Investigation of chemoselective reaction of 2-amino-8-hydroxyquinoline with arylsulfonylchloride derivatives

Article abstract of DOI:10.1080/00397910802527730

The reactions of 2-amino-8-hydroxyquinoline and 2-amino-4(1H)quinolone with different sulfonyl chlorides have been investigated. The chemoselectivity was observed to afford exclusively the arylsulfonate ester derivatives. The mechanism of the reaction is

Full text of DOI:10.1080/00397910802527730

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Investigation of
Chemoselective Reaction of
2-Amino-8-hydroxyquinoline
with Arylsulfonylchloride
Derivatives
Luiz Everson Da Silva a , Paulo Teixieira De Sousa Jr.
a & Antonio Carlos Joussef b
a Department of Chemistry , Universidade Federal
de Mato Grosso , Cuiabá, Brazil
b Department of Chemistry , Universidade Federal
de Santa Catarina , Florianópolis, Brazil
Published online: 19 Mar 2009.
To cite this article: Luiz Everson Da Silva , Paulo Teixieira De Sousa Jr. & Antonio
Carlos Joussef (2009) Investigation of Chemoselective Reaction of 2-Amino-8-
hydroxyquinoline with Arylsulfonylchloride Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:8,
1378-1388, DOI: 10.1080/00397910802527730
To link to this article: http://dx.doi.org/10.1080/00397910802527730
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Synthetic Communications1, 39: 1378–1388, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802527730
Investigation of Chemoselective Reaction of
2-Amino-8-hydroxyquinoline with
Arylsulfonylchloride Derivatives
Luiz Everson Da Silva,1 Paulo Teixieira De Sousa Jr.,1
and Antonio Carlos Joussef2
1Department of Chemistry, Universidade Federal de Mato Grosso,
ꢀ
Cuiaba, Brazil
2Department of Chemistry, Universidade Federal de Santa Catarina,
ꢀ
Florianopolis, Brazil
Abstract: The reactions of 2-amino-8-hydroxyquinoline and 2-amino-4(1H)-
quinolone with different sulfonyl chlorides have been investigated. The chemo-
selectivity was observed to afford exclusively the arylsulfonate ester derivatives.
The mechanism of the reaction is also discussed.
Keywords: 2-Amino-4(1H)quinolone, 2-amino-8-hydroxyquinoline, arylsulfonate
ester, chemoselectivity
INTRODUCTION
Historically, aromatic primary amines have been converted to the corre-
sponding sulfonamides by reaction with appropriated sulfonylchloride in
the presence of a base. The sulfonamides obtained have found many applica-
tions in organic synthesis to afford biologically active compounds.[1] On the
other hand, aminoquinolines are pivotal constituents in a variety of pharma-
ceutically important compounds classes.[2] Moreover, 8-hydroxyquinoline
derivatives show a wide spectrum of the properties as analytical reagents
Received July 5, 2008.
Address correspondence to Luiz Everson Da Silva, Department of Chemistry,
ꢀ
Universidade Federal de Mato Grosso, Cuiaba, Cep 78060-900, MT, Brazil.
E-mail: luiz_everson@yahoo.de
1378

