Photocatalytic [2+2] Cycloadditions of Enones with Cleavable Redox Auxiliaries

Abstract

α,β-Unsaturated 2-imidazolyl ketones undergo [2+2] cycloaddition with a variety of Michael acceptors upon irradiation with visible light in the presence of Ru(bpy)₃²⁺. Cleavage of the imidazolyl auxiliary from the cycloadducts affords cyclobutane carboxamides, esters, thioesters, and acids that would not be accessible from direct cycloaddition of the corresponding unsaturated carbonyl compounds.

Cyclobutanes are synthetically interesting both because of the diverse structures of cyclobutane-containing natural products¹ and because of the utility of strain-releasing ring-fragmentations in the preparation of more complex medium-sized ring systems.² Conventional photochemical methods³ for the synthesis of cyclobutanes are generally efficient only when cyclic enones are utilized; the triplet excited state of acyclic enones undergoes a rapid, energy-wasting olefin isomerization that outcompetes productive intermolecular cyclizations.⁴ We recently reported that Ru(bpy)₃²⁺ complexes are useful photocatalysts for the [2+2] cycloadditions of aryl enones upon irradiation with visible light.^5,6 This method avoids the formation of the problematic triplet excited state of the enone and thus works well with acyclic enones. However, we found the scope of this method to be limited; the involvement of an aryl enone in the reaction was found to be a strict requirement for successful cycloaddition.

We proposed a mechanism for the cycloaddition that rationalizes this constraint (Scheme 1). The key reactive intermediate in this process is an enone radical anion generated by single electron transfer from a photogenerated Ru(bpy)₃⁺ complex⁷ to a Lewis acid activated enone. The one-electron reduction of aryl enones is significantly more facile than the corresponding reduction of less-conjugated enone substrates. Enoate esters, for example, possess reduction potentials ca. 700 mV more negative than aryl enones,⁸ which precludes formation of the corresponding enoate radical anions under these photocatalytic conditions.

Scheme 1.

Mechanism of radical anion [2+2] cycloaddition.

We wondered if we might circumvent this limitation in scope by installing a cleavable auxiliary group onto the enone substrate that (1) would facilitate one-electron reduction and subsequent cycloaddition of the enone substrate and (2) could be transformed into a carboxylic acid, ester, amide, or similar carbonyl-containing functional group after the cycloaddition. This cleavable group might be considered a “redox auxiliary”^9,10 that temporarily modulates the reduction potential of an otherwise redox-inactive enoate substrate, just as a chiral auxiliary temporarily differentiates the prochiral faces of an otherwise achiral substrate.

Table 1 summarizes our studies to identify a suitable redox auxiliary for the [2+2] cycloaddition. We examined the homodimerization of a number of α,β-unsaturated carbonyl compounds that have been validated as surrogates of carboxylate esters in other synthetic methods. Upon exposure to the conditions we had optimized for intermolecular [2+2] cycloaddition of aryl enones, unsaturated acyl phosphonates¹¹ underwent rapid decomposition (entry 1). N-Acyl pyrroles¹² and pyrazoles¹³ reacted sluggishly and gave unsatisfactory yields of the corresponding dimerized cyclobutanes (entries 2 and 3). On the other hand, α,β-unsaturated 2-acylimidazoles¹⁴ reacted smoothly and furnished the desired [2+2] cyclodimer in 82% yield.¹⁵ We therefore elected to continue our studies using enones bearing an N-methylimidazol-2-yl auxiliary group.

Table 1.

Dimerizations of candidate enones^a

entry	substrate	yield
1		0%
2		16%
3		<5%
4		82%

^aReactions performed with 5% Ru(bpy)₃Cl₂, 2.0 equiv LiBF₄, 2.0 equiv i-Pr₂NEt in 0.1 M MeCN. Molar ratios for intermolecular dimerizations calculated with respect to theoretical yield of product (e.g., 2.5 mol % catalyst with respect to enone).

Next, we studied the crossed intermolecular [2+2] cyclization of acyl imidazole 1 with methyl acrylate (Table 2). The conditions we had previously reported for [2+2] cycloaddition of phenyl enones with methyl acrylate afforded only 43% of the desired crossed cycloadduct in 5:1 dr (entry 1); the undesired homodimerization of 1 was a significant competitive process. Higher concentrations of the Lewis acidic additive (LiBF₄) increased the dr without increasing the yield of 3, while lower Lewis acid loadings favored homodimerization (entries 2 and 3). We observed a modest increase in selectivity for the heterodimer when the catalyst loading was lowered to 2.5 mol % (entry 4). The best yield and highest d.r. were obtained when 1 was added slowly via syringe pump to the reaction mixture, which presumably minimizes the homodimerization by minimizing the concentration of 1 with respect to methyl acrylate while keeping the ratio of Lewis acid to substrate high. By using this slow addition protocol, the desired heterodimer 3 could be isolated in 67% yield and with excellent diastereoselectivity (entry 6).

