Synthesis of 5-substituted-1H-indol-2-yl-1H-quinolin-2-ones: A novel class of KDR kinase inhibitors

Article abstract of DOI:10.1021/jo0480545

(Chemical Equation Presented) A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of trimethylsilylnitrobenzene 26

Full text of DOI:10.1021/jo0480545

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones: A
Novel Class of KDR Kinase Inhibitors
Jeffrey T. Kuethe,* Audrey Wong, Chuanxing Qu, Jacqueline Smitrovich, Ian W. Davies, and
David L. Hughes
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
Received November 2, 2004
A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found
in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of
trimethylsilylnitrobenzene 26 with 2-methoxy-3-quinolinecarboxaldehyde 28 afforded alcohol 30,
which was the key intermediate for the preparation of the target compounds. Conversion of alcohol
30 to either nitroketone 36 or nitrostyrene 45 set the stage for reductive cyclization and the
formation of indole 25. The quinolin-2-one functionality was unmasked in the last step to provide
compound 1 in 56-60% overall yield from readily available starting materials.
Tyrosine kinases are a class of enzymes which are
believed to play a critical role in signal transduction in
a number of cellular functions and have been implicated
in a wide range of diseases and conditions including
angiogenesis, cancer, tumor growth, atherosclerosis,
diabetic retinopathy, and inflammatory diseases to name
a few.1 The kinase insert domain receptor (KDR) is a
tyrosine kinase that has a high affinity for vascular
endothelial growth factor (VEGF) and is believed to be a
primary mediator of tumor induced angiogenesis.2 Com-
pounds which inhibit, modulate, or regulate the KDR
receptor are useful for the prevention and treatment of
tumor induced angiogenesis. As part of a program to
discover and develop inhibitors of KDR kinase activity,
Merck has identified a number of potent and selective
structural feature of these molecules is the indol-2-yl
quinolin-2-one ring system bearing a substituent in the
5-position of the indole ring. In this Article we describe
our synthetic efforts toward the construction of the indol-
2-yl-quinolin-2-one ring system, the key pharmacophore
present in compounds 1-4.6
KDR inhibitors such as compounds 1-4.3-5 The key
(1) (a) Carmeliet, P.; Jain, R. K. Nature 2000, 407, 249. (b) Folkman,
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D. C.; Hoffman, W. F.; Hungate, R. W.; Kohl, N. E.; Mao, X.; McFall,
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Results and Discussion
The indole nucleus is probably the most widely dis-
tributed heterocyclic ring system found in nature. Due
to the existence of a vast array of structurally diverse
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US2002/0041880 A1, 2000. (b) Fraley, M. E.; Arrington, K. L.; Bilodeau,
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10.1021/jo0480545 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/25/2005
J. Org. Chem. 2005, 70, 2555-2567
2555

Kuethe et al.
SCHEME 1
and biologically active indoles, it is not surprising that
the indole nucleus is an important feature in many
medicinal agents.7 Conventional approaches to 2-aryl
indoles typically rely upon cross coupling of 2-indolyl
halides, boronic acids, or stannanes and silanes.8 Al-
though effective methods are available for the prepara-
tion of 2-indolyl boronic acids and silanes,9 the major
limitation with most of these approaches is the additional
steps needed for the preparation of the coupling partners
to enter the palladium-catalyzed reaction. A number of
innovative methods for the synthesis of indoles have been
developed;10 however, many have limitations due to harsh
reaction conditions which may interfere with other sensi-
tive functionality often located within the target mol-
ecule. Therefore, mild synthetic methods which provide
rapid assembly of the indole ring and tolerate a wide
range of functional groups continue to offer significant
advantages.
Retrosynthetic analysis of 1 revealed there may be a
number of intriguing methods of constructing the indol-
2-yl-quinolin-2-one ring system (Scheme 1). The Suzuki-
Miyaura cross coupling of indolyl boronic acid 5 and
3-bromo-1H-quinolin-2-one 6 for the synthesis of 1 has
previously been described.4b,11 Using this cross-coupling
approach, a great deal of effort was pre-invested in the
preparation of appropriately functionalized 5-substituted
indole 5, which in this case may be assembled via a
Fischer indole reaction of p-bromophenylhydrazone, cya-
nation, reduction, and finally amination with a protected
piperazine moiety. Formation of the iodoquinolinone 6
was a two-step process. After the cross-coupling step, two
additional steps were required to complete the synthesis.
Approaches which centered on the formation of the indole
ring as the key step for the preparation of 1-4 were
particularly attractive. Reactions leading to increasing
molecular complexity are important synthetic tools, and
it was envisioned that construction of the indole ring as
the key synthetic step would allow for the preparation
of intermediates from readily available starting materi-
als. For example, the indole ring could be prepared by a
(7) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Sundberg, R. J. Pyrroles and Their Benzoderiva-
tives: Synthesis and Applications. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, UK,
1984; Vol. 4, pp 313-376. (c) Sundberg, R. J. In Best Synthetic Methods,
Indoles; Academic Press: New York, 1996; pp 7-11. (d) Joule, J. A.
Indole and its Derivatives. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Thomas, E. J., Ed.; George
Thieme Verlag: Stuttgart, Germany, 2000; Category 2, Vol. 10,
Chapter 10.13. (e) Brown, R. K. In Indoles; Houlihan, W. J., Ed.; Wiley-
Interscience: New York, 1972.
(8) (a) Johnson, C. N.; Stemp, G.; Anand, N.; Stephen, S. C.;
Gallagher, T. Synlett 1998, 1025. (b) Danieli, B.; Lesma, G.; Martinelli,
M.; Passarell, D.; Perettlo, I.; Silvani, A. Tetrahedron 1998, 54, 14081.
(c) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155. (d)
Caron, S.; Hawkins, J. M. J. Org. Chem. 1998, 63, 2054. (e) Hiyama,
T. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1988; Chapter 10. (f)
Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051.
(g) Mowery, M.; DeShong, P. J. Org. Chem. 1999, 64, 1648. (h) Lee, H.
M.; Nolan, S. P. Org. Lett. 2000, 2, 2053. (i) Denmark, S. E.; Wehrli,
D. Org. Lett. 2000, 2, 565. (j) Denmark, S. E.; Neuville, L. Org. Lett.
2000, 2, 3221. (k) Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61. (l)
Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6, 3649.
(11) (a) Payack, J.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara,
J. J. Org. Chem. 2005, 70, 175. (b) For the synthesis of a related
compound utilizing the same stategy, see: Fraley, M. A.; Arrington,
K. L.; Buser, C. A.; Ciecko, P. A.; Coll, K. E.; Fernandes, C.; Hartman,
G. D.; Hoffman, W. F.; Lynch, J. J.; McFall, R. C.; Rickert, K.; Singh,
R.; Smith, S.; Thomas, K. A.; Wong, B. K. Bioorg. Med. Chem. Lett.
2004, 14, 351.
(9) Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem. 2002,
67, 7551.
(10) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045
and references therein. (b) Gribble, G. W. Pure Appl. Chem. 2003, 75,
1417.
2556 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
SCHEME 2
Fischer-indole cyclization of hydrazone 7, by a palladium-
mediated annulation of bromoimine 8, or reductive
cyclization of nitro styrene 9 or nitro ketone 10. Each of
these routes offered the possibility of improved synthetic
efficiency and would provide the indol-2-yl-quinolin-2-one
ring system of the target molecules in a limited number
of synthetic steps and better atom economy. Due to the
insoluble properties associated with the 1H-quinolin-2-
one ring system of 1 and all related intermediates, the
readily available and easily hydrolyzed methoxy and
chloro protected quinolines were employed for the pal-
ladium-mediated annulation and reductive cyclization
approaches. These quinolinone protecting groups were a
key design feature and imparted a significant degree of
solubility to synthetic intermediates.
Fischer-Indole Approach. Of the many methods
developed for the synthesis of indoles, the Fischer-indole
reaction is perhaps the most employed method and
involves the acid-mediated or thermal sigmatropic rear-
rangement of an N-arylhydrazone.12 It was envisioned
that rearrangement of hydrazone 7 would provide the
desired 1H-indol-2-yl-1H-quinolin-2-one ring system of
1 in four linear steps (Scheme 2). To this end, reaction
of 4-bromobenzyl bromide 11 with 1-methanesulfonylpip-
erazine (12)13 gave bromide 13 in 91% yield. Palladium-
catalyzed cross coupling of 13 with benzophenone hydra-
zone in the presence of Pd(OAc)2/BINAP14 provided
hydrazone 14 in quantitative yield. Hydrolysis of 14 with
concentrated HCl in the presence of ketone 15 afforded
hydrazone 16 in 90% isolated yield as the dihydrochloride
salt. After considerable experimentation with a variety
of Bro¨nsted and Lewis acids in a number of solvent
systems, it was found that the best conditions for effect-
ing the desired Fischer-cyclization to the corresponding
indole required refluxing in methanesulfonic acid (MsOH)
for very short periods of time (<10 min). Under these
conditions compound 1 could be obtained in 45% yield.
The major byproduct of the reaction was identified as
secondary amine 1711a (40%) where the sulfonamide
group was hydrolyzed under the harsh reaction condi-
tions. When the reaction was carried out at lower
temperatures, no conversion to 1 was observed, and
longer reaction times resulted in increased amounts of
17 together with numerous unidentified byproducts.
Under standard Fischer-indole cyclization conditions in
the presence of either a catalytic or a stoichiometric
amount of acid (HCl, H2SO4, TsOH, AcOH, TFA, H3PO4),
Lewis acid (ZnCl2, BF3‚OEt2, PCl3, P2O5), or under
thermal conditions (sealed tube) either no reaction or
significant decomposition to unidentified byproducts was
observed.
Palladium-Catalyzed Annulation Approach. The
cyclization of ortho-substituted anilines has been a
popular method for the construction of the indole nucleus.
For example, indoles have been prepared by palladium-
catalyzed cyclization of o-alkynylanilines under acidic15
and basic conditions16 or by radical cyclization of o-
alkenylbenzonitriles.17 Alternatively, o-haloanilines have
served as useful precursors to indoles by palladium cross-
coupling reaction followed by Rh-catalyzed hydroformy-
lation of the Heck adducts.18 The indole nucleus has also
been prepared from o-haloanilines by other palladium-
catalyzed couplings.19 Recently, the photostimulated
reactions of o-iodoanilines with carbanions by an SRN
1
mechanism for the preparation of 2-substituted and fused
indoles have been reported.20 While each of these meth-
(15) Cachi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem.
1994, 475, 289.
(16) (a) Kondo, Y.; Sakamoto, H. Heterocycles 1989, 29, 1013. (b)
Kondo, Y.; Kojima, S.; Sakamoto, H. J. Org. Chem. 1997, 62, 6507.
(17) Fukuyama, T.; Chen, X.; Peng, G. A. J. Am. Chem. Soc. 1994,
116, 3127.
(18) Dong, Y.; Busacca, C. A. J. Org. Chem. 1997, 62, 6464.
(19) (a) Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org.
