Synthesis and reactions of 10,10-dimethyl-10H-pyrido[1,2-a]indol-6-ones

Article abstract of DOI:10.1002/jhet.5570390224

Cyclocondensation of 2,3,3-trimethyl-3H-indoles 2 with malonates 3 gives 8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-alindol-6-ones 4, which were halogenated in position 7, 8 and 9 with sulfuryl chloride, bromine or phosphoroxychloride to give the corresponding halo-10,10-dimethyl-10H-pyrido[1,2-a]indoles 5, 6, 7 and 8. Amination affords the 8-amino-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-one 9. Nitration gives either the 10,10-dimethyl-7-nitro-10H-pyrido[1,2-a]indoles 10 or 10,10-dimethyl-7-hydroxy-10H-pyrido[1,2-a]indoles 11, depending on the conditions.

Full text of DOI:10.1002/jhet.5570390224

Mar-Apr 2002
Synthesis and Reactions of 10,10-Dimethyl-10H-
pyrido[1,2-a]indol-6-ones
391
Thomas Kappe, Franz Frühwirth, Peter Roschger, Brigitte Jocham,
Jenny Kremsner and Wolfgang Stadlbauer*
Department of Chemistry, Organic Synthesis Group, Karl-Franzens University of Graz
Heinrichstrasse 28, A-8010 Graz, Austria/Europe
Received November 12, 2001
Cyclocondensation of 2,3,3-trimethyl-3H-indoles 2 with malonates 3 gives 8-hydroxy-10,10-dimethyl-
10H-pyrido[1,2-a]indol-6-ones 4, which were halogenated in position 7, 8 and 9 with sulfuryl chloride,
bromine or phosphoroxychloride to give the corresponding halo-10,10-dimethyl-10H-pyrido[1,2-a]indoles
5, 6, 7 and 8. Amination affords the 8-amino-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-one 9. Nitration
gives either the 10,10-dimethyl-7-nitro-10H-pyrido[1,2-a]indoles 10 or 10,10-dimethyl-7-hydroxy-10H-
pyrido[1,2-a]indoles 11, depending on the conditions.
J. Heterocyclic Chem., 39, 391 (2002).
Pyrido[1,2-a]indole (A) is a ring system which is only
250-280 °C gave rather impure products; performing the
reactions in refluxing diphenylether as solvent, 8-hydroxy-
10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indol-6-ones
4a,b were obtained in about 80% yield and excellent purity.
With methyl-, ethyl-, butyl- and benzylmalonates 3b-e, the
yields of 8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-
a]indol-6-ones 4c-j were lower (10-60%), but the simple,
cheap and quick reaction overcomes this disadvantage. The
reason for the lower yields compared with 4a,b are proba-
bly the lower boiling points of the malonates, which pro-
hibit the necessary high reaction temperatures and the for-
mation of an intermediate α-oxo ketene [6]. In order to test
the higher reactivity of bis(2,4,6-trichlorophenyl)mal-
onates, the reactive butyl- and benzylmalonates 3f,g were
reacted with 2,3,3-trimethyl-3H-indole 2a to compare the
yields: with butylmalonates, the simple diethylester method
using 3d afforded the better yield of 4g (method A, 61%)
compared with the bis(2,4,6-trichlorophenyl)malonate
method of 3f (4g in method B, 53%) probably caused by
the more difficult workup in method B. With benzyl-
malonates, the bis(2,4,6-trichlorophenyl)malonate method
with 3g (method B) afforded 4i in 53%, in contrast to the
simple diethylester method using 3e (method A), which
gave 4i only in 25% yield.
described in a few samples in the literature mainly because
of its difficult approach. There are two reaction sequences
described which lead either via a high-temperature reaction
(>500 °C) to the fully aromatic system of pyrido[1,2-
a]indole [1-3] or by intramolecular alkylation to the ring
system with an saturated pyridine ring [1,4]. Further reac-
tions described hitherto are hydrogenations or acylations of
the pyridine ring [1,2,5], or nitrosation of the benzene ring
[1]. Due to our projects for new syntheses of fused hetero-
cycles containing the biologically active 4-hydroxy-2-pyri-
done moiety B, the synthesis of the target molecule C con-
taining both the hydroxypyridone structure element of B
and the pyrido[1,2-a]indole structure A was of interest.
Scheme 1
The halogenation in the pyridine part of 8-hydroxy-
10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indol-6-ones
4 can be achieved regioselectively at positions 7, 8 or 9,
depending on the halogenation reagents and conditions.
Chlorination with N-chlorosuccinimide in dioxane gives
a mono-chlorination at position 7 and forms in 80-90% 7-
chloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-
a]indole-6,8(7H)-diones 5a,b as the fixed 6,8-dioxo tau-
tomers, shown by the addidional infrared carbonyl signal
We were able to show in a large number of reactions that
malonates react easily by cyclocondensation with enam-
ines to 4-hydroxypyridones [6]; as synthon for the synthe-
sis of pyrido[1,2-a]indoles we chosed 2,3,3-trimethyl-3H-
indoles 2, which are either commercially available or eas-
ily obtained by reaction of phenylhydrazinium chlorides 1
with 3-methylbutanone in a Fischer indole synthesis. In the
next step the cyclocondensation of 2 with malonates was
planned taking advantage of our previous researches on
the cyclocondensation of enamines with commercially
available diethyl malonates instead of highly reactive
bis(2,4,6-trichlorophenyl)malonates (e.g. 3f,g) [6,7].
