Transformation of 3-nitroanilines into dioxoisothiazolo[5,4,3-k,l]acridines

Article abstract of DOI:10.1055/s-2001-18764

N-Methyl-N-3-nitroaryl benzyl sulfonamides on treatment with t-BuMe₂SiCl in the presence of DBU formed silylated oxime derivatives which were photocyclized to the dioxoisothiazolo[5,4,3-k,l]acridine systems. In one example the latter was converted to pyridoacridine derivative.

Full text of DOI:10.1055/s-2001-18764

LETTER
1927
Transformation of 3-Nitroanilines into Dioxoisothiazolo[5,4,3-k,l]acridines
T
ransformation
b
of 3-Nitroan
i
iline
s
i
g
nto
D
ioxoiso
n
thiazolo[5, 4,
i
3-k,l]a
c
e
ridine
s
w Wróbel*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: wrobel@icho.edu.pl
Received 24 August 2001
red compound precipitated which turned out to be the si-
lylated oxime form 7a of nitroso compound 6a
(Scheme 2).6
Abstract: N-Methyl-N-3-nitroaryl benzyl sulfonamides on treat-
ment with t-BuMe2SiCl in the presence of DBU formed silylated
oxime derivatives which were photocyclized to the dioxoisothiazo-
lo[5,4,3-k,l]acridine systems. In one example the latter was convert-
ed to pyridoacridine derivative.
Key words: benzyl nitroarylsulfonamides, cyclization, silylation,
nucleophilic aromatic substitution, photochemistry
Recently, we reported a 3-step conversion of 3-nitroa-
nilines into tricyclic 1H-1-alkyl-8-X-2,2-dioxoisothiazo-
lo[5,4,3-d,e]quinolines via intramolecular cyclization of
N-alkyl-N-3-nitroaryl prop-3-enyl sulfonamides in the
presence of base and Lewis acid.1 These tricyclic products
were further converted to 2,2-dioxoisothiazolo[5,4,3-
d,e]quinolines2 as well as to 1H-benzo[i,j][2,7]naphthy-
ridines.3
As we were looking for the intermediate in the synthesis
of some pyridoacridine marine alkaloids 34 we used the
phenyl ring as the equivalent of the vinyl group (1 as a
starting material), expecting the formation of a fused tet-
racyclic system 2 (Scheme 1).
Scheme 2
This compound was comparatively stable for aqueous
work-up or crystallization and (to some extent) even for
column chromatography. Its isolation supported the previ-
ously presented idea that similar reactions may proceed
via nitroso compounds as intermediates.2 The proposed
structure of 7a agrees with its 1H NMR spectrum. It seems
that 7a exists as a single, presumably anti isomer.
Scheme 1
Preliminary attempts to convert directly N-methyl-N-(3-
nitrophenyl) benzylsulfonamide 1a (prepared from 3-ni-
troaniline via sulfonylation with commercial benzylsulfo-
nyl chloride followed by alkylation with methyl iodide)5
to 2a in the presence of DBU and Lewis acids such as
MgCl2, Ti(O-iPr)4, Me3SiCl or bis-trimethyl-
silylacetamide2 in various solvents were discouraging.
Some efforts were undertaken in order to transform 7a
into 2a. Refluxing 7a in xylene produced 2a in a low 20%
yield. Further attempts to improve the yield of 2a by
changing the solvent, addition of acids or bases, photo-
chemical conditions (mercury lamp or sunlight in MeCN,
AcOEt, PhH or DCM, addition of some sensitizers) were
discouraging. The best result was obtained when the dilut-
ed acetonitrile solution of 7a containing t-BuMe2SiCl/
Et3N system and fluorenone as sensitizer was exposed to
light of an ordinary 100W bulb for several days. After col-
Unexpectedly, when 1a was treated with an excess of t-
BuMe2SiCl and DBU in dry acetonitrile solution, a deep
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1927,1928,ftx,en;G18601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1928
Z. Wróbel
LETTER
umn chromatography 2a was isolated in 68% yield.7 Oth-
er N-alkyl-N-(3-nitroaryl) benzylsulfonamides were
found to undergo the same transformations (Equation,Ta-
ble).
References
(1) (a) Wróbel, Z. Tetrahedron Lett. 2000, 41, 7365.
(b) Wróbel, Z. Tetrahedron 2001, 57, 7899.
(2) Wróbel, Z. Tetrahedron Lett. 2001, 42, 5537.
(3) Wróbel, Z. Synlett 2001, 1415.
(4) For example: (a) Delfourne, E.; Roubin, C.; Bastide, J. J.
Org. Chem. 2000, 65, 5476. (b) Nakahara, S.; Matsui, J.;