Chem. 1980, 45, 2709. (b) Kasahara, A.; Izumi, T.; Murakami, S.;
Yanai, H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927. (c) Larock,
R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291. (d) Larock, R. C.;
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Zenner, J. M. J. Org. Chem. 1995, 60, 482. (f) Desarbre, E.; Merour,
J.-Y. Tetrahedron Lett. 1996, 37, 43 and references therein. (g) Chen,
C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J.
Org. Chem. 1996, 62, 2676.
(12) For reviews on the Fischer indole reaction, see: (a) Robinson,
B. The Fischer Indole Synthesis; Wiley-Interscience: New York, 1982.
(b) Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607. (c) Gribble, G.
W. Contemp. Org. Synth. 1994, 1, 1 and references therein.
(13) Jacob, R. M. German Patent DE 828695, 1950.
(14) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 6621. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 10251.
J. Org. Chem, Vol. 70, No. 7, 2005 2557

Kuethe et al.
When TiCl4 was used as the dehydrating reagent,23 only
low conversion to 24 (30%) was noted even after pro-
longed reaction times. After extensive experimentation,
the use of P(OEt)3 as the dehydrating reagent in conjunc-
tion with a catalytic amount of H3PO4 in refluxing DMF
afforded the best results, giving bromoimine 24 in 67%
yield. Reaction of crude 24 with 3 mol % of Pd(OAc)2, 3
mol % of P(o-tolyl)3, and NEt3 in refluxing DMF in an
unoptimized process gave the methoxy-protected deriva-
tive 25 in 37% overall yield from 21. The difficulty
encountered with the formation of imine 24 and the low
isolated yield of 25 made this route less attractive than
other routes that were under parallel investigations (vida
infra).
SCHEME 3
Reductive Cyclization of Nitro Ketone 10. Reduc-
tive cyclization of 2-nitrobenzylcarbonyl compounds is one
of the oldest methods for the construction of indoles and
indolinones.7 The reductive cyclization of 2-nitrobenzyl-
carbonyl compounds has been carried out with a variety
of reagents including H2/Pd,24 H2/RaNi,25 SnCl2,26
Fe/AcOH,27 Zn/AcOH,28 TiCl3/NH4OAc,29 and Na2S2O3.30
However, the availability of starting materials has
severely limited the utility of this approach. Recent
advances by Buchwald,29a Rawal,29b RajanBabu,31 and
others32 have given ready access to 2-nitrobenzylcarbonyl
compounds which are conveniently converted to substi-
tuted indoles. While these methods are noteworthy, there
is still a need for methods which provide highly func-
tionalized 2-nitrobenzylcarbonyl compounds and their
subsequent conversion to indoles. The reductive cycliza-
tion of nitroketone 3633 was investigated in an effort to
overcome the limitations of the Fischer-indole and pal-
ladium-catalyzed annulation approaches for the synthesis
of the target compound.
ods was considered for the preparation of 1, the pal-
ladium-catalyzed annulation between an o-haloaniline 21
and ketone 23 offered a highly convergent approach to
the indol-2-yl-quinolin-2-one ring system found in 1-4.
The synthesis of o-bromoaniline 21 began with 4-ni-
trobenzyl bromide 18 (Scheme 3). Reaction of 18 with 12
for 2 h in DMF in the presence of K2CO3 at room
temperature afforded nitro derivative 19 in 95% isolated
yield. Alternatively, reaction of 18 with excess piperazine
followed by mesylation gave 19 in 65% overall yield.
Catalytic hydrogenation of 19 gave aniline 20 (85%),
which was brominated with KBr, NaBO3 in the presence
of a catalytic amount of (NH4)6Mo7O24 in acetic acid21 and
furnished o-bromoaniline 21 in 78% yield. Bromide 21
could also be prepared from aniline 2222 by reductive
amination with sodium triacetoxyborohydride in the
presence of 12 and gave 21 in 70% yield. Reaction of 21
with ketone 23 in the presence of a catalytic amount of
Pd(OAc)2 and DABCO18g did not afford indole 25. The
only detectable reaction product was aniline 20 arising
from debromination of 21 under the reaction conditions.
Since imine formation appeared to be problematic, efforts
to convert 21 to bromoimine 24 were investigated.
Reaction of 21 with 23 in refluxing toluene with water
removal via either a Dean-Stark trap or molecular sieves
did not afford any of the desired bromoimine 24. Other
dehydrating reagents (MgSO4, Cl2CHCO2H, and B(OiPr)3
also did not give any detectable amounts of imine 24.
Our first goal was the development of an efficient
synthesis of nitroketone 36. Inspired by the unique
versatility of nitrobenzenes to serve as both nucleophilic
and electrophilic partners, nitrobenzene 19 was an at-
(23) Weingarten, H.; Chupp, J. P.; White, W. A. J. Org. Chem. 1967,
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(b) Lindwall, H. G.; Mantell, G. J. J. Org. Chem. 1953, 18, 345.
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Lobachevsky, P. Aust. J. Chem. 1998, 51, 243. (b) Finger, G. C.;
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(20) Barolo, S. M.; Lukach, A. E.; Rossi, R. A. J. Org. Chem. 2003,
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(33) For a preliminary account of this work, see: Wong, A.; Kuethe,
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(22) Liedholm, B. J. Chem. Soc., Perkin Trans. 1 1992, 2235.
2558 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
SCHEME 4
tractive starting material. Addition of trimethylsilyl-
methylmagnesium chloride to a solution of 19 in THF at
-15 °C followed by oxidation of the resulting nitronate
intermediate with DDQ34 gave addition compound 26 in
85% yield (Scheme 4). Alternatively, the oxidation could
be carried out with p-chloranil and gave 26 in 83% yield.
The corresponding workup of each of these reactions
proved difficult when conducted on a larger scale (>10
g) due to the difficulty in removing the DDQ or chloranil
byproducts. After experimentation with a variety of
oxidants, it was discovered that the nitronate intermedi-
ate was cleanly oxidized with aqueous 1 N iodine solu-
tion, which greatly simplified the workup and gave 26
in 85% yield. The higher purity of crude 26 after the
aqueous iodine workup allowed for its use in the subse-
quent reaction without the need for chromatography.
Treatment of 26 with catalytic tetrabutylammonium
fluoride (TBAF, 0.10 mol %) in the presence of com-
mercially available aldehyde 27 afforded the desired
alcohol 29 in 56% isolated yield.35 The major byproduct
of this reaction was identified as 1,4-dihydroquinoline 31.
Presumably, 31 arises by addition of the carbanion to the
4-position of 27 in Michael-type fashion. Compound 31
decomposes in solution to a mixture of aldehyde 27,
peroxide 32, alcohol 33, and aldehyde 34, which made
the isolation of 31 difficult.36 We speculate that retroad-
dition of 31 would give the nitrostabilized anion (pKa )
25).37 Subsequent reaction with molecular oxygen occurs
to give 32. Compounds 33 and 34 most likely are derived
from the known decomposition pathways of 32.38 To
eliminate these unwanted side reactions between the
anion of 26 and the 4-position of the quinoline moiety,
the electron-rich 2-methoxy-3-quinoline carboxaldehyde
2839 was used. Treatment of 26 with catalytic TBAF in
the presence of 28 furnished alcohol 30 in 89% yield.
Gratifyingly, there was no evidence of the formation of
products of type 31 in the crude reaction mixture.
The oxidation of alcohols 29 and 30 was next examined.
To avoid the oxidation of the piperazine nitrogen to the
N-oxide, mild oxidative conditions were required. Oxida-
tion of 30 under standard Swern oxidation conditions
employing oxalyl chloride in DMSO40 provided chloroke-
tone 35 as the major product in 47% yield (Scheme 5).
The formation of 35 was unexpected but not unprec-
edented41 and most likely arises from deprotonation of
the initially formed ketone 36 with NEt3 followed by
reaction with excess activated DMSO. On the other hand,
oxidation of 30 with DMSO/Ac2O42 in a solution of
isopropyl acetate at 80 °C provided the desired ketone
36 in 78% yield. Also detected in the crude reaction
mixture was sulfide 38 (10%) and acetate 39 (3%). The
formation of 38 and 39 proved to be unavoidable, but
these impurities were effectively removed by the direct
crystallization of 36 from the crude reaction mixture. In
similar fashion, oxidation of 29 gave ketone 37 in 38%
yield.
With nitroketones 36 and 37 in hand, our attention
turned to the reductive cyclization of these substrates.
(38) Santamaria, J.; Jroundi, R. Tetrahedron Lett. 1991, 32, 4291.
(39) Wai, J. S.; Williams, T. M.; Bamberger, D. L.; Fisher, T. E.;
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W. S.; Thomas, C. M.; Schleif, W. A.; Anderson, P. S. J. Med. Chem.
1993, 36, 249. Also see the Experimental Section.
(40) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(41) For the chlorination of ketones under Swern conditions see:
Tidwell, T. T. Synthesis 1990, 857 and references therein.
(42) (a) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87,
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(36) Compounds 31-34 were identified by careful analysis of the
NMR of the crude reaction mixture and by comparison to previously
reported structures: see ref 6.
(37) Lelievre, J.; Farrell, P. G.; Terrier, F. J. Chem. Soc., Perkin
Trans. 2 1986, 333.
J. Org. Chem, Vol. 70, No. 7, 2005 2559

Kuethe et al.
construction of indoles.47 While a number of transition
metal catalysts have been employed including platinum,
rhodium, ruthenium, iron, nickel, and tin complexes,
complexes of palladium remain the most synthetically
useful.43,48
SCHEME 5
The preparation and reductive cyclization of nitrosty-
rene 45 is outlined in Scheme 7. Treatment of crude 30
with TFAA followed by elimination of the corresponding
trifluoroacetate with DBU at 60 °C afforded trans-
nitrostyrene 45 in 80% yield for the one-pot procedure.49
There was no detectable amount of cis-nitrostyrene 47
formed in reaction, which was unequivocally established
by photolysis of 45 in acetonitrile and gave a 1:1 mixture
of 45 and 47 by 1H NMR and HPLC analysis. In addition,
the use of DBU for the elimination of the trifluoroacetate
intermediate was crucial. When other alkylamine bases
such as NEt3, Hunigs base, or diisopropylamine were
used, little conversion to styrene 45 was observed. The
use of aqueous bases resulted in hydrolysis and alcohol
30 was re-isolated. Nitrostyrene 45 could also be pre-
pared by cross coupling of bromide 21 with methoxy
vinylquinoline 46 to give 45 in 63% yield. The reductive
cyclization of 45 was verified by the classic Cadogan/
Sundberg conditions,44-47 using refluxing P(OEt)3 to give
indole 25 in 65% yield. When the reaction was conducted
in toluene or xylene in the presence of an excess of
P(OEt)3, no reaction was observed. Due to the extremely
high reaction temperatures and difficulty in separation
of the product away from P(OEt)3 and PO(OEt)3, our
attention turned to transition metal catalyzed processes.
