Copper-catalyzed tandem annulation/enol nucleophilic addition to access multisubstituted indoles

Article abstract of DOI:10.1039/c9ob00181f

A method to access various multisubstituted indoles from propargylic alcohols and readily available enol nucleophiles by copper-catalyzed tandem annulation/enol nucleophilic addition has been developed. Compared to the expensive metal catalysts such as platinum, gold, silver, and palladium used previously, the most economical copper(i) catalyst could achieve this reaction efficiently. The fused heterocyclic compounds, pyrrolo[1,2-a] indoles, could be afforded by further transformation of the products. The allyl cation intermediate may be involved in the mechanism.

Full text of DOI:10.1039/c9ob00181f

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Takeharu Haino et al.
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DOI: 10.1039/C9OB00181F
Journal Name
ARTICLE
Copper-catalyzed Tandem Annulation/Enol Nucleophilic Addition
to Access Multisubstituted Indoles
Received 00th
January 20xx,
Wangze Song,*a Ming Li, a Junnan He, b Junhao Li, a Kun Dong a and Yubin Zheng*b
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
indoles from propargylic alcohols and 1,3-dicarbonyl
compounds (Scheme 1a).4 However, the noble metal was
required as the critical catalyst in order to active the
propargylic alcohols to accomplish the indole annulation in the
first step. In addition, the strong π-acidic Au(I) may result in
unpredicted pathways because many undesirable side
products were observed in above protocols. Therefore, it is
still urgent and necessary to develop new and efficient
strategy to prepare multisubstituted indoles and control the
different substitution patterns from propargylic alcohols.
Recently, Tang’s group reported a copper-catalyzed tandem
annulation/arylation approach for the preparation of
diindolylmethanes from propargylic alcohols using indoles as
nucleophiles (Scheme 1b).5 In Tang’s manner, the copper(I)
could realize the indole annulation firstly and avoid other side
reactions. Then the extra indoles as nucleophiles attacking the
allyl cation from the previous indole annulation gave the
A
method to access various multisubstituted indoles from
propargylic alcohols and readily available enol nucleophiles by
copper-catalyzed tandem annulation/enol nucleophilic addition
has been developed. Compared to the expensive metal such as
platinum, gold, silver, and palladium catalysts used previously, the
most economical copper(I) catalyst could achieve this reaction
efficiently. The fused heterocyclic compounds, pyrrolo[1,2-a]
indoles could be afforded by further transformation of the
products. The allyl cation intermediate may be involved in the
mechanism.
Introduction
Substituted indoles, serving as the privileged building blocks, diindolylmethanes. Inspired by Tang’s pioneering work using
are the important heterocyclic scaffolds for functional copper as catalyst to prepare indole derivatives from
materials and the core structures in natural products and propargylic alcohols, herein we proposed a novel and efficient
pharmaceutical agents.1 Thus, the development of novel and
efficient methodologies for the synthesis of substituted
indoles continuously attract significant attention of the organic
and medicinal chemists. The methods combining the indole
annulation and other transformations together in a tandem
process are particularly appealing due to the synchronized
formation of multiple bonds in a single step.2 Chan’s group first
developed
a
tandem cycloisomerization/Friedel-Crafts
alkylation approach to prepare the multisubstituted indoles
from propargylic alcohols using gold and silver as catalysts.3
Later Ramasastry’s group disclosed another gold and Brønsted
acid-catalyzed tandem cyclizations for the synthesis of fused
a. State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian, 116024, P. R. China. E-mail:
wzsong@dlut.edu.cn
b. School of Chemical Engineering, Dalian University of Technology, Dalian, 116024,
P. R. China. E-mail: zybwl@163.com
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Gold-catalyzed approach:
(a)
Cu(CH3CN)4PF6
10
11
12
13
14
15
DCE
80 oC
75
View Article Online
DOI: 10.1039/C9OB00181F
HO Ph
AuCl/AgOTf
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
CHCl3
toluene
THF
74
56
R1
R4
R1
N
NHTs
OH
Ts
R3
O
42
1) AuCl, K2CO3
R1
R1
2) 1,3-dicarbonyl
TfOH
NHR2
MeCN
H2O
trace
0
N
R2
Copper-catalyzed approach
(b)
:
H
HO R2
N
R2
Cu(CH3CN)4PF6
indole
16
a
DCE
68d
R1
Conditions: 1a (1.0 equiv), 2a (5 equiv), solvent (0.1 M), catalyst
(10 mol%), for 4h. b The yield of 3a was determined by H NMR of
the crude mixture with an internal standard. The starting material
1a was decomposed. d 1.1 equiv of 2a was used, for 12h.
NHR
R1
N
R
1
c
This work
(c)
:
R1
HO R1
Cu(CH3CN)4PF6
enol nucleophiles
O
Results and discussion
N
R
R3
R2
NHR
EWG
Scheme 1 Synthesis of Multisubstituted Indoles from Propargylic
Alcohols in Tandem Way.
N-Ts-aniline 1a and acetylacetone 2a were initial chosen as
the model substrates to optimize the reaction conditions using
1,2-dichloroethane (DCE) as the solvent (Table 1). In the
presence of CuI or CuSO4, the reaction failed to occur for the
substrate 1a (Table 1, entries 1 and 2). Only trace product was
observed under CuBr2 as catalyst (Table 1, entry 3). We were
pleased to find Cu(CH3CN)4PF6 as catalyst could provide good
yield (Table 1, entry 4). Neither the Pt(II) nor Pd(II) catalyst
could mediate the reaction well (Table 1, entries 5 and 6). The
substrate 1a was decomposed treating by Au(I) (Table 1, entry
7). The reaction was messy using metalloid boron catalyst
(Table 1, entry 8). Among the metal and metalloid catalysts we
investigated, the most economical Cu(I) catalyst gave the
highest efficiency. This transformation failed to occur at room
temperature (Table 1, entry 9). If the reaction was set up in 80
oC, the yield decreased slightly (Table 1, entry 10). The reaction
could also proceed smoothly in chloroform (Table 1, entry 11).
