Synthesis of new 2,3-disubstituted 4-chloro-1-hydroxyindoles

Article abstract of DOI:10.1002/bkcs.10410

The syntheses of new 2,3-disubstituted 4-chloro-1-hydroxyindoles were described. The conjugate nitro ketoester was reacted with various thiol and alcohol nucleophiles by the action of stannous chloride dihydrate through the unique processes of reduction o

Full text of DOI:10.1002/bkcs.10410

Article
DOI: 10.1002/bkcs.10410
BULLETIN OF THE
Y. K. Park et al.
KOREAN CHEMICAL SOCIETY
Synthesis of New 2,3-Disubstituted 4-Chloro-1-hydroxyindoles
Yeon Kyeong Park,†,‡ Hyejin Kim,†,‡ Dong Sun Kim,†,‡ Hyunsung Cho,†,‡ Aree Moon,†,‡
Choonsik Jeong,†,‡ Hye-Ran Yoon,†,‡ and Sang Hyup Lee†,‡,
*
†College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea.
*E-mail: sanghyup@duksung.ac.kr
‡Innovative Drug Center, Duksung Women's University, Seoul 132-714, Republic of Korea
Received May 6, 2015, Accepted May 27, 2015, Published online July 27, 2015
The syntheses of new 2,3-disubstituted 4-chloro-1-hydroxyindoles were described. The conjugate nitro ketoe-
ster was reacted with various thiol and alcohol nucleophiles by the action of stannous chloride dihydrate
through the unique processes of reduction of nitro group, intramolecular condensation, and addition of nucleo-
philes in one pot, to provide multisubstituted 1-hydroxyindoles. The reactions with thiol nucleophiles provided
better results than those with alcohols, and, in particular, secondary and tertiary thiols provided best yields.
Keywords: Heterocycles, Nucleophilic addition, Reduction, Tin, Cyclization
Introduction
Experimental
1-Hydroxyindoles contain a hydroxy group at N(1) instead of
the hydrogen in indoles, and are thus supposed to retain
slightly but meaningfully different physical and chemical
properties compared with indoles. Earlier studies have
revealed the general features and properties of this unique
structure.1 Because of the presence of the hydroxy group, 1-
hydroxyindoles are more polar and acidic (pKa 8.1–9.8) than
indoles.1a Although they are rarely found in natural products,
their alkoxy forms, 1-alkoxyindoles, are found in some of the
natural products.2,3 In addition, they could be useful building
blocks for complex molecules and serve as surrogates of
indoles.4 Recent studies have shown that these compounds
display several types of biological activities such as
antiproliferative,5,6 antibiotic,4 and platelet aggregation inhib-
itory activities.7 However, much remains unknown regarding
their chemistry and biological properties, and the studies on
these compounds have been somewhat limited by the scarcity
of tolerable synthetic methods and a narrow range of diversity
of the reported compounds. Because of the growing interest,
we previously reported the synthesis of 1-hydroxyindole
derivatives and their application to more elaborate molecules,
which demonstrated the potential significance of
1-hydroxyindoles.8–10 Thus, as part of our continued efforts
to generate novel multisubstituted 1-hydroxyindoles, we here
report the synthesis of new 2,3-disubstituted 4-chloro-1-
hydroxyindoles 1. This method comprises a one-pot reaction
involving reduction of a nitro group, condensation to give a
conjugate nitrone, and addition of a nucleophile. To the best
of our knowledge, these types of reactions are rarely reported
except a few cases in our previous investigations.8–10
General. Melting points were measured in open capillary
tubes using Buchi B-545 (Buchi Corp., Flawil, CH, Switzer-
land) melting point apparatus and are uncorrected. Fourier
transform-infrared spectroscopy (FT-IR) spectra were
measured on a Perkin-Elmer Spectrum GX spectrometer
(Perkin-Elmer, Waltham, MA, USA) and frequencies (ν) are
1
given in reciprocal centimeters (cm−1). H (300 MHz) and
13C (75 MHz) NMR spectra were obtained on a Bruker
DRX 300 spectrometer (Bruker Inc., Madison, WI, USA)
and the δ values for chemical shift are expressed as units rel-
ative to tetramethylsilane (TMS). Mass spectra were obtained
by EI or ESI method. Analytical thin layer chromatography
(TLC) was conducted on glass plates (0.25 mm) coated with
silica gel (20 × 20 cm; Aldrich No. Z12272-6) (Sigma-
Aldrich, St. Louis, MO, USA). Column chromatography
wasperformedusing Merck silica gels(230–400 mesh; Merck
Corp., Kenilworth, NJ, USA). Most ofthechemicals werepur-
chased commercially and, if needed, distilled before use.
