Reaction of α-oxoketene-N,S-arylaminoacetals with Vilsmeier reagents: An efficient route to highly functionalized quinolines and their benzo/hetero-fused analogues

Article abstract of DOI:10.1021/jo034053l

A simple, highly efficient, and regioselective synthesis of functionalized quinolines through Vilsmeier cyclization of a variety of α-oxoketene-N,S-anilinoacetals has been reported. The cyclization is found to be facile with N,S-acetals bearing strongly a

Full text of DOI:10.1021/jo034053l

Reaction of r-Oxoketene-N,S-arylaminoacetals with Vilsmeier
Reagents: An Efficient Route to Highly Functionalized Quinolines
and Their Benzo/Hetero-Fused Analogues‡
P. K. Mahata, C. Venkatesh, U. K. Syam Kumar, H. Ila,* and H. Junjappa*
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
hila@iitk.ac.in
Received January 16, 2003
A simple, highly efficient, and regioselective synthesis of functionalized quinolines through Vilsmeier
cyclization of a variety of R-oxoketene-N,S-anilinoacetals has been reported. The cyclization is found
to be facile with N,S-acetals bearing strongly activating groups on aniline, whereas yields of
quinolines are moderate in other cases. The reaction could also be extended for the synthesis of
substituted tricyclic benzo[h]quinoline, pyrido[2,3-h]quinoline, 4,7-diphenylphenanthroline, and
tetracyclic quino[8,7-h]quinoline by performing a Vilsmeier reaction on N,S-acetals derived from
1-naphthylamine, m-phenylenediamine, o-phenylenediamine, and 1,5-diaminonaphthalene, re-
spectively. A few of the newly synthesized quinolines are subjected to further transformation to
afford 2-unsubstituted (Raney-Ni/Ethanol), quinoline-5,8-quinone (NBS/H2SO4), or 2-alkyl/aryl
aminoquinolines through sequential m-CPBA oxidation to the corresponding (2-methylsulfonyl)-
quinoline followed by replacement with appropriate amines. Similarly, cycloannulation of a few
2-methylthio-3-benzoylquinolines with hydrazine hydrate under microwave irradiation afforded
the corresponding substituted and fused pyrazolo[3,4-b]quinolines in excellent yields, whereas
TBTH/AIBN-mediated cyclization of the corresponding 3-(2-bromobenzoyl)-2-methylthioquinolines
yielded the corresponding benzothiopyrano-fused quinolines through radical translocation.
Introduction
tant role in many fields of chemistry.3 Although numer-
ous elegant syntheses have been developed for quino-
lines4-6 and their benzo/hetero-fused derivatives,7 be-
cause of their great importance, it is still challenging to
explore new and efficient synthetic routes for this class
of compounds, particularly those with wide general
applicability to achieve more flexible substitution pattern.
Among the various routes available for the synthesis
of functionalized quinolines, the “Vilsmeier approach”8
involving reaction of enamines,9a N-arylacetamide,9b-f or
tautomeric imines10 with Vilsmeier reagents has only
recently been explored. Alternatively, a “reverse Vils-
meier approach”11 involving ring closure of Vilsmeier
reagent derived from N-aryl-N-methylformamide with
Functionalized quinolines and their benzo/hetero-fused
analogues represent an important class of organic mol-
ecules that have attracted a great deal of attention from
synthetic as well as medicinal chemists because of their
presence in numerous natural products along with the
wide spectrum of physiological activities displayed by
these class of compounds.1 Thus, substituted quinolines
have found attractive applications as pharmaceuticals
(antimalarials, antibacterials, protein kinase inhibitors),
NADH models, and agrochemicals as well as being
general synthetic blocks.1b Similarly, the benzo- and
hetero-fused quinolines are known to bind DNA with high
affinity, inhibit DNA topoisomerase I, and display cyto-
toxic and antitumor activities.2 On the other hand, 1,10-
phenanthrolines3 have been used as important ligands
for vast amount of metal complexes that play an impor-
(4) (a) Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, Chapter 5.05, p 167.
(5) For recent quinoline synthesis from anilines: (a) Cho, C. S.; Oh,
B. H.; Kim, J. S.; Kim, T.-J.; Shim, S. C. Chem. Commun. 2000, 1885.
(b) Tom, N. J.; Ruel, E. M. Synthesis 2001, 1351. (c) Baraznenok, I. L.;
Nenajdenko, V. G.; Balenkova, E. S. Eur. J. Org. Chem. 1999, 937. (d)
Cho, I.-S.; Gong, L.; Muchowski, J. M. J. Org. Chem. 1991, 56, 7288.
(e) Matsugi, M.; Tabusa, F.; Minamikawa, J-i. Tetrahedron Lett. 2000,
41, 8523. (f) Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett. 2000,
41, 531. (g) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.
Tetrahedron 1999, 55, 5947. (h) Charpentier, P.; Lobregat, V.; Le-
vacher, V.; Dupas, G.; Queguiner, G.; Bourguignon, J. Tetrahedron Lett.
1998, 39, 4013. (i) Schlosser, M.; Keller, H.; Sumida, S-i.; Yang, J.
Tetrahedron Lett. 1997, 38, 8223. (j) Mahanty, J. S.; De, M.; Das, P.;
Kundu, N. G. Tetrahedron 1997, 53, 13397. (k) Tokuyama, H.; Sato,
M.; Ueda, T.; Fukuyama, T. Heterocycles 2001, 54, 105. (l) Wiebe, J.
M. Caille, A. S.; Trimble, L.; Lan, C. K. Tetrahedron 1996, 52, 11705.
(m) Kar, G. K.; Karmakar, A. C.; Makur, A.; Ray, J. K. Heterocycles
1995, 41, 911.
‡ Dedicated to Professor Alan R. Katritzky on the occasion of his
75th birthday.
* To whom correspondence should be addressed. Fax: 91-0512-
2597436, 91-0512-2590260.
(1) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Balasubra-
manian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, Chapter 5.06, p 245.
(2) Fused quinolines biological activity: (a) Spicer, J. A.; Gamage,
S. A.; Atwell, G. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. J. Med.
Chem. 1997, 40, 1919. (b) Lyon, M. A.; Lawrence, S.; William, D. J.;
Jackson, Y. A. J. Chem. Soc., Perkin Trans. 1 1999, 437.
(3) (a) Schmittel, M.; Ammon, H. Eur. J. Org. Chem. 1998, 785 and
references therein. (b) Gladiali, S.; Chelucci, G.; Mudadu, M. S.;
Gastaut, M.-A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400.
10.1021/jo034053l CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003
3966
J. Org. Chem. 2003, 68, 3966-3975

Reactions of R-Oxoketene-N,S-arylaminoacetals
electron-rich olefins to give N-methylquinolinium salts
has also been developed. Recently, Katritzky has re-
ported10 a highly regioselective one-pot synthesis of 2,3-
diakyl/fused quinolines involving cyclocondensation of
imines (via the corresponding tautomeric secondary
enamines) with a novel Vilsmeier reagent derived from
N-(trimethylsilyl)benzotriazole, DMF, and SOCl2. All
these methods, however, suffer from some limitations
such as requiring a large excess of POCl3, nonavailability
of highly functionalized imine (or enamine) precursors,
or being restricted only for the synthesis of N-alkylquino-
linium salts. We have been engaged for several years in
exploring reactivity and synthetic applications of polar-
ized ketene N,S- and N,N-acetals representing a new
class of highly versatile functionalized enamines.12-14 The
easy accessibility of these intermediates either via direct
nucleophilic displacement on polarized ketene S,S-acetals
by a wide variety of primary and secondary amines15 or
directly from active methylene compounds12a makes them
attractive candidates for their further synthetic elabora-
tion. Besides, these intermediates are stable at room
temperature and can be stored indefinitely without any
decomposition. We have demonstrated in our earlier work
that a large variety of substituted and fused nitrogen and
sulfur heterocycles with diverse structural features and
functionalities are accessible from these precursors
through tuning of their reactivity pattern by choice of
various amines, active methylene compounds, as well as
other reactive partners.12 In continuation of these stud-
ies,13,14 we now report the reaction of R-oxoketene N,S-
acetals with Vilsmeier reagents providing a versatile
route to highly functionalized quinolines and their benzo-
and hetero-fused analogues.
(6) Other important approaches to quinolines (a) Cho, C. S.; Kim,
B. T.; Kim, T. J.; Shim, S. C. Chem. Commun. 2001, 2576. (b) Kim, J.
N.; Lee, H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42, 3737.
(c) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Synlett 1997, 445. (d)
Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1997, 70, 965. (e) Crousse, B.; Begue, J.-P.; Bonnet-Delpon,
D. J. Org. Chem. 2000, 65, 5009. (f) Brandsma, L.; Nedolya, N. A.;
Verkruijsse, H. D.; Owen, N. L.; Li, D.; Trofimov, B. A. Tetrahedron
Lett. 1997, 38, 6905. (g) Wilson, N. S.; Sarko, C. R.; Roth, G. P.
Tetrahedron Lett. 2002, 43, 581. (h) Ramana Rao, V. V.; Wentrup, C.
J. Chem. Soc., Perkin Trans. 1 1998, 2583. (i) Rossi, E.; Abbiati, G.;
Arcadi, A.; Marinelli, F. Tetrahedron Lett. 2001, 42, 3705. (j) Wang,
M.-X.; Liu, Y.; Huang, Z.-T. Tetrahedron Lett. 2001, 42, 2553.
(7) (a) Campos, P. J.; Anon, E.; Malo, M. C.; Tan, C.-Q.; Rodriguez,
M. A. Tetrahedron 1998, 54, 6929. (b) Wrobel, Z. Tetrahedron 1998,
54, 2607. (c) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron
Lett. 2001, 42, 2907. (d) Janin, Y. L.; Bisagni, E.; Carrez, D. J.
Heterocycl. Chem. 1993, 30, 1129. (e) Hsiao, Y.; Rivera, N. R.; Yasuda,
N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101. (f) Alvarez,
M.; Antoniela Bros, M.; Gras, G.; Ajana, W.; Joule, J. A. Eur. J. Org.
Chem. 1999, 1173. (g) Wrobel, Z. Tetrahedron Lett. 2001, 42, 5537. (h)
Mackay, S. P.; Meth-Cohn, O. Adv. Heterocycl. Chem. 1997, 67, 345.
(i) Charmantray, F.; Demeunynck, M.; Lhomme, J.; Duflos, A. J. Org.
Chem. 2001, 66, 8222. (j) Demeunynck, M.; Moucheron, C.; Mesmaeker,
A. K.-D. Tetrahedron Lett. 2002, 43, 261.
(8) For a general review on the chemistry of Vilsmeier reagents,
see: (a) Marson, C. M.; Giles, P. I. Synthesis Using Vilsmeier Reagents;
CRS: Boca Raton, 1994. (b) Meth-Cohn, O. Heterocycles 1993, 39, 539.