-1
at C-8 at 1720 cm ; the introduction of the additional
substituent at C-7 generated racemic molecules 5 with an
asymmetric center at C-7. The use of sulfurylchloride as
chlorination agent caused the introduction of an addi-
tional chloro substituent at position 9 and gives 7,9-
dichloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-
The reaction of diethyl phenylmalonate (3a) with 2,3,3-
trimethyl-3H-indoles 2 without solvent at temperatures of

392
T. Kappe, F. Frühwirth, P. Roschger, B. Jocham, J.Kremsner and W. Stadlbauer
Vol. 39
Scheme 3
Scheme 2
a]indole-6,8(7H)-diones 6a,b. We noticed that in the
preparation of 6a only a 3-fold excess of sulfurylchloride
was necessary, whereas 6b needed a 4-fold excess for a
complete reaction. The position of the second chloro sub-
stituent can be determined easily by the disappearance of
Whereas the halogenation reactions carried out in
Scheme 3 follow an electrophilic substitution of hydrogen
either at the CH-acidic carbon of the enolized 1,3-dicar-
bonyl system (C-7) or at the enamine position (C-9),
nucleophilic displacement of the 8-hydroxy group of 4a by
reaction with phosphorylchloride leads to the 8-chloro-
10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indol-6(7H)-
one 8. The necessary reaction time (2.5 hours) and temper-
ature (105 °C) reveals that the reactivity of the hydroxy
group in 4a is lower than in 4-hydroxy-3-phenyl-2-quino-
lines [8]. Aminolysis of the 8-hydroxy group of 4a with
benzylamine afforded after 12 hours reaction time in rather
moderate yields 8-amino-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6(7H)-ones 9; again in the 4-hydroxy-
3-phenyl-2-quinoline series a higher reactivity and better
yields in the reaction with amines has been observed [9].
The reaction of 8-hydroxy-10,10-dimethyl-7-phenyl-
10H-pyrido[1,2-a]indol-6-ones 4a,b with nitric acid
showed the formation of two products. By adaptation of
the reaction conditions we were able to isolate both com-
pounds. Nitration of 4a,b with nitric acid in glacial acetic
acid at room temperature using a small amount of sodium
nitrite as catalyst afforded 10,10-dimethyl-7-nitro-7-
phenyl-10H-pyrido[1,2-a]indole-6,8(7H)-diones 10a,b.
The dioxo structure was again proved by the ir bands at
1
the H-9 signal in the H nmr at about δ = 5.90 ppm. The
reduction with zinc in glacial acetic acid removes the
aliphatic chloro atom in position 7. The olefinic chloro
atom in position 9 and the chloro atom in the benzo part
of 7b remained unchanged. As products, the tautomeric
9-chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indole-6(7H)-ones 7a,b were obtained,
shown by the lack of the C-8 carbonyl signals at 1720
-1
cm and the appearance of the C-8 hydroxy bands at
-1
3200 cm in the infrared spectra.
The bromination of 4a,b with elementary bromine using
dioxane as the solvent at reflux temperature gives the
racemic dibromo products with the tautomeric oxo group
at C-8, 7,9-dibromo-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indole-6,8(7H)-diones 6c,d. When the reac-
tion of 4a,b with bromine was carried out in chloroform at
room temperature and the reaction mixture was then
heated subsequently with 2-propanol, the monobromo
products at C-9 with the tautomeric hydroxy group at C-8,
9-bromo-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6(7H)-ones 7c,d were obtained.

Mar-Apr 2002
Synthesis and Reactions of 10,10-Dimethyl-10H-pyrido[1,2-a]indol-6-ones
393
Scheme 4
Scheme 5
-1
1720 cm . When the nitration was performed with nitric
acid in glacial acetic acid at reflux temperatures, the sec-
ond product was formed, which could be assigned to the
structure of 7-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indole-6,8(7H)-diones 11a,b by elemental
analysis and the ir signals for both the 6,8-dioxo structure
General Procedure for the Synthesis of 2,3,3-Trimethyl-3H-
indoles 2.
-1
at 1705-1730 and 1655-1670 cm , and the hydroxy group
This procedure was performed following a general textbook
procedure [10]: A suspension of the appropriate phenylhydrazini-
umchloride 1a,b (0.5 mol) in glacial acetic acid was warmed and
to this mixture a solution of 3-methyl-2-butanone (43.07 g, 0.5
mol) in glacial acetic acid (50 mL) was added under stirring. The
reaction was exothermic and started to reflux. After the addition,
the reaction mixture was heated under reflux for further 2 hours,
then the mixture was cooled to room temperature and the solvent
removed under reduced pressure. The residue was diluted with
water (100 mL) and made alkaline with 2 M sodium hydroxide
solution. Then the product was extracted with diethylether (2 x
100 mL), dried with sodium sulfate and the solvent evaporated
under reduced pressure. The residue was then distilled in vacuo.
-1
with a sharp OH signal at 3450-3470 cm , which is in
accordance with similar hydroxy compounds of quinolines
[7]. The formation of the 7-hydroxy compounds 11 by
reaction with nitric acid cannot be explained in terms of a
simple oxidation of 4, because we found that nitro com-
pounds 10 decompose on heating in glacial acetic acid, but
also in 1-butanol or toluene to hydroxy compounds 11.
EXPERIMENTAL
Melting points were determined on a Gallenkamp Melting Point
Apparatus, Model MFB-595 in open capillary tubes. Infrared spec-
tra were taken as potassium bromide pellets on a Perkin-Elmer 298
2,3,3-Trimethyl-3H-indole (2a).
The yield was 44.3 g (56%), light yellow oil, bp 110-115 °C
(20-23 mbar); lit. bp 228-229 °C (744 mm Hg) [11].
