Cu(OAc)2-Promoted Oxidative Cross-Dehydrogenative Coupling Reaction of α-Acylmethyl Malonates with Indole Derivatives to Access 3-Functionalized Indoles and Polycyclic Indoles

Article abstract of DOI:10.1021/acs.joc.0c00624

A Cu(OAc)2-promoted oxidative cross-dehydrogenative coupling reaction of α-acylmethyl malonates with indole derivatives was developed. In the case of indoles, the regioselective coupling products were formed through a sequential dehydrogenation-addition-dehydrogenation process. When a second nucleophilic center was located in the 2-position of indoles, further successive nucleophilic cyclization occurred to give polycyclic indole derivatives. The Cu(OAc)2 was proved to act as not only an oxidant but also a catalyst.

Full text of DOI:10.1021/acs.joc.0c00624

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Article
Cu(OAc)2-Promoted Oxidative Cross-Dehydrogenative Coupling
Reaction of #-Acylmethyl Malonates with Indole Derivatives
to Access 3-Functionalized Indoles and Polycyclic Indoles
Li-Jin Zhou, Kun Wang, Hong-Rong Guan, An-Qi Zheng, Hai-Tao Yang, and Chun-Bao Miao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00624 • Publication Date (Web): 26 May 2020
Downloaded from pubs.acs.org on May 26, 2020
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Cu(OAc)2-Promoted Oxidative Cross-Dehydrogenative Coupling Reaction of
α-Acylmethyl Malonates with Indole Derivatives to Access 3-Functionalized
Indoles and Polycyclic Indoles
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Li-Jin Zhou, Kun Wang, Hong-Rong Guan, An-Qi Zheng, Hai-Tao Yang,* and Chun-Bao Miao*
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of
Petrochemical Engineering, Changzhou University, Changzhou 213164, China.
O
OH
( )n
EtO2C
O
R
N
H
R1
O
( )n
[Cu]
O
COOEt
COOEt
N
R
H
N
H
O
CO2Et
CO2Et
R
R1
O
NHR2
O
R
[Cu]
EtO2C
O
NH
R
N
N
H
R1
R2
R1
[Cu]
R1
N
O
H
ABSTRACT
A Cu(OAc)2-promoted oxidative cross-dehydrogenative coupling reaction of
α-acylmethyl malonates with indole derivatives was developed. In the case of indoles, the
regioselective
coupling
products
were
formed
through
sequential
dehydrogenation-addition-dehydrogenation process. When a second nucleophilic center
was located in the 2-positioin of indoles, further successive nucleophilic cyclization
occurred to give polycyclic indole derivatives. The Cu(OAc)2 was proved to act as not only
an oxidant but also a catalyst.
INTRODUCTION
Transition-metal-catalyzed coupling reactions have become a powerful tool in organic
synthesis. As a direct way to form C–C bonds, the oxidative cross-dehydrogenative coupling
(CDC) of two different C-H bonds constitutes an attractive strategy in the last decades because it
avoids preinstalling leaving or activating group on the substrates.1 In particular, the development
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of selective inactive C(sp3)-H functionalization to form C(sp3)-X (X = C, N, or O) bond is highly
desirable but full of challenge. Carbonyl compounds play a critical role in organic synthesis. Most
of the transformation of carbonyl primarily occurs at the electrophilic carbonyl carbon and the
nucleophilic α-carbon atom. Recently, direct functionalization of the inactive β-C(sp3)-H of
carbonyls has attracted considerable attentions. A selective C-H activation strategy was usually
adopted to achieve such transformation, which requires a transition-metal catalyst such as [Pd]2 or
[Ni],3 and the assistance of an internal or transient directing group.4 A strategy to combine a
dehydrogenation of carbonyl to yield α,β-unsaturated carbonyls with subsequent olefin
transformations represents another new avenue to realize the β-functionalization. Nevertheless,
most of the developed methods require the participation of [Pd] catalyst and an aryl halide
substrate.5 A direct dehydrogenative coupling of two different C-H bonds to realize the
β-functionalization of carbonyls is rare. The key of this strategy is rapid generation of the
electrophilic deficient species under mild conditions and easy occurrence of the subsequent
addition. Ueno and Kuwano reported the Ni-catalyzed C-N bonds formation at the β-position of
ketones.6 Su reported a Cu(II)-catalyzed direct β-functionalization of saturated ketones.7
However, the substrates were limited to those without substituents on the β-carbon in these two
transformations. Wang and Hayashi developed the use of secondary amine catalyst to generate
enamine intermediate, which was oxidized to iminium species followed by Michael addition to
realize the β-functionalization.8 Nevertheless, this method was only suitable for aldehydes. A
similar route involves the use of N-heterocyclic carbene (NHC) catalyst.9 In terms of the
α-substituted-1,3-dicarbonyl compounds, dehydrogenation affords α,β-unsaturated carbonyls with
stronger electrophilicity due to the existence of two electron-withdrawing groups, which is
beneficial to the second step of addition. Matsuo and Ishibashi reported a one-pot two-step
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functionalization of β-position of 1,3-dicarbonyls with N-tertbutylbenzenesulfinimidoyl chloride
as the oxidant.10 But the reaction conditions were too harsh involving the oxygen/water free,
strong base, and ultra-low temperature, as well as not easy availability of the oxidant. Pihko
explored the Pd-catalyzed oxidative coupling of cyclic β-keto esters with electron-rich arenes at
the β'-position (Scheme 1b).11 Chan developed a Cu(OTf)2-catalyzed β-amination and
aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhI=NTs (Scheme 1a).12
Zhang reported a hypervalent-iodine-mediated α,β'-annulation of β-ketoesters with 1,3-diketones
or nitroacetates (Scheme 1c).13 In these limited examples of β-functionalization of 1,3-dicarbonyl
compounds, expensive [Pd] catalyst or hypervalent iodine reagents were always required.
Recently, we reported a Cu(OAc)2-triggered cascade reaction of malonate tethered oxime acetates
with indole derivatives to prepare polysubtituted 3-pyrrolin-2-ones via a key vicinal dielectrophilic
2H-pyrrol-2-one intermediates.14 We speculated an electron-withdrawing acyl group on the
β-carbon atom of malonates might be beneficial to yield the electron-deficient alkene intermediate
with a low-cost [Cu] reagent to achieve the dehydrogenation process. Subsequent reaction with
nucleophiles followed by oxidation would generate coupling products. While a dinucleophiles was
employed, further intramolecular attack on carbonyl might occur to form polycyclic compounds
(Scheme 1d). To realize such transformation, the choice of suitable nucleophiles having stronger
nucleophilicity than malonates was essential because it has been reported that the dehydrogenation
of 2-methyl or 2-ethoxycarbonyl malonate underwent in situ Michael addition with itself to form a
cascade product.15
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Scheme 1 Functionalization of β-C(sp3)-H of 1,3-dicarbonyl compounds.
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
-functionalization of 1,3-dicarbonyl compounds.
O
O
O
O
N
O
O
R1
R2
Cu(OTf) 2
ref. 12
R1
R2
R1
R2
Ts
(a)
or
+
PhI=NTs
R3
H
NHTs
R3
R3
6
7
8
9
O
O
O
O
R1
OR2
[Pd]/[O]
ref. 11
R1
OR2
(b)
+
Ar-H
R3
Ar
R3
H
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O
O
O
O
R2O
R1
R2O
R1
O
O
AIBX
(metal-free)
O
O
O
N
(c) R1
R3
OR2
or
+
ref. 13
or
CO2R4
O
O
R3
R3
O
H
O2N
CO2R4
O
This work:
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Cu(OAc) 2 DTBP
/
O
(d)
R
or
R
R
Nu2 Nu1
Nu2 Nu1
Nu
or
NuH
H
H
H
RESULTS AND DISCUSSION
Indole derivatives are widely existed in the biologically active natural products isolated from
biological systems and indole alkaloids are one of the largest classes of natural alkaloids. As one
of the most important skeleton in drug discovery, indole is also called one of the “privileged
scaffolds”, which can acts as ligand for a diverse array of receptors.16 These have stimulated
medicinal chemists to apply indole chemistry to drug synthesis and inspired synthetic chemists to
develop novel chemical transformations and synthetic strategies.17 At the outset, we investigated
the direct coupling of indole 2a with diethyl α-benzoylmethyl malonate 1a (Table 1). Due to the
structural similarity of α-benzoylmethyl malonate with malonate tethered oxime acetate,14
a
primary test was conducted by performing the reaction of 1a and 1.0 equiv of indole 2a in
acetonitrile under the same conditions with Cu(OAc)2 as the oxidant. Disappointingly, no coupling
product was formed (entry 1). Adding bases such as K2CO3 and Cs2CO3 could not initiate the
reaction yet (entries 2 and 3). When the reaction were carried out in DMSO with K2CO3 as the
base, a coupling product 3aa was formed in 48% yield after 14 h (entry 4). During the reaction, the
formation of intermediate 4a and its smooth conversion to 3aa was observed. Meanwhile, many
indole 2a remained unreacted due to the self-reaction of 1a. Increasing the molar ratio of 1a : 2a to
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1.5 : 1 and tempereture to 100 C led to the full conversion of 2a within 5 h, affording 3aa in 62%
yield (entry 5). Using Na2CO3 as the base further improved the yield to 74% (entry 6). The
requirement of only 2.5 equiv of Cu(OAc)2 demonstrated that the CuII was finally reduced to Cu0.