HPLC analyses were conducted using the following Waters
Associate Units: 515 A pump, 515 B pump, dual λ absorbance
2487 detector, 717 plus autosampler, and Hypersil ODS col-
umn (4.6 × 300 mm). The product analyses were performed
using linear gradient condition: from 100% A (aqueous
0.025 M triethylammonium acetate, pH 6.5), 0% B (acetoni-
trile) to 80% A, 20% B in 1 min, then to 10% A, 90% B in
30 min. The flow rate was 1 mL/min, and the eluent was mon-
itored at 254 nm. The HPLC solvents were filtered (aqueous
solution with Millipore high-volume and low-pressure
(HVLP), 0.45 mm; acetonitrile with Millipore high-volume
(HV), 0.45 mm) and degassed before use.
Methyl
3-(20-Chloro-60-nitrophenyl)-2-oxopropanoate
(4).6 To a mixture of NaH (60% in mineral oil, 0.56 g,
14 mmol, 4.0 equiv) in anhydrous N,N-Dimethylmethana-
mide (DMF) (20 mL) at 0 ꢀC, a solution of 2-chloro-6-
nitrotoluene (3, 0.58 g, 3.4 mmol, 1.0 equiv) in anhydrous
Bull. Korean Chem. Soc. 2015, Vol. 36, 2095–2100
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BULLETIN OF THE
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4-Chloro-1-hydroxyindoles
KOREAN CHEMICAL SOCIETY
DMF(5 mL)wasadded. After stirringfor5 minat0 ꢀC, asolu-
tion of dimethyl oxalate (2.0 g, 17 mmol, 5.0 equiv) in anhy-
drous DMF (5 mL) was added, and stirring was continued for
1 h at 0 ꢀC. The reaction mixture was allowed to warm to room
temperature and stirred for an additional 3.5 h. The reaction
mixture was quenched with saturated aqueous NH4Cl (30
mL) at 0 ꢀC, extracted with EtOAc (2 × 30 mL), and washed
with H2O (2 × 30 mL). The organic layers were combined,
dried (MgSO4), and concentrated in vacuo. The residue was
purified by column chromatography (1:6 ! 1:1 EtOAc/hex-
anes) to give the title compound 4 (0.67 g, 76%) as a yellow
solid. Mp 58–59 ꢀC; Rf 0.46 (1:2 EtOAc/hexanes); HPLC tR
21.2 min; IR (KBr) 3081, 2923, 1735, 1582, 1531, 1359,
803 cm−1; 1H NMR (300 MHz, CD3CN) δ 7.97 (dd, J = 8.2,
1.2 Hz, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (t, J = 8.1
Hz, 1H), 4.65 (s, 2H), 3.89 (s, 3H); 13C NMR (75 MHz,
CD3CN) δ 190.2, 162.0, 152.2, 138.3, 135.8, 131.0, 128.9,
125.2, 54.4, 42.0; MS m/z 258 [M + H]+; HRMS (+ESI) calcd
for C10H8ClNNaO5 [M + Na]+ 279.9989, found 279.9983.
Methyl 3-(20-Chloro-60-nitrophenyl)-2-oxobut-3-enoate
(2). To a mixture of NaH (60% in mineral oil, 0.18 g, 4.4
mmol, 1.1 equiv) in anhydrous tetrahydrofuran (THF)
(90 mL) at 0 ꢀC, a solution of ketoester (4, 1.0 g, 4.0 mmol,
1.0 equiv) in anhydrous THF (43 mL) was added. After stir-
ring for 1 h, dimethylmethyleneammonium chloride (1.1 g,
12 mmol, 3.0 equiv) was added and stirring was continued
for 15 h at 25 ꢀC. After cooling to 0 ꢀC, the reaction mixture
was quenched with saturated aqueous NH4Cl (10 mL),
extracted with EtOAc (2 × 40 mL), and washed with H2O
(2 × 40 mL). The organic layers were combined, dried
(MgSO4), and concentratedin vacuo. Theresidue waspurified
by column chromatography (1:5 ! 1:1 EtOAc/hexanes) to
give the title compound 2 (0.76 g, 72%) as a yellow solid.