Chemoselectivity, Esterification, and Mechanism
1379
because of their ability to form stable complexes with many metallic ions.[3]
Recently, nitrogen (N)=oxygen (O) alkyl derivatives have been investigated
as protective agents against reactive oxygen species,[4] antiparasitic
compounds,[5] and organic fluorophores in the optoelectronic industry[6]
and in the treatment of neurodegenerative diseases.[7] We report now the
synthesis of arylsulfonate ester derivatives starting from 2-amino-8-hydro-
xyquinoline (1) and 2-amino-4(1H)quinolone (12). In exploring potential
applications of this method for polyfunctional substrates, we examined
the chemoselectivity of esterification and its reaction mechanism.
RESULTS AND DISCUSSION
This prompted us to consider the conversion of 2-amino-8-hydroxyqui-
noline (1) to 2-sulfonamide-8-hydroxyquinolines. However, the reaction
showed a high chemoselectivity to afford the sulfonate esters 2–11, con-
firmed by high-performance liquid chromatography (HPLC, Scheme 1).
In this context, we study the regioselectivity of sulfonation of the hetero-
cyclic amine toward phenolic hydroxyl or tautomeric pyridine=pyridine
hydroxyl. In this procedure, besides the compound 1, only the arylsulfo-
nylchloride is dissolved in pyridine.
The reactions were carried out at low temperature (0 ꢀC) and offered
in most cases, generally within 1 h, the O-substituted aminoquinolines in
good yields (75–85%). The products were isolated by addition of water,
filtration, and subsequent crystallization with a methanol=dichloro-
methane mixture. The results of this study are summarized in Table 1.
The chemoselectivity can be attributed to the conjugation of the lone
pair of electrons of the amino group nitrogen atom with the aromatic ring
enhancing the nucleophilicity of the quinolinic nitrogen, which, in turn,
plays the role of nucleophilic catalyst to transfer the arylsulfonyl moiety
to the phenol oxygen atom via intramolecular nucleophilic attack. Pyri-
dine in the sulfonylation reaction presented here acts as a base, and a
mechanistic proposal is shown in Scheme 2. Moreover, the chemoselectiv-
ity is also observed when an excess of sulfonylchloride is used.
Scheme 1.

1380
L. E. Da Silva, P. T. De Sousa, and A. C. Joussef
Table 1. Examples of selective O-sulfonylation products
Entry
(R)
Yield (%)
85
2
3
4
79
77
5
6
75
79
7
8
85
80
9
81
82
10
(Continued )

Chemoselectivity, Esterification, and Mechanism
1381
Table 1. Continued
Entry
(R)
Yield (%)
81
11
1
The compounds were characterized by H NMR and mass spectro-
metry. The broad signal of NH2 was assigned in the range of 5.39–
5.83 ppm. The mass spectrometry gave two feature fragments: the base
peak m=z ¼ 159 related to the lost of RSO2 [Mþ ꢁ RSO2] and the peak
m=e ¼ 131 related to the elimination of HCN with the formation of the
fragment [C6H7N2]þ.[8] In addition, the arylsulfonates 2, 4, 6, and 9 were
characterized by x-ray analysis.[9]
The same trend was also observed in the reaction of 2-amino-4(1H)-
quinolone 12 with sulfonyl chloride derivatives (Scheme 3 and Table 2).
The exclusive formation of sulfonyl esters products 13 and 14 can be
attributed by low nucleophilicity of aminic nitrogen that is conjugate
to the p-deficient system. In addition, the driving force for the chemo-
selectivity of the reaction at the oxygen atom can be attributed to the
attack at the oxygen, which is preferred because the ring nitrogen belongs
to a p-deficient system. Moreover, the arylsulfonate 13 was also charac-
terized by x-ray analysis.[10]
After establishing the general principle, it was then decided to inves-
tigate the reactivity of this class of compounds by subjecting 2 to a reac-
tion with Meldrum’s acid (15) in trimethyl ortoformate to give the
Michael addition product 16,[11] a precursor of diazaheterocycles[12]
(Scheme 4). The conversion of 16 in the tricycle 17 is under studies.
Scheme 2.

1382
L. E. Da Silva, P. T. De Sousa, and A. C. Joussef
Scheme 3.
A short and efficient route toward the synthesis of 2-aminoquinolin-
8-ylarylsulfonate ester derivatives has been developed. The reaction toler-
ates a wide range of functional groups. In addition, the reaction with
Meldrum’s acid in trimethyl orthoformate gave the Michael addition
product 16. The transformation of the 2-amino-8-hydroxyquinoline to
the corresponding 2-aminoquinoline-8-yl-arylsulfonate ester derivatives
is novel and might well prove useful as an important precursor for the
synthesis of more complex structures with biological significance.
EXPERIMENTAL
Melting points were measured using a Kofler hot-stage apparatus
´
(Microquımica APF-301) and are uncorrected. Each analytical sample
Table 2. Examples of selective O-sulfonylation products with 2-amino-4(1H)qui-
nolone 12
Entry
(R)
Yield (%)
72
13
14
80

