Heteroaryl cross-coupling as an entry toward the synthesis of lavendamycin analogues: A model study

Article abstract of DOI:10.1021/jo902287t

(Chemical Equation Presented) ABC analogues of the antitumor antibiotic lavendamycin, which contain the key metal chelation site and redox-active quinone unit essential for biological activity, were prepared via the palladium(0)-catalyzed cross-coupling reaction of various 2-haloheteroaromatics with 2-stannylated pyridines and quinolines. Using the Stille reaction, 2-bromo substituted quinolines and 1-bromoisoquinolines were found to undergo efficient coupling with 2-pyridinylstannanes to provide unsymmetrical heterobiaryl derivatives. While the Stille reaction using the reverse coupling partners (i.e., 2-quinolinylstannanes and haloheteroaromatics) had not received much attention in the literature, we found that this alternative coupling reaction efficiently provided several new heterobiaryl derivatives. The gold-catalyzed intramolecular cycloisomerization of N-(prop-2-ynyl)-1H-indole-2-carboxamide smoothly afforded a β-carbolinone derivative that was subsequently used for a Pd(0)-catalyzed cross-coupling directed toward the synthesis of lavendamycin analogues.

Full text of DOI:10.1021/jo902287t

pubs.acs.org/joc
Heteroaryl Cross-Coupling as an Entry toward the Synthesis of
Lavendamycin Analogues: A Model Study
Guido Verniest,‡,§ Xingpo Wang,*,†,z Norbert De Kimpe,‡ and Albert Padwa*,†
†Department of Chemistry, Emory University, Atlanta, Georgia 30322, zSchool of Chemistry and Chemical
Engineering, Shandong University, Shandong 250100, People’s Republic of China, and ‡Department of
Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent,
Belgium. §Postdoctoral Fellow of the Research Foundation Flanders (FWO-Vlaanderen, Belgium)
at Emory University.
chemap@emory.edu; xpw6@sdu.edu.cn
Received October 26, 2009
ABC analogues of the antitumor antibiotic lavendamycin, which contain the key metal chelation site and
redox-active quinone unit essential for biological activity, were prepared via the palladium(0)-catalyzed
cross-coupling reaction of various 2-haloheteroaromatics with 2-stannylated pyridines and quinolines.
Using the Stille reaction, 2-bromo substituted quinolines and 1-bromoisoquinolines were found to
undergo efficient coupling with 2-pyridinylstannanes to provide unsymmetrical heterobiaryl derivatives.
While the Stille reaction using the reverse coupling partners (i.e., 2-quinolinylstannanes and
haloheteroaromatics) had not received much attention in the literature, we found that this alternative
coupling reaction efficiently provided several new heterobiaryl derivatives. The gold-catalyzed intra-
molecular cycloisomerization of N-(prop-2-ynyl)-1H-indole-2-carboxamide smoothly afforded a
β-carbolinone derivative that was subsequently used for a Pd(0)-catalyzed cross-coupling directed
toward the synthesis of lavendamycin analogues.
Introduction
since their initial structural identification. The first total synth-
esis of lavendamycin methyl ester was reported by Kende and
Ebetino in 1984.4 They accomplished the synthesis of 1 through
a Bischler-Napieralski condensation of a substituted quinaldic
acid with β-methyltryptophan methyl ester followed by cycliza-
tion and functionalization of the A ring. The subsequent Boger
group’s synthesis of 1 was based on a Friedlander condensation
of a functionalized amino aldehyde with a β-carboline to build
the B-ring.5 Still another approach involves a modified
Knoevenagel-Stobbe pyridine formation and further D-ring
construction by a thermolytic nitrene insertion.6 Several
Lavendamycin (1), a highly substituted and functionalized
7-aminoquinoline-5,8-dione, was isolated and characterized in
1981 by Doyle from the fermentation broths of Streptomyces
lavendulae.1 In structure as well as in bioassays, lavendamycin
(1) is closely related to streptonigrin (2) (Figure 1), another
potent antitumor antibiotic.2 Both of these compounds have
been shown to possess cytotoxic properties and exhibit signifi-
cant activity against topoisomerases.3 Consequently, these
target molecules have been the focus of much synthetic effort
(1) (a) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.;
Gould, S. J.; Tann, C.-H.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595. (b)
Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.; O’Herron, F. A.;
Nettleton, D. E. J. Antibiot. 1982, 35, 259.
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Kende, A. S.; Ebetino, F. H.; Battista, R.; Boatman, R. J.; Lorah, D. P.;
Lodge, E. Heterocycles 1984, 21, 91.
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3539. (b) Rao, K. V.; Cullen, W. P. Antibiot. Annu. 1959, 950. (c) Rao, K. V.;
Biemann, K.; Woodward, R. B. J. Am. Chem. Soc. 1963, 85, 2532. (d) Chiu,
Y. Y. H.; Lipscomb, W. N. J. Am. Chem. Soc. 1975, 97, 2525.
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Thompson, S. C. J. Med. Chem. 1987, 30, 1918.
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Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985, 50,
5782. (c) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem.
1985, 50, 5790.
(6) Ciufolini, M. A.; Bishop, M. J. J. Chem. Soc., Chem. Commun. 1993,
1463.
424 J. Org. Chem. 2010, 75, 424–433
Published on Web 12/17/2009
DOI: 10.1021/jo902287t
r
2009 American Chemical Society

Verniest et al.
JOCArticle
SCHEME 1
FIGURE 1. Some potent antitumor antibiotics.
additional syntheses of this compound and of ester derivatives
were also carried out.7 As a consequence of the promising
bioactivity of lavendamycin (1) and analogues, the synthesis
and structure-activity relationship (SAR) studies of this class
of compounds remain an active area of research.8 A limitation
to exploiting the biological properties of lavendamycin is its
toxicity that may be partly due to the presence of the quinone
moiety in the A-ring. In this respect, several new lavendamycin
derivatives have recently been prepared that show potent
antitumor and anti-HIV reverse transcriptase activities, with
low general cellular toxicity.9 It was also observed that among
the lavendamycins tested, the presence of an acetyl group on the
C7-amino group enhanced the selectivity in cell toxicity.9 The
fascinating structural features coupled with the interesting
biological activity of lavendamycin led us to undertake an
eventual synthesis of this complex molecule as well as its
analogues, with a view of finding activity better than that of
the parent compound. A retrosynthesis of the much simpler
N-acetyl analogue of lavendamycin (i.e., 3) revealed to us that
this skeletal framework could be obtained from a Pd(0)-
catalyzed cross-coupling reaction of two key intermediates,
namely, a 2-halo- (or 2-stannyl)-5,7-dinitro-8-alkoxy substi-
tuted quinoline 4 with a 2-pyridinylstannane (or halide) 5
(Scheme 1). Using this model system, our intention was to first
reduce the nitro groups of the cross-coupled product and then
oxidize the resulting compound to give the required quinoline-
5,8-dione ring system 3. In addition, we hoped to use our
recently developed methodology of synthesizing 1-halo-β-car-
bolines of type 8via the Au(III)-catalyzed cycloisomerization of
N-propargyl indole-2-carboxamides10 to provide a new entry
toward other lavendamycin analogues (i.e., 6) employing a
related cross-coupling reaction with 2-substituted pyridines 7.
