Heterocycles from ylides. Part IX. A convenient synthesis of 1-sulfonyl-2,3-disubstituted 2,3-dihydroindoles

Article abstract of DOI:10.3987/COM-05-S(T)51

The reaction of sulfur ylides (1) with N-(2-bromomethylphenyl)benzenesulfonamides (4) gives 2,3-dihydroindoles (5) whose structure and stereochemistry were assigned on the basis of analytical and spectroscopic data. Some chemical transformations of 5 are

Full text of DOI:10.3987/COM-05-S(T)51

HETEROCYCLES, Vol. 66, 2005
557
HETEROCYCLES, Vol. 66, 2005, pp. 557 – 562. © The Japan Institute of Heterocyclic Chemsitry
Received, 28th July, 2005, Accepted, 16th September, 2005, Published online, 20th September, 2005. COM-05-S(T)51
HETEROCYCLES FROM YLIDES. PART IX1. A CONVENIENT
SYNTHESIS OF 1-SULFONYL-2,3-DISUBSTITUTED
2,3-DIHYDROINDOLES‡
Giuseppe Cremonesi,a Piero Dalla Croce,b* and Concetta La Rosaa
a
Institute of Organic Chemistry “Alessandro Marchesini”, Faculty of Pharmacy,
Via Venezian 21, I-20133 Milano, Italy
b Department of Organic and Industrial Chemistry, C.N.R.-I.S.T.M., Via Venezian
21, I-20133 Milano, Italy
Abstract – The reaction of sulfur ylides (1) with N-(2-bromomethyl-
phenyl)benzenesulfonamides (4) gives 2,3-dihydroindoles (5) whose structure and
stereochemistry were assigned on the basis of analytical and spectroscopic data.
Some chemical transformations of 5 are reported.
INTRODUCTION
As part of our interest concerning the synthesis of heterocyclic derivatives through addition-
cyclocondensation reactions of ylides, we examined their reactivity towards different compounds. Some
our previous results concerned the reaction of ylides (1) with 2-arylmethylenebenzofuran-3-ones,
phenolic Mannich base methiodides and 3-arylmethyleneindolin-2-ones to give spiro [cyclopropane-1,2’-
benzofuran-3’-ones],1 2-acyl-2,3-dihydrobenzofurans,2 spiro [cyclopropane-1,3’-indolin-2’-ones]3
respectively. We now report a simple and new method for the preparation of 2,3-dihydroindole
derivatives (5) based on the reaction of stabilized sulfur ylides (1) with benzyl bromides (4) prepared
starting from N-sulfonylamidoketones (2), via reduction to alcohols (3), and their transformation into
bromides (4).
RESULTS AND DISCUSSION
In a preliminary experiment to a solution of dimethylsulfonium 2-oxo-2-phenylethylide (1a) in
acetonitrile was added N-(2-bromophenylmethylphenyl)benzenesulfonamide (4a) (molar ratio 1a/4a =
2/1) and, after conventional work-up, 2-benzoyl-3-phenyl-1-phenylsulfonyl-2,3-dihydroindole (5a) was
isolated directly by crystallisation of the crude reaction mixture in 85% yield. Further experiments to
‡ This paper is dedicated to the memory of the late Professor Kenji Koga.
* Corresponding Author: piero.dallacroce@unimi.it

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evaluate the scope of the reaction concerned both substituents on N-sulfonylamidoketones and ylides. In
all the case investigated the sequence alkylation-cyclocondensation gave 2,3-dihydroindole derivatives
(5) (Scheme 1) in fair to good yields. (Table 1)
Scheme 1
R1
C
R1
R1
R2
R2
CH
R2
CH
OH
O
NaBH4
EtOH
PBr3
Br
CCl4 / 80°C
NH
NH
NH
SO2Ph
SO2Ph
SO2Ph
2
3
4
R1
R1
O
R2
CH
R2
CH
COR
S
COR
S
CH
CH
1
R
CH
Br
S
1
NH
N
PhSO2
PhSO2
H
R1
R2
COR
- Me2S
H
- 1.HBr
N
SO2Ph
5
1a : R = C6H5
1b : R = OEt
5a : R = C6H5; R1 = C6H5; R2 = H
5b : R = C6H5; R1 = C6H5; R2 = Cl
5c : R = C6H5; R1 = Me; R2 = H
4a : R1 = C6H5; R2 = H
4b : R1 = C6H5; R2 = Cl
4c : R1 = Me; R2 = H
5d : R = OEt;
R1 = C6H5; R2 = Cl
Table 1
Entry
Reagents
Products
Yield (%)
Time (hs)
1
2
3
4
1a+4a
1a+4b
1a+4c
1b+4b
5a
5b
5c
5d
85
82
80
65
12
16
18
12
The formation of the products can be rationalized by assuming the known behavior of sulfonium ylides
towards systems bearing an electrophilic center and a nucleophilic heteroatom.4 Analytical and

