Use of highly active palladium-phosphinous acid catalysts in Stille, Heck, amination, and thiation reactions of chloroquinolines

Article abstract of DOI:10.1021/jo034758n

An efficient synthetic route toward a variety of 2,4-disubstituted quinolines has been developed. Alkylation and arylation of 4-chloroquinoline using organolithium reagents proceed with high regioselectivity in position 2 under cryogenic conditions. The intermediate 1,2-dihydro-4-chloro-quinoline derivatives are unstable to air and are easily oxidized to the corresponding 2-substituted 4-chloroquinolines in high yields. Highly active palladium-phosphinous acid catalysts POPd, POPd1, and POPd2 have been employed in Stille cross-couplings of quinaldine with arylstannanes and in Heck additions of various 2-substituted 4-chloroquinolines to tert-butyl acrylate. In particular, POPd combines high catalytic activity for cross-coupling reactions with simplicity of use due to its stability to air. Utilizing CsF in POPd-catalyzed Stille couplings further increased the reactivity of arylstannanes, which was attributed to the fluorophilicity of organotin compounds. Basic additives were found to exhibit a significant effect on the yields of the POPd-promoted Heck reactions. In general, dicyclohexylmethylamine affords superior results than NaOAc, Cs₂CO₃, or t-BuOK. POPd was also found to tolerate amine and thiol substrates and proved to promote carbon-heteroatom bond formation of chloroquinoline derivatives with aliphatic and aromatic amines and thiols, respectively.

Full text of DOI:10.1021/jo034758n

Use of High ly Active P a lla d iu m -P h osp h in ou s Acid Ca ta lysts in
Stille, Heck , Am in a tion , a n d Th ia tion Rea ction s of
Ch lor oqu in olin es
Christian Wolf* and Rachel Lerebours
Department of Chemistry, Georgetown University, Washington, D.C. 20057
cw27@georgetown.edu
Received J une 4, 2003
An efficient synthetic route toward a variety of 2,4-disubstituted quinolines has been developed.
Alkylation and arylation of 4-chloroquinoline using organolithium reagents proceed with high
regioselectivity in position 2 under cryogenic conditions. The intermediate 1,2-dihydro-4-chloro-
quinoline derivatives are unstable to air and are easily oxidized to the corresponding 2-substituted
4-chloroquinolines in high yields. Highly active palladium-phosphinous acid catalysts POPd, POPd1,
and POPd2 have been employed in Stille cross-couplings of quinaldine with arylstannanes and in
Heck additions of various 2-substituted 4-chloroquinolines to tert-butyl acrylate. In particular, POPd
combines high catalytic activity for cross-coupling reactions with simplicity of use due to its stability
to air. Utilizing CsF in POPd-catalyzed Stille couplings further increased the reactivity of
arylstannanes, which was attributed to the fluorophilicity of organotin compounds. Basic additives
were found to exhibit a significant effect on the yields of the POPd-promoted Heck reactions. In
general, dicyclohexylmethylamine affords superior results than NaOAc, Cs2CO3, or t-BuOK. POPd
was also found to tolerate amine and thiol substrates and proved to promote carbon-heteroatom
bond formation of chloroquinoline derivatives with aliphatic and aromatic amines and thiols,
respectively.
In tr od u ction
malaria drugs. This is mostly due to the global rise of
resistance of the malarial parasite plasmodium falci-
parum to widely used quinoline-derived agents, such as
chloroquine.
Quinoline derivatives have been reported to display
pronounced biological activities.1 In particular, chloro-
quine and structurally similar 4-aminoquinolines have
successfully been employed in the treatment and pro-
phylaxis of malaria.2 The high interest in new synthetic
methodologies toward quinolines stems to some extent
from an increasing demand for new, highly efficient anti-
(1) (a) El Sayed, K.; Al-Said, M. S.; El-Feraly, F. S.; Ross, S. A. J .
Nat. Prod. 2000, 63, 995-997. (b) Ferlin, M. G.; Gatto, B.; Chiarelotto,
G.; Palumbo, M. Bioorg. Med. Chem. 2000, 8, 1415-1422. (c) Wissner,
A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B., J r.; Greenberger, L.
M.; Gruber, B. C.; J ohnson, B. D.; Mamuya, N.; Nilakantan, R.; Reich,
M. F.; Shen, R.; Tsou, H.-R.; Upeslacis, E.; Wang, Y. F.; Wu, B.; Ye,
F.; Zhang, N. J . Med. Chem. 2000, 43, 3244-3256. (d) Funayama, S.;
Murata, K.; Noshita, T. Heterocycles 2001, 54, 1139-1148. (e) Bu, X.;
Deady, L. W.; Finlay, G. J .; Baguley, B. C.; Denny, W. A. J . Med. Chem.
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L.; Scott, A. E.; Price, C. A.; Townes, H. M.; McNulty, L.; Handl, H.
L.; Summerville, K.; Hudson, S. J .; Bowen, J . P.; Kiakos, K.; Hartley,
J . A.; Lee, M. Bioorg. Med. Chem. 2002, 10, 2941-2952. (g) Filla, S.