Results and Discussion
The 2,20-bipyridine unit is a key structural feature found in
some important natural products that show antibiotic and
cytotoxic activities.11 Nowadays these substituted bipyridines
are frequently prepared by transition-metal-catalyzed cross-cou-
pling reactions.12-15 The palladium(0)-catalyzed cross-coupling
of aryl halides to form unsymmetrical biaryls corresponds to one
of the most useful reactions in synthetic organic chemi-
stry.16 Several of the more common methods for performing
this coupling are the Stille (organostannane),17 Suzuki-Miyaura
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6552. (e) Hassani, M.; Cai, W.; Koelsch, K. H.; Holley, D. C.; Rose, A. S.;
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J. Org. Chem. Vol. 75, No. 2, 2010 425

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TABLE 1. Stille Cross-Coupling Reaction of 2-Halopyridines
(organoboron),18 and Hiyama (organosilicon)19 reactions. The
more established Stille reaction has benefited from high yields,
wide functional group tolerances, and high turnovers of the
palladium catalyst.17 Furthermore, a diverse array of functiona-
lized organostannanes are readily available by a number of
different reaction types.17 While some information is available
concerning the Stille cross-coupling of stannylated pyridines and
2-halogenated quinolines,20 little is known about the related
coupling using the reverse partners (i.e., 2-stannylated quinolines
with 2-substituted pyridines).21 With the intention of gaining
additional insight into the scope of the metal-catalyzed cross-
coupling of suitably substituted quinolyl and pyridinyl precur-
sors, a number of ABC analogues of lavendamycin were
synthesized using different stannylated heteroaromatics and
halogenated pyridines, isoquinolines, and β-carbolines in order
to evaluate the efficiency of the coupling reaction.22
The first coupling experiments were conducted with vari-
ous 2-halogenated pyridines (i.e., 9a-10b)23 and 2-tributyl-
stannylpyridines 11 and 12 in DMF at 110 °C using PdCl2-
(PPh3)2 as the catalyst. The results clearly demonstrated that
higher yields of the coupled bipyridines 13,17c 14,24 and 1525
were obtained when 2-bromopyridines were used as sub-
strates as compared to the corresponding 2-chloropyridines
(Table 1).
The strategy to assemble the ABC ring system of lavenda-
mycin outlined in Scheme 1 was next applied to the synthesis of
the simpler analogue 19. In addition to providing the func-
tional groups present in the A-ring of lavendamycin, it was
anticipated that the presence of a methoxy group in precursor
18 would direct the dinitration to afford the required quinoline
19 which would be further utilized to eventually give the
desired para-quinone A-ring found in compound 3.
(19) (a) Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; Stang, P.
J., Ed.; Wiley-VCH Verlag GmbH: Weinheim, 1998; pp 421-452. (b) Hiyama,
T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61. (c) Hiyama, T. J. Organomet.
Chem. 2002, 653, 58.
The synthesis of the starting 2-bromoquinoline 18 is
depicted in Scheme 2. Commercially available 2,8-dihydroxy-
quinoline (16) was treated with acetic anhydride followed by
a subsequent reaction with POBr3 in refluxing CHCl3 to
give 8-acetoxy-2-bromoquinoline (17) in 67% overall yield.
Hydrolysis of the ester moiety in 17 followed by reaction with
methyl iodide gave the corresponding methyl ether 18,whichwas
readilyconvertedto2-bromo-8-methoxy-5,7-dinitroquinoline (19)
(20) (a) Godard, A.; Fourquez, J. M.; Tamion, R.; Marsais, F.;
ꢀ
Queguiner, G. Synlett 1994, 235. (b) Godard, A.; Rocca, P.; Pomel, V.;
Dumont, T. L.; Rovera, J. C.; Thaburet, J. F.; Marsais, F.; Queguiner, G. J.
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Organomet. Chem. 1996, 9, 2195. (c) Kimber, M.; Anderberg, P. I.; Harding,
M. M. Tetrahedron 2000, 56, 3575.
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(21) (a) Godard, A.; Rovera, J.-C.; Marsais, F.; Ple, N.; Queguiner, G.
Tetrahedron 1992, 48, 4123. (b) Rocca, P.; Marsais, F.; Godard, A.;
ꢀ
ꢀ
Queguiner, G. Tetrahedron 1993, 49, 3325.
(22) For a somewhat related approach, see: Rocca, P.; Marsais, F.;
ꢀ
Godard, A.; Queguiner, G. Tetrahedron Lett. 1993, 34, 2937.
(23) For the preparation of 2-halopyridines 10a,b, see: (a) Zhang, H.; Tse,
M. K.; Chan, K. S. Synth. Commun. 2001, 31, 1129. (b) Nicolaou, K. C.;
Scarpelli, R.; Bollbuck, B.; Werschkun, B.; Pereira, M. M. A.; Wartmann,
M.; Altmann, K.-H.; Zaharevitz, D.; Gussio, R.; Giannakakou, P. Chem.
Biol. 2000, 7, 593. (c) Bedel, S.; Ulrich, G.; Picard, C.; Tisnes, P. Synthesis
2002, 11, 1564.
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3373. (b) Potts, K. T.; Winslow, P. A. J. Org. Chem. 1985, 50, 5405.
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5, 779.
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TABLE 2. Stille Reaction of Halogenated Quinolines and Isoquinolines with 2-Stannylpyridines using PdCl2(PPh3)2
suitable precursor for the 7-amino-5,8-dione moiety of lavenda-
mycin (vide infra). We found that the cross-coupling reaction of
2-haloquinolines 20, 1-haloisoquinolines 21, and the substituted
2-bromoquinolines 17-19 proceeded in a manner similar to that
observed in the pyridine series (see Table 1). Thus, the
palladium(0)-catalyzed coupling between these halogenated
quinolines and 2-stannylated pyridines 11 and 12 using the Stille
procedure produced the expected heterobiaryls 22-31 in good
yield.27-29 The results are summarized in Table 2 and show that
SCHEME 2
(26) (a) Sigouin, O.; Beauchamp, A. L. Can. J. Chem. 2005, 83, 460. (b)
Gershan, H.; Clarke, D. D. Monatsh. Chem. 1991, 122, 935. (c) Petitjean, A.;
Kyritsakas, N.; Lehn, J.-M. Chem.;Eur. J. 2005, 11, 6818. (d) Holzapfel,
C. W.; Ferreira, A. C.; Marais, W. J. Chem. Res. 2002, 218.
(27) Martinez, R.; Ramon, D. J.; Yus, M. Tetrahedron 2006, 62, 8988.
(28) Haginiwa, J.; Higuchi, Y.; Kawashima, T.; Goto, T. Yakugaku
Zasshi 1975, 95, 204.