Initial investigations into palladium-catalyzed reduc-
tive cyclization of 45 were conducted with the So¨derberg
conditions (6 mol % of Pd(OAc)2, 24 mol % of PPh3, 70
°C, 60 psi of CO).47 These conditions afforded 25 in 95%
yield. The only detectable impurity was identified as
dimer 48, which was formed in 2-3% yield. Subjection
of cis-nitrostyrene 47 to the identical reaction conditions
furnished 25 in 92% yield, thereby establishing that both
cis- and trans-nitrostyrenes could be employed in the
reductive cyclization reaction. Due to the high catalyst
loading and difficulty in removing both triphenylphos-
phine oxide and indole dimer 48 without resorting to
chromatography, the reaction was optimized with regard
to catalyst, ligand, solvent, temperature, and CO pres-
sure.50 Optimized conditions involved heating 45 with 0.1
mol % of Pd(TFA)2, 0.7 mol % of 3,4,7,8-tetrameth-
ylphenanthroline (TMP) in DMF at 80 °C, and 15 psi of
CO and gave 25 in 95% isolated yield with no detectable
amount of dimer 48. These improved reaction conditions
allowed for 25 to be isolated in analytically pure form
after filtering of the reaction mixture over Celite followed
by crystallization of the product by the addition of MeOH.
A variety of conditions were examined for the conversion
of 36 to indole 25 (Scheme 6).33 Optimal conditions for
the conversion of 36 to 25 involved the use of 40 wt % of
Ra/Ni 2800 (H2O), 40 psi of H2, and 65 °C in THF for 7.5
h and gave 25 in 95% yield. Other detectable impurities
present in the crude reaction mixture were identified as
aniline 40 (1.3%) and tolyl derivatives 41 (0.7%) and 42
(0.6%). Each of these impurities was authenticated by
independent synthesis. The isolation of 25 was simply a
matter of filtering the catalyst, concentrating the filtrate,
and adding MeOH, which precipitated the product in
analytically pure form in 90% isolated yield. Reaction of
nitroketone 37 under the optimized reaction conditions
afforded the expected indole 43 in 46% yield. However,
the reductive cyclization of 37 was complicated by the
further reduction of the chloroquinoline to give quinoline
44 in 23% yield.
Reductive Cyclization of Nitrostyrene 11. The
reductive cyclization of aromatic nitrostyrene compounds
for the formation of indoles has received considerable
attention as an important synthetic tool.43 For example,
Cadogan44 and Sundberg45 pioneered the synthesis of a
variety of substituted indoles by the deoxygenation of
aromatic nitro compounds by trivalent phosphorus com-
pounds. Triethyl phosphite is the most commonly used
reagent for this transformation; however, triphenylphos-
phine, phosphorus trihalides, and diethoxy methylphos-
phine have also been employed.46 Transition metal
catalyzed reductive cyclization of aromatic nitro com-
pounds in the presence of carbon monoxide has emerged
in recent years as a highly versatile method for the
The reductive cyclization reactions of nitrostryrenes 50
and 51 were also examined (Scheme 8). Reaction of TMS-
(47) (a) So¨derberg, B. C.; Shiver, J. A. J. Org. Chem. 1997, 62, 5838.
(b) Ragaini, F.; Sportiello, P.; Cenini, S. J. Organomet. Chem. 1999,
577, 283. (c) So¨derberg, B. C.; Rector, S. R.; O’Neil, S. N. Tetrahedron
Lett. 1999, 40, 3657. (d) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron
Lett. 2002, 43, 1621. (e) Dantale, S. W.; So¨derberg, B. C. G. Tetrahedron
2003, 59, 5507.
(48) Tolari, S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal. 1994,
87, 203.
(49) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721.
(50) For a preliminary report see: Smitrovich, J.; Davies, I. W. Org.
Lett. 2004, 6, 533.
(43) For a recent review see: So¨derberg, B. C. G. Curr. Org. Chem.
2000, 4, 727.
(44) (a) Cadogan, J. I. G.; Cameron-Wood, M. Proc. Chem. Soc. 1962,
361. (b) Cadogan, J. I. G.; Mackie, R. K.; Todd, M. J. J. Chem. Soc.,
Chem. Commun. 1966, 491.
(45) (a) Sundberg, R. J. J. Org. Chem. 1965, 30, 3604. (b) Sundberg,
R. J.; Tamazaki, T. J. Org. Chem. 1967, 32, 290.
(46) Cadogan, J. I. G.; Todd, M. J. J. Chem. Soc. 1969, 2808.
2560 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
SCHEME 6
SCHEME 7
SCHEME 8
the HCl salt in quantitative yield. Hydrolysis of chloro-
quinoline 43 in a 1:1 mixture of AcOH/H2O gave freebase
1 in 93% yield.
nitro compound 26 with aldehyde 49 followed by elimina-
tion gave nitrostyrene 50 in 63% overall yield. Nitrosty-
rene 51 (72%) was prepared in analogous fashion from
alcohol 29. Reductive cyclization of each of these com-
pounds with P(OEt)3 afforded 43 (61%) and 44 (72%).
Reaction of each of these substrates under the optimized
conditions for reductive cyclization of 45 (0.1 mol % of
Pd(TFA)2, 0.7 mol % of TMP, 15 psi of CO, DMF, 80 °C)
led to low conversions to 43 and 44, respectively.
The deprotection of the masked quinolin-2-one moiety
of chloroquinoline 43 and methoxyquinoline 25 was
accomplished in a straightforward manner under acidic
conditions. Reaction of 25 with concentrated HCl in DMF
at 70 °C gave the crystalline KDR kinase inhibitor 1 as
Conclusion
In summary, we have demonstrated a number of
concise syntheses of the potent and selective KDR kinase
inhibitor 1. While the Fischer-indole and palladium-
catalyzed annulation approaches provided access to the
1H-indol-2-yl-1H-quinolin-2-one ring system of 1, the
reductive cyclization approaches proved to be an ex-
tremely efficient and high-yielding method for construc-
tion of the target substrates. Reaction of trimethylsilyl
nitro compound 26 with aldehyde 28 provided the key
alcohol intermediate, which could be converted to either
J. Org. Chem, Vol. 70, No. 7, 2005 2561

Kuethe et al.
one (16). To a slurry of 900 mg (2.00 mmol) of 14 and 410 mg
(2.19 mmol) of 15 in 6 mL of a 1:1 mixture of EtOH:toluene
was added 1.00 mL of concentrated HCl. The mixture was then
heated to 100 °C for 12 h and cooled to room temperature,
and the orange solid was filtered. The solid was washed with
1:1 EtOH:toluene (3 mL) and dried in a vacuum oven to give
820 mg (90%) of analytically pure 16: mp 198 °C dec; 1H NMR
(DMSO-d6, 400 MHz) δ 2.24 (s, 3H), 2.94 (s, 3H), 3.04 (m, 2H),
3.30 (m, 4H), 3.65 (d, 2H, J ) 12.7 Hz), 4.20 (s, 2H), 4.60 (br
s, 2H), 7.15 (t, 1H, J ) 7.4 Hz), 7.23 (d, 2H, J ) 8.5 Hz), 7.32
(d, 1H, J ) 8.1 Hz), 7.43 (m, 3H), 7.73 (d, 1H, J ) 7.8 Hz),
8.03 (s, 1H), 11.5 (br s, 1H), 11.90 (br s, 1H); 13C NMR
((CD3)2SO, 100 MHz) δ 16.3, 35.7, 42.7, 50.0, 58.9, 113.3,
115.3, 119.5, 119.8, 122.5, 128.9, 130.8, 132.3, 132.9,
137.5, 139.0, 143.5, 147.3, 161.8. Anal. Calcd for C23H27N5O3S‚
2HCl: C, 52.47; H, 5.55; N, 13.30. Found: C, 52.34; H, 5.64;
N, 12.95.
Fischer-Indole Cyclization of Hydrazone 16. A slurry
of 100 mg (0.230 mmol) of 16 in 2 mL of methanesulfonic acid
was heated to 130 °C for 7 min. The resulting solution was
cooled to room temperature and analyzed by quantitative
HPLC (Zorbax SB C-18, 5 µm, 4.6 × 25 cm, 40 °C, 1.5
mL/min; Elutant A: 0.1% H3PO4/20 mM NaClO4 pH 2.2;
Eluent B: acetonitrile; time ) 0 min, 80% Eluent A/20%
Eluent B; time ) 20 min, 60% Eluent A/40% Eluent B; time
) 35 min, 40% Eluent A/60% Eluent B; retention time for 17
) 8.5 min; retention time for 1 ) 14.0 min). Compound 17
(3-[5-(piperazine-1-ylmethyl)-1H-indol-2-yl]quinolin-2(1H)-
one) was characterized as its bis-HCl salt after stirring the
slurry in 5 N HCl and filtering the resulting solid: mp 332 °C
dec; 1H NMR (DMSO-d6, 400 MHz) δ 3.46 (br m, 8H), 4.42 (s,
2H), 7.20 (t, 1H, J ) 7.8 Hz), 7.38 (m, 3H), 7.46 (t, 1H, J ) 7.1
Hz), 7.56 (d, 1H, J ) 8.4 Hz), 7.69 (d, 1H, J ) 7.8 Hz), 7.81 (s,
1H), 8.61 (s, 1H), 9.90 (br s, 2H), 11.84 (s, 1H), 12.19 (s, 1H);
13C NMR (DMSO-d6, 100 MHz) δ 47.4, 60.0, 102.8, 112.5, 115.5,
119.9, 122.6, 122.9, 124.4, 125.5, 128.4, 130.8, 135.1, 135.4,
137.4, 138.1, 161.0. Anal. Calcd for C22H22N4O‚2HCl: C, 61.26;
H, 5.61; N, 12.99. Found: C, 61.20; H, 5.59; N, 13.09.
Preparation of 1-Methanesulfonyl-4-(4-nitrobenzyl)-
piperazine (19). Method A: To a slurry of 184.0 g (1.12 mol)
of 1-methanesulfonylpiperazine (12)13 and 118.0 g (1.12 mol)
of Na2CO3 in 700 mL of DMF at 0 °C was added dropwise 219.0
g (1.01 mol) of 4-nitrobenzyl bromide 18 in 300 mL of DMF.
After stirring for 2 h at room temperature, the reaction
mixture was cooled to 10 °C and 3 L of water was slowly added
via an addition funnel. The resulting slurry of the product was
stirred for 1 h at room temperature and filtered, and the
product was washed with an additional 500 mL of water. The
product was dried in a vacuum oven at 40 °C to give 300 g
(99%) of 19 as a colorless solid: mp 116-117 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.58 (m, 4H), 2.80 (s, 3H), 3.27 (m, 4H),
3.65 (s, 2H), 7.51 (d, 2H, J ) 8.8 Hz), 8.18 (d, 2H, J ) 8.8 Hz);
13C NMR (CDCl3, 100 MHz) δ 34.5, 46.0, 52.6, 61.8, 123.8,
129.6, 145.7, 147.5. Anal. Calcd for C12H17N3O4S: C, 48.15;
H, 5.72; N, 14.04. Found: C, 48.16; H, 5.52; N, 13.91.
Method B: A solution of 1.0 g (4.63 mmol) of 4-nitrobenzyl
bromide (18) in 5 mL of isopropyl acetate was added dropwise
over a period of 20 min to a stirred solution of 4 g (46.4 mmol)
of piperazine in 8 mL of 95% EtOH. The resulting suspension
was allowed to stir at room temperature for 30 min, filtered
over a pad of Celite, and concentrated under reduced pressure.