Mp 67–68 ꢀC; Rf 0.44 (1:2 EtOAc/hexanes); HPLC tR 21.7
min; IR (KBr) 3444, 2923, 2849, 1682, 1533, 1492, 1028
cm−1; 1H NMR (300 MHz, CD3CN) δ 8.01 (dd, J = 8.3, 1.2
Hz, 1H), 7.85 (dd, J = 8.1, 1.2 Hz, 1H), 7.62 (t, J = 8.2 Hz,
1H), 6.73 (s, 1H), 6.40 (s, 1H), 3.92(s, 3H); 13C NMR (75
MHz, CD3CN) δ 186.2, 164.6, 151.3, 141.0, 137.2, 136.8,
135.9, 132.1, 131.0, 124.6, 54.3; MS m/z 270 [M + H]+;
HRMS (+ESI) calcd for C11H8ClNNaO5 [M + Na]+
291.9989, found 291.9983.
2.5 equiv) in general procedure (1.5 h) afforded the title com-
pound 1a (27 mg, 75%) as a yellow solid. Mp 101–102 ꢀC; Rf
0.55 (1:2 EtOAc/hexanes); HPLC tR 28.0 min; IR (KBr) 2924,
1600, 1451, 1265, 1028, 841, 749 cm−1; 1H NMR (300 MHz,
CD3CN) δ 9.30 (br s, 1H), 7.41 (dd, J = 8.3, 0.9 Hz, 1H),
7.37–7.16 (m, 6H), 7.12 (dd, J = 7.5, 0.9 Hz, 1H), 4.43
(s, 2H), 3.85 (s, 3H), 3.79 (s, 2H); 13C NMR (75 MHz,
CD3CN) δ 163.0, 140.4, 138.3, 130.2, 129.8, 129.0, 128.2,
127.7, 125.8, 123.6, 119.6, 118.1, 110.3, 53.2, 37.8, 27.7;
MS m/z 362 [M + H]+; HRMS (+EI) calcd for C18H16ClNO3S
[M]+ 361.0539, found 361.0537.
Methyl
3-[(n-Butylthio)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1b). Use of 1-butanethiol (54 μL,
0.50 mmol, 5.0 equiv) and SnCl2ꢁ2H2O (52 mg, 0.25 mmol,
2.5 equiv) in general procedure (1.5 h) afforded the title com-
pound 1b (25 mg, 75%) as a yellow solid. Mp 53–54 ꢀC; Rf
0.46 (2:98 EtOAc/CHCl3); HPLC tR 22.4 min; IR (KBr)
1
3393, 2924, 1713, 1492, 1252, 756 cm−1; H NMR (300
MHz, CD3CN) δ 9.24 (br s, 1H), 7.41 (dd, J = 8.3, 0.9 Hz,
1H), 7.28 (dd, J = 8.3, 7.5 Hz, 1H), 7.13 (dd, J = 7.5, 0.9 Hz,
1H), 4.45 (s, 2H), 3.93 (s, 3H), 2.48 (t, J = 7.3 Hz, 2H),
1.55–1.40 (m, 2H), 1.39–1.20 (m, 2H), 0.87 (t, J = 9.6 Hz,
3H); 13C NMR (75 MHz; CD3CN) δ 162.9, 138.4, 128.8,
127.6, 125.8, 123.4, 119.4, 119.1, 110.2, 53.1, 33.1, 32.3,
26.8, 23.1, 14.3; MS m/z 328 [M + H]+; HRMS (+EI) calcd
for C15H18ClNO3S [M]+ 327.0696, found 327.0697.
