One-pot Fluorination and Organocatalytic Robinson Annulation for Asymmetric Synthesis of Mono- and Difluorinated Cyclohexenones

Abstract

A one-pot fluorination and organocatalytic Robinson annulation sequence has been developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-1-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three stereocenters in good to excellent yields with up to 99% ee and 20:1 dr.

1. Introduction

The development of new synthetic methods for organofluorine compounds is an active topic in organic and medicinal chemistry. Introduction of fluorine atom(s) could have significant impact on molecules’ biological activity, bioavailability, and metabolic property [1,2,3,4]. Shown in Figure 1 are bioactive fluorinated cyclohexenones [5] including intermediate for antitumor agent COTC (Figure 1A) [6], aromatase inhibitor (Figure 1B) [7], and retinal protein bacteriorhodopsin (Figure 1C) [8].

The β-ketoester scaffold is a versatile synthon for being both electrophilic and nucleophilic sites [9]. The asymmetric Michael addition reactions of α-fluoro-β-keto esters [10,11,12,13,14,15] and other monofluorinated nucleophiles [16,17,18,19] is an attractive topic. These nucleophiles have been used to react with nitroolefins [10,11,13,14,16,17], N-alkyl maleimides [12,15], chalcones [18], and α,β-unsaturated aldehydes [19]. Beside the Michael addition reactions, some Michael addition-initiated reactions involving α-fluoro-β-keto esters have also been reported [20,21,22]. Those reactions include Michael/aldol (Robinson) [20], Michael/Michael/aldol [21], and Michael/aza-Henry/lactamization sequences [22] for the construction of cyclohexenones, cyclohexanones, and 2-piperidinones bearing multiple stereocenters.

As part of our recent effort on the synthesis of organofluorine compounds using α-fluoro-β-keto esters [23,24,25], we have reported a one-pot fluorination/Robinson annulation sequence for fluorinated cyclohexenones 1 (Scheme 1A) [23], Robinson annulation/dehydrofluorination/aromatization sequence for phenols 2 (Scheme 1B) [24], and pyridines [25]. We envisioned that in the presence of an organocatalyst, such as cinchona alkaloid primary amine cat-1, the one-pot asymmetric synthesis could be developed for the preparation of monofluorocyclohexenones 3 and difluorocyclohexenones 4 (Scheme 1C).

2. Results and Discussions

A number of six organocatalysts were screened for the asymmetric Robinson annulation reaction of chalcone 6a and α-fluoro-β-ketoester 5a (

Table 1. Screening of catalysts for the Robinson annulation ^a.

Entry	Cat	Additive	Yield (%) b	dr c	ee (%) d
1	cat-1	C6H5CO2H	79	5:1	99
2	cat-2	C6H5CO2H	NR	-	-
3	cat-3	C6H5CO2H	NR	-	-
4	cat-4	C6H5CO2H	NR	-	-
5	cat-5	C6H5CO2H	trace	-	-
6	cat-6	C6H5CO2H	27	3:1	85
7	cat-1	None	42	5:1	92
8	cat-1	AcOH	52	6:1	92
9	cat-1	TsOH	45	5:1	95
10	cat-1	CF3C6H4CO2H	89	9:1	99
11	cat-1	CCl3CO2H	75	8:1	90
12	cat-1	CF3CO2H	77	8:1	90
13e	cat-1	CF3C6H4CO2H	51	12:1	99

^a Reaction of 0.1 mmol of 5a and 0.15 mmol of 6a in 0.5 mL of MeCN. ^b Isolated yield. ^c Determined by ¹H-NMR of crude reaction mixture. ^d Determined by chiral HPLC. ^e Reaction was carried out at −20 °C.

, entries 1–6). It was found that the reaction with 20 mol% of cat-1 gave the desired product 3a in 79% yield with 5:1 dr and 99% ee (entry 1), while other catalysts did not give good results. Acidity of the reaction system plays an important role in amine catalysis for lowering the LUMO energy of iminium ions [26]. Thus, an investigation of the reactions in the presence of different acids was carried out. The best result was achieved by adding CF₃C₆H₄CO₂H to afford 3a in 89% yield with 9:1 dr and 99% ee (entry 10). We lowered the reaction temperature to −20 °C which slightly increased the dr to 12:1, but significantly decreased the yield to 51% (entry 13). Because we failed to get the crystal of 3 for X-ray structure analysis, the absolute configuration of 3a was deduced based on the information reported in the literature [27]. The S-amine catalyst promoted a highly selective Re-face attack at the Michael acceptor. We believed that our reactions also catalyzed by the S-amine cat-1 could have the same stereochemistry outcome.

