Palladium-Catalyzed Enantioselective Intramolecular Dearomative Heck Reaction

Article abstract of DOI:10.1021/jacs.8b09186

Enantioselective intramolecular dearomative Heck reactions have been developed by Pd-catalyzed cross-coupling of aryl halides or aryl triflates with the internal C=C bond of indoles, benzofurans, pyrroles, and furans. A variety of structurally unique spir

Full text of DOI:10.1021/jacs.8b09186

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Article
Palladium-Catalyzed Enantioselective
Intramolecular Dearomative Heck Reaction
Xiang Li, Bo Zhou, Run-Ze Yang, Fu-Ming Yang, Ren-Xiao Liang, Ren-Rong Liu, and Yi-Xia Jia
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Sep 2018
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Palladium-Catalyzed Enantioselective Intramolecular Dearomative
Heck Reaction
Xiang Li,‡ Bo Zhou,‡ Run-Ze Yang,‡ Fu-Ming Yang, Ren-Xiao Liang, Ren-Rong Liu, and Yi-Xia
Jia*
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College of Chemical Engineering, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou 310014, China
ABSTRACT: Enantioselective intramolecular dearomative Heck reactions have been developed by Pd-catalyzed cross-
coupling of aryl halides or aryl triflates with the internal C=C bond of indoles, benzofurans, pyrroles, and furans. A variety
of structurally unique spiroheterocycles and benzofused heterocycles having N/O-substituted quaternary carbon stereo-
centers and exocyclic olefin moieties were afforded in moderate to excellent yields with good to excellent enantioselec-
tivities, showing a broad scope of the present protocol. A series of new BINOL- and H8-BINOL-based phosphoramidite
ligands were synthesized and proved to be efficient chiral ligands in the reactions of C2-tethered substrates to form spiro-
heterocycles. (S)-SEGPHOS turned out to be a good ligand for the reaction delivering benzofused indolines and pyr-
rolines. Synthetic applications based on transformations of the exocyclic double bonds were realized without loss of enan-
tiopurities, including hydrogenation, hydroborylation, and stereospecific ring-expanding rearrangement.
Introduction
achieving enantiocontrol and breaking the aromaticity,
enantioselective dearomative Heck reaction has remained
underdeveloped. So far, a few enantioselective dearoma-
tive Heck arylation and related domino sequences have
been reported. In 2012, Yao and Wu reported a racemic
dearomative Heck reaction of N-2-halobenzoyl 2,3-
disubstituted indoles.10a The asymmetric variant was then
established in 2016 by Kitamura, Fukuyama, and co-
workers and applied as a key step in the total synthesis of
(+)-hinckdentine A, but only two single substrates were
tested in their report and the ee was up to 86% (Scheme
1b).10b In 2015, our group disclosed a reductive Heck reac-
tion of 2-substituted N-2-halobenzoyl indoles, which af-
forded chiral indolines bearing C2-quaternary carbocen-
ters in excellent enantioselectivities.11a Zhou and co-
workers showed a chiral nickel catalyst was also efficient
for the same reaction with zinc powder as a reducing
agent.12 Moreover, dearomative difunctionalization reac-
tions of indoles and furans have been developed by
Lautens, Yin, and our groups via domino Heck/anionic-
capture sequences employing a range of nucleophiles to
terminate the alkyl-Pd species.13 Despite of the above pro-
gress, most of the examples furnished in their racemic
versions and the dearomative Heck reaction to form het-
erocyclic alkylidene prodcuts has remained much less
developed.
Heck reaction, the cross-coupling of organohalides and
olefins to form new alkene derivatives, represents one of
the most important carbon-carbon forming reactions,
which has been extensively applied in organic synthesis.1,2
The asymmetric intramolecular Heck reaction, pioneered
by Shibasaki and Overman in 1989,3 has been intensely
studied in the past few decades and shows an important
role in the synthesis of natural products (Scheme 1a).4
Considerable advances have also been achieved for enan-
tioselective intermolecular Heck reactions since Hayashi
and co-workers reported the first example of arylation of
cyclic olefin in 1991.5 From then on, a range of Heck reac-
tions of cyclic olefins have been realized based on the
development of new chiral ligands.4,6 More recently, by
employing a redox-relay strategy Sigman and co-workers
have developed a series of highly enantioselective inter-
molecular Heck reactions of acyclic olefins with aryldia-
zonium salts or arylboronic acids as coupling partners.7
Catalytic asymmetric dearomatization reaction has
been extensively developed in the past few years, which
constitutes a straightforward access to optically active
alicyclic molecules as key moieties of bioactive natural
products and pharmaceuticals.8 Many of current enanti-
oselective dearomatization reactions relied on the trans-
formations of aromatic substrates containing free N-H or
O-H bonds, such as anilines, indoles, pyrroles, and phe-
nols, where dearomatization was facilitated via keto-enol
tautomerism under basic condition.8,9 Dearomative Heck
reaction, the arylation of internal C=C bonds of aromatic
compounds, would provide another avenue for dearoma-
tization reaction. However, due to the challenging in
As part of our ongoing work on enantioselective Heck
reactions, we report herein a protocol of asymmetric in-
tramolecular dearomative Heck reaction of indoles, ben-
zofurans, pyrroles, and furans, which serves as a straight-
forward synthetic approach to chiral spiroheterocyclic
and benzofused heterocyclic scaffolds (Scheme 1c).
