Synthesis of N-protected/free indole-7-carboxaldehyde

Article abstract of DOI:10.1080/00397910701578586

A direct method for the preparation of N-protected/free indole-7-carboxaldehyde is reported from the corresponding N-protected 7-bromomethylindoles using three different conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701578586

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Synthesis of N‐Protected/Free
Indole‐7‐Carboxaldehyde
Arasambattu K. Mohanakrishnan a , Ramalingam Balamurugan a ,
Neelamegam Ramesh a , Manoharan Mathiselvam a & Subramaniam
Manavalan a
a Department of Organic Chemistry, University of Madras, Chennai, India
Published online: 14 Dec 2007.
To cite this article: Arasambattu K. Mohanakrishnan , Ramalingam Balamurugan , Neelamegam
Ramesh , Manoharan Mathiselvam & Subramaniam Manavalan (2007) Synthesis of N‐Protected/Free
Indole‐7‐Carboxaldehyde, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:24, 4343-4352, DOI: 10.1080/00397910701578586
To link to this article: http://dx.doi.org/10.1080/00397910701578586
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Synthetic Communicationsw, 37: 4343–4352, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701578586
Synthesis of N-Protected/Free Indole-7-
Carboxaldehyde
Arasambattu K. Mohanakrishnan,
Ramalingam Balamurugan, Neelamegam Ramesh,
Manoharan Mathiselvam, and Subramaniam Manavalan
Department of Organic Chemistry, University of Madras, Chennai, India
Abstract: A direct method for the preparation of N-protected/free indole-7-carboxal-
dehyde is reported from the corresponding N-protected 7-bromomethylindoles using
three different conditions.
Keywords: bromomethylindole, 7-cyanomethylindole, 7-hydroxyindole, indole-7-
carboxaldehyde
INTRODUCTION
Synthesis of 3- and 2-substituted indoles are easily achieved through direct
electrophilic substitution[1] and lithiation[2] procedures, respectively. However,
the syntheses of indoles having substituents at the benzene portion (4-, 5-, 6-,
and 7-positions) are very limited.[3] In particular, the synthesis of 7-substituted
indoles are difficult.
Moyer and coworkers reported the first synthesis of indole-7-carboxalde-
hyde[4] using halogen–metal exchange reaction of 7-bromoindole followed by
its subsequent reaction with dry dimethylformamide (DMF). Bartoli et al.
reported a synthesis of 7-substituted indoles[5] via the reaction of 2-substituted
nitrobenzene with vinylmagnesium bromide. Dobson et al. reported a facile
synthesis of 7-formylindole[6] following the procedure developed by Bartoli
and coworkers. Dobbs et al. reported a simple synthesis of 7-bromoindole
Received in India May 15, 2007
Address correspondence to Arasambattu K. Mohanakrishnan, Department of
Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
E-mail: mohan_67@hotmail.com
4343

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A. K. Mohanakrishnan et al.
derivatives[7] involving the Bartoli protocol. Recently, Pirrung and coworkers
reported a novel synthesis of a variety of 7-substituted indoles[8] involving an
improved Bartoli protocol. Kolis and coworkers reported[9] a simple synthesis
of 7-cyanomethylindoles and 7-acetamidomethylindoles starting from the N-
protected indole-7-carboxaldehydes. Hartung and coworkers reported[10]
a
facile synthesis of 7-substituted indoles, involving a directed lithiation of N-
protected-2-trimethylsilylindole. Ishiyama and Yamada reported a simple
synthesis of 7-hydroxyindole,[11] a crucial intermediate of natural product
AJ-9766, a potent and selective adrenaline b-3 agonist. Over the years, N-
protected bromomethylindoles at the 2/3-position have been extensively
used for the synthesis of various indole alkaloids.[12]
RESULTS AND DISCUSSION
The required 7-methylindole 2 was prepared using a published procedure.[13]
Attempted phenylsulfonylation of 2 using various conditions (NaH/THF or
LDA/THF) did not afford the N-phenylsulfonyl-7-methylindole; instead,
only the starting material was recovered. However, t-butoxycarbonylation
of 2 was smoothly achieved in 85% yield using Boc2O and 4-dimethylamino-
pyridine (DMAP) in acetonitrile. Similarly, a carbethoxylation of 2 was also
achieved in 69% yield using the phase transfer catalyst (PTC) condition via
a slow addition of ethyl chloroformate. The N-protected 7-methylindoles 3a
and 3b were smoothly converted into the respective bromomethylindoles 4a
and 4b using N-bromosuccinimide (NBS) in the presence of a catalytic
amount of benzoylperoxide in CCl4 at reflux. The bromo compound 4a or
4b was smoothly converted into the indole-7-carboxaldehyde 1 using
NaHCO3 and dry DMSO under microwave irradiation conditions in 47%
and 54% yields, respectively. The hydrolysis of the N-carbethoxybromo-
methylindole 4b using 10% NaOH in ethanol followed by MnO2 oxidation
afforded indole-7-carboxaldehyde 1 in 40% overall yield (Scheme 1).
