Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

Abstract

In the presence of a commercially available Cinchona alkaloid as catalyst, the asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates, with α-fluoro-β-keto esters as nucleophiles, have been successfully developed. A series of important fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, was achieved in good yields (up to 93%), with good to excellent enantioselectivities (up to 96% ee) and moderate diastereoselectivities (up to 4:1 dr).

Introduction

Fluorine is the most electronegative element in the periodic table, resulting in a highly polar C–F bond. This gives fluoro-organic compounds unique properties, compared with their parent compounds [1]. Due to the rareness of organofluorine compounds in nature, synthetic fluorinated compounds have been widely applied in numerous areas, including materials, agrochemicals, pharmaceuticals and fine chemicals [2–4]. In this context, the stereoselective introduction of fluorine atoms in molecules has become one of the most exciting and intense research areas in the recent years.

Lewis base-catalyzed asymmetric allylic alkylations (AAA) of Morita–Baylis–Hillman (MBH) adducts [5–6], such as acetates and carbonates, have become an attractive option to access various chiral C- [7–19], N- [20–25], O- [26–30], P- [31–33] and S-allylic [34] and spirocyclic compounds [35–37]. Several protocols have been established to introduce fluorine atoms in AAA of MBH adducts. For example, to introduce a CF₃ group, Shibata and co-workers [13] and Jiang and co-workers [14] successively reported the asymmetric allylic trifluoromethylation of MBH adducts with Ruppert’s reagent [(trifluoromethyl)trimethylsilane, Me₃SiCF₃] in the presence of (DHQD)₂PHAL as catalyst. In 2011, our research group [15], Shibata and co-workers [16] and Rios and co-workers [17] reported the addition of fluoromethyl(bisphenylsulfones) to MBH carbonates to access chiral monofluoromethyl derivatives. Furthermore, Rios and co-workers presented an asymmetric substitution of MBH carbonates with 2-fluoromalonates in good enantioselectivities [38]. Notably, the reaction between an achiral fluorocarbon nucleophile with MBH carbonates, to afford compounds with chiral quaternary carbon centres bearing a fluorine atom, remains a formidable task. Since 2009, we developed a highly enantioselective and diastereoselective guanidine-catalyzed conjugate addition and Mannich reaction of α-fluoro-β-ketoesters with excellent results [38–40]. Herein, we wish to report the first allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters in excellent enantioselectivities and moderate diastereoselectivities, furnishing enantiopure fluorinated compounds with chiral quaternary carbon centres containing a fluorine atom.

Results and Discussion

In the preliminary experiments, we investigated the reaction of α-fluoro-β-ketoester 1a with MBH carbonate 2a as the model substrate, in the presence of several commercially available Cinchona alkaloids as Lewis base catalysts (Table 1). First, the reaction was conducted in the presence of quinine at 50 °C in dichloroethane (DCE) as the solvent (Table 1, entry 1). The desired adduct 3aa was obtained in 53% yield with poor enantio- and diastereoselectivity. Cinchonine provided similarly poor results (Table 1, entry 2). Next, we screened a series of C₂-symmetric bis-Cinchona alkaloids as catalysts under the same conditions (Table 1, entries 3–7). (DHQD)₂PHAL showed moderate catalytic activity; 3aa was obtained in 67% yield with 71% ee and 60:40 dr (entry 3). The effects of solvent were then investigated (Table 1, entries 8–18). The best-performing solvent was mesitylene with respect to enantio- and diastereoselectivity; providing 3aa in 78% yield with 89% ee and 71:29 dr (entry 18). The reaction temperature can be decreased to 25 °C and 67% yield of 3aa with 92% ee and 74:26 dr was obtained (entry 19). A slight increase in enantio- and diastereoselectivity could be obtained when the reaction temperature was decreased to 10 °C, but the reaction rate became too sluggish to be useful (Table 1, entry 20).

Table 1.

Catalyst screening^a.

Entry	Catalyst	Solvent	Yield (%)b	ee (%)c	drc
1	quinine	DCE	53	32 (27)	55:45
2	cinchonine	DCE	59	21 (10)	55:45
3	(DHQD)2PHAL	DCE	67	71 (57)	60:40
4	(DHQD)2AQN	DCE	53	–5 (–5)	56:44
5	(DHQ)2PHAL	DCE	64	–35 (–1)	52:48
6	(DHQ)2PYR	DCE	60	–25 (–1)	59:41
7	(DHQ)2AQN	DCE	47	–11 (–10)	55:45
8	(DHQD)2PHAL	DCM	56	69 (55)	58:42
9	(DHQD)2PHAL	toluene	78	85 (65)	67:33
10	(DHQD)2PHAL	Et2O	59	45 (30)	55:45
11	(DHQD)2PHAL	EA	58	55 (30)	55:45
12	(DHQD)2PHAL	THF	61	31 (49)	63:37
13	(DHQD)2PHAL	MeCN	57	49 (19)	65:35
14	(DHQD)2PHAL	MeOH	63	35 (20)	60:40
15	(DHQD)2PHAL	o-xylene	74	85 (65)	72:28
16	(DHQD)2PHAL	m-xylene	65	87 (74)	70:30
17	(DHQD)2PHAL	p-xylene	72	85 (55)	68:32
18	(DHQD)2PHAL	mesitylene	78	89 (72)	71:29
19d	(DHQD)2PHAL	mesitylene	67	92 (69)	74:26
20e	(DHQD)2PHAL	mesitylene	45	94 (55)	75:25