1
spectrophotometer. The H nmr spectra were recorded on a Varian
Gemini 200 (200 MHz) or a Bruker AM 360 instrument (360
13
MHz); C nmr spectra were recorded on a Bruker AM 360 instru-
5-Chloro-2,3,3-trimethyl-3H-indole (2b).
ment (90 MHz). Chemical shifts are reported in ppm from internal
tetramethylsilane standard and are given in δ-units. The solvent for
NMR spectra was deuteriodimethylsulfoxide unless otherwise
stated. Microanalyses were performed on a Fisons elemental ana-
lyzer, Mod. EA1108 and are within ±0.4 of the theoretical percent-
ages. Mass spectra were taken on on a FINNIGAN 4000 (EI: 70
eV, CI: 120 eV, methane). All reactions were monitored by thin
layer chromatography, carried out on 0.2 mm silica gel 60 F-254
(Merck) plates using uv light (254 and 366 nm) for detection.
Common reagent-grade chemicals are either commercially avail-
able and were used without further purification or prepared by
standard literature procedures.
The yield was 58.2 g (60%) light yellow oil, bp. 115-116 °C (2
mm Hg), lit. bp 80-82 °C (0.3 mm Hg) [12].
General Procedure for the Synthesis of Pyrido[1,2-a]indoles 4a-j.
Method A.
A mixture of the appropriate trimethylindole 2a,b and the cor-
responding diethyl malonate 3a-e in diphenylether was heated in
a metal bath using a 25 cm Vigreux column as air condenser for
the time and temperature (bath temperature) given at the individ-
ual procedure. During this time, ethanol was liberated and
removed by distillation equipment. When the formation of

394
T. Kappe, F. Frühwirth, P. Roschger, B. Jocham, J.Kremsner and W. Stadlbauer
Vol. 39
ethanol had stopped, the reaction mixture was cooled to room
temperature and diluted with the same volume of diethyl ether.
The obtained solid was isolated by suction filtration and washed
with diethylether.
d ): δ = 1.46 (s, 6 H, 2 Me at C-10), 1.87 (s, 3 H, 7-Me), 6.20 (s, 1
H, H-9), 7.42 (dd, J = 2 and 8 Hz, H-3), 7.70 (d, J = 2 Hz, 1 H, H-
1), 8.51 (dd, J = 2 and 8 Hz, 1 H, H-4), 10.52 (s, b, OH).
6
Anal. Calcd. for C
H ClNO (275.74): C, 65.34; H, 5.12; N,
15 14 2
5.08. Found: C, 65.62; H, 5.01; N, 5.31.
Method B.
7-Ethyl-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (4e).
A mixture of the appropriate trimethylindole 2a,b and the cor-
responding bis-(2,4,6-trichlorophenyl)malonate 3f,g [13] was
heated for 30 minutes to 200-220 °C (bath temperature). Then the
mixture was cooled to room temperature and triturated several
times with diethylether and hexane until the formed 2,4,6-
trichlorophenol was removed and the gum-like reaction product
became solid. Then the precipitate was recrystallized from the
solvent listed below.
Method A: 4e was obtained from trimethylindole 2a (7.95 g,
50 mmol), ethylmalonate 3c (10.35 g, 55 mmol) and
diphenylether (25 g) after heating for 3 hours at 220 °C and 1
hour at 250 °C. The yield was 6.82 g (50%) light yellow prisms,
mp 264 °C (dec.) (glacial acetic acid); ir: 3160 - 2850 m, b, 2620
-1
1
w, 1660 sh, 1650 s, 1610 s, 1580 m cm ; H nmr (DMSO-d ): δ
6
= 1.00 (t, J = 7 Hz, 3 H, Et-CH ), 1.44 (s, 6 H, 2 Me), 2.42 (q, J =
3
8-Hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indol-6-
one (4a).
7 Hz, 2 H, CH ), 6.18 (s, 1 H, H-9), 7.25 and 7.33 (2 dd, J = 2 and
2
8 Hz, 2 H, H-2, H-3), 7.53 (dd, J = 2 and 8 Hz, 1 H, H-1), 8. 53
(dd, J = 2 and 8 Hz, 1 H, H-4).
Method A: 4a was obtained from trimethylindole 2a (15.9 g,
0.1 mol), phenylmalonate 3a (26.0 g, 0.11 mol) and
diphenylether (50 g) after heating for 1 hour to 260 °C. The yield
was 24.4 g (81%), pale yellow prisms, mp 274-276.5 °C (glacial
Anal. Calcd. for C
H NO (255.32): C, 75.27; H, 6.71; N,
16 17 2
5.49. Found: C, 75.55; H, 6.65; N, 5.36.
2-Chloro-7-ethyl-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-
a]indol-6-one (4f).
-1
1
acetic acid); ir: 3350-2700 b, 1640 s, 1610 s, 1545 cm ; H nmr
(DMSO-d ): δ = 1.50 (s, 6 H, 2 Me), 6.30 (s, 1 H, H-9), 7.10-7.60
6
(m, 8 H, ArH), 8.45 (d, J = 8 Hz, 1 H, H-4), 10.50 (s, 1 H, OH).
Method A: 4f was obtained from chloro-trimethylindole 2b
(9.65 g, 50 mmol), ethylmalonate 3c (10.35 g, 55 mmol) and
diphenylether (25 g) after heating for 3 hours at 220 °C and 1 hour
at 250 °C. The yield was 4.08 g (28%) light yellow prisms, mp
279 °C (glacial acetic acid); ir: 3250-3020 m, b, 2980 w, 2920 w,
Anal. Calcd. for C
H NO (303.36): C, 79.19; H, 5.65; N,
20 17 2
4.62. Found: C, 78.79; H, 5.81; N, 4.53.
2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-
a]indol-6-one (4b).