In order to reduce the use of Cu(OAc)2 to catalytic amount, a series of external oxidants were
evaluated. The results showed di-tert-butyl peroxide (DTBP) and pyridine N-oxide were effective,
and DTBP gave a slightly higher yield of 55% (entries 7-11). A copper catlyst survey showed that
Cu(OAc)2 was the most effective (entries 12-14). However, the reaction with catalytic amount of
Cu(OAc)2 combined with DTBP proceeded much slower than that of using 2.5 equiv of Cu(OAc)2
directly and much longer reaction time was needed (entry 7). A possible reason was that partial
CuII was reduced to Cu0, which could not be oxidized to CuI/CuII to enter the next oxidation cycle,
thus decreasing the oxidation efficiency greatly. Increasing the amount of Cu(OAc)2 to 1 equiv
significantly improved the yield to 77% (entries 15-17). An effort to decrease the amount of
Cu(OAc)2 by using a ligand was alao attempted. However, the addition of ligand such as 2,2'-Bpy,
Phen, TMEDA, Me2NCH2CO2H, or DMAP had no significant improvement on the yield (entries
18-22). It was worth noting that using DMSO as the solvent was crutial because no reaction was
observed in other solvents such as toluene, DMF, and 1,4-dioxane (entries 23-25).
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Table 1 Screening of the Reaction Conditionsa
O
COOEt
COOEt
O
COOEt
COOEt
O
COOEt
COOEt
[Cu]
N
NH
4a
NH
3aa
H
1a
2a
entr
y
time yield of
[Cu]
additive
ratiob
solvent
T (ºC)
(h)
12
12
12
14
5
3aa
0
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
-
1:1:2.5
CH3CN
CH3CN
CH3CN
DMSO
DMSO
80
80
80
80
100
2
K2CO3
Cs2CO3
K2CO3
K2CO3
1:1:2.5:2.5
1:1:2.5:2.5
1:1:2.5:2.5
0
3
0
4
48
62
5
1.5:1:2.5:2.5
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Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Na2CO3
1.5:1:2.5:2.5
1.5:1:0.2:1:3
1.5:1:0.2:1:3
DMSO
DMSO
DMSO
100
100
100
5
74
Na2CO3, DTBP
Na2CO3, K2S2O8
13
13
55
trace
6
7
8
N
O
Na2CO3,
9
Cu(OAc)2
1.5:1:0.2:1:3
DMSO
100
13
49
9
N
10
11
12
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O
Me
Na2CO3,
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
CuCl2
1.5:1:0.2:1:3
1.5:1:0.2:1:3
1.5:1:0.2:2:3
1.5:1:0.2:2:3
1.5:1:0.2:2:3
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
11
12
16
16
11
15
38
20
17
52
Na2CO3, MCPBA
Na2CO3, DTBP
Na2CO3, DTBP
Na2CO3, DTBP
Cu(OTf)2
CuI
15
16
17
18
19
20
21
22
23
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Na2CO3, DTBP
Na2CO3, DTBP
Na2CO3, DTBP
1.5:1:0.4:0.8:3
1.5:1:0.6:1.2:3
1.5:1:1:2:3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PhCH3
100
100
100
100
100
100
100
100
100
12
10
6
59
66
77
47
57
42
50
51
0
2,2'-Bpy, Na2CO3, DTBP
Phen, Na2CO3, DTBP
1.5:1:0.2:0.2:1:3
1.5:1:0.2:0.2:1:3
1.5:1:0.2:0.2:1:3
13
6
TMEDA, Na2CO3, DTBP
16
14
10
8
Me2NCH2CO2H, Na2CO3, DTBP 1.5:1:0.2:0.2:1:3
DMAP, Na2CO3, DTBP
Na2CO3, DTBP
1.5:1:0.2:0.4:1:3
1.5:1:1:2:3
24
25
Cu(OAc)2
Cu(OAc)2
Na2CO3, DTBP
Na2CO3, DTBP
1.5:1:1:2:3
1.5:1:1:2:3
DMF
100
8
8
trace
0
1,4-dioxane 100
a 1a (0.4 mmol), other reactants and reagents, and 8 mL of solvent. b 1a/2a/additive.
Under the optimized conditions (Table 1, entry 17), the scope of this cross-dehydrogenative
coupling reaction was examined. As illustrated in Table 2, a variety of indoles with different
substitution patterns afforded the corresponding products in moderate to good yields. Both
electron-donating and electron-withdrawing substituents like methoxy, alkyl, bromo, chloro, and
fluorine groups were well compatible (3aa-3ad and 3af-3ah). However, when a strong
electron-withdrawing group such as -NO2 linked to the phenyl ring of indole, the coupling product
3ae was obtained in a low yield (23%). 2-Methyl indole also provided 3ai in 63% yield, while
2-phenyl indole only give 25% yield of 3aj probably due to the big steric hindrance. Meanwhile,
an analogue of indole, 7-azaindole also provided 3ak in 70% yield. Next, the scope of
α-acylmethyl malonates connecting different substituents (R1) on the carbonyl carbon was also
assessed. Regardless of either electron-rich or electron-deficient aryl groups of R1, the reaction
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was performed well to give 3ba-3fa moderate to good yields. When a nitro group was located at
the phenyl ring, a relatively low yield of 3ga or 3ha was obtained. Heteroaryls such as furyl and
pyridyl were also tolerated in the reaction (3ia and 3ja). In addition, when R1 was an alkenyl group
and alkyl group, the desired products 3ka and 3la were also obtained in 60% and 42% yield,
respectively. While an tert-butyl of R1 only provided the coupling product 3ma without further
oxidation. Changing the acyl to ester or amide group, similar result was obtained with relatively
low yield (3na and 3oa).
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13
14
15
16
17
18
19
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21
22
23
24
25
26
27
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Table 2. Substrate scopes of indoles and α-acylmethyl malonates.
O
COOEt
COOEt
Cu(OAc)2 (1 equiv),
Na2CO3 (2 equiv),
DTBP (3 equiv)
R2
R1
O
O
CO2Et
CO2Et
+
R1
DMSO, 100 oC, N2
R2
N
NH
H
1
(1.5 equiv)
2
3
COOEt
COOEt
O
COOEt
COOEt
O
COOEt
COOEt
NH
R
NH
NH
a
3aa
3ab
, R = H, 6 h, 77% (72% )
, R = OMe, 5 h, 79%
R
3af
, R = Cl, 5 h, 57%
3ag
3ah,
5.5 h, 84%
3ac, R = Cl, 5 h, 56%
3ad, R = Br, 5.5 h, 62%
3ae, R = NO2, 5 h, 23%
, R = CO2Me, 5.5 h, 51%
O
COOEt
O
COOEt
COOEt
O
COOEt
COOEt
COOEt
Ph
NH
9 h, 63%
O COOEt
COOEt
NH
4 h, 70%
COOEt
COOEt
NH
17 h,25%
, R = 4-OMe, 12 h, 54%
N
3ai,
3ak,
3aj,
O
3ba
R
3ca, R = 4-Me, 6 h, 70%
3da, R = 4-Br, 4 h, 61%
O
3ea
, R = 4-Cl, 4 h, 60%
3fa, R = 2-F, 4 h, 75%
3ga, R = 4-NO2, 2 h, 32%
NH
3ia, 7 h, 78%
COOEt
COOEt
NH
3ha
, R = 3-NO2, 4 h, 32%
O
COOEt
COOEt
O
COOEt
COOEt
O
N
NH
HN
NH
3la, 5 h, 42%
COOEt
COOEt
3ka, 1 h, 60%
COOEt
COOEt
3ja, 4.5 h, 40%
COOEt
COOEt
O
O
O
EtO
N
O
NH
7 h, 37%
NH
3ma, 12 h, 32%
NH
11 h, 37%
3na,
3oa,
a The yield of a 2 mmol scale reaction.
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Encouraged by these results obtained from indoles, we envisaged that a second nucleophilic site
linking to the 2-position of indole might attack on the carbonyl, leading to the formation of
polycyclic indoles. Accordingly, indole-2-methanol 5a and indole-2-formamide 7a were subjected
to the reaction with 1a, respectively (Scheme 2). Pleasingly, the reaction of 1a with 5a under the
optimized conditions afforded the anticipated product 6aa in 65% yield. Using K2CO3 as the base
gave slightly high yield (68%). Meanwhile, the intermediate 6aa' was also determined and
transformed to 6aa smoothly. It was noteworthy that this reaction showed perfect regioselectivity
with indole-3-carbon coupling with sp3-carbon and oxygen atom attacking on the carbonyl carbon.
The reaction of 1a with 7a with Na2CO3 as the base only furnished 24% yield of 8aa. Replacing
Na2CO3 by K2CO3 improved the yield to 41%. Using Li2CO3 as the base gave a comparable yield
with that of Na2CO3, however, the reaction proceeded very slowly (8 h vs 1 h). The K3PO4 was
also inferior to the K2CO3. An organic base like Et3N and pyridine could not initiate the reaction.
