Unusual friedlander reactions: A route to novel quinoxaline-based heterocycles

Article abstract of DOI:10.1021/ol301550e

Acid catalyzed Friedlander reactions of a number of 2,3-dihydro-1H- cyclopenta[b]quinoxaline-1-ones with 2-aminobenzaldehyde yield, unexpectedly, 8H-indolo[3,2-a]phenazine and quinolino[2,3-c]cyclopentadienone[2,3-b] quinoxalines, the structures of derivatives of which were confirmed by X-ray crystallography. Easy routes to novel quinoxaline-based indoles, quinolones, and quinoxaline-1,4-dioxides are reported, and proposed mechanisms for the unexpected products are discussed.

Full text of DOI:10.1021/ol301550e

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3704–3707
Unusual Friedlander Reactions: A Route
to Novel Quinoxaline-Based Heterocycles
Tharallah A. Shoker,† Khaled I. Ghattass,† James C. Fettinger,‡ Mark J. Kurth,*,‡ and
Makhluf J. Haddadin*,†
Department of Chemistry, American University of Beirut, Beirut, Lebanon, and
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
haddadin@aub.edu.lb; mjkurth@ucdavis.edu
Received June 5, 2012
ABSTRACT
Acid catalyzed Friedlander reactions of a number of 2,3-dihydro-1H-cyclopenta[b]quinoxaline-1-ones with 2-aminobenzaldehyde yield,
unexpectedly, 8H-indolo[3,2-a]phenazine and quinolino[2,3-c]cyclopentadienone[2,3-b]quinoxalines, the structures of derivatives of which
were confirmed by X-ray crystallography. Easy routes to novel quinoxaline-based indoles, quinolones, and quinoxaline-1,4-dioxides are
reported, and proposed mechanisms for the unexpected products are discussed.
Indoloquinoxalines are well-known heterocycles gener-
ally prepared through the reaction of o-phenylenediamine
with isatin.1 In contrast, quinoxaline-based quinolines and
quinoxaline-1,4-dioxides are either rare or unknown in the
chemical literature.2 Recent reviews of the biological activ-
ities of indoles, quinolines, and quinoxalines point out
their medicinal chemistry importance.3 Indeed, quinoxa-
lines and their 1,4-dioxides have shown activity as anti-
cancer, antifungal, antibacterial, and anti-inflammatory
agents.4 The biological effects of quinoxalines as inhibitors
of platelet-derived growth factor receptor tyrosine kinase
[PDGF-RTK] are of particular interest, and several were
reported to be superior in this regard to quinolines and
indoles.5
The objective of the work reported here was to develop
synthetic routes to novel quinoxaline-based indoles, qui-
nolines, and quinoxaline-1,4-dioxides. We envisaged that
introduction of a ketomethylene (ÀCOCH2À) moiety at
† American University of Beirut.
‡ University of California.
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Org. Lett. 2012, 14, 740. (b) Dawtatabadi, R.; Khataj, A.; Rahimian, S.;
Montazeri, M.; Amini, M.; Shahverdi, A.; Mahjub, E. Synth. Commun.
2011, 41, 1650. (c) Verma, A. K.; Jeha, R. R.; Sankar, V. K.; Aggarwal,
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Venkateswararao, A.; Thomas, K. R. J. J. Org. Chem. 2011, 76, 4571. (e)
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Ankati, H.; Biehl, E. R. ARKIVOC 2011, No. ix, 94.
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37, 4452. (b) Page, S. E.; Flood, A.; Gordon, K. C. J. Chem. Soc., Dalton
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(4) (a) Haddadin, M., J.; El-Khatib, M.; Shoker, T. A.; Beaver,
B. M.; Olmstead, M. M.; Fettinger, J. C.; Farber, K. M.; Kurth, M. J.
J. Org. Chem. 2011, 76, 8421 and references cited therein. (b) Sarges, R.;
Howard, H. R.; Browne, R. C.; Label, L. A.; Seymour, P. A. J. Med.
Chem. 1990, 33, 2240. (c) Kinashi, H.; Otten, S. L; Dunkan, J. S.;
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Roller, A.; Galanski, M.; Reithofer, M.; Berger, W.; Keppler, B. K. J.
Med. Chem. 2012, 55, 3398. (b) Husain, A.; Medhesia, D. J. Pharm. Res.
2011, 4, 924. (c) Gonzales, M.; Cerecetto, H.; Monge, A. Top. Heterocyl.
Chem. 2007, 11, 179. (d) Kumar, S.; Bawa, S.; Gupta, H. Mini-Rev. Med.
Chem. 2009, 9, 1648. (e) Hradil, P.; Hlavac, J.; Soural, M.; Hajduch, M.;
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r
10.1021/ol301550e
Published on Web 07/11/2012
2012 American Chemical Society

