Cyclohepta[ b]indole Synthesis through [5 + 2] Cycloaddition: Bifunctional Indium(III)-Catalyzed Stereoselective Construction of 7-Membered Ring Fused Indoles

Article abstract of DOI:10.1021/acs.joc.8b01407

A new approach for the synthesis of highly functionalized tetrahydrocyclohepta[b]indoles through [5 + 2] cycloaddition was developed. Two carbon-carbon bonds were formed by the simple addition of an indium catalyst, which acted as both a δ-Lewis acid and σ-Lewis acid to activate the alkyne and unsaturated ester, respectively. The reaction could be applied to various substrates and proceeded regio- and diastereoselectively in all cases.

Full text of DOI:10.1021/acs.joc.8b01407

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Article
Cyclohepta[b]indole Synthesis through [5+2] Cycloaddition:
Bifunctional Indium(III)-Catalyzed Stereoselective
Construction of 7-Membered Ring Fused Indoles
Takuya Takeda, Shinji Harada, Akito Okabe, and Atsushi Nishida
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01407 • Publication Date (Web): 04 Sep 2018
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Page 1 of 32
The Journal of Organic Chemistry
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Cyclohepta[b]indole Synthesis through [5+2] Cycloaddition: Bifunctional Indium(III)-Catalyzed
Stereoselective Construction of 7-Membered Ring Fused Indoles
†
†,‡,
†
†,‡,
Takuya Takeda, Shinji Harada, * Akito Okabe, and Atsushi Nishida. *
†
1
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Graduate School of Pharmaceutical Sciences, Chiba University, 1ꢀ8ꢀ1 Inohana, Chuoꢀku, Chiba, JAPAN.
‡
Molecular Chirality Research Center, Chiba University, 1ꢀ33 Yayoiꢀcho, Inageꢀku, Chiba, JAPAN.
*Eꢀmail: s.harada@faculty.chibaꢀu.jp, anishida@faculty.chibaꢀu.jp
I In
3
R3
R3
R2
R3
R2
R1
R1
R2
InI3
R1
CO Me
OMe
2
CO Me
2
N
O
N
N
InI3
PG
PG
PG
•
•
•
18 examples, up to 96% yield
regio- and diastereoselective
- and σ-Lewis acidic indium(lll)
π
Abstract
A new approach for the synthesis of highly functionalized tetrahydrocyclohepta[b]indoles through [5+2] cycloaddition was
developed. Two carbonꢀcarbon bonds were formed by the simple addition of an indium catalyst, which acted as both a πꢀLewis
acid and σꢀLewis acid to activate the alkyne and unsaturated ester, respectively. The reaction could be applied to various
substrates and proceeded regioꢀ and diastereoselectively in all cases.
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Introduction
The cyclohepta[b]indole skeleton has been found in various natural and nonꢀnatural compounds that show a wide range of
1
1d
biological activity (Figure 1). For instance, 4 has antitubercular activity (MIC = 3.12 ꢀg/mL), 5 was reported to be an
1
e
0
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7
8
9
0
adipocyte fattyꢀacid binding protein inhibitor (IC50 = 450 nM), and 6 inhibited one of the histone decarboxylase SIRT1 (IC50 =
1f
6
3 nM). Thus, the cyclohepta[b]indole skeleton is attracting interest in the field of medicinal chemistry as a potential
therapeutic compound. This interest, along with the difficulty of constructing its sevenꢀmembered ring, has inspired organic
2
chemists to develop methods for synthesizing the cyclohepta[b]indole skeleton. A common approach to this skeleton in an
intermolecular fashion is through the use of indole derivatives as a donorꢀacceptor type (DꢀA) substrate. Scheme 1 shows
3
examples of indoles as a Cꢀ3 (7 or 8, Scheme 1, A) or Cꢀ4 (11, Scheme 1, B) DꢀA substrate in [4+3] cycloaddition.
Cl
N
OH
O
OH NC
OMe
H
N
H
N
COOH
O
H
O
NH
Actinophyllic Acid (1) Ambiguine K
Isonitrile (2)
Exotine A (3)
Cl
Cl
N
N
N O
N
Bn
CO H
CONH2
H
H
2
antitubercular agent (4) A-FABP
inhibitor (5)
SIRT1 inhibitor (6)
Figure 1. Representative Compounds Containing Cyclohepta[b]indole
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Scheme 1. Cyclohepta[b]indole Synthesis Using Indole Derivative as a Donor-Acceptor Type Substrate
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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3
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5
5
5
5
5
5
5
5
5
5
6
A) Cꢀ3 DꢀA Indole Substrate 7 or 8
R
N
PG
R
7
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
or
N
PG
N
10
PG
8
B) Cꢀ4 DꢀA Indole Substrate 11
OAc
OAc
[
Au]
1
2
R
R
N
N
PG
PG
13
11
Recently, we achieved the synthesis of cyclopenta[b]indoles 15 from indole derivative 14 via enantioselective Nazarov
4
cyclization (Scheme 2, A). This indole derivative 14 contains both nucleophilic carbon (C
a
) and electrophilic carbon (C
b
), and
therefore compound 14 and its derivatives would act as Cꢀ5 donorꢀacceptor type (DꢀA) substrates in an intermolecular reaction.
Thus, we designed suitable Cꢀ5 DꢀA indole substrate 16 for intermolecular cycloaddition by removal of the carbonyl group
adjacent to the indole ring in 14 to improve the nucleophilicity of the indole as well as to suppress Nazarov cyclization.
Cycloheptannulation would be achieved by using an appropriate Cꢀ2 DꢀA type substrate, and we found that alkynes were
5
suitable for this purpose. Alkynes introduce an olefin moiety in the resulting sevenꢀmembered ring, which is amenable to
various functionalizations. Herein, we report a novel [5+2] cycloaddition between indole 16 and alkyne using indium(III) as a
sole catalyst that acts as both a πꢀ and σꢀLewis acid to construct a cyclohepta[b]indole skeleton in oneꢀstep (Scheme 2, B).
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5
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Scheme 2. Cyclization of C-5 Donor-Acceptor Type Indole Derivatives
A) Previous Work: Enantioselective Nazarov Cyclization
Chiral
Ni
Complex
R
b
R
EWG
O
a
EWG
N
O
0
1
2
3
4
5
6
7
8
9
0
1
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8
9
0
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9
0
1
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3
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5
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9
0
1
2
3
4
5
6
7
8
9
0
N
PG
PG
15
1
4
B) This Work: Intermolecular [5+2] Cyclization
R2
R3
R2
R3
R1
R1
17
CO R
2
In(lll)
CO R
2
N
N
PG
PG
18
1
6
Inlll
R2
R2
R1
R3
R3
R1
OR
CO R
2
O
N
N
Inlll
PG
19
PG
20
Results and Discussion
The [5+2] cycloaddition of indole 16 and alkyne requires the activation of both an alkyne and unsaturated ester depicted as
19 and 20. Therefore a catalyst that can act as both a πꢀ and σꢀLewis acid is required for the reaction to proceed. Indium(III)
6
salts have been used as a Lewis acidic catalyst in various transformations, in which they were used to activate functional
groups such as carbonyl groups, epoxides, aziridines, halides, alkenes and alkynes. These results indicated that indium(III) salts
could act as both πꢀ and σꢀLewis acids. As an initial trial, the reaction of indole 16a and phenylacetylene (17a) was carried out
3
under InBr catalysis at 80 ºC, and we obtained the cyclized product 18aa in 85% yield (Table 1, entry 1). To optimize the
reaction conditions, we surveyed suitable solvents and catalysts. The reaction proceeded smoothly to give 18aa in good yield in
aromatic solvents (entries 1 and 2). On the contrary, the reactivity was much lower when the reaction was carried out in
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1
1
2
2 3
,2ꢀDCE, MeNO or MeCN (entries 3ꢀ5). InI also gave 18aa in 89% yield in 5 hours in toluene (entry 6), while we still
3
4
3
recovered 16a in 4%. With the use of 10 mol% of InI and 4 equivalents of 17a, 16a was consumed to give 18aa in 92% (entry
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
7). In(OTf) catalyzed the cycloaddition, however, the catalytic activity was much lower than that of indium halides (entry 8).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
7
8
9
0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
GaI
3
had lower reactivity than indium(III) halides (entry 9). Although FriedelꢀCrafts alkenylation using GaCl
3
at a lower
7
reaction temperature has been reported, GaCl
3
could not catalyze the reaction and gave 18aa in moderate yield even with a
stoichiometric amount of reagent (entries 10 and 11). When gold(I) catalyst, which has been used as an activator of alkynes in
8
various reactions, was examined, it gave 18aa in 64% yield after 24 hours (entry 12). Although other Lewis acids that have
9
been used in FriedelꢀCrafts alkenylation were examined, those trials resulted in lower catalytic activity than in the case of
indium(III) halides.
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Table 1. Optimization of the Reaction Conditions
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9
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
Ph
H
17a
Ph
Lewis acid
(5 mol%)
(
2 equiv.)
+
CO Me
2
8
0 °C
N
CO Me
2
Me
N
18aa
Me
16a
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
entry
Lewis acid
solvent time yield
(h) (%)
1
2
3
4
5
6
InBr
InBr
InBr
InBr
InBr
3
3
3
3
3
toluene
PhCl
6
7
85
83
32
7
1,2ꢀDCE 24
MeNO
2
24
24
5
MeCN
toluene
toluene
toluene
toluene
toluene
20
89
92
15
64
7
InI
InI
3
3
a
7
5
8
9
In(OTf)
3
6
GaI
3
6
b
c
10
GaCl
3
3
22
1
11
GaCl
CH Cl
2 2
61
64
12 (PPh
3
)AuCl/AgSbF
6
toluene
24
a
b
3
The reaction was carried out using 10 mol% of InI and 4 equivalents of 17a. The reaction was carried out at room
c
temperature. The reaction was carried out at 0 ºC using 100 mol% of GaCl
3
.