However, other solvents, such as toluene and THF, could not
promote this reaction efficiently (Table 1, entries 12 and 13).
Acetonitrile may interrupt the catalytic cycles in this
transformation (Table 1, entry 14). Notably, Cu(CH3CN)4PF6
was senstivie to the water and this reaction could not be set
up in aqueous media (Table 1, entry 15). The nucleophile
stoichiometry of 2a could be reduced in spite of the lower
yield and longer reaction time (Table 1, entry 16).6
strategy to access various multisubstituted indoles from
propargylic alcohols and readily available enol nucleophiles by
copper-catalyzed tandem annulation/enol nucleophilic
addition. These enol species were demonstrated to promote
the multisubstituted indole formation, which provide the
unique and alternative method featuring interesting structural
moieties, such as all-carbon quaternary carbon centres and
more functional groups manipulation. Remarkably, the fused
heterocyclic compounds, pyrrolo[1,2-a] indoles could be
afforded by further transformation of our products.
Table 1 Selected Optimization of the Reaction Conditions. a
O
Me
Me
O
HO Me
O
O
cat. (10 mol%)
Me
+
solvent
temperature
N
Ts
Me
Me
NHTs
3a
1a
2a
Entry
Catalyst
Solvent
Temper
ature
60 oC
Yieldb
(%)
Table 2 Substrate Scope of Multisubstituted Indoles.a,b
1
2
CuI
DCE
DCE
0
60 oC
CuSO4
CuBr2
Cu(CH3CN)4PF6
PtCl2
Pd(OAc)2
Au(PPh3)Cl
B(C6F5)3
0
3
4
5
6
7
8
9
DCE
DCE
DCE
DCE
DCE
DCE
DCE
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
rt
trace
81
62
44
tracec
messy
0
Cu(CH3CN)4PF6
2 | J. Name., 2012, 00, 1-3
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O
Table 3 Substrate Scope of Enol Nucleophiles.a,b
View Article Online
DOI: 10.1039/C9OB00181F
HO R1
Me
O
R1
Cu(CH3CN)4PF6(10 mol%)
O
O
+
DCE, 60 o
C
Me
R2
R2
Me
O
Me
N
R
Me
NHR
1
Me
HO
2a
3
Nu
Cu(CH3CN)4PF6(10 mol%)
DCE, 60 o
Nucleophile
+
C
O
O
N
Ts
3
NHTs
O
Me
O
Me
O
Me
Me
Me
1a
2
Me
Me
Me
Me
N
S
N
S
O
O
O
O
O
N
Ts
O
O
Ph
O
Me
O
N
Me
3c
Et
O
3b
78%
Me
N
Me
Me
N
3a
Me
75%
76%
Ph
Me
Et
Me
N
OMe
Me
Ts
Ts
3o
Ts
3n
3m
78%
O
O
O
70%
71%
Me
O
Me
O
Me
O
Me
Me
Me
O
O
O
Me
Me
Me
Me
O
tBu
O
iPr
Me
O
Me
Me
N
S
N
S
N
S
O
O
O
OEt
tBu
O
O
O
iPr
N
N
N
Ts
3r
Ts
Ts
3f
65%
3e
70%
3d
3q
40%
3p
65%
62%
Me
73%
tBu
Me
Br
Cl
O
O
O
O
Me
O
O
Me
O
Me
Me
Me
O
Me
Me
O
O
Et
Me
Me
O
OMe
Me
Me
Me
Me
N
S
N
O
N
Ts
N
Ts
N
O
N
Ts
O
3s
3u
Boc
3t
Ts
3h
3i
71%
3g
65%[c]
45%c
57%c
55%[c]
60%
a
O
Standard conditions: 1a (1.0 equiv), 2 (5 equiv), DCE (0.1 M),
O
O
Me
Me
O
Me
nBu
Br
Me
O
O
Cu(CH3CN)4PF6 (10 mol%), for 4h. b Isolated yield. c For 12h.
Me
Cl
Br
Me
Me
Me
N
Ts
N
Ts
N
Ts
3j
3k
3l
After the effects of substitution on the N-protected anilines
were examined, a variety of enol nucleophiles were next
explored (Table 3). β-Diketones, ketoesters, and ketoamides all
could add to the indole rings successfully. β-Ketoamide could
provide good yield for this tandem reaction (3m). Other β-
diketones, such as diphenyl, diethyl, diisopropyl, and di-tert-
butyl diketones could be used as enol nucleophiles (3n-3q).
However, the yields for the diisopropyl, and di-tert-butyl
diketones were much lower than others due to the strong
steric hindrance effect. β-Ketoester as substrate gave a little
lower yield (3r) than β-ketoamide and β-diketones.
Encouragingly, all-carbon quaternary centres could be
generated using the enol nucleophiles with an additional α-
substituent albeit lower relative yields and longer reaction
time (3s-3u). The acyclic tertiary carbon nucleophile worked
better (3s) than cyclic carbon nucleophiles (3t and 3u). The
reaction failed to occur for the less formation of enol species
in equilibrium (malonates and ketonitriles) under the standard
conditions.
53%c
60%
61%
a
Standard conditions: 1 (1.0 equiv), 2a (5 equiv), DCE (0.1 M),
Cu(CH3CN)4PF6 (10 mol%), for 4h. b Isolated yield. c For 12h.
With the optimized conditions in hand, we explored the
scope of the multisubstituted indoles. Various N-protected
anilines 1 and acetylacetone 2a were used as substrates at 60
oC with the copper catalyst to afford multisubstituted indoles
(Table 2). The N-protected anilines 1 were prepared according
to the literature reported.[3] Besides the 4-toluene sulfonyl
group, other sulfonyl groups, such as 4-methoxyphenyl, 2,4,6-
trimethylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-tert-
butylphenyl and 4-phenyl sulfonyl group could also participate
in the tandem annulation/enol nucleophilic addition reaction
smoothly (3a-3g). The yields (3a-3c) for the substrates
containing electron-donating groups were slightly higher than
the ones containing electron-withdrawing groups (3d and 3e).