An attempt to further improve the yield was failed because large amount of 9a was formed from
the self-reaction of 1a. A main reason for the low yield lied in the electronegativity of 2-amide
group reduced the nucleophilicity of indole-3-carbon, which made the addition reaction difficult.
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Scheme 2 The reaction of 1a with 5a/7a and the self-reaction of 1a.
O
O
COOEt
COOEt
OH
Cu(OAc)2 (1 equiv),
base (2 equiv)
DTBP (3 equiv)
H
EtO2C
OH
N
O
Ph
1a
Ph
O
DMSO, 100 oC, N2
5a (0.9 equiv)
NH
N
6aa
6aa'
H
Na2CO3, 2.5 h
K2CO3, 2 h,
65%
68%
O
EtO2C
H
O
N
O
Cu(OAc)2 (1 equiv),
K2CO3 (2 equiv)
DTBP (3 equiv)
R1
Me
N
Me
1a
N
O
H
DMSO, 100 oC, N2
N
7a (0.9equiv)
H
8aa
Na2CO3, 2 h
24%
41%
26%
34%
K2CO3, 1 h,
Li2CO3, 8 h
K3PO4, 1.5 h
Cu(OAc)2 (1 equiv),
K2CO3 (2 equiv)
DTBP (3 equiv)
O
COOEt
O
COOEt
COOEt
Ph
COOEt
Ph
DMSO, 100 oC, N2
30 min
EtOOC
9a
COOEt
(57%)
1a
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To evaluate the generality of this process, various indole-2-alcohols and indole-2-carboxamides
were subjected to the reaction with 1 (Tables 3 and 4). For the indole-2-alcohols 5, the substituent
R2 on the phenyl ring had siginficant influence on the reaction. Both strong electron-donating and
electron-withdrawing group were unfavorable to the reaction. While other groups such as bromo,
fluoro have no influence on the reaction, delivering the corresponding products in modest yields.
When R2 is methoxy, 6ab was obtained in a very low yield of 17%. While a nitro group led to the
corresponding product 6af in only 7% yield accompanied by the formation of 6af' in 29% yield. A
tertiary alcohol tethered indole gave the corresponding products 6ah in 22% yield.
Indole-2-ethanol 5i was also tolerated in the reaction to give 6ai in 17% yield accompanied by 6ai'
in 39% yield. Notably, when R1 was 4-methoxyphenyl, only the coupling intermediate 6ba' was
formed in 31% yield due to the strong electon-donating character of methoxy group, which
recduced the electrophilicity of carbonyl. While R1 was a 4-nitrophenyl, the product 6ga was
formed in 58% yield.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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Table 3 Reaction of indole-2-alcohols with α-acylmethyl malonates.
O
Cu(OAc)2 (1 equiv)
EtO2C
O
K2CO3 (2 equiv)
OH
R3
O
CO2Et
CO2Et
DTBP (3 equiv)
DMSO, 100 oC, N2
R1
O
+
R1
N
H
R2
1
N
H
5 (0.9 equiv)
R3
R2
6
O
COOEt
COOEt
OH
O
O
O
EtO2C
EtO2C
R
O2N
6aa, R = H, 2 h, 68%
6ab, R = OMe, 2 h, 17%
O
+
Ph
O
6ac
, R = Me, 2.5 h, 42%
Ph
6ad, R = Br, 2 h, 41%
6ae, R = F, 2.5 h, 43%
O
NH
O2N
N
H
N
H
6af
, 1 h, 7%
6af
', 1 h, 29%
O
O
COOEt
O
O
EtO2C
O
O
Me
EtO2C
EtO2C
COOEt
OH
O
Ph
O
+
Ph
Ph
O
NH
O
N
Me
N
H
Me
N
H
6ag
H
6ai, 1.5 h, 17%
6ai'
, 1.5 h, 39%
, 2 h, 31%
6ah, 3 h, 22%
O
O
O
COOEt
EtO2C
COOEt
OH
MeO
O
N
H
NO2
NH
6ga
, 40 min, 58%
6ba', 40 min, 31%
In the case of reaction of indole-2-carboxamides 1 with 7 (Table 4), the substituents on both of
the substrates had a great influence on the reaction. An electon-withdrawing group on the indole
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ring was extremely unfavorable to the reaction (8ad and 8ae), and a nitro group led to no
formation of the anticipated product, impling that a proper nuclephilicity of indole-3-carbon to
trigger the second step of addition was crucial to the success of reaction. Changing the substituent
on nitrogen atom from methyl to butyl, cyclopropyl, or 4-methylphenyl, the reaction still worked
but the yield was unsatisfatory. A tert-butyl group only gave the uncycled product in 15% yield. In
addition, the position of the amide carbony group had great influence on the reaction, when
N-acetyl indole-2-mehthylamine 7j was used instead of indole-2-formide 7a, only coupling
product 8aj' was obtained in 39% yield without further cyclization.
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Table 4 Reaction of indole-2-carboxamides with α-acylmethyl malonates.
O
EtO2C
Cu(OAc)2 (1 equiv),
K2CO3 (2 equiv)
DTBP (3 equiv)
DMSO, 100 oC, N2
O
NHR3
O
O
CO2Et
CO2Et
R1
R3
+
N
R1
N
H
7
R2
1
N
O
R2
H
8
O
O
O
O
O
EtO2C
NH
EtO2C
EtO2C
NH
OMe
Me
O
Ph
Ph
Ph
N
N
N
NH
Me
Me
Me
O
O
O
8ac,
8aa, 1 h, 41%
8ab, 1 h, 42%
1 h, 40%
O
O
O
O
EtO2C
EtO2C
EtO2C
Br
F
O
O
Ph
Ph
Ph
N
N
N
n
NH
NH
NH
Me
Me
C4H9
O
O
O
8ae, 1 h, 14%
8af, 1 h, 20%
8ad,
1.5 h, 16%
O
O
EtO2C
EtO2C
O
COOEt
COOEt
O
O
Ph
O
Ph
N
N
N
H
NH
N
H
NH
O
O
8ai,
1.5 h, 27%
8ah', 1 h, 15%
8ag, 30min, 18%
COOEt
COOEt
O
EtO2C
O
O
O
NO2
N
N
N
H
H
Me
NH
O
8ga,
1 h, 31%
8aj', 4 h, 39%
To confirm the role of acyl and malonate group in the cross-dehydrogenative coupling reaction,
substrates 1p-r were prepared and subjected to the reaction with 2a (Scheme 3). Replacing one of
the two ester groups by hydrogen or mehtyl resulted in no reaction occurring (1p and 1q). When
the benzoyl group was replaced by a phenyl group, no coupling product 3ra was formed yet.
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Scheme 3 Try of Other Substrates
5
6
7
8
O
O
H
CO2Et
standard conditions
+
CO2Et
N
H
1p
2a
2a
2a
NH
10 (0%)
9
O
Me
10
11
12
13
14
15
16
17
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22
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O
Me
CO2Et
CO2Et
standard conditions
+
N
H
1q
NH
11 (0%)
CO2Et
Ph
CO2Et
CO2Et
CO2Et
standard conditions
+
Ph
N
H
NH
1r
3ra (0%)
To have a deep insight into the reaction, compound 12 was prepared through the Wittig reaction
of benzoylmethylenetriphenylphosphorane with diethyl 2-oxomalonate. Stirring the mixture of 12
and 1 equiv of Cu(OAc)2 in DMSO at 100 C for 6 h, most of 12 was recovered. However, when
the mixture of 12 and 1 equiv of Na2CO3 was stirred at 100 C, full conversion of 12 was observed
after 3 h and 9a was isolated in 88% yield. When 1 equiv of diethyl malonate was added, the
Michael addition to 12 proceeded quickly at room temperature in the presence of Na2CO3, giving
9a in 96% yield (Scheme 4a). This reavealed that the dehydrogenative reaction to generate C=C
double bonds was a rate-determine step and therefore we did not observe the formation of 12
during the reaction of 1 with 2/5/7. The reaction of 2a with 12 in the pesence of 1 equiv of Na2CO3
at 100 C only furnished trace of addition product 4a, and most of 12 was converted to 9a. While
in the presence of 0.2 equiv of Cu(OAc)2, the addition product 4a was obtained in 86% yield
within 4 h (Scheme 4b). Similary, the reaction of 5a with 12 in the presence of 0.2 equiv of
Cu(OAc)2 generated 93% yield of 6aa' within 1 h (Scheme 4c). These results indicated that the
Cu(OAc)2 acted as not only an oxidant but also a catalyst and the base was crucial to the step of
dehydrogenation. When the indole 2a was reacted with equal amount of 12 under standard
conditions, 3aa was obained in 72% yield (Scheme 4b).
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Scheme 4 Control experiments and preliminary mechanistic studies.