3
The substrate scope and limitations of InI ꢀcatalyzed intermolecular [5+2] cycloaddition were performed using 10 mol%
3
of InI and 4 equivalents of alkyne (Table 2). Although 17b required a higher reaction temperature, oꢀ, mꢀ, and pꢀtolylacetylenes
(17b, c, d) gave 18 in excellent yields (entries 2ꢀ4). 17e with an electronꢀrich aromatic ring gave 18ae in moderate yield
because of the instability of 17e (entry 5). On the contrary, electronꢀdeficient alkynes 17f and 17g gave 18 in excellent yields
(
entries 6 and 7). Alkynes with a heteroaromatic ring were also reacted with indole 16a to give 18 in good to excellent yields
(entries 8ꢀ11). Because aliphatic acetylene 17l and internal alkyne 17m showed lower reactivity than aromatic terminal alkynes,
a higher reaction temperature was required to promote the reaction. As a result, isomerization of olefin of 16a occurred
preferentially, and desired 18 was obtained in low yield (entries 12 and 13). Notably, the reaction using 17l gave a complex
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mixture of products. Among them, we detected 18al as a minor cyclized product, and unexpected product 21 was obtained in
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
8% yield. Next, we examined several types of indole substrates. Not only Nꢀbenzyl indole 16b, but also nonꢀprotected
derivative 16c could be used in this reaction (entries 14 and 15). The reaction of 16c proceeded at the indole C3 position
selectively and no Nꢀalkenylated product was observed at all. Additionally, indole substrates with a βꢀsubstituted unsaturated
ester moiety (16d, e, f) gave 18 in good to excellent yields with excellent diastereoselectivity, although the reaction using these
indole derivatives required a longer reaction time (entries 16ꢀ18). The stereochemistry of 18da was determined by Xꢀray
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
10
crystallographic analysis.
Table 2. Substrate Generality
R2
R3
R1
R1
CO Me
CO Me
InI
(10 mol%)
3
2
R3
R2
+
2
toluene, 80°C
N
N
PG
PG
18
1
6
17
4 equiv.)
(
1
2
3
2
3
Ph
16a: PG=Me, R =H
17a: R =H, R =Ph
17h: R =H, R =2-thiophenyl
1
2
3
2
3
1
1
1
1
6b: PG=Bn, R =H
17b: R =H, R =2-Me-C H - 17i: R =H, R =3-thiophenyl
6 4
1
2
3
2
3
6c: PG=H, R =H
17c: R =H, R =3-Me-C H - 17j: R =H, R =2-benzofuranyl
6 4
1
2
3
2
3
CO Me
2
6d: PG=Me, R =4-MeO-C H - 17d: R =H, R =4-Me-C H - 17k: R =H, R =N-Ts-indol-3-yl
6
4
6 4
1
2
3
2
3
6e: PG=Me, R =2-furyl
17e: R =H, R =4-MeO-C H - 17l: R =H, R =benzyl
N
6
4
1
2
3
2
3
Me
16f: PG=Me, R =n-Pr
17f: R =H, R =4-Br-C H -
17m: R =Me, R =Ph
6
4
2
3
21
1
7g: R =H, R =4-CF -C H -
3 6 4
time
(h)
5
yield
dr
entry indole 16
alkyne 17
product 18
(%)
92
86
96
82
51
95
89
74
72
66
72
(trans/cis)
1
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
17a
17b
17c
17d
17e
17f
18aa
18ab
18ac
18ad
18ae
18af
18ag
18ah
18ai
18aj
18ak
—
—
—
–
—
—
—
—
—
—
—
a
2
24
6
3
4
6
5
10
4
6
7
17g
17h
17i
4
8
10
10
4
9
10
17j
b
1
1
17k
5
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8alc
<6
38
29
89
80
80
56
60
—
1
2
3
4
5
6
7
8
9
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
a
a
1
2
16a
17l
24
21
—
—
13
16a
16b
16c
16d
16e
16f
17m
17a
17a
17a
17a
17a
72
2
18am
18ba
18ca
18da
18ea
18fa
14
—
1
1
1
1
5
6
7
8
6
—
22
24
72
>20/1
>20/1
>20/1
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
a
b
c
The reaction was carried out at 80 to 100 °C. The reaction was carried out using 2 equivalents of 17k. Including inseparable
byproducts.
A plausible reaction mechanism is shown in Scheme 3. Indium(III) saltꢀcatalyzed FriedelꢀCrafts alkenylation has been
11
reported to form zwitterionic intermediate 23. Carbonꢀindium bondꢀformation would occur to form a more stable cationic
carbon center, hence FriedelꢀCrafts alkenylation would proceed regioselectively and subsequent
rearomatization/protonation gave alkenylated indole 24. InI also activated the unsaturated ester moiety as a σꢀLewis
3
12
acid and 7ꢀmembered ring construction proceeded from 25 through intramolecular Michael addition. This step would be slow
among these sequential reactions, because substrates with a βꢀsubstituted unsaturated ester moiety (16d, e, f) required a longer
reaction time. A possible 5ꢀendo cyclization mode (path b) should be much slower than observed 7ꢀendo cyclization (path a).
The resulting indium enolate 26 was protonated from the less hindered convex face, and 18 was diastereoselectively obtained as
a transꢀisomer. When the reaction was performed using aliphatic alkyne 17l, the alkenylated indole 24al could be isomerized to
internal alkene 24al’ and would give cyclized product 21 (Figure 2).
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Scheme 3. Plausible Reaction Mechanism
2
3
4
5
6
7
8
9
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
R2
R3
R1
R3
R2
1
7
CO R
2
InI3
N
InI3
PG
8
1
R3
R2
2
2
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
R2
InI3
R3
1
R
O
InI3
PG
OR
H
OR
R3
N
R2
R1
O
InI
N
3
R1
2
3
R2
R3
PG
26
CO R
2
2
6'
N
R2
a
R2
R1
PG
1
6
R3
R3
R1
OR
OR
b
O
O
N
InI3
N
+ InI3
PG
PG
24
2
5
Ph
Ph
CO Me
CO Me
2
2
N
N
Me
Me
2
4al
24al'
2
1
Figure 2. Isomerization of Alkenylindole Intermediate
To confirm this mechanism, we examined the cyclization of hypothetical intermediate 24. Indole 16g was reacted with
phenylacetylene (17a) to give 24ga in 90% yield and cyclized 18ga was obtained in 3% yield after 2 hours (Scheme 4). Isolated
2
3
4ga was again reacted under InI catalysis and consequently 18ga was obtained in 49% yield after 48 hours. This result
3
indicated that alkenylated indole 24 was an intermediate for the cyclization, and InI activated both the alkyne and unsaturated
ester in the reaction.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Scheme 4. Stepwise Ring Construction under InI Catalysis
1
7a
(
2 equiv.)
Ph
iPr
InI
3
iPr
CO Me (10 mol%)
2
CO Me
2
toluene
0 °C, 2 h
N
8
N
Me
Me
24ga
2
1
4ga: 90%
8ga: 3%
16g
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
Ph
iPr
CO Me
InI3 (10 mol%)
2
toluene
80 °C, 48 h
N
Me
1
8ga
4
9%, dr = >20/1
We next examined the synthesis of different types of 7ꢀmembered ring fused indole skeleton using this methodology. Indole 27
and 17a were reacted under optimized conditions and cyclohepta[c,d]indole 28 was obtained in 84% yield (Scheme 5).
13
Compounds containing a cyclohepta[c,d]indole skeleton have been reported as natural and biologically active compounds.
10
Indole 27 also gave 29 in 9% yield, which was obtained by the reaction with 2 molecules of 17a, while indole 16 did not give
this type of overreacted product. Additionally, 29 was obtained as a major product in 55% yield under an elevated temperature
and prolonged reaction time. Therefore, 29 would be generated from 28 with excess alkyne as shown in Scheme 6. An
intramolecular interaction of ester moiety and indium to form 31 would contribute to the diastereoselctivity.
Scheme 5. Cyclohepta[c,d]indole Synthesis
MeO C
2
1
7a (4 equiv.)
InI3 (10 mol%)
toluene
N
Me
2
7
Ph
MeO C
2
Ph
MeO C
2
+
N
Me
N
Me
29
2
0 °C, 6 h: 84%
0 ºC, 5 h, then 100 °C, 39 h: 28%
8
8
9% (dr = 6/1)
55% (dr = 6/1)
8
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Scheme 6. Plausible Mechanism for the Generation of 29
2
3
4
5
6
7
8
9
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
Ph
Ph
H
1
InI3
7a
MeO C
MeO C
2
2
Ph
N
N
Me
Me
29
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
28
InI3
InI3
Ph
H
I In
3
Ph
In
Ph
Ph
O
Ph
Ph
MeO C
2
MeO
I
3
MeN
O
MeO
N
+ InI3
N
Me
Me
3
0
31
31’
Conclusion
In conclusion, we developed a novel method for the synthesis of the cyclohepta[b]indole skeleton through an
ꢀcatalyzed [5+2] cycloaddition. The reaction proceeded under catalysis by an indium(III) salt as both a πꢀ and σꢀLewis acid,
InI
3
which enabled two types of carbonꢀcarbon bondꢀformation under a single catalytic system. Additionally, various indole
derivatives and alkynes could be used in this reaction to give not only cyclohepta[b]indole but also cyclohepta[c,d]indole in
good to excellent yield. Further studies on synthetic applications and enantioselective reactions are underway.
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7
8
9
1
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1
1
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1
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2
2
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2
2
2
2
2
2
3
3
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3
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3
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5
5
6
Experimental Section
1
13
General Information. NMR spectra were recorded at 400 or 600 MHz for H NMR and at 100 or 150 MHz for C NMR.
