Pd-Catalyzed Dearomatization of Indole Derivatives via Intermolecular Heck Reactions?

Article abstract of DOI:10.1002/cjoc.201900509

Pd-catalyzed intermolecular dearomative Heck reaction of indoles with aryl iodides is described. The challenges on both reactivity and regioselectivity are addressed by the judicious regulation of the geometric and electronic properties of the substrates. An array of indoline derivatives bearing C2-quaternary center is obtained in good to excellent yields (up to 93%) with exclusive regioselectivity under operationally simple conditions. The mechanistic proposal is supported by detailed DFT calculations.

Full text of DOI:10.1002/cjoc.201900509

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Pd-Catalyzed Dearomatization of Indole Derivatives via Intermolecular Heck
Reactions
Authors: Ping Yang, Ren-Qi Xu, Chao Zheng,* and Shu-Li You*
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Pd-Catalyzed Dearomatization of Indole Derivatives via Intermolecular
Heck Reactions
Ping Yang,+,a Ren-Qi Xu,+,a Chao Zheng,* and Shu-Li You*
,a
,a
a
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
+
These authors contributed equally.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Pd-catalyzed intermolecular dearomative Heck reaction of indoles with aryl iodides is described. The chal-
lenges on both reactivity and regioselectivity are addressed by the judicious regulation of the geometric and electronic properties of the substrates. An
array of indoline derivatives bearing C2-quaternary center is obtained in good to excellent yields (up to 93%) with exclusive regioselectivity under opera-
tionally simple conditions. The mechanistic proposal is supported by detailed DFT calculations.
Background and Originality Content
for this purpose (Scheme 1(b)). The desired isomerization of the
olefinic bond in the 5,5-bicyclic ring system might somewhat re-
lease the ring strain, which could probably compensate to some
extent the energetic uphill required for the dearomatization pro-
cess, and thus facilitate the proposed intermolecular Heck reac-
tion. In addition, an appropriate electron-withdrawing
N-protecting group might regulate the distribution of the electron
density of the indole ring, and direct the regioselectivity of the
Heck reaction. Recently, we successfully executed this design plan
and realized the first Pd-catalyzed intermolecular dearomative
Heck reaction of indoles with aryl iodides. Herein, we report the
results from this study.
Indolines serve as vital structural cores of numerous natural
products and pharmaceutically-relevant molecules. Their efficient
and convenient syntheses have attracted considerable attention
1
of the synthetic chemistry community. In this regard, dearomati-
zation of indole derivatives has been widely recognized as a
straightforward approach to access diverse indolines. Over the
2,3
4
,5
past decades, transition-metal-catalyzed Heck reactions have
6
been applied in the dearomatization of indoles, as exemplified by
7
8
the elegant contributions from the groups of Yao and Wu, Jia,
9
10
11
12
Lautens, Jing and Liang, Zhou, and Wu (Scheme 1(a)). Nota-
bly, Kitamura and Fukuyama completed the total synthesis of
Scheme 1 Pd-Catalyzed dearomatization of indole derivatives via Heck reac-
tion.
(
+)-hinckdentine A with the dearomative Heck reaction as a key
13
step. In all the known examples, an indole-tethered aryl halides
first underwent oxidative addition to a Pd- or Ni-catalyst. Subse-
quently, the regioselective insertion of the corresponding aryl–Pd
or aryl–Ni species into the C2=C3 double bond of the indole ring
afforded the C3–Pd or C3–Ni intermediate which subsequently
underwent β-hydride elimination or received external nucleophilic
attack. However, the intramolecular reaction design was crucial to
guarantee both the reactivity and the regioselectivity via the
structurally well-organized precursors of the dearomatization step.
Although intriguing polycyclic scaffolds could be readily assem-
bled in this way, yet additional synthetic elaborations were gener-
ally required. To be noted, the intermolecular C2-arylative
dearomatization of indoles have been realized via the cross
(a) Previous works: intramolecular Heck reaction
R1
Nu
R1 Nu
R1
[TM]
R2
[TM]
R2
R2
Ar
N
X
N
regioselective
insertion
N
Ar
nucleophilic
attack
Ar
O
O
O
or
H
[
TM]
R2
R2
N
β-hydride
elimination
Ar
N
O
Ar
O
(
b) This
work: intermolecular Heck reaction
14
coupling reactions under oxidative conditions.
