A New Difluoromethylene Linchpin/Synthon. Application in Conjunction with Anion Relay Chemistry (ARC) Permits Ready Access to Diverse Difluoromethylene Scaffolds

Abstract

Organodifluorine synthons, in conjuction with three-component diastereoselective Anion Relay Chemistry (ARC), permit ready access to diverse difluoromethylene scaffolds. Initiated via [1,2]-addition of an organolithium reagent to a β-difluoromethylene silyl aldehyde, an alkoxide intermediate is formed, which is capable of undergoing a [1,4]-Brook rearrangement to generate a stabilized α-difluoromethylene carbanion, which upon electrophile capture, affords a three-component adduct. This three component synthetic tactic represents a novel one-pot divergent strategy for the construction of diverse organodifluorine containing compounds.

Graphical Abstract

Organofluorine compounds are ubiquitous in modern society, with polyfluorotetraethylene (PFTA) polymers and hydrofluorocarbon (HFC) refrigerants seeing widespread use.¹ Over the last several decades, the role of fluorine in small molecule therapeutics has gained significant attention, with approximately 20% of approved active pharmaceutical ingredients and 35% agrochemicals containing at least one fluorine atom.² The strong polarization of the C – F bond, in conjunction with the short bond length and small Van der Waals radius of the fluorine atom, results in a variety of useful properties.³ In medicinal chemistry, these properties manifest in myriad ways, permitting fluorine to serve as a bioisostere,⁴ to modify the basicity and acidity of adjacent functional groups,⁵ to effect the solubility of compounds,⁶ to alter metabolism,7 and/or to control the conformation of structures,⁸ among other attributes.

Accordingly, numerous methods for the incorporation of fluorine atoms into organic compounds have been developed, which utilize either direct or indirect fluorination tactics, either adding a single fluorine atom, for instance employing DAST or SelectFluor, or an activated organofluorine reagent such as the Ruppert-Prakash reagent (TMS-CF₃).⁹ However, most existing fluorination methods employ mono-valent synthons, which in general permit only linear syntheses (Figure 1a). Ideally, fluorination could be performed as a convergent synthetic step, permitting the reaction to serve as a point of diversification, which is often desirable from the perspective of the medicinal chemist. Recently, Dilman has exploited di-valent difluoromethylene synthons for use in multi-component coupling tactics (Figure 1b).¹⁰ While highly effective, this method lacks a broad scope of coupling partners and requires multiple steps to achieve.

Figure 1.

(a) Fluorination synthons; (b) Prior coupling tactic employing a dianion synthon; (c) fluoroorganic synthon and three-component coupling tactic via Type II Anion Relay Chemistry (ARC).

We reasoned that a one-pot three-component union (Figure 1c) could be achieved by employing an ambiphilic linchpin in which the anionic carbon is stabilized by geminal fluorine substituents, in a tactic comprising [1,2]-addition of an organolithium reagent to aldehyde linchpin 1 to afford an alkoxide intermediate (2). Subsequent [1,4]-Brook rearrangement of alkoxide 2 with electrophile capture could then afford a three-component adduct (3), with the relative stereochemistry of the Anion Relay Chemistry (ARC) adduct under Felkin-Anh stereocontrol.¹¹ Such a method would hold great promise if: (a) the scope of each component is broad, (b) the diastereoselectivity is high, (c) the reaction is performed in a single pot, and (d) the linchpin is readily constructed.

We set out first to validate a synthetic route to access diverse difluoro-linchpins (1), which would be amenable to varied substitution at the α-position. Drawing inspiration from the work of Mikami and co-workers,¹² we sought to construct β-difluoro-linchpins via a direct α-silyldifluoro-methylation of an oxazolidinone derived lithium enolate. Initially, oxazolidinone 4 was acylated with an acid chloride to afford 5 (Scheme 1). Next, the lithium enolate of 5 was generated with LiHMDS and subsequently α-silyldifluoro-methylated, to furnish 6 as a single diastereomer. The absolute stereochemistry of 6 was determined unambiguously by X-ray crystallography (Supporting Information). The desired linchpin was then obtained via reduction of oxazolidinone 6 with LiAlH₄ to provide 7, followed by oxidation with Dess-Martin Periodinane (DMP) to afford 8 in good yield.