Chemical shifts for proton are reported in parts per million downfield from tetramethylsilane and are referenced to residual
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
protium in the NMR solvent (CDCl δ: 7.26 ppm). For C NMR, chemical shifts are reported relative to the NMR solvent
(
3
CDCl δ: 77.0 ppm) as an internal reference. Infrared spectra were recorded on an ATR. Mass spectra were recorded using ESI
mode with a TOF analyzer. Xꢀray crystallographic data were collected at −180±1 °C using filtered Cu−Kα radiation. Reactions
were carried out in dry solvents under an argon atmosphere, unless otherwise noted. Dry toluene, Lewis acids and alkynes were
purchased from a commercial supplier. Other solvents and reagents were purified by usual methods. Flash column
chromatography was performed on silica gel (60 ꢁm particles) unless otherwise noted.
General Procedure for the Synthesis of Indole 16. A mixture of 1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (1.6 g, 10 mmol),
trimethyl phosphonoacetate (2.0 g, 11 mmol), AcOH (290 ꢀL, 5.0 mmol) and piperidine (100 ꢀL, 1.0 mmol) in benzene (20
mL) was stirred at refluxing temperature for 1 day. The resulting mixture was concentrated under reduced pressure and purified
by a short pad of silica gel to remove unreacted aldehyde. The Knoevenagel product was used without further purification.
4
NaBH (378 mg, 10 mmol) was added to the solution of the Knoevenagel product in MeOH (20 mL) at 0 °C. The mixture was
gradually warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue
was diluted with water and AcOEt. The layers were separated and the aqueous layer was extracted three times with AcOEt. The
2 4
combined organic layers were dried over Na SO , filtrated through a cotton plug and concentrated under reduced pressure.
The residue was dissolved in THF (20 mL) and paraformaldehyde (601 mg, 20 mmol) and K
2
3
CO (2.8 g, 20 mmol) were added.
®
The mixture was stirred at refluxing temperature for 1 day and filtrated through a pad of Celite . The solution was concentrated
2
under reduced pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/15) to afford 16a
as a pale yellow viscous liquid (1355 mg, 59% yield in 3 steps).
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Methyl 2-((1-methyl-1H-indol-2-yl)methyl)acrylate (16a); H NMR (400 MHz, CDCl
3
) δ: 3.61 (s, 3H), 3.79 (s, 5H), 5.36 (s,
2
3
4
5
6
7
8
9
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
1
H), 6.29 (s, 1H), 6.31 (s, 1H), 7.08 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 8.0 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.55 (d, J
13
=
3
7.6 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 29.1, 29.5, 52.1, 101.1, 108.9, 119.4, 120.0, 120.9, 126.7, 127.7, 136.7, 137.5,
ꢀ1
+
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
2
137.8, 167.1; IR (neat) ν: 1721, 1631, 741 cm ; HRMS (ESI) m/z calcd for C14H16NO [M+H] 230.1181, found 230.1182.
Methyl 2-((1-benzyl-1H-indol-2-yl)methyl)acrylate (16b); The reaction was carried out on a 2.8 mmol scale of aldehyde
2
following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/12) to
1
afford 16b as a pale yellow viscous liquid (409 mg, 48% yield in 3 steps. H NMR (400 MHz, CDCl
3
) δ: 3.71 (s, 2H), 3.72 (s,
3H), 5.27 (s, 2H), 5.43 (s, 1H), 6.25 (s, 1H), 6.36 (s, 1H), 6.95 (d, J = 6.9 Hz, 2H), 7.08 (ddd, J = 1.4, 6.9, 6.9 Hz, 1H), 7.12
13
(ddd, J = 1.4, 6.9, 6.9 Hz, 1H), 7.18ꢀ7.26 (m, 4H), 7.58 (dd, J = 2.8, 6.9 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 29.1, 46.5,
3
52.0, 101.7, 109.5, 119.6, 120.1, 121.2, 125.9, 126.9, 127.2, 127.9, 128.7, 137.2, 137.3, 137.6, 137.7, 167.0; IR (neat) ν: 1722,
ꢀ1
+
2
1634, 735 cm ; HRMS (ESI) m/z calcd for C20H20NO [M+H] 306.1494, found 306.1497.
Methyl 2-((1H-indol-2-yl)methyl)acrylate (16c); The reaction was carried out on a 5.0 mmol scale of aldehyde following the
2
general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/5) to afford 16c as a
1
pale yellow solid (116 mg, 11% yield in 3 steps). Mp: 65ꢀ67 ºC. H NMR (400 MHz, CDCl
3
) δ: 3.71 (s, 2H), 3.76 (s, 3H), 5.67
(d, J = 0.8 Hz, 1H), 6.23 (s, 1H), 6.26 (d, J = 0.8 Hz, 1H), 7.05 (ddd, J = 0.8, 8.0, 8.0 Hz, 1H), 7.11 (ddd, J = 1.2, 8.0, 8.0 Hz,
13
3
1H), 7.26 (dd, J = 0.8, 7.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 8.37 (brs, 1H); C NMR (100 MHz, CDCl ) δ: 31.3, 52.2, 100.5,
ꢀ1
110.6, 119.5, 119.9, 121.2, 127.2, 128.5, 136.0, 136.2, 137.9, 167.8; IR (neat) ν: 3394, 1714, 1631, 746 cm ; HRMS (ESI) m/z
+
2
calcd for C13H14NO [M+H] 216.1025, found 216.1019.
Methyl (E)-3-(4-methoxyphenyl)-2-((1-methyl-1H-indol-2-yl)methyl)acrylate (16d); The reaction was carried out on a 4.7
4
mmol scale of aldehyde following the general procedure. After reduction with NaBH , NaH (72 mg, 1.8 mmol, 60% dispersion)
was added to a mixture of the residue and pꢀanisaldehyde (183 ꢀL, 1.5 mmol) in toluene (7.5 mL). The mixture was stirred
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8
9
1
1
1
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1
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1
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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
4
overnight at 60 °C, and the reaction was quenched with sat. NH Cl aq. The layers were separated and the aqueous layer was
2 4
extracted three times with AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton plug and
2
concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10)
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
to afford 16d as a pale yellow amorphous solid (354 mg, 26% yield in 3 steps, E/Z = 2.2/1). Further purification was achieved
2
by recrystallization from Et O to afford the (E)ꢀisomer as a colorless solid. Crystals suitable for Xꢀray crystallographic analysis
9
1
2 3
were obtained by slow diffusion of hexane into an Et O solution of 16d. Mp: 123ꢀ124 ºC. H NMR (400 MHz, CDCl ) δ: 3.73
(
s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 3.96 (s, 3H), 6.24 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.07 (dd, J = 7.3, 7.3 Hz, 1H), 7.19 (dd, J
1
3
=
7.8, 7.8 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H); C NMR (100
MHz, CDCl ) δ: 26.1, 29.5, 52.2, 55.3, 99.3, 108.7, 114.1, 119.2, 120.0, 120.8, 126.2, 127.5, 127.8, 131.1, 137.7, 138.2, 141.3,
3
ꢀ1
+
3
160.2, 168.6; IR (neat) ν: 1710, 1605, 1512, 1258, 1177, 841, 750 cm ; HRMS (ESI) m/z calcd for C21H22NO [M+H]
336.1603, found 336.1600.
Methyl (E)-3-(furan-2-yl)-2-((1-methyl-1H-indol-2-yl)methyl)acrylate (16e); The reaction was carried out on a 6.3 mmol
4
scale of aldehyde following the general procedure. After the reduction with NaBH , NaH (380 mg, 9.5 mmol, 60% dispersion)
was added to the residue in THF (13 mL) at 0 °C and stirred for 0.5 h. Furfural (787 ꢀL, 9.5 mmol) was added to the mixture
4
and stirred for additional 2 h. The reaction was quenched with sat. NH Cl aq. The layers were separated and the aqueous layer
2 4
was extracted three times with AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton plug
2
and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane =
1
/10) to afford 16e as a red solid (1167 mg, 63% yield in 3 steps, E/Z = 3/1). Further purification was achieved by washing the
1
2 3
solid with Et O to afford the (E)ꢀisomer as a pale yellow solid (345 mg). Mp: 110ꢀ111 ºC. H NMR (400 MHz, CDCl ) δ: 3.76
(s, 3H), 3.78 (s, 3H), 4.20 (s, 2H), 6.11 (s, 1H), 6.43 (dd, J = 1.8, 3.2 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 7.03 (dd, J = 7.8, 7.8 Hz,
13
1H), 7.15 (dd, J = 7.8, 7.8 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.67 (s, 1H); C NMR (100
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MHz, CDCl
3
) δ: 25.8, 29.6, 52.3, 99.0, 108.7, 112.1, 116.1, 119.1, 119.8, 120.5, 124.9, 127.5, 127.8, 137.5, 138.0, 144.7, 150.9,
2
3
4
5
6
7
8
9
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
ꢀ1
+
1
3
68.3; IR (neat) ν: 1710, 1636, 1283, 1214, 749 cm ; HRMS (ESI) m/z calcd for C18H18NO [M+H] 296.1287, found
296.1286.
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
Methyl (E)-2-((1-methyl-1H-indol-2-yl)methyl)hex-2-enoate (16f); The reaction was carried out on a 2.0 mmol scale of
4
aldehyde following the general procedure. After reduction with NaBH , NaH (80 mg, 2.0 mmol, 60% dispersion) was added to
the residue in THF (8.0 mL) at 0 °C and stirred for 0.5 h. A solution of butyraldehyde (180 ꢀL, 2.0 mmol) in THF (2.0 mL) was
4
added to the mixture and stirred for another 5 h. The reaction was quenched with sat. NH Cl aq. The layers were separated and
2 4
the aqueous layer was extracted three times with AcOEt. The combined organic layers were dried over Na SO , filtrated
through a cotton plug and concentrated under reduced pressure. The residue was purified by flash column chromatography
(
SiO
2
, AcOEt/Hexane = 1/10) to afford (E)ꢀ16f as a yellow viscous liquid (127 mg, 24% yield in 3 steps) and (Z)ꢀ16f as a
1
yellow viscous liquid (48 mg, 15% yield in 3 steps). (E)ꢀ16f; H NMR (400 MHz, CDCl
3
) δ: 0.89 (t, J = 7.3 Hz, 3H), 1.40 (tq, J
=
7.3, 7.3 Hz, 2H), 2.45 (dt, J = 7.3, 7.3 Hz, 2H), 3.62 (s, 3H), 3.73 (s, 5H), 5.79 (t, J = 7.3 Hz, 1H), 6.25 (s, 1H), 7.07 (dd, J =
13
7
3
.8, 7.8 Hz, 1H), 7.16 (dd, J = 8.2, 8.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl )
δ: 13.8, 22.5, 29.5, 31.3, 31.5, 51.4, 100.8, 108.8, 119.2, 120.0, 120.8, 127.7, 128.6, 137.5, 137.9, 144.4, 167.9; IR (neat) ν:
ꢀ1
+
2
1718, 1644, 1217, 749 cm ; HRMS (ESI) m/z calcd for C17H22NO [M+H] 272.1651, found 272.1648.