H
Apparently, formidable challenges would be encountered for
the corresponding intermolecular dearomative Heck reactions.
The key issues to be addressed include (i) how to enhance the
reactivity of the indole ring toward the intermolecular Heck reac-
tion, and (ii) how to control the regioselectivity of the insertion
across the C2=C3 double bond. We envisioned that tetrahydro-
cyclopenta[b]indole derivatives might serve as suitable candidates
5
I
5
[Pd]
[Pd]
Ar
+
N
Ar
N
N
EWG
Ar
EWG
EWG
Challenges
Strategies
1
5
Reactivity
Regioselectivity
Releasing
Regulating electron density distribution
of indole ring
of
ring-strain 5,5-bycyclic
rings
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First author et al.
Reaction Development
We began our investigation by testing the model reactions of
N-acyl tetrahydrocyclopenta[b]indole 1a and iodobenzene 2a (1.5
4
5
6
7
8
9
rac-BINAP
AgOAc
AgOAc
DMF
DMF
46
35
49
79
81
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
42
17
AgSbF
AgBF
AgOTf
AgNTf
Ag CO
6
DMF
equiv) (Table 1). With Pd(OAc)
precursor, AgOAc (1.0 equiv) as an additive and Na
2.0 equiv) as a base, the effects of different ligands were initially
examined in DMF at 80 °C. When monophosphine ligands (Q-Phos,
PPh , XPhos) were utilized, the desired product 3aa (confirmed by
2
(10 mol%) as a palladium
4
DMF
15
2
HPO •12H
4
2
O
(
DMF
11
82
85 (82c)
2
DMF
trace
92
3
1
0
2
3
2
2
2
2
2
2
DMF
7
91
X-ray crystallographic analysis) was obtained in moderate NMR
yields (45-48%), while 1a could be recovered with good mass
balance (entries 1-3). However, the reaction with rac-BINAP
provided 3aa in a lower NMR yield (35%) (entry 4). Notably, when
the reaction proceeded without phosphine ligand, product 3aa
could still be afforded in 49% NMR yield (entry 5), comparable
with that obtained with monophosphine ligands. Subsequently,
the effect of additives was tested in the absence of phosphine
ligand (entries 6-10). It was revealed that the reaction tolerated
11
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
DMA
MeOH
tBuOH
toluene
DMA
DMA
DMA
DMA
DMA
DMA
DMA
trace
11
1
1
2
3
79
47
51
14
73
17
1
5d
6e
94
trace
17
1
82
various Ag salts (AgSbF
AgNTf was identified as the optimal one, which afforded 3aa in
5% NMR yield and 82% isolated yield (entry 9). Interestingly, the
desired reaction was prohibited significantly when Ag CO was
6
, AgBF
4
, AgOTf or AgNTf
2
) as an additive.
17
f
AgNTf2
92
trace
2
8g
9h
1
1
AgNTf
AgNTf
--
2
53
--
8
trace
77
97 (91c)
18
2
2
3
employed (92% of 1a recovered, entry 10). Screening of solvents
showed a clear connection between the reaction outcomes and
the polarity of the solvent. When non-polar solvent like toluene
was employed, the reaction was quite sluggish, and only 17%
NMR yield of 3aa was observed. Alcoholic solvents including
MeOH and tBuOH provided 3aa in moderate NMR yields (51-79%).
To our delight, when DMA was applied, the NMR yield of 3aa was
further improved to 91% (entry 11). Surprisingly, the judicious
choice of a base was quite critical to this reaction. Among tested,
0i
2
2
1h,j
AgNTf
2
quant.
