An efficient synthesis of novel 2,4-disubstituted tetrahydroquinolines and quinolines

Article abstract of DOI:10.1016/j.tetlet.2012.02.043

A series of novel tetrahydroquinolines have been synthesized via the acid-catalyzed reaction of an azaflavan-4-ol with a variety of reactive nucleophiles. The tetrahydroquinolines were found to undergo oxidation in the presence of iodine as catalyst to ge

Full text of DOI:10.1016/j.tetlet.2012.02.043

Tetrahedron Letters 53 (2012) 2269–2272
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of novel 2,4-disubstituted tetrahydroquinolines
and quinolines
⇑
Ruth Devakaram, David StC. Black, Naresh Kumar
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel tetrahydroquinolines have been synthesized via the acid-catalyzed reaction of an aza-
flavan-4-ol with a variety of reactive nucleophiles. The tetrahydroquinolines were found to undergo oxi-
dation in the presence of iodine as catalyst to generate the corresponding novel 2,4-disubstituted
quinolines.
Received 24 November 2011
Revised 30 January 2012
Accepted 10 February 2012
Available online 26 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolo[3,2,1-i,j]quinoline
Indole
Isoflavonoid
Phytoestrogen
Quinoline derivatives represent a major class of heterocycles
found in the framework of various pharmacologically active com-
pounds and natural products. For example, the chimanine alkaloids
comprising of simple 2,4-disubstituted quinolines such as 1–4
were isolated from the bark of Galipea longiflora trees of the Ruta-
ceae family1 and found to be effective against the parasites of
Leishmania species, which are the agents of leishmaniasis, a proto-
zoan disease of the tropical areas in South America.
be directed into the development of efficient methodologies to
new quinoline-based structures due to their importance as sub-
structures in a broad range of natural and synthetic bioactive
products.
In general, a recent trend is evident in which aza-analogs of
natural oxygen heterocycles are synthesized and screened for bio-
logical properties. As part of an ongoing investigation into the
development of biologically active 2,4-disubstituted flavonoids,
we envisaged that novel aza-analogs could be developed in a simi-
lar fashion from tetrahydroquinolines. The tetrahydroquinoline
moiety is the core structure in many important natural products
such as flindersine, oricine, and veprisine. Derivatives of these alka-
loids possess a wide range of biological activities including psycho-
tropic, antiallergic and anti-inflammatory behavior,6 and are used
as potent pharmaceuticals.7 Hence, a variety of synthetic ap-
proaches to the tetrahydroquinoline skeleton have been developed,
with the most common methodology reported being the Diels–Al-
der reaction of N-arylaldimines with electron-rich olefins.8
It was anticipated that novel 2,4-disubstituted tetrahydroquin-
olines could be prepared via treatment of azaflavan-4-ols with
reactive nucleophiles in the presence of a Lewis acid. In turn, the
azaflavan-4-ols could be prepared by reduction of the correspond-
ing azaflavan-4-ones.
O
N
N
N
OMe
R
OMe
4
2 R = H
1
3
R = OMe
The biological activity associated with quinoline compounds
has encouraged the development of many methodologies for their
synthesis. The quinoline core has been synthesized previously by
various conventional reactions such as the Skraup,2 Doebner-von
Miller,3 Pfitzinger,4 Conrad–Limpach,5 and Combes synthesis.3
Recent developments have involved the use of metal-catalyzed
coupling cyclizations and acid-catalyzed cycloaddition reactions
that can surpass the classical methods in terms of efficacy and
rapidity of quinoline construction. Significant effort continues to
Azaflavan-4-ones are typically prepared via acid- or base-cata-
lyzed isomerization of substituted 20-aminochalcones, though
these methods use corrosive reagents such as orthophosphoric
acid, acetic acid, or strong alkalis.9 Recently, however, Chandrase-
khar et al. demonstrated that 20-hydroxyacetophenones and aryl
aldehydes undergo a smooth one-pot condensation cyclization in
⇑
Corresponding author. Tel.: +61 293854698; fax: +61 293856141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
the presence of L-proline as an organocatalyst to furnish flavanones
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.043

2270
R. Devakaram et al. / Tetrahedron Letters 53 (2012) 2269–2272
in high yields.10 This methodology was further extended to the
related azaflavanones.11 Hence, equimolar quantities of 20-amino-
acetophenone (5) and 4-chlorobenzaldehyde (6) were heated at re-
Table 1
Synthesis of 4-aryl- and 4-heteroarylazaflavans
Entry
Azaflavan
Structure
Yield (%)
flux in the presence of L-proline (30 mol %) in methanol. This
Cl
Cl
furnished 2-(40-chorophenyl)-2,3-dihydroquinolin-4(1H)-one (7)
in high purity and 50% yield (Scheme 1).
