Synthesis of N-protected indolaldehydes using modified Hass procedure

Article abstract of DOI:10.1016/j.tet.2007.08.035

A detailed study on oxidation of N-protected bromomethylindoles into the respective aldehydes was carried out. Using a modified Hass procedure, synthesis of aryl-/hetero-aryl aldehydes in particular indolaldehydes is achieved in reasonable yields.

Full text of DOI:10.1016/j.tet.2007.08.035

Tetrahedron 63 (2007) 11078–11085
Synthesis of N-protected indolaldehydes using
modified Hass procedure
*
Ramalingam Balamurugan and Arasambattu K. Mohanakrishnan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 7 May 2007; revised 24 July 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract—A detailed study on oxidation of N-protected bromomethylindoles into the respective aldehydes was carried out. Using a modified
Hass procedure, synthesis of aryl-/hetero-aryl aldehydes in particular indolaldehydes is achieved in reasonable yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Hibino and co-workers14 recently utilized 2-phenylvinyl-
indole-3-carboxaldehyde as a crucial intermediate for the
synthesis of calothrixin. Nagarathnam reported a synthesis of
N-phenylsulfonylindole-3-carboxaldehyde15 via hydrolysis
of the corresponding dibromomethylindole. Li et al.
observed a facile preparation of 1,3-disubstituted indole-
2-carboxaldehydes16 by the reactions of the corresponding
dibromomethylindole with DMSO. Moreover, neither the
spectral data of the reported indolaldehyde were given nor
was the reaction extended to the synthesis of any other indo-
laldehydes. However, the methodology has been well
exploited for the synthesis of several benzaldehydes.
Oxidation of benzylic bromide into the corresponding alde-
hydes is one of the most significant transformations in or-
ganic synthesis. Plenty of methods have been developed
for the conversion of benzyl halides into their corresponding
carbonyl compounds. Most commonly used reagents for
conversion of benzylic bromides into the corresponding
aldehydes are hexamethylene tetramine,1 dimethyl sulfoxide,2
(Bu4N)2Cr2O7,3 pyridine-N-oxide,4 3,6-bis(triphenylphos-
phonium)cyclohexene peroxodisulfate (BTPCP),5 MnO2,6
H2O2,7 and NaIO4/DMF.8 However, all of these reagents
have their own limitations and in some cases, the reaction
needs to be carried out at elevated temperature. Hydrolysis
and succeeding oxidation of benzylic a,a-dihalides9 and
diacetates10 have been traditionally known for the preparation
of aldehydes. The above-mentioned methods, which are
routinely employed for the conversion of benzylic halides
into the respective aldehydes, are yet to be adopted to the
synthesis of indolaldehydes.
The synthesis of the highly expensive indole-7-carboxalde-
hyde, which was widely used as a crucial starting material
for the synthesis of carbazole alkaloids,17 was realized
through the Bartoli protocol.18 A simple synthesis of
N-tosylindole-4-carboxaldehyde19 was realized through the
reactions of the corresponding bromomethylindole with
DMSO in the presence of NaHCO3. Suhana and Srinivasan
recently observed the synthesis of N-protected indolalde-
hydes through the reactions of bromomethylindole20 with
tetrabutylammonium dichromate. Our recent studies on
preparation of indolaldehydes using enamine methodology
led us to the synthesis of carbazoles.21
Indolaldehydes are crucial intermediates for the synthesis of
several indole alkaloids.11,12,17b The multi-step syntheses of
quino[4,3-b]carbazole and quino[3,4-b]carbazoles12 have
been achieved using 1-phenylsulfonyl-2-methylindole-3-
carboxaldehyde and 1-phenylsulfonyl-3-methylindole-2-
carboxaldehyde, respectively. Zhang and Larock reported13
a versatile synthesis of b- and g-carbolines starting from the
respective indolaldehydes.
Hass and Bender22 transformed a variety of substituted benz-
yl halides into the corresponding benzaldehydes using
sodium-2-propane nitronate in ethanol as a solvent. In the
case of o/p-nitrobenzylchloride and 2,4-dinitrobenzylchlor-
ide, stable C-alkylation products are isolated rather than
the expected aldehydes. Later, Hass methodology was
extended to the synthesis of several heterocyclic and other
carboxaldehydes23 except for indolaldehydes. We have re-
cently reported our preliminary results on the synthesis of
indolaldehydes24 using a modified Hass procedure.
Keywords: Bromomethylindole; Modified Hass procedure; Indolaldehydes;
Aryl-/hetero-aryl aldehydes.
* Corresponding author. Tel.: +91 44 24451108; fax: +91 44 22352494;
e-mail: mohan_67@hotmail.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.035

R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
11079
2. Results and discussion
of bromo compound 1a0 led to the formation of the aldehyde
2a as major product (40%) along with 10% yield of formate
ester 5.
In an ongoing project, we required different types of indol-
aldehydes as starting materials for the synthesis of indole
alkaloids. Since the existing methods for the preparation of
indolaldehydes are not scalable to any reasonable extent,
a detailed study on smooth transformation of N-protected
bromomethylindoles into the corresponding aldehydes is un-
dertaken. Initially, the bromo compound 1a0 was reacted
with NaHCO3 in dry DMSO at 60 ꢀC (Kornblum reaction)25
for 2 h. The usual workup followed by column chromato-
graphic purification afforded aldehyde 2a (35%) and alcohol
3 (30%), Scheme 1.
