Novel 3,4,7-substituted benzofuran derivatives having binding affinity to κ-opioid receptor

Article abstract of DOI:10.1248/cpb.c16-00302

A series of novel 3,4,7-trisubstituted benzofuran derivatives were synthesized, and their binding affinity to κ- (KOR) and μ-opioid receptors (MOR) were evaluated. Several aryl ethers showed moderate binding activities to KOR (IC₅₀=3.9-11 μM) without binding to MOR.

Full text of DOI:10.1248/cpb.c16-00302

996
Chem. Pharm. Bull. 64, 996–1003 (2016)
Vol. 64, No. 7
Special Collection of Papers
This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.
Note
Novel 3,4,7-Substituted Benzofuran Derivatives Having Binding Affinity to
κ-Opioid Receptor
Daisuke Nishiyama, Yuki Sakai, Haruka Sekiguchi, Hiroaki Chiba,† Ryosuke Misu, Shinya Oishi,
Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University; Sakyo-ku, Kyoto 606–8501, Japan.
Received April 1, 2016; accepted April 11, 2016
A series of novel 3,4,7-trisubstituted benzofuran derivatives were synthesized, and their binding affin-
ity to κ- (KOR) and μ-opioid receptors (MOR) were evaluated. Several aryl ethers showed moderate binding
activities to KOR (IC50=3.9–11µM) without binding to MOR.
Key words κ-opioid receptor; opioid; benzofuran; morphine
Morphine (1)1) is the biological component of opium, which Therefore, selective ligands for DOR or KOR that do not in-
is obtained from the immature seedpod of poppy flowers teract with MOR are promising no-dependency therapeutic
(Fig. 1). When administered to patients, morphine causes a agents for pain and pruritus.8,9) One example, the non-peptide
sense of euphoria and is a potent analgesic. The use of mor- selective KOR agonist nalfurafine (4),10) was approved for
phine to relieve pain is strictly controlled because of its high treatment of pruritus in 2009.
dependence-forming potential. Since the discovery of en-
The morphinan skeleton features a highly fused A–E ring
kephalin (6)2,3) and dynorphin (7)4) from mammalian bodies, system, where the B/E rings form a saturated azocine ring
multiple morphine-like endogenous opioids were identified in fused with the benzofuran moiety (A/D rings). Modification of
rapid succession. Opioids exert their functions through one or the C-ring of the morphinan skeleton is important for the sub-
more of three major receptor subtypes, defined as μ- (MOR), type selectivity. For example, naltrindole (NTI) (3)11) and nor-
δ- (DOR), and κ-opioid receptors (KOR).5–7) Portoghese and binaltorphimine (norBNI) (5),12) each relatively large DOR- or
colleagues reported that MOR are primarily involved in form- KOR-selective antagonists, have an indole or pyrrole-fused
ing dependence, while DOR and KOR participate in the action C-ring, whereas the MOR selective ligand naltrexone (2)13) has
of analgesic effects with less risk for forming dependence. a cyclohexanone as the C-ring. Our group is thus involved in
development of a novel synthetic route to morphine deriva-
tives where the C-ring is constructed in a late synthetic stage,
with the intent of identifying novel KOR-selective ligands
(Chart 1). During the course of this research, we found that
several synthetic intermediates before the C-ring formation
showed moderate binding activities to KOR without binding to
MOR. In this contribution, we report the synthesis and KOR
binding affinity of our synthetic intermediates.
Synthesis of the 3,4,7-trisubstituted benzofuran derivatives
16–19 is shown in Chart 2. Benzofuran derivative 11, bearing
a methyl acetate moiety at the C3 position, was obtained by
MOM protection of the hydroxy group of phenol 8, o-lithia-
tion–iodination, O-alkylation with methyl 4-bromocrotonate,
followed by an intramolecular Heck reaction.14) Reduction of
the ester 11 using LiAlH4 and protection with a tert-butyldi-
methylsilyl (TBS) group afforded silyl ether 12. Addition of
a Grignard reagent derived from 12 to 2-tetrahydropyranyl
(THP)-protected (S)-glycidol 13 in the presence of CuI fol-
lowed by a Mitsunobu reaction of the resulting alcohol with
phthalimide gave benzofuran derivative 9. After removal of
Fig. 1. Active Ligands for the μ- (MOR), δ- (DOR), and κ-Opioid Re-
ceptors (KOR)
the THP group, Swern oxidation followed by homologation
using Ohira–Bestmann reagent15,16) afforded alkyne 14. After
removal of phthalimide with 2-aminoethanol, reductive meth-
ylation and deprotection of the TBS group with tetrabutylam-
† Present address: Department of Chemistry, Graduate School of Science,
Tohoku University; 6–3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980–8578,
Japan.
*To whom correspondence should be addressed. e-mail: nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp
© 2016 The Pharmaceutical Society of Japan

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
997
Table 1. Biological Activities of the Benzofuran Derivatives to MOR
and KORa)
Chart 1. A Possible Synthetic Route to Morphine Derivatives
IC50 (µM)
Compound
R1
R2
Ar
H
MOR
KOR
b)
15
Me
Me
C≡CH
C≡CH
—
>30
16a
>30
4.9 2.1
16b
16c
16d
16e
Me
Me
Me
Me
C≡CH
C≡CH
C≡CH
C≡CH
>30
7.7 0.5
3.9 1.5
11 3.1
9.7 2.2
>30
>30
>30
>10
Reagents and conditions: (a) MOMCl, K2CO3, acetone, 70°C; (b) lithium diisopro-
pyl amide (LDA) then I2, THF, −78 to 0°C, (c) p-TsOH·H2O, MeOH, 0°C; (d) methyl
4-bromocrotonate, K2CO3, DMF, 0°C; (e) Pd(OAc)2, HCO2Na, Na2CO3, BnEt3NCl,
DMF, 70°C, 34% in 5 steps; (f) LiAlH4, THF, 0°C; (g) TBSCl, imidazole, DMF,
0°C, 84% in 2 steps; (h) Mg, THF, 65°C; (i) 13, CuI, THF, 0°C; (j) phthalimide
(=HNPhth), PPh3, DEAD, THF, 0°C, 48% in 3 steps (based on epoxide 13); (k)
Me2AlCl, CH2Cl2, –78°C; (l) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0°C; (m)
Ohira–Bestmann reagent, K2CO3, MeOH, 0°C, 54% in 3 steps; (n) 2-aminoethanol,
toluene, 70°C; (o) HCHO aq., NaBH(OAc)3, CH3CN, r.t.; (p) TBAF, THF, r.t., 67% in
3 steps; (q) ArOH, PPh3, bis(2-methoxyethyl) azodicarboxylate (DMEAD), THF, r.t.,
32–63%; (r) iodobenzene, PdCl2(PPh3)2 (2mol%), CuI (2mol%), Et3N, THF, r.t., 13%.
17
Me
Ns
C≡CPh
C≡CH
CH2OH
11 1.5
>30
b)
18
—
19
Me
>30
>30
>30
Chart 2. Synthesis of 3,4,7-Trisubstituted Benzofuran Derivatives
22a
>30
monium fluoride (TBAF) gave alcohol 15. Finally, aryl ether
formation under Mitsunobu conditions with various phenols
gave 16a–f. For comparison with internal alkyne, 16a was
converted to phenylethynyl-substituted derivative 17 using
Sonogashira coupling. Other trisubstituted benzofurans 18 and
19 bearing a nosylamide or amino alcohol moiety (Table 1)
were prepared in a similar manner (see Experimental).
22b
>30
>30
23
>30
>30
a) Binding inhibition assays were performed using membranes from MOR- or
KOR-expressing CHO cells. b) Not evaluated.