Methyl 4-Chloro-3-[(n-hexylthio)methyl]-1-hydroxy-1H-
indole-2-carboxylate (1c). Use of 1-hexanethiol (75 μL,
0.50 mmol, 5.0 equiv) and SnCl2ꢁ2H2O (52 mg, 0.25 mmol,
2.5 equiv) in general procedure (4 h) afforded the title com-
pound 1c (26 mg, 74%) as a yellow solid. Mp 47–48 ꢀC; Rf
0.63 (1:2 EtOAc/hexanes); HPLC tR 31.8 min; IR (KBr)
1
3444, 3025, 1711, 1492, 757 cm−1; H NMR (300 MHz,
CD3CN) δ 9.20 (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),
4.42 (s, 2H), 3.94 (s, 3H), 2.49 (t, J = 7.3 Hz, 2H),
1.55–1.43 (m, 2H), 1.40–1.20 (m, 6H), 0.87 (t, J = 9.6 Hz,
3H); 13C NMR (75 MHz, CD3CN) δ 163.0, 138.5, 128.9,
127.7, 125.8, 123.5, 119.5, 119.3, 110.3, 53.2, 32.8, 32,6.
31.0, 29.8, 27.0, 23.7, 14.7; MS m/z 356 [M + H]+; HRMS
(+EI) calcd for C17H22ClNO3S [M]+ 355.1009, found
355.1011.
General Procedure for 2,3-Disubstituted 4-Chloro-1-
hydroxyindoles (1). To a stirred mixture of SnCl2ꢁ2H2O
(2.5–3.3 equiv) and 4 Å molecular sieves (10 wt %) in
DME (0.5 mL), nucleophile (5.0 equiv) was added, and the
mixture was stirred for 30 min at room temperature. Then,
the conjugate ketoester (2, 27 mg, 0.10 mmol, 1.0 equiv)
was added at 25 ꢀC and the reaction mixture was warmed to
45 ꢀC. After stirring for 1.5–6.5 h in the dark, the reaction mix-
ture was cooled to room temperature and purified by prepar-
ative thin layer chromatography (PTLC) or column
chromatography to afford the title compounds 1.
Methyl
4-Chloro-3-[(cyclohexylthio)methyl]-1-hydroxy-
1H-indole-2-carboxylate (1d). Use of cyclohexanethiol
(63 μL, 0.50 mmol, 5.0 equiv) and SnCl2ꢁ2H2O (52 mg,
0.25 mmol, 2.5 equiv) in general procedure (1.5 h) afforded
the title compound 1d (30 mg, 84%) as a yellow solid. Mp
96–97 ꢀC; Rf 0.64 (3:97 EtOAc/CHCl3); HPLC tR 30.0 min;
IR (KBr) 3435, 3025, 2923, 1601, 1492, 701 cm−1; 1H
NMR (300 MHz; CD3CN) δ 9.24 (br s, 1H), 7.43 (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), 4.45 (s, 2H), 3.94 (s, 3H), 2.72–2.60
(m, 1H), 1.80–1.15 (m, 10H); 13C NMR (75 MHz, CD3CN)
δ 163.0, 138.4, 128.9, 128.7, 127.6, 125.7, 123.5, 119.4,
110.3, 53.3, 44.7, 35.2, 27.4, 27.0, 25.6; MS m/z 354 [M +
Methyl
3-[(Benzylthio)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1a). Use of benzyl mercaptan (60 μL,
0.50 mmol, 5.0 equiv) and SnCl2ꢁ2H2O (52 mg, 0.25 mmol,
Bull. Korean Chem. Soc. 2015, Vol. 36, 2095–2100
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BULLETIN OF THE
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4-Chloro-1-hydroxyindoles
KOREAN CHEMICAL SOCIETY
H]+; HRMS (+EI) calcd for C17H20ClNO3S [M]+ 353.0852,
found 353.0850.
117.3, 115.2, 108.7, 69.4, 61.4, 51.9, 31.7, 19.2, 13.1; MS
m/z 312 [M + H]+; HRMS (+EI) calcd for C15H18ClNO4
[M]+ 311.0924, found 311.0926.