26
by treatment with HNO3/H2SO4. This dinitroquinoline deri-
vative can be easily obtained on multigram scale and serves as a
(29) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961.
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TABLE 3. Stille Reaction of 2-Stannylquinolines with Halogenated Heteroaromatics
PdCl2(PPh3)2 is an efficient catalyst for these haloquinoline
coupling reactions. Yields refer to isolated materials, and reac-
tions were carried out with 10 mol % of catalyst in DMF or
toluene for 6 h at 105 °C.
SCHEME 3
Experiments were also undertaken to compare the effi-
ciency of the cross-coupling reaction using 2-stannylated
quinolines (i.e., 36 and 37; see Table 3) as the reaction
partners. Our first attempt to prepare 2-tributylstannyl-
quinoline 36 is outlined in Scheme 3. 2-Chloro-8-methoxy-
5,7-dinitroquinoline (35) was synthesized by the dinitration
of 2-chloro-8-hydroxyquinoline (32)26 to give 33 followed by
O-methylation using dimethyl sulfate. An alternative and
somewhat higher-yielding approach to 35 involved carrying
out the O-methylation in the first step to first furnish
2-chloro-8-methoxyquinoline (34) in nearly quantitative
yield, and this was followed by a subsequent dinitration
reaction to give 35. Unfortunately, the lithiodechlorination
of 35 using n-BuLi and then reacting the resultant aromatic
anion with n-Bu3SnCl failed to give any of the desired
stannylated product. It was found, however, that the coup-
ling of the corresponding 2-bromoquinoline 19 with
Bu3SnSnBu3 and PdCl2(PPh3)2 in dioxane at 85 °C for 3 h
produced the desired 2-stannylquinoline 36 in 61% yield
after silica gel chromatography.
A Stille reaction using the above 2-stannylated quinoline 36
as well as the simpler stannane 37 derived from commercially
available 2-bromoquinoline was carried out with the halo-
genated pyridine 10a, quinoline 20a, isoquinoline 21a, and
β-carboline 40 as the coupling partners. While the reactivity of
heteroaryl chlorides such as 1-chloroisoquinoline 21b (X=Cl)
in Stille couplings is well-established, higher yields may be
obtained under Negishi conditions.30 We found that the
coupling of stannane 37 with 1-chloroisoquinoline (21b) under
either standard Pd(0)17 or Ni(0) catalysis30 gave poor overall
yields of the coupled product 38. However, 1-bromoisoquino-
line (21a) underwent smooth coupling with stannane 37 to
furnish the biaryl product 38 in 49% yield. Similarly,
2-bromoquinoline 20a was also coupled with stannane 37 to
(30) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
428 J. Org. Chem. Vol. 75, No. 2, 2010

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SCHEME 4
SCHEME 5
afford the expected biaryl coupled product 39 in 68% yield
(Table 3). We then extended this procedure to the coupling
reaction of 2-stannylated dinitroquinoline 36, which represents
a more advanced compound for the synthesis of lavendamycin
analogues. It was found that the Stille cross-coupling of
36 with 2-bromopyridine 10a gave the expected 2-pyridylqui-
noline 31 in 63% yield. Likewise, the reaction of 36 with
1-chloro-β-carboline 40 proceeded smoothly to give the
coupled product 41 in 63% yield (Table 3). 1-Chloro-β-carbo-
line 40 was easily accessible in bulk and in 51% overall yield
in three steps from N-propargyl-N-tosyl-1-benzylindole-2-
carboxamide 42 using our recently reported method to
access β-carbolines via a gold(III)-catalyzed cycloisomeriza-
tion.10 Thus, the reaction of 42 with a catalytic quantity of
AuCl3 afforded 2-tosyl-β-carbolinone 43, which was subjected
to N-detosylation with sodium naphthalenide, and the result-
ing amide 44 was subsequently treated with POCl3 to give 40 in
62% yield from 43 (Scheme 4).
SCHEME 6
In conclusion, 2-bromo substituted quinolines effi-
ciently couple with 2-pyridinylstannanes to provide unsym-
metrical heterobiaryl derivatives. The overall approach
shows a good convergence and is currently being extended
to the synthesis of lavendamycin and analogues starting
from functionalized quinolines and β-carboline building
blocks.
To determine whether 7-aminoquinolinediones could be
used directly as coupling partners for the synthesis of laven-
damycin analogues, 7-amino-2-chloroquinolinedione 47 was
prepared from 2-chloro-8-hydroxyquinoline (32) (Scheme 5).
This was accomplished by treating quinoline 32 with
bromine to give 5,7-dibromo-2-chloro-8-hydroxyquinoline
45. Further reaction of quinoline 45 with nitric/sulfuric acid
furnished 7-bromo-2-chloroquinolin-5,8-dione 46 in 77%
yield. Treatment of 46 with sodium azide afforded 7-azido-2-
chloroquinoline-5,8-dione. Unfortunately, the reduction of
the azido group to the corresponding amino functionality
produced only 47 in low yield (ca. 25%). Furthermore, all
attempts to convert quinolinedione 47 into the corresponding
stannyl derivative 48 failed, and consequently we abandoned
this particular approach toward the synthesis of lavendamycin
and its analogues.
An alternate strategy for an eventual synthesis of laven-
damycin was also evaluated using 2-(pyridin-2-yl)quinoline
31 as a potential precursor (Scheme 6). Hydrogenation
of 31 over Pd/C followed by subsequent acylation of 49 with
acetic anhydride gave the diacetamido substituted quinoline
50 in 89% yield. Oxidation of 50 with cerium ammonium
nitrate (CAN) furnished 7-acetamido-5,8-dione 51 in
93% yield. Thus, this sequence of reactions allows for
the construction of the ABC skeleton of lavendamycin by
using a Stille cross-coupling at a much earlier stage of the
synthesis.
Experimental Section
2-Bromo-8-methoxy-5,7-dinitroquinoline (19). A mixture con-
taining 2.7 g (10 mmol) of 8-acetoxy-2-bromoquinoline (17),26c
2.0 g (30 mmol) of KOH, and 25 mL of ethanol was stirred for
1 h at ambient temperature. After removal of the solvent under
reduced pressure, water was added to form a clear solution
which was brought to pH 7 with hydrochloric acid. The mixture
was extracted with chloroform, dried over sodium sulfate,
filtered, and concentrated under reduced pressure to give 2.15
g (88%) of 2-bromo-8-quinolinol as a white solid: mp 81-82 °C
(lit.26a mp 81-82 °C); 1H NMR (400 MHz, CDCl3) δ 7.21 (dd,
1H, J = 7.6 and 1.2 Hz), 7.32 (dd, 1H, J = 8.4 and 1.2 Hz), 7.68
(s, 1H), 7.52 (m, 2H) and 7.98 (d, 1H, J = 8.8 Hz).