(c) Meth-Cohn, O.; Stanforth, S. P. In Comprehensive Organic Syn-
thesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol.
2, p 777. (d) Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem.
1987, 31, 207. (d) Marson, C. M. Tetrahedron 1992, 48, 3659,
Tetrahedron Report No. 312.
(9) (a) Adams, D. R.; Dominguez, J. N.; Perez, J. A. Tetrahedron
Lett. 1983, 24, 517. (b) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J.
Chem. Soc., Perkin Trans. 1 1981, 1520, 1531. (c) Meth-Cohn, O.
Heterocycles 1993, 35, 539. (d) Kerry, M. A.; Boyd, G. W.; Mackay, S.
P.; Meth-Cohn, O.; Platt, L. J. Chem. Soc., Perkin Trans. 1 1999, 2315.
(e) Alonso, M. A.; Ubeda, J. I.; Avendano, C.; Menendez, J. C.;
Villacampa, M. Tetrahedron 1993, 49, 10997. (f) Ali, M. M.; Tasneem,
Rajanna, K. C.; Sai Prakash, P. K. Synlett 2001, 251.
(10) Katritzky, A. R.; Arend, M. J. Org. Chem. 1998, 63, 9989.
(11) (a) Meth-Cohn, O.; Taylor, D. L. Tetrahedron 1995, 51, 12869.
(b) Meth-Cohn, O.; Taylor, D. L. Tetrahedron Lett. 1993, 34, 3629. (c)
For related approach see also Katritzy, A. R.; Semenzin, D.; Yang, B.;
Pleynet, D. P. M. J. Heterocycl. Chem. 1998, 35, 467 and references
therein. (d) Hibino, S.; Sugino, E. Heterocycles 1987, 26, 1883.
(12) Reviews: (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423, Tetrahedron Report No. 278. (b) Dieter, R. K.
Tetrahedron 1986, 42, 3029, Tetrahedron Report No. 202. (c) Tominaga,
Y. J. Heterocycl. Chem. 1989, 26, 1167. (d) Ila, H.; Junjappa, H.;
Mohanata, P. K. Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: New York, 2001; Vol. 13, Chapter 1,
p 1.
(13) (a) Barun, O.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synlett
2000, 653. (b) Barun, O.; Ila, H.; Junjappa, H.; Singh, O. M. J. Org.
Chem. 2000, 65, 1583. (c) Reddy, K. R.; Basaveswara Rao; Ila, H.;
Junjappa, H. Synth. Commun. 1996, 26, 4157. (d) Reddy, K. R.; Ila,
H.; Junjappa, H. Synthesis 1995, 929. (e) Gupta, A. K.; Reddy, K. R.;
Ila, H.; Junjappa, H. J. Chem. Soc., Perkin Trans. 1 1995, 1725.
(14) (a) Syam Kumar, U. K.; Ila, H.; Junjappa, H. Org. Lett. 2001,
3, 4193. (b) Barun, O.; Chakrabarty, S.; Ila, H.; Junjappa, H. J. Org.
Chem. 2001, 66, 4457. (c) Basaveswara Rao, M. V.; Suresh, J. R.;
Kumar, A.; Ila, H.; Junjappa, H. J. Indian Chem. Soc. 1997, 74, 955.
Results and Discussion
The required R-oxoketene-N,S-arylaminoacetals 1a-l
(Table 1) were prepared by modification of our previously
reported procedure by displacement of one of the meth-
ylthio groups of the corresponding R-oxoketene dithio-
acetals by the appropriate aniline in the presence of
n-BuLi in THF.15 The Vilsmeier cyclization of N,S-
anilinoacetals 1a-d bearing a strongly activating group
(i.e., methoxy group) was first examined. Thus, the N,S-
acetal 1a derived from m-methoxyaniline underwent
spontaneous reaction on treatment with DMF/POCl3 at
80 °C to afford only one product (81%), which was
characterized as 2-methylthio-3-benzoyl-7-methoxyquino-
line (2a) on the basis of its spectral and analytical data
(Scheme 1, Table 1). The corresponding (2-bromobenzoyl)-
(1b) and the other N,S-acetals 1c-e from 3,4-dimethoxy-
and 2,5-dimethoxyanilines also reacted smoothly with
Vilsmeier reagent under similar conditions to give the
respective quinolines 2b-e in high yields (Table 1,
entries 2-5). However, the reactions of N,S-acetals 1f-h
without any activating group on aniline were found to
be sluggish with Vilsmeier reagent requiring prolonged
heating at higher temperature to afford the respective
quinolines in poor yields (entries 6-8). Thus, the 3-fluo-
roanilino-N,S-acetal 1f gave a regioisomeric mixture of
quinolines 2fa and 2fb (entry 6) in low yields, whereas
with unsubstituted (1g) and 4-chloroanilino (1h) N,S-
acetals, the corresponding unsubstituted (2g) and 2,6-
dichloroquinoline (2h) were isolated in 25% and 30%
yields, respectively (entries 7 and 8). On the other hand,
the N,S-acetal 1i derived from R-naphthylamine was
efficiently transformed into the condensed 2,3-substituted
benzo[h]quinoline 2i in nearly quantitative yield on
treatment with Vilsmeier reagent under identical condi-
tions as for 1a-e (Table 1, entry 9). The N,S-acetals 1a-
c,i also underwent rapid cyclization with Vilsmeier
reagent derived from N,N-dimethylacetamide to furnish
the respective 2-methylthio-3-benzoyl-4-methylquinolines
3a-c and the corresponding benzo[h]quinoline derivative
3i in excellent yields (entries 10-13).
To further study the scope this facile quinoline syn-
thesis, the reaction of R-acetyl-N,S-anilinoacetal 1j with
(15) Singh, O. M.; Junjappa, H.; Ila, H. J. Chem. Soc., Perkin Trans.
1 1997, 3561.
J. Org. Chem, Vol. 68, No. 10, 2003 3967

Mahata et al.
SCHEME 1a
TABLE 1. Synthesis of Quinolines 2 and 3 by Reaction
of r-Oxoketene-N,S-acetals with Vilsmeier Reagentsa
a Key: (a) HCONMe2/POCl3/∆, 80 °C; (b) HCONMe2/POCl3/
Cl2CHCHCl2/∆, 80 °C; (c) MeCONMe2/POCl3/∆, 80 °C.
SCHEME 2a
a Key: (a) HCONMe2/POCl3/∆/80-90 °C.
Vilsmeier reagent was examined with a view to synthe-
size 3-acetylquinoline 2j (Scheme 2). However, only
intractable reaction mixtures were obtained under vary-
ing conditions due to the competing side reaction of the
acetyl group,8 and in one of the reactions, the diketone
aldehyde enamine 4 was isolated as the only identifiable
product in 50% yield (Scheme 2). On the other hand, the
corresponding N,S-acetals 1k,l obtained from pyruval-
dehyde dimethyl acetal afforded the respective 3-(bis-
methoxy)acetylquinolines 2k,l in reasonable yields (51-
54%) when subjected to Vilsmeier reaction under described
conditions (Table 1, entries 14-15).
The validity of this new quinoline synthesis was
further evaluated by performing the Vilsmeier reaction
on bisketene-N,S-acetals 5, 8, and 11 with a view to
synthesize planar tricyclic and tetracyclic heterocyclo-
fused quinolines as shown in Schemes 3-5.The desired
N,S-acetals 5, 8, and 11 were readily accessible by
displacement reaction of m-phenylenediamine, o-phen-
ylenediamine, and 1,5-diaminonaphthalene, respectively,
on 2 equiv of R-benzoylketene dithioacetals in the pres-
ence of n-BuLi (Schemes 3-5).15
Thus, when the N,S-acetal from m-phenylenediamine
was reacted with 2.5 equiv of Vilsmeier reagent, the
product isolated (48%) was characterized as the angularly
fused azaphenanthridine 7 and the corresponding
linearly fused bisquinoline could not be isolated from the
reaction mixture.16 The bisketene-N,S-acetal 8 from
o-phenylenediamine did not yield any of the expected
symmetrical phenanthroline derivative 9 when exposed
to varying Vilsmeier reaction conditions (HCONMe2/
POCl3 at rt or at 130 °C) and only intractable reaction
a Method: (a) HCONME2/POCl3/∆, 80 °C; (b) HCONMe2/POCl3/
Cl2CHCHCl2/∆, 80 °C; (c) MeCONMe2/POCl3/∆, 80 °C.
(16) Column chromatography of the reaction mixture gave along
with 7 another solid which could not be identified.
3968 J. Org. Chem., Vol. 68, No. 10, 2003

Reactions of R-Oxoketene-N,S-arylaminoacetals
SCHEME 3
SCHEME 5
SCHEME 6a
SCHEME 4a
a Key: (a) Raney Ni/EtOH/∆; (b) NBS/H2SO4/THF/H2O.
bisketene-N,S-acetal 11 from 1,5-diaminonaphthalene
underwent smooth cyclization with Vilsmeier reagent to
afford the 2,8-bis(benzoyl)-3,9-bis(methylthio)quinolino-
[8,7-h]quinoline 12 in 60% yield (Scheme 5). The struc-
tures of the products 7, 10, and 12 were confirmed with
the help of spectral and analytical data.
With a variety of multifunctional, substituted, and
fused quinolines in hand, we further explored the possible
transformations of these functionalities to afford new
quinolines (Schemes 6 and 7). Thus, the 2-methylthio
group in the quinolines 2a and 2c could be reductively
removed with Raney-Ni to afford 2-unsubstituted quino-
lines 13a and 13c in good yields (Scheme 6).17 Similarly,
the corresponding 2-methylthio-3-benzoyl-5,8-dimethoxy-
a Key: (a) DMA/POCl3/TCE/130 °C; 10A, X ) OH (60%); (b)
POCl3/70 °C/3 h; 10B, X ) Cl (54%).
mixtures were formed. However, when 8 was heated with
POCl3 in DMA/TCE at 130 °C, the product isolated after
workup was characterized as 2-methylthio-9-hydroxy-4,7-
diphenylphenanthroline (10A) on the basis of its spectral
and analytical data. This was further confirmed by
subjecting the bisketene-N,S-acetal 8 to treatment with
POCl3 at 70 °C for 3 h, when the product obtained (54%)
was characterized as the 2-methylthio-9-chloro-4,7-diphen-
ylphenanthroline 10B (Scheme 4). Apparently, in the
absence of any activation at the site of cyclization with
Vilsmeier reagent, intramolecular Combes4-type cycliza-
tion of the enaminone functionality is the preferred
cyclization mode to yield the observed product 10. The
quinoline 1e was subjected to oxidative demethylation
18a
in the presence of aqueous NBS/H2SO4
to afford
quinoline-5,8-quinone 14 in high yield (Scheme 6).18
The 2-methylthio group in one of the quinolines 2a
could be oxidized with m-chloroperbenzoic acid to afford
the corresponding 2-(methylsulfonyl)quinoline 15a in
(17) Bhat, N. B.; Bhaduri, A. P. Z. Naturforsch., B: Anorg. Chem.,
Org. Chem. 1985, 40B(7), 990.
