An efficient one-pot synthesis of tetrahydroquinoline derivatives via an aza Diels-Alder reaction mediated by CAN in an aqueous medium and oxidation to heteroaryl quinolines

Article abstract of DOI:10.1016/j.tetlet.2006.03.046

Various tetrahydroquinoline derivatives have been synthesized by employing ceric ammonium nitrate in an aqueous medium. Subsequently, the tetrahydroquinolines were oxidized to biheterocycles.

Full text of DOI:10.1016/j.tetlet.2006.03.046

Tetrahedron Letters 47 (2006) 3589–3593
An efficient one-pot synthesis of tetrahydroquinoline derivatives
via an aza Diels–Alder reaction mediated by CAN in an
aqueous medium and oxidation to heteroaryl quinolines
G. Savitha and P. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 11 November 2005; revised 25 February 2006; accepted 9 March 2006
Abstract—Various tetrahydroquinoline derivatives have been synthesized by employing ceric ammonium nitrate in an aqueous
medium. Subsequently, the tetrahydroquinolines were oxidized to biheterocycles.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Tetrahydroquinoline derivatives are an important class
of natural products exhibiting a broad spectrum of bio-
logical activity.1,2 Substituted tetrahydroquinolines are
the core structures in many important pharmacological
agents and drug molecules such as anti-arrhythmic and
cardiovascular agents, anticancer drugs, immunosup-
pressants and as ligands for 5-HTIA and NMDA recep-
tors.3 Hence, there has been considerable interest in the
development of new and efficient protocols for the
synthesis of tetrahydroquinoline derivatives.4
provide economical synthetic strategies.9 Replacing
toxic solvents with ionic liquids or with water and min-
imizing the use of chlorinated hydrocarbons are impor-
tant. However, ionic liquids are very expensive. Though
recycling of ionic liquids justifies the expenditure, their
purity can become reduced. Hence, a catalyst that drives
the reaction purely in water or in an aqueous medium is
preferred.
Recently, the use of ceric ammonium nitrate10 has re-
ceived considerable attention as it is an inexpensive,
nontoxic catalyst for various organic transformations
providing excellent yields. A report on the use of
CAN,10c for deprotecting ketal groups in an aqueous
medium prompted us to explore the catalytic properties
of CAN for the synthesis of tetrahydroquinolines in an
aqueous medium.
The aza Diels–Alder reaction constitutes an attractive
strategy for the synthesis of substituted tetrahydroquino-
line derivatives5 due to its efficiency and its potential
application in combinatorial synthesis.6 The appropriate
choice of aldehyde in an aza Diels–Alder reaction pro-
vides a facile entry to biheterocyclic systems which is
an essential moiety in many active pharmaceuticals
and in liquid crystals.7
The reaction was first explored by stirring a mixture of
1a, 2g and 3 with 5 mol % CAN at rt in water for
20 min. The product was obtained in good yield
(92%). Similar conditions were required for the alde-
hydes 2e and 2f. However, for aldehydes 2a–d and 2h,
a water–acetonitrile mixture was used (1:1). Among
the various solvents studied, acetonitrile was found to
give the highest yield. In all cases, the reaction pro-
ceeded smoothly affording tetrahydroquinoline deriva-
tives (Schemes 1 and 2) in good yields with high levels
of selectivity and in short reaction times (Table 1).
Considering the extraordinary biological potential8 of
various heterocyclic moieties such as quinoline, chro-
mone, b-lactams, etc., we decided to prepare these
heteroaryl substituted quinolines which are anticipated
to be more potent than the parent heterocycle.
In recent times there has been a great deal of interest in
developing environmentally benign technologies that
*
Tetrahydroquinolines 4a–j were obtained as single
Corresponding author. Fax: +91 44 4911589; e-mail addresses:
savithagurunathan@yahoo.co.in; ptperumal@hotmail.com
regioisomers and diastereoisomers.11 No other isomers
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.046