To a solution of 2.2 g (10 mmol) of the above 2-bromo-
8-quinolinol in 50 mL of acetone was added 4.1 g (30 mmol) of
K2CO3 at room temperature, and the heterogeneous solution
was rapidly stirred under a dry nitrogen atmosphere. A 2.0 mL
(30 mmol) sample of MeI was added over 5 min, and the solution
was stirred overnight at room temperature. The solvent was
removed under reduced pressure, and then 75 mL of water was
added. The mixture was extracted with CH2Cl2, dried over
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Verniest et al.
JOCArticle
MgSO4, and filtered, and the solvent was removed under
reduced pressure to give 2.33 g (97%) of 2-bromo-8-methoxy-
quinoline (18)26d as a white solid: mp 83-84 °C; 1H NMR (400
MHz, CDCl3) δ 4.01 (s, 3H), 7.14 (dd, 1H, J = 7.9 and 1.0 Hz),
7.31 (dd, 1H, J = 7.9 and 1.0 Hz), 7.48 (m, 2H), and 7.91 (d, 1H,
J = 8.8 Hz).
pressure. The crude residue was subjected to flash silica gel
chromatography to give 0.068 g (49%) of the titled compound
27 as a light yellow solid: mp 157-159 °C; IR (neat) 2921, 2852,
1767, 1597, 1196, and 767 cm-1; 1H NMR (400 MHz, CDCl3) δ
2.41 (s, 3H), 2.57 (s, 3H), 7.39 (m, 1H), 7.50 (m, 1H), 7.66 (m,
1H), 7.74 (m, 1H), 8.28 (d, 1H, J = 8.8 Hz), 8.44 (d, 1H, J = 8.6
Hz), 8.53 (s, 1H) and 8.59 (d, 1H, J = 8.6 Hz); 13C NMR (100
MHz, CDCl3) δ 18.4, 21.0, 119.4, 121.2, 121.3, 125.7, 126.2,
129.4, 134.0, 136.8, 137.4, 140.4, 147.7, 149.5, 153.5, 156.0,
169.7. Anal. Calcd for C17H14N2O2: C, 73.35; H, 5.07; N,
10.07. Found: C, 73.36; H, 5.23; N, 9.98.
Preparation of 8-(Methoxy-2-pyridin-2-yl)quinoline (28). To a
solution of 2-bromo-8-methoxyquinoline (18) (0.12 g, 0.5 mmol)
in 1 mL of dry degassed DMF were added 2-tri-n-butylstannyl-
pyridine (11) (0.18 g, 0.5 mmol) and dichlorobis(triphenyl-
phosphine)palladium(II) (35 mg, 0.05 mmol) under an argon
atmosphere. The mixture was heated at 105 °C for 6 h and
cooled to rt, water was added, and the mixture was extracted
with diethyl ether. The combined organic layer was washed with
water and brine and dried over Na2SO4. The organic extracts
were filtered and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.092 g (78%) of the titled compound 28 as a white solid:
mp 74-76 °C; IR (neat) 2925, 2853, 1589, 1458, 1260, and
783 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 3H), 7.08 (d,
1H, J = 7.2 Hz), 7.34 (m, 1H), 7.45 (m, 2H), 7.86 (m, 1H), 8.27
(d, 1H, J = 8.4 Hz), 8.60 (d, 1H, J = 8.8 Hz) and 8.70 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 56.3, 108.1, 119.6, 120.0, 122.2,
124.1, 127.1, 129.5, 136.9, 137.0, 142.6, 149.1, 155.2, 155.7, and
156.4. Anal. Calcd for C15H12N2O: C, 76.24; H, 5.12; N, 11.86.
Found: C, 76.28; H, 5.14; N, 11.76
Preparation of 8-Methoxy-2-(5-methylpyridin-2-yl)quinoline
(29). To a solution of 2-bromo-8-methoxyquinoline (18) (0.12
g, 0.5 mmol) in 1 mL of dry degassed DMF were added 2-tri-n-
butylstannyl-5-methylpyridine (12) (0.19 g, 0.5 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05
mmol) under an argon atmosphere. The mixture was heated at
105 °C for 6 h and cooled to rt, water was added, and the mixture
was extracted with diethyl ether. The combined organic layer
was washed with water and brine and dried over Na2SO4. The
organic extracts were filtered and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
chromatography to give the titled compound 29 (82%) as a light
yellow solid: mp 94-95 °C; IR (neat) 2924, 2853, 1599, 1462,
1259, and 834 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H),
4.11 (s, 3H), 7.07 (dd, 1H, J = 7.2 and 1.2 Hz), 7.43 (m, 2H), 7.66
(d, 1H, J = 7.2 Hz), 8.24 (d, 1H, J = 8.4 Hz) and 8.56 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 18.6, 56.4, 108.1, 119.6, 120.0,
121.9, 127.0, 129.5, 134.0, 137.0, 137.7, 140.0, 149.7, 154.0,
155.5, and 155.7. Anal. Calcd for C16H14N2O: C, 76.77; H,
5.64; N, 11.20. Found: C, 76.62; H, 5.66; N, 11.06.
Preparation of 8-(Methoxy-5,7-dinitro-2-pyridin-2-yl)quino-
line (30). To a solution of 2-bromo-8-methoxy-5,7-dinitroqui-
noline (19) (0.16 g, 0.5 mmol) in 1 mL of dry degassed toluene
were added 2-tri-n-butylstannylpyridine (11) (0.18 g, 0.5 mmol)
and dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05
mmol) under an argon atmosphere. The mixture was heated at
100 °C for 6 h and cooled to rt, water was added, and the mixture
was extracted with diethyl ether. The combined organic layer
was washed with water and brine and dried over Na2SO4. The
organic extracts were filtered and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
chromatography to give 0.099 g (61%) of the titled compound
30 as a light yellow solid: mp 182-184 °C; IR (neat) 2921, 2851,
1568, 1529, 968, and 853 cm-1; 1H NMR (400 MHz, CDCl3) δ
4.67 (s, 3H), 7.50 (m, 1H), 7.96 (m, 1H), 8.65 (d, 1H, J = 7.6 Hz),
8.81 (d, 1H, J = 4.4 Hz), 8.82 (s, 1H), 9.02 (d, 1H, J = 9.2 Hz),
9.29 (d, 1H, J = 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 65.7,
To 12 mL of a stirred solution of HNO3-H2SO4 (3:1 v/v) was
added 2.38 g (10 mmol) of 2-bromo-8-methoxyquinoline (18) in
small portions. The mixture was allowed to stir at 0 °C for 2 h
and then poured into 150 mL of ice . The bright yellow solid that
formed was filtered, washed with ice-water, and then dried
overnight to give 2.47 g (65%) of 2-bromo-8-methoxy-5,7-
dinitroquinoline (19) as a light yellow solid: mp 97-98 °C; IR
1
(neat) 3106, 2955, 1573, 1526, 1341, and 843 cm-1; H NMR
(400 MHz, CDCl3) δ 4.52 (s, 3H), 7.88 (d, 1H, J = 9.2 Hz), 8.78
(s, 1H) and 9.00 (d, 1H, J = 9.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 65.5, 121.6, 123.9, 131.3, 135.1, 138.7, 140.0, 142.8,
143.6 and 154.9. Anal. Calcd for C10H6BrN3O5: C, 36.70; H,
1.85; N, 12.85. Found: C, 36.80; H, 1.76; N, 12.70.
