Controlled and efficient synthesis of quinoline derivatives from Morita-Baylis-HILLMAN adducts by palladium-catalyzed heck reaction and cyclization

Article abstract of DOI:10.1055/s-0034-1379938

An efficient synthesis of 2,3-disubstituted quinoline derivatives from easily accessible (het)aryl-substituted Morita-Baylis-Hillman (MBH) adducts was achieved by an approach involving a palladium-catalyzed Heck reaction and cyclization. This strategy converts the MBH adducts into α-benzyl β-keto ester derivatives that can cyclize into the corresponding quinolines in good yields.

Full text of DOI:10.1055/s-0034-1379938

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 646–650
letter
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K. Selvakumar et al.
Letter
Synlett
Controlled and Efficient Synthesis of Quinoline Derivatives from
Morita–Baylis–Hillman Adducts by Palladium-Catalyzed Heck
Reaction and Cyclization
Kodirajan Selvakumar*a
Kandapalam Arun Prasath Lingamb
Rama Varma Luxmi Varmac
Veerappan Vijayabaskara
OH
Z
H2N
O
NH2
I
Z
Pd(OAc)2
+
N
1. one-pot cyclization
2. C–C and C–N bond
formation
R
Z
R
a Department of Chemistry, Sethu Institute of Technology,
Pulloor, Tamil Nadu 626 115, India
R
b Department of Chemistry, Kamaraj Collage, Tuticorin, Tamil
Nadu 628 003, India
c Chemical Sciences and Technology Division, National Institute
for Interdisciplinary Science and Technology, Thiruvanantha-
puram, Kerala 695 019, India
selvaramkumar@yahoo.co.in
Received: 08.10.2014
Accepted after revision: 27.11.2014
Published online: 20.01.2015
Larock developed a palladium-catalyzed synthesis of
quinoline derivatives from allyl alcohols through α-benzyl
β-keto ester intermediates.4 Recently, a number of stepwise
syntheses of quinoline derivatives have been reported that
use allyl alcohols and enones as starting materials.5 As an
extension of our interest in novel synthetic applications of
Morita–Baylis–Hillman (MBH) adducts, we proposed their
use in a one-pot synthesis of quinolines. However, the pal-
ladium-catalyzed Heck reaction of MBH adducts I with
halobenzenes II (X = Br, I; Y = H) has been shown to give
mixtures of α-benzyl β-keto esters IV and β-aryl-substitut-
ed derivatives III (Scheme 1).6 The slight difference in acidi-
ty between adjacent protons Ha and Hb of the organopalla-
dium complex causes the Heck reaction of MBH adduct to
be very sluggish during the β-hydride elimination step.7 To
avoid this limitation, Gowrisankar and co-workers reported
a stepwise strategy for the synthesis of quinoline deriva-
tives from MBH adducts, but the procedure required pro-
longed reaction times (seven days).8 Furthermore, no one-
pot difunctionalization of the MBH adduct of benzaldehyde
has yet been achieved.5d,9 We surmised that the formation
of the β-aryl-substituted derivative might be suppressed if
DOI: 10.1055/s-0034-1379938; Art ID: st-2014-d0843-l
Abstract An efficient synthesis of 2,3-disubstituted quinoline deriva-
tives from easily accessible (het)aryl-substituted Morita–Baylis–Hillman
(MBH) adducts was achieved by an approach involving a palladium-cat-
alyzed Heck reaction and cyclization. This strategy converts the MBH
adducts into α-benzyl β-keto ester derivatives that can cyclize into the
corresponding quinolines in good yields.
Key words quinolines, cyclizations, catalysis, palladium, Heck reac-
tions, tandem reactions
Quinolines are an important class of compounds, owing
to their significant applications in areas of materials and
pharmaceutical chemistry.1 In particular, disubstituted
quinoline derivatives have shown a broad spectrum of bio-
logical activities, such as antimalarial, antidiabetic, antiin-
flammatory, antiasthmatic, and antihypertensive activities
and tyrosine kinase inhibiting properties.2 Consequently,
numerous approaches to the synthesis of these compounds
have been developed.3
O
H
OH
H
OH
Ha
Z
Z
Z
Pd-X
+
OH
Hb
R
R
X
R
Z
IV
III
Y
β-aryl substituted MBH
α-alkyl-β-keto ester
+
Y
R
derivative
derivative
Pd0
Z
I
II
Y= H; X = Br, I (previous work)
Y= NH2; X = Br, I (this work)
N
V
R
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 646–650

647
K. Selvakumar et al.
Letter
Synlett
the α-benzyl β-keto ester derivative were to be continuous-
ly converted into quinolines V during the reaction. Here, we
describe an efficient one-pot synthesis of (het)aryl quino-
line derivatives from isolable intermediates from MBH ad-
ducts by a palladium-catalyzed Heck reaction and cycliza-
tion.