--
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd(OAc)
ligand (0.02 mmol), Na
solvent (1.0 mL) at 80 °C. Yield determined by H NMR using CH
mmol) as an internal standard. Isolated yield.
as the base. K
h. Without Ag salts. Without Pd(OAc)
2
(0.02 mmol),
2
4
HPO •12H
2
O (0.4 mmol), Ag salt (0.2 mmol) in
b
1
2
Br (0.2
2
c
d
e
K
2
CO
3
as the base. Et N
3
f
g
h
3
PO
4
as the base. tBuOK as the base. AgNTf
2
(0.24 mmol),
i
j
5
2
.
Na
2
HPO
4
•12H
2
O was the optimal one. Other commonly used
CO , Et N, K PO , and tBuOK were ineffective
entries 15-18). Finally, the optimal results (3aa, 97% NMR yield,
With the optimal conditions in hand, various indoles were
bases including K
2
3
3
3
4
allowed to react with iodobenzene to examine the generality of
this reaction (Scheme 2(a)). Firstly, the effects of the protecting
group on the nitrogen atom of indoles were investigated.
(
9
1% isolated yield) were obtained when the loading of AgNTf
2
was increased to 1.2 equiv (entry 19). Of particular note, the
desired reaction was hampered without Ag salt (entry 20), and
Electron-withdrawing groups like Boc (3ab, 92% yield), CO
2
Me
(
3ac, 87% yield), and Bz (3ad, 63% yield) were well tolerated,
2
could not proceed without Pd(OAc) (entry 21).
while electron-donating ones (Me and Bn) were not (not shown).
Notably, a large array of electronically and sterically varied
substituents including alkyl (Me and tBu), alkoxyl (MeO), halogen
Table 1 Optimization of the reaction conditions.a
Pd(OAc)2
(
10 mol%)
(F, Cl and Br), ketone (Ac), and ester (CO Me) were
2
ligand (10 mol%)
+
PhI
accommodated at the 4- to 7-positions of the indole ring. The
corresponding products (3ae-3ap) were generally obtained in
moderate to high yields (49-84%). In addition, benzo-fused indole
substrates also underwent the dearomatization reactions
smoothly, leading to desired products 3aq and 3ar in 88% and 61%
yields, respectively. The structure of 3aq was also confirmed by
X-ray crystallographic analysis. The reaction of 1a and 2a could
proceed with the loading of the Pd-catalyst lowered to 5 mol%,
affording 3aa in a gram scale (1.20 g).
N
Na HPO •12H O
N
2
4
2
Ph
Ac
Ag salt, solvent
Ac
8
0 °C, 8 h
1
a
2a
3aa
t
P Bu2
PCy2
iPr
Fe
iPr
PPh2
PPh2
Ph
Ph
Ph
Ph
Ph
iPr
XPhos
Q-Phos
rac-BINAP
Next, the scope of aryl iodides was considered (Scheme 2(b)).
Aryl iodides bearing substituents at the para- or meta-positions
could participate the desired dearomatization reactions (3ba-3na,
entry
ligand
Ag salt
solvent
DMF
1a (%)b
3aa (%)b
45
4
1-93% yields). Particularly, the reaction efficiency was
1
2
3
Q-Phos
AgOAc
AgOAc
AgOAc
45
42
38
significantly influenced by the electronic property of
para-substituted aryl iodides. Electron-rich benzene rings (p-OMe,
p-tBu, etc.) could be installed with excellent yields, while the
PPh
3
DMF
48
XPhos
DMF
48
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Running title
Chin. J. Chem.
2 3
reactions with electron-poor aryl iodides (p-NO , p-CF , etc.) were
rather sluggish. This phenomenon provided useful clues for
further mechanistic studies (vide infra). Probably due to the
unfavorable steric congestion in the key transition state,
ortho-substituted aryl iodides were relatively less reactive, leading
to the corresponding products 3oa (o-Me) and 3pa (o-OMe) in
moderate yields (51-53%). In addition, 2-iodothiophene was also a
viable reaction partner. Desired product 3qa could be delivered in
6
1% yield. Indeed, the 5,5-bicyclic ring system was crucial for the
reactivity, In addition, 2-iodothiophene was also a viable reaction
partner. Desired product 3qa could be delivered in 61% yield.