1-(5-Methylpyridin-2-yl)isoquinoline (25). To a solution of
1-bromoisoquinoline (21a) (0.1 g, 0.5 mmol) in 1 mL of dry
degassed DMF were added 2-tri-n-butylstannyl-5-methylpyridine
(12) (0.19 g, 0.5 mmol) and dichlorobis(triphenylphosphine)-
palladium(II) (35 mg, 0.05 mmol) under an argon atmosphere.
The mixture was heated at 110 °C for 18 h. After cooling to rt,
water was added, and the mixture was extracted with diethyl ether.
The combined organic layers were washed with water and brine
and then dried over Na2SO4. The organic extracts were filtered
and concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.048 g (44%)
of the titled compound 25 as a pale yellow oil: IR (neat) 3049, 2922,
1553, 1484, 1134, and 828 cm-1; 1H NMR (400 MHz, CDCl3) δ
2.45 (s, 3H), 7.58 (m, 1H), 7.69 (m, 3H), 7.90 (t, 2H, J = 8.4 Hz)
and 8.60 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 18.4, 121.0,
124.7, 126.7, 126.8, 127.5, 127.8, 130.0, 132.9, 137.1, 137.4, 141.9,
149.0, 155.6, and 157.7. HRMS Calcd for [(C15H12N2) þ Hþ]:
221.1079. Found: 221.1075.
Preparation of 2-(Pyridin-2-yl)quinolin-8-yl Acetate (26). To a
solution of 2-bromo-8-acetoxyquinoline (17) (0.13 g, 0.5 mmol)
in 1 mL of dry degassed DMF were added 2-tri-n-butylstannyl-
pyridine (11) (0.18 g, 0.5 mmol) and dichlorobis(triphenyl-
phosphine)palladium(II) (35 mg, 0.05 mmol) under an argon
atmosphere. The mixture was heated at 105 °C for 6 h and
cooled to rt, water was added, and the mixture was extracted
with diethyl ether. The combined organic layer was washed with
water and brine and dried over Na2SO4. The organic extracts
were filtered and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.076 g (57%) of the titled compound 26 as a light yellow
solid: mp 145-147 °C; IR (neat) 2923, 2852, 1767, 1597, 1204,
and 783 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.39
(m, 1H), 7.47 (m, 1H), 7.54 (m, 1H), 7.74 (m, 1H), 7.87 (m, 1H),
8.32 (d, 1H, J = 8.8 Hz), 8.56 (d, 1H, J = 8.6 Hz), 8.65 (d, 1H,
J = 8.8 Hz) and 8.73 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
21.2, 119.8, 121.6, 121.9, 124.4, 125.9, 126.6, 129.7, 137.0, 137.1,
140.7, 148.0, 149.3, 156.1, 156.2, 170.0. Anal. Calcd for
C16H12N2O2: C, 72.70; H, 4.58; N, 10.60. Found: C, 72.63; H,
4.61; N, 10.44.
Preparation of 2-(5-Methylpyridin-2-yl)quinolin-8-yl Acetate
(27). To a solution of 2-bromo-8-acetoxyquinoline (17) (0.13 g,
0.5 mmol) in 1 mL of dry degassed DMF were added 2-tri-n-
butylstannyl-5-methylpyridine (12) (0.19 g, 0.5 mmol), and
dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05
mmol) under an argon atmosphere. The mixture was heated at
105 °C for 6 h and cooled to rt, water was added, and the mixture
was extracted with diethyl ether. The combined organic layer
was washed with water and brine and dried over Na2SO4. The
organic extracts were filtered and concentrated under reduced
430 J. Org. Chem. Vol. 75, No. 2, 2010

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JOCArticle
120.9, 122.2, 124.3, 124.9, 125.6, 128.6, 128.8, 132.1, 132.3,
132.4, 133.9, 137.5, 149.9 and 154.4. Anal. Calcd for
C15H10N4O5: C, 55.20; H, 3.09; N, 17.18. Found: C, 55.19; H,
3.14; N, 17.20.
with CH2Cl2. After drying over MgSO4, the solution was
concentrated under reduced pressure to give 2.1 g (10.7 mmol,
97%) of 2-chloro-8-methoxyquinoline (34) as a white solid: mp
77-78 °C; IR (neat) 1591, 1566, 1496, 1465, 1418, 1263, 1122,
and 1100 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.07 (s, 3H), 7.09
(dd, 1H, J = 0.8 Hz, J = 7.9 Hz), 7.37 (d, 1H, J = 7.9 Hz), 7.39
(t, 1H, J = 8.4 Hz), 7.48 (t, 1H, J = 8.4 Hz), and 8.79 (d, 1H, J =
8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 56.1, 108.9, 119.3,
123.1, 127.3, 128.0, 138.9, 139.5, 149.9, and 154.6.
To 3.0 mL of fuming HNO3, freshly distilled at reduced
pressure from a 1:1 mixture of 70% HNO3/H2SO4, keeping
the bp <70 °C, was carefully added 1.0 mL of concentrated
H2SO4 at 0 °C. To this mixture was added 0.5 g (2.6 mmol) of
2-chloro-8-methoxyquinoline (34) in portions over 2 min at
0 °C. After stirring under a dry nitrogen atmosphere for 2 h at
0 °C, the mixture was carefully poured over 50 mL of crushed
ice. The resulting solid was filtered, washed with ice-cold water,
and dried overnight under high vacuum to give 0.51 g (70%) of
2-chloro-8-methoxy-5,7-dinitroquinoline (35): mp 114-116 °C;
IR (neat) 1590, 1523, 1397, and 1360 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.56 (s, 3H), 7.78 (d, 1H, J = 9.2 Hz), 8.84 (s, 1H) and
9.17 (d, 1H, J = 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 65.6,
121.5, 123.7, 128.0, 135.9, 138.8, 140.2, 142.5, 152.7, and
154.9. HRMS Calcd for [C10H6ClN3O5 þ Hþ]: 284.0074.
Found: 284.0079.
8-Methoxy-2-(5-methylpyridin-2-yl)-5,7-dinitroquinoline (31).