The residue was dissolved in 30 mL of isopropyl acetate and
washed with 25 mL of water. The isopropyl acetate layer was
separated and concentrated to a final volume of 20 mL. To
the solution was added 610 mg (6.01 mmol) of NEt3 followed
by 560 mg (4.86 mmol) of methanesulfonyl chloride. After
stirring for 30 min the reaction mixture was filtered over a
pad of Celite and concentrated to a final volume of 20 mL. To
the resulting mixture was added 20 mL of heptane and the
slurry of the product was stirred for 20 min and filtered
affording 900 mg (65%) of 19, which was identical to the
product isolated from Method A.
nitroketone 36 or nitrostyrene 45. Reductive cyclization
of each of these intermediates followed by hydrolysis
provided of the potent and selective KDR kinase inhibitor
1 in six synthetic steps from readily available bulk
chemicals in 56% overall yield for the nitroketone route
and 60% overall yield for the nitrostyrene route.
Experimental Section
Melting points are uncorrected. All solvents and reagents
were used as received from commercial sources. Analytical
samples were obtained by chromatography on silica gel, using
an ethyl acetate-hexane mixture as the eluent unless specified
otherwise. Water content (KF) was determined by Karl Fisher
titration on a Metrohm 737 KF Coulometer.
Preparation of 1-(4-Bromobenzyl)-4-methansulfonyl-
piperazine (13). To a solution of 10 g (40.0 mmol) of
4-bromobenzyl bromide (11) in 75 mL of THF was added 7.25
mL (52.0 mmol) of NEt3 followed by 8.94 g (48.0 mmol) of
1-methanesulfonylpiperazine13 in 20 mL of THF. After stirring
for 3 h, the reaction mixture was diluted with 75 mL of EtOAc
and washed with 100 mL of water. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
crude product was crystallized from an EtOAc/hexane mixture
to give 12.93 g (91%) of 13 as a colorless solid: mp 105-106
1
°C; H NMR (CDCl3, 400 MHz) δ 2.53 (m, 4H), 2.77 (s, 3H),
3.21 (m, 4H), 3.48 (s, 2H), 7.18 (d, 2H, J ) 8.4 Hz), 7.43 (d,
2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 34.2, 46.0,
52.3, 61.9, 121.2, 130.8, 131.6, 136.7. Anal. Calcd for
C12H17BrN2O2S: C, 43.25; H, 5.14; N, 8.41. Found: C, 43.10;
H, 5.12; N, 8.27.
Preparation of N-Benzhydrylidene-N′-[4-(4-methane-
sulfonylpiperazin-1-ylmethyl)phenyl]hydrazine (14). To
a 250 mL round-bottom flask was added sequentially 100 mg
(0.450 mmol) of Pd(OAc)2, 420 mg (0.670 mmol) of racemic
BINAP, 9.72 g (50 mmol) of benzophenone hydrazone, and 90
mL of toluene. The reaction mixture was purged (3×) with
vacuum/nitrogen. The reddish solution was then heated to 105
°C for 5 min and then cooled to room temperature. To the
resulting purple solution was added 15.0 g (45.0 mmol) of
bromide 13 followed by 6.06 g (63.0 mmol) of sodium tert-
butoxide. The reaction mixture was heated to 105 °C for 4 h,
cooled to room temperature, and filtered over a pad of silica
gel eluting with EtOAc. The solvent was removed under
reduced pressure and the residue purified by silica gel chro-
matography to give 20.1 g (100%) of 14 as a light yellow solid:
1
mp 103-104 °C; H NMR (CDCl3, 400 MHz) δ 2.54 (m, 4H),
2.77 (s, 3H), 3.24 (m, 4H), 3.48 (s, 2H), 7.06 (d, 2H, J ) 8.4
Hz), 7.19 (d, 2H, J ) 8.4 Hz), 7.34 (m, 6H), 7.53 (m, 1H), 7.60
(m, 4H); 13C NMR (CDCl3, 100 MHz) δ 34.1, 46.0, 52.5, 62.3,
112.9, 126.6, 128.2, 128.3, 128.9, 129.2, 129.4, 129.8, 130.3,
132.8, 138.4, 144.1, 144.4. Anal. Calcd for C25H28N4O2S: C,
66.94; H, 6.29; N, 12.49. Found: C, 67.08; H, 6.27; N, 12.15.
Preparation of 3-Acetyl-1H-quinolin-2-one (15). To a
solution of 14.5 g (70.5 mmol) of 3-acetyl-2-chloroquinoline48
was added 210 mL of 6 N HCl. The mixture was heated to
reflux for 3 h, cooled to room temperature, and filtered over a
pad of Celite. To the solution was added 750 mL of water,
which precipitated the product as an orange solid. The solid
was filtered and washed with water until the pH of the filtrate
was 7.0. The product was dried in a vacuum oven at 40 °C
under a stream of nitrogen to give 11.1 g (84%) of 15. An
analytical sample was obtained by recrystallization from
EtOAc: mp 236-237 °C; 1H NMR ((CD3)2SO, 400 MHz) δ 2.58
(s, 3H), 7.19 (t, 1H, J ) 7.5 Hz), 7.31 (d, 1H, J ) 8.4 Hz), 7.57
(t, 1H, J ) 7.1 Hz), 7.83 (d, 1H, J ) 7.9 Hz), 8.42 (s, 1H), 12.08
(br s, 1H); 13C NMR ((CD3)2SO, 100 MHz) δ 31.1, 115.5, 118.6,
122.8, 129.8. 130.6, 133.3, 141.0, 143.5, 160.9, 197.8. Anal.
Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C,
70.43; H, 4.78; N, 7.40.
Preparation of 3-(1-{[4-(4-Methanesulfonylpipera-
zin-1-ylmethyl)phenyl]hydrazono}ethyl)-1H-quinolin-2-
2562 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
Preparation of 4-(4-Methanesulfonylpiperazine-1-yl-
methyl)aniline (20). To a solution of 25.0 g (83.5 mmol) of
19 in 1.50 L of EtOAc was added 5.00 g of 5% Pd/C. The
resulting mixture was stirred at room temperature under an
atmosphere of hydrogen (15 psi) for 4 h. The reaction mixture
was filtered over a pad of Celite and concentrated under
reduced pressure to give 19.0 g (84%) of 4-(4-methanesulfo-
nylpiperazin-1-ylmethyl)aniline (20) as a colorless solid: mp
concentrated under reduced pressure. The residue was purified
by silica gel chromatography to afford 239 mg (37%) of 25 as
a light yellow solid: mp 197-198 °C; 1H NMR (CDCl3, 400
MHz) δ 2.61 (m, 4H), 2.78 (s, 3H), 3.27 (m, 4H), 3.66 (s, 2H),
4.31 (s, 3H), 7.07 (s, 1H), 7.18 (dd, 1H, J ) 8.3 and 1.4 Hz),
7.44 (m, 2H), 7.57 (s, 1H), 7.64 (t, 1H, J ) 8.4 Hz), 7.81 (d,
1H, J ) 8.1 Hz), 7.88 (d, 1H, J ) 8.4 Hz), 8.48 (s, 1H), 9.68 (br
s, 1H); 13C NMR (CDCl3, 100 MHz) δ 34.0, 46.0, 52.3, 54.1,
63.3, 101.5, 111.3, 116.8, 121.1, 124.2, 124.8, 125.5, 127.0,
127.6, 128.3, 129.0, 129.6, 134.0, 135.2, 136.0, 145.3, 158.3.
Anal. Calcd for C24H26N4O3S: C, 63.98; H, 5.82; N, 12.44.
Found: C, 64.28; H, 5.68; N, 12.05.
Preparation of 1-Methanesulfonyl-4-(4-nitro-3-tri-
methylsilanylmethylbenzyl)piperazine (26). To a 5.0 L
4-neck flask equipped with a thermocouple and overhead
stirrer was added 1.0 L of THF followed by 184.1 g (0.615 mol)
of solid 19. The sides of the reaction flask were rinsed with
an additional 200 mL of THF and the mixture was cooled to
-20 °C. To the mixture was added dropwise 800 mL of
trimethylsilylmethylmagnesium chloride (0.800 mol, 1.0 M in
ether) at such a rate that the internal temperature did not
rise above -5 °C. The mixture was stirred for 30 min and then
poured directly into 800 mL of 1 N iodine solution and stirred
for 3 h at room temperature. To the biphasic reaction mixture
was added 300 mL of 0.3 M Na2S2O3 pentahydrate and 1.2 L
of isopropyl acetate. The bottom aqueous layer was then
removed. The organic layer was washed with 500 mL of water
and then 500 mL of brine. The isopropyl acetate layer was
then azeotropically dried to a Kf below 200 and a final volume
of 1.3 mL in IPAC for use in the next reaction. Assay amount
of 26: 201.3 g (85%). An analytical sample could be obtained
by crystallization from EtOAc/hexane: mp 57-58 °C; 1H NMR
(CDCl3, 400 MHz) δ -0.01 (s, 9H), 2.57 (m, 4H), 2.59 (s, 2H),
2.79 (s, 3H), 3.25 (m, 4H), 3.55 (s, 2H), 7.11 (s, 1H), 7.16 (d,
1H, J ) 8.4 Hz), 7.90 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3,
100 MHz) δ -1.40, 25.0, 34.4, 45.9, 52.4, 61.7, 125.3, 125.5,
131.7, 137.8, 143.2, 146.9. Anal. Calcd for C16H27N3O4SSi: C,
49.84; H, 7.06; N, 10.90. Found: C, 49.62; H, 7.08; N, 10.82.
Preparation of 2-[5-(4-Methanesulfonylpiperazin-1-
ylmethyl)-2-nitrophenyl]-1-(2-chloroquinolin-3-yl)etha-
nol (29). To a mixture of 9.50 g (24.7 mmol) of 26 and 4.73 g
(24.7 mmol) of aldehyde 27 in 175 mL of isopropyl acetate was
added dropwise 6.20 mL (2.47 mmol) of a 1 M solution of
TBAF. After 30 min, the reaction mixture was diluted with
100 mL of isopropyl acetate and washed with 100 mL of
saturated NH4Cl and 50 mL of water. The organic layer was
dried over MgSO4 and concentrated under reduced pressure
to give 6.95 g (56%) of 29 as a colorless foam: 1H NMR (CDCl3,
400 MHz) δ 2.40 (m, 4H), 2.78 (s, 3H), 2.89 (d, 1H, J ) 4.3
Hz), 3.13 (m, 4H), 3.48 (s, 3H), 3.55 (m, 2H), 5.55 (m, 1H),
7.34 (d, 1H, J ) 1.7 Hz), 7.36 (dd, 1H, J ) 8.4 and 1.7 Hz),
7.61 (m, 1H), 7.78 (m, 1H), 7.92 (d, 1H, J ) 8.4 Hz), 8.03 (d,
1H, J ) 8.4 Hz), 8.32 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
34.3, 40.2, 45.7, 52.2, 61.3, 70.6, 125.0, 127.3, 127.5, 127.8,
128.0, 128.1, 130.7, 132.3, 133.1, 135.5, 136.6, 143.9, 146.9,
148.5, 149.6. Anal. Calcd for C23H25ClN4O5S: C, 54.70; H, 4.99;
N, 11.09. Found: C, 54.76; H, 4.66; N, 11.33.
