Intramolecular Larock indole synthesis for the preparation of tricyclic indoles and its application in the synthesis of tetrahydropyrroloquinoline and fargesine

Article abstract of DOI:10.1016/j.tet.2014.05.108

A general and efficient strategy for fused tricyclic indoles from substituted 2-halogenanilines via the palladium-catalyzed intramolecular Larock indolization process has been developed. Using this strategy, a number of 3,4- and 3,5-fused indoles with a variety of ring sizes can been prepared. The utility of this method is demonstrated through the synthesis of the known tetrahydropyrrolo[4,3,2-de]quinoline 10 and the first total synthesis of fargesine.

Full text of DOI:10.1016/j.tet.2014.05.108

Accepted Manuscript
Intramolecular Larock Indole Synthesis for the Preparation of Tricyclic Indoles and Its
Application in the Synthesis of Tetrahydropyrroloquinoline and Fargesine
Yan Gao , Dong Shan , Yanxing Jia
PII:
S0040-4020(14)00826-6
10.1016/j.tet.2014.05.108
TET 25657
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 April 2014
Revised Date: 22 May 2014
Accepted Date: 29 May 2014
Please cite this article as: Gao Y, Shan D, Jia Y, Intramolecular Larock Indole Synthesis for the
Preparation of Tricyclic Indoles and Its Application in the Synthesis of Tetrahydropyrroloquinoline and
Fargesine, Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.108.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Intramolecular Larock Indole Synthesis for
the Preparation of Tricyclic Indoles and Its
Application in the Synthesis of
Tetrahydropyrroloquinoline and Fargesine
Yan Gao, Dong Shan, Yanxing Jia*
Leave this area blank for abstract info.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
3
8 Xueyuan Road, Beijing 100191, China.

1
ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Tetrahedron
journal homepage: www.elsevier.com
Intramolecular Larock Indole Synthesis for the Preparation of Tricyclic Indoles and
Its Application in the Synthesis of Tetrahydropyrroloquinoline and Fargesine
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
a
a
a,b,
Yan Gao , Dong Shan , and Yanxing Jia 
a
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general and efficient strategy for fused tricyclic indoles from substituted 2-halogenanilines
via the palladium-catalyzed intramolecular Larock indolization process has been developed.
Using this strategy, a number of 3,4- and 3,5-fused indoles with a variety of ring sizes can been
prepared. The utility of this method is demonstrated through the synthesis of the known
tetrahydropyrrolo[4,3,2-de]quinoline 10 and the first total synthesis of fargesine.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 Palladium-catalyzed
Keyword_2 Total synthesis
Keyword_3 Natural product
Keyword_4 Indole alkaloids
Keyword_5 Tetrahydropyrroloquinoline
Me
O
1
. Introduction
Cl
HO2C
Me
H
Me
SCN
N
N
Me
N
H
N
The indole nucleus is present in many biological important
Me
HO
Me
Me
1
natural products and pharmaceuticals. The family of the 3,4-
fused indoles (those in which the 3-position of the indole is
bridged to the 4-position) also comprise a number of biologically
O
H
O
N
N
N
H
N
H
N
H
Me
welwistatin
Me
communesin F
2
dehydrobufotenine lysergic acid
active natural and unnatural products. These include the well-
3
4
5
9
8 known dehydrobufotenine,
9 communesin F, dragmacidin E, decursivine, penitrem D,
lysergic acid,
welwistatin,
O
NH2
6
7
8
H
N
HN
O
Me
Me
Me
O
H
H
H
N
OH
1
0
11
NH
N
H
0 indolactam V, and diazonamide A, where the indole is bridged
1 with different ring sizes (6-, 7-, 8-, 9-, and 12-membered rings)
2 and various tethers linked by carbon, nitrogen, and oxygen atoms
3 in different positions (Figure 1). Accordingly, lysergic acid is a
4 representative natural product of the ergot alkaloid family and is
5 also a precursor for a wide range of ergoline alkaloids, its
6 derivatives, such as -ergocryptine, bromocryptine, and
N
Br
N
O
O
N
H
O
HO
N
H
N
H
N
H
dragmacidin E
O
decursivine
Me
indolactam V
Me
Me
HO
Me
N
H
H
N
H
N
ergometrine are clinically used. Indolactam V, the core structure
of tumor-promoting teleocidins, can not only selectively activate
the protein kinase C (PKC), but also direct differentiation of
human embryonic stem cells (ESCs) into pancreatic progenitors.
Diazonamide A exhibits potent antimitotic activity.
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
H
N
O
Cl
O
O
Cl
OH
O
N
H
OH
NH
O
H
H
N
H
O
penitrem D
diazonamide A
The synthesis of 3,4-fused indole moieties have been
investigated by many organic chemists, and various strategies
have been developed (Scheme 1): 1) cyclization at 4-position of
indole starting from 3-substituted indole derivatives; 2)
cyclization at 3-position of indole starting from 4-substituted
Figure 1. Selected examples of 3,4-fused indole alkaloids.
1
3
indole derivatives; 3) cyclization at bridged ring starting from
3,4-substituted indole derivatives; 4) formation of the benzene
ring starting from substituted pyrrole derivatives; 5) Formation
of the pyrrole ring starting from substituted benzene
1
2
14
1
5
1
6
derivatives. However, most of the synthesis of 3,4-fused indole
—
——

Corresponding author. Tel.: +86-10-8280-5166; fax: +86-10-8280-2724; e-mail: yxjia@bjmu.edu.cn

2
Tetrahedron
adopted the strategy 1-3, which are based on tAheCinCtroEdPucTtioEnDof MANTUo SteCstRthIePTfeasibility of this concept, terminal alkynes
functional groups to the 3- and/or 4-positions of existing indoles
followed by cyclization. As a further complication, the direct
functionalization of the indole 4-position is extremely difficult
since most electrophiles prefer attacking the 5- or 7-position. The
preparation of 4-substituted indole derivatives, the precursor of
compound 4a′-4c′ were initially prepared and subjected to the
typical Larock indolization condition (Scheme 3). Unfortunately,
no desired product 6a′-6c′ was obtained. We gradually realize
that the terminal alkynes don’t work well for the Larock indole
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1
9
synthesis. Thus, the internal alkyne 4a was then prepared and
subjected to the typical Larock indolization condition.
Gratifyingly, the desired 3,4-fused tricyclic indole product 6a
was obtained cleanly in 96% yield as the only product (Scheme
3
,4-fused tricyclic indoles, normally requires multi-step
synthesis. Thus, the development of general synthetic methods
for the rapid synthesis of these skeletons in a single operation
remains an important challenge facing organic chemists. We
1
7
3). It is worth to mention that although the use of Pd(OAc) (10
2
have recently reported a palladium-catalyzed intramolecular
Larock indolization process. Herein, we report a full account of
our exploration in the developing this method.
mol%) and PPh (20 mol%) at the same substrate concentration
3
18
gave 6a in 87% yield, the use of a lower amount of Pd(OAc) (5
2
mol%) and PPh (10 mol%) or higher substrate concentration
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
(0.05 M) resulted in decreased reaction efficiency.
Cyclization at bridged ring
O
Cyclization at
-position of indole
Cyclization at
3-position of indole
O
2 3 2 3
Pd(OAc) , PPh , K CO , LiCl
4
Y
I

DMF, 100 °C
N
R
Formation of
the pyrrole ring
Formation of the
benzene ring
R
NHR
N
H
4a': R = H
6a': R = H
6b': R = Boc
6c': R = Ts
?
4
b': R = Boc
4c': R = Ts
Scheme 1. Strategy for the synthesis of 3,4-fused tricyclic indoles.
OCH3
Pd(OAc)2 (20 mol%)
PPh3 (40 mol%)
K CO , LiCl
O
O
2
3
I
OCH3
2
. Results and discussions
DMF, 100 °C, 2 h
c = 0.01 M
N
H
NH2
96%
2.1. Preparation of allylic alcohol substrates
4a
6a
In connection with some of our work on the total synthesis of
4a,4b,8b-d,10a,14a-d
3
3
,4-fused indole alkaloids,
we have synthesized the
Scheme 3. Realization of the intramolecular Larock indolization.
,4-briged ring by using Witkop photocyclization, Heck reaction,
SN2 reaction et al. It is almost one molecular, one strategy. We
then envisaged if we could identify a general approach for the
rapid access to a variety of 3,4-fused tricyclic indoles, which
would not only expedite the total synthesis of 3,4-fused indole
alkaloids, but also enable the modular construction of a library of
their analogues for further medicinal chemistry studies. Further
considering palladium-catalyzed transformations generally
require only a catalytic amount of a metal complex and tolerate a
With this encouraging initial result in hand, we examined the
substrate scope by using different sets of 2-iodoanilines
containing carbon, oxygen or nitrogen tethers (Table 1). In all
cases, good to excellent yields of the desired tricyclic indoles
(6a-6q) were obtained. The substrates leading to six- and seven-
membered ring fused indoles were first examined and the desired
cyclization products were obtained in excellent yield (Table 1,
6a-6h). The intramolecular reaction was next applied to generate
3,4-medium-ring (8- to 11-membered rings) fused indoles, which
7 large number of functional groups, and have thus made a major
8 impact on the synthesis of indoles. We were curious whether a
9 palladium-catalyzed intramolecular Larock indolization process
0 could be applied for the preparation of such polycyclic indoles
2
1
were thought to be more hard to prepare. To our surprise, the
desired 3,4-fused tricyclic indole products could be still obtained
in good to excellent yield (Table 1, 6i-6n), although the 10-
membered and 11-membered tricyclic products 6o and 6p were
formed in moderate yield. Our method could be also applied to
the synthesis of 3,4-macrocycle (>12-membered rings) indoles.
In this case, the 18-membered tricyclic product 6q could be
obtained in 78% yield.
1
9
1 (Scheme 2).
To the best of our knowledge, although
2 intramolecular Larock indolization has been reported in the
3 literaure, the synthesis of 3,4-fused tricyclic indole moieties via
4 intramolecular Larock indole synthesis has never been reported.
2
0
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
R3
R3
I
Pd(OAc)2
Base
+
R2
(1)
(2)
NH
R
N
1
R2
2
R1
1
3
Y
Y
Y
4
R
3
X
R
R
Pd
N
H
N
H
NH2
4
: X = I, Br
5
6: Y= C, N, O
Y = C, N, O
Scheme 2. Synthesis of 3,4-fused tricyclic indoles via intramolecular Larock
indolization.

