Unique 11b-substituted indeno[2,1-c]quinolin-6-one ring system

Article abstract of DOI:10.1081/SCC-200051700

A unique 11b-substituted indeno[2,1-c]quinolin-6-one ring system was prepared in good yield and the structure of the product was unequivocally determined by X-ray crystallography.

Full text of DOI:10.1081/SCC-200051700

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Unique 11b‐Substituted
Indeno[2,1‐c]quinolin‐6‐one Ring System
Lorna H. Mitchell a & Brian Samas a
a Department of Chemistry and Department of Pharmaceutical Sciences ,
Pfizer Global R&D , Ann Arbor, Michigan, USA
Published online: 21 Aug 2006.
To cite this article: Lorna H. Mitchell & Brian Samas (2005) Unique 11b‐Substituted
Indeno[2,1‐c]quinolin‐6‐one Ring System, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:7, 955-959, DOI: 10.1081/SCC-200051700
To link to this article: http://dx.doi.org/10.1081/SCC-200051700
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Synthetic Communicationsw, 35: 955–959, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051700
Unique 11b-Substituted
Indeno[2,1-c]quinolin-6-one Ring System
Lorna H. Mitchell and Brian Samas
Department of Chemistry and Department of Pharmaceutical Sciences,
Pfizer Global R&D, Ann Arbor, Michigan, USA
Abstract: A unique 11b-substituted indeno[2,1-c]quinolin-6-one ring system was
prepared in good yield and the structure of the product was unequivocally determined
by X-ray crystallography.
Keywords: Indenoquinolone, X-ray, crystal structure
Some indeno[2,1-c]quinolin-6-ones have been reported to be potent antitumor
agents.[1] However, there have been few syntheses of this ring system in the
literature.[1–4] Here we report the synthesis of an indeno[2,1-c]quinolone
that is uniquely substituted in the ring-junction position 11b (2).
During an attempted synthesis of the 8-acetyl quinolone 1 in a two-step
process (Scheme 1) by Conrad–Limpach quinolone synthesis,[5] approxi-
mately 10% of an unidentified product was obtained.† The NMR and MS
spectra and microanalysis data all indicated that this product had incorporated
toluene in addition to the two starting materials. The identity of this
Received in the USA December 9, 2004
Address correspondence to Lorna H. Mitchell, Department of Chemistry and
Department of Pharmaceutical Sciences, Pfizer Global R&D, 2800 Plymouth Road,
Ann Arbor, MI 48105, USA. E-mail: lorna.mitchell@pfizer.com
†This product was cleanly obtained as a pale yellow precipitate after the crude
reaction mixture had been poured onto ice.