The bromomethylindole 4b can be smoothly converted into N-carbethox-
yindole-7-carboxaldehyde 5 in 61% yield using a modified Hass condition.[14]
Alternatively, on refluxing bromo compound 4b with tetrabutylammonium
dichromate[15] in dry chloroform led to the isolation of N-carbethoxyindole-
7-carboxaldehyde 5 in 73% yield. The attempted Baeyer–Villiger reaction
of N-carbethoxyindole-7-carboxaldehyde 5 using m-CPBA in dicholoromethane
(DCM) was complicated. However, a smooth Baeyer–Villiger reaction of N-
carbethoxyindole-7-carboxaldehyde 5 was performed using a 30% solution of
H2O2 containing a catalytic amount of sulfuric acid in methanol at reflux.

N-Protected/Free Indole-7-Carboxaldehyde
4345
Scheme 1. Reagents and conditions: (i) Boc2O/DMAP, CH3CN 85%; (ii) (a) ben-
zene/50% NaOH, n-Bu4NHSO4 (cat.), (b) ClCO2 Et (slow addition), 69%; (iii) NBS/
(PhCOO)2 (cat.), CCl4, reflux; (iv) NaHCO3/DMSO, MW (3 ꢀ 10 s), 47%, 54%; (v)
(a) 10% NaOH/EtOH, (b) MnO2/DCM, rt, 40%.
Removal of methanol followed by column chromatographic purification
afforded 7-hydroxy-N-carbethoxyindole 6 in 57% yield. Finally, the bromo
compound 4b was converted into the 7-cyanomethylindole 7 in 60% yield
(Scheme 2).
In conclusion, we have reported an efficient preparation of N-protected/
free indole-7-carboxaldehydes. In comparison to the existing procedures,[4,7]
the methods described herein are simple, straightforward, and cost-effective.
We hope the N-protected 7-bromomethylindoles, N-protected indole-7-carbox-
aldehydes, and N-protected 7-hydroxyindole will be useful as intermediates for
the synthesis of cyclin dependent kinase (CDK) inhibitors,[9,16] and 7-hydroxyl-
ated indole alkaloids.[11,17]
Scheme 2. Reagents and conditions: (i) n-(Bu4N)2Cr2O7/CHCl3, N2, reflux, 73%; (ii)
2-nitropropane/NaH, DMF, N2, 08C to rt, 61%; (iii) 30% H2O2/MeOH, H2SO4 (cat.),
reflux, 57%; (iv) (a) NaCN/DMSO-THF, (b) 40% aq. KOH, EtOH, 60%.
EXPERIMENTAL
All melting points were uncorrected. Reagents were purchased from commer-
cial sources and used as received without purification. Solvents were dried by

4346
A. K. Mohanakrishnan et al.
standard procedures. Column chromatography was carried on silica gel (grade
60, mesh size 230–400, Merck). IR spectra were recorded on a Shimadzu
8300 instrument. 1H and 13C NMR spectra were recorded on a Jeol
400-MHz spectrometer with solvent signals as internal standard. Chemical
shift values were quoted in parts per million (ppm), and coupling constants
were quoted in hertz. Chemical shift multiplicities were reported as
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, and
br ¼ broad. Mass spectra were obtained on a Jeol DX-303 (electron impact,
70 ev) spectrometer. Elemental analyses were carried out on a Perkin-Elmer
240B analyzer.
