Regiospecific synthesis of 4-(2-oxoalkyl)pyridines.
ABSTRACT [reaction: see text]. A new and operationally simple method has been developed for the regiospecific syntheses of 4-(2-oxoalkyl)pyridines from ketones and pyridine in good yields, using triflic anhydride to activate the pyridine ring.
Regiospecific Synthesis of
Alan R. Katritzky,*Suoming Zhang,‡Thomas Kurz,§and Mingyi Wang
Department of Chemistry, Center for Heterocyclic Compounds, UniVersity of Florida,
GainesVille, Florida 32611-7200
Peter J. Steel⊥
Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand
Received June 1, 2001
A new and operationally simple method has been developed for the regiospecific syntheses of 4-(2-oxoalkyl)pyridines from ketones and
pyridine in good yields, using triflic anhydride to activate the pyridine ring.
Functionalization of nitrogen heterocycles constitutes a
powerful tool for the synthesis of natural products and
bioactive substances. The regioselective introduction of a
?-oxo-alkyl group into the 4-position of a pyridine has
attracted considerable attention (Scheme 1): (i) classically,
the preparation of 4-(2-oxoalkyl)pyridines involves the
treatment of a deprotonated 4-alkylpyridine with an ester or
acid chloride.1(ii) Comins and Brown have prepared 4- (2-
oxoalkyl)pyridines by the treatment of 1-oxycarbonylpyri-
dinium salts with lithium or titanium enolates followed by
reaction with sulfur and 5% Pd/C in naphthalene.2(iii) Akiba
and co-workers reacted trimethylsilyl enol ethers with
1-ethoxycarbonylpyridinium chloride to afford 1-ethoxycar-
(iv) Doering and McEwen treated ketones with pyridine and
benzoyl chloride, or acetic anhydride, to obtain 4-substituted
dihydropyridines.4(v) Our group developed regiospecific
syntheses of 4-substituted (including 4-(?-oxoalkyl)) pyri-
dines via N-(2,6-dimethyl-4-oxo-1,4-dihydropyrid-1-yl)pyri-
dinium salt.5We now present a practical route for the
regiospecific synthesis of 4-(2-oxoalkyl)pyridines using triflic
‡Present address: Neurogen Corporation, 35 Northeast Industrial Road,
Branford, CT 06405.
§Present address: Institute of Pharmacy, University of Hamburg,
Bundesstrasse 45, D-10146 Hamburg, Germany.
(1) (a) Katritzky, A. R.; Rees, C. W. ComprehensiVe Heterocyclic
Chemistry; Pergamon Press: Oxford, 1984; Vol. 2. (b) Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V. ComprehensiVe Heterocyclic Chemistry II;
Pergamon Press: Oxford, 1996; Vol. 2.
(2) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1984, 25, 3297.
anhydride to activate the pyridine ring, which complements
the previous routes and offers an advantage in terms of
convenience and yield.
of ketones 3a-i with pyridine 1 (4 equiv) and triflic
anhydride (3 equiv) in CH2Cl2at 0 °C gave 4-(2-oxoalkyl)-
1,4-dihydropyridines 5a-i (in an average yield of 88%)
rather than enol triflates 2 (Scheme 2). No regioisomeric 2-(2-
oxoalkyl)-1,2-dihydropyridines were detected from the NMR
spectra of the crude products 5a-i. In the case of 5i, the
starting material 3i was recovered in 15% yield. The
structures of these novel 1,4-dihydropyridines 5a-i were
supported by their NMR spectra, and structure 5f was
confirmed by X-ray crystallography (Figure 1). This crystal
structure determination confirmed the regiochemistry of the
reaction. The dihydropyridine ring has a conformation similar
to those previously reported for three other 1-triflyl-1,4-
5a-d,f-i on treatment with t-BuOK in DMSO or t-BuOH
afforded 6a-d,9,10f-i (average 92% yield). Treatment of
5h with KOH in DMSO at 70oC gave 3h in quantitative
yield. Pyridine derivative 6e was not obtained as a result of
(3) (a) Akiba, Y.; Nishihara, Y.; Wada, M. Tetrahedron Lett. 1983, 24,
5269. (b) Wada, M.; Nishihara, Y.; Akiba, Y. Tetrahedron Lett. 1985, 26,
(4) Doering, W. von E.; McEwen, W. E. J. Am. Chem. Soc. 1951, 73,
(5) (a) Katritzky, A. R.; Beltrami, H.; Keay, J. G.; Rogers, D. N.;
Sammes, M. P.; Leung, C. W. F.; Lee, C. M. Angew. Chem., Int. Ed. Engl.
