A Highly Regio- and Stereoselective Synthesis of α-Fluorinated-Imides via Fluorination of Chiral Enamides

Abstract

A highly π-facial selective and regioselective fluorination of chiral enamides is described. The reaction involves an enantioselective fluorination exclusively at the electron-rich enamide olefin with N-F reagents such as Selectfluor^™ and N-fluoro-benzenesulfonimide [NFSI] accompanied by trapping of the β-fluoro-iminium cationic intermediate with water. The resulting N,O-hemiacetal could be oxidized using Dess-Martin periodinane, leading to an asymmetric sequence for syntheses of chiral α-fluoro-imides and optically enriched α-fluoro-ketones.

The importance of organo-fluorine compounds has been abundantly validated through a broad range of applications in medicinal chemistry and drug development¹ as well as material² and agrochemical sciences.³ The incorporation of fluorine and/or fluorine-containing groups into an organic compound has often provided agents and materials with unique chemical, physical, and biological properties.⁴ One of the major synthetic challenges in fluoro-organic chemistry is to asymmetrically construct fluorinated stereogenic carbon centers. Differding⁵ demonstrated the first stoichiometric asymmetric fluorination of β-ketoester enolates with a chiral N-F (N-fluoroamine) reagent in 1988. Given the number of impressive examples of enantioselective fluorinations being reported over the last decade,⁶ asymmetric fluorinations represent an area of immense interest from the synthetic community. In relevance to our work, Davis⁷ reported an elegant synthesis of α-fluoro-imides using enolate derived from chiral imide 1 substituted with chiral oxazolidinone auxiliary⁸ (1→2 in Scheme 1). Our longstanding interest in the chemistry of enamides has drawn us to develop stereoselective fluorination methods using chiral enamides,⁹ which has remained elusive. Such an approach in combination with an oxidative process (3→4) would represent a complementary approach to Davis’ asymmetric approach to α-fluoro-imides.

Scheme 1.

Stereoselective Synthesis of α-Fluoro-Imides

With the nitrogen atom being substituted with an electron withdrawing functionality, chiral enamides possess superior stability to their enamine counterparts, while maintaining excellent reactivities. This is evident by their recent emergence as another powerful chiral building blocks in organic synthesis.^10,11 In particular, chiral enamides have been employed in highly regio- and/or stereoselective Diels–Alder cycloadditions,¹² [2 + 2] cycloadditions,¹³ cy-clopropa-nation,¹⁴ epoxidation,¹⁵ and halo-etherification.¹⁶ We wish to report here a highly regio- and stereoselective fluorination of chiral enamides for the synthesis of chiral α-fluoro-imides and optically enriched α-fluoro-ketones.

Our efforts commenced with exploring the right fluorination conditions using chiral enamide 3a as the testing enamide, and with Selectflur^™,¹⁷ N-fluoropyridinium triflate [Py-F]¹⁸ and N-fluoro-benzenesulfonimide [NFSI]¹⁹ as the fluorinating agent. When reactions were carried out in CH₃CN at 40 °C, we found that it was faster with Select-flur^™ (entry 1 in Table 1) and much slower with Py-F (entry 2), and that NFSI was the best N-F reagent²⁰ in terms of diastereoselectivity, leading to α-fluoro-imides 4a and 4a’ as an isomeric mixture in 57% yield after DMP oxidation (entry 3).²¹ We note here that attempts to directly work-up the crude fluorination mixture without any oxidation protocols failed to give us the desired N,O-hemiacetal products, or the corresponding α-fluoro-aldehydes via hydrolysis.

Table 1.

Optimization of the Fluorination Conditions^a

entry	solvent	reagenta	time [h]	yield [%]b [dr]c
1	CH3CN	Selectfluor	0.5	29 [57:43]
2	CH3CN	Py-F	24	26 [61:39]
3	CH3CN	NFSI	9.5	57 [89:11]
4	anhyd CH3CNd	NFSI	8	<10 [85:15]
5	2.0 equiv H2O in CH3CN	NFSI	8	43 [89:11]
6	1 % H2O in CH3CN	NFSI	12	62 [91:9]
7	2 % H2O in CH3CN	NFSI	12	68 [91:9]
8	5 % H2O in CH3CN	NFSI	31	29 [91:9]
9e	2 % H2O in CH CN	NFSI	6	22 [71:29]

^aIn all reactions, 1.1 equiv N-F reagent was added. Unless otherwise noted, reactions were run at 40 °C. DMP: Dess-Marin Periodinane; NSFI: N-fluoro-benzenesulfonimide; Py-F: N-fluoropyridinium triflate;

^bYields were determined by ¹HNMR analysis using mesitylene as the internal standard.

^cDiastereomeric ratios [dr] were determined using ¹H or/and ¹⁹F NMR spectroscopy.

^dCH₃CN distilled over CaH₂.

^eThe reaction temperature is 80 °C.

Most notably, H₂O plays a significant role in this reaction. The use of anhydrous CH₃CN did afforded comparable diastereoselectivity, but the yield is very low (entry 4). The addition of 2.0 equiv, 1%, 2%, and 5% H₂O in the CH₃CN appeared to improve the efficiency (entries 5–8) with 2% H₂O being the most optimal (entry 7). On the other hand, when we increased the temperature from 40 °C to 80 °C, neither the dr ratio nor the yield was satisfactory.

