Formal synthesis of (±) —quebrachamine through regio- and stereoselective hydrocyanation of arylallene

Article abstract of DOI:10.1016/j.tet.2018.04.044

This article describes the formal synthesis of quebrachamine based on regio- and stereoselective hydrocyanation of 1,3-disubstituted allenes. Allenyl C–C double bonds are effectively discriminated through Ni-catalyzed hydrocyanation and a CN group is utilized as a synthon of piperidine ring. Several steps from HCN adduct afforded known intermediates to quebrachamine.

Full text of DOI:10.1016/j.tet.2018.04.044

Accepted Manuscript
Formal synthesis of (±) —quebrachamine through regio- and stereoselective
hydrocyanation of arylallene
Koki Matsumoto, Shigeru Arai, Atsushi Nishida
PII:
S0040-4020(18)30433-2
10.1016/j.tet.2018.04.044
TET 29459
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 March 2018
Revised Date: 13 April 2018
Accepted Date: 16 April 2018
Please cite this article as: Matsumoto K, Arai S, Nishida A, Formal synthesis of (±) —quebrachamine
through regio- and stereoselective hydrocyanation of arylallene, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.04.044.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Formal synthesis of (±) —quebrachamine through regio- and stereoselective
hydrocyanation of arylallene
Koki Matsumotoa, Shigeru Arai a,b, and Atsushi Nishidaa,b
aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan 260-8675
bMolecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba, Japan 263-8522
[Abstract] This article describes the formal synthesis of quebrachamine based on regio- and stereoselective
hydrocyanation of 1,3-disubstituted allenes. Allenyl C-C double bonds are effectively discriminated through
Ni-catalyzed hydrocyanation and a CN group is utilized as a synthon of piperidine ring. Several steps from HCN
adduct afforded known intermediates to quebrachamine.
Keywords: Alkaloid; Allene; Hydrocyanation; Nickel catalysis; Quebrachamine.
1. Introduction
A cyano group is a key element or precursor for the synthesis of nitrogen heterocycles or
biologically important molecules.[1] Therefore, its facile introduction to organic molecules,
particularly to non-activated C-C multiple bonds under metal catalysis, has been major challenge in
synthetic chemistry. One of the most reliable and well-investigated cyanation protocols is Ni-catalyzed
hydrocyanation, which allows to use various C-C multiple bonds such as alkenes,[2-4] alkynes,[5]
conjugated dienes[6] and allenes.[7] Based on these background, we established new protocols of
hydrocyanative transformations such as cyclization,[8] cross coupling reaction,[9] cyclopropane
cleavage[10] and chirality transfer[11] using allenyl substrates. Through these investigation, we
realized that the aromatic substituents in 1,3-disubstituted allenes are key to determine the regio- and
stereoselectivity of the hydrocyanation adducts (Scheme 1).[10a] This reaction selectively installs C-H
and C-CN bonds to give trans-olefin that conjugates aromatic rings, and these observation prompted
us to realize their synthetic utility. In this article, we report a formal synthesis of biologically
important molecule using above regio- and stereoselective hydrocyanation of allenes as a key step.
1

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Scheme 1. Ni-catalyzed hydrocyanation of arylallenes
Quebrachamine (1) has been isolated from Aspidosperma quebracho tree bark over a centry
ago.[12] Its intriguing tetracyclic core involving indole and nine-membered heterocycle as well as
biological activity such as α-adrenergic blocking behavior in urogenital tissue[13] have been attractive
features as a synthetic target and more than 60 synthetic examples[14] have been reported to date
since the Stork’s first total synthesis in 1963.[15]
2. Results and discussion
Retrosynthetic analysis of 1 is outlined in Scheme 2. A cyano group would be a key synthon for
construction of piperidine ring in known intermediates (2a-c).[16] Their precursor (3) is a carbonitrile
involving a quaternary carbon, which could be constructed by α-alkylation of 4 and regioselective
hydrocyanation of allenylindole (5) would give 4 as a single isomer. Finally, a known formylindole
derivative (6) is set as a starting material.