956
L. H. Mitchell and B. Samas
Scheme 1. (a) Toluene, reflux; conc. H2SO4, 1008C.
product was shown to be 9,11b-dimethyl-7-trifluoromethyl-5,11b-dihydro-
indeno[2,1-c]quinolin-6-one (2) by X-ray crystallography. An Oak Ridge
Thermal Ellipsoid Plot (ORTEP) drawing of the final crystallographic
model is shown in Figure 1.‡
To understand the formation of this interesting product and to determine
if its yield could be increased, the reactions were repeated stepwise. The
intermediate amide was isolated as the hydrate 3 from reflux of 2-amino-
acetophenone and ethyl 4,4,4-trifluoroacetoacetate in toluene (Scheme 2).
To ensure that no toluene remained in the amide sample (3), it was repeatedly
concentrated from hexanes and then recrystallized from dichloromethane.
When a solution of amide 3 in toluene was heated in concentrated
sulfuric acid the yield of the indeno[2,1-c]quinolone 2 was increased to
72%. If the reaction was repeated without the addition of toluene the aldol
product 4 was formed exclusively. Treatment of 4 with toluene and sulfuric
acid failed to give any 2, indicating that the dehydrated aldol product
is not an intermediate in the formation of the indeno[2,1-c]quinolone
(Scheme 2).
These observations suggest that a likely mechanism for formation of the
indeno[2,1-c]quinolone (2) is as shown in Scheme 3, where initial cyclization
is followed by dehydration to give a tertiary carbocation (6). In the absence of
a nucleophile, 6 gives the dehydrated aldol product 4, however, when toluene
is present nucleophilic addition of this affords a 4-phenylquinolone (7).
Interestingly, the isomeric product that would result from nucleophilic
addition at the ortho position of toluene was not seen.
‡For a single crystal (0.40 ꢀ 0.25 ꢀ 0.25 mm3) of 2 (racemate), grown from ethyl
acetate/methanol, X-ray intensity data were collected at 299 K on a Bruker-AXS
APEX diffractometer. A total of 3526 independent reflections were observed. Laue
symmetry revealed a triclinic crystal system with unit cell dimensions: a ¼
6.6089(10), b ¼ 8.5087(13), c ¼ 15.193(2) A8 and angles a ¼ 98.289(3)8, b ¼
101.993(3)8, g ¼ 107.184(2)8. The space group was assigned as P-1. The structure
was solved by direct methods using the SHELXTL suite v6.10. All nonhydrogen
atoms were refined with anisotropic thermal parameters. Hydrogen atoms located on
heteroatoms were found from the Fourier difference map. All remaining hydrogen
atoms were fixed in idealized positions. The final model refined to a goodness fit of
1.033 with R1 ¼ 0.0590 (I . 2s) and wR2 ¼ 0.1438.

Unique Substituted Indenoquinolone Ring System
957
Figure 1. ORTEP drawing of 2.
Intermediate 7 can then cyclize by intramolecular electophilic aromatic
substitution, similar to a previously reported mechanism for indeno[2,1-c]
quinolone synthesis from 3-vinyl-4-phenylquinolines.[3] Dehydration then
delivers the isolated indeno[2,1-c]quinolone 2.
When the toluene was replaced with either benzene or anisole, only the
aldol product (4) was observed, presumably because of the weaker nucleo-
phility of benzene and protonated anisole.
This indeno[2,1-c]quinolin-6-one (2) is unique because it is substituted
in the ring junction, at position 11b. The methyl group in this position is
derived from the acetyl group of the starting 2-aminoacetophenone. Perhaps
analogs with different substitution at this center could be obtained by
starting with appropriately substituted ketones, and it may also be feasible
to modify the trifluoromethyl substituent by reaction with appropriately
substituted b-ketoesters.
Scheme 2. (a) Toluene, reflux; (b) conc. H2SO4, 1008C; (c) conc. H2SO4, toluene,
1008C.

958
L. H. Mitchell and B. Samas
Scheme 3.
EXPERIMENTAL
N-(2-Acetyl-phenyl)-4,4,4-trifluoro-3,3-dihydroxy-butyramide (3)
A mixture of 20-aminoacetophenone (5.0 g, 37 mmol) and 4,4,4-trifluoroa-
ceoacetate (8.1 mL, 55.5 mmol) in toluene (50 mL) was heated at reflux
overnight. The solvent was removed on the rotovap; the yellow oily residue
was concentrated from hexanes three times. Upon standing a white solid
crystallized, dichloromethane was added, and the solid collected by filtration.
The mother liquor was concentrated and then dichloromethane and hexane
were added and the resulting white solid was collected by filtration.
The material was combined to give N-(2-acetyl-phenyl)-4,4,4-trifluoro-3,3-
dihydroxy-butyramide (3) as a white solid, 8.3 g (77%), dH (400 MHz,
DMSO-d6) 11.42 (s, 1H), 8.35 (d, J ¼ 8.5 Hz, 1H), 7.96 (dd, J ¼ 8.1,
1.5 Hz, 1H), 7.56 (ddd, J ¼ 8.5, 8.1, 1.5 Hz, 1H), 7.38 (s, 2H), 7.20 (ddd,
J ¼ 8.5, 8.1, 1.5 Hz), 2.74 (s, 2H), 2.59 (s, 3H). MS (APCI) m/z 274
(M þ 1–18). Anal. calcd. for C12H12F3NO4: C, 49.49; H, 4.15; N, 4.81%.
Found: C, 49.70; H, 4.08; N, 4.75%.
9,11b-Dimethyl-7-trifluoromethyl-5,11b-dihydro-
indeno[2,1-c]quinolin-6-one (2)
N-(2-Acetyl-phenyl)-4,4,4-trifluoro-3,3-dihydroxy-butyramide (3) was heated
at 908C in toluene (2 mL) until dissolved. Concentrated sulfuric acid (3 mL)
was added and the reaction mixture heated at 908C with rapid stirring for
2 h. The mixture was poured into an ice-water mixture and the resulting
yellow solid was collected by filtration. The crude product was triturated
with methanol to give 9,11b-dimethyl-7-trifluoromethyl-5,11b-dihydro-
indeno[2,1-c]quinolin-6-one (2) as a pale yellow solid, 0.18 g (72%),

