Synthesis of 5,6-Dihydropyridin-2(1H)-ones, 1,5,6,8,8a-Hexa-hydroisoquinolin-3(2H)-ones and 4a,5,6,7,8,8a-Hexahydro-quinolin-2(1H)-ones by Intramolecular Wittig Reaction

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.

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.

Table 1.

Melting Points and Yields of Compounds 4a-g.

Compound	4a	4b	4c	trans-4d	trans-4e	trans-4f	trans-4g
m.p. °C	135-61)	>210 decom	147-81)	176-71)	183-41)	Oil	172-31)
Yield %	94	292)	96	97	91	85	91

¹ sealed capillary, compound sublimes; ² unstable compound, decomposes in air

Table 2.

¹H-NMR Data of Compounds 4a-g.

Compound	Chemical shifts δ (ppm) and coupling constants J (Hz)
	=C-H (3J, 4J)	R1(3J, 4J)	R2(2J, 3J)	R3(2J, 3J)	R4	NCH (3J, 4J)	R6
4a	5.79 m (1.5,1.5,1.5)	1.93 m (1.5,1.0)	2.58-2.40 m		7.36 s	4.72 m (9.0, 7.5, 0.6)	5.70 s
4b	5.53 d (3.8)	7.30-7.01 m	2.85 dd (16.1,7.0)	2.67 dd (16.1,10.1)	7.30-7.01 m	3.93 m (10.1, 7.0, 3.8)	8.10 m
4c	5.86 dd (10.1, 2.0)	6.30 dd (10.1, 1.3)	1.57 s	1.43 s	–	3.97 dd (4.6,1.3)	7.37 s
trans-4d	5.72 m (1.6, 1.6, 1.6)	1.86 dd (1.6,1.6)	2.17-1.02 m			3.15 m (12.4, 10.8, 3.6)	6.47 s
trans-4e	5.76 dd (2.1, 2.1, 2.1)	2.58-1.06 m			7.37 s	4.25 d (11,1)	5.39 s
trans-4f	5.82 dd (2.5, 2.5)	2.53-0.60 m		3.10-2.94 m	7.30-7.15 m	4.42 d (8.2)	2.82 s
trans-4g	5.70 dd (1.4, 1.4, 1.4)	2.47-1.23 m		2.80-2.72 m	–	3.82 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 (³J_1,8a 8.2-11.1 Hz) C₍₄₎-H (⁴J_4,8a 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 (³J_1,8a 1.3, ³J_1,NH 3.5, ⁴J_4,8a 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).