Synthesis of new highly substituted and hindered 1-hydroxyindole-2-carboxylates

Article abstract of DOI:10.1002/bkcs.10630

The synthesis of new, highly substituted, and hindered 1-hydroxyindole-2-carboxylates 1 is described. Substrates 2, prepared through a two-step synthetic sequence, were treated with relatively weak nucleophiles in the presence of SnCl₂ · 2H₂O to afford compounds 1. In particular, nucleophiles of low reactivity and/or high steric hindrance reacted efficiently to give 1 in good to modest yields.

Full text of DOI:10.1002/bkcs.10630

Article
DOI: 10.1002/bkcs.10630
BULLETIN OF THE
Y. K. Park et al.
KOREAN CHEMICAL SOCIETY
Synthesis of New Highly Substituted and Hindered
1-Hydroxyindole-2-carboxylates
*
Yeon Kyeong Park, Hyejin Kim, and Sang Hyup Lee
College of Pharmacy and Innovative Drug Center, Duksung Women’s University, Seoul 132-714, Republic of
Korea. *E-mail: sanghyup@duksung.ac.kr
Received August 21, 2015, Accepted November 7, 2015, Published online December 17, 2015
The synthesis of new, highly substituted, and hindered 1-hydroxyindole-2-carboxylates 1 is described. Sub-
strates 2, prepared through a two-step synthetic sequence, were treated with relatively weak nucleophiles in the
presence of SnCl2 ꢀ 2H2O to afford compounds 1. In particular, nucleophiles of low reactivity and/or high
steric hindrance reacted efficiently to give 1 in good to modest yields.
Keywords: Hydroxyindoles, Nitro reduction, Condensation, Tin, Steric hindrance
Introduction
particular, efficient synthetic methodologies to construct
highly substituted 1-hydroxyindole derivatives are in high
demand in order to expand the understanding of the physico-
chemical and medicinal properties of these compounds.
In our exploration of methods to construct diverse 1-
hydroxyindole derivatives, we previously disclosed the syn-
thesis of 1-hydroxyindole derivatives and their applications
to more elaborated molecules.13–15 Thus, as a part of our con-
tinued efforts with 1-hydroxyindole compounds, we here
report the synthesis of new, highly substituted, and hindered
1-hydroxyindole-2-carboxylates 1. This method focuses on
a one-pot reaction that combines 1-hydroxyindole formation
(reduction of nitro group followed by condensation) and addi-
tion of a nucleophile. To the best of our knowledge, studies on
this reaction combination have rarely been reported except for
our previous studies.13–17
Recently, 1-hydroxyindole derivatives have attracted much
interest due to their unique structures and related biological
significance. As a result of the presence of a hydroxy group
atN(1), thesecompoundsdisplaydifferent physical andchem-
ical properties and medicinal profiles compared to indoles.
Although 1-hydroxyindoles were first reported several dec-
ades ago by Acheson et al.,1 studies of these compounds have
not been broadly conducted until recently. Around 2000, their
general features and properties were described with an appro-
priate level of chemical information.2,3 It is known that simple
unsubstituted 1-hydroxyindole compounds are unstable and
that their stabilities improve as substituents are introduced
to the 1-, 2-, and 3-positions of the hydroxyindole structure.2
Interestingly, it is also known that electron-withdrawing sub-
stituents increase their stability, while electron-donating sub-
stituents decrease the stability.4 Among spectral data, proton
Nu
X
4
3
1
2
signals of the 1-hydroxy group in the H NMR are mostly
CO2Me
N
observed at δ 8–10, and the absorption maxima (λmax) in
UV spectra are observed at 222 nm.2 Several synthetic meth-
ods employing reduction of an aromatic nitro group and cycli-
zation have been described with somewhat limited
applicability and functional group tolerance. As reducing
reagents, Zn/NH4Cl,5 Pd/H2,6 and Pb (TEAF)7 were typically
used, leading to the generation of 1-hydroxyindole com-
pounds. Similar to indoles, 1-hydroxyindoles are known to
be biologically and environmentally friendly functional moi-
eties, which serve as surrogates for indoles.8 As a result, the
1-hydroxyindole structure could serve as a useful building
block for complex biomolecules and natural products. Recent
studies have shown that these compounds display several
types of biological activity such as antiproliferative9,10 and
antibiotic activities,8 platelet aggregation inhibition,11 and
the ability to spin-trap hydroxy radicals.12 However, studies
on these compounds have suffered from few preparative syn-
thetic methods and the lack of a broad range of derivatives. In
1
OH
1
Experimental
General. Melting points were measured using a Buchi B-545
melting point apparatus (Flawil, Switzerland) and are uncor-
rected. 1H (300 MHz) and 13C (75 MHz) NMR spectra were
obtained on a Bruker DRX 300 spectrometer (Rheinstetten,
Germany), and the chemical shift values are expressed in δ
units relative to tetramethylsilane (TMS). Mass spectra were
obtained by EI or electrospray ionization (ESI). Fourier trans-
form infrared (FT-IR) spectra were recorded on a Perkin-
Elmer Spectrum GX spectrometer (Santa Clara, CA, USA),
and the frequencies (ν) are expressed in reciprocal centimeters
(cm−1). Analytical thin-layer chromatography (TLC) was
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
82

Article
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
conducted on glass plates (0.25 mm) coated with silica gel
(20 × 20 cm; Aldrich No. Z12272-6 [St. Louis, MO, USA]).