J. Org. Chem, Vol. 68, No. 10, 2003 3969

Mahata et al.
SCHEME 7a
SCHEME 9
a Key: (a) PhNH2/MW.
[3,4-b]quinolin-4-one has been shown to display pH-
dependent fluorescent properties for extreme pH mea-
surement.21 Thus, the reaction of 2c with hydrazine
hydrate afforded the hydrazone 21c in nearly quantita-
tive yield. The hydrazone 21c failed to undergo cycliza-
tion to pyrazolo[3,4-b]quinoline 20c even after prolonged
refluxing which is presumably due to the adoption of the
unfavorable E-configuration. However the pyrazoloquino-
lines 20a and 20c could be obtained directly from the
corresponding quinolines 2a and 2c in high yields by
reacting them with hydrazine hydrate under microwave
irradiation conditions20 (Scheme 8). Similarly, the syn-
thesis of the corresponding tetracyclic 10H-benzo[h]-
pyrazolo[3,4-b]quinoline 20i could be achieved from
benzo[h]quinoline precursor 2i following a similar pro-
cedure (Scheme 8). Many of these pyrazolo-fused benzo-
[h]quinolines are shown to bind with DNA inhibiting
topoisomerase I activity.9d Finally, further scope of the
functional group manipulation in these quinolines was
demonstrated by performing radical cyclization on the
3-(o-bromobenzoyl)quinolines 2b by treatment with Bu3-
SnH/AIBN (Scheme 9). The product formed in nearly
quantitative yield was found to be not the tetracyclic
quinoline 22b, but was characterized as the novel ben-
zothiopyrano[2,3-b]quinoline derivative 21b on the basis
of its spectral and analytical data (Scheme 9). Similarly,
the 3-(o-bromobenzoyl)-6,7-dimethoxyquinoline 2d af-
forded the tetracyclic benzothiopyrano fused quinoline
21d in 98% yield (Scheme 9). The probable mechanistic
pathway for the formation of 21b and 21d is shown in
Scheme 9. The initially formed o-benzoyl radical 23
undergoes radical translocation22 by attack on the meth-
ylthio group to give radical intermediate 24, which on
loss of the methyl radical affords the benzothiopyrano-
quinolines 21b and 21d in excellent yields (Scheme 9).
SCHEME 8
75% yield (Scheme 7). The 2-methylsulfonyl group in 15a
could be easily displaced19 by primary and secondary
amines under varying conditions to afford the corre-
sponding 2-alkyl/arylaminoquinolines 16-19 in high
yields (Scheme 7).
The quinolines 2a, 2c, and 2i were next subjected to
annulation reaction with hydrazine hydrate with a view
to synthesize pyrazolo[3,4-b]quinolines 20a, 20c, and 20i
(Scheme 8), which are known to exhibit various biological
activities such as antiviral, antimalarial, and lowering
of serum choelsterol.20 Recently, the 3-phenylpyrazolo-
(18) (a) Kim, D. W.; Choi, H. Y.; Lee, K.-J.; Chi, D. Y. Org. Lett.
2001, 3, 445. (b) Cossy, J.; Belotti, D. Tetrahedron Lett. 2001, 42, 4329.
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Wu, J.-P. J. Antibiot. 1985, 38, 516. (e) Boger, D. L.; Yasuda, M.;
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Chem. 1987, 30, 1918. (f) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.;
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Lett. 1981, 4595. (g) Kitahara, Y.; Tamura, F.; Kubo, A. Chem. Pharm.
Bull. 1994, 42, 1363. (h) Shaikh, I. A.; Johnson, F.; Grollman, A. P. J.
Med. Chem. 1986, 29, 1329.
Conclusion
In conclusion, we have developed a simple, highly
efficient, and regioselective synthesis of functionalized
(21) Su, M.; Liu, Y.; Ma, H.; Ma, Q.; Wang, Z.; Yang, J.; Wang, M.
Chem. Commun. 2001, 960.
(22) Ooi, T.; Furuya, M.; Sakai, D.; Hokke, Y.; Maruoka, K. Synlett
2001, 541.
(19) Anderson, R. J.; Morris, J. C. Tetrahedron Lett. 2001, 42, 8697.
(20) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Tetrahedron Lett.
2001, 42, 3827 and references therein.
3970 J. Org. Chem., Vol. 68, No. 10, 2003

Reactions of R-Oxoketene-N,S-arylaminoacetals
δ 14.8, 55.3, 88.8, 110.4, 112.2, 117.2, 127.0, 128.3, 129.7, 130.9,
139.2, 140.1, 160.1, 167.3, 186.1.
quinolines through Vilsmeier cyclization of a variety of
R-oxoketene N,S-anilinoacetals. Despite the fact that the
cyclization is facile with the N,S-acetals bearing a
strongly activating group (i.e., methoxy group) on aniline
and the yields are only moderate in other cases, the
reaction provides highly efficient access to multifunc-
tionalized quinolines which are useful intermediates for
further chemical manipulation for preparation of either
2-alkyl/arylaminoquinolines or quinoline-fused hetero-
cycles such as pyrazolo[3,4-b]quinolines and benzo-
thiopyrano[b]quinoline through ring annulation with
hydrazine hydrate or via radical cyclization. In addition,
the reaction can be extended to include condensed
functionalized quinolines such as benzo[h]quinoline and
pyrido[3,2-h]quinoline, phenanthroline, and quino[8,7-h]-
quinoline with potential biological activities. A number
of benzo[h]quinolines and azaphenanthridines are known
to bind DNA with high affinity inhibiting topisomerase
I activity.9d We are currently investigating the possibili-
ties of achieving a more flexible substitution pattern on
the quinoline ring, especially the synthesis of 3-cyano-
or -carbethoxy-2-methylthioquinolines as precursors of
quinoline-based models of NADH, which will be pub-
lished later.
3-(1-Aminonaphthyl)-3-methylthio-1-phenylprop-2-en-
1-one (1i): yield 90% (2.87 g); light yellow solid (CHCl3-
hexane); mp 120-121 °C; Rf 0.55 (9:1 hexanes-EtOAc); IR
(KBr) 1522, 1465, 1252 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.38 (s, 3H, SCH3), 6.0 (brs, 1H, CH), 7.45-7.50 (m, 4H, ArH),
7.52-7.56 (m, 3H, ArH), 7.81 (d, J ) 8.32 Hz, 1H, ArH), 7.88
(dd, J ) 8.32, 1.96 Hz, 1H, ArH), 7.98 (dd, J ) 7.82, 1.48 Hz,
2H, ArH), 8.14 (d, J ) 7.56 Hz, 1H, ArH), 13.82 (brs, 1H, NH);
13C NMR (100 MHz, CDCl3) δ 14.7, 88.6, 122.7, 124.0, 125.0,
126.6, 126.9, 127.1, 127.6, 128.2, 128.3, 129.6, 130.9, 134.2,
134.3, 140.2, 169.3, 186.3.
4-(3-Methoxyanilino)-4-methylthio-3-buten-2-one (1j):
yield 75% (1.77 g); red liquid; Rf 0.50 (3:1 hexanes-EtOAc);
1
IR (DCM) 2955, 1591, 1469, 1269 cm-1; H NMR (400 MHz,
CDCl3): δ 2.14 (s, 3H, CH3), 2.33 (s, 3H, SCH3), 3.79 (s, 3H,
OCH3), 5.19 (s, 1H, CH), 6.77 (dd, J ) 8.2, 2.8 Hz, 1H, ArH),
6.80 (s, 1H, ArH), 6.85 (d, J ) 8.4 Hz, 1H, ArH), 7.22-7.26 (t,
J ) 8.0 1H, ArH), 12.95 (brs, 1H, NH); 13C NMR (100 MHz,
CDCl3) δ 14.6, 29.2, 55.3, 91.6, 110.5, 112.0, 117.3, 129.6, 139.2,
160.0, 165.7, 193.0; MS m/z 237 (M+, 22). Anal. Calcd for
C12H15NO2S (237.33): C, 60.73; H, 6.37; N, 5.90. Found: C,
60.64, H, 6.44; N, 5.80.
1-Bis(methoxy)-4-(3-methoxyanilino)-4-(methylthio)-3-
buten-2-one (1k): yield 75% (2.23 g); deep red viscous liquid;
Rf 0.45 (8.5:1.5 hexanes-EtOAc); IR (DCM) 2952, 2839, 1554,
1
1477 cm-1; H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H, SCH3),
3.36 (s, 6H, OCH3), 3.70 (s, 3H, OCH3), 4.57 (s, 1H, CH), 5.52
(s, 1H, CH), 6.70 (d, J ) 8.00 Hz, 1H, ArH), 6.74 (s, 1H, ArH),
6.79 (d, J ) 8.00 Hz, 1H, ArH), 7.17 (t, J ) 8.40 Hz, 1H, ArH),
13.04 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3) δ 14.4, 53.8,
55.0, 87.4, 103.5, 110.3, 112.1, 117.0, 129.5, 138.6, 159.8, 168.9,
187.7.
Experimental Section
General Methods. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded in CDCl3 or DMSO-d6, and TMS
was used as an internal reference. Melting points are uncor-
rected. Chromatographic purification was conducted by column
chromatography using 60-120 mesh silica gel obtained from
Acme Synthetic Chemicals. DMF was distilled over CaH2 and
stored over molecular sieves. THF was distilled over sodium/
benzophenone prior to use. Tetrachloroethane was distilled
over P2O5. Toluene was distilled and stored over sodium wire.
POCl3, AIBN, TBTH, n-BuLi (15% in hexane), substituted
anilines, and hydrazine hydrate (80% LR) were purchased
from standard firms and used directly. The R-oxoketene-S,N-
acetal 1h was reported earlier15 and prepared accordingly.
General Procedure for Preparation of r-Oxoketene-
N,S-acetals 1a-l and Bisketene-N,S-acetals 5, 8, and 11.