3
Table 1
ACCEPTED MATa
NUSCRIPT
ble
2
Synthesis of 3,4-fused tricyclic indole systems via an intramolecular Larock
indole synthesis
Synthesis of 3,5-fused tricyclic indole systems via an intramolecular Larock
a,b
a,b
indole synthesis
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Pd(OAc)2 (20 mol%)
PPh3 (40 mol%)
Pd(OAc) (20 mol%)
2
PPh (40 mol%)
3
Y
Y
K2CO3 (2 equiv.)
K CO (2 equiv.)
2
3
I
I
LiCl (1 equiv.)
DMF, 100 °C, 2 h
c = 0.01 M
R
LiCl (1 equiv.)
DMF, 100 °C, 2 h
c = 0.01 M
R
R
R
N
H
6
NH2
N
H
NH2
4
7
8
O
O
TsN
TsN
MeO2C
MeO2C
MeO2C
MeO2C
1
2
9
OCH3
TES
TES
TMS
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
N
H
N
H
N
H
TMS
TMS
6
a, 96%
6b, 96%
6c, 77%
N
H
N
H
MeO2C
CO2Me
8a, 47%
8b, 67%
O
MeO2C CO2Me
MeO2C
MeO2C
TMS
TMS
N
H
N
H
N
H
6
d, 89%
6e, 96%
6f, 87%
MeO C
MeO C
2
2
19
16
MeO2C
MeO2C
CO2Me
MeO C
2
O
O
TMS
TMS
N
H
N
H
TES
TES
TES
8
c, 80%
8d, 60%
N
H
N
H
N
H
6
g, 96%
6h, 99%
6i, 97%
CO2Me
MeO2C
a
O
TsN
General reaction conditions: concentration 0.01M in DMF, 0.20 equiv of
Pd(OAc) , 0.40 equiv of Ph P, 2.0 equiv of K CO , 1.0 equiv of LiCl, 120 C.
2 3 2 3
o
OCH3
TES
TMS
b
N
H
N
H
N
H
Isolated yield.
6j, 50%
6k, 65%
6l, 98%
MeO2C CO2Me
9
O
9
O
After examining the reaction of 2-iodoaniline derivatives, we
next investigated the substrate scope by using the inert 2-
bromoaniline derivatives, because of their lower cost and the
wider of diversity of available compounds. Compound 9 was
synthesized and used as a model compound. When compound 9
was subjected to the optimal reaction condition, the desired
product was obtained in only 27% yield along with recovery of
some starting material. Thus, a variety of electron-rich bulky
10
TMS
N
H
TES
N
H
TES
N
H
6
m, 94%
6n, 74%
6o, 45%
CO2Me
MeO2C
18
MeO2C
MeO2C
MeO2C
2
1
1
22
MeO C
phosphine ligands were screened to increase the yield. As
shown in Table 3, Me-phos and dppp turned out to be the ligands
of choice and gave the desired product in 95% yield, although all
tested ligands could furnish the desired product.
TMS
TMS
N
H
N
H
6p, 40%
6q, 78%
Table 3
Reaction optimization of 2-bromoaniline derivative 9
a
General reaction conditions: concentration 0.01M in DMF, 0.20 equiv of
Pd(OAc) , 0.40 equiv of Ph P, 2.0 equiv of K CO , 1.0 equiv of LiCl, 100 C.
2 3 2 3
o
b
OCH3
Isolated yield.
Pd(OAc)2 (20 mol%)
O
ligand (40 mol%)
O
K2CO3, LiCl
Br
Encouraged by the results for the 3,4-fused tricyclic indoles,
without individual optimization, the scope of the intramolecular
larock reaction was examined for the preparation of 3,5-fused
tricyclic indoles from their corresponding precursor 7 (Table 2).
The reaction was found to be compatible with a variety of ring
sizes. The medium-ring (9-membered rings) fused indoles 8a
could be obtained in 47% yield. The macrocycle (12-membered
OCH3
DMF, 100 °C, 3 h
c = 0.01 M
N
H
NH2
9
6a
PPh3
PCy3
47%
dppp
2
Cy P
(t-Bu) P
2
6 rings) fused indoles 8b was obtained in 67% yield. Again
7 surprisingly, the macrocycle (16 or 19-membered rings) 3,5-
8 fused tricyclic indoles 8c and 8d could be obtained in 80% and
9 60% yield, respectively.
0
1
2
3
4
5
2
7%
95%
37%
95%

4
Tetrahedron
ACCEPTED MANUSCRIPT
2
.2. Synthesis of compound 10
H
N
To probe the utility of our method, conversion of compound
c to known tetrahydropyrroloquinoline 10 was firstly made.
CHO
NaBH4
MeOH
2
3
H2N
6
HO
I
+
HO
I
TES
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
The 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline ring system
was first recognized as an important structural motif of natural
products when the structure of the toad poison dehydrobufotenine
TES
TES
rt
78%
NO2
NO2
17
15
16
2
3
was elucidated (Figure 2). Since then, several marine alkaloids,
such as damirones, discorhabdines, and makaluvamines, have
NaBH CN
3
N
N
I
conditions
HCHO
been
isolated
and
characterized
based
on
the
HO
I
RO
TES
CH3CN
5%
tetrahydropyrroloquinoline nucleus.
8
NO2
NO2
1
8
19a: R = TBS, 50%
19b: R = MOM, 46%
9c: R = Bn, 48%
19d: R = Ac, 0%
1
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
Br
Me
N
Me
Me
N
N
O
N
O
HN
reduction
RO
I
TES
S
N
Ts
N
H
N
H
N
H
NH2
20
O
H2N
N
H
OMe
1
O
0
damirone B
makaluvamine C
discorhabdin A
Scheme 5. Preparation of allylic alcohols 3a-3h.
Figure 2. Selected examples of 3,4-fused indole alkaloids.
Our synthesis of fargesine was illustrated in Scheme 5.
Reductive coupling of the known aldehyde 15 and the primary
amine 16 afforded the secondary amine 17 in 78% yield.
Reductive amination of 17 with formaldehyde with NaBH CN
Bromination of compound 6c gave the desired 7-bromide 11a
0 in 40% yield, 2-bromide 11b in 26% yield as well as 2-de-TES 7-
27
2
4
1 bromide 11c in 23% yield (Scheme 4). It is worth to mention
2 that this bromination reaction is very sensitive to the reaction
3 condition. When the reaction was conducted at room temperature,
4 the main product was 2-bromine product 11b. Compound 11a
5 could be readily converted to 11c by treatment with HCl in
6 MeOH. Ullmann reaction of 11c with NaOMe provided the
3
provided tertiary amine 18 in 85% yield. Firstly, protection of
phenol with TBSCl gave the desired product 19a in 50% yield.
However, attempts to reduction of the nitro group with Zn in
HOAc did not give the desired aniline 20. Changing the
protection group to MOM or Bn gave the same results. We
gradually realize the reason might be the special structure of
compounds 19 and/or 20, which is liable to undergo an
elimination of protonated amino group under acidic conditions to
generate the chemically labile ortho-quinone methide
intermediates. Attempt to protection of phenol using Ac did not
afford the desired product due to compound 18 is a good leaving
group. Taking these problems into consideration, an electron-
withdrawing group was next planned to be introduced at the
secondary amine 17 to reduce these effects.
2
5
7 corresponding product 12 in 77% yield. Reductive removal of
Ts group gave the compound 13 in quantitative yield. Finally,
reductive amination of 13 with formaldehyde with NaBH4
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
followed by protection of indole NH with TsCl gave the known
product 10 in 80% yield.
TsN
TsN
NBS
CH2Cl2
TsN
6c
+
+
TES
Br
0
1
°C
2 h
N
H
N
H
N
H
Br
1
Br
1a (40%)
11b (26%)
11c (23%)
TsN
TsN
TsN
HCl
MeOH
CuI, NaOMe
DMF, 120 °C
TES
HN
rt
N
H
N
H
7
7%
N
H
98%
Br
Br
11c
OMe
12
1
1a
Me
Me
N
N
SmI2, H2O
pyrrolidine
CH2O
NaBH4
TsCl, NaOH
Bu4N•HSO4
THF, rt
100%
MeOH
quant
CH2Cl2
80%
N
H
N
H
N
Ts
OMe
OMe
14
OMe
10
1
3
Scheme 4. Synthesis of compound 10.
2
.3. Total synthesis of fargesine
To further probe the utility of our method, we applied it to the
total synthesis of the natural product fargesine. Fargesine, a new
N-oxide alkaloid, was isolated by Zhu and co-workers from the
root and stem of Evodia fargesii Dode, whose fruits are
employed as a traditional medicine used as an analgesic against
Scheme 6. Total synthesis of fargesine.
2
6
bellyache and to relieve cough after measles. In addition, the
total synthesis of fargesine has not been reported.
The completion of the synthesis of fargesine is depicted in
Scheme 6. Protection of both phenol and nitrogen of amine 17

