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Article

Synthesis of 5,6-Dihydropyridin-2(1H)-ones, 1,5,6,8,8a-Hexahydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-Hexahydroquinolin-2(1H)-ones by Intramolecular Wittig Reaction

Department of Organic Chemistry, Omsk State University, Omsk, 644077, Russian Federation
*
Author to whom correspondence should be addressed.
Molecules 2002, 7(2), 124-128; https://doi.org/10.3390/70200124
Submission received: 7 May 2001 / Revised: 15 January 2002 / Accepted: 16 January 2002 / Published: 28 February 2002

Abstract

:
A new, universal and diastereospecific method has been developed for the synthesis of 5,6-dihydropyridin-2(1H)-ones, 1,5,6,8,8a-hexahydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-hexahydroquinolin-2(1H)-ones (4) based on the intramolecular Wittig cyclization of the triphenyphosphonium salts 2 derived from the N-(3-oxoalkyl)–chloroacetamides 1.

Introduction

5,6-Dihydropyridin-2(1H)-ones possess significant importance due to both their biological activity [1] and their utilization in the synthesis of more complex compounds [2]. The main method for their synthesis is dehydrogenation of δ-valerolactams, but this route is limited by the availability of the required starting materials [1,3]. Although the Wittig reaction is widely used for the synthesis of heterocycles [4], the cyclization of N-(3-oxoalkyl)amides derivatives using this reaction has not been investigated until now. N-(3-Oxoalkyl)amides can be obtained by a number of synthetic methods [5,6,7], including diastero- and enantioselective ones [8], that makes them very promising precursors for the synthesis of 5,6-dihydropyridin-2(1H)-ones. The development of the methodology for pyrid-2-ones and the formation their hydrogenated derivatives formation led to our interest in this reaction [9].

Results and Discussion

It is known that α-haloacetamides can be reduced in some cases when reacted with PPh3 [10]. The interaction of compounds 1a-g with PPh3 under heating in ethanolic or dioxane [11] solutions proceeds with low yields and in some cases is accompanied by the formation of side products. For instance, the acetal 3 has been separated as a side product by reaction of compound 1c with PPh3 in ethanolic solution in presence of KI. We succeeded in finding of reaction conditions which afforded phosphonium salts 2a-g in 80-90 % yields (Scheme 1).
Scheme 1.
Scheme 1.
Molecules 07 00124 g001
a) R1=Me, R2=R3=R5=H, R4= Ph; b) R1=R4=Ph, R2=R3=R5=H;
c) R1=R5=H, R2=R3=Me, R4=CCl3; d) R1=Me, R2=R5=H, R3+R4= –(CH2)4–;
e) R1+R2= –(CH2)4–, R3=R5=H, R4=Ph; f) R1+R2= –(CH2)4–, R3=H, R4=Ph, R5= Me;
g) R1+R2= –(CH2)4–, R3=R5=H, R4=CCl3
5,6-Dihydropyridin-2(1H)-ones 4a-c have been obtained in high yields from compounds 2a-c by treatment with an equimolar amount of methanolic sodium methoxide at room temperature. Cyclization of the anti-2d-g phosphonium salts under the same conditions proceeds diasterospecifically and leads to 1,8a-trans-1,5,6,7,8,8a-hexahydroisoquinolin-3(2H)-ones (4e-g) and 4a,8a-trans-4a,5,6,7,8,8a-hexa-hydroquinolin-2(1H)-one (4d) (Scheme 2, Table 1 and Table 2).
Scheme 2.
Scheme 2.
Molecules 07 00124 g002
Table 1. Melting Points and Yields of Compounds 4a-g.
Table 1. Melting Points and Yields of Compounds 4a-g.
Compound4a4b4ctrans-4dtrans-4etrans-4ftrans-4g
m.p. °C135-61)>210 decom147-81)176-71)183-41)Oil172-31)
Yield %94292)9697918591
1 sealed capillary, compound sublimes; 2 unstable compound, decomposes in air
Table 2. 1H-NMR Data of Compounds 4a-g.
Table 2. 1H-NMR Data of Compounds 4a-g.
CompoundChemical shifts δ (ppm) and coupling constants J (Hz)
=C-H (3J, 4J)R1(3J, 4J)R2(2J, 3J)R3(2J, 3J)R4NCH (3J, 4J)R6
4a5.79 m
(1.5,1.5,1.5)
1.93 m
(1.5,1.0)
2.58-2.40 m7.36 s4.72 m
(9.0, 7.5, 0.6)
5.70 s
4b5.53 d
(3.8)
7.30-7.01 m2.85 dd
(16.1,7.0)
2.67 dd
(16.1,10.1)
7.30-7.01 m3.93 m
(10.1, 7.0, 3.8)
8.10 m
4c5.86 dd
(10.1, 2.0)
6.30 dd
(10.1, 1.3)
1.57 s1.43 s3.97 dd
(4.6,1.3)
7.37 s
trans-4d5.72 m
(1.6, 1.6, 1.6)
1.86 dd
(1.6,1.6)
2.17-1.02 m3.15 m
(12.4, 10.8, 3.6)
6.47 s
trans-4e5.76 dd
(2.1, 2.1, 2.1)
2.58-1.06 m7.37 s4.25 d
(11,1)
5.39 s
trans-4f5.82 dd
(2.5, 2.5)
2.53-0.60 m3.10-2.94 m7.30-7.15 m4.42 d
(8.2)
2.82 s
trans-4g5.70 dd
(1.4, 1.4, 1.4)
2.47-1.23 m2.80-2.72 m3.82 dd
(3.5,1.3)
7.00 s
When an excess of the base is used, an epimerisation of the α-carbonyl asymmetric center occurs and consequently a mixture of cis- and trans-4d-g is obtained. The spin-spin coupling constants of the C(1)-H (3J1,8a 8.2-11.1 Hz) C(4)-H (4J4,8a 2.1-2.5 Hz) hydrogen atoms shows that trans-4e,f compounds exist in a conformation with an equatorial arrangement of the C(1)-Ph substituent and a quasitransoidal ring junction (Table 1). At the same time, in compound trans-4g the C(1)-CCl3 substituent arranges axially and the rings are joined quasicisoidly (3J1,8a 1.3, 3J1,NH 3.5, 4J4,8a 1.4 Hz). The structures of all the compounds obtained have been confirmed by 13C- and 1H-NMR spectroscopy and elemental analysis. Assignment of 1H-NMR spin-spin constants was performed using COSY 1H-1H 2D spectroscopy.

