Novel facile synthesis of 2,2,4 substituted 1,2-dihydroquinolines via a modified Skraup reaction

Article abstract of DOI:10.1016/S0040-4039(02)00614-7

A variety of 2,2,4 substituted 1,2-dihydroquinolines were synthesized from substituted anilines or aminoheterocycles and the corresponding ketones in good yield via the use of lanthanide catalysts and microwave technology. This method can be readily applied to the general synthesis of combinatorial libraries of dihydroquinolines.

Full text of DOI:10.1016/S0040-4039(02)00614-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3907–3910
Novel facile synthesis of 2,2,4 substituted 1,2-dihydroquinolines
via a modified Skraup reaction
Maria-Elena Theoclitou* and Leslie A. Robinson
Bristol-Myers Squibb, Pharma Research Laboratories, 4570 Executive Drive, San Diego, CA 92121, USA
Received 21 December 2001; revised 27 March 2002; accepted 29 March 2002
Abstract—A variety of 2,2,4 substituted 1,2-dihydroquinolines were synthesized from substituted anilines or aminoheterocycles
and the corresponding ketones in good yield via the use of lanthanide catalysts and microwave technology. This method can be
readily applied to the general synthesis of combinatorial libraries of dihydroquinolines. © 2002 Elsevier Science Ltd. All rights
reserved.
Dihydroquinoline moieties can be found in a variety of
natural products8–11 and in a large number of com-
pounds which display biological activity. For example,
2,2,4 substituted 1,2-dihydroquinolines have been used
to produce potent compounds that possess antibacte-
rial,1 antidiabetic2 and anti-inflammatory3 activities.
Compounds possessing this motif have also been shown
to act as lipid peroxidation inhibitors,4 HMG-CoA
reductase inhibitors,5 ileal bile acid transporter
We were interested in synthesizing 2,2,4 substituted
1,2-dihydroquinolines in a combinatorial library format
and determined that these literature procedures, involv-
ing lengthy periods at high temperatures, were not
amenable to library synthesis. To circumvent these
problems, we investigated the use of microwaves as a
means to accelerate the reaction and improve yields.
Through the use of the Personal Chemistry Smith Syn-
thesizer™25 microwave system, the yields of the Skraup
cyclization were only increased slightly (i.e. 45–55%), in
the best of conditions. However, the reaction times
were shortened from 60 to 1 h (140°C).
inhibitors12
and
progesterone
agonists13
and
antagonists.6
Dihydroquinolines of the type shown in Fig. 1, have
been synthesized in the past via a variety of methods.14–
21 Typically these routes have been low yielding14–17 or
have required very detailed synthesis of the precur-
sors.18–21 The best method used to date, has been the
Skraup cyclization,7 which involves reaction of the
respective aniline and acetone (or the desired ketone),
in the presence of iodine, at 145°C under pressure for
2–3 days.
In our effort to adapt and broaden the scope of the
Skraup synthesis further, we investigated the use of
lanthanide catalysts at room temperature. In reference
to Scheme 1, where R1=H and R2,R3=Me, scandium-,
indium- and ytterbium-trifluoromethane sulphonates
gave yields of 65, 63 and 60%, respectively. These yields
and reaction times once compared to those mentioned
by the traditional Skraup route and the improved
microwave technique, above indicated to us that lan-
thanide catalysts were extremely useful in this type of
synthesis. Neither of the lanthanide catalysts offered
any significant advantage over each other and hence
further reactions were all carried out with the use of
scandium trifluoromethane sulphonate. Yields obtained
by the use of this catalyst will be quoted throughout for
reference (Table 1).
Figure 1. 2,2,4 Substituted 1,2-dihydroquinoline.
Scheme 1. Synthesis of 2,2,4 substituted 1,2-dihydroquino-
* Corresponding author. Tel.: +1-858-625-6435; fax: +1-858-625-9293;
lines.
e-mail: maria-elena.theoclitou@dupontpharma.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00614-7

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M.-E. Theoclitou, L. A. Robinson / Tetrahedron Letters 43 (2002) 3907–3910
Table 1. Yields of 2,2,4-methyl 1,2 dihydroquinoles synthesized
pounds of this nature would be significantly sterically
hindered and hence the synthesis of the cyclized prod-
ucts would be more difficult. Increasing the tempera-
The cyclization reaction of a variety of anilines with
acetone in the presence of scandium trifluoromethane
sulphonate, proceeded very smoothly at room
temperature22 to give the desired products in yields of
59–98% (Scheme 1). In certain cases two regioisomeric
products were isolated, as is commonly seen in the
Skraup cyclization. The products were purified via a PE
Sciex LC/MS system with mass triggered fraction col-
lection.26–28 Secondary anilines were also tested, but
these reactions proceeded in 10–15% yield at room
temperature. Elevated temperatures did not produce
significantly higher yields. The method was extended to
incorporate a variety of aminoheterocycles, resulting in
a synthesis of several interesting fused bicyclic heterocy-
cles (Table 2) in moderate yields.
Table 2. Product yields with aminoheterocycles
Due to the success of the modified conditions with
acetone, we explored incorporation of other ketones.
Consequently, reactions were carried out with 2-
butanone, acetophenone24 and a variety of other
ketones. While the reactions with more hindered
ketones (e.g. 2-butanone) appeared to proceed well23
(Table 3), albeit in lower yields than their acetone
counterparts (minor amounts (2%) of 2-ethyl-2,3,4-
trimethyl-1,2-dihydroquinoline were isolated), the reac-
tions with e.g. acetophenone did not proceed at all at
room temperature. It can be envisioned that com-