H
N
1
9
62
Reduction of ketone 7 with sodium borohydride was performed
at room temperature in ethanol over four hours and afforded the
corresponding tetrahydroquinolinol 8 in 95% yield as the cis-iso-
mer. Azaflavanol 8 was subsequently reacted with 2-naphthol in
the presence of BF3ꢀOEt2 at room temperature for 12 h.12 After
aqueous work-up, the crude product was column chromatographed
to give azaflavan 9 in 62% yield (Scheme 2, Table 1, entry 1). The 1H
NMR spectrum of compound 9 showed a multiplet at d 2.15–2.41
corresponding to two H3 protons. The H4 proton appeared as a trip-
let at d 4.80 (J = 3.0 Hz), whereas a doublet of doublets at d 4.51
(J = 3.3, 10.3 Hz) corresponded to the H2 proton. The substitution
at the C1 position of 2-naphthol was indicated by the presence of
doublets at d 7.14 and 7.24 (J = 8.3 Hz), corresponding to H300 and
H400, respectively.
This reaction was not expected to be stereoselective as the
incoming nucleophile can possibly attack from either face of the
carbocation intermediate, giving rise to a mixture of cis and trans
isomers. Interestingly, however, exclusive formation of the trans
product was observed. This phenomenon can potentially be
explained by the presence of the C2-aryl group, which directs the
attack of the incoming nucleophile to the opposite side of the inter-
mediate carbocation due to steric hindrance. Thus, the BF3ꢀOEt2-cat-
alyzed arylation reaction was found to be stereoselective and
although the cis isomer of the starting azaflavanol 8 was employed,
only the trans product was obtained in good yield.
OH
OH
H
N
2
10
31
Cl
H
N
3
11
24
MeO
OH
OMe
Cl
Cl
H
N
4
5
12
13
64
67
N
H
N
Azaflavanol 8 similarly underwent acid-catalyzed substitution
with other activated phenolic compounds such as 1-naphthol
and 3,5-dimethoxyphenol. The resulting 4-arylazaflavans 10 and
11 were also produced as the trans isomers in 31% and 24% yields,
respectively (Table 1, entries 2 and 3).
NH
Cl
With these encouraging results, the methodology was subse-
quently extended to other heterocyclic systems. The reaction of
azaflavanol 8 with N-methylindole resulted in the formation of
the substituted tetrahydroquinoline 12 in 64% yield. In this case,
substitution was observed at the most reactive C3 indole position
(Table 1, entry 4). The structure and the trans configuration of com-
pound 12 were further confirmed by X-ray crystallography as
shown in Figure 1.
H
N
Br
6
14
47
NH
MeO
OMe
Cl
Similarly, azaflavanol 8 was reacted with 2-phenylindole, 3-(40-
bromophenyl)-4,6-dimethoxyindole, and 2,3-diphenyl-4,6-dim-
H
N
H
7
8
15
16
63
25
MeO
N
NH2
Cl
Cl
OMe
H
N
H
N
O
5
L-proline, MeOH
reflux, 50%
NaBH4, EtOH
r.t., 95%
Cl
Cl
H
N
OH
O
CHO
7
8
6
O
Scheme 1. Synthesis of azaflavanol.
Cl
H
N
Cl
Cl
H
N
H
ArOH,
BF3.OEt2
N
MeO
9
17
20
CH2Cl2, r.t., 12 h
OH
Ar
O
8
9-17
OMe
Scheme 2. Synthesis of 4-arylazaflavans.