Column chromatography was conducted using Merck silica
gels (St. Louis, MO, USA) (230–400 mesh). The chemicals
were purchased commercially and, if needed, distilled before
use. High-performance liquid chromatography (HPLC) ana-
lyses were conducted using the following Waters Associates
Units: 515 A pump, 515 B pump, dual λ absorbance 2487
detector, 717 plus autosampler, and C18 μBondapak (stainless
steel) column (3.9 × 300 mm). The product analyses were per-
formed using a linear gradient condition: 80% A (aqueous
0.025 M triethylammonium acetate, pH 6.5), 20% B (acetoni-
trile) isocratic for 3 min, then to 10% A, 90% B in 30 min. The
flow rate was 1 mL/min, and the eluent was monitored at
254 nm. The HPLC solvents were filtered (aqueous solution
with Millipore HVLP [Billerica, MA, USA], 0.45 mm; aceto-
nitrile with Millipore HV, 0.45 mm) and degassed before use.
General Procedure for the Synthesis of Ketoesters 4. To a
stirred mixture of NaH (60% in mineral oil, 0ꢁ.56 g, 14 mmol,
4.0 equiv) in anhydrous DMF (20 mL) at 0 C was added a
solution of nitrotoluene (3, 3.4 mmol, 1.0 equiv) in anhydrous
reaction mixture was cooled to room temperature and purified
by Preparative thin layer chromatography (PTLC) or column
chromatography to afford the title compound 1.
Methyl 3-[(acetylthio)methyl]-4-bromo-1-hydroxy-1H-
indole-2-carboxylate (1xa). Use of thiolacetic acid (36 μL,
0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (6 h) afforded the title compound 1xa (24 mg,
o
67%) as a yellow solid. M.p. 127–128 C; Rf 0.24 (1:3
EtOAc/Hexanes); HPLC tR 22.2 min; IR (KBr) 3435, 3025,
1
2924, 1601, 1492, 1452, 1028, 757, 697, 540 cm−1; H
NMR (300 MHz, CD3CN) δ 9.38 (br s, 1H), 7.47 (d, J =
8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz,
1H), 4.83 (s, 2H), 3.95 (s, 3H), 2.27 (s, 3H); 13C NMR
(75 MHz, CD3CN) δ 196.3, 162.5, 137.9, 127.8, 127.2,
127.0, 120.7, 116.0, 115.0, 110.9, 53.3, 30.9, 25.3; MS m/z
379 [M + Na]+; HRMS (+ESI) calcd for C13H12BrNNaO4S
[M + Na]+ 379.9568, found 379.9562.
Methyl 3-[(benzoylthio)methyl]-4-bromo-1-hydroxy-
1H-indole-2-carboxylate (1xb). Use of thiobenzoic acid
(59 μL, 0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (6 h) afforded the title compound 1xb
ꢁ
DMF (5 mL). After stirring for 5 min at 0 C, a solution of
dimethyl oxalate (2.0 g, 17 mmol, 5.0 equiv) in anhydrous
DMF (5 mL) was added, and stirring was continued for 1 h
ꢁ
(19 mg, 45%) as a yellow solid. Mp 64–66 C; Rf 0.24 (1:3
ꢁ
at 0 C. The reaction mixture was allowed to warm to room
EtOAc/hexanes); HPLC tR 26.3 min; IR (KBr) 3434, 3025,
1
temperature and stirring was continued until the completion
2923, 1601, 1493, 1452, 1028, 757, 701, 540 cm−1; H
of the reactions (3–23 h). The reaction mixture was quenched
with saturated aqueous NH4Cl (30 mL) at 0 C, extracted with
NMR (300 MHz, CDCl3) δ 9.51 (br s, 1H), 7.91 (d, J = 8.4
Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.52–7.42 (m, 3H), 7.35
(d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 5.04 (s, 2H),
3.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.5, 162.5,
138.3, 137.9, 135.0, 130.3, 128.3, 127.8, 127.3, 127.1,
120.8, 116.1, 114.6, 110.9, 53.4, 25.5; MS m/z 441 [M +
Na]+; HRMS (+ESI) calcd. for C18H14BrNNaO4S [M +
Na]+ 441.9725, found 441.9718.
ꢁ
EtOAc (2 × 30 mL), and washed with H2O (2 × 30 mL). The
organic layers were combined, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by column chroma-
tography (1:6 ! 1:1 EtOAc/hexanes) to give the title
compounds 4x13 (66%), 4y10 (76%), and 4z15 (54%).
