Cu-Catalyzed Arylation/Acyl Migration Cascade Reaction of Enaminones: Access to N-Fused Polycyclic and 2,3-Disubstituted Indoles

Article abstract of DOI:10.1021/acs.joc.9b00866

An efficient synthesis of N-fused polycyclic and 2,3-disubstituted indoles by copper-catalyzed direct annulation/acyl migration reaction of enaminones is reported. This strategy features cheap and low loading of the catalyst/ligand, readily available starting materials, and good functional group compatibilities. Notably, allyl-containing substrates are also tolerated, which allows the downstream derivatization toward indole alkaloids.

Full text of DOI:10.1021/acs.joc.9b00866

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Article
Cu-Catalyzed Arylation/Acyl Migration Cascade Reaction of Enaminones:
Access to N-Fused Polycyclic and 2,3-Disubstituted Indoles
Weishuang Li, Zhan Dong, Yan Zhang, Zhen Zeng, Muhammad Usman, and Wen-Bo Liu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 May 2019
Downloaded from http://pubs.acs.org on May 29, 2019
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Cu-Catalyzed Arylation/Acyl Migration Cascade Reaction of Enaminones:
Access to N-Fused Polycyclic and 2,3-Disubstituted Indoles
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Weishuang Li, Zhan Dong, Yan Zhang, Zhen Zeng, Muhammad Usman and Wen-Bo Liu*
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of
Education, College of Chemistry and Molecular Sciences, Wuhan University
2
99 Bayi Rd, Wuhan 430072, Hubei, China
wenboliu@whu.edu.cn
R1
R2
K CO
2
3
N
N
OH ligand
n
I
O
n
CuI (1 mol%)
R2
28 examples, up to 83% yield
ligand (2 mol%)
DMSO, 120 ºC
O
N
H
R1
R1
R2
O
n
LiOH
N
OH
H
11 examples, up to 86% yield
Abstract:ꢀAn efficient synthesis of N-fused polycyclic and 2,3-disubstituted indoles by copper-catalyzed
direct annulation/acyl migration reaction of enaminones is reported. This strategy features cheap and
low-loading of catalyst/ligand, readily available starting materials, and good functional group
compatibilities. Notably, allyl containing substrates are also tolerated which allows the downstream
derivatization toward indole alkaloids.
Introduction
For complex natural products and pharmaceuticals syntheses, efficient methods providing a rapid
construction of versatile building blocks are becoming increasingly important. In this regard, cascade
reactions enable the formation of multiple bonds and provide the structural complexity to target
1
molecules in a single operation. Consequently, cascade reactions have attracted much attention
2
and been proven to significantly improve the efficiency of overall synthetic process. N-Fused
polycyclic indoles, dihydropyrido[1,2-a]indolones (DHPIs) in particular, widely exist in indole
3
alkaloids and bioactive compounds (Scheme 1a). Numerous efforts toward the assembly of such
4
–7
useful scaffolds have been devoted.
Acid-mediated Fischer reaction of hydrazines with
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-substituted 1,3-cyclicdiketones provided polycyclic indoles, while this method not only is
2
4
,7b
intrinsically sensitive to electronic and steric properties of the substrates,
but also lacks of
regioselectivities for meta-substituted hydrazines. Recently, expedient strategies have been
4
achieved under acid free conditions whilst primarily using precious metal catalysts. For instance,
–6
0
1
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both intramolecular and intermolecular cyclization/acyl migration were realized using rhodium
6a
6b
catalysts by the Driver group and the Zu group respectively. Pd-catalyzed intramolecular
annulation protocols with alkynes and alkenes that afforded polycyclic indole skeletons were also
5c
reported by the Zhu, Lu and the Oestreich groups independently. Notable work by Parmee et
5d,e
5g
al. established a tandem reaction of 3-aminocyclohexenone with 1,2-dibromobenzene, but with
5a
only one example. Our group also realized a Pd-catalyzed arylation/acyl migration process of
5b
enaminones for the synthesis of DHPIs.
Due to the relative abundance and inexpensive nature, copper catalysis has stimulated significant
8
research interest in indole synthesis. An initial report by Osuka and Suzuki found that a
stoichiometric copper (I) iodide could promote the cyclization of N-2-haloaryl enaminones to form
9
carbazolones and 2,3-disubstituted indoles (Scheme 1b). Catalytic transformations were then
1
0a
10b
10c
11
developed by Miura,
N-fused polycylic indoles. Recently, the Zu group developed an elegant copper-catalyzed coupling
of 2-alkynylanilines with -diazoketones/acid-promoted fragmentation sequential approach to
Jiang,
Cacchi,
and others, but none of those processes delivers
a
3
g
synthesis DHPIs which led to the total synthesis of goniomitine (Scheme 1c). Construction of
N-fused polycyclic indoles starting from easily accessible N-2-haloaryl enaminones by direct
intramolecular arylation/acyl migration is an appealing alternation as demonstrated previously by
5
a,5b
palladium catalysis.
However, aside from the costly catalysts, allyl substituents, commonly
used as a functional handle for further diverse transformations, are not tolerated due to the fact that
1
2
the olefin is prone to insert into arylpalladium intermediate to form Heck type product. To
address those issues, we sought to develop a copper-catalyzed method that is capable of turning
over the cyclization/migration cascade reaction (Scheme 1d). We speculated that the
copper-catalyzed intramolecular arylation of enaminone
1 forms indolenine 2, which could be
readily attacked by nucleophiles/bases (i.e., K
cleavage of the carbon-carbon bond (from
2
CO
3
or LiOH) followed by a retro-Claisen type
13
to II). Then the lactamization (path a) and
I
protonation (path b) of II lead to the formation of N-fused cyclic indole
3 and 2,3-disubstituted
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indole
4
respectively. The procedure can be used as an efficient tool for the synthesis of a variety
of complex indole moieties with good economic attractiveness and functional group tolerance.
Scheme 1. Representative Bioactive N-Fused Polycyclic Indoles and their Synthetic
Approaches by Copper Catalysis.
1
1
1
1
1
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1
1
1
2
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(a) Selected dihydropyrido[1,2-a]indolone-containing bioactive compounds
Me
CONH2
OH
R
H
N
N
N
O
H
Et
N
OH
HN
H
Me
Me
N
R = H: alstoscholarisine A
O
goniomitine
R = CO Me: alstoscholarisine B
HSP90 inhibitor
2
(
b) Cu-promoted/catalyzed cyclization of N-2-haloarylenaminones
O
O
CuI (stoichiometric)
X
(Osuka & Suzuki)
R1
R1
or
Cu-cat
N
H
N
H
(Jiang, Cacchi, etc)
(c) Cu-Catalyzed N-H Insertion and Michael Addition/BF -Promoted Acyl Migration
3
EWG
EWG
EWG
R1
2
)
1)
Cu-cat
R1
Ar
BF •Et O
3 2
N2
R2
Ar
+
N
(
Zu)
Ar
NH3
n
N
H
O
n
n
O
O
(d) Cu-catalyzed cyclization and acyl migration cascade of N-2-haloarylenaminones
R1
R1
I
n
Ar
Cu-cat
Ar
O
Ar
or
O
base
(this research)
N
N
H
n
n
N
H
OH
R1
1
3
4
O
path a
path b
α-arylation
base = K CO
base = LiOH
2
3
R1
O
O
B
R1
B
R1
Ar
II
Ar
n
Ar
N
a
n
n
N
b
N
B
2
I
C–C bond cleavage
O
H O
2
Results and Discussion
Our initial studies commenced with enaminone 1a as a model substrate (Table 1). With CuI alone
as the catalyst, no product was observed (Table 1, entry 1). A series of ligands, including proline,
bipyridine, BINOL, and 8-hydroxyquinoline (8-HQ), commonly employed in copper-catalyzed
14
o
coupling reactions were first investigated using Cs
–5). It was found that 8-HQ led to the formation of the desired product 3a in 67% yield in 30 min
entry 5). By further screening the bases (entries 6–9), we found that the reaction proceeded more
2 3
CO as the base in DMSO at 120 C (entries
2
(
efficiently with K
2
CO
3
(entry 9). Although a full conversion of starting material was observed with
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a
Table 1 Reaction Condition Optimization
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
1
2
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0
1
2
3
4
5
6
7
8
9
0
b
b
entry
[Cu] (mol %) ligand (mol %)
base (equiv)
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
t (h)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
12
3a (%)
ND
4a (%)
ND
ND
ND
ND
ND
ND
77
1
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (2)
_
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
(4)
(4)
(4)
(4)
(4)
2
L-proline (20)
2,2'-bpy (20)
BINOL (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (20)
8-HQ (4)
8-HQ (2)
8-HQ (1)
8-HQ (2)
8-HQ (2)
8-HQ (2)
8-HQ (2)
8-HQ (2)
22
c
3
(50)
4
64
67
61
5
6
KOAc (4)
LiOH (4)
7
ND
c
8
K
K
K
K
K
K
K
K
K
K
K
K
3
2
2
2
2
2
2
2
2
2
2
2
PO
4
(4)
(>95) (3a:4a = 1:3)
9
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
(4)
74
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
c
c
10
(2)
82 (>95)
85 (>95)
75
1
1
1
2
(1.5)
(1)
c
13
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(29)
d
d
d
1
1
1
1
1
1
4
5
6
7
8
9
toluene
ND
dioxane 12
ND
THF
12
12
12
1.5
1.5
2
ND
DCM
ND
d
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
ND
c
c
84 (>95)
83 (>95)
71
20
CuI (1)
CuI (0.5)
CuI (1)
K
2
CO
3
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
2
2
1
2
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
e
f
3
3
3
3
3
3
59
c
23
CuI (1)
12
12
2
(33)
g
c
2
2
2
4
5
6
CuI (1)
(<5)
CuCl (1)
CuBr (1)
71
76
2
a
Reactions conditions: 0.02 mmol of CuI (10 mol %), 0.04 mmol of ligand (20 mol %), 0.2 mmol of 1a and 0.8 mmol of base
in 2 mL of solvent. Isolated yield. Conversion of 1a as determined by H NMR of the crude mixture. Reflux. 100 C. 80 C.
b
c
1
d
e
o
f
o
g
o
6
0 C. ND = not detected.
4
equivalent of K
decomposition of enaminone or the product probably occurred during the reaction. Thus we tested
the reaction by lowering the base equivalents (entries 10–12) and the use of 2 equivalent of K CO
2 3
CO , the desired product was isolated in only 74% yield indicating thatꢀ the
2
3
resulted in an increased yield consequently (85%, entry 10). When screening the solvents, DMSO
stood best among others (entries 13–18). Furthermore, the catalyst loadings, reaction temperature,
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and other copper sources were also investigated (entries 19–26), and we identified the optimal
conditions as 1 mol % of CuI and 2 mol % of 8-HQ, 1.5 equivalent of K
2 3
CO in DMSO, which
delivered the product in 83% yield (entry 20). Notably, the product 3a could be converted to a
3
b
5
-HT3 receptor antagonist, FK 1052 according to the known procedure.