Methyl (E)-4-methyl-2-((1-methyl-1H-indol-2-yl)methyl)pent-2-enoate (16g); The reaction was carried out on a 2.1 mmol
4
scale of aldehyde following the general procedure. After reduction with NaBH , NaH (60 mg, 1.5 mmol, 60% dispersion) was
added to the residue in THF (5.0 mL) at 0 °C and stirred for 0.5 h. Isobutyraldehyde (137 ꢀL, 1.5 mmol) was added to the
4
mixture and stirred for 24 h at room temperature. The reaction was quenched with sat. NH Cl aq. The layers were separated and
2 4
the aqueous layer was extracted three times with AcOEt. The combined organic layers were dried over Na SO , filtrated
through a cotton plug and concentrated under reduced pressure. The residue was purified by flash column chromatography
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5
5
5
5
5
5
5
5
6
(
SiO
2
, AcOEt/Hexane = 1/15) to afford (E)ꢀ16g as a pale brown liquid (50 mg, 9% yield in 3 steps) and (Z)ꢀ16g as a pale
1
yellow solid (12 mg, 2% yield in 3 steps). (E)ꢀ16g ; H NMR (400 MHz, CDCl
3
) δ: 0.97 (d, J = 6.4 Hz, 6H), 3.20ꢀ3.29 (m, 1H),
3.62 (s, 3H), 3.71 (s, 2H), 3.73 (s, 3H), 5.58 (d, J = 11.0 Hz, 1H), 6.25 (s, 1H), 7.07 (ddd, J = 0.9, 6.9, 7.9 Hz, 1H), 1.17 (ddd, J
13
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
3
= 1.4, 6.9, 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 22.6, 28.6, 29.6, 31.5,
ꢀ1
5
1.6, 100.9, 109.0, 119.4, 120.1, 120.9, 126.4, 127.9, 137.7, 138.0, 150.8, 168.1; IR (neat) ν: 1719, 1646, 1215, 749 cm ;
+
2
HRMS (ESI) m/z calcd for C17H22NO [M+H] 272.1649, found 272.1651.
14
2
-Ethynylbenzofuran (17j); To a solution of 2,3ꢀbenzofuran (591 mg, 5.0 mmol) in THF (25 mL) was added nꢀBuLi (3.9 mL,
6
.0 mmol, 1.55 M in hexane) at –78 °C. The resulting solution was stirred for 1 h and DMF (580 ꢀL, 7.5 mmol) was added. The
4
reaction mixture was stirred for additional 1.5 h and quenched with sat. NH Cl aq. The layers were separated and the aqueous
2 4
layer was extracted three times with AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton
2
plug and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane
=
1/10) to afford 2ꢀbenzofurancarboxaldehyde.
3 4 2 2
A mixture of PPh (2.9 g, 11 mmol) and CBr (1.8 g, 5.5 mmol) in CH Cl (20 mL) was stirred at 0 °C for 0.5 h. To this
2 2
solution was added the synthesized aldehyde in CH Cl (5.0 mL). The reaction mixture was gradually warmed to room
temperature, stirred overnight, and concentrated under reduced pressure. The residue was filtrated through a short pad of silica
gel. The solvent was removed under reduced pressure and the residue was dissolved in THF (20 mL). n-BuLi (5.9 mL, 9.1
mmol, 1.55 M in hexane) was added to the solution at –78 °C and the mixture was stirred for 1.5 h. The reaction was quenched
4
with sat. NH Cl aq. The layers were separated and the aqueous layer was extracted three times with AcOEt. The combined
2 4
organic layers were dried over Na SO , filtrated through a cotton plug and concentrated under reduced pressure. The residue
2
was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/20) to afford 17j as a pale yellow liquid (264 mg, 41%
1
yield in 3 steps). H NMR (400 MHz, CDCl
3
) δ: 3.50 (s, 1H), 7.01 (s, 1H), 7.25 (ddd, J = 0.9, 7.8, 7.8 Hz, 1H), 7.35 (ddd, J =
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.4, 8.2, 8.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H).
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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4
4
5
5
5
5
5
5
5
5
5
5
6
15
3
-Ethynyl-1-tosyl-1H-indole (17k); A mixture of indoleꢀ3ꢀcarboxaldehyde (726 mg, 5.0 mmol), TsCl (1049 mg, 5.5 mmol)
3 2 2
and NEt (1.4 mL, 10 mmol) in CH Cl (10 mL) was stirred at room temperature for 2 h. The reaction was quenched with sat.
0
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2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
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8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4 2 2
NH Cl aq. The layers were separated and the aqueous layer was extracted three times with CH Cl . The combined organic
2 4
layers were dried over Na SO , filtrated through a cotton plug and concentrated under reduced pressure. The residue was used
without further purification.
A mixture of PPh
3
(2.9 g, 11 mmol) and CBr
4
(1.8 g, 5.5 mmol) in CH
Cl
2 2
(20 mL) was stirred at 0 °C for 0.5 h. To this
solution was added the prepared 1ꢀtosylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde in CH Cl (5.0 mL). The reaction mixture was gradually
2 2
warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was filtrated through a
short pad of silica gel. The solvent was removed under reduced pressure and the residue was dissolved in THF (9.0 mL).
n-BuLi (2.2 mL, 3.5 mmol, 1.55 M in hexane) was added to the solution at –78 °C and stirred for 18 h from –78 °C to room
4
temperature. The reaction was quenched with sat. NH Cl aq. The layers were separated and the aqueous layer was extracted
2 4
three times with AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton plug and concentrated
2
under reduced pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10) to afford 17k
1
as a pale purple solid (281 mg, 19% yield in 3 steps). H NMR (400 MHz, CDCl
3
) δ: 2.35 (s, 3H), 3.26 (s, 1H), 7.24 (d, J = 8.7
Hz, 2H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 7.37 (dd, J = 7.3, 7.3 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.78 (d, J= 8.7 Hz, 2H), 7.79 (s,
1H), 7.97 (d, J = 8.2 Hz, 1H).
3
General Procedure for InI -Catalyzed [5+2] Cycloaddition. A mixture of indole 16 (0.2 mmol), alkyne 17 (0.8 mmol) and
3
InI (9.9 mg, 0.02 mmol) in toluene (2.0 mL) was stirred at 80 °C for an appropriate time. The reaction mixture was then
directly purified by flash column chromatography.
Methyl 5-methyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18aa); The reaction was carried out
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1
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2
2
2
2
2
2
2
3
3
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3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/12) to
1
afford 18aa as a pale yellow solid (61 mg, 92% yield). Mp: 105ꢀ106 ºC. H NMR (600 MHz, CDCl
3
) δ: 2.31 (ddd, J = 6.6, 10.2,
12.6 Hz, 1H), 2.50 (ddd, J = 5.4, 7.2, 12.6 Hz, 1H), 3.00 (dd, J = 7.8, 15.6 Hz, 1H), 3.28 (dd, J = 4.8, 15.6 Hz, 1H), 3.43 (dddd,
J = 5.4, 5.4, 5.4, 7.8 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 6.29 (dd, J = 7.2, 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.88 (dd, J =
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
13
8
.4, 8.4 Hz, 1H), 7.14 (dd, J = 8.4, 8.4 Hz, 1H), 7.29ꢀ7.30 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H), 7.37ꢀ7.39 (m, 2H); C NMR (150
MHz, CDCl ) δ: 25.4, 29.7, 29.8, 51.7, 52.6, 109.1, 111.6, 119.1, 120.2, 120.7, 123.5, 125.9, 127.2, 127.6, 128.0, 136.9, 140.0,
3
ꢀ1
+
1
2
40.6, 140.8, 175.1; IR (neat) ν: 1733, 1610, 1469, 1202, 759, 746, 701 cm ; HRMS (ESI) m/z calcd for C22H22NO [M+H]
332.1651, found 332.1653.
Methyl 5-methyl-10-(o-tolyl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ab); The reaction was carried out
following the general procedure and the mixture was stirred at 80 °C for 5 h and 100 °C for 19 h. The residue was purified by
1
flash column chromatography (SiO
2
, AcOEt/Hexane = 1/10) to afford 18ab as a yellow viscous liquid (59 mg, 86% yield). H
NMR (400 MHz, CDCl ) δ: 1.98 (s, 3H), 2.50 (ddd, J = 6.4, 9.6, 14.2 Hz, 1H), 2.61 (ddd, J = 4.1, 7.8, 14.2 Hz, 1H), 3.11ꢀ3.18
3
(
m, 1H), 3.31ꢀ3.40 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 5.84 (dd, J = 6.0, 7.3 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.75 (ddd, J =
13
0
.9, 6.9, 7.8 Hz, 1H), 7.07 (ddd, J = 1.4, 7.3, 8.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.19ꢀ7.30 (m, 4H); C NMR (100 MHz,
CDCl ) δ: 20.0, 27.9, 29.7, 30.3, 48.3, 51.9, 108.7, 112.4, 119.3, 119.6, 120.9, 124.2, 125.6, 126.2, 127.1, 129.7, 129.9, 136.4,
3
ꢀ1
1
36.7, 137.8, 139.8, 142.6, 175.3; IR (neat) ν: 1734, 1610, 1469, 1200, 765, 747 cm ; HRMS (ESI) m/z calcd for C23H24NO
2
+
[
M+H] 346.1807, found 346.1809.