Through the Pd-catalyzed Heck arylation of internal C=C
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oselectivity, to 77% for L8, 79% for L9, and 82% for L10 (en-
bonds of the abovementioned heteroaromatics, a range of
structurally unique spiro- or benzofused heterocycles
bearing N/O-substituted quaternary carbon stereocenters
and exocyclic olefin moieties were afforded in moderate
to good yields with excellent enantioselectivities. New
BINOL- and H8-BINOL-based phosphoramidite ligands
were developed and showed good asymmetric induction
ability in achieving spiroheterocycles, while ligand (S)-
SEGPHOS proved to be efficient in the formation of ben-
zofused indolines and pyrrolines. Synthetic transfor-
mations of the products were realized based on the con-
version of the exocyclic C=C bonds, including hydrogena-
tion, hydroboration, and stereospecific ring-expanding rear-
rangement followed by nucleophilic additions.
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tries 13–15). We were pleased to find that the enantioselectiv-
ity could be further improved to 89% or 92% by lowering the
temperature to 60 °C or 40 °C, respectively (entries 16 and
17). In the end, 2a could be obtained in 92% yield with 93%
ee by increasing the amounts of Cs2CO3 and HCO2H (entry
18).
Table 1. Condition optimization of the reaction of 1a.a
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Scheme 1. Enantioselective intramolecular Heck re-
action.
ee
(%)
Yield
(%)
Entry
L*
Additive
Solvent
1
2
L1
L1
--
Toluene
MTBE
83
44
87
85
87
90
93
89
79
83
70
76
87
94
90
92
86
92
28
24
32
35
52
53
39
20
29
42
30
58
77
79
82
89
92
93
--
3
L1
--
THF
4
L1
--
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
5
L1
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
6
L1
7
L2
L3
8
9
L4
L5
L6
L7
L8
L9
L10
L10
L10
L10
10
11
Results and Discussions
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13
14
15
16b
17c,d
18c,e
Reaction of Indoles and Benzofurans. At the beginning,
the model reaction of 2-aminocarbonyl indole 1a was studied
(Table 1). In the presence of Pd(OAc)2 (5 mol %), phospho-
ramidite L1 (10 mol %), and Cs2CO3 (1.0 equiv), the desired
product 2a was isolated in 83% yield with 28% ee in toluene
at 100 °C (entry 1). Higher enantioselectivities were observed
when the reaction carried out in THF or 1,4-dioxane (entries
3 and 4), whereas the yield was poor in methyl tert-butyl
ether (entry 2). Interestingly, adding HCO2H to the reaction
mixture improved the ee value to 52%, while no reductive
Heck product was detected (entry 5). Comparable enantiose-
lectivities were achieved in the presence of PhCO2H (50% ee)
or AcOH (51% ee). The use of Pd(dba)2 led to 2a in 90% yield
with 53% ee (entry 6). Various chiral phosphoramidite lig-
ands were then examined. Ligands L2–L5 bearing different
substituents on the nitrogen atom did not improve the enan-
tioselectivities (entries 7–10). Although the ee was poor for
iminodibenzyl ligand L6 (entry 11), its analogous ligand, H8-
BINOL-based L7, gave a higher ee than did ligand L1 (com-
paring entries 12 and 6). Ligands L8–L10, which are aryl-
substituted derivatives of L7, markedly improved the enanti-
aReaction conditions: 1a (0.2 mmol), [Pd] (5 mol%; Pd(OAc)2
for entries 1–5; Pd(dba)2 for entries 6–18.), L* (10 mol%),
Cs2CO3 (1 equiv), additive (1 equiv), and solvent (2 mL) at
100 °C for 24 h; MTBE = methyl tert-butyl ether; Isolated
yield; ee was determined by chiral HPLC. bAt 60 °C. cAt 40 °C.
dFor 3d. eCs2CO3 (1.5 equiv) and HCO2H (1.5 equiv).