Azocine-fused benzofuran derivatives 22a and b were
synthesized as follows (Chart 3): After phthalimide 9 was con-
verted to nosylamide 20, the eight-membered ring fused ben- were evaluated as the inhibitory activities against [3H]-
zofuran 21 was obtained via deprotection of the TBS group diprenorphine binding to MOR and KOR. The tertiary amine
with TBAF, cyclization by intramolecular Mitsunobu reaction, derivatives 16a–e possessing an ethynyl group showed moder-
and removal of the THP group. After construction of a termi- ate affinity to KOR (IC50=3.9–11 µM), whereas all the tested
nal alkyne, deprotection of the Ns group and reductive amina- compounds did not measurably bind to MOR. The alcohol 15
tion with formaldehyde gave alkyne 10. Sonogashira cross- exhibited no KOR binding at 30µM, suggesting that the aryl
coupling reactions using iodobenzene derivatives having a substituent on the hydroxy group is important for KOR bind-
para-substituent (Me or CN) afforded compounds 22a and b. ing. Interestingly, no significant difference in KOR inhibitory
The dimeric compound 23, produced during the Sonogashira activities was observed among the aryl-modified derivatives
coupling reaction, was also used for the biological evaluations 16a–e having a basic pyridinyl group (IC50=4.9µM; 16a),
considering the related dimeric structure of norBNI (5).
electron-donating anisyl group (IC50=7.7 µM; 16b), electron-
The results of the biological evaluations of the benzofuran withdrawing nitrophenyl (IC50=3.9 µM; 16c), cyanophenyl
derivatives are shown in Table 1. The biological activities (IC50=11 µM; 16d) or dihalophenyl groups (IC50=9.7 µM;

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Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
trometer at 500MHz. Chemical shifts are reported in δ (ppm)
relative to Me4Si (in CDCl3) as internal standard. 13C-NMR
spectra were recorded using a JEOL AL-500 and referenced
to the residual solvent signal. Melting points (mp) were mea-
sured by a hot stage melting points apparatus (uncorrected).
For flash chromatography, silica gel (Wakogel C-300E; Wako
Pure Chemical Industries, Ltd., Osaka, Japan) or NH silica gel
(Chromatorex NH-DM1020: Fuji Silysia Chemical Ltd., Japan)
was employed.
Methyl
2-(4-Bromo-7-methoxybenzofuran-3-yl)acetate
(11) This compound was prepared according to the reported
procedure14) with slight modifications: To a solution of the
5-bromo-2-methoxyphenol (8) (42.1g, 201mmol) in acetone
(504mL) were added K2CO3 (83.5g, 604mmol) and MOMCl
(22.7mL, 302mmol) at room temperature (r.t.), and the mixture
was stirred at 70°C for 1.5h. The mixture was concentrated in
vacuo and diluted with Et2O. The organic layer was washed
with water and brine, dried over Na2SO4, and concentrated in
vacuo. The residue (24.5g, ca. 99.0mmol) was dissolved in
THF (178mL), and LDA (1.0M in THF; 69.9mL, 119mmol)
was added to the mixture at –78°C under the argon. After the
Reagents and conditions: (a) 2-aminoethanol, toluene, 70°C; (b) NsCl, diisopro-
pylethylamine (DIPEA), CH2Cl2, r.t., 89% in 2 steps; (c) TBAF, THF, r.t.; (d) PPh3,
DMEAD, THF, r.t.; (e) PPTS, i-PrOH, 80°C, 68% in 3 steps; (f) (COCl)2, DMSO,
Et3N, CH2Cl2, −78 to 0°C; (g) Ohira–Bestmann reagent, K2CO3, MeOH, 0°C; (h)
thiophenol, K2CO3, CH3CN, r.t.; (i) HCHO aq. NaBH(OAc)3, CH3CN, r.t., 55% in 4
steps; (j) Ar-I, PdCl2(PPh3)2 (5mol%), CuI (5mol%), Et3N, THF, r.t. (34% for 22a;
27% for 22b).
Chart 3. Synthesis of Azocine-Fused Benzofuran Derivatives
16e).17) These results suggest that the presence of an aromatic mixture was stirred at the same temperature for 1.5h, iodine
substituent with a suitable size is more important for binding (30.2g, 119mmol) in THF (248mL) was added to the mix-
to KOR than polar interactions including hydrogen bonding. A ture. After the mixture was stirred at 0°C for 1.5h, saturated
phenyl group at the alkyne terminus is tolerated (IC50=11 µM; Na2S2O3 was added to the mixture, and the whole was extract-
17), which shows a possibility for further modification at this ed with Et2O three times. The combined organic layer was
position. On the other hand, KOR binding activity disappeared washed with saturated Na2S2O3, water and brine, dried over
with nosylamide 18 and alcohol 19 having a pyridyl group. MgSO4, and concentrated in vacuo. The residue was dissolved
Disappointingly, azocine-fused benzofurans 22a,b and 23 in MeOH (198mL), and p-toluenesulfonic acid monohydrate
showed no binding to KOR.
(56.5g, 297mmol) was added to mixture at 0°C. After stirring
It should be noted that the alcohol 19 that inhibits neither at the same temperature for 1.5h, the mixture was concen-
KOR nor MOR has the characteristic substructure having a trated in vacuo. The residue was dissolved in Et2O, and the
hydroxy group found in synthetic opioids including 2–5 (Fig. organic layer was washed with saturated NaHCO3 and brine,
1). Furthermore, the saturated azocine ring commonly present dried over MgSO4, and concentrated in vacuo. The residue
in many opioids apparently hinders binding of 22 to KOR. was dissolved in N,N-dimethylformamide (DMF) (330mL),
These results suggest that the binding mode and/or conforma- and K2CO3 (20.6g, 149mmol) was added to the mixture at
tions of the potent derivatives 16 might be different from the 0°C. After the mixture was stirred at the same temperature
well-known opioids.
for 0.5h, methyl 4-bromocrotonate (17.9mL, 149mmol) was
In summary, we have identified novel 3,4,7-trisubstituted added to the mixture. After stirring at the same temperature
benzofuran derivatives that selectively bind to KOR but not for 1.5h, the mixture was poured into water, and the resulting
MOR. Although the potency of these compounds is not suf- solid was filtrated. The solid (22.2g, 52.0mmol) was dissolved
ficient for therapeutic uses, this study demonstrated that struc- in DMF (130mL), and sodium formate (3.54g, 52.0mmol),
turally simplified benzofuran derivatives can be considered sodium carbonate (13.8g, 130mmol), benzyltriethylammonium
as lead compounds for development of therapeutic agents for chloride (13.0g, 57.2mmol) and palladium acetate (584mg,
pain and pruritus with less drug dependence. Further studies 2.60mmol) was added to the mixture at r.t. under argon. After
to improve KOR binding activity, including removal of the stirring at 70°C for 1h, water was added to mixture and the
methyl group on the phenolic hydroxy group and modifica- whole was filtrated through celite and washed with Et2O. The
tions of the alkyne terminus, are in progress in our laboratory. organic layer was washed with water and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (silica gel; hexane–EtOAc=10:1
Experimental
Chemistry Unless otherwise stated, reagents and anhy- to 3:1) to give 11 (9.93g, 34% in 5 steps) as white solid: mp
drous solvents (except for tetrahydrofuran (THF)) were used 145°C; IR (neat) 1725 (C=O); 1H-NMR (500MHz, CDCl3)
as purchased from commercial suppliers without further δ: 3.75 (s, 3H), 3.94 (s, 2H), 3.98 (s, 3H), 6.67 (d, J=8.6Hz,
purification. THF was distilled from sodium benzophenone 1H), 7.26–7.28 (m, 1H), 7.64 (s, 1H); 13C-NMR (125MHz,
ketyl prior to use. Lithium diisopropylamide (LDA) solution DMSO-d6) δ: 29.0, 51.9, 56.1, 103.2, 108.4, 114.2, 127.0, 127.3,
was prepared at the time of use from diisopropylamine and n- 144.5, 145.0, 145.6, 171.1; HR-MS [electrospray ionization
BuLi solution (2.6M in hexane). Glassware was dried at 65°C (ESI)] Calcd for C12H11BrNaO4 (MNa+; 79Br) 320.9733. Found
prior to use. IR spectra were determined on a JASCO FT/ 320.9738.