-1
1
1670 s, 1655 m, 1610 s, 1595 m cm ; H nmr (DMSO-d ): δ =
6
Method A: 4b was obtained from chloro-trimethylindole 2b
(19.3 g, 0.1 mol), phenylmalonate 3a (26.0 g, 0.11 mol) and
diphenylether (50 g) after heating for 1 hour to 260 °C. The yield
was 26.3 g (78%), pale yellow prisms, mp 256-259 °C (ethanol);
0.99 (t, J = 7 Hz, 3 H, Et-CH ), 1.45 (s, 6 H, 2 Me), 2.44 (q, J = 7
3
Hz, 2 H, CH ), 6.19 (s, 1 H, H-9), 7. 41 (dd, J = 2 and 8 Hz, H-3),
2
7.69 (d, J = 2 Hz, 1 H, H-1), 8.51 (dd, J = 2 and 8 Hz, 1 H, H-4).
Anal. Calcd. for C
H ClNO (289.76): C, 66.32; H, 5.57; N,
16 16 2
-1 1
ir: 3250-2600 b, 1655 s, 1610 m, 1545 cm ; H nmr (DMSO-d ):
4.83. Found: C, 66.65; H, 5.32; N, 4.67.
6
δ = 1.50 (s, 6 H, 2 Me), 6.30 (s, 1 H, H-9), 7.10-7.50 (m, 6 H,
ArH), 7.70 (d, J = 2 Hz, 1 H, H-1), 8.45 (d, J = 8 Hz, 1 H, H-4).
7-Butyl-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (4g).
Anal. Calcd. for C
H ClNO (337.81): C, 71.11; H, 4.77; N,
20 16 2
4.15. Found: C, 71.45; H, 4.78; N, 4.14.
Method A: 4g was obtained from trimethylindole 2a (3.18 g,
20 mmol), butylmalonate 3d (4.75 g, 22 mmol) and
diphenylether (10 g) after heating for 1 hour to 260 °C. The yield
was 3.45 g (61%), colorless prisms, mp 213-215 °C (methanol).
Method B: 4g was obtained from trimethylindole 2a (1.0 g, 63
mmol) and butylmalonate 3f (3.15 g, 65 mmol). The yield was
8-Hydroxy-7,10,10-trimethyl-10H-pyrido[1,2-a]indol-6-one
(4c).
Method A: 4c was obtained from trimethylindole 2a (7.95 g,
50 mmol), methylmalonate 3b (9.6 g, 55 mmol) and
diphenylether (25 g) after heating for 3 hours at 220 °C and 1
hour at 250 °C. The yield was 3.71 g (31%), light yellow prisms,
mp 296.5 °C (glacial acetic acid); ir: 3250-2800 m, b, 2660 w,
0.90 g (53%), colorless prisms, mp 204 °C (tetrachloromethane);
-1 1
ir: 3200-2400 m, 1660 s, 1625 s, 550 m cm ; H nmr (CDCl ): δ
3
= 0.80-1.10 (m, 7 H, CH -CH CH ), 1.40 (s, 6 H, 2 Me), 2.50-
3
2
2
-1
1
1665 sh, 1650 s, 1610 s, 1575 m cm ; H nmr (DMSO-d ): δ =
2.80 (m, 2 H, CH ), 6.55-7.35 (m, 4 H, ArH), 8.5 (s, 1 H, H-4),
6
2
+
1.44 (s, 6 H, 2 Me at C-10), 1.88 (s, 3 H, 7-Me), 6.20 (s, 1 H, H-
9), 7.25 and 7.33 (2 dd, J = 2 and 8 Hz, H-2 and H-3), 7.53 (dd,
J = 2 and 8 Hz, H-1), 8.53 (dd, J = 2 and 8 Hz, H-4).
10.2 (s, 1 H, OH); MS: m/e (%) = 283 (28.6, M ), 241 (100), 268
(10.9), 266 (8.7), 254 (30.5), 250 (5.4), 226 (62.0), 169 (32,6).
Anal. Calcd. for C
H NO (283.37): C, 76.30; H, 7.47; N,
18 21 2
Anal. Calcd. for C
H NO (241.29): C, 74.67; H, 6.27; N,
4.94. Found: C, 76.03; H, 7.38; N, 4.88.
15 15 2
5.80. Found: C, 74.34; H, 6.38; N, 5.65.
7-Butyl-2-chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]-
indol-6-one (4h).
2-Chloro-8-hydroxy-7,10,10-trimethyl-10H-pyrido[1,2-a]indol-
6-one (4d).
Method A: 4h was obtained from chloro-trimethylindole 2b
(3.86 g, 20 mmol), butylmalonate 3d (4.75 g, 22 mmol) and
diphenylether (10 g) after heating for 1 hour to 260 °C. The yield
was 4.0 g (63%), pale yellow prisms, mp 220-222.5 °C
(methanol); ir: 3300-2500 b, 1650 s, 1610 m, 1580 m, 1545 s
Method A: 4d was obtained from chloro-trimethylindole 2b
(9.65 g, 50 mmol), methylmalonate 3b (9.6 g, 55 mmol) and
diphenylether (25 g) after heating for 3 hours at 220 °C and 1 hour
at 250 °C. The yield was 4.21 g (31%) light yellow prisms, mp
297 °C (dec) (glacial acetic acid); ir: 3270 - 2820 m, b, 2615 w,
-1
1
cm ; H nmr (DMSO-d ): δ = 0.90 (t, J = 7 Hz, 3 H, Bu-CH ),
6
3
-1
1
1660 sh, 1650 s, 1605 m, 1595w, 1580 m cm ; H nmr (DMSO-
1.20-1.70 (m, 10 H, 2 Me and 2 Bu-CH ), 2.50 (t, J = 7 Hz, 2 H,
2

Mar-Apr 2002
Synthesis and Reactions of 10,10-Dimethyl-10H-pyrido[1,2-a]indol-6-ones
395
Bu-CH ), 6.20 (s, 1 H, H-9), 7.35 (dd, J = 8 and 2 Hz, 1 H, H-3),
7.60 (d, J = 2 Hz, 1 H, H-1), 8.50 (d, J = 8 Hz, 1 H, H-4).