Me
Me
CHO
Me
CH2OCHO
Me
O2N
1a'
Li2CO3/DMF
rt, 10 h
N
N
SO2Ph
SO2Ph
2a
5
Me
Me
O
H
N
Me
5
N
SO2Ph
Me
CHO
NaHCO3/
DMSO
Me
CH2OH
Me
6
Br
60 °C, 2 h
N
N
N
Scheme 3.
SO2Ph
SO2Ph
SO2Ph
1a'
2a
3
Conditions such as K2CO3/DMF, Cs2CO3/DMF, and NaOEt/
DMF were also explored without any appreciable change in
the aldehyde yield. Among the various conditions tried for
oxidation of bromomethylindole, NaH/DMF at room tem-
perature was found to be the most efficient.
Scheme 1.
All the conditions tried for the oxidation of bromomethyl-
indole 1a0 using dry DMSO in the presence of NaHCO3
yielded the corresponding indolylmethanol 3 as a side prod-
uct. Use of Li2CO3/K2CO3 in place of NaHCO3 also led to
the formation of aldehyde and alcohol in almost comparable
yields. Further changes in the reaction temperature or pro-
longing the reaction period was also not useful. Hence, we
decided to explore the sodium-2-propane nitronate tech-
nique for the oxidation of N-phenylsulfonyl-3-methyl-
2-bromomethylindole 1a0. The reaction of the bromo
compound 1a0 with sodium-2-propane nitronate in ethanol at
room temperature for 10 h led to the formation of a mixture
of the N-protected and free aldehydes 2a and 4 in 40 and
25% yields, respectively, Scheme 2.
Thus, usingNaH/DMFconditionvarioustypes ofN-protected
bromomethylindoles 1a0–q were smoothly converted into
the corresponding aldehydes 2a–q. The conditions followed
and the products obtained along with their yields are pre-
sented in Table 1.
In most of the cases, N-protected aldehydes were obtained in
reasonable yields with the exception of bromo compound 1o
wherein the oxidation completely failed (entry 15). The re-
action of bromo compounds with 2-nitropropane using
NaH/DMF produced the corresponding aldehydes in much
better yields than the NaOEt/EtOH condition (entries 2–4,
16, and 18). The oxidation was relatively much faster using
the NaH/DMF condition. The N-protected chloromethyl-
indoles 1a00 and 1b00 were also smoothly converted into the
respective aldehydes 2a and 2b in reasonable yields (entries
1 and 2). The N-protected indole-7-carboxaldehyde 2e17b
was prepared in 61% yield (entry 5). The preparation of
N-protected aldehydes 2f–i containing one more carbonyl
unit either as ester/ketone was also achieved (entries 6–9).
Vinyl ester tethered aldehydes 2j–l were prepared from
the corresponding bromo compounds (entries 10–12).
2-Nitroarylvinyl-indole-3-carboxaldehydes 2m and 2n are
prepared in good yields (entries 13 and 14). Even though
the C-alkylation of 2-nitropropanoate anion is common to
benzylic and heterocyclic chloro compounds,27 we have
not observed any alkylation products with N-protected
bromo-/chloro-methylindoles.
Me
Me
Me
CHO
Me
CHO
Me
O2N
Br
NaOEt/EtOH
rt, 10 h
N
N
N
H
SO2Ph
SO2Ph
1a'
2a
4
Scheme 2.
In particular, NaOEt being nucleophilic may cleave the
N-phenylsulfonyl unit. Hass procedure for the conversion
of bromomethylindole into the respective aldehyde is having
its own limitations such as longer reaction time, large
amount of solvent and cleavage of phenylsulfonyl unit. In
order to overcome these problems, we decided to modify
the Hass procedure.
Initially, the reaction of bromo compound 1a0 with 2-nitro-
propane using Li2CO3 in DMF at room temperature led to
the isolation of formate ester 5 in 56% yield along with
minor amount of expected aldehyde 2a, Scheme 3. The
formation of compound 5 can be visualized through the
nucleophilic displacement of the bromo compound with
DMF to form intermediate 6. The latter on aqueous workup
led to compound 5. However, the reaction of 2-nitropropane
with Li2CO3 in DMF at 60 ꢀC for 2 h, followed by addition
In addition to the indolaldehydes, tribromomethyl mesity-
lene 1p could be converted into the respective aldehyde 2p
in relatively better yield (67%) using modified Hass proce-
dure (entry 16). 2,7-Bis(bromomethyl)-9,9-diethyl-9H-
fluorene 1q was smoothly converted into the corresponding
aldehyde 2q in 55% yield (entry 17). Finally, 3,4-bis(bromo-
methyl)-2,5-dimethylthiophene 1r was converted into 2,5-
dimethylthiophene-3,4-dicarboxaldehyde 2r in relatively
better yield using modified Hass procedure (entry 18).

