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01563 • Publication Date (Web): 01 Aug 2019
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Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with Bo-
ronic Acids: Exploiting Isoindolinones as a Weak Directing Group
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Yu-Chao Yuan, Christian Bruneau, Thierry Roisnel, and Rafael Gramage-Doria*
Univ Rennes, CNRS, ISCR–UMR6226, F-35000 Rennes, France
ABSTRACT:
Biologically relevant N-arylisoindolinones efficiently underwent arylation reactions under ruthenium catalysis via C-H bond
functionalization. The reactions exclusively led to mono-arylated products and only ortho selectivity was observed in the
aromatic ring connected to the nitrogen atom. Interestingly, no C-H bond functionalization was observed in the other
benzene ring being in ortho position with respect to the carbonyl group. This ruthenium-catalyzed reaction displayed a
high functional group tolerance, and it employed readily available and benchmark stable boronic acid and potassium ar-
yltrifluoroborate derivatives as coupling partners. An appealing late-stage functionalization of indoprofen applying this
methodology is showcased.
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¢ INTRODUCTION
(RCONHR) behave differently than tertiary amides
(RCONR2) when transiently coordinating to the metal cat-
alyst throughout the catalytic cycle. Whereas in the former
case the nitrogen atom strongly binds to the metal center
due to amide tautomerization,15 in the latter case it is the
oxygen atom that weakly binds to the catalyst.16
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Isoindolinones are an important class of compounds
which combine a benzene ring fused with a five-mem-
bered cyclic tertiary amide.1 For instance, N-arylisoindo-
linones are present in many relevant pharmaceutical and
medicinal compounds2 as well as building blocks for pig-
ments and other molecular materials.3 For example, in-
doprofen (A) displays anti-inflammatory activity,4
DWP205190 (B) is known to be an inhibitor for the pro-
duction of tumor necrosis factor TNF-α5 and C behaves as
a potent and selective 5-HT2C antagonist (Figure 1).6 Con-
sequently, the access to molecular diversity arising from
the isoindolinone motif is receiving increasing attention.7
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In particular, the use of weak directing groups in transi-
tion metal-catalyzed C-H bond functionalization8 has
emerged as a powerful strategy for implementation in the
late-stage derivatization of biologically active molecules in
the last years.9 In this context, transition metal-catalyzed
carbon-carbon bond-forming reactions via C-H bond
functionalization occupy a central place as they represent
a sustainable approach compared to traditional Suzuki,
Heck or Stille cross-coupling reactions that generate over-
stoichiometric amounts of organometallic species starting
from highly pre-functionalized building blocks.10
Figure 2. State-of-the-art for the site-selective transition
metal-catalyzed carbon-carbon bond formations via aro-
matic C-H bond functionalizations of acyclic vs cyclic N-
substituted arylbenzamides as weak coordinating groups
(A-C) and present work (D).
In view of the need for methodologies available to target
selective C-H bond functionalizations with biologically
relevant molecules, we report herein on site-selective ru-
thenium-catalyzed arylation reactions applied to the iso-
indolinone motif (Figure 2D). The carbonyl group of the
cyclic tertiary amide turned out to act as an excellent weak
directing group enforcing the catalysis to take place selec-
tively at the ortho position of the acetanilide aromatic ring
B employing readily available boronic acid derivatives and
potassium aryltrifluoroborates as coupling partners (Fig-
ure 2D). The methodology was applied to the late-stage
derivatization of a biologically relevant target: indoprofen
(Figure 1). Selective C-H bond arylation reactions occur-
ring in the acetanilide aromatic ring B of tertiary phe-
nylbenzamides (Ar1-CONR-Ar2) are unknown to date, alt-
hough ruthenium-catalyzed C-H bond arylations with bo-
ronic acid derivatives containing a single aromatic frag-
ment using weak directing groups have been reported.16,17
Figure 1. Examples of important N-arylisoindolinones.
However, the use of N-substituted phenylbenzamides
(Ar1-CONR-Ar2), the acyclic version of N-arylisoindo-
linones, as weak directing groups for the formation of new
carbon-carbon bonds via transition metal-catalyzed C-H
bond functionalizations remains rare with limited exam-
ples reported to date (Figure 2). For instance, Miura and
co-workers described a ruthenium-catalyzed hydroaryla-
tion of N,N-diphenylbenzamide with diphenylacetylene in
2012 (Figure 2A).11 Two years later, Glorius and co-workers
described an example of rhodium-catalyzed alkynylation
of N-isopropyl phenylbenzamide with TIPS-EBX (TIPS-
EBX = 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-
one) as reagent (Figure 2B)12 and a ruthenium-catalyzed
cyanation of N-methyl phenylbenzamide with NCTS
(NCTS = N-cyano-N-phenyl-p-toluenesulfonamide) was
developed by Ackermann and co-workers (Figure 2C).13 In
these three examples,11-13 the C-H bond belonging to the
benzamide aromatic ring A was the one that was function-
alized (Figure 2A-C). These observations highlight the
challenge to reverse the site-selectivity for discriminating
between two chemically similar aromatic C-H bonds
where a carbon-carbon bond forming reaction can take
place.11-14 It is important to note that secondary amides
¢ RESULTS AND DISCUSSION
Encouraged by the use of aryl boronic acids as coupling
partners for ruthenium-catalyzed C-H bond arylation of
tertiary amides containing a sole aromatic fragment by
Szostak and co-workers,16a N-phenylisoindolinone 1a was
reacted with phenylboronic acid as an aryl source under
different reaction conditions in the presence of [RuCl2(p-
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cymene)]2 as pre-catalyst to study the formation of ary-
Table 1. Survey for the Optimal Reaction Conditions
for the Site-Selective Ru-Catalyzed C-H Bond Aryla-
tion of 1a with Phenylboronic Acida
lated products (Table 1). Initially, the reaction conditions
developed by Szostak were employed leading to 51% yield
of the arylated product 2a, in which the C-H bond aryla-
tion occurred at the ortho position of the aromatic ring B
(Table 1, entry 1). Gratifyingly, no C-H bond arylation oc-
curred in the benzamide aromatic ring A according to the
NMR analyses of the reaction mixture. Whereas the reac-
tion conditions developed by Szostak are sought to pro-
ceed via a 5-membered ruthenacycle species,16a in our case,
a 6-membered ruthenacycle species might form consider-
ing the outcome of the reaction. In contrast to observa-
tions from Szostak,16a we noticed that the absence of water
led to an increase of reactivity with 72% yield of the tar-
geted compound 2a (Table 1, entry 2). Changing THF as
solvent for 2-MeTHF or NMP led to 2a in yields as low as
34% and 10%, respectively (Table 1, entries 3 and 4). The
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entry
oxidant
additive
solvent
T
(oC)
Yield
(%)b
1c
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Cu(OTf)2 THF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
70
51
72
34
10
2
Cu(OTf)2 THF
3
Cu(OTf)2 2-MeTHF
Cu(OTf)2 NMP
Cu(OTf)2 DMF
Cu(OTf)2 DCE
4
5
<5
<5
<5
<5
<5
<5
0
t
use of DMF, DCE, dioxane, AmOH, toluene and acetoni-
6
trile as solvents, respectively, completely inhibited the re-
action (Table 1, entries 5-10). Reactions using different ox-
idants [Cu(OAc)2•H2O, (NH4)2S2O8, Ag2CO3, AgOAc] and
triflate metal salts as additives [AgOTf, Zn(OTf)2] in place
of Ag2O and Cu(OTf)2 led to low yields of the product (Ta-
ble 1, entries 11-16). In the presence of one equivalent of
Cu(OTf)2 instead of 20 mol%, the same reactivity was ob-
served (Table 1, entry 17). Other ruthenium complexes
such as [Ru(NCtBu)6](BF4)2 and [Ru(p-cymene)(O2CMes)2]
were catalytically unproductive (Table 1, entries 18 and 19).
These observations suggest that (i) the catalytically active
species could involve para-cymene coordinated ruthe-
nium complexes and (ii) the carboxylate anions inhibit the
reactions to some extent (see also Table 1, entries 11 and
14). The reaction performed under air atmosphere still af-
forded 2a in 55% yield (Table 1, entry 20). Additionally,
control experiments revealed the necessity of all reagents
for the favorable outcome of the reaction (Table 1, entries
21-24). We found that the reaction was also operating at
temperatures lower than 110 oC. For instance, 74% yield of
2a was obtained in a reaction conducted at 90 oC (Table 1,
entry 25), 66% at 70 oC (Table 1, entry 26) and 59% at room
temperature (Table 1, entry 27). This constitutes a unique
example of ruthenium-catalyzed C-H bond arylation at
room temperature and mild conditions using weak direct-
ing groups.18 We noted that the reaction did not proceed
when replacing phenylboronic acid by phenylboronic acid
glycol ester (Table 1, entry 28), indicating the preference of
this methodology for aryl boronic acids rather than aryl-
boronate derivatives. The catalysis performed at larger
scale (starting from 1 mmol of 1a) afforded the correspond-
ing product 2a in 71% isolated yield (Table 1, entry 29) us-
ing the optimal reaction conditions.
7
Cu(OTf)2 dioxane
Cu(OTf)2 tAmOH
Cu(OTf)2 toluene
Cu(OTf)2 MeCN
8
9
10
11
.
Cu(OAc)2 H2O Cu(OTf)2 THF
12
13
(NH4)2S2O8
Ag2CO3
AgOAc
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
-
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
0
34
9
14
15
16
17d
18e
19f
20g
21h
22i
23
24
25
26
27
28j
29 k
AgOTf
THF
0
Zn(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
0
75
0
0
55
0
<5
<5
13
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
-
THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
Cu(OTf)2 THF
74 (72)
66
59
<5
71
25
110
100
aReaction conditions: 1a (0.1 mmol, 1 equiv.), phenylboronic acid (0.25
mmol, 2.5 equiv.), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%),
oxidant (0.1 mmol, 1 equiv.), additive (20 mol%), solvent (0.5 mL), 20
h, Argon. bDetermined by 1H NMR spectroscopy analysis using dibro-
momethane as internal standard; isolated yields obtained after puri-
fication by column chromatograph are displayed in parentheses.
d
e
cH2O (3 equiv.). Cu(OTf)2 (1 equiv.). [Ru(NCtBu)6](BF4)2 instead of
f
[RuCl2(p-cymene)]2. [Ru(p-cymene)(O2CMes)2] instead of [RuCl2(p-
cyme-ne)]2. gAir instead of Argon. hWithout [RuCl2(p-cymene)]2.
j
iWithout AgSbF6. Phenylboronic acid glycol ester instead of phenyl-
k
boronic acid. Reaction conditions: 1a (1 mmol, 1 equiv.), phenyl-
boronic acid (2.5 mmol, 2.5 equiv.), [RuCl2(p-cymene)]2 (5 mol%),
AgSbF6 (20 mol%), Ag2O (1 mmol, 1 equiv.), Cu(OTf)2 (20 mol%), THF
(5 mL), 20 h, Argon.