IR-4100 spectrometer. High resolution-mass spectra (HR-MS)
{2-(4-Bromo-7-methoxybenzofuran-3-yl)ethoxy}(tert-bu-
were recorded on Shimadzu LC-ESI-IT-TOF-MS equipment. tyl)dimethylsilane (12) To a suspension of LiAlH4 (1.90g,
1H-NMR spectra were recorded using a JEOL AL-500 spec- 50.1mmol) in dry THF (251mL) was added a solution of 11

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
999
(10.0g, 33.4mmol) in dry THF (167mL) at 0°C. After the 4.57–4.62 (m, 1H), 4.76–4.79 (m, 1H), 6.54 (t, J=8.6Hz, 1H),
mixture was stirred at the same temperature for 10min, satu- 6.81 (t, J=8.0Hz, 1H), 7.49 (d, J=2.3Hz, 1H), 7.67–7.69 (m,
rated potassium sodium tartrate was added to the mixture at 2H), 7.75–7.79 (m, 2H); 13C-NMR (125MHz, CDCl3) δ: −5.4
the same temperature. After stirring at r.t. for 16h, the whole (2C), 18.2, 19.0, 19.1, 25.26, 25.34, 25.9 (3C), 26.0, 28.48,
was extracted with EtOAc three times, and the combined 28.51, 29.1, 30.3, 30.4, 31.4, 31.5, 52.2, 52.8, 55.9, 61.90, 61.92,
organic layer was washed with water and brine, dried over 62.9, 63.0, 66.4, 66.6, 69.8, 80.9, 98.3, 98.8, 105.6, 106.7,
MgSO4 and concentrated in vacuo. After the residue was dis- 118.0, 123.09, 123.12, 123.2, 123.4, 123.5, 123.6, 123.9, 127.79,
solved in DMF (129mL), imidazole (4.55g, 66.8mmol) and 127.81, 131.7, 131.8, 131.9, 133.8, 134.2, 134.3, 142.6, 142.7,
TBSCl (10.1g, 66.8mmol) were added to the mixture at 0°C. 144.4, 144.88, 144.90, 167.9, 168.4, 168.5; HR-MS (ESI) Calcd
After the mixture was stirred at r.t. for 2h, saturated NH4Cl for C33H43NO7SiNa (MNa+) 616.2701. Found 616.2700.
was added to the mixture, the whole was extracted with Et2O
(R)-2-[1-(3-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-7-
twice, and the combined organic layer was washed with water methoxybenzofuran-4-yl)but-3-yn-2-yl]isoindoline-1,3-di-
and brine, dried over MgSO4 and concentrated in vacuo. The one (14) To a solution of 9 (3.87g, 6.52mmol) in CH2Cl2
residue was purified by column chromatography (silica gel; (53.0mL) was added a solution of dimethyl aluminium chlo-
hexane–EtOAc=10:1) to give 12 (10.8g, 84% in 2 steps) ride (1.09M in hexane; 18.0mL, 19.6mmol) at –78°C under
as a colorless oil: IR (neat) 1247 (ArOMe), 1095 (ArOMe); argon. After stirring at the same temperature for 1h and at
1H-NMR (500MHz, CDCl3) δ: 0.02 (s, 6H), 0.88 (s, 9H), 3.10 0°C for further 1.5h, saturated potassium sodium tartrate was
(t, J=6.6Hz, 2H), 3.93 (t, J=6.6Hz, 2H), 3.98 (s, 3H), 6.65 added to the mixture, and the mixture was stirred at r.t. for
(d, J=8.5Hz, 1H), 7.26–7.29 (m, 1H), 7.51 (s, 1H); 13C-NMR 16h. The whole was extracted with CH2Cl2 twice, the com-
(125MHz, CDCl3) δ: 5.3 (2C), 25.9 (3C), 27.5, 56.3, 56.4, 63.0, bined organic layer was washed with brine, dried over MgSO4
104.5, 106.2, 107.2, 118.3, 126.8, 128.0, 143.7, 145.2; HR-MS and concentrated in vacuo. To a solution of oxalyl chloride
(ESI) Calcd for C17H25BrNaO3 (MNa+; 79Br) 407.0649. Found (1.12mL, 13.0mmol) in CH2Cl2 (7.2mL) was added a DMSO
407.0654.
(1.30mL, 19.6mmol) in CH2Cl2 (14.4mL) at −78°C under
2-{(2R)-1-[3-(2-{(tert-Butyldimethylsilyl)oxy}ethyl)-7- argon. After the mixture was stirred at the same tempera-
methoxybenzofuran-4-yl]-3-[(tetrahydro-2H-pyran-2-yl)- ture for 1h, the above crude alcohol (6.52mmol) in CH2Cl2
oxy]propan-2-yl}isoindoline-1,3-dione
(9) Magnesium (43.6mL) was added to the mixture at the same temperature.
(440mg, 18.1mmol) was heated at 500°C for 2h with vigorous After the mixture was stirred at the same temperature for
stirring under reduced pressure. After cooling at room temper- 1.5h, triethylamine (5.45mL, 39.1mmol) was added to the
ature, THF (5.00mL), iodide (192mg, 0.755mmol) and 1,2-di- mixture. After 0.5h at 0°C under stirring, saturated NH4Cl
bromoethane (65µL, 0.755mmol) were successively added was added to the mixture, and the whole was extracted with
under argon. After heating to 65°C, a solution of bromide 12 CH2Cl2 twice, the combined organic layer was washed with
(5.80g, 15.1mmol) in THF (10.0mL) was added to the mixture water and brine, dried over MgSO4 and concentrated in vacuo.
at the same temperature. After consumption of 12 (monitored The residue was dissolved in MeOH (65.2mL), and K2CO3
by GC-MS analysis), the mixture was cooled to r.t. The con- (1.80g, 13.0mmol) and Ohira–Bestmann reagent (1.27mL,
centration of the Grignard reagent was determined by titration 8.48mmol) were added to the mixture at 0°C. After stirring
with MeOH in the presence of 1,10-phenanthroline as indica- at the same temperature for 3h, the mixture was filtrated,
tor. To a solution of epoxide 13 (2.17g, 13.7mmol) in THF and washed with methanol. The filtrate was concentrated in
(122mL) were added CuI (653mg, 3.43mmol) and the above vacuo and the residue was purified by column chromatogra-
Grignard reagent (1.0M in THF; 15.1mL, 15.1mmol) at 0°C phy (silica gel; hexane–EtOAc=10:1 to 2:1) to give 14 (1.79g,
under argon. After stirring at the same temperature for 2h, the 54% in 3 steps) as a pale yellow oil: [α]D27 +26.2 (c=0.375,
mixture was quenched with saturated NH4Cl and 5% NH4OH, CHCl3); IR (neat) 3274 (C≡CH), 2323 (C≡C), 1716 (C=O);
and the whole was extracted with EtOAc twice. The combined 1H-NMR (500MHz, CDCl3) δ: 0.01 (s, 6H), 0.86 (s, 9H),
organic layer was washed with saturated NH4Cl, water and 2.33 (d, J=2.5Hz, 1H), 3.07–3.16 (m, 2H), 3.56 (dd, J=13.7,
brine, dried over MgSO4 and concentrated in vacuo. The low- 8.0Hz, 1H), 3.78 (dd, J=13.7, 8.0Hz, 1H), 3.93 (s, 3H), 3.96 (t,
polar impurities present in the residue was removed by short J=6.0Hz, 2H), 5.28–5.32 (m, 1H), 6.61 (d, J=8.0Hz, 1H), 6.94
column chromatography (silica gel; hexane–EtOAc=3:1). (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.71–7.74 (m, 2H), 7.81–7.84
After the crude product (5.33g, 11.5mmol) was dissolved in (m, 2H); 13C-NMR (125MHz, CDCl3) δ: −5.4 (2C), 18.2, 25.8
THF (57.5mL), phthalimide (5.08g, 34.5mmol), triphenylphos- (3C), 28.5, 35.5, 42.8, 55.9, 62.9, 72.7, 79.6, 105.6, 117.9, 121.6,
phine (9.05g, 34.5mmol) and diethyl azodicarboxylate (2.2M 123.5 (2C), 124.6 (2C), 128.0, 131.6 (2C), 134.1 (2C), 142.8,
in toluene; 15.7mL, 34.5mmol) were added to the mixture at 144.8, 166.9 (2C); HR-MS (ESI) Calcd for C29H33NO5SiNa
0°C. After stirring at the same temperature for 16h, the mix- (MNa+) 526.2020. Found 526.2021.
ture was filtrated through celite and concentrated in vacuo.