The combination of fluorination and the Robinson annulation as a one-pot reaction for fluorinated cyclohexenone 3a was then attempted (

Table 2. One-pot synthesis of 6-fluorocyclohex-2-en-1-ones 3 ^a.

Entry	Base (equiv)	Yield (%) b	dr c	ee (%) d
1	None	<10	-	-
2	Na2CO3 (0.5)	42	9:1	99
3	K2CO3 (0.5)	67	3:1	85
4	Cs2CO3(0.5)	85	1.5:1	52
5	Na2CO3 (1.0)	57	9:1	99
6	Na2CO3 (1.5)	82	9:1	99
7	Na2CO3 (2.0)	83	9:1	99

^a Reaction of 0.1 mmol of 8, 0.15 mmol of SelectFluor™, 0.15 mmol of 6a in 0.5 mL of MeCN. ^b Yield of isolated product 3a. ^c Determined by ¹H-NMR. ^d Determined by HPLC on Venusil Chiral OD-H column with 90:10 hexane/i-PrOH.

). The fluorination step does not need to be asymmetric because both stereocenters were generated during the subsequential Michael addition. The fluorination reaction of β-ketoester 8 with SelectFluor™ was conducted under microwave heating at 120 °C for 20 min without using a catalyst. After the completion of the fluorination, chalcone 6a, CF₃C₆H₄CO₂H and catalyst cat-1 were added to the reaction mixture at 25 °C for the Robinson annulation. But this one-pot fluorination/Robinson annulation only gave 3a in <10% yield probably due to the effect of the acidic SelectFluor™ derivative in the reaction mixture. To address this issue, bases including Na₂CO₃, K₂CO₃, and Cs₂CO₃ were used for the reaction. It was found that addition of 1.5 equiv. of Na₂CO₃ gave 3a in 82% yield with a good ee and dr (Table 2, entry 6).

With the optimized conditions in hand, the scope of the one-pot synthesis of 6-fluorocyclohexenones 3a–j using different Michael acceptor 6 was investigated (Scheme 2). Substrates 6 with electron-donating (SMe, Ph) and electron-withdrawing (Br, CF₃) groups on Ar¹ gave products 3b–f in 82–90% yields with >96% ee and >9:1 dr. Reaction of a chalcone bearing a thiophene ring also gave product 3h in a good yield and ee. The introduction of substituents on Ar² of 6 gave products 3i and 3j with decreased ee, probably due to an unfavorable stereoelectronic effect.

We have recently reported a one-pot Robinson annulation/dehydrofluorination/aromtization sequence for fluorinated phenols 2 using α-fluoro-β-ketoesters and α-fluoro-α,β-unsaturated ketones as substrates [24]. We envisioned that α-fluoro-α,β-unsaturated ketones 6 could be used for asymmetric synthesis of 4,6-difluorocyclohexanones 4 under organocatalytic conditions. Indeed, one-pot reactions of β-ketoester 8 went smoothly to afford 4a–c in 53–65% yields with 5:1-8:1 dr and 89–93% ee (Scheme 3). However, all of these reactions afforded 4a–c as decarboxylated products, even at low reaction temperatures (−30–0 °C). No aromatization products were observed under the reaction temperature without heating [24]. The products 4a–c were found not to be stable during the workup and rotary vapor concentration of the crude product.

3. Conclusions

In summary, a one-pot fluorination and cinchona alkaloid amine-promoted organocatalytic Robinson sequence for asymmetric synthesis of fluorocyclohexenones bearing two stereocenters has been developed. Both stereocenters were established during the step of Michael addition to afford fluorinated cyclohexanones with up to 99% ee and 20:1 dr. Using fluorinated chalcones as Michael acceptors, 4,6-diflorocyclohexanones bearing three stereocenters were also synthesized stereoselectively and in good yields.