General Procedure for the Synthesis of Conjugate Ketoe-
sters 2. To a stirred mixture of NaH (60% in mineral oꢁil, 0.18
g, 4.4 mmol, 1.1equiv) inanhydrous THF (90 mL)at0 C was
added a solution of the ketoesterꢁ(4, 4.0 mmol, 1.0 equiv) in
anhydrous THF (43 mL) at 0 C. After stirring for 1 h,
dimethylmethyleneammonium chloride (1.1 g, 12ꢁ mmol,
3.0 equiv)wasadded, andstirring wascontinued at25 C unꢁ til
the completion of the reaction (1–15 h). After cooling to 0 C,
the reaction mixture was quenched with saturated aqueous
NH4Cl (50 mL), extracted with EtOAc (2 × 100 mL), and
washed with H2O (2 × 100 mL). The organic layers were com-
bined, dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography (1:5 ! 1:1 EtOAc/
hexanes) to give the title compounds 2x13 (68%), 2y16
(72%), and 2z15 (30%).
Methyl
4-bromo-3-[(t-butylthio)methyl]-1-hydroxy-
1H-indole-2-carboxylate (1xc). Use of t-butanethiol
(56 μL, 0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (7 h) afforded the title compound 1xc
o
(29 mg, 78%) as a yellow solid. Mp 95–97 C; Rf 0.51
(2:98 EtOAc/CHCl3); HPLC tR 25.8 min; IR (KBr) 3434,
3025, 2924, 1601, 1493, 1452, 1028, 756, 701, 540 cm−1;
1H NMR (300 MHz, CD3CN) δ 9.36 (s, 1H), 7.45 (dd, J =
8.3, 0.9 Hz, 1H), 7.33 (dd, J = 7.5, 0.9 Hz, 1H), 7.19 (dd,
J = 8.3, 7.5 Hz, 1H), 4.50 (s, 2H), 3.94 (s, 3H), 1.37 (s,
9H); 13C NMR (75 MHz, CD3CN) δ 162.9, 138.0, 127.8,
127.3, 126.2, 120.9, 117.8, 116.5, 110.8, 53.3, 44.0, 31.6,
23.7; MS m/z 394 [M + Na]+; HRMS (+ESI) calcd. for
C15H18BrNNaO3S [M + Na]+ 394.0088, found 394.0066.
Methyl 4-bromo-1-hydroxy-3-[(i-propylthio)methyl]-
1H-indole-2-carboxylate (1xd). Use of i-propanethiol
(47 μL, 0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (4 h) afforded the title compound 1xd
General procedure for 2,3-disubstituted-4-chloro-1-
hydroxyindoles (1). To a mixture of SnCl2 ꢀ 2H2O (0.33–-
0.48 mmol, 3.3–4.8 equiv) and 4 Å molecular sieves (10 wt
%) in DME (0.5 mL) was added nucleophile (0.50 mmol,
5.0 equiv), and the mixture was stirred for 30 min at room tem-
perature. Then, the conjuꢁgate ketoester (2, 0.10 mmol, 1.0
equiv) was added at 25 C and the reaction mixture was
ꢁ
(25 mg, 69%) as a yellow solid. M.p. 38–39 C; Rf 0.52
ꢁ
warmed to 45 C. After stirring for 3–25 h in the dark, the
(1:1 EtOAc/hexanes); HPLC tR 24.3 min; IR (KBr) 3434,
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
83

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
3025, 2924, 1601, 1493, 1452, 1028, 756, 699, 540 cm−1; 1H
NMR (300 MHz, CD3CN) δ 9.18 (br s, 1H), 7.47 (dd, J = 8.3,
0.9Hz, 1H), 7.35(dd, J=7.5, 0.9Hz, 1H), 7.21(dd, J=8.3, 7.5
Hz, 1H), 4.49 (s, 2H), 3.95 (s, 3H), 2.99 (septet, J = 6.7 Hz,
1H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CD3CN)
δ 163.0, 138.3, 127.9, 127.2, 125.9, 120.6, 119.4, 116.6,
110.9, 53.3, 36.5, 25.6, 24.5; MS m/z 379 [M + Na]+; HRMS
(+ESI) calcd. for C14H16BrNNaO3S [M + Na]+ 379.9932,
found 379.9923.
Methyl 3-[(acetylthio)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1ya). Use of thiolacetic acid (36 μL,
0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (6 h) afforded the title compound 1ya (17 mg,
o
55%) as a yellow solid. M.p. 105–107 C; Rf 0.31 (1:2
EtOAc/Hexanes); HPLC tR 22.4 min; IR (KBr) 3435, 3025,
2923, 1492, 1258, 756 cm−1; 1H NMR (300 MHz, CD3CN)
δ 9.23 (br s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.28 (t, J = 7.9
Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 4.80 (s, 2H), 3.95 (s,
3H), 2.27 (s, 3H); 13C NMR (75 MHz, CD3CN) δ 196.3,
162.5, 138.0, 128.4, 127.6, 126.7, 123.5, 119.5, 114.8,
110.3, 53.3, 30.8, 25.6; MS m/z 336 [M + Na]+; HRMS
(+ESI) calcd. for C13H12ClNNaO4S [M + Na]+ 336.0073,
found 336.0068.