With the optimal conditions in hand, we investigated
the scope of the reaction with various substrates 1
(Scheme 2). The yield and ee of spiro product 2a were
slightly lower for an iodinated substrate (X = I) than for
the corresponding brominated substrate (X = Br). The
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prolonging the reaction time. The absolute configuration of
absolute configuration of 2a was determined to be R
based on X-ray crystallographic analysis of its derivative
15 (Scheme 9).14 We also explored the effect of substitu-
ents on the indole ring. Various groups at C5 and C7, such
as Me, F, and Cl, were compatible with the reaction con-
ditions, furnishing spiro products 2b–2f in moderate to
excellent yields with 90–96% ee values. The protecting
group on the indole nitrogen was also investigated. Prod-
uct 2g, which bears an N-benzyl group, was obtained in
92% yield with 95% ee, whereas the ee observed for 2h, a
product with an N-Boc group, was considerably lower
(69%). The presence of an n-propyl group or a benzyl
group at C3 led to a sluggish reaction, but the correspond-
ing products (2i and 2j) were obtained with good enanti-
oselectivities, albeit with lower E/Z isomer ratios. Next,
various substituents on the aniline ring were screened.
Substrates with either an electron-donating or electron-
withdrawing group were well-tolerated, furnishing de-
sired products 2l–2s in good yields with excellent enanti-
oselectivities (up to 99%). Notably, we obtained a poor
yield of product 2t, which bears a naphthalene ring, even
after a prolonged reaction time (5 d), although the ee was
excellent (95%).
1
2
3
4
5
6
7
8
4a was determined to be R by the X-ray crystallographic
analysis.14
Scheme 3. Ligand effect for the reaction of 3a or 3a’.a
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aReaction conditions: 3a or 3a’ (0.2 mmol), Pd(dba)2 (5
mol%), L* (10 mol%), and NEt3 (3 equiv) in 1,4-dioxane (2
mL) at 100 oC for 12 h; bAt 40 oC for 3 d.
To investigate the scope, we tested a variety of benzofu-
rans under the above conditions (Scheme 4). Methyl, Cl, and
methoxy substituents bearing at C5 or C6 of the benzofuran
ring were well tolerated. Products 4b–4e were afforded in
excellent enantioselectivities, although the yield of chlorinat-
Scheme 2. Scope of indole 1.a
R3
R3
ed product 4d was relatively low. Reaction of
a 3-
5 mol% Pd(dba)2
10 mol% L10
X
Ar
R2
N
ethylbenzofuran afforded product 4f in 63% yield as a 1:1 mix-
ture of E and Z isomers with 92% ee and 93% ee, respectively.
Moreover, N-benzyl product 4g was obtained in 90% yield
with 79% ee. Gratifyingly, product 4h containing a pyridine
moiety was obtained in 91% yield and 96% ee. We also exam-
ined the effect of substituents on the aniline ring. The reac-
tion was impeded by the presence of substituents (such as
Me, F, Cl, and CF3) para to the amide nitrogen atom; prod-
ucts 4i–4l were obtained in moderate to good yields and ee
values after 4 d at 60 °C. We were pleased to find that sub-
strates bearing a substituent para to the iodine atom afforded
products 4m–4q in moderate to good yields with excellent
enantioselectivities (90–96%). Note that the bromine atom
of 4p survived the reaction conditions.
Ar'
Ar'
1.5 equiv HCO2H
1.5 equiv Cs2CO3
N
Ar
R2
N
N
R1
1 O
O
1,4-dioxane, 40 o
C
R
for 2a, X = Br/I
for 2b-2t, X = Br
1
2
R
N
N
O
N
N
N
N
O
R
2b R = Me 68%, 90% eeb
2c R = F 85%, 95% ee
2d R = Cl 90%, 96% ee
O
2a
2e R = Me 74%, 92% ee
2f R = Cl 80%, 95% ee
R
92%, 93% ee (X = Br)
89%, 88% ee (X = I)
R
N
N
N
N
N
N
N
N
Bn
R
O
O
O
O
2g R= Bn 92%, 95% ee
2h R= Boc 94%,69% ee
2k 60%, 86% ee 2l R = Me 88%, 94% ee
2i R = Ph 4/1 isomer
78%, 95% ee, 92% eec
2j R = Et 1:1 isomer
80%, 87% ee, 89% eeb
2m R = Cl 93%, 97% ee
F
F
Scheme 4. Scope of benzofuran 3.a
R
2n R = Me 74%, 94% ee
2o R = MeO 78%, 94% ee
2p R = CF3 70%, 98% ee
2q R = F 80%, 97% ee
2r R = Cl 79%, 98% ee
N
N
N
N
N
N
O
O
O
2t 36%, 95% eed
2s 87%, 99% ee
aReaction conditions: 1 (0.2 mmol), Pd(dba)2 (5 mol%), L10
(10 mol%), Cs2CO3 (1.5 equiv), and HCO2H (1.5 equiv) in 1,4-
dioxane (2 mL) at 40 °C for 20-36 h. bfor 60 h. cfor 6 d. dfor 5 d.
