New approach for the synthesis of N-indolyl ketones and aldehydes

Article abstract of DOI:10.1080/00397910500212965

A new approach for the synthesis of N-indolyl ketones and aldehydes was developed. In the reaction of N-indolyl carboxylic acids with alkyl lithium, an interesting phenomenon appeared when using THF as solvent instead of ethyl ether. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500212965

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New Approach for the
Synthesis of N‐Indolyl Ketones
and Aldehydes
Hua‐Sheng Ding a b , Dr. Chun‐Hao Yang a b & Yu‐Yuan
Xie a b
a State Key Laboratory of Drug Research , Shanghai
Institute of Materia Medica , Shanghai, China
b Graduate School of the Chinese Academy of
Science , Beijing, China
Published online: 22 Aug 2006.
To cite this article: Hua‐Sheng Ding , Dr. Chun‐Hao Yang & Yu‐Yuan Xie (2005)
New Approach for the Synthesis of N‐Indolyl Ketones and Aldehydes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:20, 2625-2632
To link to this article: http://dx.doi.org/10.1080/00397910500212965
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Synthetic Communicationsw, 35: 2625–2632, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500212965
New Approach for the Synthesis of
N-Indolyl Ketones and Aldehydes
Hua-Sheng Ding
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai, China and Graduate School of the Chinese Academy
of Science, Beijing, China
Chun-Hao Yang and Yu-Yuan Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai, China
Abstract: A new approach for the synthesis of N-indolyl ketones and aldehydes
was developed. In the reaction of N-indolyl carboxylic acids with alkyl lithium,
an interesting phenomenon appeared when using THF as solvent instead of ethyl
ether.
Keywords: Alkyl lithium, N-indolyl aldehyde, N-indolyl ketone, solvent effect
INTRODUCTION
In our recent studies of anticancer agents, we have found some interesting
indole a-methylene-g-butyrolactone compounds, prepared from the inter-
mediates indolyl aldehydes or ketones (such as compound 1), which can sig-
nificantly inhibit AKT-mTOR signaling pathway kinases. Furthermore, the
indole ring system found in a wide range of naturally occurring compounds
has attracted great interest for its biological activities.[1,2] So, those
Received in Japan March 22, 2005
Address correspondence to Dr. Chun-Hao Yang, State Key Laboratory of
Drug Research, Shanghai Institute of Materia Medica, SIBS, CAS 555 Zuchongzhi
Road, Shanghai 201203, China. Tel./Fax: 86-21-50806770; E-mail: chyang@
mail.shcnc.ac.cn
2625

2626
H.-S. Ding, C.-H. Yang, and Y.-Y. Xie
intermediates could be a useful component in the organic synthesis. Here we
report a novel method for the synthesis of this type of compound.
For the synthesis of 1, we first tried to treat indole with sodium hydride in
dry DMF followed by addition of a-bromoacetone but failed. Then, we tried to
protect the carbonyl group with ketal, but the cleavage of ketal encountered
many difficulties. Many methods appearing in References 3 to 5 have been
tested, but no desired product could be obtained. Gianluca Araldi et al.
reported a method of synthesis of carbonyl indole by the reaction of indole
with propylene oxide followed by oxidization via the Moffat reaction.[6] But
in our studies, we found that the alkylation of the indole system occurs not
only at 1-position, but also at 3-position. Furthermore, the 1-alkyl product,
3-alkyl product, and the 1,3-dialkyl product are very close to each other on
the silica-gel plate and it’s difficult to separate them. Besides, the yield is
low for the 2-phenyl indole. Also, only a few types of N-carbonyl indoles
could be obtained by this method.
Finally, we used ethyl a-bromoacetate as the alkylation agent (Scheme 1).
The obtained indole derivatives 3 could be reduced with LiAlH4 to alcohol,
which was subsequently oxidized to corresponding aldehydes just as
Gianluca Araldi et al. reported. 3 could also be hydrolyzed to their correspond-
ing carboxylic acids 6 and treated with alkyl lithium; thus, the ketones were
obtained with little indoles 2 (Scheme 2). In view of the availability of
many kinds of a-bromocarboxylic esters and alkyl lithium, we can get
many more kinds of carbonyl indoles.
Interestingly, we found when indole carboxylic acids 6 were treated with
alkyl lithium in dry Et2O, the products 7 were obtained readily. But when the
Scheme 1. i: BrR3CHCOOEt, NaH, DMF; ii: LiAlH4, THF; and iii: DCC, Py, TFA,
DMSO, benzene.