A.; Winter, M. A.; J ohnson, K. W.; Bleakman, D.; Bell, M. G.; Bleisch,
T. J .; Castano, A. M.; Clemens-Smith, A.; del Prado, M.; Dieckman,
D. K.; Dominguez, E.; Escribano, A.; Ho, K. H.; Hudziak, K. J .;
Katofiasc, M. A.; Martinez-Perez, J . A.; Mateo, A.; Mathes, B. M.;
Mattiuz, E. L.; Ogden, A. M. L.; Phebus, L. A.; Stack, D. R.; Stratford,
R. E.; Ornstein, P. L J . Med. Chem. 2002, 45, 4383-4386. (h) Hachem,
A.; Le Floc’h, Y.; Gree, R.; Cerletti, C.; Rolland, Y.; Simonet, S.;
Verbeuren, T. Tetrahedron Lett. 2002, 43, 5221-5223. (i) Strekowski,
L.; Say, M.; Henary, M.; Ruiz, P.; Manzel, L.; MacFarlane, D. E.;
Bojarski, A. J . Med. Chem. 2003, 46, 1242-1249.
The synthesis of quinoline derivatives thus continues
to be an active area of heterocyclic chemistry.3 To date,
the usefulness of haloquinolines as synthetic intermedi-
ates has been limited because of the unstable nature of
bromo- and iodoquinolines and the low reactivity of chloro
hetaryls. Consequently, many synthetic strategies toward
quinolines involve ring construction using monocyclic
precursors such as aniline derivatives.4
From a synthetic standpoint, aryl chlorides are a very
interesting class of compounds because of their high
availability and low cost. The usefulness of aryl chlorides
as synthetic intermediates has somehow been limited
because of their low reactivity in coupling reactions,
(2) (a) O’Neill, P. M.; Bray, P. G.; Hawley, S. R.; Ward, S. A.; Park,
B. K. Pharmacol. Ther. 1998, 77, 29-58. (b) Blauer, G.; Akkawi, M.;
Fleischhacker, W.; Hiessboeck, R. Chirality 1998, 10, 556-563. (c)
Egan, T. J .; Hunter, R.; Kaschula, C. H.; Marques, H. M.; Misplon, A.;
Walden, J . J . Med. Chem. 2000, 43, 283-291.
(3) For a recent review, see: Gilchrist, T. L. J . Chem. Soc., Perkin
Trans. 1 2001, 2491-2515.
10.1021/jo034758n CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003
J . Org. Chem. 2003, 68, 7077-7084
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Wolf and Lerebours
SCHEME 1. Syn th esis of 3-5
which has been attributed to their reluctance to undergo
oxidative addition to transition metals. The recent de-
velopment of highly active transition metal complexes
provides new venues for employing aryl chlorides in
Suzuki, Negishi, Hiyama, Kumada, Stille, and Heck
reactions.5 DeShong showed that aryl chlorides also
undergo Pd-catalyzed cross-coupling reactions with hy-
pervalent siloxanes.6 However, only a few studies utiliz-
ing chloroquinolines in cross-coupling reactions have been
reported to date. Dondoni and co-workers employed
2-chloroquinoline in a Pd-catalyzed Stille coupling with
2-trimethylstannyloxazoles to prepare the corresponding
heteroaryl oxazole in 75%.7 Heck and Stille coupling
reactions of chloroquinolines have also been utilized in
the synthesis of tricyclic azakynurenic acids and the
quinoline-5,8-quinone moiety of streptonigrin.8 Shiota et
al. developed a regioselective Negishi coupling protocol
for 2,4-dichloroquinolines that affords 4-substituted 2-chlo-
roquinolines in moderate to high yields.9 Ciufolini et al.
reported that Pd-mediated alkylations and carbonyla-
tions of 2-chloroquinolines proceed with good to high
yields.10 Legros and co-workers obtained moderate to
good yields employing Pd(dba)2 in Stille couplings of
4-chloroquinolines and 1-ethoxyvinyl-tri-butylstannane.11
Notably, they reported that 4-chloroquinoline does not
undergo a Pd-catalyzed Heck reaction with butyl vinyl
ether.
Herein, we report a new synthetic strategy toward 2,4-
disubstituted quinolines that is based on regioselective
alkylation or arylation of commercially available 4-chlo-
roquinoline, 1, followed by transition-metal-catalyzed
cross-coupling with organostannanes, tert-butyl acrylate,
amines, or thiols. Our approach provides access to a
variety of quinoline derivatives in just two synthetic
steps.
(4) (a) Boix, C.; de la Fuente, J . M.; Poliakoff, M. New J . Chem. 1999,
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7476. (w) Yin, J . J .; Rainka, M. P.; Zhang, X. X.; Buchwald, S. L. J .
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Chem., Int. Ed. 2002, 41, 4176-4211.
Resu lts a n d Discu ssion
We found that 1 undergoes an unprecedented Ziegler
reaction12 with organolithium reagents at -78 °C with
high regioselectivity, Scheme 1.13 Comparison of Et2O and
THF revealed that the latter solvent affords superior
results. Thus, quinolines 2-5 were obtained in 67-90%
yield after reaction of organolithium reagents with
quinoline 1 followed by treatment with CAN. We were
able to isolate intermediate 2-substituted 4-chloro-1,2-
dihydroquinolines that proved to be unstable to air and
are readily oxidized to quinolines 3-5 in the presence of
CAN.14 Undesirable side reactions such as dehalogena-
tion of the starting material and of the Ziegler reaction
product can be avoided through careful reaction control.