Kubo, A. Tetrahedron Lett. 1998, 39, 5521. (c) Kitahara,
Y.; Tamura, F.; Nishimura, M.; Kubo, A. Tetrahedron 1998,
54, 8421. (d) Ozturk, T.; Mc Killop, A. Can. J. Chem. 2000,
78, 1158.
Equation
(5) Typical conditions: (a) : Sulfonylation: 3-Nitroaniline (1.38
g, 10 mmol); benzylsulfonyl chloride (2.30 g, 12 mmol); dry
pyridine (20 mL); 0 °C to r.t.; 6 h; 75%; (b):Methylationto
1a: (1.17g, 4 mmol); K2CO3 (2.7 g, 20 mmol); MeI (excess,
1 mL); dry DMF (10 mL); r.t.; 3 h; 90%.
(6) Typical procedure: 1a (306 mg, 1 mmol); t-BuMe2SiCl (452
mg, 3 mmol); DBU (746 L, 5 mmol); dry MeCN (20 mL);
8 days at r.t.; 130 mg of 7a (85%); mp 191–192 °C (PhCH3-
hexane); H (200 MHz, CDCl3): –0.12 (s, 6 H), 0.78 (s, 9 H),
3.16 (s, 3 H), 5.51 (d, J = 6.6 Hz, 1 H), 6.45 (dd, J = 10.0, 6.6
Hz, 1 H), 6.69 (dd, J = 10.0, 0.6 Hz, 1 H), 7.39-7.50 (m, 3
H), 7.56-7.66 (m, 2 H); m/z (EI, int.%): 403 (27.9), 402
(100.0), 401 (11.8), 346 (10.9), 345 (46.4), 297 (8.5), 282
(21.6), 281 (87.6), 280 (22.1), 272 (23.6), 271 (43.9); UV
(CHCl3): 465.8 nm.
(7) Typical procedure: 7a (50 mg, 0.125 mmol); t-BuMe2SiCl
(19 mg, 0.125 mmol), Et3N (20 L, 0.130 mmol); fluorenone
(20 mg); dry MeCN (25 mL); 100 W bulb; 2 days; yield: 23
mg of 2a (68%): H (500 MHz, DMSO-d6): 3.44 (s,3 H),
7.08 (d, J = 7.2 Hz, 1 H), 7.76 (d, J = 9.0 Hz, 1 H,), 7.94 (dd,
J = 9.0, 7.2 Hz, 1 H), 7.96-8.00 (m, 1 H), 8.10 (ddd, J = 8.4,
6.8, 1.3 Hz, 1 H), 8.33 (app d, J = 8.4 Hz, 1 H), 8.44 (d, J =
8.8 Hz, 1 H); c (125 MHz, DMSO-d6): 150.1 (Cq), 146.0
(Cq), 136.5 (Cq), 134.3, 132.8 (Cq), 131.9, 130.6, 130.4,
122.1, 119.3, 117.4 (Cq), 112.5 (Cq), 102.9, 27.0 (CH3);
m/z (EI, int.%): 271 (9.6), 270 (100.0), 223 (7.55), 222
(41.7), 221 (11.0), 206 (8.4), 205 (42.4), 179 (27.0), 178
(19.9); HRMS: calcd. for C14H10O2N2S [270.0463], found:
270.0458.
Table Conversion of 1 to 7 and Photocyclization of 7 to 2
1
a
b
c
X
R
7
a
–
–
d
e
Yield[%]a
88
2
a
b
c
Yield[%]a
68
H
Me
allyl
Bn
b
H
–
22c
b
H
–
25c
d
e
Cl
Cl
Me
allyl
82
d
e
88d
b
–
23d
a Isolated yield.
b Conversion to 2 performed on crude mixture resulted from silylation
of 1 after addition of t-BuMe2SiCl and fluorenone.
c Yield after two steps based on 1.
d 150 W bulb.
In the cases where 7 was difficult to separate, the cycliza-
tion step was conducted on the crude silylation mixture af-
ter addition of more t-BuMe2SiCl and fluorenone.
The nature of cyclization remained unclear so far. It seems
that the photochemical conrotation might be favoured
over the thermal disrotation process for steric reasons.
Addition of a base and silylating agent would facilitate
elimination of t-butyldimethylsilanol from the cyclized
intermediate 8 to form aromatized system.
(8) Following procedure:3 2a (68 mg, 0.25 mmol), methyl
acetoacetate (0.56 mL, 5 mmol) and K2CO3 (345 mg, 2.5
mmol) were stirred in DMF (5 mL) for 20 h at r.t. After
evaporation of the solvent and the excess of methyl
acetoacetate the residue was chromatographed on silica gel
with CH2Cl2–MeOH (1:5) mixture as eluent to give 3 as red
crystals (35 mg; 45%): H (500 MHz, DMSO-d6): 2.45 (s, 3
H), 3.49 (s, 3 H), 3.85 (s, 3 H), 6.65 (d, J = 7.8 Hz, 1 H, H-
8), 7.23 (ddd, J = 8.7, 6.6, 1.3 Hz, 1 H, H-9), 7.32 (dd, J =
8.6, 0.7 Hz, 1 H, H-4), 7.56 (app d, J = 8.6 Hz, 1 H, H-11),
7.59 (ddd, J = 8.6, 6.6, 1.3 Hz, 1 H, H-10), 7.63 (t, J = 8.6
Hz, 1 H, H-5), 7.71 (dd, J = 8.6, 0.7 Hz, 1 H, H-6); m/z (EI,
int.%): 305 (21,6), 304 (100.0), 290 (3.7), 289 (15.7), 274
(10.3), 273 (5.47), 258 (3.1), 248 (6.3), 245 (10.1), 229
(11.3); HRMS: calcd. for C19H16O2N2 [304.1212], found:
304.1205.
As an illustration of the versatility of dioxoisothiazo-
lo[5,4,3-k,l]acridines as intermediates in synthesis of py-
ridoacridine systems 2a was converted to 3a (X = H, R =
R’ = Me, Y = CO2Me)8 on treatment with methyl aceto-
acetate in K2CO3/DMF system.3
Acknowledgement
This study was funded by the State Committee of Scientific Rese-
arch Grant No. PBZ 6.01.
Synlett 2001, No. 12, 1927–1928 ISSN 0936-5214 © Thieme Stuttgart · New York