Synthesis of substituted quinolines using the dianion addition of N-Boc-anilines and α-tolylsulfonyl-α,β-unsaturated ketones

Article abstract of DOI:10.1021/jo0203387

A short and versatile synthesis of substituted quinolines is provided. Alkylation of sodium tolylsulfinate with bromomethyl- or chloromethyl ketones generates β-keto sulfones. Knoevenagel condensation of the β-keto sulfones with an aldehyde provides α-tolylsulfonyl-α,β-unsaturated ketones. Michael addition of the dianion of N-Boc-anilines in the presence of CuCN and LiCl with the unsaturated ketone generates a 1,4-adduct, which after deprotection of the Boc group and thermal elimination of the tolyl sulfone provides the quinoline.

Full text of DOI:10.1021/jo0203387

Syn th esis of Su bstitu ted Qu in olin es Usin g th e Dia n ion Ad d ition of
N-Boc-a n ilin es a n d r-Tolylsu lfon yl-r,â-u n sa tu r a ted Keton es
Rolf E. Swenson,*,† Thomas J . Sowin, and Henry Q. Zhang*
Department of Medicinal Chemistry Technologies (R-4CP), Pharmaceutical Product Division,
Abbott Laboratories, Abbott Park, Illinois 60064
henry.zhang@abbott.com
Received May 17, 2002
A short and versatile synthesis of substituted quinolines is provided. Alkylation of sodium
tolylsulfinate with bromomethyl- or chloromethyl ketones generates â-keto sulfones. Knoevenagel
condensation of the â-keto sulfones with an aldehyde provides R-tolylsulfonyl-R,â-unsaturated
ketones. Michael addition of the dianion of N-Boc-anilines in the presence of CuCN and LiCl with
the unsaturated ketone generates a 1,4-adduct, which after deprotection of the Boc group and
thermal elimination of the tolyl sulfone provides the quinoline.
In tr od u ction
quinoline ring system, mainly due to the limited avail-
ability of the starting material (especially isatin deriva-
tives). Recently, there have been reports of improved
Doebner reaction conditions for preparing diverse quino-
lines via solid-phase synthesis.11 There has also been
several reports of novel or improved methods for synthe-
sizing functionalized quinolines.12 In this paper, we
disclose an efficient and regiocontrolled synthesis of 2,4,6-
trisubstituted quinolines from commercially available
bromomethyl or chloromethyl ketones, aldehydes and
anilines. The chemistry exploits the dual nature of the
tolyl sulfone group both as an electron-withdrawing
group and later as a leaving group. The chemistry is
versatile. Both aliphatic and aromatic ketones or alde-
hydes as well as anilines with electron-withdrawing or
-donating groups can be employed. In contrast to the
existing synthetic approaches for the quinoline ring
system, modification of position 6 of the quinoline can
be made in the last step of the synthesis.
The quinoline ring system is found in natural products.
Compounds containing the quinoline ring have diverse
biological activity1 and have been developed for the
treatment of malaria,2 antibacterial infections,3 and HIV
disease.4 Substituted quinolines have also been reported
to have biological activity as antagonists of endothelin,5
5HT3,6 and NK-3 receptors.7 They also function as
inhibitors of gastric (H+/K+)-ATPase8 and dihydroorotate
dehydrogenase.9
Current methods for quinoline synthesis10 often do not
allow for adequate diversity and substitution on the
* Corresponding authors. H.Q.Z. address: Abbott Laboratories,
R-4CP, AP10, Abbott Park, IL 60064. Phone: (847)-935-5250. Fax:
(847)-935-0310.
† Present address: Bracco Research USA Inc., 305 College Road
East, Princeton, NJ 08540.
(1) Yates, F. S. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 2, p 511.