However, for 4-tert-butylphenyl and 4-phenyl sulfonyl
substrates, lower yields were observed (3f and 3g) than other
sulfonyl substrates. If the N-Boc aniline was used instead of
the N-sulfonyl one, the yield would decrease dramatically (3h).
The ethyl and n-butyl groups in the propargylic alcohol motifs
could be well tolerated in this transformation (3i and 3j),
despite the yield of 3j was lower than 3i. The presence of
electron-withdrawing groups attached to the indole rings
could result in lower yields (3k and 3l). Unfortunately, the
reaction was very sluggish with the internal alkynes substrates.
For the secondary propargylic alcohols, unknown products
were afforded instead of the desired multisubstituted indoles.7
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(a) Synthesis of the fused heterocyclic compound
To further understand the copper-catalyzed tandem process,
View Article Online
O
Me
the mechanism was preliminarily investDigOaIt:e10d..10A39n/Cu9cOleBo0p01h8i1leF
competition experiment between the methanol and
acetylacetone 2a was conducted (Scheme 3a). The enol
nucleophilic addition was completely selective because only
indole 3a was observed. 5a could be acquired in the absence
of the nucleophiles, which was the crucial intermediate for the
further tandem addition reactions. When 5a was treated with
2a in our standard conditions, product 3a was afforded in 72%
yield. Brønsted acid could also achieve this transformation, but
no fused indoles were isolated due to the steric hindrance at
C3 position of indoles.11 No reaction occurred between 5a and
2a without metal or Brønsted acid. Brønsted acid was
demonstrated to be ineffective to convert 1a to 3a directly
(Scheme 3b).
Me
Me
O
CSA (2 equiv)
toluene, 90 o
Me
N
Me
N
C
Boc
Me
4h
64% yield
O
3h
(b) The cascade annulation/enol nucleophilic addition/Suzuki coupling reaction
HO Me
O
Me
Me
O
Br
NHTs
1v
(1) Cu(CH3CN)4PF6(10 mol%)
(2) Pd(PPh3)4 (5 mol%)
Me
+
N
Ts
Ph
O
O
Phenylboronic Acid (2 equiv)
K2CO3 (5 equiv)
3v
51% yield
Me
Me
2a
Based on above experiments, a general mechanism for the
copper-catalyzed tandem annulation/enol nucleophilic
addition reaction is proposed in Scheme 4. The copper could
active the triple bond of 1a to undergo the 5-exo-dig
intramolecular hydroamination firstly to afford intermediate
5a via the cation intermediate A. Then an allyl cation
intermediate B may be generated under acidic or copper
catalyst conditions. Enol nucleophiles 2 would like to attack
intermediate B at 2α position rather than other positions due
to the steric hindrance to yield 3 in excellent regioselectivities.
Scheme 2 Applications of the Indole Products.
The fused heterocyclic compound could be synthesized from
the multisubstituted indoles products with the dicarbonyl
groups. Treating 3h with acidic conditions (CSA, toluene, heat),
pyrrolo[1,2-a]indole 4h was afforded by the simultaneous Boc
removal and condensation with the methyl ketone (Scheme
2a).2h,8 Pyrrolo[1,2-a]indole was the core structure of
mitomycins.9 In addition, the palladium-catalyzed Suzuki
coupling reaction could be compatible with the copper-
catalyzed tandem annulation/enol nucleophilic addition. A
new cascade annulation/enol nucleophilic addition/Suzuki
coupling reaction was developed and 3v was obtained in
moderate yield (Scheme 2b).10
Me
HO
HO
HO Me
Me
Me
[Cu]
[Cu]
[Cu]
2
-[Cu]
N
N
N
NHTs
H
Ts
Ts
Ts
1a
A
B
5a
Me
Nu
Enol nucleophile
(a) Nucleophile competition experiment
N
O
3
Ts
HO Me
Me
Me
O
O
O
Cu(CH3CN)4PF6(10 mol%)
+
+
Me
MeOH
(5 equiv)
Me
Scheme 4 Proposed Mechanism for the Tandem Reaction.
Me
DCE, 60 o
C
(5 equiv)
NHTs
1a
N
Ts
2a
3a
62% yield
Conclusions
Me
OMe
N
Ts
In summary, we have developed a novel copper-catalyzed
tandem annulation/enol nucleophilic addition to access
various multisubstituted indoles from propargylic alcohols and
readily available enol nucleophiles. The cheap copper(I)
catalyst could achieve this reaction efficiently instead of the
expensive metal such as platinum, gold, silver, and palladium
catalysts used before. The fused heterocyclic compounds,
pyrrolo[1,2-a] indoles could be afforded by further
transformation of the products. The allyl cation intermediate
may be involved in the mechanism. It provides an efficient and
alternative method to synthesize related indole derivatives for
both organic and medicinal chemistry.
3a'
Not observed
(b) Preliminary investigation of the mechanism
HO
Me
HO Me
Cu(CH3CN)4PF6(10 mol%)
DCE, 60 o
C
N
NHTs
1a
5a
Ts
92% yield
O
HO
Me
Me
O
Me
O
O
DCE, 60 o
C
Me
+
Me
Me
N
N
Ts
Ts
2a
3a
5a
3a
yield of
conditions:
72%
25%
0%
a) Cu(CH3CN)4PF6(10 mol%)
b) TsOH (1 equiv)
c) no catalyst
O
Me
Me
O
HO Me
O
O
Experimental
TsOH (1 equiv)
DCE, 60 o
Me
+
Me
Me
C
N
NHTs
Ts
2a
1a
3a
0% yield
General information
Scheme 3 Preliminary Investigation of the Mechanism.