Next, we applied the optimal reaction conditions we
found (Table 1, entry 25) to N-arylisoindolinones 1 and bo-
ronic acid derivatives containing both different substitu-
tion patterns in order to determine the scope and limita-
tions for this transformation (Table 2). Isoindolinones
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para-substituted with methyl, methoxy and chloro groups
Table 2. Scope and Limitations for the C-H Bond Ary-
lation of N-arylisoindolinonesa
were well tolerated leading to the corresponding arylated
products 2b-2d in 60-86% yield. Notably, carboxylic acid
ester groups were suitable for the ruthenium-catalyzed C-
H bond arylation protocol affording 2e in 55% yield. Alt-
hough ester groups are known to direct some ruthenium-
catalyzed C-H bond functionalizations,19 in the present
case the isoindolinone core seems to be more appropriate
for coordination to ruthenium and thus, it exclusively dic-
tates the selectivity of the reaction. Unfortunately, nitrile-
containing partners are not compatible with the catalysis
(2f) as it appeared to be the case in other ruthenium-cata-
lyzed C-H bond functionalizations as well.15-17 Dioxolane-
containing isoindolinone led to a single isomer 2g in 40%
isolated yield. Methyl- and methoxy-substituted isoindo-
linones in meta position led exclusively to 2h and 2i, re-
spectively, in 55% and 59% yield. Moreover, the reactions
were sensitive to the steric hindrance found in some sub-
strates. For instance, ortho-substituted coupling partners
did not react as evidenced in the absence of formation of
2j-2k. However, the reaction did operate using ortho-
fluorophenylboronic acid and ortho-methoxyphenyl-
boronic acid as coupling partners leading to 2l and 2m in
55% and 44% yield, respectively. meta-Substituted phenyl-
boronic acids are overall well tolerated with the only ex-
ception of the chloride derivative, which led to 2n in 15%
yield. On the other hand, the reactions with methyl-,
methoxy- and nitro-containing boronic acids afforded the
corresponding products 2o, 2p and 2q in 74%, 32% and
60% yields, respectively. As such, the reaction seems to be
sensitive to the electronic effects imposed by the boronic
acids substituted in meta position. The reaction for 3,5-di-
methylphenylboronic acid gave rise to the corresponding
arylated product 2r in 70% yield. para-Substituted phenyl-
boronic acids were also used in this C-H bond arylation
protocol. Methyl- and methoxy-containing products 2s
and 2t were formed in comparable yields of 77% and 79%.
In the case of reactions with substrates containing halides
in the para position of the phenylboronic acid, a trend was
observed following the order of reactivity F < Cl < Br with
2u, 2v and 2w respectively obtained in 19%, 55% and 81%
yield. The main by-product observed during the formation
of 2u is the one resulting from the homocoupling of the
corresponding boronic acid derivative. Naphthalene-con-
taining boronic acids efficiently reacted leading to 2x and
2y in 83% and 70% yield, respectively. The reaction with
very bulky 1-naphthaleneboronic acid still afforded the
corresponding product 2z but in a low yield of 10%.
4
5
6
7
8
9
ArB(OH)
2 (0.75 mmol)
H
H
[RuCl2(p-cymene)]2 (5 mol%)
O
O
Ar
H
AgSbF6 (20 mol%)
Z
Z
N
N
Ag2O (0.3 mmol), Cu(OTf)2 (20 mol%)
THF, 90 oC, 20 h, Argon
1a 1z
(0.3 mmol)
2a-2z
-
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O
N
O
O
Me
OMe
N
N
2a, 72%b
2b, 60% (65%)b
2c, 84%b
O
N
O
N
X-ray
CO2Et
Cl
b
b
2d
, 86%
2e
, 55% (65%)
O
N
O
N
b
O
O
X-ray
CN
b
2f
2g
, 40% (57%)
, 0%
O
O
X-ray
N
N
Me
OMe
b
2i, 59% (65%)b
2h
, 55% (63%)
F
Me
O
N
O
N
R
O
b
2ja
2jb
2jc
, R = Me, 0%
N
b
, R = OMe, 0%
b
b
2k
2l
, 55% (60%)
Me
, R = F, 0%
, 0%
Cl
OMe
O
O
N
O
N
N
2m
2n
2o
, 74%
, 44% (52%)
, 15% (21%)
X-ray
X-ray
X-ray
OMe
NO2
Me
Me
O
N
O
O
N
N
2q
2r
, 60% (67%)
, 62% (70%)
2p
, 32% (40%)
Me
OMe
F
Cl
O
N
O
O
N
O
Moreover, single crystal X-ray diffraction studies estab-
lished the molecular structures of 2c, 2d, 2g, 2m, 2n and
2o (Table 2), thus unambiguously supporting the control
of the site- and regio-selectivity during the catalysis. It is
worthy to mention that the traditional synthetic route to-
wards this types of products require the use of over-stoi-
chiometric amounts of metal zinc and highly pre-func-
tionalized starting materials, which require an important
number of additional steps that significantly decreases the
overall yield and generates significant chemical waste.20a
As such, the presented ruthenium-catalyzed arylation is
appealing in terms of an atom- and step-economy meth-
odology. Importantly, analogs to products 2 have been
studied against the spinal muscular atrophy.20b
N
N
2s
, 77%
2t
2u
2v
, 79%
, 19% (25%)
, 55% (61%)
MeO
Br
O
O
N
O
O
N
N
N
2w
, 81%
2x, 83%
2y, 70%
2z, 10% (15%)
aIsolated yields obtained after purification by column chromatog-
raphy are displayed whereas conversions are shown in parentheses.
b110 oC instead of 90 oC.
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Interestingly, no C-H bond bis-arylation was observed
Scheme 1. Simplified, Plausible Catalytic Cycle for the
Ru-Catalyzed C-H Bond Arylation of Isoindolinones 1
for any of the cases presented in Table 2. In some cases,
the product resulting from the homocoupling of the bo-
ronic acid derivative was detected as illustrated by the iso-
lation of 3 (vide infra) during the purification of 2n. This
homocoupling reaction appears to be a side reaction that
may explain the relatively low yields obtained in some of
the cases in Table 2. We noted that very challenging bo-
ronic acids such as alkyl boronic ones (e.g. 1-butylboronic
acid) and heteroaromatic-containing ones (e.g. 3-thiophe-
neboronic acid) did not react under the studied reaction
conditions illustrating the current limitations of the meth-
odology as it has been shown before with other sub-
strates.16a,17
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In order to study the relevance of the carbonyl group
from the isoindolinone core as a weak directing group in
the catalysis, we performed a control reaction employing a
substrate featuring no ketone group. Under the studied re-
action conditions, isoindoline 4 did no afford any arylated
product (Eq. 1). The same outcome was observed in the ca-
talysis with the cyclic imides 5 and 6 as substrates (Eq. 2
and Eq. 3). These findings suggest that (i) the carbonyl
group of the isoindolinone 1 acts as a weak directing unit
throughout the catalytic cycle and (ii) that the flexibility
and less steric hindrance of cyclic amides (i.e. 1) when
compared to cyclic imides (i.e. 5-6) enable to accommo-
date key ruthenacycle species. Deuteration experiments
using N-phenylisoindolinone 1a were performed and they
were not conclusive at this stage.
To further demonstrate the potential and utility of this
methodology, we decided to apply it to the late-stage func-
tionalization of biologically relevant indoprofen A (Figure
1 and Scheme 2), which is known to display anti-inflamma-
tory activity.4 Indoprofen A contains a carboxylic acid that,
unfortunately, is not compatible under the standard reac-
tion conditions. However, it can readily be converted into
an ester group, which in turn, is compatible with our
methodology (see 2e in Table 2). Consequently, we per-
formed a reaction sequence involving (1) esterification, (2)
ruthenium-catalyzed C-H bond arylation and (3) ester hy-
drolysis. In this manner, the corresponding ortho-arylated
indoprofen 7 was obtained in 76% overall yield starting
from indoprofen over three steps (Scheme 2). The regio-
and site-selectivity observed in the resulting product 7 was
determined by multinuclear NMR spectroscopy studies.
During the sequence, only one column chromatography
was performed in the second step as the first and third
steps are almost quantitative and require a trivial
acid/base workup for the isolation of the products. As
such, this sequence can be considered as sustainable to
some extent.
Scheme 2. Application of the Ru-Catalyzed Site-Selec-
tive C-H Bond Arylation to the Late-Stage Functional-
ization of Indoprofena
These data, combined with previous observations,16a,17,21
enabled us to suggest a plausible reaction mechanism for
the C-H bond arylation of N-arylisoindolinones (Scheme
1). Initially, chloride-free ruthenium(II) complexes coordi-
nate to substrate 1 via the oxygen lone pair of the ketone
group to from species I. Then, base-assisted C-H bond ac-
tivation enabled by triflate anions led to a six-membered
ruthenacycle species II. In the presence of boronic acids,
intermediate III forms that undergoes reductive elimina-
tion giving product 2 and the resulting ruthenium(0) spe-
cies were regenerated into active ruthenium(II) species
upon oxidation with Ag2O.
aReaction conditions: (i) H2SO4 (cat.), EtOH, reflux, 12 h, 99%; (ii)
Ph(BOH)2 (2.5 equiv.), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20
mol%), Ag2O (1 equiv.), Cu(OTf)2 (20 mol%), THF, 90 oC, 20 h, 85%;
(iii) NaOH (2 M), MeOH:THF, r.t., 12 h, 90%.
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In addition, we reasoned that potassium organotri-
polycyclic aromatic hydrocarbons] at different positions
fluoroborates, which are nowadays well recognized as effi-
cient coupling partners in cross-coupling chemistry,22 may
eventually be used for site-selective ruthenium-catalyzed
C-H bond arylation reactions as well. As a proof of con-
cept, N-phenylisoindolinone 1a was submitted to our
standard reaction conditions but employing potassium
phenyltrifluoroborate as the aryl source for the C-H bond
functionalization instead of phenylboronic acid. Gratify-
ingly, the reaction was equally efficient leading to the
mono-arylated product 2a in 68% yield (Eq. 4).
(ortho, meta, para) within the different coupling partners
are tolerated by the catalysis due to the mild conditions
employed. This catalysis represents a type of general selec-
tive functionalization in which combining a ruthenium(II)
catalyst with a weak coordinating group (i.e. cyclic amide)
promotes the discrimination of one out of two aromatic C-
H bonds with similar bond dissociation energies. In addi-
tion, mono-arylated products were exclusively obtained in
the above-described catalysis. The previously neglected
homocoupling side-products observed during the C-H
bond arylation reaction are likely originating from a sim-
ultaneous reaction that competes with the C-H bond ary-
lation. Importantly, this methodology shows the relevance
of ruthenium(II) pre-catalysts leading to the formation of
six-membered ruthenacycles during the catalysis even
when using weak coordinating groups within the sub-
strate. In addition, and considering the availability of the
developed ruthenium-based catalytic systems, one could
expect manifold implementations of this strategy in the
late-stage derivatization of potential drug candidates (as it
is shown here with indoprofen) and (supra)molecular ma-
terials that feature such relevant organic skeleton or simi-
lar chemical motifs.
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Finally, for comparison purposes, N-phenylisoindo-
linone 1a was submitted to the reaction conditions tradi-
tionally used for ruthenium-catalyzed C-H bond arylation
reactions with strong nitrogen-containing directing
units.23 They consist of [RuCl2(p-cymene)]2 (5 mol%),
KOAc (20 mol%), K2CO3 as base, bromobenzene as aryl
o
source in NMP as solvent at 150 C (Eq. 5). Under these
¢ EXPERIMENTAL SECTION
reaction conditions, the starting material 1a was found un-
reactive. This shows the true potential of boronic acids and
related derivatives17 as an alternative to replace aryl halides
and aryl pseudo-halides as coupling partners for challeng-
ing C-H bond arylation reactions with transition metal
catalysts, as it is the case here for weak directing groups.
General Methods. All reagents were obtained from com-
mercial sources and used as supplied. All reactions were
carried out in flame-dried glassware under argon atmos-
phere unless otherwise noted. Catalytic experiments were
performed in Schlenk-type flasks under argon atmosphere
unless otherwise noted. Organic solutions were concen-
trated under reduced pressure using a rotary evaporator.