(2) (a) Lutz, R. E.; Bailey, P. S.; Clark, M. T.; Codington, J . F.;
Deinet, A. J .; Freek, J . A.; Harnest, G. H.; Leake, N. H.; Martin, T. A.;
Rowlett, R. J .; Salisbury, J . M.; Shearer, N. H.; Smith, J . D.; Wilson,
J . W. J . Am. Chem. Soc. 1946, 68, 1813. (b) Surrey, A. E.; Hammer,
H. F. J . Am. Chem. Soc. 1950, 72, 1814. (c) Burckhalter, J . H.; Brinigar,
W. S.; Thompson, P. S. J . Org. Chem. 1961, 26, 4070.
Resu lts a n d Discu ssion
The feasibility of this methodology for preparing 2,4,6-
trisubstituted quinolines was demonstrated by using
three different chloromethyl or bromomethyl ketones,
four different aldehydes, and three different N-Boc-
anilines. Alkylation of sodium tolylsulfinate with bromo-
methyl or chloromethyl ketones 1a -c under reflux for 2
h in ethanol gave â-keto sulfones 2a -c in 62-90% yields
after crystallization. The Knoevenagel condensation con-
ditions employed an aldehyde, 0.2 equiv of piperidine,
and 0.4 equiv of acetic acid in toluene under dehydrating
conditions (Scheme 1).13 Conditions for the formation of
(3) Desai, P. K.; Desai, P.; Machhi, D.; Desai, C. M.; Patel, D. Indian
J . Chem. Sect. B 1996, 35, 871.
(4) (a) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.; J anda,
L.; Strekowski, L. Med. Chem. Res. 1992, 2, 102. (b) Strekowski, L.;
Mokrosz, J . L.; Honkan, V. A.; Czarny, A.; Cegla, M. T.; Wydra, R. L.;
Patterson, S. E.; Schinazi, R. F. J . Med. Chem. 1991, 34, 1739.
(5) Cheng, X.-M.; Lee, C.; Klutchko, S.; Winters, T.; Reynolds, E.
E.; Welch, K. M.; Flynn, M. A.; Doherty, A. M. Bioorg. Med. Chem.
Lett.; 1996, 6, 2999.
(6) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer, T.;
Hamon, M.; Merahi, N.; Emerit, B. M.; Cagnotto, A.; Skorupska, M.;
Mennini, T.; Pinto, J . C. J . Med. Chem. 1995, 38, 2692.
(7) Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst, A. D.;
Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio, R.; Luttmann, M.;
Vecchietti, V.; Hay, D. W. P. J . Med. Chem. 1997, 50, 1794.
(8) Ife, R. J .; Brown, T. H.; Keeling, D. J .; Leach, C. A.; Meeson, M.
L.; Parsons, M. E.; Reavill, D. R.; Theobald, C. J .; Wiggall, K. J . J .
Med. Chem. 1992, 35, 3413.
(10) Cheng, C.-C.; Yan, S.-J . Org. React. 1982, 28, 37.
(11) Gopalsamy, A.; Pallai, P. V. Tetrahedron Lett. 1997, 38, 907.
(12) (a) Kobayashi, S.; Nagayama, S. J . Am. Chem. Soc. 1996, 118,
8977. (b) Campos, P. J .; Tan, C.-Q.; Rodriguez, M. A.; Anon, E. J . Org.
Chem. 1996, 61, 7195. (c) Strekowski, L.; J anda, L.; Patterson, S. E.;
Nguyen, J . Tetrahedron 1996, 52, 3273. (d) Strekowski, L.; J anda, L.;
Lee, H. J . Org. Chem. 1997, 63, 4193.
(9) (a) Chen, S.-F., Papp, L. M.; Ardecky, R. J .; Rao, G. V.; Hesson,
D. P.; Forbes, M.; Desxter, D. L. Biochem. Pharmacol. 1990, 40, 709.
(b) Zeevi, A.; Yao, G.-Z.; Venkataramanan, R.; Duqesnoy, R. J .; Todo,
S.; Fung, J . J .; Starzl, T. E. Transplant. Proc. 1993, 25, 781.
