Simple synthesis of 7-formyl-indole

Article abstract of DOI:10.1080/00397910500503470

A simple route to 7-formyl-indole (5) is described in which appropriately functionalized o-nitrotoluenes (1) are converted to 7-hydroxymethyl-indole (4) using the Batcho-Leimgruber process. Condensation of 3-methyl-2-nitrobenzyl alcohol (1a) with N,N-dimethylformamide dimethyl acetal yields the enamine 2a, which upon catalytic hydrogenation affords 4 in 22% yield. When the hydroxyl function in 1 is protected with pivaloyl or tetrahydropyranyl group, the yields of 4 are increased to 39% and 48%, respectively. Finally, 4 is oxidized with pyridinium chlorochromate (PCC) to afford 5 in 86% yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500503470

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Simple Synthesis of 7‐Formyl‐indole
Vinod R. Uchil a , Machhindra Gund a & Apparao Satyam a
a Discovery Chemistry Division, Glenmark Research Centre, Glenmark
Pharmaceuticals, Mumbai, India
Version of record first published: 16 Aug 2006.
To cite this article: Vinod R. Uchil , Machhindra Gund & Apparao Satyam (2006): Simple Synthesis of
7‐Formyl‐indole, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:8, 1051-1056
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Synthetic Communicationsw, 36: 1051–1056, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500503470
Simple Synthesis of 7-Formyl-indole
Vinod R. Uchil, Machhindra Gund, and Apparao Satyam
Discovery Chemistry Division, Glenmark Research Centre, Glenmark
Pharmaceuticals, Mumbai, India
Abstract: A simple route to 7-formyl-indole (5) is described in which appropriately
functionalized o-nitrotoluenes (1) are converted to 7-hydroxymethyl-indole (4) using
the Batcho–Leimgruber process. Condensation of 3-methyl-2-nitrobenzyl alcohol
(1a) with N,N-dimethylformamide dimethyl acetal yields the enamine 2a, which
upon catalytic hydrogenation affords 4 in 22% yield. When the hydroxyl function in
1 is protected with pivaloyl or tetrahydropyranyl group, the yields of 4 are increased
to 39% and 48%, respectively. Finally, 4 is oxidized with pyridinium chlorochromate
(PCC) to afford 5 in 86% yield.
Keywords: Batcho–Leimgruber reaction, benzyltriethylammonium borohydride,
7-formyl-indole, 7-hydroxymethyl-indole, pyridinium chlorochromate
INTRODUCTION
In the context of our ongoing research on 7-substituted-indole-based b3-
agonists, it became necessary for us to prepare substantial amounts of
7-formyl-indole. Literature methods[1] to prepare 7-formyl-indole have limit-
ations, and therefore a simple alternative method that utilizes cheap or easily
synthesizable starting materials was desirable to overcome difficulties such as
the use of highly toxic, air- and moisture-sensitive organometallic reagents
and extremes in reaction temperature, and that is amenable to large-scale
production.
Received in India October 5, 2005
Dedicated to Professors H. Junjappa and H. Ila in recognition of their contribution
to organosulfur chemistry.
Address correspondence to Apparao Satyam, Nicholas Piramal Research Centre, 1,
Nirlon Complex, Goregaon (East), Mumbai 400 063, India. Tel.: 91-22-3081-8324/
8325; Fax: 91-22-3081-8043; E-mail: apparaosvgk@hotmail.com
1051

1052
V. R. Uchil, M. Gund, and A. Satyam
As depicted in Scheme 1, 3-methyl-2-nitrobenzyl alcohol (1a)[2] was
condensed with N,N-dimethylformamide dimethyl acetal to yield the
corresponding enamine 2a, which was subjected to catalytic hydrogenation
over Raney nickel (type W-2) in the presence of hydrazine hydrate to afford
7-hydroxymethyl-indole (4)[1b] in only 22% yield. To improve the yield of 4,
we protected the hydroxyl with a pivaloyl group and subjected (1b) to the
Batcho–Leimgruber process[3] to obtain 7-hydroxymethyl-indole (4) in 39%
yield. The pivaloyl group cleaved during the reaction. However, using 2-nitro-
3-tetrahydropyranyloxymethyltoluene (1c), in which the hydroxyl group was
protected as a THP-ether, the Batcho–Leimgruber reaction gave the correspond-
ing 7-tetrahydropyranyloxymethyl-indole (3c) in 48% yield. Subsequent
cleavage of the THP group gave, almost quantitatively, 7-hydroxymethyl-
indole (4). Finally, oxidation of 7-hydroxymethyl-indole (4) with pyridinium
chlorochromate (PCC) afforded 7-formyl-indole (5) in 86% yield.
Scheme 1. Reagents and conditions: (a) pivaloyl chloride, pyridine, reflux, 3 h, 99%;
(b) 3,4-dihydro-2H-pyran, pyridinium p-toluenesulfonate (catalytic amount), CH2Cl2,
rt, 3 h, 79%; (c) Me2NCH(OMe)2, pyrrolidine/DMF, 130–140 8C, 3–6 h; (d) Raney
nickel, THF/MeOH, hydrazine–hydrate, 40–50 8C, 1–1.5h; (e) Raney nickel, THF/
MeOH, hydrazine–hydrate, rt, 45 min; (f) p-toluenesulfonic acid monohydrate (catalytic
amount), MeOH, 60 8C, 30min; and (g) pyridinium chlorochromate, CH2Cl2, rt, 1.5h.