1.60 (2 s, 6 H, 2 Me), 5.90 (s, 1 H, H-9), 7.10-7.60 (m, 8 H, ArH),
8.25 (d, J = 8 Hz, 1 H, H-4).
2
Anal. Calcd. for C
H Cl NO (372.25): C, 64.53; H, 4.06;
Anal. Calcd. for C
H ClNO (317.82): C, 68.03; H, 6.34; N,
20 15 2 2
18 20 2
N, 3.76. Found: C, 64.47; H, 4.25; N, 3.70
4.41. Found: C, 67.85; H, 6.30; N, 4.30.
7,9-Dichloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (6a).
7-Benzyl-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-
one (4i).
A suspension of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (9.10 g, 30 mmol) in chloroform
(150 mL) was laced with sulfurylchloride (7.35 mL, 90 mmol).
The mixture was stirred at room temperature for 20 minutes; dur-
ing this time, the reaction products dissolved. Then all volatile
parts were distilled under reduced pressure, and the oily residue
was digested with methanol and cooled for 12 hours at 4 °C. The
precipitate was then isolated by suction filtration and washed
with cold methanol. The yield was 10.4 g (93%) yellow prisms,
mp 165.5-166.5 °C (ethanol); ir: 2980 w, 1730 m, 1720 m, 1690
Method A: 4i was obtained from trimethylindole 2a (7.95 g, 50
mmol), benzylmalonate 3e (13.67 g, 55 mmol) and diphenylether
(25 g) after heating for 3 hours at 220 °C and 1 hour at 250 °C.
The yield was 4.31 g (25%), pale yellow prisms, mp 282 °C
(glacial acetic acid).
Method B: 4i was obtained from trimethylindole 2a (1.0 g, 63
mmol) and benzylmalonate 3g (3.35 g, 65 mmol). The yield was
1.2 g (63%), colorless prisms, mp 280 °C (glacial acetic acid); ir:
-1 1
3300-2400 m, 1670 m, 1640 s, 1630 m, 1615 w, 1605 m cm ; H
nmr (DMSO-d ): δ = 1.45 (s, 6 H, 2 Me), 3.77 (s, 2 H, benzyl-
6
-1 1
s, 1625 s, 1600 s cm ; H nmr (CDCl ): δ = 1.70 and 1.80 (2 s, 6
CH ), 6.23 (s, 1 H, H-1), 7.11 and 7.21 (2 dd, J = 2 and 8 Hz, H-
3
2
H, 2 Me), 7.20-7.60 (m, 8 H, ArH), 8.25 (d, J = 8 Hz, 1 H, H-4).
2 and H-3), 7.24-7.35 (m, 5 H, PhH), 7.54 (dd, J = 2 and 8 Hz, 1
H, 1-H), 8.52 (dd, J = 2 and 8 H, 1 H, H-4), 10.66 (s, b, OH).
Anal. Calcd. for C
H Cl NO (372.25): C, 64.53; H, 4.06;
20 15 2 2
Anal. Calcd. for C
H
NO (317.39): C, 79.47; H, 6.03; N,
N, 3.76. Found: C, 64.52; H, 4.05; N, 3.71.
21 19
2
4.41. Found: C, 79.22; H, 6.24; N, 4.65.
2,7,9-Trichloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (6b).
7-Benzyl-2-chloro-8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-
a]indol-6-one (4j).
A mixture of 2-chloro-8-hydroxy-10,10-dimethyl-7-phenyl-
10H-pyrido[1,2-a]indol-6-one (4b) (6.12 g, 18 mmol) and sul-
furylchloride (5.9 mL, 72 mmol) in chloroform (90 mL) was
reacted and work up was as described for 6a. The yield was 6.70
g (92%), yellow prisms, mp 207-208 °C (ethanol); ir: 2980 w,
Method A: 4j was obtained from chloro-trimethylindole 2b
(7.14 g, 37 mmol), benzylmalonate 3e (10.18 g, 41 mmol) and
diphenylether (20 g) after heating for 3 hours at 220 °C and 1
hour at 250 °C. The yield was 1.27 g (9.8%), pale yellow prisms,
mp 259.8 °C (glacial acetic acid); ir: 3250-2820 m, b, 1660 s,
-1 1
1720 s, 1685 s, 1620 m, 1590 m cm ; H nmr (CDCl ): δ = 1.70
3
-1
1
and 1.80 (2 s, 6 H, 2 Me), 7.20-7.50 (m, 7 H, ArH), 8.20 (d, J = 8
Hz, 1 H, H-4).
1610 m, 1585 w cm ; H nmr (DMSO-d ): δ = 1.47 (s, 6 H, 2
6
Me), 3.76 (s, 2 H, benzyl-CH ), 6.23 (s, 1 H, H-9), 7.10 (dd, J = 2
2
Anal. Calcd. for C
N, 3.44. Found: C, 58.86; H, 3.49; N, 3.34.
H Cl NO (406.70): C, 59.07; H, 3.47;
and 8 Hz, H-3), 7.23 (d, J = 2 and 8 Hz, 2 H, ArH), 7.29 (dd, J =
2 and 8 Hz, 2 H, ArH), 7.40 (dd, J = 2 and 8 Hz, 1 H, ArH), 7.71
(d, J = 2 Hz, 1 H, H-1), 8.50 (dd, J = 2 and 7 Hz, 1 H, H-4).
20 14 3 2
7,9-Dibromo-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (6c).
Anal. Calcd. for C
H ClNO (351.84): C, 71.69; H, 5.16; N,
21 18 2
3.98. Found: C, 71.43; H, 5.02; N, 3.77.
A mixture of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol) and bromine
(2.5 mL) in dioxane (75 mL) was heated under reflux, until the
mixture was dissolved. Then the reaction mixture was poured
into ice/water (1000 mL) and allowed to stand for 48 hours. The
solid was isolated by suction filtration, and washed with water.