4 | J. Name., 2012, 00, 1-3
All reactions in non-aqueous media were conducted under a
positive pressure of dry argon in glassware that had been oven
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dried prior to use unless noted otherwise. Anhydrous solutions J = 8.0 Hz, 2H), 7.37-7.26 (m, 3H), 7.12 (d, J = 8.0VHiezw,A2rtHic)le,O4n.l6in4e
were transferred via an oven dried syringe or cannula. All (t, J = 8.0 Hz, 1H), 3.44 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 2.19 (s,
DOI: 10.1039/C9OB00181F
solvents were dried prior to use unless noted otherwise. Thin 6H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 203.4, 144.9,
layer chromatography was performed using precoated silica 136.9, 135.1, 132.7, 131.5, 129.8, 126.2, 124.9, 123.9, 120.1,
gel plates and visualized with UV light at 254 nm. Flash column 119.0, 115.4, 66.5, 30.8, 25.6, 21.5, 9.2. HRMS (ESI-TOF) m/z
1
chromatography was performed with silica gel (40-60 μm). H calcd for C22H23NO4S (M+Na)+ 420.1240, found 420.1239.
and 13C nuclear magnetic resonance spectra (NMR) were
obtained on a Bruker Avance II 400 MHz or Bruker Avance III
3-((1-((4-Methoxyphenyl)sulfonyl)-3-methyl-1H-indol-2-
500 MHz recorded in ppm (δ) downfield of TMS (δ = 0) in CDCl3
unless noted otherwise. Signal splitting patterns were
described as singlet (s), doublet (d), triplet(t), quartet (q),
quintet (quint), or multiplet (m), with coupling constants (J) in
hertz (Hz). High resolution mass spectra (HRMS) were
performed by an Agilent apparatus (TOF mass analyzer type)
on an Electron Spray Injection (ESI) mass spectrometer.
Melting points were determined by an XP-4 melting point
apparatus.
yl)methyl)pentane-2,4-dione (3b). 32 mg, 78% yield, yellow
o
1
solid, m.p. = 135-137 C. H NMR (400 MHz, CDCl3, TMS): δ
8.18 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.36-7.23 (m,
3H), 6.78 (d, J = 8.0 Hz, 2H), 4.63 (t, J = 8.0 Hz, 1H), 3.75 (s, 3H),
3.42 (d, J = 8.0 Hz, 2H), 2.17 (s, 6H), 2.10 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 203.4, 163.7, 137.0, 132.7, 131.5, 129.5, 128.4,
124.9, 123.9, 120.1, 119.0, 115.4, 114.3, 66.5, 56.6, 30.8, 25.6,
9.2. HRMS (ESI-TOF) m/z calcd for C22H23NO5S (M+Na)+
436.1189, found 436.1191.
Representative procedures for the synthesis of
multisubstituted indoles
3-((1-(Mesitylsulfonyl)-3-methyl-1H-indol-2-
yl)methyl)pentane-2,4-dione (3c). 32 mg, 75% yield, yellow oil.
1H NMR (400 MHz, CDCl3, TMS): δ 7.48 (d, J = 8.0 Hz, 1H), 7.42
(d, J = 8.0 Hz, 1H), 7.19-7.13 (m, 2H), 6.90 (s, 2H), 4.45 (t, J =
8.0 Hz, 1H), 3.37 (d, J = 8.0 Hz, 2H), 2.32 (s, 6H), 2.26 (s, 3H),
2.14 (s, 3H), 2.11 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 203.5,
143.8, 139.6, 136.2, 134.8, 133.5, 132.3, 129.7, 124.3, 122.7,
119.1, 116.5, 113.5, 65.8, 30.8, 25.2, 22.1, 21.0, 8.9. HRMS
(ESI-TOF) m/z calcd for C24H27NO4S (M+Na)+ 448.1553, found
448.1554.
To a vial containing Cu(CH3CN)4PF6 (3.7 mg, 0.1 equiv, 0.01
mmol) in DCE (2 mL) was added N-Ts-aniline 1a (31.5 mg, 1
equiv, 0.1 mmol) and acetylacetone 2a (50 mg, 5 equiv, 0.5
mmol). The vial was closed and the mixture was stirred at 60
oC for 4 h. The mixture was purified with flash column
chromatography (33% EtOAc in petroleum ether) to give the
pure product (30.2 mg, 76%) as a white solid.
Representative procedures for the synthesis of pyrrolo[1,2-
a]indole
3-((1-((4-Bromophenyl)sulfonyl)-3-methyl-1H-indol-2-
To a vial containing 3h (34 mg, 0.1 mmol, 1 equiv) in toluene (1
yl)methyl)pentane-2,4-dione (3d). 34 mg, 73% yield, yellow
o
1
mL) was added CSA (49 mg, 2.1 equiv, 0.21 mmol). The vial
solid, m.p. = 116-118 C. H NMR (400 MHz, CDCl3, TMS): δ
8.17 (d, J = 8.0 Hz, 1H), 7.51-7.46 (m, 4H), 7.39-7.27 (m, 3H),
4.61 (t, J = 8.0 Hz, 1H), 3.44 (d, J = 4.0 Hz, 2H), 2.20 (s, 6H), 2.14
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 203.2, 136.8, 136.7, 132.5,
132.5, 131.6, 129.1, 127.7, 125.2, 124.3, 120.9, 119.3, 115.3,
66.5, 30.8, 25.6, 9.2. HRMS (ESI-TOF) m/z calcd for
C21H20BrNO4S (M+Na)+ 484.0188, found 484.0189.
o
was closed and the mixture was stirred at 90 C for 5 h. The
mixture was concentrated in vacuo. The residue was purified
with flash column chromatography (20% EtOAc in petroleum
ether) to give the pure product (14 mg, 64%) as a yellow oil.