10.1021/jo0203387 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/28/2002
9182
J . Org. Chem. 2002, 67, 9182-9185

Synthesis of Substituted Quinolines
SCHEME 1
SCHEME 2
3d employed acetic anhydride as the dehydrating agent
in a sealed reaction vessel, due to the volatility of the
reagents.14 The stereochemistry of the E-olefin was
confirmed by 2D NOE experiments for compounds 3a and
3c. It is assumed that this is the thermodynamic product,
since piperidine elimination and addition to the R,â-
unsaturated double bond is reversible. Compound 3c was
not stable at room temperature for extended periods of
time, due to isomerization of the double bond.
1,4- as well as 1,2-addition adducts (both adducts could
be taken on to different substituted quinolines). This is
in contrast to several recent reports that alkyllithium and
Grignard reagents give 1,4-addtion adduct selectively in
the absence of CuI or CuCN when the double bond is
doubly activated with two electron-withdrawing groups
on the R-carbon.18 In our examples, selectivity for 1,4-
addition was obtained by addition of 0.5 equiv of CuCN
and 0.5 equiv of LiCl after the dianion was formed.
Toluene was found to accelerate the reaction.19 Typically,
the last steps of our quinoline synthesis were performed
as a dianion addition, an aqueous workup and filtration
through silica gel to remove the residual N-Boc-aniline,
addition of TFA for 3 h to remove the Boc group,
concentration, addition of mesitylene or 1,2,3,5-tetra-
methylbenzene, and heating overnight (Scheme 2). The
initial addition of the N-Boc-aniline dianion generates
diasteriomers 5, which produce a single quinoline product
after deprotection of the Boc group and thermal elimina-
tion of the tolyl sulfone. Since concerted thermal elimina-
tion of tolyl sulfone is syn to the hydrogen, it is suggested
that the trans isomer is equilibrated to the cis isomer
via an imine-enamine equilibration. It is also possible
that the tolyl sulfone eliminates and then proton loss
occurs. Either mechanism is consistent with the results.
Table 1 lists the yields for the quinolines formed by
the dianion addition to R-tolylsulfonyl-R,â-unsaturated
Three possibilities for dianion formation were explored.
We found that dianion from N-2-(4-biphenyl)isopropyl-
oxycarbonyl (Bpoc) protected anilines, used successfully
by Ellman in his benzodiazepine synthesis,15 failed to give
good results in this system. Dianion from trifluoroacetate-
o-bromoaniline16 allowed formation of the quinolines after
deprotection of the trifluoroacetate and thermolysis of the
tolyl sulfone. However, this approach is limited by the
availability of o-bromoanilines. The preferred method for
the dianion formation was finally introduced by using
N-Boc-anilines with 2.5 equiv of t-BuLi.17 These N-Boc-
anilines 4a -c were prepared from the anilines and di-
tert-butyl dicarbonate with NaOH in THF (4a , R3
)
methyl, 87%; 4b, R3 ) methoxy, 89%; 4c, R3 ) trifluoro-
methyl, 88%). Our initial attempts at the dianion addition
to the R-tolylsulfonyl-R,â-unsaturated ketones 3 afforded
(13) Chodroff, S.; Whitmore, W. F. J . Am. Chem. Soc. 1950, 72, 1073.
(14) Goss, F. R.; Ingold, C. K.; Thorpe, J . F. J . Chem. Soc. 1921,
123, 3342.
(15) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1997, 62, 3885.
(16) Wender, P. A.; White, A. W. Tetrahedron Lett. 1981, 22, 1475.
(17) Muchowski, J . M.; Venuti, M. C. J . Org. Chem. 1980, 45, 4798.
(b) Maggi, R.; Schlosser, M. J . Org. Chem. 1996, 61, 5430.
(18) (a) Fleming, F. F.; Pu, Y.; Tercek, F. J . Org. Chem. 1997, 62,
4883. (b) Klemeyer, H. J .; Paquette, L. A. J . Org. Chem. 1994, 59, 7924.
(c) Cooke, M. P., J r. J . Org. Chem. 1993, 58, 6833. (d) Hunt, D. A.
Org. Prep. Proc. Int. 1989, 21, 705.
(19) Corey, E. J .; Houpis, I. N. Tetrahedron Lett. 1993, 34, 2421.