Scheme 1.

Linchpin synthesis

With the desired linchpin 8 in hand, we next sought to validate the proposed reaction sequence (Figure 2). High diastereoselectivity of the initial [1,2]-addition was deemed critical for the utility of this transformation. We thus first performed the initial [1,2]-addition of n-BuLi to linchpin 8 at −78 °C in Et₂O, with subsequent reaction with HCl in Et₂O to arrive at alcohols 9a and 9b as separable diastereomers. High diastereoselectivity was observed (9:1 by ¹H-NMR analysis), with the absolute configuration of 9a determined by Mosher ester analysis, demonstrating that Felkin-Anh diastereoselectivity was operative.¹³ Next, deprotonation of 9a was achieved with n-BuLi at −78 °C in Et₂O, and benzaldehyde added. The envisioned [1,4]-Brook rearrangement was then triggered via the use of the polar additive HMPA. Pleasingly, tricomponent adduct 10 was obtained in 72% yield as an expected 1:1 mixture of diastereomers at the benzylic position. Having demonstrated the proof-of-concept via a two-pot ARC sequence utilizing 9a, we next turned our attention to validation of the one-pot, three-component coupling ARC tactic. To this end, employing the defined conditions, three-component adduct 10 was observed as the major product from the one-pot sequence in 64% yield.

Figure 2.

Stepwise evaluation of ARC sequence

Having validated the ARC sequence, we turned to explore the electrophile scope. Reactions were performed using n-BuLi as the nucleophile and linchpin 8, with a variety of electrophiles (Figure 3). Evaluation of (E)-cinnamaldehyde as an electrophile demonstrated that α,β-unsaturated aldehyde electrophiles are amendable to the ARC sequence to provide allyl alcohol 11a. Next, a series of alkyl halide electrophiles were employed, with MeI affording 11b in good yield and benzyl and allyl bromide affording three-component adducts 11c and 11d in modest yield. Pleasingly, enantioenriched sulfonyl imine electrophiles also served as successful electrophiles in the ARC sequence, providing β-difluoroamine substrates as three-component adducts as single diastereomers; both (S)- and (R)-phenyl sulfonyl amine furnished ARC adducts 11e and 11f with high diastereoselectivity in moderate yield. Additionally, employing the (R)-α,β-unsaturated sulfonyl imine of cinnamaldehyde permitted access to β-difluoro-allyl amine 11g in 62% yield. Thus, this ARC tactic holds the promise of a viable method for the construction of enantioenriched β-difluoroamines, for which limited methods are currently available.¹⁴

Figure 3.

Electrophile scope^a

^an-BuLi (1.0 eq); linchpin (1.0 eq); electrophile (2.0 eq); TBAF deprotection of crude product;^bdiastereomeric ratio pertains to α-position of amine

At first glance it may appear that the three-component adducts obtained from aldehyde electrophiles are less than ideal, as there is no diastereoselectivity in the second [1,2]-addition. However, such diol products can be used to access difluorocyclopentyl ketals (Scheme 2). Similar pseudo-pentose structural motifs are found in a number of bioactive compounds, such as the approved drug Gemcitabine (Gemzar^™). For example, benzylic oxidation of 10 with MnO₂ leads spontaneously to ketal formation to arrive at 12, as a 4:1 mixture of diastereomers in excellent yield. A similar strategy may be adapted to permit the synthesis of other difluorocyclopentyl ketals from the corresponding aldehyde adducts.

Scheme 2.