5
6
7
8
CH2(CO2Et)2 (1 equiv)
(a)
Na2CO3 (1 equiv)
O
COOEt
COOEt
DMSO, rt., N2, 0.5 h
96%
Cu(OAc)2 (1 equiv)
O
CO2Et
CO2Et
Ph
EtOOC
N. R.
DMSO, 100 oC, N2 Ph
6 h
COOEt
Na2CO3 (1 equiv)
12
9a
DMSO, 100 oC, N2, 3 h
88%
9
10
11
12
13
14
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60
O
COOEt
COOEt
(b)
Na2CO3 (1 equiv)
DMSO, 100 oC, N2
2 h
+
9a (77%)
NH
4a
O
CO2Et
CO2Et
(trace)
Ph
12
Cu(OAc)2 (0.2 equiv)
4a
DMSO, 100 oC, N2, 4 h
86%
+
N
O
COOEt
COOEt
H
Cu(OAc)2 (1 equiv),
K2CO3 (2 equiv)
DTBP (3 equiv)
2a (1 equiv)
DMSO, 100 oC, N2
5 h
NH
3aa (72%)
(c)
O
COOEt
O
CO2Et
CO2Et
OH
Cu(OAc)2 (0.2 equiv)
Ph
COOEt
OH
DMSO, 100 oC, N2, 1 h
93%
Ph
N
H
5a
12
NH
6aa'
(d)
OH
Cu(OAc)2 (1 equiv), Na2CO3 (1 equiv), DTBP (3 equiv)
DMSO, 100 oC, N2, 45 min
complex mixture
N
H
5a
On the basis of above results, a plausible reaction mechanism was proposed to clarify the
oxidative dehydrogenative coupling reaction (Scheme 5). Deprotonation of 1 followed by
single-electron oxidation with Cu(OAc)2 afforded radical B, which was further oxidized by
Cu(OAc)2 accompanied by release of CuOAc and HOAc to deliver the key intermediate C.
Coordination of Cu(OAc)2 with the two ester groups increased the electrophilicity of the β-C(sp2).
Reaction of D with 2 or 5/7 afforded the coupling product E or F, respectively. Further oxidation
of E by Cu(OAc)2 under basic conditions furnished 3 with the concurrent release of CuOAc.
Similar oxidation of F afforded G. Under basic conditions, a cascade intramolecular nucleophilic
reaction occurred to furnish 6/8. The oxidation process could be promoted by CuII, which was
recycled by oxidation of CuI with DTBP. Under basic conditions, intermediate C might react with
the trace amount of water in solvent to yield the addition product H, which underwent retro-Aldol
reaction to give diethyl malonate and I. The Michael addition of diethyl malonate with C afforded
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the main byproduct J. The competition reaction of C with H2O or the coupling partner determined
the reaction efficiency. When an electron-withdrawing amide group was linked to the 2-position of
indoles, the nucleophilicity of indoles decreased significantly and thus resulted in the increased
difficulty of addition with C. Additionally, we also observed that stirring the single 5a under
standard conditions gave a complex mixture within 45 min (Scheme 4d). In combined with the
steric hindrance of 2-substituent, these were the partial reasons for the low reaction efficiency
between 1 and indole-2-alcohols or indole-2-carboxamides.
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Scheme 5 Plausible mechanism.
B-
O
CO2Et
CO2Et
O
O
CO2Et
CO2Et
Cu(OAc)2
Cu(OAc)2
O
H2O
-CuOAc
-AcO-
-CuOAc
-HOAc
R
R
R
I
B
OH
CO2Et
CO2Et
CO2Et
H
O
O
CO2Et
O
R
CO2Et
CO2Et
B-
1
CO2Et
CO2Et
R
C
B-
R
CO2Et
C
A
EtO2C
J
O
CO2Et
Nu
O
CO2Et
H
OAc
Cu
EtO
R
CO2Et
CO2Et
NuH
O
R
NH
OAc
N
O
H
O
R
NH
NH
OEt
D
E
F
CuII
CuII
B-
B-
O
DTBP
DTBP
CuI
CuI
O
O
EtO
CO2Et
O
EtO2C
O
R
R
CO2Et
B-
R
EtO2C
H
Nu
Nu
-EtOH
NH
NH
N
H
3
6 and 8
G
CONCLUSIONS
In summary, we have presented a Cu(OAc)2-promoted oxidative dehydrogenative coupling
reaction of α-acylmethyl malonates with indole derivatives. A new C(sp2)−C(sp2) bonds was
directely constructed by connecting the 3-C(sp2) of indoles and the β-C(sp3) of malonates under
mild conditions. In the case of indoles, a sequential dehydrogenation-addition-dehydrogenation
process was involved in the reaction. In terms of indole-2-methanols and indole-2-carboxamides, a
futher cascade intramolecular nucleophilic cyclization occurred to give polycyclic indole
derivatives. The Cu(OAc)2 acts as not only an oxidant in the step of dehydrogenation but also a
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catalyst in the step of addition. The base was essential to the step of oxidative dehydrogenation but
at the same time cause the decomposition of intermediate, which is the main reason for the low
yield in the reaction of α-acylmethyl malonates with indole-2-methanols and
indole-2-carboxamides. An effort to improve the reaction efficiency are ongoing.
EXPERIMENTAL SECTION
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General Information
All the reaction was performed on a preheated oil bath (the reaction temperature refers to the
1
temperature of the oil bath). H and 13C NMR (proton broadband decoupling) spectra were
recorded on 300 and 400 MHz (75 and 100 MHz for 13C NMR) spectrometer at ambient
temperature, using TMS as an internal standard. Flash column chromatography was performed
over silica gel (200-300 mesh). HRMS was obtained on LTQ Orbitrap XL mass spectrometer.
Straring materials 1a-e,1g,1i,1l-q, 5a-f, 5h, 5i, 7f-i,14 7j,18 and 1219 were prepared according to
reported method.
General Procedure Preparation of Diethyl Malonate Substituted ketone 1f, 1h, and 1j. The
o
diethyl malonate (12 mmol) was dissolved in dry THF (15 mL). After cooling to 0 C, NaH (520
mg, 60 % in oil, 13 mmol) was added in one portion and the mixture was stirred for 30 min at 0
oC. The corresponding α-bromokenone (10 mmol) was dissolved in THF (15 mL) and added
slowly to the reaction mixture. The reaction was warmed to room temperature and quenched by
the addition of an equal volume of aq. NH4Cl. The mixture was extracted with ethyl acetate (3 ×
40 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by column chromatography to
provide α-acylmethyl manolates 1.
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1f (eluent: ethyl acetate / petroleum ether = 1/25-1/15, colorless oil, 2.03 g, 69%): 1H NMR (300
MHz, CDCl3) δ 7.89 (td, J = 7.6, 1.7 Hz, 1H), 7.61-7.46 (m, 1H), 7.24 (td, J = 7.6, 0.7 Hz, 1 H),
7.16 (dd, J = 11.3, 8.3 Hz, 1H), 4.34-4.16 (m, 4H), 4.05 (t, J = 7.1 Hz, 1H), 3.36 (dd, J = 7.0, 3.2
Hz, 2H), 1.29 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 194.8, 194.7, 169.0, 164.0, 160.6,
135.3, 135.2, 130.8, 130.7, 124.7, 124.6, 124.6, 124.5, 117.0, 116.7, 61.8, 47.4, 47.3, 42.5, 42.4,
14.1; HRMS (ESI) m/z [M+H]+ Calcd for C15H18FO5 297.1138, found 297.1127.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
30
31
32
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34
35
36
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1h (eluent: ethyl acetate / petroleum ether = 1/20-1/10, colorless solid, 1.87 g, 58%, mp 53-55
C): 1H NMR (300 MHz, CDCl3) δ 8.81 (t, J = 1.8 Hz, 1H), 8.46 (ddd, J = 8.2, 2.2, 1.0 Hz, 1 H),
8.32 (dt, J = 7.8, 1.3 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 4.34-4.17 (m, 4H), 4.09 (t, J = 7.1 Hz,
1H), 3.67 (d, J = 7.0 Hz, 2H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 194.7, 168.8,
148.5, 137.4, 133.8, 130.1, 127.9, 123.2, 62.1, 47.2, 38.0, 14.1; HRMS (ESI) m/z [M+H]+ Calcd
for C15H18NO7 324.1083, found 324.1075.
1
1j (eluent: ethyl acetate / petroleum ether = 1/20-1/12, brown oil, 969.0 mg, 35%): H NMR
(300 MHz, CDCl3) δ 8.70 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.03 (dd, J = 7.9, 1.0 Hz, 1 H), 7.85 (td,
J = 7.7, 1.7 Hz, 1 H), 7.50 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 4.31-4.18 (m, 4H), 4.03 (t, J = 7.2 Hz,
1H), 3.88 (d, J = 6.9 Hz, 2H), 1.29 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 198.3, 169.1,
152.6, 149.1, 136.9, 127.5, 121.8, 61.7, 47.2, 37.3, 14.0; HRMS (ESI) m/z [M+H]+ Calcd for
C14H18NO5 280.1185, found 280.1180.
Preparation of 1k. The process is the same as above only with the
(E)-1-iodo-4-phenylbut-3-en-2-one (2 mmol) as halide.
1
1k (eluent: ethyl acetate / petroleum ether = 1/20-1/10, light yellow oil, 346.9 mg, 57%): H
NMR (300 MHz, CDCl3) δ 7.61 (d, J = 16.3 Hz, 1 H), 7.58-7.50 (m, 2 H), 7.45-7.34 (m, 3 H), 6.76
(d, J = 16.3 Hz, 1 H), 4.234 (q, J = 7.2 Hz, 2H), 4.229 (q, J = 7.1 Hz, 2H), 3.99 (t, J = 7.2 Hz, 1H),
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3.34 (d, J = 7.2 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.4, 169.1,
143.7, 134.3, 130.8, 129.1, 128.5, 125.5, 62.2, 61.8, 47.1, 39.4, 14.1, 14.0; HRMS (ESI) m/z
[M+H]+ Calcd for C17H21O5 305.1389, found 305.1378.