Scheme 2. Retrosynthetic analysis of 1
2

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Initially, 6 was subjected to alkynylation using Li trimethylsilyl acetylide to give the corresponding
alcohol (7). After removal of a TMS group to 8, sequential acylation using ClCO2Me gave 9 in 97% (2
steps). This 3-step reaction can be modified to increase practicality, step-economy and operational
simplicity. The one-pot procedure is as follows; the first step is the addition of Li-acetylide to 6, the
second step is acylation of resulting alkoxide intermediate with ClCO2Me and the third step is the
removal of a TMS group using TBAF to give 8 in 92% yield (3 steps). Next Cu-mediated alkylation
using EtMgBr with LiBr gave the allenylindole (5a) in 92% yield (Scheme 3).
The substrate in hand, we next investigated Ni-catalyzed hydrocyanation of 5a. As described in
Table 1, this reaction was completed within 30 min under thermal conditions and sensitive in the
external phosphorous ligand, for example, PAr3 or MePPh2 gave 4 in the range of 25-34% yield
(entries 1-3) and PCy3 resulted in slower reaction (entry 4). On the other hand, 2-PyPPh2 improved the
yield of 4 to 53% (entry 5). A bidentate phosphine such as dppb (20 mol%) did not work well to
improve the yield of 4 (entry 6). This reaction did not give any isolable regio- and stereoisomers of 4
however its yield was difficult to increase even after ligand optimization. One of the reason would be
the higher reactivity of 4 with Ni(0) species to cause decomposition or polymerization triggered by
metalacycle formation.
This hydrocyanation reaction was quite sensitive for the steric environment around allenyl double
bonds. When tri-substituted allene such as 5b was subjected to similar conditions, the reaction efficacy
dramatically decreased to give any desired product with recovery of 5b in 18% yield even after 11 h.
3-Substituted indole 5c was also inert to give the trace amount of the desired HCN adduct,
unfortunately.[17]
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Scheme 3. Synthetic transformation to 4
Entry
Ligand
Time
(min)
Yield of 4 (%)
1
2
3
4
5
6
PPh3
30
30
20
60
20
31
25
34
34
53
20
P(4-MeOPh)3
MePPh2
PCy3
2-PyPPh2
Ph2P(CH2)4PPh2* 20
*20 mol% was used.
Table 1. Ni-catalyzed hydrocyanation of 5a
Next task is piperidine formation utilizing a CN group in 4 as an aminomethyl group. Initially,
hydrogenation of 4 was employed to give 10 in 90% yield, and then the α-alkylation to construct the
quaternary carbon successfully proceeded to give 3 in 78% yield. This 2-step protocol was found to be
reasonable because the alkylation of 4 with LHMDS gave a complex mixture with lower conversion of
the desired alkylated product. Sequential reduction of 3 to the corresponding primary amine (11)
followed by nosylation gave 12 in 78% (2 steps). After removal of a TBS group with TBAF,
Mitsunobu cyclization of 13 gave the piperidine (14) in 98% yield (2 steps). Sulfonyl functionalities in
14 were then removed under basic media to give 2a as a known intermediate for (±)-quebrachamine,
however its NMR spectra did not show good agreement to the reported value.[16a] So piperidine 2a
4

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was next transformed to 2b and its structure was fully characterlized to be Pagenkopf’s
intermediate.[16a] The removal of a Ns group in 14 gave 15, which was converted to 16 by reductive
amination. Final deprotection of a Bs group gave Kerr’s intermediate (2c), which was identified by
NMR spectra.[16b] The syntheses of above two known intermediates (2b,c) indicates the completion
of the formal synthesis of (±)-quebrachamine (1).
Scheme 4. Synthesis of 2
3. Conclusion
In summary, our protocol of hydrocyanation using arylallenes is key technology to control the
regio- and stereoselectivity in the products, which could be applied to formal synthesis of
(±)-quebrachamine (1). These results prove the synthetic utility of Ni-catalyzed regio- and
stereoselective hydrocyanation and the further investigation is currently undergoing.
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4. Experimental
4.1 General
All reactions were performed with dry solvents under argon atmosphere and the reagents were
purified by the standard methods. Reactions were monitored by thin-layer chromatography carried out
on 0.25 mm Merck silica gel plates (60F-254). Column chromatography was performed with silica gel
(Fuji Silysia, PSQ-60B) or NH-silica (Fuji Silysia, DM2035). NMR spectra were recorded on
spectrometers of JEOL JMN-ECS-400, ECP-400, ECZ-400, ECZ-600, and ECA-600 operating at 400
1
or 600 MHz for H NMR and 100 or 150 MHz for 13C NMR with calibration using residual
undeuterated solvent as an internal reference. IR spetra were recorded on JASCO FT/IR-4700. High
resolution mass spectra were measured by The AccuTOFLC-plus JMS-T100LP (Ionization method:
ESI).