1
161-162 °C; H NMR (CDCl3, 400 MHz) δ 2.52 (m, 4H), 2.76
(s, 3H), 3.22 (m, 4H), 3.42 (s, 2H), 3.67 (br s, 2H), 6.63 (d, 2H,
J ) 8.4 Hz), 7.06 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100
MHz) δ 34.1, 46.0, 52.1, 62.3, 115.0, 127.2, 130.4, 145.8. Anal.
Calcd for C12H19N3O2S: C, 53.51; H, 7.11; N, 15.60. Found:
C, 53.71; H, 7.09; N, 15.48.
Preparation of 2-Bromo-4-(4-methanesulfonylpiper-
azin-1-ylmethyl)aniline (21). Method A: To a solution of
7.40 g (37.0 mmol) of 4-amino-3-bromobenzaldehyde (22)22 in
100 mL of CH2Cl2 was added 7.90 g (48.1 mmol) of 1-meth-
anesulfonylpiperazine (12)13 followed by 16.0 g (75.5 mmol) of
triacetoxyborohydride. The resulting mixture was stirred for
4 h, quenched with 100 mL of saturated NH4Cl, and extracted
with 150 mL of EtOAc. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography to afford 9.01 g (70%) of 21 as a
colorless solid: mp 117-118 °C; 1H NMR (CDCl3, 400 MHz) δ
2.51 (m, 4H), 2.77 (s, 3H), 3.21 (m, 4H), 3.39 (s, 2H), 4.09 (br
s, 2H), 7.01 (dd, 1H, J ) 8.1 and 1.7 Hz), 7.35 (d, 1H, J ) 8.1
Hz), 7.78 (d, 1H, J ) 1.7 Hz); 13C NMR (CDCl3, 100 MHz) δ
34.1, 46.0, 52.1, 61.6, 109.2, 115.6, 128.6, 129.3, 133.1, 143.4.
Anal. Calcd for C12H18BrN3O2S: C, 41.39; H, 5.21; N, 12.07.
Found: C, 41.75; H, 5.22; N, 11.67.
Method B: To a solution of 1.00 g (3.71 mmol) of 20 in 8
mL of AcOH was added sequentially 530 mg (4.45 mmol) of
solid KBr, 45 mg (0.04 mmol) of (NH4)6Mo7O24‚4H2O, and 600
mg (3.90 mmol) of sodium perborate. After stirring for 4 h at
room temperature the reaction mixture was diluted with
EtOAc and neutralized with saturated K2CO3 to a pH of
8.0. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. The crude product was recrys-
tallized from an EtOAc/hexane mixture to give 1.00 g (78%)
of 21, which was identical with the material prepared by
Method A.
Preparation of 1-Acetyl-2-methoxyquinoline (23). To
a solution of 11.0 g (53.3 mmol) of 3-acetyl-2-chloroquinoline51
in 160 mL of MeOH was added 50 mL (0.268 mol) of a 5.4 M
solution of NaOMe in MeOH. The mixture was heated to reflux
for 1 h, cooled to room temperature, and diluted with 300 mL
of EtOAc and 300 mL of water. The EtOAc layer was
separated, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy to provide 8.60 g (80%) of 23 as a colorless solid: mp
99-100 °C; 1H NMR (CDCl3, 400 MHz) δ 2.69 (s, 3H), 4.14 (s,
3H), 7.39 (t, 1H, J ) 7.3 Hz), 7.68 (t, 1H, J ) 7.2 Hz), 7.79 (d,
1H, J ) 8.0 Hz), 7.83 (d, 1H, J ) 8.4 Hz), 8.48 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 31.5, 53.9, 123.9, 124.6, 125.0, 127.2,
129.3, 131.9, 141.3, 148.1, 159.7, 198.5. Anal. Calcd for
C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.48; H,
5.52; N, 7.00.
Preparation of 2-Methoxyquinoline-3-carboxaldehyde
(28).39 To a solution of 5 g (75.7 mmol) of KOH in 100 mL of
MeOH was added 10 g (52.2 mmol) of 2-chloro-3-quinolinecar-
boxaldehyde 27. The mixture was heated to reflux for 2.5 h
and then cooled to room temperature. To the solution was
added 300 mL of water and the precipitated product was
collected by filtration to afford 8.69 g (89%) of 28 as a tan solid.
An analytical sample could be prepared by recrystallization
from CH2Cl2/hexanes: mp 92-93 °C; 1H NMR (CDCl3, 400
MHz) δ 4.14 (s, 3H), 7.37 (dd, 1H, J ) 8.0 and 6.9 Hz), 7.67
(m, 1H), 7.76 (d, 1H, J ) 8.0 Hz), 7.80 (d, 1H, J ) 8.4 Hz),
8.48 (s, 1H), 10.40 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 53.8,
120.0, 124.4, 125.0, 127.3, 129.7, 132.5, 139.9, 148.9, 161.1,
189.2. Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48.
Found: C, 70.44; H, 4.70; N, 7.39.
Preparation of 2-Methoxy-3-[5-[[4-(methysulfonyl)-1-
piperazinyl]methyl]-1H-indol-2-yl]quinoline (25). To a
solution of 500 mg (1.44 mmol) of 21 and 288 mg (1.44 mmol)
of 23 in 5 mL of DMF was added 0.31 mL (1.82 mmol) of
P(OEt)3 and 5 µL of 85% aqueous H3PO4. The mixture was
heated to reflux for 6 h and the solvent was removed under
reduced pressure. The residue was redissolved in 8 mL of DMF
and 43 mg (0.140 mmol) of P(o-tolyl)3, 32 mg (0.140 mmol) of
Pd(OAc)2, and 1 mL of NEt3 were added and the mixture
heated to reflux for 6 h. The reaction mixture was cooled to
room temperature and diluted with 30 mL of EtOAc and 30
mL of water. The organic layer was dried over MgSO4 and
(51) Bhat, B.; Bhaduri, A. P. Synthesis 1984, 673.
J. Org. Chem, Vol. 70, No. 7, 2005 2563

Kuethe et al.
Preparation of 2-[5-(4-Methanesulfonylpiperazin-
1-ylmethyl)-2-nitrophenyl]-1-(2-methoxyquinolin-3-
yl)ethanol (30). To a mixture of 5.03 g (13.0 mmol) of 26 and
2.44 g (13.0 mmol) of 28 in 60 mL of isopropyl acetate was
added dropwise 3.3 mL (3.25 mmol) of a 1 M solution of TBAF.
After 30 min, the reaction mixture was diluted with 35 mL of
isopropyl acetate and washed with 50 mL of saturated NH4Cl
and 50 mL of water. The organic layer was dried over MgSO4
and concentrated under reduced pressure to give 5.80 g (89%)
of 30 as a colorless foam, which was used in the next step
without further purification. An analytical sample could be
obtained by chromatography on silica gel: 1H NMR (CDCl3,
400 MHz) δ 2.35 (m, 4H), 2.75 (s, 3H), 3.06 (m, 5H), 3.50 (m,
4H), 4.08 (s, 3H), 5.28 (t, 1H, J ) 6.0 Hz), 7.11 (s, 1H), 7.29
(dd, 1H, J ) 8.3 and 1.8 Hz), 7.38 (m, 1H), 7.60 (m, 1H), 7.67
(m, 1H), 7.83 (d, 1H, J ) 8.3 Hz), 7.90 (d, 1H, J ) 8.4 Hz),
7.96 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 34.3, 40.4, 45.8,
52.2, 53.6, 61.5, 70.3, 124.5, 125.0, 125.2, 126.9, 127.2, 127.5,
127.8, 129.6, 133.2, 133.4, 135.1, 143.3, 145.8, 149.2, 159.4.
Anal. Calcd for C24H28N4O6S‚1/2H2O: C, 56.57; H, 5.74; N,
10.99. Found: C, 56.65; H, 5.44; N, 10.83.
3H), 3.04 (m, 4H), 3.48 (m, 4H), 4.03 (s, 3H), 4.34 (d, 1H, J )
11.6 Hz), 4.66 (d, 1H, J ) 11.6 Hz), 5.41 (dd, 1H, J ) 5.6, 6.4),
7.06 (d, 1H, J ) 1.6 Hz), 7.29 (dd, 1H, J ) 1.6, 8.8 Hz), 7.39,
(ddd, 1H, J ) 1.2, 6.8, 8.0 Hz), 7.63 (ddd, 1H, J ) 1.2, 7.2, 8.4
Hz), 7.69 (dd, 1H, J ) 1.2, 8.0 Hz), 7.83 (d, 1H, J ) 8.4 Hz),
7.88 (d, 1H, J ) 8.4 Hz), 7.92 (s, 1H);
13C NMR (CDCl3, 100
MHz) δ 13.8, 34.3, 39.1, 45.6, 52.2, 53.5, 61.4, 72.4, 73.3, 124.3,
124.6, 124.8, 125.1, 127.0, 127.4, 127.5, 129.6, 132.7, 133.3,
135.3, 142.7, 145.9, 149.6, 159.8. HRMS calcd for C26H32N4O6S2
561.1836 (M + H), found 561.1808 (M + H).
1-(2-Methoxyquinolin-3-yl)-2-(5-{[4-(methylsulfonyl)-
piperazin-1-yl]methyl}-2-nitrophenyl)ethyl Acetate (39a).
To a solution of 500 mg (1.00 mmol) of alcohol 30 in 2 mL of
isopropyl acetate was added 5.80 g (57.0 mmol) of acetic
anhydride. The reaction was heated to 80 °C overnight. The
reaction mixture was cooled to room temperature, diluted with
an additional 5 mL of isopropyl acetate, and neutralized with
saturated NaHCO3 to pH 6-7. The organic layer was washed
with 5.0 mL of saturated NaHCO3 and the organic layer dried
over MgSO4. The solvent was removed under reduced pressure
and the residue purified by silica gel chromatography, eluting
with 70% EtOAc/hexanes to yield 350 mg (65%) of acetate 39a
as a white foam: 1H NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H),
2.29 (m, 4H), 2.76 (s, 3H), 3.05 (m, 4H), 3.40 (q, 2H, J ) 14.0
Hz), 3.58 (dd, 1H, J ) 7.2, 14.1 Hz), 3.66 (dd, 1H, J ) 5.2,
14.1 Hz), 4.09 (s, 3H), 6.40 (dd, 1H, J ) 5.2, 6.8 Hz), 7.00 (d,
1H, J ) 1.2 Hz), 7.28 (dd, 1H, J ) 1.6, 8.4 Hz), 7.37 (dt, 1H,
J ) 1.2, 8.4 Hz), 7.63 (m, 2H), 7.74 (s, 1H), 7.82 (d, 1H, J )
8.4 Hz), 7.87 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz)
δ 21.0, 34.4, 37.4, 45.7 52.2, 53.7, 61.5, 70.3, 124.0, 124.4,
124.87, 124.92, 127.1, 127.5, 128.0, 129.8, 131.7, 133.2, 134.7,
143.1, 146.0, 149.6, 158.9, 169.5; HRMS calcd for C26H30N4O7S
543.1907 (M + H), found 543.1915 (M + H).