A
dearomative intramolecular Heck reaction of 2-
aminocarbonyl benzofurans 3 was also established. The effect
of chiral ligands was shown in scheme 3.15 A new H8-BINOL-
based phosphoramidite ligand L15, bearing a 8-methyl tetra-
hydroquinoline moiety, led to product 4a in 72% yields and
77% ee in the reaction of bromo-substrate 3a’ with Pd(dba)2
as a catalyst and NEt3 as a base in 1,4-dioxane at 100 oC. Other
ligands L11-L14 gave inferior results, while L10, the best lig-
and for the reaction of 1, led to 4a in 79% yield and 73% ee.
The ee value was improved to 84% for iodo-substrate 3a and
further to 92% by lowering the temperature to 40 oC and
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aReaction conditions: 3 (0.2 mmol), Pd(dba)2 (5 mol%), L15
(10 mol%), and Et3N (3 equiv) in 1,4-dioxane (2 mL) at 40 °C
for 2-3 d. bAt 60 °C, for 4 d.
and 7). Product 8a was isolated in 66% yield and 94% ee in
DMF solvent (entry 8). As a comparison, a BINOL-based
analogous ligand L14 led to 8a in inferior yield and ee (entry
9). The scope of N-Ts-pyrrole was subsequently examined
(Scheme 6). Substituent effect on the benzene ring of aniline
was investigated in the reactions of substrates bearing MeO,
CF3, F, Cl, and Me groups. Products 8a-8h were isolated in
moderate yields with good to excellent enantioselectivities.
Substituents para to amide nitrogen atom resulted in slightly
lower yields and ees (8f-8h vs 8a-8e). To our delight, the
reaction of C2-substituted furans could also proceed smooth-
ly to give 8i-8m in excellent enantioselectivities by lowering
the temperature and adding 4Å molecular sieves to the reac-
tion, but the yields for these products were still lower. Sub-
strate bearing a Cl para to amide nitro atom failed to furnish
product 8n and no desired product 8o was detected in the
reaction of a thiophene substrate.
1
2
3
4
5
6
7
8
Dearomative Heck reaction of a modified indole 5 was also
realized, which led to chiral spiro-[5.6]-heterocycles. BINOL-
based chiral phosphoramidite L14 was found to be the best
ligand, furnishing product 6a in 91% yield with 94% ee using
TMEDA as a base and HCO2H as an additive.15 The absolute
configuration of 6a was determined to be S according to the
X-ray crystallographic analysis of a single crystal of iminium
salt 18, which derived through a stereospecific rearrangement
(Scheme 9). The scope of substrate 5 was then investigated
(Scheme 5). N-Benzyl product 6b was obtained in 93% yield
with 91% ee. Substrates bearing substituents on either the
indole ring or the benzene ring of the bromobenzoyl moiety
were examined. Reactions of 5c-5f having substituents para
to the bromine atom furnished 6c–6f with 92–94% ee values.
Cl, F, and Me substituents at C5–C7 of the indole ring were
well tolerated and their reactions furnished 6g–6l in modest
to excellent yields with excellent enantioselectivities. In addi-
tion, an N-phenylethyl substrate was also suitable for this
reaction, furnishing 6m in 90% yield with 93% ee.
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Table 2. Condition optimization of the reaction of
7a.a
Scheme 5. Scope of indole 5.a
Entry
R
L*
Solvent
Yield (%)
Ee (%)
1
Me
Bz
Ts
Ts
Ts
Ts
Ts
Ts
Ts
L15
L15
L15
L15
L15
L15
L15
L15
L14
1,4-dioxane
1,4-dioxane
1,4-dioxane
Toluene
THF
nd
nd
<10
nd
<10
34
--
--
2
3
4
5
6
7
8
9
92
--
93
92
93
94
79
MeCN
NMP
49
66
35
DMF
DMF
aReaction conditions: 7a (0.2 mmol), Pd(dba)2 (5 mol%), L*
(10 mol%), and NEt3 (3 equiv) in solvent (2 mL) at 100 C for
o
24 h; nd = not detected.