Representative procedures for the cascade annulation/enol
nucleophilic addition/Suzuki coupling reaction
3-((1-((4-Chlorophenyl)sulfonyl)-3-methyl-1H-indol-2-
yl)methyl)pentane-2,4-dione (3e). 29 mg, 70% yield, yellow
To a vial containing Cu(CH3CN)4PF6 (3.7 mg, 0.1 equiv, 0.01
mmol) in DCE (2 mL) was added N-Ts-aniline 1v (40 mg, 1 equiv,
0.1 mmol) and acetylacetone 2a (50 mg, 5 equiv, 0.5 mmol).
The vial was closed and the mixture was stirred at 60 oC for 4 h.
Then phenylboronic acid (24.4 mg, 2 equiv, 0.2 mmol),
Pd(PPh3)4 (5.7 mg, 0.05 equiv, 0.005 mmol), K2CO3 (69 mg, 5
equiv, 0.5 mmol) and DMF (4 mL) were added to the mixture.
o
1
solid, m.p. = 88-91 C. H NMR (400 MHz, CDCl3, TMS): δ 8.17
(d, J = 8.0 Hz, 1H), 7.56 (d, J = 4.0 Hz, 2H), 7.37-7.28 (m, 5H),
4.61 (t, J = 8.0 Hz, 1H), 3.44 (d, J = 8.0 Hz, 2H), 2.21 (s, 6H), 2.14
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 203.2, 140.5, 136.8, 136.1,
132.5, 131.6, 129.5, 127.6, 125.2, 120.9, 119.3, 115.3, 66.5,
30.8, 25.6, 9.2. HRMS (ESI-TOF) m/z calcd for C21H20ClNO4S
(M+Na)+ 440.0693, found 440.0694.
o
The mixture was stirred at 70 C overnight. The mixture was
quenched with water and then extracted with EtOAc. The
organic phase was washed by brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified with flash
column chromatography (33% EtOAc in petroleum ether) to
give the pure product (24 mg, 51%) as a yellow oil.
3-((1-((4-(tert-Butyl)phenyl)sulfonyl)-3-methyl-1H-indol-2-
yl)methyl)pentane-2,4-dione (3f). 29 mg, 65% yield, yellow
o
1
solid, m.p. = 155-157 C. H NMR (400 MHz, CDCl3, TMS): δ
8.22 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.38-7.27 (m,
5H), 4.65 (t, J = 8.0 Hz, 1H), 3.45 (d, J = 8.0 Hz, 2H), 2.19 (s, 6H),
2.14 (s, 3H), 1.25 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 203.4,
157.7, 136.9, 135.2, 132.6, 131.3, 126.3, 126.0, 124.9, 123.8,
119.8, 119.0, 115.3, 66.4, 35.2, 30.9, 30.9, 25.6, 9.2. HRMS
3-((3-Methyl-1-tosyl-1H-indol-2-yl)methyl)pentane-2,4-
dione (3a). 30 mg, 76% yield, white solid, m.p. = 103-105 oC. 1H
NMR (400 MHz, CDCl3, TMS): δ 8.20 (d, J = 8.0 Hz, 1H), 7.51 (d,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 9
COMMUNICATION
Journal Name
(ESI-TOF) m/z calcd for C25H29NO4S (M+Na)+ 462.1709, found
462.1709.
3-((4,5-Dibromo-3-methyl-1-tosyl-1H-indol-2-
View Article Online
yl)methyl)pentane-2,4-dione (3l). 29 mg, 53% yield, yellow
DOI: 10.1039/C9OB00181F
o
1
solid, m.p. = 47-49 C. H NMR (400 MHz, CDCl3, TMS): δ 7.67
(s, 1H), 7.26 (s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz,
2H), 4.56 (t, J = 8.0 Hz, 1H), 3.28 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H),
2.20 (s, 6H), 1.90 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 203.0,
145.2, 139.1, 139.1, 138.0, 133.4, 132.5, 129.2, 126.5, 124.1,
121.2, 119.4, 112.8, 66.1, 30.5, 26.4, 21.6, 9.2. HRMS (ESI-TOF)
m/z calcd for C22H21Br2NO4S (M+Na)+ 575.9450, found
575.9452.
3-((3-Methyl-1-(phenylsulfonyl)-1H-indol-2-
yl)methyl)pentane-2,4-dione (3g). 23 mg, 60% yield, yellow oil.
1H NMR (400 MHz, CDCl3, TMS): δ 8.21 (d, J = 8.0 Hz, 1H), 7.63
(d, J = 8.0 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.39-7.25 (m, 5H),
4.65 (t, J = 8.0 Hz, 1H), 3.46 (d, J = 8.0 Hz, 2H), 2.20 (s, 6H), 2.14
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 203.4, 137.9, 136.9, 133.8,
132.7, 131.5, 129.2, 126.2, 125.0, 124.0, 120.3, 119.1, 115.3,
66.5, 30.8, 25.6, 9.2. HRMS (ESI-TOF) m/z calcd for C21H21NO4S
(M+Na)+ 406.1083, found 406.1085.
N,N-Dimethyl-2-((3-methyl-1-tosyl-1H-indol-2-yl)methyl)-3-
oxobutanamide (3m). 33 mg, 78% yield, white solid, m.p. =
o
1
145-147 C. H NMR (400 MHz, CDCl3, TMS): δ 8.21 (d, J = 8.0
Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.37-7.25 (m, 3H), 7.16 (d, J =
8.0 Hz, 2H), 4.55 (dd, J = 8.0, 4.0 Hz, 1H), 3.59 (dd, J = 12.0, 4.0
Hz, 1H), 3.42 (dd, J = 16.0, 8.0 Hz, 1H), 2.87 (s, 3H), 2.85 (s, 3H),
2.32 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 202.5, 169.4, 144.9, 136.7, 135.2, 132.8, 131.4, 129.8,
126.3, 124.7, 123.8, 120.0, 118.9, 115.1, 56.9, 37.7, 36.9, 28.5,
26.0, 21.5, 9.0. HRMS (ESI-TOF) m/z calcd for C23H26N2O4S
(M+Na)+ 449.1505, found 449.1506.
tert-Butyl
2-(2-acetyl-3-oxobutyl)-3-methyl-1H-indole-1-
1
carboxylate (3h). 19 mg, 55% yield, yellow oil. H NMR (400
MHz, CDCl3, TMS): δ 8.01 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz,
1H), 7.31-7.23 (m, 2H), 4.28 (t, J = 8.0 Hz, 1H), 3.57 (d, J = 8.0
Hz, 2H), 2.22 (s, 3H), 2.17 (s, 6H), 1.72 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 203.9, 150.7, 135.6, 132.7, 130.5, 124.1, 122.6,
118.6, 116.5, 115.6, 84.0, 66.8, 30.2, 28.3, 25.8, 8.8. HRMS
(ESI-TOF) m/z calcd for C20H25NO4 (M+Na)+ 366.1677, found
366.1676.