4.2.1. Methyl (1-(1-(phenylsulfonyl)-1H-indol-2-yl)prop-2-yn-1-yl) carbonate (9)
To a solution of trimethylsilyl acetylene (521.2 mg, 5.31 mmol, 1.2 equiv.) in THF (78.4 mL), n-butyl
lithium (1.55 M in n-hexane, 3.7 mL, 5.75 mmol, 1.3 equiv.) was added dropwise at –78 °C. A
solution of 6 (1.26 g, 4.42 mmol) in THF (10 mL) was then added slowly and the reaction mixture was
stirred at –78 °C for 1 h and 0 °C for 1 h. After cooling at –78 °C, methyl chloroformate (0.68 mL,
8.84 mmol, 2.0 equiv.) was added slowly to above reaction mixture. Then the resulting mixture was
stirred at –78 °C for 1 h and 0 °C for 1 h respectively. Finally, tetrabutylammonium fluoride (1.0 M in
THF, 8.84 mL, 8.84 mmol, 2.0 equiv.) was added at –78 °C and the reaction mixture was allowed to
be warmed to room temperature gradually with stirring for 1 h. The reaction was quenched by the
addition of sat. NH4Cl (80 mL) at 0 °C and the resulting mixture was stirred for 12 h. The separated
aqueous layer was extracted with AcOEt (40 mL × 3). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by flash column
chromatography (n-hexane:AcOEt = 8:1) to give 9 (1.50 g, 4.07 mmol) in 92% yield as a colorless
solid. 1H NMR (CDCl3, 400 MHz) δ: 2.76 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 6.99 (d, J = 2.4 Hz, 1H),
7.22 (s, 1H), 7.25 (dd, J = 7.2 Hz, 1H), 7.35 (dd, J = 7.2, 7.2 Hz, 1H), 7.43 (dd, J = 7.6, 8.0 Hz, 2H),
7.52-7.55 (m, 2H), 7.88 (d, J = 7.6 Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
6

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55.3, 62.6, 75.9, 78.2, 114.5, 114.6, 121.7, 123.9, 125.9, 126.7, 128.1, 129.1, 133.9, 134.2, 137.3,
138.1, 154.3; IR (ATR) ν: 3297, 2955, 2124, 1749, 1446, 1375, 1255, 1174, 639 cm-1; HRMS (ESI)
m/z: calcd for C19H15NNaO5S [M+Na]+ 392.0569, found 392.0573; mp: 102-103 °C.
4.2.2. 2-(Penta-1,2-dien-1-yl)-1-(phenylsulfonyl)-1H-indole (5a)
To a solution of flame dried LiBr (1.18 g, 13.6 mmol, 6.0 equiv.) and CuI (1.29 g, 6.80 mmol, 3.0
equiv.) in THF (34 mL), EtMgBr (3.0 M in Et2O, 2.27 mL, 6.80 mmol, 3.0 equiv.) was added at 0 °C.
After being stirred for 30 min, the solution of 9 (836.8 mg, 2.27 mmol) in THF (14 mL) was added to
the reaction mixture at 0 °C. After being stirred at the same temperature for 30 min, the reaction was
quenched by the addition of sat. NH4Cl (50 mL). The aqueous layer was extracted with Et2O (30 mL ×
3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude residue was purified by flash column chromatography (n-hexane:Et2O = 20:1) to
give 5a (677.2 mg, 2.09 mmol) in 92% yield as a pale yellow oil. Note: 5a should be used immediately
1
without storage because of its unstability. H NMR (CDCl3, 400 MHz) δ: 1.06 (t, J = 7.6 Hz, 3H),
2.13 (ddq, J = 3.2, 6.4, 7.6 Hz, 2H), 5.62 (dt, J = 6.4, 6.4 Hz, 1H), 6.60 (s, 1H), 7.01 (dt, J = 6.4, 3.2
Hz, 1H), 7.19 (dd, J = 7.6, 8.0 Hz, 1H), 7.25 (dd, J = 7.6, 8.0 Hz, 1H), 7.34-7.39 (m, 3H), 7.47 (t, J =
7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 13.2,
21.6, 86.4, 95.9, 109.2, 115.0, 120.3, 123.9, 124.1, 126.5, 129.0, 130.1, 133.6, 135.6, 137.3, 138.4,
206.3; IR (ATR) ν: 2965, 1945, 1446, 1368, 1171 cm-1; HRMS (ESI) m/z: calcd for C38H34N2NaO4S2
[2M+Na]+ 669.1858, found 669.1866.