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Preparation of 5g. To a stirred solution of ethyl 7-methyl-indole-2-carboxylate (1.0 mmol) in 5
mL of THF was added LiALH4 (5 mmol) at room temperature. After completion of the reaction as
monitored by TLC, a small amount aqueous NaOH solution was slowly added. The mixture was
stirred for 20 minutes and then filtered. The filtrate was added 20 mL of water and then extracted
with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column
chromatography (ethyl acetate : petroleum ether = 1 : 2) to provide 5g (reddish brown solid, 151.0
1
mg, 94%, mp 63-65 C): H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 7.40 (d, J = 7.5 Hz, 1H),
7.01 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 6.9 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.69 (s, 2 H), 2.51-2.34
13
(m, 4 H); C NMR (75 MHz, CDCl3) δ 137.2, 136.2, 127.6, 122.8, 120.4, 120.2, 118.4, 101.2,
58.7, 16.7; HRMS (ESI) m/z [M+H]+ Calcd for C10H12NO 162.0919, found 162.0910.
Indole-2-carboxamides 7a-e were prepared according to literature procedure.20 A mixture
of indole-2-carboxylate (1.0 mmol) and 15 mL of aqueous solution of methylamine (25 wt %) was
stirred at room temperature until the completion of the reaction as monitored by TLC (about 24-48
h). After filtration, the solid was washed with water and then dried to provide 7a-e.
7c (white solid, 179.9 mg, 96%, mp 250-253 C): 1H NMR (300 MHz, d6-DMSO) δ 11.44 (br,
1H), 8.48-8.33 (m, 1H), 7.37 (d, J = 0.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.99 (dd, J = 8.4, 1.5
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Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.36 (s, 3 H); C NMR (75 MHz,
d6-DMSO) δ 161.9, 134.9, 131.9, 128.4, 127.6, 125.2, 120.9, 112.2, 101.8, 26.0, 21.3; HRMS
(ESI) m/z [M+H]+ Calcd for C11H13N2O 189.1028, found 189.1014.
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7d (white solid, 229.2 mg, 91%, mp 296-297 C): 1H NMR (300 MHz, d6-DMSO) δ 11.82 (br,
1H), 8.67-8.49 (m, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.7, 1.9
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Hz, 1H), 7.07 (s, 1H), 2.83 (d, J = 4.6 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ 161.2, 135.0,
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133.2, 129.0, 125.8, 123.7, 114.4, 112.2, 101.6, 25.9; HRMS (ESI) m/z [M+H]+ Calcd for
C10H10BrN2O 252.9977, found 252.9959.
General Procedure for the Preparation of 3. A mixture of α-acylmethyl manolates 1 (0.45
mmol), indoles 2 (0.3 mmol), DTBP (0.9 mmol), Na2CO3(0.6 mmol), and Cu(OAc)2 (0.3 mmol) in
o
DMSO (3.0 mL) was stirred at 100 C under N2 atmosphere. After completion of the reaction as
determined by TLC, the mixture was cooled to room temperature and ammonia solution (10%, 30
mL) was added. The mixture was extracted with ethyl acetate (3  30 mL). The combined organic
phase were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography to give the products 3.
3aa (eluent: ethyl acetate / petroleum ether = 1/5, yellow solid, 90.0 mg, 77%, mp 178-180 C):
1H NMR (300 MHz, d6-DMSO) δ 11.94 (br, 1H), 7.86 (d, J = 7.1 Hz, 2H), 7.62-7.54 (m, 2H), 7.47
(t, J = 7.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.14 (td, J = 7.5, 0.8 Hz,
1H), 7.04 (td, J = 7.5, 0.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 1.09 (t, J =
7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 193.8, 165.8, 163.2, 149.6,
136.8, 135.4, 133.6, 128.9, 128.6, 124.5, 122.6, 120.9, 120.5, 119.2, 112.7, 108.1, 61.5, 61.3, 13.6,
13.5; HRMS (ESI) m/z [M+Na]+ Calcd for C23H21NNaO5 414.1317, found 414.1315.
3ab (eluent: ethyl acetate / petroleum ether = 1/5, yellow solid, 99.6 mg, 79%, mp 186-188 C):
1H NMR (300 MHz, CDCl3) δ 8.67 (br, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.48 (tt, J = 7.3, 1.3 Hz,
1H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 3.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 2.3
Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.77 (s,
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3H), 1.09 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.5, 166.9,
163.9, 155.3, 150.6, 135.9, 133.5, 131.6, 129.1, 128.8, 128.1, 125.5, 121.7, 113.7, 112.8, 109.9,
101.8, 62.0, 61.8, 55.7, 13.8, 13.7; HRMS (ESI) m/z [M+H]+ Calcd for C24H24NO6 422.1604,
found 422.1595.
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3ac (eluent: ethyl acetate / petroleum ether = 1/5, yellow solid, 71.0 mg, 56%, mp 168-172 C):
1H NMR (300 MHz, CDCl3) δ 9.00 (br, 1H), 7.92 (d, J = 7.0 Hz, 2H), 7.61 (s, 1H), 7.48 (tt, J =
7.3, 1.3 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.11-7.13 (m, 2H), 7.09 (d, J = 2.9 Hz, 1H), 4.26 (q, J =
7.2 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 194.1, 166.7, 163.8, 150.3, 135.5, 135.2, 133.6, 129.1, 128.8, 127.2, 125.4,
123.6, 122.6, 119.1, 113.3, 109.2, 62.6, 61.9, 13.9, 13.7; HRMS (ESI) m/z [M+H]+ Calcd for
C23H21ClNO5 426.1108, found 426.1104.
3ad (eluent: ethyl acetate / petroleum ether = 1/6, yellow solid, 86.8 mg, 62%, mp 186-188 C):
1H NMR (300 MHz, CDCl3) δ 9.05 (br, 1H), 7.91 (d, J = 7.0 Hz, 2H), 7.77 (d, J = 1.8 Hz, 1H),
7.48 (tt, J = 7.4, 1.3 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.24 (dd, J = 8.6, 1.8 Hz, 1H), 7.06 (d, J =
8.7 Hz, 1H), 7.03 (d, J = 2.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.28 (t, J
= 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.0, 166.7, 163.8, 150.3,
135.5, 135.5, 133.6, 129.1, 129.0, 128.8, 126.2, 126.0, 122.7, 122.2, 114.8, 113.8, 109.1, 62.7,
61.9, 14.0, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21BrNO5 470.0603, found 470.0591.
3ae (eluent: ethyl acetate / dichloromethane = 1/90, yellow solid, 29.8 mg, 23%, mp 216-218
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C): H NMR (300 MHz, CDCl3) δ 9.51 (br, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 9.0, 2.1
Hz, 1H), 7.93 (d, J = 7.1 Hz, 2H), 7.51 (tt, J = 7.4, 1.2 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.24 (d, J
= 9.0 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.33 (t,
J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.8, 166.5, 163.5, 149.0,
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142.9, 139.8, 135.2, 133.9, 130.7, 129.2, 129.0, 123.8, 118.8, 116.7, 112.5, 111.5, 63.0, 62.2, 13.9,
13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21N2O7 437.1349, found 437.1339.
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3af (eluent: ethyl acetate / petroleum ether = 1/5, yellow solid, 72.4 mg, 57%, mp 165-168 C):
1H NMR (300 MHz, CDCl3) δ 8.93 (br, 1H), 7.94 (d, J = 7.1 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H),
7.48 (tt, J = 7.3, 1.3 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 1.6 Hz,
1H), 7.09 (dd, J = 8.7, 1.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 1.13 (t, J =
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7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 194.4, 166.6, 163.7, 149.8,
137.1, 135.6, 133.7, 129.2, 129.1, 128.8, 128.2, 123.3, 123.0, 122.1, 120.8, 112.0, 109.9, 62.2,
62.0, 13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21ClNO5 426.1108, found 426.1092.
3ag (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/1, yellow solid, 68.6 mg,
51%, mp 151-153 C): 1H NMR (300 MHz, CDCl3) δ 9.29 (br, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.85
(s, 1H), 7.79 (dd, J = 8.6, 1.3 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.43-7.33
(m, 3H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H),
13
1.10 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 194.3, 167.6, 166.5, 163.7, 149.9, 136.1,
135.5, 133.7, 130.4, 129.1, 128.9, 128.1, 124.8, 123.4, 122.2, 119.4, 114.4, 110.0, 62.3, 62.0, 52.2,
13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C25H24NO7 450.1553, found 450.1540.