5
+
with Boc O gave 21 in 90% yield. GratefullyA, rCedCucEtioPnToEf tDhe MA(2NMU+SNCa)R7I6P9.T3311, found: 769.3279; IR (KBr) 3411, 2951,
2
-
1
nitro group of 21 with Zn in HOAc provided the desired
cyclization precursor 2-iodoaniline 22 in 60% yield. Treatment of
2172, 1732, 1253, 1163, 840, 758, 636 cm .
4
.2.2. The preparation of indole 8b.
White solid. Isolated yield: 67%. Mp 119-121 C. H NMR
400 MHz, CDCl ) δ 7.85 (s, 1H), 7.82 (br s, 1H), 7.19 (d, J = 8.0
Hz, 1H), 6.64 (dd, J = 0.8, 8.0 Hz, 1H), 3.74 (s, 6H), 3.48 (s, 2H),
3.05 (m, 2H), 1.59-0.84 (m, 10H), 0.35 (s, 9H); C NMR (100
MHz, CDCl ) δ 172.2, 137.8, 134.4, 128.8, 125.8, 123.5, 123.0,
21.7, 110.7, 58.9, 52.3, 37.9, 29.4, 26.9, 26.2, 25.7, 21.3, 19.3, -
.9; HRMS (ESI) m/z calcd for C H NO Si (M + H) 416.2252,
found 416.2247; IR (KBr) 3420, 2951, 2917, 1728, 1635, 1431,
2
2 under our optimized reaction condition successfully afforded
1
2
3
4
5
6
7
8
9
0
1
o
1
the desired tricyclic product 23 in nearly quantitative yield.
Selective deprotection of N-Boc and TES with TFA gave 24 in
(
3
6
2
6% yield. Reductive amination of 24 followed by oxidation of
5 with m-CPBA provided the desired N-oxide 26 in 70% yield.
13
28
3
Finally, removal of O-Boc of 26 under basic condition gave
fargesine (27) in 95% yield, whose physical properties (NMR,
MS) were essentially identical to those reported for the natural
material. Thus, our first total synthesis of fargesine was
achieved in eight steps and in 15% overall yield from the known
1
0
+
2
3
34
4
26
-
1
1
035, 855, 648 cm .
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
aldehyde 15.
4
.2.3. The preparation of indole 8c.
o
1
White solid. Isolated yield: 80%. Mp 105-106 C. H NMR
400 MHz, CDCl ) δ 7.81 (br s, 1H), 7.29 (s, 1H), 7.21 (d, J = 8.4
2 3. Conclusion
3
(
3
In conclusion, we have developed a new and general strategy
Hz, 1H), 6.67 (dd, J = 1.2, 8.4 Hz, 1H), 3.74 (s, 6H), 3.70 (s, 6H),
3.33 (s, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.03-1.99 (m, 2H), 1.89-
1.84 (m, 2H), 1.77-1.73 (m, 2H), 1.57-1.15 (m, 6H), 1.13-1.11
(m, 4H), 0.36 (s, 9H); C NMR (100 MHz, CDCl ) δ 172.0,
171.8, 137.3, 133.1, 128.9, 126.0, 125.6, 123.0, 120.1, 111.0,
59.2, 57.2, 52.4, 52.3, 37.3, 31.1, 30.4, 30.1, 29.9, 27.4, 27.3,
25.7, 21.4, 18.6, -0.6; HRMS (ESI) m/z calcd for C31H46NO Si
(M + H) 588.2987, fonud 588.2991; IR (KBr) 3465, 2950, 2927,
2171, 1735, 1365, 1218, 843, 753 cm .
4
5
6
7
8
9
0
1
2
3
4
for the construction of 3,4-fused and 3,5-fused tricyclic indoles,
the key structural motif of a number of natural products and
bioactive molecules, via an intramolecular Larock indolization
reaction. The scope and generality of the reaction was examined.
The utility of this method is demonstrated through the synthesis
of the known tetrahydropyrroloquinoline 10 and the first total
synthesis of fargesine. The application of this methodology in the
total synthesis of other natural products and related systems for
bioactivity studies is in progress in our laboratory and will be
reported in due course.
1
3
3
8
+
-1
4.2.4. The preparation of indole 8d.
o
1
White solid. Isolated yield: 60%. Mp 127-128 C. H NMR
5 4. Experimental Section
6
(400 MHz, CDCl ) δ 7.84 (br s, 1H), 7.29 (s, 1H), 7.20 (d, J = 8.4
Hz, 1H), 6.75 (dd, J = 1.5, 8.4 Hz, 1H), 3.74 (s, 6H), 3.70 (s, 6H),
3.37 (s, 2H), 2.76 (t, J = 7.9 Hz, 2H), 1.95-1.87 (m, 4H), 1.77-
1.75 (m, 2H), 1.68-1.61 (m, 2H), 1.51-1.20 (m, 10H), 1.19-1.08
(m, 4H), 0.36 (s, 9H); C NMR (100 MHz, CDCl
172.1, 137.4, 133.2, 128.6, 126.0, 125.8, 123.6, 120.7, 110.7,
58.8, 57.2, 52.3, 52.1, 39.3, 32.1, 32.0, 30.6, 30.2, 30.0, 29.8,
2
C H NO Si (M + H) 630.3457, found 630.3464; IR (KBr)
3
3
4
.1. General
7
8
9
0
1
2
3
4
5
6
7
8
Infrared spectra were recorded on Thermo Nicolet Nexus-470
FT-IR spectrometers. Mass spectra were recorded on a Bruker
APEX IV FT-MS (ESI) spectrometer. H NMR spectra were
recorded at Bruker Avance III 400 MHz NMR spectrometer,
NMR spectra were obtained by using the same NMR
spectrometers unless otherwise stated. Chemical shifts (in ppm)
were referenced to tetramethylsilane (δ = 0 ppm) in the
deuterated solvent as an internal standard. Flash column
chromatography was performed using silica gel (200-300 mesh)
with solvents distilled prior to use. Visualization was achieved
under a UV lamp (254 nm and 365 nm), and by developing the
13
) δ 172.4,
3
1
13
C
9.5, 28.8, 26.7, 24.3, 23.3, 22.6, -0.6; HRMS (ESI) m/z calcd for
+
34 52
8
-1
412, 2950, 2931, 2172, 1731, 1434, 1219, 841, 758 cm .
4
.3. Preparation of compound 10
4.3.1. The preparation of compound 11a.
To a stirred solution of compound 6c (86 mg, 0.20 mmol) in
o
9 plates with phosphomolybdic acid in ethanol.
CH Cl (9 mL) at 0 C was added NBS (36 mg, 0.20 mmol). The
solvent was stirred until completion of the reaction. The reaction
mixture was extracted with CH Cl , dried over Na SO ,
concentrated in vacuo and purified by FCC (PE/EtOAc, 15 : 1) to
give the product 11a (40.3 mg) as a colorless oil. H NMR (400
2
2
0
4
.2. Preparation of 3,5-fused tricyclic indoles 8a-8d
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
2
2
2
4
To a stirred solution of the 2-iodo aniline (0.10 mmol) in
anhydrous DMF (10 mL) was added PPh (0.04 mmol), K CO
1
3
2
3
MHz, CDCl ) δ 7.80 (br s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.26 (d,
3
(0.20 mmol) and LiCl (0.10 mmol) successively under argon
J = 5.2 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.02 (t, J = 5.6 Hz, 2H),
2.62 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H), 0.90 (t, J = 8.0 Hz, 9H),
0.75 (q, J = 8.0 Hz, 6H).
atmosphere. After discharging oxygen with argon for 0.5 h,
Pd(OAc) (0.02 mmol) was added under argon, then the solution
2
o
was heated at 100 C for 2 h. The mixture was cooled down to
room temperature, diluted with EtOAc, washed with brine, dried
over Na SO and filtered. The filtrate was evaporated under
4
.3.2. The preparation of compound 11c.
To a stirred solution of compound 11a (40.3 mg, 0.08 mmol)
2
4
reduced pressure and the resulting residue was purified by FCC
to give the pure products.
in anhydrous MeOH (1.7 mL) at room temperature was added
concentrated hydrochloric acid (0.02 mL). After stirred for 5 h,
the mixture was evaporated under reduced pressure and purified
by FCC (PE/EtOAc, 15 : 1) to give the product 11c (30.6 mg,
4
.2.1. The preparation of indole 8a.
White solid. Isolated yield: 47%. Mp 168-169 C. H NMR
400 MHz, CDCl ) δ 7.83 (br s, 1H), 7.56 (s, 1H), 7.25 (d, J = 8.4
o
1
o
1
9
8%) as a white solid. Mp 197-198 C. H NMR (400 MHz,
(
3
CDCl ) δ 8.01 (br s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
8
6.79 (s, 1H), 4.04 (t, J = 5.6 Hz, 2H), 2.65 (t, J = 5.2 Hz, 2H),
2
1
2
3
Hz, 1H), 6.81 (dd, J = 1.2, 8.4 Hz, 1H), 3.69 (s, 6H), 3.40 (s, 2H),
.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H),
2
0
1
2
.89 (t, J = 8.4 Hz, 2H), 2.12-2.08 (m, 2H), 0.90-0.84 (m, 2H),
.35 (s, 9H); C NMR (100 MHz, CDCl ) δ 171.6, 137.5, 133.4,
28.8, 126.4, 124.8, 124.1, 120.0, 110.9, 58.7, 52.2, 36.7, 30.8,
7.1, 27.0, -0.8; HRMS (ESI) m/z calcd for C H N NaO Si
1
3
3
13
.33 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.6, 136.9, 133.3,
3
30.8, 129.6, 126.8, 125.4, 121.6, 117.9, 112.5, 110.3, 99.2, 47.7,
4
0
54
2
8
2
+
1.5, 21.3; HRMS (ESI) m/z calcd for C H BrN O S (M + H)
1
7
16
2
2