Methyl 5-methyl-10-(m-tolyl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ac); The reaction was carried out
following the general procedure and the mixture was stirred for 6 h. The residue was purified by flash column chromatography
1
(SiO
2
, AcOEt/Hexane = 1/10) to afford 18ac as a yellow viscous liquid (66 mg, 96% yield). H NMR (400 MHz, CDCl
3
)
δ: 2.30 (ddd, J = 6.9, 10.1, 13.3 Hz, 1H), 2.32 (s, 3H), 2.49 (ddd, J = 5.5, 7.3, 13.3 Hz, 1H), 3.00 (dd, J = 7.3, 15.1 Hz, 1H),
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.27 (dd, J = 5.0, 14.7 Hz, 1H), 3.43 (dddd, J = 5.5, 5.5, 7.3, 10.1 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 6.28 (dd, J = 7.3, 7.3 Hz,
2
3
4
5
6
7
8
9
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
13
1
H), 6.77 (d, J = 8.2 Hz, 1H), 6.88 (ddd, J = 0.9, 6.9, 8.2 Hz, 1H), 7.11ꢀ7.23 (m, 5H), 7.33 (d, J = 8.2 Hz, 1H); C NMR (100
MHz, CDCl ) δ: 21.5, 25.5, 29.8, 29.9, 51.9, 52.8, 109.1, 111.8, 119.2, 120.4, 120.7, 123.5, 125.0, 126.0, 127.9, 128.0, 128.3,
3
ꢀ1
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
137.0, 137.6, 140.1, 140.7, 140.8, 175.3; IR (neat) ν: 1733, 1603, 1469, 1202, 786, 746 cm ; HRMS (ESI) m/z calcd for
+
C
23
H
24NO
2
[M+H] 346.1807, found 346.1805.
Methyl 5-methyl-10-(p-tolyl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ad); The reaction was carried out
2
following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10) to
1
afford 18ad as a colorless solid (56 mg, 82% yield). Mp: 153ꢀ155 ºC. H NMR (400 MHz, CDCl
3
) δ: 2.29 (ddd, J = 6.9, 10.5,
13.3 Hz, 1H), 2.37 (s, 3H), 2.47 (ddd, J = 5.5, 7.3, 13.3 Hz, 1H), 2.98 (dd, J = 7.3, 15.1 Hz, 1H), 3.27 (dd, J = 5.0, 15.1 Hz, 1H),
3
6
.42 (dddd, J = 5.0, 5.0, 7.3, 10.5 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 6.27 (dd, J = 6.9, 6.9 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H),
.89 (dd, J = 7.3, 7.3 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.14 (dd, J = 7.3, 7.3 Hz, 1H), 7.28 (d, J = 7.8, Hz, 2H), 7.33 (d, J = 8.2
13
Hz, 1H); C NMR (100 MHz, CDCl
3
) δ: 21.2, 25.4, 29.8, 29.9, 51.9, 52.9, 109.1, 111.8, 119.2, 120.4, 120.7, 122.8, 126.0,
ꢀ1
1
27.6, 128.8, 136.9, 137.0, 137.9, 140.1, 140.5, 175.3; IR (neat) ν;:1733, 1610, 1469, 1201, 809, 746 cm ; HRMS (ESI) m/z
+
2
calcd for C23H24NO [M+H] 346.1807, found 346.1806.
Methyl 10-(4-methoxyphenyl)-5-methyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ae); The reaction was
2
carried out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane =
1
1
1
/10) to afford 18ae as a yellow viscous liquid (47 mg, 51% yield). H NMR (400 MHz, CDCl
3
) δ: 2.28 (ddd, J = 6.9, 10.5,
3.3 Hz, 1H), 2.46 (ddd, J = 5.5, 7.3, 13.3 Hz, 1H), 2.98 (dd, J = 7.3, 15.1 Hz, 1H), 3.26 (dd, J = 5.0, 15.1 Hz, 1H), 3.43 (dddd,
J = 5.0, 5.0, 7.3, 10.1 Hz, 1H), 3.0 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 6.22 (dd, J = 7.3, 7.3 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H),
6.84 (d, J = 8.7 Hz, 2H), 6.89 (dd, J = 7.8, 7.8 Hz, 1H), 7.14 (dd, J = 7.3, 7.3 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 7.8
13
Hz, 1H); C NMR (100 MHz, CDCl
3
) δ: 25.4, 29.80, 29.84, 51.9, 53.1, 55.3, 109.1, 111.9, 113.4, 119.2, 120.4, 120.7, 122.0,
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5
5
5
5
5
6
ꢀ1
1
26.0, 128.8, 133.5, 137.0, 140.1, 140.2, 159.0, 175.3; IR (neat) ν: 1733, 1607, 1249, 1034, 809, 745 cm ; HRMS (ESI) m/z
+
calcd for C23
H24NO
3
[M+H] 362.1756, found 362.1755.
Methyl 10-(4-bromophenyl)-5-methyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18af); The reaction was
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
2
carried out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane =
1
1
1
5
/10) to afford 18af as a pale yellow foam (78 mg, 95% yield). H NMR (400 MHz, CDCl
3
) δ: 2.30 (ddd, J = 6.9, 10.1, 13.3 Hz,
H), 2.49 (ddd, J = 5.5, 7.3, 13.3 Hz, 1H), 2.98 (dd, J = 7.3, 15.1 Hz, 1H), 3.27 (dd, J = 5.0, 15.1 Hz, 1H), 3.43 (dddd, J = 5.5,
.5, 7.3, 10.5 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 6.28 (dd, J = 7.3, 7.3 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.90 (dd, J = 8.2, 8.2
13
Hz, 1H), 7.15 (dd, J = 7.8, 7.8 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H); C NMR
(100 MHz, CDCl ) δ: 25.5, 29.8, 29.9, 51.9, 52.6, 109.3, 111.1, 119.4, 120.1, 120.9, 121.2, 124.1, 125.7, 129.3, 131.2, 137.0,
3
ꢀ1
139.65, 139.72, 140.3, 175.1; IR(neat) ν: 1732, 1610, 1470, 1201, 1009, 809, 746 cm ; HRMS (ESI) m/z calcd for
+
C
22
H
21BrNO
2
[M+H] 410.0756, found 410.0754.
Methyl 5-methyl-10-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ag); The
2
reaction was carried out following the general procedure. The residue was purified by flash column chromatography (SiO ,
1
AcOEt/Hexane = 1/10) to afford 18ag as a pale yellow foam (71 mg, 89% yield). H NMR (400 MHz, CDCl
3
) δ: 2.35 (ddd, J =
6.9, 10.1, 13.3 Hz, 1H), 2.53 (ddd, J = 5.5, 7.3, 13.3 Hz, 1H), 3.00 (dd, J = 7.3, 15.1 Hz, 1H), 3.29 (dd, J = 5.0, 15.1 Hz, 1H),
3
6
.45 (dddd, J = 5.5, 5.5, 7.3, 10.1 Hz, 1H), 3.71 (s, 3H), 3.87 (s, 3H), 6.36 (dd, J = 6.9, 6.9 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H),
.90 (dd, J = 7.3, 7.3 Hz, 1H), 7.16 (dd, J = 7.3, 7.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.7
13
Hz, 2H); C NMR (100 MHz, CDCl
3
) δ: 25.6, 29.8, 29.9, 51.9, 52.5, 109.3, 110.8, 119.5, 120.0, 121.0, 124.4 (q, J = 272.2 Hz),
1
25.0 (q, J = 2.9 Hz), 125.6, 127.9, 129.1 (q, J = 31.6 Hz), 137.0, 139.6, 140.3, 144.3, 175.1; IR (neat) ν: 1733, 1613, 1326,
ꢀ1
+
21 3 2
1201, 831, 747 cm ; HRMS (ESI) m/z calcd for C23H F NO [M+H] 400.1524, found 400.1526.
Methyl 5-methyl-10-(thiophen-2-yl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ah); The reaction was carried
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out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10)
2
3
4
5
6
7
8
9
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
1
to afford 18ah as a dark red viscous liquid (50 mg, 74% yield). H NMR (400 MHz, CDCl
3
) δ: 2.25 (ddd, J = 6.9, 10.1, 12.8 Hz,
1H), 2.42 (ddd, J = 6.0, 7.3, 13.3 Hz, 1H), 2.96 (dd, J = 7.8, 15.1 Hz, 1H), 3.25 (dd, J = 4.6, 15.1 Hz, 1H), 3.39ꢀ3.46 (m, 1H),
13
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
3.69 (s, 3H), 3.86 (s, 3H), 6.41 (dd, J = 7.3, 7.3 Hz, 1H), 6.96ꢀ6.99 (m, 3H), 7.13ꢀ7.20 (m, 3H), 7.34 (d, J = 8.2 Hz, 1H); C
NMR (100 MHz, CDCl ) δ: 24.9, 29.5, 29.8, 51.9, 53.4, 109.3, 111.3, 119.4, 120.4, 120.9, 122.8, 124.0, 125.4, 125.7, 127.2,
3
ꢀ1
1
2
34.4, 137.0, 140.1, 144.5, 175.1; IR (neat) ν; 1732, 1609, 1469, 1200, 748 cm ; HRMS (ESI) m/z calcd for C20H20NO S
+
[
M+H] 338.1215, found 338.1217.