Scheme 6. Scope of C2-tethered pyrrole and furan.a
X
5 mol% Pd(dba)2
10 mol% L15
Ar
R
aReaction conditions: 5 (0.2 mmol), Pd(OAc)2 (5 mol%), L14
(10 mol%), TMEDA (2 equiv), and HCO2H (2 equiv) in THF
(2 mL) at 100 °C for 2-3 d.
N
Ar
3.0 equiv Et3N
DMF, 100 °C
N
Z
R
Z
O
O
7a-7h, Z = NTs, X = Br
7i-7m, Z = O, X = I
8
Cl
CF3
F
OMe
Reaction of C2-Tethered Pyrroles and Furans. Having
conducted the Heck reactions of indoles and benzofurans,
we further moved our attention to more challenging het-
eroaromatic substrates, such as pyrroles and furans. Thus,
the reaction of N-(2-bromophenyl)-pyrrole-2-carboxamide
bearing a C3-methyl group was tested. It was found that the
N-protecting group of pyrrole was crucial to the reactivity.
Only N-Ts-pyrrole 7a could give the spiro-product 8a in a
poor yield but with excellent ee with L15 as a chiral ligand
N
N
N
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
O
O
O
O
O
8a 66%, 94% ee 8b 61%, 90% ee
8c 64%, 94% ee
8d 67%, 93% ee 8e 67%, 93% ee
F
F
Me
F
F
N
N
N
N
N
N
O
O
N
N
Ts
Ts
Ts
O
O
O
O
O
8i 52%, 96% eeb
8j 47%, 98% eeb
8f 48%, 90% ee
8g 53%, 81% ee
8h 40%, 90% ee
o
Cl
and NEt3 as a base at 100 C in 1,4-dioxane (Table 2, entry 3).
Cl
No target products were detected for N-Me-pyrrole and N-
Bz-pyrrole (entries 1 and 2). The yield of 8a was improved
when the reaction carried out in MeCN and NMP (entries 6
O
N
O
O
N
O
N
O
S
N
O
N
O
Bn
O
O
8k 37%, 98% eeb
8l 32%, 96% eeb
8m 34%, 98% eeb
8n n.d.
8o n.d.
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aReaction conditions: 7 (0.2 mmol), Pd(dba)2 (5 mol%), L15
(10 mol%), NEt3 (3 equiv) in DMF (2 mL) at 100 °C for 24-60 h.
b100 mg 4Å molecular sieves, at 80 °C for 48 h.
10f were observed for the substrates having electron-
donating substituents para to bromide atom. Substituents (F,
Me, and MeO) para to amide tether also impeded the reac-
tions, resulting in lower yields for products 10g-10i.
1
2
3
4
5
6
7
8
9
Reaction of N-tethered Pyrroles and Indoles. Encour-
aged by the results achieving in the reaction of N-Ts-pyrroles
7, we further tested the reaction of N-2-halobenzyol 2,5-
dimethylpyrrole 9 to access chiral benzofused pyrrolines.16
Pyrrole 9a was used as a model substrate for condition opti-
mization. As shown in Table 3, phosphoramidite ligands L14
and L15 resulted in the desired product 10a in moderate
Scheme 7. Scope of N-tethered pyrrole 9.a
o
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yields and enantioselectivities in DMF at 100 C for 16 h (en-
tries 1 and 2), while better results (76% yield and 84% ee)
were obtained when chiral diphosphine (S)-BINAP L16 was
used as a ligand (entry 3). Changing the solvent to 1,4-
dioxane, toluene, and THF did not improve either yield or ee
(entries 4-6), however, 10a was isolated in an increased yield
(82%) in NMP solvent (entry 7). (S)-Xyl-BINAP L17 could
further improve the ee to 90% but the yield was poor (entry
8). (S)-SEGPHOS L18 led to 10a in 78% yield and 93% ee (en-
try 9). In this case, the yield was further improved to 81% in a
mixed solvent of DMF/NMP (1:1) and the excellent ee was
kept (entry 11).
aReaction conditions: 9 (0.2 mmol), Pd(dba)2 (5 mol%), (S)-
SEGPHOS (6 mol%), and NEt3 (3 equiv) in a mixed solvent of
DMF/NMP (2 mL, 1:1) at 100 °C for 16-48 h.