Chemoselectivity, Esterification, and Mechanism
1383
Scheme 4.
was homogeneous as confirmed by thin-layer chromatography
(TLC) performed on silica-gel (Kieselgel 60 F 254-Merck) plates, which
were visualized with ultraviolet (UV) light. Flash chromatography
was performed with Merck silica gel 60 (230–400 mesh). 1H NMR
spectra were determined on a Bruker DRX-300 (300-MHz) instrument,
with tetramethylsilane (TMS) as the internal standard, and 13C NMR
spectra were recorded on a Bruker (75.5-MHz) spectrometer. Mass
spectra were obtained with on a Shimadzu GC-MS-2000A instru-
ment. Microanalyses were carried out with a Carlo Erba EA 1110
instrument.
Typical Experimental Procedure for Compounds 2–11 and 16–17
2-Amino-8-hydroxyquinoline (1 mmol) or 2-amino-4(1H)quinolone was
added to a stirred solution of the arylsulfonyl choride (1.1 mmol) in pyr-
idine (2 ml) at 0 ꢀC. The mixture was stirred for 1 h, and 5 ml of water
were added. A colored solid immediately appeared, which was filtered
and washed with water until no pyridine was present in the filtrate. Puri-
fication by crystallization from a methanol=dichloromethane solution
(1:1) gave the desired products.

1384
L. E. Da Silva, P. T. De Sousa, and A. C. Joussef
Data
2-Aminoquinolin-8-yl-4-methylbenzenesulfonate (2)
Colorless crystalline solid (85%). Mp 205 ꢀC. 1H NMR (CDCl3,
300 MHz) d 2.37 (s, 3H), 5.83 (s, br, 2H), 6.76 (d, J ¼ 8.9 Hz, 1H),
7.47–7.26 (m, 4H), 7.49 (dd, J ¼ 8 Hz, 1H), 7.84 (t, J ¼ 8 Hz, 3H). 13C
NMR (CDCl3) d 29.94, 113.00, 115.09, 121.99, 123.33, 125.04, 126.79,
129.13, 129.43, 133.46, 138.19, 143.03, 145.16, 157.38. MS m=z: 314
(Mþ.; 100), 250 (25), 159 (100), 131 (60). C16H14N2O3S requires C,
61.13; H, 4.49; N, 8.91; S, 10.20. Found: C, 61.09; H, 4.26; N, 8.80;
S, 10.06.
2-Aminoquinolin-8-yl-5-bromo-6-chloropyridin-3-yl-sulfonate (3)
Brown solid (79%). Mp: 183–185 ꢀC. 1H NMR (CDCl3, 300 MHz) d 5.32
(s, br, 2H), 6.70 (d, J ¼ 8.5 Hz, 1H), 7.23 (t, J ¼ 8.5 Hz, 1H), 7.57 (dd,
J ¼ 8.5 Hz, 1H), 7.60 (d, J ¼ 8 Hz, 1H), 7.80 (d, J ¼ 8 Hz, 1H), 8.55
(s, 1H), 8.72 (s, 1H). MS m=z: 415 (Mþ. þ 2), 187 (55), 160 (100).
C14H9BrClN3O3S requires C, 40.55; H, 2.19; N, 10.13; S, 7.73. Found:
C, 40.52; H, 2.23; N, 10.06; S, 7.56.
2-Aminoquinolin-8-yl-4-fluorobenzenesulfonate (4)
Brown solid (77%). Mp: 194–196 ꢀC. 1H NMR (CDCl3, 300 MHz) d 5.32
(s, br, 2H), 6.70 (d, J ¼ 9 Hz, 1H), 6.99 (t, J ¼ 9 Hz, 1H), 7.11 (t, J ¼ 8 Hz,
1H), 7.19 (dd, J ¼ 8 Hz, 2H), 7.49 (dd, J ¼ 8 Hz, 1H), 7.71 (d, J ¼ 8.5 Hz,
1H), 7.89 (dd, J ¼ 8 Hz, 2H); 13C NMR (CDCl3) d 113.10, 115.80, 116.10,
121.61, 123.23, 127.05, 125.17, 131.97, 132.10, 137.88, 140.62, 143.07,
157.65, 164.34, 167.74. MS m=z: 318 (Mþ.; 18), 159 (100), 131 (35).
C15H11FN2O3S requires C, 56.60; H, 3.48; N, 8.80; S, 10.07. Found: C,
56.71; H, 3.52; N, 8.75; S, 9.95.
2-Aminoquinolin-8-yl-4-nitrobenzenesulfonate (5)
1
White solid (75%). Mp 243–244 ꢀC. H NMR (CDCl3, 300 MHz) d 6.49
(s, br, 2H), 6.67 (d, J¼ 9 Hz, 1H), 7.13 (t, J¼ 6 Hz, 1H), 7.40 (d, J¼ 6Hz,
1H), 7.42 (d, J ¼ 6 Hz,1H), 7.60 (d, J ¼ 9 Hz, 1H), 7.86 (d, J ¼ 9 Hz,
1H), 8.23 (d, J ¼ 9 Hz, 2H), 8.34 (d, J ¼ 9 Hz, 2H); MS m=z: 345 (Mþ.
;
18); 159 (100); 131 (28). C15H11N3O5S requires C, 52.17; H, 3.21;
N, 12.17; S, 9.29. Found: C, 52.14; H, 3.28; N, 12.11; S, 9.02.