Simple Synthesis of 7-Formyl-indole
1053
In summary, we have developed a simple synthetic method for 7-formyl-
indole by utilizing easily synthesizable or commercially available cheap
starting materials and reagents.
EXPERIMENTAL
General
Melting points were recorded on Labindia MR-VIS apparatus and are uncor-
1
rected. H NMR spectra were recorded in CDCl3 on a Varian Mercury 300
(300-MHz) instrument. Chemical shifts are given in parts per million (ppm)
relative to tetramethylsilane (TMS). Mass spectra (MS) were obtained on
Finnegan Navigator ESI instrument, and the data are reported as m/z (mass
spectral service was obtained from Ashco Labs, Mumbai). Microanalysis was
done on a Perkin-Elmer CHN Analyzer 2400. Column chromatography was
done on silica gel, 100–200 mesh (Sisco Labs., India). Thin-layer chromato-
graphy (TLC) was done on aluminum plates precoated with Merck silica gel
60 F254. If not otherwise indicated, commercially available chemicals were
used as received. All solvents were laboratory grade, and anhydrous solvents
were prepared according to literature procedures and handled under nitrogen.
3-Methyl-2-nitrobenzyl Alchol (1a)
Chlorotrimethylsilane (2.12 mL, 14.3 mmol) in dichloromethane (5 mL) was
added to a stirred solution of benzyltriethylammonium borohydride[2d]
(2.98 g, 14.3 mmol) in dry dichloromethane (10 mL) at 0 8C. The mixture
was stirred for 20 min. Then, a solution of 1.3 g (7.1 mmol) of 3-methyl-2-
nitrobenzoic acid[4] in dichloromethane (5 mL) was added to the mixture,
and it was stirred at rt for 24 h. The reaction was quenched by adding
saturated NaHCO3 solution (20 mL) with cooling. The organic layer was
separated and washed with a brine solution (2 Â 20 mL), dried (CaCl2), and
concentrated to afford 0.7 g (58%) of 3-methyl-2-nitrobenzyl alcohol (1a) as
a light yellow solid, mp 44–46 8C (lit.[2a] mp: 45–47 8C). 1H NMR
(300 MHz, CDCl3): d 2.19 (bs, 1H, D2O exchangeable) 2.37 (s, 3H, –CH3),
4.66 (s, 2H, CH2-OH), 7.22–7.43 (m, 3Harom).
2-Nitro-3-pivaloyloxymethyltoluene (1b)
Pivaloyl chloride (2.16 g, 17.96 mmol) was added to a stirred mixture of 1a
(1.0 g, 5.98 mmol) and pyridine (3 mL). The mixture was stirred under
reflux for 3 h. Volatiles were removed under vacuum, and the residue was
purified on silica gel by using 5% ethyl acetate in light petroleum as eluent

1054
V. R. Uchil, M. Gund, and A. Satyam
to afford 1.48 g (99%) of 1b as a yellow liquid. 1H NMR (300 MHz, CDCl3): d
1.19 (s, 9H), 2.36 (s, 3H), 5.12 (s, 2H), 7.26–7.39 (m, 3Harom).
2-Nitro-3-tetrahydropyranyloxymethyltoluene (1c)
3,4-Dihydro-2H-pyran (0.55 g, 6.58 mmol) was added to a stirred solution of
benzyl alcohol 1a (1.0 g, 5.98 mmol) in dry methylene chloride (15 mL) at
0 8C, followed by pyridinium-p-toluene sulfonate (0.18 g). The mixture
stirred at room temperature for 3 h. The mixture was concentrated, and the
residue was purified on silica gel by using 5% ethyl acetate in light
petroleum containing 0.5% triethylamine. The fractions containing the pure
1
product were concentrated to afford 1.2 g (79%) of 1c as a yellow liquid. H
NMR (300 MHz, CDCl3): d 1.5–1.82 (m, 6H), 2.34 (s, 3H), 3.49–3.56
(m, 1H), 3.79–3.86 (m, 1H), 4.52 (d, 1H, J ¼ 12.6 Hz), 4.63 (t, 1H,
J ¼ 3.3 Hz), 4.81 (d, 1H, J ¼ 12.9 Hz), 7.20–7.35 (m, 3Harom).
7-Hydroxymethyl-indole, General Procedures
A mixture of appropriately substituted o-nitrotoluene 1 (5 mmol), N,N-
dimethylformamide dimethyl acetal (10 mmol), and pyrrolidine (10 mmol)
in DMF (3 mL) was stirred at rt for 10 min. The reaction flask was then
heated at 130 8C for 4 h. (Note: In the case of hydroxymethyl derivative 1a,
an additional 2 equivalents of dimethylformamide dimethyl acetal and pyrro-
lidine were added after 3 h of reaction time and the mixture continued stirring
at 130 8C for additional 3 h to drive the reaction to completion.) TLC indicated
completion of the reaction. The mixture was concentrated in vacuo to afford
the crude enamine 2 as highly viscous dark red oil, which was used as such
in the next step. Raney nickel (type W-2, 0.42 g) and hydrazine hydrate
(6.74 mmol) were added to the solution of crude enamine 2 (ꢀ4.2 mmol) in
dry methanol (15 mL) and THF (10 mL) at rt under nitrogen atmosphere.
The mixture stirred for 3 h. Hydrazine hydrate (1.6 equiv) was added to the
mixture, which continued stirring at rt for additional 3 h, when TLC
indicated completion of the reaction. The mixture was filtered through a
Celite pad and washed with hot methanol (25 mL). The filtrate was concen-
trated to afford the crude 7-hydroxymethyl-indole (4). (Note: In the case of
O-THP derivative 1c, the corresponding 7-tetrahydropyranyloxymethyl-
indole (3c) was obtained.) It was purified on silica gel to furnish pure 7-hydro-
xymethyl-indole (4), mp 53–54 8C (lit.[1b] mp: 56–56.5 8C). 1H NMR
(300 MHz, CDCl3): d 1.83–2.08 (bs, 1H, D2O exchangeable), 4.98 (s, 2H),
6.54 (dd, 1H, J ¼ 2.1, 1.8 Hz), 6.95–7.06 (m, 2H), 7.24 (dd, 1H, J ¼ 6.6,
2.7 Hz), 7.58 (d, 1H, J ¼ 8.1 Hz), 8.88 (bs, 1H); IR (neat): 3423, 1438,
1338, 730 cm21. Anal. calcd for C9H9NO: C, 73.44; H, 6.16; N, 9.51.
Found C, 73.32; H, 6.67; N, 9.72.