11080
R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
Table 1. Preparation of aryl-/hetero-aryl aldehydes using 2-nitropropane
Entry
Bromo/chloro compounds26
Conditions
Aldehydes
Yield (%)
Me
X
Me
63
58
N
CHO
1
NaH/DMF, rt, 2 h
N
SO2Ph
SO2Ph
2a11g
1a' X = Br
1a" X = Cl
SPh
X
SPh
NaOEt/EtOH, rt, 24 h
NaH/DMF, rt, 2 h
NaH/DMF, rt, 3 h
58
65
57
CHO
N
2
3
N
SO2Ph
1b' X = Br
1b" X = Cl
SO2Ph
2b
Br
Br
Br
NaOEt/EtOH, rt, 15 h
NaH/DMF, rt, 4 h
42
65
CHO
N
N
SO2Ph
SO2Ph
1c
2c
Br
CHO
NaOEt/EtOH, rt, 15 h
NaH/DMF, rt, 3 h
55
65
4
N
N
SO2Ph
SO2Ph
2d
1d
N
CO2Et
N
CO2Et
5
6
NaH/DMF, rt, 0.5 h
NaH/DMF, rt, 2.5 h
61
57
OHC
Br
2e
1e
MeO
MeO
CO2Et
CO2Et
Br
CHO
SO2Ph
2f
N
N
SO2Ph
1f
CO2Me
Br
CO2Me
CHO
7
8
NaH/DMF, rt, 2 h
63
67
N
N
SO2Ph
SO2Ph
1g
2g
O
O
CH3
CH3
CHO
Br
NaH/DMF, rt, 3 h
N
N
SO2Ph
1h
SO2Ph
2h
CHO
CO2Et
SO2Ph
2i
Br
CO2Et
SO2Ph
N
9
NaH/DMF, rt, 3 h
65
69
N
1i
CHO
Br
CO2Et
CO2Et
N
10
NaH/DMF, rt, 0.5 h
N
SO2Ph
1j
SO2Ph
2j
(continued)

R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
11081
Table 1. (continued)
Entry
Bromo/chloro compounds26
CO2Me
Conditions
Aldehydes
CO2Me
Yield (%)
Br
11
NaH/DMF, rt, 0.5 h
68
CHO
N
N
SO2Ph
SO2Ph
1k
2k
CO2Et
CO2Et
Br
12
NaH/DMF, rt, 0.5 h
65
CHO
N
N
SO2Ph
SO2Ph
1l
2l
NO2
NO2
Br
CHO
13
14
15
NaH/DMF, rt, 3 h
NaH/DMF, rt, 3 h
NaH/DMF, rt, 15 h
65
68
0
N
N
OMe
OMe
SO2Ph
SO2Ph
OMe
OMe
2m
1m
NO2
NO2
Br
CHO
N
N
SO2Ph
2n
SO2Ph
1n
CN
CN
Br
CHO
N
N
SO2Ph
SO2Ph
2o
1o
Br
CHO
H3C
CH3
H3C
CH3
NaH/DMF, rt, 3 h
NaOEt/EtOH, rt, 5 h
67
55
16
OHC
CHO
CH3
Br CH3 Br
2p
1p
Br
Br
OHC
CHO
17
18
NaH/DMF, rt, 4 h
55
Et
Et
Et
Et
2q
1q
Br
CH3
NaH/DMF, rt, 2.5 h
NaOEt/EtOH, rt, 4.5 h
74
65
OHC
H3C
Br
CHO
CH3
H3C
S
S
2r
1r
When modified Hass procedure was tried for in situ prepared
1-phenylsulfonyl-3-phenylthio-2-iodomethylindole, the ex-
pected aldehyde 2b was isolated in 69% yield, Scheme 4.
The slight enhancement in the yield of the aldehyde 2b
may be due to the relatively better hard-electrophilic charac-
ter of the iodo compound.
Reaction of p-nitrobenzyl chloride 1q with sodium salt of
2-nitropropane led to the isolation of stable C-alkylation
product.22,27 We presumed that the conversion of chloride
into the corresponding iodide may enhance the feasibility of
labile O-alkylation intermediate, which will collapse into the
aldehyde. Indeed, when in situ prepared p-nitrobenzyl iodide
was subjected to modified Hass procedure, p-nitrobenzalde-
hyde was isolated in 62% yield, Scheme 5.
SPh
CHO
SPh
i) NaI/DMF
Cl
ii) NaH/DMF
Me
N
N
SO2Ph
SO2Ph
Me
O2N
1b"
2b
Scheme 4.

11082
R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
Me
the reaction mixture was quenched with ice water (10 mL),
NO2
Me
Cl
extracted with CHCl3 (2ꢁ10 mL), and dried (Na2SO4). Re-
moval of the solvent, followed by column chromatographic
purification (silica gel, EtOAc/hexane 1:9) afforded 2b as
a colorless solid.
CHO
i) NaI/DMF
NaH/DMF
Me
Me
ii) NaH/DMF
Me
O2N
Me
NO2
NO2
3s
NO2
1s
O2N
4.2.1. 3-Methyl-1-(phenylsulfonyl)-1H-indole-2-carbal-
dehyde, 2a. Following the general procedure, compound
2a was obtained as a colorless solid in 63% yield; mp
2s
Scheme 5.
210 ꢀC; IR (KBr) nmax: 1672, 1556, 1363, 1176, 1089 cmꢂ1
.
dH (400 MHz, CDCl3): 2.56 (3H, s, CH3), 7.40–7.58 (2H, m,
ArH), 7.63–7.74 (2H, m, ArH), 7.81–7.95 (3H, m, ArH),
8.27 (2H, d, J¼7.8 Hz, ArH), 10.65 (1H, s, CHO). dC
(100 MHz, CDCl3): 185.0, 137.4, 136.9, 132.3, 130.5,
129.1, 129.0, 128.2, 126.5, 126.1, 121.5, 115.7, 10.4; MS
(EI) m/z (%): 299 (M+, 35%); found: elemental analysis:
C, 64.11; H, 4.45; N, 4.71; S, 10.79%. C16H13NO3S requires
elemental analysis: C, 64.20; H, 4.38; N, 4.68; S, 10.71.