To a stirred solution of aniline or a substituted aniline (10
mmol) in dry THF (50 mL) was added n-BuLi (5.2 mL, 12
mmol) under nitrogen atmosphere over a period of 10 min at
-78 °C. The reaction mixture was brought to room tempera-
ture and further stirred for 45 min. A solution of an R-oxo-
ketene-S,S-acetal (10 mmol) in dry THF (25 mL) was added
at 0 °C, and the reaction mixture was further stirred at room
temperature for 2 h. It was refluxed for 18-20 h to complete
the reaction, cooled, poured into saturated NH4Cl solution (100
mL), and extracted with CHCl3 (2 × 50 mL). The combined
extracts were washed with water (2 × 50 mL) and brine (50
mL), dried (Na2SO4), and evaporated to give crude product
which was purified by column chromatography over silica gel
using hexanes-EtOAc as eluent.
1,3-Bis[(2′-methylthio)-1′-benzoyl-2′-ethenyl]diami-
nobenzene (5): yield 75% (3.45 g); light yellow solid (CHCl3-
hexane); mp 164-165 °C; Rf 0.55 (7:3 hexanes-EtOAc); IR
(KBr) 1556, 1470, 1268 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.89 (s, 6H, SCH3), 5.78 (s, 2H, CH), 7.05 (d, J ) 8.08 Hz, 2H,
ArH), 7.14-7.32 (m, 8H, ArH), 7.79 (d, J ) 7.32 Hz, 4H, ArH),
13.51 (brs, 2H, NH); 13C NMR (100 MHz, CDCl3) δ 14.6, 89.0,
120.8, 122.2, 126.9, 128.2, 129.5, 130.8, 138.8, 139.8, 166.9,
185.9; MS m/z 460 (M+, 15). Anal. Calcd for C26H24N2O2S2
(460.59): C, 67.79; H, 5.25; N, 6.08. Found: C, 67.91, H, 5.17;
N, 6.14.
1,2-Bis[(2′-methylthio)-1′-benzoyl-2′-ethenyl]diami-
nobenzene (8): yield 68% (3.13 g); white solid (CHCl3-
hexane); mp 152-153 °C; Rf 0.50 (4:1 hexanes-EtOAc); IR
(KBr) 2925, 1552, 1463 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.42 (s, 6H, SCH3), 5.81 (s, 2H, CH), 7.34 (t, J ) 7.04 Hz, 6H,
ArH), 7.40 (d, J ) 7.36 Hz, 2H, ArH), 7.42-7.46 (m, 2H, ArH),
7.76 (d, J ) 7.08 Hz, 4H, ArH), 13.00 (brs, 2H, NH); 13C NMR
(100 MHz, CDCl3) δ 14.7, 89.7, 127.1, 127.8, 128.2, 128.4,
130.7, 135.4, 140.1, 168.5, 186.4; MS m/z 460 (M+, 20). Anal.
Calcd for C26H24N2O2S2 (460.59): C, 67.79; H, 5.25; N, 6.08.
Found: C, 67.72, H, 5.14; N, 6.27.
1,5-Bis[(2′-methylthio)-1′-benzoyl-2′-ethenyl]diamino-
naphthalene (11): yield 85% (4.34 g); light yellow solid
(CHCl3-hexane); mp 206-207 °C; Rf 0.45 (7:3 hexanes-
EtOAc); IR (KBr) 2922, 1552, 1465 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.36 (s, 6H, SCH3), 5.99 (s, 2H, CH), 7.46 (d, J ) 6.6
Hz, 6H, ArH), 7.51-7.59 (m, 4H, ArH), 7.95 (d, J ) 6.56 Hz,
4H, ArH), 8.09 (d, J ) 8.04 Hz, 2H, ArH), 13.84 (brs, 2H, NH);
13C NMR (100 MHz, CDCl3) δ 14.8, 88.9, 122.4, 124.8, 126.1,
127.2, 128.4, 130.6, 131.0, 134.8, 140.1, 169.1, 186.5.
General Procedure for Vilsmeier Cyclization of N,S-
Acetals: Synthesis of Substituted Quinolines 2a-i, 3a-
c,i, and 2k,l. A solution of R-oxoketene-N,S-acetal (1a-e,i,k,l)
(5 mmol) in DMF or DMA (5 mL) or in Cl2CHCHCl2 (5 mL)
was added dropwise at 0 °C to a solution of Vilsmeier reagent
[prepared from POCl3 (0.7 mL, 7.5 mmol) and DMF or DMA
(7.5 mmol) at 0-5 °C] under nitrogen atmosphere. After
The bisketene-N,S-acetals 5, 8, and 11 were also prepared
following a similar procedure from the corresponding diamines
(10 mmol), n-BuLi (10.4 mL, 24 mmol), and R-oxoketene-S,S-
acetal (4.48 g, 20 mmol).
3-(3-Methoxyanilino)-3-methylthio-1-phenylprop-2-en-
1-one (1a): yield 82% (2.45 g); light yellow crystals (CHCl3-
hexane); mp 75-76 °C; Rf 0.59 (9:1 hexanes-EtOAc); IR (KBr)
1
3002, 2925, 1564 cm-1; H NMR (400 MHz, CDCl3) δ 2.41 (s,
3H, SCH3), 3.77 (s, 3H, OCH3), 5.86 (s, 1H, CH), 6.76 (ddd, J
) 8.30, 2.44, 0.76 Hz, 1H, ArH), 6.85 (t, J ) 2.2 Hz, 1H, ArH),
6.90 (ddd, J ) 7.93, 1.94, 0.76 Hz, 1H, ArH), 7.24 (t, J ) 8.04
Hz, 1H, ArH), 7.38-7.46 (m, 3H, ArH), 7.88 (dd, J ) 7.8, 1.96
Hz, 2H, ArH), 13.52 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3)
J. Org. Chem, Vol. 68, No. 10, 2003 3971

Mahata et al.
further stirring for 5-6 h at room temperature, the reaction
mixture was heated to 80-90 °C for 3-4 h (monitored by TLC).
It was then cooled, poured into ice cold saturated NaHCO3
solution (100 mL), and extracted with chloroform (4 × 50 mL).
The combined organic extracts were washed with water (3 ×
50 mL) and brine (1 × 25 mL) and dried (Na2SO4), and the
solvent was evaporated under reduced pressure to afford crude
quinoline which was purified by column chromatography over
silica gel using hexanes-EtOAc as eluent. The quinolines
2a-d crystallize out directly after workup without any column
chromatographic purification.
3-Benzoyl-7-fluoro-2-methylthioquinoline (2fa): yield
30% (0.45 g); low-melting yellow solid; Rf 0.48 (9.5:0.5 hex-
anes-EtOAc); IR (DCM) 1661, 1622, 1560, 1492 cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.67 (s, 3H, SCH3), 7.26 (s, 1H, ArH), 7.51
(dt, J ) 7.2, 1.68 Hz, 2H, ArH), 7.62-7.68 (m, 2H, ArH), 7.74
(q, J ) 8.92, 6.12 Hz, 1H, ArH), 7.83 (dd, J ) 7.48, 1.0 Hz,
2H, ArH), 8.05 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ
13.8, 112.1, 116.2, 120.9, 128.6, 130.1, 130.5, 133.5, 137.1,
137.4, 160.4, 165.8, 180.2, 184.5, 195.0; MS m/z 297 (M+, 28).
Anal. Calcd for C17H12FNOS (297.34): C, 68.67; H, 4.07; N,
4.71. Found: C, 68.81, H, 3.89; N, 4.50.
3-Benzoyl-2-methylthio-5-fluoroquinoline (2fb): yield
10% (0.15 g); low-melting yellow solid; Rf 0.40 (9.5:0.5 hex-
anes-EtOAc); IR (DCM) 1674, 1624, 1562, 1488 cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.44 (s, 3H, SCH3), 7.39 (dt, J ) 8.76,
2.44 Hz, 2H, ArH), 7.45-7.49 (m, 2H, ArH), 7.67-7.69 (m, 2H,
ArH), 7.81 (dd, J ) 10.0, 2.44 Hz, 1H, ArH), 7.91 (q, J ) 8.9,
6.12 Hz, 1H, ArH), 8.48 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 12.7, 113.3 (JF-C ) 20.5 Hz), 118 (JF-C ) 25.5 Hz),
122.6, 128.3, 129.0, 129.3, 130.4, 131.9, 136.8, 139.1, 149.5,
157.5, 163.1, 194.0; MS m/z 297 (M+, 8). Anal. Calcd for C17H12-
FNOS (297.34): C, 68.67; H, 4.07; N, 4.71. Found: C, 68.45,
H, 4.13; N, 4.85.
3-Benzoyl-7-methoxy-2-methylthioquinoline (2a): yield
81% (1.25 g); light yellow solid (CHCl3-hexane); mp 105-106
°C; Rf 0.60 (9:1 hexanes-EtOAc); IR (KBr) 3904, 3000, 1618,
1
1500 cm-1; H NMR (400 MHz, CDCl3) δ 2.70 (s, 3H, SCH3),
4.00(s, 3H, OCH3), 7.12 (d, J ) 8.8 Hz, 1H, ArH), 7.41 (s, 1H,
ArH), 7.49 (t, J ) 8.04 Hz, 2H, ArH), 7.61 (d, J ) 8.8 Hz, 2H,
ArH), 7.81 (d, J ) 7.56 Hz, 2H, ArH), 8.03 (s, 1H, ArH); 13C
NMR (100 MHz, CDCl3) δ 13.9, 55.7, 106.4, 118.8, 119.0, 127.8,
128.5, 129.6, 130.1, 133.1, 137.6, 138.4, 150.2, 159.8, 162.8,
195.2; MS m/z 309 (M+, 18). Anal. Calcd for C18H15NO2S
(309.37): C, 69.88; H, 4.89; N, 4.53. Found: C, 69.85, H, 4.91;
N, 4.55.
3-Benzoyl-2-methylthioquinoline (2g): yield 25% (0.42
g); low-melting yellow solid; Rf 0.50 (9.5:0.5 hexanes-EtOAc);
IR (DCM) 2928, 1660, 1586 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.72 (s, 3H, SCH3), 7.48-7.53 (m, 3H, ArH), 7.64 (t, J ) 7.56
Hz, 1H, ArH), 7.75 (d, J ) 7.32 Hz, 2H, ArH), 7.85 (dd, J )
7.82, 1.48 Hz, 2H, ArH), 8.08 (s, 2H, ArH); 13C NMR (100 MHz,
CDCl3) δ 13.7, 123.1, 124.1, 126.0, 128.0, 128.4, 128.6, 128.8,
130.2, 131.5, 133.5, 137.2, 137.5, 148.5, 176.4; MS m/z 279 (M+,
30). Anal. Calcd for C17H13NOS (279.34): C, 73.09; H, 4.69;
N, 5.01. Found: C, 73.06, H, 4.70; N, 5.04.