Methyl 4-bromo-3-[(t-butyloxy)methyl]-1-hydroxy-1H-
indole-2-carboxylate (1xe). Use of t-butanol (48 μL,
0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (3 h) afforded the title compound 1xe (8.9 mg,
o
25%) as a yellow solid. M.p. 106–112 C; Rf 0.45 (1:2
EtOAc/hexanes); HPLC tR 23.5 min; IR (KBr) 3168, 3025,
2924, 1601, 1492, 1181 cm−1; 1H NMR (300 MHz, CD3CN)
δ 9.28 (br s, 1H), 7.45 (dd, J = 8.3, 0.8 Hz, 1H), 7.35 (dd, J =
7.5, 0.8 Hz, 1H), 7.18 (dd, J = 8.3, 7.5 Hz, 1H), 5.01 (s, 2H),
3.94 (s, 3H), 1.30 (s, 9H); 13C NMR (75 MHz, CD3CN) δ
162.9, 137.6, 127.4, 127.2, 127.1, 121.4, 117.7, 116.5,
110.6, 74.3, 54.1, 53.3, 28.5; MS m/z 378 [M + Na]+; HRMS
(+ESI) calcd. for C15H18BrNNaO4 [M + Na]+ 378.0317,
found 378.0310.
Methyl 3-[(benzoylthio)methyl]-4-chloro-1-hydroxy-
1H-indole-2-carboxylate (1yb). Use of thiobenzoic acid
(59 μL, 0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (5 h) afforded the title comꢁpound 1yb
(20 mg, 53%) as a yellow solid. M.p. 110–111 C; Rf 0.40
(1:1 EtOAc/hexanes); HPLC tR 27.4 min; IR (KBr) 3435,
1
3025, 2923, 1492, 756 cm−1; H NMR (300 MHz, CDCl3)
δ 9.40 (br s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.65–7.58 (m,
1H), 7.54–7.40 (m, 3H), 7.29 (t, J = 8.3 Hz, 1H), 7.14 (d,
J = 7.4 Hz, 1H), 5.01 (s, 2H), 3.96 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 192.5, 162.5, 138.2, 137.9, 134.9,
130.2, 128.4, 128.2, 127.6, 126.8, 123.6, 119.6, 114.4,
110.3, 53.3, 25.7; MS m/z 398 [M + Na]+; HRMS (+ESI)
calcd. for C18H14ClNNaO4S [M + Na]+ 398.0230, found
398.0224.
Methyl 4-bromo-1-hydroxy-3-[(i-propyloxy)methyl]-
1H-indole-2-carboxylate (1xf ). Use of i-propanol (38 μL,
0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (4 h) afforded the title compound 1xf (11 mg,
ꢁ
33%) as a yellow solid. Mp 68–70 C; Rf 0.49 (1:1 EtOAc/
hexanes); HPLC tR 21.5 min; IR (KBr) 3433, 3025, 2925,
1
1601, 1493, 1452, 1028, 757, 703, 540 cm−1; H NMR
Methyl 4-chloro-1-hydroxy-3-[(i-propylthio)methyl]-
1H-indole-2-carboxylate (1yc). Use of i-propanethiol
(51 μL, 0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (5 h) afforded the title compound 1yc
(300 MHz, CD3CN) δ 9.27 (br s, 1H), 7.44 (dd, J = 8.3, 0.7
Hz, 1H), 7.34 (dd, J = 7.5, 0.7 Hz, 1H), 7.17 (dd, J = 8.3,
7.5 Hz, 1H), 5.04 (s, 2H), 3.95 (s, 3H), 3.81 (septet, J = 6.1
Hz, 1H), 1.19 (d, J =6.1Hz, 6H); 13C NMR (75 MHz, CD3CN)
δ 162.8, 137.7, 127.5, 127.3, 127.2, 121.5, 117.3, 116.6,
110.7, 72.4, 60.2, 53.3, 23.0; MS m/z 364 [M + Na]+; HRMS
(+ESI) calcd. for C14H16BrNNaO4 [M + Na]+ 364.0160,
found 364.0157.
o
(24 mg, 77%) as a yellow solid. M.p. 49–50 C; Rf 0.52
(1:1 EtOAc/hexanes); HPLC tR 24.0 min; IR (KBr) 3433,
3025, 2924, 1601, 1493, 1452, 1028, 757, 704, 540 cm−1;
1H NMR (300 MHz, CD3CN) δ 9.18 (br s, 1H), 7.42 (dd,
J = 8.3, 0.9 Hz, 1H), 7.29 (dd, J = 8.3, 7.5 Hz, 1H), 7.14
(dd, J = 7.5, 0.9 Hz, 1H), 4.46 (s, 2H), 3.95 (s, 3H), 2.97 (sep-
tet, J = 6.7 Hz, 1H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR
(75 MHz, CD3CN) δ 162.9, 138.5, 128.8, 127.5, 125.8,
123.4, 121.8, 119.5, 110.3, 53.2, 36.4, 26.0, 24.4; MS m/z
336 [M + Na]+; HRMS (+ESI) calcd. for C14H16ClNNaO3S
[M + Na]+ 336.0437, found 336.0430.