Hopefully the aldehydes 2n and 2m could be converted into
indolo[3,2-j]phenanthridine alkaloids and their analog using
Hibino’s protocol.14
O
NO2
CHO
Hibino's
protocol
N
N
R2
N
H
R2
SO2Ph
O
R1
4.2.2. 1-(Phenylsulfonyl)-3-(phenylthio)-1H-indole-2-
carbaldehyde, 2b. Following the general procedure, com-
pound 2b was obtained as a colorless solid in 65% yield;
mp 112 ꢀC; IR (KBr) nmax: 1654, 1562, 1492, 1373, 1180,
1080 cmꢂ1. dH (400 MHz, CDCl3): 6.90 (1H, d, J¼7.8 Hz,
ArH), 7.00 (1H, m, ArH), 7.10–7.28 (5H, m, ArH), 7.34
(2H, t, J¼7.8 Hz, ArH), 7.40 (1H, t, J¼3.4 Hz, ArH), 7.47
(1H, t, J¼7.3 Hz, ArH), 7.70 (2H, d, J¼7.3 Hz, ArH), 8.20
(1H, d, J¼8.3 Hz, ArH), 10.48 (1H, s, CHO). dC (100 MHz,
CDCl3): 181.9, 134.5, 134.3, 130.4, 129.5, 129.2, 128.2,
127.6, 127.2, 126.9, 126.8, 124.6, 124.5, 123.0, 121.2,
115.7, 114.5; MS (EI) m/z (%): 393 (M+, 60%); found: ele-
mental analysis: C, 64.21; H, 4.09; N, 3.50; S, 16.19%.
C21H15NO3S2 requires elemental analysis: C, 64.10; H,
3.84; N, 3.56; S, 16.30.
2m/2n
R1
3. Summary
After adjudicating various methods for synthesizing indol-
aldehydes, the modified Hass procedure was found to be the
most reliable and better yielding procedure for the smooth
transformation of indole methyl halides into their corre-
sponding aldehydes. The existing Hass procedure for the
conversion of benzylic halide into the aldehydes has been
modified for the benzylic system. Using the modified proce-
dure the synthesis of several aromatic and hetero-aromatic
aldehydes was achieved in good yields. For the first time
a mild procedure has been developed for the conversion
of N-protected bromomethylindole into the indolylmethyl
formate ester using DMF. Further studies on the synthetic
utility of the indolaldehydes will be explored.
4.2.3. 3-Bromo-1-(phenylsulfonyl)-1H-indole-2-carbal-
dehyde, 2c. Following the general procedure, compound
2c was obtained as a colorless solid in 65% yield; mp
142 ꢀC; IR (KBr) nmax: 1685, 1512, 1369, 1257, 1176,
1068 cmꢂ1. dH (400 MHz, CDCl3): 7.24–7.41 (2H, m,
ArH), 7.48–7.58 (2H, m, ArH), 7.71–7.75 (2H, m, ArH),
7.85 (1H, d, J¼7.3 Hz, ArH), 8.17 (2H, d, J¼8.3 Hz, ArH),
10.37 (1H, s, CHO). dC (100 MHz, CDCl3): 181.9, 137.0,
134.4, 132.1, 130.0, 129.2, 129.0, 126.8, 125.3, 122.3,
115.5, 111.8; MS (EI) m/z (%): 365 (M+, 15%); found: ele-
mental analysis: C, 49.37; H, 2.93; N, 3.76; S, 8.73%.
C15H10BrNO3S requires elemental analysis: C, 49.47; H,
2.77; N, 3.85; S, 8.80.
4. Experimental
4.1. General
All melting points are uncorrected. IR spectra were recorded
on a SHIMADZU FT-IR 8300 instrument. 1H and 13C NMR
spectra were recorded in CDCl3 using TMS as an internal
standard on a JEOL 400, 90 and Bruker 300 MHz spectro-
meters, respectively. Mass spectra were recorded on a JEOL
DX 303 HF spectrometer. Elemental analyses were carried
out on a Perkin–Elmer 240 B instrument.
4.2.4. 1-(Phenylsulfonyl)-1H-indole-4-carbaldehyde, 2d.
Following the general procedure, compound 2d was ob-
tained as a colorless solid; mp 102 ꢀC; IR (KBr) nmax
:
1693, 1577, 1450, 1377, 1184, 1145 cmꢂ1. dH (400 MHz,
CDCl3): 7.36–7.43 (4H, m, ArH), 7.48 (1H, t, J¼7.32 Hz,
ArH), 7.65 (1H, d, J¼7.33 Hz, ArH), 7.68 (1H, d,
J¼3.42 Hz, ArH), 7.79 (2H, t, J¼4.39 Hz, ArH), 8.20 (1H,
d, J¼8.3 Hz, ArH), 10.09 (1H, s, CHO); MS (EI) m/z (%):
285 (M+, 54%); found: elemental analysis: C, 63.05; H,
3.69; N, 4.94; S, 11.09%. C15H11NO3S requires elemental
analysis: C, 63.14; H, 3.89; N, 4.91; S, 11.24.
