Quinoline derivatives by cyclocondensation of N-(2-bromophenylmethylphenyl) benzenesulfonamide with enol ethers and enamines

Article abstract of DOI:10.3987/COM-08-S(F)50

The reaction of N-(2-bromophenylmethylphenyl)benzenesulfonamide (1) with electron rich alkenes (enol ethers (2), (3) and enamines (4)) gives quinoline derivatives 5 and ring fused quinoline 6, 7 whose structures were assigned on the basis of analytical an

Full text of DOI:10.3987/COM-08-S(F)50

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HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1341 - 1345. © The Japan Institute of Heterocyclic Chemistry
Received, 18th July, 2008, Accepted, 12th September, 2008, Published online, 18th September, 2008
DOI: 10.3987/COM-08-S(F)50
QUINOLINE DERIVATIVES BY CYCLOCONDENSATION OF N-(2-
BROMOPHENYLMETHYLPHENYL)BENZENESULFONAMIDE WITH
ENOL ETHERS AND ENAMINES§
Giuseppe Cremonesi,a Piero Dalla Croce,b* Francesco Fontana,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 N-(2-bromophenylmethylphenyl)benzenesulfonamide
(1) with electron rich alkenes (enol ethers (2), (3) and enamines (4)) gives
quinoline derivatives 5 and ring fused quinoline 6, 7 whose structures were
assigned on the basis of analytical and spectroscopic data. The chemical behavior
of adducts 5 and 7 is reported.
INTRODUCTION
In previous papers1,2 we reported the use of benzyl bromides 1 as starting material for the preparation of
different classes of heterocyclic systems. In continuation of our interest in this field and considering the
significant applications of quinoline derivatives in synthetic organic-, bioorganic- and medicinal
chemistry we describe an approach to the quinoline ring system.
RESULTS AND DISCUSSION
The treatment of 1 with 2, 3, 4 in DMF solution and sodium hydride at 0 °C, leads to the formation of
cycloadducts 5, 6, 7 in good to fair yields3 (Scheme 1). The structure of compounds 5, 6, 7 was assigned
on the basis of analytical and spectroscopic data.
§ This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.
* Corresponding author: piero.dallacroce@unimi.it

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HETEROCYCLES, Vol. 77, No. 2, 2009
Scheme 1
OMe
PhSO2
N
OMe
Me
Me
2
Ph H
5
6
7
O
SO2Ph
NH
PhSO2
N
H
H
O
3
Br
CH
O
Ph
Ph H
Ph H
N
1
4
N
N
PhSO2
O
The formation of adducts 5, 6, 7 can be rationalized assuming the behaviour of enol ethers and enamines
(carbon anion in character) towards the N-(2-bromophenylmethylphenyl)benzenesulfonamide 1, bearing
an electrophilic center and a nucleophilic heteroatom (Scheme 2 – pathway a).
Scheme 2
SO2Ph
NH
SO2Ph
N
X
Br
X
X
NaH
SO2Ph
NH
a
b
C
C
Ph H
Ph H
5,6,7
Br
CH
SO2Ph
N
SO2Ph
N
Ph
X
NaH
Br
+
CH
CH
Ph
(α)
Ph

HETEROCYCLES, Vol. 77, No. 2, 2009
1343
Alternatively, the dehydrohalogenation of 1 by the enolate to o-azaxylylene (α), a highly reactive
intermediate, cannot be ruled out. Starting from (α) it is possible a direct aza Diels-Alder cycloaddition
with electron rich alkenes to give the final products. Some attempts to isolate (α) or detect its presence in
the reaction mixture were unsuccessful as previously reported4 for other cases of intermediate o-
azaxylylenes.
The adducts 5 and 7 can be considered possible intermediate for the preparation of quinoline derivatives.
With this purpose we treated 5 and 7 in THF solution with 40% HBr solution in acetic acid and observed
their complete transformation into 8 and 9 respectively (Scheme 3).
Scheme 3
PhSO2
N
Me
N
Me
5
Ph
Ph H
KOtBu
HBr/MeCO2H
THF
8
10
DMF
Ph H
Ph
7
N
N
PhSO2
9
11
Finally, according to the known behaviour of N-phenylsulfonyl protected heterocycles under basic
conditions, it is possible to eliminate this group with potassium t-butoxide in DMF solution and gain
aromaticity to quinoline systems 10 and 11 in high yields.
EXPERIMENTAL
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental analyses
were performed by the Microanalytical Laboratory of the Department. 1H NMR spectra were recorded in
CDCl3 solution using a Bruker AMX 300 MHz spectrometer, and chemical shifts are given in ppm relative
to TMS. The MS spectra were determined using a VG Analytical 7070 EQ mass spectrometer with an
attached VG analytical 11/250 data system.