To improve the diastereoselectivity, we examined a range of chiral auxiliaries as shown in Table 2. Enamide 3b with the i-Pr-substituted Evans chiral auxiliary²² gave α-fluoro-imide 4b in 58% yield with a 93:7 dr ratio. Fluorination of chiral enamide 3c substituted with the Sibi auxiliary²³ afforded 4c in 51% (entry 2). When using the Ph-substituted Evans auxiliary, fluorinations of 3d and ent-3d with NFSI at 40 °C in 2% H₂O in CH₃CN led to 4d and ent-4d, respectively, in good yields and essentially as a single diastereomer (entries 3 and 4). X-Ray structures of α-fluoro-imide 4b and ent-4d allowed for unambiguous assignment of both stereochemical and structural integrity (Figure 1).

Table 2.

Effect of the Chiral Auxiliary on Selectivity^a

entry	enamides	products	time [h]	yield [%]b[dr]c
1	3b	4b	14	58 [93:7]
2	3c	4c	12	51 [91:9]
3	3d	4d	12	72 [>95:5]
4	ent-3d	ent-4d	12	63 [>95:5]

^aReaction condition: 1.1 equiv NFSI, 2 % H₂O in CH₃CN, 40 °C; and then, DMP, NaHCO₃, CH₂Cl₂, rt.

^bIsolated yields.

^cDiastereomeric ratios [dr] were determined by ¹H or/and ¹⁹F NMR spectroscopy.

Figure 1.

X-Ray Structures of α-Fluoro-Imides 4b and ent-4d

Success in finding chiral amides that can provide a high level of diastereoselectivity allowed us to broaden the scope of this fluorination significantly as shown in Table 3. For all examples in which a variety of different R substituents were evaluated, and excellent diastereoselectivities of more than 92:8 ratio and middle to good yields were obtained. It is noteworthy that while electron-donating and electron-withdrawing substitutions groups at aryl does not influence on diastereoselectivity, with a strong electron-withdrawing group, reactions indeed took a much longer time (see entry 3). Lastly, although predictable, these asymmetric fluorinations can indeed be highly regioselective in favor of the electron-rich enamide-olefin as demonstrated with fluorinations of chiral enamides 7 and 9 (Scheme 2).

Table 3.

Stereoselective Fluorination of Chiral Enamides

entry	α–fluoro-imides: R =	time [h]	yield [%]a [dr]b
1	4-MeC6H4 (6a)	10	67 [94:4]
2	4-MeOC6H4 (6b)	12	42 [92:8]
3	4-NO2C6H4 (6c)	140	71 [>95:5]
4	4-FC6H4 (6d)	12	61 [>95:5]
5	4-ClC6H4 (6e)	12	65 [>95:5]
6	4-BrC6H4 (6f)	14	69 [95:5]
7	2-ClC6H4 (6g)	12	59 [>95:5]
8	n-Pent (6h)	11	53 [>95:5]

^aIsolated yields.

^bThe diastereomeric ratio [dr] was determined by ¹H or/and ¹⁹F NMR spectroscopy.

Scheme 2.

A Regioselective Fluorination

While synthetically this method represents a stereoselective approach for constructing chiral α-fluoro-imides, mechanistically, this fluorination provides some insight to the chemistry of chiral enamides. On the basis of the observed stereo-chemical outcome, a proposed mechanistic model is shown in Scheme 3. We had calculated that the most stable conformation of these chiral enamides being that the chiral oxazolidinone ring is essentially coplanar with alkene to maximize the delocalization of nitrogen lone pair into the olefin.²⁴ With this conformational preference, the chiral oxazolidinone auxiliary plays a distinct role in providing a key facial bias for the fluorine to approach from the Si-face as represented in ent-3d. Subsequent trapping of the N-acyl iminium ion A with water can in principle be stereoselective, but this stereochemical information is lost in the ensuing oxidation.

Scheme 3.

A Proposed Stereochemical Model

On the other hand, for Z-enamides such as 3e, predicted selectivity would be poor based on this conformational model. To alleviate the allylic strain shown in 3e, the chiral oxazolidinone ring needs to rotate away and can no longer be coplanar with the alkene, thereby leading much less differentiated π-faces [see C]. To support this model, we prepared Z-enamide 3e and found that not only is the yield of its fluorination inferior to those of E-enamides, but also diastereoselectivity is diminished significantly.

Lastly, as a useful synthetic application, we examined asymmetric fluorinations of trisubstituted enamides. As shown in Scheme 4, optically enriched 2-fluorocyclohexanone 13²⁵ could be obtained directly from trisubstituted enamide 11 after a simple work up with the fluorinated N,O-hemiacetal intermediate 12 being insufficiently stable for isolation. Likewise, the use of enamide 14 led to α-fluorinated aryl ketone 15 in 78% yield with an er of ≥95:5. This is in direct contrast with our earlier attempts to isolate α-fluoro-aldehydes via hydrolysis of the corresponding N,O-hemiacetal intermediate from fluorinations of disubstituted enamides.

Scheme 4.

Fluorinations of Trisubstituted Enamides

We have reported an asymmetric synthesis of α-fluoro-imides via fluorinations of chiral enamides. The reaction involves selectively fluorinating the electron-rich enamide olefin using Selectfluor^™ and N-fluoro-benzenesulfonimide [NFSI] followed by trapping of β-fluoro-iminium cationic intermediate with water and oxidation of resulting N,O-hemiacetal. From a practical perspective, the reaction is operationally simple, requires inexpensive reagents and mild conditions, and provides chiral α-fluoro-imides and optically enriched α-fluoro-ketones in good yields and high selectivities.