We observed the formation of significant amounts of
quinoline and 2-substituted quinolines at elevated reac-
tion temperatures or increased reaction times. For in-
stance, arylation of 1 using phenyllithium in THF at
-78 °C provided 4-chloro-2-phenylquinoline (5) in 67%
yield. However, 5 was obtained in only 54% yield at
-15 °C. It is assumed that the decrease in yield is mainly
a result of enhanced halogen-metal exchange under less
cryogenic conditions since halogen-directed ortho-meta-
lation in position 3 of 1 was not observed.15
Recently, Li et al. developed palladium-phosphinous
acid complexes [(t-Bu)2P(OH)]2PdCl2 (POPd), [[(t-Bu)2P-
(OH)(t-Bu)2PO)]PdCl]2 (POPd1), and [(t-Bu)2P(OH)PdCl2]2
(9) Shiota, T.; Yamamori, T. J . Org. Chem. 1999, 64, 453-457.
(10) Ciufolini, M. A.; Mitchell, J . W.; Roschangar, F. Tetrahedron
Lett. 1996, 37, 8281-8284.
(11) Legros, J .-Y.; Primault, G.; Fiaud, J .-C. Tetrahedron 2001, 57,
2507-2514.
(12) Wolf, C.; Ghebremariam, B. T. Synthesis 2002, 749-752.
(13) To prove that the Ziegler reaction proceeds in position 2 of
4-chloroquinoline, we synthesized 4-chloro-2-methylquinoline, 2, using
methyllithium in 90% yield. The NMR spectrum was found to be
identical to that of commercially available 2.
(14) We observed that the isolated 2-substituted 4-chloro-1,2-dihy-
droquinolines oxidize within a few days when exposed to air.
(6) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
(7) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,
P. Synthesis 1987, 693-696.
(8) (a) Godard, A.; Fourquez, J . M.; Tamoin, R.; Marsais, F.;
Queguiner, G. Synlett 1994, 235-236. (b) Hume, W. E.; Nagata, R.
Synlett 1997, 473-474.
(15) For
a review of halogen-directed ortho meatallations, see:
Mongin, Florence; Queguiner, G. Tetrahedron 2001, 57, 4059-4090.
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Reactions of Chloroquinolines
TABLE 1. P d -Ca ta lyzed Heck Rea ction s Usin g ter t-Bu tyl Acr yla te
a
b
The reaction time was 48 h. The reaction temperature was 100 °C. c In refluxing toluene.
(POPd2), which have successfully been used in a variety
of cross-coupling reactions, Figure 1.16 Employing this
new class of Pd catalysts in Heck and Stille cross-coupling
reactions of 4-chloroquinolines 1-5 with arylstannanes
and tert-butyl acrylate, respectively, we found that these
catalysts exhibit high activity and greatly facilitate
operation due to their stability to air, Scheme 2.17
(16) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (b)
Li, G. Y.; Zheng, G.; Noonan, A. F. J . Org. Chem. 2001, 66, 8677-
8681. (c) Li, G. Y. J . Org. Chem. 2002, 67, 3643-3650.
POPd-promoted Heck reactions were found to proceed
with high diastereoselectivity (E/Z > 25:1), and quino-
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Wolf and Lerebours
TABLE 2. P d -Ca ta lyzed Stille Cou p lin gs
SCHEME 2. P OP d -Ca ta lyzed Cr oss-Cou p lin g
Rea ction sa
a
F IGURE 1. Structures of POPd, POPd1, and POPd2.
Reagents and conditions: (a) 6 mol % POPd, 5 equiv of tert-
butyl acrylate, 1.2 equiv of base, DMF, 135 °C, 24 h. (b) 6 mol %
POPd, 1.3 equiv of Rm′SnMe3 (R′SnBu3), 1.1 equiv of Cy2NMe,
DMF, 135 °C, 24 h.
lines 6-10 were obtained in good to high yields using
DMF as the solvent, Table 1 (entries 1-9, 11-15). The
use of various bases, for example, NaOAc, Cs2CO3,
t-BuOK/t-BuOH, and Cy2NMe, was investigated to opti-
mize the reaction procedure. Using Cy2NMe as the base,
(E)-tert-butyl 3-(2-methyl-4-quinolyl)acrylate (7) was ob-
tained in 75% yield, whereas other bases give lower yields
or require longer reaction times (compare entries 3 and
5-8). Noteworthy, we observed that replacing Cy2NMe
with inorganic bases such as NaOAc or Cs2CO3 greatly
facilitates product purification because the chromato-
graphic separation of the aliphatic amine from quinolyl
acrylates proved to be difficult in some cases.
The anionic nature of palladium-phosphinous acids
under basic conditions might limit the solubility and
therefore accessibility and activity of these catalysts. We
anticipated that the employment of ion pair reagents in
the Heck reaction would result in homogeneous reaction
conditions and further increase the activity of POPd.
Addition of 20 mol % tetrabutylammonium bromide
indeed improved the yields of the Heck addition of 2 to
tert-butyl acrylate in the presence of POPd (entries 3 and
4). However, results obtained with 2-n-butyl-4-chloro-
(17) POPd, POPd1, and POPd2 can be purchased from Combiphos
Catalysts, Inc., New J ersey. Website: www.combiphos.com.