Indeed, the 5,5-bicyclic ring system was crucial for the reactivity,
In addition, several synthetic transformations were performed
for dearomatized products 3 (Scheme 3). The newly formed
double bond of 3aa could be hydrogenated to obtain 4 in 94%
yield with high diastereoselectivity (>20:1 dr). The relative
configuration of 4 was determined by X-ray crystallographic
analysis. Besides, the N-Boc group of 3ab could be removed
smoothly by the treatment of TMSOTf, leading to 5 in 86% yield.
Moreover, 3am could undergo Suzuki coupling reaction with
PhB(OH)
2
to afford 6 in 96% yield.
Chin. J. Chem. 2019, 37, XXX－XXX
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Scheme 2 Substrate scope.
R
R
I
5
5
Pd(OAc)
2
(10 mol%)
+
Ar
N
N
(1.2 equiv)
AgNTf
2
Na HPO
2
4
•12H
2
O
EWG Ar
EWG
DMA, 80 °C, time
1
2
3
X-ray of 3aq
(
a) Variation at indole ring
(b) Variation at aryl iodide
Me
N
3
3
3
ba (R = Me) 86% yield (4 h) 3ga (R = Cl) 74% yield (20 h)
ca (R = tBu) 89% yield (6 h) 3ha (R = Br) 59% yield (10 h)
N
da (R = OMe) 93% yield (5 h) 3ia (R = CO Me) 70% yield (8 h)
N
N
2
N
N
Ph
Ac
Ph
Ph
Ph
Ph
3ea (R = Ph) 93% yield (5 h)
3ja (R = CF
3
) 63% yield (26 h)
Ac
Boc
3ab
92% yield (5 h)
MeO
2
C
Bz
Ac
3fa (R = F) 85% yield (9 h)
3ka
= NO 41%
h)
(R
2
)
yield (26
3
aa
3ac
3ad
3ae at 120 °C
72% yield (5 h)
R
9
1% yield (5 h)
87% yield (5 h)
63% yield (24 h)
R
3af (R = Me) 76% yield (8 h)
Me
N
OMe
3
3
3
3
3
ag (R
=
OMe) 63%
yield (7
h)
Cl
Br
N
N
N
ah (R = tBu) 49% yield (17 h)
ai (R = F) 53% yield (10 h)
aj (R = Ac) 66% yield (20 h)
N
N
Ac
Ac
Ac
Ac
Ph
Ph
Me
F
N
Ph
Ph
Ac
Ac
Ac
3la
3ma
91% yield (23 h)
3oa
51% yield (2 h)
ak (R = CO Me) 53% yield (18 h)
3al
3am
3pa
53% yield (10 h)
2
8
5% yield (9 h)
8
0% yield (10 h)
80% yield (10 h)
F
(
c) Unreactive substrates
Me
Me
N
N
S
N
N
N
N
Ac
Ac
Ph
F
Ph
Ph
Me
F
N
Me
6
Ac
Ac
Ac
Ac
Ph
Ac
Me
N
N
3
an
3ao
3ap at 100 °C
3aq
88% yield (3 h)
3ar at 100 °C
61% yield (15 h)
3na
3qa at 100 °C
Ac
Ac
8
4% yield (2 h) 83% yield (8 h) 54% yield (15 h)
76% yield (7 h) 61% yield (8 h)
Scheme 3 Product transformations.