1-(2-Chloroquinolin-3-yl)-2-(5-{[4-(methylsulfonyl)pip-
erazin-1-yl]methyl}-2-nitrophenyl)ethanone (37). To a
solution of 550 mg (1.09 mmol) of alcohol 29 in 3 mL of
isopropyl acetate was added 2.2 mL (31.0 mmol) of DMSO
followed by 670 mg (6.54 mmol) of acetic anhydride. The
reaction was stirred for 16 h at room temperature. To the
reaction mixture was added 10 mL of saturated NaHCO3 to
adjust the pH to 8-9, followed by 10 mL of chloroform. The
organic layer was washed with 40 mL of water and dried over
MgSO4 and the solvent was removed under reduced pressure.
The product was purified by silica chromatography, eluting
with 70% EtOAc/hexane to afford 210 mg (38%) of 37 as a pale
yellow foam: 1H NMR (CDCl3, 400 MHz) δ 2.61 (m, 4H), 2.82
(s, 3H), 3.29 (m, 4H), 3.67 (s, 2H), 4.80 (s, 2H), 7.45 (s, 1H),
7.50 (m, 1H), 7.67 (m, 1H), 7.87 (m, 1H), 7.96 (d, 1H, J ) 8.0
Hz), 8.08 (d, 1H, J ) 8.4 Hz), 8.19 (m, 1H), 8.52 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 34.4, 45.9, 48.5, 52.5, 61.5, 125.8,
126.3, 128.1, 128.5, 128.7, 129.0, 130.2, 132.5, 132.9, 134.2,
139.6, 145.0, 145.3, 147.5, 148.2, 196.9. Anal. Calcd for
C23H23ClN4O5S: C, 54.92; H, 4.61; N, 11.14. Found: C, 54.64;
H, 4.35; N, 10.56.
Preparation of 25 by Reductive Cyclization of Ketone
36. To a solution of 5.22 g (10.50 mmol) of ketone 30 in 60 mL
of THF was added 2.10 g of Raney Nickel 2800 (H2O). The
reaction slurry was then heated to 65 °C for 7.5 h under 40
psi of H2. The cooled reaction mixture was filtered over Celite
and the solution concentrated under reduced pressure. The
product was crystallized by addition of MeOH to the concen-
trated solution to yield 4.23 g (90%) of 25, which was identical
with that obtained above.
2-(2-Amino-5-{[4-methylsulfonyl)piperazin-1-yl]methyl}-
phenyl)-1-(2-methoxyquinolin-3-yl)ethanol (40). To a so-
lution of 1.00 g (2.00 mmol) of the alcohol 30 in 10 mL of THF
was added 0.60 g of Ra/Ni 2800 (H2O). The reaction mixture
was heated at 65 °C for 6 h under 40 psi of H2. The cooled
reaction mixture was filtered over Celite and concentrated
under reduced pressure, and the residue was purified over
silica gel eluting with MeOH/CHCl3 (5:95) to afforded 810 mg
(86%) of the aniline alcohol 40 as a white foam: 1H NMR
2-Chloro-1-(2-methoxyquinolin-3-yl)-2-(5-{[4-(methyl-
sulfonyl)piperazin-1-yl]methyl}-2-nitrophenyl)etha-
none (35). To a solution of 910 mg (7.20 mmol) of oxalyl
chloride in 3 mL of CH2Cl2 and was added dropwise 1.12 g
(14.3 mmol) of DMSO, maintaining the internal temperature
below -40 °C. After 10 min, 600 mg (1.20 mmol) of alcohol 30
in 1 mL of CH2Cl2 was added dropwise to the reaction mixture.
The reaction was stirred for 45 min at -65 °C, and 1.90 g (19.0
mmol) of triethylamine was added dropwise and the mixture
warmed to room temperature overnight. The reaction mixture
was diluted with 15 mL of water and 30 mL of EtOAc. The
layers were separated and the organic layer was dried over
MgSO4. The solvent was removed under reduced pressure and
the crude residue purified by silica gel chromatography to give
300 mg (47%) of chloride 35 as a yellow solid: mp 148-149
1
°C; H NMR (CDCl3, 400 MHz) δ 2.52 (m, 4H), 2.79 (s, 3H),
3.21 (m, 4H), 3.63 (s, 2H), 4.16 (s, 3H), 7.42 (s, 1H), 7.47 (m,
2H), 7.75 (ddd, 1H, J ) 8.4, 7.2, and 1.2 Hz), 7.80 (d, 1H, J )
1.6 Hz), 7.85 (m, 2H), 8.09 (d, 1H, J ) 8.4 Hz), 8.70 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 34.3, 45.6, 52.2, 54.0, 60.7, 61.3,
120.3, 124.2, 125.1, 125.3, 127.0, 129.0, 129.6, 131.3, 131.5,
132.5, 143.3, 144.8, 146.6, 148.1, 158.3, 190.6. Anal. Calcd for
C24H25ClN4O6S: C, 54.08; H, 4.73; N, 10.51. Found: C, 53.94;
H, 4.71; N, 10.13.
1-(2-Methoxyquinolin-3-yl)-2-(5-{[4-(methylsulfonyl)-
piperazin-1-yl]methyl}-2-nitrophenyl)ethanone (36). To
a heated (80 °C) solution of 19.7 g (39.4 mmol) of alcohol 30 in
79 mL of isopropyl acetate and 36.9 g (473 mmol) of DMSO
was added 24.1 g (236 mmol) of acetic anhydride. The reaction
mixture was heated at 80 °C for 2 h. After cooling to room
temperature, the reaction was neutralized with saturated
NaHCO3 (175 mL) to a final pH of 8.0. The layers were
separated and the organic layer was washed with water (250
mL). The solvent was removed under reduced pressure and
the residue was purified by silica gel chromatography to give
15.3 g (78%) of 36. An analytical sample was obtained by
recrystallization from THF/MeOH: mp 122-123.5 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.58 (m, 4H), 2.80 (s, 3H), 3.27 (m, 4H),
3.63 (s, 2H), 4.22 (s, 3H), 4.80 (s, 2H), 7.36 (s, 1H), 7.43 (ddd,
2H, J ) 1.2, 8.0, 9.2 Hz), 7.73 (ddd, 1H, J ) 1.6, 6.8, 8.4 Hz),
7.85 (d, 1H, J ) 15.6), 7.87 (d, 1H J ) 14.7 Hz), 8.12 (d, J )
9.1), 8.59 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 20.6,
34.3, 45.8, 48.8, 52.3, 53.9, 61.5, 122.9, 124.4, 124.9, 125.4,
127.0, 128.4, 129.2, 131.2, 131.9, 132.9, 133.9, 141.8, 144.2,
147.9, 159.1, 195.9. Anal. Calcd for C24H26N4O6S: C, 57.82;
H, 5.26; N, 11.24. Found: C, 57.71; H, 5.20; N, 10.96.
2-Methoxy-3-{2-(5-{[4-(methylsulfonyl)piperazin-1-yl]-
methyl}-2-nitrophenyl)-1-[(methylthio)methoxy]ethyl}-
quinoline (38a). The methylthiomethyl ether 38a was iso-
lated after chromatography on silica gel as a yellow foam: 1H
NMR (CDCl3, 400 MHz) δ 1.90 (s, 3H), 2.33 (m, 4H), 2.75 (s,
2564 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
(CDCl3, 400 MHz) δ 2.41 (m, 4H), 2.75 (s, 3H), 2.83 (dd, 2H, J
) 14.5, 8.4 Hz), 3.12 (m, 4H), 3.23 (dd, 1H, J ) 14.5, 3.2 Hz),
3.37 (dd, 2H, J ) 12.9, 16.6 Hz), 4.10 (br s, 2H), 4.18 (s, 3H),
5.27 (dd, 1H, J ) 2.8, 8.4 Hz), 6.71 (d, 1H, J ) 8.0 Hz), 6.87
(d, 1H, J ) 1.6 Hz), 7.00 (dd, 1H, J ) 2.0, 8.0 Hz), 7.40 (t, 1H,
J ) 6.8 Hz), 7.62 (ddd, 1H, J ) 1.2, 7.2, 8.4 Hz), 7.71 (d, 1H,
J ) 8.0 Hz), 7.87 (d, 1H, J ) 8.4 Hz), 8.08 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 34.2, 39.9, 45.8, 52.1, 53.7, 62.2, 69.6,
116.2, 123.5, 124.4, 125.4, 127.0, 127.4, 127.5, 128.0, 128.9,
129.3, 132.5, 134.3, 144.6, 145.6, 159.2; HRMS calcd for
C24H30N4O4S 471.2060 (M + H), found 471.2071 (M + H).
Preparation of 2-(2-Amino-5-methylphenyl)-1-(2-
methylquinolin-3-yl)ethanol (41). To a mixture of 13.0 g
(58.3 mmol) of 3-trimethylsilylmethyl-4-nitrotoluene52 and 10.9
g (58.0 mmol) of aldehyde 28 in 150 mL of isopropyl acetate
was added 8.80 mL (8.80 mmol, 1 M solution) of TBAF in THF.
The mixture was stirred at room temperature for 30 min and
quenched with 60 mL of saturated NH4Cl. The layers were
separated and the organic layer was washed with 60 mL of
water and the organic layer dried over MgSO4. The solvent
was removed under reduced pressure and the residue was
purified over silica gel to give 12.0 g (74%) of 1-(2-methoxy-
quinolin-3-yl)-2-(5-methyl-2-nitrophenyl)ethanol, which was
used in the next step directly.
650 mg (76%) of 42 as a yellow solid: mp 139.5-141 °C; 1H
NMR (CDCl3, 400 MHz) δ 2.49 (s, 3H), 4.3 (s, 3H), 7.02 (d,
1H, J ) 2.0 Hz), 7.07 (dd, 1H, J ) 1.6, 8.4 Hz), 7.37 (d, 1H, J
) 8.0 Hz), 7.43 (ddd, 1H J ) 1.2, 6.8, 8.0 Hz), 7.63 (ddd, 1H,
J ) 1.6, 6.8, 8.4 Hz), 7.79 (dd, 1H, J ) 0.8, 8.0 Hz), 7.89 (d,
1H, J ) 8.0 Hz), 8.46 (s, 1H), 9.57 (br s, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.4, 48.9, 53.9, 123.3, 124.6, 124.9, 125.5, 127.1,
128.9, 129.2, 131.2, 131.9, 134.5, 141.5, 141.8, 144.8, 148.0,
159.2, 196.3. Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N,
9.72. Found: C, 78.88; H, 5.47; N, 9.61.
2-Chloro-3-[5-[[4-(methysulfonyl)-1-piperazinyl]methyl]-
1H-indol-2-yl]quinoline (43). To a solution of 75 mg (0.149
mmol) of 37 in 1 mL of THF was added 50 mg of Raney Nickel
2800 (55 wt % of slurry in EtOH). The mixture was stirred at
room temperature for 20 h under 40 psi of H2. The reaction
was filtered through a 0.45 µm syringe filter and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give 29.1 mg (46%) of 43 as a yellow foam:
1H NMR (CDCl3, 400 MHz) δ 2.62 (m, 4H), 2.79 (s, 3H), 3.27
(m, 4H), 3.68 (s, 2H), 6.98 (s, 1H), 7.25 (d, 1H, J ) 8.4 Hz),
7.44 (d, 1H, J ) 8.4 Hz), 7.62 (m, 2H), 7.78 (t, 1H, J ) 8.4
Hz), 7.87 (d, 1H, J ) 8.4 Hz), 8.06 (d, 1H, J ) 8.4 Hz), 8.42 (s,
1H), 8.86 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 34.0, 45.8,
52.1, 63.0, 104.7, 111.1, 121.4, 124.7, 125.8, 127.0, 127.5, 127.6,
128.1, 128.3, 130.8, 133.4, 136.2, 138.3, 146.6, 147.6, 158.2.