Preparation of 7-Methylindole 2
To a solution of anhydrous FeCl3 (12.5 g, 77.06 mmol) in dry methanol
(300 mL), (E)-1-(3-methyl-2-nitrostyryl)pyrrolidine[13] (43.78 g, 0.19 mol)
was added. To a solution of anhydrous FeCl3 (12.5 g, 77.06 mmol) in dry
methanol (300 ml), activated charcoal (32.0 g) was added and refluxed in a
water bath. After 10 min, 80% hydrazine hydrate (34 mL) was carefully
added drop wise via addition funnel (1 h). After the addition of hydrazine
hydrate was completed, the reaction mixture was refluxed for 3 h. It was
then cooled to room temperature, and the insoluble residue was filtered off
through a Celitew bed. The insoluble residue was washed with methylene
chloride (4 ꢀ 30 mL). The combined organic layer was dried (Na2SO4), and
the solvent was removed in vacuo to afford a dark liquid. The crude product
was purified via Soxhlet extraction (pure hexane) to give compound 4
(16.6 g, 67%) as a colorless solid, mp 828C (lit.[13] 83–848C).
Preparation of 1-Tert-butyloxycarbonyl-7-methylindole 3a
To a solution of 7-methylindole 2 (1.0 g, 7.63 mmol) in acetonitrile (25 mL)
under nitrogen atmosphere, di-tert-butyl dicarbonate (2 mL, 8.71 mmol) and
DMAP (0.18 g, 1.47 mmol) were added and stirred at room temperature for
30 min. The solvent was removed in vacuo, and the resultant crude product
was diluted with ethyl acetate and washed with an aqueous solution of 1 N
HCl (2 ꢀ 50 mL) and brine (100 mL) and dried (Na2SO4). After the removal
of solvent, the crude product was purified by column chromatography
(silica gel) using pure hexane as an eluant to afford product 3a (1.50 g, 85%)
as a thick colorless liquid. IR (KBr): 1749 (CO2 tBu) cm21 1H NMR
.
(400 MHz, CDCl3): d ¼ 1.68 (s, 9H), 2.70 (s, 3H), 6.58 (d, J ¼ 3.2 Hz, 1H),
7.14–7.20 (m, 2H), 7.44 (d, J ¼ 7.2 Hz, 1H), 7.57 (d, J ¼ 3.2 Hz, 1H). Anal.
calcd. for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.76; H, 7.36;
N, 6.10.

N-Protected/Free Indole-7-Carboxaldehyde
4347
Preparation of 1-Carbethoxy-7-methylindole 3b
7-Methylindole 2 (5 g, 38.1 mmol) was dissolved in benzene (70 mL). To this,
50% NaOH solution (30 mL) and a catalytic amount of tetrabutylammonium
hydrogen sulfate were added and stirred vigorously for 15 min. Ethyl chloro-
formate (7.3 mL, 76.3 mmol) was slowly added (15 min). Then the two-phase
system was stirred at room temperature for 10 min and diluted with water
(30 mL). The organic layer was separated, and the aqueous layer was
extracted with benzene (2 ꢀ 10 mL). The combined organic layer was dried
(Na2SO4). Benzene was then removed completely, and the crude product
was purified by flash column chromatography (silica gel) using pure hexane
as an eluant to afford product 3b (5.34 g, 69%). IR (KBr): 1740 cm21
1
(CO2Et). H NMR (400 MHz, CDCl3): d ¼ 1.43 (t, J ¼ 7.1 Hz, 3H), 2.65
(s, 3H), 4.44 (q, J ¼ 7.2 Hz, 2H), 6.56 (d, J ¼ 3.6 Hz, 1H), 7.09–7.17
(m, 2H), 7.39 (d, J ¼ 7.4 Hz, 1H), 7.59 (d, J ¼ 3.7 Hz, 1H). MS (EI, 70 eV):
m/z (%): 203.4 (Mþ, 59.7), 144.2 (61.8), 131.2, 130.3 (52.3). Anal. calcd.
for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.83; H, 6.49; N, 6.78.