2-((3-Methyl-1-tosyl-1H-indol-2-yl)methyl)-1,3-
3-((3-Ethyl-1-tosyl-1H-indol-2-yl)methyl)pentane-2,4-dione
(3i). 29 mg, 71% yield, yellow oil. H NMR (400 MHz, CDCl3,
diphenylpropane-1,3-dione (3n). 37 mg, 71% yield, white solid,
m.p. = 135-137 oC. 1H NMR (400 MHz, CDCl3, TMS): δ 8.18 (d, J
= 8.0 Hz, 1H), 7.91-7.89 (m, 4H), 7.57 (d, J = 8.0 Hz, 2H), 7.43-
7.39 (m, 2H), 7.28-7.26 (m, 5H), 7.16-7.12 (m, 4H), 6.22 (t, J =
8.0 Hz, 1H), 3.77 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 1.87 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 196.3, 144.9, 136.7, 136.0, 135.4,
133.3, 132.0, 131.0, 129.8, 128.6, 128.4, 126.2, 124.6, 123.6,
120.4, 118.7, 115.0, 55.4, 27.5, 21.5, 8.9. HRMS (ESI-TOF) m/z
calcd for C32H27NO4S (M+Na)+ 544.1553, found 544.1551.
1
TMS): δ 8.23 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.45 (d,
J = 8.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.71
(t, J = 8.0 Hz, 1H), 3.48 (d, J = 8.0 Hz, 2H), 2.65 (q, J = 8.0 Hz,
2H), 2.36 (s, 3H), 2.24 (s, 6H), 1.12 (t, J = 8.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 203.4, 144.8, 137.3, 134.9, 132.3, 130.6,
129.7, 126.5, 126.2, 124.7, 123.9, 119.2, 115.7, 66.7, 30.9, 25.6,
21.5, 17.4, 14.5. HRMS (ESI-TOF) m/z calcd for C23H25NO4S
(M+Na)+ 434.1396, found 434.1397.
4-((3-Methyl-1-tosyl-1H-indol-2-yl)methyl)heptane-3,5-
dione (3o). 30 mg, 70% yield, white solid, m.p. = 125-127 oC. 1H
NMR (400 MHz, CDCl3, TMS): δ 8.21 (d, J = 8.0 Hz, 1H), 7.52 (d,
J = 8.0 Hz, 2H), 7.35-7.26 (m, 3H), 7.14 (d, J = 8.0 Hz, 2H), 4.63
(t, J = 8.0 Hz, 1H), 3.46 (d, J = 8.0 Hz, 2H), 2.56-2.45 (m, 2H),
2.43-2.37 (m, 2H), 2.31 (s, 3H), 2.09 (s, 3H), 0.98 (t, J = 8.0 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 206.0, 144.8, 136.9, 135.1,
132.8, 131.4, 129.8, 126.2, 124.8, 123.9, 119.9, 119.0, 115.3,
64.7, 37.2, 25.9, 21.5, 9.1, 7.6. HRMS (ESI-TOF) m/z calcd for
C24H27NO4S (M+Na)+ 448.1553, found 448.1555.
3-((3-Butyl-1-tosyl-1H-indol-2-yl)methyl)pentane-2,4-dione
(3j). 26 mg, 60% yield, yellow oil. H NMR (400 MHz, CDCl3,
1
TMS): δ 8.20 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 (d,
J = 8.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 4.66
(t, J = 8.0 Hz, 1H), 3.43 (d, J = 8.0 Hz, 2H), 2.59 (t, J = 8.0 Hz, 2H),
2.32 (s, 3H), 2.20 (s, 6H), 1.43-1.37 (m, 2H), 1.19-1.13 (m, 2H),
0.84 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 203.4,
144.8, 137.5, 134.6, 132.8, 131.2, 129.6, 126.1, 125.5, 124.8,
124.0, 119.2, 115.9, 66.8, 31.9, 30.8, 25.7, 23.7, 22.3, 21.5,
13.9. HRMS (ESI-TOF) m/z calcd for C25H29NO4S (M+Na)+
462.1709, found 462.1710.
2,6-Dimethyl-4-((3-methyl-1-tosyl-1H-indol-2-
yl)methyl)heptane-3,5-dione (3p). 29 mg, 65% yield, white
o
1
3-((5-Chloro-3-methyl-1-tosyl-1H-indol-2-
solid, m.p. = 108-110 C. H NMR (400 MHz, CDCl3, TMS): δ
8.08 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.21-7.13 (m,
3H), 7.02 (d, J = 12.0 Hz, 2H), 4.89 (t, J = 8.0 Hz, 1H), 3.32 (d, J =
4.0 Hz, 2H), 2.56-2.49 (m, 2H), 2.20 (s, 3H), 1.97 (s, 3H), 0.97 (d,
J = 8.0 Hz, 6H), 0.81 (d, J = 8.0 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 207.0, 144.8, 136.8, 135.0, 132.8, 131.5, 129.8, 126.2,
124.8, 123.9, 120.1, 118.9, 115.3, 62.1, 41.7, 26.5, 21.5, 18.0,
17.9, 9.1. HRMS (ESI-TOF) m/z calcd for C26H31NO4S (M+Na)+
476.1866, found 476.1866.