N-Indole Ketones and Aldehydes
2627
Scheme 2. i: NaOH, EtOH and ii: R4Li, Et2O.
reaction was carried out in dry THF, the corresponding indoles 2 were
obtained and no ketones were produced (Scheme 3).
EXPERIMENTAL
Melting points were determined using a Bu¨chi 510 apparatus and are uncor-
rected. IR spectra were measured with a Perkin-Elmer 983 grating IR spectro-
1
photometer in KBr pellets. H NMR (400.13-MHz) spectra were recorded on
a Brucker-400 NMR spectrometer with TMS as internal standard. The mass
spectra were determined using Finnigan MAT 95, EI: 70eV. Microanalyses
were carried out on a Leco CHN-2000 elemental analyzer. Starting indoles 2
were prepared according to the literature procedure.[7]
2-(2-Phenyl-1H-indol-1-yl)ethanol (4a)
A solution of 2-phenyl-1H-indole (470 mg, 2.4 mmol) 2a in dry DMF (3 mL)
was added dropwise to a stirred suspension of sodium hydride (144 mg,
3.6 mmol) in dry DMF (2 mL) under N2 at 08C. After 20 min, ethyl a-bromo-
acetate (600 mg, 3.6 mmol) in dry DMF (2 mL) was added dropwise and the
mixture was stirred at room temperature for 8 h. The resulting mixture was
then poured into ice water (10 mL) and extracted with ethyl acetate
(3 ꢀ 10 mL). The obtained organic phase was washed with brine, dried over
anhydrous Na2SO4, and evaporated to dryness. The residue was purified by
column chromatography (1/40 EtOAc/petroleum) to produce 350 mg of
ethyl 2-(2-phenyl-1H- indol-1-yl)acetate as a pale yellow oil.
Table 1. Substituent groups of compounds in Schemes 1–3
Compound
R1
R2
R3
R4
a
b
c
d
e
H
OCH3
H
H
H
H
H
CH3
CH3
CH3
CH3
n-Bu
OCH3
H
H
H
CH3
H
H
H