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HETEROCYCLES, Vol. 77, No. 2, 2009
N-(2-Bromophenylmethylphenyl)benzenesulfonamide (1) was prepared according to the reported
procedure.2
Enol ethers 2, 3 and enamine 4 are commercially available.
Preparation of adducts (5, 6, 7): general procedure.
To a solution of 1 (3.0 mmol) and suitable 2, 3, 4 (6.0 mmol) in dimethylacetamide (10 mL) cooled to -
10 °C NaH (3.0 mmol, 50% in oil) was added and the mixture was stirred at rt for 16 h. Treatment with
water (20 mL), extraction with AcOEt (3 x 15 mL) and evaporation of the solvent gave the crude products.
After column chromatography (SiO2 – toluene/AcOEt : 90/10) were obtained:
2-Methoxy-2-methyl-4-phenyl-1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (5): Solid, mp 113-
115 °C (i-Pr2O). Yield 75%. 1H NMR δ : 1.92 (s, 3H, CH3); 2.20 (dd, 1H, J = 9.1 Hz, J = 14.0 Hz, H-3);
2.33 (dd, 1H, J = 7.8 Hz, J = 14.0 Hz, H-3); 3.15 (s, 3H, OCH3); 3.20 (dd, 1H, J = 7.8 Hz, J = 9.1 Hz, H-
1); 6.80-7.80 (m, 14H, Ar). MS (IE) m/z = 393 [M+]. Anal. Calcd for C23H23NO3S: C, 70.20; H, 5.89; N,
3.56. Found: C, 70.19; H, 5.79; N, 3.47.
4-Phenyl-9-phenylsulfonyl-2,3,3a,4,9,9a-hexahydrofuro[2,3-b]quinoline (6): Solid, mp 164-166 °C
(MeCN). Yield 71%. 1H NMR δ : 1.60 (m, 1H, H-3); 1.98 (m, 1H, H-3); 3.18 (dq, 1H, J = 3.4 Hz, J = 8.6
Hz, H-3a); 3.40 (d, 1H, J = 3.4 Hz, H-4); 3.70 (m, 1H, H-2); 3.82 (dt, 1H, J = 3.6 Hz, J = 8.5 Hz, H-2);
6.35 (d, 1H, J = 8.1, H-9a); 6.75-7.85 (m, 14H, Ar). Anal. Calcd for C23H21NO3S: C, 70.56; H, 5.41; N,
3.58. Found: C, 70.52; H, 5.33; N, 3.60.
4a-Morpholin-4-yl-9-phenyl-10-phenylsulfonyl-1,2,3,4,4a,9,9a,10-octahydroacridine (7): Solid, mp
1
176-177 °C (MeOH). Yield 92%. H NMR δ : 1.50-2.00 (m, 8H, cyclohexane); 2.75 (t, 4H, N(CH2)2);
3.75 (t, 4H, O(CH2)2); 4.50 (d, 1H, J = 7.2 Hz, H-4a); 5.50 (d, 1H, J = 7.2 Hz, H-9); 6.75-7.75 (m, 14H,
Ar). MS (IE) m/z = 488 [M+]. Anal. Calcd for C29H32NO3S: C, 71.28; H, 6.60; N, 5.73. Found: C, 71.28;
H, 6.51; N, 5.68.
Transformation of adducts (5, 7): general procedure.
To a solution of 5/7 (10.0 mmol) in THF (10 mL) 40% HBr solution in acetic acid (0.2 mL) was added
and the mixture was stirred at 60 °C for 6 h. The solvent was evaporated off and the residue was taken up
with water/AcOEt. The organic phase was separated, washed with 5% aqueous NaHCO3 (5 mL), dried
(Na2SO4) and evaporated off. The residue was purified by crystallization. In this way were obtained:
2-Methyl-4-phenyl-1-phenylsulfonyl-1,4-dihydroquinoline (8): Solid, mp 168-170 °C (toluene). Yield
1
84%. H NMR δ : 2.22 (s, 3H, CH3); 5.54 (d, 1H, J = 7.7 Hz, H-4); 6.30 (d, 1H, J = 7.7 Hz, H-3); 6.90-

HETEROCYCLES, Vol. 77, No. 2, 2009
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7.80 (m, 14H, Ar). MS (IE) m/z = 361 [M+]. Anal. Calcd for C22H19NO2S: C, 73.10; H, 5.30; N, 3.88.
Found: C, 73.09; H, 5.21; N, 3.84.
9-Penyl-10-phenylsulfonyl-1,2,3,4,9,10-hexahydroacridine (9): Solid, mp 165-167 °C (AcOEt). Yield
1
81%. H NMR δ : 1.50-2.50 (m, 8H, (CH2)4); 6.50 (s, 1H, H-9); 7.10-7.80 (m, 14H, Ar). MS (IE) m/z =
401 [M+]. Anal. Calcd for C25H23NO2S: C, 74.78; H, 5.77; N, 3.49. Found: C, 74.65; H, 5.68; N, 3.45.
Aromatisation of compounds (8, 9): general procedure.
To a solution of 8/9 (10 mmol) in DMF (10 mL), potassium t-butoxide (10 mL) was added and the
mixture stirred at 65 °C for 4 h. The reaction was poured in water (20 mL), and the product was extracted
with AcOEt (2x15 mL). The organic layer was washed with H2O (10 mL), dried (Na2SO4) and the solvent
was evaporated off. The residue was crystallized and afforded:
2-Methyl-4-phenylquinoline (10): Solid, mp 96-98 °C (i-Pr2O). Yield 70%. Lit.,5 97-98 °C.
9-Penyl-1,2,3,4-tetrahydroacridine (11): Solid, mp 143-145 °C (i-Pr2O). Yield 85%. Lit.,6 142-143 °C.
The spectroscopic data (1H NMR and MS) agree with those reported.
REFERENCES
1. G. Cremonesi, P. Dalla Croce, F. Fontana, and C. La Rosa, Heterocycles, 2006, 69, 475.
2. G. Cremonesi, P. Dalla Croce, and C. La Rosa, Heterocycles, 2005, 66, 557.
1
3. In the case of compounds 6 and 7 a little part of another diastereoisomer (5%) was detected by H
NMR on the crude reaction mixture, but it was impossible to isolate it.
4. H. Steinhagen and E. J. Corey, Angew. Chem. Int. Ed., 1999, 38, 1928.
5. E. A. Fehnel, J. Org. Chem., 1966, 31, 2899.
6. C. Wolf and K. Ekoue-Kovi, Eur. J. Org. Chem., 2006, 8, 1917.