3-(2-Bromobenzoyl)-7-methoxy-2-methylthioquino-
line (2b): yield 95% (1.84 g); light yellow solid (CHCl3-
hexane); mp 133-134 °C; Rf 0.45 (8.5:1.5 hexanes-EtOAc);
IR (KBr) 2909, 1658, 1614, 1404 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.73 (s, 3H, SCH3), 3.97 (s, 3H, OCH3), 7.06 (dd, J )
8.8, 2.44 Hz, 1H, ArH), 7.35-7.45 (m, 4H, ArH), 7.54 (d, J )
8.8 Hz, 1H, ArH), 7.64 (d, J ) 7.8 Hz, 1H, ArH), 7.96 (s, 1H,
ArH); 13C NMR (100 MHz, CDCl3) δ 14.3, 55.8, 106.1, 118.8,
119.2, 119.9, 125.5, 127.4, 129.4, 130.2, 131.5, 133.3, 140.5,
142.3, 150.5, 161.5, 163.9, 194.5; MS m/z 388 (M+, 3.47). Anal.
Calcd for C18H14NO2SBr (388.27): C, 55.68; H, 3.63; N, 3.61.
Found: C, 55.56, H, 3.72; N, 3.75.
3-Benzoyl-2,6-dichloroquinoline (2h): yield 30% (0.45 g);
white solid (CHCl3-hexane); mp 168-169 °C; Rf 0.45 (7:3
1
hexanes-EtOAc); IR (KBr) 1665, 1591, 1539 cm-1; H NMR
2-Benzoyl-6,7-dimethoxy-2-methylthioquinoline (2c):
yield 98% (1.66 g); pale yellow solid (CHCl3-hexane); mp 154-
155 °C; Rf 0.60 (8.5:1.5 hexanes-EtOAc); IR (KBr) 2922, 1646,
(400 MHz, CDCl3) δ 7.53-7.55 (m, 3H, ArH), 7.60-7.62 (m,
2H, ArH), 7.83 (dd, J ) 9.0, 2.44 Hz, 1H, ArH), 8.15 (d, J )
9.0 Hz, 1H, ArH), 8.43 (dd, J ) 8.44, 2.2 Hz, 1H, ArH), 10.23
(s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 124.2, 126.1, 126.6,
128.8, 129.9, 130.0, 131.3, 133.8, 134.8, 137.2, 143.5, 146.8,
159.6, 189.8; MS m/z 301 (M+, 83), 303 (M+, 65). Anal. Calcd
for C16H9NOCl2 (301.23): C, 63.79; H, 3.01; N, 4.64. Found:
C, 63.45; H, 3.10; N, 4.73.
1500, 1419 cm-1 1H NMR (400 MHz, CDCl3) δ 2.67 (s, 3H,
;
SCH3), 3.98 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 6.98 (s, 1H,
ArH), 7.39 (s, 1H, ArH), 7.50 (t, J ) 7.20 Hz, 2H, ArH), 7.62
(t, J ) 7.60 Hz, 1H, ArH), 7.82 (d, J ) 7.60 Hz, 2H, ArH), 7.98
(s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 13.9, 56.1, 56.3,
105.9, 107.1, 119.0, 128.2, 128.5, 130.1, 133.0, 137.0, 137.7,
146.0, 149.3, 154.2, 156.9, 195.4; MS m/z 339 (M+, 38). Anal.
Calcd for C19H17NO3S (339.40): C, 67.23; H, 5.05; N, 4.13.
Found: C, 67.20, H, 5.07; N, 4.15.
3-Benzoyl-2-methylthiobenzo[h]quinoline (2i): yield
95% (1.56 g); yellow solid (CHCl3-hexane); mp 144-145 °C;
Rf 0.54 (9.5:0.5 hexanes-EtOAc); IR (KBr) 1653, 1582, 1498,
1
1366 cm-1; H NMR (400 MHz, CDCl3) δ 2.81 (s, 3H, SCH3),
3-(2-Bromobenzoyl)-6,7-dimethoxy-2-methylthioquin-
oline (2d): yield 95% (1.98 g); yellow solid (CHCl3-hexane);
mp 149-150 °C; Rf 0.58 (8.5:1.5 hexanes-EtOAc); IR (KBr)
7.48 (t, J ) 7.68 Hz, 2H, ArH), 7.55 (d, J ) 8.76 Hz, 1H, ArH),
7.61 (t, J ) 7.44 Hz, 1H, ArH), 7.67-7.73 (m, 3H, ArH), 7.82-
7.87 (m, 3H, ArH), 8.09 (s, 1H, ArH), 9.25 (dd, J ) 8.30, 2.44
Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 14.1, 121.5, 124.9,
125.0, 126.9, 127.1, 127.8, 128.6, 128.9, 130.0, 130.1, 130.5,
133.2, 134.7, 137.4, 137.9, 146.7, 158.3, 195.4; MS m/z 329 (M+,
26). Anal. Calcd for C21H15NOS (329.40): C, 76.57; H, 4.59;
N, 4.25. Found: C, 76.75, H, 4.47; N, 4.32.
1661, 1585, 1502, 1427 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.67 (s, 3H, SCH3), 3.92 (s, 3H, OCH3), 4.05 (s, 3H, OCH3),
6.89 (s, 1H, ArH), 7.31 (s, 1H, ArH), 7.34-7.43 (m, 3H, ArH),
7.65 (dd, J ) 7.18, 1.24 Hz, 1H, ArH), 7.89 (s, 1H, ArH); 13C
NMR (100 MHz, CDCl3) δ 14.0, 56.1, 56.4, 106.1, 107.1, 118.9,
119.9, 125.7, 127.4, 129.3, 131.3, 133.3, 140.7, 140.9, 146.7,
149.3, 155.2, 158.7, 194.7; MS m/z 418 (M+, 95). Anal. Calcd
for C19H16NO3SBr (418.30): C, 54.55; H, 3.86; N, 3.35. Found:
C, 54.62, H, 3.75; N, 3.40.
3-[1-Bis(methoxy)acetyl]-7-methoxy-2-methylthioquin-
oline (2k): yield 51% (0.78 g); yellow solid (CHCl3-hexane);
mp 122-123 °C; Rf 0.80 (9.6:0.4 hexanes-EtOAc); IR (KBr)
1612, 1486, 1345, 1217 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2-Benzoyl-5,8-dimethoxy-2-methylthioquinoline (2e):
yield 90% (1.53 g); yellow solid (CHCl3-hexane); mp 139-140
°C; Rf 0.54 (8.5:1.5 hexanes-EtOAc); IR (KBr) 2923, 1656,
2.79 (s, 3H, SCH3), 3.61(s, 6H, OCH3), 4.97 (s, 3H, OCH3), 5.69
(s, 1H, CH), 7.12 (dd, J ) 8.76, 2.44 Hz, 1H, ArH), 7.34 (s, 1H,
ArH), 7.69 (d, J ) 9.04 Hz, 1H, ArH), 8.59 (s, 1H, ArH); 13C
NMR (100 MHz, CDCl3) δ 13.4, 55.6, 59.0, 91.2, 105.5, 106.8,
119.0, 119.3, 128.2, 129.7, 136.4, 148.3, 157.4, 162.2; MS m/z
307 (M+, 40). Anal. Calcd for C15H17NO4S (307.38): C, 58.61;
H, 5.57; N, 4.56. Found: C, 58.80, H, 5.45; N, 4.44.
1569, 1470 cm-1 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H,
;
SCH3), 3.87 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 6.68 (d, J )
8.32 Hz, 1H, ArH), 7.05 (d, J ) 8.52 Hz, 1H, ArH), 7.46 (t, J
) 7.84 Hz, 2H, ArH), 7.60 (dt, J ) 7.08, 0.48 Hz, 1H, ArH),
7.81 (dd, J ) 7.90, 1.48 Hz, 2H, ArH), 8.45 (s, 1H, ArH); 13C
NMR (100 MHz, CDCl3) δ 13.7, 55.7, 57.0, 103.4, 111.6, 117.2,
128.5, 129.9, 130.2, 132.9, 133.3, 137.2, 140.4, 148.4, 149.7,
158.5, 195.3; MS m/z 339 (M+, 76). Anal. Calcd for C19H17NO3S
(339.40): C, 67.23; H, 5.05; N, 4.13. Found: C, 67.30, H, 5.00;
N, 4.09.
3-[1-(Bismethoxy)acetyl]-6,7-dimethoxy-2-methylthio-
quinoline (2l): yield 54% (0.91 g); yellow solid (CHCl3-
hexane); mp 87-88 °C; Rf 0.60 (9:1 hexanes-EtOAc); IR (KBr)
1
2924, 1687, 1500 cm-1; H NMR (400 MHz, CDCl3) δ 2.56 (s,
3H, SCH3), 3.45 (s, 6H, OCH3), 3.95 (s, 3H, OCH3), 4.01 (s,
3972 J. Org. Chem., Vol. 68, No. 10, 2003

Reactions of R-Oxoketene-N,S-arylaminoacetals
3H, OCH3), 5.04 (s, 1H, CH), 7.03 (s, 1H, ArH), 7.19 (s, 1H,
ArH), 8.80 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 14.1,
55.4, 55.5, 56.1, 56.4, 106.0, 106.4, 106.9, 118.7, 122.6, 139.6,
146.1, 149.2, 155.0, 159.0; MS m/z 337 (M+, 14). Anal. Calcd
for C16H19NO5S (337.48): C, 56.94; H, 5.67; N, 4.15. Found:
C, 56.75, H, 5.77; N, 4.20.
121.1, 127.0, 128.5, 128.6, 130.0, 130.1, 130.2, 130.4, 131.0,
133.2, 133.4, 135.1, 137.0, 137.2, 137.7, 146.1, 150.5, 160.1,
162.1, 194.9, 195.2; MS m/z 481 (M + 1, 42). Anal. Calcd for
C28H20N2O2S2 (480.58): C, 69.98; H, 4.19; N, 5.83. Found: C,
69.71, H, 4.32; N, 5.65.
2,8-Bis(benzoyl)-3,9-bis(methylthio)quino[8,7-h]quino-
line (12): yield 60% (0.79 g); yellow solid (CHCl3-hexane); mp
325-326 °C; Rf 0.65 (9:1 hexanes-EtOAc); IR (KBr) 2924,
3-Benzoyl-7-methoxy-4-methyl-2-methylthioquino-
line (3a): yield 80% (1.29 g); white solid (CHCl3-hexane); mp
194-195 °C; Rf 0.55 (9.5:0.5 hexanes-EtOAc); IR(KBr) 2925,
1656, 1265 cm-1 1H NMR (400 MHz, CDCl3) δ 2.81 (s, 6H,
;
1667, 1573, 1498, 1404 cm-1 1H NMR (400 MHz, CDCl3) δ
;
SCH3), 7.48 (t, J ) 7.56 Hz, 4H, ArH), 7.61 (t, J ) 7.08 Hz,
2H, ArH), 7.84 (d, J ) 7.56 Hz, 4H, ArH), 7.88 (d, J ) 8.56
Hz, 2H, ArH), 8.20 (s, 2H, ArH), 9.26 (d, J ) 8.8 Hz, 2H, ArH);
13C NMR (100 MHz, CDCl3) δ 15.0, 122.5, 124.3, 124.8, 124.9,
126.1, 127.2, 128.4, 128.41, 130.5, 131.1, 134.7, 140.0, 186.5;
MS m/z 531 (M+, 100). Anal. Calcd for C32H22N2O2S2 (530.64):
C, 72.43; H, 4.18; N, 5.28. Found: C, 72.33, H, 4.09; N, 5.48.