4.2. Representative procedure for the preparation of
aldehyde
A suspension of 50% NaH (78 mg, 1.64 mmol) in dry DMF
(5 mL) was treated with 2-nitropropane (0.2 mL,
2.19 mmol) at 0 ꢀC. 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
1b0 (0.5 g, 1.09 mmol) dissolved in dry DMF (3 mL). After
the bromo compound was consumed (monitored by TLC)
4.2.5. Ethyl 7-formyl-1H-indole-1-carboxylate, 2e. Fol-
lowing the general procedure, compound 2e was obtained

R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
11083
as a colorless solid; mp 54 ꢀC; IR (KBr) nmax: 1739, 1672,
1315, 1041 cmꢂ1. dH (400 MHz, CDCl3): 1.41 (3H, t,
J¼7.3 Hz, CO2CH2CH3), 4.44 (2H, q, J¼7.3 Hz,
CO2CH2CH3), 6.66 (1H, d, J¼3.9 Hz, Indole 3H), 7.33
(1H, t, J¼7.6 Hz, ArH), 7.64 (1H, d, J¼3.9 Hz, Indole
2H), 7.71–7.74 (2H, m, ArH), 10.54 (1H, s, CHO). dC
(100 MHz, CDCl3): 190.8, 151.3, 132.7, 132.0, 127.8,
125.9, 125.5, 125.0, 123.3, 108.5, 64.1, 14.1; MS (EI) m/z
(%): 217 (M+, 8%); found: elemental analysis: C, 66.48;
H, 5.31; N, 6.43%. C12H11NO3 requires elemental analysis:
C, 66.35; H, 5.10; N, 6.45.
(1H, t, J¼7.6 Hz, ArH), 7.45 (1H, t, J¼7.5 Hz, ArH),
7.50–7.54 (2H, t, J¼8.2 Hz, ArH), 7.61 (1H, t, J¼7.8 Hz,
ArH), 7.90–8.00 (1H, d, J¼7.2 Hz, Indole 7H), 8.09–8.11
(2H, d, J¼7.2 Hz, ArH), 8.27–8.29 (1H, d, J¼7.2 Hz, Indole
4H), 10.16 (1H, s, CHO). dC (100 MHz, CDCl3): 185.1,
160.8, 138.9, 137.2, 135.1, 134.7, 129.4, 127.5, 127.3,
125.6, 125.1, 123.0, 120.9, 113.9, 63.5, 13.9; MS (EI) m/z
(%): 357 (M+, 86%); found: elemental analysis: C, 60.41;
H, 4.29; N, 3.86; S, 9.06%. C18H15NO5S requires elemental
analysis: C, 60.49; H, 4.23; N, 3.92; S, 8.97.
4.2.10. (E)-Ethyl 3-(3-formyl-1-(phenylsulfonyl)-1H-
indol-2-yl)acrylate, 2j. Following the general procedure,
compound 2j was obtained as a white solid; mp 152 ꢀC;
4.2.6. Ethyl 2-formyl-5-methoxy-1-(phenylsulfonyl)-1H-
indole-3-carboxylate, 2f. Following the general procedure,
compound 2f was obtained as a white solid; mp 132 ꢀC; IR
(KBr) nmax: 1721, 1685, 1609, 1381, 1188, 1054 cmꢂ1. dH
(400 MHz, CDCl3): 1.30 (3H, t, J¼7.4 Hz, CO2CH2CH3),
3.76 (3H, s, OCH3), 4.32 (2H, q, J¼7.2 Hz, CO2CH2CH3),
7.03 (1H, s, Indole 4H), 7.41–7.51 (4H, m, ArH), 7.90–
7.96 (3H, m, ArH), 10.45 (1H, s, CHO). dC (100 MHz,
CDCl3): 184.4, 163.0, 157.4, 139.1, 137.7, 134.4, 131.0,
129.2, 127.3, 126.9, 118.1, 117.6, 115.4, 103.8, 61.5, 55.5,
14.0; MS (EI) m/z (%): 387 (M+, 80%); found: elemental
analysis: C, 58.76; H, 4.53; N, 3.81; S, 8.16%.
C19H17NO6S requires elemental analysis: C, 58.91; H,
4.42; N, 3.62; S, 8.28.
IR (KBr) nmax
:
1700, 1670, 1370, 1180 cmꢂ1. dH
(90 MHz, CDCl3): 1.33 (3H, t, J¼7.4 Hz, CO2CH2CH3),
4.3 (2H, q, J¼7.3 Hz, CO2CH2CH3), 6.61–8.01 (11H, m,
ArH), 9.92 (1H, s, CHO); MS (EI) m/z (%): 383 (M+,
57%); found: elemental analysis: C, 62.73; H, 4.18; N,
3.59; S, 8.30%. C20H17NO5S requires elemental analysis:
C, 62.65; H, 4.47; N, 3.65; S, 8.36.
4.2.11. (E)-Methyl 3-(2-formyl-1-(phenylsulfonyl)-1H-
indol-3-yl)acrylate, 2k. Following the general procedure,
compound 2k was obtained as a colorless solid; mp
152 ꢀC; IR (KBr) nmax
: 1716, 1668, 1546, 1373,
1176 cmꢂ1. dH (400 MHz, CDCl3): 3.79 (3H, s, CO2CH3),
6.61 (1H, d, J¼16 Hz, vinyl H), 7.33–7.40 (2H, m, ArH),
7.51–7.56 (2H, m, ArH), 7.70–7.72 (2H, d, J¼8.0 Hz,
ArH), 7.80–7.82 (2H, d, J¼7.6 Hz, ArH), 8.07 (1H, d,
J¼16 Hz, vinyl H), 8.22–8.24 (1H, d, J¼7.6 Hz, Indole
4H), 10.63 (1H, s, CHO). dC (100 MHz, CDCl3): 184.1,
166.5, 137.4, 136.8, 135.0, 134.2, 129.4, 128.9, 126.9,
126.6, 125.5, 124.8, 122.8, 122.6, 115.61, 51.9; MS (EI)
m/z (%): 369 (M+, 77%); found: elemental analysis: C,
61.71; H, 4.13; N, 3.72; S, 8.63%. C19H15NO5S requires
elemental analysis: C, 61.78; H, 4.09; N, 3.79; S, 8.68.