3ah (eluent: ethyl acetate / petroleum ether =1/6, yellow solid, 102.3 mg, 84%, mp 170-172 C):
1H NMR (300 MHz, CDCl3) δ 8.85 (br, 1H), 7.94 (d, J = 7.0 Hz, 2H), 7.51-7.41 (m, 2H), 7.35 (t, J
= 7.4 Hz, 2H), 7.19 (d, J = 3.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz,
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3H); C NMR (75 MHz, CDCl3) δ 194.2, 166.8, 163.9, 151.1, 136.3, 135.8, 133.4, 129.1, 128.7,
127.7, 124.3, 123.8, 122.1, 121.6, 121.5, 117.5, 110.2, 62.1, 61.7, 16.4, 13.9, 13.8; HRMS (ESI)
m/z [M+H]+ Calcd for C24H24NO5 406.1654, found 406.1644.
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3ai (eluent: ethyl acetate / petroleum ether =1/5, yellow solid, 76.8 mg, 63%, mp 113-116 C):
1H NMR (300 MHz, CDCl3) δ 8.38 (br, 1H), 7.92 (d, J = 7.0 Hz, 2H), 7.64-7.55 (m, 1H), 7.44 (tt,
J = 7.3, 1.3 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.20-7.14 (m, 1H), 7.14-7.05 (m, 2H), 4.12 (q, J =
7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.17 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz,
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3H); C NMR (75 MHz, CDCl3) δ 194.2, 166.0, 164.4, 151.3, 136.9, 135.9, 135.6, 133.3, 129.1,
128.6, 126.6, 126.5, 122.2, 120.8, 118.8, 111.2, 106.4, 61.8, 61.8, 13.8, 13.6, 13.0; HRMS (ESI)
m/z [M+H]+ Calcd for C24H24NO5 406.1654, found 406.1641.
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3aj (eluent: ethyl acetate / petroleum ether =1/5, yellow oil, 35.3 mg, 25%): H NMR (300
MHz, CDCl3) δ 8.54 (br, 1H), 7.63 (d, J = 7.1 Hz, 3H), 7.51-7.43 (m, 2H), 7.38-7.31 (m, 4H),
7.30-7.24 (m, 1H), 7.22-7.12 (m, 4H), 4.04 (q, J = 7.1 Hz, 2H), 3.93 (q, J = 7.1 Hz, 2H), 1.00 (t, J
= 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.9, 165.4, 164.4, 149.9,
138.9, 136.2, 136.0, 132.9, 131.1, 129.9, 129.1, 128.9, 128.6, 128.3, 127.1, 123.1, 121.2, 119.4,
111.6, 107.5, 61.9, 61.6, 13.6, 13.5; HRMS (ESI) m/z [M+H]+ Calcd for C29H26NO5 468.1811,
found 468.1801.
3ak (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/1, white solid, 82.3 mg,
1
70%, mp 199-200 C): H NMR (300 MHz, CDCl3) δ 12.38 (br, 1H), 8.32 (dd, J = 4.7, 1.2 Hz,
1H), 8.05 (dd, J = 8.1, 1.4 Hz, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.72 (s, 1H), 7.49 (tt, J = 7.3, 1.3 Hz,
1H), 7.39 (t, J = 7.4 Hz, 2H), 7.14 (dd, J = 8.1, 4.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.12 (q, J =
13
7.1 Hz, 2H), 1.113 (t, J = 7.1 Hz, 3H) , 1.107 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
194.1, 166.5, 163.3, 149.2, 148.7, 143.4, 135.5, 133.6, 129.9, 129.1, 128.8, 128.3, 123.1, 118.5,
117.3, 108.2, 62.0, 61.9, 13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C22H21N2O5 393.1450,
found 393.1434.
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3ba (eluent: ethyl acetate / petroleum ether = 1/4, yellow solid, 68.4 mg, 54%, mp 174-175 C):
1H NMR (300 MHz, CDCl3) δ 8.89 (br, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H),
7.27 (d, J = 6.4 Hz, 2H), 7.16 (td, J = 7.1, 1.3 Hz, 1H), 7.11 (td, J = 7.1, 1.2 Hz, 1H), 6.82 (d, J =
8.9 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.10 (t, J = 7.1 Hz,
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3H), 1.07 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 193.4, 166.9, 163.9, 163.8, 150.6,
136.7, 131.4, 128.9, 127.8, 124.8, 123.2, 121.9, 121.3, 120.0, 114.1, 112.2, 110.2, 62.0, 61.7, 55.5,
13.79, 13.76; HRMS (ESI) m/z [M+H]+ Calcd for C24H24NO6 422.1604, found 422.1591.
3ca (eluent: ethyl acetate / petroleum ether = 1/6, yellow solid, 85.3 mg, 70%, mp 189-190 C):
1H NMR (300 MHz, CDCl3) δ 8.76 (br, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H),
7.26-7.31 (m, 2H), 7.21-7.08 (m, 4H), 4.14 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.32 (s,
3H), 1.10 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.2, 166.8,
163.9, 150.8, 144.4, 136.7, 133.3, 129.5, 129.2, 127.8, 124.8, 123.2, 122.0, 121.3, 120.0, 112.1,
110.0, 62.0, 61.8, 21.8, 13.79, 13.78; HRMS (ESI) m/z [M+H]+ Calcd for C24H24NO5 406.1654,
found 406.1635.
3da (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/1, yellow solid, 85.6 mg,
61%, mp 196-198 C): 1H NMR (300 MHz, CDCl3) δ 8.82 (br, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.60
(d, J = 7.7 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.34-7.26 (m, 2H), 7.23-7.08 (m, 2H), 4.16 (q, J =
7.1 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 193.4, 166.6, 163.8, 150.0, 136.8, 134.6, 132.1, 130.5, 128.6, 127.8, 124.7,
123.5, 122.4, 121.6, 119.9, 112.2, 109.6, 62.1, 61.9, 13.9, 13.8; HRMS (ESI) m/z [M+Na]+ Calcd
for C23H20BrNNaO5 492.0423, found 492.0414.
3ea (eluent: ethyl acetate / petroleum ether = 1/9, yellow solid, 76.8 mg, 60%, mp 200-202 C):
1H NMR (300 MHz, CDCl3) δ 8.82 (br, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H),
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= 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
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193.2, 166.6, 163.8, 150.0, 139.8, 136.8, 134.2, 130.4, 129.1, 127.8, 124.7, 123.5, 122.4, 121.6,
119.9, 112.2, 109.6, 62.1, 61.9, 13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21ClNO5
426.1108, found 426.1102.
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3fa (eluent: ethyl acetate / petroleum ether = 1/9, yellow solid, 92.2 mg, 75%, mp 175-176 C):
1H NMR (300 MHz, CDCl3) δ 8.73 (br, 1H), 8.05 (td, J = 7.6, 1.8 Hz, 1H), 7.66 (d, J = 8.0 Hz,
1H), 7.48-7.38 (m, 1H), 7.31-7.25 (m, 2H), 7.23-7.10 (m, 3H), 6,98 (ddd, J = 10.9, 8.3, 0.8 Hz, 1
H), 4.16 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, d6-DMSO) δ 190.4, 166.1, 164.0, 161.8 (1JC-F = 257.8 Hz), 151.7, 137.2,
136.4 (3JC-F = 9.3 Hz), 131.0, 129.6, 125.2 (JC-F = 3.2 Hz), 125.1, 124.0 (3JC-F = 9.5 Hz), 122.9,
121.2, 119.8 (JC-F = 3.0 Hz), 119.4, 117.3 (2JC-F = 21.9 Hz), 113.0, 107.3, 61.7, 13.9, 13.9; HRMS
(ESI) m/z [M+H]+ Calcd for C23H21FNO5 410.1404, found 410.1394.
3ga (eluent: dichloromethane / petroleum ether = 1/2-1/1, yellow solid, 42.0 mg, 32%, mp
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179-180 C): H NMR (300 MHz, CDCl3) δ 8.78 (br, 1H), 8.21 (d, J = 9.0 Hz, 2H), 8.10 (d, J =
9.0 Hz, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 3.0 Hz, 1H ), 7.33 (d, J = 7.6 Hz, 1H), 7.23 (td,
J = 7.4, 1.3 Hz, 1H), 7.17 (td, J = 7.3, 1.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.15 (q, J = 7.1 Hz,
2H), 1.18 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.5, 166.3,
163.9, 150.2, 149.6, 140.3, 136.8, 129.8, 128.1, 124.5, 124.0, 123.7, 122.5, 121.8, 119.8, 112.3,
108.9, 62.3, 62.2, 13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21N2O7 437.1349, found
437.1334.
3ha (eluent: ethyl acetate / petroleum ether = 1/4, yellow solid, 41.4 mg, 32%, mp 152-155 C):
1H NMR (300 MHz, CDCl3) δ 8.87-8.73 (m, 2H), 8.30 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 8.23 (ddd, J
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= 7.7, 1.3, 0.9 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 2.9 Hz, 1H),
7.32 (dd, J = 7.2, 1.3 Hz, 1H), 7.26-7.14 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz,
2H), 1.18 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.0, 166.3,
163.9, 149.5, 148.6, 137.2, 136.8, 134.5, 130.0, 127.9, 127.5, 124.6, 123.7, 123.6, 122.8, 121.8,
119.8, 112.2, 108.9, 62.3, 62.1, 13.9, 13.8; HRMS (ESI) m/z [M+H]+ Calcd for C23H21N2O7
437.1349, found 437.1344.