Methyl 5-methyl-10-(thiophen-3-yl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ai); The reaction was carried
2
out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10)
1
to afford 18ai as a yellow foam (49 mg, 72% yield). H NMR (400 MHz, CDCl
3
) δ: 2.27 (ddd, J = 6.9, 10.1, 13.3 Hz, 1H), 2.44
(
ddd, J = 6.0, 7.3, 13.3 Hz, 1H), 2.96 (dd, J = 7.3, 14.6 Hz, 1H), 3.24 (dd, J = 5.0, 14.6 Hz, 1H), 3.36ꢀ3.43 (m, 1H), 3.69 (s, 3H),
3
.84 (s, 3H), 6.35 (dd, J = 7.3, 7.3 Hz, 1H), 6.95 (dd, J = 7.8, 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.13ꢀ7.17 (m, 3H), 7.25 (dd,
13
J = 3.2, 4.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ: 25.2, 29.5, 29.8, 51.8, 52.8, 109.2, 111.8, 119.3,
1
20.3, 120.8, 122.0, 122.4, 124.9, 125.9, 127.1, 135.3, 137.0, 139.8, 142.4, 175.2; IR (neat) ν: 1732, 1610, 1469, 1202, 739
ꢀ1
+
2
cm ; HRMS (ESI) m/z calcd for C20H20NO S [M+H] 338.1215, found 338.1215.
Methyl 10-(benzofuran-2-yl)-5-methyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18aj); The reaction was
2
carried out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane =
1
1
1
/10) to afford 18aj as a brown solid (49 mg, 66% yield). Mp: 138ꢀ140 ºC. H NMR (400 MHz, CDCl
3
) δ: 2.32 (ddd, J = 7.3,
0.5, 13.3 Hz, 1H), 2.53 (ddd, J = 6.0, 7.3, 13.3 Hz, 1H), 2.96 (dd, J = 7.8, 15.1 Hz, 1H), 3.27 (dd, J = 4.6, 15.1 Hz, 1H),
3.43ꢀ3.50 (m, 1H), 3.71 (s, 3H), 3.88 (s, 3H), 6.63 (s, 1H), 6.90 (dd, J = 7.8, 7.8 Hz, 1H), 7.05 (dd, J = 7.3, 7.3 Hz, 1H), 7.19
(dd, J = 7.8, 7.8 Hz, 1H), 7.22 (dd, J = 8.2, 8.2 Hz, 1H), 7.28 (dd, J = 1.4, 7.3 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.8
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Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H); C NMR (100 MHz, CDCl ) δ: 24.7, 29.2, 29.9, 51.9, 53.2, 104.6, 109.2, 109.5, 110.9, 119.6,
3
1
20.3, 120.9, 121.0, 122.6, 124.2, 124.5, 125.6, 129.1, 130.3, 137.0, 140.2, 154.6, 155.4, 175.1; IR (neat) ν: 1732, 1611, 1452,
ꢀ1
+
3
1200, 750 cm ; HRMS (ESI) m/z calcd for C24H22NO [M+H] 372.1600, found 372.1597.
0
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0
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Methyl 5-methyl-10-(1-tosyl-1H-indol-3-yl)-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ak); The reaction was
carried out following the general procedure using 0.4 mmol of alkyne. The residue was purified by flash column
1
chromatography (SiO
2
, AcOEt/Hexane = 1/4) to afford 18ak as a pale brown foam (76 mg, 72% yield). H NMR (400 MHz,
CDCl ) δ: 2.34ꢀ2.41 (m, 1H), 2.37 (s, 3H), 2.53 (ddd, J = 5.6, 8.0, 13.6 Hz, 1H), 3.04 (dd, J = 7.2, 14.8 Hz, 1H), 3.30 (dd, J =
3
5
.6, 15.2 Hz, 1H), 3.42 (dddd, J = 5.2, .5.2, 7.2, 10.0 Hz, 1H), 3.69 (s, 3H), 3.86 (s, 3H), 6.41 (dd, J = 7.2, 7.2 Hz, 1H), 6.60 (d,
J = 7.6 Hz, 1H), 6.68 (dd, J = 7.6, 7.6 Hz, 1H), 7.10 (ddd, J = 1.2, 8.4, 8.4 Hz, 1H), 7.11 (ddd, J = 0.8, 8.0, 8.0 Hz, 1H), 7.24 (d,
J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.8 Hz,
13
2
3
H), 8.04 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 21.6, 25.7, 29.7, 29.8, 51.9, 52.4, 109.2, 111.4, 113.7, 119.2,
1
19.9, 120.8, 121.1, 123.3, 123.8, 124.3, 124.56, 124.63, 125.7, 126.9, 129.8, 129.9, 131.7, 135.1, 135.5, 137.0, 139.7, 144.8,
ꢀ1
+
1
75.1; IR (neat) ν: 1732, 1597, 1469, 1371, 1175, 813, 747 cm ; HRMS (ESI) m/z calcd for C31
29 2 4
H N O S [M+H] 525.1848,
found 525.1848.
Methyl
10-benzyl-5-methyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate
(18al)
and
methyl
5
,10-dimethyl-9-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (21); The reaction was carried out following
the general procedure and the mixture was stirred at 80 ºC for 9 h and 100 °C for 15 h. The residue was purified by flash
column chromatography (SiO
2
, AcOEt/Hexane = 1/12) to afford 18al with inseparable impurities as a yellow viscous liquid (4.0
1
mg, <6% yield) and 21 as a yellow viscous liquid (25 mg, 38% yield). 18al; H NMR (600 MHz, CDCl
3
) δ: 2.15 (ddd, J = 6.9,
11.0, 13.8 Hz, 1H), 2.33 (ddd, J = 6.9, 6.9, 13.8 Hz, 1H), 2.75 (dd, J = 6.9, 14.4 Hz, 1H), 3.12 (dd, J = 4.1, 14.4 Hz, 1H),
3.31ꢀ3.35 (m, 1H), 3.67 (s, 3H), 3.77 (s, 3H), 3.94 (d, J = 15.1 Hz, 1H), 4.03 (d, J = 15.1 Hz, 1H), 5.81 (dd, J = 6.9, 6.9 Hz, 1H),
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.09 (dd, J = 7.6, 7.6 Hz, 1H), 7.11ꢀ7.13 (m, 1H), 7.17 (dd, J = 7.6, 7.6 Hz, 1H), 7.19ꢀ7.20 (m, 4H), 7.29 (d, J = 7.6 Hz, 1H),
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5
5
5
5
5
5
5
6
13
7
.69 (d, J = 8.3 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ: 25.2, 29.2, 29.7, 42.1, 51.8, 52.8, 109.4, 113.0, 119.4, 119.7, 120.7,
ꢀ1
1
23.3, 125.6, 125.7, 128.1, 128.8, 136.9, 139.1, 140.3, 140.6, 175.4; IR (neat) ν: 1733, 1201, 764, 744, 701 cm ; HRMS (ESI)
+
1
0
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8
9
0
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9
0
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2
3
4
5
6
7
8
9
0
2 3
m/z calcd for C23H24NO [M+H] 346.1807, found 346.1807. 21; H NMR (400 MHz, CDCl ) δ: 2.21 (s, 3H), 2.56 (dd, J = 12.8,
1
3
1
1.5 Hz, 1H), 2.64 (dd, J = 5.5, 12.8 Hz, 1H), 2.92 (dd, J = 7.8, 14.7 Hz, 1H), 3.31 (dd, J = 3.2, 14.7 Hz, 1H), 3.48 (dddd, J =
.2, 5.5, 7.8, 11.0 Hz, 1H), 3.60 (s, 3H), 3.84 (s, 3H), 7.11 (dd, J = 7.8, 7.8 Hz, 1H), 7.20 (dd, J = 7.8, 7.8 Hz, 1H), 7.23ꢀ7.27 (m,
13
H), 7.31ꢀ7.39 (m, 5H), 7.69 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ: 19.3, 24.6, 29.7, 37.4, 51.7, 53.1, 109.5,
1
15.4, 119.4, 119.9, 120.7, 125.8, 126.1, 128.1, 128.9, 131.6, 134.3, 137.0, 138.2, 143.8, 175.4; IR (neat) ν: 1732, 1608, 1469,
ꢀ1
+
2
1203, 763, 745, 703 cm ; HRMS (ESI) m/z calcd for C23H24NO [M+H] 346.1807, found 346.1805.
Methyl 5,9-dimethyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18am); The reaction was carried out
following the general procedure and the mixture was stirred at 80 ºC for 9 h and 100 °C for 63 h. The residue was purified by
1
flash column chromatography (SiO
2
, AcOEt/Hexane = 1/12) to afford 18am as a yellow viscous liquid (20 mg, 29% yield). H
NMR (400 MHz, CDCl ) δ: 2.04 (s, 3H), 2.44 (d, J = 7.8 Hz, 2H), 2.99 (dd, J = 7.8, 15.1 Hz, 1H), 3.29 (dd, J = 4.6, 14.7 Hz,
3
1
H), 3.49 (ddt, J = 5.0, 7.8, 7.8 Hz, 1H), 3.71 (s, 3H), 3.83 (s, 3H), 6.48 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 7.8, 7.8 Hz, 1H), 7.06
1
3
(dd, J = 8.2, 8.2 Hz, 1H), 7.21ꢀ7.30 (m, 6H); C NMR (100 MHz, CDCl ) δ: 21.3, 25.1, 29.7, 37.0, 51.9, 52.0, 108.9, 114.6,
3
1
19.1, 119.9, 120.5, 126.2, 126.4, 127.8, 130.1, 131.0, 134.2, 136.8, 138.9, 141.0, 175.5; IR (neat) ν: 1733, 1469, 1202, 772,
ꢀ1
+
7
2
44, 704 cm ; HRMS (ESI) m/z calcd for C23H24NO [M+H] 346.1807, found 346.1808.
Methyl 5-benzyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ba); The reaction was carried out
2
following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10) to
1
afford 18ba as a colorless solid (73 mg, 89% yield). Mp: 158ꢀ159 ºC. H NMR (400 MHz, CDCl
3
) δ: 2.33ꢀ2.48 (m, 2H), 2.96
(dd, J = 6.9, 14.6 Hz, 1H), 3.16ꢀ3.27 (m, 2H), 3.62 (s, 3H), 5.50 (d, J = 16.9 Hz, 1H), 5.60 (d, J = 16.9 Hz, 1H), 6.32 (dd, J =
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.3, 7.3 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 7.3, 7.3 Hz, 1H), 7.30 (d, J = 6.9 Hz, 2H), 7.08 (dd, J = 7.3, 7.3 Hz, 1H),
13
.22ꢀ7.43 (m, 9H); C NMR (100 MHz, CDCl
3
) δ: 25.7, 29.9, 46.5, 51.8, 52.7, 109.6, 112.5, 119.5, 120.5, 121.2, 124.1, 125.9,
26.2, 127.30, 127.32, 128.1, 128.8, 136.9, 137.9, 140.1, 140.5, 140.8, 175.1; IR (neat) ν: 1732, 1604, 1463, 1200, 762, 736,
ꢀ1
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9
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
700 cm ; HRMS (ESI) m/z calcd for C28H26NO [M+H] 408.1964, found 408.1965.