4.2.3. (E)-2-Ethyl-4-(1-(phenylsulfonyl)-1H-indol-2-yl)but-3-enenitrile (4)
A suspension of Ni[P(OPh)3]4 (25.9 mg, 0.020 mmol, 10 mol%) and 2-PyPPh2 (21.1 mg, 0.080 mmol,
40 mol%) in toluene (0.20 mL) was heated at 100 °C for 10 min, and the mixture became a dark
brown clear solution. After cooling to room temperature, the solution of 5a (64.3 mg, 0.20 mmol) and
acetonecyanohydrin (0.091 mL, 1.0 mmol, 5.0 equiv.) in toluene (0.30 mL) was added, and the
reaction mixture was heated at 100 °C for 20 min. After cooling to room temperature, the reaction
mixture was charged on silica gel column and eluted with solvent (n-hexane:AcOEt = 8:1) to give 4
(36.7 mg, 0.11 mmol) in 53% yield as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ: 1.15 (t, J = 7.6
Hz, 3H), 1.86 (dq, J = 7.6, 7.6 Hz, 2H), 3.43 (dt, J = 7.2, 7.6 Hz, 1H), 5.98 (dd, J = 7.2, 15.6 Hz, 1H),
6.71 (s, 1H), 7.24 (dd, J = 7.6, 8.0 Hz, 1H), 7.31-7.41 (m, 4H), 7.45 (d, J = 8.0 Hz, 1H), 7.51 (t, J =
7

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7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 8.21 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.3,
26.5, 35.8, 109.6, 115.0, 119.6, 120.9, 124.1, 124.5, 125.2, 126.5, 127.1, 129.1, 129.5, 133.9, 137.2,
137.3, 138.2; IR (ATR) ν: 2970, 2246, 1447, 1362, 965 cm-1; HRMS (ESI) m/z: calcd for
C20H18N2NaO2S [M+Na]+ 373.0987, found 373.0986; mp: 112-113 °C.
4.2.4. 2-Ethyl-4-(1-(phenylsulfonyl)-1H-indol-2-yl)butanenitrile (10)
To a solution of 4 (101.7 mg, 0.29 mmol) in MeOH/AcOEt (2:1, 7.3 mL), Pd/C (10% Pd, 30.5 mg,
30%w/w) was added. The suspension was degassed, charged with H2 gas and stirred vigorously for 3 h
at 60 °C. The reaction mixture was cooled to room temperature, filtered through a Celite® pad eluting
with AcOEt, combined eluents were concentrated in vacuo. The crude residue was purified by flash
column chromatography (n-hexane:AcOEt = 9:1) to give 10 (91.8 mg, 0.26 mmol) in 90% yield as a
colorless solid. 1H NMR (CDCl3, 400 MHz) δ: 1.10 (t, J = 7.6 Hz, 3H), 1.68 (dq, J = 7.2, 7.6 Hz, 2H),
1.98-2.07 (m, 1H), 2.09-2.17 (m, 1H), 2.50-2.57 (m, 1H), 3.08-3.16 (m, 1H), 3.26-3.33 (m, 1H), 6.48 (s,
1H), 7.23 (dd, J = 7.2, 7.2 Hz, 1H), 7.29 (dd, J = 7.2, 8.0 Hz, 1H), 7.39-7.44 (m, 3H), 7.51 (t, J = 7.2 Hz,
13
1H), 7.72 (d, J = 7.2 Hz, 2H), 8.17 (d, J = 8.0 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: 11.6, 25.5, 27.1,
31.7, 32.7, 110.5, 114.9, 120.4, 121.8, 123.9, 124.4, 126.2, 129.3, 129.5, 133.8, 137.3, 138.5, 139.6; IR
(ATR) ν: 2968, 2236, 1447, 1364, 728 cm-1; HRMS (ESI) m/z: calcd for C20H20N2NaO2S [M+Na]+
375.1143, found 375.1141; mp: 113-114 °C.
4.2.5.