Based on the literature reports, a plausible catalytic cycle was
proposed (Scheme 4(b)). In the presence of AgNTf , the oxidative
2
addition of aryl iodide 2 to the Pd(0) catalyst delivers the aryl–
Pd(II) species I. Subsequently, the coordination and insertion of I
across the C2=C3 double bond of 1 provide intermediate II. Finally,
base-assisted β-hydride elimination affords desired product 3. Our
calculations confirmed that the regioselectivity of the reaction
was determined in the insertion step (vide infra). The optimized
structures of the most stable insertion transition states leading to
3aa (TS-A-5-III) and the unobserved regioisomer (TS-A-5-II) are
shown in Figure 1. The relative Gibbs free energy of the latter one
is higher than that of the former one by 3.1 kcal/mol, which is in
good agreement with the experimental results. Although the
geometric features around the bond-forming/breaking area in the
two structures (highlighted in green) are rather similar [B(Pd···C3)
= 2.08 Å, B(Cipso···C2) = 2.16 Å, and B(Pd···Cipso) = 2.06 Å in
Pd/C, H
2
N
MeOH, 30 °C
N
Ph
Ph
Ac
Ac
3
aa
4
9
>
4% yield
20:1 dr
TMSOTf
,6-lutidine
2
N
N
H
Ph
DCM, 0 °C
Ph
Boc
ab
5
3
8
6% yield
Pd(PPh
PhB(OH)
3
)
2
4
Br
Ph
N
N
Ph
Na
CO
, DME
O, MeOH
Ph
2
3
Ac
am
H
Ac
2
3
6
TS-A-5-III; B(Pd···C2) = 2.10 Å, B(Cipso···C3) = 2.17 Å, and B(Pd···Cipso
2.05 Å in TS-A-5-II], natural population analysis (NPA) revealed
)
96% yield
=
that the preference of TS-A-5-III might stem from the electronic
match of the bond-forming atom pairs [between Pd (0.308) and
C3 (-0.072), and between Cipso (-0.120) and C2 (0.298)]. On the
other hand, in TS-A-5-II the connection between two positive-
ly-charged atoms [Pd (0.308) and C2 (0.156)] makes the reversed
insertion pathway energetically unfavorable.
Mechanistic studies
In order to shed light on the reaction mechanism, detailed
DFT calculations were performed. Initially, the thermodynamic
aspect of the reaction was evaluated (Scheme 4(a)). As expected,
the isomerization of the double bond of cyclic or acyclic
16
Activation strain model (ASM) analysis was performed on
the systems derived from 1a with phenyl iodide (2a), p-OMeC
2d), and p-NO I (2k), respectively (Figure 2). As the electron
density of the aryl group is getting lower (from p-OMe to p-NO ),
2
,3-disubstituted indoles is generally endergonic. The energetic
6 4
H I
uphill of dihydrocyclobuta[b]indole, tetrahydrocarbazole (n = 4
and 6), and 2,3-dimethylindole (acyclic) is about 9.4-9.6 kcal/mol.
However, this value of tetrahydrocyclopenta[b]indole (n = 5) drops
to 7.9 kcal/mol. We believe that this outlier implies the energy
compensation gained from the strain release of the 5,5-bicyclic
system during the dearomatization process.
(
2 6 4
C H
2
the insertion transition state appeared at a later stage with a
higher activation energy [ΔE(act)] (Figure 2(a)), which well
reproduced the experimental results with 2a, 2d, and 2k (Scheme
2(b)). Notably, a good superposition of the curves of the total
a
c
Department, Institution, Address 1
Department, Institution, Address 3
E-mail:
E-mail:
b
Department, Institution, Address 2
E-mail:
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Running title
Chin. J. Chem.
distortion energy [ΔE(dist)] was disclosed (Figure 2(b)). It
suggested that when the aryl–Pd(II) species and 1a approached to
each other, their respective geometric distortions were rather
similar in the three systems. However, the interaction energy
between the bended substrates [ΔE(int)] varied significantly
(
Figure 2(c)). In addition, at any given point along the reaction
coordinate, the interaction between indole and electron-rich aryl–
Pd(II) species (R = OMe) was stronger compared with the parent
system (R = H), and that between indole and electron-deficient
2
aryl–Pd(II) species (R = NO ) was even weaker. Moreover, the
calculated NPA charges (Figure 2(d)) corroborated that the
favorable electronic match between the bond-forming atom pairs
was reinforced for the case of electron-rich aryl–Pd(II) species
[
between Cipso (-0.157) and C2 (0.316), R = OMe] but attenuated
for the case of electron-deficient aryl–Pd(II) species [between Cipso
-0.083) and C2 (0.279), R = NO ]. In this regard, the influence of
(
2
the electronic property of substrates to the regioselectivity and
the reactivity could be well understood.