(R)-2-{4-[2-(Dimethylamino)but-3-yn-1-yl]-7-methoxy-
The residue was purified by column chromatography (silica benzofuran-3-yl}ethan-1-ol (15) To a solution of 14 (1.77g,
gel; hexane–EtOAc=10:1 to 1:1) to give 9 (3.89g, 48%, 3 3.51mmol) in toluene (35.0mL) was added 2-aminoethanol
steps, based on epoxide 13) as a mixture of diastereomers (ca. (2.12mL, 35.1mmol) at r.t. After stirring at 70°C for 16h,
1:1) derived from a THP ether moiety; pale yellow gummy water was added to the mixture and the whole was extracted
solid: [α]D28 +56.8 (c=0.450, CHCl3); IR (neat) 2930 (ArH), with EtOAc twice. The combined organic layer was washed
1
1709 (C=O); H-NMR (500MHz, CDCl3) δ: 0.01 (s, 6H), 0.86 with water and brine, dried over Na2SO4 and concentrated
(s, 9H), 1.35–1.62 (m, 6H), 3.08–3.12 (m, 2H), 3.37–3.41 (m, in vacuo. After the residue was dissolved in acetonitrile
1H), 3.50–3.63 (m, 3H), 3.79–3.81 (m, 1H), 3.89–3.92 (m, 3H), (35.1mL), formaldehyde (37% in water; 1.14mL, 14.0mmol)
3.94–3.97 (m, 2H), 4.08–4.11 (m, 0.5H), 4.24–4.27 (m, 0.5H), and NaBH(OAc)3 (80%; 2.78g, 10.5mmol) were added to the

1000
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
mixture at r.t. After the mixture was stirred at the same tem- solid (yield: 63%): mp 140°C; [α]D28 −16.1 (c=1.12, CHCl3);
perature for 16h, saturated NaHCO3 was added to the mixture IR (neat) 3126 (C≡CH), 2938 (ArH), 2084 (C≡C), 1504
1
and extracted with EtOAc three times. The combined organic (NO2), 1310 (NO2); H-NMR (500MHz, CDCl3) δ: 2.24 (d,
layer was washed with brine, dried over Na2SO4 and concen- J=2.5Hz, 1H), 2.33 (s, 6H), 3.16 (dd, J=13.2, 10.3Hz, 1H),
trated in vacuo. The residue was dissolved in THF (35.1mL), 3.23 (dd, J=13.2, 4.6Hz, 1H), 3.32–3.42 (m, 2H), 3.61 (ddd,
and tetrabutylammonium fluoride (TBAF; 1.0M in THF; J=10.0, 4.0, 1.5Hz, 1H), 3.99 (s, 3H), 4.34–4.42 (m, 2H), 6.76
5.27mL, 5.27mmol) was added to the mixture at r.t. After 2h (d, J=8.0Hz, 1H), 6.97 (d, J=9.0Hz, 2H), 7.07 (d, J=8.6Hz,
under stirring, saturated NH4Cl was added to the mixture, and 1H), 7.52 (s, 1H), 8.20 (d, J=9.0Hz, 2H); 13C-NMR (125MHz,
the whole was extracted with EtOAc three times. The com- CDCl3) δ: 25.0, 36.7, 41.5 (2C), 55.9, 59.9, 68.1, 74.8, 79.6,
bined organic layer was washed with brine, dried over Na2SO4 106.0, 114.5 (2C), 116.8, 123.6, 124.9, 125.9 (2C), 127.3, 141.6,
and concentrated in vacuo. The residue was purified by col- 142.5, 144.5, 145.0, 163.6; HR-MS (ESI) Calcd for C23H25N2O5
umn chromatography (NH-silica gel, hexane–EtOAc=5:1 to (MH+) 409.1758. Found 409.1759.
1:2) to give 15 (672mg, 67% in 3 steps) as a colorless oil:
(R)-4-(2-{4-[2-(Dimethylamino)but-3-yn-1-yl]-7-methoxy-
[α]D28 −39.0 (c=1.04, CHCl3); IR (neat) 3273 (C≡CH), 3189 benzofuran-3-yl}ethoxy)benzonitrile (16d) White solid
(OH), 2105 (C≡C); 1H-NMR (500MHz, CDCl3) δ: 1.85 (t, (yield: 63%): mp 136°C; [α]D28 −15.8 (c=0.760, CHCl3); IR
J=3.5Hz, 1H), 2.28 (d, J=2.3Hz, 1H), 2.33 (s, 6H), 3.03–3.12 (neat) 3116 (C≡CH), 2953 (ArH), 2226 (C≡N), 2085 (C≡C);
(m, 3H), 3.26 (dd, J=13.2, 4.0Hz, 1H), 3.60 (ddd, J=10.5, 1H-NMR (500MHz, CDCl3) δ: 2.24 (d, J=2.3Hz, 1H), 2.32
4.5, 2.5Hz, 1H), 3.83–3.89 (m, 1H), 3.92–3.96 (m, 1H), 3.98 (s, 6H), 3.15 (dd, J=13.5, 10.0Hz, 1H), 3.22 (dd, J=13.5,
(s, 3H), 6.74 (d, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 7.50 4.6Hz, 1H), 3.30–3.40 (m, 2H), 3.61 (ddd, J=10.5, 4.5, 2.5Hz,
(s, 1H); 13C-NMR (125MHz, CDCl3) δ: 28.6, 36.8, 41.3 (2C), 1H), 3.98 (s, 3H), 4.29–4.37 (m, 2H), 6.76 (d, J=8.6Hz,
55.9, 59.8, 62.4, 74.9, 79.5, 105.9, 117.3, 123.6, 124.8, 127.4, 1H), 6.95–6.98 (m, 2H), 7.06 (d, J=8.6Hz, 1H), 7.51 (s, 1H),
142.5, 144.5, 145.1; HR-MS (ESI) Calcd for C17H22NO3 (MH+) 7.57–7.60 (m, 2H); 13C-NMR (125MHz, CDCl3) δ: 24.9, 36.6,
288.1594. Found 288.1593.
41.5 (2C), 55.9, 59.9, 67.6, 74.8, 79.6, 104.2, 106.0, 115.2 (2C),
General Procedure for Synthesis of Aryl Ethers 16: 116.9, 119.1, 123.6, 124.9, 127.4, 134.0 (2C), 142.5, 144.5, 145.0,
Synthesis of (R)-1-{7-Methoxy-3-[2-(pyridin-2-yloxy)ethyl]- 161.9; HR-MS (ESI) Calcd for C24H25N2O3 (MH+) 389.1860.
benzofuran-4-yl}-N,N-dimethylbut-3-yn-2-amine (16a) To Found 389.1858.
a solution of 15 (25.0mg, 0.0870mmol) in THF (0.87mL)
(R)-1-{3-[2-(4-Bromo-3-fluorophenoxy)ethyl]-7-methoxy-
(16e)
were added 2-hydroxypyridine (24.8mg, 0.261mmol), tri- benzofuran-4-yl}-N,N-dimethylbut-3-yn-2-amine
phenylphosphine (68.5mg, 0.261mmol) and bis(2-methoxy- White solid (yield: 60%): mp 142°C; [α]D28 −15.3 (c=1.00,
ethyl) azodicarboxylate (DMEAD; 93%; 65.7mg, 0.261mmol) CHCl3); IR (neat) 3118 (C≡CH), 2943 (ArH), 2088 (C≡C),
1
at r.t. After stirring at the same temperature for 16h, the 1167 (ArF); H-NMR (500MHz, CDCl3) δ: 2.24 (d, J=1.7Hz,
mixture was concentrated in vacuo. The residue was purified 1H), 2.33 (s, 6H), 3.15 (dd, J=13.5, 10.0Hz, 1H), 3.22 (dd,
by column chromatography (silica gel; hexane–EtOAc=5:1 to J=13.5, 4.6Hz, 1H), 3.26–3.37 (m, 2H), 3.61 (ddd, J=10.0, 4.6,
1:1) to give 16a (13.2mg, 42%). Compounds 16b–f were pre- 1.7Hz, 1H), 3.98 (s, 3H), 4.22–4.29 (m, 2H), 6.62 (dd, J=9.2,
pared using the corresponding phenols. Compound 16a: white 2.9Hz, 1H), 6.72 (dd, J=10.6, 2.9Hz, 1H), 6.75 (d, J=8.0Hz,
solid: mp 122–123°C; [α]D28 −14.9 (c=0.525, CHCl3); IR (neat) 1H), 7.06 (d, J=8.0Hz, 1H), 7.40 (dd, J=10.6, 9.2Hz, 1H),
3120 (C≡CH), 2952 (ArH), 2087 (C≡C), 1272 (ArOMe), 1016 7.50 (s, 1H); 13C-NMR (125MHz, CDCl3) δ: 25.0, 36.6, 41.4
1
(ArOMe); H-NMR (500MHz, CDCl3) δ: 2.22 (d, J=2.3Hz, (2C), 55.9, 59.9, 67.9, 74.8, 79.7, 103.4, 103.6, 106.0, 111.87,
1H), 2.33 (s, 6H), 3.16–3.21 (m, 1H), 3.24–3.38 (m, 3H), 3.64 111.89, 117.0, 123.6, 124.8, 127.4, 133.4, 142.4, 144.4, 144.9,
(ddd, J=10.0, 5.0, 2.0Hz, 1H), 3.98 (s, 3H), 4.64 (t, J=6.6Hz, 159.2; HR-MS (ESI) Calcd for C23H24BrFNO3 (MH+; 79Br)
2H), 6.74 (d, J=8.0Hz, 2H), 6.86 (dd, J=6.6, 5.4Hz, 1H), 7.04 460.0919. Found 460.0920.