Thin-layer chromatography (TLC) were carried out on 0.25
mm Merck silica gel (60-F254). Flash column chromatog-
raphy was performed using silica gel Silica 60 M, 0.04-
0.063 mm. Technical grade petroleum ether (40-60), n-
heptane and ethyl acetate were used for column chroma-
tography. CDCl3 was stored under nitrogen over molecular
sieves. NMR spectra were recorded on an AVANCE III 400
spectrometer. 1H NMR spectra were referenced to residual
Furthermore, the same reaction conditions applied to
N-phenylphthalimide 5 did not produce any arylated prod-
uct, but N-phenylbenzamide was formed to some extent
(Eq. 6). We have previously reported improved reaction
conditions, and substrate scope and limitations regarding
this unexpected ruthenium-catalyzed protodecarbonyla-
tion reaction.24
protiated solvent (
DMSO-d6 and
= 2.05 ppm for acetone-d6) and 13C chemi-
cal shifts are reported relative to deuterated solvents (
77.0 ppm for CDCl3, = 39.5 ppm for DMSO-d6 and
δ = 7.26 ppm for CDCl3, δ = 2.50 ppm for
δ
δ
δ
=
=
δ
29.8 ppm for acetone-d6) [Note: acetone-d6 contains traces
of water at ca. 3 ppm]. The peak patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet, and br. for broad. GC-MS analyses were performed
with a GCMS-QP2010S (Shimadzu) instrument with a GC-
2010 equipped with a 30 m capillary column (Supelco,
SLBTM-5ms, fused silica capillary column, 30 m x 0.25 mm
x 0.25 mm film thickness), which was used with helium as
the vector gas. The following GC conditions were used: in-
itial temperature 80 oC for 2 minutes, then 20 oC/min until
280 oC and 280 oC for 28 minutes. HRMS were recorded on
a Waters Q-Tof 2 mass spectrometer at the corresponding
facilities of the CRMPO, Centre Régional de Mesures Phy-
siques de l’Ouest, Université de Rennes 1.
¢ CONCLUSIONS
In conclusion, we have disclosed an efficient and site-se-
lective ruthenium-catalyzed C-H bond arylation protocol
to form unique aromatic C(sp2)-C(sp2) bonds within the
biologically relevant isoindolinone skeleton. A large num-
ber of number of useful functional chemical groups [e.g.
fluoro, chloro, bromo, nitro, alkyl, (a)cyclic ethers, esters,
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Synthesis and characterization of N-arylisoindo-
4.89 (s, 2H) ppm. The spectral data match those previously
linone substrates (1): A mixture of 2-formylbenzoic acid
(0.751 g, 5 mmol, 1 equiv.), the corresponding aniline de-
rivative (6 mmol, 1.2 equiv.), DABCO (1.122 g, 10 mmol, 2
equiv.), HCOOH (1.25 mL, 1.525 g, 33.1 mmol), Pd(OAc)2
(0.056 g, 0.25 mmol, 5 mol%) in 1,4-dioxane (5 mL) was
heated in an oil bath at 80 oC for 3 hours. After completion
of the reaction, the mixture was cooled to room tempera-
ture, and diluted with DCM (50 mL). The solid was re-
moved by filtration, and the filtrate was washed with water
(50 mL) and brine (50 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel (petroleum ether/acetone = 5/1, v/v) to
afford the desired product 1.
reported.25
2-(Benzo[d][1,3]dioxol-5-yl)isoindolin-1-one
(1g):
starting from 3,4-(methylenedioxy)aniline (0.823 g, 6
1
mmol) in 58% isolated yield (0.73 g). H NMR (400 MHz,
CDCl3):
δ = 7.92 (d, J = 8.0 Hz, 1H), 7.61-7.57 (m, 2H), 7.51
(dd, J = 6.4, 5.6 Hz, 2H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 6.85
(d, J = 8.4 Hz, 1H), 5.99 (s, 2H), 4.81 (s, 2H) ppm. The spec-
tral data match those previously reported.25
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2-(m-Tolyl)isoindolin-1-one (1h): starting from m-tolui-
dine (0.64 mL, 0.643 g, 6 mmol) in 65% isolated yield (0.73
g). 1H NMR (400 MHz, CDCl3):
δ = 7.93 (d, J = 6.8 Hz, 1H),
7.73 (s, 1H), 7.65-7.58 (m, 2H), 7.51 (dd, J = 7.2, 6.8 Hz, 2H),
7.32 (dd, J = 8.0, 8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 4.86
(s, 2H), 2.41 (s, 3H) ppm. The spectral data match those
previously reported.25
2-Phenylisoindolin-1-one (1a): starting from aniline
(0.55 mL, 0.559 g, 6 mmol) in 98% isolated yield (1.03 g).
1H NMR (400 MHz, CDCl3):
δ = 7.93 (d, J = 7.6 Hz, 1H),
2-(m-Methoxyphenyl)isoindolin-1-one (1i): starting
from m-anisidine (0.67 mL, 0.739 g, 6 mmol) in 80% iso-
lated yield (0.96 g). 1H NMR (400 MHz, CDCl3):
δ = 7.93 (d,
J = 7.2 Hz, 1H), 7.69 (dd, J = 2.0, 1.6 Hz, 1H), 7.62-7.58 (m,
1H), 7.51 (dd, J = 7.6, 7.6 Hz, 2H), 7.34-7.32 (m, 2H), 6.76-
6.73 (m, 1H), 4.86 (s, 2H), 3.87 (s, 3H) ppm. The spectral
data match those previously reported.25
7.89-7.86 (m, 2H), 7.62-7.58 (m, 1H), 7.53-7.49 (m, 2H),
7.43 (dd, J = 8.4, 7.2 Hz, 2H), 7.18 (dd, J = 7.2, 7.2 Hz, 1H),
4.87 (s, 2H) ppm. The spectral data match those previously
reported.25
2-(p-Tolyl)isoindolin-1-one (1b): starting from p-tolui-
dine (0.66 mL, 0.643 g, 6 mmol) in 80% isolated yield (0.89
g). 1H NMR (400 MHz, CDCl3):
δ = 7.92 (d, J = 7.2 Hz, 1H),
2-(o-Tolyl)isoindolin-1-one (1ja): starting from o-tolui-
dine (0.64 mL, 0.643 g, 6 mmol) in 68% isolated yield (0.76
g). 1H NMR (400 MHz, CDCl3):
δ = 7.96 (d, J = 7.6 Hz, 1H),
7.61 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.35-
7.32 (m, 1H), 7.30-7.24 (m, 3H), 4.74 (s, 2H), 2.27 (s, 3H)
ppm. The spectral data match those previously reported.25
7.74 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 7.6, 7.6 Hz, 1H), 7.50
(dd, J = 6.8, 6.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.84 (s,
2H), 2.36 (s, 3H) ppm. The spectral data match those pre-
viously reported.25
2-(p-Methoxyphenyl)isoindolin-1-one (1c): starting
from p-anisidine (0.739 g, 6 mmol) in 62% isolated yield
(0.74 g). 1H NMR (400 MHz, CDCl3):
δ = 7.92 (d, J = 7.6 Hz,
1H), 7.74 (d, J = 9.2 Hz, 2H), 7.58 (dd, J = 7.6, 7.6 Hz, 1H),
7.52-7.48 (m, 2H), 6.97 (d, J = 9.2 Hz, 2H), 4.83 (s, 2H), 3.83
(s, 3H) ppm. The spectral data match those previously re-
ported.25
2-(2-Methoxyphenyl)isoindolin-1-one (1jb): starting
from o-anisidine (X.XX mL, X.XX g, X mmol) in 61% iso-
1
lated yield (X.XX g). H NMR (400 MHz, CDCl3):
δ = 7.94
(d, J = 7.6 Hz, 1H), 7.58 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.49
(dd, J = 7.6, 7.2 Hz, 2H), 7.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.32
(ddd, J = 8.0, 8.0, 1.2 Hz, 1H), 7.06-7.00 (m, 2H), 4.80 (s,
2H), 3.82 (s, 3H) ppm.. The spectral data match those pre-
viously reported.25
2-(p-Chlorophenyl)isoindolin-1-one (1d): starting from
p-chloroaniline (0.765 g, 6 mmol) in 61% isolated yield
(0.74 g). 1H NMR (400 MHz, CDCl3):
δ = 7.92 (d, J = 7.2 Hz,
1H), 7.74 (dd, J = 9.2, 2.4 Hz, 2H), 7.61 (ddd, J = 7.6, 7.6, 1.2
Hz, 1H), 7.54-7.50 (m, 2H), 7.39 (dd, J = 9.2, 2.4 Hz, 2H),
4.84 (s, 2H) ppm. The spectral data match those previously
reported.25
2-(2-Fluorophenyl)isoindolin-1-one (1jc): starting from
o-fluoroaniline (0.19 mL, 0.222 g, 2 mmol) in 76% isolated
1
yield (0.35 g). H NMR (400 MHz, CDCl3):
δ = 7.97 (d, J =
7.4 Hz, 1H), 7.67-7.60 (m, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.33-
7.27 (m, 1H), 7.25-7.18 (m, 2H), 4.88 (s, 2H) ppm. 19F{1H}
Ethyl 4-(1-oxoisoindolin-2-yl)benzoate (1e): starting
from ethyl 4-aminobenzoate (0.991 g, 6 mmol) in 96% iso-
NMR (376 MHz, CDCl3): δ = -120.5 ppm. The spectral data
match those previously reported.26
lated yield (1.35 g). 1H NMR (400 MHz, CDCl3):
δ = 8.11 (d,
Synthesis and characterization of isoindoline (4): 1,2-
Bis(bromomethyl)benzene (1.32 g, 5 mmol, 1 equiv.),
DIPEA (2.18 mL, 1.62 g, 12.5 mmol, 2.5 eq.), and aniline
(0.68 mL, 0.698 g, 7.5 mmol, 1.5 equiv.) were dissolved in
toluene (25 mL) and added to a sealed tube before vigor-
J = 8.4 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 7.6 Hz,
1H), 7.63 (dd, J = 7.6, 7.6 Hz, 1H), 7.53 (dd, J = 7.6, 7.6 Hz,
2H), 4.90 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz,
3H) ppm. The spectral data match those previously re-
ported.25
o
ously stirring at 110 C in an oil bath under a N2 atmos-
phere. The resulting mixture was cooled to down to room
temperature and extracted with ethyl acetate (3 x 10 mL).