J . Org. Chem, Vol. 67, No. 26, 2002 9183

Swenson et al.
TABLE 1. Yield s of P r od u cts 8 fr om
r-Tolylsu lfon yl-r,â-u n sa tu r a ted Keton es 3
Exp er im en ta l Section
1
Gen er a l. All reactions were performed under nitrogen. H
NMR and 13C NMR spectra were recorded in ppm (δ) on a 300
MHz instrument using TMS as internal standard. Elemental
analyses were performed by Robertson Micolit Laboratories.
Anhydrous THF, toluene, and tert-butyllithium in pentane (1.7
M) were purchased. Flash chromatography was performed
with silica gel 60 (230-400 mesh). Melting points were
determined and are uncorrected.
compd
R1
R2
R3
yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-ClPh
4-MePh
4-MePh
4-MePh
4-ClPh
4-ClPh
4-ClPh
2-MePr
2-MePr
2-MePr
Me
Me
54
60
55
56
61
60
52
58
50
51
58
59
51
55
50
48
51
60
2-(p-Tolu en esu lfon yl)-4′-m eth oxya cetop h en on e (2a ). A
mixture of 2-bromo-4′-methoxyacetophenone (45.8 g, 200
mmol) and p-toluenesulfinic acid sodium hydrate (35.6 g, 200
mmol) in ethanol (1 L) was heated at reflux for 1.5 h. The
mixture was stirred and cooled to room temperature, and the
resulting solid was collected, washed with ethanol (2 × 50 mL),
dried to give 54.6 g (90%) of pure 2a : mp 126.0-127.0 °C; IR
OMe
CF3
Me
OMe
CF3
Me
OMe
CF3
Me
OMe
CF3
Me
OMe
CF3
Me
OMe
CF3
1
2951, 2906, 1676, 1599, 1572 cm-1; H NMR (CDCl3) 2.45 (s,
3H), 3.90 (s, 3H), 4.67 (s, 2H), 6.95 (d, J ) 8.8 Hz, 2H), 7.34
(d, J ) 8.2 Hz, 2H), 7.76 (d, J ) 8.2 Hz, 2H), 7.95 (d, J ) 8.8
Hz, 2H); 13C NMR 20.9, 55.1, 62.5, 113.4 (2C), 127.7 (2C),
128.3, 129.1 (2C), 131.1 (2C), 135.8, 144.3, 163.7, 186.0. Anal.
Calcd for C16H16O4S: C, 63.14; H 5.30; S, 10.54. Found: C,
63.49; H, 5.35; S, 10.33.
Me
Me
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-ClPh
4-ClPh
Me
Me
1-(4′-Meth oxyph en yl)-3-(4′-m eth ylph en yl)-2-(p-tolu en e-
su lfon yl)-2-(E)-p r op en -1-on e (3a ). A mixture of 2a (4.6 g,
15 mmol), p-tolualdehyde (2.0 g, 16.5 mmol), piperidine (0.18
g, 2 mmol), and acetic acid (0.42 g, 7 mmol) in toluene (40 mL)
was heated at reflux for 2 h with azeotropic removal of water
using a Dean-Stark trap.13 The mixture was cooled to room
temperature and concentrated in vacuo. The residue was
purified by flash chromatography (hexane/EtOAc/toluene 3:1:
1) to give 5.5 g (90%) of pure 3a as a solid: mp 141.0-142.0
°C; IR 2939, 1650, 1597, 1572 cm-1; 1H NMR (CDCl3) 2.26 (s,
3H), 2.43 (s, 3H), 3.82 (s, 3H), 6.84 (d, J ) 8.8 Hz, 2H), 7.01
(d, J ) 8.1 Hz, 2H), 7.17 (d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 8.0
Hz, 2H), 7.78 (d, J ) 8.0 Hz, 2H), 7.89 (d, J ) 8.8 Hz, 2H),
7.93 (s, 1H); 13C NMR 21.3, 21.5, 55.4, 114.0 (2C), 128.4 (2C),
128.7, 128.8, 129.5 (2C), 129.6 (2C), 130.2 (2C), 132.2 (2C),
136.9, 138.7, 140.3, 141.5, 144.4, 164.5, 190.4. The E-confor-
mation was assigned by a 2D NOE experiment. Anal. Calcd
for C24H22O4S: C, 70.91; H, 5.46; S, 7.89. Found: C, 70.52; H,
5.62; S, 7.69.