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Reactions of Chloroquinolines
TABLE 3. P d -Ca ta lyzed Ca r bon -Heter oa tom Bon d F or m a tion
a
Reaction temperature was 100 °C.
quinoline (3) show that Bu4NBr/NaOAc does not provide
similar yields as Cy2NMe (entries 11 and 12). Replace-
ment of DMF by toluene or a decrease of the reaction
temperature were found to be detrimental, which might
be a consequence of decreased solubility and thus reduced
availability of POPd and the inorganic base used (entries
9 and 10). In contrast to POPd, POPd1 and POPd2 do
not significantly promote the Heck reaction of chloro-
quinolines. Only low yields were obtained employing
POPd1 and POPd2 as catalysts in the Heck reaction of
chloroquinoline 2, and most of the starting material was
recovered after workup (entries 16 and 17).
2-methylquinolines (11) and 4-(2-thienyl)-2-methyl-
quinolines (12) were obtained in good to high yields,
Table 2 (entries 1 and 5-7). Similar to our observations
with Heck reactions, POPd was found to be superior over
POPd1 and POPd2. Using 6 mol % POPd, we obtained
quinoline 11 in 85% yield, whereas POPd1 and POPd2
were found to afford 11 in only 43% and 65% yields,
respectively. The reduced yields are likely to be a
consequence of the lower activity of these catalysts, since
we were able to recover the remaining starting materials
in both cases. Noteworthy, all phosphinous acid-Pd
catalysts investigated herein afford significantly better
results than Pd(PPh3)2Cl2 and Pd(dppf)Cl2, which provide
11 in low yields, Table 2 (entries 2-4).18 Following a
recent finding of Fu et al., we utilized 2 equiv of CsF to
further activate fluorophilic phenyltrimethyltin for Stille
We were pleased to find that POPd, POPd1, and
POPd2 catalyze the Stille cross-coupling of 4-chloro-
quinolines with 2-(tributylstannyl)thiophene and phen-
yltrimethyltin, respectively, Scheme 2. Thus, 4-phenyl-
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Wolf and Lerebours
SCHEME 4. Ca ta lytic Cycle for th e
SCHEME 3. Syn th esis of Qu in olin e-Der ived
Am in es a n d Su lfid esa
P OP d -Ca ta lyzed Am in a tion Rea ction
a
Reagents and Conditions: (a) 1.6 equiv of R′SH, 1.1 equiv of
base, DMF, 135 °C, 24 h. (b) 1.1 equiv of R′′NH2/R′′2NH, 1.1 equiv
of. t-BuOK/t-BuOH, DMF, 135 °C, 24 h.
promoted nucleophilic displacement of chloride and sub-
sequent reductive elimination, Scheme 4. Employing
POPd1 and POPd2, respectively, in the amination or
thiation of chloroquinolines 2 and 5 did not reveal any
catalytic effects. The same yields of 2-methyl-4-phenyl-
thioquinoline (13) were obtained in the absence and
presence of these catalysts (compare entries 1, 5, and 6).
Moreover, POPd1 and POPd2 proved to be detrimental
to the amination of 5 using aniline (compare entries 8,
13, and 14).
coupling.19 For all three phosphinous acid-Pd catalysts,
we observed that the yields of the Stille coupling of 2 and
phenyltrimethyltin are indeed enhanced by the addition
of CsF (entries 8-10). In particular, a significant increase
of the yield of 11 using CsF as an additive in the POPd1-
catalyzed coupling of quinaldine 2 and phenyltrimeth-
yltin was observed (compare entries 6 and 9).
Some aryl chlorides have been reported to undergo
transition metal-mediated carbon-heteroatom bond for-
mation. Thus, aromatic amines and sulfides have been
prepared utilizing palladium(II) complexes.13a,b,20 Ami-
nation and thiation reactions of 4-chloroquinolines are
also known to proceed via nucleophilic aromatic substitu-
tion in absence of a transition metal catalyst.21 Accord-
ingly, treatment of 2 and 5, respectively, with various
thiols or amines in the absence of a palladium catalyst
in DMF at 135 °C provided quinolines 13-17 in good
yields, Scheme 3 and Table 3 (entries 1, 3, 7, 8, and 11).
Interestingly, employing 6 mol % POPd in the presence
of Cy2NMe or t-BuOK under the same reaction conditions
improved results in most cases; that is, sulfides 13 and
14 as well as amines 16 and 17 were obtained in superior
yields by Pd-mediated catalysis (entries 2, 4, 9, and 12).
Accordingly, a Pd-catalyzed amination reaction of 4-chlo-
roquinoline has recently been utilized by J onckers et al.
for the synthesis of isocryptolepine.22 The POPd-catalyzed
amination and thiation of 4-chloroquinoline are expected
to proceed via oxidative addition followed by base-
Con clu sion
We have developed an efficient route toward 2,4-
disubstituted quinolines. Ziegler reaction using organo-
lithium reagents at -78 °C followed by treatment with
CAN allows regioselective alkylation or arylation in
position 2 of 4-chloroquinoline. Palladium-phosphinous
acids, POPd, POPd1, and POPd2, were found to be highly
useful catalysts for a variety of cross-coupling reactions.