Procedure for Vilsmeier Cyclization of Bisketene-N,S-
acetal 8 to Phenanthroline 10A. The phenanthroline 10A
was obtained by adding a solution of bisketene-N,S-acetal 8
(1.15 g, 2.5 mmol) in Cl2CHCHCl2 (5 mL) to Vilsmeier reagent
prepared from POCl3 (0.58 mL, 6.25 mmol) and DMA (0.58
mL, 6.25 mmol) and heating the reaction mixture at 120-130
°C for 7-8 h. Workup and column chromatographic purifica-
tion of the reaction mixture as described earlier yielded the
phenanthroline 10A.
2.39 (s, 3H, SCH3), 2.63 (s, 3H, CH3), 3.97 (s, 3H, OCH3), 7.14
(dd, J ) 9.0, 2.0 Hz, 1H, ArH), 7.35 (d, J ) 2.8 Hz, 1H, ArH),
7.45 (t, J ) 7.6 Hz, 2H, ArH), 7.60 (d, J ) 7.2 Hz, 1H, ArH),
7.82 (d, J ) 9.2 Hz, 1H, ArH), 7.86 (d, J ) 7.6 Hz, 2H, ArH);
13C NMR (100 MHz, CDCl3) δ 13.3, 15.6, 55.5, 107.2, 118.1,
120.0, 125.1, 128.9, 129.6, 130.0, 134.1, 136.8, 140.2, 149.4,
156.1, 161.1, 197.2; MS m/z 323 (M+, 42). Anal. Calcd for
C19H17NO2S (323.40): C, 70.56; H, 5.30; N, 4.33. Found: C,
70.36, H, 5.45; N, 4.50.
3-(2-Bromobenzoyl)-7-methoxy-4-methyl-2-methylthio-
quinoline (3b): yield 95% (1.90 g); white solid (CHCl3-
hexane); mp 165-166 °C; Rf 0.70 (9:1 hexanes-EtOAc); IR
(KBr) 2925, 1667, 1573, 1498, 1404 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.47 (s, 3H, SCH3), 2.67 (s, 3H, CH3), 3.98 (s, 3H,
OCH3), 7.15 (dd, J ) 9.28, 2.68 Hz, 1H, ArH), 7.32-7.39 (m,
2H, ArH), 7.45 (s, 1H, ArH), 7.59 (dd, J ) 7.44, 2.2 Hz, 1H,
ArH), 7.72 (dd, J ) 7.68, 1.48 Hz, 1H, ArH), 7.86 (d, J ) 9.28
Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 13.9, 15.7, 55.6,
106.8, 118.5, 120.1, 122.0, 125.5, 127.5, 130.5, 132.6, 133.5,
135.2, 138.1, 142.2, 149.1, 156.6, 161.6, 195.8; MS m/z 402 (M+,
3). Anal. Calcd for C19H16NO2SBr (402.30): C, 56.72; H, 4.01;
N, 3.48. Found: C, 56.56, H, 4.14; N, 3.54.
4,7-Diphenyl-9-hydroxy-2-methylthiopyrido[3,2-h]quin-
oline (10A): yield 60% (0.59 g); reddish orange solid (CHCl3-
hexane); mp 215-216 °C; Rf 0.45 (9:1 hexanes-EtOAc); IR
(KBr) 2921, 1637, 1452 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.33 (s, 3H, SCH3), 6.94 (brs, 1H, OH), 7.14 (dt, J ) 7.2, 2.2
Hz, 2H, ArH), 7.23-7.29 (m, 1H, ArH), 7.44-7.49 (m, 5H,
ArH), 7.52-7.56 (m, 2H, ArH), 7.65-7.67 (m, 2H, ArH), 7.79-
7.82 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3) δ 15.8, 109.2,
117.6, 125.2, 125.9, 126.1, 128.6, 128.9, 129.3, 129.4, 129.9,
130.8, 131.2, 131.8, 132.4, 140.3, 141.7, 157.7, 159.4, 159.9,
160.8; MS m/z 395 (M + 1, 100). Anal. Calcd for C25H18N2OS
(394): C, 69.98; H, 4.19; N, 5.83. Found: C, 69.71, H, 4.32; N,
5.65.
3-Benzoyl-6,7-dimethoxy-4-methyl-2-methylthioquino-
line (3c): yield 98% (1.73 g); light brown solid (CHCl3-
hexane); mp 200-201 °C; Rf 0.60 (8.5:1.5 hexanes-EtOAc);
IR (KBr) 2926, 1666, 1571, 1507, 1428 cm-1 1H NMR (400
;
MHz, CDCl3) δ 2.40 (s, 3H, SCH3), 2.65 (s, 3H, CH3), 4.02 (s,
3H, OCH3), 4.08 (s, 3H, OCH3), 7.14 (s, 1H, ArH), 7.49 (t, J )
7.8 Hz, 3H, ArH), 7.62 (t, J ) 7.56 Hz, 1H, ArH), 7.86 (dt, J )
7.68, 1.2 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) δ 13.5,
15.8, 56.0, 56.1, 102.1, 107.7, 120.2, 128.9, 129.6, 130.4, 134.1,
136.8, 139.0, 144.7, 149.0, 152.6, 153.0, 197.3; MS m/z 353 (M+,
55). Anal. Calcd for C20H19NO3S (353.42): C, 67.96; H, 5.42;
N, 3.96. Found: C, 67.74, H, 5.65; N, 3.80.
Procedure for POCl3Cyclization of Bisketene-N,S-
acetal 8 to Phenanthroline 10B. The phenanthroline 10B
was obtained by heating bisketene-N,S-acetal 8 (0.51 g, 1
mmol) with POCl3 (0.55 mL, 6 mmol) at 70 °C for 3 h. Workup
and column chromatographic purification of the reaction
mixture as described earlier yielded the phenanthroline 10B.
4,7-Diphenyl-9-chloro-2-methylthiopyrido[3,2-h]quin-
oline (10B): yield 54% (0.22 g); red crystals (CHCl3-hexane);
mp 205-206 °C; Rf 0.75 (1:5 hexanes-EtOAc); IR (KBr) 3057,
3-Benzoyl-4-methyl-2-methylthiobenzo[h]quinoline (3i):
yield 93% (1.59 g); light brown solid (CHCl3-hexane); mp 170-
171 °C; Rf 0.60 (9.5:0.5 hexanes-EtOAc); IR (KBr) 2920, 1659,
1572, 1443 cm-1 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H,
;
1
1637, 1362, 763 cm-1; H NMR (400 MHz, CDCl3) δ 2.32 (s,
CH3), 2.80 (s, 3H, SCH3), 7.48 (t, J ) 7.80 Hz, 2H, ArH), 7.63
(t, J ) 7.32 Hz, 1H, ArH), 7.70-7.74 (m, 2H, ArH), 7.82 (d, J
) 9.04 Hz, 1H, ArH), 7.87-7.93 (m, 4H, ArH), 9.32 (dd, J )
8.42, 2.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 13.6,
16.0, 121.0, 122.4, 124.8, 126.5, 126.9, 127.6, 128.3, 128.9,
129.6, 131.0, 132.3, 133.8, 134.2, 136.6, 140.5, 145.5, 154.4,
197.2; MS m/z 343 (M+, 66.7). Anal. Calcd for C22H17NOS
(343.43): C, 76.94; H, 4.99; N, 4.08. Found: C, 76.72, H, 5.12;
N, 4.15.
General Procedure for Vilsmeier Cyclization of Bis-
ketene-N,S-acetals 5, 8, and 11: Synthesis of Condensed
Quinolines 7, 10, and 12. The bisquinolines 7 and 12 were
prepared following a similar procedure for quinolines 2 by
adding 2.5 mmol of N,S-acetal in DMF (5 mL) to Vilsmeier
reagent prepared from DMF (0.48 mL, 6.25 mmol) and POCl3
(0.58 mL, 6.25 mmol).
3,9-Dibenzoyl-2,8-(bismethylthio)pyrido[2,3-h]quino-
line (7): yield 48% (0.57 g); bright yellow solid (CHCl3-
hexane); mp 186-187 °C; Rf 0.77 (4:1 hexanes-EtOAc); IR
(KBr) 2918, 1651, 1598, 1446 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.53 (s, 3H, SCH3), 2.72 (s, 3H, SCH3), 7.51 (q, J ) 14.64,
7.32 Hz, 4H, ArH), 7.62-7.66 (m, 2H, ArH), 7.83 (d, J ) 7.32
Hz, 2H, ArH), 7.89-7.94 (m, 4H, ArH), 8.13 (s, 1H, ArH), 9.42
(s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 13.9, 13.9, 120.9,
3H, SCH3), 7.09-7.17 (m, 2H, ArH), 7.25 (t, J ) 6.8 Hz, 2H,
ArH), 7.44-7.48 (m, 5H, ArH), 7.54 (t, J ) 7.3 Hz, 1H, ArH),
7.64 (d, J ) 7.8 Hz, 2H, ArH), 7.81 (dd, J ) 6.8, 2.9 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3) δ 15.9, 108.7, 117.2, 125.3,
126.1, 128.7, 128.9, 129.3, 129.5, 129.9, 130.9, 131.0, 132.0,
132.2, 139.6, 141.5, 158.4, 159.4, 159.9, 160.4, 160.9.
General Procedure for Reductive Dethiomethylation
of 2a,b Using Raney-Ni. To a solution of 2a or 2b (1.3 mmol)
in ethanol (25 mL) was added Raney-Ni (W2 or W5, 5 times
by weight), and the suspension was refluxed with stirring for
2-3 h (monitored by TLC). The reaction mixture was then
cooled and filtered through a sintered funnel, and the residue
was washed with ethanol. The filtrate was evaporated under
vacuum to give crude products that were purified by column
chromatography using hexanes-EtOAc (4:1) as eluent.