Methyl
3-[(t-Butylthio)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1e). Use of t-butanethiol (56 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (52 mg, 0.25 mmol, 2.5
equiv) in general procedure (1.5 h) afforded the title com-
pound 1e (27 mg, 83%) as a yellow solid. Mp 126–128 ꢀC;
Rf 0.61 (2:98 EtOAc/CHCl3); HPLC tR 27.2 min; IR (KBr)
Methyl 4-Chloro-1-hydroxy-3-[(n-pentyloxy)methyl]-1H-
indole-2-carboxylate (1i). Use of n-pentanol (54 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (1.5 h) afforded the title com-
pound 1i (14 mg, 43%) as a yellow solid. Mp 59–61 ꢀC; Rf
0.50 (1:2 EtOAc/hexanes); HPLC tR 27.0 min; IR (KBr)
1
3444, 3025, 2924, 1601, 1492, 756 cm−1; H NMR (300
1
MHz, CD3CN) δ 9.20 (br s, 1H), 7.46 (dd, J = 8.3, 0.9 Hz,
1H), 7.34 (dd, J = 7.5, 0.9 Hz, 1H), 7.20 (dd, J = 8.3, 7.5 Hz,
1H), 4.52 (s, 2H), 3.95 (s, 3H), 1.38 (s, 9H); 13C NMR (75
MHz, CD3CN) δ 162.9, 138.2, 128.8, 127.6, 126.0, 123.5,
119.7, 117.6, 110.3, 53.3, 43.9, 31.5, 24.1; MS m/z 328 [M
+ H]+; HRMS (+EI) calcd for C15H18ClNO3S [M]+
327.0696, found 327.0699.
3445, 2924, 1451, 757 cm−1; H NMR (300 MHz, CD3CN)
δ 9.27 (br s, 1H), 7.42 (dd, J = 8.3, 0.8 Hz, 1H), 7.33 (t, J =
7.3 Hz, 1H), 7.16 (dd, J = 7.5, 0.8 Hz, 1H), 5.01 (s, 2H),
3.95 (s, 3H), 3.51 (t, J = 6.5 Hz, 2H), 1.64–1.46 (m, 2H),
1.40–1.17 (m, 4H), 0.95–0.80 (m, 3H); 13C NMR (75 MHz,
CD3CN) δ 162.8, 137.8, 128.9, 127.3, 127.1, 123.6, 120.3,
116.7, 110.1, 71.2, 62.9, 53.3, 30.7, 29.7, 23.6, 14.8; MS m/
z 326 [M + H]+; HRMS (+EI) calcd for C16H20ClNO4 [M]+
325.1081, found 325.1080.
Methyl
4-Chloro-1-hydroxy-3-[(phenylthio)methyl]-1H-
indole-2-carboxylate (1f ). Use of thiophenol (52 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (5.5 h) afforded the title com-
pound 1f (20 mg, 57%) as a yellow solid. Mp 35–38 ꢀC; Rf
0.36 (1:2 EtOAc/hexanes); HPLC tR 26.4 min; IR (KBr)
Methyl
4-Chloro-1-hydroxy-3-[(n-octyloxy)methyl]-1H-
indole-2-carboxylate (1j). Use of n-octanol (79 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (1.5 h) afforded the title com-
pound 1j (18 mg, 48%) as a yellow solid. Mp 52–54 ꢀC; Rf
0.48 (3:97 EtOAc/CHCl3); HPLC tR 33.1 min; IR (KBr)
1
3435, 3025, 2923, 1492, 1258, 756 cm−1; H NMR (300
MHz, CD3CN) δ 9.25 (br s, 1H), 7.42 (d, J = 8.0 Hz, 1H),
7.18–7.31 (m, 6H), 7.12–7.18 (m, 1H), 4.80 (s, 2H), 3.71
(s, 3H); 13C NMR (75 MHz, CD3CN) δ 162.5, 138.2,
136.9, 133.4, 130.2, 128.8, 128.5, 127.6, 126.1, 123.5,
119.3, 116.9, 110.3, 53.1, 31.0; MS m/z 348 [M + H]+; HRMS
(+EI) calcd for C17H14ClNO3S [M]+ 347.0383, found
347.0381.
