Photoredox-Catalyzed Multicomponent Petasis Reaction with Alkyltrifluoroborates

Abstract

A redox-neutral alkyl Petasis reaction has been developed that proceeds via photoredox catalysis. A diverse set of primary, secondary, and tertiary alkyltrifluoroborates participate effectively in this reaction through a single-electron transfer mechanism, in contrast to the traditional two-electron Petasis reaction, which accommodates only unsaturated boronic acids. This protocol is ideal to diversify benzyl-type and glyoxalate-derived aldehydes, anilines, and alkyltrifluoroborates toward the rapid assembly of libraries of higher molecular complexity important in pharmaceutical and agrochemical settings.

Graphical Abstract

Multicomponent reactions (MCRs) have emerged as powerful transformations to condense three or more partners to deliver novel scaffolds with inherent molecular complexity.^[1] The advantages of MCRs include the preservation of atom- and step economies, shorter reaction times, and the ability to access highly diverse chemical space rapidly and efficiently. These integral benefits make MCRs highly attractive for diversity-oriented synthesis of small molecule libraries in drug discovery,^[2] as well as in a variety of other useful endeavors.^[3]

Presently, the tool box of a synthetic chemist is composed of many MCRs, including Mannich,^[4] Biginelli,^[5] Passerini,^[6] and Ugi transformations.^[7] The Petasis reaction^[8] is another such reaction, and is perhaps unique by virtue of its generation of amines and amino acid derivatives with pivotal activity in biology. The majority of traditional Petasis applications require adjacent heteroatoms as directing groups to form the key boron “ate” complex intermediate (Scheme 1a).^[9] This initial complexation is followed by an irreversible, two-electron nucleophilic addition to an imine or iminium ion intermediate, stemming from a condensation reaction of the aldehyde and amine. The propensity of the boron “ate” complex to migrate depends on its ability to stabilize negative charge: alkynyl > aryl ≈ alkenyl > alkyl.^[10] Thus, the traditional Petasis reaction is restricted to alkenyl, aryl, alkynyl, allyl, benzyl, and allylic boronic acid derivatives.^{[8, 9]} As far as we are aware, there are no reports of multicomponent Petasis reactions using alkylboron derivatives. A widely utilized alternative approach to amines stemming from two-electron nucleophilic addition to imines or iminium ions uses strongly nucleophilic organometallic reagents.^[11] These transformations, however, rely on harsh reaction conditions that compromise functional group tolerability, restricting their widespread use in late-stage functionalization of complex molecules. It is also important to note that the formation of water as a byproduct under a multicomponent platform would hinder the efficacy of these pyrophoric reagents. In the context of single-electron transfer (SET) in the multicomponent Petasis reaction, the only examples reported require preformed imines^[12] or the use of stoichiometric indium as a reductant with limited scope, being restricted to secondary alkyl iodides.^[13]

Scheme 1. Mechanistic Rationale: SET-based Petasis reaction and phenylalkyl amine bioactive molecules.

Other SET approaches to C═N bond alkylation, including Minisci reactions, are well documented.^[14] Our group, as well as others, recently demonstrated that photoredox catalysis enables the generation of alkyl radicals from organotrifluoroborates, while maintaining broad functional group tolerance.^[15] Given the robust stability of alkyl radicals to aqueous conditions, a photoredox approach to a multicomponent Petasis-type reaction would appear feasible. We envisioned that a suitable photocatalyst in its excited state ([PC]*, II) would initiate the process by oxidizing an alkyltrifluoroborate IV to the desired alkyl radical V (Scheme 1b), generating BF₃ as a byproduct. The radical V could then add to the in situ condensed imine VIII to form the amine radical cation IX. A subsequent reduction of IX by the reduced state of the photocatalyst III terminates the photocatalytic cycle. The use of trifluoroborates as radical precursors was viewed as critical for the success of the proposed protocol, because the BF₃ Lewis acid generated in the SET process was anticipated to facilitate the condensation between the aldehyde and the amine, and could also activate the resultant imine toward radical addition.

Relevant to the present investigation, the Doyle^[16] and Gaunt^[17] groups recently reported elegant multicomponent reactions to access benzhydryl amines as well as tertiary amines, respectively. In a unique transformation, Li reported a Ru-catalyzed addition of aldehydes to preformed aryl imines, accessing phenylalkyl amines. The scope of this process was restricted predominantly to benzaldehydes.^[18] The multicomponent synthesis of analogous phenylalkyl amines is thus underexplored.

After a systematic survey of reaction parameters (see Supporting Information), we were able to identify suitable reaction conditions. Thus, in exploratory studies a mixture of methyl 4-formylbenzoate (1), aniline (2, 1.5 equiv), and potassium cyclohexyltrifluoroborate (3, 1.5 equiv), was catalyzed by [Ir{dF(CF₃)ppy}₂(bpy)]PF₆ (2 mol %, E_1/2^red[*Ir^III/Ir^II] = +1.32 V vs. SCE)^[19] in the presence of sodium bisulfate (1.0 equiv) in 1,4-dioxane (0.1 M) (Scheme 2). The desired product (4) was afforded in 84% isolated yield under irradiation with blue LEDs for 24 hours at rt.^{[20, 21]} In expanding the method, diverse secondary alkyltrifluoroborates, including heteroaromatic-based systems, were found to be amenable substrates in this transformation. In the heteroaromatic substructures (e.g., 10), no Minisci byproduct was detected. Sterically disfavored tertiary alkyltrifluoroborates gave excellent yields (12, 13). Surprisingly, primary aliphatic alkyltrifluoroborates, with a markedly higher oxidation potential (E_1/2^red = +1.90 V vs. SCE)^[22] reacted well under the reaction conditions (14-16).