5-((tert-Butyldimethylsilyl)oxy)-2-ethyl-2-(2-(1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pentanenitrile (3)
To a solution of 10 (194.7 mg, 0.55 mmol) and TBSO(CH2)3I (198.9 mg, 0.66 mmol, 1.2 equiv.) in
THF (2.8 mL), LHMDS (1.0 M in THF, 1.4 mL, 1.4 mmol, 2.5 equiv.) was added dropwise at –78 °C
and the reaction mixture was allowed to be warmed to room temperature gradually. After being stirred
for 12 h, the reaction mixture was added sat. NH4Cl (3 mL) at 0 °C. The aqueous layer was extracted
with AcOEt (3 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude residue was purified by flash column chromatography
1
(n-hexane:AcOEt = 100:0 to 10:1) to give 3 (225.5 mg, 0.43 mmol) in 78% yield as a yellow oil. H
NMR (CDCl3, 400 MHz) δ: 0.06 (s, 6H), 0.90 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H), 1.61-1.76 (m, 6H),
2.00-2.05 (m, 2H), 3.12-3.17 (m, 2H), 3.67 (t, J = 5.6 Hz, 2H), 6.45 (s, 1H), 7.21 (dd, J = 7.6, 7.6 Hz,
1H), 7.20-7.31 (m, 2H), 7.38-7.42 (m, 3H), 7.52 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 8.17 (d,
8

ACCEPTED MANUSCRIPT
13
J = 8.4 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: –5.3, 8.6, 18.3, 24.8, 25.9, 27.5, 28.9, 31.9, 35.8,
40.9, 62.6, 109.8, 114.9, 120.3, 123.5, 123.8, 124.3, 126.2, 129.3, 129.6, 133.8, 137.2, 138.6, 140.5;
IR (ATR) ν: 2929, 2229, 1448, 1247, 1175, 1091, 775, 727 cm-1; HRMS (ESI) m/z: calcd for
C29H40N2NaO3SSi [M+Na]+ 547.2427, found 547.2435.
4.2.6.
N-(5-((tert-Butyldimethylsilyl)oxy)-2-ethyl-2-(2-(1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pentyl)-2-nitr
obenzenesulfonamide (12)
To a stirred solution of 3 (43.9 mg, 0.084 mmol) and CoCl2·6H2O (86.9 mg, 8.0 equiv.) in MeOH (2.8
mL), NaBH4 (25.3 mg, 8.0 equiv.) was added portionwise at –20 °C. After being stirred at the same
temperature for 1 h, the reaction mixture was added same amount of CoCl2·6H2O and NaBH4 at –20
°C, and was stirred for additional 1 h. Then the reaction was quenched by the addition of sat. NH4Cl (5
mL) at 0 °C. The aqueous layer was extracted with AcOEt (5 mL × 3). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in vacuo. To a solution of the above
residue in DCM (0.84 mL) were added Et3N (13 µL, 0.092 mmol, 1.1 equiv.) and
2-nitrobenzenesulfonyl chloride (20.5 mg, 0.092 mmol, 1.1 equiv.) at 0 °C. The reaction was
quenched by the addition of sat. NH4Cl (3 mL) at room temperature after 16 h. The aqueous layer was
extracted with DCM (3 mL × 3). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The resulting residue was purified by flash column
chromatography (n-hexane:AcOEt = 8:1) to give 12 (46.2 mg, 0.065 mmol) in 77% yield for 2 steps
from 3 as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ: 0.05 (s, 6H), 0.81 (t, J = 7.2 Hz, 3H), 0.89
(s, 9H), 1.30-1.46 (m, 6H), 1.65-1.69 (m, 2H), 2.86-2.91 (m, 2H), 2.97 (d, J = 6.4 Hz, 2H), 3.59 (t, J =
6.0 Hz, 2H), 5.42 (t, J = 6.4 Hz, 1H), 6.38 (s, 1H), 7.19-7.27 (m, 2H), 7.37-7.41 (m, 3H), 7.50 (dd, J =
7.6, 7.6 Hz, 1H), 7.61-7.67 (m, 1H), 7.69-7.72 (m, 3H), 7.77 (dd, J = 1.2, 7.6 Hz, 1H), 8.11-8.14 (m,
13
2H); C NMR (CDCl3, 100 MHz) δ: –5.3, 7.1, 18.3, 22.9, 25.9, 26.1, 26.5, 29.7, 33.8, 38.6, 48.0,
63.3, 109.1, 114.7, 120.2, 123.7, 124.0, 125.2, 126.1, 129.2, 129.8, 131.1, 132.7, 133.2, 133.5, 133.7,
137.1, 138.7, 141.9, 148.0; IR (ATR) ν: 3338, 2929, 1541, 1448, 1362, 1242, 1172, 1092, 728 cm-1;
HRMS (ESI) m/z: calcd for C35H47N3NaO7S2Si [M+Na]+ 736.2522, found 736.2526.