Stille reactions of chloroquinoline derivatives and aryl-
stannanes as well as Heck additions of aryl chlorides to
tert-butyl acrylate proceed with high yield and diaste-
reoselectivity. In general, POPd exhibits higher catalytic
activity toward cross-coupling reactions of 4-chloroquino-
lines than POPd1 and POPd2. Using tetrabutylammo-
nium bromide and CsF slightly enhances the yields of
POPd-catalyzed Heck and Stille reactions, respectively.
Electron-deficient 2-substituted-4-chloroquinolines un-
dergo nucleophilic aromatic substitution by amines or
thiols at elevated temperature. However, employing
POPd under the same reaction conditions affords superior
yields. By contrast, POPd1 and POPd2 do not promote
carbon-heteroatom bond formation under the reaction
conditions employed in this study. The usefulness of
palladium-phosphinous acid complexes POPd, POPd1,
and POPd2 for the synthesis of a broad variety of biaryls
using aryl stannanes or aryl siloxanes is currently under
investigation in our laboratories.
(18) It should be noted that tri-n-butylethynylstannane and tri-n-
butylvinylstannane did not undergo POPd-catalyzed Stille coupling
with quinolines 2 and 5, respectively.
(19) Littke, A. F.; Schwarz, L.; Fu, G. C. J . Am. Chem. Soc. 2002,
124, 6343-6348 and references therein.
(20) (a) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald,
S. L. J . Org. Chem. 2000, 65, 1158-1174 and references therein. (b)
Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41,
2875-2879. (c) Kondo, T.; Mitsudo, T. A. Chem. Rev. 2000, 100, 3205-
3220. (d) Harris, M. C.; Buchwald, S. L. J . Org. Chem. 2000, 65, 5327-
5333. (e) Grasa, G. A.; Viviu, M. S.; Huang, J .; Nolan, S. P. J . Org.
Chem. 2001, 66, 7729-7737. (f) Yin, J .; Buchwald, S. L. J . Am. Chem.
Soc. 2002, 124, 6043-6048. (g) Kuwano, R.; Utsunomiya, M.; Hartwig,
J . F. J . Org. Chem. 2002, 67, 6479-6486.
(21) (a) Sicker, D.; Reifegerste, D.; Hauptmann, S.; Wilde, H.; Mann,
G. Synthesis 1985, 331-333. (b) Galanakis, D.; Davis, c. A.; Ganellin,
C. R.; Dunn, P. M. J . Med. Chem. 1996, 39, 359-370. (c) Takashiro,
E.; Nakamura, Y.; Fujimoto, K. Tetrahedron Lett. 1999, 40, 5565-
5568.
Exp er im en ta l Section
Meth od s. Chemicals were of reagent grade and used
without further purification. All reactions were carried out
under a nitrogen atmosphere and anhydrous conditions. Flash
chromatography was carried out on SiO2 (particle size 0.032-
0.063 mm). Triethylamine (1%) was always used as a mobile
(22) J onckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts,
G.; Pieters, L.; Haemers, A.; Dommisse, R. A. Synlett 2003, 615-618.
7082 J . Org. Chem., Vol. 68, No. 18, 2003

Reactions of Chloroquinolines
1
phase additive to reduce tailing of the quinolines during
chromatography. NMR spectra were obtained at 300 MHz (1H
NMR) and 75 MHz (13C NMR) using CDCl3 as the solvent.
Chemical shifts are reported in ppm relative to TMS. GC-
MS was performed using a 15 m DB-1 GC column.
using Cy2NMe), mp 40-42 °C. H NMR: δ 1.56 (s, 9H), 2.76
(s, 3H), 6.56 (d, J ) 16.0 Hz, 1H), 7.43 (s, 1H), 7.54 (ddd, J )
1.4 Hz, 7.0 Hz, 8.0 Hz, 1H), 7.71 (ddd, J ) 1.4 Hz, 7.0 Hz, 8.5
Hz, 1H), 8.05 (dd, J ) 1.4 Hz, 8.0 Hz, 1H), 8.09 (dd, J ) 1.4
Hz, 8.5 Hz, 1H), 8.30 (d, J ) 16.0 Hz, 1H). 13C NMR: δ 25.4,
28.2, 81.2, 118.9, 123.1, 124.5, 126.2, 126.2, 129.2, 129.6, 138.1,
140.2, 148.2, 158.5, 165.2. EIMS (70 eV) m/z (%): 269 (30, M+),
254 (50, M+-Me), 181 (10, M+-Me, -OC4H9), 153 (100, M+-
Me, -CO2C4H9). Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11;
N, 5.20. Found: C, 75.46; H, 7.48; N, 5.06.
(E)-ter t-Bu tyl 3-(2-n -Bu tyl-4-qu in olyl)a cr yla te (8). Pu-
rification by flash chromatography (hexane/Et2O 5:1) gave a
yellow oil (70% using Cy2NMe). 1H NMR: δ 0.97 (t, J ) 7.0
Hz, 3H), 1.44 (m, 2H), 1.57 (s, 9H), 1.79 (m, 2H), 2.96 (t, J )
7.9 Hz, 2H) 6.56 (d, J ) 16.0 Hz, 1H), 7.43 (s, 1H), 7.54 (ddd,
J ) 1.3 Hz, 7.3 Hz, 7.8 Hz, 1H), 7.71 (ddd, J ) 1.3 Hz, 6.5 Hz,
7.8 Hz, 1H), 8.03 (dd, J ) 1.3 Hz, 6.5 Hz, 1H), 8.10 (dd, J )
1.3 Hz, 7.3 Hz, 1H), 8.30 (d, J ) 16.0 Hz, 1H). 13C NMR: δ
14.4, 23.1, 28.5, 32.6, 39.4, 81.5, 118.6, 123.4, 124.8, 125.8,
126.4, 129.0, 129.8, 138.6, 140.5, 148.5, 162.9. EIMS (70 eV):
m/z (%): 311 (50, M+), 296 (70, M+-Me), 254 (60, M+-C4H9),
181 (21, M+-OC4H9, -C4H9), 153 (100, M+-CO2C4H9, -C4H9).
Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found:
C, 77.46; H, 8.18; N, 4.51.
(E)-ter t-Bu tyl 3-(2-ter t-Bu tyl-4-qu in olyl)a cr yla te (9).
Flash chromatography (hexane/Et2O 25:1) gave a yellow oil
(66% using Cy2NMe). 1H NMR: δ 1.47 (s, 9H), 1.58 (s, 9H),
6.56 (d, J ) 16.0 Hz, 1H), 7.53 (ddd, J ) 1.3 Hz, 7.6 Hz, 7.7
Hz, 1H), 7.63 (s, 1H), 7.71 (ddd, J ) 1.3 Hz, 7.6 Hz, 7.7 Hz,
1H), 8.03-8.11 (m, 2H), 8.30 (d, J ) 16.0 Hz, 1H). 13C NMR:
δ 28.3, 30.2, 44.1, 81.2, 104.3, 115.2, 122.2, 122.9, 124.2, 125.8,
126.1, 129.2, 130.0, 139.0, 139.8, 165.3. EIMS (70 eV) m/z
(%): 311 (32, M+), 296 (80, M+-Me), 281 (49, M+-2Me), 254
(40, M+-C4H9), 181 (40, M+-C4H9, -OC4H9), 153 (100, M+-
CO2C4H9, -C4H9). Anal. Calcd for C20H25NO2: C, 77.14; H,
8.09; N, 4.50. Found: C, 76.81; H, 8.25; N, 4.61.
(E)-ter t-Bu tyl 3-(2-P h en yl-4-qu in olyl)a cr yla te (10). Pu-
rification by flash chromatography (hexane/Et2O 100:1) gave
a clear oil (72% using Cy2NMe). 1H NMR: δ 1.59 (s, 9H), 6.65
(d, J ) 15.7 Hz, 1H), 7.45-7.55 (m, 3H), 7.59 (ddd, J ) 1.3
Hz, 7.6 Hz, 7.7 Hz, 1H), 7.76 (ddd, J ) 1.3 Hz, 7.5 Hz, 7.7 Hz,
1H), 8.00 (s, 1H), 8.12-8.24 (m, 4H), 8.40 (d, J ) 15.7 Hz,
1H). 13C NMR: δ 28.3, 81.3, 116.1, 123.1, 125.0, 126.4, 126.8,
127.4, 128.8, 129.4, 129.8, 130.3, 138.4, 139.2, 140.8, 148.6,
164.5. EIMS (70 eV): m/z (%): 331 (59, M+), 254 (23, M+-
Ph), 197 (33, M+-C4H9, -Ph), 181 (50, M+-Ph, -OC4H9), 153
(100, M+-Ph, -CO2C4H9). Anal. Calcd for C22H21NO2: C,
79.73; H, 6.39; N, 4.23. Found: C, 79.45; H, 6.03; N, 4.38.
Gen er a l P r oced u r e for th e Syn th esis of 2-Su bstitu ted
4-Ch lor oqu in olin es 2-5. To a stirred solution of 4-chloro-
quinoline (300 mg, 1.8 mmol) in 10 mL of anhydrous THF was
added the organolithium reagent (1.5 mL, 1.5 M in hexanes)
dropwise at -78 °C. The reaction mixure was allowed to
proceed for 4 h at -78 °C, quenched with 10% NH4OH, and
extracted with CH2Cl2. The combined organic layers were
washed with water and concentrated in vacuo. The residue
was dissolved in 2 mL of acetone and treated with an aqueous
solution of ammonium cerium(IV) nitrate (2.0 g in 10 mL) for
30 min. The orange solution was extracted with CH2Cl2 and
dried over MgSO4, and the filtrate was concentrated under
reduced pressure. The crude products were purified by flash
chromatography on silica gel as indicated for each example.
Gen er a l P r oced u r e for Heck Rea ction s. A mixture of
POPd (16.0 mg, 6 mol %) quinoline derivative (0.56 mmol),
tert-butyl acrylate (356 mg, 2.8 mmol), and base (0.61 mmol)
was stirred in 5 mL of anhydrous DMF at 135 °C for 24 h.
The reaction mixture was allowed to cool to room temperature,
quenched with water, and extracted with Et2O. The combined
organic layers were washed with water and dried over MgSO4,
and the solvents were removed under vacuum. The crude
products were purified by flash chromatography on silica gel
as indicated for each example.
Gen er a l P r oced u r e for Stille Cou p lin gs. A mixture of
POPd (16.0 mg, 6 mol %) quinoline derivative (0.56 mmol),
organostannane (0.7 mmol), and Cy2NMe (120 mg, 0.61 mmol)
was stirred in 5 mL of anhydrous DMF at 135 °C for 24 h.