Methyl 4-bromo-1-hydroxy-3-[(pentyloxy)methyl]-1H-
indole-2-carboxylate (1xg). Use of n-pentanol (54 μL,
0.50 mmol, 5.0 equiv), 2x (31 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (3 h) afforded the title compoꢁund 1xg (18.5 mg,
50%) as a yellow solid. M.p. 53–55 C; Rf 0.57 (2:98
EtOAc/CHCl3); HPLC tR 26.1 min; IR (KBr) 3435, 3025,
1
2924, 1601, 1493, 1452, 1028, 757, 701, 540 cm−1; H
Methyl 3-[(t-butyloxy)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1yd). Use of t-butanol (48 μL,
0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (3 h) afforded the title compound 1yd (7.8 mg,
NMR (300 MHz, CD3CN) δ 9.36 (br s, 1H), 7.47–7.38 (m,
1H), 7.37–7.27 (m, 1H), 7.22–7.11 (m, 1H), 5.02 (s, 2H),
3.93 (s, 3H), 3.53 (t, J = 6.5 Hz, 2H), 1.64–1.41 (m, 2H),
1.40–1.16 (m, 4H), 0.97–0.76 (m, 3H); 13C NMR (75 MHz,
CD3CN) δ 162.8, 137.7, 127.5, 127.3, 127.2, 121.4, 116.9,
116.5, 110.6, 71.1, 62.3, 53.3, 30.7, 29.7, 23.6, 14.7; MS
m/z 371 [M+H]+; HRMS (+ESI) calcd. for C16H20BrNNaO4
[M+Na]+ 392.0473, found 392.0470.
ꢁ
23%) as a yellow solid. M.p. 118–119 C; Rf 0.45 (1:2
EtOAc/hexanes); HPLC tR 23.1 min; IR (KBr) 3161, 3025,
2923, 1601, 1492, 757 cm−1; 1H NMR (300 MHz, CD3CN)
δ 9.44 (br s, 1H), 7.37 (dd, J = 8.3, 0.9 Hz, 1H), 7.23 (t, J =
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
84

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
7.9Hz, 1H), 7.11(dd, J=7.5, 0.9Hz, 1H), 4.97(s, 1H), 3.91(s,
3H), 1.26 (s, 9H); 13C NMR (75 MHz, CD3CN) δ 162.8,
137.7, 128.7, 127.1, 127.0, 123.5, 120.2, 117.3, 110.0,
74.2, 54.7, 53.2, 28.4; MS m/z 334 [M + Na]+; HRMS
(+ESI) calcd. for C15H18ClNNaO4 [M + Na]+ 334.0822,
found 334.0817.
HPLC tR 25.0 min; IR (KBr) 3433, 3025, 2924, 1601, 1493,
1452, 1028, 757, 696, 540 cm−1; 1H NMR (300 MHz,
CD3CN) δ 9.22 (br s, 1H), 7.96–7.89 (m, 2H), 7.82 (d, J =
8.2 Hz, 1H), 7.66–7.58 (m, 1H), 7.54–7.43 (m, 3H), 7.39 (t,
J = 7.1 Hz, 1H), 7.18 (t, J = 7.1 Hz, 1H), 4.82 (s, 2H), 3.95
(s, 3H); 13C NMR (75 MHz, CD3CN) δ 192.8, 162.9,
138.2, 136.8, 135.0, 130.3, 138.3, 127.5, 125.0, 122.9,
122.4, 122.0, 116.9, 111.1, 53.0, 24.6; MS m/z 364 [M +
Na]+; HRMS (+ESI) calcd. for C18H15NNaO4S [M + Na]+
364.0619, found 364.0614.
Methyl 3-[(t-butylthio)methyl]-1-hydroxy-1H-indole-2-
carboxylate (1zc). Use of t-butanethiol (56 μL, 0.50 mmol,
5.0 equiv), 2z (24 mg, 0.10 mmol, 1.0 equiv), and SnCl2 ꢀ 2
H2O (75 mg, 0.33 mmol, 3.3 equiv) in general procedure
(5 h) afforded the tiꢁtle compound 1zc (18 mg, 60%) as a yellow
solid. M.p. 88–90 C; Rf 0.61 (1:1 EtOAc/hexanes); HPLC tR
23.7min;IR(KBr)3435, 3025, 2924, 1601, 1493, 1452, 1028,
757, 703, 540 cm−1; 1H NMR (300 MHz, CD3CN) δ 9.07 (s,
1H), 7.81–7.67 (m, 1H), 7.49–7.30 (m, 2H), 7.21–7.07 (m,
1H), 4.26 (s, 2H), 3.93 (s, 3H), 1.38 (s, 9H); 13C NMR
(75 MHz, CD3CN) δ 162.8, 136.8, 130.2, 127.1, 124.2,
123.1, 121.9, 121.8, 110.8, 52.6, 43.5, 31.1, 23.3; MS m/z
316 [M + Na]+; HRMS (+ESI) calcd. for C15H19NNaO3S
[M + Na]+ 316.0983, found 316.0977.
Methyl 4-chloro-1-hydroxy-3-[(methyloxy)methyl]-1H-
indole-2-carboxylate (1ye). Use of methanol (20 μL,
0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (3 h) afforded the title compound 1ye (16 mg,
ꢁ
59%) as a yellow solid. M.p. 67–69 C; Rf 0.47 (1:1
EtOAc/hexanes); HPLC tR 17.6 min; IR (KBr) 3437, 3025,
1
2924, 1601, 1493, 1452, 1028, 757, 703, 540 cm−1; H
NMR (300 MHz, CDCl3) δ 10.49 (s, 1H), 7.29–7.21 (m,
1H), 7.16–6.96 (m, 2H), 5.06 (s, 2H), 3.96 (s, 3H), 3.51 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 164.0, 134.5, 128.0,
126.0, 122.5, 121.6, 118.5, 114.1, 108.6, 63.8, 58.1, 52.7;
MS m/z 292 [M + Na]+; HRMS (+ESI) calcd. for
C12H12ClNNaO4 [M + Na]+ 292.0353, found 292.0315.