3-Benzoyl-7-methoxyquinoline (13a): yield 70% (0.24 g);
light brown solid (CHCl3-hexane); mp 79-80 °C; Rf 0.50 (3:2
1
hexanes-EtOAc); IR (KBr) 3058, 1653, 1614, 1485 cm-1; H
NMR (400 MHz, CDCl3) δ 3.99 (s, 3H, OCH3), 7.28 (dd, J )
9.04, 2.44 Hz, 1H, ArH), 7.50-7.55 (m, 3H, ArH), 7.63 (t, J )
8.32 Hz, 1H, ArH), 7.79-7.84 (m, 3H, ArH), 8.54 (s, 1H, ArH),
9.23 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 55.9, 106.7,
121.4, 122.0, 128.1, 128.6, 129.9, 130.3, 132.9, 133.0, 137.1,
139.2, 150.2, 163.2, 194.5; MS m/z 263 (M+, 100). Anal. Calcd
J. Org. Chem, Vol. 68, No. 10, 2003 3973

Mahata et al.
for C17H13NO2 (263.27): C, 77.55; H, 4.98; N, 5.32. Found: C,
77.45, H, 4.72; N, 5.50.
Hz, 1H, ArH), 7.63 (d, J ) 7.32 Hz, 2H, ArH), 8.09 (s, 1H,
ArH), 8.51 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3) δ 13.9,
20.4, 31.4, 41.0, 55.6, 104.5, 113.9, 115.2, 115.7, 128.4, 129.2,
130.6, 131.6, 139.4, 145.6, 148.5, 155.4, 164.2, 198.0; MS m/z
335 (M + 1, 100). Anal. Calcd for C21H22N2O2 (334.41): C,
75.42; H, 6.63; N, 8.38. Found: C, 75.25, H, 6.74; N, 8.44.
3-Benzoyl-2-benzylamino-7-methoxyquinoline (17): yield
93% (0.34 g); yellow solid (CHCl3-hexane); mp 109-110 °C;
Rf 0.85 (8.5:1.5 hexanes-EtOAc); IR (KBr) 1592, 1538, 1401
3-Benzoyl-6,7-dimethoxyquinoline (13c): yield 75% (0.28
g); yellow solid (CHCl3-hexane); mp 142-143 °C; Rf 0.45 (4:1
1
hexanes-EtOAc); IR (KBr) 2935, 1643, 1500, 1254 cm-1; H
NMR (400 MHz, CDCl3) δ 4.00 (s, 3H, OCH3),4.07 (s, 3H,
OCH3), 7.12 (s, 1H, ArH), 7.51 (t, J ) 7.56 Hz, 2H, ArH), 7.60-
7.64 (m, 2H, ArH), 7.80 (m, 2H, ArH), 8.48 (d, J ) 1.97 Hz,
1H, ArH), 9.08 (d, J ) 1.92 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 56.2, 56.5, 106.0, 106.9, 122.7, 128.6, 129.9, 132.9,
137.2, 137.6, 145.9, 147.4, 150.9, 155.0, 175.6, 194.5; MS m/z
293 (M+, 60). Anal. Calcd for C18H15NO3 (293.31): C, 73.70;
H, 5.15; N, 4.78. Found: C, 73.57, H, 5.22; N, 4.84.
1
cm-1; H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H, OCH3), 4.96
(brs, 2H, N-CH2), 6.83 (d, J ) 8.76 Hz, 1H, ArH), 7.27 (d, J
) 7.32 Hz, 1H, ArH), 7.34 (t, J ) 7.56 Hz, 2H, ArH), 7.40 (d,
J ) 8.8 Hz, 1H, ArH), 7.45-7.51 (m, 5H, ArH), 7.58 (t, J )
7.32 Hz, 1H, ArH), 7.64 (d, J ) 7.32 Hz, 2H, ArH). 8.15 (s,
1H, ArH), 8.86 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3) δ
45.2, 55.6, 104.8, 114.0, 115.5, 116.1, 127.1, 127.9, 127.9, 128.4,
128.5, 128.6, 129.2, 129.6, 130.5, 131.7, 131.9, 139.3, 145.4,
197.9; MS m/z 368 (M+, 100). Anal. Calcd for C24H20N2O2
(368.42): C, 78.24; H, 5.47; N, 7.60. Found: C, 78.33, H, 5.51;
N, 7.42.
Procedure for Synthesis of 2-Anilinoquinoline 18 from
2-Methylthiosulfonylquinoline 15a. A mixture of 15a (0.17
g, 0.5 mmol) and aniline (0.22 mL, 2.5 mmol) in 25 mL of
conical was irradiated by domestic microwave oven for 5 min.
The reaction mixture was cooled and purified by column
chromatography over silic agel using hexanes-EtOAc as
eluent to afford 18.
Procedure for Oxidation of Quinoline 2e to Quinone
14 with NBS/H2SO4. A suspension of 2e (0.34 g, 1.0 mmol),
NBS (0.19 g, 1.1 mmol) in THF (10 mL), water (3 mL), and
sulfuric acid (0.05 mL) at room temperature was rigorously
stirred for 10 min followed by basification with aqueous
NaHCO3 solution (10 mL). The reaction mixture was extracted
with CHCl3 (3 × 20 mL), washed with water (2 × 25 mL), dried
(Na2SO4), and evaporated under vacuum to give crude product
14, which was purified by column chromatography over silica
gel using hexanes-EtOAc (20:1) as eluent.
3-Benzoyl-2-methylthioquinoline-5,8-quinone (14): yield
70% (0.22 g); yellow solid (CHCl3-hexane); mp 79-80 °C; Rf
0.55 (4:1 hexanes-EtOAc); IR (KBr) 1668, 1577, 1252 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.72 (s, 3H, SCH3), 7.02 (d, J )
10.48 Hz, 1H, ArH), 7.10 (d, J ) 10.52 Hz, 1H, ArH), 7.49 (t,
J ) 8.08 Hz, 2H, ArH), 7.65 (t, J ) 7.56 Hz, 1H, ArH), 7.76 (d,
J ) 7.68 Hz, 2H, ArH), 8.20 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 14.0, 124.1, 129.0, 130.0, 134.1, 134.3, 135.1, 135.9,
138.0, 138.6, 146.6, 167.2, 182.5, 184.0, 193.7; MS m/z 309 (M+,
52.7). Anal. Calcd for C17H11NO3S (309.33): C, 66.00; H, 3.58;
N, 4.53. Found: C, 66.15; H, 3.42; N, 4.64.
2-Anilino-3-benzoyl-7-methoxyquinoline (18): yield 77%
(0.14 g); yellow solid (CHCl3-hexane); mp 168-169 °C; Rf 0.95
(3:1 hexanes-EtOAc); IR (KBr) 1613, 1525, 1210 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 3.94 (s, 3H, OCH3), 6.89 (dd, J )
8.76, 2.44 Hz, 1H, ArH), 7.08 (t, J ) 7.32 Hz, 1H, ArH), 7.15
(d, J ) 2.2 Hz, 1H, ArH), 7.34-7.44 (m, 3H, ArH), 7.51 (t, J )
7.56 Hz, 2H, ArH), 7.60 (t, J ) 7.08 Hz, 1H, ArH), 7.69 (d, J
) 7.32 Hz, 2H, ArH), 7.95 (d, J ) 7.6 Hz, 2H, ArH), 8.21 (s,
1H, ArH), 10.69 (s, 1H, NH); 13C NMR (100 MHz, CDCl3) δ
55.6, 105.3, 114.5, 116.5, 116.7, 118.8, 120.6, 121.5, 122.8,
128.4, 128.8, 129.3, 130.3, 131.9, 139.0, 139.8, 145.5, 153.4,
164.1, 198.1; MS m/z 355 (M + 1, 100). Anal. Calcd for
C23H18N2O2 (354.39): C, 77.95 H, 5.12; N, 7.90. Found: C,
77.74, H, 5.24; N, 8.05.
Procedure for m-CPBA Oxidation of 2-Methylthio-
quinoline 2a to 2-Methylsulfonylquinoline 15a. To a
stirred solution of 2a (0.92 g, 3 mmol) in dry CH2Cl2 (25 mL)
was added dropwise a solution of m-CPBA (1.14 g, 6.6 mmol)
in CH2Cl2 (25 mL) over a period of 30 min. The mixture was
further stirred at room temperature for 3 h, washed with 10%
NaHCO3 solution (2 × 50 mL) and brine (50 mL), dried (Na2-
SO4), and evaporated under vacuum to afford crude product
which was purified by column chromatography over silica gel
using hexanes-EtOAc as eluent.
Procedure for Synthesis of 2-N-(Morpholino)-3-ben-
zoylquinoline 19. A mixture of 15a (0.17 g, 0.5 mmol) and
morpholine (0.43 mL, 5 mmol) was heated at 100 °C for 48 h
monitored by TLC. The reaction mixture was cooled and
purified by column chromatography over silica gel using
hexanes-EtOAc as eluent to afford 19.
3-Benzoyl-7-methoxy-2-methylsulfonylquinoline (15a):
yield 75% (0.76 g); colorless solid (CHCl3-hexane); mp 154-
155 °C; Rf 0.81 (1:4 hexanes-EtOAc); IR (KBr) 3021, 1665,
1
1618, 1478, 1307 cm-1; H NMR (400 MHz, CDCl3) δ 3.34 (s,
3-Benzoyl-7-methoxy-2-morpholinoquinoline (19): yield
70% (0.12 g); light yellow solid (CHCl3-hexane); mp 168-169
°C; Rf 0.75 (3:1 hexanes-EtOAc); IR (KBr) 2847, 1651, 1610,
3H, SO2CH3), 3.97(s, 3H, OCH3), 7.37 (dd, J ) 9.04, 2.44 Hz,
1H, ArH), 7.44 (t, J ) 7.6 Hz, 2H, ArH), 7.57 (dt, J ) 7.81,
0.72 Hz, 2H, ArH), 7.76 (d, J ) 9.04 Hz, 1H, ArH), 7.83 (d, J
) 7.32 Hz, 2H, ArH), 8.16 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 42.4, 55.9, 107.7, 122.9, 124.0, 128.6, 128.9, 129.1,
130.2, 133.9, 136.5, 137.3, 148.7, 155.0, 162.8, 193.7; MS m/z
342 (M + 1, 100). Anal. Calcd for C18H15NO4S (341.37): C,
63.33; H, 4.43; N, 4.10. Found: C, 63.45, H, 4.36; N, 4.21.
Procedure for Synthesis of 2-Aminoquinolines 16 and
17 from 2-Methylsulfonylquinoline 15a. A solution of
2-methylsulfonylquinoline 15a (0.34 g, 1 mmol) and n-butyl-
amine or benzylamine (5 mmol) was refluxed for 8-11 h
(monitored by TLC) in dry THF (25 mL). It was then cooled
and evaporated under reduced pressure to afford the product
16 or 17, which was purified by column chromatography over
silica gel using hexanes-EtOAc as eluent.