With the optimal parameters for this intramolecular annulation/acyl migration reaction
established, its applicability to different enaminones was then investigated (Table 2). A series of
emaninones (1a 1ab) are readily accessed by the condensation of 2-iodoanilines with
,3-diketones in moderate to good yields (eq 1). Enaminones with methyl attached on various
positions of the N-aryl moiety, afforded the corresponding 4-methyl (3b), 5-methyl (3c), and
-methyl (3d) DHPIs in 72–82% yields. 5,7-Dimethyl DHPI 3e was obtained in 74% yield.
Substituents such as fluoro, chloro, bromo, trifluoromethyl, and nitro groups on aryl ring were all
tolerated and delivered products 3f 3j in 69–81% yields. The electronic effects of the different
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
6
–
groups on the yields seem clear with the fact electron-withdrawing substituted substrates showed
lower efficiency (i.e., 3c, 82% vs 3j, 69%). However, a substrate with a methyl substituent ortho to
iodo group (1b) delivered a comparatively low yield (3b, 72% vs 3c, 82%), suggesting that the
oxidative addition is sensitive to the steric hindrance. Importantly, pyridine derived substrate 1k
was converted smoothly under the standard reaction conditions to 7-azaindole 3k in 73% yield
1
5
without needing the chromatographic purification, indicating the compatibility of our method
with heterocycles. Substituents on the emaminone moiety were then explored. Substrates bearing
benzyl and n-butyl groups were found to provide 3l and 3m in 63% and 64% yields, respectively.
Ester containing DHPI 3n was successfully obtained albeit in low yield. Apart from aliphatic
groups, emaminones with
a
-aryl substitutions (phenyl and trifluoromethyl phenyl) gave the DHPIs
3
3
o and 3p in 52% and 62% yields correspondingly. Five membered pyrrolo[1,2-a]indoles 3q and
5
, which were challenging to synthesize by palladium catalysis, were accessed in good yield
b
r
under copper-catalyzed conditions. Notably, indoles with olefin-containing substituents are useful
intermediates toward the synthesis of complex molecules since the diverse transformations of
alkene groups into other functionalities being well established. We were pleased to find that the
copper-catalyzed method is capable of converting the a-allyl substituted enaminones to the desired
products. An array of substituents on the aniline moiety (i.e., methyl, fluoro, chloro, bromo and
nitro), were all well tolerated in the reaction to afford the corresponding allyl substituted DHPIs
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
s
–
3z in 62–83% yields. Again, a nitro substituted substrate 1z gave a comparatively low yield
(
62%) of the corresponding indole 3z. When internal alkene-substituted enaminones (1aa and 1ab)
were used, the desired products 3aa and 3ab were also obtained in moderate to good yields.
Finally, subjection of a linear 1,3-diketone derived substrate 1ac to the reaction delivered a mixture
of the acyl migration product 3ac and 2,3-dimethylindole 3ac’ in 11% yield and 75% yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
respectively.
O
p-TsOH·H O
I
2
I
R1
O
Dean-Stark
R2
R2
+
(eq 1)
toluene, reflux
N
H
O
NH2
R1
1a-1ab: 31–84% yield
a
Table 2. Scope for the Synthesis of N-Fused Polycyclic Indoles
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R1
R2
I
CuI (1 mol%)
n
8-HQ (2 mol%)
R2
O
K CO (1.5 equiv)
N
N
H
2
3
R1
DMSO, 120 ºC
n = 1, 2
n
1
3
O
Me
3a: R = H; 83% yield
3f: R = 5-F; 76% yield
3g: R = 5-Cl; 76% yield
3h: R = 5-Br; 81% yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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0
1
2
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5
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0
1
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0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
b: R = 4-Me; 72% yield
c: R = 5-Me; 82% yield
R
3
N
3d: R = 6-Me; 80% yield
3i: R = 5-CF
; 79% yield
3
O
3e: R = 5,7-(Me) ; 74% yield
3j: R = 5-NO
2
; 69% yield
2
R
Ar
Me
CO t-Bu
2
N
N
O
N
N
N
3
6
l: R = Bn;
3% yield
O
O
O
3
3
o: Ar = Ph; 52% yield c
k, 73% yield b 3m: R = n-Bu; 64% yield 3n, 39% yield
3
c
p: Ar = 4-CF C H ; 62% yield
3
6 4
Me
R
3
3
3
s: R = H; 75% yield
t: R = 4-Me; 70% yield
u: R = 5-Me; 83% yield
R
N
O
N
O
3v: R = 6-Me; 69% yield
3
q: R = H;
2% yield d
3r: R = Me;
73% yield d
6
Me
Ph
Me
R2
N
y: R2 = Br;
3
N
N
O
7
6% yield
O
w: R2 = F; 3x: R2 = Cl; 3z: R2 = NO
7% yield 76% yield 62% yield e
3
7
;
2
O
3aa, 54% yield
3ab, 75% yield
O
Me
Me
Me
Me
Me
H
N
standard
conditions
Me
N
Me
N
H
I
O
Me
1
ac
3
ac, 11% yield
3ac', 75% yield
a
b
c
Reactions conducted under the conditions of entry 12, Table 1. Yield without silica gel chromatography. With CuI (10
mol %) and 8-HQ (20 mol %). With CuI (2 mol %) and 8-HQ (4 mol %). With CuI (5 mol %) and 8-HQ (10 mol %).
d
e
During the optimization of reaction conditions, we observed that the formation of polycyclic
indoles was completely interrupted when LiOH was used as base. Instead, the generation of
2
,3-dialkylindole 4a was achieved in a significant amount (see Table 1, entry 7). Encouraged by
this finding, we inquired whether we could apply this method to synthesize 2,3-disubstituted
indoles. It is worth noting that the previous studies on copper-catalyzed reactions mainly focused
9
,10,16
on the formation of disubstituted indoles that contained 3-carbonyl substituents.
Our method
provides an orthogonal access to the disubstituted indoles with 3-alkyl (allyl) and aryl groups. A
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quick survey of the substrate scope was conducted and the results were summarized in Table 3.
Enaminone 1a led to a 77% isolated yield of the desired product 4a. Enaminones with methyl
substitutions at different positions on the aryl ring all gave the corresponding indole-2-butyric
acids (4b
limited impact on the outcomes of the reactions and the indole-2-butyric acids (4e
isolated in 65–70% yields. 3-Aryl and 3-allyl substituted indole-2-butyric acids (4i 4j) were also
synthesized from -aryl and -allyl substituted enaminones in 39% and 67% yields, respectively.
–
4d) in moderate to good yields (69–86%). Halides and nitro groups on the substrates had
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
4h) were
–
a
a
Finally, 3-methyl substituted indole-2-propanoic acid
cyclopentane-1,3-dione derived enaminones in 57% yield.
(
4k
)
was obtained from
a
Table 3. Scope for the Synthesis of 2,3-Disubstituted Indoles
R1
I
CuI (10 mol%)
R2
n
8-HQ (20 mol%)
R2
O
O
LiOH (4 equiv)
DMSO, 120 ºC
n
N
H
N
H
OH
R1
1
4
Me
Me
Me
Me
O
O
O
Me
OH
OH
OH
OH
3
3
3
N
H
N
H
N
H
4
a, 77% yield
4b, 86% yield
4c, 69% yield
Me
Me
Me
O
O
O
O N
2
X
OH
OH
3
3
3
N
H
N
H
N
H
Me
4
h, 70% yield
4
d, 77% yield
4e: X = F; 4f: X = Cl; 4g: X = Br;
6
5% yield 64% yield 68% yield b
Ph
Me
O
O
OH
OH
OH
3
3
O
N
H
N
H
N
H
4
i, 39% yield
4j, 67% yield
4k, 57% yield
a
Reactions conducted with CuI (10 mol %), 8-HQ (20 mol %), enaminone 1 (0.2 mmol), and LiOH (0.8 mmol) in 2 mL of
o
b
DMSO at 120 C. With CuI (5 mol %) and 8-HQ (10 mol %).
The potential utility of the method was showcased by a scale-up synthesis and product
derivatizations (Scheme 2). 3-Allylindole (3s) was obtained in 56% yield (1.3 g) under the standard
reaction conditions on a gram-scale. Dihydroxylation and oxidative cleavage of the olefin of 3s
4
into aldehyde followed by NaBH reduction provided alcohol 5, a core structure of alkaloid
goniomitine, in 75% overall yield. The amide group of 3a was readily reduced by borane to the
corresponding amine 6a in 95% yield. Meanwhile, Suzuki coupling of the bromo-containing
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compound 3h proceeded smoothly to give the aryl substituted indoles (
yields, respectively.
7 and 8) in 81% and 83%
Scheme 2. Gram-Scale Reaction and Product Derivatizations.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
OH
a
b
N
1
s
H
N
N
HN
Et
3
s
5
O
O
1
.30 gram
goniomitine
Me
Me
Me
R
Ar
c
d
N
N
N
from 3a
from 3h
6
3a: R = H
h: R = Br
O
7: Ar = Ph
8: Ar = 2-NHTs-C H
O
3
6
4
o
Reaction conditions: (a) CuI (1 mol %), 8-HQ (2 mol %), K
2
CO
O (1/1), 25 C; ii) NaIO (1.5 equiv), THF/H
(2/1), 0 C; 75% yield of 3-step. (c) BH •DMS (2 equiv), THF, 95% yield. (d) For 7: Pd(dppf)Cl
(1.5 equiv), K CO (2.5 equiv), dioxane/H O (3/1), 70 C, 81% yield; for 8: Pd(dppf)Cl
-Bpin (1.1 equiv), dioxane/H O (3/1), 70 C, 83% yield.
3
(1.5 equiv), DMSO, 120 C, 56%. (b) i) K
2
OsO
4
•2H
(2 equiv),
(10 mol %),
(10 mol %), Cs CO (1.4
2
O (5
o
o
mol %), NMO (5 equiv), THF/H
2
4
2 4
O (1/1), 25 C; iii) NaBH
o
MeOH/CH
PhB(OH)
2
Cl
2
3
2
o
2
2
3
2
2
2
3
o
equiv), 2-NHTs-C
6
H
4
2
2
Conclusions
In summary, we have developed an efficient copper-catalyzed intramolecular cyclization and
acyl migration cascade reaction of enaminones. The robustness of this reaction was demonstrated
by 39 examples with as low as 1 mol % catalyst loading. This approach represents potentially
powerful and attractive alternative (to noble-metal catalysts) route for direct access to a wide range
of fused polycyclic indoles and 2,3-disubstituted indoles, prevailed motifs found in numerous
biologically active molecules. Further transformations of the products provided access to
structurally diverse and highly functionalized indoles.