Table 3. Condition optimization of the reaction of
9a.a
Table 4. Condition optimization of the reaction of
11a.a
Entry
L*
Solvent
Yield (%)
Ee (%)
1
2
L16
L16
L16
L18
L19
L18
L18
L18
L18
L18
MeOH
MeOH
EtOH
80
75
76
76
73
72
30
76
75
95
45
75
79
85
82
88
89
89
96
95
Entry
L*
Solvent
Yield (%)
Ee (%)
3
1
2
L14
L15
L16
L16
L16
L16
L16
L17
L18
L19
L18
DMF
DMF
43
48
76
53
30
54
82
20
75
79
81
65
57
84
60
67
60
80
90
93
90
93
4
EtOH
5
EtOH
3
DMF
6b
7c
8b
9b
10b,d
EtOH
4
5
1,4-dioxane
Toluene
THF
EtOH
THF
6
7
1,4-dioxane
1,4-dioxane
NMP
8
9
10
11
DMF
aReaction conditions: 11a (0.2 mmol), Pd(OAc)2 (5 mol%), L*
DMF
(8 mol%), and Na2HPO4 (1 equiv) in solvent (2 mL) at 100 oC
DMF
DMF/NMPb
b
for 24 h; for entries 2-10, HCO2H (0.8 equiv) was added. At
80 oC. cAt 60 oC. d100 mg 4Å molecular sieves was added.
aReaction conditions: 9a (0.2 mmol), Pd(dba)2 (5 mol%), L*
(12 mol% for L14 and L15; 6 mol% for L16-L19), and NEt3 (3
equiv) in solvent (2 mL) at 100 oC for 16 h. bVDMF/VNMP = 1:1.
The successful application of chiral diphosphine ligand in
the Heck reaction of N-tethered pyrroles to approach ben-
zofused products promoted us to examine the reaction of N-
2-halobenzoyl 2,3-disubstituted indoles. Although it has been
reported by Kitamura, Fukuyama, and co-workers, only two
substrates were tested in their report and the highest ee was
86% by using excess amount of chiral MonoPhos-PE lig-
and.10b Herein, the reaction of a bromo substrate 11a’ was first
tested with Pd(OAc)2 as a catalyst and (S)-BINAP L16 as a
A range of N-substituted 2,5-dimethylpyrroles were then
investigated (Scheme 7). In comparison to bromo-substrate
9a, the reaction of iodo-substrate 9a’ gave product 10a in a
relatively lower yield (70%) but a slightly improved ee (94%).
Substituents bearing on the benzene ring were tested and the
reactions afforded products 10b-10j in excellent enantioselec-
tivities (88-94%). Markedly lower yields for products 10e and
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ligand. Target product 12a could be isolated, while the reac-
and 100 mg 4Å molecular sieves in 1,4-dioxane (2 mL) at
1
2
3
4
5
6
7
8
tion was in poor reproducibility with ee ranging from 15% to
78%. A triflate substrate 11a was then synthesized and ap-
plied as a substrate. As shown in Table 4, by using Pd(OAc)2
as a catalyst and Na2HPO4 as a base, the reaction of 11a in
MeOH proceeded smoothly to afford 12a in 80% yield and 45%
ee (entry 1). The enantioselectivity was remarkably improved
to 75% by adding HCO2H to the reaction mixture, and fur-
ther to 79% in EtOH solvent (entries 2 and 3). Ligand (S)-
SEGPHOS (L18) gave a better ee (85%) (entry 4). Lowering
80 °C for 24-80 h.
Synthetic Transformations. We further carried out the
synthetic transformations of two typical products 2a and 6a
based on the conversion of their exocyclic C=C bonds
(Scheme 9). A Pd/C-catalyzed hydrogenation of the exocyclic
olefin of 2a under H2 (50 atm) at room temperature afforded
compound 13 in 75% yield. Subsequent reduction of the car-
bonyl group with LiAlH4 in refluxing THF converted 13 to
amine 14 in 62% yield. Hydroboration of 2a with 9-BBN fol-
lowed by an oxidation with H2O2 furnished alcohol 15 in 70%
yield. The absolute configuration of 15 was determined to be
(2’R, 3’R) by its X-ray crystallographic analysis.14 Compounds
13–15 were all isolated as single isomer and without any loss
of ee. Moreover, a stereospecific ring-expanding rearrange-
ment of 2a promoted by Me3OBF4 took place to give iminium
salt 16, which was treated with NaBH4 without further purifi-
cation to deliver dihydroquinolinone-fused indoline 17 in 61%
yield (for two steps) with 92% ee. Product 6a was also readily
converted to iminium salt 1814 having a seven-membered
lactam moiety by treating with Me3OBF4. In fact, aqueous
HBF4 could also promote this rearrangement reaction of 2a
o
9
the temperature to 80 C further improved the ee to 88%,
and further to 89% albeit with a poor yield at 60 oC (entries 6
and 7). Comparable results were observed in THF solvent
(entry 8), while the enantioselectivity was sharply improved
to 96% when the reaction carried out in 1,4-dioxane (entry 9).