yl)methyl)pentane-2,4-dione (3k). 26 mg, 61% yield, colorless
oil. 1H NMR (400 MHz, CDCl3, TMS): δ 8.11 (d, J = 12.0 Hz, 1H),
7.49 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 4.0 Hz, 1H), 7.28-7.25 (m,
1H), 7.17 (d, J = 8.0 Hz, 2H), 4.61 (t, J = 8.0 Hz, 1H), 3.42 (d, J =
8.0 Hz, 2H), 2.34 (s, 3H), 2.20 (s, 6H), 2.09 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 203.1, 145.2, 135.2, 134.7, 134.3, 132.8, 129.9,
129.8, 126.2, 125.0, 119.5, 118.8, 116.4, 66.4, 30.8, 25.6, 21.6,
9.1. HRMS (ESI-TOF) m/z calcd for C22H22ClNO4S (M+Na)+
454.0850, found 454.0850.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 9
Organic & Biomolecular Chemistry
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Journal Name
2,2,6,6-Tetramethyl-4-((3-methyl-1-tosyl-1H-indol-2-
COMMUNICATION
1-(3,9-Dimethyl-9H-pyrrolo[1,2-a]indol-2-yl)ethanone (4h).
yl)methyl)heptane-3,5-dione (3q). 19 mg, 40% yield, colorless 14 mg, 64% yield, yellow oil. 1H NMR (400 MHz, CVDieCwlA,rtTicMle OSn)l:inδe
DOI: 10.1039/C9OB00181F
3
1
oil. H NMR (400 MHz, CDCl3, TMS): δ 8.13 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0
7.42 (d, J = 12.0 Hz, 2H), 7.32-7.22 (m, 3H), 7.10 (d, J = 8.0 Hz, Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.40 (s, 1H), 4.00 (q, J = 8.0 Hz,
2H), 5.55 (t, J = 8.0 Hz, 1H), 3.41 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H), 1H), 2.92 (s, 3H), 2.45 (s, 3H), 1.51 (d, J = 8.0 Hz, 3H). 13C NMR
2.14 (s, 3H), 1.25-1.09 (m, 18H). 13C NMR (125 MHz, CDCl3): δ (100 MHz, CDCl3): δ 199.5, 144.6, 138.6, 138.3, 129.6, 128.7,
209.4, 144.7, 136.9, 134.8, 132.8, 131.8, 129.7, 126.1, 124.8, 126.7, 125.3, 123.4, 119.7, 115.0, 31.1, 29.7, 18.3, 13.6. HRMS
124.0, 121.6, 119.0, 115.5, 53.6, 45.2, 30.3, 26.9, 21.5, 9.5. (ESI-TOF) m/z calcd for C15H15NO (M+Na)+ 248.1047, found
HRMS (ESI-TOF) m/z calcd for C28H35NO4S (M+Na)+ 504.2179, 248.1046.
found 504.2179.
3-((3-Methyl-6-phenyl-1-tosyl-1H-indol-2-
Ethyl
2-((3-methyl-1-tosyl-1H-indol-2-yl)methyl)-3- yl)methyl)pentane-2,4-dione (3v). 24 mg, 51% yield, white
1
o
1
oxobutanoate (3r). 26 mg, 62% yield, colorless oil. H NMR solid, m.p. = 103-105 C. H NMR (400 MHz, CDCl3, TMS): δ
(400 MHz, CDCl3, TMS): δ 8.20 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.44 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.54-7.47 (m, 5H), 7.41-
8.0 Hz, 2H), 7.36-7.26 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 4.41 (t, J 7.38 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.66 (t, J = 8.0 Hz, 1H),
= 8.0 Hz, 1H), 4.13 (q, J = 8.0 Hz, 2H), 3.50 (d, J = 8.0 Hz, 2H), 3.45 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 2.20 (s, 6H), 2.14 (s, 3H).
2.33 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 203.4, 145.0, 141.4, 138.3, 137.5,
13C NMR (100 MHz, CDCl3): δ 202.9, 169.0, 144.7, 136.9, 135.3, 135.0, 133.2, 130.7, 129.9, 128.9, 127.5, 127.3, 126.3, 123.5,
132.7, 131.5, 129.8, 126.2, 124.7, 123.7, 120.0, 118.9, 115.3, 120.0, 119.2, 113.9, 66.4, 30.9, 25.7, 21.6, 9.2. HRMS (ESI-TOF)
61.5, 59.1, 30.3, 25.2, 21.5, 13.9, 9.2. HRMS (ESI-TOF) m/z m/z calcd for C28H27NO4S (M+Na)+ 496.1553, found 496.1556.
calcd for C23H25NO5S (M+Na)+ 450.1345, found 450.1347.
Conflicts of interest
There are no conflicts to declare.
3-Methyl-3-((3-methyl-1-tosyl-1H-indol-2-
yl)methyl)pentane-2,4-dione (3s). 27 mg, 65% yield, white
o
1
solid, m.p. = 148-150 C. H NMR (400 MHz, CDCl3, TMS): δ
8.19 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.32-7.24 (m,
3H), 7.09 (d, J = 8.0 Hz, 2H), 3.79 (s, 2H), 2.29 (s, 3H), 2.15 (s,
6H), 2.05(s, 3H), 1.52 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
207.5, 144.6, 137.5, 134.5, 132.6, 131.9, 129.5, 126.4, 124.9,
124.1, 122.2, 118.8, 116.3, 66.1, 29.2, 27.2, 21.5, 18.5, 9.8.
HRMS (ESI-TOF) m/z calcd for C23H25NO4S (M+Na)+ 434.1396,
found 434.1398.
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (21702025), Natural Science
Foundation of Liaoning Province (20180550576), the
Fundamental Research Funds for the Central Universities
(DUT18LK25). We thank Professor Baomin Wang (Dalian
University of Technology) for his enthusiastic help.