Methyl 10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ca); The reaction was carried out following the
2
general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/8) to afford 18ca as a
1
yellow viscous liquid (51 mg, 80% yield). H NMR (400 MHz, CDCl
3
) δ: 2.39 (ddd, J = 6.9, 9.6, 13.7 Hz, 1H), 2.53 (ddd, J =
5
.5, 7.3, 13.3 Hz, 1H), 3.05 (dd, J = 7.8, 15.1 Hz, 1H), 3.23 (dd, J = 6.0, 15.1 Hz, 1H), 3.38 (dddd, J = 6.0, 6.0, 7.8, 9.6 Hz, 1H),
3.70 (s, 3H), 6.25 (dd, J = 7.3, 7.3 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.86 (ddd, J = 0.9, 6.9, 8.2 Hz, 1H), 7.08 (ddd, J = 0.9, 7.3,
13
8.2 Hz, 1H), 7.29ꢀ7.30 (m, 4H), 7.37ꢀ7.39 (m, 2H), 8.38 (brs, 1H); C NMR (100 MHz, CDCl ) δ: 28.0, 30.2, 51.3, 52.0, 110.6,
3
111.9, 119.5, 120.4, 121.2, 123.9, 127.1, 127.3, 127.7, 128.1, 135.5, 138.7, 140.2, 140.9, 175.4; IR (neat) ν: 3377, 1732, 1617,
ꢀ1
+
2
1205, 738, 702 cm ; HRMS (ESI) m/z calcd for C21H20NO [M+H] 318.1494, found 318.1496.
Methyl trans-8-(4-methoxyphenyl)-5-methyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18da); The
2
reaction was carried out following the general procedure. The residue was purified by flash column chromatography (SiO ,
AcOEt/Hexane = 1/5) to afford 18da as a pale yellow solid (70 mg, 80% yield). Crystals suitable for Xꢀray crystallographic
9
1
analysis were obtained by slow diffusion of hexane into an AcOEt solution of the product. Mp: 183ꢀ185 ºC. H NMR (400
MHz, CDCl ) δ: 3.16 (dd, J = 2.3, 14.7 Hz, 1H), 3.23 (dd, J = 7.3, 15.1 Hz, 1H), 3.47 (s, 3H), 3.61 (ddd, J = 2.3, 6.9, 12.4 Hz,
3
1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.81ꢀ3.84 (m, 1H), 6.27 (d, J = 6.0 Hz, 1H), 6.82 (dd, J = 8.2, 8.2 Hz, 1H), 6.84 (d, J = 8.4 Hz,
13
2H), 6.92 (ddd, J = 0.9, 6.9, 9.2 Hz, 1H), 7.16ꢀ7.20 (m, 3H), 7.27ꢀ7.29 (m, 3H), 7.36ꢀ7.38 (m, 3H); C NMR (100 MHz,
CDCl ) δ: 26.5, 29.9, 47.9, 51.6, 55.3, 61.8, 109.4, 111.8, 114.0, 119.5, 120.4, 121.0, 126.0, 127.5, 128.0, 128.2, 129.3, 129.6,
3
ꢀ1
135.3, 137.3, 138.9, 140.62, 140.65, 158.3, 174.5; IR (neat) ν: 1733, 1610, 1513, 1469, 1251, 1034, 831, 766, 748, 701 cm ;
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HRMS (ESI) m/z calcd for C29H28NO [M+H] 438.2069, found 438.2068.
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4
5
6
7
8
9
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1
1
1
1
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1
1
1
2
2
2
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Methyl trans-8-(furan-2-yl)-5-methyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ea); The reaction
2
was carried out following the general procedure. The residue was purified by flash column chromatography (SiO ,
1
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
AcOEt/Hexane = 1/10) to afford 18ea as a brown foam (44 mg, 56% yield, dr = >20/1). H NMR (400 MHz, CDCl
3
) δ: 3.161
(d, J = 4.1 Hz, 1H), 3.163 (d, J = 5.5 Hz, 1H), 3.57 (s, 3H), 3.75 (ddd, J = 4.1, 5.5, 11.9 Hz, 1H), 3.79 (s, 3H), 3.98 (dd, J = 6.0,
11.5 Hz, 1H), 6.03 (d, J = 3.2 Hz, 1H), 6.27 (dd, J = 1.8, 2.8 Hz, 1H), 6.35 (d, J = 6.4 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.92
(dd, J = 7.8, 7.8 Hz, 1H), 7.17 (ddd, J = 0.9, 6.9, 8.2 Hz, 1H), 7.29ꢀ7.36 (m, 5H), 7.396 (d, J = 7.8 Hz, 1H), 7.404 (d, J = 6.0 Hz,
13
1
3
H); C NMR (100 MHz, CDCl ) δ: 25.8, 29.7, 41.3, 51.7, 58.8, 105.9, 109.4, 110.1, 111.6, 119.5, 120.2, 121.0, 125.1, 125.7,
127.5, 127.8, 128.1, 137.2, 139.5, 140.0, 140.3, 141.7, 155.3, 174.2; IR (neat) ν: 1734, 1611, 1469, 1213, 1013, 767, 745, 701
ꢀ1
+
3
cm ; HRMS (ESI) m/z calcd for C26H24NO [M+H] 398.1756, found 398.1756.
Methyl trans-5-methyl-10-phenyl-8-propyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18fa); The reaction was
2
carried out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane =
1
1
/12) to afford 18fa as a yellow solid (45 mg, 60% yield, dr = >20/1). Mp: 120ꢀ122 ºC. H NMR (400 MHz, CDCl
3
) δ: 0.89 (dd,
J = 7.3, 7.3 Hz, 3H), 1.26ꢀ1.53 (m, 4H), 2.56ꢀ2.63 (m, 1H), 3.05 (d, J = 5.0 Hz, 2H), 3.17 (ddd, J = 5.0, 5.0, 11.5 Hz, 1H), 3.70
(s, 3H), 3.75 (s, 3H), 6.04 (d, J = 6.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.89 (ddd, J = 0.9, 6.9, 6.9 Hz, 1H), 7.14 (ddd, J = 1.4,
1
3
6
1
1
3
.9, 8.2 Hz, 1H), 7.28ꢀ7.33 (m, 4H), 7.36ꢀ7.39 (m, 2H); C NMR (100 MHz, CDCl ) δ: 14.2, 26.4, 29.7, 35.9, 40.5, 51.5, 59.2,
09.2, 112.2, 119.2, 120.3, 120.7, 125.8, 127.3, 127.7, 128.1, 130.0, 137.1, 139.3, 140.5, 140.8, 175.2; IR (neat) ν: 1733, 1611,
ꢀ1
+
2
469, 1208, 763, 744, 701 cm ; HRMS (ESI) m/z calcd for C25H28NO [M+H] 374.2120, found 374.2120.
Methyl trans-8-isopropyl-5-methyl-10-phenyl-5,6,7,8-tetrahydrocyclohepta[b]indole-7-carboxylate (18ga); The reaction
was carried out on a 0.1 mmol scale of 16g following the general procedure using 0.2 mmol of 17a. After the mixture was
2
stirred for 2 h, the residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/12) to afford 24ga as a pale
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1
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4
5
5
5
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5
5
5
5
5
5
6
1
red solid (34 mg, 90% yield) and 18ga (1.0 mg, 3% yield). 24ga; Mp: 106ꢀ107 ºC. H NMR (400 MHz, CDCl ) δ: 0.88 (d, J =
3
6
.4 Hz, 6H), 3.16ꢀ3.25 (m, 1H), 3.65 (s, 3H), 3.74 (s, 3H), 3.75 (s, 2H), 5.24 (d, J = 1.8 Hz, 1H), 5.28 (d, J = 10.1 Hz, 1H), 5.67
(d, J = 1.8 Hz, 1H), 6.98 (ddd, J = 0.9, 6.9, 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.19 (ddd, J = 1.4, 6.9, 8.2 Hz, 1H), 7.24ꢀ7.27
13
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7
8
9
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7
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9
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6
7
8
9
0
3
(m, 3H), 7.30 (d, J = 8.2 Hz, 1H), 7.36ꢀ7.38 (m, 2H); C NMR (100 MHz, CDCl ) δ: 22.5, 28.5, 29.0, 29.9, 51.6, 108.9, 114.7,
1
15.9, 119.4, 120.3, 121.4, 126.7, 127.4, 127.5, 127.6, 128.2, 134.9, 137.0, 141.7, 142.6, 149.8, 168.1; IR (neat) ν: 1719, 1469,
ꢀ1
+
1
2
221, 768, 743, 699 cm ; HRMS (ESI) m/z calcd for C25H28NO [M+H] 374.2116, found 374.2120.