The combined organic phase was washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography
(petroleum ether) to obtain the desired product 4 (89%
4-(1-Oxoisoindolin-2-yl)benzonitrile (1f): starting from
4-aminobenzonitrile (0.709 g, 6 mmol) in 64% isolated
1
yield (0.71 g). H NMR (400 MHz, CDCl3):
δ = 8.06 (d, J =
9.2 Hz, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H),
7.65 (dd, J = 7.6, 7.2 Hz, 1H), 7.54 (dd, J = 7.6, 7.2 Hz, 2H),
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isolated yield, 0.87 g) as a light yellow solid. 1H NMR (400
MHz, CDCl3): = 7.38-7.31 (m, 6H), 6.78 (dd, J = 7.6, 7.6
Hz, 1H), 6.71 (d, J = 7.6 Hz, 2H), 4.68 (s, 4H) ppm. The
spectral data match those previously reported.27
2-(5-Methyl-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2b):
54.3 mg (60% yield), white solid, Mp: 167-169 C. 1H NMR
(400 MHz, CDCl3): = 7.93 (d, J = 7.2 Hz, 1H), 7.51-7.44 (m,
2H), 7.40-7.35 (m, 3H), 7.31-7.22 (m, 6H), 4.16 (s, 2H), 2.44
(s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
= 169.1, 141.7,
o
δ
δ
δ
Synthesis
and
characterization
of
N-phe-
139.7, 139.2, 138.2, 133.3, 132.3, 131.7, 131.6, 129.4, 128.9, 128.6,
128.4, 128.1, 127.5, 124.3, 122.7, 52.4, 21.3 ppm. HRMS (ESI)
calcd. for [M + Na]+ C21H17NONa 322.1202, found 322.1202
(0 ppm).
nylphthalimide (5): In a Schlenk tube, Phthalic anhy-
dride (0.74 g, 5 mmol, 1 equiv.), aniline (0.47 g, 5 mmol, 1
equiv.) and acetic acid (30 mL) were refluxed in an oil bath
for 2-5 h. Once at room temperature, water was added and
the solid recovered by filtration. After drying under vac-
uum the desired phthalimide 5 (80% isolated yield, 0.89 g)
was obtained. 1H NMR (400 MHz, CDCl3):
δ = 7.96 (dd, J =
5.6, 3.2 Hz, 2H), 7.80 (dd, J = 5.2, 3.2 Hz, 2H), 7.52 (dd, J =
7.6, 7.6 Hz, 2H), 7.34-7.27 (m, 3H) ppm. The spectral data
match those previously reported.28
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2-(5-Methoxy-[1,1'-biphenyl]-2-yl)isoindolin-1-one
o
1
(2c): 79.1 mg (84% yield), white solid, Mp: 162-164 C. H
NMR (400 MHz, CDCl3): = 7.92 (d, J = 7.2 Hz, 1H), 7.51-
δ
7.43 (m, 2H), 7.41-7.36 (m, 3H), 7.31-7.22 (m, 4H), 7.01-6.98
13
(m, 2H), 4.14 (s, 2H), 3.86 (s, 3H) ppm. C{1H} NMR (100
MHz, CDCl3): δ = 169.2, 159.2, 141.6, 141.2, 139.0, 132.2, 131.5,
130.2, 128.6, 128.3, 128.0, 127.7, 124.2, 122.6, 116.1, 114.1, 55.7,
52.6 ppm. HRMS (ESI) calcd. for [M + Na]+ C21H17NO2Na
338.1152, found 338.1153 (0 ppm). Single crystals suitable for
X-ray diffraction studies were obtained after evaporation
of a solution of 2c in acetone.
Synthesis and characterization of 2-Phenylhexahy-
dro-1H-isoindole-1,3(2H)-dione (6): Hexahydrophthalic
anhydride (1.54 g, 10 mmol, 1 equiv.) and aniline (0.91 mL,
0.93 g, 10 mmol, 1 equiv.) and THF (15 mL) were added to
a 100 mL round bottom flask. The solution was stirred for
30 min. at 40 oC in an oil bath. Removal of the solvent us-
ing a rotary evaporator gave the corresponding carboxylic
acid-amide as a white solid. The white solid was then
2-(5-Chloro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2d):
o
1
82.8 mg (86% yield), white solid, Mp: 121-123 C. H NMR
(400 MHz, CDCl3): = 7.91 (d, J = 7.2 Hz, 1H), 7.53-7.42 (m,
5H), 7.37-7.34 (m, 2H), 7.33-7.26 (m, 4H), 4.14 (s, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3):
= 169.1, 141.6, 141.4, 137.9,
δ
o
heated at 190 C under Ar for 4 h. The desired hexahy-
drophthalimide 6 (86% isolated yield, 1.97 g) was purified
δ
by silica gel column chromatography (petroleum
134.6, 133.8, 131.92, 131.90, 131.0, 130.4, 128.9, 128.7, 128.3,
128.24, 128.16, 124.4, 122.8, 52.1 ppm. HRMS (ESI) calcd. for
[M + Na]+ C20H14NO35ClNa 342.0656, found 342.0658 (1
ppm). Single crystals suitable for X-ray diffraction studies
were obtained after evaporation of a solution of 2d in ace-
tone.
1
ether/EtOAc gradient 10:1 to 2:1). H NMR (400 MHz,
CDCl3):
δ = 7.48-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.27
(m, 2H), 3.06-3.00 (m, 2H), 1.95-1.85 (m, 4H), 1.53-1.50 (m,
4H) ppm. The spectral data match those previously re-
ported.29
General procedure for the arylation reactions, and
characterization of products 2: [RuCl2(p-cymene)]2 (9.2
mg, 0.015 mmol, 5 mol%), AgSbF6 (20.6 mg, 0.06 mmol, 20
mol%), Ag2O (69.5 mg, 0.3 mmol, 1.0 equiv.), Cu(OTf)2
(21.7 mg, 0.06 mmol, 20 mol%), the corresponding N-aryl-
isoindolinone derivative 1 (0.3 mmol, 1.0 equiv.) and the
corresponding phenylboronic acid derivative (0.75 mmol,
2.5 equiv.) were taken in a 15 mL Schlenk tube, which was
equipped with a magnetic stirrer bar. THF (1.5 mL) was
added to the Schlenk tube via a syringe, and the reaction
mixture was degassed with Argon three times. The reac-
tion mixture was allowed to stir at 90 or 110 °C for 20 h in
an oil bath. After being cooled to ambient temperature,
the reaction mixture was diluted with DCM and then fil-
tered through Celite. After evaporation of the solvent in
vacuo, the crude product was purified by column chroma-
tography on silica gel (n-heptane/EtOAc gradient 10:1 to
5:1) to give the desired product 2.
Ethyl
boxylate (2e): 59.2 mg (55% yield), white solid, Mp: < 50
oC. 1H NMR (400 MHz, CDCl3):
= 8.15 (d, J = 2.0 Hz, 1H),
6-(1-oxoisoindolin-2-yl)-[1,1'-biphenyl]-3-car-
δ
8.12 (dd, J = 8.4, 2.0 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.61 (d,
J = 8.0 Hz, 1H), 7.54-7.45 (m, 2H), 7.40 (dd, J = 8.0, 1.6 Hz,
2H), 7.35-7.27 (m, 4H), 4.41 (q, J = 7.2 Hz, 2H), 4.17 (s, 2H),
1.40 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ
= 168.9, 166.0, 141.6, 140.2, 139.4, 138.5, 132.6, 132.0, 131.9,
130.0, 129.7, 129.0, 128.4, 128.3, 128.0, 124.4, 122.8, 61.3, 51.9,
14.5 ppm. HRMS (ESI) calcd. for [M + Na]+ C23H19NO3Na
380.1257, found 380.1259 (0 ppm).
2-(4-Phenylbenzo[d][1,3]dioxol-5-yl)isoindolin-1-one
o
1
(2g): 39.8 mg (40% yield), white solid, Mp: 212-214 C. H
NMR (400 MHz, CDCl3): = 7.90 (d, J = 7.2 Hz, 1H), 7.51-
δ
7.41 (m, 4H), 7.32-7.23 (m, 4H), 6.95 (d, J = 8.0 Hz, 1H), 6.89
13
(d, J = 8.0 Hz, 1H), 6.02 (s, 2H), 4.17 (s, 2H) ppm. C{1H}
NMR (100 MHz, CDCl3):
δ = 169.4, 147.3, 146.2, 141.6, 132.7,
132.2, 131.7, 130.0, 129.1, 128.7, 128.2, 128.1, 124.4, 122.69,
122.65, 122.55, 108.0, 101.9, 52.9 ppm. HRMS (ESI) calcd. for
[M + Na]+ C21H15NO3Na 352.0944, found 352.0947 (1 ppm).
Single crystals suitable for X-ray diffraction studies were
obtained after evaporation of a solution of 2g in acetone.
2-([1,1'-Biphenyl]-2-yl)isoindolin-1-one (2a): 61.6 mg
o
1
(72% yield), white solid, Mp: < 50 C. H NMR (400 MHz,
CDCl3): = 7.93 (d, J = 7.2 Hz, 1H), 7.52-7.43 (m, 6H), 7.40-
7.38 (m, 2H), 7.32-7.24 (m, 4H), 4.17 (s, 2H) ppm. C{1H}
NMR (100 MHz, CDCl3): = 169.0, 141.7, 139.9, 139.2, 135.9,
δ
13
δ
132.2, 131.7, 131.1, 129.1, 128.7, 128.6, 128.4, 128.3, 128.1, 127.6,
124.3, 122.7, 52.3 ppm. HRMS (ESI) calcd. for [M + Na]+
C20H15NONa 308.1046, found 308.1050 (1 ppm).
2-(4-Methyl-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2h):
49.8 mg (55% yield), white solid, Mp: < 50 oC. 1H NMR (400
MHz, CDCl3):
δ = 7.93 (d, J = 6.8 Hz, 1H), 7.52-7.44 (m, 2H),
7.38-7.35 (m, 3H), 7.30-7.23 (m, 6H), 4.16 (s, 2H), 2.43 (s,
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(ESI) calcd. for [M + Na]+ C21H17NONa 322.1202, found
322.1203 (0 ppm). Single crystals suitable for X-ray diffrac-
tion studies were obtained after evaporation of a solution
of 2o in acetone.
13
3H) ppm. C{1H} NMR (100 MHz, CDCl3):
δ = 169.2, 141.7,
139.2, 138.8, 137.0, 135.7, 132.3, 131.7, 131.0, 129.6, 129.3, 128.7,
128.5, 128.1, 127.4, 124.3, 122.7, 52.4, 21.2 ppm. HRMS (ESI)
calcd. for [M + Na]+ C21H17NONa 322.1202, found 322.1205
(1 ppm).
2-(3'-Methoxy-[1,1'-biphenyl]-2-yl)isoindolin-1-one
(2p): 30.7 mg (32% yield), white solid, Mp: < 50 oC. 1H NMR
2-(4-Methoxy-[1,1'-biphenyl]-2-yl)isoindolin-1-one
(2i): 55.6 mg (59% yield), white solid, Mp: 142-144 C. H
NMR (400 MHz, CDCl3): = 7.93 (d, J = 7.2 Hz, 1H), 7.52-
o
1
(400 MHz, CDCl3): δ = 7.93 (d, J = 7.2 Hz, 1H), 7.53-7.42 (m,
6H), 7.29 (d, J = 7.2 Hz, 1H), 7.20 (dd, J = 8.0, 8.0 Hz, 1H),
9
δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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53
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55
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58
59
60
7.00-6.94 (m, 2H), 6.82-6.79 (m, 1H), 4.19 (s, 2H), 3.65 (s,
7.44 (m, 2H), 7.38-7.34 (m, 3H), 7.29-7.20 (m, 4H), 7.03-
6.99 (m, 2H), 4.17 (s, 2H), 3.85 (s, 3H) ppm. C{1H} NMR
3H) ppm. C{1H} NMR (100 MHz, CDCl3):
δ
= 169.1, 159.7,
13
13
141.8, 140.5, 139.8, 135.9, 132.2, 131.7, 131.0, 129.8, 129.2, 128.8,
128.4, 128.2, 124.3, 122.8, 120.9, 114.0, 113.3, 55.3, 52.3 ppm.
HRMS (ESI) calcd. for [M + Na]+ C21H17NO2Na 338.1152,
found 338.1149 (1 ppm).
(100 MHz, CDCl3): δ = 169.0, 159.7, 141.7, 139.0, 136.7, 132.22,
132.18, 131.9, 131.7, 128.7, 128.5, 128.1, 127.2, 124.3, 122.7, 114.7,
113.8, 55.6, 52.2 ppm. HRMS (ESI) calcd. for [M + Na]+
C21H17NO2Na 338.1152, found 338.1155 (1 ppm).