Preparation of 1-Tert-butyloxycarbonyl-7-bromomethylindole 4a
A mixture of 1-tert-butyloxycarbonyl-7-methylindole 3a (1.2 g, 5.19 mmol)
and finely powdered NBS (0.92 g, 5.19 mmol) in dry CCl4 (20 mL) containing
a catalytic amount of dibenzoyl peroxide was refluxed for 1 h and cooled. The
floated succinimide was filtered off and washed with CCl4 (5 mL). The solvent
was then completely removed in vacuo to afford bromo compound 4a (1.40 g,
1
87%) as a colorless liquid. H NMR (400 MHz, CDCl3): d ¼ 1.66 (s, 9H),
5.24 (s, 2H), 6.55 (d, J ¼ 3.2 Hz, 1H), 7.17 (t, J ¼ 7.2 Hz, 1H), 7.25
(d, J ¼ 7.2 Hz, 1H), 7.55 (d, J ¼ 3.9 Hz, 1H), 8.06 (d, J ¼ 8.4 Hz, 1H). 13C
NMR (CDCl3, 100.6 MHz): d ¼ 28.01, 35.89, 83.86, 107.10, 122.01,
122.96, 127.12, 128.28, 128.38, 128.78, 134.21, 149.28.
Preparation of 1-Carbethoxy-7-bromomethylindole 4b
A mixture of 1-carbethoxy-7-methylindole 3b (1.0 g, 4.92 mmol) and finely
powdered NBS (0.88 g, 4.92 mmol) in dry CCl4 (20 mL) containing a
catalytic amount of dibenzoyl peroxide was refluxed for 1 h and cooled.
The floated succinimide was filtered off and washed with CCl4 (5 mL).
The solvent was then completely removed under vacuo to afford bromo
compound 4b (1.21 g, 87%) as an orange liquid. 1H NMR (400 MHz,
CDCl3): d ¼ 1.40 (t, J ¼ 7.2 Hz, 3H), 4.43 (q, J ¼ 7.2 Hz, 2H), 5.12
(s, 2H), 6.53 (d, J ¼ 4.0 Hz, 1H), 7.11–7.22 (m, 2H), 7.39 (d, J ¼ 7.6 Hz,
1H), 7.55 (d, J ¼ 4.0 Hz, 1H). MS (EI, 70 eV): m/z (%): 281.1 (Mþ, 39.1),
283.1 (Mþ þ 2, 36.5), 202.16 (100), 176.2 (93.9), 129.1 (69.5), 77.1 (39.0).

4348
A. K. Mohanakrishnan et al.
Preparation of Indole-7-carboxaldehyde 1 from 4a using
Microwave Irradiation
To a solution of 1-tert-butyloxy-7-bromomethylindole 4a (0.4 g, 1.33 mmol)
in dry DMSO (2 mL), anhydrous NaHCO3 (0.36 g, 2.6 mmol) was added. The
reaction mixture was irradiated in a microwave oven for 30 s. Then it was
poured over crushed ice, and the crude product was extracted with ethyl
acetate (2 ꢀ 20 mL). The organic layer was washed with brine solution
(20 mL) followed by water (2 ꢀ 25 mL). The combined organic layer was
dried (Na2SO4). The solvent was completely removed, and the crude
product was purified by flash column chromatography (silica gel; hexane–
EtOAc, 97:3) to afford compound 1 (0.09 g, 47%) as a colorless solid, mp
86–878C (lit.[4] 87–898C).