Methyl 4-chloro-3-[(heptyloxy)methyl]- 1-hydroxy-1H-
indole-2-carboxylate (1yf ). Use of n-heptanol (78 μL,
0.50 mmol, 5.0 equiv), 2y (27 mg, 0.10 mmol, 1.0 equiv),
and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in general
procedure (4 h) afforded the title compound 1yf (20.5 mg,
Methyl
3-[(cyclohexylthio)methyl]-1-hydroxy-1H-
ꢁ
58%) as a yellow solid. M.p. 43–45 C; Rf 0.49 (2:98
indole-2-carboxylate (1zd). Use of cyclohexyl thiol
(61 μL, 0.50 mmol, 5.0 equiv), 2z (24 mg, 0.10 mmol, 1.0
equiv), and SnCl2 ꢀ 2H2O (75 mg, 0.33 mmol, 3.3 equiv) in
general procedure (4 h) afforded the title compound 1zd
EtOAc/CHCl3); HPLC tR 28.4 min; IR (KBr) 3434, 3025,
1
2924, 1601, 1493, 1452, 1028, 757, 703, 540 cm−1; H
NMR (300 MHz, CD3CN) δ 9.40 (br s, 1H), 7.38–7.31 (m,
1H), 7.28–7.18 (m, 1H), 7.15–7.07 (m, 1H), 5.00 (s, 2H),
3.92 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 1.60–1.47 (m, 2H),
1.39–1.13 (m, 8H), 0.93–0.79 (m, 3H); 13C NMR (75 MHz,
CD3CN) δ 162.7, 137.8, 128.8, 127.3, 127.0, 123.6, 120.2,
116.5, 110.1, 71.2, 62.9, 53.3, 33.0, 31.0, 30.2, 27.4, 23.8,
14.8; MS m/z 355 [M + H]+; HRMS (+ESI) calcd. for
C18H24ClNNaO4 [M + Na]+ 376.1292, found 376.1289.
Methyl 3-[(acetylthio)methyl]-1-hydroxy-1H-indole-2-
carboxylate (1za). Use of thiolacetic acid (36 μL, 0.50 mmol,
5.0 equiv), 2z (24 mg, 0.10 mmol, 1.0 equiv), and SnCl2ꢀ2H2O
(108 mg, 0.48 mmol, 4.8 equiv) in general procedure (25 h)
afforded the title compound 1za (15 mg, 55%) as a yellow
ꢁ
(12.8 mg, 40%) as a yellow solid. M.p. 49–51 C; Rf 0.36
(1:3 EtOAc/hexanes); HPLC tR 25.8 min; IR (KBr) 3434,
3025, 2924, 1601, 1493, 1452, 1028, 757, 696, 540 cm−1;
1H NMR (300 MHz, CD3CN) δ 9.18 (br s, 1H), 7.72 (dd,
J = 8.1, 1.6 Hz, 1H), 7.50–7.34 (m, 2H), 7.23–7.10 (m,
1H), 4.23 (s, 2H), 3.92 (s, 3H), 2.73–2.53 (m, 1H),
1.13–1.80 (m, 10H); 13C NMR (75 MHz, CD3CN) δ 163.3,
137.3, 127.4, 124.7, 123.3, 122.3, 122.1, 119.9, 111.1,
52.9, 44.8, 35.0, 27.3, 27.0, 25.1; MS m/z 320 [M + H]+;
HRMS (+ESI) calcd. for C17H21NNaO3S [M + Na]+
342.1140, found 342.1129.
o
solid. M.p. 38–40 C; Rf 0.46 (7:3 Ether/Hexanes); HPLC
Results and Discussion
tR 20.1 min; IR (KBr) 3434, 3025, 2925, 1601, 1493, 1452,
1
1028, 757, 703, 540 cm−1; H NMR (300 MHz, CD3CN) δ
In order to perform reactions for the formation of the intended
highly substituted and hindered 1-hydroxyindole-2-carboxy-
lates, it was necessary to first prepare the appropriate sub-
strates, conjugate ketoesters 2. Thus, two-step synthetic
procedures with minor modifications based on our previous
procedure13 were applied leading to the synthesis of conjugate
ketoesters 2x,13 2y,16 and 2z,15 as shown in Scheme 1. First,
toluene derivatives 3 were treated with NaH and dimethyl oxa-
late to give ketoesters 4x,13 4y,10 and 4z.15 Then, subsequent
treatment of 4 with dimethylmethyleneammonium chloride in
the presence of NaH produced the conjugate ketoesters 2. The
results of these reactions fluctuated with the substituent group
(X) in 3. In general, the first steps for all three derivatives
9.25 (s, 1H), 7.78–7.69 (m, 1H), 7.50–7.33 (m, 2H),
7.21–7.10 (m, 1H), 4.60 (s, 2H), 3.93 (s, 3H), 2.29 (s, 3H);
13C NMR (75 MHz, CD3CN) δ 196.6, 162.8, 136.8, 128.5,
127.5, 122.3, 122.0, 118.0, 117.3, 111.0, 52.9, 30.8, 24.4;
MS m/z 302 [M + Na]+; HRMS (+ESI) calcd. for
C13H13NNaO4S [M + Na]+ 302.0463, found 302.0468.