Finally, an excellent yield (95%) was obtained by adding 4Å
molecular sieves to the reaction mixture and the ee was 95%
ee (entry 10).
10
11
12
13
14
15
16
17
18
19
20
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Scheme 8 disclosed the scope of the reaction 11→12 under
the optimal conditions. All of the reactions afforded products
12a-12o in moderate to good yields and good to excellent
enantioselectivities. Substituents bearing at C5 or C7 of the
indole ring, including Me, CF3O, and halides, were well toler-
ated to afford products 12b-12g. C5-Br in product 12f could
survive albeit with a lower product yield. Lower yield was
also observed for product 12g having a C7-Cl group. Other
than methyl group, ethyl and aryl substituents at C2 of the
indole were also investigated; all these substrates reacted
smoothly to give products 12h-12l in good to excellent ees.
Lower yield was observed for 12j having a 3-chlorophenyl
group, indicating a possible influence of steric hindrance on
the reactivity. Moreover, substrates having chloro substitu-
ent at the benzene ring of 2-bromobenzoyl moiety were also
tested, which afforded 12m and 12n in good yields and excel-
lent enantioselectivities. It’s worth to note that product 12o,
which has been used as a key starting material for the total
synthesis of (+)-hinckdentine A, was obtained in 76% yield
and 91% ee, and its absolute configuration was determined to
be R by comparison to the reported value.10b
o
and 6a at 80 C albeit with a lower yield. Reduction of the
unpurified 18 by NaBH4 gave amine 19 in 77% yield (for two
steps) and 96% ee. Hemiaminal 20 was obtained in 80% yield
and 94% ee by treating 18 with H2O. Indolines 21 and 22 hav-
ing vicinal quaternary stereocenters were obtained in excel-
lent enantioseletivities as single isomers by the addition of
Grignard reagents to 18. The relative configuration of com-
pound 19 and 21 was determined by 2D-NOSEY spectrum.
Scheme 9. Synthetic transformations of 2a and 6a.a
Scheme 8. Scope of the reaction with respect to 11.a
aReaction conditions: (a) Pd/C (10 mol%), H2 (50 atm) in
ethyl acetate at r.t. for 60 h; (b) LiAlH4 (10 equiv) in refluxing
THF for 55 h; (c) 9-BBN (2 equiv) in THF at 40 °C for 2 h,
then 3 M NaOH and 30% H2O2 at r.t. for 15 h; (d) Me3OBF4 (2
equiv) in CH2Cl2 at r.t. for 8 h; (e) NaBH4 (3 equiv) in
aReaction conditions: 11 (0.2 mmol), Pd(OAc)2 (5 mol%), (S)-
SEGPHOS (8 mol%), Na2HPO4 (1 equiv), HCO2H (0.8 equiv),
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CH2Cl2/MeOH (4:1) at 0 oC for 30 min; (f) NaBH4 (3 equiv) in
MeOH at 0 oC for 30 min; (g) H2O (2 equiv) in CH2Cl2 at r.t.
for 12 h; (h) RMgBr (2 equiv) in CH2Cl2/THF at r.t. for 12 h.
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488. (g) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500.
(4) (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945. (b) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104,
3453. (c) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth.
Catal. 2004, 346, 1533. (d) Mc Cartney, D.; Guiry, P. J. Chem. Soc.
Rev. 2011, 40, 5122. (e) Li, H.; Ding, C.; Xu, B.; Hou, X. Acta Chim.
Sinica 2014, 72, 765.
1
2
3
4
5
6
7
8
Conclusions
We have developed a protocol for Pd-catalyzed enantiose-
lective intramolecular dearomative Heck reactions of indoles,
benzofurans, pyrroles, and furans. This protocol offers a
straightforward access to a range of chiral spiro- and ben-
zofused heterocycles bearing nitrogen-/oxygen-substituted
quaternary carbon stereocenters. By the help of new BINOL-
or H8-BINOL-based chiral phosphoramidite ligands and
chiral diphosphine ligand, the reactions were accomplished
in moderate to excellent yields with good to excellent enan-
tioselectivities. Synthetic transformations of the typical
products were conducted based on the conversion of the
exocyclic C=C bonds, which led to structurally unique heter-
ocycles in excellent enantioselectivities.
(5) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417.