Anal. Calcd for C23H23ClN4O2S: C, 60.72; H, 5.10; N, 12.31.
Found: C, 60.45; H, 5.12; N, 12.11.
The second product to elute from the column (14.4 mg, 23%)
was identified as 3-[5-[[4-(methysulfonyl)-1-piperazinyl]meth-
yl]-1H-indol-2-yl]quinoline (44), which was obtained as a
yellow-green solid: mp 211-212 °C; 1H NMR (DMSO-d6, 400
MHz) δ 2.46 (m, 4H), 2.84 (s, 3H), 3.08 (m, 4H), 3.56 (s, 2H),
7.09 (d, 1H, J ) 8.3 Hz), 7.14 (s, 1H), 7.38 (d, 1H, J ) 8.3 Hz),
7.47 (s, 1H), 7.62 (t, 1H, J ) 7.7 Hz), 7.71 (t, 1H, J ) 7.7 Hz),
7.95 (d, 1H, J ) 8.3 Hz), 8.00 (d, 1H, J ) 8.3 Hz), 11.77 (br s,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 34.2, 46.0, 52.2, 62.7,
100.9, 111.7, 121.2, 124.4, 126.0, 127.8, 128.1, 128.6, 129.0,
129.4, 129.8, 130.2, 137.4, 147.1, 149.0. Anal. Calcd for
C23H24N4O2S‚H2O: C, 62.99; H, 5.98; N, 12.78. Found: C,
63.02; H, 5.62; N, 12.47.
trans-3-{2-[5-(4-Methanesulfonylpiperazine-1-ylmethyl)-
2-nitrophenyl]vinyl}-2-methoxyquinoline (45). Method
A: To a solution of 3.50 g (7.00 mmol) of alcohol 30 in 50 mL
of isopropyl acetate was added 1.76 g (8.40 mmol) of TFAA.
After the solution was stirred for 30 min at room temperature,
1.39 g (9.10 mmol) of DBU was added and the mixture was
heated to 60 °C for 30 min. The reaction mixture was cooled
to room temperature and diluted with 20 mL of brine, and the
layers were separated. The organic layer was washed with 25
mL of water and concentrated under reduced pressure. The
crude residue was slurried in MTBE to give 2.71 g (80%) of
45 as a yellow solid: mp 156-157 °C; 1H NMR (CDCl3, 400
MHz) δ 2.63 (m, 4H), 2.81 (s, 3H), 3.31 (m, 4H), 3.67 (s, 2H),
4.18 (s, 3H), 7.42 (m, 3H), 7.63 (dt, 1H, J ) 6.9 and 1.4 Hz),
7.83 (m, 4H), 7.98 (d, 1H, J ) 8.4 Hz), 8.24 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 34.5, 45.9, 52.5, 53.8, 61.8, 121.8, 124.6,
125.2, 125.4, 126.4, 127.0, 127.8, 127.9, 128.5, 128.6, 129.9,
133.4, 135.1, 143.9, 146.3, 147.1, 159.8. Anal. Calcd for
C24H26N4O5S: C, 59.74; H, 5.43; H, 11.61. Found: C, 59.51;
H, 5.17; N, 11.53.
To a solution of 600 mg (1.78 mmol) of the above alcohol in
8.0 mL of THF was added 360 mg of Ra/Ni 2800 (H2O). The
reaction mixture was heated at 65 °C for 6 h under 40 psi of
H2. The cooled reaction mixture was filtered over Celite and
concentrated under reduced pressure, and the residue was
purified over silica gel eluting with MeOH/CHCl3 (5:95) to
afforded 320 mg (58%) of the aniline alcohol 41 as a white
1
solid: mp 139-140 °C; H NMR (CDCl3, 400 MHz) δ 2.25 (s,
3H), 2.71 (dd, 1H, J ) 9.6, 14.1 Hz), 2.83 (br s, 1H), 3.17 (dd,
1H, J ) 2.4, 14.1 Hz), 3.92 (br s, 2H), 4.18 (s, 3H), 5.22 (dd,
1H, J ) 1.6, 9.6 Hz), 6.67 (d, 1H, J ) 7.6 Hz), 6.91 (s, 1H),
6.92 (d, 1H, J ) 7.6 Hz), 7.40 (ddd, 1H J ) 1.2, 6.8, 8.0 Hz),
7.62 (ddd, 1H, J ) 1.6, 6.8, 8.4 Hz), 7.75 (dd, 1H, J ) 0.8, 8.0
Hz), 7.88 (d, 1H, J ) 8.0 Hz), 8.18 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 20.5, 40.3, 53.6, 59.6, 116.5, 123.9, 124.3, 125.5,
126.9, 127.6, 128.2, 128.3, 128.6, 129.2, 131.9, 134.1, 142.6,
145.7, 159.2. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N
9.08. Found: C, 73.62; H, 6.60; N, 8.86.
Preparation of 2-Methoxy-3-(5-methyl-1H-indol-2-yl)-
quinoline (42). To a solution of 3.50 g (10.0 mmol) of 1-(2-
methoxyquinolin-3-yl)-2-(5-methyl-2-nitrophenyl)ethanol in 20
mL of isopropyl acetate was added 9.70 g (120 mmol) of DMSO
followed by 6.38 g (62.0 mmol) of acetic anhydride. The mixture
was heated to 80 °C for 4 h. The reaction mixture was cooled
to room temperature and quenched with saturated NaHCO3.
The organic layer was washed with saturated NaHCO3 (3 ×
20 mL), water (20 mL), and brine (20 mL). The organic layer
was concentrated and the solid slurried in MTBE and filtered
to afford 2.40 g (69%) of 1-(2-methoxyquinolin-3-yl)-2-(5-
methyl-2-nitrophenyl)ethanone as a solid: mp 173.3-175 °C;
1H NMR (CDCl3, 400 MHz) δ 2.46 (s, 3H), 4.22 (s, 3H), 4.77
(s, 2H), 7.21 (s, 1H), 7.26 (dd, 1H, J ) 1.2, 8.4 Hz), 7.43 (ddd,
1H, J ) 1.2, 6.8, 8.0 Hz), 7.72 (ddd, 1H, J ) 1.6, 6.8, 8.4 Hz),
7.84 (dd, 1H, J ) 1.2, 8.0 Hz), 7.88 (d, 1H, J ) 8.4 Hz), 8.1 (d,
1H, J ) 8.4 Hz), 8.58 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
21.4, 48.9, 53.9, 123.3, 124.6, 124.9, 125.5, 127.1, 128.9, 129.2,
131.2, 131.9, 134.5, 141.5, 141.8, 144.8, 148.0, 159.2, 196.3.
Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33.
Found: C, 67.69; H, 4.58; N, 8.33.
Method B: To a solution of 1.00 g (2.87 mmol) of 21 in 10
mL of DMF was added 532 mg (2.87 mmol) of 46, 19.3 mg
(0.086 mmol) of Pd(OAc)2, and 87.4 mg (0.287 mmol) of P(o-
tolyl)3. The solution was degassed by bubbling nitrogen
through the solution for 30 min. To the mixture was added
436 mg (4.31 mmol) of NEt3 and the mixture was heated to
100 °C in a sealed tube for 4 h. The reaction mixture was cooled
to room temperature and diluted with 50 mL of EtOAc and
50 mL of water. The layers were separated and the organic
layer dried over MgSO4. The solvent was removed under
reduced pressure and the residue purified by silica gel chro-
To a solution of 1.00 g (2.97 mmol) of the above ketone in
20 mL of THF was added 600 mg of Raney Nickel 2800 (H2O).
The reaction slurry was then heated to 65 °C for 7.5 h under
40 psi of H2. The cooled reaction mixture was filtered over
Celite and the solution concentrated under reduced pressure.
The product was purified by silica gel chromatography to give
(52) Bartoli, G.; Palmieri, G.; Petrini, M.; Bosco, M.; Dalpozzo, R.
Tetrahedron 1990, 46, 1379.
J. Org. Chem, Vol. 70, No. 7, 2005 2565

Kuethe et al.
matography to give 873 mg (63%) of 45, which was identical
line (51). To a solution of 1.00 g (1.98 mmol) of 29 in 25 mL
of isopropyl acetate was added 500 mg (2.38 mmol) of TFAA.
After the solution was stirred for 30 min at room temperature,
904 mg (5.94 mmol) of DBU was added and the mixture was
heated to 60 °C for 30 min. The reaction mixture was cooled
to room temperature and diluted with 30 mL of brine, and the
layers were separated. The organic layer was washed with 35
mL of water and concentrated under reduced pressure. The
crude residue was purified by silica gel chromatography to give
800 mg (83%) of 51 as a yellow solid: mp 199-200 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.64 (m, 4H), 2.82 (s, 3H), 3.31 (m, 4H),
3.70 (s, 2H), 7.45 (s, 1H), 7.50 (d, 1H, J ) 15.9 Hz), 7.60 (m,
1H), 7.77 (m, 3H), 7.90 (d, 1H, J ) 8.2 Hz), 8.02 (d, 1H, J )
5.0 Hz), 8.04 (d, 1H, J ) 5.0 Hz), 8.46 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 34.4, 46.0, 52.5, 61.7, 125.3, 127.5, 127.7, 127.9,
128.4, 128.5, 128.6, 129.0, 129.4, 132.7, 135.0, 144.5, 147.0,
147.3, 149.9. Anal. Calcd for C23H23ClN4O4S: C, 56.73; H, 4.76;
N, 11.51. Found: C, 56.55; H, 4.48; N, 11.34.
Preparation of 25 by Palladium-Catalyzed Reductive
Cyclization of 45. Method A. In an autoclave was added
sequentially 45.0 g (93.3 mmol) of 45, 210 mg (0.935 mmol) of
Pd(OAc)2, 336 mg (0.187 mmol) of 1,10-phenanthroline, and
1.3 L of DMF. The vessel was purged three times successively
with N2 and CO and then pressurized to 15 psig of CO and
stirred at 70 °C for 14 h. The reaction mixture was cooled to
room temperature, filtered over a pad of solka floc (filter aid),
and concentrated to a final volume of 150 mL. The resulting
solution was heated to 50 °C and 50 mL of MeOH was added.
Upon cooling the product crystallized and was collected by
filtration to afford 39.4 g (94%) of 25, which was identical with
that isolated from the reductive cyclization of ketone 37.
with that prepared by Method A.