Experimental Section
General Methods
：
Unless otherwise stated, all experiments were carried out in flame-dried glassware
using argon manifolds or in an argon-filled glovebox. Reactions were monitored by thin-layer
chromatography (TLC) or gas chromatography (GC). TLC was performed using Huanghai 8±0.2 µm
precoated glass plates (0.25 mm). Huanghai silica gel (particle size 300 – 400 mess) was used for
o
chromatography. Petroleum ether (PE) (60 ~ 90 C), ethyl acetate (EA), dichloromethane (DCM) and
acetone were used as eluents for silica gel chromatography. NMR spectra were recorded at room
13
1
temperature on a 400 MHz spectrometer. C and H chemical shifts in NMR spectra were referenced
1
13
1
relative to signals of CDCl
3
(δ 7.26 ppm for H and 77.16 ppm for C). Data for H NMR were reported as
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chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration) using standard abbreviations for
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet and br = broad
1
3
1
19
signal. Data for
C{ H}NMR and F NMR were reported in terms of chemical shifts (δ ppm). IR spectra
were obtained on a Thermo Scientific Spectrum Nicolet iS10 spectrometer using thin films deposited on
0
1
2
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8
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0
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3
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
KBr plates (Thermo Fisher Scientific) and were reported in frequency of absorption (cm ). High
resolution mass spectra (HRMS) were recorded by the electron spray ionization (ESI) method on a Q-TOF
Micro with a lock spray source. All reagents were purchased commercially and used without further
purification. Dry solvents were purchased commercially or were dried by passage through an activated
17
alumina column under argon. Known compounds data have been compared with the reported data, and
references were given appropriately. Characterization data for new compounds is given below, and copies
1
13
of H and C NMR spectra for all new compounds are given in the Supporting Information.
General Procedure for Synthesis of N-Fused Polycyclic Indoles (3a-3aa).
To a vial equipped with a magnetic stirring bar were added 0.2 mL of CuI stock solution
[
containing 0.002 mmol of CuI (1 mol %); the stock solution was prepared by dissolving 2.2 mg
CuI and 4.7 mg 8-HQ in 1.2 mL DMSO under argon atmosphere, and stir at room temperature for
30 min; all the experiments below were carried out using the CuI stock solution unless otherwise
noted], substrate 1a (65.8 mg, 0.2 mmol), K
2
CO
3
(41.5 mg, 0.3 mmol), and DMSO (1.8 mL) in an
o
argon-filled glovebox. After the vial was sealed and stirred at 120 C (heating mantle) for 1.5 h, the
reaction was cooled to room temperature and brought out from the glovebox. The mixture was
diluted with EA (15 mL) and water (15 mL), then separated, and the aqueous phase was extracted
with EA (20 mL × 3). The combined organic phase was washed with water (20 mL × 3), brine and
dried over anhydrous Na
2 4
SO . Then the solvents were removed under vacuum. The desired product
3
a
(33.2 mg, 83% yield) was obtained as a white solid after purification by silica gel
1
chromatography (PE/EA = 10/1). H NMR (400 MHz, CDCl
3
) δ 8.46 – 8.43 (m, 1H), 7.44 –7.42
(
m, 1H), 7.32 – 7.26 (m, 2H), 2.90 (t, J = 6.2 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 2.18 (s, 3H), 2.11 –
5b
2
.04 (m, 2H).
1
1
,10-Dimethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3b. White solid (30.6 mg, 72% yield); H
NMR (400 MHz, CDCl
3
) δ 8.35 (d, J = 8.2 Hz, 1H), 7.19 – 7.11 (m, 1H), 6.99 (d, J = 7.4 Hz, 1H),
5b
2
.88 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.67 (s, 3H), 2.36 (s, 3H), 2.13 – 2.01 (m, 2H).
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,10-Dimethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3c. White solid (34.9 mg, 82% yield); H
NMR (400 MHz, CDCl ) δ 8.30 (d, J = 8.3 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 2.88 (t,
J = 6.2 Hz, 2H), 2.79 – 2.68 (m, 2H), 2.46 (s, 3H), 2.15 (s, 3H), 2.12 – 2.00 (m, 2H).
,10-Dimethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3d. White solid (34.2 mg, 80% yield); H
3
5
b
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (400 MHz, CDCl
3
) δ 8.28 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 2.88 (t,
5b
J = 6.2 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.48 (s, 3H), 2.16 (s, 3H), 2.10 – 2.04 (m, 2H).
2
,4,10-Trimethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3e. White solid (33.6 mg, 74% yield);
1
H NMR (400 MHz, CDCl
3
) δ 7.03 (s, 1H), 6.91 (s, 1H), 2.89 (t, J = 6.2 Hz, 2H), 2.77 (t, J = 6.4
5b
Hz, 2H), 2.60 (s, 3H), 2.41 (s, 3H), 2.13 (s, 3H), 2.11 – 2.02 (m, 2H).
2
-Fluoro-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3f. White solid (32.9 mg, 76%
1
yield); H NMR (400 MHz, CDCl
3
) δ 8.37 (dd, J = 8.9, 4.8 Hz, 1H), 7.06 (dd, J = 8.9, 2.5 Hz, 1H),
6
2
.98 (td, J = 9.1, 2.6 Hz, 1H), 2.90 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), 2.14 (s, 3H), 2.12 –
5
b
.06 (m, 2H).
2
-Chloro-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3g. White solid (35.4 mg, 76%
1
yield); H NMR (400 MHz, CDCl
3
) δ 8.34 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.22 (dd, J
= 8.7, 2.1 Hz, 1H), 2.90 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), 2.14 (s, 3H), 2.12 – 2.07 (m,
5
b
2H).
2-Bromo-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3h. White solid (44.9 mg, 81%
1
yield); H NMR (400 MHz, CDCl
3
) δ 8.29 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.36 (dd, J
=
8.7, 2.0 Hz, 1H), 2.90 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 2.12 – 2.07 (m,
5
b
2
H).
1
0-Methyl-2-(trifluoromethyl)-8,9-dihydropyrido[1,2-a]indol-6 (7H)-one 3i. White solid (42.1 mg,
1
9% yield); H NMR (400 MHz, CDCl
7
3
) δ 8.52 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 8.5,
1
H), 2.94 (t, J = 6.2 Hz, 2H), 2.81 (t, J = 6.2 Hz, 2H), 2.21 (s, 3H), 2.15 – 2.09 (m, 2H). The
5
b
spectroscopic characterization data were found consistent with those reported in the literature.
1
0-Methyl-2-nitro-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3j. Yellow solid (33.5 mg, 69% yield);
1
H NMR (400 MHz, CDCl
3
) δ 8.50 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 9.0,
5b
2
.2 Hz, 1H), 2.96 (t, J = 6.2 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.23 (s, 3H), 2.19 – 2.08 (m, 2H).
5
-Methyl-7,8-dihydropyrido[3,2-b]indolizin-9(6H)-one 3k. The desired analytic pure product 3k
(
29.1 mg, 73% yield) was obtained after workup following the general procedure. Further isolation
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5
5
5
5
5
6
using short column silica gel chromatography (5 cm, PE/EA = 1/1) resulted in 41% yield (16.2 mg)
1
as it was found unstable on the silica gel; H NMR (400 MHz, C
6
D
6
) δ 8.52 (dd, J = 4.7, 1.6 Hz,
1
H), 7.27 (dd, J = 7.7, 1.6 Hz, 1H), 6.82 (dd, J = 7.7, 4.7 Hz, 1H), 2.17 (t, J = 6.4 Hz, 2H), 2.01 (t,
5
b
J = 6.2 Hz, 2H), 1.73 (s, 3H), 1.17 – 1.03 (m, 2H).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
0-Benzyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3l. White solid (34.6 mg, 63% yield); H
NMR (400 MHz, CDCl
3
) δ 8.48 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.32 – 7.16 (m, 7H),
5a
4
.03 (s, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.17 – 2.03 (m, 2H).
1
1
0-Butyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3m. Yellow solid (30.7 mg, 64%), H NMR
400 MHz, CDCl ) δ 8.45 – 8.44 (m, 1H), 7.45 – 7.44 (m, 1H), 7.29 – 7.24 (m, 2H), 2.89 (t, J = 6.4
(
3
Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.09 – 2.03 (m, 2H), 1.63 – 1.55 (m,
5b
2
H), 1.41 – 1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).
tert-Butyl 2-(6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate 3n. Brown oil (22.9 mg,
1
9%), H NMR (400 MHz, CDCl
3
3
) δ 8.46 – 8.44 (m, 1H), 7.50 – 7.48 (m, 1H), 7.32 – 7.25 (m,
2
H), 3.55 (s, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.12 – 2.09 (m, 2H), 1.42 (s,
1
3
1
9H);
3
Cꢀ{ H}NMR (100 MHz, CDCl ) δ 170.2, 169.5, 135.4, 134.6, 130.0, 124.5, 124.0, 118.2,
–
116.5, 110.4, 81.3, 34.5, 31.7, 28.2, 22.0, 21.2. IR ν (cm ): 3435, 3054, 3002, 2977, 2923, 1722,
1
1695, 1461, 1366, 1337, 1320, 1216, 1171, 1147, 1129, 1104, 1051, 795; HRMS (ESI+) calc’d for
+
[M+Na] : 322.1414, found 322.1415.
C
18
H
21NNaO
3
1
10-Phenyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3o. White solid (27.4 mg, 52%), H NMR
400 MHz, CDCl ) δ 8.57 – 8.54 (m, 1H), 7.61 – 7.59 (m, 1H), 7.51 – 7.49 (m, 4H), 7.36 – 7.19
m, 3H), 3.07 (t, J = 6.2 Hz, 2H), 2.85 (t, J = 6.2 Hz, 2H), 2.12 – 2.06 (m, 2H). The spectroscopic
(
3
(
6
a
characterization data were found consistent with those previously reported in the literature.
1
0-(4-(Trifluoromethyl)phenyl)-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3p. White solid (40.6
1
mg, 62%), H NMR (400 MHz, CDCl
3
) δ 8.56 (dd, J = 7.6, 0.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H),
7
2
.61 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.39 – 7.29 (m, 2H), 3.07 (t, J = 6.3 Hz, 2H),
6a
.87 (t, J = 6.5 Hz, 2H), 2.15 – 2.09 (m, 2H).
1
9
-Methyl-1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-one 3q. White solid (23.0 mg, 62% yield); H
NMR (400 MHz, CDCl
3
) δ 8.05 – 8.02 (m, 1H), 7.50 – 7.35 (m, 1H), 7.30 – 7.26 (m, 2H), 3.08 (m,
5b
4
H), 2.19 (s, 3H).
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,9-Dimethyl-1H-pyrrolo[1,2-a]indol-3(2H)-one 3r. White solid (28.9 mg, 73% yield); H NMR
(
400 MHz, CDCl ) δ 7.90 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 3.06 (s, 4H),
3
1
3
1
2
1
1
.46 (s, 3H), 2.16 (s, 3H);
3
Cꢀ{ H}NMR (100 MHz, CDCl ) δ 171.4, 139.4, 136.6, 133.5, 128.6,
–
24.5, 118.7, 113.3, 108.6, 35.0, 21.9, 18.6, 8.4; IR ν (cm ): 3426, 2920, 2857, 1728, 1633, 1457,
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
444, 1403, 1382, 1358, 1292, 1228, 1180, 1094, 881, 809; HRMS (ESI+) calc’d for C13
H
13NNaO
+
M+Na] : 222.0889, found 222.0892.