1979, 18, 792. (b) Lee, C. M.; Sammes, M. P.; Katritzky, A. R. J. Chem.
Soc., Perkin Trans. 1 1980, 2458.
(6) Typical Procedure for the Preparation of 5. To a cooled (0 °C)
solution of a ketone 3 (10 mmol) in CH2Cl2(50 mL) was added pyridine
(dried over NaOH, 3.2 mL, 40 mmol), and then triflic anhydride (5.0 mL,
30 mmol) was added dropwise over 30 min at 0 °C. The ice bath was
removed, and the reaction mixture stirred at room temperature overnight.
The reaction mixture was washed with saturated NH4Cl (2 × 50 mL) and
H2O (2 × 50 mL). The organic layer was dried over MgSO4. The crude
products were purified by recrystallization or chromatography to afford the
desired 1,4-dihydropyridines 5 in good to excellent yields.
(7) (a) Toscano, R. A.; Hernadez-Galindo, M. del C.; Rosas, R.; Garcia-
Mellado, O.; Portilla, F. del R.; Amabile-Cuevas, C.; Alvarez-Toledano,
C. Chem. Pharm. Bull. 1997, 45, 957. (b) Toscano, R. A.; Rosas, R.;
Hernadez-Galindo, M. del C.; Alvarez-Toledano, C.; Garcia-Mellado, O.
Transition Met. Chem. 1998, 23, 113.
(8) Typical Procedure for the Preparation of 6. To a solution of
compound 5 (5 mmol) in DMSO (20 mL) was added t-BuOK (1.68 g, 15
mmol) at 10 °C. The reaction mixture was stirred at room temperature for
10-30 min. The reaction was quenched with brine and extracted with
EtOAc. The organic layer was washed with H2O and dried over MgSO4.
Recrystallization from hexanes-ethyl acetate afforded product 6 in 81-
(9) Anders, E.; Will, W.; Stankowiak, A. Chem. Ber. 1983, 116, 3192.
(10) Raynolds, S.; Levine, R. J. Am. Chem. Soc. 1960, 82, 472.
aConditions and reagents: (i) CH2Cl2, 0 °C; (ii) t-BuOK, DMSO
or t-BuOH, rt; (iii) TBAF in THF, 70 °C; (iv) KOH in DMSO, 70
Figure 1. Perspective view of the X-ray crystal structure of 5f.
4-Substituted 1,4-Dihydropyridines 5
mp (°C)yield (%)
aRecovered starting material in parentheses.
the instability of compound 5e. The structures of the pyridine
derivatives 6a-d,f-i were characterized by their NMR and
mass spectra. In the
characteristic doublets (J ) ca. 5.5 Hz, 2H) at ca. 8.50 and
7.20 ppm were assigned to the pyridine ring and a charac-
teristic singlet at ca. 6.0 or 7.5 ppm was assigned to the
methine group attached to the pyridine moiety.
However, several other attempts to eliminate the triflate
group from 4-(2-oxoalkyl)-1,4-dihydropyridines 5 under
various reaction conditions, including (i) reflux with isopro-
pylamine, (ii) NaOCH3in methanol or toluene, and (iii) NaH
in THF, failed. Use of TBAF in THF afforded the desired
4-(2-oxoalkyl)pyridine 6f in 55% yield. In the case of 5d,h,
the application of TBAF failed to afford the corresponding
products 6d,h and gave instead 711and 8, respectively.
In conclusion, we have developed a new and operationally
simple method for the regiospecific synthesis of 4-(2-
oxoalkyl)pyridines from ketones and pyridine, using triflic
anhydride to activate the pyridine ring. This method comple-
1H NMR spectra of 6a-d,f-i two
ments the existing methods as it is highly regioselective and
Supporting Information Available: Characterization
data for compounds 5a-d,f-i, 6a-d,f-i, 7, 8, and X-ray
data for 5f. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Chia, W.-L.; Shiao, M.-J. Tetrahedron Lett. 1991, 32, 2033.
4-(2-Oxoalkyl) Pyridines 6
mp (°C)yield (%)
aCompound 5f was treated with TBAF in THF at 70 °C.