^aUnless otherwise noted, reactions were performed with 0.05 mmol of 1a, 0.15 of 2a, and 0.005 mmol of catalyst in 0.5 mL solvent. ^bYield of isolated product. ^cDetermined by HPLC methods. The data in parenthesis is the ee value of the minor diastereoisomer ^dThe reaction was conducted at 25 °C, 1.0 mmol scale in 1.0 mL of mesitylene. ^eThe reaction was conducted at 10 °C, 1.0 mmol scale in 1.0 mL of mesitylene.

Using the established conditions, allylic alkylations of α-fluoro-β-ketoesters 1b–g with MBH carbonate 2a were found to afford the products 3ba–ga in 67–79% yield with 88–96% ee and 3:1 to 4:1 dr (Table 2, entries 1–6). The results showed that the introduction of various aryl substituents in α-fluoro-β-ketoesters did not affect the reactivity and stereoselectivity. Subsequently, the scope of the allylic alkylation with respect to various MBH carbonates 2 and α-fluoro-β-ketoester 1a was investigated (Table 2, entries 7–20). The desired allylic alkylation adducts 3ab–o were achieved in moderate to good yields with good to excellent enantioselectivities and moderate diastereoselectivities. MBH carbonates (Table 2, 2b–k) with electron-withdrawing groups appended on the aromatic rings were more active than those (Table 2, 2l–m) with electron-neutral and donating groups. Excellent ee values with moderate dr values were obtained when the phenyl groups of MBH carbonates were replaced with hetereoaromatic groups, such as thiophene and furan (Table 2, 2n–o).

Table 2.

Allylic alkylation of α-fluoro-β-ketoesters 1 with MBH carbonates 2^a.

Entry	Ar1, 1	Ar2, 2	Time (h)	3	Yield (%)b	ee (%)c	drd
1	p-FPh, 1b	Ph, 2a	40	3ba	71	88	3:1
2	p-ClPh, 1c	Ph, 2a	70	3ca	79	93	3:1
3	p-BrPh, 1d	Ph, 2a	70	3da	75	96	3:1
4	m-BrPh, 1e	Ph, 2a	70	3ea	72	90	3:1
5	3,5-Cl2Ph, 1f	Ph, 2a	70	3fa	69	88	3:1
6	p-MePh, 1g	Ph, 2a	50	3ga	67	94	4:1
7	Ph, 1a	p-NO2Ph, 2b	70	3ab	91	95	3:1
8	Ph, 1a	p-CF3Ph, 2c	70	3ac	65	87	4:1
9	Ph, 1a	p-FPh, 2d	70	3ad	71	90	3:1
10	Ph, 1a	p-ClPh, 2e	70	3ae	73	93	4:1
11	Ph, 1a	p-BrPh, 2f	96	3af	64	91	4:1
12	Ph, 1a	m-NO2Ph, 2g	96	3ag	93	95	3:1
13	Ph, 1a	m-ClPh, 2h	70	3ah	81	91	3:1
14	Ph, 1a	m-BrPh, 2i	70	3ai	78	90	4:1
15	Ph, 1a	o-FPh, 2j	96	3aj	73	86	4:1
16	Ph, 1a	o-ClPh, 2k	70	3ak	84	86	4:1
17	Ph, 1a	p-MePh, 2l	70	3al	53	91	4:1
18	Ph, 1a	p-MeOPh, 2m	70	3am	50	91	3:1
19	Ph, 1a	2-thienyl, 2n	90	3an	78	92	4:1
20	Ph, 1a	2-furyl, 2o	96	3ao	73	84	3:1

^aReactions were performed with 0.1 mmol of 1, 0.3 mmol of 2, and 0.005 mmol of (DHQD)₂PHAL in 1.0 mL mesitylene. ^bYield of isolated product. ^cDetermined by chiral HPLC on the major diastereoisomer. ^dDetermined by ¹H NMR analysis.

Conclusion

We have developed an asymmetric allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters, catalyzed by a commercially available Cinchona alkaloid. Several fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, were successfully prepared in 50–93% yields with 84–96% ee and a dr of 3:1 to 4:1. The absolute configurations of adducts still have to be determined and will be reported in due course.

Experimental

Representative procedure for the synthesis of 3aa: α-Fluoro-β-ketoester 1a (21.0 mg, 1.0 equiv, 0.1 mmol) and (DHQD)₂PHAL (7.8 mg, 0.1 equiv, 0.01 mmol) were dissolved in mesitylene (1.0 mL) at 25 °C. After the addition of MBH carbonate 2a (3.0 equiv, 0.3 mmol) the reaction mixture was stirred at 25 °C. The reaction was monitored by TLC. After 96 hours, flash chromatography affords product 3aa (25.7 mg, 67% yield) as colorless oil.

Supporting Information

File 1

Experimental details and spectroscopic data.

This article is part of the Thematic Series "Transition-metal and organocatalysis in natural product synthesis".