Scheme 4 (a) Thermodynamics of the dearomatization process and (b) The
proposed catalytic cycle.
Figure 2 (a) to (c) Diagrams of activation energy ΔE(act), total distortion
energy ΔE(dist), and interaction energy ΔE(int) in kcal/mol relative to the
bond length of forming C2–Cipso bond for the system derived from 1a with
2
a (R = H), 2d (R = p-OMe), and 2k (R = p-NO ), respectively. Calculated
2
based on the IRC plots of the insertion transition states obtained at
M06/SDD/6-31G** level of theory. (d) NPA charges on certain atoms in
the corresponding insertion transition states. Calculated at
M06/SDD/6-31+G** level of theory.
Table 2 Energy profiles for indole substrates with varied ring sizes.a
DMA
∆
G
NTf2
H
Pd
n
NTf2
n
Pd
N
Ph
Ac
N
Ph
Ac
TS-A-n
DMA
INT-A-n
TS-B-n
DMA
H
n
NTf2
INT-C-n
Pd
INT-B-n
NHTf2
Pd
DMA
NTf2
Pd
N
n
Ph
n
Ac
N
Ph
N
Ph
Ac
Ac
n
INT-A-n
0.0
TS-A-n
3.1
INT-B-n
-26.4
TS-B-n
INT-C-n
1.3
4
4.9
2.6
0.6
-2.5
5
6
0.0
6.1
-15.2
-0.4
0.0
8.7
-12.6
-0.4
acyclic
0.0
8.2
-13.6
-3.2
a
Relative Gibbs free energies (ΔG) in kcal/mol are listed. Calculated at
M06/SDD/6-31+G** level of theory.
Figure 1 Optimized structures and relative Gibbs free energies (ΔG) of
TS-A-5-III and TS-A-5-II in kcal/mol (relative to the direct precursor
INT-A-5, see Table 2 for details). Calculated at M06/SDD/6-31+G** level of
theory. Values in bold are bond distances in angstrom. Values in italic are
NPA charges of the corresponding atoms.
Finally, the influence of ring size of indole substrates to the
reaction outcomes was investigated (Table 2). The energy profiles
of the key transition states and intermediates for both insertion
and
β-hydride
elimination
steps
for
N-Ac
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First author et al.
dihydrocyclobuta[b]indole,
tetrahydrocyclopenta[b]indole,
mixture was filtered through celite, and the filtrate was concen-
trated under reduced pressure. The crude product was purified by
silica gel column chromatography (PE/EtOAc = 10/1) to afford the
desired product.
The full experimental details can be found in the Supporting
Information.
tetrahydrocarbazole (n = 4-6), and 2,3-dimethylindole (acyclic)
were calculated. In all cases, the insertion of aryl–Pd(II) species
across the C2=C3 double bond of the indole substrate is an
irreversible step. Notably, the energy barriers of this step for N-Ac
tetrahydrocarbazole (TS-A-6, 8.7 kcal/mol) and 2,3-dimethylindole
(
TS-A-acyclic, 8.2 kcal/mol), respectively, are very similar. When
Computational methods. All the DFT calculations in this work
18
the fused ring of the indole substrates became smaller, the
corresponding barrier height decreased (TS-A-5, 6.1 kcal/mol and
TS-A-4, 3.1 kcal/mol). Accordingly, the stability of the following
intermediates increased monotonously (INT-B-6, -12.6 kcal/mol;
INT-B-5, -15.2 kcal/mol and INT-B-4, -26.4 kcal/mol). These trends
confirmed our initial conjecture about the strain release of the
small-ring-fused indole substrates which was probably caused by
the favorable shift of the hybridization scenarios of C2 and C3
from sp to sp during the insertion step. However, the extremely
stable INT-B-4 hampered the subsequent β-hydride elimination
step (TS-B-4, 31.3 kcal/mol relative to INT-B-4). Whereas this step
was feasible in all other cases (TS-B-n, 11.1-17.8 kcal/mol relative
to INT-B-n, n = 5, 6, and acyclic). Based on all these results, the
uniqueness of tetrahydrocyclopenta[b]indole derivatives in the
intermolecular dearomative Heck reactions became reasonable.