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559
spectroscopic data of the compounds prepared are consistent with the assigned structures. In particular a
trans relationship was assigned to H-2 and H-3 on the basis of the values of their coupling constants.5
Compounds (5) may be useful intermediates for the preparation of other classes of indole derivatives. The
dehydrogenation with NBS/TEA gives the corresponding indoles (6) whereas the elimination of sulfonyl
group, under basic conditions, affords N-unsubstituted indoles (7) proving the role of sulfonyl residue, as
leaving group, in the aromatization of heterocyclic compounds.6 (Scheme 2)
Scheme 2
C6H5
COC6H5
N
NBS / TEA
MeONa
SO2Ph
6
5a
C6H5
COC6H5
N
H
7
The reported reaction provides a ready, simple and mild access to 1-phenylsulfonyl-2,3-disubstituted 2,3-
dihydroindoles.
EXPERIMENTAL
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental analyses
1
were performed by the Microanalytical Laboratory of the Department. H and 13C NMR spectra were
recorded in CDCl3 solution using a Bruker AC 300 MHz spectrometer, and chemical shifts are given in
ppm relative to TMS. IR spectroscopy was performed using a Perkin-Elmer 1725X FT-IR
spectrophotometer. The sulfonium bromide (1a7, 1b8) and the benzenesulfonamides (2a9, 2b10, 2c11) were
prepared according to the reported procedures.
Preparation of benzyl alcohol (3a-c): general procedure.
To a suspension of sodium borohydride (4.62 g, 0.125 mol) in EtOH (50 mL), solid benzenesulfonamide
(2a-c) (0.1 mol) was added portionwise and the mixture was stirred 12 h at rt. Ethanol was removed under
reduced pressure and the residue was treated with a 10% hydrochloric acid solution (25 mL) and ethyl
acetate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and the solvent was
evaporated:

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N-[2-(Hydroxyphenylmethyl)phenyl]benzenesulfonamide (3a).
Solid, mp 110-112°C (toluene). Yield 90%. 1H NMR δ: 2.70 (s, 1H, OH); 5.65 (s, 1H, CHOH); 6.90-7.20
(m, 14H, Ph); 8.10 (s, 1H, NH). IR (nujol, cm-1): 3255 (OH). Anal. Calcd for C19H17NO3S: C, 67.25; H,
5.01; N, 4.12. Found: C, 67.32; H, 4.95; N, 4.23.
N-[2-(Hydroxyphenylmethyl)-4-chlorophenyl]benzenesulfonamide (3b).
Solid, mp 121-123°C (toluene). Yield 95%. 1H NMR δ: 2.90 (s, 1H, OH); 5.62 (s, 1H, CHOH); 6.80-7.30
(m, 13H, Ph); 8.20 (s, 1H, NH). IR (nujol, cm-1): 3250 (OH). Anal. Calcd for C19H16NO3ClS: C, 61.04; H,
4.28; N, 3.74. Found: C, 61.18; H, 4.22; N, 3.62.
N-[2-(α-Hydroxyethyl)phenyl]benzenesulfonamide (3c).
Solid, mp 103-104°C (i-Pr2O). Yield 90%. 1H NMR δ: 1.38 (d, 3H, J = 6.6 Hz, CH3); 2.20 (s, 1H, OH);
4.76 (s, 1H, J = 6.6 Hz, CHOH); 7.00-7.90 (m, 9H, Ph); 8.50 (s, 1H, NH). IR (nujol, cm-1): 3260 (OH).
Anal. Calcd for C14H15NO3S: C, 60.64; H, 5.41; N, 5.05. Found: C, 60.41; H, 5.31; N, 5.01.
Preparation of benzyl bromides (4a-c): general procedure.
A mixture of 3a-c (0.05 mol) in CCl4 (20 mL) and phosphorus tribromide (6.76 g, 0.025 mol) was heated
to 80°C for 16-18h. After cooling to 0°C the mixture was treated with water (20 mL). The organic phase
was separated, dried (Na2SO4) and the solvent was evaporated off. The reaction progress was monitored
by TLC. NMR spectra confirmed the structure of crude bromides which were used directly in the next
step without purification.
N-[2-(Bromophenylmethyl)phenyl]benzenesulfonamide (4a).
Oil. Yield 85%. 1H NMR δ: 5.97 (s, 1H, CHBr); 7.00-8.00 (m, 14H, Ph); 8.10 (s, 1H, NH).
N-[2-(Bromophenylmethyl)-4-chlorophenyl]benzenesulfonamide (4b).
Wax. Yield 80%. 1H NMR δ: 6.05 (s, 1H, CHBr); 7.00-8.00 (m, 13H, Ph); 8.20 (s, 1H, NH).
N-[2-(α-Bromoethyl)phenyl]benzenesulfonamide (4c).
Foam. Yield 85%. 1H NMR δ: 1.15 (d, 3H, J = 5.9 Hz, CH3); 5.17 (t, 1H, J = 6.0 Hz, CHCH3); 7.00-8.00
(m, 9H, Ph); 8.40 (s, 1H, NH).
Synthesis of products (5a-d): general procedure.
To a solution of 1a-b (10 mmol) in acetonitrile (25 mL), cooled to 0°C, 4a-c (5 mmol) was added and the
mixture stirred at rt for 12h. The solvent was evaporated and the residue was taken up with 5%
hydrochloric acid solution (20 mL) and ethyl acetate (25 mL). The organic phase was separated and the
solvent was evaporated off. The residue was purified by recrystallization. In this way were prepared:
2-Benzoyl-3-phenyl-1-phenylsulfonyl-2,3-dihydroindole (5a):
Solid, mp 121-123°C (EtOH). Yield 85%. 1H NMR δ: 4.20 (d, 1H, J = 5.1 Hz, H-3 indole); 5.55 (d, 1H, J
= 5.1 Hz, H-2 indole); 6.50-7.75 (m, 19H, Aromatics). Anal. Calcd for C27H21NO3S: C, 73.80; H, 4.78; N,
3.18. Found: C, 73.60; H, 4.85; N, 3.15.