6
Tetrahedron
1
3
91.0117, found 391.0110; IR (KBr) 3355, 2A92C2,C2E85P1,T1E74D0, MAoiNl. UHSNCMRR I(4P0T0 MHz, CDCl ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.32
3
-1
1
347, 1221, 1162, 806, 671 cm .
(s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 6.24(d,
J = 8.4 Hz, 1H), 3.70 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.99 (t, J =
4
.3.3. The preparation of compound 12.
5
.6 Hz, 2H), 2.87 (s, 3H), 2.37 (s, 3H); HRMS (ESI) m/z calcd
1
2
3
4
5
6
7
8
9
0
To a round bottom flask containing anhydrous MeOH (0.12
+
for C H N O S (M + H) 357.1277, found 357.1273.
1
9
21
2
3
mL) was added compound 11c (19 mg, 0.05 mmol) in DMF (1
mL) and CuI (19 mg, 0.10 mmol) in which metallic sodium (11.5
mg, 0.5 mmol) was dissolved, then the solution was heated at
reflux for 1 h. After cooled down to room temperature, the
mixture was filtered through a pad of Celite and washed with
EtOAc. The filtrate was evaporated under reduced pressure,
washed with 2% NaOH, extracted with EtOAc, dried over
Na SO and filtered. The filtrate was evaporated under reduced
Acknowledgments
This research was supported by the National Natural Science
Foundation of China (Nos. 21372017, 21290183), the National
Basic Research Program of China (973 Program, NO.
2
010CB833200).
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
pressure and the resulting residue was purified by FCC
Supplementary data
1 (PE/EtOAc, 4 : 1) to give the product 12 (13 mg, 77%) as a white
2 solid. Mp 227-229 C. H NMR (400 MHz, CDCl ) δ 8.04 (br s,
3 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.09 (d, J
4 = 8.0 Hz, 2H), 6.70 (s, 1H), 6.60 (d, J = 8.4 Hz, 1H), 4.02 (t, J =
5 5.6 Hz, 2H), 3.94 (s, 3H), 2.56 (t, J = 5.2 Hz, 2H), 2.31 (s, 3H);
o
1
3
Supplementary data associated with this article can be found,
in the online version, at doi: .
References and notes
1
3
6
C NMR (100 MHz, CDCl
3
) δ 143.4, 143.2, 137.3, 129.5, 126.9,
7 124.5, 124.4, 122.5, 117.2, 112.1, 109.6, 103.1, 55.5, 47.8, 21.5,
1
.
(a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875-2911; (b)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-2920; (c) Gribble, G.
W. J. Chem. Soc. Perkin Trans. 1 2000, 1045-1075; (d) Saxton, J. E. The
Chemistry of Heterocyclic Compounds, Vol. 25, Part IV, Wiley, New
York, 1983.
+
8 21.0; HRMS (ESI) m/z calcd for C18
9 343.1111, found 343.1113; IR (KBr) 3368, 2969, 2928, 1738,
H N O S (M + H)
19 2 3
-1
1
348, 1217, 1088, 803, 672 cm .
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
.3.4. The preparation of compound 13.
2. Shan, D.; Jia, Y. Chin. J. Org. Chem. 2013, 33, 1144-1156.
3
.
For a recent synthesis, see: Peat, A. J.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 1028-1030.
Preparation of SmI in THF (0.13 M): To a stirred solution of
2
the Sm (230 mg) in anhydrous THF (10 mL) was added I (330
2
4
.
For recent total synthesis of lysergic acid, see: (a) Liu, Q.; Zhang, Y.-A.;
Xu, P.; Jia, Y. J. Org. Chem. 2013, 78, 10885-10893; (b) Liu, Q.; Jia, Y.
Org. Lett. 2011, 13, 4810-4813; (c) Umezaki, S.; Yokoshima, S.;
Fukuyama, T. Org. Lett. 2013, 15, 4230-4233; (d) Iwata, A.; Inuki, S.;
Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 5506-5512.
mg) under argon atmosphere. Then the solution was heated at
reflux until the color became deep-blue.
To a round bottom flask containing compound 12 (13 mg,
0
.038 mmol) was added the solution of SmI (3 mL, 0.13 M, 0.38
5. For total synthesis of N-methylwelwitindolinone, see: (a) Huters, A. D.;
Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011,
2
mmol), H O (0.02 mL) and pyrrolidine (0.07 mL). The solution
2
1
33, 15797-15799; (b) Bhat, V.; Allan, K. M.; Rawal, V. H. J. Am.
was stirred at room temperature for 1 h. The mixture was diluted
Chem. Soc. 2011, 133, 5798-5801.
with EtOAc, washed with NaHCO , extracted with EtOAc, dried
3
6. For total synthesis of communesin F, see: (a) Yang, J.; Wu, H.; Shen, L.;
Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794-13795; (b) Zuo, Z.; Xie, W.;
Ma, D. J. Am. Chem. Soc. 2010, 132, 13226-13228; (c) Liu, P.; Seo, J. H.;
Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000-2003; (d) Belmar,
J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941-16943.
over Na SO and filtered. The filtrate was evaporated under
2
4
reduced pressure and the resulting residue was purified by FCC
PE/EtOAc, 4:1) to give product 13 (7 mg, quant) as a white solid.
(
o
1
Mp 140-143 C. H NMR (400 MHz, CDCl ) δ 8.00 (br s, 1H),
3
7
.
For total synthesis of dragmacidin E, see: Feldman, K. S.; Ngernmeesri,
P. Org. Lett. 2011, 13, 5704-5707.
6
3
.74 (s, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H),
13
.89 (s, 3H), 3.45 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 5.2 Hz, 2H);
C
8
.
(a) Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem. Int. Ed. 2011,
50, 4445-4446; (b) Qin, H.; Xu, Z.; Cui, Y.; Jia, Y. Angew. Chem. Int.
Ed. 2011, 50, 4447-4449; (c) Hu, W.; Qin, H.; Cui, Y.; Jia, Y. Chem.
Eur. J. 2013, 19, 3139-3147; (d) Guo, L.; Zhang, F.; Hu, W.; Li, L.; Jia,
Y. Chem. Commun. 2014, 50, 3299-3302; (e) Sun, D.; Zhao, Q.; Li, C.
Org. Lett. 2011, 13, 5302-5305; (f) Leduc, A. B.; Kerr, M. A. Eur. J.
Org. Chem. 2007, 237-240; (g) Koizumi, Y.; Kobayashi, H.; Wakimoto,
T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am. Chem. Soc. 2008, 130,
NMR (100 MHz, CDCl ) δ 139.5, 135.3, 125.1, 119.9, 115.6,
3
1
11.2, 103.9, 99.3, 56.0, 43.9, 23.1; HRMS (ESI) m/z calcd for
+
C H N O (M + H) 189.1022, found 189.1027; IR (KBr) 3352,
2
1
1
13
2
-1
955, 2926, 2854, 1738, 1713, 1366, 1216, 1051, 797 cm .
2 4.3.5. The preparation of compound 14.
To a stirred solution of compound 13 (5 mg, 0.027 mmol) in
4 MeOH was added CH O (9 μL), NaBH (4 mg, 0.108 mmol).
3
1
6854-16855.
2
4
9. Smith, A. B.; Kanoh, III, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.;
5 The solution was stirred at room temperature for 0.5 h. The
6 mixture was diluted with EtOAc, washed with water, extracted
7 with EtOAc, dried over Na
8 14 (5.4 mg, quant) as a colorless oil without further purification.
Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem. Soc. 2003,
1
25, 8228-8237.
0. (a) Xu, Z.; Zhang, F.; Zhang, L.; Jia, Y. Org. Biomol. Chem. 2011, 9,
512-2517; (b) Bronner, S. M.; Goetz, A. E.; Garg, N. K. Synlett. 2011,
1
1
SO and filtered to give the product
2
4
2
2599-2604; (c) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem.
Soc. 2011, 133, 3832-3835; d) Mari, M.; Bartoccini, F.; Piersanti, G. J.
Org. Chem. 2013, 78, 7727-7734.
1
9
H NMR (400 MHz, CDCl
) δ 7.98 (br s, 1H), 6.73 (s, 1H), 6.51
3
0 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.22 (t,
1. (a) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem. Int.
Ed. 2003, 42, 4961-4966; (b) Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.;
Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888-
12896; (c) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias,
G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.;
Giuseppone, N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,
126, 12897-12906; (d) Knowles, R. R.; Carpenter, J.; Blakey, S. B.;
Kayano, A.; Mangion, I. K.; Sinz, C. J.; MacMillan, D. W. C. Chem. Sci.
2011, 2, 308-311; (e) Cheung, C.-M.; Goldberg, F. W.; Magnus, P.;
Russell, C. J.; Turnbull, R.; Lynch, V. J. Am. Chem. Soc. 2007, 129,
J = 6.0 Hz, 2H), 3.07 (t, J = 5.2 Hz, 2H), 2.91 (s, 3H). HRMS
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
+
(
ESI) m/z calcd for C H N O (M + H) 203.1180, found
12 15 2
2
03.1184.
4
.3.6. The preparation of compound 10.
To a solution of 14 (2 mg, 0.01 mmol), Bu N·HSO (3.4 mg,
4
4
0
0
.01 mmol) in CH Cl (1 mL) was added powered NaOH (1.6 mg,
.04 mmol) and TsCl (2.9 mg, 0.02 mmol). The reaction mixture
2 2
was stirred under argon overnight. Water was added and the
mixture was extracted with EtOAc, dried over Na SO and
1
2320-12327; (f) Mai, C.-K.; Sammons, M. F.; Sammakia, T. Angew.
2
4
Chem. Int. Ed. 2010, 49, 2397-2400.
filtered. The resulting residue was purified by FCC (CH Cl /
12. For application of Witkop photocyclization, see: (a) Yonemitsu, O.;
2
2
MeOH, 99 : 1) to give product 10 (2.7 mg, 80%) as a colorless
Cerutti, P.; Witkop, B. J. Am. Chem. Soc. 1966, 88, 3941-3945; (b)