1
3445, 3925, 1718, 1492, 757 cm−1; H NMR (300 MHz,
CD3CN) δ 9.33 (br s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.27 (t,
J = 7.9 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 5.00 (s, 2H), 3.93
(s, 3H), 3.50 (t, J = 6.4 Hz, 2H), 1.59–1.45 (m, 2H),
1.40–1.15 (m, 10H), 0.93–0.80 (m, 3H); 13C NMR (75
MHz, CD3CN) δ 162.7, 137.7, 129.8, 128.7, 127.1, 123.4,
120.1, 116.6, 109.9, 70.9, 62.7, 53.1, 32.8, 30.8, 30.3, 30.2,
27.2, 23.6, 14.6; MS m/z 368 [M + H]+; HRMS (+EI) calcd
for C19H26ClNO4 [M]+: 367.1550, found 367.1553.
Methyl
3-[(Benzyloxy)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1g). Use of benzyl alcohol (52 μL,
0.50 mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol,
3.3 equiv) in general procedure (1.5 h) afforded the title com-
pound 1g (16 mg, 45%) as a yellow solid. Mp 96–97 ꢀC; Rf
0.41 (1:2 EtOAc/hexanes); HPLC tR 26.2 min; IR (KBr)
Methyl 4-Chloro-1-hydroxy-3-[(isopropyloxy)methyl]-1H-
indole-2-carboxylate (1k). Use of isopropanol (38 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (1.5 h) afforded the title com-
pound 1k (19 mg, 63%) as a yellow solid. Mp 93–95 ꢀC; Rf
0.47 (1:2 EtOAc/hexanes); HPLC tR 26.0 min; IR (KBr)
1
3444, 3161, 2923, 2849, 696 cm−1; H NMR (300 MHz,
CDCl3) δ 9.31 (br s, 1H), 7.44 (d, J = 8.3 Hz, 1H),
7.40–7.22 (m, 6H), 7.17 (d, J = 7.5 Hz, 1H), 5.11 (s, 2H),
4.60 (s, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 162.8, 140.5, 137.8, 129.6, 129.3, 128.9, 128.8, 127.4,
127.1, 123.7, 120.3, 116.2, 110.2, 73.2, 62.9, 53.4; MS m/z
346 [M + H]+; HRMS (+ESI) calcd for C18H16ClNNaO4
[M + Na]+ 368.0666, found 368.0661.
1
3444, 3001, 1666, 1600, 701 cm−1; H NMR (300 MHz,
CD3CN) δ 9.27 (br s, 1H), 7.39 (dd, J = 8.3, 0.9 Hz, 1H),
7.25 (dd, J = 8.3, 7.5 Hz, 1H), 7.14 (dd, J = 7.5, 0.9 Hz, 1H),
5.02 (s, 2H), 3.94 (s, 3H), 3.79 (septet, J = 6.1 Hz, 1H), 1.18
(d, J = 6.1 Hz, 6H); 13C NMR (75 MHz, CD3CN) δ 162.8,
137.8, 128.8, 127.3, 127.0, 123.6, 120.2, 116.9, 110.1,
72.4, 60.7, 53.3, 23.0; MS m/z 298 [M + H]+; HRMS
(+ESI) calcd for C14H16ClNNaO4 [M + Na]+ 320.0666, found
320.0660.