[
1
1
0-Allyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3s. White solid (34.0 mg, 75% yield); H NMR
(
400 MHz, CDCl
3
) δ 8.50 – 8.40 (m, 1H), 7.51 – 7.37 (m, 1H), 7.33 – 7.19 (m, 2H), 5.92 (ddt, J =
1
6.2, 10.1, 6.1 Hz, 1H), 5.24 – 4.87 (m, 2H), 3.38 (d, J = 6.0 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 2.75
13
t, J = 6.4 Hz, 2H), 2.06 (quint, J = 6.4 Hz, 2H); C
1
{ H}NMR (100 MHz, CDCl
(
ꢀ
3
) δ 169.4, 135.6,
–1
34.7, 134.0, 130.3, 124.2, 123.8, 118.2, 116.4, 115.6, 114.2, 34.5, 28.3, 21.8, 21.2; IR ν (cm ):
1
3
376, 3065, 3048, 2972, 2949, 2877, 1698, 1615, 1459, 1367, 1327, 1309, 1176, 1131, 899, 748;
+
HRMS (ESI+) calc’d for C15
H
15NNaO [M+Na] : 248.1046, found 248.1053.
1
0-Allyl-1-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3t. White solid (33.5 mg, 70% yield);
1
3
H NMR (400 MHz, CDCl ) δ 8.39 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.4
Hz, 1H), 6.03 (ddt, J = 17.1, 10.2, 5.2 Hz, 1H), 5.05 (dq, J = 10.2, 1.8 Hz, 1H), 4.89 (dq, J = 17.1,
1.9 Hz, 1H), 3.53 (dt, J = 5.0, 1.9 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.61
1
3
1
(s, 3H), 2.07 (quint, J = 6.4 Hz, 2H);
3
Cꢀ { H}NMR (100 MHz, CDCl ) δ 169.4, 136.7, 135.2,
–
134.5, 129.9, 128.6, 126.1, 124.2, 115.5, 114.6, 114.3, 34.7, 29.3, 21.7, 21.2, 19.8; IR ν (cm ):
1
3
375, 3092, 2956, 2932, 2893, 1697, 1618, 1463, 1426, 1366, 1332, 1287, 1182, 1119, 924, 782;
+
HRMS (ESI+) calc’d for C16
H
17NNaO [M+Na] : 262.1202, found 262.1207.
1
0-Allyl-2-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3u. White solid (39.3 mg, 83% yield);
1
3
H NMR (400 MHz, CDCl ) δ 8.32 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.95
(
ddt, J = 16.2, 10.1, 6.0 Hz, 1H), 5.16 – 4.99 (m, 2H), 3.38 (d, J = 6.0 Hz, 2H), 2.88 (t, J = 6.2 Hz,
1
H), 2.76 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H), 2.07 (quint, J = 6.4 Hz, 2H); Cꢀ{ H}NMR (100 MHz,
3
1
2
CDCl
3
) δ 169.2, 135.6, 134.1, 133.3, 132.8, 130.5, 125.4, 118.3, 116.1, 115.6, 114.0, 34.5, 28.2,
–1
1.8, 21.7, 21.3; IR ν (cm ): 3374, 3002, 2949, 1699, 1614, 1476, 1462, 1373, 1331, 1314, 1290,
2
1
2
+
175, 1146, 1041, 922, 814; HRMS (ESI+) calc’d for C16
62.1200.
H17NNaO [M+Na] : 262.1202, found
1
0-Allyl-3-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3v. White solid (33.3 mg, 69% yield);
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
H NMR (400 MHz, CDCl
3
) δ 8.31 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 5.93
(
ddt, J = 16.4, 10.8, 6.0 Hz, 1H), 5.15 – 4.97 (m, 2H), 3.38 (d, J = 5.9 Hz, 2H), 2.88 (t, J = 6.2 Hz,
1
H), 2.77 (t, J = 6.3 Hz, 2H), 2.48 (s, 3H), 2.07 (quint, J = 6.3 Hz, 2H); C
3
1
ꢀ{ H}NMR (100 MHz,
2
CDCl
3
) δ 169.5, 135.7, 135.1, 134.3, 133.3, 128.1, 125.1, 117.9, 116.8, 115.6, 114.1, 34.6, 28.4,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
1.91, 21.87, 21.3; IR ν (cm ): 3385, 3089, 2941, 1702, 1618, 1435, 1369, 1333, 1310, 1177,
2
1
2
+
109, 1035, 997, 898, 882, 809; HRMS (ESI+) calc’d for C16
62.1210.
H17NNaO [M+Na] : 262.1202, found
1
0-Allyl-2-fluoro-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3w. White solid (37.6 mg, 77% yield);
H NMR (400 MHz, CDCl ) δ 8.39 (dd, J = 8.9, 4.8 Hz, 1H), 7.09 (dd, J = 8.9, 2.6 Hz, 1H), 6.98
td, J = 9.1, 2.6 Hz, 1H), 5.95 – 5.86 (m, 1H), 5.19 – 4.98 (m, 2H), 3.35 (dt, J = 6.2, 1.7 Hz, 2H),
1
3
(
13
1
2
.90 (t, J = 6.2 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 2.09 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100
) δ 169.2, 160.0 (d, JC-F = 238.5 Hz), 135.8, 135.2, 131.6 (d, JC-F = 9.5 Hz), 131.0,
17.4 (d, JC-F = 9.0 Hz), 116.0, 114.0 (d, JC-F = 3.8 Hz), 111.6 (d, JC-F = 24.5 Hz), 104.3 (d, JC-F
MHz, CDCl
3
1
2
=
1
9
–1
3
3.9 Hz), 34.4, 28.3, 21.9, 21.3; F NMR (376 MHz, CDCl ) δ – 118.90; IR ν (cm ): 3427, 2945,
1698, 1617, 1603, 1470, 1372, 1334, 1179, 1144, 1085, 1003, 929, 887, 850, 814; HRMS (ESI+)
+
calc’d for C15
H
14FNNaO [M+Na] : 266.0952, found 266.0919.
10-Allyl-2-chloro-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3x. White solid (39.5 mg, 76% yield);
1
H NMR (400 MHz, CDCl
3
) δ 8.36 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.7,
2.1 Hz, 1H), 6.02 – 5.78 (m, 1H), 5.15 – 5.00 (m, 2H), 3.36 (d, J = 6.0 Hz, 2H), 2.90 (t, J = 6.4 Hz,
1
H), 2. 78 (t, J = 6.4 Hz, 2H), 2.10 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz, CDCl
3
1
2
1
3
) δ
69.3, 135.6, 135.1, 133.1, 131.8, 129.4, 124.3, 118.1, 117.4, 116.0, 113.7, 34.4, 28.2, 21.9, 21.2;
–
IR ν (cm ): 3384, 2951, 1698, 1614, 1457, 1367, 1316, 1276, 1179, 1148, 1067, 1044, 995, 902,
1
+
8
21, 807; HRMS (ESI+) calc’d for C15
H
14ClNNaO [M+Na] : 282.0656, found 282.0662.
1
0-Allyl-2-bromo-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3y. White solid (46.3 mg, 76% yield);
H NMR (400 MHz, CDCl ) δ 8.31 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.7,
.9 Hz, 1H), 5.91 (ddt, J = 17.3, 9.4, 6.0 Hz, 1H), 5.17 – 4.95 (m, 2H), 3.35 (d, J = 5.9 Hz, 2H),
1
3
1
2
13
1
.90 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.09 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100
MHz, CDCl
3
) δ 169.3, 135.5, 135.1, 133.4, 132.2, 127.0, 121.2, 117.8, 117.2, 116.1, 113.6, 34.4,
–1
8.2, 21.9, 21.2; IR ν (cm ): 3423, 2949, 1694, 1638, 1617, 1458, 1435, 1376, 1332, 1177, 1145,
2
1
+
054, 999, 919, 861, 805; HRMS (ESI+) calc’d for C15H14BrNNaO [M+Na] : 326.0151, found
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26.0151.
0-Allyl-2-nitro-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3z. Yellow solid (33.4 mg, 62% yield);
H NMR (400 MHz, CDCl ) δ 8.51 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 9.0,
.2 Hz, 1H), 5.93 (ddt, J = 16.3, 10.4, 6.0 Hz, 1H), 5.17 – 4.99 (m, 2H), 3.43 (d, J = 5.9 Hz, 2H),
1
1
3
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.96 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 2.14 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100
3
1
MHz, CDCl
3
) δ 169.5, 144.4, 137.8, 137.5, 134.7, 130.5, 119.6, 116.5, 116.4, 114.7, 114.5, 34.4,
–1
8.0, 21.9, 20.9; IR ν (cm ): 3428, 3088, 2958, 1705, 1624, 1514, 1457, 1377, 1362, 1336, 1177,
2
1
2
+
[M+Na] : 293.0897, found
128, 997, 924, 793, 745; HRMS (ESI+) calc’d for C15
93.0902.
H
14
N
2
NaO
3
1
1
0-Cinnamyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3aa. Yellow oil (32.6 mg, 54% yield); H
NMR (400 MHz, CDCl
3
) δ 8.53 – 8.46 (m, 1H), 7.51 (dd, J = 7.3, 1.6 Hz, 1H), 7.36 – 7.28 (m,
6
H), 7.25 – 7.18 (m, 1H), 6.51 – 6.42 (m, 1H), 6.40 – 6.29 (m, 1H), 3.59 (d, J = 6.1 Hz, 2H), 2.97
1
t, J = 6.3 Hz, 2H), 2.81 (t, J = 6.4 Hz, 2H), 2.12 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz,
3
1
(
CDCl ) δ 169.5, 137.3, 134.8, 134.2, 130.7, 130.4, 128.6, 127.5, 127.3, 126.2, 124.4, 123.9, 118.3,
3
–
116.5, 114.4, 34.6, 27.6, 22.0, 21.3; IR ν (cm ): 3319, 3025, 2926, 2850, 1702, 1616, 1457, 1369,
1
+
1333, 1309, 1174, 1129, 1102, 1054, 963, 749; HRMS (ESI+) calc’d for C21
324.1359, found 324.1364.