Me
ketones 3. Compounds 8p -r required more elevated
temperatures for elimination of the tolyl sulfone group.
The four-step synthesis of trisubstituted quinolines, from
readily available bromomethyl or chloromethyl ketones,
aldehydes, and N-Boc-anilines, proceeds in overall yields
of 23-50%. Methyl or substituted phenyls are introduced
at positions 2 and 4 of the quinoline ring system. Position
6 is substituted with methyl, trifluoromethyl, or methoxy
groups.
Con clu sion
An efficient, flexible, and regiocontrolled synthesis of
2,4,6-trisubstituted quinolines from readily available
bromomethyl ketones, aldehydes, and anilines is dem-
onstrated. A tolyl sulfone group has been used to direct
the chemistry, from 1,4-addition of N-Boc-aniline dianion
to the electron-deficient olefin to the elimination of the
tolyl sulfone to form the quinoline. The chemistry allows
both aliphatic and aromatic ketones or aldehydes as well
as anilines with electron-withdrawing or -donating groups
to be employed. The overall yields in four-step synthesis
are from 23 to 50%. Some differences were observed in
the ease of elimination of the tolyl sulfone based on the
structure of the aniline or aldehyde. Electron-rich anilines
or aromatic aldehydes facilitated elimination. In contrast
to traditional methods of quinoline synthesis, this reac-
tion sequence sets position 2, then position 4, and last
adds the 6 position from a 4-substituted aniline. Com-
pound 5 or 6 provides for the possibility of alkylation
prior to sulfone elimination to functionalize the 3-position
of the quinoline. The known regioselectivity of dianion
formation in other substituted N-Boc-anilines or N-Boc-
aminoheterocycles20 suggests the ease with which these
substituted quinolines and heterocyclic pyridines could
also be formed. These studies are currently in progress.
1-(4′-Meth oxyph en yl)-2-(p-tolu en esu lfon yl)-2(E)-bu ten -
1-on e (3d ). A mixture of 2a (6.08 g, 20 mmol), acetaldehyde
(2.5 mL, 45 mmol), and acetic anhydride (3.0 mL, 32 mmol)
in toluene (8 mL) was heated at 100 °C in a sealed reaction
vessel for 3 days.14 The mixture was cooled to room temper-
ature and concentrated in vacuo. The residue was purified by
flash chromatography (hexane/EtOAc/toluene 3:1:1) to give 4.4
g (67%) of pure 3d as a solid: mp 118.0-119.9 °C; IR 3072,
1
1654, 1608, 1584 cm-1; H NMR (CDCl3) 1.72 (d, J ) 7.0 Hz,
3H), 2.42 (s, 3H), 3.89 (s, 3H), 6.94 (d, J ) 8.8 Hz, 2H), 7.25
(m, 1H), 7.29 (d, J ) 8.1 Hz, 2H), 7.72 (d, J ) 8.1 Hz, 2H),
7.89 (d, J ) 8.8 Hz, 2H); 13C NMR 15.5, 21.5, 55.5, 114.1 (2C),
128.3 (2C), 129.3, 129.5 (2C), 132.2 (2C), 136.8, 140.6, 143.2,
144.4, 164.6, 189.1. Anal. Calcd for C18H18O4S: C, 65.43; H,
5.49; S, 9.71. Found: C, 64.84; H, 5.68; S, 9.56.