Chemoselectivity, Esterification, and Mechanism
1385
2-Aminoquinolin-8-yl-2,4,6-triisopropylbenzenesulfonate (6)
Colorless crystalline solid (79%). Mp 173–176 ꢀC. 1H NMR (CDCl3,
300 MHz) d 1.08 (s, 18 H), 2.78 (m, 1H), 4.59 (m, 2H), 6.86 (s, 2H),
7.10 (d, J ¼ 9 Hz, 1H), 7.21–7.37 (m, 3H), 8.33 (d, J ¼ 9 Hz, 1H), 8.42
(t, J ¼ 9 Hz, 1H), 8.85 (d, J ¼ 6 Hz, 1H). 13C NMR (CDCl3) d 23.90,
24.80, 30.10, 34.51, 112.99, 121.42, 122.11, 123.87, 125.45, 126.58,
132.54, 137.71, 141.62, 144.15, 151.03, 153.77, 157.55. MS m=z: 428
(Mþ.ꢁ2), 363 (30), 159 (100). C24H30N2O3S requires C, 67.58; H, 7.09;
N, 6.57; S, 7.52. Found: C, 67.54; H, 7.08; N, 6.51; S, 7.48.
2-Aminoquinolin-8-yl-4-biphenylsulfonate (7)
Colorless crystalline solid (85%). Mp 210–211 ꢀC. 1H NMR (CDCl3,
300 MHz) d 6.59 (s, br, 2H), 6.75 (d, J ¼ 6 Hz, 1H), 7.18 (t, J ¼ 6 Hz,
1H), 7.42 (d, J ¼ 6 Hz, 1H), 7.49–7.62 (m; 6H), 7.77 (dd, J ¼ 9 Hz, 1H),
7.90 (dd, J ¼ 9 Hz, 1H), 8.02 (d, J ¼ 8 Hz, 2H); MS m=z: 376 (Mþ.),
312 (40), 159 (100), 131 (25). C21H16N2O3S requires C, 67.00; H, 4.28;
N, 7.44; S, 8.52. Found: C, 67.02; H, 4.25; N, 7.43; S 8.50.
2-Aminoquinolin-8-yl-4,5-dibromothiophene-2-sulfonate (8)
Pale crystalline solid (80%). Mp 269–270 ꢀC. 1H NMR (CDCl3,
300 MHz) d 5.54 (s, br, 2H), 6.74 (d, J ¼ 8.9 Hz, 1H), 7.18 (t, J ¼ 8.0 Hz,
Hz, 2H), 7.32 (s, 1H), 7.50 (d, J ¼ 7.9, 1H), 7.78 (d; J ¼ 8.9 Hz, 1H). 13C
NMR (CDCl3) d 113.04, 114.80, 121.92, 123.85, 125.17, 127.55, 137.25,
138.10, 136.32, 140.65, 142.90, 153.21, 157.52. MS m=z: 464 (Mþ.), 400
(15), 159 (100), 131 (35). C13H8Br2N2O3S2 requires C, 33.64; H, 1.74;
N, 6.04; S,13.82. Found: C, 33.62; H, 1.71; N, 6.04; S, 13.84.
2-Aminoquinolin-8-yl-3,5-difluorobenzenesulfonate (9)
Brown solid (81%). Mp 167–168 oC. 1H NMR (CDCl3, 300 MHz) d 5.72
(s, br, 2H), 6.68 (d, J ¼ 8.9 Hz, 1H), 6.92 (t, J ¼ 7 Hz, 2H), 7.20 (d,
J ¼ 9 Hz, 1H), 7.29 (s, 1H), 7.53 (s, 2H), 8.08 ( d, J ¼ 9 Hz, 1H); 13C
NMR (CDCl3) d 109.65, 109.99, 112.70, 113.08, 121.83, 123.40, 125.32,
127.37, 138.03, 140.53, 142.89, 157.49, 160.81, 164.17, 164.02. MS m=z:
336 (Mþ.;18), 159 (100), 131 (80). MS m=z: 336 (Mþ.;18), 159 (100),
131 (80). C15H10F2N2O3S requires C, 53.57; H, 3.00; N, 8.33; S, 9.53.
Found: C, 53.55; H, 3.08; N, 8.38; S, 9.55.