H
19NNaO [M+Na] :
10-(3-Methylbut-2-en-1-yl)-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 3ab. White solid (38.0 mg,
1
75% yield); H NMR (400 MHz, CDCl
3
) δ 8.42 – 8.32 (m, 1H), 7.41 – 7.32 (m, 1H), 7.25 – 7.13
(
m, 2H), 5.18 – 5.13 (m, 1H), 3.25 (d, J = 7.0 Hz, 2H), 2.84 (d, J = 6.4 Hz, 2H), 2.68 (d, J = 6.4
1
3
Hz, 2H), 2.00 (quint, J = 6.4 Hz, 2H), 1.73 (s, 3H), 1.63 (d, J = 1.2 Hz, 3H); C{ H}NMR (100
1
MHz, CDCl ) δ 169.4, 134.8, 133.2, 132.3, 130.5, 124.2, 123.8, 122.0, 118.3, 116.5, 116.3, 34.6,
3
–
5.8, 23.1, 21.9, 21.3, 18.1; IR ν (cm ): 3373, 2907, 1698, 1619, 1457, 1370, 1336, 1306, 1174,
1
2
1
2
+
141, 1128, 1110, 1019, 940, 767, 755; HRMS (ESI+) calc’d for C17H19NNaO [M+Na] :
76.1359, found 276.1362.
1
,3-Dimethyl-1H-indole 3ac. Yellow solid (21.9 mg, 75% yield); H NMR (400 MHz, CDCl
2
3
) δ
7
2
.69 (br s, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 – 7.05 (m, 2H), 2.37 (s, 3H),
18
.23 (s, 3H).
General Procedure for the Synthesis of 2,3-Disubstituted Indoles (4a–4k)
To a vial equipped with a magnetic stirring bar were added CuI (3.8 mg, 10 mol %), 8-HQ (5.8 mg,
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2
0 mol %), substrate 1a (65.4 mg, 0.2 mmol), LiOH (20.7 mg, 0.8 mmol), and DMSO (2.0 mL) in
o
an argon-filled glovebox. After the vial was sealed and stirred at 120 C (heating mantle) for 0.5 h,
the reaction was cooled to room temperature and brought out from the glovebox. The mixture was
diluted with EA (15 mL) and water (15 mL), separated, and the aqueous phase was extracted with
EA (20 mL × 3). The combined organic phase was washed with water (20 mL × 3), brine and dried
0
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4
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8
9
0
1
2
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4
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9
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8
9
0
1
2
3
4
5
6
7
8
9
0
over anhydrous Na
2
SO
4
. Then the solvents were removed under vacuum. The desired product 4a
(
(
33.6 mg, 77% yield) was obtained as a white solid after purification by silica gel chromatography
1
PE/EA = 5/1). H NMR (400 MHz, DMSO-d
6
) δ 12.07 (br s, 1H), 10.66 (br s, 1H), 7.36 (d, J =
7
2
.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.00 – 6.96 (m, 1H), 6.94 – 6.89 (m, 1H), 2.70 (t, J = 7.4 Hz,
13
1
H), 2.21 (t, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.86 (quint, J = 7.5 Hz, 2H); C{ H}NMR (100 MHz,
DMSO-d
6
) δ 174.3, 135.3, 134.9, 128.7, 120.1, 118.0, 117.5, 110.4, 105.2, 33.0, 24.8, 24.7, 8.3; IR
–
ν (cm ): 3406, 2973, 2938, 1698, 1469, 1454, 1430, 1411, 1326, 1317, 1306, 1251, 1222, 949,
1
–
[M–H] : 216.1030, found 216.1033.
8
57, 802; HRMS (ESI–) calc’d for C13
H
14NO
2
1
2
-(3,4-Dimethyl-1H-indol-4-yl) butyric acid 4b. White solid (39.7 mg, 86% yield); H NMR (400
MHz, DMSO-d ) δ 12.08 (br s, 1H), 10.59 (br s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.81 (t, J = 7.5 Hz,
1H), 6.61 (d, J = 7.0 Hz, 1H), 2.66 (t, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 2.21 (t, J = 7.4
6
1
3
1
6
Hz, 2H), 1.82 (quint, J = 7.5 Hz, 2H); C{ H}NMR (100 MHz, DMSO-d ) δ 174.4, 135.5, 134.5,
–
129.1, 127.0, 120.1, 119.6, 108.6, 106.0, 33.0, 24.8, 24.5, 20.0, 11.2; IR ν (cm ): 3380, 2958,
1
–
[M–H] :
2920, 1695, 1454, 1417, 1331, 1277, 1213, 778, 747; HRMS (ESI–) calc’d for C14
30.1187, found 230.1192.
H
16NO
2
2
1
2
-(3,5-Dimethyl-1H-indol-4-yl) butyric acid 4c. White solid (32.0 mg, 69% yield); H NMR (400
MHz, CDCl
3
) δ 7.75 (br s, 1H), 7.28 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.99 – 6.92 (m, 1H), 2.78 (t,
J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.97 (quint, J = 7.2 Hz, 2H);
1
3
1
3
C{ H}NMR (100 MHz, CDCl ) δ 179.6, 133.8, 133.7, 129.6, 128.3, 122.8, 118.1, 110.1, 107.2,
–
3.0, 25.2, 24.8, 21.6, 8.6; IR ν (cm ): 3390, 2967, 2936, 2858, 1701, 1482, 1428, 1411, 1307,
1
3
1
2
–
[M–H] : 230.1187, found
243, 1222, 954, 866, 801; HRMS (ESI–) calc’d for C14
30.1188.
H
16NO
2
1
2
-(3,6-Dimethyl-1H-indol-4-yl) butyric acid 4d. White solid (35.7 mg, 77% yield); H NMR (400
MHz, CDCl
3
) δ 7.70 (br s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H),
2
.78 (t, J = 7.3 Hz, 2H), 2.46 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 2.22 (s, 3H), 1.98 (quint, J = 7.2 Hz,
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H); C{ H}NMR (100 MHz, CDCl ) δ 179.7, 135.8, 132.9, 131.1, 127.2, 120.8, 118.0, 110.5,
–
07.6, 33.0, 25.2, 24.8, 21.8, 8.7; IR ν (cm ): 3408, 2922, 2854, 1708, 1626, 1467, 1332, 1241,
1
–
[M–H] : 230.1187, found 230.1192.
210, 1153, 797; HRMS (ESI–) calc’d for C14
H
16NO
2
1
2
-(5-Fluoro-3-methyl-1H-indol-4-yl) butyric acid 4e. White solid (30.6 mg, 65% yield); H NMR
400 MHz, CD CN) δ 8.99 (br s, 1H), 7.22 (dd, J = 8.7, 4.5 Hz, 1H), 7.10 (dd, J = 10.1, 2.6 Hz,
H), 6.84 – 6.79 (m, 1H), 2.75 (t, J = 7.5 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.93 –
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3
1
1
1
13
1
3
.87 (m, 2H); C{ H}NMR (100 MHz, CD CN) δ 174.8, 158.3 (d, JC – F = 229.2 Hz), 138.0,
33.0, 130.4 (d, JC – F = 9.6 Hz), 111.9 (d, JC – F = 9.7 Hz), 109.1 (d, JC – F = 26.1 Hz), 107.6 (d, JC –
19
F
3
= 4.5 Hz), 103.3 (d, JC – F = 23.1 Hz), 33.3, 25.7, 25.4, 8.4; F NMR (376 MHz, CD CN) δ –
–1
27.52; IR ν (cm ): 3429, 2933, 2871, 1719, 1691, 1486, 1454, 1411, 1303, 1289, 1217, 1177,
1
–
[M–H] : 234.0936, found 234.0938.
1
151, 941, 847, 794; HRMS (ESI–) calc’d for C13
H
13FNO
2
1
2
-(5-Chloro-3-methyl-1H-indol-4-yl) butyric acid 4f. White solid (32.1 mg, 64% yield); H NMR
(
400 MHz, DMSO-d
6
) δ 12.09 (br s, 1H), 10.90 (br s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.23 (d, J =
8
.5 Hz, 1H), 6.97 (dd, J = 8.5, 2.1 Hz, 1H), 2.69 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 2.12
1
3
1
6
(s, 3H), 1.84 (quint, J = 7.4 Hz, 2H); C{ H}NMR (100 MHz, DMSO-d ) δ 174.3, 137.1, 133.7,
–
129.9, 122.7, 119.9, 116.9, 111.9, 105.4, 32.9, 24.8, 24.5, 8.2; IR ν (cm ): 3407, 2930, 1702, 1472,
1
–
[M–H] :
1432, 1327, 1307, 1252, 1222, 954, 857, 805; HRMS (ESI–) calc’d for C13
250.0640, found 205.0642.
H
13ClNO
2
1
2-(5-Bromo-3-methyl-1H-indol-4-yl) butyric acid 4g. White solid (40.2 mg, 68% yield); H NMR
400 MHz, CD CN) δ 9.09 (br s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.5, 0.6 Hz, 1H), 7.13
dd, J = 8.5, 1.9 Hz, 1H), 2.75 (t, J = 7.5 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.93 – 1.87
(
(
(
3
1
3
1
3
m, 2H); C{ H}NMR (100 MHz, CD CN) δ 175.0, 137.5, 135.1, 131.9, 123.9, 121.1, 113.0,
–
1
12.1, 107.2, 33.3, 25.5, 25.4, 8.4; IR ν (cm ): 3406, 2973, 2938, 1698, 1469, 1454, 1430, 1411,
1
1
2
–
[M–H] : 294.0135, found
306, 1251, 1222, 949, 857, 802; HRMS (ESI–) calc’d for C13
94.0135.
H
13BrNO
2
1
2
-(3-Methyl-5-nitro-1H-indol-4-yl) butyric acid 4h. Yellow solid (36.5 mg, 70% yield); H NMR
(
400 MHz, DMSO-d
6
) δ 12.11 (br s, 1H), 11.53 (br s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 7.92 (dd, J =
8
.9, 2.3 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 2.75 (t, J = 7.5 Hz, 2H), 2.25-2.21 (m, 5H), 1.87 (quint,
13
1
6
J = 7.4 Hz, 2H); C{ H}NMR (100 MHz, DMSO-d ) δ 174.2, 140.0, 139.3, 138.7, 128.1, 115.9,
–1
14.7, 110.8, 108.5, 32.9, 24.8, 24.3, 8.1; IR ν (cm ): 3381, 2924, 1702, 1626, 1513, 1477, 1431,
1
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–
[M–H] : 261.0881,
1
328, 1291, 1255, 1221, 1192, 1121, 737; HRMS (ESI–) calc’d for C13
H
13
N
2
O
4
found 261.0882.
1
2
-(3-Phenyl-1H-indol-4-yl) butyric acid 4i. White solid (21.5 mg, 39% yield); H NMR (400
MHz, CD
3
CN) δ 9.35 (br s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.50 – 7.40 (m, 4H), 7.36 (d, J = 8.0 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
H), 7.32 – 7.25 (m, 1H), 7.11 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.02 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H),
13
.92 – 2.82 (m, 2H), 2.27 (t, J = 7.3 Hz, 2H), 1.98 – 1.90 (m, 2H); C{ H}NMR (100 MHz,
1
CD
3
CN) δ 174.7, 136.6, 136.4, 130.3, 129.5, 128.3, 126.7, 122.2, 120.4, 119.1, 114.5, 111.7, 33.5,
–1
6.2, 25.6; IR ν (cm ): 3404, 3320, 3057, 2926, 2854, 1707, 1602, 1496, 1459, 1434, 1407, 1331,
2
1
2
–
[M–H] : 278.1187, found
243, 1017, 771, 751, 703; HRMS (ESI–) calc’d for C18
78.1185.