The 5,5-bicyclic ring system was not only capable of releasing the
ring-strain sufficiently for the dearomative intermolecular
insertion (not available for tetrahydrocarbazole and
were performed with Gaussian16. The density functional theory
1
9
(DFT) method was employed using the M06 functional. The SDD
basis set with the associated effective core potential was used for
Pd, and the 6-31+G** basis sets for all other atoms unless other-
wise specified. Optimizations were conducted without any
20
constraint using implicit solvation model (SMD) in DMA (ε =
37.781). Frequency analyses were carried out to confirm each
structure being a minimum (no imaginary frequency) or a
transition state (only one imaginary frequency). The Gibbs free
energies in DMA (ΔG) were discussed throughout this paper
unless otherwise specified. The 3D images of the calculated
2
3
21
structures were prepared using CYLview.
The full computational details can be found in the Supporting
Information.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
2
,3-dimethylindole systems), but also suitable for promoting the
following β-hydride elimination to furnish the final products (not
1
7
available for dihydrocyclobuta[b]indole system).
Acknowledgement
We thank MOST (2016YFA0202900), NSFC (21772219,
1821002, 91856201), Science and Technology Commission of
Conclusions
2
Shanghai Municipality (18QA1404900), Chinese Academy of Sci-
ences (XDB20000000, QYZDY-SSW-SLH012) and Youth Innovation
Promotion Association (2017302) of CAS for generous financial
support.
In summary, we have developed the first Pd-catalyzed
intermolecular dearomatization of indoles via Heck reaction. A
series of indolines bearing a quaternary center could be accessed
efficiently under mild conditions in good to excellent yields (up to
9
3%) with exclusive regioselectivity. Detailed DFT calculations
revealed that the successful execution of this unprecedented References
reaction design relied on the judicious regulation of the geometric
(
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derivatives well balanced the feasibility of both insertion and
β-hydride elimination steps. On the other hand, the electronic
match of the bond-forming atom pairs in the insertion step
guided the regioselectivity of the intermolecular Heck reaction.
Further exploration on advancing the dearomatization of diverse
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3
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Experimental
General procedure for intermolecular dearomative Heck re-
action. A flame-dried Schlenk tube was cooled to room tempera-
ture under argon. To this tube were added indole derivative (0.2
mmol), Pd(OAc)
2
(4.5 mg, 0.02 mmol), Na
2 4 2
HPO •12H O (143.3 mg,
0
.4 mmol), AgNTf
2
(93.1 mg, 0.24 mmol), DMA (1.0 mL) and aryl
iodide (0.3 mmol). The reaction mixture was stirred at 80 °C. After
completion (monitored by TLC), the reaction mixture was cooled
to room temperature and diluted with ethyl acetate (3 mL). The
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This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
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Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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Entry for the Table of Contents
Page No.
R
Pd-Catalyzed Dearomatization of Indole Deriva-
tives via Intermolecular Heck Reactions
R
5
I
5
[Pd]
+
Ar
N
N
EWG
Ar
EWG
Intermocular Dearomative Heck Reaction
34 examples
up to 93% yield
Pd-catalyzed intermolecular dearomative Heck reaction of indoles with aryl iodides is described.
The challenges on both reactivity and regioselectivity are addressed by the judicious regulation of
the geometric and electronic properties of the substrates. An array of indoline derivatives bearing
C2-quaternary center is obtained in good to excellent yields (up to 93%) and exclusive regioselec-
tivity under operationally simple conditions. The mechanistic proposal is supported by detailed
DFT calculations.
Ping Yang, Ren-Qi Xu, Chao Zheng,* and Shu-Li
You*
a
c
Department, Institution, Address 1
Department, Institution, Address 3
E-mail:
E-mail:
b
Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.