3590
G. Savitha, P. T. Perumal / Tetrahedron Letters 47 (2006) 3589–3593
NH2
O
N
5 mol% CAN
RT stirring
R
+ R1 - CHO +
N
O
H2O or aq CH3CN
R1
N
H
4a-4j
R
1a-1d
2a-2g
3
1a R = H; 1b R = Cl; 1c R = Me; 1d R = OMe
Scheme 1.
O
O
N
N
H
H
H
H
H
H
H
H
OHC
NH2
aq CH3CN
N
H
N
H
N
O
+
N
N
N
O
O
O
+
+
5 mol% CAN
RT stirring/40 min
MeO
80%
MeO
MeO
1a
2h
3
4k
4l
Scheme 2.
Table 1. Synthesis of tetrahydroquinoline derivatives
Entry
Aniline
Aldehyde
Product
Time (min)
45
Yielda (%)
85
CHO
Cl
1
1a
4a
N
2a
2
3
1b
1a
2a
4b
4c
50
50
82
87
CHO
Me
N
Cl
2b
CHO
Cl
MeO
4
5
1a
1a
4d
4e
50
40
86
80
N
2c
O
O
CHO
2d
6
7
1c
1d
2d
2d
4f
4g
35
35
82
85
8
9
1a
1a
4hb
30
30
90
89
CHO
S
2e
2f
4ib
CHO
CHO
O
10
1a
4jb
20
92
2g
a Isolated overall yield.
b Reaction carried out in water.

G. Savitha, P. T. Perumal / Tetrahedron Letters 47 (2006) 3589–3593
3591
(trans) relationship can be deduced, whereas the
coupling constants of Ja,c = 6.3 Hz and Jd,c = 7.45 Hz
indicated an axial–equatorial relationship for these
protons.12
O
Ha
N
Hb
Hc
Hd
N
However, the reaction of 1a, 2h and 3 afforded tetra-
hydroquinolines 4k and 4l as a chromatographically separ-
able mixture (60:40) of diastereoisomers (Scheme 2).
H
S
Figure 1. Characteristic NOEs of compound 4h.
The structures of all the compounds were confirmed by
1H and C NMR and mass spectroscopy12 and the ste-
13
reochemistry of the products were assigned by coupling
constants and NOE measurements.
O
N
Subsequently, the tetrahydroquinolines were oxidized to
the corresponding heteroaryl substituted quinolines by
reaction with 2.5 equiv of CAN in MeCN at 0 ꢁC under
an N2 atmosphere for 20 min. The structures of the
R
R
2.5 eq CAN/N2
0 °C / CH3CN
N
R1
R1
N
H
1
resulting biheterocycles were confirmed by H and 13C
NMR and mass spectroscopy (Scheme 3).13 The results
are summarized in Table 2.
4
5
Scheme 3.
In conclusion, we have described a simple, convenient
and efficient aza Diels–Alder approach for the synthesis
of heteroaryl-substituted tetrahydroquinolines and the
oxidation of tetrahydroquinolines into the correspond-
ing heteroaryl substituted quinolines which are antici-
pated to be biologically active.7,14 Further studies on
these compounds are underway.
could be detected. The relative configuration of the
substituents in the tetrahydroquinolines were cis which
was confirmed from coupling constants and NOE
1
measurements. In the H NMR spectrum of compound
4h, two doublets of doublets at d 4.87 and 5.68 were
attributed to protons Hd and Ha, respectively. When
these protons were irradiated, NOEs (Fig. 1) were
observed between protons Ha/Hc and Ha/Hd indicating
that the protons Ha, Hc and Hd were on the same side
of the ring. Moreover, from the coupling constants of
Ja,b = 11.45 Hz and Jd,b = 11.3 Hz, an axial–axial
Acknowledgements
One of the authors G.S. expresses her gratitude to CSlR,
New Delhi, for a research fellowship.
Table 2. Oxidation of tetrahydroquinolinesa
Entry
Tetrahydroquinoline
R
H
R1
Product
Yield (%)
92
1
4a
5a
N
O
Cl
Me
2
3
4c
4e
H
H
5b
5c
90
88
Cl
N
O
O
4
4f
Me
5d
90
O
5
6
4h
4i
H
H
5e
5f
95
93
S
O
a All reactions were complete within 20 min.