C2 of a quinoxaline would access a number of heterocycles
ligated to the quinoxaline ring system. A series of steps
involving a Beirut reaction6a (1 f 2À4) followed by
Polonovski rearrangement6 (2À4 f 5À7), base hydrolysis
(5/7 f 8/9), and HOAc-mediated oxidation/reduction
(8/9 f 13/14) gives the expected 1H-cyclopolymethylene-
[b]quinoxaline-1-one starting materials for this study. In
contrast, 6 leads to 12, which undergoes two consecutive
base-mediated tautomerizations followed by a N1,N4-
dehydration and air oxidation of the resulting 5,10-dihy-
drophenazine intermediate to yield 1-hydroxyphenazine
(15a; Scheme 1).
mechanism proposed by Bjorsvik et al. for the deoxygena-
tion of N-heteroarene N-oxides.7
Scheme 2
Scheme 1
Having secured quinoxalino ketone 13, we attempted
the Friedlander reaction6a of it with 2-aminobenzaldehyde
under acid catalysis; 13 decomposes under basic condi-
tions. We were surprised to find that the expected quino-
linoquinoxaline 16 (yellow) was formed (Scheme 3), but in
only trace amounts, and that the major products were
indolophenazine 17 (20%, yellow) and quinolinoquinox-
1
alinone 18 (50%, orange). The H NMR of 17 indicated
Scheme 3
Somewhat surprisingly, saponification of hydroxyqui-
noxaline 5 or 7 leads unexpectedly to quinoxaline N-oxide
10 or 11, respectively, in modest yields (10, 27%; 11, 24%).
While the exact details of how these unique dehydroxyla-
tion reactions proceed are not clear, we speculate that
methanol plays a pivotal role because this reaction does
not take place in tert-butyl alcohol/KOH. We propose a
methoxide-based mechanism for this reaction (Scheme 2),
but a radical mechanism cannot be excluded. This spec-
ulation is analogous, in its initial steps, to the recent
that a rearrangement had taken place as the spectrum
showed two sharp doublets at 8.00 and 8.16 ppm, which
evidenced only 1,2-splitting and, therefore, independence
from other neighboring protons. Initial mechanistic con-
sideration suggested that the structure of 17 might be
(6) (a) Mundy, B. P.; Ellerd, M. G.; Favaloro, F. G., Jr. Name
Reactions and Reagents in Organic Synthesis, 2nd ed.; Wiley-Interscience:
NJ, 2005. (b) Albini, A.; Pietra, S. J. Heterocyclic N-Oxides; CRC Press:
Boston, 1991.
(7) Bjorsvik, H.-R.; Gambarotti, C.; Jensen, V. R.; Gonzalez, R. R.
J. Org. Chem. 2005, 70, 3218.
Org. Lett., Vol. 14, No. 14, 2012
3705

indolophenazine 19; however, X-ray crystallography
(Figure 1) left no doubt that this indolophenazine has
structure 17. In addition to indolophenazine 17, quinoli-
noquinoxaline 18 was also formed as confirmed by X-ray
crystallography (Figure 2).
Scheme 4
Figure 1. X-ray crystallography of 2,3-dimethyl-8H-indolo-[3,2-a]-
phenazine (17).
This unique rearrangement in a Friedlander-like reac-
tion is unprecedented, constituting a simple and direct
method for the synthesis of the novel parent ring system
as well as substituted indolophenazines 17a/b from keto
quinoxaline 13a/b. Moreover, the second products of this
reaction, quinolinoquinoxalines 18a/b, are also previously
unknown heterocycles.
Figure 2. X-ray crystallography of 3,4-dimethylquinolino[2,3-c]-
cyclopentadienone[2,3-b]quinoxalines (18).
Mechanistic steps to explain the formation of these
unexpected products (17 and 18) are presented in
Scheme 4. We suggest that both arise from common inter-
mediate [20], which is formed from 13 through two con-
secutive 1,3-prototropic shifts, the second of which is
induced by conjugation with the carbonyl group. The
relative higher yield of quinolinoquinoxaline 18 (50% vs
20% for 17) can be rationalized on the basis that inter-
mediate [20] undergoes oxidative (air) aromatization of the
dihydroquinoxaline moiety to produce the highly reactive
cylcopentadieneone-like intermediate [21]. This intermediate
performs a 1,4-addition of 2-aminobenzaldehyde followed
by aldol condensation, dehydration, and air oxidation to
give quinolinoquinoxaline 18. A competing 1,2-addition of
2-aminobenzaldehyde onto the carbonyl group of inter-
mediate [20] followed by aldol condensation and a re-
arrangement eventually leads to indolophenazine 17.
As outlined in Scheme 5, we next turned our focus to the
synthesis of novel quinoxaline-based indolo-, quinolino-,
and quinoxalino-1,4-dioxides from 14. It should be added
that although quinoxaline 14 can be synthesized from 9
(77% yield; Scheme 1), it can also be prepared directly
from 7 under base catalysis (KOH/MeOH) in 40% yield.
Reaction of quinoxaline 14 with phenylhydrazine (Fischer
indole reaction6a), 2-aminobenzaldehyde (Friedlander
reaction6a), and benzofuran oxide (Beirut reaction6a)
yielded 12,13,14-trihydroindolo[2,3-c]cyclohepta[2,3-b]-
quinoxaline (22, 74%), 12,14,15-trihydroquinolino[2,3-
c]cyclohepta[2,3-b]quinoxaline (23, 68%), and 13,14,15-
trihydroquinoxalino[2,3-c]cyclohepta[2,3-b]quinoxaline 1,6-
dioxide (24, 65%), respectively, in good yields.
In conclusion, we have synthesized a variety of novel
heterocycles, which include indolophenazines, quinolino-
quinoxalinones, indoloquinoxalines, quinolinoquinoxalines,
3706
Org. Lett., Vol. 14, No. 14, 2012

outcome of their subsequent base-mediated hydrolysis
reactions (5/7 f 8/9 vs 6 f [12] f 15a; Scheme 1). A similar
C-ring dichotomy is noted in the Friedlander reactions of 13
(f 17/18; Scheme 3) vs 14 (f 23; Scheme 5).
Scheme 5
Acknowledgment. This work is dedicated to Professor
Musa Z. Nazer of the University of Jordan on his 75th
birthday. We thank the National Science Foundation
(Grant 0840444) for the dual source X-ray diffractometer
and the National Science Foundation (CHE-0910870)
and the National Institutes of Health (GM089153) for
generous financial support of this work.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, and LC/MS) for all new compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
and quinoxalinoquinoxaline 1,4-dioxides. The work pre-
sented here also underscores how the C-ring size in Polo-
novski rearrangement products dramatically affects the
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3707