2628
H.-S. Ding, C.-H. Yang, and Y.-Y. Xie
Scheme 3.
The indole ester 3a (165 mg, 0.6 mmol) was added to a solution of LiAlH4
(0.19 g, 1.8 mmol) in Et2O (5 mL) and the mixture was stirred at rt for 3 h.
Then, the reaction was quenched with ice water (10 mL) and acidified with
1 mL of hydrochloric acid (2.5 mol/L), followed by extraction with EtOAc
(2 ꢀ 10 mL). Evaporation of the dried organic phase gave an oil, which was
purified by silica-gel chromatography (1/4 EtOAc/petroleum) to give 4a
1
(130 mg, 47.8%) as a colorless oil. H NMR (CDCl3): d 7.54–7.14 (m, 9H,
ArH), 6.56 (s, 1H, H-3), 4.34 (t, J ¼ 6.0 Hz, 2H, NCH2), 3.85
(t, J ¼ 6.0 Hz, 2H, CH2O). Compounds 4b and 4d were prepared using the
same method.
2-(5-Methoxy-2-phenyl-1H-indol-1-yl)ethanol (4b)
Yield 44.8%, pale yellow oil. 1H NMR (CDCl3): d 7.53–6.88 (m, 8H, ArH),
6.48 (s, 1H, H-3), 4.29 (t, J ¼ 6.0 Hz, 2H, CH2), 3.87 (s, 3H, OCH3), 3.82
(t, J ¼ 6.0 Hz, 2H, CH2).
2-(2-Phenyl-1H-indol-1-yl)propanol (4d)
Yield 35.1%, pale yellow oil. 1H NMR (CDCl3): d 7.67–7.13 (m, 9H, ArH),
6.52 (s, 1H, H-3), 4.71–4.64 (m, 1H, CH), 4.33–3.76 (m, 2H, CH2), 1.58–
1.51 (dd, J ¼ 2.0, 9.6 Hz, 3H, CH3).
2-(2-Phenyl-1H-indol-1-yl)acetaldehyde (5a)
2-(2-Phenyl-1H-indol-1-yl)ethanol (130mg, 0.55mmol) in anhydrous dimethyl-
sulfoxide (4mL) and N, N0- dicyclohexylcarbodiimide (339mg, 1.65mmol)
were added to a solution of pyridine (43 mg, 0.55mmol) and trifluoroacetic
acid (31 mg, 0.27mmol) in benzene (10 mL). After stirring at 258C for 30h,
diethylether (3mL) was added followed by a solution of oxalic acid (276mg,
2.19mmol) in methanol (3 mL). After the gas had stopped evoluting, water
(10 mL) was added and the produced 1,3-dicyclohexylurea (DCU) was
removed by filtration. The organic phase was then washed with 5% aqueous
NaHCO3 (2 ꢀ 10mL) and water (10 mL), dried over anhydrous Na2SO4, and

N-Indole Ketones and Aldehydes
2629
evaporated to dryness. The residue was purified by column chromatography
(SiO2, 1/5 EtOAc/petroleum) to give 90mg (69.8%) of white solid 5a. It can
be recrystallized from ethanol. Mp 106–1078C. IR (KBr) 1726 (C55O) cm21
;
1H NMR (CDCl3): d 9.69 (s, 1H, CHO), 7.70–7.18 (m, 9H, ArH), 6.67
(s, 1H, H-3), 4.85 (s, 2H, CH2); MS: m/z 235 (Mþ), 206 (indole-CH2þ);
HRMS: m/z calcd. for C16H13NO 235.0997 (M); found 235.1001. Anal.
calcd. for C16H13NO.0.1C2H5OH: C, 81.11; H, 5.71; N, 5.84; found: C, 81.06;
H, 5.61; N, 5.81. Compounds 5b and 5d were prepared using the same method.
2-(5-Methoxy-2-phenyl-1H-indol-1-yl)acetaldehyde (5b)
1
Yield 61.7%, pale solid, Mp 117–1198C. IR (KBr) 1724 (C55O) cm21; H
NMR (CDCl3): d 9.66 (s, 1H, CHO), 7.48–6.90 (m, 8H, ArH), 6.60 (s, 1H,
H-3), 4.81 (s, 2H, CH2), 3.88 (s, 3H, OCH3). MS: m/z 265 (Mþ), 236
(indole-CHþ2 ); HRMS: m/z calcd. for C17H15NO2 265.1103 (M); found
265.1090. Anal. calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28; found:
C, 76.88; H, 5.97; N, 5.14.
2-(2-Phenyl-1H-indol-1-yl)propionaldehyde (5d)
1
Yield 72.1%, white solid, Mp 80–828C. IR (KBr) 1734 (C55O) cm21; H
NMR (CDCl3): d 9.77 (s, 1H, CHO), 7.70–7.15 (m, 8H, ArH), 6.65 (s, 1H,
H-3), 4.98–4.90 (q, J ¼ 9.6 Hz, 1H, CH), 1.69 (d, J ¼ 9.6 Hz, 3H, CH3);
MS: m/z 249 (Mþ), 220 (indole-CHCHþ3 ); HRMS: m/z calcd. for
C17H15NO 249.1154 (M); found 249.1169. Anal. calcd. for C17H15NO: C,
81.90; H, 6.06; N, 5.62; found: C, 81.61; H, 5.98; N, 5.60.
2-(2-Phenyl-1H-indol-1-yl)acetic acid (6a)
The ester 3a (165 mg) was dissolved in EtOH (4 mL) and 1 mL of NaOH
solution (3 mol/L) was added. The solution was heated at 808C for 30 min.
After cooling to room temperature, 10 ml of water was added and the
mixture was washed with CH2Cl2 (2 ꢀ 10 mL). Then, the water phase was
acidified with dilute hydrochloride solution. Product 6a (140 mg, 48.6%)
was obtained after filtration and drying as a white solid. Mp 172–1748C
(lit.[8] 1818C). 1H NMR (acetone-d6): d 7.67–7.17 (m, 9H, ArH), 6.62
(s, 1H, H-3), 4.86 (s, 2H, CH2). Compounds 6b–d were prepared using the
same method.
2-(5-Methoxy-2-phenyl-1H-indol-1-yl)acetic acid (6b)
Yield 41.6%, white solid, mp 173–1758C. 1H NMR (acetone-d6): d 7.48–6.77
(m, 8H, ArH), 6.45 (s, 1H, H-3), 4.81 (s, 2H, CH2), 3.75 (s, 3H, CH3).