3
A mixture of 24ga (7.5 mg, 0.02 mmol) and InI (1.0 mg, 0.002 mmol) in toluene (0.4 mL) was stirred at 80 °C for 2 days. The
reaction mixture was purified by flash column chromatography (SiO
2
AcOEt/Hexane = 1/12) to afford 18ga as a pale yellow
1
solid (4 mg, 49% yield, E/Z = >20/1) and 24ga (3 mg, 35%). 18ga; Mp: 140ꢀ141 ºC. H NMR (600 MHz, CDCl
3
) δ: 0.97 (d, J
=
6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 1.73 (dqq, J = 41, 6.9, 6.9 Hz, 1H), 2.66 (ddd, J = 3.4, 6.2, 11.0 Hz, 1H), 3.01ꢀ3.07 (m,
2
H), 3.37 (ddd, J = 2.8, 6.2, 11.0 Hz, 1H), 3.70 (s, 3H), 3.76 (s, 3H), 6.14 (d, J = 6.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 6.89 (d,
1
3
J = 7.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.30ꢀ7.33 (m, 4H), 7.37ꢀ7.39 (m, 2H); C NMR (150 MHz, CDCl ) δ: 17.7, 22.0,
3
2
6.4, 29.0, 29.7, 46.2, 51.6, 56.9, 109.2, 112.4, 119.3, 120.3, 120.7, 125.81, 125.84, 127.3, 127.7, 128.1, 137.2, 140.0, 140.5,
ꢀ1
+
1
2
41.2, 175.4; IR (neat) ν: 1732, 1611, 1469, 1214, 765, 745, 701 cm ; HRMS (ESI) m/z calcd for C25H28NO [M+H]
374.2120, found 374.2119.
Methyl 2-(1-methyl-1H-indol-4-yl)acrylate (27); To a solution of 4ꢀbromoꢀ1ꢀmethylꢀ1Hꢀindole (670 mg, 3.2 mmol) in THF
(
13 mL) was added n-BuLi (2.3 mL, 3.8 mmol, 1.55 M in hexane) at –78 °C and the mixture was stirred for 0.5 h. A solution of
dimethyl oxalate (449 mg, 3.8 mmol) in THF (3.0 mL) was added, and the reaction mixture was stirred for another 0.5 h. The
4
reaction was quenched with sat. NH Cl aq. The layers were separated and the aqueous layer was extracted three times with
2 4
AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton plug and concentrated under reduced
2
pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/3) to afford methyl
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2
3
ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ4ꢀyl)ꢀ2ꢀoxoacetate as a yellow viscous liquid (269 mg, 39% yield). H NMR (400 MHz, CDCl ) δ: 3.88
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
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13
(
3
s, 3H), 4.00 (s, 3H), 7.28ꢀ7.32 (m, 3H), 7.65 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 33.0,
ꢀ1
5
2.5, 102.3, 116.5, 120.4, 123.6, 126.1, 127.2, 132.8, 137.4, 165.2, 187.3; IR (neat) ν: 1739, 1666, 1231, 762 cm ; HRMS
+
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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6
7
8
9
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3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(ESI) m/z calcd for C12
H
11NNaO
3
[M+Na] 240.0637, found 240.0631.
To a suspension of methyltriphenylphosphonium bromide (643 mg, 1.8 mmol) in THF (4 mL) was added tꢀBuOK (202 mg, 1.8
mmol) at 0 °C. The mixture was stirred for 0.5 h and added to a solution of methyl 2ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ4ꢀyl)ꢀ2ꢀoxoacetate
(
269 mg, 1.2 mmol) in THF (2.0 mL). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. The
4
reaction was quenched with sat. NH Cl aq. The layers were separated and the aqueous layer was extracted three times with
2 4
AcOEt. The combined organic layers were dried over Na SO , filtrated through a cotton plug and concentrated under reduced
2
pressure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/5) to afford 27 as a pale yellow
1
liquid (148 mg, 56% yield). H NMR (400 MHz, CDCl
3
) δ: 3.78 (s, 6H), 5.97 (s, 1H), 6.37 (d, J = 3.2 Hz, 1H), 6.53 (s, 1H),
13
7
.05 (d, J = 3.7 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 7.22 (dd, J = 7.3, 7.3 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H); C NMR (100 MHz,
CDCl ) δ: 32.9, 52.1, 100.0, 109.3, 119.9, 121.3, 127.1, 127.7, 129.0, 129.5, 136.7, 140.6, 167.8; IR (neat) ν: 1723, 1618, 1435,
3
ꢀ1
+
1
2
223, 753 cm ; HRMS (ESI) m/z calcd for C13H13NNaO [M+Na] 238.0844, found 238.0845.
Methyl
2-methyl-9-phenyl-6,7-dihydro-2H-cyclohepta[cd]indole-6-carboxylate
(28)
and
methyl
6
,12-dimethyl-6-phenyl-4,5,6,12-tetrahydrobenzo[2,3]azuleno[4,5,6-cd]indole-4-carboxylate (29); The reaction was carried
2
out following the general procedure. The residue was purified by flash column chromatography (SiO , AcOEt/Hexane = 1/10)
to afford 28 as a colorless foam (55 mg, 84% yield) and 29 as a colorless solid (7.0 mg, 9% yield, dr = 6/1). Crystals of 29
9
suitable for Xꢀray crystallographic analysis were obtained by slow diffusion of hexane into a toluene solution of the product.
1
28; Mp: 173ꢀ175 ºC. H NMR (400 MHz, CDCl
3
) δ: 2.76 (ddd, J = 1.4, 5.0, 14.7 Hz, 1H), 3.16 (ddd, J = 6.9, 7.8, 14.7 Hz, 1H),
3.62 (s, 3H), 3.73 (s, 3H), 4.28 (dd, J = 1.8, 6.4 Hz, 1H), 5.72 (dd, J = 5.0, 7.8 Hz, 1H), 6.77 (s, 1H), 6.93 (d, J = 6.9 Hz, 1H),
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13
7
1
7
.21ꢀ7.28 (m, 3H), 7.31ꢀ7.37 (m, 3H), 7.42ꢀ7.44 (m, 2H); C NMR (100 MHz, CDCl
3
) δ: 31.4, 32.9, 50.3, 52.0, 108.5, 116.5,
20.0, 121.7, 121.9, 125.3, 127.0, 127.9, 128.9, 129.1, 133.5, 137.5, 139.2, 143.4, 173.6; IR (neat) ν: 1737, 1610, 1460, 1193,
ꢀ1
+
1
2
50, 703 cm ; HRMS (ESI) m/z calcd for C21H20NO [M+H] 318.1494, found 318.1494. 29; Mp: 186 ºC (decomp.). H NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
(400 MHz, CDCl ) δ: 1.70 (s, 3H), 2.72 (dd, J = 2.3, 16.0 Hz, 1H), 3.02 (dd, J = 6.4, 16.0 Hz, 1H), 3.54 (s, 3H), 3.89 (s, 3H),
4
.20 (dd, J = 2.3, 6.0 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 7.10ꢀ7.21 (m, 8H), 7.31 (d, J = 7.8 Hz, 1H), 7.33 (ddd, J = 1.4, 7.3, 7.3
1
3
Hz, 1H), 7.78 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ: 20.7, 30.4, 33.1, 49.6, 51.8, 58.0, 108.6, 111.3,
3
1
20.2, 120.4, 122.0, 122.8, 125.1, 125.7, 125.9, 126.3, 126.4, 128.3, 131.6, 132.8, 137.1, 142.5, 142.7, 146.6, 154.8, 173.4; IR
ꢀ1
+
(
2
neat) ν: 1749, 1618, 1458, 1164, 750, 700 cm ; HRMS (ESI) m/z calcd for C29H26NO [M+H] 420.1964, found 420.1963.
Associated Content
Supporting Information
The Supporting Information is available free of charge on the website. NMR spectra for obtained compounds. ORTEP figures of
compounds 16d, 18da, and 29.
Acknowledgments
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers 17J03524 (TT),
1
6K08154 (SH), and 17H03969 (AN)], and the Tokyo Biochemical Research Foundation [Grant Number 16ꢀB1ꢀ5 (SH)]. We
acknowledge the Institute for Global Prominent Research, Chiba University, for providing financial support.
References
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Inhibitor of the Coupled Enzyme Assay Carboxypeptidase U/Hippuricase from the Leaves of Alstonia actinophylla
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K.ꢀW.; Li, J.; Guo, X.ꢀY.; Zhao, M.ꢀB.; Tu, P.ꢀF.; Jiang, Y. Exotines A and B, Two Heterodimers of IsopentenylꢀSubstituted
Indole and Coumarin Derivatives from Murraya exotica. Org. Lett. 2015, 17, 4380ꢀ4383. (d) Yamuna, E.; Kumar, R. A.; Zeller,
M.; Prasad, K. J. R. Synthesis, antimicrobial, antimycobacterial and structureeactivity relationship of substituted pyrazoloꢀ,
isoxazoloꢀ, pyrimidoꢀ and mercaptopyrimidocyclohepta[b]indoles. Eur. J. Med. Chem. 2012, 47, 228ꢀ238. (e) Barf, T.;
Lehmann, F.; Hammer, K.; Haile, S.; Axen, E.; Medina, C.; Uppenberg, J.; Svensson, S.; Rondahl, L.; Lundbäck, T.
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DiStefano, P. S.; Curtis, R. Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1. J. Med. Chem.
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005, 48, 8045ꢀ8054.
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Motif in Natural Products and Drug Design. Acc. Chem. Res. 2016, 49, 2390ꢀ2402.
(3) For recent examples, see: (a) Li, Y.; Zhu, C.ꢀZ.; Zhang, Z. GoldꢀCatalyzed [4+3] Cycloaddition/C–H Functionalization
Cascade: Regioꢀ and Diastereoselective Route to Cyclohepta[b]indoles. Eur. J. Org. Chem. 2017, 6609ꢀ6613. (b) Mishra, U. K.;
Yadav, S.; Ramasastry, S. S. V. OneꢀPot Multicatalytic Approaches for the Synthesis of Cyclohepta[b]indoles, Indolotropones,
and Tetrahydrocarbazoles. J. Org. Chem. 2017, 82, 6729ꢀ6737. (c) Challa, C.; Varughese, S.; Suresh, C. H.; Lankalapalli, R. S.
MetalꢀFree Multiple CarbonꢀCarbon and CarbonꢀHydrogen Bond Activations via ChargeꢀSwitching Mechanism in Unstrained
Diindolylmethanes. Org. Lett. 2017, 19, 4219ꢀ4222. (d) Kroc, M. A.; Prajapati, A.; Wink, D. J.; Anderson, L. L. Cascade
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