The yield was 4.37 g (95%) yellow prisms, mp 182-183.5 °C
7-Chloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indole-
6,8(7H)-dione (5a).
A mixture of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (0.61 g, 2.0 mmol) and N-chloro-
succinimide (0.54 g, 4.0 mmol) in dry dioxane (10 mL) was
heated for 10 minutes under reflux. The hot mixture was filtered
and the filtrate poured into ice/water (100 mL). An oil separated,
which solidified after a short period. The solid product was iso-
lated by suction filtration and washed with water. The yield was
0.54 g (80%) bright yellow prisms, mp 144.5-147 °C (ethanol);
-1 1
(glacial acetic acid); ir: 1705 s, 1670 s, 1615 m, 1590 m cm ; H
nmr (CDCl ): δ = 1.80 and 1.85 (2 s, 6 H, 2 Me), 7.10-7.60 (m, 8
3
H, ArH), 8.20 (d, J = 8 Hz, 1 H, H-4).
Anal. Calcd. for C
H Br NO (461.16): C, 52.09; H, 3.28;
20 15 2 2
-1 1
ir: 3060 w, 2970 w, 1720 m, 1675 s, 1650 s, 1605 m cm ; H nmr
N, 3.04. Found: C, 52.28; H, 3.40; N, 3.02.
(CDCl ): δ = 1.45 and 1.55 (2 s, 6 H, 2 Me), 5.85 (s, 1 H, H-9),
7.10-7.70 (m, 8 H, ArH), 8.25 (d, J = 8 Hz, 1 H, H-4).
3
7,9-Dibromo-2-chloro-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indole-6,8(7H)-dione (6d).
Anal. Calcd. for C
H ClNO (337.81): C, 71.11; H, 4.77; N,
20 16 2
2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4b) (3.38 g, 10 mmol) and bromine
(2.5 mL) were reacted and work up was as described for 6c. The
yield was 4.81 g (97%), mp 161-162.5 °C (glacial acetic acid); ir:
4.15. Found: C, 71.34; H, 4.56; N, 4.28.
2,7-Dichloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (5b).
-1
1
1710 s, 1680 s, 1610 m, 1590 s cm ; H nmr (CDCl ): δ = 1.80
2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4b) (0.68 g, 2.0 mmol) were reacted
and work up was as described for 5a. The yield was 0.66 g
(89%), yellow prisms, mp 157-158 °C (ethanol); ir: 2980 w, 1720
3
and 1.85 (2 s, 6 H, 2 Me), 7.10-7.60 (m, 8 H, ArH), 8.20 (d, J = 8
Hz, 1 H, H-4).
Anal. Calcd. for C
H
Br ClNO (495.60); C, 48.47; H,
20 141 2 2
-1
1
s, 1670 s, 1640 s, 1595 m cm ; H nmr (CDCl ): δ = 1.50 and
2.85; N, 2.83. Found C, 48.39; H, 2.83; N, 2.75.
3

396
T. Kappe, F. Frühwirth, P. Roschger, B. Jocham, J.Kremsner and W. Stadlbauer
Vol. 39
9-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6(7H)-one (7a).
8-Chloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indol-
6(7H)-one (8).
A solution of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol) in phosphoryl
chloride (9 ml) was heated under reflux for 2.5 hours. The excess
of phosphoryl chloride was removed under reduced pressure, and
after cooling the mixture was poured onto crushed ice (100 g).
After warming to room temperature the mixture was brought to
pH~6 and the resulting solid isolated by suction filtration. The
yield was 2.18 g (68%), light yellowish prisms, mp 157 °C
(acetic acid/water); ir: 3075 w, 2975 w, 1650 sh, 1645 s, 1620 m,
A refluxing solution of 7,9-dichloro-10,10-dimethyl-7-
phenyl-10H-pyrido[1,2-a]indole-6,8(7H)-dione (6a) (3.72 g
(10 mmol) in glacial acetic acid (180 mL) was laced quickly
with zinc-dust (4.1 g) and the reaction mixture stirred until
decolorization took place (about 30 seconds). The solution was
filtered quickly while still hot to remove excess zinc-dust and
the filtrate was taken to dryness under reduced pressure. The
residue was treated with ice/water (200 mL) and the precipitate
was isolated by filtration after standing for some hours. The
yield was 3.14 g (93%) pale yellow prisms, mp 234-236 °C
-1 1
1590 s cm ; H nmr (DMSO-d ): δ = 1.56 (s, 6 H, 2 Me, 6.97 (s,
6
-1
1
1 H, H-9), 7.40-7.44 (m, 7 H, PhH, H-2 and H-3), 7.63 (dd, J = 2
and 8 Hz, 1 H, H-1), 8.49 (dd, J = 2 and 8 Hz, 1 H, H-4).
(ethanol); ir: 3250 b, 1635 s, 1610 m, 1545 s cm ; H nmr
(DMSO-d ): δ = 1.70 (s, 6 H, 2 Me), 7.10-1.75 (m, 8 H, ArH),
6
Anal. Calcd. for C
H ClNO (321.81): C, 74.65; H, 5.01; N,
8.45 (d, J = 8 Hz, 1 H, H-4).
20 16
4.35. Found: C, 74.40; H, 4.92; N, 4.22.
Anal. Calcd. for C
H ClNO (337.81): C, 71.11; H, 4.77; N,
20 16 2
4.15. Found: C, 71.27; H, 4.79; N, 4.10.
8-Benzylamino-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indol-6(7H)-one (9).
2,9-Dichloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indole-6(7H)-one (7b).
A solution of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol) in benzylamine
(30 mL) was heated under reflux using a short column as air con-
denser for about 12 hours. During this time, water was liberated.