Simple Synthesis of 7-Formyl-indole
1055
7-Tetrahydropyranyloxymethyl-indole (3c)
1
It was obtained as a light yellow solid, mp 60–61 8C; H NMR (300 MHz,
CDCl3): d 1.55–1.82 (m, 6H), 3.53–3.57 (m, 1H), 3.86–3.92 (m, 1H), 4.73
(bs, 1H), 4.98 (d, 1H, J ¼ 11.7 Hz), 5.31 (d, 1H, J ¼ 11.7 Hz), 6.31 (d, 1H,
J ¼ 3.3 Hz). 6.96–7.06 (m, 2Harom), 7.21–7.23 (t, 1H, J ¼ 3.6 Hz), 7.53
(d, 1Harom, J ¼ 7.8 Hz), 9.60 (s, 1H, indole –NH). Anal. calcd. for
C14H17NO2: C, 72.70; H, 7.40; N, 6.05. Found: C, 72.33; H, 7.69; N, 6.20.
Deprotection of THP Derivative 3c
p-Toluenesulfonic acid monohydrate (ꢀ10 mg) was added to a stirred solution
of 7-tetrahydropyranyloxymethyl-indole (3c) (200 mg, 0.86 mmol) in
anhydrous methanol (10 mL) at room temperature under nitrogen atmosphere.
The mixture stirred at 60 8C for 0.5 h. The mixture was concentrated, diluted
with ethyl acetate (50 mL), and washed with brine solution (2 Â 25 mL). The
organic layer was dried (Na2SO4) and concentrated in vacuo to give 130 mg
(quantitative) of 4, and the product was identical (1H NMR, mp, and TLC
Rf value) to that obtained from other approaches.
7-Formyl-indole (5)
A solution of 4 (70 mg, 0.47 mmol) in dichloromethane (3 mL) was added to a
stirred solution of pyridinium chlorochromate (PCC) (153 mg, 0.71 mmol) in
dry dichloromethane (2 mL) at room temperature under inert atmosphere. The
mixture was stirred at rt for 1.5 h. The mixture was filtered through a Celite
pad and washed with dichloromethane (20 mL). The filtrate, on concentration,
afforded 59 mg (86%) of 7-formyl indole (5) as a light yellow solid,
mp 86–87 8C (lit.[1b] mp: 86.5–87 8C). TLC Rf: 0.5 (1 : 4 ethyl acetate/
petroleum ether). 1H NMR (300 MHz, DMSO-d6): d 6.58 (t, 1H,
J ¼ 2.4 Hz), 7.22 (t, 1H, J ¼ 7.2, 7.8 Hz), 7.39 (t, 1H, J ¼ 2.7 Hz), 7.72
(d, 1H, J ¼ 7.2 Hz), 7.93 (d, 1H, J ¼ 7.5 Hz), 10.12 (s, 1Haldehyde), 11.51
(bs, 1H, NHindole). Anal. calcd. for C9H7NO: C, 74.46; H, 4.86; N, 9.65.
Found: C, 74.39; H, 5.24; N, 9.87.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the support from Glenmark Research
Centre. The authors thank B. Gopalan for stimulating discussions and sugges-
tions on the subject. The authors also thank Nauzer P. Dubash and Naveen
Kumar Mangu for providing technical help.

1056
V. R. Uchil, M. Gund, and A. Satyam
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