1386
L. E. Da Silva, P. T. De Sousa, and A. C. Joussef
2-Aminoquinolin-8-yl-3,5-bis(trifluoromethyl)benzenesulfonate (10)
Yellow solid (82%). Mp 177–179 ꢀC. 1H NMR (CDCl3, 300 MHz) d 4.71
(s, 2H), 6.60 (d, J ¼ 8.7 Hz, 1H), 7.26 (t, J ¼ 6.6 Hz, 1H), 7.58 (d, J ¼ 8 Hz,
1H), 7.67 (d, J ¼ 8 Hz, 1H), 7.80 (d, J ¼ 8 Hz, 1H), 8.01 (s, 1H), 8.36 (s,
2H). MS m=z: 436 (Mþ.; 20), 159 (100), 131 (22). C17H10F6N2O3S
requires C, 46.80; H, 2.31; N, 6.42; S, 7.35. Found: C, 46.74; H, 2.30;
N, 6.40; S, 7.36.
2-Aminoquinolin-8-yl-5-(dimethylamino)naphthalen-1-yl-sulfonate (11)
Yellow solid (81%). Mp 205–206 ꢀC. 1H NMR (CDCl3, 300 MHz) d 2.91
(s, 6H), 4.46 (s, 2H), 6.53 (d,J ¼ 8.7 Hz, 1H), 7.12 (t, J ¼ 7.8 Hz, 1H),
7.26–7.39 (m, 4H), 7.66 (d, J ¼ 8.7 Hz, 1H), 7.73 (t, J ¼ 8.7 Hz, 1H),
8.08 (d, J ¼ 6 Hz, 1H), 8.56 (d, J ¼ 8.4 Hz, 1H), 8.78 (d, J ¼ 8.7 Hz,
1H). MS m=z: 393 (Mþ.; 39), 329 (45), 170 (75), 159 (100), 131 (90).
C21H19N3O3S requires C, 64.10; H, 4.87; N, 10.68; S, 8.15. Found:
C, 64.08; H, 4.88; N, 10.66; S, 8.15.
2-Aminoquinolin-4-yl-2,4,6-triisopropylbenzenesulfonate (13)
Yellow solid: 97 mg (72%). Mp: 207–209 ꢀC. 1H NMR (CDCl3, 300 MHz)
d 1.28 (s, 18H), 2.99 (m,1H), 4.16 (m, 2H), 4.76 (s, 2H), 6.49 (s, 1H), 7.20
(d, J ¼ 6 Hz, 1H), 7.26 (s, 2H), 7.54 (d, J ¼ 7.5 Hz, 1H), 7.64 (d,
J ¼ 7.8 Hz, 1H), 7.79 (d, J ¼ 7.2 Hz, 1H). EM m=z (relative intensity):
426 (Mþ, 100), 267 (70), 160 (45), 91 (42), 43 (39). C24H30N2O3S requires
C, 67.58; H, 7.09; N, 6.57; S, 7.52. Found: C, 67.54; H, 7.10; N, 6.59; S,
7.55.
2-Aminoquinolin-4-yl-5-(dimethylamino)naphthalene-1-sulfonate (14)
Crystalline solid: 97 mg (80%). Mp: 191–193 ꢀC. 1H NMR (CDCl3,
300 MHz) d 2.82 (s, 6H), 4.80 (s, 2H), 6.51 (s, 1H), 7.02 (t, J ¼ 7.2 Hz,
1H), 7.19 (d, J ¼ 7.5 Hz, 1H), 7.50 (t, J ¼ 8.4 Hz, 1H), 7.51 (d, J ¼
8.4 Hz, 1H), 7.60 (t, J ¼ 4.2 Hz, 1H), 8.18 (d, J ¼ 7.5 Hz, 2H), 8.44 (d,
J ¼ 8.7 Hz, 2H), 8.55 ( d, J ¼ 8.4 Hz, 1H).13C NMR (CDCl3) d 45.65,
101.93, 116.04, 117.94, 119.37, 121.89, 123.22, 123.25, 125.81, 129.54,
130.11, 130.23, 131.04, 131.33, 132.80, 142.76, 149.28, 152.23, 154.75,
157.17. EM m=z (relative intensity): 393 (Mþ, 20), 170 (100), 28 (50).
C21H19N3O3S requires C, 64.10; H, 4.87; N, 10.68; S, 8.15. Found: C,
64.14; H, 4.88; N, 10.65; S, 8.16.