H
16NO
2
1
2
-(3-Allyl-1H-indol-4-yl) butyric acid 4j. White solid (32.4 mg, 67% yield); H NMR (400 MHz,
CD
8.1, 7.1, 1.3 Hz, 1H), 6.98 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 5.97 (ddt, J = 17.2, 10.1, 6.2 Hz, 1H),
.02 (dq, J = 17.0, 1.8 Hz, 1H), 4.94 (dq, J = 10.0, 1.6 Hz, 1H), 3.43 (dt, J = 6.2, 1.7 Hz, 2H), 2.76
3
CN) δ 9.02 (br s, 1H), 7.43 (d, J = 7.8, 1.0 Hz, 1H), 7.28 (dt, J = 8.0, 0.9 Hz, 1H), 7.04 (ddd, J
=
5
1
(t, J = 7.4 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 1.92 – 1.86 (m, 2H); C{ H}NMR (100 MHz,
3
1
CD CN) δ 174.7, 139.0, 136.5, 136.2, 129.3, 121.6, 119.4, 118.9, 114.5, 111.3, 109.5, 33.4, 29.0,
3
–
1
25.7, 25.6; IR ν (cm ): 3404, 3320, 3266, 3058, 2926, 2854, 1708, 1461, 1438, 1407, 1334, 1219,
–
[M–H] : 242.1187, found
1127, 1053, 913, 804, 744; HRMS (ESI–) calc’d for C15
242.1188.
H
16NO
2
1
2
-(3-Methyl-1H-indol-3-yl) propanoic acid 4k. White solid (23.2 mg, 57% yield); H NMR (400
3
MHz, CDCl ) δ 8.12 (br s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.18-7.07 (m,
1
H), 3.05 (t, J = 6.7 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.25 (s, 3H); C{ H}NMR (100 MHz,
3
1
2
–
1
3
CDCl ) δ 179.1, 135.3, 133.2, 129.1, 121.6, 119.2, 118.4, 110.6, 107.6, 34.0, 20.8, 8.6; IR ν (cm ):
3
391, 3049, 2921, 1708, 1618, 1462, 1430, 1411, 1299, 1241, 1211, 1173, 930,750; HRMS (ESI–)
–
calc’d for C12
Gram Scale Synthesis of 3s. The reaction was performed followed the general procedure of 3a
To a 250 mL Schlenk flask were added CuI (19.7 mg, 0.1 mmol, 1 mol %), 8-HQ (29.1 mg, 0.2
2
H12NO [M–H] : 202.0874, found 202.0875.
.
2 3
mmol, 2 mol %), 1s (3.54 g, 10 mmol), K CO (2.08 g, 15 mmol, 1.5 equiv), and DMSO (100 mL).
o
The mixture was stirred at 120 C (oil bath) for 9 h and then cooled to room temperature and
brought out from the glovebox. Most portion of the solvent was removed under reduced pressure,
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and diluted with EA (100 mL) and water (100 mL). The separated aqueous phase was extracted
with EA (100 mL × 3). The combined organic phase was washed with water (100 mL × 3), brine
2 4
and dried over anhydrous Na SO . The desired product 3s (1.30 g, 56% yield) was obtained after
purification by silica gel chromatography (PE/EA = 10/1).
1
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Synthesis of 10-(2-Hydroxyethyl)-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 5. The reported
19
2
procedure was followed. To a solution of 3s (113.9 mg, 0.5 mmol) in THF/H O (5 mL/5 mL)
were added K
equiv). The reaction mixture was stirred at 25 C and monitored by TLC. After completion of the
material 3s, saturated aqueous Na solution (15 mL) was added and the reaction mixture was
extracted with DCM (15 mL × 3). The combined organic phase was washed with brine, dried over
anhydrous MgSO , filtered, and concentrated under vacuum to give a crude product, which was
directly used for next step without further purification.
2 4 2
OsO •2H O (9.8 mg, 0.025 mmol, 5 mol %) and NMO (293.4 mg, 2.5 mmol, 5.0
o
2 2 3
S O
4
To a solution of above crude product in THF/H
2
4
O (5 mL/5 mL) was added NaIO (160.3 mg,
o
.75 mmol, 1.5 equiv), and the resultant mixture was stirred at 25 C until the completion of the
0
reaction. Then saturated aqueous Na
extracted with DCM (15 mL × 3). The combined organic phase was washed with brine, dried over
anhydrous MgSO , filtered, and concentrated under vacuum to provide the corresponding aldehyde
2 2 3
S O solution (15 mL) was added and the mixture was
4
as a white solid (115.6 mg, crude), which was used directly without further purification.
o
At 0 C, to a solution of the crude aldehyde (23.0 mg, 0.1 mmol) in MeOH/DCM (2 mL/1 mL)
o
was added NaBH
monitored by TLC. After completion of the reaction, saturated aqueous NH
and the reaction mixture was extracted with DCM (10 mL × 3). The combined organic phase was
4
(7.5 mg, 0.02 mmol, 2.0 equiv), then the reaction was stirred at 25 C and
4
Cl solution was added,
washed with water and dried over anhydrous MgSO
4
. The desired alcohol
5
(17.2 mg, 75% yield)
1
was obtained as a white solid after purification by silica gel chromatography (PE/EA = 1/1). H
NMR (400 MHz, CDCl
3
) δ 8.45 (dd, J = 6.9, 2.0 Hz, 1H), 7.47 (dd, J = 6.4, 2.2 Hz, 1H), 7.23 –
7
.27 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 2.97 – 2.91 (m, 4H), 2.74 (d, J = 6.4 Hz, 2H), 2.07 (quint, J
13
1
6.4 Hz, 2H); C NMR{ H} (100 MHz, CDCl
=
3
) δ 169.5, 135.3, 134.8, 130.3, 124.5, 124.0, 118.0,
–1
16.6, 113.1, 62.2, 34.5, 27.7, 22.0, 21.3; IR ν (cm ): 3301, 2938, 2876, 1704, 1617, 1457, 1371,
1
1
2
+
[M+Na] :
338, 1313, 1179, 1131, 1051, 1002, 755, 711; HRMS (ESI+) calc’d for C14
52.0995, found 252.0996.
H
15NNaO
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Synthesis of 10-Methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole 6. The reported procedure was
2
followed. To a solution of compound 3a (19.9 mg, 0.2 mmol, 2.0 equiv) in anhydrous THF (1.5
0
o
•DMS (16.8 mg, 2 equiv) dropwise at 25 C. The solution was heating to
mL) was added BH
3
reflux and monitored by TLC until the completion of the reaction. Then the mixture was cooled to
°C, and quenched with EtOH (1.0 mL). The organic solvents were removed under vacuum and
0
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8
9
0
0
the desired product
6
(15.5 mg, 95% yield) was obtained as a white solid after purification by silica
1
gel chromatography (PE/EA = 100/1). H NMR (400 MHz, CDCl
3
) δ 7.52 (dd, J = 7.0, 1.2 Hz,
1
2
H), 7.25 – 7.23 (m, 1H), 7.19 – 7.06 (m, 2H), 4.03 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H),
21
.24 (s, 3H), 2.12 – 2.02 (m, 2H), 1.98 – 1.84 (m, 2H).
Synthesis of 10-Methyl-2-phenyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one 7. To a Schlenk tube were
added 3h (54.6 mg, 0.2 mmol), Pd(dppf)Cl (14.8 mg, 0.02 mmol, 10 mol %), PhB(OH) (36.5 mg,
.3 mmol, 1.5 equiv) and K CO (69.1 mg, 0.5 mmol, 2.5 equiv) separately under argon, followed
2
2
0
2
3
2
by the addition of solvents (dioxane/H O = 3/1, 2.0 mL, degassed). The reaction was conducted
o
under 70 C (heating mantle) and monitored by TLC and GC. After completion of the starting
material, the reaction was cooled to room temperature and extracted with EA (10 mL × 3). The
2 4
combined organic phase was washed with brine, dried over anhydrous Na SO , filtered and
concentrated under vacuum. The desire product
7
(44.0 mg, 81% yield) was obtained as a white
1
solid after purification by silica gel chromatography (PE/EA = 10/1). H NMR (400 MHz, CDCl
3
)
δ 8.49 (d, J = 8.4 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.62 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.4, 1.8 Hz,
1
2
1
3
H), 7.48 – 7.43 (m, 2H), 7.37 – 7.31 (m, 1H), 2.93 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H),
1
3
1
3
.22 (s, 3H), 2.10 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz, CDCl ) δ 169.3, 142.0, 137.2,
–
34.0, 131.8, 128.9, 127.5, 127.0, 123.7, 116.6, 116.5, 112.5, 34.6, 21.9, 21.3, 8.7; IR ν (cm ):
1
366, 2942, 2918, 2854, 1695, 1625, 1466, 1363, 1334, 1296, 1175, 956, 823, 762, 752; HRMS
+
(
ESI+) calc’d for C19
H
17NNaO [M+Na] : 298.1202, found 298.1209.
Synthesis
of
4-Methyl-N-(2-(10-methyl-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)phenyl)
(17.3
(97.5 mg, 0.22 mmol, 1.1 equiv) and Cs CO
O =
benzenesulfonamide 8. To a Schenk tube were added 3h (55.8 mg, 0.2 mmol), Pd(dppf)Cl
mg, 0.02 mmol, 10 mol %), 2-NHTs-C -Bpin
2
6
H
4
2
2
3
(
92.8 mg, 0.5 mmol, 1.4 equiv) under argon followed by the addition of solvents (dioxane/H
2
o
/1, 2.0 mL, degassed). The reaction was conducted under 70 C (heating mantle) and monitored
3
by TLC until the completion of the starting material. Then the reaction was cooled to room
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temperature and extracted with EA (10 mL × 3). The combined organic phase was washed with
brine, dried over anhydrous Na
2 4
SO , filtered and concentrated under vacuum. The desired product
8
(73.9 mg, 83% yield) was obtained as a white solid after purification by silica gel
1
3
chromatography (PE/EA = 20/1 to PE/EA = 5/1). H NMR (400 MHz, CDCl ) δ 8.37 (d, J = 8.3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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9
0
Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.37 – 7.30 (m, 1H), 7.17 (d, J = 8.4
Hz, 2H), 7.15 – 7.12 (m, 2H), 7.00 (d, J = 1.7 Hz, 1H), 6.66 – 6.64 (m, 2H), 2.95 (t, J = 6.2 Hz,
13
1
2
3
H), 2.82 (t, J = 6.4 Hz, 2H), 2.40 (s, 3H), 2.18 – 2.09 (m, 5H); C{ H}NMR (100 MHz, CDCl )
δ 169.4, 143.9, 136.2, 134.7, 134.5, 134.1, 132.6 131.8, 130.7, 129.7, 128.6, 127.3, 124.9, 124.8,
–1
21.1, 118.4, 116.9, 112.2, 34.6, 21.9, 21.7, 21.3, 8.6; IR ν (cm ): 3302, 2947, 1697, 1619, 1495,
1
1
24 2 3
464, 1387, 1369, 1334, 1166, 1092, 903, 813, 765; HRMS (ESI+) calc’d for C26H N NaO S [M+
+
Na] : 467.1400, found 467.1400.