4.2.7. Methyl 2-formyl-1-(phenylsulfonyl)-1H-indole-3-
carboxylate, 2g. Followingthegeneralprocedure, compound
2g was obtained as a pale yellow solid; mp 134–136 ꢀC; IR
(KBr) nmax: 1701, 1662, 1545, 1383, 1185, 1098 cmꢂ1. dH
(400 MHz, CDCl3): 4.0 (3H, s, CO2CH3), 7.41–7.45 (1H, t,
J¼7.4 Hz, ArH), 7.53–7.59 (2H, t, J¼7.4 Hz, ArH), 7.65–
7.69 (2H, t, J¼8.4 Hz, ArH), 8.09–8.11 (2H, d, J¼8.4 Hz,
ArH), 8.14–8.16 (1H, d, J¼8.0 Hz, ArH), 8.19–8.21 (1H, d,
J¼8.4 Hz, Indole 4H), 10.62 (1H, s, CHO). dC (100 MHz,
CDCl3): 184.6, 163.3, 139.1, 137.7, 136.3, 134.5, 129.3,
127.8, 127.5, 126.1, 125.0, 123.0, 117.6, 114.4, 52.3; MS
(EI) m/z (%): 343 (M+, 36%); found: elemental analysis: C,
59.39; H, 3.96; N, 4.00; S, 9.12%. C17H13NO5S requires ele-
mental analysis: C, 59.47; H, 3.82; N, 4.08; S, 9.34.
4.2.12. (E)-Ethyl 3-(2-formyl-1-(phenylsulfonyl)-1H-in-
dol-3-yl)acrylate, 2l. Following the general procedure, com-
pound 2l was obtained as a colorless solid; mp 141 ꢀC; IR
(KBr) nmax: 1720, 1668, 1512, 1367, 1174, 1087 cmꢂ1. dH
(400 MHz, CDCl3): 1.34 (3H, t, J¼6.92 Hz, CO2CH2CH3),
4.29 (2H, q, J¼6.92 Hz, CO2CH2CH3), 6.61–6.65 (1H, d,
J¼16.4 Hz, vinyl H), 7.37–7.41 (3H, m, ArH), 7.53–7.59
(2H, m, ArH), 7.73–7.75 (2H, d, J¼7.6 Hz, ArH), 7.85–
7.87 (1H, d, J¼7.8 Hz, Indole 7H), 8.10–8.14 (1H, d,
J¼16.4 Hz, vinyl H), 8.26–8.28 (1H, d, J¼8.4 Hz, Indole
4H), 10.67 (1H, s, CHO). dC (100 MHz, CDCl3): 183.6,
165.6, 136.9, 136.3, 134.2, 134.0, 133.7, 128.9, 128.7,
126.5, 126.1, 125.0, 124.9, 122.0, 115.1, 60.3, 13.7; MS
(EI) m/z (%): 383 (M+, 65%); found: elemental analysis: C,
62.72; H, 4.35; N, 3.61; S, 8.41%. C20H17NO5S requires
elemental analysis: C, 62.65; H, 4.47; N, 3.65; S, 8.36.
4.2.8. 3-Acetyl-1-(phenylsulfonyl)-1H-indole-2-carbalde-
hyde, 2h. Following the general procedure, compound 2h
was obtained as a white solid; mp 113 ꢀC; IR (KBr) nmax
:
1685, 1670, 1557, 1450, 1371, 1180, 1108 cmꢂ1. dH
(400 MHz, CDCl3): 2.55 (3H, s, COCH3), 7.37 (1H, t,
J¼7.4 Hz, ArH), 7.45–7.49 (2H, t, J¼8.4 Hz, ArH), 7.54–
7.61 (2H, m, ArH), 7.72–7.74 (1H, d, J¼7.9 Hz, Indole
7H), 7.84–7.86 (2H, d, J¼8.0 Hz, ArH), 8.19–8.21 (1H, d,
J¼8.4 Hz, Indole 4H), 10.67 (1H, s, CHO). dC (100 MHz,
CDCl3): 196.8, 183.8, 136.6, 136.1, 134.8, 134.2, 129.0,
128.8, 128.3, 126.4, 125.6, 124.9, 121.9, 114.3, 30.2; MS
(EI) m/z (%): 327 (M+, 65%); found: elemental analysis:
C, 62.31; H, 4.13; N, 4.32; S, 9.71%. C17H13NO4S requires
elemental analysis: C, 62.37; H, 4.00; N, 4.28; S, 9.80.
4.2.13. (E)-2-(4,5-Dimethoxy-2-nitrostyryl)-1-(phenyl-
sulfonyl)-1H-indole-3-carbaldehyde, 2m. Following the
general procedure, compound 2m was obtained as a yellow
solid; mp 220 ꢀC; IR (KBr) nmax: 1662, 1517, 1379, 1325,
1272, 1176 cmꢂ1. dH (500 MHz, CDCl3): 4.00 (3H, s,
OCH3), 4.09 (3H, s, OCH3), 7.24 (1H, s, ArH), 7.34 (1H,
t, J¼7.4 Hz, ArH), 7.39–7.47 (4H, m, ArH), 7.52–7.58
(2H, m, ArH), 7.7 (1H, s, ArH), 7.80–7.82 (2H, d,
4.2.9. Ethyl 3-formyl-1-(phenylsulfonyl)-1H-indole-2-
carboxylate, 2i. Following the general procedure,
compound 2i was obtained as a pale white solid; mp
176 ꢀC; IR (KBr) nmax: 1726, 1681, 1541, 1373, 1193,
1083 cmꢂ1. dH (400 MHz, CDCl3): 1.47 (3H, t, J¼7.0 Hz,
CO2CH2CH3), 4.59 (2H, q, J¼7.2 Hz, CO2CH2CH3), 7.37

11084
R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
2. Dave, P.; Byum, H. S.; Engel, R. Synth. Commun. 1986, 16,
1343–1346.