Our retrosynthetic analysis (Scheme 2) suggested that
quinoline derivatives C might be synthesized from the MBH
adducts A and 2-iodoaniline (B) by a palladium-catalyzed
Heck reaction and cyclization strategy.
though 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-mediat-
ed aromatization of heterocyclic compounds is well
established,10 attempts to perform a DBU-mediated one-
pot tandem cyclization and aromatization resulted in de-
composition of the starting material (entry 11).10c Other ad-
ditives such as 4-(N,N-dimethylamino)pyridine, triphenyl-
phosphine, quinuclidine, or diisopropylamine either gave
low yields or recovery of the starting materials (entries 12–
16).
Table 1 Optimization of the Palladium-Mediated Tandem Cyclizationa
OH
CO2Me
I
CO2Me
C–C and
Entry
Solvent
Base
Product ratio Yield (%) of
+
3a/4b
3a + 4b
C–N bond
formation
N
NH2
1
2
THF
NaHCO3
0.5:1
0.5:1
0.5:1
0.5:1
–
35
R
C
B
A
MeCN
DMF
NaHCO3
NaHCO3
NaHCO3
K2CO3
46
R
Scheme 2 Retrosynthetic analysis
3
32
4
MeCNb
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
51
5
decomposed
In a preliminary study, a mixture of MBH adduct 1a, 2-
iodoaniline (2a; 2.1 equiv.), Pd(OAc)2 (10 mol%), NaHCO3
(2.5 equiv), and tetrabutylammonium bromide (2.1 equiv)
in refluxing tetrahydrofuran was stirred for 12 hours to give
a mixture of dihydroquinoline 3a and quinoline 4a in 35%
yield after column chromatography (Scheme 3).
6
KHCO3
pyridine
DABCO
DABCOc
DABCOc
DBUc
–
decomposed
7
0.4:1
1:1
1:1
1:1
–
54
8
62
9
84
10
11
12
13
14
15
16
43d
In the 1H NMR spectrum of dihydroquinoline 3a, the
characteristic methylene and N–H protons appeared as a
singlet and a broad singlet at δ = 3.91 and 5.77 ppm, respec-
tively.
decomposed
45e
Et3N
1:1
–
DMAP
no reaction
traces
23e
To establish a suitable solvent system for the reaction of
with 1a and 2a, we screened a number of solvents such as
acetonitrile, tetrahydrofuran, and N,N-dimethylformamide
(Table 1, entries 1–3). Of these, acetonitrile (entry 3)
showed promise for the tandem cyclization. A slight im-
provement in yield was achieved when the MBH adduct
was added to the reaction mixture after a 15 minute delay
(entry 4). In screening various bases,6a we observed that po-
tassium bases resulted in decomposition of the starting ma-
terial (entries 5 and 6). When pyridine was used, the prod-
uct was obtained in moderate yield (entry 7). The best re-
sult, however, was obtained when the reaction was carried
out with 0.6 equivalents of 1,4-diazabicyclo[2.2.2]octane
(DABCO), which gave an 84% yield (entry 9). The use of ex-
cess base or catalyst led to a reduction in the yield or de-
composition of the starting material (entries 8 and 10). Al-
Ph3P
–
quinuclidine
(i-Pr)2NH
1:1
1:1
48e
a Reaction conditions: 1a (100 mg, 0.442 mmol), Pd(OAc)2 (10 mol%), 2a
(2.1 equiv), solvent (2 mL), base (1.0 equiv), reflux, 12 h.
b 1a added after a delay of 15 min.
c 0.6 equiv.
d Pd(OAc)2 (30 mol%).
e Some starting material was present even after 24 h.
Next, we examined the substrate scope for a broad
range of MBH adducts of various aryl and hetaryl aldehydes
under the optimized reaction conditions.11 All the sub-
strates gave the desired products in moderate to good
yields (48–82%); the results are summarized in Scheme 4
and Scheme 5.
OH
CO2Me
CO2Me
NH2
CO2Me
a
+
+
N
H
N
I
Cl
1a
2a
Cl
Cl
3a
4a
Scheme 3 Synthesis of quinolines from the MBH adduct of benzaldehyde. Reaction conditions: (a) Pd(OAc)2 (10 mol%), TBAB (2.1 equiv), NaHCO3 (2.5
equiv), THF, reflux, 12 h.