Methyl 3-[(benzoylthio)methyl]-1-hydroxy-1H-indole-
2-carboxylate (1zb). Use of thiobenzoic acid (59 μL,
0.50 mmol, 5.0 equiv), 2z (24 mg, 0.10 mmol, 1.0 equiv),
andSnCl2ꢀ2H2O(97mg, 0.43mmol, 4.3equiv)ingeneralpro-
cedure (23 h) afforded the titleꢁ compound 1zb (29 mg, 86%) as
a yellow solid. M.p. 59–60 C; Rf 0.43 (7:3 Ether/hexanes);
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
85

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
X
X
X
higher yield (entry 3, 78%) than a secondary thiol (entry
4, 69%) and primary thiols (e.g., BnSH, 55%).13 The good
results with thiols were consistent with our previous results
usingdifferentsubstrates suchas2-(20-nitrophenyl)-1-phenyl-
prop-2-en-1-one.17 Then, the reactions of 2x with alcohols as
nucleophiles were executed to afford the products 1xe and 1xg
in modest to low yields. In general, reactions with alcohols
provided lower yields of products than the corresponding
thiols. Inthereaction usingatertiary alcohol(entry5, t-BuOH)
as a hindered nucleophile, the product was acquired through
intensive effort despite of low yield (25%). The secondary
alcohol (entry 6, i-PrOH) gave a better yield than the tertiary
alcohol. Similarly, the primary alcohol (entry 7, n-PenOH)
afforded a better yield than secondary alcohol. Next, the sub-
strate 2y containing a chloro substituent in phenyl ring was
employed, leading to the generation of the corresponding pro-
ducts 1ya–1yf in modest to low yields. In general, the reaction
results were found to be similar to those with the bromo sub-
strates 2x. A secondary thiol provided the best yield (entry
10, 77%) among the nucleophiles used. Primary alcohols
(entries 12 and 13) also provided the products in modest yields
(59% and 58%, respectively). Finally, substrate 2z containing
no substituent in the phenyl ring was employed, and the cor-
responding products 1za–1zd were obtained. The reactions
with thiocarboxylic acids and thiols afforded good to modest
yields. However, in contrast to the results of substrates 2x and
2y, reactions of substrate 2z with alcohols did not provide the
corresponding 1-hydroxyindole products. In addition, we
were interested in the mechanism for this transformation. As
depicted in Scheme 2, these reactions are believed to occur
through reduction of the nitro group in 2 to give hydroxyla-
mine (or nitroso) 5, condensation of 5 to give the conjugate
nitrone 6, and 1,5-addition of 6 with a nucleophile, finally
leading to the generation of 1, which is consistent with our pre-
vious studies.13 Taken together, these results provided an
efficient method to synthesize highly substituted and hindered
1-hydroxyindole-2-carboxylates1usingweaknucleophiles of
low reactivity and/or high steric hindrance.
NaH
(CO2Me)2
Me
CO2Me
CO2Me
N
Cl
O
O
DMF
3-23 h
NaH
THF
8-15 h
NO2
NO2
NO2
3x X=Br
3y X=Cl
3z X=H
4x X= Br (66%)
4y X= Cl (76%)
4z X= H (54%)
2x X = Br (68%)
2y X = Cl (72%)
2z X = H (30%)
Scheme 1. Synthesis of conjugate ketoesters 2.
worked in reasonable yields. In the second steps, halogenated
substrates 4x and 4y underwent the reactions under the general
conditions (e.g., time and amounts of reagents) to provide sub-
strates 2x and 2y in good yields. However, substrate 4z con-
taining a hydrogen instead of a halogen gave a poorer
result. In particular, the reaction did not go to completion even
after a prolonged time, and the longer reaction time led to
lower yields of the products and gradual formation of a side
product that was polar and poorly soluble in organic solvents.
Unfortunately, extensive efforts to clarify the reaction and to
identify the structure of the side product were inconclusive. It
was supposed that the product 2z underwent further
reaction(s) due to the reactivity of the vinyl group in 2z.
Finally, upon modulating the reaction conditions, such as
the amount of dimethylmethyleneammonium chloride, tem-
perature, and reaction time, 2z was obtained in 30% yield.
Taken together, the three substrates 2 were efficiently synthe-
sized in reasonable yields.
With the goal of synthesizing new target compounds 1,
stannous chloride (SnCl2) was chosen based on its appropriate
reducing power18 and our previous results.13 Thus, we set out
to expand the scope of the reactions of 2 by incorporating rel-
atively weak nucleophiles. In particular, we focused on the use
of nucleophiles of low reactivity and/or high steric hindrance,
such as thiocarboxylic acids, and secondary and tertiary thiols
and alcohols to provide new, highly substituted, and hindered
1-hydroxyindole-2-carboxylates 1, which would be difficult
to construct otherwise. Thus, conjugate ketoesters 2 were trea-
ted with SnCl2 ꢀ 2H2O (3.3–4.8 equiv) in the presence of a
nucleophile and 4 Å molecular sieves to give 1, and the results
are shown in Table 1.