4.2.7. 2-(2-(3-Ethyl-1-((2-nitrophenyl)sulfonyl)piperidin-3-yl)ethyl)-1-(phenylsulfonyl)-1H-indole (14)
9

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To a solution of 12 (117.2 mg, 0.16 mmol) in THF (1.6 mL), tetrabutylammonium fluoride (1.0 M in
THF, 0.33 mL, 0.33 mmol, 2.0 equiv.) was added at 0 °C. After being stirred at room temperature for
12 h, the reaction was quenched by the addition of sat. NH4Cl (3 mL) at 0 °C. The aqueous layer was
extracted with AcOEt (3 mL × 3). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was used in the next reaction without further
purification. To a solution of the above residue and PPh3 (86.3 mg, 0.33 mmol, 2.0 equiv.) in toluene
(13.4 mL), di-2-methoxyethyl azodicarboxylate (76.9 mg, 0.33 mmol, 2.0 equiv.) in toluene (3.0 mL)
was added at room temperature under Ar atmosphere. After being stirred for 30 min, the reaction
mixture was added H2O (15 mL) and the aqueous layer was extracted with toluene (10 mL × 3). The
combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (n-hexane:AcOEt = 3:1) to give 14 (93.9 mg,
0.16 mmol) in 98% yield for 2 steps from 12 as a colorless foam. 1H NMR (CDCl3, 600 MHz) δ: 0.85
(t, J = 7.2 Hz, 3H), 1.39-1.45 (m, 2H), 1.46-1.53 (m, 2H), 1.68-1.80 (m, 4H), 2.83-2.93 (m, 2H), 2.98
(d, J = 12.6 Hz, 1H), 3.15-3.19 (m, 2H), 3.32-3.36 (m, 1H), 6.39 (s, 1H), 7.20 (dd, J = 7.2, 7.2 Hz,
1H), 7.26 (dd, J = 7.2, 7.2 Hz, 1H), 7.38-7.41 (m, 3H), 7.49-7.52 (m, 2H), 7.59 (dd, J = 7.2, 7.2 Hz,
1H), 7.64 (dd, J = 7.2, 7.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.4
13
Hz, 1H); C NMR (CDCl3, 150 MHz) δ: 7.1, 21.1, 22.7, 27.2, 30.0, 33.0, 35.8, 46.8, 54.3, 109.0,
114.7, 120.2, 123.6, 124.0, 126.2, 129.2, 129.8, 130.8, 131.4, 131.7, 133.3, 133.6, 137.2, 138.9, 142.2,
148.4; IR (ATR) ν: 2932, 1546, 1449, 1371, 1175, 755 cm-1; HRMS (ESI) m/z: calcd for
C29H31N3NaO6S2 [M+Na]+ 604.1552, found 604.1545.
4.2.8. 2-(2-(3-Ethylpiperidin-3-yl)ethyl)-1H-indole (2a)
A solution of 14 (24.1 mg, 0.041 mmol) and KOH (46.5 mg, 0.83 mmol) in MeOH (0.41 mL) was
heated under reflux conditions for 12 h. Then the reaction mixture was cooled to room temperature
and added H2O (2 mL). The reaction mixture was extracted with AcOEt (2 mL × 3). The combined
organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (NH silica; AcOEt:MeOH = 20:1) to give 2a (7.5 mg,
1
0.029 mmol) in 71% yield as a yellow oil. H NMR (CDCl3, 600 MHz) δ: 0.86 (t, J = 7.8 Hz, 3H),
1.28-1.37 (m, 2H), 1.40-1.45 (m, 1H), 1.46-1.56 (m, 2H), 1.59-1.68 (m, 2H), 1.95 (ddd, J = 6.0, 14.4,
14.4 Hz, 1H), 2.51 (d, J = 12.0 Hz, 1H), 2.61-2.75 (m, 6H), 2.91-2.93 (m, 1H), 6.23 (s, 1H), 7.05 (dd,
10

ACCEPTED MANUSCRIPT
J = 7.2, 7.2 Hz, 1H), 7.09 (dd, J = 7.2, 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H),
8.93 (brs, 1H); 13C NMR (CDCl3, 150 MHz) δ: 7.2, 21.8, 22.1, 28.1, 33.1, 34.1, 34.7, 47.1, 54.9, 99.0,
110.3, 119.4, 119.6, 120.8, 128.8, 135.9, 140.5; IR (ATR) ν: 3245, 2930, 2856, 1458, 1422, 1285, 782,
749 cm-1; HRMS (ESI) m/z: calcd for C17H25N2 [M+H]+ 257.2018, found 257.2015.