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2-Benzoyl-5-chloro-3-phenyl-1-phenylsulfonyl-2,3-dihydroindole (5b):
Solid, mp 205-206°C (EtOH). Yield 82%. 1H NMR δ: 4.18 (d, 1H, J = 4.9 Hz, H-3 indole); 5.44 (d, 1H, J
= 4.9 Hz, H-2 indole); 6.50-7.90 (m, 18H, Ph). Anal. Calcd for C27H20NO3ClS: C, 68.42; H, 4.22; N, 2.95.
Found: C, 68.21; H, 4.18; N, 2.77.
2-Benzoyl-3-methyl-1-phenylsulfonyl-2,3-dihydroindole (5c):
1
Solid, mp 140-142°C (EtOH). Yield 80%. H NMR δ: 1.10 (d, 3H, J = 6.9 Hz, CH3CH); 3.35 (m, 1H,
CH3CH); 5.11 (d, 1H, J = 5.1 Hz, CHCO); 7.00-8.00 (m, 14H, Ph). Anal. Calcd for C22H19NO3S: C,
70.02; H, 5.03; N, 3.71. Found: C, 70.10; H, 5.09; N, 3.79.
2-Ethoxycarbonyl-5-chloro-3-phenyl-1-phenylsulfonyl-2,3-dihydroindole (5d):
Solid, mp 82-83°C (i-Pr2O). Yield 65%. 1H NMR δ: 1.30 (t, 3H, J = 7.1 Hz, CH3); 4.10 (q, 2H, J = 7.1 Hz,
CH2); 4.25 (d, 1H, J = 5.1 Hz, H-3 indole); 5.55 (d, 1H, J = 5.1 Hz, H-2 indole); 6.50-7.75 (m, 13H, Ph).
Anal. Calcd for C23H20NO4ClS: C, 62.51; H, 4.53; N, 3.17. Found: C, 62.43; H, 4.49; N, 3.12.
2-Benzoyl-3-phenyl-1-phenylsulfonylindole (6).
A solution of 5a (0.439 g, 1 mmol) in CCl4 (20 mL) was treated with N-bromosuccinimide (0.19 g, 1.1
mmol) and refluxed for 2 h. Triethylamine (0.11 g, 1.1 mmol) was added and the reaction mixture was
heated for further 2 h. The mixture was cooled, succinimide and TEA.HBr were removed by filtration and
the solvent was evaporated. The product was crystallized. Yield 90%. mp 166-168°C (EtOH). 1H NMR δ:
7.25-8.24 (m, 19H, Ph). Anal. Calcd for C27H19NO3S: C, 74.14; H, 4.34; N, 3.20. Found: C, 74.24; H,
4.41; N, 3.12.
2-Benzoyl-3-phenylindole (7).
A solution of 5a (0.439 g, 1 mmol) in MeOH (20 mL) was treated with sodium methoxide (0.054 g, 1
mmol) and the mixture was stirred at rt overnight. The solvent was evaporated off and the residue was
taken up with water. The product was filtered and crystallized. Yield 90%. mp 204-206°c (MeOH). lit.,12
mp 203-204°C.
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