3592
G. Savitha, P. T. Perumal / Tetrahedron Letters 47 (2006) 3589–3593
Lacova, M.; Stankovicova, H. Biol. Plant. 1995, 38, 397;
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12. General procedure: Synthesis of tetrahydroquinoline 4b
(Scheme 1). A mixture of 1b (0.128 g, 1 mmol), 2a (0.192 g,
1 mmol) and 3 (0.11 g, 1 mmol) was stirred in water
(5 mL)–acetonitrile (5 mL) in the presence of CAN
(0.027 g, 0.049 mmol, 5 mol %) at rt for 50 min until
completion of the reaction as followed by TLC. Water was
added to the mixture and the product was extracted into
ethyl acetate (2 · 20 mL) and the extract was dried over
anhydrous sodium sulfate. Removal of the solvent under
reduced pressure gave the crude product, which was
further purified by column chromatography on silica gel,
ethyl acetate–hexane (6:4) as eluent, to afford the pure
product 0.337 g (82%).
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J.-P. Tetrahedron Lett. 2003, 44, 217.
5. (a) Larock, R. C.; Yang, H.; Pace, P. Tetrahedron Lett.
1998, 39, 1885; (b) Padwa, A.; Brodney, M. A.; Liu, B.;
Satake, K.; Wu, T. J. Org. Chem. 1999, 64, 3595; (c)
Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S.
J. Org. Chem. 2001, 66, 2822; (d) Zhang, W.; Guo, Y.; Liu,
Z.; Jin, X.; Yang, L.; Liu, Z.-L. Tetrahedron 2005, 61,
1325.
Spectral values for selected compounds. Compound 4b
(Table 1): mp 287 ꢁC; mmax (KBr): 3351, 1660 cmÀ1 1H
;
NMR (500 MHz, CDCl3): d 1.89–1.96 (m, 1H), 2.01–2.04
(m, 2H), 2.29–2.34 (m, 1H), 2.43–2.57 (m, 2H), 3.14–3.18
(m, 1H), 3.22–3.27 (dd, 1H, J1 = 7.65 Hz, J2 = 16.85 Hz),
4.58 (br s, 1H, NH), 4.82–4.85 (d, 1H, J = 10.7 Hz), 5.67–
5.70 (dd, 1H, J1 = 6.15 Hz, J2 = 11.45 Hz), 6.58 (d, 1H,
J = 8.4 Hz), 6.78 (s, 1H), 6.95–6.97 (d, 1H, J = 8.4 Hz),
7.13–7.16 (t, 1H, J = 7.65 Hz), 7.35–7.42 (m, 2H), 7.47–
7.48 (d, 1H, J = 7.6 Hz), 7.87 (s, 1H). 13C NMR
(125 MHz, CDCl3): d 18.3, 31.3, 42.4, 48.2, 49.7, 49.8,
115.8, 116.9, 119.7, 121.0, 122.8, 123.1, 126.3, 127.9, 128.3,
132.9, 133.2, 135.7, 137.7, 144.7, 163.3, 176.0. MS m/z
(%) = 412 M+. Anal. Calcd for C22H19Cl2N3O (412.311):
C, 64.09; H, 4.64; N, 10.19. Found: C, 64.18; H, 4.56; N,
10.0.
Compound 4f (Table 1): mp 118 ꢁC; mmax (KBr): 3245,
1672, 1642 cmÀ1 1H NMR (500 MHz, CDCl3): d 1.93–
;
6. Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996,
118, 8977.
7. Waldrogel, S. R.; Cepanec, I. Synthesis of Biaryls;
Elsevier: Amsterdam, 2004; p 368.
2.00 (m, 3H), 2.18 (s, 3H), 2.24–2.30 (m, 1H), 2.39–2.54
(m, 2H), 3.13–3.15 (m, 1H), 3.20–3.22 (m, 1H), 4.47 (br s,
1H, NH), 4.73–4.75 (d, 1H, J = 9.95 Hz), 5.65–5.67 (dd,
1H, J1 = 6.1 Hz, J2 = 12.25 Hz), 6.52–6.53 (d, 1H,
J = 8.4 Hz), 6.63 (s, 1H), 6.82–6.83 (d, 1H, J = 7.65 Hz),
7.35–7.38 (t, 1H, J = 7.65 Hz), 7.41–7.43 (d, 1H,
J = 8.4 Hz), 7.62–7.65 (m, 1H), 8.04 (s, 1H), 8.16–8.18
(m, 1H).13C NMR (125 MHz, CDCl3): d 18.3, 20.7, 31.5,
31.5, 42.4, 48.0, 48.1, 116.2, 118.2, 119.6, 123.8, 125.3,
125.4, 125.9, 127.1, 128.2, 129.0, 133.9, 143.4, 153.1, 156.2,
175.8, 177.0. MS m/z (%) = 374 M+. Anal. Calcd for
C23H22N2O3 (374.432): C, 73.78; H, 5.92; N, 7.48. Found:
C, 73.74; H, 5.98; N, 7.50.
8. (a) Dewick, P. M. In The Flavonoids: Advances in Research
Since 1986; Harborne, J. B., Ed.; Chapmann & Hall: New
York, 1994; p 23; (b) Gill, M. In The Chemistry of Natural
Products; 2nd ed.; Thomson, R. H., Ed.; Blackie: Surrey,
1993; p 60; (c) Flavonoids in the Living Systems: Advances
in Experimental Medicine and Biology; Manthey, J. A.,
Buslig, B. S., Eds.; Plenum: New York, 1998; Vol. 439; (d)
Wilkinson, D. M. Ecology Lett. 1999, 2, 207; (e) Grigg, R.;
Thornton-Pett, M.; Xu, J.; Xe, L. H. Tetrahedron 1999,
13841; (f) Vaccaro, W. D.; Daris, H. R., Jr. Bioorg. Med.
Chem. Lett. 1998, 8, 313; (g) Vaccaro, W. D.; Sher, R.;
Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35; (h)
Burnett, D. A. Tetrahedron Lett. 1994, 35, 7339; (i)
Borthwick, A. D.; Weingarte, G.; Haley, T. M.; Tome-
szewski, M.; Wang, W.; Hu, Z.; Bedard, J.; Jin, H.; Yuen,
L.; Mansour, T. S. Bioorg. Med. Chem. Lett. 1998, 8, 365;
(j) Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici,
M. E.; Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem.
1995, 3, 1123; (k) Nohara, A.; Umetani, T.; Sanno, Y.
Tetrahedron 1974, 30, 3553; (l) Kralova, K.; Sersen, F.;
Compound 4h (Table 1): mp 56 ꢁC; mmax (KBr): 3330,
1670 cmÀ1 1H NMR (500 MHz, CDCl3): d 1.96–2.00
;
(m, 2H), 2.13–2.20 (m, 2H), 2.40–2.50 (m, 2H), 3.13–3.23
(m, 2H), 4.20 (br s, 1H, NH), 4.87 (dd, 1H, J1 = 7.45 Hz,
J2 = 11.3 Hz), 5.68 (dd, 1H, J1 = 6.3 Hz, J2 = 11.45 Hz),
6.56 (d, 1H, J = 8 Hz), 6.60–6.70 (t, 1H, J = 7.45 Hz), 6.84
(d, 1H, J = 8.05 Hz), 6.96 (m, 1H), 7.00 (m, 2H), 7.20
(d, 1H, J = 5.15 Hz). 13C NMR (125 MHz, CDCl3): d
18.3, 31.4, 36.2, 42.4, 48.2, 52.2, 115.3, 118.7, 119.0, 124.2,
124.3, 124.4, 126.8, 126.8, 145.4, 146.9, 175.9. MS