When the formation of water had stopped, the excess benzylamine
was removed under reduced pressure. The residue was dissolved in
dimethylformamide (2 mL) and quenched with ethanol (about 10
mL). The precipitate was isolated by suction filtration. The yield
2,7,9-Trichloro-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-
a]indole-6,8(7H)-dione (6b) (4.07 g, 10 mmol) was reacted and
worked up as described for 7a. The yield was 3.28 g (88%) pale
yellow prisms, mp 223-225 °C (ethanol); ir: 3200-2700 b, 1640 s,
-1
1
1610 m, 1545 s cm ; H nmr (DMSO-d ): δ = 1.70 (s, 6 H, 2
6
Me), 7.20-7.50 (m, 6 H, ArH), 7.70 (d, J=2 Hz, H-1), 8.50 (d, J =
8 Hz, 1 H, H-4).
1
was 1.2 g (29 %), yellow prisms, mp 252 °C (ethanol); H nmr
Anal. Calcd. for C
H Cl NO (372.25): C, 64.53; H, 4.06;
20 15 2 2
(DMSO-d ): δ = 1.64 (s, 6 H, 2 Me), 3.63 (d, J = 8 Hz, CH ), 7.32
6
2
N, 3.76. Found: C, 64.76; H, 4.07; N, 3.66.
(s, 1 H, H-9), 7.41-7.86 (m, 9 H, ArH), 8.01-8.09 (m, 2 H, ArH),
8.79 (dd, J = 2 and 8 Hz, 1 H, H-4), 10.17 (t, J = 7 Hz, 1 H, NH).
9-Bromo-8-hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indol-6(7H)-one (7c).
Anal. Calcd. for C
H N O (392.51): C, 82.62; H, 6.16; N,
27 24 2
7.14. Found: C, 82.40; H, 6.07; N, 7.16.
A suspension of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol) and bromine
(2.5 mL) in chloroform (50 mL) was stirred for 15 minutes at
room temperature. The solvent was then removed under
reduced pressure and the residue treated with 2-propanol (20
mL) and heated to boiling. The color of the suspension
became nearly colorless and the mixture was heated for fur-
ther 5 minutes, cooled and then kept for 12 hours at 4 °C. The
precipitate was isolated by suction filtration and washed with
a small amount of cold methanol. The yield was 3.35 g (88%),
pale yellow prisms, mp 237.5-239 °C (ethanol); ir: 3200-2400
10,10-Dimethyl-7-nitro-7-phenyl-10H-pyrido[1,2-a]indole-
6,8(7H)-dione (10a).
A mixture of 8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol), concentrated
nitric acid (2.5 mL, d = 1.41) and sodium nitrite (0.05 g) in glacial
acetic acid (100 mL) was stirred at room temperature for 15 min-
utes. The reaction mixture was then poured into ice/water (1000
mL), the formed precipitate was isolated by suction filtration,
washed several times with water and air dried. The yield was 3.37
g (97%) dark yellow prisms, mp 156 °C dec. (ethanol); ir: 3070 w,
-1
1
b, 1630 s, 1610 m, 1545 s cm ; H nmr (DMSO-d ): δ = 1.80
-1
1
6
2960 w, 1720 s, 1635 s, 1600 m, 1565 a cm ; H nmr (DMSO-
(s, 6 H, 2 Me), 7.20-7.70 (m, 8 H, ArH), 8.50 (d, J = 8 Hz, 1 H,
H-4).
d ): δ = 1.30 and 1.55 (2 s, 6 H, 2 Me), 6.35 (s, 1 H, H-9), 7.15-
6
7.65 (m, 8 H, ArH), 8.10 (dd, J = 8 and 2 Hz, 1 H, H-4).
Anal. Calcd. for C
H BrNO (382.27): C, 62.84; H, 4.22; N,
20 16 2
Anal. Calcd. for C
H N O (348.36): C, 68.96; H, 4.63; N,
20 16 2 4
3.66. Found: C, 62.46; H, 4.28; N, 3.60.
8.04. Found: C, 69.31; H, 4.69; N, 8.00.
9-Bromo-2-chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6(7H)-one (7d).
2-Chloro-10,10-dimethyl-7-nitro-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (10b).
2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido-
[1,2-a]indol-6-one (4b) (3.38 g, 10 mmol) was reacted and work
up was as described for 7a. The yield was 3.70 g (89%), pale yel-
low prisms, mp 218-219.5 °C (glacial acetic acid); ir: 3200 -2500
2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-10H-
pyrido[1,2-a]indol-6-one (4b) (3.38 g, 10 mmol) was reacted and
work up was as described for 10a. The yield was 3.50 g (91%),
mp 155 °C dec. (ethanol); ir: 2960 w, 1720 s, 1665 s, 1635 s,
-1 1
-1 1
b, 1630 s, 1610 m, 1545 s cm ; H nmr (DMSO-d ): δ = 1.75 (s,
1600 m, 1565 s cm ; H nmr (DMSO-d ): δ = 1.40 and 1.60 (2 s,
6
6
6 H, 2 Me), 7.10-7.50 (m, 6 H, ArH), 7.70 (d, J = 2 Hz, 1 H, H-1),
8.50 (d, J = 8 Hz, 1 H, H-4).
6 H, 2 Me), 5.85 (s, 1 H, H-9), 7.15-7.55 (m, 7 H, ArH), 8.25 (d,
J = 8 Hz, 1 H, H-4).
Anal. Calcd. for C
H BrClNO (416.71): C, 57.65; H, 3.63;
Anal. Calcd. for C
H ClN O (382.81): C, 62.75; H, 3.95;
20 15 2
20 15 2 4
N, 3.36. Found: C, 58.04; H, 3.70; N, 3.35.
N, 7.32. Found: C, 63.05; H, 4.06; N, 7.06.