(6) For recent selected examples of asymmetric intermolecular
Heck reaction of cyclic olefins: (a) Wu, W.-Q.; Peng, Q.; Dong,
D.-X.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 9717. (b)
Yang, Z.; Zhou, J. J. Am. Chem. Soc. 2012, 134, 11833. (c) Hu, J.;
Hirao, H.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed. 2013, 52, 8676. (d)
Wu, C.; Zhou, J. J. Am. Chem. Soc. 2014, 136, 650. (e) Patel, H. H.;
Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 3462. (f) Zhang, Q.-S.;
Wan, S.-L.; Chen, D.; Ding, C.-H.; Hou, X.-L. Chem. Commun.
2015, 51, 12235. (g) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc.
2015, 137, 16028. (h) Borrajo-Calleja, G. M.; Bizet, V.; Burgi, T.;
Mazet, C. Chem. Sci. 2015, 6, 4807. (i) Bao, X.; Wang, Q.; Zhu, J.
Angew. Chem., Int. Ed. 2017, 56, 9577. (j) Jiao, Z.; Shi, Q.; Zhou, J.
Angew. Chem., Int. Ed. 2017, 56, 14567.
(7) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Science 2012, 338, 1455. (b) Mei, T.-S.; Patel, H. H.; Sigman, M. S.
Nature 2014, 508, 340. (c) Zhang, C.; Santiago, C. B.; Kou, L.;
Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 7290. (d) Patel, H. H.;
Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 14226. (e) Avila, C. M.;
Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.;
Sigman, M. S.; Sunoj, R. B.; Toste, F. D. Angew. Chem., Int. Ed.
2017, 56, 5806.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
1
Full experimental and characterization data, including H
and 13C NMR for all the new compounds, chiral HPLC spectra
for the products (PDF)
Crystallographic data for 4a, 15, and 18 (CIF)
AUTHOR INFORMATION
(8) (a) Pape, A. R.; Kaliappan, K. P.; Kündig, E. P. Chem. Rev.
2000, 100, 2917. (b) Lopez Ortiz, F.; Iglesias, M. J.; Fernandez, I.;
Andujar Sanchez, C. M.; Gomez, G. R. Chem. Rev. 2007, 107, 1580.
(c) Roche, S. P.; Porco, Jr., J. A. Angew. Chem., Int. Ed. 2011, 50,
4068. (d) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int.
Ed. 2012, 51, 12662. (e) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc.
Chem. Res. 2014, 47, 2558. (f) Wu, W.-T.; Zhang, L.; You, S.-L.
Chem. Soc. Rev. 2016, 45, 1570. (g) Zheng, C.; You, S.-L. Chem
2016, 1, 830, 15361. (h) Wu, W.-T.; Zhang, L.-M.; You, S.-L. Chem.
Soc. Rev. 2016, 45, 1570.
(9) For selected recent examples of Pd(0)-catalyzed dearoma-
tive arylation of anilines, indoles, pyrroles, and phenols: (a) Gar-
cía-Fortanet, J.; Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 6676. (b) Bedford, R. B.; Butts, C. P.; Haddow, M. F.;
Osborne, R.; Sankey, R. F. Chem. Commun. 2009, 45, 4832. (c)
Bedford, R. B.; Fey, N.; Haddow, M. F.; Sankey, R. F. Chem.
Commun. 2011, 47, 3649. (d) Rousseaux, S.; García-Fortanet, J.;
Del Aguila Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011,
133, 9282. (e) Wu, K.-J.; Dai, L.-X.; You, S,-L. Org. Lett. 2012, 14,
3772. (f) Wu, K.-J.; Dai, L.-X.; You, S.-L. Chem. Commun. 2013, 49,
8620. (g) Xu, R.-Q.; Gu, Q.; Wu, W.-T.; Zhao, Z.-A.; You, S.-L. J.
Am. Chem. Soc. 2014, 136, 15469. (h) Du, K.; Guo, P.; Chen, Y.;
Cao, Z.; Wang, Z.; Tang, W.-J. Angew. Chem., Int. Ed. 2015, 54,
3033. (i) Xu, R.-Q.; Yang, P.; Tu, H.-F.; Wang, S.-G.; You, S.-L.
Angew. Chem., Int. Ed. 2016, 55, 15137. (j) Xu, R.-Q.; Gu, Q.; You,
S.-L. Angew. Chem., Int. Ed. 2017, 56, 7252.
Corresponding Author
*yxjia@zjut.edu.cn
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for generous support from the National Natural
Science Foundation of China (nos. 21522207, 21702184, and
21772175).
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(14) See SI files for the X-ray structures of compounds 4a, 15
and 18.
(15) See SI files for the detail of condition optimization.
(16) The racemic reaction of pyrrole 9 has been reported, see:
Ren, H.; Li, Z.; Knochel, P. Chem. Asia J. 2007, 2, 416.
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