Preparation of Indole-7-carboxaldehyde 1 from 3b
To a stirred suspension of bromo compound 4b (0.5 g, 1.77 mmol) in ethanol
(10 mL), 10% NaOH (5 mL) was added and stirred at room temperature for
30 min. Thin-layer chromatography (TLC) monitoring shows the disappear-
ance of starting material. The crude product was extracted with EtOAc
(2 ꢀ 15 mL), washed with water (2 ꢀ 30 mL), and dried (Na2SO4). Solvent
was completely removed and the resulting crude indoly-7-methanol (0.38 g,
2.58 mmol) was dissolved in dry methylene chloride (20 mL). To this,
active MnO2 (1.76 g, 20.23 mmol) was added and stirred at room temperature
for 2 h. The reaction mixture was then passed through the Celitew bed, and the
filtrate was concentrated. The crude product was purified by column chrom-
atography (silica gel; hexane–EtOAc, 97:3) to afford compound 1 (0.15 g,
40%), mp 86–878C (lit.[4] 87–898C).
Preparation of Indole-7-carboxaldehyde 1 under Microwave
Conditions
To a solution of bromo compound 4b (2 g, 7.01 mmol) in dry DMSO (5 mL),
anhydrous NaHCO3 (1.2 g, 14.2 mmol) was added. The reaction mixture was
irradiated in a household microwave oven for 3 ꢀ 10 s. Then it was poured
over crushed ice, and the crude product was extracted with ethyl acetate
(2 ꢀ 30 mL). The combined organic layer was washed with brine solution
(30 mL) followed by water (25 mL) and dried (Na2SO4). Removal of
solvent followed by flash-column chromatographic purification (silica gel;
hexane–EtOAc, 97:3) afforded 1 (0.56 g, 54%), mp 86–878C (lit.[4]
87–898C).

N-Protected/Free Indole-7-Carboxaldehyde
4349
Preparation of 1-Carbethoxyindole-7-carboxaldehyde 5 using
(Bu4N)2Cr2O7
To a solution of bromo compound 4b (2 g, 7.1 mmol) in dry chloroform
(20 mL), tetrabutylammonium dichromate (4.97 g, 7.1 mmol) was added
and refluxed under a nitrogen atmosphere for 2 h. The reaction mixture was
then filtered through Celitew. Removal of solvent followed by flash-column
chromatographic purification (silica gel; hexane–EtOAc, 99:1) afforded
product 5 (1.12 g, 72.7%) as a colorless solid, mp 54–568C. IR (KBr):
1
1739 (CO2Et), 1672 (CHO) cm21. H NMR (400 MHz, CDCl3): d ¼ 1.43
(t, J ¼ 7.3 Hz, 3H), 4.47 (q, J ¼ 7.3 Hz, 2H), 6.66 (d, J ¼ 3.9 Hz, 1H), 7.32
(t, J ¼ 7.3 Hz, 1H), 7.65 (d, J ¼ 3.9 Hz, 1H), 7.72–7.74 (m, 2H), 10.55
(s, 1H, CHO). 13C NMR (100.6 MHz, CDCl3): d ¼ 14.18, 64.14, 108.51,
123.37, 125.05, 125.58, 125.99, 127.80, 132.03, 132.79, 151.34, 190.85. MS
(EI, 70 eV): m/z (%) ¼ 218 (Mþ, 8), 186 (12), 106 (41), 85 (24), 58 (100).
Anal. calcd. for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.17;
H, 5.20; N; 6.58.
Preparation of 1-Carbethoxyindole-7-carboxaldehyde 5
To a suspension of hexane-washed sodium hydride (80 mg, 1.67 mmol) in dry
DMF (5 mL) at 08C, 2-nitropropane (0.2 mL, 2.23 mmol) was added. The
mixture was stirred for 15 min at the same temperature under a nitrogen
atmosphere and was treated dropwise with a solution of bromo compound
4b (0.3 g, 1.06 mmol) dissolved in dry DMF (3 mL). After the bromo
compound was consumed (monitored by TLC), the reaction mixture was
quenched with ice water (10 mL), extracted with chloroform (2 ꢀ 10 mL),
and dried (Na2SO4). Removal of solvent followed by column chromato-
graphic purification (silica gel; hexane–EtOAc, 99:1) afforded aldehyde 5
(0.14 g, 61%) as a colorless solid, mp 54–568C.