N-(ter t-Bu toxyca r bon yl)-p-tolu id in e (4a ). To a solution
of p-toluidine (6.5 g, 60 mmol) in THF (30 mL) and 2 N NaOH
(30 mL) was added di-tert-butyl dicarbonate (65 mL, 1.0 M in
THF) slowly at room temperature. The mixture was stirred
at room temperature overnight and concentrated in vacuo. The
residue was diluted with EtOAc (150 mL), and the organic
phase was washed with water (2 × 70 mL) and brine (50 mL)
and dried (MgSO4). The solution was then concentrated in
vacuo. The residue was purified by flash chromatography
(hexane/EtOAc 6:1) to give 10.8 g (87%) of pure 4a as a solid:
mp 92.5-93.5 °C; IR 3355, 3336, 3000, 1697, 1597, 1529 cm-1
;
1H NMR (CDCl3) 1.55 (s, 9H), 2.30 (s, 3H), 6.32 (br s, 1H),
7.07 (d, J ) 8.3 Hz, 2H), 7.22 (d, J ) 8.3 Hz, 2H); 13C NMR
20.6, 28.3 (3C), 80.2, 118.7 (2C), 129.4 (2C), 132.4, 135.7, 152.9.
(20) Snieckus, V. Chem. Rev. 1990, 90, 879.
9184 J . Org. Chem., Vol. 67, No. 26, 2002

Synthesis of Substituted Quinolines
Anal. Calcd for C12H17NO2: C, 69.54; H 8.27; N, 6.67. Found:
C, 69.52; H, 8.26; N, 6.67.
overnight and then concentrated in vacuo. The resulting
residue was purified by flash chromatography (hexane/EtOAc
6:1) to give 183 mg (54%) of pure 8a as a solid. mp 135.0-
137.0 °C; IR 2918, 1605, 1589, 1545, 1514, 1250 cm-1; 1H NMR
(CDCl3) 2.43 (s, 3H), 2.45 (s, 3H), 3.83 (s, 3H), 7.00 (d, J ) 8.9
Hz, 2H), 7.32 (d, J ) 8.0 Hz, 2H), 7.42 (d, J ) 8.0 Hz, 2H),
7.50 (dd, J ) 1.5, 8.5 Hz, 1H), 7.63 (br s, 1H), 7.69 (s, 1H),
8.09 (d, J ) 8.5 Hz, 1H), 8.12 (d, J ) 8.9 Hz, 2H); 13C NMR
21.2, 21.7, 55.3, 114.1 (2C), 118.8, 124.4, 125.5, 128.7 (2C),
129.2 (2C), 129.4 (2C), 129.5, 131.5, 132.3, 135.6, 135.7, 138.0,
147.3, 148.3, 155.5, 160.6; MS (APCI) (M + H)+ 340. Anal.
Calcd for C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C,
84.70; H, 6.42; N, 4.04.
2-(4′-Meth oxyph en yl)-4-(4′-m eth ylph en yl)-6-m eth ylqu in -
olin e (8a ). To 4a (518 mg, 2.5 mmol) in THF (10 mL) at -30
°C was added t-BuLi (3.7 mL, 6.25 mmol, 1.7 M in pentane)
dropwise. The mixture was stirred at -20 °C for 2.5 h and
then cooled to -50 °C. A solution of CuCN (112 mg, 1.25 mmol)
and LiCl (53 mg, 1.25 mmol) in THF (1.5 mL) was added to
the above mixture. After 10 min, 3a (406 mg, 1 mmol) in THF
(4 mL) was added, followed by toluene (10 mL). The mixture
was stirred from -50 to -10 °C for 1 h and quenched with
saturated aqueous ammonium chloride (5 mL). The reaction
mixture was warmed to room temperature and diluted with
EtOAc (20 mL). The organic phase was separated, washed with
water (10 mL) and brine (2 × 10 mL), dried (Na2SO4), and
concentrated in vacuo. Filtration through silica gel (hexane/
EtOAc 3:1, then 1:3) was performed to remove 4a , and the
intermediate 5a was collected. To the intermediate 5a was
added TFA (5 mL), and the mixture was stirred at room
temperature for 3 h. After removal of TFA, mesitylene (10 mL)
was added to the residue. The mixture was heated at reflux
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and proton and carbon NMR data for compounds 2b,c,
3b,c,e,f, 4b,c, and 8b-r . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0203387
J . Org. Chem, Vol. 67, No. 26, 2002 9185