7
Kobayashi, T.; Spande, T. F.; Aoyagi, H.; Witkop, B. J. Med. Chem.
see: (b) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc.
2014, 136, 2272-2275.
ACCEPTED MANUSCRIPT
1
969, 12, 636-638; (c) Mascal, M.; Moody, C. J.; Slawin, A. M. Z.;
Williams, D. J. J. Chem. Soc., Perkin Trans. 1 1992, 823-830. For
application of Friedel–Crafts reaction, see: Teranishi, K; Wayasbi, S.;
Nakatsuka, S.-I.; Goto, T. Tetrahedron Lett. 1994, 35, 8173-8176.
19. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689-6690;
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652-7662.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
3. Selected example of intramolecular Friedel-Crafts reaction, see: (a)
Rafferty, R. J.; Williams, R. M. J. Org. Chem. 2012, 77, 519-524; (b)
Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920-2923; Selected
example of Pictet-Spengler reaction, see: (c) Schonherr, H.; Leighton, J.
L. Org. Lett. 2012, 14, 2610-2613; (d) Cheng, D.-J.; Wu, H.-B.; Tian, S.-
K. Org. Lett. 2011, 13, 5636-5639; (e) Yamada, K.; Namerikawa, Y.;
Haruyama, T.; Miwa, Y.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem.
20. (a) Garfunkle, J.; Kimball, F. S.; Trzupek, J. D.; Takizawa, S.;
Shimamura, H.; Tomishima, M.; Boger, D. L. J. Am. Chem. Soc. 2009,
131, 16036-16038; (b) Shimamura, H.; Breazzano, S. P.; Garfunkle, J.;
Kimball, F. S.; Trzupek, J. D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132,
7776-7783; (c) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S.
J. Am. Chem. Soc. 2010, 132, 7119-7137; (d) Liu, J.; Shen, M.; Zhang,
Y.; Li, G.; Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.;
Senanayake, C. H.; Lu, B. Z. Org. Lett. 2006, 8, 3573-3575.
21. (a) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106,
911-939; (b) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29, 899-934.
(c) Ma, S.; Negishi, E.-I. J. Am. Chem. Soc. 1995, 117, 6345-6357.
22. (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176-4211;
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338-
6361.
2
009, 5752-5759. For other method, see: (f) Xu, Q.-L.; Dai, L.-X.; You,
S.-L. Chem. Sci. 2013, 4, 97-102; (g) Zheng, C.; Chen, J. J.; Fan, R. Org.
Lett. 2014, 16, 816-819.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
14. (a) Xu, Z.; Li, Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2009, 74, 6859-6862;
b) Xu, Z.; Hu, W.; Liu, Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2010, 75,
(
7
1
626-7635; (c) Zhang, Y.-A.; Liu, Q.; Wang, C.; Jia, Y. Org. Lett. 2013,
5, 3662-3665; (d) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15,
4528-4531; (e) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y.
K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745-
23. (a) Estevez, C.; Venemalm, L.; Alvarez, M.; Joule, J. A. Tetrahedron
1994, 50, 7879-7888; (b) Dubovitskii, S. V.; Gruzdev, V. Yu.; Kaminskii,
V. A. Russ. J. Org. Chem. 1996, 32, 113-116.
1
3754; (f) Brak, K.; Ellman, J. A. Org. Lett. 2010, 12, 2004-2007; (g)
Baran, P. S.; Thomas, J.; Maimone, T. J.; Richter, J. M. Nature 2007,
24. Li, Y.; Wang, Z. Org. Lett. 2009, 11, 1385-1387.
4
7
46, 404-408; (h) Hellal, M.; Singh, S.; Cuny, G. D. J. Org. Chem. 2012,
7, 4123-4128; (i) Lim, H. J.; Gallucci, J. C.; RajanBabu, T. V. Org.
25. Miyake, F.Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2004, 6, 711-713.
26. Qu, S.; Liu, Q.; Tan, C.; Jiang, S.; Zhu, D. Planta Med. 2006, 72, 264-
266.
27. Inouye, M.; Akamatsu, K.; Nakazumi, H. J. Am. Chem. Soc. 1997, 119,
9160-9165.
28. (a) Qu, S.; Wang, G.; Duan, W.; Yao, S.; Zuo, J.; Tan, C.; Zhu, D.
Bioorg. Med. Chem. 2011, 19, 3120-3127; (b) Sundbert, R. J.; Bloom, J.
D. J. Org. Chem. 1981, 46, 5393-5395.
Lett. 2010, 12, 2162-2165.
1
5. Selected example of intramolecular Diels-Alder reaction, see: (a) Trost,
B. M.; McDougall, P. J. Org. Lett. 2009, 11, 3782-3785; (b) Lauchli, R.;
Shea, K. J.; Org. Lett. 2006, 8, 5287-5289; (c) Bur, S. K.; Padwa, A.
Org. Lett. 2002, 4, 4135-4137. For 6-electrocyclization, see: Greshock, T.
J.; Funk, R. L. J. Am. Chem. Soc. 2006, 128, 4946-4947.
1
1
6. (a) Park, I.-K.; Park, J.; Cho, C.-G. Angew. Chem. Int. Ed. 2012, 55,
2
2
496-2499; (b) Park, J.; Kim, S.-Y.; Kim, J.-E.; Cho, C.-G. Org. Lett.
014, 16, 178-181.
7. Shan, D.; Gao, Y.; Jia, Y. Angew. Chem., Int. Ed. 2013, 52, 4902-4905.
18. For a similar work, see: (a) Breazzano, S. P.; Poudel, Y. B.; Boger, D. L.
Click here to remove instruction text...
J. Am. Chem. Soc. 2013, 135, 1600-1606. For a recent excellent work,

ACCEPTED MANUSCRIPT
Supporting Information
Intramolecular Larock Indole Synthesis for the Preparation of
Tricyclic Indoles and Its Application in the Synthesis of
Tetrahydropyrroloquinoline and Fargesine
†
†
,†,‡
Yan Gao, Dong Shan, Yanxing Jia*
†
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
‡
Peking University, 38 Xueyuan Road, Beijing 100191, China, and State Key Laboratory of
Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Table of contents
Table
Page
2
General experimental
Preparation of starting materials
NMR Spectrum of those compounds
3
10
1

ACCEPTED MANUSCRIPT
General Experimental
All reagents were obtained from commercial sources unless otherwise mentioned. N,
N-Dimethylformamide (DMF) was distilled from magnesium sulfate under vacuum. Tetrahydro-
furan (THF) was distilled from potassium sodium alloys. Acetonitrile and dichloromethane were
distilled from calcium hydride. Flasks were flame-dried under vacuum and cooled under argon
atmosphere.
The following abbreviations are used: Boc: tert-butoxycarbonyl; DCM: dichloromethane; DMF:
N, N-dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DEAD:
diethyl azodicarboxylate; EtOAc: ethyl acetate; FCC: flash column chromatography; HMPA:
hexamethylphosphoramide; HOAc: acetic acid; m-CPBA: meta-chloroperoxybenzoic acid; PE:
petroleum ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran.
1
13
H NMR spectra were recorded at Bruker Avance III 400 MHz NMR spectrometer; C NMR
spectra were obtained by using the same NMR spectrometers unless otherwise stated. Mass
spectra were recorded on a Bruker APEX IV FT-MS (ESI) spectrometer. Infrared spectra were
recorded on Thermo Nicolet Nexus-470 FT-IR spectrometers.
2