2630
H.-S. Ding, C.-H. Yang, and Y.-Y. Xie
2-(2-(4-Methoxyphenyl)-1H-indol-1-yl)acetic acid (6c)
1
Yield 49.6%, white solid, Mp 166–1688C. H NMR (acetone-d6): d 7.58–
7.05 (m, 8H, ArH), 6.50 (s, 1H, H-3), 4.88 (s, 2H, CH2) 3.86 (s, 3H, CH3).
2-(2-Phenyl-1H-indol-1-yl)propionic acid (6d)
Yield 38.0%, white solid, Mp 177–1798C (lit.[8] 2508C). 1H NMR (acetone-
d6): d 7.60–7.05 (m, 9H, ArH), 6.51 (s, 1H, H-3), 5.25–5.20 (q, J ¼ 7.2 Hz,
1H, CH), 1.63 (d, J ¼ 7.2 Hz, 3H, CH3).
1-(2-Phenyl-1H-indol-1-yl)propan-2-one (7a)
Under nitrogen, 0.5 mL of methyl lithium (1.6 mol/L in ether) was added dropwise
to a solution of compound 6a (100 mg, 0.40 mmol) in 5 mL of dry Et2O cooled
with ice salt. After stirring at room temperature for 2 h, 5 mL of water was
added and acidified with 1 mL of hydrochloric acid (3 mol/L). Then extracted
the mixture with EtOAc (2 ꢀ 20 mL) and the combined organic phase was
washed with water. Evaporation of the dried organic phase gave an oil that was
purified by silica-gel chromatography (1/25 EtOAc/petroleum) to give 60 mg
(60.6%) of white solid. The product can be recrystallized from ethanol. Mp
1
116–1188C. IR (KBr) 1732 (C55O) cm21; H NMR (CDCl3): d 7.67–7.14
(m, 9H, ArH), 6.65 (s, 1H, H-3), 4.84 (s, 2H, CH2), 1.96 (s, 3H, CH3); MS: m/z
249 (Mþ), 206 (indole-CHþ2 ); HRMS: m/z calcd. for C17H15NO 249.1154 (M);
found 249.1154. Anal. calcd. for C17H15NO: C, 81.90; H, 6.06; N, 5.62; found:
C, 81.78; H, 5.98; N, 5.61. Compounds 7b–e were prepared using the same
method.
1-(5-Methoxy-2-phenyl-1H-indol-1-yl)propan-2-one (7b)
Yield 58.0%, white solid, Mp 126–1288C. IR (KBr) 1720 (C55O) cm21; 1H
NMR (CDCl3): d 7.46–6.89 (m, 8H, ArH), 6.58 (s, 1H, H-3), 4.80 (s, 2H,
CH2), 3.87 (s, 3H, OCH3), 1.93 (s, 3H, CH3); MS: m/z 279 (Mþ), 236
(indole-CHþ2 ); HRMS: m/z calcd. for C18H17NO2 279.1259 (M); found
.
279.1240. Anal. calcd. for C18H17NO2 0.1C2H5OH: C, 76.99; H, 6.25; N,
4.93; found: C, 76.98; H, 6.18; N, 4.94.
1-(2-(4-Methoxyphenyl)-1H-indol-1-yl)propan-2-one (7c)
Yield 58.6%, white solid, Mp 108–1098C. IR (KBr) 1716 (C55O) cm21; 1H NMR
(CDCl3): d 7.66–6.98 (m, 8H, ArH), 6.58 (s, 1H, H-3), 4.80 (s, 2H, CH2), 3.87
(s, 3H, OCH3), 1.95 (s, 3H, CH3); MS: m/z 279 (Mþ), 236 (indole-CH2þ);