(d, J=8.0Hz, 1H), 7.54–7.58 (m, 2H), 8.15 (dd, J=4.9, 2.0Hz,
(R)-1-[7-Methoxy-3-(2-phenoxyethyl)benzofuran-4-yl]-
1H); 13C-NMR (125MHz, CDCl3) δ: 25.0, 36.5, 41.5 (2C), N,N-dimethylbut-3-yn-2-amine (16f) White solid (yield:
55.9, 59.9, 64.8, 74.7, 79.8, 105.8, 111.2, 116.8, 117.6, 123.9, 32%): mp 114–115°C; [α]D28 −17.8 (c=0.575, CHCl3); IR (neat)
124.6, 127.7, 138.6, 142.3, 144.3, 144.9, 146.8, 163.5; HR-MS 3257 (C≡CH), 2937 (ArH), 2088 (C≡C), 1243 (ArOMe), 1037
(FAB) Calcd for C22H25N2O3 (MH+) 365.1860. Found 365.1861. (ArOMe); H-NMR (500MHz, CDCl3) δ: 2.23 (d, J=1.7Hz,
1
(R)-1-{7-Methoxy-3-[2-(4-methoxyphenoxy)ethyl]benzo- 1H), 2.33 (s, 6H), 3.16 (dd, J=13.5, 10.0Hz, 1H), 3.24 (dd,
furan-4-yl}-N,N-dimethylbut-3-yn-2-amine (16b) White J=14.0, 5.0Hz, 1H), 3.30–3.38 (m, 2H), 3.63 (ddd, J=10.3,
gummy solid (yield: 57%): [α]D28 −6.4 (c=0.345, CHCl3); 4.5, 1.5Hz, 1H), 3.98 (s, 3H), 4.26–4.34 (m, 2H), 6.74 (d,
IR (neat) 3389 (C≡CH), 2931 (ArH), 2322 (C≡C), 1230 J=8.0Hz, 1H), 6.92–6.97 (m, 3H), 7.05 (d, J=8.6Hz, 1H),
1
(ArOMe), 1041 (ArOMe); H-NMR (500MHz, CDCl3) δ: 2.22 7.27–7.30 (m, 2H), 7.54 (s, 1H); 13C-NMR (125MHz, CDCl3)
(d, J=1.7Hz, 1H), 2.33 (s, 6H), 3.13–3.18 (m, 1H), 3.23 (dd, δ: 25.3, 36.5, 41.4 (2C), 55.9, 59.9, 67.1, 74.8, 79.7, 105.9,
J=13.5, 4.9Hz, 1H), 3.27–3.32 (m, 2H), 3.61–3.64 (m, 1H), 114.6 (2C), 117.5, 120.9, 123.7, 124.7, 127.7, 129.5 (2C), 142.5,
3.77 (s, 3H), 3.98 (s, 3H), 4.21–4.29 (m, 2H), 6.74 (d, J=8.0Hz, 144.4, 144.9, 158.6; HR-MS (ESI) Calcd for C23H26NO3 (MH+)
1H), 6.82–6.88 (m, 4H), 7.04 (d, J=8.0Hz, 1H), 7.53 (s, 1H); 364.1907. Found 364.1909.
13C-NMR (125MHz, CDCl3) δ: 25.3, 36.5, 41.4 (2C), 55.7,
(R)-1-{7-Methoxy-3-[2-(pyridin-2-yloxy)ethyl]benzofu-
55.9, 59.8, 67.9, 74.7, 79.7, 105.9, 114.6 (2C), 115.6 (2C), 117.5, ran-4-yl}-N,N-dimethyl-4-phenylbut-3-yn-2-amine (17)
123.7, 124.7, 127.7, 142.4, 144.4, 144.9, 152.7, 154.0; HR-MS To a solution of 16a (30.0mg, 0.0823mmol) in Et3N (1.20mL)
(ESI) Calcd for C24H28NO4 (MH+) 394.2013. Found 394.2018.
and THF (0.80mL) were added iodobenzene (18mL,
(R)-1-{7-Methoxy-3-[2-(4-nitrophenoxy)ethyl]benzofu- 0.165mmol), CuI (0.3mg, 1.65µmol) and PdCl2(PPh3)2
ran-4-yl}-N,N-dimethylbut-3-yn-2-amine (16c) White (1.2mg, 1.65µmol; 2mol%) at r.t. under argon. After stir-

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
1001
ring at the same temperature for 2h, the mixture was filtered (MNa+) 671.2429. Found 671.2430.
and concentrated in vacuo. The residue was purified by N-{(2R)-1-(3-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-7-
column chromatography (silica gel; hexane–EtOAc=5:1 to methoxybenzofuran-4-yl)-3-[(tetrahydro-2H-pyran-2-yl)-
1:1) to give 17 (4.6mg, 13%) as a white gummy solid: [α]D28 oxy]propan-2-yl}-N-methyl-2-nitrobenzenesulfonamide (24)
−80.8 (c=0.150, CHCl3); IR (neat) 2931 (ArH), 2310 (C≡C); To a solution of 20 (900mg, 1.39mmol) in DMF (13.9mL)
1H-NMR (500MHz, CDCl3) δ: 2.41 (s, 6H), 3.30 (d, J=8.0Hz, were added K2CO3 (289mg, 2.09mmol) and MeI (104µL,
2H), 3.37–3.39 (m, 2H), 3.83 (t, J=8.0Hz, 1H), 3.98 (s, 3H), 1.69mmol) at r.t. After the mixture was stirred at the same
4.62 (t, J=6.6Hz, 2H), 6.72 (dd, J=8.0, 2.6Hz, 1H), 6.75 (d, temperature for 16h, water was added to the mixture and the
J=8.0Hz, 1H), 6.84–6.86 (m, 1H), 7.09 (d, J=8.0Hz, 1H), whole was extracted with EtOAc twice. The combined organic
7.22–7.28 (m, 5H), 7.53–7.57 (m, 2H), 8.13 (dd, J=5.2, 1.1Hz, layer was washed with water and brine, dried over Na2SO4
1H); 13C-NMR (125MHz, CDCl3) δ: 25.2, 36.4, 41.8 (2C), and concentrated in vacuo. The residue was purified by col-
56.0, 60.9, 64.8, 85.9, 87.3, 106.0, 111.2, 116.9, 117.8, 123.2, umn chromatography (silica gel; hexane–EtOAc=5:1 to 2:1)
124.2, 124.8, 127.9, 128.0, 128.1 (2C), 131.6 (2C), 138.6, 142.3, to give 24 (772mg, 84%) as a mixture of diastereomers (ca.
144.3, 144.9, 146.8, 163.6; HR-MS (ESI) Calcd for C28H29N2O3 1:1) derived from a THP ether moiety: yellow oil; [α]D28 −60.3
(MH+) 441.2173. Found 441.2175.