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648
K. Selvakumar et al.
Letter
Synlett
OH
CO2Me
CO2Me
CO2Me
a
+
+
2a
N
H
N
R
R
R
b
1b–f
3b–f
4b–f
CO2Me
CO2Me
CO2Me
F
NO2
N
N
N
NO2
4d, 79% (3d/4d = 0:1)
4c, 81% (3c/4b = 0.5:1)
4b, 67% (3b/4b = 1:1)
CO2Et
CO2Me
Cl
Br
N
N
4f, 80% (3f/4f = 1:1)
4e, 83% (3e/4e = 0.5:1)
Scheme 4 Synthesis of quinoline derivatives via tandem cyclization. Reaction conditions: (a) 1 (100 mg), Pd(OAc)2 (10 mol%), 2a (2.1 equiv), MeCN (2
mL), DABCO (1.0 equiv), reflux. (b) DBU (1.5 equiv), MeCN, 24 h. Product ratios were determined by 1H NMR analysis of the crude samples. Reported
yields are isolated yields after column chromatography based on the MBH adducts 1.
An obvious trend was observed in that MBH adducts
containing electron-withdrawing substituents gave better
yields of mixtures of products 3 and 4 than did MBH ad-
ducts containing electron-donating substituents (Schemes
4 and 5).
The crude product mixtures were filtered through a pad
of Celite and, where necessary, subjected to one-pot DBU-
mediated aromatization to convert the 1,4-dihydroquino-
lines 3 into quinolines 4. The 3-nitro MBH adduct 1c proved
to be a better substrate than the 4-nitro MBH adduct 1b.
The 4-fluoro MBH adduct 1d gave quinoline 4d in 79% yield,
whereas the 4-bromo MBH adduct 1e gave a good yield of a
mixture of compounds 3e + 4e, and 4-chloro MBH adduct
ethyl ester 1f gave a good yield of 3f + 4f; these mixtures
were subjected to subsequent aromatization to give the ap-
propriate quinolines 4.
The Heck reaction and cyclization of MBH adducts 1
containing electron-donating substituents with 2-iodoani-
line gave the desired products 4g–i, along with the corre-
sponding α-methyl β-keto ester derivatives 5a–c as byprod-
ucts in 8–12% yield in short reaction times (3–5 h). The for-
mation of 5 is implies that a palladium species generated by
β-hydride elimination might undergo coupling with the
MBH adduct 1 (see Supporting Information).12 The unpro-
tected 4-hydroxylated MBH adduct and the benzaldehyde
MBH adduct gave the desired compounds 4j and 4k, respec-
tively, in moderate to good yields. Interestingly, the 2- and
4-pyridine-substituted MBH adducts gave the correspond-
ing quinoline derivatives 4l and 4m in good yields (74 and
82%, respectively). Furthermore, the less-stable hetaryl
MBH adducts gave the corresponding hetaryl-substituted
quinoline derivatives 4n and 4o in moderate yields. Howev-
er, the corresponding pyrrole-substituted MBH adduct and
2-iodoaniline did not give the desired product under the
optimized reaction conditions.
O
CO2Me
optimized
conditions
CO2Me
+
1g–o 2a
+
N
R
R
4g–o
5a–c
CO2Me
CO2Me
CO2Me
N
N
N
Me
Me
OMe
Me
4g, 68%
CO2Me
4h, 64%
4i, 61%
CO2Me
CO2Me
N
N
N
N
OH
CO2Me
4j, 64%
4k, 74%
4l, 74%
CO2Me
CO2Me
N
N
N
O
S
N
4m, 82%
4n, 52%
4o, 57%
Scheme 5 Synthesis of quinoline derivatives via tandem cyclization.
Reaction conditions: (a) 1 (100 mg), Pd(OAc)2 (10 mol%), 2a (2.1 equiv),
MeCN (2 mL), DABCO (1.0 equiv), reflux. (b) DBU (1.5 equiv), MeCN, 24
h. Product ratios were determined by 1H NMR analysis of the crude
samples. Reported yields are isolated yields after column chromato-
graphy based on the MBH adducts 1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 646–650

649
K. Selvakumar et al.
Letter
Synlett
OH
O
optimized
conditions
O
NH2
2a
no reaction
+
Cl
Cl
O
1p
Scheme 6 Competitive tandem cyclization of MBH adduct 1p
When MBH adduct 1p was subjected to tandem cycliza-
tion under the optimized conditions, the substrate did not
undergo a Heck reaction (Scheme 6).13
The palladium-catalyzed Heck reaction and cyclization
described here can be rationalized by invoking a mecha-
nism proposed in an earlier report.7
In conclusion, we have demonstrated an efficient one-
pot synthesis of 2,3-disubstituted quinoline derivatives
from readily available multifunctionalized MBH adducts of
(het)aryl aldehydes. The isolable α-benzyl β-keto ester de-
rivatives can be converted into the corresponding quinoline
derivatives under the optimized conditions.