General Procedure for the Synthesis of Enaminones 1
2
2
The enaminones
1ꢀ can be conveniently prepared according to the known literature procedures.
5
b
Among them, compounds 1a–1m, 1o–1q are known.
tert-Butyl 2-(2-((2-iodophenyl)amino)-6-oxocyclohex-1-en-1-yl)-acetate 1n. To a cooled
(0°C) solution of 1,3-cyclohexanedione (1.68 g, 15 mmol) in water (2.0 mL), DIPEA (2.1 mL, 12.0
mmol) and tert-butyl-2-bromoacetate (1.98 g, 10.1 mmol) were added dropwise. The mixture was
stirred at room temperature and monitored by TLC. After the completion, the solution was
acidified by concentrated hydrochloric acid. Then it was extracted by EA (3 × 20 mL) and then
separated, the organic phase was dried over anhydrous MgSO
4
, filtered and concentrated under
reduced pressure. The desired product tert-butyl-2-(2-hydroxy-6-oxocyclohex-1-en-1-yl)acetate s-1n
(
0.94 g, 42% yield) was obtained as a white solid after purification by silica gel chromatography
1
PE/EA = 5/1 to PE/EA = 1/1). H NMR (400 MHz, DMSO-d
(
6
) δ 3.00 (s, 2H), 2.32 (t, J = 6.3 Hz,
1
H), 1.90 – 1.78 (m, 2H), 1.35 (s, 9H); C{ H}NMR (100 MHz, DMSO-d6) δ 170.5, 109.2, 79.1,
3
1
4
2
1
2
–
8.5, 27.8, 20.5; IR ν (cm ): 3192, 2999, 2979, 2946, 1716, 1588, 1459, 1398, 1339, 1281, 1225,
1
+
+
[M+Na] : 249.1097, found
189, 1153, 1074, 1018; HRMS (ESI ) calc’d for C12
H
18NaO
4
23
49.1100.
The next step was conducted with 2-iodoaniline (1.66 g, 7.6 mmol), compound s-1n (1.14 g, 5.0
mmol), p-TsOH•H O (25.5 mg, 0.13 mmol), and 35 mL toluene. The mixture was refluxed (oil
2
bath) and monitored by TLC. After completion of the reaction, it was cooled to room temperature
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and neutralized with solid K
dried over anhydrous Na
2
CO
3
, then extracted with DCM (50 mL × 2), washed with brine and
2
SO
4
. The desired product tert-butyl 2-(2-((2-iodophenyl)amino)
-
6-oxocyclohex-1-en-1-yl)-acetate 1n (1.29 g, 60% yield) was obtained as a white solid after
1
purification by silica gel chromatography (PE/EA = 10/1 to PE/EA = 5/1). H NMR (400 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
) δ 7.87 (dd, J = 8.0, 1.4 Hz, 1H), 7.48 (br s, 1H), 7.33 (td, J = 7.6, 1.5 Hz, 1H), 7.14 (dd, J =
7
.9, 1.6 Hz, 1H), 6.94 (td, J = 7.6, 1.6 Hz, 1H), 3.46 (s, 2H), 2.40 (dd, J = 7.1, 5.8 Hz, 2H), 2.34 (t,
13
J = 6.1 Hz, 2H), 1.95 – 1.88 (m, 2H), 1.44 (s, 9H); C{ H}NMR (100 MHz, CDCl
1
3
) δ 195.1,
1
72.5, 160.4, 140.8, 139.7, 129.2, 127.7, 126.8, 108.2, 97.7, 81.2, 36.7, 31.0, 28.2, 27.6, 21.6; IR ν
–1
cm ): 3246, 2943, 1726, 1597, 1551, 1476, 1417, 1401, 1326, 1304, 1153, 1018, 758, 729;
(
+
+
HRMS (ESI ) calc’d for C18
-((2-Iodo-4-methylphenyl)amino)-2-methylcyclopent-2-enone 1r. To
-iodo-4-methylaniline (1.16 g, 5 mmol), 2-methylcyclopentane- 1,3-dione (0.48 g, 10 mmol),
p-TsOH•H O (50.8 mg, 0.27 mmol), and 30 mL of toluene. The mixture was refluxed (oil bath) and
monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and
neutralized with solid K CO , then extracted with DCM (50 mL × 2), washed with brine and dried over
anhydrous Na SO . The solvents were removed under reduced pressure. The desired product
3
H22INNaO [M+Na] : 450.0537, found 450.0535.
3
a
flask were added
2
2
2
3
2
4
3-((2-Iodo-4-methylphenyl)amino)-2-methylcyclopent-2-enone 1r (1.26 g, 77% yield) was btained as a
1
white solid after purification by silica gel chromatography (PE/EA = 1/1). H NMR (400 MHz,
3
CDCl ) δ 7.69 (s, 1H), 7.18 – 7.13 (m, 2H), 6.52 (br s, 1H), 2.57 – 2.51 (m, 2H), 2.44 – 2.38 (m,
1
3
1
2
1
1
3
H), 2.31 (s, 3H), 1.71 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 203.8, 169.6, 139.9, 137.7,
–
37.4, 130.1, 124.3, 112.2, 96.0, 33.3, 26.0, 20.5, 7.0; IR ν (cm ): 3431, 3157, 3100, 3026, 2917,
1
+
659, 1606, 1574, 1488, 1437, 1413, 1346, 1281, 1226, 1101, 1037, 785; HRMS (ESI ) calc’d for
+
C
13
H
14INNaO [M+Na] : 350.0012, found 350.0011.
Enaminones 1s
-Allyl-3-((2-iodophenyl)amino)cyclohex-2-enone 1s. White solid (5.90 g, 84% yield); H NMR
400 MHz, CDCl ) δ 7.86 (dd, J = 7.9, 1.4 Hz, 1H), 7.34 (td, J = 7.7, 1.4 Hz, 1H), 7.12 (dd, J =
.9, 1.4 Hz, 1H), 6.92 (td, J = 7.7, 1.5 Hz, 1H), 6.56 (br s, 1H), 5.85 (ddt, J = 17.0, 10.0, 6.0 Hz,
H), 5.29 – 4.95 (m, 2H), 3.28 (d, J = 6.0 Hz, 2H), 2.49 – 2.39 (m, 2H), 2.36 (t, J = 6.1 Hz, 2H),
–1ab were synthesized according the general procedure of 1r.
1
2
(
3
7
1
1
1
13
.93 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz, CDCl
1
3
) δ 195.6, 159.4, 140.4, 139.7, 136.1,
–1
29.1, 127.4, 126.3, 115.8, 111.1, 97.1, 36.7, 27.6, 27.3, 22.0; IR ν (cm ): 3235, 3059, 3012, 2941,
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+
588, 1539, 1455, 1394, 1369, 1300, 1277, 1192, 1116, 1017, 988, 908, 731; HRMS (ESI ) calc’d
1
+
for C15
H
16INNaO [M+Na] : 376.0169, found 376.0168.
2
-Allyl-3-((2-iodo-3-methylphenyl)amino)cyclohex-2-enone 1t. White solid (230.9 mg, 31% yield);
H NMR (400 MHz, CDCl ) δ 7.21 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 7.7
Hz, 1H), 6.60 (br s, 1H), 5.86 (ddt, J = 16.1, 10.0, 6.0 Hz, 1H), 5.19 (dd, J = 17.2, 1.7 Hz, 1H),
.10 (dd, J = 10.0, 1.6 Hz, 1H), 3.29 (d, J = 6.0 Hz, 2H), 2.49 (s, 3H), 2.42 (t, J = 6.4 Hz, 2H), 2.33
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
13
1
t, J = 6.0 Hz, 2H), 1.91 (quint, J = 6.3 Hz, 2H); C NMR{ H} (100 MHz, CDCl
(
3
) δ 195.6, 159.8,
1
43.8, 140.7, 136.3, 128.3, 127.2, 123.1, 115.7, 110.7, 104.7, 36.7, 29.6, 27.6, 27.3, 22.0; IR ν
–1
cm ): 3266, 2938, 2919, 1638, 1589, 1550, 1450, 1426, 1390, 1365, 1290, 1192, 1120, 1096,
(
+
+
1
015, 914, 733; HRMS (ESI ) calc’d for C16
H
18INNaO [M+Na] : 390.0325, found 390.0320.
2
-Allyl-3-((2-iodo-4-methylphenyl)amino)cyclohex-2-enone 1u. White solid (1.10 g, 60 % yield);
1
3
H NMR (400 MHz, CDCl ) δ 7.70 (s, 1H), 7.14 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.40
(
br s, 1H), 5.85 (ddt, J = 16.1, 10.1, 6.0 Hz, 1H), 5.19 (dq, J = 17.2, 1.9 Hz, 1H), 5.09 (dq, J =
0.1, 1.7 Hz, 1H), 3.28 (d, J = 5.9 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.31-2.29 (m, 5H), 1.93 (quint,
1
1
3
1
3
J = 5.9 Hz, 2H); C{ H}NMR (100 MHz, CDCl ) δ 195.6, 159.6, 140.0, 138.1, 137.9, 136.3,
–
129.9, 126.6, 115.7, 110.2, 97.9, 36.8, 27.6, 27.2, 22.0, 20.5; IR ν (cm ): 3442, 3252, 2953, 1593,
1
+
1578, 1540, 1483, 1429, 1395, 1367, 1302, 1189, 1112, 1042, 997, 983, 908; HRMS (ESI ) calc’d
+
for C16
H
18INNaO [M+Na] : 390.0325, found 390.0330.
2-Allyl-3-((2-iodo-5-methylphenyl)amino)cyclohex-2-enone 1v. White solid (1.27 g, 69% yield);
1
H NMR (400 MHz, CDCl
.0 Hz, 1H), 6.44 (br s, 1H), 5.85 (ddt, J = 17.2, 10.0, 6.0 Hz, 1H), 5.19 (dq, J = 17.2, 1.8 Hz, 1H),
.10 (dq, J = 10.0, 1.7 Hz, 1H), 3.27 (dt, J = 6.1, 1.8 Hz, 2H), 2.41 (t, J = 6.4 Hz, 2H), 2.35 (t, J =
3
) δ 7.70 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.1,
2
5
6
1
1
3
1
.1 Hz, 2H), 2.31 (s, 3H), 1.93 (quint, J = 6.5 Hz, 2H); C{ H}NMR (100 MHz, CDCl
3
) δ 195.7,
59.2, 140.2, 139.5, 139.3, 136.2, 128.6, 127.3, 115.7, 110.8, 93.2, 36.8, 27.6, 27.3, 22.1, 21.1; IR
–
ν (cm ): 3247, 3066, 3008, 2939, 1581, 1539, 1483, 1453, 1433, 1391, 1300, 1276, 1192, 1118,
1
+
+
1
015, 909, 801; HRMS (ESI ) calc’d for C16
H
18INNaO [M+Na] : 390.0325, found 390.0326.