Scheme 2. Scope of alkyltrifluoroborates, aldehydes and anilines^a.

^a Reaction conditions: aldehyde (0.5 mmol), alkyltrifluoroborate (0.75 mmol), aniline (0.75 mmol), [Ir{dF(CF₃)ppy}₂(bpy)]PF₆ (0.01 mmol), NaHSO₄ (0.5 mmol) and 1,4-dioxane (5 mL) under blue LED irradiation for 24 h. Isolated yields are given. ^bIrradiated by 34 W Kessil lamp.

Assessing the aldehyde scope, halo-substituted benzaldehyde derivatives whose products are suitable for further processing provided the targets in good yield (25-27). The reaction is highly chemoselective. In a dicarbonyl substrate, only the aldehyde derivative reacted, while the ketone remained untouched (24). Electron-donating groups are amenable structural motifs (32-37). Given that heteroarenes represent prevalent substructures in pharmaceutically relevant molecules,^[23] a variety of such systems were evaluated and proved to be effective partners (38–43). Additionally, an unnatural α-amino acid derivative is accessible using glyoxyl aldehyde instead of a benzaldehyde derivative (44).

Next, we turned our attention to the aniline partner, where a wide array of functional groups was tolerated, such as chloro (45, 46, 49, 50), trifluoromethyl (47), ester (48), and methoxy (54). The electronic effect on the aniline component was inconspicuous. Meanwhile, the reactions were not sensitive to steric hindrance at the ortho position of the aniline (52, 53).

To demonstrate the utility of this protocol for late-stage modification of intricate molecules, we prepared benzaldehyde derivatives from commercially available drug cores.^[24] Both Indomethacin and Fenofibrate were successfully converted to the corresponding products in excellent yields (55, 56). Sulfadimethoxine was also elaborated with acceptable yield, especially considering its high functional group density (57). To highlight the application of this photoredox alkyl Petasis reaction further, we utilized this method to expedite the synthesis of a key intermediate toward a Pfizer glucagon receptor modulator (Scheme 3b).^[25] The key intermediate (60) was assembled with good yield in one step using this newly developed, convergent MCR reaction.

Scheme 3. Late-stage functionalization of pharmaceutical analogues and modular bioactive molecule synthesis^a.

^a See Supporting Information for details.

To highlight the amplification of this method, a transformation was successfully performed on a larger scale, whereby the desired product 54 was obtained in 51% yield, in agreement with the small-scale reaction. It is worth indicating that the para-methoxyphenyl (PMP) group of 54 could be readily removed by ceric ammonium nitrate (CAN) oxidation to release the primary amine (61).^[26]

To probe the reaction pathway, we conducted preliminary mechanistic studies. The ring-opening product was exclusively observed when potassium (cyclopropylmethyl)trifluoroborate was used as the starting material (Scheme 4a). In the presence of the radical scavenger TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl], the reaction was completely inhibited, and a TEMPO-alkyl adduct was isolated, as well as the imine (Scheme 4b). This is suggestive of the involvement of alkyl radical generation under this reaction manifold. When the preformed imine was used instead of the aldehyde/aniline partners, a yield similar to that obtained in the multicomponent reaction was observed (Scheme 4c). Furthermore, during the course of the reaction, the reductive dimerization byproduct of the imine was not observed.^[27] Although Stern-Volmer studies indicate no significant quenching of the excited state of the photocatalyst (E_1/2^red [Ir^IV/*Ir^III] = −1.00 V vs. SCE)^[19] by the imine intermediate, we cannot rule out the possibility of direct reduction of the imine (E_1/2^red= −1.91 V vs. SCE)^{[14e, 28]} by the reduced state of the photocatalyst (E_1/2 [Ir^III/Ir^II] = −1.37 V vs. SCE).^[19] In particular, variabilities in reaction concentration and pH levels could exert an impact on redox potential values.^[29]

Scheme 4. Large-scale reaction and removal of the PMP group^a.

^aSee Supporting Information for details.

In conclusion, a multicomponent alkyl Petasis reaction under photoredox conditions has been developed. This procedure employs bench stable, commercially available alkyltrifluoroborates, easily accessible benzaldehydes, and anilines as feedstock. Taking advantage of the stability of alkyl radicals in water, preformed imines are no longer required, providing a highly step-efficient process that should be amenable to the industrial setting. Other favorable factors include the elimination of harsh reaction conditions (elevated temperatures and strong organometallic reagents), and the toleration of an exceptional array of functional groups as well as complex structural scaffolds. The facile diversification inherent in this MCR positions this technology as being extremely suitable for diversity-oriented synthesis in drug discovery scenarios.

Scheme 5. Preliminary mechanistic studies^a.

^aSee Supporting Information for details.