To a solution of 2-bromo-8-methoxy-5,7-dinitroquinoline (19)
(0.16 g, 0.5 mmol) in 1 mL of dry degassed toluene were added 2-
tri-n-butylstannyl-5-methyl-pyridine (14) (0.19 g, 0.5 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05
mmol) under an argon atmosphere, and the mixture was heated
at 100 °C for 6 h. After cooling to rt, water was added, and the
mixture was extracted with diethyl ether. The combined organic
layer was washed with water and brine and then dried over
Na2SO4. The organic extract was filtered and concentrated
under reduced pressure. The crude residue was subjected to
flash silica gel chromatography to give the titled compound 31 in
60% as a light yellow solid: mp 197-199 °C; IR (neat) 2921,
1
2851, 1557, 1531, 1321, and 832 cm-1; H NMR (400 MHz,
CDCl3) δ 2.46 (s, 3H), 4.66 (s, 3H), 7.73 (d, 1H, J = 8.4 Hz), 8.52
(d, 1H, J = 8.0 Hz), 8.60 (s, 1H), 8.79 (s, 1H), 8.96 (d, 1H, J =
9.2 Hz) and 9.25 (d, 1H, J = 9.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 18.8, 65.6, 120.7, 121.7, 124.1, 128.6, 128.8, 132.1,
132.3, 132.4, 133.7, 135.8, 137.9, 150.3, 151.8 and 157.5. Anal.
Calcd for C16H12N4O5: C, 56.46; H, 3.56; N, 16.47. Found: C,
56.38; H, 3.64; N, 16.38.
8-Methoxy-2-(5-methylpyridin-2-yl)-5,7-dinitroquinoline (31)
could also be prepared by the coupling of 2-tri-n-butylstannyl-8-
methoxy-5,7-dinitroquinoline (36) with 2-bromo-5-methylpyr-
idine (10a). To a solution of 2-bromo-8-methoxy-5,7-dinitroqui-
noline (19) (0.16 g, 0.5 mmol) in 5 mL of dry degassed dioxane
were added bis(tributyltin) (0.32 g, 0.55 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) under an
argon atmosphere, and the mixture was heated at 85 °C for 3 h.
After cooling to rt, water was added, and the mixture was
extracted with diethyl ether. The combined organic layer was
washed with water and brine and then dried over Na2SO4. The
organic extract was filtered and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
chromatography to give 0.17 g (61%) of 2-tri-n-butylstannyl-8-
methoxy-5,7-dinitroquinoline (36) as a light yellow oil, IR (neat)
2956, 2925, 1557, 1528, 1336, and 808 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.90 (t, 9H, J = 7.2 Hz), 1.25 (m, 6H), 1.35 (m, 6H),
1.62 (m, 6H), 4.62 (s, 3H), 7.87 (d, 1H, J = 8.4 Hz), 8.77 (s, 1H)
and 8.90 (d, 1H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ
10.6, 13.8, 27.7, 29.2, 65.4, 120.4, 124.0, 128.1, 133.2, 139.3, 143.0,
156.0, 181.2. HRMS Calcd for [C22H33N3O5Sn þ Hþ]: 540.1520.
Found: 540.1518.
2-Tri-n-butylstannyl-8-methoxy-5,7-dinitroquinoline (36) (0.27
g, 0.5 mmol) and dichlorobis(triphenylphosphine)palladium(II)
(35 mg, 0.05 mmol) were added to a solution of 2-bromo-5-
methylpyridine (10a) (0.086 g, 0.5 mmol) in 5 mL dry degassed
toluene under an argon atmosphere, and the mixture was heated at
100 °C for 6 h. After cooling to rt, water was added, and the
mixture was extracted with diethyl ether. The combined organic
layer was washed with water and brine and then dried over
Na2SO4. The organic extract was filtered and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.16 g (63%) of the titled
compound 31.
Preparation of 9-Benzyl-1-chloro-4-methyl-9H-β-carboline
(40). To a stirred solution of 0.5 g (2.0 mmol) of 1-benzyl-1H-
indole-2-carboxylic acid in 8 mL of benzene containing 2 drops
of N,N-dimethylformamide was added 0.26 mL (2.0 mmol) of
oxalyl chloride. The resulting solution was stirred at rt for 3 h,
after which time the solvent was removed under reduced pres-
sure, and the residue was taken up in 10 mL of CH2Cl2. To this
solution were added 1 mL of pyridine and 0.41 g (2 mmol) of
4-methyl-N-prop-2-ynyl-benzenesulfonamide dissolved in 3 mL
of CH2Cl2. The solution was allowed to stir at rt overnight. The
solution was then quenched with water and extracted with
CH2Cl2. The combined organic layer was washed with aq
10% HCl, brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.72 g (81%) of N-(1-benzyl-
1H-indole-2-carbonyl)-4-methyl-N-prop-2-ynylbenzenesulfon-
amide (42) as a pale yellow oil: IR (neat) 3290, 3060, 2924, 2127,
1673, 1596, 1514, 936, and 815 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.39 (t, 1H, J = 2.4 Hz), 2.45 (s, 3H), 4.55 (d, 2H, J =
2.8 Hz), 5.49 (s, 2H), 7.01 (m, 2H), 7.22 (m, 4H), 7.34 (m, 5H),
7.74 (d, 1H, J = 8.0 Hz) and 7.90 (d, 2H, J = 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.9, 38.5, 47.9, 73.9, 78.9, 110.7, 111.0,
121.4, 123.2, 125.9, 126.2, 127.2, 127.8, 128.9, 129.1, 129.7,
129.9, 135.7, 137.9, 139.5, 145.3, and 163.9. HRMS Calcd for
[C26H22N2O3S þ Hþ]: 443.1429. Found: 443.1425.
A 0.44 g (1 mmol) sample of indole 42 was stirred with 15 mg
of Au(III) chloride in 10 mL of CH2Cl2 at rt overnight. The
mixture was filtered through a plug of silica gel, washed with
triethylamine, and rinsed with ethyl acetate, and the filtrate was
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.36 g (82%)
of
9-benzyl-4-methyl-2-(4-methylbenzenesulfonyl)-2,9-dihy-
dro-β-carbolin-1-one (43) as a white solid: mp 181-182 °C; IR
(neat) 3107, 3063, 2925, 1668, 1598, 1366, 1174, 1089, and 739
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.60 (d, 3H,
J = 0.8 Hz), 5.93 (s, 2H), 7.01 (m, 2H), 7.12 (m, 3H), 7.22 (m,
1H), 7.34 (m, 4H), 7.72 (d, 1H, J = 1.2 Hz), 8.00 (d, 2H, J = 8.4
Hz) and 8.06 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 17.6, 21.9, 48.1, 111.5, 113.4, 120.1, 121.3, 122.3, 123.2, 125.8,
126.0, 127.2, 127.4, 127.5, 128.7, 129.6, 129.7, 134.9, 137.9,
141.1, 145.6 and 154.7. Anal. Calcd for C26H22N2O3S: C,
70.57; H, 5.01; N, 6.33. Found: C, 70.43; H, 4.82; N, 6.45.
Preparation of 2-Chloro-8-methoxy-5,7-dinitroquinoline (35).