M.-E. Theoclitou, L. A. Robinson / Tetrahedron Letters 43 (2002) 3907–3910
3909
Table 3. Yields of 2,2,4-methyl 1,2 dihydroquinolines synthesized
ture, in the presence of scandium triflate, to 80°C
overnight gave the desired cyclized products, from ace-
tophenone, in 23% yield.
thesizer™.24 Optimal yields were obtained when the
reaction mixtures were microwaved at 150°C for 50 min
(Table 3). Secondary anilines were also evaluated, but
these reactions, once again, were either very low yield-
ing (8–12%) or produced no product at all at room
temperature.
We then decided to limit the reaction times by reacting
the components using a Personal Chemistry SmithSyn-

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M.-E. Theoclitou, L. A. Robinson / Tetrahedron Letters 43 (2002) 3907–3910
The work presented here demonstrates a straightfor-
ward and mild procedure for the efficient synthesis of
2,2,4 substituted 1,2 dihydro-quinolines using scandium
triflate catalysis. A variety of anilines and unsymmetri-
cal ketones can be used to expand the scope of the
substituents, particularly five-membered ring heterocy-
cles to yield a variety of fused dihydropyridines. Com-
pounds that were almost impossible to synthesize via
the standard routes have also been produced in reason-
able yields via the use of microwave technology. The
mild conditions developed make this procedure espe-
cially amenable to combinatorial library synthesis.
17. Arduini, A.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori,
G. Syntheses 1981, 975–980.
18. Cossy, J.; Poitevin, C.; Gomez Pardo, D.; Peglion, J.-L.;
Dessinges, A. J. Org. Chem. 1998, 63, 4554–4557.
19. Edwards, J. P.; Ringgenberg, J. D.; Jones, T. K. Tetra-
hedron Lett. 1998, 39, 5139–5142.
20. Walter, H.; Schneider, J. Heterocycles 1995, 41, 1251–
1269.
21. Walter, H. Helv. Chim. Acta 1994, 77, 608–614.
22. Experimental: 0.5 mmol of the desired aniline were dis-
solved in 3 mL anhydrous acetone. To this solution was
added scandium triflate (0.1 equiv.; 0.05 mmol; 25 mg).
The reaction mixture was shaken for 2 h at rt. After
reaction was complete, by LC/MS monitoring, the mix-
ture was evaporated to dryness, resuspended in 1:1
DMSO:CH3CN, and filtered. Purification was carried out
on a semipreparative YMC ODS-A reverse phase column
(20×50 mm, particle size S-5) via use of a 10–99% gradi-
ent of 0.05% TFA in water/0.035% TFA in acetonitrile
(flow rate 35 ml/min) on a Shimadzu HPLC system with
an API150EX single quadropole mass spectrometer.
23. Experimental: 0.5 mmol of the desired aniline were dis-
solved in 3 mL anhydrous acetonitrile. To this solution
was added scandium triflate (0.1 equiv.; 0.05 mmol; 25
mg) and 2-butanone (5 equiv.; 2.5 mmol; 223 mL). The
reaction mixture was shaken for 6 h at rt. The workup
was identical to that of Ref. 22.
24. Experimental for lanthanide catalyst reaction with Per-
sonal Chemistry SmithSynthesizer™ microwave: 0.5
mmol of the desired aniline were dissolved in 3 mL
anhydrous acetonitrile. To this solution was added scan-
dium triflate (0.1 equiv.; 0.05 mmol; 25 mg) and ace-
tophenone (5 equiv.; 2.5 mmol; 291 mL). The reaction
mixture was microwaved for 50 min at 150°C using a
Smith Personal Workmate. The workup was identical to
that of Ref. 22.
25. Experimental for Skraup conditions with Personal Chem-
istry SmithSynthesizer™ microwave: 0.5 mmol of the
desired aniline were dissolved in 3 mL anhydrous ace-
tone. To this solution was added iodine (0.1 equiv.; 0.05
mmol; 12.7 mg) and the reaction mixture was
microwaved for 1 h at 140°C using a Smith Personal
Workmate. The workup was identical to that of Ref. 22.
26. Zeng, L.; Kassel, D. B. Anal. Chem. 1998, 70 (20),
4380–4388.
27. Zeng, L.; Wang, X.; Wang, T.; Kassel, D. B. J. Comb.
Chem. High Thr. Screening 1998, 1, 101–111.
28. Zeng, L.; Burton, L.; Yung, K.; Shushan, B.; Kassel, D.
B. J. Chromatogr. 1998, 794, 3–13.
Acknowledgements
The authors wish to thank their colleagues, especially
Ingo Hardt, John Pham and Erik Evensen for their
continued assistance in this project. The support and
efforts of Mark Suto and Peter Myers are also grate-
fully acknowledged.
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