First, the substrate 2x containing a bromo substituent in
phenyl ringwasemployed. So, thereactionsof 2xwithnucleo-
philes of low reactivity such as thiocarboxylic acids were
examined. Significantly, the reaction with thiolacetic acid suc-
cessfully provided product 1xa in good yield (entry 1, 67%).
Similarly, reaction with thiobenzoic acid provided product
1xb in modest yield (entry 2, 45%), which supported the high
reactivity of the electrophile involved in this reaction. In par-
ticular, thioacids are known to display much lower nucleophi-
licity than thiols or alcohols and, therefore, the successful
application of these nucleophiles deserved to be emphasized,
which differed from our previous study16 using common thiol
and alcohol nucleophiles. Then, the reactions of 2x with ster-
ically hindered tertiary and secondary thiols as nucleophiles
were conducted to give the products 1xc and 1xd in good
yields. Interestingly, reactions with hindered thiols provided
good results, and, in particular, a tertiary thiol gave a slightly
Conclusion
The syntheses of new, highly substituted, and hindered 1-
hydroxyindole-2-carboxylates 1arereported. UsingSnCl2 ꢀ 2
H2O and substrates 2, obtained by two-step synthetic
sequences, the synthesis of 1-hydroxyindole-2-carboxylates
1 was achieved, particularly with relatively weak nucleophiles
of low reactivity and/or high steric hindrance, such as thiocar-
boxylic acids, and tertiary thiols and alcohols. We believe that
these reactions occurred through reduction, condensation, and
nucleophilic 1,5-addition, leading to the generation of 1.
Acknowledgments. This Research was supported by the
Duksung Women’s University Research Grant 2013.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
86

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
87

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
88

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
89

BULLETIN OF THE
Article
1-Hydroxyindole-2-carboxylates
KOREAN CHEMICAL SOCIETY
5. M. Somei, Chem. Pharm. Bull. 1986, 34, 4109.
6. F. J. Reboredo, M. Treus, J. C. Estevez, L. Castedo, R. J. Setevez,
Synlett 2002, 999.
X
X
reduction
CO2Me condensation
CO2Me
O
7. A. Wong, J. T. Kuethe, I. W. Davies, J. Org. Chem. 2003,
68, 9865.
8. S. N. Lavrenov, A. M. Korolev, Nucleos. Nucleot. Nucl. 2001,
20, 1881.
O
NO2
NHOH
(or N=O)
2
5
9. C. Granchi, E. C. Calvaresi, T. Tuccinardi, I. Paterni,
M. Macchia, A. Martinelli, F. Minutolo, Org. Biomol. Chem.
2013, 11, 6588.
10. C. Granchi, S. Roy, C. Giacomelli, M. Macchia,
T. Tuccinardi, A. Martinelli, F. Minutolo, J. Med. Chem.
2011, 54, 1599.
11. M. Somei, K. Yamada, M. Hasegawa, M. Tabata,
Y. Nagahama, H. Morikawa, F. Yamada, Heterocycles 1996,
43, 1855.
X
X
Nu
CO2Me
1,5-addition
NuH
CO2Me
N
N
O
12. G. M. Rosen, P. Tsai, E. D. Barth, G. Dorey, P. Casara,
M. Spedding, H. J. Halpen, J. Org. Chem. 2000, 65, 4460.
13. K. C. Nicolaou, S. H. Lee, A. A. Estrada, M. Zak, Angew. Chem.
Int. Ed. 2005, 44, 3736.
14. K. C.Nicolaou, A. A. Estrada, S. H. Lee,G. C. Freestone, Angew.
Chem. Int. Ed. 2006, 45, 5364.
OH
conjugate nitrone
1
6
Scheme 2. Proposed pathway for the formation of 1-hydroxyindole-
2-carboxylates 1.
15. K. C. Nicolaou, A. A. Estrada, G. C. Freestone, S.
H. Lee, X. Alvarez-Mico, Tetrahedron 2007, 63, 6088.
16. Y. K. Park, H. Kim, D. S. Kim, H. Cho, A. Moon,
C. Jeong, H.-R. Yoon, S. H. Lee, Bull. Korean Chem. Soc.
2015, 36, 2095.
17. S. H. Lee, H. Kim, Y. K. Park, H. Cho, Synlett 2015,
26, 1069.
18. F. D. Bellamy, K. Ou, Tetrahedron Lett. 1984, 25, 839.
References
1. R. M. Acheson, D. M. Littlewood, H. E. Rosenburg, J. Chem.
Soc. Chem. Commun. 1974, 671.
2. M. Somei, Heterocycles 1999, 50, 1157.
3. M. Somei, Adv. Heterocycl. Chem. 2002, 82, 101.
4. K. Nakagawa, N. Aoki, H. Mukaiyama, M. Somei, Heterocycles
1992, 34, 2269.
Bull. Korean Chem. Soc. 2016, Vol. 37, 82–90
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
90