2-Methyl-2-((3-methyl-1-tosyl-1H-indol-2-
yl)methyl)cyclohexane-1,3-dione (3t). 24 mg, 57% yield, white
o
1
solid, m.p. = 160-162 C. H NMR (400 MHz, CDCl3, TMS): δ
8.13 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.36-7.25 (m,
3H), 7.08 (d, J = 8.0 Hz, 2H), 3.61 (s, 2H), 2.95-2.87 (m, 2H),
2.68-2.61 (m, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 2.13-2.08 (m, 1H),
1.88-1.74 (m, 1H), 1.26 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
210.2, 144.5, 137.3, 134.5, 131.9, 131.5, 129.4, 126.3, 125.1,
124.1, 123.1, 118.9, 116.3, 64.6, 38.9, 33.8, 21.5, 19.2, 17.3,
10.3. HRMS (ESI-TOF) m/z calcd for C24H25NO4S (M+Na)+
446.1396, found 446.1398.
Notes and references
1
For selected reviews, see: (a) M. Somei and F. Yamada, Nat.
Prod. Rep., 2005, 22, 73; (b) T. Kawasaki and K. Higuchi, Nat.
Prod. Rep., 2005, 22, 761; (c) S. Cacchi and G. Fabrizi, Chem.
Rev., 2005, 105, 2873; (d) K. Higuchi and T. Kawasaki, Nat.
Prod. Rep., 2007, 24, 843; (e) J. Barluenga, F. Rodriguez and
F. J. Fananas, Chem. – Asian J., 2009, 4, 1036; (f) K. Krüger, A.
Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153; (g)
M. Platon, R. Amardeil, L. Djakovitch and J.-C. Hierso, Chem.
Soc. Rev., 2012, 41, 3929.
For selected examples, see: (a) D. Shu, W. Song, X. Li and W.
Tang, Angew. Chem., Int. Ed., 2013, 52, 3237; (b) X. Han, H.
Li, R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51,
10390; (c) D. Shu, G. N. Winston-McPherson, W. Song and W.
Tang, Org. Lett., 2013, 15, 4162; (d) K. Saito, H. Sogou, T.
Suga, H. Kusama and N. Iwasawa, J. Am. Chem. Soc., 2011,
133, 689; (e) P. A. Allegretti and E. M. Ferreira, Org. Lett.,
2011, 13, 5924; (f) P. A. Allegretti and E. M. Ferreira, Chem.
Sci., 2013, 4, 1053; (g) K. Matcha and A. P. Antonchick,
Angew. Chem., Int. Ed., 2014, 53, 11960; (h) P. A. Allegretti,
K. Huynh, T. J. Ozumerzifon and E. M. Ferreira, Org. Lett.,
2016, 18, 64.
2
Methyl
1-((3-methyl-1-tosyl-1H-indol-2-yl)methyl)-2-
oxocyclopentanecarboxylate (3u). 20 mg, 45% yield, yellow
o
1
solid, m.p. = 126-128 C. H NMR (400 MHz, CDCl3, TMS): δ
8.21 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.36-7.25 (m,
3H), 7.12 (d, J = 8.0 Hz, 2H), 3.95 (d, J = 16.0 Hz, 1H), 3.76 (s,
3H), 3.67 (d, J = 16.0 Hz, 1H), 2.59-2.55 (m, 1H), 2.40-2.33 (m,
3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.94-1.88 (m, 1H), 1.80-1.73 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 215.5, 171.5, 144.6, 137.0,
135.0, 132.3, 131.7, 129.6, 126.3, 124.8, 123.8, 121.0, 118.9,
115.9, 60.7, 52.8, 38.0, 32.5, 29.2, 21.5, 19.8, 9.4. HRMS (ESI-
TOF) m/z calcd for C24H25NO5S (M+Na)+ 462.1345, found
462.1347.
3
(a) P. Kothandaraman, W. Rao, S. J. Foo and P. W. H. Chan,
Angew. Chem., Int. Ed., 2010, 49, 4619; (b) D. Susanti, F. Koh,
J. A. Kusuma, P. Kothandaraman and P. W. H. Chan, J. Org.
Chem., 2012, 77, 7166; (c) S. R. Mothe, P. Kothandaraman, S.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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COMMUNICATION
Journal Name
J. L. Lauw, S. M. W. Chin and P. W. H. Chan, Chem. – Eur. J.,
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View Article Online
DOI: 10.1039/C9OB00181F
4
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H. Li, X. Li, H.-Y. Wang, G. N. Winston-McPherson, H.-M. J.
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The efficiency of the addition process is correlated to the
concentration of the enol nucleophile, see: (a) J. L. Burdett
and M. T. Rogers, J. Am. Chem. Soc. 1964, 86, 2105; (b) S. G.
Mills and P. Beak, J. Org. Chem., 1985, 50, 1216.
7
8
For the details, see the Supporting Information.
(a) G. Blay, I. Fernández, J. R. Pedro and C. Vila, Tetrahedron
Lett., 2007, 48, 6731; (b) T. Sakamoto, J. Itoh, K. Mori and T.
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9
(a) K. Takahashi and T. Kametani, Heterocycles, 1979, 13, 411;
(b) J.-C. Andrez, Beilstein J. Org. Chem., 2009, 5, 33.
10 For selected examples about tandem Suzuki coupling
reaction, see: (a) S. P. Miller, J. B. Morgan, F. J. Nepveux and
J. P. Morken, Org. Lett., 2004, 6, 131; (b) C. Sun and B. Xu, J.
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2981.
11 According to reference 4, the Friedel-Crafts alkylation may
occur to obtain fused indole under Brønsted acid conditions.
But in our case, no fused indole was observed.
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB00181F
Me
R1
HO R1
NHR
Cu(CH3CN)4PF6
enol nucleophiles
R2
O
R2
N
N
R
Me
O
R4
R3
EWG
Me
Pyrrolo[1,2-a]indole
Various multisubstituted indoles are prepared from propargylic alcohols and enol nucleophiles by
copper-catalyzed tandem annulation/enol nucleophilic addition.