Conclusions

We have developed a new, universal and diastereospecific synthetic method which affords 5,6-dihydropyridin-2(1H)-ones, 1,8a-trans-1,5,6,7,8,8a-hexahydroisoquinolin-3(2H)-ones and 4a,8a-trans-4a,5,6,7,8,8a-hexahydroquinolin-2(1H)-ones in high yields from versatile N-(3-oxoalkyl)chloro-acetamides.

Experimental

General

1H-NMR spectra (CDCl3 solutions) were obtained using a Bruker AC-200 NMR spectrometer and were recorded at 200 MHz. N-(3-Oxoalkyl)amides 1a (56%, m.p. 90-91°C); 1b (81 %, m.p. 104-105°C) and anti-1e (14%, m.p.156-157°C) were obtained from the α,β-unsaturated ketones and chloroacetonitrile [6,9]; compounds 1c (69%, m.p. 109-110°C) and anti-1g (55%, m.p. 74-75°C) — by reaction of Cl3CCH=NCOCH2Cl with enamines [7]; compound anti-1d (88%, m.p.124-125°C) — by acylation of 1-(trans-2-aminocyclohexyl)-1-ethanone with chloroanhydride of chloroacetic acid [9]; compound 1f (19%, m.p. 201-202°C) — by interaction of (1-cyclohexenyloxy)(trimethyl)silane with PhCH=NMe and ClCH2COCl in the presence of TiCl4 [9]. Compounds anti-1e, anti-1f were separated by column chromatography on silica (eluent 95:5 CHCl3–EtOAc).

Typical experimental procedure for the synthesis of salts 2a-g.

KI (2.52 mmol) was added to a solution of 1a-g (2.50 mmol) and PPh3 (2.64 mmol) in DMF at 0 °C. The reaction mixture was kept at 0-7°C for 2-3 days and then poured into a 30 % aqueous solution of KI (30 mL). The reaction was monitored by TLC. After adding water (10 mL) the residue was extended until crystallization ocurred. The product was filtered off, dried over P4O10, recrystallized from chloroform-ether and dried again. Yields, melting points: 2a - 74%, 191-192°C; 2b - 93%, 119-120°C; 2c - 78%, 203-205°C; anti-2d - 93%, 187-188°C; anti-2e - 83%, 200-201°C; anti-2f - 78%, 160-161°C; anti-2g - 89%, 159-150°C.

Typical experimental procedure for the syntheses of 4a-g.

An equimolar amount of sodium methoxide (concentration: 2.5-3 mg Na/mL of methanol) was added dropwise to a solution of 0.40 g of phosphonium salt 2a-g in methanol (10 mL) at 18-25 °C. The reaction mixture was kept at this temperature for 12 h and afterwards the solvent was evaporated under reduced pressure. The residue was treated with benzene, filtered and filtrate was evaporated again. Compounds 4a-g were separated by column chromatography on silicagel. Eluents: 4c (2:1 CCl4 - AcOEt); 4g (2:1 CCl4 - AcOEt,); 4a,e (gradient of n-C6H14→ 1:1 n-C6H14 - DME); 4d (gradient of CHCl3 → 1:1 CHCl3 - AcOEt, 1:1). Compound 4b was separated by flash-chromatography on a dry column (silica, CHCl3).

Acknowledgments

We are grateful to the Russian Foundation for Basic Research (grant No 99-03-33013) and Russian Ministry of Education (grant No E00-5.0-282) for financial support of this work.

References

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MDPI and ACS Style

Fisyuk, A.S.; Poendaev, N.V. Synthesis of 5,6-Dihydropyridin-2(1H)-ones, 1,5,6,8,8a-Hexahydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-Hexahydroquinolin-2(1H)-ones by Intramolecular Wittig Reaction. Molecules 2002, 7, 124-128. https://doi.org/10.3390/70200124

AMA Style

Fisyuk AS, Poendaev NV. Synthesis of 5,6-Dihydropyridin-2(1H)-ones, 1,5,6,8,8a-Hexahydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-Hexahydroquinolin-2(1H)-ones by Intramolecular Wittig Reaction. Molecules. 2002; 7(2):124-128. https://doi.org/10.3390/70200124

Chicago/Turabian Style

Fisyuk, Alexander S., and Nikolai V. Poendaev. 2002. "Synthesis of 5,6-Dihydropyridin-2(1H)-ones, 1,5,6,8,8a-Hexahydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-Hexahydroquinolin-2(1H)-ones by Intramolecular Wittig Reaction" Molecules 7, no. 2: 124-128. https://doi.org/10.3390/70200124

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