R. Devakaram et al. / Tetrahedron Letters 53 (2012) 2269–2272
2271
catalyst in glacial acetic acid in the presence of potassium acetate
has been successful for the transformation of biflavanones into
biflavones.17,18
Hence, azaflavans 9, 10, 11, and 16 were stirred at room tem-
perature for seven days in acetic acid, in the presence of I2 and
potassium acetate.19 The desired oxidized products 18–21 were
generated in 19–24% yields as off-white solids (Scheme 3, Table
2), though in some cases the half oxidized intermediate, bearing
a double bond between C2 and C3, was also observed. The reaction
was presumed to involve iodination of the tetrahydroquinolines at
C4 followed by dehydrohalogenation. The disappearance of the ali-
phatic protons corresponding to H2, H3, and H4 in compound 9
along with the appearance of a singlet at d 7.95 corresponding to
H3 in compound 18 indicated that the desired product had been
produced. Similarly, in the 13C NMR spectrum, the aliphatic carbon
C4 present at d 32.8 in compound 9 became an aromatic quater-
nary carbon at d 148.5 in quinoline 18.
In conclusion, a new strategy for the synthesis of 2,4-disubsti-
tuted tetrahydroquinolines has been developed which paved the
way to novel 2,4-diaryl- and 2-aryl-4-heteroaryl quinolines. The
BF3ꢀOEt2-catalyzed reactions of azaflavan-4-ols with activated aryl
and heteroaryl compounds were found to produce stereoselective-
ly trans 4-arylazaflavans and 4-heteroarylazaflavans and oxidation
of these systems to the corresponding quinolines was achieved in
the presence of iodine.
Figure 1. ORTEP diagram of compound 12.13
Cl
Cl
H
N
N
I2, KOAc, AcOH
r.t., 7 d
Ar
Ar
9,10,11,16
18-21
Acknowledgments
Scheme 3. Synthesis of 2,4-disubstituted quinolines.
We thank the University of New South Wales and the Australian
Research Council for financial support.
Table 2
Oxidation of 4-aryl- and 4-heteroarylazaflavans
References and notes
Quinoline
Ar
Yield (%)
18
19
20
21
2-Naphthol
1-Naphthol
3,5-Dimethoxyphenol
Furan
24
19
22
20
1. Fournet, A.; Vagneur, B.; Richomme, P.; Bruneton, J. Can. J. Chem. 1989, 67,
2116–2118.
2. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59–98.
3. Bergstrom, F. W. Chem. Rev. 1944, 35, 77–277.
4. Jones, G. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E.
C., Eds.; John Wiley and Sons: Chichester, 1977; Vol. 32, pp 93–318.
5. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68.
6. Kadowaki, S.; Takahashi, K.; Umezu, K. Biochem. Pharmacol. 1992, 44, 1211–
1213.
ethoxyindole resulting in the formation of 2-aryl-4-heteroaryl aza-
flavans 13, 14, and 15 in moderate yields (Table 1, entries 5–7). In
all cases, the indole substitution occurred at the most reactive site,
namely C3, C2, and C7, providing a diverse array of configurations.
The acid-catalyzed reaction of azaflavanol 8 was found to be
highly versatile, whereupon reaction with other heterocycles such
as furan and 7,40-dimethoxyisoflavene afforded the corresponding
furan-2-yl and chromen-6-yl tetrahydroquinolines 16 and 17 in
25% and 20% yields, respectively (Table 1, entries 8 and 9).
For the reactions which gave low yields of 20–31%, the azaflav-
anol was also found to undergo simple dehydration (elimination
instead of substitution) to give quinoline and the further reduced
tetrahydroquinoline. This observation can be attributed to the fact
that the intermediate 1,2-dihydroquinoline, being unsubstituted at
the nitrogen and having at least one hydrogen at C2, is unstable
and therefore can be rapidly oxidized by air to quinoline, or
undergoes disproportionation by trace acids to give a mixture of
quinoline and tetrahydroquinoline.14 Hence, furan, 1-naphthol,
3,5-dimethoxyphenol, and 7,40-dimethoxyisoflavene acted as
weaker nucleophiles in comparison to the others investigated.