Preparation of N-Carbethoxy-7-hydroxyindole 6
To a solution of 1-carbethoxy-7-carboxaldehyde 5 (0.3 g, 1.38 mmol) in
methanol (15 mL), 30% H2O2 (1 mL) and conc. H2SO4 (5 drops) were
added and refluxed under a nitrogen atmosphere for 3 h. After completion
of the reaction (monitored by TLC), the reaction mixture was cooled to
room temperature and diluted with DCM (25 mL). The organic layer was
then washed with NaHCO3 (2 ꢀ 10 mL) followed by brine solution
(2 ꢀ 10 mL) and dried (Na2SO4). Removal of solvent followed by column
chromatographic purification (silica gel; hexane–EtOAc, 98:2) afforded
product 6 (0.16 g, 57%) as a colorless solid, mp 608C. IR (KBr): 1697
(CO2Et), 3146 (O-H) cm21
.
1H NMR (400 MHz, CDCl3): d 1.44

4350
A. K. Mohanakrishnan et al.
(t, J ¼ 7.3 Hz, 3H), 4.47 (q, J ¼ 7.3 Hz, 2H), 6.54 (d, J ¼ 3.4 Hz, 1H), 6.84
(d, J ¼ 7.8 Hz, 1H), 7.02 (d, J ¼ 7.8 Hz, 1H), 7.14 (t, J ¼ 7.8 Hz, 1H), 7.46
(d, J ¼ 3.9 Hz, 1H), 10.63 (s, 1H, OH). Anal. calcd. for C11H11NO3: C,
64.38; H, 5.40; N, 6.83. Found: C, 64.47; H, 5.34; N, 6.78.
Preparation of 7-Cyanomethylindole 7
To a stirred suspension of NaCN (0.36 g, 7.34 mmol) in DMSO (10 mL), dry
THF (5 mL) was added, and the reaction mixture was stirred at 08C for
10 min. To this, 1-carbethoxy-7-bromomethylindole 4b (1.38 g, 4.89 mmol)
was added. The reaction mixture was stirred at 08C for 4 h. Then the
reaction mixture was diluted with water (20 mL). The product was extracted
with EtOAc (3 ꢀ 5 mL). The aqueous layer was extracted with EtOAc
(3 ꢀ 5 mL). The combined organic layer was dried (Na2SO4) and concen-
trated in vacuo. The crude 1-carbethoxy-7-cyanomethylindole was treated
with 40% aqueous KOH (5 mL) in ethanol (15 mL). The reaction mixture
was stirred at room temperature for 2 h. The solvent was evaporated under
vacuo, and the residue so obtained was diluted with water (15 mL),
extracted with EtOAc (2 ꢀ 10 mL), and dried (Na2SO4). Removal of the
solvent followed by column chromatographic purification (silica gel;
hexane–EtOAc, 97:3) afforded 8 (0.46 g, 60%) as a brown liquid. IR
1
(KBr): 3359 (N-H), 2253 (CN) cm21. H NMR (400 MHz, CDCl3): d 3.89
(s, 2H), 6.61 (t, J ¼ 3.1 Hz, 1H), 7.10–7.14 (m, 2H), 7.24 (t, J ¼ 3.1 Hz,
1H), 7.66 (d, J ¼ 2.4 Hz, 1H), 8.61 [s (broad), 1H]. 13C NMR (100.6 MHz,
CDCl3): d 29.83, 103.45, 112.27, 117.85, 120.23, 121.32, 122.17, 125.20,
128.83, 133.95. MS (EI, 70 eV): m/z (%): 156.6 (Mþ, 100), 130.4 (38.8),
85.4 (68.3). Anal. calcd. for C10H8N2: C, 76.90; H, 5.16; N, 17.94. Found:
C, 76.93; H, 5.25; N, 17.89.
ACKNOWLEDGMENTS
We thank Council of Scientific and Industrial Research (CSIR), New Delhi
[01(207)/06/EMR-II] for the financial support and Department of Science
and Technology-Fund for Improvement of Science and Technology Infrastuc-
ture (DST-FIST) for the 300-MHz NMR facility.
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N-Protected/Free Indole-7-Carboxaldehyde
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