ACCEPTED MANUSCRIPT
Preparation of starting materials.
For all analytical data of the compounds in Table 1 and Scheme 6, see our previous
communication paper (Ref. [17]).
Synthesis of compound 7a
CO Me
2
CO Me TMS
2
TMS
CO Me
2
MeO C
2
MeO C
2
CO Me
2
TMS
3
3
Zn, HOAc
CH Cl
I
3
2
2
S3a
I
I
0o
9%
C
I
NO2
NaH, DMF
4%
NO2
S2a
6
NH2
7
S1
7a
To a stirred solution of S1 (254 mg, 0.65 mmol) in anhydrous DMF (6.5 mL) was added NaH (28
mg, 0.71 mmol) at room temperature. The reaction mixture was stirred for 1 h and the iodide S3a
(
344 mg, 1.30 mmol) was added dropwisely. The solution was stirred until completion of the
reaction. The mixture was diluted with water and extracted with EtOAc. The combined organic
phases were dried over Na
SO and filtered. The filtrate was evaporated under reduced pressure
2
4
and the resulting residue was purified by FCC (PE/EtOAc, 10 : 1) to afford compound S2a (253
1
mg, 74%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.78 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 1.7
3
Hz, 1H), 7.25 (dd, J = 1.72, 8.56 Hz, 1H), 3.72 (s, 6H), 3.22 (s, 2H), 2.24 (t, J = 7.0 Hz, 2H),
1
3
1
1
3
.93-1.87 (m, 2H), 1.53-1.45 (m, 2H), 0.13 (s, 9H); C NMR (100 MHz, CDCl ) δ 170.7, 151.5,
43.3, 142.9, 130.6, 125.2, 105.9, 86.2, 85.4, 58.7, 52.6, 37.9, 32.2, 23.7, 19.9, 0.1; HRMS (ESI)
+
m/z calcd for C20
528, 1250, 1175, 844, 760 cm .
To a stirred solution of the 2-indo nitrobenzene S2a (252 mg, 0.47 mmol) in CH Cl (5.8 mL) was
H27INO
6
Si (M + H) 532.0647; found 532.0651; IR (KBr) 2955, 2173, 1578,
-
1
1
2
2
o
added activated zinc dust (1.76 g, 28.2 mmol). The solution was cooled down to 0 C and HOAc
o
(
0.43 mL) was added dropwisely. After stirred for 10 min at 0 C, the mixture was filtered through
a pad of Celite and the Celite was washed with EtOAc. The filtrate was neutralized with saturated
aqueous NaHCO solution, extracted with EtOAc, dried over Na SO and filtered. The filtrate was
3
2
4
evaporated under reduced pressure and the resulting residue was purified by FCC (PE/EtOAc, 8 :
1
1
1
2
) to afford 7a (163 mg, 69%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.32 (d, J = 1.8 Hz,
3
H), 6.86 (dd, J = 1.8, 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.02 (br s, 2H), 3.71 (s, 6H), 3.07 (s,
13
H), 2.22 (t, J = 7.2 Hz, 2H), 1.87-1.83 (m, 2H), 1.52-1.44 (m, 2H), 0.14 (s, 9H); C NMR (100
MHz, CDCl
3
) δ 171.4, 145.7, 139.9, 130.8, 127.3, 114.4, 106.4, 85.0, 83.9, 58.9, 52.3, 37.2, 31.5,
+
2
3.8, 20.0, 0.1; HRMS (ESI) m/z calcd for C20
H29INO
4
Si (M + H) 502.0905; found 502.0905; IR
-
1
(
KBr) 3465, 3371, 2953, 1732, 1619, 1501, 1250, 843, 665 cm .
3

ACCEPTED MANUSCRIPT
Synthesis of compound 7b
CO Me
2
CO Me TMS
2
TMS
CO Me
2
MeO C
2
MeO C
2
CO Me
2
TMS
6
6
Zn, HOAc
CH Cl
I
6
2
2
S3b
I
I
0o
3%
C
I
NO2
NaH, DMF
1%
NO2
7
NH2
5
S1
S2b
7b
To a stirred solution of S1 (275 mg, 0.70 mmol) in anhydrous DMF (7 mL) was added NaH (30.8
mg, 0.77 mmol) at room temperature. The reaction mixture was stirred for 1 h and the iodide S3b
(
320 mg, 1.04 mmol) was added dropwisely. The solution was stirred until completion of the
reaction. The mixture was diluted with water and extracted with EtOAc. The combined organic
phases were dried over Na SO and filtered. The filtrate was evaporated under reduced pressure
2
4
and the resulting residue was purified by FCC (PE/EtOAc, 10 : 1) to afford compound S2b (203
1
mg, 51%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.79 (d, J = 8.3Hz, 1H), 7.77 (d, J = 1.8
3
Hz, 1H), 7.20 (dd, J = 1.8, 8.3 Hz, 1H), 3.72 (s, 6H), 3.22 (s, 2H), 2.22 (t, J = 7.0 Hz, 2H),
13
1
.80-1.76 (m, 2H), 1.54-1.47 (m, 2H), 1.43-1.23 (m, 6H), 0.14 (s, 9H); C NMR (100 MHz,
CDCl
3
) δ 171.0, 151.5, 143.4, 143.1, 130.5, 125.3, 107.3, 86.2, 84.5, 58.9, 52.6, 37.7, 32.6, 29.1,
+
2
5
8.4, 24.1, 19.8, 0.2; HRMS (ESI) m/z calcd for C23
H33INO
6
Si (M + H) 574.1116; found
-
1
74.1120; IR (KBr) 2952, 2931, 2171, 1730, 1527, 1249, 844, 759, 698 cm .
To a stirred solution of the 2-indo nitrobenzene S2b (135.5 mg, 0.24 mmol) in CH Cl (3 mL) was
2
2
o
added activated zinc dust (922 mg, 14.20 mmol). The solution was cooled down to 0 C and
o
HOAc (0.2 mL) was added dropwisely. After stirred for 10 min at 0 C, the mixture was filtered
through a pad of Celite and the Celite was washed with EtOAc. The filtrate was neutralized with
3 2 4
saturated aqueous NaHCO solution, extracted with EtOAc, dried over Na SO and filtered. The
filtrate was evaporated under reduced pressure and the resulting residue was purified by FCC
1
(
(
PE/EtOAc, 8 : 1) to afford 7b (93.5 mg, 73%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.32
3
d, J = 1.8 Hz, 1H), 6.82 (dd, J = 1.8, 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 4.01 (br s, 2H), 3.71 (s,
6
6
8
H), 3.08 (s, 2H), 2.21 (t, J = 7.0 Hz, 2H), 1.77-1.73 (m, 2H), 1.55-1.47 (m, 2H), 1.42-1.21 (m,
1
3
3
H), 0.14 (s, 9H); C NMR (100 MHz, CDCl ) δ 171.7, 145.7, 140.0, 130.7, 127.5, 114.4, 107.5,
4.4, 83.9, 59.1, 52.3, 37.0, 31.8, 29.7, 29.2, 28.5, 24.0, 19.8, 0.2; HRMS (ESI) m/z calcd for
+
C
23
H
34INNaO
4
Si (M + Na) 566.1194; found 566.1195; IR (KBr) 3463, 3369, 2928, 2171, 1732,
-
1
1
618, 1204, 841, 759 cm .
4

ACCEPTED MANUSCRIPT
Synthesis of compound 7c
CO Me
2
MeO C CO Me
MeO C CO Me
2
2
2
2
MeO C CO Me
S4a
2
2
CO Me
2
3
3
3
NaH
I
Cl
3
Cl
I
NaI
I
I
CH (CO Me)
2
2
2
COOMe
COOMe
acetone
reflux
quant
THF
70%
NaH, DMF
I
I
9
4%
NO2
NO2
S5a
NO2
NO2
S7a
S1
S6a
I
CO Me
CO Me
2
2
CO Me
CO Me
2
2
MeO C
Zn, HOAc MeO2C
2
S3b
3
2
CH Cl2
3 CO Me
2
CO Me
2
TMS
NaH, DMF
0o
C
75%
I
I
64%
NO2
TMS
NH2
TMS
S2c
7c
To a suspension of NaH (22 mg, 0.85 mmol) in DMF (2.0 mL) was added S1 (305 mg, 0.78 mmol)
in DMF (1.5 mL). After 10 min at room temperature, S4a (0.20 mL, 1.53 mmol) was added to this
mixture, and the reaction mixture was stirred at room temperature for 6 h, diluted with ether,
washed with water and dried over Na
2
SO
4
. Purification by FCC (PE/EtOAc, 8 : 1) gave the
1
chloride S5a (344 mg, 94%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.81 (d, J = 1.8 Hz,
3
1
3
1
H), 7.80 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.8, 7.9 Hz, 1H), 3.74 (s, 6H), 3.54 (t, J = 6 Hz, 2H),
13
.23 (s, 2H), 1.98-1.94 (m, 2H), 1.80-1.73 (m, 2H); C NMR (100 MHz, CDCl
3
) δ 170.6, 151.7,
43.4, 142.6, 130.6, 125.3, 86.3, 58.4, 52.7, 44.4, 37.9, 30.3, 27.6.
A solution of S5a (312 mg, 0.66 mmol) and NaI (199 mg, 1.33 mmol) in acetone (2.5 mL) was
refluxed overnight. The mixture was then cooled to room temperature and partitioned between
2 4
hexanes and water. The organic layer was dried over Na SO and concentrated in vacuo to give
iodide S6a (367 mg, quant) without further purification.
To a slurry of NaH (14.4 mg, 0.60 mmol) in THF (2 mL) was added dimethylmalonate (63 μL,
.55 mmol) via syrige. The reaction mixture was stirred until no more gas was evolved and a
0
solution of crude iodide S6a (306 mg, 0.55 mmol) in THF (1 mL) was added. The resulting
mixture was stirred at room temperature overnight, diluted with water and extracted with EtOAc.
The combined organic phases were dried over Na SO . Purification by FCC (PE/EtOAc, 8 : 1)
2
4
o
1
gave compound S7a (213 mg, 70%) as a yellow solid. Mp 71-72 C. H NMR (400 MHz, CDCl )
3
δ 7.80 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 1.8, 8.3 Hz, 1H), 3.74 (s, 6H),
3
1
8
1
.72 (s, 6H), 3.36 (t, J = 7.4 Hz, 1H), 3.20 (s, 2H), 1.93-1.87 (m, 2H), 1.83-1.78 (m, 2H),
13
3
.34-1.25 (m, 2H); C NMR (100 MHz, CDCl ) δ 170.7, 169.5, 151.6, 143.3, 142.8, 130.6, 125.3,
6.3, 58.7, 52.7, 52.6, 51.1, 37.7, 32.2, 28.7, 22.0; IR (KBr) 3649, 2953, 1730, 1527, 1435, 1157,
-
1
033, 871, 699 cm .
To a suspension of NaH (4.2 mg, 0.17 mmol) in DMF (1 mL) was added S7a (84.6 mg, 0.15
mmol) in DMF (0.5 mL). After 10 min at room temperature, iodide S3b (92.4 mg, 0.30 mmol)
was added, and the reaction mixture was stirred at room temperature for 4 h, diluter with ether,
washed with water and dried over Na
2 4
SO . Purification by FCC (PE/EtOAc, 6 : 1) gave compound
o
1
S2c (71 mg, 64%) as a yellow solid. Mp 105-106 C. H NMR (400 MHz, CDCl ) δ 7.78 (d, J =
3
8
3
.3 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 1.6, 8.3 Hz, 1H), 3.71 (s, 6H), 3.70 (s, 6H),
.19 (s, 2H), 2.19 (t, J = 7.04 Hz, 2H), 1.87-1.81 (m, 4H), 1.78-1.74 (m, 2H), 1.52-1.44 (m, 2H),
5