N-Indole Ketones and Aldehydes
2631
HRMS: m/z calcd. for C18H17NO2 279.1259 (M); found 279.1271. Anal. calcd.
for C18H17NO2: C, 77.40; H, 6.13; N, 5.01; found: C, 77.21; H, 6.26; N, 5.01.
3-(2-Phenyl-1H-indol-1-yl)butan-2-one (7d)
Yield 61.2%, pale yellow solid, Mp 65–678C. IR (KBr) 1720 (C55O) cm21
;
1H NMR (CDCl3): d 7.68–7.14 (m, 8H, ArH), 6.64 (s, 1H, H-3), 4.92–4.85
(q, J ¼ 9.2 Hz, 1H, CH), 1.74 (d, J ¼ 9.2 Hz, 3H, CHCH3), 1.70 (s, 3H,
COCH3); MS: m/z 263 (Mþ), 220 (indole-CHCHþ3 ); HRMS: m/z calcd. for
C18H17NO 263.1310 (M); found 263.1305. Anal. calcd. for
.
C18H17NO 0.1C2H5OH: C, 81.58; H, 6.62; N, 5.23; found: C, 81.70; H,
6.52; N, 5.22.
1-(2-Phenyl-1H-indol-1-yl)hexan-2-one (7e)
1
Yield 51.8%, white solid, Mp 83–848C. IR (KBr) 1716 (C55O) cm21; H
NMR (CDCl3): d 7.68–7.12 (m, 9H, ArH), 6.64 (s, 1H, H-3), 4.84 (s, 2H,
NCH2), 2.21 (t, J ¼ 7.2 Hz, 2H, COCH2CH2), 1.58–1.43 (m, 2H,
COCH2CH2), 1.24–1.15 (m, 2H, CH2CH3), 0.81 (t, J ¼ 7.2 Hz, 3H, CH3);
MS: m/z 291 (Mþ), 206 (indole-CH2þ); HRMS: m/z calcd. for C20H21NO
.
291.1623 (M); found 291.1625. Anal. calcd. for C20H21NO 0.1C2H5OH: C,
81.97; H, 7.36; N, 4.74; found: C, 82.01; H, 7.35; N, 4.70.
General Procedure for the Reaction in Scheme 3
Methyl lithium (0.5 mL, 1.6 mol/L in ether) was added to a solution of
compound 6 (0.4 mmol) in 5 mL of dry THF cooled to 08C under nitrogen
atmosphere. After stirring at room temperature for several hours, the
reaction was quenched with water (5 mL) and acidified with 1 mL of hydro-
chloric acid (3 mol/L). THF was evaporated in vacuum and the residue was
extracted with Et2O (2 ꢀ 10 mL). The combined organic phase was washed
with water and dried over anhydrous Na2SO4. After removal of the solvent
under reduced pressure, the column chromatography of the residue over
silica gel (EtOAc/petroleum) gave the corresponding indoles 2.
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