Attention subsequently turned to the oxidation of these tetra-
hydroquinolines in order to furnish the corresponding quinolines.
In general, dehydrogenation can typically be achieved with a num-
ber of reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), iodine, ceric ammonium nitrate (CAN), manganese
triacetate [Mn(OAc)3], thallium salts, selenium dioxide (SeO2), or
N-bromosuccinimide (NBS).15,16 In particular, the use of I2 as a
7. Mohamed, E. A. Chem. Pap. 1994, 48, 261. Chem. Abstr. 1995, 123, 9315x.
8. Zhang, W.; Jia, X.; Yang, L.; Liu, Z.-L. Tetrahedron Lett. 2002, 43, 9433–9436.
9. Tokes, A. L.; Litkei, G.; Szilagyi, L. Synth. Commun. 1992, 22, 2433–2445.
10. Chandrasekhar, S.; Vijeender, K.; Reddy, K. V. Tetrahedron Lett. 2005, 46, 6991–
6993.
11. Chandrasekhar, S.; Vijeender, K.; Sridhar, Ch. Tetrahedron Lett. 2007, 48, 4935–
4937.
12. Representative procedure for the synthesis of 4-arylazaflavan: To
a stirred
solution of azaflavanol (250 mg, 0.96 mmol) and 2-naphthol (166 mg,
8
1.16 mmol) in CH2Cl2 (20 mL) was added BF3ꢀOEt2 (10 drops). The mixture
was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3
solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer
separated. The aqueous layer was extracted with CH2Cl2 (25 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated under vacuum. Chromatography over silica gel using CH2Cl2/
light petroleum (50:50) gave compound 9, as a white solid (230 mg, 62%). Mp
141–143 °C; UV (MeOH): kmax (log
e
) 212 (5.02), 229 (5.12) nm; IR (KBr): mmax
3407, 1601, 1488, 1398, 1315, 1308, 1254, 1091, 1013, 816, 747 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 2.15–2.41 (m, 2H, H3), 4.38 (s, 1H, NH), 4.51 (dd, J = 3.3,
10.3 Hz, 1H, H2), 4.80 (t, J = 3.0 Hz, 1H, H4), 6.61 (ddd, J = 1.1, 6.3, 7.4 Hz, 1H,
H6), 6.68 (dd, J = 1.1, 7.4 Hz, 1H, H8), 6.98 (d, J = 8.9 Hz, 2H, H30, H50), 7.10 (ddd,
J = 1.1, 6.3, 7.4 Hz, 1H, H7), 7.14 (d, J = 8.3 Hz, 1H, H300), 7.17 (dd, J = 1.1, 7.4 Hz,
1H, H5), 7.19 (dd, J = 1.0, 8.0 Hz, 1H, H500), 7.22 (ddd, J = 1.0, 6.9, 8.0 Hz, 1H,
H600), 7.24 (d, J = 8.3 Hz, 1H, H400), 7.35 (ddd, J = 1.0, 6.9, 8.0 Hz, 1H, H700), 7.62
(d, J = 8.9 Hz, 2H, H20, H60), 7.72 (dd, J = 1.0, 8.0 Hz, 1H, H800); 13C NMR
(75.6 MHz, CDCl3): d 32.8 (C4), 36.2 (C3), 53.0 (C2), 115.2 (C8), 118.7 (C6),
119.0 (C100), 120.3 (C300), 121.0 (C4a), 121.8 (C600), 123.3 (C800), 127.0 (C700),
127.8 (C20, C60), 128.8 (C30, C50), 128.9 (C400), 129.1 (C500), 129.2 (C7), 129.3
(C400a), 129.7 (C5), 132.9 (C40), 133.1 (C800a), 142.8 (C10), 144.5 (C8a), 152.9
(C200); MS (TOF-ESI) m/z Calcd. for C25H20ClNO (M+1)+ 386.13. Found 386.04;
Anal. Calcd for C25H20ClNO: C, 77.81; H, 5.22; N, 3.63. Found: C, 77.60; H, 5.46;
N, 3.58.