ACCEPTED MANUSCRIPT
1
3
1
1
1
3
.40-1.14 (m, 8H), 0.12 (s, 9H); C NMR (100 MHz, CDCl ) δ 171.9, 170.7, 151.6, 143.3, 142.9,
30.5, 125.3, 107.4, 86.2, 84.4, 58.7, 57.5, 52.5, 52.3, 37.8, 33.1, 33.0, 32.8, 29.2, 28.4, 24.0, 19.7,
+
9.3, 0.1; HRMS (ESI) m/z calcd for C31
H
44INNaO10Si (M + Na) 768.1671; found 768.1667; IR
-
1
(
KBr) 3469, 2953, 1739, 1527, 1255, 1029, 844, 760, 639 cm .
To a stirred solution of the 2-indo nitrobenzene S2c (71 mg, 0.10 mmol) in CH Cl (1.2 mL) was
2
2
o
added activated zinc dust (374 mg, 5.76 mmol). The solution was cooled down to 0 C and HOAc
o
(
0.09 mL) was added dropwisely. After stirred for 10 min at 0 C, the mixture was filtered through
a pad of Celite and the Celite was washed with EtOAc. The filtrate was neutralized with saturated
aqueous NaHCO solution, dried over Na SO and filtered. The filtrate was evaporated under
3
2
4
reduced pressure and the resulting residue was purified by FCC (PE/EtOAc, 7 : 1) to gave
1
compound 7c (51 mg, 75%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.30 (d, J = 1.6 Hz,
3
1
6
2
1
3
7
H), 6.80 (dd, J = 1.6, 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.02 (br s, 2H), 3.71 (s, 6H), 3.70 (s,
H), 3.05 (s, 2H), 2.20 (t, J = 7.0 Hz, 2H), 1.87-1.82 (m, 4H), 1.76-1.72 (m, 2H), 1.53-1.46 (m,
1
3
3
H), 1.42-1.25 (m, 4H), 1.18-1.07 (m, 4H), 0.14 (s, 9H); C NMR (100 MHz, CDCl ) δ 172.0,
71.4, 145.7, 140.0, 130.7, 127.2, 114.4, 107.5, 84.4, 83.9, 58.9, 57.5, 52.3, 52.3, 37.1, 32.8, 32.7,
+
2.1, 29.3, 28.5, 28.5, 24.0, 19.8, 19.2, 0.2; HRMS (ESI) m/z calcd for C31
8
H47INO Si (M + H)
-
1
16.2110; found 716.2117; IR (KBr) 3370, 2951, 2171, 1732, 1500, 1249, 1113, 842, 760 cm .
Synthesis of compound 7d
CO Me
2
MeO C CO Me
MeO C CO Me
2
2
2
2
MeO C CO Me
2
2
S4b
CO Me
2
6
6
NaI
acetone
6
NaH
I
Cl
6
Cl
I
I
I
CH (CO Me)
2
2
2
COOMe
COOMe
reflux
quant
THF
NaH, DMF
I
I
5
6%
8
4%
NO2
NO2
S5b
NO2
NO2
S7b
S1
S6b
I
CO Me
CO Me
2
CO Me
2
CO Me
2
2
MeO C
Zn, HOAc MeO2C
2
S3b
6
2
CH Cl2
6 CO Me
2
CO Me
2
TMS
NaH, DMF
0o
C
43%
I
I
43%
NO2
TMS
NH2
TMS
S2d
7d
To a suspension of NaH (19.4 mg, 0.77 mmol) in DMF (2.0 mL) was added S1 (273 mg, 0.70
mmol) in DMF (1.5 mL). After 10 min at room temperature, S4b (0.22 mL, 1.40 mmol) was
added to this mixture, and the reaction mixture was stirred at room temperature for 6 h, diluted
with ether, washed with water and dried over Na
2 4
SO . Purification by FCC (PE/EtOAc, 8 : 1) gave
o
1
chloride S5b (299 mg, 84%) as a yellow solid. Mp 72-73 C. H NMR (400 MHz, CDCl ) δ 7.79
3
(
d, J = 8.3 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 1.5, 8.3 Hz, 1H), 3.72 (s, 6H), 3.53 (t, J
13
=
6.6 Hz, 2H), 3.22(s, 2H), 1.80-1.73 (m, 4H), 1.49-1.41 (m, 2H), 1.37-1.24 (m, 4H); C NMR
) δ 170.9, 151.5, 143.4, 143.1, 130.5, 125.3, 86.2, 58.8, 52.6, 44.9, 37.7, 32.5,
2.4, 28.9, 26.5, 24.1.
(
100 MHz, CDCl
3
3
A solution of S5b (289 mg, 0.57 mmol) and NaI (170 mg, 1.13 mmol) in acetone (2 mL) was
refluxed overnight. The mixture was then cooled to room temperature and partitioned between
6