Methyl
3-[(n-Butyloxy)methyl]-4-chloro-1-hydroxy-1H-
indole-2-carboxylate (1h). Use of n-butanol (46 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (1.5 h) afforded the title com-
pound 1h (15 mg, 47%) as a yellow solid. Mp 61–63 ꢀC; Rf
0.44 (1:2 EtOAc/hexanes); HPLC tR 23.4 min; IR (KBr)
Methyl 4-Chloro-3-[(cyclohexyloxy)methyl]-1-hydroxy-1H-
indole-2-carboxylate (1l). Use of cyclohexanol (52 μL, 0.50
mmol, 5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3
equiv) in general procedure (1.5 h) afforded the title com-
pound 1l (14 mg, 41%) as a yellow solid. Mp 101–104 ꢀC;
Rf 0.43 (1:2 EtOAc/hexanes); HPLC tR 27.3 min; IR (KBr)
1
3445, 3025, 1493, 700 cm−1; H NMR (300 MHz, CD3CN)
δ 9.37 (br s, 1H), 7.41 (dd, J = 8.3, 0. 9 Hz, 1H), 7.31–7.23
(m, 1H), 7.15 (dd, J = 7. 5, 0.9 Hz, 1H), 5.01 (s, 2H), 3.94
(s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 1.51–1.49 (m, 2H),
1.49–1.20 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (75
MHz, CD3CN) δ 161.3, 136.4, 127.4, 125.8, 125.6, 122.1,
1
3444, 2924, 1493, 757 cm−1; H NMR (300 MHz, CD3CN)
δ 9.43 (br s, 1H), 7.36 (dd, J = 8.4, 0.8 Hz, 1H), 7.23 (t, J =
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4-Chloro-1-hydroxyindoles
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7.9 Hz, 1H), 7.12 (dd, J = 7.5, 0.8 Hz, 1H), 5.05 (s, 2H), 3.93
(s, 3H), 3.40–3.50 (m, 1H), 1.13–1.80 (m, 10H); 13C NMR
(75 MHz, CD3CN) δ 162.8, 137.8, 128.9, 127.2, 127.1,
123.6, 120.3, 117.0, 110.1, 78.3, 60.5, 53.3, 33.6, 27.2,
25.3; MS m/z 338 [M + H]+; HRMS (+EI) calcd for
C17H20ClNO4 [M]+ 337.1081, found 337.1082.
for aromatic nitro group and our previous results.8 So, we per-
formed the reactions employing 2 and various nucleophiles in
the presence of SnCl2ꢁ2H2O (2.5–3.3 equiv) and 4 Å molecu-
lar sieve in DME in the dark, leading to the generation of new
2,3-disubstituted 4-chloro-1-hydroxyindoles 1, as summar-
ized in Table 1. Given that the presumed intermediate (e.g.,
5) is a highly reactive electrophile, we also tried to employ
nucleophiles of high hindrance and/or low reactivity to con-
struct new multisubstituted 1-hydroxyindoles that would be
otherwise difficult to prepare.
Methyl
4-Chloro-1-hydroxy-3-(4-hydroxybenzyl)-1H-
indole-2-carboxylate (1m). Use of phenol (44 μL, 0.50 mmol,
5.0 equiv) and SnCl2ꢁ2H2O (69 mg, 0.33 mmol, 3.3 equiv) in
general procedure (4 h) afforded the title compound 1m (13
mg, 40%) as a yellow solid. Mp 154–156 ꢀC; Rf 0.34 (1:2
EtOAc/hexanes); HPLC tR 24.6 min; IR (KBr) 3434, 2924,
1654, 1260, 1181, 757 cm−1; 1H NMR (300 MHz, CDCl3) δ
9.23 (br s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.8 Hz,
1H), 7.09 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.66
(d, J = 8.6 Hz, 2H), 4.58 (s, 2H), 3.88 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.2, 156.3, 140.3, 134.2, 130.5,
127.5, 126.6, 123.3, 120.9, 120.6, 120.1, 116.3, 110.3,
53.1, 30.7; MS m/z 332 [M + H]+; HRMS (+ESI) calcd for
C17H14ClNNaO4 [M + Na]+ 354.0509, found 354.0504.
We first examined thiols as nucleophiles and obtained pro-
ducts 1a–1f in good to modest yields. The reactions with pri-
mary thiols (entries 1–3) provided good yields (74–75%).