(c=0.555, CHCl3); IR (neat) 2950 (ArH), 1542 (NO2), 1347
1
N-{(2R)-1-(3-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-7- (NO2), 1162 (SO2); H-NMR (500MHz, CDCl3) δ: 0.10–0.12
methoxybenzofuran-4-yl)-3-[(tetrahydro-2H-pyran-2-yl)- (m, 6H), 0.88 (s, 9H), 1.52–1.75 (m, 6H), 2.90–3.07 (m, 3H),
oxy]propan-2-yl]}-2-nitrobenzenesulfonamide (20) (Chart 3.15 (s, 3H), 3.32–3.36 (m, 0.5H), 3.44–3.53 (m, 2H), 3.57–3.60
4) To a solution of 9 (1.12g, 1.89mmol) in toluene (18.9mL) (m, 0.5H), 3.78–3.82 (m, 1H), 3.89–3.93 (m, 5.5H), 3.98–4.01
was added 2-aminoethanol (1.14mL, 18.9mmol) at r.t. After (m, 0.5H), 4.25–4.32 (m, 1H), 4.58–4.61 (m, 1H), 6.40–6.44
the mixture was stirred at 70°C for 16h, water was added to (m, 1H), 6.82–6.86 (m, 1H), 7.20–7.23 (m, 1H), 7.40–7.43 (m,
the mixture and the whole was extracted with EtOAc twice. 1H), 7.45–7.50 (m, 3H); 13C-NMR (125MHz, CDCl3) δ: −5.5
The combined organic layer was washed with water and (2C), 13.2, 19.1, 19.2, 25.26, 25.28, 25.8 (3C), 28.27, 28.33,
brine, dried over Na2SO4 and concentrated in vacuo. After 29.7, 29.8, 30.26, 30.30, 31.5, 31.7, 55.7, 59.0, 59.1, 61.9, 62.1,
the residue was dissolved in CH2Cl2 (18.9mL), diisopropyl- 62.9, 68.13, 68.22, 98.7, 98.9, 105.19, 105.24, 118.06, 118.12,
ethylamine (DIPEA; 495µL, 2.84mmol) and NsCl (439mg, 122.70, 122.74, 123.6, 123.7, 124.9, 125.0, 127.3, 130.38,
1.98mmol) were successively added to the mixture at r.t. 130.42, 130.9, 132.19, 132.23, 133.4, 133.5, 142.2, 142.3, 144.06,
After the mixture was stirred at the same temperature for 2h, 144.09, 144.26, 144.31, 146.9, 147.0; HR-MS (ESI) Calcd for
saturated NaHCO3 was added to the mixture and the whole C32H46N2O9SSiNa (MNa+) 685.2585. Found 685.2587.
was extracted with CH2Cl2 twice. The combined organic layer
(R)-N-[1-[7-Methoxy-3-{2-(pyridin-2-yloxy)ethyl}benzo-
was washed with brine, dried over MaSO4 and concentrated furan-4-yl]but-3-yn-2-yl]-N-methyl-2-nitrobenzenesulfon-
in vacuo. The residue was purified by column chromatog- amide (18) By the similar procedures for the synthesis
raphy (silica gel; hexane–EtOAc=5:1 to 1:1) to give 20 of 16 from compound 9, the compound 18 was obtained as
(1.09g, 89%) as a mixture of diastereomers (ca. 1:1) derived pale yellow gummy solid (yield: 25% in 5 steps): [α]2D6 −34.4
from a THP ether moiety: yellow oil; [α]D28 −45.4 (c=0.260, (c=0.490, CHCl3); IR (neat) 3279 (C≡CH), 2927 (ArH),
1
CHCl3); IR (neat) 2934 (ArH), 1541 (NO2), 1355 (NO2), 1169 2113 (C≡C), 1543 (NO2), 1349 (NO2), 1165 (SO2); H-NMR
(SO2); 1H-NMR (500MHz, CDCl3) δ: −0.01 (s, 6H), 0.86 (500MHz, CDCl3) δ: 2.25 (d, J=2.3Hz, 1H), 3.10 (s, 3H),
(s, 9H), 1.55–1.63 (m, 4H), 1.70–1.77 (m, 1H), 1.80–1.85 (m, 3.23–3.36 (m, 3H), 3.44 (dd, J=14.7, 8.0Hz, 1H), 3.94 (s, 3H),
1H), 2.89–2.99 (m, 2.5H), 3.33–3.40 (m, 1.5H), 3.52–3.54 (m, 4.59–4.68 (m, 2H), 4.98 (ddd, J=8.0, 8.0, 2.0Hz, 1H), 6.62 (d,
1H), 3.65–3.68 (m, 0.5H), 3.74–3.77 (m, 0.5H), 3.82–3.94 (m, J=8.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.87 (dd, J=6.9, 5.2Hz,
8H), 4.55–4.60 (m, 1H), 5.71–5.72 (m, 0.5H), 6.07–6.09 (m, 1H), 6.98 (d, J=8.0Hz, 1H), 7.43–7.47 (m, 1H), 7.53–7.60 (m,
0.5H), 6.40–6.42 (m, 1H), 6.78–6.81 (m, 1H), 7.34–7.40 (m, 4H), 7.75 (dd, J=8.0, 1.1Hz, 1H), 8.16 (dd, J=4.9, 1.5Hz, 1H);
2H), 7.50–7.54 (m, 1H), 7.57–7.59 (m, 1H), 7.65–7.67 (m, 1H); 13C-NMR (125MHz, CDCl3) δ: 24.9, 30.2, 36.3, 52.2, 55.8,
13C-NMR (125MHz, CDCl3) δ: −5.5 (2C), 14.2, 18.2, 19.3, 64.8, 75.1, 79.1, 105.7, 111.1, 116.9, 117.4, 121.0, 124.1, 125.4,
19.7, 21.0, 25.2, 25.3, 25.8 (3C), 28.3, 28.4, 30.3, 30.6, 35.2, 127.6, 130.5, 131.3, 132.2, 133.2, 138.7, 142.46, 142.47, 144.7,
35.2, 55.6, 56.95, 57.03, 60.38, 62.2, 62.75, 62.79, 70.01, 70.9, 146.9, 147.8, 163.4; HR-MS (ESI) Calcd for C27H25N3O7SNa
99.3, 99.7, 105.2, 105.3, 118.0, 122.7, 122.8, 125.0, 125.29, (MNa+) 558.1305. Found 558.1306.
125.33, 127.4, 129.4, 129.5, 132.3, 134.3, 134.5, 142.27, 142.34,
N-{[(2R)-1-{7-Methoxy-3-[2-(pyridin-2-yloxy)ethyl]ben-
144.2, 146.4; HR-MS (ESI) Calcd for C31H44N2NaO10SSi zofuran-4-yl}-3-[(tetrahydro-2H-pyran-2-yl)oxy]propan-
2-yl]-N-methy}-2-nitrobenzenesulfonamide (25) (Chart 5)
Pale yellow gummy solid (yield 40% in two steps; mixture
of diastereomers (ca. 1:1) derived from a THP ether moiety):
[α]D28 −30.2 (c=0.465, CHCl3); IR (neat) 2922 (ArH), 1543
1
(NO2), 1363 (NO2), 1160 (SO2); H-NMR (500MHz, CDCl3) δ:
1.48–1.77 (m, 6H), 2.91–3.03 (m, 1H), 3.15 (s, 3H), 3.26–3.43
(m, 2.5H), 3.48–3.54 (m, 2H), 3.58–3.61 (m, 0.5H), 3.73–3.85
(m, 1H), 3.88 (s, 3H), 3.91–3.96 (m, 0.5H), 3.98–4.02 (m,
0.5H), 4.25–4.33 (m, 1H), 4.56–4.66 (m, 3H), 6.40–6.43 (m,
1H), 6.73–6.75 (m, 1H), 6.84–6.89 (m, 2H), 7.16–7.20 (m,
Reagents and conditions: (a) 2-aminoethanol, toluene, 70°C; (b) NsCl, DIPEA,
CH2Cl2, r.t., 89% in 2 steps; (c) MeI, K2CO3, DMF, r.t., 84%; (d) Me2AlCl, CH2Cl2,
−78°C; (e) (COCl)2, DMSO, CH2Cl2, −78 to 0°C; (f) Ohira–Bestmann reagent,
K2CO3, MeOH, 0°C; (g) TBAF, THF, r.t.; (h) pyridin-2-ol, PPh3, DMEAD, THF,
r.t., 25% in 5 steps.