13. Crystallographic data for the structure of compound 12 have been deposited
with the Cambridge Crystallographic Data Centre as supplementary

2272
R. Devakaram et al. / Tetrahedron Letters 53 (2012) 2269–2272
publication no. CCDC 832933. The X-ray crystal structure was obtained by
Mohan Bhadbhade, Crystallography Laboratory, Analytical Centre, The
University of New South Wales, Sydney, Australia.
over silica gel using 100% CH2Cl2 eluted compound 18 as a white solid (48 mg,
24%). Mp 254–256 °C; UV (MeOH): kmax (log ) 228 (5.21), 263 (4.94), 326
(4.40) nm; IR (KBr): mmax 3416, 1620, 1596, 1545, 1495, 1194, 1143, 1322,
1288, 1130, 1099, 1013, 819, 745 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 7.03
e
14. (a) Ogata, Y.; Kawasaki, A.; Suyama, S. Tetrahedron 1969, 25, 1361–1366; (b)
Dauphinee, G. A.; Forrest, T. P. Can. J. Chem. 1978, 56, 632–634.
15. Akiyama, T.; Nakashima, S.; Yokota, K.; Fuchibe, K. Chem. Lett. 2004, 33, 922–
923.
16. Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem. 2008, 73,
7451–7456.
17. Rahman, M.; Riaz, M.; Desai, U. R. Chem. Biodivers. 2007, 4, 2495–2527.
18. Garazd, M. M.; Garazd, Y. L.; Khilya, V. P. Chem. Nat. Compd. 2005, 41, 245–271.
19. Representative procedure for the synthesis of 2,4-disubstituted quinoline 18: To a
solution of 9 (200 mg, 0.52 mmol) in AcOH (10 mL) were added I2 (132 mg,
0.52 mmol) and KOAc (102 mg, 1.04 mmol). The mixture was stirred at r.t. for
7 d and then poured into ice (100 g) and washed with Na2S2O3 solution
(3 ꢂ 50 mL, 25%) to remove unreacted I2 from the mixture. A brown solid
separated which was filtered and air-dried. Purification of the crude product
;
(dd, J = 1.0, 7.0 Hz, 1H, H8), 7.20 (ddd, J = 1.5, 6.2, 7.0 Hz, 1H, H600), 7.26 (ddd,
J = 1.5, 6.2, 7.0 Hz, 1H, H700), 7.32 (dd, J = 1.5, 7.0 Hz, 1H, H500), 7.34–7.37 (m, 2H,
H5, H6), 7.50 (d, J = 8.7 Hz, 2H, H30, H50), 7.68–7.73 (m, 1H, H7), 7.83 (dd,
J = 1.5, 7.0 Hz, 1H, H800), 7.88 (d, J = 8.4 Hz, 1H, H300), 7.95 (s, 1H, H3), 8.16 (d,
J = 8.4 Hz, 1H, H400), 8.28 (d, J = 8.7 Hz, 2H, H20, H60), 9.52 (s, 1H, 200 OH); 13C
NMR (75.6 MHz, DMSO-d6): d 103.2 (C3), 116.7 (C4a), 118.6 (C300), 122.9 (C600),
124.1 (C5), 126.1 (C100), 126.5 (C800), 126.7 (C700), 127.4 (C6), 128.1 (C400a), 128.2
(C500), 128.9 (C30, C50), 129.1 (C20, C60), 129.8 (C7), 129.9 (C400), 130.0 (C8), 133.6
(C40), 135.0 (C800a), 137.9 (C10), 145.5 (C8a), 148.5 (C4), 152.7 (C2), 155.0 (C200);
MS (TOF-ESI) m/z Calcd. for C25H16ClNO (M+1)+ 382.10. Found 382.10; Anal.
Calcd for C25H16ClNO: C, 78.63; H, 4.22; N, 3.67. Found: C, 78.42; H, 4.33; N,
3.46.