2-(3'-Nitro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2q):
58.8 mg (60% yield), yellow solid, Mp: 226-228 oC. 1H NMR
2-(2'-Fluoro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2l):
o
1
49.7 mg (55% yield), white solid, Mp: 153-155 C. H NMR
(400 MHz, CDCl3): = 7.85 (d, J = 7.6 Hz, 1H), 7.53-7.42 (m,
6H), 7.39-7.32 (m, 2H), 7.27-7.21 (m, 1H), 7.10-7.01 (m, 2H),
4.39 (s, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
= 168.2,
(400 MHz, CDCl3):
δ = 8.25 (dd, J = 2.0, 2.0 Hz, 1H), 8.10
δ
(dd, J = 8.0, 2.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.73 (d, J =
7.6 Hz, 1H), 7.55-7.41 (m, 7H), 7.35 (d, J = 7.6 Hz, 1H), 4.36
δ
(s, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 168.7,
159.4 (d, JC-F = 245.0 Hz), 141.6, 136.9, 133.9, 132.1, 131.8 (d, JC-
148.4, 141.3, 141.0, 138.0, 136.1, 134.7, 132.0, 131.8, 130.9, 129.8,
129.6, 129.0, 128.7, 128.4, 124.3, 123.3, 122.8, 122.5, 52.8 ppm.
HRMS (ESI) calcd. for [M + Na]+ C20H14N2O3Na 353.0897,
found 353.0898 (0 ppm).
= 1.4 Hz), 131.7, 131.5 (d, JC-F = 3.1 Hz), 129.6 (d, JC-F = 8.0
F
Hz), 129.3, 128.4, 128.1, 127.9, 126.7 (d, JC-F = 15.4 Hz), 124.4
(d, JC-F = 3.6 Hz), 124.3, 122.7, 115.7 (d, JC-F = 22.1 Hz), 52.3 (d,
JC-F = 1.4 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3):
116.4 ppm. HRMS (ESI) calcd. for [M + Na]+ C20H14NOFNa
326.0952, found 326.0952 (0 ppm).
δ = -
2-(3',5'-Dimethyl-[1,1'-biphenyl]-2-yl)isoindolin-1-one
o
1
(2r): 58.7 mg (62% yield), white solid, Mp: 169-171 C. H
NMR (400 MHz, CDCl3): = 7.94 (d, J = 7.2 Hz, 1H), 7.52-
δ
2-(2'-Methoxy-[1,1'-biphenyl]-2-yl)isoindolin-1-one
o
1
7.41 (m, 6H), 7.29 (d, J = 6.8 Hz, 1H), 6.99 (s, 2H), 6.88 (s,
1H), 4.17 (s, 2H), 2.19 (s, 6H) ppm. 13C{1H} NMR (100 MHz,
(2m): 41.3 mg (44% yield), white solid, Mp: 120-122 C. H
NMR (400 MHz, CDCl3): = 7.88 (d, J = 7.6 Hz, 1H), 7.51-
δ
CDCl3):
δ = 169.1, 141.8, 139.9, 139.1, 138.2, 135.9, 132.3, 131.6,
7.40 (m, 6H), 7.30-7.22 (m, 3H), 6.91 (dd, J = 7.6, 7.2 Hz,
1H), 6.84 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H), 3.66 (s, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3):
δ = 168.2, 156.4, 141.7, 137.0,
136.3, 132.5, 132.1, 131.5, 131.1, 129.3, 128.5, 128.4, 128.1, 128.0,
127.5, 124.2, 122.6, 120.9, 110.8, 55.6, 52.0 ppm. HRMS (ESI)
calcd. for [M + Na]+ C21H17NO2Na 338.1152, found 338.1150
(0 ppm). Single crystals suitable for X-ray diffraction stud-
ies were obtained after evaporation of a solution of 2m in
acetone.
131.1, 129.3, 129.1, 128.4, 128.2, 128.1, 126.2, 124.3, 122.7, 52.2,
21.3 ppm. HRMS (ESI) calcd. for [M + Na]+ C22H19NONa
336.1359, found 336.1363 (1 ppm).
2-(4'-Methyl-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2s):
o
1
68.8 mg (77% yield), white solid, Mp: 132-134 C. H NMR
(400 MHz, CDCl3): = 7.94 (d, J = 7.6 Hz, 1H), 7.53-7.42 (m,
6H), 7.29-7.26 (m, 3H), 7.10 (d, J = 7.2 Hz, 2H), 4.20 (s, 2H),
2.30 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
= 169.0,
δ
δ
2-(3'-Chloro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2n):
141.7, 139.8, 137.3, 136.2, 135.9, 132.3, 131.6, 131.2, 129.5, 129.1,
128.4, 128.29, 128.28, 128.1, 124.3, 122.8, 52.2, 21.2 ppm.
HRMS (ESI) calcd. for [M + Na]+ C21H17NONa 322.1202,
found 322.1201 (0 ppm).
o
1
14.8 mg (15% yield), yellow solid, Mp: 128-130 C. H NMR
(400 MHz, CDCl3): = 7.93 (d, J = 7.2 Hz, 1H), 7.55-7.44 (m,
δ
6H), 7.40 (s, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.28-7.23 (m, 2H),
7.18 (dd, J = 7.6, 7.6 Hz, 1H), 4.23 (s, 2H) ppm. 13C{1H} NMR
2-(4'-Methoxy-[1,1'-biphenyl]-2-yl)isoindolin-1-one
(2t): 74.5 mg (79% yield), white solid, Mp: < 50 oC. 1H NMR
(100 MHz, CDCl3):
δ = 169.1, 141.6, 141.0, 138.7, 136.1, 134.6,
132.1, 131.9, 131.0, 130.0, 129.3, 129.2, 128.6, 128.5, 128.3, 127.8,
126.8, 124.4, 122.8, 52.5 ppm. HRMS (ESI) calcd. for [M +
Na]+ C20H14NO35ClNa 342.0656, found 342.0654 (1 ppm).
Single crystals suitable for X-ray diffraction studies were
obtained after evaporation of a solution of 2n in acetone.
(400 MHz, CDCl3):
6H), 7.33-7.28 (m, 3H), 6.83 (dd, J = 6.8, 2.0 Hz, 2H), 4.20
(s, 2H), 3.75 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 7.93 (d, J = 6.8 Hz, 1H), 7.51-7.41 (m,
δ
= 169.0, 159.1, 141.7, 139.5, 135.9, 132.3, 131.6, 131.4, 131.1, 129.6,
129.1, 128.3, 128.2, 128.1, 124.2, 122.8, 114.2, 55.2, 52.2 ppm.
HRMS (ESI) calcd. for [M + Na]+ C21H17NO2Na 338.1152,
found 338.1147 (1 ppm).
2-(3'-Methyl-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2o):
66.7 mg (74% yield), white solid, Mp: 146-148 oC. 1H NMR
(400 MHz, CDCl3):
δ = 7.94 (d, J = 6.4 Hz, 1H), 7.52-7.40
2-(4'-Fluoro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2u):
(m, 6H), 7.27 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.20-7.14 (m,
2H), 7.06 (d, J = 7.2 Hz, 1H), 4.18 (s, 2H), 2.26 (s, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3):
δ = 169.0, 141.7, 139.9, 139.0,
138.3, 135.9, 132.2, 131.6, 131.0, 129.1, 129.0, 128.52, 128.48,
128.3, 128.2, 128.0, 125.4, 124.2, 122.7, 52.2, 21.4 ppm. HRMS
o
1
16.9 mg (19% yield), yellow solid, Mp: 108-110 C. H NMR
(400 MHz, CDCl3): = 7.92 (d, J = 7.6 Hz, 1H), 7.54-7.43 (m,
6H), 7.38-7.30 (m, 3H), 7.01-6.96 (m, 2H), 4.21 (s, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3):
= 169.1, 162.4 (d, JC-F
δ
δ
=
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7.33 (m, 4H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 141.7,
245.4 Hz), 141.6, 139.1, 136.0, 135.1 (d, JC-F = 3.5 Hz), 132.1,
135.0, 130.2, 128.0, 127.4, 125.4 ppm. MS (EI): m/z 222 (M+,
100), 152 (77), 93 (20), 75 (22). The spectral data match
those previously reported.30
131.8, 131.1, 130.1 (d, JC-F = 8.0 Hz), 129.2, 128.9, 128.5, 128.3,
124.4, 122.8, 115.7 (d, JC-F = 21.3 Hz), 52.4 ppm. 19F{1H} NMR
(376 MHz, CDCl3): δ = -114.6 ppm. HRMS (ESI) calcd. for
[M + Na]+ C20H14NOFNa 326.0952, found 326.0951 (0 ppm).
Large scale synthesis of product 2a: [RuCl2(p-cymene)]2
(30.6 mg, 0.05 mmol, 5 mol%), AgSbF6 (68.7 mg, 0.2 mmol,
20 mol%), Ag2O (231.7 mg, 1 mmol, 1.0 equiv.), Cu(OTf)2
(72.3 mg, 0.2 mmol, 20 mol%), N-pheylisoindolinone 1a
(209.2 mg, 1 mmol, 1.0 equiv.) and phenylboronic acid
(304.8 mg, 2.5 mmol, 2.5 equiv.) were taken in a 25 mL
Schlenk tube, which was equipped with a magnetic stirrer
bar. THF (5 mL) was added to the Schlenk tube via a sy-
ringe, and the reaction mixture was degassed with Argon
three times. The reaction mixture was allowed to stir at 110
°C for 20 h in an oil bath. After being cooled to ambient
temperature, the reaction mixture was diluted with DCM
and then filtered through Celite. After evaporation of the
solvent in vacuo, the crude product was purified by col-
umn chromatography on silica gel (n-heptane/EtOAc gra-
dient 10:1 to 5:1) to give the desired product 2a (202.6 mg,
71% yield).
7
8
9
2-(4'-Chloro-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2v):
o
1
52.4 mg (55% yield), white solid, Mp: 141-143 C. H NMR
(400 MHz, CDCl3): = 7.92 (d, J = 7.6 Hz, 1H), 7.55-7.42 (m,
6H), 7.34-7.31 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 4.23 (s, 2H)
ppm. 13C{1H} NMR (100 MHz, CDCl3):
= 169.0, 141.5, 138.9,
δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
137.6, 135.9, 133.7, 132.0, 131.9, 131.0, 129.8, 129.2, 129.1, 128.9,
128.5, 128.3, 124.3, 122.8, 52.4 ppm. HRMS (ESI) calcd. for
[M + Na]+ C20H14NO35ClNa 342.0656, found 342.0657 (0
ppm).
2-(4'-Bromo-[1,1'-biphenyl]-2-yl)isoindolin-1-one (2w):
o
1
88.7 mg (81% yield), white solid, Mp: 138-140 C. H NMR
(400 MHz, CDCl3): = 7.91 (d, J = 7.2 Hz, 1H), 7.55-7.40 (m,
8H), 7.32 (d, J = 7.2 Hz, 1H), 7.27 (ddd, J = 8.0, 2.8, 1.6 Hz,
2H), 4.24 (s, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ
δ
=
169.0, 141.5, 138.8, 138.1, 135.8, 132.0, 131.9, 131.8, 130.9, 130.1,
129.2, 129.1, 128.5, 128.2, 124.3, 122.8, 122.0, 52.4 ppm. HRMS
(ESI) calcd. for [M + Na]+ C20H14NO79BrNa 386.0151, found
386.0155 (1 ppm).