1
1494, 1445 cm-1; H NMR (400 MHz, CDCl3) δ 3.35 (brs, 4H,
CH2), 3.37 (brs, 4H, CH2), 3.92 (s, 3H, OCH3), 6.97 (dd, J )
8.78, 2.44 Hz, 1H, ArH), 7.17 (brs, 1H, ArH), 7.44 (t, J ) 7.56
Hz, 2H, ArH), 7.55-7.60 (m, 2H, ArH), 7.79 (d, J ) 8.9 Hz,
2H, ArH), 8.06 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ
49.5, 55.5, 66.2, 105.7, 116.9, 118.2, 122.2, 128.3, 129.4, 130.0,
133.3, 136.6, 140.6, 150.0, 157.4, 162.5, 196.2; MS m/z 349 (M
+ 1, 100). Anal. Calcd for C21H20N2O3 (348.39): C, 72.39; H,
5.79; N, 8.04. Found: C, 72.53, H, 5.85; N, 7.82.
General Procedure for Synthesis of Pyrazolo[2,3-b]-
quinolines 20a,c,i. A mixture of quinolines (2a-i) (2 mmol)
and excess hydrazine hydrate (0.8 mL, 20 mmol) (80%) and
PTSA (100 mg) in a 25 mL beaker was irradiated by a domestic
microwave oven for 3 min (monitored by TLC). The reaction
mixture was cooled, dissolved in CHCl3 (100 mL), washed with
water (2 × 50 mL), dried (Na2SO4), and then evaporated under
reduced pressure to afford crude product which was purified
by column chromatography using hexanes-EtOAc as eluent.
In the case of 20i, pure product was obtained by recrystalli-
zation from hexane-CHCl3 (1:9) mixture.
3-Benzoyl-2-butylamino-7-methoxyquinoline (16): yield
86% (0.28 g); yellow solid (CHCl3-hexane); mp 98-99 °C; Rf
0.95 (3:1 hexanes-EtOAc); IR (KBr) 2926, 1608, 1533, 1397
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.99(t, J ) 7.32 Hz, 3H,
CH3), 1.48-1.53 (m, 2H, CH2), 1.68-1.74 (m, 2H, CH2), 3.70
(d, J ) 5.12 Hz, 2H, N-CH2), 3.92 (s, 3H, OCH3), 6.78 (dd, J
) 8.8, 2.2 Hz, 1H, ArH), 7.12 (brs, 1H, ArH), 7.36 (d, J ) 8.76
Hz, 1H, ArH), 7.48 (t, J ) 7.32 Hz, 2H, ArH), 7.57 (t, J ) 7.32
7-Methoxy-3-phenylpyrazolo[3,4-b]quinoline (20a): yield
71% (0.39 g); yellow solid (CHCl3-hexane); mp 217-218 °C;
3974 J. Org. Chem., Vol. 68, No. 10, 2003

Reactions of R-Oxoketene-N,S-arylaminoacetals
Rf 0.40 (1:1 hexanes-EtOAc); IR (KBr) 2840, 1620, 1498, 1222
7.42 (m, 3H, ArH), 7.64 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 12.8, 56.0, 56.1, 105.4, 105.5, 107.0, 107.1, 120.6,
123.4, 125.8, 128.4, 134.9, 137.3, 145.48, 149.1, 153.2, 155.5.
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H, OCH3), 7.17
(dd, J ) 9.04, 2.44 Hz, 1H, ArH), 7.47-7.51 (m, 2H, ArH), 7.58
(t, J ) 7.8 Hz, 2H, ArH), 7.89 (d, J ) 9.04 Hz, 1H, ArH), 8.07
(d, J ) 7.56 Hz, 2H, ArH), 8.86 (s, 1H, ArH); 13C NMR (100
MHz, CDCl3) δ 55.7, 104.3, 113.3, 118.7, 120.3, 127.2, 128.8,
129.0, 130.5, 131.7, 132.9, 145.3, 149.3, 152.5, 162.5; MS m/z
275 (M+, 74.07). Anal. Calcd for C17H13N3O (275.29): C, 74.17;
H, 4.76; N, 15.26. Found: C, 74.27, H, 4.63; N, 15.34.
General Procedure for TBTH-Mediated Radical Cy-
clization of Quinolines 2b and 2d. A solution of quinoline
(2b or 2d) (0.72 mmol) in toluene (70 mL) and TBTH (0.50
mL, 1.8 mmol) and AIBN (catalytic) was refluxed for 8-10 h
under nitrogen atmosphere (monitored by TLC). The reaction
mixture was cooled, evaporated under vacuum, extracted with
CHCl3 (3 × 50 mL), washed with water (2 × 50 mL), dried
(Na2SO4), and evaporated to give pure products which were
recrystallized from hexane/CHCl3 mixture.
6,7-Dimethoxy-3-phenylpyrazolo[3,4-b]quinoline (20c):
yield 74% (0.45 g); yellow solid (CHCl3-hexane); mp 250-251
°C; Rf 0.45 (2:3 hexanes-EtOAc); IR (KBr) 2927, 1621, 1497,
1
1245 cm-1; H NMR (400 MHz, CDCl3) δ 4.01 (s, 3H, OCH3),
7-Methoxybenzothiopyrano[2,3-b]quinoline (21b): yield
4.07 (s, 3H, OCH3) 7.14 (s, 1H, ArH), 7.41-7.45 (m, 2H, ArH),
7.53 (t, J ) 7.6 Hz, 2H, ArH), 8.05 (d, J ) 7.8 Hz, 2H, ArH),
8.69 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 56.0, 56.3,
105.4, 105.7, 113.0, 120.4, 127.1, 128.5, 128.9, 128.9, 133.3,
144.3, 145.4, 148.4, 151.9, 154.5; MS m/z 305 (M+, 100). Anal.
Calcd for C18H15N3O2 (305.32): C, 70.80; H, 4.95; N, 13.76.
Found: C, 70.65, H, 5.12; N, 13.82.
98% (0.21 g); yellow solid (CHCl3-hexane); mp 239-240 °C; Rf
0.40 (9:1 hexanes-EtOAc); IR (KBr) 1629, 1487, 1373 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H, OCH3), 7.23 (dd, J
) 9.04, 2.44 Hz, 1H, ArH), 7.36 (d, J ) 2.16, 1H, ArH), 7.49
(t, J ) 8.04 Hz, 1H, ArH), 7.62-7.68 (m, 2H, ArH), 7.91 (d, J
) 9.0 Hz, 1H, ArH), 8.59 (d, J ) 8.42 Hz, 1H, ArH), 9.27 (s,
1H, ArH); 13C NMR (100 MHz, CDCl3) δ 55.9, 105.2, 120.9,
121.9, 122.5, 126.3, 126.4, 128.5, 130.0, 131.0, 133.1, 137.2,
139.3, 157.3, 164.1, 181.0, 187.9; MS m/z 293 (M+, 100). Anal.
Calcd for C17H11NO2S (293.33): C, 69.60; H, 3.78; N, 4.78.
Found: C, 69.74, H, 3.63; N, 4.85.
10H-3-Phenylbenzo[h]pyrazolo[3,4-b]quinoline (20i):
yield 85% (0.50 g); light yellow solid (CHCl3-hexane); mp 270-
271 °C; Rf 0.60 (9:1 hexanes-EtOAc); IR (KBr) 3174, 1615,
1499, 1377 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J )
7.32 Hz, 1H, ArH), 7.51 (t, J ) 7.56 Hz, 2H, ArH), 7.62-7.68
(m, 3H, ArH), 7.77 (d, J ) 8.8 Hz, 1H, ArH), 7.83-7.85 (m,
1H, ArH), 8.06 (d, J ) 8.08 Hz, 2H, ArH), 8.87 (s, 1H, ArH),
9.29 (d, J ) 7.7 Hz, 1H, ArH); 13C NMR (100 MHz, DMSO-d6)
δ 112.9, 121.8, 124.2, 124.4, 126.1, 126.4, 126.4, 127.4, 127.8,
128.3, 128.5, 129.7, 130.4, 133.0, 133.7, 142.9, 145.9, 151.8;
MS m/z 295 (M+, 100). Anal. Calcd for C20H13N3 (295.32): C,
81.34; H, 4.44; N, 14.23. Found: C, 81.21, H, 4.57; N, 14.31.
Procedure for Preparation of Hydrazone 21c. To a
stirred solution of 2c (0.33 g, 1 mmol) in 95% ethanol was
added excess hydrazine hydrate (80%), and the mixture was
refluxed for 4 h and monitored by TLC. The reaction mixture
was cooled, solvent removed under vacuum, poured into ice-
cold water, extracted with CHCl3 (2 × 25 mL), washed with
H2O (2 × 20 mL) and brine (25 mL), dried (Na2SO4), and
concentrated to give crude product which was recrystallized
from hexanes-EtOAc (20:1) mixture.
6,7-Dimethoxybenzothiopyrano[3,4-b]quinoline (21d):
yield 98% (0.23 g); yellow solid (CHCl3-hexane); mp 274-275
°C; Rf 0.45 (9:1 hexanes-EtOAc); IR (KBr) 1634, 1507, 1265
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H, OCH3), 4.06
(s, 3H, OCH3) 7.19 (s, 1H, ArH), 7.36 (s, 1H, ArH), 7.45-7.49
(m, 1H, ArH), 7.60-7.66 (m, 2H, ArH), 8.57 (d, J ) 8.43 Hz,
1H, ArH) 9.17 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 56.2,
56.5, 105.9, 106.0, 122.4, 122.8, 126.3, 126.5, 128.5, 130.1,
132.9, 137.3, 137.4, 147.4, 150.3, 154.5, 156.2, 181.0; MS m/z
324 (M + 1, 90). Anal. Calcd for C18H13NO3S (323.35): C, 66.86;
H, 4.05; N, 4.33. Found: C, 66.69, H, 4.16; N, 4.42.
Acknowledgment. P.K.M., C.V., and U.K.S.K. thank
CSIR, New Delhi, for senior research fellowships.
Financial assistance under a DST project is also ac-
knowledged.
2-Methylthio-6,7-dimethoxy-quinoyl-3-phenylhydra-
zone (21c): yield 99% (0.35 g); colorless solid (CHCl3-hexane);
mp 199-200 °C; Rf 0.4 (1:4 hexanes-EtOAc); IR (KBr) 3424,
Supporting Information Available: 1H and 13C NMR
spectral data for compounds 1b-g,l. This material is available
free of charge via the Internet at http://pubs.acs.org.
3297, 1586, 1499, 1239 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.58 (s, 3H, SCH3), 3.91 (s, 3H, OCH3), 4.01 (s, 3H, OMe), 6.94
(s, 1H, ArH), 7.18 (s, 1H, ArH) 7.21-7.25 (m, 2H, ArH), 7.40-
JO034053L
J. Org. Chem, Vol. 68, No. 10, 2003 3975