ACCEPTED MANUSCRIPT
2 4
hexanes and water. The organic layer was dried over Na SO and concentrated in vacuo to give
iodide S6b (344 mg, quant) without further purification.
To a slurry of NaH (14.0 mg, 0.59 mmol) in THF (2 mL) was added dimethylmalonate (61 μL,
.53 mmol) via syrige. The reaction mixture was stirred until no more gas was evolved and a
0
solution of crude iodide S6b (320 mg, 0.53 mmol) in THF (1 mL) was added. The resulting
mixture was stirred at room temperature overnight, diluted with water and extracted with EtOAc.
The combined organic phases were dried over Na SO . Purification by FCC (PE/EtOAc, 6 : 1)
2
4
o
1
gave compound S7b (181 mg, 56%) as a yellow solid. Mp 88-89 C. H NMR (400 MHz, CDCl )
3
δ 7.80 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 1.8, 8.3 Hz, 1H), 3.74 (s, 6H),
3
1
8
1
.72 (s, 6H), 3.35 (t, J = 7.5 Hz, 1H), 3.22 (s, 2H), 1.92-1.88 (m, 2H), 1.79-1.75 (m, 2H),
13
3
.32-1.24 (m, 8H); C NMR (100 MHz, CDCl ) δ 170.9, 169.8, 151.5, 143.4, 143.1, 130.5, 125.3,
6.2, 58.9, 52.5, 52.4, 51.6, 37.7, 32.5, 29.2, 28.8, 28.7, 27.1, 24.0; IR (KBr) 3467, 2952, 2259,
-
1
735, 1527, 1347, 1202, 844, 698 cm .
To a suspension of NaH (2.8 mg, 0.11 mmol) in DMF (0.6 mL) was added S7b (60.4 mg, 0.10
mmol) in DMF (1.0 mL). After 10 min at room temperature, iodide S3b (61.6 mg, 0.20 mmol)
was added, and the reaction mixture was stirred at room temperature overnight, diluter with ether,
washed with water and dried over Na
2
SO
4
. Purification by FCC (PE/EtOAc, 7 : 1) gave compound
1
S2d (34 mg, 43%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.77 (d, J = 8.3 Hz, 1H), 7.76 (d,
3
J = 1.7 Hz, 1H), 7.20 (dd, J = 1.7, 8.3 Hz, 1H), 3.71 (s, 6H), 3.70 (s, 6H), 3.20 (s, 2H), 2.19 (t, J =
7
1
1
2
8
.0 Hz, 2H), 1.87-1.83 (m, 4H), 1.79-1.74 (m, 2H), 1.52-1.45 (m, 2H), 1.40-1.24 (m, 10H),
1
3
3
.17-1.13 (m, 4H), 0.13 (s, 9H); C NMR (100 MHz, CDCl ) δ 172.3, 170.9, 151.5, 143.4, 143.1,
30.5, 125.3, 107.5, 86.2, 84.4, 58.9, 57.6, 52.5, 52.2, 37.7, 32.6, 29.5, 29.3, 29.2, 28.5, 24.1, 24.0,
+
4.0, 19.8, 0.1; HRMS (ESI) m/z calcd for C34
H
50INNaO10Si (M + Na) 810.2141; found
-
1
10.2125; IR (KBr) 3466, 2950, 2260, 1734, 1528, 1245, 1048, 843, 697 cm .
To a stirred solution of the 2-indo nitrobenzene S2d (80 mg, 0.10 mmol) in CH Cl (1.3 mL) was
2
2
o
added activated zinc dust (390 mg, 6 mmol). The solution was cooled down to 0 C and HOAc
o
(
0.09 mL) was added dropwisely. After stirred for 10 min at 0 C, the mixture was filtered through
a pad of Celite and the Celite was washed with EtOAc. The filtrate was neutralized with saturated
aqueous NaHCO solution, dried over Na SO and filtered. The filtrate was evaporated under
3
2
4
reduced pressure and the resulting residue was purified by FCC (PE/EtOAc, 7 : 1) to give
1
compound 7d (33 mg, 43%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.31 (d, J = 1.8 Hz,
3
1
2
H), 6.81 (dd, J = 1.8, 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.02 (br s, 2H), 3.69 (s, 12H), 3.06 (s,
H), 2.19 (t, J = 7.1 Hz, 2H), 1.87-1.83 (m, 4H), 1.75-1.71 (m, 2H), 1.52-1.45 (m, 2H), 1.40-1.11
13
(
m, 14H), 0.14 (s, 9H); C NMR (100 MHz, CDCl
3
) δ 172.3, 171.6, 145.7, 140.0, 130.7, 127.5,
1
14.4, 107.5, 84.4, 83.9, 59.0, 57.6, 52.2, 36.9, 32.5, 32.5, 31.8, 29.7, 29.5, 29.4, 29.3, 28.5, 24.1,
+
2
4.0, 19.8, 0.2; HRMS (ESI) m/z calcd for C34
H
8
52INNaO Si (M + Na) 780.2399; found 780.2406;
-
1
IR (KBr) 3464, 2926, 2170, 1731, 1249, 1014, 843, 796, 761 cm .
7

ACCEPTED MANUSCRIPT
Synthesis of compound 17
H
CHO
NaBH4
N
H N
MeOH
HO
I
2
+
HO
I
TES
TES
rt
78%
NO2
NO2
1
5
16
17
To a stirred solution of the aldehyde 15 (645 mg, 2.2 mmol) and amine 16 (403 mg, 2.2 mmol) in
methanol (6.6 mL) at room temperature was added NaBH (171 mg, 4.4 mmol). The mixture was
4
stirred at room temperature for 1 h. The reactioin mixture was extracted with EtOAc and dried
over Na SO . Purification by FCC (PE/EtOAc, 2 : 1) gave compound 17 (790 mg, 78%) as a
2
4
o
1
yellow solid. Mp 75-77 C. H NMR (400 MHz, CDCl
3
) δ 7.64 (d, J = 8.8 Hz, 1H), 6.80 (d, J =
8
0
9
4
.8 Hz, 1H), 4.36 (s, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 0.98 (t, J = 8.0 Hz, 9H),
1
3
.59 (q, J = 8.0 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ 162.4, 146.4, 126.1, 125.4, 116.8, 103.7,
+
2.8, 85.1, 58.0, 46.2, 20.0, 7.5, 4.4; HRMS (ESI) m/z calcd for C17
2 3
H26IN O Si (M + H)
-
1
61.0752; found 461.0750; IR (KBr) 2954, 2874, 2174, 1524, 1453, 1338, 1243, 829, 727 cm .
Synthesis of compound 18
H
N
N
NaBH CN
3
HCHO
HO
I
TES
HO
I
TES
CH CN
85%
3
NO2
NO2
1
7
18
To a stirred solution of amine 17 (100 mg, 0.22 mmol) and HCHO (30%) (44 mg, 0.44 mmol) in
anhydrous CH CN (2.2 mL) at room temperature was added NaBH CN (21 mg, 0.33 mmol). The
3
3
mixture was stirred at room temperature for 1 h. The reactioin mixture was extracted with EtOAc
and dried over Na SO . Purification by FCC (PE/EtOAc, 5 : 1) gave compound 18 (89 mg, 85%)
2
4
o
1
as a yellow solid. Mp 71-73 C. H NMR (400 MHz, CDCl
3
) δ 7.66 (d, J = 8.8 Hz, 1H), 6.81 (d, J
=
8.8 Hz, 1H), 4.11 (s, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 0.98 (t,
13
J = 8.0 Hz, 9H), 0.59 (q, J = 8.0 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ 162.3, 146.3, 126.3,
1
25.1, 116.6, 103.8, 93.0, 84.5, 66.9, 55.3, 40.8, 18.3, 7.4, 4.3; HRMS (ESI) m/z calcd for
+
C
18 2 3
H28IN O Si (M + H) 475.0909; found 475.0910; IR (KBr) 2954, 2912, 2873, 2174, 1572,
-
1
1
337, 1242, 1017, 726, 650 cm .
Synthesis of compound 19a
TBSCl, TEA,
DMAP, CH Cl
N
N
2
2
TBSO
I
TES
HO
I
TES
5
0%
NO2
NO2
18
19a
To a stirred solution of compound 18 (20 mg, 0.04 mmol) in anhydrous CH
2
Cl
2
(1 mL) was added
o
DMAP (2 mg, 0.01 mmol). The solution was cooled to 0 C, then TEA (18 μL) and TBSCl (13 mg,
8

ACCEPTED MANUSCRIPT
o
0
.08 mmol) was added. The mixture was stirred at 0 C for 1 h. The mixture was quenched with
water and extracted with CH
2
Cl
2
and dried over Na
2
SO
4
. Purification by FCC (PE/EtOAc, 7 : 1)
1
gave compound 19a (12.5 mg, 50%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.54 (d, J =
3
8
.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 3.73 (s, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.44 (t, J = 8.0 Hz,
H), 2.22 (s, 3H), 1.03 (s, 9H), 0.97 (t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H), 0.29 (s, 6H).
2
Synthesis of compound 19b
N
N
MOMCl, K2CO3 MOMO
I
TES
HO
I
TES
DMF, 40 o
46%
C
NO2
NO2
1
8
19b
To a solution of compound 18 (15 mg, 0.03 mmol) in anhydrous DMF (1 mL) were added K
2
CO
3
o
(
5.3 mg, 0.04 mmol) and MOMCl (5 μL) at 40 C. The mixture was stirred at that temperature for
an hour. Water was added and the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine and dried over Na
2
SO
4
. Purification by FCC (PE/EtOAc, 10 : 1)
1
gave compound 19b (7.6 mg, 46%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 9.2
3
Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 5.26 (s, 2H), 3.80 (s, 2H), 3.49 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H),
2
.48 (t, J = 8.0 Hz, 2H), 2.29 (s, 3H), 0.97 (t, J = 7.6 Hz, 9H), 0.55 (q, J = 7.6 Hz, 6H).
Synthesis of compound 19c
N
N
K CO , BnBr
2
3
HO
I
TES
BnO
I
TES
Actone
48%
NO2
NO2
18
19c
To a stirred solution of compound 18 (14 mg, 0.03 mmol) in anhydrous acetone (1 mL) at room
temperature was added K CO (8.3 mg, 0.06 mmol) and BnBr (4 μL). After stirring at room
temperature overnight, the solvent was neutralized with NH Cl solution, extracted with EtOAc
and dried over Na SO . Purification by FCC (PE/EtOAc, 7 : 1) gave compound 19c (8 mg, 48%)
2
3
4
2
4
1
as a yellow oil. H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 9.0 Hz, 1H), 7.42-7.37 (m, 5H), 6.95 (d,
J = 8.8 Hz, 1H), 5.15 (s, 2H), 3.84 (s, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.28
(
s, 3H), 0.97 (t, J = 7.6 Hz, 9H), 0.56 (q, J = 7.6 Hz, 6H).
9

1
3
H NMR of compound 8a (CDCl , 400 MHz)
10

1
3
3
C NMR of compound 8a (CDCl , 100 MHz)
11

1
3
H NMR of compound 8b (CDCl , 400 MHz)
12

1
3
3
C NMR of compound 8b (CDCl , 100 MHz)
13

1
3
H NMR of compound 8c (CDCl , 400 MHz)
14

1
3
3
C NMR of compound 8c (CDCl , 100 MHz)
15

1
3
H NMR of compound 8d (CDCl , 400 MHz)
16

1
3
3
C NMR of compound 8d (CDCl , 100 MHz)
17

1
3
H NMR of compound 11c (CDCl , 400 MHz)
18

1
3
3
C NMR of compound 11c (CDCl , 100 MHz)
19

1
3
H NMR of compound 12 (CDCl , 400 MHz)
20

1
3
3
C NMR of compound 12 (CDCl , 100 MHz)
21