(d) Beesu, M.; Malladi, S. S.; Fox, L. M.; Jones, C. D.; Dixit, A.;
David, S. A. J. Med. Chem. 2014, 57, 7325. (e) Nobuhide, M.;
Yoshinobu, Y.; Hiroshi, I.; Yoshio, O.; Tamejiro, H. Tetrahedron
Lett. 1993, 24, 8263. (f) Trécourt, F.; Mongin, F.; Mallet, M.;
Quéguiner, G. Synth. Commun. 1995, 25, 4011.
(4) Larock, R. C.; Kuo, M.-Y. Tetrahedron Lett. 1991, 32, 569.
(5) (a) Ramesh, C.; Lei, P.-M.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Mole-
cules 2012, 17, 5081. (b) Korivi, R. P.; Cheng, C.-H. J. Org. Chem.
2006, 71, 7079. (c) McNaughton, B. R.; Miller, B. L. Org. Lett.
2003, 5, 4257. (d) Kim, S. C.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1001.
(6) (a) Basavaiah, D.; Muthukumaran, K. Tetrahedron 1998, 54,
4943. (b) Sundar, N.; Bhat, S. V. Synth. Commun. 1998, 28, 2311.
(c) Kumareswaran, R.; Vankar, Y. D. Synth. Commun. 1998, 28,
2291. (d) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett.
2003, 5, 3803. (e) Kim, J. M.; Kim, K. H.; Kim, T. H.; Kim, J. N. Tet-
rahedron Lett. 2008, 49, 3248.
Acknowledgment
(7) Perez, R.; Veronese, D.; Coelho, F.; Antunes, O. A. C. Tetrahedron
Lett. 2006, 47, 1325.
(8) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron Lett.
2008, 49, 1670.
K.S. and V.V. thank the Sethu Institute of Technology, Kariapatti, for
providing laboratory facilities. R.V.L.V. thanks the Directors of NIIST
for providing infrastructure facilities. Thanks are due to Mrs. Viji and
Mrs. Saumini Mathew for providing mass and NMR spectra.
(9) (a) Ribière, P.; Declerck, V.; Nédellec, Y.; Yadav-Bhatnagar, N.;
Martinez, J.; Lamaty, F. Tetrahedron 2006, 62, 10456.
(b) Declerck, V.; Ribière, P.; Nédellec, Y.; Allouchi, H.; Martinez,
J.; Lamaty, F. Eur. J. Org. Chem. 2007, 201. (c) Vasudevan, A.;
Tseng, P.-S.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8591.
(10) (a) Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2007, 48,
4119. (b) Kudryavtsev, K. V.; Ivantcova, P. M.; Churakov, A. V.;
Vasin, V. A. Tetrahedron Lett. 2012, 53, 4300. (c) Because of the
large difference in the pKa values of DABCO (pKa = 8.8) and DBU
(pKa = 12), one-pot tandem cyclization and aromatization
resulted in decomposition of the starting materials.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379938.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) (a) Zhang, X.; Shetty, A. S.; Jenekhe, S. A. Macromolecules 1999,
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16812. (d) Rose, M. J.; Fry, N. L.; Marlow, R.; Hinck, L.;
Mascharak, P. K. J. Am. Chem. Soc. 2008, 130, 8834.
(2) (a) Bilker, O.; Lindo, V.; Panico, M.; Etiene, A. E.; Paxton, T.; Dell,
A.; Rogers, M.; Sinden, R. E.; Morris, H. R. Nature 1998, 392, 289.
(b) Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Bioorg.
Med. Chem. Lett. 2000, 10, 1831. (c) Chen, Y.-L.; Fang, K.-C.;
Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001, 44,
2374. (d) Waters, N. C.; Dow, G. S.; Kozar, M. P. Expert Opin. Ther.
Pat. 2004, 14, 1125. (e) Michael, J. P. Nat. Prod. Rep. 1997, 14,
605.