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3ia (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/1, yellow solid, 89.7 mg,
78%, mp 165-167 C): 1H NMR (300 MHz, CDCl3) δ 8.92 (br, 1H), 7.63-7.50 (m, 2H), 7.40-7.29
(m, 2H), 7.23-7.05 (m, 3H), 6.44 (dd, J = 3.6, 1.7 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.14 (q, J =
7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 182.6,
166.6, 163.8, 151.9, 148.2, 147.3, 136.6, 127.8, 125.1, 123.3, 123.0, 121.4, 120.0, 119.5, 112.5,
112.1, 110.0, 62.0, 61.9, 13.83, 13.76; HRMS (ESI) m/z [M+H]+ Calcd for C21H20NO6 382.1291,
found 382.1279.
3ja (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/1, yellow solid, 47.1 mg,
1
40%, mp 167-169 C): H NMR (300 MHz, CDCl3) δ 9.11 (br, 1H), 8.56 (ddd, J = 4.7, 1.6, 0.8
Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.33
(ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.27 (d, J = 2.9 Hz, 1H), 7.25-7.19 (m, 1H), 7.16-7.02 (m, 2H),
4.12 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 194.4, 166.6, 164.1, 153.0, 151.8, 149.6, 137.1, 136.7, 127.7, 127.0,
125.2, 123.0, 122.3, 121.1, 120.4, 112.0, 109.6, 61.8, 61.7, 13.9, 13.8; HRMS (ESI) m/z [M+H]+
Calcd for C22H21N2O5 393.1450, found 393.1439.
3ka (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/6/1, yellow solid, 75.0 mg,
60%, mp 178-180 C): 1H NMR (300 MHz, CDCl3) δ 8.93 (br, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.56
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(d, J = 16.3 Hz, 1H), 7.47-7.39 (m, 2H), 7.38-7.27 (m, 5H), 7.23-7.09 (m, 2H), 6.86 (d, J = 16.3
Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1
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Hz, 3H); C NMR (75 MHz, CDCl3) δ 194.7, 166.7, 164.0, 150.4, 145.1, 136.7, 134.3, 130.8,
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128.9, 128.6, 127.7, 125.9, 125.1, 123.3, 122.2, 121.4, 120.1, 112.1, 109.9, 61.95, 61.86, 14.0,
13.8; HRMS (ESI) m/z [M+H]+ Calcd for C25H24NO5 418.1654, found 418.1642.
3la (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/7/1, yellow oil, 45.0 mg,
42%): 1H NMR (300 MHz, CDCl3) δ 8.82 (br, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.8 Hz,
1H), 7.30 (d, J = 2.9 Hz, 1H), 7.22 (td, J = 7.5, 1.1 Hz, 1H), 7.15 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H),
4.27 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.11 (tt, J = 7.9, 4.6 Hz, 1H), 1.31 (t, J = 7.1 Hz,
3H), 1.25-1.21 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.97-0.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
205.4, 166.7, 164.2, 151.8, 136.6, 127.7, 125.4, 123.2, 121.2, 121.1, 120.1, 112.0, 109.1, 61.9,
61.8, 21.8, 14.1, 13.8, 13.2; HRMS (ESI) m/z [M+H]+ Calcd for C20H22NO5 356.1498, found
356.1485.
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3ma (eluent: ethyl acetate / petroleum ether = 1/8, brown oil, 35.3 mg, 32%): H NMR (300
MHz, CDCl3) δ 8.33 (br, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.22-7.08 (m,
2H), 6.96 (d, J = 2.2 Hz, 1H), 5.15 (d, J = 11.2 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.14-4.25 (m,
2H), 3.82-3.60 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.10 (s, 9H), 0.76 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 213.6, 168.7, 168.6, 136.4, 126.4, 124.0, 122.5, 120.1, 119.2, 111.4, 109.1,
61.7, 61.4, 56.3, 44.7, 43.7, 27.8, 14.1, 13.5; HRMS (ESI) m/z [M+H]+ Calcd for C21H26NO5
374,1967, found 374.1953.
3na (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/8/2, brown oil, 40.2 mg,
37%): 1H NMR (300 MHz, CDCl3) δ 8.35 (br, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.4 Hz,
1H), 7.21-7.07 (m, 3H), 4.64 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 4.30-4.20 (m, 2H),
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1.17 (t, J = 7.1 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 172.5, 168.3,
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167.7, 136.2, 126.4, 123.5, 122.4, 119.9, 119.4, 111.4, 109.5, 62.0, 61.5, 61.4, 55.1, 42.5, 14.11,
14.10, 13.6; HRMS (ESI) m/z [M+H]+ Calcd for C19H24NO6 362.1604, found 362.1591.
3oa (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/3/1, yellow oil, 45.0 mg,
37%): 1H NMR (300 MHz, CDCl3) δ 8.66 (br, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz,
1H), 7.18 (td, J = 7.4, 1.0 Hz, 1H), 7.14-7.06 (m, 2H), 4.85 (d, J = 11.1 Hz, 1H), 4.42 (d, J = 11.1
Hz, 1H), 4.32-4.10 (m, 2H), 3.86-3.69 (m, 2H), 3.67-3.42 (m, 6H), 3.40-3.26 (m, 1H), 3.14-2.96
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(m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.5,
168.8, 168.5, 136.1, 126.0, 123.7, 122.5, 120.1, 118.8, 111.5, 109.6, 66.8, 66.3, 61.8, 61.4, 56.4,
46.3, 42.8, 39.9, 14.1, 13.6; HRMS (ESI) m/z [M+H]+ Calcd for C21H27N2O6 403.1869, found
403.1855.
4a (eluent: ethyl acetate / petroleum ether = 1/6, yellow oil, it is an intermediate in the reaction
of 1a with 2a and can be isolated within a short reaction time): 1H NMR (300 MHz, CDCl3) δ 8.26
(br, 1H), 8.00(d, J = 7.1 Hz, 2H), 7.73-7.82 (m, 1H), 7.42 (tt, J = 7.3, 1.3 Hz, 1H), 7.32 (t, J = 7.5
Hz, 2H), 7.24-7.29 (m, 1H), 7.12-7.19 (m, 2H), 7.04 (d, J = 2.6 Hz, 1H), 5.65 (d, J = 11.3 Hz, 1H),
4.54 (d, J = 11.3 Hz, 1H), 4.10-4.27 (m, 2H), 3.70-3.89 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.73 (t, J
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= 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 197.4, 168.6, 136.3, 136.0, 133.1, 128.8, 128.6,
126.2, 124.2, 122.5, 120.2, 119.0, 111.5, 109.2, 61.9, 61.5, 55.9, 44.2, 14.1, 13.6; HRMS (ESI)
m/z [M+H]+ Calcd for C23H24NO5 394.1654, found 394.1644.
Synthesis of 3aa with 2 mmol of 2a and 3 mmol of 1a. A 50 mL round-bottom flask was
charged with diethyl α-benzoylmethyl manolate 1a (3 mmol), indole 2a (2 mmol), DTBP (6
mmol), Na2CO3 (4 mmol), Cu(OAc)2 (2 mmol), and DMSO (15 mL). The mixture was stirred at
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100 C under N2 atmosphere for 8 h. After cooling to room temperature, water (150 mL) and
ammonium hydroxide (25%, 15 mL) were added and the mixture was extracted with ethyl acetate
(3  80 mL). The combined organic phase were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column chromatography (ethyl
acetate/petroleum ether = 1/6 to 1/4) to give the product 3aa (565.1 mg, 72%).
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General Procedure for the Preparation of 6. A mixture of α-acylmethyl manolates 1 (0.33
mmol), indole-2-alcohols 5 (0.3 mmol), DTBP (0.9 mmol), K2CO3 (0.6mmol), and Cu(OAc)2 (0.3
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mmol) in DMSO (3.0 mL) was stirred at 100 C under N2 atmosphere. After completion of the
reaction as determined by TLC, the mixture was cooled to room temperature and ammonia
solution (10%, 30 mL) was added. The mixture was extracted with ethyl acetate (3  30 mL). The
combined organic phase were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography to give the products 6.
6aa (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/4, yellow solid, 76.4 mg,
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68%, mp 237-240 C): H NMR (300 MHz, d6-DMSO) δ 12.37 (br, 1H), 7.82-7.71 (m, 1H),
7.55-7.47 (m, 1H), 7.47-7.40 (m, 5H), 7.37-7.25 (m, 2H), 5.43 (d, J = 17.1 Hz, 1H), 4.70 (d, J =
17.0 Hz, 1H), 4.51-4.30 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 165.5,
162.2, 158.6, 142.3, 137.6, 135.4, 130.0, 128.9, 126.4, 123.7, 123.5, 122.2, 121.7, 112.6, 107.8,
105.6, 102.5, 61.5, 61.2, 14.1; HRMS (ESI) m/z [M+H]+ Calcd for C22H18NO5 376.1185, found
376.1169.