Late-stage ruthenium-catalyzed site-selective C-H
bond arylation of indoprofen (A): Indoprofen (A) was
synthesized according to a literature procedure.31 Esterifi-
cation step: Indoprofen (140.7 mg, 0.5 mmol, 1 equiv.) and
concentrated H2SO4 (1 drop) were stirred together in EtOH
(2 mL) under reflux in an oil bath during 12 hours with a
Dean-Stark condenser. Back at room temperature, solid
sodium bicarbonate was added and the reaction mixture
was filtered and concentrated under vacuum to afford the
carboxylic acid ethyl ester indoprofen intermediate (7a) in
quantitative yield and it was used without further purifi-
cation for the next step. Ethyl 2-(4-(1-oxoisoindolin-2-
2-(2-(Naphthalen-2-yl)phenyl)isoindolin-1-one (2x):
83.1 mg (83% yield), white solid, Mp: 204-206 oC. 1H NMR
(400 MHz, CDCl3): δ = 7.97-7.95 (m, 1H), 7.92 (s, 1H), 7.83-
7.77 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.60-7.57 (m, 1H),
7.56-7.44 (m, 8H), 7.19-7.17 (m, 1H), 4.17 (s, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3):
δ = 169.1, 141.6, 139.7, 136.8,
136.2, 133.5, 132.6, 132.1, 131.6, 131.4, 129.2, 128.8, 128.34, 128.31,
128.2, 128.1, 127.7, 127.4, 126.5, 126.3, 126.2, 124.2, 122.8, 52.3
ppm. HRMS (ESI) calcd. for [M + Na]+ C24H17NONa
358.1202, found 358.1206 (1 ppm).
yl)phenyl)propanoate (7a): 153.0 mg (99% yield), yellow
1
solid. H NMR (400 MHz, CDCl3):
δ = 7.84 (d, J = 7.6 Hz,
2-(2-(6-Methoxynaphthalen-2-yl)phenyl)isoindolin-1-
one (2y): 76.7 mg (70% yield), brown solid, Mp: 76-78 oC.
1H), 7.79-7.77 (m, 2H), 7.54-7.50 (m, 1H), 7.45-7.41 (m, 2H),
7.33-7.30 (m, 2H), 4.74 (s, 2H), 4.15-4.05 (m, 2H), 3.68 (q, J
= 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 174.4, 167.3, 140.1,
1H NMR (400 MHz, CDCl3):
δ = 7.96-7.94 (m, 1H), 7.82 (s,
1H), 7.69 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.58-
7.55 (m, 1H), 7.53-7.44 (m, 6H), 7.20-7.18 (m, 1H), 7.12 (dd,
J = 9.2, 2.8 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 4.16 (s, 2H), 3.89
138.4, 136.6, 133.0, 132.0, 128.3, 128.1, 123.9, 122.6, 119.4, 60.7,
50.6, 44.9, 18.5, 14.1 ppm ppm. The spectral data match
those previously reported.32 Ru-catalyzed C-H bond aryla-
tion: [RuCl2(p-cymene)]2 (15.3 mg, 0.025 mmol, 5 mol%),
AgSbF6 (34.4 mg, 0.1 mmol, 20 mol%), Ag2O (115.9 mg, 0.5
mmol, 1.0 equiv.), Cu(OTf)2 (36.2 mg, 0.1 mmol, 20 mol%),
indoprofen derivative 7a (153.0 mg, 0.5 mmol, 1.0 equiv.)
and phenylboronic acid (152.4 mg, 1.25 mmol, 2.5 equiv.)
were taken in a 15 mL Schlenk tube, which was equipped
with a magnetic stirrer bar. THF (2.5 mL) was added to the
Schlenk tube via a syringe, and the reaction mixture was
degassed with Argon three times. The reaction mixture
was allowed to stir at 110 °C for 20 h in an oil bath. After
being cooled to ambient temperature, the reaction mix-
ture was diluted with DCM and then filtered through
Celite. After evaporation of the solvent in vacuo, the crude
product was purified by column chromatography on silica
gel (n-heptane/EtOAc gradient 10:1 to 5:1) to give the ary-
lated product 7b. Ethyl 2-(6-(1-oxoisoindolin-2-yl)-[1,1'-
(s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 169.2,
158.1, 141.7, 139.8, 136.2, 134.6, 133.9, 132.2, 131.7, 131.4, 129.7,
129.2, 129.1, 128.6, 128.4, 128.1, 127.2, 127.1, 124.3, 122.8, 119.2,
105.7, 55.4, 52.3 ppm. HRMS (ESI) calcd. for [M + Na]+
C25H19NO2Na 388.1308, found 388.1310 (0 ppm).
2-(2-(Naphthalen-1-yl)phenyl)isoindolin-1-one (2z):
9.8 mg (10% yield), brown solid, Mp: < 50 oC. 1H NMR (400
MHz, CDCl3): δ = 7.83-7.75 (m, 4H), 7.62 (d, J = 8.0 Hz, 1H),
7.58-7.35 (m, 9H), 7.09 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 16.8
13
Hz, 1H), 3.87 (d, J = 16.8 Hz, 1H) ppm. C{1H} NMR (100
MHz, CDCl3): δ = 168.6, 141.5, 137.9, 137.4, 136.7, 133.7, 132.5,
132.1, 131.7, 131.5, 128.9, 128.34, 128.30, 128.0, 127.7, 127.3,
126.4, 126.1, 125.8, 125.6, 124.2, 122.6, 52.2 ppm. HRMS (ESI)
calcd. for [M + Na]+ C24H17NONa 358.1202, found 358.1202
(0 ppm).
1
3,3'-Dichloro-1,1'-biphenyl (3): Colorless oil. H NMR
biphenyl]-3-yl)propanoate (7b): 160.1 mg (85% yield),
(400 MHz, CDCl3):
δ
= 7.55 (s, 2H), 7.45-7.42 (m, 2H), 7.40-
1
colourless oil. H NMR (400 MHz, CDCl3):
δ = 7.92 (d, J =
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6.8 Hz, 1H), 7.52-7.39 (m, 7H), 7.32-7.23 (m, 4H), 4.23-4.10
(m, 4H), 3.81 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H), 1.27
(t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
Bhatia, R. K. Isoindole Derivatives: Propitious Anticancer
Structural Motifs. Curr. Top. Med. Chem. 2017, 17, 189-207.
δ
=
(3) Iqbal, A.; Herren, F.; Wallquist, O. in High Performance
Pigments, 2nd ed., (Eds.: E. B. Faulkner, R. J. Schwartz), Wiley-
VCH, Weinheim, 2009, pp. 243-259).
174.2, 169.0, 141.6, 140.6, 139.8, 138.9, 134.7, 132.0, 131.6, 130.2,
129.1, 128.6, 128.3, 128.0, 127.7, 127.6, 124.2, 122.6, 60.9, 52.2,
45.3, 18.7, 14.2 ppm. HRMS (ESI) calcd. for [M + Na]+
C25H23NO3Na 408.1570, found 408.1573 (1 ppm). Ester hy-
drolysis: 7b (106 mg, 0.27 mmol, 1 equiv.) and 2 M NaOH
(1 mL) were stirred in a mixture of MeOH (1 mL) and THF
(1 mL) at room temperature for 12 hours. Then, the reac-
tion mixture was basified to pH 14 and washed with ethyl
acetate three times. The aqueous layer was acidified to pH
1 with concentrated HCl and the product 7 precipitated
out. After washing with pentane and drying under vac-
uum, product 7 was isolated. 2-(6-(1-Oxoisoindolin-2-
yl)-[1,1'-biphenyl]-3-yl)propanoic acid (7): 86.8 mg
(4) Lunn, M. R.; Root, D. E.; Martino, A. M.; Flaherty, S. P.;
Kelley, B. P.; Coovert, D. D.; Burghes, A. H.; Man, Nguyen, T.
M.; Morris, G. E.; Zhou, J.; Androphy, E. J.; Sumner, C. J.;
Stockwell, B. R. Indoprofen Upregulates the Survival Motor
Neuron Protein through a Cyclooxygenase-Independent
Mechanism. Chem. Biol. 2004, 11, 1489-1493.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) (a) Miyachi, H.; Azuma, A.; Hioki, E.; Kobayashi, Y.; Iwa-
saki, S.; Hashimoto, Y. Inducer-specific regulators of tumor
necrosis factor alpha production. Chem. Pharm. Bull. 1996, 44,
1980-1982. (b) Park, J. S.; Moon, S. C.; Baik, K. U.; Cho, J. Y.;
Yoo, E. S.; Byun, Y. S.; Park, M. H. Synthesis and SAR studies
for the inhibition of TNF-α production. Part 2. 2-[3-(Cyclo-
pentyloxy)-4-methoxyphenyl]-substituted-1-isoindolinone
derivatives. Arch. Pharm. Res. 2002, 25, 137-142.
o
1
(90% yield), white solid, Mp: 208-210 C. H NMR (400
MHz, CDCl3): = 7.92 (d, J = 7.6 Hz, 1H), 7.52-7.41 (m, 5H),
δ
7.39-7.35 (m, 2H), 7.31-7.24 (m, 4H), 4.16 (s, 2H), 3.83 (q, J
= 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100
MHz, CDCl3):
δ = 179.2, 169.4, 141.7, 140.2, 140.0, 138.9,
(6) Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.;
Donati, D.; Petrone, M.; Terreni, S.; Wood, M. Isoindolone de-
rivatives, a new class of 5-HT2C antagonists: Synthesis and bi-
ological evaluation. Bioorg. Med. Chem. Lett. 2007, 17, 428-433.
134.9, 132.0, 131.8, 130.5, 129.3, 128.8, 128.5, 128.2, 128.0, 127.7,
124.4, 122.7, 52.4, 45.2, 18.4 ppm. HRMS (ESI) calcd. for [M
+ Na]+ C23H19NO3Na 380.1257, found 380.1263 (2 ppm).
ASSOCIATED CONTENT
Supporting Information.
(7) (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. Approaches to the synthesis of non-racemic 3-substituted
isoindolinone derivatives. J. Chem. Soc., Perkin Trans. 1 2000,
2000, 1715-1721. (b) Enders, D.; Braig, V.; Raabe, G. Asymmetric
synthesis of 3-aryl-substituted 2,3-dihydro-1H-isoindol-1-ones.
Can. J. Chem. 2001, 79, 1528-1535. (c) Hunter, R.; Richards, P.
Stereoselective tetrapyrido[2,1-a]isoindolone synthesis via
carbanionic and radical intermediates: a model study for the
Tacaman alkaloid D/E ring fusion. Org. Biomol. Chem. 2003,
1, 2348-2356. (d) Csende, F.; Stajer, G. Approaches to the for-
mation of condensed isoindolones. Curr. Org. Chem. 2005, 9,
1261-1276. (e) Stajer, G.; Csende, F. Advanced methods for the
synthesis of 3-substituted 1H-isoindol-1-ones. Curr. Org.
Chem. 2005, 9, 1277-1286. (f) Yuan, Y.-C.; Bruneau, C.;
Gramage-Doria, R. Merging Transition-Metal Catalysis with
Phthalimides: A New Entry to Useful Building Blocks. Synthe-
sis 2018, 50, 4216-4228. (g) Thapa, P.; Corral, E.; Sardar, S.;
Pierce, B. S.; Foss Jr., F. W. Isoindolinone Synthesis: Selective
Dioxane-Mediated Aerobic Oxidation of Isoindolines. J. Org.
Chem. 2019, 84, 1025-1034.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxx.
1H NMR spectra for known compounds, and H and 13C{1H}
1
NMR spectra for all new compounds, and X-ray crystallog-
raphy data (PDF)
X-ray crystallography of 2c (CIF)
X-ray crystallography of 2d (CIF)
X-ray crystallography of 2g (CIF)
X-ray crystallography of 2m (CIF)
X-ray crystallography of 2n (CIF)
X-ray crystallography of 2o (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: rafael.gramage-doria@univ-rennes1.fr
ORCID
Christian Bruneau: 0000-0002-2220-1458
Thierry Roisnel: 0000-0002-6088-4472
Rafael Gramage-Doria: 0000-0002-0961-4530
Notes
(8) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Co-
ordination as a Powerful Means for Developing Broadly Use-
ful C-H Functionalization Reactions. Acc. Chem. Res. 2012, 45,
788-802. (b) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Acker-
mann, L. Weakly Coordinating Directing Groups for Ruthe-
nium(II)-Catalyzed C-H Activation. Adv. Synth. Catal. 2014,
356, 1461-1479. (c) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.;
You, J. Rhodium-catalyzed annulation of arenes with alkynes
through weak chelation-assisted C-H activation. Chem. Com-
mun. 2016, 52, 2872-2884. (d) Sambiagio, C.; Schoenbauer, D.;
Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger,
T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.;
Schnuerch, M. A comprehensive overview of directing groups
applied in metal-catalyzed C-H functionalization chemistry.