Unique Substituted Indenoquinolone Ring System
959
dH (400 MHz, DMSO-d6) 10.80 (s, 1H), 7.99 (d, J ¼ 7.6 Hz, 1H), 7.49 (dd,
J ¼ 8.1, 1.2 Hz, 1H), 7.44–7.39 (m, 2H), 7.21 (td, J ¼ 7.6, 1.5 Hz, 1H),
6.98–6.94 (m, 2H), 2.39 (s, 3H), 1.48 (s, 3H); dC (400 MHz, DMSO-d6)
160.5, 147.2, 145.1, 138.7, 137.8, 136.8, 130.3, 130.0, 127.4, 126.0, 123.7,
123.6, 117.4, 55.5, 25.1, 21.6. MS (APCI) m/z 330 (M þ 1). Anal. calcd.
for C19H14F3NO þ 0.2 H2O: C, 68.55; H, 4.36; N, 4.21%. Found: C, 68.30;
H, 4.23; N, 4.08%.
4-Methyl-3-(2,2,2-trifluoro-acetyl)-1H-quinolin-2-one (4)
A mixture of N-(2-acetyl-phenyl)-4,4,4-trifluoro-3,3-dihydroxy-butyramide
(3) and concentrated sulfuric acid (2 mL) was heated at 100 8C for 1 h. The
reaction mixture was poured into an ice-water mixture and the resulting
pale yellow solid was collected by filtration. The crude product was triturated
with diethyl ether to give 4-methyl-3-(2,2,2-trifluoro-acetyl)-1H-quinolin-2-
one (4) as a pale yellow solid, 0.15 g (86%), dH (400 MHz, DMSO-d6)
12.32 (s, 1H), 7.88 (dd, J ¼ 8.2, 0.9 Hz, 1H), 7.64 (ddd, J ¼ 8.2, 8.2,
1.1 Hz, 1H), 7.35 (dd, J ¼ 8.2, 0.9 Hz, 1H), 7.29 (ddd, 8.2, 8.2, 1.1 Hz, 1H),
2.45 (s, 3H). MS (APCI) m/z 256 (M þ 1). Anal. calcd. for
C12H8F3NO2 þ 0.75 H2O: C, 53.64; H, 3.56; N, 5.21%. Found: C, 53.52;
H, 3.17; N, 5.23%.
REFERENCES
1. Okazaki, S.; Asao, T.; Wakida, M.; Ishida, K.; Washinosu, M.; Utsugi, T.;
Yamada, Y. Preparation and formulation of indenoquinolines as antitumor agents.
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2. Afsah, E.-S.; Zimaity, T. Bull. Chem. Soc. Jpn 1979, 52, 3092.
3. Paramasivam, K.; Veeramani, K.; Ramasamy, K.; Shanmugam, P. Synthesis 1978,
12, 889.
4. Perold, G. W.; Reiche, F. V. K. J. S. Afr. Chem. Inst. 1957, 10, 5–10.
5. Conrad, M.; Limpach, L. Ber. Dtsch Chem. Ges. 1891, 20, 944.