The reaction mixture was allowed to cool to room temperature,
quenched with water, and extracted with Et2O. The combined
organic layers were washed with brine and dried over MgSO4,
and the solvents were removed under vacuum. The residue
was purified by flash chromatography on silica gel as indicated
for each example.
Gen er a l P r oced u r e for Am in a tion of 4-Ch lor oqu in o-
lin es. A mixture of POPd (16.0 mg, 6 mol %) quinoline
derivative (0.56 mmol), amine (0.72 mmol), and base (0.61
mmol) was stirred in 5 mL of anhydrous DMF at 135 °C for
24 h. The reaction mixture was allowed to cool to room
temperature, quenched with water, and extracted with Et2O.
The combined organic layers were washed with brine and dried
over MgSO4, and the solvents were removed under vacuum.
The crude products were purified by flash chromatography on
silica gel as indicated for each example.
Gen er a l P r oced u r e for Th ia tion of 4-Ch lor oqu in o-
lin es. A mixture of POPd (16.0 mg, 6 mol %) quinoline
derivative (0.56 mmol), thiol (0.73 mmol), and base (0.61 mmol)
was stirred in 5 mL of anhydrous DMF at 135 °C for 24 h.
The reaction mixture was allowed to cool to room temperature,
quenched with water, and extracted with EtOAc. The com-
bined organic layers were washed with brine and dried over
MgSO4, and the solvents were removed under vacuum. The
crude products were purified by flash chromatography on silica
gel as indicated for each example.
2-Meth yl-4-p h en ylqu in olin e (11). Purification by flash
chromatography (hexane/EtOAc 25:1) gave a colorless oil
(85%). 1H NMR: δ 2.78 (s, 3H), 7.23 (s, 1H), 7.43 (ddd, J ) 1.4
Hz, 7.6 Hz, 8.5 Hz, 1H), 7.47-7.51 (m, 5H), 7.69 (ddd, J ) 1.4
Hz, 7.6 Hz, 8.4 Hz, 1H), 7.86 (dd, J ) 1.4 Hz, 8.4 Hz, 1H),
8.08 (dd, J ) 1.4 Hz, 8.5 Hz, 1H). 13C NMR: δ 25.4, 122.1,
125.0, 125.5, 125.6, 128.2, 128.4, 128.9, 129.2, 129.4, 138.0,
148.2, 148.3, 158.3. EIMS (70 eV) m/z (%): 219 (100, M+), 204
(22, M+-Me), 142 (10, M+-Ph), (11, 127 (15, M+-Me, -Ph).
Anal. Calcd for C16H13N: C, 87.64; H, 5.98; N, 6.39. Found:
C, 87.52; H, 5.82; N, 6.35.
2-Meth yl-4-(2-th ien yl)qu in olin e (12). Purification by flash
(E)-ter t-Bu tyl 3-(4-Qu in olyl)a cr yla te (6). Flash chroma-
tography (hexane/Et2O 1:1) gave a colorless oil (85% using Cy2-
NMe). 1H NMR: δ 1.59 (s, 9H), 6.59 (d, J ) 15.9 Hz, 1H), 7.54
(d, J ) 4.6 Hz, 1H), 7.70 (dd, J ) 6.6 Hz, 8.8 Hz, 1H), 7.81
(dd, J ) 6.6 Hz, 7.4 Hz), 8.14-8.16 (m, 2H), 8.33 (d, J ) 15.9
Hz, 1H), 8.9 (d, J ) 4.6 Hz, 1H). 13C NMR: δ 28.2, 81.3, 118.0,
123.3, 126.0, 126.5, 127.1, 129.6, 130.1, 135.7, 135.8, 137.8,
140.1, 165.1. EIMS (70 eV) m/z (%): 255 (15, M+), 182 (35,
M+-OC4H9), 154 (100, M+-CO2C4H9), 127 (25, M+-CO2C4H9,
-HCN). Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49.
Found: C, 74.92; H, 6.42; N, 5.32.
chromatography (hexane/EtOAc 10:1) gave a colorless oil
1
(61%). H NMR: δ 2.77 (s, 3H), 7.22 (dd, J ) 3.6 Hz, 5.0 Hz,
1H), 7.35 (s, 1H), 7.38 (dd, J ) 1.1 Hz, 3.6 Hz, 1H), 7.47-7.53
(m, 2H), 7.70 (ddd, J ) 1.4 Hz, 7.6 Hz, 8.3 Hz, 1H), 8.07 (d,
J ) 8.0 Hz, 1H), 8.22 (dd, J ) 1.4 Hz, 8.3 Hz, 1H). 13C NMR:
δ 25.4, 121.0, 122.5, 126.0, 126.9, 127.6, 128.3, 129.4, 138.9,
142.1, 146.1, 165.5. EIMS (70 eV) m/z (%): 225 (100, M+), 210
(10, M+-Me), 127 (5, M+-Me, -C4H3S). Anal. Calcd for C14H11
-
NS: C, 74.63; H, 4.92; N, 6.22. Found: C, 75.01; H, 5.02; N,
6.35.