1H), 7.38–7.51 (m, 4H), 7.55–7.59 (m, 1H), 8.15–8.17 (m, 1H);
13C-NMR (125MHz, CDCl3) δ: 19.1, 19.3, 24.8, 24.9, 25.2, 25.3,
Chart 4. Synthesis of Nosylamide 18

1002
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
concentrated in vacuo. After the residue was dissolved in
THF (39.8mL), triphenylphosphine (3.12mg, 11.9mmol) and
DMEAD (2.79mg, 11.9mmol) were added to the mixture at
r.t. After stirring at the same temperature for 1.5h, saturated
NaHCO3 was added to the mixture and the whole was ex-
tracted with EtOAc twice. The combined organic layer was
washed with water and brine, dried over MgSO4 and concen-
trated in vacuo. After the residue was dissolved in i-PrOH
(39.8mL), pyridinium p-toluenesulfonate (150mg, 0.597mmol)
was added to the mixture at r.t. After stirring at 80°C for 2h,
Et3N (166µL, 1.19mmol) was added to the mixture and the
Reagents and conditions: (a) TBAF, THF, r.t.; (b) pyridin-2-ol, PPh3, DMEAD,
THF, r.t., 40% in 2 steps; (c) thiophenol, K2CO3, CH3CN, r.t.; (d) HCHO aq.,
NaBH(OAc)3, CH3CN, r.t.; (e) pyridinium p-toluenesulfonate, EtOH, r.t., 79% in
3 steps.
Chart 5. Synthesis of Alcohol 19
29.75. 29.81, 30.26, 30.28, 31.5, 31.7, 55.7, 59.06, 59.14, 61.9, whole was concentrated in vacuo. The residue was purified
62.2, 64.9, 65.0, 68.2, 68.4, 98.8, 99.0, 105.38, 105.45, 111.10, by column chromatography (silica gel; hexane–EtOAc=3:1
111.13, 116.9, 117.6, 122.7, 122.8, 123.7, 123.8, 125.17, 125.21, to 1:2) to give 21 (1.17g, 68% in 3 steps) as a colorless oil:
130.48, 130.53, 130.92, 130.94, 132.2, 133.4, 133.6, 138.7, 141.9, [α]D28 +27.2 (c=0.370, CHCl3); IR (neat) 2927 (OH), 1541
1
142.1, 144.12, 144.14, 144.4, 146.7, 146.9, 163.5; HR-MS (ESI) (NO2), 1373 (NO2), 1162 (SO2); H-NMR (500MHz, CDCl3)
Calcd for C31H36N3O9 (MH+) 626.2167. Found 626.2169.
δ: 1.97 (t, J=5.7Hz, 1H), 2.85 (dd, J=13.7, 5.2Hz, 1H), 2.96
(R)-2-(Dimethylamino)-3-{7-methoxy-3-[2-(pyridin-2- (dd, J=14.9, 7.4Hz, 1H), 3.13–3.24 (m, 2H), 3.73 (dd, J=14.9,
yloxy)ethyl]benzofuran-4-yl}propan-1-ol (19) To a solution 6.9Hz, 1H), 3.90 (t, J=6.3Hz, 2H), 3.94 (s, 3H), 4.28–4.35
of 25 (55.0mg, 0.0879mmol) in acetonitrile (0.900mL) were (m, 1H), 4.53–4.57 (m, 1H), 6.56 (d, J=7.4Hz, 1H), 6.87 (d,
added K2CO3 (121mg, 0.879mmol) and thiophenol (45µL, J=8.0Hz, 1H), 7.01 (d, J=7.4Hz, 1H), 7.17 (d, J=7.4Hz, 1H),
0.440mmol) at r.t. After the mixture was stirred at the same 7.22 (d, J=7.4Hz, 1H), 7.26–7.27 (m, 1H), 7.42 (d, J=7.4Hz,
temperature for 2h, saturated NaHCO3 was added to the 1H); 13C-NMR (125MHz, CDCl3) δ: 23.2, 32.9, 42.8, 55.8,
mixture, and the whole was extracted with EtOAc twice. The 60.1, 62.5, 105.9, 117.3, 122.6, 122.7, 123.8, 128.7, 129.8, 130.5,
combined organic layer was washed with water and brine, 132.4, 133.0, 141.2, 143.8, 144.3, 147.2; HR-MS (ESI) Calcd
dried over Na2SO4 and concentrated in vacuo. The remain- for C20H20N2O7SK (MK+) 471.0623. Found 471.0623.
ing thiophenol in the residue was removed by short column
(R)-7-Ethynyl-3-methoxy-8-methyl-7,8,9,10-tetra-
chromatography (silica gel; CHCl3 to CHCl3–MeOH=10:1) hydro-6H-benzofuro[3,4-de]azocine (10) By a procedure
to afford the corresponding amine (36.6mg) as crude prod- similar to that described for synthesis of 14 from 9, the alcohol
uct. To this amine (15.0mg, ca. 0.0340mmol) in acetonitrile 21 (510mg, 1.18mmol) was converted to the corresponding al-
(0.400mL) were added formaldehyde (6.0µL, 0.0680mmol) kyne (338mg) as a crude product (Me2AlCl treatment was not
and sodium triacetoxyborohydride (14.0mg, 0.0510mmol) at applied). To this alkyne (150mg, 0.352mmol) in DMF (3.5mL)
r.t. After the mixture was stirred at the same temperature were added K2CO3 (147mg, 1.06mmol) and thiophenol (90µL,
for 16h, saturated NaHCO3 was added to the mixture, and 0.880mmol) at 0°C. After the mixture was stirred at the same
the mixture was extracted with EtOAc twice. The combined temperature for 1h, saturated NaHCO3 was added to the mix-
organic layer was washed with water and brine, dried over ture, and the whole was extracted with EtOAc three times.
Na2SO4 and concentrated in vacuo. After the residue dissolved The combined organic layer was washed with 1N NaOH,
in EtOH (330µL), pyridinium p-toluenesulfonate (1.2mg, water and brine, dried over Na2SO4 and concentrated in
4.95µmol) was added to the mixture at r.t. After stirring at vacuo. The remaining thiophenol in the residue was removed
the same temperature for 2h, the mixture was concentrated in by short column chromatography (silica gel; CHCl3 to CHCl3–
vacuo. The residue was purified by column chromatography MeOH=10:1) to afford the corresponding amine (82.9mg)
(silica gel; hexane–EtOAc=5:1 to 1:1) to give 19 (10.1mg, as crude product. To this amine (82.0mg, 0.340mmol) in
79%) as a white gummy solid: [α]D28 −10.5 (c=0.425, CHCl3); acetonitrile (3.40mL) were added formaldehyde (37%; 57µL,
1
IR (neat) 2923 (OH), 1273 (ArOMe), 1013 (ArOMe); H-NMR 0.680mmol) and sodium triacetoxyborohydride (135mg,
(500MHz, CDCl3) δ: 2.39 (s, 6H), 2.70 (dd, J=13.7, 10.3Hz, 0.510mmol) at r.t. After stirring at the same temperature for
1H), 2.96–3.02 (m, 1H), 3.23–3.37 (m, 5H), 3.98 (s, 3H), 4.62 3h, the mixture was concentrated in vacuo. The residue was
(t, J=6.9Hz, 2H), 6.71 (d, J=8.0Hz, 1H), 6.74 (d, J=8.6Hz, purified by column chromatography (NH-silica gel, hexane/
1H), 6.86–6.89 (m, 2H), 7.54 (s, 1H), 7.56–7.59 (m, 1H), 8.15 EtOAc=10/1 to 2/1) to give 10 (75.5mg, 55% in 4 steps) as a
(dd, J=5.4, 1.4Hz, 1H); 13C-NMR (125MHz, CDCl3) δ: 25.3, white solid: mp 112°C; [α]D28 +32.7 (c=0.980, CHCl3); IR (neat)
26.8, 40.2 (2C), 56.0, 60.3, 64.8, 66.0, 106.0, 111.2, 116.9, 3257 (C≡CH), 2097 (C≡C); 1H-NMR (500MHz, CDCl3)
117.3, 124.3, 124.5, 127.5, 138.7, 142.4, 144.2, 145.0, 146.8, δ: 2.26 (s, 3H), 2.42 (s, 1H), 2.53–2.59 (m, 1H), 2.74–2.80
163.4; HR-MS (ESI) Calcd for C21H27N2O4 (MH+) 371.1965. (m, 1H), 3.00 (dd, J=14.3, 5.7Hz, 1H), 3.10–3.20 (m, 2H),
Found 371.1967.