3. Mehta, G.; Panda, G. Tetrahedron Lett. 1997, 38, 2145–2148.
4. Makaiyama, S.; Inanaga, J.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1981, 54, 2221–2222.
5. Badri, R.; Soleymani, M. Synth. Commun. 2003, 33, 1325–
1332.
6. Goswami, S.; Jana, S.; Dey, S.; Adak, A. K. Chem. Lett. 2005,
34, 194–195.
J¼7.6 Hz, ArH), 8.16–8.18 (1H, d, J¼8.4 Hz, ArH), 8.27–
8.29 (1H, d, J¼7.6 Hz, ArH), 10.12 (1H, s, CHO). dC
(125 MHz, CDCl3): 187.1, 153.7, 149.6, 147.5, 140.5,
137.4, 137.4, 135.8, 134.8, 129.6, 126.9, 126.8, 126.7,
125.7, 122.5, 121.3, 119.8, 114.3, 110.6, 108.0, 56.7, 56.6;
MS (EI) m/z (%): 492 (M+, 55%); found: elemental analysis:
C, 61.04; H, 4.17; N, 5.48; S, 6.57%. C25H20N2O7S requires
elemental analysis: C, 60.97; H, 4.09; N, 5.69; S, 6.51.
7. Tang, J.; Zhu, J.; Shen, Z.; Zhang, Y. Tetrahedron Lett. 2007,
48, 1919–1921.
8. Das, S.; Panigrahi, A. K.; Maikap, G. C. Tetrahedron Lett.
2003, 44, 1375–1377.
9. Bensssley, B.; Kohnstam, G. J. Chem. Soc. 1956, 287–296.
10. Walton, A. F.; Tipson, R. S.; Gretcher, L. H. J. Am. Chem. Soc.
1945, 67, 1501–1503.
4.2.14. (E)-2-(2-Nitrostyryl)-1-(phenylsulfonyl)-1H-in-
dole-3-carbaldehyde, 2n. Following the general procedure,
compound 2n was obtained as a yellow solid; mp 182–
184 ꢀC; IR (KBr) nmax: 1670, 1555, 1385, 1340, 1220, 1165,
1035 cmꢂ1. dH (300 MHz, CDCl3): 7.29–7.40 (5H, m, ArH),
7.47–7.55 (2H, m, ArH), 7.58–7.63 (1H, d, J¼16 Hz, vinyl
H), 7.71 (1H, t, J¼7.4 Hz, ArH), 7.75–7.78 (2H, d,
J¼7.6 Hz, ArH), 7.82–7.85 (1H, d, J¼7.2 Hz, ArH), 8.05–
8.17 (2H, m, ArH), 8.26–8.28 (1H, d, J¼7.4 Hz, ArH),
10.07 (1H, s, CHO). dC (75 MHz, CDCl3): 186.9, 147.9,
147.0, 137.5, 136.2, 135.8, 134.7, 134.0, 131.6, 129.9,
129.5, 126.9, 126.8, 126.6, 125.6, 125.1, 122.5, 121.5,
121.0, 114.3; MS (EI) m/z (%): 432 (M+, 37%); found: ele-
mental analysis: C, 63.57; H, 3.93; N, 6.39; S, 7.57%.
C23H16N2O5S requires elemental analysis: C, 63.88; H,
3.73; N, 6.48; S, 7.41.
11. (a) Magnus, P.; Gallagher, T. Tetrahedron 1981, 37, 3889–
3897; (b) Magnus, P.; Gallagher, T.; Huffman, J. C. J. Am.
Chem. Soc. 1982, 104, 1140–1141; (c) Gribble, G. W.;
Saulnier, M. G.; Sibi, M. P.; Obaza-Nutaitis, J. A. J. Org.
Chem. 1984, 49, 4518–4523; (d) Hibino, S.; Sugino, E.;
Kuwada, T.; Ogura, N.; Sato, K.; Chosi, T. J. Org. Chem.
1992, 57, 5917–5921; (e) Sha, C.-K.; Yang, J. F. Tetrahedron
1992, 48, 10645–10654; (f) Love, B. E.; Raje, P. S. J. Org.
Chem. 1994, 59, 3219–3222; (g) Zhang, H.; Larock, R. C.
J. Org. Chem. 2002, 67, 9318–9330; (h) Kusurkar, R. S.;
Goswami, S. K.; Vyas, S. M. Tetrahedron Lett. 2003, 44,
4761–4763.
12. Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995,
60, 1939–1946.
13. (a) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083–3086; (b)
Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359–
1362; (c) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67,
7048–7056.
4.2.15. 2,4,6-Trimethylbenzene-1,3,5-tricarbaldehyde,
2p.28 Following the general procedure, compound 2p was
obtained as a colorless solid; mp 169–170 ꢀC (dec); repor-
tedlit. mp 171 ꢀC (dec); IR (KBr) nmax: 1685, 1560, 1435,
1050 cmꢂ1. dH (400 MHz, CDCl3): 2.64 (9H, s, CH3),
10.60 (3H, s, CHO). dC (100 MHz, CDCl3): 194.1, 143.0,
134.8, 16.1; MS (EI) m/z (%): 204 (M+, 18%).
14. Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.;
Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005,
46, 5263–5264.