G. Savitha, P. T. Perumal / Tetrahedron Letters 47 (2006) 3589–3593
3593
m/z = 298 M+. Anal. Calcd for C17H18N2OS (298.404): C,
68.42; H, 6.08; N, 9.39. Found: C, 68.47; H, 6.00; N, 9.30.
13. General procedure: Synthesis of biheteroaryl 5f (Scheme
3). To tetrahydroquinoline 4i (0.282 g, 1 mmol) in aceto-
nitrile (5 mL), CAN (1.37 g, 2.5 mmol) dissolved in
acetonitrile (10 mL) was added dropwise, under a nitrogen
atmosphere at 0 ꢁC. The reaction was stirred for 20 min
until completion of the reaction as monitored by TLC.
Water was added to the mixture and the product was
extracted into ethyl acetate (2 · 20 mL) and the extract
was dried over anhydrous sodium sulfate. Removal of the
solvent under reduced pressure gave a crude product,
which was further purified by column chromatography on
silica gel, ethyl acetate–hexane (4:6) as eluent to afford the
product 0.181 g (93%).
Spectral data for compound. Compound 5f (Table 2): mp
110 ꢁC; 1H NMR (500 MHz, CDCl3): d 6.60 (m, 1H),
7.24–7.25 (m, 2H), 7.64 (d, 1H, J = 1.5 Hz), 7.85–7.87 (d,
1H, J = 8.4 Hz), 8.00–8.10 (d, 2H, J = 7.65 Hz), 8.22–8.24
(d, 2H, J = 8.4 Hz). 13C NMR (125 MHz, CDCl3): d
110.4, 112.4, 118.1, 125.7, 127.4, 129.5, 130.0, 136.9, 138.0,
144.3, 147.7, 149.2, 153.7. MS m/z = 195 M+. Anal. Calcd
for C13H9NO (195.217): C, 79.98; H, 4.65; N, 7.17. Found:
C, 79.90; H, 4.50; N, 7.25.
14. Ismail, F. M.; Dascombe, M. J.; Carr, P.; Merette, S. A.;
Rouault, P. J. Pharm. Pharmacol. 1998, 50, 483.