3.54 (dd, J=14.0, 12.5Hz, 1H), 3.64–3.67 (m, 1H), 3.97 (s,
(R)-{3-Methoxy-8-[(2-nitrophenyl)sulfonyl]-7,8,9,10- 3H), 6.66 (d, J=8.0Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 7.35 (d,
tetrahydro-6H-benzofuro[3,4-de]azocin-7-yl}methanol (21) J=1.1Hz, 1H); 13C-NMR (125MHz, CDCl3) δ: 23.6, 38.4, 47.0,
To a stirred solution of 20 (2.58g, 3.98mmol) in THF 52.3, 55.9, 57.6, 73.4, 81.0, 105.6, 119.8, 122.6, 123.8, 132.2,
(19.9mL) was added TBAF (1.0M in THF; 19.9mL, 19.9mmol) 140.1, 143.6, 144.6; HR-MS (ESI) Calcd for C16H18NO2 (MH+)
at r.t. After stirring at the same temperature for 2h, satu- 256.1332. Found 256.1337.
rated NaHCO3 was added to the mixture and the whole was
extracted with EtOAc twice. The combined organic layer tetrahydro-6H-benzofuro[3,4-de]azocine
was washed with water and brine, dried over MgSO4 and 1,4-Bis[(R)-3-methoxy-8-methyl-7,8,9,10-tetrahydro-6H-
(R)-3-Methoxy-8-methyl-7-( p-tolylethynyl)-7,8,9,10-
(22a) and

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
1003
benzofuro[3,4-de]azocin-7-yl]buta-1,3-diyne (23) To a so- with 0.3% polyethyleneimine. Filters were washed with [50mM
lution of 1-iodo-4-methylbenzene (17.1mg, 0.0784mmol) in HEPES (pH 7.4), 500mM NaCl, 0.1% BSA] and dried at 55°C.
THF (0.400mL) and Et3N (0.400mL) were added CuI (0.4mg, Bound radioactivity was measured by TopCount (PerkinElmer,
1.96µmol) and PdCl2(PPh3)2 (1.4mg, 1.96µmol) at r.t. under Inc. Life Sciences) in the presence of MicroScint-O
argon. To the mixture was added 10 (10.0mg, 0.0392mmol) at (30 µL) (PerkinElmer, Inc. Life Sciences). PF-445524219)
the same temperature. After stirring for 2h, the mixture was (IC50=0.28 0.11 µM for KOR) and [Met]enkephalin (6a)
concentrated in vacuo and the residue was purified by column (IC50=0.29 0.07µM for MOR) were used as positive controls.
chromatography (silica gel; hexane–EtOAc=5:1 to 1:1) to
give 22a (4.6mg, 34%) and 23 (5.5mg, 55%).
Compound 22a
Acknowledgments This work was supported by Grants-
in-Aid for the Encouragement of Young Scientists (A) (H.O.)
Pale red solid; mp 127–128°C; [α]D28 +32.7 (c=0.980, and Scientific Research (B) (N.F.); the Platform for Drug
CHCl3); IR (neat) 2933 (ArH), 2324 (C≡C); 1H-NMR Design, Discovery, and Development from the Ministry of
(500MHz, CDCl3) δ: 2.32 (s, 3H), 2.36 (s, 3H), 2.57–2.61 Education, Culture, Sports, Science and Technology (MEXT)
(m, 1H), 2.78 (dd, J=14.9, 6.9Hz, 1H), 3.07–3.08 (m, 1H), of Japan; and Technology Research Promotion Program for
3.15–3.22 (m, 1H), 3.28 (dd, J=12.0, 6.9Hz, 1H), 3.61 (dd, Agriculture, Forestry, Fisheries and Food Industry from
J=14.0, 13.5Hz, 1H), 3.83–3.86 (m, 1H), 3.98 (s, 3H), 6.67 MAFF, Japan. H.C. is grateful for Research Fellowships from
(d, J=7.4Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 7.14 (d, J=8.0Hz, the Japan Society for the Promotion of Science (JSPS) for
2H), 7.36 (d, J=1.1Hz, 1H), 7.38–7.40 (m, 2H); 13C-NMR Young Scientists.
(125MHz, CDCl3) δ: 21.5, 23.7, 38.6, 47.3, 52.5, 56.0 (2C),
58.4, 86.1, 105.7, 120.0, 120.1, 122.6, 124.1, 129.0 (2C), 131.7
Conflict of Interest The authors declare no conflict of
(2C), 131.9, 138.1, 140.1, 143.6, 144.5; HR-MS (ESI) Calcd for interest.
C23H24NO2 (MH+) 346.1802. Found 346.1804.
Compound 23
References and Notes
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cological Basis of Therapeutics,” 12th ed., McGraw-Hill Medical,
New York, 2011, pp. 481–526.
Pale red solid; mp 156°C; IR (neat) 2936 (ArH), 2327
1
(C≡C); H-NMR (500MHz, CDCl3) δ: 2.31 (s, 6H), 2.57–2.63
(m, 2H), 2.79 (dd, J=14.9, 7.4Hz, 2H), 3.01 (dd, J=14.9,
6.0Hz, 2H), 3.14–3.20 (m, 2H), 3.25 (dd, J=12.6, 6.9Hz, 2H),
3.58 (dd, J=14.0, 12.5Hz, 2H), 3.75 (dd, J=12.6, 5.7Hz, 2H),
3.97 (s, 6H), 6.66 (d, J=8.0Hz, 2H), 6.84 (d, J=8.0Hz, 2H),
7.36 (d, J=1.1Hz, 2H); 13C-NMR (125MHz, CDCl3) δ: 23.6
(2C), 38.1 (2C), 47.2 (2C), 52.5 (2C), 56.0 (2C), 58.4 (2C),
70.1 (2C), 105.7 (4C), 119.7 (2C), 122.6 (2C), 123.4 (2C),
140.2 (4C), 143.6 (2C), 144.6 (2C); HR-MS (ESI) Calcd for
C32H33N2O4 (MH+) 509.2435. Found 509.2434.
2) Hughes J., Smith T. W., Kosterlitz H. W., Fothergill L. A., Morgan
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17) Phenyl ether derivative 16f (>90% purity) also showed a moderate
affinity to KOR (IC50=32µM; n=2).
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(R)-4-[(3-Methoxy-8-methyl-7,8,9,10-tetrahydro-6H-
benzofuro[3,4-de]azocin-7-yl)ethynyl]benzonitrile
(22b)
By a procedure similar to that described for the synthesis of
22a, 10 (30.0mg, 0.117mmol) was converted to 22b (11.1mg,
27%) and 23 (5.2mg, 17%) using 4-iodobenzonitrile.
Compound 22b
White solid; mp 119°C; [α]D28 +0.935 (c=0.550, CHCl3);
IR (neat) 2933 (ArH), 2334 (C≡C), 2219 (C≡N); 1H-NMR
(500MHz, CDCl3) δ: 2.33 (s, 3H), 2.61–2.65 (m, 1H), 2.80
(dd, J=14.6, 7.2Hz, 1H), 3.08–3.09 (m, 1H), 3.14–3.26 (m,
2H), 3.61 (dd, J=13.5, 13.0Hz, 1H), 3.83–3.92 (m, 1H), 3.98
(s, 3H), 6.68 (d, J=7.4Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 7.37 (s,
1H), 7.57–7.63 (m, 4H); 13C-NMR (125MHz, CDCl3) δ: 23.7,
38.2, 47.2, 52.5, 56.0, 58.4, 84.9, 92.0, 105.7, 111.3, 118.5, 119.7,
122.7, 123.5, 128.1, 131.8, 132.0 (2C), 132.3 (2C), 140.2, 143.6,
144.6; HR-MS (ESI) Calcd for C23H21N2O2 (MH+) 357.1598.
Found 357.1597.
Evaluation of MOR and KOR Binding Inhibition Bind-
ing inhibition assays were performed by the similar protocols
as described previously.18) Membranes from MOR- or KOR-
expressing CHO cells were incubated with 50µL of compound
solution, 25µL of radioactive ligand [[15,16-3H]-diprenorphne,
0.4nM, PerkinElmer, Inc. Life Sciences] solution, and 25µL of
membrane solution in assay buffer [50mM N-(2-hydroxyethyl)-
piperazine-N′-2-ethanesulfonic acid (HEPES) (pH 7.4), 5mM
MgCl2, 1mM CaCl2, 0.1% bovine serum albumin (BSA)]. Re-
action mixtures were filtered through GF/B filters, pretreated
Chem., 21, 2413–2417 (2013).
19) Verhoest P. R., Basak A. S., Parikh V., Hayward M., Kauffman G.
W., Paradis V., McHardy S. F., McLean S., Grimwood S., Schmidt
A. W., Vanase-Frawley M., Freeman J., Van Deusen J., Cox L.,
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