(E)-ter t-Bu tyl 3-(2-Meth yl-4-qu in olyl)a cr yla te (7). Flash
chromatography (hexane/Et2O 5:1) gave white crystals (75%
2-Meth yl-4-p h en ylth ioqu in olin e (13). Purification by
flash chromatography (hexane/EtOAc 5:1) gave white crystals
J . Org. Chem, Vol. 68, No. 18, 2003 7083

Wolf and Lerebours
(85%), mp 76-78 °C. 1H NMR: δ 2.53 (s, 3H), 6.68 (s, 1H),
7.40-7.60 (m, 6H), 7.71 (ddd, J ) 1.4 Hz, 7.7 Hz, 8.4 Hz, 1H),
7.98 (dd, J ) 1.1 Hz, 8.4 Hz, 1H), 8.17 (dd, J ) 1.4 Hz, 8.2 Hz,
1H). 13C NMR: δ 25.4, 118.8, 123.2, 124.3, 125.5, 128.9, 129.2,
129.6, 129.7, 129.8, 134.7, 147.2, 147.7, 157.9. EIMS (70 eV):
m/z (%): 251 (70, M+), 250 (100, M+-H), 236 (31, M+-Me),
142 (20, M+-PhS), 127 (5, M+-Me, -PhS). Anal. Calcd for
16H13NS: C, 76.46; H, 5.21; N, 5.57. Found: C, 76.28; H, 4.85;
N, 5.44.
2-P h en yl-4-p h en ylth ioqu in olin e (14). Purification by
flash chromatography (hexane/EtOAc 5:1) gave white crystals
(85% using Cy2NMe), mp 110-112 °C. 1H NMR: δ 7.30 (s,
1H), 7.39-7.64 (m, 9H), 7.75 (dd, J ) 7.7 Hz, 8.4 Hz, 1H),
7.88-7.91 (m, 2H), 8.16 (d, J ) 8.4 Hz, 1H), 8.22, (d, J ) 8.7
Hz, 1H). 13C NMR: δ 116.4, 123.4, 125.1, 126.3, 127.4, 128.7,
129.2, 129.4, 129.9, 130.8, 134.7, 137.1, 139.4, 157.2. EIMS
(70 eV) m/z (%): 313 (72, M+), 312 (100, M+-H), 236 (31, M+-
Ph), 204 (12, M+-PhS). Anal. Calcd for C21H15NS: C, 80.48;
H, 4.82; N, 4.47. Found: C, 79.89; H, 4.70; N, 4.37.
4-n -P en tylth io-2-p h en ylqu in olin e (15). Flash chroma-
tography (hexane/Et2O 6:1) gave white crystals (73%, using
t-BuOK and no catalyst), mp 61-63 °C. 1H NMR: δ 0.94 (t,
J ) 7.3 Hz, 3H), 1.44 (m, 2H), 1.58 (m, 2H), 1.90 (m, 2H), 3.17
(t, J ) 7.3 Hz, 2H), 7.42-7.55 (m, 3H), 7.62 (s, 1H), 7.71-7.78
(m, 2H), 7.85 (m, 1H), 8.08-8.21 (m, 3H). 13C NMR: δ 14.1,
22.4, 28.0, 31.3, 31.4, 114.0, 123.3, 125.5, 125.9, 126.2, 127.5,
128.7, 129.2, 129.5, 130.2, 136.6, 148.1, 164.5. EIMS (70 eV)
m/z (%): 307 (80, M+), 306 (100, M+-H), 230 (20, M+-Ph),
215 (5, M+-Ph, -Me), 159 (31, M+-Ph, -C5H11), 127 (10, M+-
Ph, -SC5H11). Anal. Calcd for C20H21NS: C, 78.13; H, 6.88;
N, 4.56. Found: C, 77.69; H, 6.98; N, 4.44.
N-(2-P h en yl-4-qu in olyl)p yr r olid in e (17). Flash chroma-
tography (hexane/Et2O 6:1) gave white crystals (86%, using
1
t-BuOK), mp 131-133 °C. H NMR: δ 2.07 (m, 4H), 3.76 (m,
C
4H), 6.91 (s, 1H), 7.31 (ddd, J ) 1.4 Hz, 7.6 Hz, 8.6 Hz, 1H),
7.38-7.56 (m, 4H), 7.61 (ddd, J ) 1.4 Hz, 7.6 Hz, 8.4 Hz, 1H),
8.02-8.08 (m, 2H), 8.11 (dd, J ) 1.4 Hz, 8.6 Hz, 1H). 13C
NMR: δ 26.1, 52.3, 100.8, 122.9, 124.8, 125.1, 125.2, 127.6,
128.5, 128.7, 133.1, 144.7, 161.8, 163.8. EIMS (70 eV) m/z
(%): 274 (100, M+), 204 (35, M+-C4H8N), 197 (5, M+-Ph), 127
(10, M+-Ph, -C4H8N). Anal. Calcd for C19H18N2: C, 83.18; H,
6.61; N, 10.21. Found: C, 82.81; H, 6.40; N, 9.85.
Ack n ow led gm en t. We thank Combiphos Catalysts,
Inc., New J ersey (www.combiphos.com) for a generous
supply of POPd, POPd1, and POPd2.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
chromatographic purification of quinolines 3, 4, 5, and 16 and
NMR spectroscopy and mass spectrometry data. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O034758N
7084 J . Org. Chem., Vol. 68, No. 18, 2003