2
-Allyl-3-((4-fluoro-2-iodophenyl)amino)cyclohex-2-enone 1w. White solid (1.14 g, 61% yield);
1
3
H NMR (400 MHz, CDCl ) δ 7.59 (dd, J = 7.6, 2.7 Hz, 1H), 7.18 – 7.03 (m, 2H), 6.34 (br s, 1H),
5
1
.85 (ddt, J = 17.1, 10.0, 6.0 Hz, 1H), 5.18 (dq, J = 17.2, 1.8 Hz, 1H), 5.09 (dq, J = 10.0, 1.7 Hz,
H), 3.27 (d, J = 6.0 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H), 2.26 (t, J = 6.1 Hz, 2H), 1.92 (quint, J =
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1
.4 Hz, 2H); C{ H}NMR (100 MHz, CDCl
3
1
6
3
) δ 195.5, 160.2 (d, JC–F = 252.1 Hz), 159.8, 137.0
(
d, JC–F = 3.2 Hz), 136.2, 128.0 (d, JC–F = 8.5 Hz), 126.4 (d, JC–F = 24.4 Hz), 116.2 (d, JC–F = 22.2
1
Hz), 115.8, 110.5, 98.1 (d, JC–F = 8.5 Hz), 36.5, 27.5, 27.1, 21.8; F NMR (376 MHz, CDCl
9
3
) δ –
–
13.88; IR ν (cm ): 3239, 3071, 2947, 1632, 1591, 1545, 1482, 1460, 1390, 1365, 1304, 1249,
1
1
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
186, 1112, 1027, 906, 856; HRMS (ESI ) calc’d for C15
H
15FINNaO [M+Na] : 394.0075, found
94.0072.
1
2
-Allyl-3-((4-chloro-2-iodophenyl)amino)cyclohex-2-enone 1x. White solid (1.19 g, 61% yield); H
NMR (400 MHz, CDCl
Hz, 1H), 6.41 (br s, 1H), 5.84 (ddt, J = 17.3, 10.0, 6.0 Hz, 1H), 5.18 (dq, J = 17.2, 1.8 Hz, 1H),
.10 (dq, J = 10.0, 1.7 Hz, 1H), 3.27 (d, J = 6.0 Hz, 2H), 2.42 (t, J = 6.4 Hz, 2H), 2.35 (t, J = 6.1
3
) δ 7.84 (d, J = 2.3 Hz, 1H), 7.32 (dd, J = 8.5, 2.4 Hz, 1H), 7.03 (d, J = 8.5
5
13
1
3
Hz, 2H), 1.95 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz, CDCl ) δ 195.8, 158.5, 139.3,
–
38.9, 136.1, 131.7, 129.2, 126.4, 116.0, 111.8, 97.0, 36.8, 27.7, 27.3, 22.1; IR ν (cm ): 3432,
1
1
3
187, 3071, 2931, 1591, 1578, 1537, 1464, 1422, 1403, 1392, 1363, 1300, 1185, 1141, 911, 737;
+
+
HRMS (ESI ) calc’d for C15
2-Allyl-3-((4-bromo-2-iodophenyl)amino)cyclohex-2-enone 1y. White solid (0.81 g, 44% yield); H
NMR (400 MHz, CDCl ) δ 7.98 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.96 (d, J = 8.5
H15ClINNaO [M+Na] : 409.9779, found 409.9782.
1
3
Hz, 1H), 6.40 (br s, 1H), 5.84 (ddt, J = 16.1, 10.0, 6.0 Hz, 1H), 5.19 (dd, J = 17.2, 1.7 Hz, 1H),
5.11 (dd, J = 10.0, 1.6 Hz, 1H), 3.26 (d, J = 6.0 Hz, 2H), 2.43 (d, J = 6.4 Hz, 2H), 2.36 (t, J = 6.1
1
3
1
3
Hz, 2H), 1.95 (quint, J = 6.3 Hz, 2H); C{ H}NMR (100 MHz, CDCl ) δ 195.8, 158.3, 141.6,
–
39.8, 136.1, 132.1, 126.6, 119.1, 116.0, 112.1, 97.2, 36.8, 27.7, 27.3, 22.1; IR ν (cm ): 3435,
1
1
3
192, 3069, 2972, 2931, 1590, 1571, 1537, 1464, 1402, 1390, 1361, 1299, 1185, 1029, 910, 731;
+
+
HRMS (ESI ) calc’d for C15
-Allyl-3-((2-iodo-4-nitrophenyl)amino)cyclohex-2-enone 1z. Yellow solid (0.77 g, 39% yield); H
NMR (400 MHz, CDCl ) δ 8.69 (d, J = 2.5 Hz, 1H), 8.18 (dd, J = 8.9, 2.5 Hz, 1H), 7.00 (d, J = 9.0
Hz, 1H), 6.84 (br s, 1H), 5.99 – 5.65 (m, 1H), 5.33 – 5.03 (m, 2H), 3.24 (d, J = 5.9 Hz, 2H), 2.62
H15BrINNaO [M+Na] : 453.9274, found 453.9270.
1
2
3
13
t, J = 5.9 Hz, 2H), 2.51 (t, J = 6.4 Hz, 2H), 2.05 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz,
1
(
CDCl
3
) δ 196.4, 155.4, 146.3, 142.6, 135.4, 135.2, 124.7, 119.3, 118.4, 116.6, 89.9, 37.1, 28.1,
–1
7.9, 22.6; IR ν (cm ): 3447, 3317, 2950, 1623, 1596, 1576, 1515, 1499, 1374, 1333, 1288, 1273,
2
1
4
+
+
178, 1113, 1006, 928, 822; HRMS (ESI ) calc’d for C15
3
H15IN2NaO [M+Na] : 421.0020, found
21.0031.
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-Cinnamyl-3-((2-iodophenyl)amino)cyclohex-2-enone 1aa. White solid (1.39 g, 65% yield); H
NMR (400 MHz, CDCl ) δ 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.41 – 7.34 (m, 3H), 7.34 – 7.28 (m,
H), 7.27 – 7.19 (m, 1H), 7.16 (dd, J = 8.0, 1.5 Hz, 1H), 6.94 (td, J = 7.7, 1.5 Hz, 1H), 6.62 (d, J =
.6 Hz, 1H), 6.57 (br s, 1H), 6.35 – 6.23 (m, 1H), 3.48 (dd, J = 6.5, 1.7 Hz, 2H), 2.50 (t, J = 6.0
3
2
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Hz,2H), 2.44 (t, J = 6.1 Hz, 2H), 2.01 (quint, J = 6.4 Hz, 2H); C{ H}NMR (100 MHz,
3
1
DMSO-d
6
) δ 193.6, 159.2, 141.4, 139.0, 137.7, 129.5, 129.2, 128.71, 128.70, 128.65, 128.5, 126.6,
–1
25.8, 108.1, 101.4, 36.4, 27.1, 25.6, 21.4; IR ν (cm ): 3251, 3056, 3024, 2942, 1544, 1452, 1393,
1
1
4
+
+
366, 1318, 1266, 1177, 1139, 1082, 960, 750, 731; HRMS (ESI ) calc’d for C21
30.1288, found 430.1291.
H21INO [M+H] :
3
-((2-Iodophenyl)amino)-2-(3-methylbut-2-en-1-yl)cyclohex-2-enone 1ab. White solid (1.30 g,
1
8% yield); H NMR (400 MHz, CDCl
6
1
1
3
) δ 7.85 (dd, J = 7.9, 1.4 Hz, 1H), 7.33 (td, J = 7.8, 1.3 Hz,
H), 7.11 (dd, J = 7.9, 1.3 Hz, 1H), 6.91 (td, J = 7.8, 1.4 Hz, 1H), 6.45 (br s, 1H), 5.11 – 5.07 (m,
H), 3.19 (d, J = 6.6 Hz, 2H), 2.41 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 6.1 Hz, 2H), 1.92 (quint, J = 6.3
1
Hz, 2H), 1.73 (s, 3H), 1.71 (d, J = 5.9 Hz, 3H); C{ H}NMR (100 MHz, CDCl
3
1
3
) δ 195.8, 158.6,
140.7, 139.7, 133.4, 129.1, 127.1, 126.0, 122.8, 113.4, 96.3, 36.8, 27.2, 26.3, 22.1, 18.3; IR ν
–
(cm ): 3198, 2973, 2935, 2913, 1593, 1538, 1466, 1414, 1394, 1364, 1298, 1176, 1138, 1018,
1
+
+
761, 730, 722; HRMS (ESI ) calc’d for C17H20INNaO [M+Na] : 404.0482, found 404.0481.
(E)-4-((2-Iodophenyl)amino)-3-methylpent-3-en-2-one 1ac. Light yellow solid (480.5 mg,
1
31% yield); H NMR (400 MHz, C
6
D
6
) δ 13.84 (br s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 6.80 (t, J = 7.4
Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.39 (t, J = 8.5 Hz, 1H), 2.08 (s, 3H), 1.59 (s, 3H), 1.47 (s, 3H);
1
3
1
C { H}NMR (100 MHz, C
6
D
6
) δ 196.9, 156.2, 142.6, 139.7, 128.6, 126.8, 126.7, 102.1, 97.6,
–
8.7, 16.7, 14.8; IR ν (cm ): 2924, 2360, 2341, 1733, 1573, 1553, 1415, 1257, 1196, 1016, 976,
1
2
7
+
+
55, 737; HRMS (ESI ) calc’d for C12H15INO [M+H] : 316.0193, found 316.1083.
Associated Content
Supporting Information
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1
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H NMR of all known compounds, H and C{ H} NMR spectra of all new compounds synthesized
during this study (pdf). This material is available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
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E-mail: wenboliu@whu.edu.cn
Notes
The authors declare no competing financial interest.
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Acknowledgements
We gratefully acknowledge the NSFC (21772148, 21602160) and Wuhan University (WHU) for financial
support. We also thank the Qiang-Hui Zhou, Guoyin Yin, Xumu Zhang, Aiwen Lei, Chun-Jiang Wang, and
Hong-Ding Tang groups at WHU for providing access to their instrumentations and chemicals.
Notes and References
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(
(
(
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12) Treatment of N-2-haloaryl a-allyl enaminone (1s) with Pd(OAc) /Phox resulted in the formation of
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Heck product 3s’ in 84% yield without the observation of the desired indole formation, see SI for
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(
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(
(
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