To a solution of 2.0 g (11.1 mmol) of 2-chloro-8-hydroxyquino-
line (32) in 50 mL of acetone was added 3.5 g (25.4 mmol) of
K2CO3 at room temperature, and the heterogeneous solution
was stirred under a dry nitrogen atmosphere for 30 min. To this
mixture was added 1.7 mL (25.4 mmol) of MeI over a 5 min
period, and the solution was stirred overnight at room tempera-
ture. The solvent was removed under reduced pressure, 75 mL of
water was added to the residue, and the mixture was extracted
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To a solution of 25 mg (0.06 mmol) of 43 in 2 mL of dry THF
was added a 1.3 M solution of sodium naphthalenide in 1,2-
dimethoxyethane (freshly prepared from sodium metal and
naphthalene) dropwise at -78 °C until the green color persisted
for more than 2 min. The solution was stirred for 30 min at
-78 °C and then quenched with a saturated aqueous solution of
NH4Cl. After the addition of 5 mL of water, the mixture was
extracted with CH2Cl2, and the extracts were dried over MgSO4.
The mixture was filtered, the solvent was removed under
reduced pressure, and the crude residue was subjected to flash
silica gel chromatography to give 13 mg (82%) of 9-benzyl-4-
methyl-2,9-dihydro-β-carbolin-1-one (44) as a white solid: mp
256-258 °C; IR (neat) 2965, 2939, 1644, 1622, 1456, 1435, 744,
and 700 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 2.53 (s, 3H),
6.12 (s, 2H), 6.91 (s,1H), 7.23 (m, 6H), 7.43 (t, 1H, J = 7.2 Hz),
7.62 (d, 1H, J = 8.8 Hz), 8.11 (d, 1H, J = 8.4 Hz) and 11.38 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 17.2, 48.1, 111.2, 113.1,
120.5, 121.9, 122.9, 123.2, 126.4, 126.6, 126.8, 127.2, 127.4,
128.8, 138.6, 140.5 and 157.0. Anal. Calcd for C19H16N2O: C,
79.13; H, 5.60; N, 9.72. Found: C, 79.28; H, 5.46; N, 9.78.
A 0.29 g (1 mmol) sample of 44 in 5 mL of POCl3 was heated
at reflux for 24 h. The solution was slowly quenched with a
saturated aqueous solution of NaHCO3 and then extracted with
EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
chromatography to give 0.23 g (76%) of 9-benzyl-1-chloro-4-
methyl-9H-β-carboline (40) as a white solid: mp 157-159 °C; IR
(neat) 3033, 1616, 1562, 1496, 1444, 1060, 954, and 730 cm-1; 1H
NMR (400 MHz, CDCl3) δ 2.79 (s, 3H), 5.96 (s, 2H), 7.04 (m,
2H), 7.22 (m, 3H), 7.32 (t, 1H, J = 8.0 Hz), 7.42 (d, 1H, J = 8.4
Hz), 7.56 (t, 1H, J = 8.4 Hz), 7.99 (s, 1H) and 8.20 (d, 1H, J =
8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 17.4, 47.9, 110.6, 120.9,
121.9, 123.7, 126.2, 127.2, 127.6, 128.7, 129.0, 130.7, 131.2,
132.1, 137.9, 139.0, and 142.3. Anal. Calcd for C19H15N2Cl:
C, 74.49; H, 4.94; N, 9.15. Found: C, 74.45; H, 4.78; N, 8.99.
Preparation of 9-Benzyl-1-(8-methoxy-5,7-dinitroquinolin-2-
yl)-4-methyl-9H-β-carboline (41). To a solution of the above
β-carboline 40 (0.15 g, 0.5 mmol) in 5 mL of dry toluene were
added 2-tri-n-butylstannyl-8-methoxy-5,7-dinitroquinoline (36)
(0.27 g, 0.5 mmol) and dichlorobis(triphenylphosphine)-
palladium(II) (35 mg, 0.05 mmol) under an argon atmosphere.
The mixture was heated at 100 °C for 3 h and cooled to rt, water
was added, and the mixture was extracted with diethyl ether.
The combined organic layer was washed with water and brine
and dried over Na2SO4. The organic extracts were filtered and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.13 g (63%)
of the titled compound 41 as a light yellow solid: mp 215-
217 °C, IR (neat) 2924, 2854, 1570, 1528, 1246, and 737 cm-1; 1H
NMR (400 MHz, CDCl3) δ 2.99 (s, 3H), 4.36 (s, 3H), 5.81 (s,
2H), 6.01 (d, 2H, J = 7.6 Hz), 6.75 (t, 2H, J = 8.0 Hz), 6.92 (t,
1H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.2 Hz), 7.60 (d, 1H, J = 8.4
Hz), 7.65 (t, 1H, J = 7.2 Hz), 8.00 (d, 1H, J = 8.8 Hz), 8.37 (d,
1H, J = 8.0 Hz), 8.40 (s, 1H), 8.86 (s, 1H) and 8.92 (d, 1H, J =
9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 18.1, 48.8, 65.7, 110.4,
120.8, 120.9, 122.1, 123.9, 124.1, 125.1, 127.3, 128.4, 128.5,
128.7, 128.9, 130.7, 132.5, 134.2, 136.3, 139.1, 139.4, 140.0,
140.2, 141.5, 143.1, 155.9 and 159.2. Anal. Calcd for
C29H21N5O5: C, 67.03; H, 4.08; N, 13.49. Found: C, 66.92; H,
3.94; N, 13.58.
was quenched by the addition of aqueous Na2SO3. To this
mixture was added 50 mL of CH2Cl2, and the heterogeneous
solution was filtered. The filtrate was washed with water and
extracted with CH2Cl2. Removal of the solvent under reduced
pressure afforded a yellow solid which was purified by silica gel
chromatography to give 0.82 g (87%) of 5,7-dibromo-2-chloro-
8-hydroxyquinoline (45) as a white solid: mp 155-156 °C; IR
(neat) 3355, 1572, 1479, 1444, 1340, and 1309 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.52 (d, 1H, J = 8.7 Hz), 7.91 (s, 1H), 8.07
(s, 1H), and 8.39 (d, 1H, J = 8.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 106.0, 110.3, 124.4, 125.5, 134.4, 138.1, 139.2, 148.9,
and 151.1. HRMS Calcd for [C9H4Br2ClNO) þ Hþ]: 335.8427.
Found: 335.8421.
Preparation of 2-Chloro-7-bromoquinoline-5,8-dione (46). To
a solution of 1.9 g (5.6 mmol) of 5,7-dibromo-2-chloro-8-
hydroxyquinoline (45) in 4.0 mL of concentrated sulfuric acid
was added 1.2 mL of HNO3 (aq 70%) at 0 °C over a 5 min
period. After stirring for 30 min at 0 °C, the solution was poured
over ice and extracted with CH2Cl2. The resulting solution was
dried over MgSO4, filtered and the solvent was removed under
reduced pressure to give 1.1 g (77%) of 7-bromo-2-chloroquino-
line-5,7-dione (46) as a yellow solid: mp 187-188 °C; IR (neat)
1692, 1654, 1572, and 1309 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 7.82 (s, 1H), 7.98 (d, 1H, J = 8.9 Hz), and 8.38 (d, 1H, J =
8.9 Hz); 13C NMR (100 MHz, DMSO-d6) δ 128.0, 129.1, 137.9,
139.1, 139.9, 147.0, 154.7, 174.9, and 181.6. HRMS Calcd for
[C9H3BrClNO2) þ Hþ]: 271.9114. Found: 271.9113.