Chem. Soc. Rev. 2018, 47, 6603-6743. (e) Banerjee, A.; Santra,
The authors declare no competing financial interest.
ACKNOWLEDGMENT
CNRS, Université de Rennes 1, Rennes Metropole, China
Scholarship Council (PhD grant to Y.-C.Y.), Agence Nationale
de la Recherche (ANR-JCJC) and COST Action CA15106
(CHAOS) are acknowledged.
REFERENCES
(1) Donohoe, T. J. Product class 14: 1H- and 2H-isoindoles. Sci.
Synth. 2001, 10, 653-692.
(2) (a) Speck, K.; Magauer, T. The chemistry of isoindole nat-
ural products. Beilstein J. Org. Chem. 2013, 9, 2048-2078. (b)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
2
3
4
5
6
7
8
S. K.; Mohanta, P. R.; Patel, B. K. Ruthenium(II) Catalyzed Re-
C-H Bond Cleavage/Alkyne Insertion under Ruthenium Ca-
giospecific C−H/O−H Annulations of Directing Arenes via
Weak Coordination. Org. Lett. 2015, 17, 5678-5681. (f) Modi,
A.; Sau, P.; Chakraborty, N.; Patel, B. K. A “Thiocarbonyl-Di-
rected” Regiospecific C-H/S-H Annulation of Quinoline-
4(1H)-thiones with Alkynes. Adv. Synth. Catal. 2019, 361, 1368-
1375.
talysis. J. Org. Chem. 2013, 78, 638-646.
(12) Collins, K. D.; Lied, F.; Glorius, F. Preparation of conju-
gated 1,3-enynes by Rh(III)-catalysed alkynylation of alkenes
via C-H activation. Chem. Commun. 2014, 50, 4459-4461.
(13) Liu, W.; Ackermann, L. Versatile ruthenium(II)-catalyzed
C-H cyanations of benzamides. Chem. Commun. 2014, 50,
1878-1881.
9
(9) (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond
Functionalization: Emerging Synthetic Tools for Natural
Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51,
8960-9009. (b) Brueckl, T.; Baxter, R. D.; Ishihara, Y.; Baran,
P. S. Innate and Guided C-H Functionalization Logic. Acc.
Chem. Res. 2012, 45, 826-839. (c) Hartwig, J. F. Evolution of C-
H Bond Functionalization from Methane to Methodology. J.
Am. Chem. Soc. 2016, 138, 2-24. (d) Abrams, D. J.; Provencher,
P. A.; Sorensen, E. J. Recent applications of C-H functionali-
zation in complex natural product synthesis. Chem. Soc. Rev.
2018, 47, 8925-8967.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Examples of site-selective C-O bond forming reactions via
aromatic C-H bond functionalizations are also rare, see: (a)
Sun, Y.-H.; Sun, T.-Y.; Wu, Y.-D.; Zhang, X.; Rao, Y. A diver-
sity-oriented synthesis of bioactive benzanilides via a regiose-
lective C(sp2)-H hydroxylation strategy. Chem. Sci. 2016, 7,
2229-2238. (b)Yuan, Y.-C.; Bruneau, C.; Roisnel, T.; Gramage-
Doria, R. Ru-Catalyzed Selective C-H Bond Hydroxylation of
Cyclic Imides. J. Org. Chem. 2019, 84, 1898-1907.
(15) (a) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V.
Ruthenium-Catalyzed Oxidative C-H Alkenylations of Ani-
lides and Benzamides in Water. Org. Lett. 2012, 14, 728-731.
(b) Padala, K.; Jeganmohan, M. ortho-Benzoxylation of N-Al-
kyl Benzamides with Aromatic Acids Catalyzed by Ruthe-
nium(II) Complex. Chem. Eur. J. 2014, 20, 4092-4097. (c)
Manikandan, R.; Madasamy, P.; Jeganmohan, M. Ruthenium-
Catalyzed ortho Alkenylation of Aromatics with Alkenes at
Room Temperature with Hydrogen Evolution. ACS Catal.
2016, 6, 230-234. (d) Das, R.; Kumar, G. S.; Kapur, M. Amides
as Weak Coordinating Groups in Proximal C-H Bond Activa-
tion. Eur. J. Org. Chem. 2017, 2017, 5439-5459. (e) Ping, L.;
Chung, D. S.; Bouffard, J.; Lee, S.-G. Transition metal-cata-
lyzed site- and regio-divergent C-H bond functionalization.
Chem. Soc. Rev. 2017, 46, 4299-4328.
(10) (a) Miura, M.; Satoh, T. Arylation reactions via C-H bond
cleavage. Top. Organomet. Chem. 2005, 14, 55-83. (b) Jia, C.;
Kitamura, T.; Fujiwara, Y. Catalytic Functionalization of
Arenes and Alkanes via C-H Bond Activation. Acc. Chem. Res.
2001, 34, 633-639. (c) Bouffard, J.; Itami, K. Rhodium-cata-
lyzed C-H bond arylation of arenes. Top. Curr. Chem. 2010,
292, 231-280. (d) Ping, Y.; Wang, L.; Ding, Q.; Peng, Y. Nitrile
as a Versatile Directing Group for C(sp2)-H Functionaliza-
tions. Adv. Synth. Catal. 2017, 359, 3274-3291. (e) Theveau, L.;
Schneider, C.; Fruit, C.; Hoarau, C. Orthogonal Palladium-
Catalyzed Direct C-H Bond Arylation of Heteroaromatics
with Aryl Halides. ChemCatChem 2016, 8, 3183-3194. (f) Li, B.;
Dixneuf, P. H. Ruthenium(II)-Catalysed sp2 C-H Bond Func-
tionalization by C-C Bond Formation. Top. Organomet. Chem.
2015, 48, 119-193. (g) Bheeter, C. B.; Chen, L.; Soule, J.-F.;
Doucet, H. Regioselectivity in palladium-catalysed direct ary-
lation of 5-membered ring heteroaromatics. Catal. Sci. Tech-
nol. 2016, 6, 2005-2049. (h) Sharma, U.; Modak, A.; Maity, S.;
Maji, A.; Maiti, D. Direct Arylation via C-H Activation in New
Trends in Cross-Coupling: Theory and Applications (Eds.: T.
Colacot), RSC, Cambridge, 2014, pp. 551-609. (i) Hussain, I.;
Singh, T. Synthesis of biaryls through aromatic C-H bond ac-
tivation. A review of recent developments. Adv. Synth. Catal.
2014, 356, 1661-1696. (j) Rossi, R.; Bellina, F.; Lessi, M.; Manzini,
C. Cross-Coupling of Heteroarenes by C-H Functionalization:
Recent Progress towards Direct Arylation and Heteroaryla-
tion Reactions Involving Heteroarenes Containing One Het-
eroatom. Adv. Synth. Catal. 2014, 356, 17-117. (k) Zhou, L.; Lu,
W. Towards ideal synthesis. Alkenylation of aryl C-H bonds
by a Fujiwara-Moritani reaction. Chem. Eur. J. 2014, 20, 634-
642. (l) Baudoin, O. Transition metal-catalyzed arylation of
unactivated C(sp3)-H bonds. Chem. Soc. Rev. 2011, 40, 4902-
4911. (m) Saget, T.; Cramer, N. Enantioselective C-H Arylation
Strategy for Functionalized Dibenzazepinones with Quater-
nary Stereocenters. Angew. Chem. Int. Ed. 2013, 52, 7865-7868.
(n) Li, S.; Ji, H.; Cai, L.; Li, G. Pd(II)-catalyzed remote re-
giodivergent ortho- and meta-C–H functionalizations of phe-
nylethylamines. Chem. Sci. 2015, 6, 5595-5600.
(16) (a) Nareddy, P.; Jordan, F.; Brenner-Moyer, S. E.; Szostak,
M. Ruthenium(II)-Catalyzed Regioselective C-H Arylation of
Cyclic and N,N-Dialkyl Benzamides with Boronic Acids by
Weak Coordination. ACS Catal. 2016, 6, 4755-4759. (b) Hash-
imoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.; Miura,
M. Ru/Ag-catalyzed oxidative alkenylation of benzamides
and phenylazoles through regioselective C-H bond cleavage.
Chem. Lett. 2012, 41, 151-153. (c) Das, R.; Kapur, M. Product
Control using Substrate Design: Ruthenium-Catalysed Oxida-
tive C-H Olefinations of Cyclic Weinreb Amides. Chem. Eur.
J. 2016, 22, 16986-16990. (d) Das, R.; Kapur, M. Fujiwara-Mori-
tani Reaction of Weinreb Amides using a Ruthenium-Cata-
lyzed C-H Functionalization Reaction. Chem. Asian J. 2015, 10,
1505-1512. (e) Yang, Z.; Qiu, F.-C.; Gao, J.; Li, Z.-W.; Guan, B.-
T. Palladium-Catalyzed Oxidative Arylation of Tertiary Ben-
zamides: Para-Selectivity of Monosubstituted Arenes. Org.
Lett. 2015, 17, 4316-4319. (f) Nareddy, P.; Jordan, F.; Szostak, M.
Highly chemoselective ruthenium(II)-catalyzed direct aryla-
tion of cyclic and N,N-dialkyl benzamides with aryl silanes.
Chem. Sci. 2017, 8, 3204-3210. (g) Huang, Z.; Lim, H. N.; Mo,
F.; Young, M. C.; Dong, G. Transition metal-catalyzed ketone-
directed or mediated C-H functionalization. Chem. Soc. Rev.
2015, 44, 7764-7786.
(17) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. A
Ruthenium-Catalyzed Reaction of Aromatic Ketones with
Arylboronates: A New Method for the Arylation of Aromatic
Compounds via C-H Bond Cleavage. J. Am. Chem. Soc. 2003,
125, 1698-1699. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani,
(11) (a) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.;
Miura, M. Ruthenium(II)-Catalyzed Regio- and Stereoselec-
tive Hydroarylation of Alkynes via Directed C-H Functionali-
zation. Org. Lett. 2012, 14, 2058-2061. (b) Hashimoto, Y.;
Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M. Regioselective
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
N. A RuH2(CO)(PPh3)3-Catalyzed Regioselective Arylation of
(21) (a) Ackermann, L. Carboxylate-Assisted Transition-
Metal-Catalyzed C-H Bond Functionalizations: Mechanism
and Scope. Chem. Rev. 2011, 111, 1315-1345. (b) Ackermann, L.
Carboxylate-Assisted Ruthenium-Catalyzed Alkyne Annula-
tions by C-H/Het-H Bond Functionalizations. Acc. Chem. Res.
2014, 47, 281-295. (c) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Mechanistic Insight into Direct Arylations
with Ruthenium(II) Carboxylate Catalysts. Org. Lett. 2010, 12,
5032-5035. (d) Fabre, I.; von Wolff, N.; Le Duc, G.; Ferrer
Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. Autocata-
lytic intermolecular versus intramolecular deprotonation in
C-H bond activation of functionalized arenes by ruthe-
nium(II) or palladium(II) complexes. Chem. Eur. J. 2013, 19,
7595-7604. (e) Ackermann, L.; Vicente, R.; Althammer, A. As-
sisted Ruthenium-Catalyzed C-H Bond Activation: Carboxylic
Acids as Cocatalysts for Generally Applicable Direct Aryla-
tions in Apolar Solvents. Org. Lett. 2008, 10, 2299-2302. (f)
Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. Au-
tocatalysis for C-H Bond Activation by Ruthenium(II) Com-
plexes in Catalytic Arylation of Functional Arenes. J. Am.