6aa' (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/4/4, coloreless oil, it is an
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intermediate in the reaction of 1a with 5a and can be isolated within a short reaction time): H
NMR (300 MHz, d6-DMSO) δ 11.16 (br, 1H), 8.06 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H),
7.55-7.37 (m, 3 H), 7.31 (d, J = 7.6 Hz, 1H), 7.14-6.85 (m, 2H), 5.59 (d, J = 11.4 Hz, 1H), 5.52
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(br, 1H), 4.57-5.09 (m, 2H), 4.49 (d, J = 10.2 Hz, 1H), 4.27-4.06 (m, 2H), 3.62-4.01 (m, 2H), 1.19
(t, J = 7.1 Hz, 3H), 0.77 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 196.7, 167.9, 167.6,
137.6, 135.5, 135.4, 133.2, 128.6, 128.5, 120.9, 119.1, 118.3, 111.5, 101.8, 61.3, 60.9, 55.0, 53.3,
44.1, 13.9, 13.3; HRMS (ESI) m/z [M+H]+ Calcd for C24H26NO6 424.1760, found 424.1746.
6ab (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/5, yellow solid, 20.4 mg,
17%, mp 284-286 C): 1H NMR (300 MHz, d6-DMSO) δ 12.21 (br, 1H), 7.47-7.33 (m, 6H), 7.25
(d, J = 2.1 Hz, 1H ), 6.92 (dd, J = 8.8, 2.2 Hz, 1H), 5.35 (d, J = 16.9 Hz, 1H), 4.62 (d, J = 16.9 Hz,
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1H), 4.50-4.22 (m, 2H), 3.82 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ
165.5, 162.4, 158.8, 154.9, 142.5, 135.6, 132.3, 130.0, 128.9, 126.4, 124.5, 113.2, 112.7, 107.3,
105.7, 105.3, 102.6, 61.5, 61.2, 55.3, 14.1; HRMS (ESI) m/z [M+H]+ Calcd for C23H20NO6
406.1291, found 406.1278.
6ac (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/5, yellow solid, 49.4 mg,
42%, mp 239-242 C): 1H NMR (400 MHz, CDCl3) δ 9.87 (br, 1H), 7.52 (s, 1H), 7.37 (d, J = 7.0
Hz, 2H), 7.33-7.22 (m, 4H), 7.09 (d, J = 8.3 Hz, 1H), 5.11 (d, J = 16.7 Hz, 1H), 4.62 (d, J = 16.7
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Hz, 1H), 4.54-4.43 (m, 1H), 4.43-4.32 (m, 1H), 2.50 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); C NMR
(75 MHz, d6-DMSO) δ 165.5, 162.2, 158.3, 142.2, 135.9, 135.5, 130.6, 130.0, 128.9, 126.4, 125.0,
123.7, 121.8, 112.3, 107.4, 105.3, 102.6, 61.5, 61.2, 21.3, 14.0; HRMS (ESI) m/z [M+H]+ Calcd
for C23H20NO5 390.1341, found 390.1332.
6ad (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/5, yellow solid, 56.2 mg,
41%, mp 274-278 C): 1H NMR (300 MHz, d6-DMSO) δ 12.49 (br, 1H), 7.95 (dd, J = 1.5, 0.7 Hz,
1H), 7.48-7.36 (m, 7H), 5.40 (d, J = 17.1 Hz, 1H), 4.67 (d, J = 17.1 Hz, 1H), 4.49-4.22 (m, 2H),
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1.28 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ 165.3, 161.9, 158.5, 143.3, 136.4,
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135.2, 130.0, 128.9, 126.5, 126.1, 125.3, 124.9, 114.5, 114.2, 108.4, 105.1, 102.4, 61.4, 61.3, 14.0;
HRMS (ESI) m/z [M+H]+ Calcd for C22H17BrNO5 454.0290, found 454.0282.
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mp 241-245 C): 1H NMR (300 MHz, d6-DMSO) δ 12.43 (br, 1H), 7.56 (dd, J = 10.4, 2.5 Hz, 1H),
7.48 (dd, J = 8.9, 4.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.15 (td, J = 9.1, 2.6 Hz, 1H), 5.39 (d, J = 17.1
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Hz, 1H), 4.66 (d, J = 17.1 Hz, 1H), 4.46-4.27 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); C NMR (75
MHz, d6-DMSO) δ 165.28, 162.03, 158.0 (1JC-F = 235.0 Hz), 156.39, 143.85, 135.34, 134.25,
130.05, 128.93, 126.47, 124.4 (3JC-F = 11.2 Hz), 113.7 (3JC-F = 10.0 Hz), 111.6 (2JC-F = 25.8 Hz),
108.2 (2JC-F = 26.1 Hz), 107.99, 105.8 (4JC-F = 4.1 Hz), 102.44, 61.48, 61.21, 14.05; HRMS (ESI)
m/z [M+H]+ Calcd for C22H17FNO5 394.1091, found 394.1080.
6af (eluent: methanol / dichloromethane = 1/150, yellow solid, 8.2 mg, 7%, mp 281-283 C): 1H
NMR (300 MHz, d6-DMSO) δ 12.91 (br, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 9.0, 2.1 Hz,
1H), 7.67 (d, J = 9.0 Hz, 1H), 7.52-7.36 (m, 5H), 5.46 (d, J = 17.3 Hz, 1H), 4.73 (d, J = 17.3 Hz,
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1H), 4.52-4.47 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ 165.5, 162.0,
158.5, 145.9, 142.5, 141.3, 135.0, 130.5, 129.3, 126.8, 123.4, 119.5, 119.2, 113.6, 109.8, 107.1,
102.8, 61.8, 14.2; HRMS (ESI) m/z [M+H]+ Calcd for C22H17N2O7 421.1036, found 421.1020.
6af' (eluent: methanol / dichloromethane = 1/150, off-white solid, 40.8 mg, 29%, mp 183-186
C): 1H NMR (300 MHz, d6-DMSO) δ 11.94 (br, 1H), 8.49 (br, 1H), 8.04 (d, J = 7.5 Hz, 2H), 7.94
(dd, J = 9.0, 2.2 Hz, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.37-7.49 (m, 3H), 5.73 (s, 1 H), 5.64 (d, J =
11.3 Hz, 1H), 4.56-5.02 (m, 2H), 4.47 (d, J = 11.2 Hz, 1H), 4.23-4.09 (m, 2H), 3.63-3.97 (m, 2H),
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1.16 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.0 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ 167.7, 167.6,
142.2, 140.9, 139.2, 135.3, 133.7, 128.9, 128.6, 116.6, 115.5, 112.1, 104.2, 61.7, 61.2, 55.1, 53.4,
43.6, 13.9, 13.4; HRMS (ESI) m/z [M+Na]+ Calcd for C24H24N2NaO8 491.1430, found 491.1423.
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6ag (eluent: ethyl acetate / dichloromethane = 1/10, yellow solid, 36.4 mg, 31%, mp 231-236
C): 1H NMR (300 MHz, d6-DMSO) δ 12.27 (br, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.49-7.35 (m, 5H),
7.17 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 5.39 (d, J = 17.0 Hz, 1H), 4.65 (d, J = 17.0 Hz,
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H), 4.46-4.25 (m, 2H), 2.43 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, d6-DMSO) δ
165.5, 162.2, 158.5, 142.0, 137.0, 135.5, 130.0, 128.9, 126.4, 124.4, 123.3, 121.91, 121.87, 119.7,
107. 8, 106.0, 102.6, 61.5, 61.2, 16.5, 14.1; HRMS (ESI) m/z [M+H]+ Calcd for C23H20NO5
390.1341, found 390.1328.
6ah (eluent: ethyl acetate / petroleum ether = 1/4, yellow solid, 26.3 mg, 22%, mp 229-233 C):
1H NMR (300 MHz, CDCl3) δ 9.85 (br, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H),
13
7.34-7.16 (m, 7H), 4.50-4.25 (m, 2H), 1.65 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H), 1.15 (s, 3H); C
NMR (75 MHz, CDCl3) δ 167.8, 162.8, 160.1, 148.8, 139.7, 137.9, 129.6, 128.3, 127.3, 124.3,
123.7, 123.0, 122.4, 112.7, 109.2, 105.4, 103.0, 76.1, 61.7, 32.5, 26.8, 14.4; HRMS (ESI) m/z
[M+H]+ Calcd for C24H22NO5 404.1498, found 404.1486.
6ai (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/5/5, yellow solid, 20.9 mg,
17%, mp 285-287 C): 1H NMR (300 MHz, d6-DMSO) δ 11.95 (br, 1H), 7.42-7.25 (m, 5H), 7.23
(d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 0.9 Hz, 1H), 6.71 (s, 1H), 4.48-4.20 (m, 2H), 4.20-3.98 (m,
2H), 3.52 (ddd, J = 18.6, 10.5, 4.2 Hz, 1H), 3.27 (d, J = 18.8 Hz, 1H), 2.27 (s, 3H), 0.96 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 166.6, 162.0, 161.8, 142.0, 138.8, 134.8, 129.3, 128.6,
125.7, 125.2, 123.8, 118.6, 116.0, 111.4, 111.2, 103.4, 64.5, 61.2, 30.7, 21.2, 13.6; HRMS (ESI)
m/z [M+H]+ Calcd for C24H22NO5 404.1498, found 404.1487.
6ai' (eluent: ethyl acetate / petroleum ether / dichloromethane = 1/4/5, brown solid, 52.5 mg,
39%, mp 52-54 C): 1H NMR (300 MHz, CDCl3) δ 8.64 (br, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.48 (s,
1H), 7.40 (t, J = 7.3 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 7.1 Hz,
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