Chemoselectivity, Esterification, and Mechanism
1387
2,2-Dimethyl-5-[8-(4-methylbenzenesulfonate)quinolin-2-ylamino)]-
methylene-1,3-dioxane-4,6-dione (16)
1
White solid (71%). Mp 223–225 ꢀC. H NMR (CDCl3, 300 MHz) d 1.73
(s, 6H), 2.29 (s, 3H), 7.15 (d, J ¼ 8.7 Hz, 2H), 7.25 (d, J ¼ 8.1 Hz, 2H),
7.56 (t, J ¼ 8 Hz, 1H), 7.69 (d, J ¼ 6 Hz, 1H), 7.77 (d, J ¼ 6 Hz, 1H),
7.86 (d, J ¼ 8 Hz, 2H), 8.13 (d, J ¼ 13 Hz, 1H), 9.25 (d, J ¼ 13 Hz, 1H).
13C NMR (CDCl3) d 27.43, 90.07, 105.74, 112.65, 113.25, 118.39,
127.18, 127.62, 136.58, 140.41, 146.81, 151.39, 151.62, 163.46, 165.69.
MS m=z: 468 (Mþ.), 239 (50), 211 (45), 195 (100), 155 (40), 91 (35).
C23H20N2O7S requires C, 58.97; H, 4.30; N, 5.98; S, 6.84. Found:
C, 58.96; H, 4.31; N, 5.97; S, 6.82.
ACKNOWLEDGMENTS
This work was supported by grants from the Brazilian agency Coordina-
tion for the Improvement of Higher Education Service (CAPES) and
from DAAD (German Academic Exchange Service).
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