4.2.9. 1-(3-(2-(1H-Indol-2-yl)ethyl)-3-ethylpiperidin-1-yl)-2-chloroethan-1-one (2b)
To a stirred solution of 2a (5.3 mg, 0.021 mmol) in DCM (0.20 mL), iPr2NEt (9.0 µL, 0.052 mmol,
2.5 equiv.) and chloroacetyl chloride (2.0 µL, 0.025 mmol, 1.2 equiv.) were added at 0 °C. After being
stirred at room temperature for 30 min, the reaction was quenched by the addition of sat. NH4Cl (2
mL) at 0 °C. The aqueous layer was extracted with DCM (2 mL × 3). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexane:AcOEt = 1:1) to give 2b (4.8 mg, 0.014 mmol) in 70% yield
1
as a pale yellow oil. H NMR (CDCl3, 600 MHz) δ: 0.93 (t, J = 7.2 Hz, 3H), 1.38-1.53 (m, 3H),
1.61-1.69 (m, 5H), 2.65-2.70 (m, 2H), 2.78 (dt, J = 2.4, 12.0 Hz, 1H), 3.17-3.22 (m, 1H), 3.71 (d, J =
13.8 Hz, 1H), 4.14 (d, J = 12.0 Hz, 1H), 4.19 (d, J = 12.0 Hz, 1H), 4.25 (d, J = 12.6 Hz, 1H), 6.19 (s,
1H), 7.03 (dd, J = 7.2, 7.8 Hz, 1H), 7.09 (dd, J = 7.2, 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.50 (d, J
= 7.8 Hz, 1H), 8.70 (brs, 1H); 13C NMR (CDCl3, 150 MHz) δ: 7.1, 22.0, 22.6, 28.5, 32.9, 34.6, 37.1,
41.2, 47.8, 50.3, 98.9, 110.6, 119.2, 119.5, 120.7, 128.6, 136.2, 140.4, 166.0; IR (ATR) ν: 2931,
1635, 1456, 1252, 747 cm-1; HRMS (ESI) m/z: calcd for C19H25ClN2NaO [M+Na]+ 355.1553, found
355.1559.
4.2.10. 2-(2-(3-Ethylpiperidin-3-yl)ethyl)-1-(phenylsulfonyl)-1H-indole (15)
A solution of 14 (65.7 mg, 0.11 mmol) in DMF (0.57 mL) with K2CO3 (62.5 mg, 0.45 mmol, 4.0
equiv.) and 4-tert-butylthiophenol (38 µL, 0.23 mmol, 2.0 equiv.) was heated at 40 °C for 12 h. Then
the reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant residue
was purified by flash column chromatography (NH silica, n-hexane/AcOEt = 1/1 to AcOEt:MeOH =
20:1) to give 15 (44.4 mg, 0.11 mmol) in 99% yield as a pale yellow oil. 1H NMR (CDCl3, 400 MHz)
δ: 0.80 (t, J = 7.2 Hz, 3H), 1.36-1.52 (m, 5H), 1.65-1.82 (m, 3H), 2.59 (d, J = 12.4 Hz, 1H), 2.64 (d, J
= 12.4 Hz, 1H), 2.72-2.81 (m, 2H), 2.86 (t, J = 7.6 Hz, 2H), 6.43 (s, 1H), 7.18-7.27 (m, 2H), 7.36-7.40
(m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ: 7.2, 22.5, 22.8, 27.6, 33.8, 34.1, 34.6, 47.2, 55.3, 108.7, 114.8, 120.1, 123.6, 123.9,
11

ACCEPTED MANUSCRIPT
126.1, 129.2, 129.8, 133.6, 137.3, 139.1, 143.0; IR (ATR) ν: 2929, 1448, 1365, 1174, 748, 727 cm-1;
HRMS (ESI) m/z: calcd for C23H29NaO2S [M+Na]+ 397.1950, found 397.1947.