Difluorocyclopentyl ketal synthesis

Next, our attention turned to the scope of organolithium reagents that could be employed as initiating nucleophiles in this ARC sequence. Standard reaction conditions were employed, utilizing linchpin 8 to evaluate a variety of organolithium reagents (Figure 4). Having demonstrated that n-butyllithium with methyl iodide as the electrophile is amenable to the ARC tactic, we attempted commercially available PhLi. Accordingly, the three-component adduct 13a was obtained as a single diastereomer in moderate yield. Vinyl- and alkynyllithium reagents were also successfully employed to afford allyl- and propargyl alcohols 13b and 13c in moderate to good yield and with high diastereoselectivity. Equally pleasingly, lithiated 1,3-dithiane can be utilized successfully in the ARC sequence, permitting the incorporation of this versatile functionality in adduct 13d. Thus, alkyl, vinyl, alkynyl, aryl, and dithianyllithium reagents comprise viable nucleophiles in this three-component ARC coupling tactic.

Figure 4.

Nucleophile scope^a

^aNu-Li (1.0 eq); linchpin (1.0 eq); MeI (2.0 eq); TBAF deprotection of crude product;

Arguably, the most significant aspect of this coupling tactic would be the tolerance on variability of the linchpin. At this juncture, we had examined exclusively the viability of linchpin 8, bearing an α-Me substitution. While this substitution is useful for polyketide synthetic targets, larger substituents or functional handles would serve to provide access to a more diverse pool of difluoromethylene scaffolds. We therefore set out to examine several linchpins with varied α-substitution. For the evaluation of linchpins 8a-8d, standard reaction conditions were employed, utilizing n-BuLi as the nucleophile and MeI as the electrophile. Increasing the size of the substituent from Me to Et had a small negative effect on yield, arriving at the three-component adduct 14a in 63% yield. Olefin moieties were well tolerated at the α-position, affording homoallyl and allyl products 14b and 14c. Pleasingly, Ph and vinyl α-substitutions were also well tolerated, despite the expected increased acidity of the corresponding linchpins. Furthermore, the synthesis of three-component adduct 14d demonstrates that this ARC methodology is amenable to both epimers of the linchpins.

A number of synthetic methods are predicated upon the manipulation of difluoromethyl radicals.¹⁵ The σ-withdrawing, π-donating properties of the fluorine atom permit access to difluoromethyl radicals, anions,¹⁶ and carbenes.¹⁷ Mechanistic studies were performed to provide support in this case for an anionic reaction mechanism for the [1,4]-Brook rearrangement with alkylation (Scheme 3). Here, the principle concern was the [1,4]-Brook rearrangement, rather than the [1,2]-carbonyl addition. Thus, the ARC sequence was entered via the deprotonation of alcohol 9a. Next, the [1,4]-Brook rearrangement was triggered via the addition of a solution of benzaldehyde in Et₂O/HMPA, with or without an equivalent of TEMPO. In both cases, three-component adduct 10 was obtained in good yield. Additionally, TEMPO adduct 15 was not identified in the trapping experiment. Next, to offer support for a [1,4]-Brook rearrangement we demonstrated the isolation of silyl ether ARC product 16. The labile nature of TMS ethers led us to remove this group prior to purification for simplicity. However, isolation of 16 here demonstrates that C – Si to O – Si migration indeed occurs.

Scheme 3.

Mechanistic studies

In summary, we disclose here a new ambiphilic organodifluoromethylene synthon which can be employed in a three-component ARC coupling tactic to afford a variety of difluoromethylene adducts with high diastereoselectivity. Moreover, we have disclosed a synthetic route that permits access to these β-difluorosilyl aldehyde linchpins in which the α-substituent and absolute stereochemical configuration can be readily achieved by selecting the appropriate acid chloride and oxazolidione substrates, respectively, many of which are commercially available. The value of this synthon and the corresponding three-component coupling tactic is also apparent in the great variety of nucleophiles, linchpins, and electrophiles that can be employed. Thus, one can envision numerous difluoromethylene scaffolds that can be prepared employing this tactic as a key disconnection, which may otherwise be laborious to construct.

Figure 5.

Scope of linchpin substrates^a

^an-BuLi (1.0 eq); linchpin (1.0 eq); MeI (2.0 eq); TBAF deprotection of crude product; linchpins: R = Et (8a); allyl (8b); vinyl (8c); Ph (8d); Me (8).