Preparation of 7-Amino-2-chloroquinoline-5,8-dione (47). To a
solution of 0.16 g (0.57 mmol) of 7-bromo-2-chloroquinoline-
5,8-dione (46) in 15 mL of acetone at -30 °C was added 39 mg
(0.60 mmol) of sodium azide under a dry nitrogen atmosphere.
After stirring for 1 h at -30 °C, the solution was allowed to
warm to 0 °C and was rapidly chromatographed on silica gel to
give 70 mg (52%) of 7-azido-2-chloro-quinoline-5,8-dione as an
orange solid which was immediately subjected to reduction. To a
solution of 0.18 g (0.75 mmol) of the crude 7-azido-2-chloro-
quinoline-5,8-dione in 5 mL of CH2Cl2 was added a solution of
0.21 g (0.78 mmol) of PPh3 in 2 mL of CH2Cl2 at 0 °C over a 10
min period. After stirring for an additional 20 min at 0 °C, 2 mL
of an aqueous 0.5 M HCl solution was added to the mixture.
After stirring for 30 min at 0 °C, the mixture was treated with
Et3N to obtain a neutral pH (pH 7). Subsequently, the organic
solvent was removed under reduced pressure and the residue was
subjected to silica gel chromatography to give 62 mg (22%) of 7-
amino-2-chloroquinoline-5,8-dione (47) as a dark red solid: mp
279-280 °C; IR (neat) 3457, 1693, 1629, 1563, 1436, 1377, and
1
1339 cm-1; H NMR (400 MHz, DMSO-d6) δ 5.84 (s, 1H),
7.20-7.60 (brs, 2H), 7.88 (d, 1H, J = 8.3 Hz), and 8.27 (d, 1H,
J = 8.3 Hz); 13C NMR (100 MHz, DMSO-d6) δ 101.4, 129.1,
129.3, 137.1, 146.9, 151.1, 153.0, 178.9, and 179.9. HRMS Calcd
for [C9H5ClN2O2) þ Hþ]: 209.0118. Found: 209.0116.
5,7-Diacetamido-8-methoxy-2-(5-methylpyridin-2-yl)quinoline
(50). To a suspension of finely powdered 2-(5-methylpyridin-2-
yl)-8-methoxy-5,7-dinitroquinoline (31) (0.34 g, 1 mmol) in 2 mL
of MeOH was added a catalytic amount of Pd/C. The mixture
was subjected to hydrogenation (30 psi) for 15 h using a Parr
hydrogenator. The reaction mixture was filtered and washed
with MeOH, and the solvent was removed under reduced
pressure to afford quinoline 49 as a brown solid. Without
purification, the solid material was taken up in 5 mL of CH2Cl2,
and to this solution was added acetic anhydride (0.19 mL,
2 mmol) and Et3N (0.28 mL, 2 mmol). The mixture was stirred
overnight at room temperature, water was added, and the
mixture was extracted with CH2Cl2. The combined organic layer
was washed with water and brine and dried over Na2SO4. The
organic extracts were filtered and evaporated under reduced
pressure to give 0.33 g (89%) of 5,7-diacetamido-8-methoxy-
2-(5-methylpyridin-2-yl)quinoline (50): mp 273-274 °C; IR
Preparation of 5,7-Dibromo-2-chloro-8-hydroxyquinoline
(45). To a solution of 0.5 g (2.8 mmol) of 2-chloro-8-quinolinol
(32) in 10 mL of methanol/CH2Cl2 (1:1) was added 0.7 g (8.4
mmol) of NaHCO3. A solution of 1.33 g (8.4 mmol) of Br2 in
10 mL of MeOH/CH2Cl2 (1:1) was slowly added dropwise at
room temperature to the above solution. After the addition, the
mixture was stirred for another 30 min at room temperature and
432 J. Org. Chem. Vol. 75, No. 2, 2010

Verniest et al.
JOCArticle
(neat) 3013, 2985, 1669, 1523, 1312, 854, and 730 cm-1; 1H NMR
(400 MHz, DMSO-d6) δ 2.17 (s, 3H), 2.20 (s, 3H), 2.41 (s, 3H),
4.21 (s, 3H), 7.88 (dd, 1H, J = 8.0 and 2.0 Hz), 8.41 (s, 1H), 8.45
(s, 2H), 8.54 (d, 1H, J = 8.4 Hz), 8.60 (t,1H, J = 0.8 Hz), 9.67 (s,
1H) and 10.01 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 18.6,
23.9, 24.7, 62.8, 117.1, 118.9, 121.3, 121.7, 129.1, 129.6, 131.6,
134.0, 135.0, 138.5, 142.0, 150.3, 153.4, 155.2, 169.7 and 169.8.
Anal. Calcdfor C20H20N4O3: C, 65.91; H, 5.54; N, 15.38. Found:
C, 65.68; H, 5.47; N, 15.03.
7-Acetamido-2-(5-methylpyridin-2-yl)quinoline-5,8-dione (51).
A solution of CAN (0.21 g, 0.4 mmol) in 1 mL of water was
added to a solution of quinoline 50 (0.07 g, 0.2 mmol) in 1.5 mL
of CH3CN at 0 °C. After stirring for 10 min at 0 °C, water was
added, and the mixture was extracted with CH2Cl2. The com-
bined organic extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The result-
ing residue was purified by flash column chromatography to give
the titled compound 51 as a yellow solid (57 mg, 93%): mp
247-249 °C; IR (neat) 3352, 2941, 1672, 1518, 1334, 833, and
737 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.45 (s,
3H), 7.71 (d, 1H, J = 9.2 Hz), 7.97 (s, 1H), 8.45 (brs, 1H), 8.53
(m, 3H) and 8.83 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 18.8, 25.3, 116.8, 122.4, 125.7, 129.1, 135.4, 135.5,
137.9, 140.7, 145.8, 150.2, 151.7, 160.7, 169.7, 179.6 and 184.7.
Anal. Calcdfor C17H13N3O3: C, 66.43; H, 4.27; N, 13.68. Found:
C, 66.57; H, 4.14; N, 13.57.
Acknowledgment. A.P. appreciates the financial support
provided by the National Science Foundation (CHE-
0742663), G.V. the support from the Research Foundation-
Flanders (FWO-Vlaanderen, Belgium) and X.P.W. thanks the
Youth Award of Shandong Province (Grant No. 2007BS03033)
as well as the Natural Science Foundation of Shandong Pro-
vince (Grant No. Y2005 C35) for financial assistance during his
stay at Emory University.
Supporting Information Available: Spectroscopic and
experimental procedures for compounds 11-15, 17, 22-24,
1
and 37-39, as well as H and 13C NMR data of various key
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 2, 2010 433