15. Nagarathnam, D. J. Heterocycl. Chem. 1992, 29, 953–958.
16. Li, W.; Li, J.; DeVincentis, D.; Mansour, T. Tetrahedron Lett.
2004, 45, 1071–1074.
17. (a) Engler, T. A.; Furness, K.; Malhotra, S.; Diefenbacher, C.;
Clayton, J. R. Tetrahedron Lett. 2003, 44, 2903–2906; (b)
Kolis, S. P.; Clayton, M. T.; Grutsch, J. L.; Faul, M. M.
Tetrahedron Lett. 2003, 44, 5707–5710; (c) Zhu, G.; Conner,
S. E.; Zhou, X.; Chan, H.-K.; Shih, C.; Engler, T. A.;
Al-awar, R. S.; Brooks, H. B.; Watkins, S. A.; Spencer,
C. D.; Schultz, R. M.; Dempsey, J. A.; Considine, E. L.;
Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L. Bioorg.
Med. Chem. Lett. 2004, 14, 3057–3061.
4.2.16. 9,9-Diethyl-9H-fluorene-2,7-dicarbaldehyde,
2q.29 Following the general procedure, compound 2q was
obtained as a white solid; mp 140 ꢀC; reportedlit. mp 140–
141 ꢀC; IR (KBr) nmax: 1693, 1604, 1541, 1201 cmꢂ1. dH
(400 MHz, CDCl3): 0.23 (6H, t, J¼7.2 Hz, CO2CH2CH3),
2.11 (4H, q, J¼7.2 Hz, CO2CH2CH3), 7.66–7.90 (6H, m,
ArH), 10.54 (2H, s, CHO). dC (100 MHz, CDCl3): 192.1,
151.9, 145.9, 136.3, 130.4, 123.1, 121.2, 56.5, 31.8, 8.3;
MS (EI) m/z (%): 278 (M+, 42%).
4.2.17. 2,5-Dimethylthiophene-3,4-dicarbaldehyde, 2r.30
Following the general procedure, compound 2r was obtained
as a colorless crystalline solid; mp 94 ꢀC; IR (KBr) nmax
:
1672, 1521, 1483, 1058 cmꢂ1. dH (400 MHz, CDCl3): 2.72
(6H, s, CH3), 10.33 (2H, s, CHO). dC (100 MHz, CDCl3):
186.6, 149.4, 135.0, 14.2; MS (EI) m/z (%): 168 (M+, 37%).
18. Dobson, D. R.; Gilmore, J.; Long, D. A. Synlett 1992, 79–80.
19. Muratake, H. H.; Natsume, M. Heterocycles 1989, 29,
783–794.
20. Suhana, H.; Srinivasan, P. C. Synth. Commun. 2003, 33, 3097–
3102.
Acknowledgements
21. Mohanakrishnan, A. K.; Balamurugan, R. Tetrahedron Lett.
2005, 46, 4045–4048.
22. Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71, 1767–
1769.
We thank CSIR (01(2071)/06/EMR-II), New Delhi for the
financial support. R.B. thanks CSIR-SRF for fellowship.
Authors thank DST-FIST for 300 MHz NMR facility.
23. (a) Brown, T. M.; Carruthers, W.; Pellatt, M. G. J. Chem. Soc.,
Perkin Trans. 1 1982, 483–487; (b) Sha, C.-K.; Tsou, C.-P.; Li,
Y.-C.; Lee, R.-S.; Tsai, F.-Y.; Yeh, R.-H. J. Chem. Soc., Chem.
Commun. 1988, 1081–1083; (c) Sha, C.-K.; Wang, D.-C.
Tetrahedron 1994, 50, 7495–7502.
References and notes
1. Dunn, F. W.; Waugh, T. D.; Dittmer, K. J. Am. Chem. Soc. 1946,
68, 2118.

R. Balamurugan, A. K. Mohanakrishnan / Tetrahedron 63 (2007) 11078–11085
11085
24. Mohanakrishnan, A. K.; Balamurugan, R.; Ramesh, N.
Tetrahedron Lett. 2005, 46, 8189–8193.
28. Narasimha Moorthy, J.; Mal, P.; Natarajan, R.; Venugopalan, P.
J. Org. Chem. 2001, 66, 7013–7019.
25. Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc.
1959, 81, 4113–4114.
29. Belfield, K. D.; Morales, A. R.; Kang, B.-S.; Hales, J. M.;
Hagan, D. J.; Van Stryland, E. W.; Chapela, V. M.; Percino,
J. Chem. Mater. 2004, 16, 4634–4641.
30. Sha, C.-K.; Tsou, C.-P. Tetrahedron 1993, 49, 6831–6836.
31. Van der Made, A. W.; Van der Made, R. H. J. Org. Chem. 1993,
58, 1262–1263.
32. Belfield, K. D.; Yao, S. J. Org. Chem. 2005, 70, 5126–
5132.
33. Snyder, C. A.; Selegue, J. P.; Dosunmu, E.; Tice, N. C.; Parkin,
S. J. Org. Chem. 2003, 68, 7455–7459.
26. The required bromo-/chloro-indoles 1a–o are prepared via the
allylic bromination/chlorination of the corresponding methyl-
indoles using NBS/NCS in the presence of catalytic amount
of benzoyl peroxide in dry CCl4 under refluxing condition.
The required tribromo 1p31 and dibromo compounds 1q32
and 1r33 are prepared using bromomethylation reaction.
27. Vanelle, P.; Gellis, A.; Kaafarani, M.; Maldonado, J.; Crozet,
M. P. Tetrahedron Lett. 1999, 40, 4343–4346.