Surprisingly, the reactions with secondary and tertiary thiols
(entries 4 and 5) provided better yields than those with primary
thiols (entries 1–3), and in particular, the reaction with
t-butanethiol afforded good yield (83%). Based on these
observations, it was believed that the electronic effect on
nucleophilicity by the alkyl groups in secondary and tertiary
thiols was more significant than the steric effect. When thio-
phenol was used (entry 6), the reaction provided S-alkylated
adduct 1f without C-alkylated adduct. Then, we used alcohols
as nucleophiles and obtained 1g–1m (entries 7–13). The reac-
tions with primary and secondary alcohol nucleophiles pro-
vided the products in modest yields. Among these alcohol
nucleophiles, isopropyl alcohol (entry 11) provided the best
yield (63%), which again implied the significance of the elec-
tronic effect on nucleophilicity. However, the reaction with
tertiary alcohol (e.g., t-BuOH) did not provide appreciable
amount of product in similar reaction conditions, andthe result
was inconclusive (datanot shown), whichdiffer from thatwith
t-butanethiol (entry 5). Interestingly, the reaction with phenol
(entry 13) afforded C-alkylated adduct 1m without O-
alkylated adduct, which is consistent with the previous obser-
vation.8 This result was also found to be different from that
with thiophenol, which was attributed to the lower reactivity
of alcohols than thiols. When comparing these results of thiol
and alcohol nucleophiles, we found that thiol nucleophiles
provided better results than alcohol nucleophiles, and the
striking difference was observed between t-butanethiol and
Results and Discussion
Synthesis of 2,3-Disubstituted 4-Chloro-1-hydroxyindoles
1. Prior to the synthesis of the intended multisubstituted
1-hydroxyindoles1, we needed toprepare theappropriatesub-
strate. We applied our previous procedure8 with minor
modificationstothesynthesisofnewconjugateketoester2that
contains an o-chloro substituent, as shown in Scheme 1. A tol-
uene derivative 3 was treated with NaH and dimethyl oxalate
to give ketoester compound 4.6 Subsequent reaction of 4 and
dimethylmethyleneammonium chloride in the presence of
NaH produced a new substrate, conjugate ketoester 2.
In order to synthesize new derivatives 1, we set out to
expand the scope of the reaction with o-chloro substrate. As
depicted in Scheme 2, we initially presumed that these reac-
tions occur through the reduction of the nitro group and con-
densation to give conjugate nitrone 5, which would then
undergo 1,5-addition8 with nucleophile, leading to the gener-
ation of 1-hydroxyindoles 1. We also presumed that this path-
way could not be the only way and therefore speculated other
pathways to produce 1. For example, we might suggest
another plausible pathway in which 1,4-addition occurs first
and then reduction and condensation follow. Although we
were interested in the mechanistic aspects and are presently
investigating the related pathways, the identification of the
pathways was inconclusive, due to the reversibility of the
1,4-addition and the related complexities.
For the synthesis of target compounds, we chose stannous
chloride (SnCl2) considering its appropriate reducing power11
Scheme 2. Presumed pathway for the formation of 1-hydroxyin-
doles 1.
Scheme 1. Synthesis of conjugate ketoester 2.
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4-Chloro-1-hydroxyindoles
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Table 1. Synthesis of 1-hydroxyindoles 1.a
Entry
1
SnCl2ꢁ2H2O (equiv)
NuH
Time (h)
1.5
Product
Yieldb (%)
75
2.5
BnSH
1a
1b
2
3
4
2.5
2.5
2.5
BuSH
HexSH
1.5
1.5
1.5
75
74
84
1c
c-HexSH
1d
5
6
2.5
3.3
t-BuSH
1.5
5.5
83
57
1e
PhSH
1f
1g
1h
7
3.3
3.3
3.3
3.3
BnOH
BuOH
PenOH
OctOH
5.0
6.5
6.5
5.0
45
47
43
48
8
9
1i
10
1j
(continued overleaf )
Bull. Korean Chem. Soc. 2015, Vol. 36, 2095–2100
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4-Chloro-1-hydroxyindoles
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Table 1 (continued)
Entry
11
SnCl2ꢁ2H2O (equiv)
NuH
Time (h)
Product
Yieldb (%)
63
3.3
3.3
3.3
i-PrOH
5.0
5.0
5.0
1k
12
13
c-HexOH
41
40
1l
PhOH
1m
a All reactions were run in 27 mg (0.10 mmol) scale of 2.
b Isolated yields were given.
t-butanol. Taken together, these results demonstrated the
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Conclusion
We report the synthesis of new 2,3-disubstituted 4-chloro-1-
hydroxyindoles 1. Using substrate 2 obtained by a two-step
synthetic sequence, weperformedthereactions inone potwith
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is available in the online version of this article.
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