Chem. Soc. 2011, 133, 10161-10170. (g) Arockiam, P. B.; Bruneau,
C.; Dixneuf, P. H. Ruthenium(II)-Catalyzed C-H Bond Activa-
tion and Functionalization. Chem. Rev. 2012, 112, 5879-5918.
(h) Shan, C.; Zhu, L.; Qu, L.-B.; Bai, R.; Lan, Y. Mechanistic
view of Ru-catalyzed C-H bond activation and functionaliza-
tion: computational advances. Chem. Soc. Rev. 2018, 47, 7552-
7576.
Aromatic Ketones with Arylboronates via Carbon-Hydrogen
Bond Cleavage. J. Am. Chem. Soc. 2005, 127, 5936-5945. (c) Pu-
cheault, M.; Darses, S.; Genet, J.-P. Direct access to ketones
from aldehydes via rhodium-catalyzed cross-coupling reac-
tion with potassium trifluoro(organo)borates. J. Am. Chem.
Soc. 2004, 126, 15356-15357. (d) Park, Y. J.; Jo, E.-A.; Jun, C.-H.
Ruthenium-catalyzed coupling of aldimines with arylboro-
nates: new synthetic method for aromatic ketones. Chem.
Commun. 2005, 2005, 1185-1187. (e) Pastine, S. J.; Gribkov, D.
V.; Sames, D. sp3 C-H Bond Arylation Directed by Amidine
Protecting Group: α-Arylation of Pyrrolidines and Piperidines.
J. Am. Chem. Soc. 2006, 128, 14220-14221. (f) Nakazono, S.; Eas-
waramoorthi, S.; Kim, D.; Shinokubo, H.; Osuka, A. Synthesis
of arylated perylene bisimides through C-H bond cleavage un-
der ruthenium catalysis. Org. Lett. 2009, 11, 5426-5429. (g) Li,
H.; Wei, W.; Xu, Y.; Zhang, C.; Wan, X. Ru-catalyzed aerobic
oxidative coupling of arylboronic acids with arenes. Chem.
Commun. 2011, 47, 1497-1499. (h) Chinnagolla, R. K.; Jegan-
mohan, M. Regioselective Ortho-Arylation and Alkenylation
of N-Alkyl Benzamides with Boronic Acids via Ruthenium-
Catalyzed C-H Bond Activation: An Easy Route to Fluo-
renones Synthesis. Org. Lett. 2012, 14, 5246-5249. (i) Chinna-
golla, R. K.; Jeganmohan, M. Ruthenium-catalyzed ortho-ary-
lation of acetanilides with aromatic boronic acids. An easy
route to prepare phenanthridines and carbazoles. Chem.
Commun. 2014, 50, 2442-2444. (j) Zhao, Y.; Snieckus, V. C-H
Activation by Amide Chelation Control: Ruthenium-Cataly-
zed Direct Synthesis of 2-Aryl-3-furanamides. Adv. Synth. Ca-
tal. 2014, 356, 1527-1532. (k) Hubrich, J.; Himmler, T.; Rodefeld,
L.; Ackermann, L. Ruthenium(II)-catalyzed C-H arylation of
anilides with boronic acids, borinic acids and potassium tri-
fluoroborates. Adv. Synth. Catal. 2015, 357, 474-480. (l) Sollert,
C.; Devaraj, K.; Orthaber, A.; Gates, P. J.; Pilarski, L. T. Ru-
Catalysed C-H Arylation of Indoles and Pyrroles with Boronic
Acids: Scope and Mechanistic Studies. Chem. Eur. J. 2015, 21,
5380-5386. (m) Hu, F.; Szostak, M. Ruthenium(0)-Catalyzed
C-H Arylation of Aromatic Imines under Neutral Conditions:
Access to Biaryl Aldehydes. Org. Lett. 2016, 18, 4186-4189. (n)
Siopa, F.; Cladera, V.-A. R.; Alfonso, C. A. M.; Oble, J.; Poli, G.
Ruthenium-Catalyzed C-H Arylation and Alkenylation of Fur-
fural Imines with Boronates. Eur. J. Org. Chem. 2018, 2018,
6101-6106 and references cited therein.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) (a) Molander, G. A.; Ellis, N. Organotrifluoroborates:
Protected Boronic Acids That Expand the Versatility of the
Suzuki Coupling Reaction. Acc. Chem. Res. 2007, 40, 275-286.
(b) Darses, S.; Genet, J.-P. Potassium Organotrifluoroborates:
New Perspectives in Organic Synthesis. Chem. Rev. 2008, 108,
288-325.
(23) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.;
Inoue, Y. Ruthenium complex-catalyzed direct ortho aryla-
tion and alkenylation of 2-arylpyridines with organic halides.
Org. Lett. 2001, 3, 2579-2581. (b) Oi, S.; Ogino, Y.; Fukita, S.;
Inoue, Y. Ruthenium Complex Catalyzed Direct Ortho Aryla-
tion and Alkenylation of Aromatic Imines with Organic Ha-
lides. Org. Lett. 2002, 4, 1783-1785. (c) Oi, S.; Aizawa, E.; Ogino,
Y.; Inoue, Y. Ortho-selective direct cross-coupling reaction of
2-aryloxazolines and 2-arylimidazolines with aryl and alkenyl
halides catalyzed by ruthenium complexes. J. Org. Chem.
2005, 70, 3113-3119. (d) Oi, S.; Sakai, K.; Inoue, Y. Ruthenium-
Catalyzed Arylation of 2-Alkenylpyridines with Aryl Bro-
mides: Alternative E,Z-Selectivity to Mizoroki-Heck Reaction.
Org. Lett. 2005, 7, 4009-4011. (e) Ackermann, L.; Born, R.; Al-
varez-Bercedo, P. Ruthenium(IV) alkylidenes as precatalysts
for direct arylations of alkenes with aryl chlorides and an ap-
plication to sequential catalysis. Angew. Chem. Int. Ed. 2007,
46, 6364-6367. (f) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gour-
laouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. Direct Ary-
lation of Arene C-H Bonds by Cooperative Action of NHCar-
bene-Ruthenium(II) Catalyst and Carbonate via Proton Abs-
traction Mechanism. J. Am. Chem. Soc. 2008, 130, 1156-1157. (g)
Pozgan, F.; Dixneuf, P. H. Ruthenium(II) acetate catalyst for
direct functionalisation of sp2-C-H bonds with aryl chlorides
and access to tris-heterocyclic molecules. Adv. Synth. Catal.
2009, 351, 1737-1743. (h) Prades, A.; Poyatos, M.; Peris, E. (η6-
Arene)ruthenium(N-heterocyclic carbene) Complexes for the
(18) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord,
J. Mild metal-catalyzed C-H activation: examples and con-
cepts. Chem. Soc. Rev. 2016, 45, 2900-2936.
(19) Manikandan, R.; Jeganmohan, M. Recent advances in the
ruthenium(II)-catalyzed chelation-assisted C-H olefination of
substituted aromatics, alkenes and heteroaromatics with al-
kenes via the deprotonation pathway. Chem. Commun. 2017,
53, 8931-8947.
(20) For the only previous synthesis of 2a reported to date,
see: (a) Ahmed, M.; Vernon, J. M. Ring-chain tautomerism of
o-benzoylbenzanilides. J. Chem. Soc. Perkin Trans. 1, 1975, 1975,
2048-2051. (b) Heemskerk, J.; Barnes, K. D.; McCall, J. M.;
Johnson, G.; Fairfax, D.; Johnson, M. R. Preparation of oxoiso-
indolinylphenylpropanoates and its analogs for the treatment
of spinal muscular atrophy and other uses. PCT Int. Appl. 2007,
WO2007 109211 A2 20070927.
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2
Chelation-Assisted Arylation and Deuteration of Arylpyri-
dines: Catalytic Studies and Mechanistic Insights. Adv. Synth.
Catal. 2010, 352, 1155-1162. (i) Bruneau, C.; Gramage-Doria, R.
One-Pot Directing Group Formation/C-H Bond Functionali-
zation via Copper(I) and Ruthenium(II) Catalysis. Adv. Synth.
Catal. 2016, 358, 3847-3856. (j) Nareddy, P.; Jordan, F.; Szostak,
M. Recent Developments in Ruthenium-Catalyzed C-H Ary-
lation: Array of Mechanistic Manifolds. ACS Catal. 2017, 7,
5721-5745. (k) Gramage-Doria, R.; Achelle, S.; Bruneau, C.; Ro-
bin-le Guen, F.; Dorcet, V.; Roisnel, T. Ruthenium(II)-
Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n
= 2, 3, and 4): Scope, Mechanism, and Application in Tandem
Hydrogenations. J. Org. Chem. 2018, 83, 1462-1477. (l) Gra-
mage-Doria, R.; Roisnel, T. Ruthenium-Catalyzed C-H Bond
Heteroarylation of Triazoles Enabled by a Deconvolution
Strategy. Eur. J. Org. Chem. 2018, 2018, 6083-6087 and refe-
rences cited therein.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) Yuan, Y.-C.; Kamaraj, R.; Bruneau, C.; Labasque, T.; Rois-
nel, T.; Gramage-Doria, R. Unmasking Amides: Ruthenium-
Catalyzed Protodecarbonylation of N-Substituted Phthali-
mide Derivatives. Org. Lett. 2017, 19, 6404-6407.
(25) Zhou, Y.; Chen, P.; Lv, X.; Niu, J.; Wang, Y.; Lei, M.; Hu,
L. A facile and efficient method for the synthesis of N-substi-
tuted isoindolin-1-one derivatives under Pd(OAc)2/HCOOH
system. Tetrahedron Lett. 2017, 58, 2232-2235.
(26) Kim, E.; Jeong, M.; Lee, B. M.; Kim, B. H. One-Pot Synthe-
sis of Isoindolin-1-ones from Nitroarenes and o-Phtha-
laldehyde via Indium-Mediated Reductive Condensation
Reactions. Heterocycles 2018, 96, 1759-1770.
(27) Lin, C.; Zhen, L.; Cheng, Y.; Du, H.-J.; Zhao, H.; Wen, X.;
Kong, L.-Y.; Xu, Q.-L.; Sun, H. Visible Light-Induced Isoindole
Formation To Trigger Intermolecular Diels-Alder Reactions
in the Presence of Air. Org. Lett. 2015, 17, 2684-2687.
(28) Hsieh, J.-C.; Cheng, C.-H. Nickel-catalyzed coupling of
isocyanates with 1,3-iodo esters and halobenzenes: a novel
method for the synthesis of imide and amide derivatives.
Chem. Commun. 2005, 36, 4554-4556.
(29) Kaminski, K.; Wiklik, B.; Obniska, J. Synthesis, Anticon-
vulsant Properties, and SAR Analysis of Differently Substi-
tuted Pyrrolidine-2,5-diones and Piperidine-2,6-diones. Arch.
Pharm. Chem. Life Sci. 2014, 347, 840-852.
(30) Vogler, T.; Studer, A. Rhodium-catalyzed oxidative ho-
mocoupling of boronic acids. Adv. Synth. Catal. 2008, 350,
1963-1967.
(31) Verma, A.; Patel, S.; Meenakshi; Kumar, A.; Yadav, A.; Ku-
mar, S.; Jana, S.; Sharma, S.; Prasad, C. D.; Kumar, S. Transi-
tion metal free intramolecular selective oxidative C(sp3)-N
coupling: synthesis of N-aryl-isoindolinones from 2-alkylben-
zamides. Chem. Commun. 2015, 51, 1371-1374.
(32) T. Thatikonda, S. K. Deepake, U. Das, α-Angelica Lactone
in a New Role: Facile Access to N-Aryl Tetrahydroisoquinoli-
nones and Isoindolinones via Organocatalytic α-CH2 Oxyge-
nation. Org. Lett. 2019, 21, 2532-2535.
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