Mar-Apr 2002
Synthesis and Reactions of 10,10-Dimethyl-10H-pyrido[1,2-a]indol-6-ones
397
7-Hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]indole-
6,8(7H)-dione (11a).
(s, 1 H, OH), 7.10-7.55 (m, 6 H, ArH), 7.70 (d, J = 2 Hz, 1 H,
H-1), 8.10 (d, J = 8 Hz, 1 H, H-4).
Anal. Calcd. for C
3.96. Found: C, 67.85; H, 4.57; N, 4.01.
H ClNO (353.81): C, 67.90; H, 4.56; N,
20 16 3
Method A) A solution of 8-hydroxy-10,10-dimethyl-7-phenyl-
10H-pyrido[1,2-a]indol-6-one (4a) (3.03 g, 10 mmol) and con-
centrated nitric acid (2.5 mL, d = 1.41) in glacial acetic acid (100
mL) was heated under reflux for 15 minutes, then concentrated to
10 mL under reduced pressure and poured into ice/water (150
mL). The precipitate was isolated by suction filtration and
washed with water. The yield was 3.11 g (97%), light yellow
prisms, mp 166-169 °C (toluene).
REFERENCES AND NOTES
[1] J. v. Braun and J. Nelles, Ber. Dtsch. Chem. Ges., 70, 1767
(1937).
[2] A. T. Soldatenkov, M. V. Bagdadi, A. A. Fomichev and N.
S. Prostakov, Zh. Org. Khim., 18, 902 (1982); A. T. Soldatenkov, M. V.
Bagdadi, P. K. Radzhan, O. S. Brindka and S. L. Edogiaverie, Zh. Org.
Khim., 19, 1326 (1983).
[3] A. Ohsawa, T. Kawaguchi and H. Igeta, Chem. Lett., 1737
(1981); A. Ohsawa, T. Kawaguchi and H. Igeta, J. Org. Chem., 47,
3497 (1982).
[4] S. Ozaki, S. Mitoh and H. Ohmori, Chem. Pharm. Bull., 44,
2020 (1996).
[5] R. A. Khorkhe, S. A. Soldatova, A. T. Soldatenkov, M. A.
Ryashentseva and N. S. Prostakov, Izv. Akad. Nauk. SSSR Ser. Khim.,
1413 (1991).
[6] W. Stadlbauer, E.-S. Badawey, G. Hojas , P. Roschger and
T. Kappe, Molecules, 6, 345 (2001).
Method B) A solution of 10,10-dimethyl-7-nitro-7-phenyl-
10H-pyrido[1,2-a]indole-6,8(7H)-dione (10a) (0.35 g, 1.0 mmol)
in glacial acetic acid (10 mL) was heated under reflux for 10 min-
utes, then concentrated to 1.0 mL under reduced pressure and
poured into ice/water (10 mL). The precipitate was isolated by
suction filtration and washed with water. The yield was 0.31 g
(97%), the mp and tlc was identical with the product of Method A.
-1 1
Ir: 3450 s, 2970 w, 1730 m, 1655 m, 1635 s, 1605 m cm ; H
nmr (CDCl ): δ = 1.50 and 1.55 (2 s, 6 H, 2 Me), 4.30 (s, 1 H,
3
OH), 5.85 (s, 1 H, H-9), 7.10-7.60 (m, 8 H, ArH), 8.20 (dd, J = 8
and 2 Hz, 1 H, H-4).
Anal. Calcd. for C
H NO (319.36): C, 75.22; H, 5.37; N,
20 17 3
4.39. Found: C, 75.26; H, 5.36; N, 4.39.
[7] R. Laschober and W. Stadlbauer, Lieb. Ann. Chem., 1083
(1990).
[8] W. Stadlbauer, R. Laschober and T. Kappe, Monatsh.
Chem., 122, 853 (1991).
2-Chloro-7-hydroxy-10,10-dimethyl-7-phenyl-10H-pyrido[1,2-a]-
indole-6,8(7H)-dione (11b).
[9] W. Stadlbauer and T. Kappe, Synthesis, 833 (1981).
[10] L.-F. Tietze and T. Eicher, Reaktionen und Synthesen im
Organischen Praktikum, G. Thieme, Stuttgart, New York 1981, p. 288.
[11] J. S. Lindsey, P. A. Brown and D. A. Siesel, Tetrahedron,
45, 4845 (1989); R. M. Letcher, D. W. M. Sin and K.-K. Cheung, J.
Chem. Soc., Perkin Trans. 1, 939 (1993).
[12] H. Laas, A. Nissen and A. Nürrenbach, Synthesis, 958
(1981); S. Arakawa, H. Kondo and J. Seto, Chem. Lett., 1805 (1985).
[13] T. Kappe, Bis(2,4,6-trichlorophenyl) malonate, in
Encylopedia of Reagents for Organic Synthesis, Vol. 1, 577, L. A.
Paquette, ed; John Wiley & Sons, Chichester - New York - Brisbane -
Toronto - Singapore, 1995.
Method A) 2-Chloro-8-hydroxy-10,10-dimethyl-7-phenyl-
10H-pyrido[1,2-a]indol-6-one (4b) (3.38 g, 10 mmol) was
reacted and work up was as described for 11a. The yield was 3.45
g (98%), light yellow prisms, mp 206-208 °C (toluene).
Method B) 2-Chloro-10,10-dimethyl-7-nitro-7-phenyl-10H-
pyrido[1,2-a]indole-6,8(7H)-dione (10b) (0.38 g, 10 mmol)
was reacted and work up was as described for 11b. The yield
was 0.35 g (98%); the mp and tlc was identical with the product
of Method A.
-1
1
Ir: 3470 m, 2870 w, 1705 s, 1670 s, 1650 s, 1600 w cm ; H
nmr (DMSO-d ): δ = 1.55 (s, 6 H, 2 Me), 6.0 (s, 1 H, H-9), 6.50
6