Preparation of 2-Methoxy-3-vinylquinoline (46). To a
solution of 5.90 g (16.4 mmol) of methyltriphenylphosphonium
bromide in 30 mL of THF was added 10.3 mL (16.4 mmol) of
a 1.6 M solution of n-BuLi and the resulting mixture was
stirred at room temperature for 30 min. To the solution was
added dropwise 3.00 g (14.9 mmol) of aldehyde 28 in 30 mL of
THF and the resulting mixture was stirred at room temper-
ature for 1 h. The reaction mixture was filtered to remove
insoluble salts and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to afford
2.40 g (81%) of 46 as a yellow oil, which was used immediately
in the next reaction: 1H NMR (CDCl3, 400 MHz) δ 4.13 (s,
3H), 5.43 (d, 1H, J ) 10.6 Hz), 5.94 (d, 1H, J ) 17.0 Hz), 7.00
(dd, 1H, J ) 17.7 and 11.2 Hz), 7.36 (t, 1H, J ) 7.5 Hz), 7.59
(t, 1H, J ) 7.1 Hz), 7.72 (d, 1H, J ) 7.9 Hz), 7.83 (d, 1H, J 8.4
Hz), 8.06 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 53.7, 117.2,
123.0, 124.2, 125.5, 127.0, 127.5, 129.3, 131.3, 134.3, 146.0,
160.0. Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56.
Found: C, 77.47; H, 5.61; N, 7.34.
Preparation of cis-3-{2-[5-(4-Methanesulfonylpipera-
zine-1-ylmethyl)-2-nitrophenyl]vinyl}-2-methoxyquino-
line (47) by Photolysis of 45. A solution of 1.0 g (2.10 mmol)
of 45 in 10 mL of DMF was irradiated at 300 nm for 16 h. The
reaction mixture was concentrated in vacuo to a yellow oil. A
yellow solid crystallized upon standing. The oily solid was
diluted with EtOAc (5 mL) and filtered by washing with
EtOAc. The filtrate was concentrated to an oil, from which a
solid crystallized upon standing. The oily solid was diluted with
EtOAc (5 mL) and filtered. The filtrate was concentrated in
vacuo to afford 400 mg (40%) of pure 47 as a yellow oil: 1H
NMR (CDCl3, 400 MHz) δ 2.05 (m, 4H), 2.54 (m, 4H), 2.63 (s,
3H), 3.32 (s, 2H), 4.05 (s, 3H), 6.92 (d, 1H, J ) 12.0 Hz), 7.15
(d, 1H, J ) 12.0 Hz), 7.20 (s, 1H), 7.30 (m, 2H), 7.36 (d, 1H, J
) 8.0 Hz), 7.47 (s, 1H), 7.60 (m, 1H), 7.78 (d, 1H, J ) 8.3 Hz),
8.12 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 33.6,
45.2, 51.8, 53.7, 61.1, 121.0, 124.4, 124.6, 125.0, 126.0, 126.9,
127.1, 128.4, 129.6, 129.8, 131.9, 133.7, 138.0, 144.0, 145.8,
147.0, 160.1.
Method B: In an autoclave was added sequentially 4.00 g
(8.30 mmol) of 45, 112 mg (0.500 mmol) of Pd(OAc)2, 520 mg
(2.00 mmol) of PPh3, and 40 mL of MeCN. The vessel was
purged three times successively with N2 and CO and then
pressurized to 60 psig of CO and stirred at 70 °C for 15 h. The
reaction mixture was filtered while hot through a sintered
glass frit that removed the insoluble indole dimer 48. The
filtrate was concentrated in vacuo to provide 3.55 g (95%) of
25, which was identical with that isolated from the reductive
cyclization of ketone 37. The indole dimer 48 (2,2′-bis(2-
methoxyquinolin-3-yl)-5,5′-bis{[4-(methylsulfonyl)piperazin-1-
yl]methyl}-1H,1′H-3-3′-biindole) was isolated as a light yellow
Preparation of trans-3-{2-[5-(4-Methanesulfonylpip-
erazine-1-ylmethyl)-2-nitrophenyl]vinyl}quinoline (50).
To a mixture of 1.87 g (4.85 mmol) of 26 and 762 mg (4.85
mmol) of aldehyde 49 in 25 mL of isopropyl acetate was added
dropwise 1.00 mL (1.00 mmol) of a 1 M solution of TBAF. After
30 min, the reaction mixture was diluted with 15 mL of
isopropyl acetate and washed with 30 mL of saturated NH4Cl
and 30 mL of water. The organic layer was dried over MgSO4
and concentrated under reduced pressure to give 1.84 g (81%)
of the alcohol, which was used in the next step without further
purification.
1
solid: mp 324-326 °C; H NMR (DMSO-d6, 400 MHz) δ 2.15
(m, 4H), 2.22 (m, 4H), 2.82 (s, 6H), 2.92 (m, 8H), 3.22 (d, 2H,
J ) 12.4 Hz), 3.44 (d, 2H, J ) 12.4 Hz), 3.67 (s, 6H), 7.01 (m,
4H), 7.29 (dt, 2H, J ) 7.9 and 0.8 Hz), 7.37 (d, 2H, J ) 8.3
Hz), 7.50 (d, 2H, J ) 7.9 Hz), 7.57 (dt, 2H, J ) 7.0 and 1.2
Hz), 7.67 (d, 2H, J ) 8.3 Hz), 7.96 (s, 2H), 11.3 (br s, 2H); 13
C
NMR (DMSO-d6, 100 MHz) δ 33.8, 45.1, 51.3, 52.8, 62.4, 108.2,
110.9, 118.2, 120.2, 123.1, 124.3, 126.1, 126.9, 127.3, 129.3,
130.2, 135.6, 138.4, 144.8,159.0; HRMS calcd for C48H51N8O6S2
899.3373 (M + H), found 899.3372 (M + H).
To a solution of 1.59 g (3.38 mmol) of the above alcohol in
45 mL of isopropyl acetate was added 852 mg (4.06 mmol) of
TFAA. After the solution was stirred for 30 min at room
temperature, 772 mg (5.07 mmol) of DBU was added and the
mixture was heated to 60 °C for 30 min. The reaction mixture
was cooled to room temperature and diluted with 20 mL of
brine, and the layers were separated. The organic layer was
washed with 25 mL of water and concentrated under reduced
pressure. The crude residue was purified by silica gel chro-
matography to give 1.10 g (72%) of 50 as a yellow solid: mp
General Procedure for the Reductive Cyclization of
Nitrostyrenes with P(OEt)3. A solution of 1.00 mmol of the
appropriate nitrostyrene in 5 mL of P(OEt)3 was heated to 155
°C for 2 h and the solvent was removed under reduced
pressure. The residue was purified by flash silica gel chroma-
tography to give the product.
Preparation of 25 by Reductive Cyclization of 45 with
P(OEt)3. According to the general procedure, reaction of 1.50
g (3.10 mmol) of 45 with 15.5 mL of P(OEt)3 afforded 908 mg
(62%) of 25, which was identical with that isolated from the
reductive cyclization of ketone 36.
Preparation of 43 by Reductive Cyclization of 51 with
P(OEt)3. According to the general procedure, reaction of 1.06
g (2.18 mmol) of 51 in 11 mL of P(OEt)3 gave 600 mg (61%) of
43, which was identical with that isolated from the reductive
cyclization of ketone 37.
Preparation of 44 by Reductive Cyclization of 50 with
P(OEt)3. According to the general procedure, reaction of 700
mg (1.55 mmol) of 50 in 7.5 mL of P(OEt)3 gave 468 mg (72%)
1
211-212 °C; H NMR (CDCl3, 400 MHz) δ 2.86 (s, 3H), 2.91
(m, 4H), 3.48 (m, 4H), 3.94 (s, 2H), 7.32 (s, 1H), 7.48 (d, 1H, J
) 7.3 Hz), 7.71 (t, 1H, J ) 7.3 Hz), 7.87 (m, 3H), 7.98 (d, 1H,
J ) 8.4 Hz), 8.06 (d, 1H, J ) 8.4 Hz), 8.28 (d, 1H, J ) 8.4 Hz),
8.52 (s, 1H), 9.28 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
33.4, 42.6, 50.0, 58.1, 123.6, 124.0, 125.9, 126.4, 126.9, 128.1,
128.4, 128.6, 128.8, 128.9, 130.8, 132.3, 145.4, 146.1, 147.6.
Anal. Calcd for C23H24N4O4S: C, 61.05; H, 5.35; N, 12.38.
Found: C, 61.32; H, 5.33; N, 12.02.
Preparation of trans-3-{2-[5-(4-Methanesulfonylpip-
erazine-1-ylmethyl)-2-nitrophenyl]vinyl}-2-chloroquino-
2566 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 5-Substituted-1H-indol-2-yl-1H-quinolin-2-ones
of 44, which was identical with that isolated from the reductive
cyclization of ketone 37.
11.86 (s, 1H), 12.21 (s, 1H); 13C NMR (DMSO-d6, 126 MHz) δ
35.2, 42.2, 49.7, 53.4, 102.2, 112.0, 115.0, 119.3, 119.9, 122.1,
122.3, 123.7, 124.9, 127.8, 130.3, 134.6, 134.8, 136.8, 137.7,
160.5. Anal. Calcd for C23H24N4O3S‚HCl: C, 58.40; H, 5.33;
N, 11.85. Found: C, 58.38; H, 5.26; N, 11.71.
Preparation of 3-(5-{[4-(Methanesulfonyl)-1-piperazi-
nyl]methyl}-1H-indol-2-yl)quinolin-2(1H)one Hydrochlo-
ride (1). To a stirred solution of 10.2 g (22.6 mmol) of 25 in
100 mL of DMF at 70 °C was added 11.2 mL (135.8 mmol) of
concentrated HCl. The resulting slurry was stirred at 70 °C
for 2 h. To the slurry was added dropwise 300 mL of 2-propanol
and the mixture was allowed to cool to room temperature and
the solid collected by filtration. The wet filter cake was washed
with 25 mL of 2-propanol and dried at 40 °C under vacuum/
nitrogen sweep for 12 h to give 10.7 g (100%) of 1 as a mono
Acknowledgment. The authors would like to thank
Dr. Jinsong Guo for preliminary experiments and Dr.
Peter G. Dormer for valuable NMR assistance.
Supporting Information Available: Spectroscopic data
for compounds 38-40, 47, and 48. This material is available
free of charge via the Internet at http://pubs.acs.org. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
HCl salt and a yellow solid: mp 250 °C; H NMR (DMSO-d6,
500 MHz) δ 2.98 (s, 3H), 3.12 (m, 2H), 3.33 (t, 2H, J ) 12.6
Hz), 3.39 (m, 2H), 3.70 (d, 2H, J ) 12.6 Hz), 4.42 (m, 2H),
7.25 (m, 1H), 7.39 (m, 2H), 7.41 (d, 1H, J ) 8.2 Hz), 7.52 (ddd,
1H, J ) 8.2, 7.2, and 1.2 Hz), 7.60 (d, 1H, J ) 8.4 Hz), 7.73 (d,
1H, J ) 7.7 Hz), 7.82 (s, 1H), 8.63 (s, 1H), 11.45 (br s, 1H),
JO0480545
J. Org. Chem, Vol. 70, No. 7, 2005 2567