4.2.11. 2-(2-(1-Benzyl-3-ethylpiperidin-3-yl)ethyl)-1-(phenylsulfonyl)-1H-indole (16)
To a solution of 15 (34.2 mg, 0.086 mmol) in DCM (0.58 mL), benzaldehyde (10.6 µL, 0.103 mmol,
1.2 equiv.) and NaBH(OAc)3 (27.3 mg, 0.129 mmol, 1.5 equiv.) were added. After being stirred at
room temperature for 12 h, the reaction was quenched by the addition of sat. NaHCO3 (2 mL) at 0 °C.
The aqueous layer was extracted with DCM (2 mL × 3). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexane:AcOEt = 7:1) to give 16 (7.8 mg, 0.016 mmol) in 79% yield as a pale
yellow oil. 1H NMR (CDCl3, 400 MHz) δ: 0.74 (t, J = 7.6 Hz, 3H), 1.27-1.52 (m, 4H), 1.57-1.62 (m,
2H), 1.75 (t, J = 8.4 Hz, 2H), 2.13 (br, 2H), 2.35 (br, 2H), 2.72-2.90 (m, 2H), 3.39 (d, J = 13.2 Hz,
1H), 3.46 (d, J = 13.2 Hz, 1H), 6.40 (s, 1H), 7.19-7.37 (m, 9H), 7.41 (d, J = 7.2 Hz, 1H), 7.47 (t, J =
13
7.2 Hz, 1H), 7.68 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: 7.3,
21.9, 22.7, 28.0, 33.7, 34.1, 35.9, 54.7, 62.7, 63.5, 108.4, 114.7, 120.0, 123.5, 123.8, 126.2, 126.7,
128.1, 128.8, 129.1, 129.9, 133.5, 137.3, 139.2, 129.3, 143.2; IR (ATR) ν: 2931, 1448, 1366, 1174,
744, 727 cm-1; H RMS (ESI) m/z: calcd for C30H35N2O2S [M+Na]+ 487.2419, found 487.2418.
4.2.12. 2-(2-(1-Benzyl-3-ethylpiperidin-3-yl)ethyl)-1H-indole (2c)
A solution of 16 (3.3 mg, 0.0068 mmol) and KOH (7.6 mg, 0.136 mmol) in MeOH/THF (3:1, 0.14
mL), was heated under reflux conditions for 12 h. Then the reaction mixture was cooled to room
temperature and added H2O (3 mL). The aqueous layer was extracted with AcOEt (3 mL × 3). The
combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (n-hexane:AcOEt = 10:1) to give 2c (2.0 mg,
1
0.0058 mmol) in 85% yield as an orange oil. H NMR (CDCl3, 600 MHz) δ: 0.80 (t, J =7.8 Hz, 3H),
1.21-1.28 (m, 2H), 1.29-1.34 (m, 1H), 1.36-1.46 (m, 2H), 1.56-1.62 (m, 1H), 1.66-1.72 (m, 2H),
1.87-2.02 (m, 2H), 2.17-2.31 (m, 2H), 2.45-2.51 (m, 1H), 2.52-2.61 (m, 2H), 3.41 (d, J = 12.6 Hz, 1H),
3.46 (d, J = 12.6 Hz, 1H), 6.22 (s, 1H), 7.05 (dd, J = 7.2, 7.2 Hz, 1H), 7.09 (dd, J = 7.2, 7.2 Hz, 1H),
7.23-7.27 (m, 2H), 7.30-7.34 (m, 4H), 7.52 (d, J = 7.2 Hz, 1H), 8.02 (brs, 1H); 13C NMR (CDCl3, 150
MHz) δ: 7.3, 21.92, 21.94, 28.6, 29.7, 33.9, 35.7, 55.0, 62.2, 63.4, 99.0, 110.2, 119.5, 119.6, 120.8,
12

ACCEPTED MANUSCRIPT
126.9, 128.1, 128.8, 128.9, 135.8, 139.1, 140.7; IR (ATR) ν: 3407, 2931, 2856, 1456, 1288, 779, 744,
699 cm-1; HRMS (ESI) m/z: calcd for C24H31N2 [M+H]+ 347.2487, found 347.2481.
Acknowledgements
This research was supported by a JSPS KAKENHI Grant (21590003), The Uehara Memorial
Foundation and The Naito Foundation (to S.A.).
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Supplementary Material
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/
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