(11) 1,4-Dihydroquinolines 3 and Quinolines 4; General Proce-
dure
A mixture of 2-iodoaniline (2a; 2.1 equiv), Pd (OAc)2 (10 mol%),
DABCO (0.6 equiv), and TBAB (2.1 equiv.) in MeCN (2 mL) was
refluxed under argon. After 15 min, the MBH adduct 1 (100 mg)
was added. When the reaction was complete (TLC), the mixture
was allowed to cool to r.t. and filtered through a Celite pad. The
resulting mixture of compounds 3 and 4 was subjected to aro-
matization with DBU and purified by column chromatography
(silica gel) to give the quinoline 4.
Methyl 2-(4-Chlorophenyl)-1,4-dihydroquinoline-3-carbox-
ylate (3a) + Methyl 2-(4-Chlorophenyl)quinoline-3-carboxyl-
ate
Yellow oil; yield: 110 mg (84%); IR (CH2Cl2): 3389, 3096, 1728,
1622, 1593, 1485, 1366, 755cm–1; 1H NMR (500.1 MHz, CDCl3):
δ = 3.50 (s, 3 H), 3.78 (s, 3 H), 3.91 (s, 2 H), 5.77 (br s, 1 H), 6.57
(m, 1 H), 6.94 (m, 1 H), 6.96 (m, 2 H), 7.08 (m, 2 H), 7.38 (m, 2
H), 7.45 (m, 2 H), 7.58 (m, 2 H), 7.62 (t, J = 7.0 Hz, 1 H), 7.83 (m,
(3) (a) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120.
(b) Fu, Y.-h.; Di, Y.-t.; He, H.-p.; Li, S.-l.; Zhang, Y.; Hao, X.-j.
J. Nat. Prod. 2014, 77, 57. (c) Ren, X.; Wen, P.; Shi, X.; Wang,
Y.; Li, J.; Yang, S.; Yan, H.; Huang, G. Org. Lett. 2013, 15, 5194.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 646–650

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K. Selvakumar et al.
Letter
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1 H), 7.92 (d, J = 8 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 8.65 (s, 1 H);
13C NMR (125.7 MHz, CDCl): δ = 27.94, 50.87, 52.53, 95.58,
114.31, 121.38, 123.34, 124.61, 125.88, 127.08, 127.52, 128.30
(2 C), 128.43 (2 C), 128.59 (2 C), 129.09 (2 C), 129.31 (2 C),
129.53 (2 C), 130.01, 131.88, 134.81, 134.90, 136.62, 139.04,
139.58, 148.45, 156.89, 167.57, 168.00; FAB: m/z [M + 1]+ calcd
for C17H12ClNO2: 297.06; found: 298.31: m/z [M + 1]+ calcd for
Methyl 2-(2-Thienyl)quinoline-3-carboxylate (4n)
Pale-yellow oil; yield: 71 mg (52%); IR (KBr): 2932, 1722, 1624,
1585, 1492 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 3.92 (s, 3 H), 7.12 (m, 1 H), 7.26
(s, 1 H), 7.40 (m, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.57 (d, J = 7.5 Hz,
1 H), 7.78 (m, 1 H), 8.12 (m, 1 H), 8.45 (s, 1 H); 13C NMR (125.7
MHz, CDCl3): δ = 52.08, 99.39, 99.89, 107.19, 110.43, 115.44,
116.74, 118.95, 126.88, 128.08, 139.39, 142.39, 147.42, 154.11,
166.48; FAB: m/z [M+] calcd for C15H11NO2S: 269.05; found:
269.37.
C17H14ClNO2: 299.07; found: 300.28.
Methyl 2-Pyridin-2-ylquinoline-3-carboxylate (4l)
Pale-yellow solid; yield: 101 mg (74%); mp 109–110 °C; IR
(KBr): 2932, 1718, 1625, 1598, 1488 cm–1; 1H NMR (300.1 MHz,
CDCl3): δ = 3.93 (s, 3 H), 6.49 (m, 1 H), 6.77 (m, 1 H), 7.14 (t, J =
8.0 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.50 (m, 1 H), 7.83 (m, 2 H),
8.13 (m, 1 H), 8.47 (s, 1 H); 13C NMR (125.7 MHz, CDCl3): δ =
52.46, 120.09, 122.19, 122.45, 122.90, 124.52, 125.97, 126.99,
127.47, 127.84, 128.67, 130.31, 130.77, 135.61, 144.18, 166.47;
FAB: m/z [M+] calcd for C16H12N2O2: 264.09; found: 264.45.
(12) Usually, short-lived H–Pd–I species undergo immediate reduc-
tive elimination with a base, but MBH adducts with electron-
donating substituents can undergo coupling with H–Pd–I, pre-
sumably under the influence of the +I effect of the electron-
donating group.
(13) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009,
5496.
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