Table 2.

Optimization studies.^a

entry	mol % Ru	equiv LiBF4	% yield 2b	% yield 3 (dr) b
1	5.0	2	24	43 (5:1)
2	5.0	4	13	42 (10:1)
3c	5.0	0.5	50	21 (2:1)
4d	2.5	2	19	51 (5:1)
5e	2.5	2	<5	67 (>10:1)

^aReactions performed with 2.0 equiv i-Pr₂NEt in 0.1 M MeCN, and indicated amounts of photocatalyst and LiBF₄ with respect to the theoretical yield of product 3 and an irradiation time of 90 min.

^bIsolated yields with respect to theoretical yield of 2 or 3, respectively.

^cIrradiated for 120 min.

^dIrradiated for 150 min.

^eAryl enone added dropwise over a 45 min period.

Figure 1 summarizes experiments probing the scope of the crossed intermolecular [2+2] cycloaddition using 2-acyl imidazoles. A variety of Michael acceptors, including α,β-unsaturated esters, thioesters, and ketones, provided good yields and high diastereoselectivites in cycloadditions with 1 (Figure 1, 3–5). As we had observed in our previous studies, high selectivity for the crossed cycloadduct requires the use of a β-unsubstituted Michael acceptor as the reaction partner. However, β-substitution on the acyl imidazole is easily accomodated. Substrates of increased steric demand worked well in this reaction (6–8), and protected heteroatomic functional groups were tolerated under optimized reaction conditions (9–11).

Figure 1.

Scope of the intermolecular coupling reaction.a,b

^a Unless otherwise noted, reactions performed with 5.0 equiv Michael acceptor with respect to 1.0 equiv of aryl enone, 2.5 mol % Ru(bpy)₃Cl₂, 2.0 equiv LiBF₄, 2.0 equiv i-Pr₂NEt in 0.1 M MeCN; aryl enone added dropwise over a 45 min period. ^b Isolated yields and diastereomer ratios are the averaged results of two reproducible experiments. ^c 0.5 equiv LiBF₄. ^d 4.0 equiv LiBF₄; aryl enone was added in one portion.

We also explored intramolecular [2+2] cycloadditions of 2-acylimidazoles. In these experiments, we observed somewhat higher yields when the loading of LiBF₄ was reduced to 0.5 equiv. These conditions enabled intramolecular cycloadditions with a variety of acceptor moieties, including esters, ketones, and amides (Figure 2, 12–15). The use of an α-substituted Michael acceptor required prolonged reaction times, but the expected cycloadduct bearing a quaternary stereocenter (16) was produced with excellent diastereoselectivity.

Figure 2.

Scope of intramolecular [2+2] reaction.a,b

^a Unless otherwise noted, reactions performed using 2.5 mol % Ru(bpy)₃Cl₂, 0.5 equiv LiBF₄, 2.0 equiv i-Pr₂NEt in 0.1 M MeCN. ^b Isolated yields and diastereomer ratios are the averaged results of two reproducible experiments. ^c Reaction conducted using 0.5 equiv i-Pr₂NEt.

Finally, we investigated conditions for transformation of the 2-acylimidazole moiety into carboxylic acid derivatives¹⁴ (Table 3). The auxiliary group of cycloadduct 12 can easily be N-alkylated with MeOTf to afford the corresponding imidazolium salt. Upon recrystallization, this white crystalline material is stable to prolonged storage on the bench for at least six months.¹⁶ Displacement of the imidazolyl group proceeds smoothly with a variety of oxygen nucleophiles without loss of stereochemical integrity (entries 1–3). While bulky tertiary alcohols did not react with the imidazolium salt (entry 4), the more nucleophilic t-butyl thiol produced the corresponding thioester in quantitative yield (entry 5). Finally, the 2-acylimidazolium moiety could be transformed into an amide functional group upon treatment with either primary or secondary amines (entries 6 and 7). Thus, the use of this redox auxiliary strategy enables the synthesis of a variety of cyclobutane carboxylic acid derivatives that would not otherwise be accessible using our previously reported photocatalytic [2+2] cycloaddition methodology.

Table 3.

Cleavage of the redox auxiliary.^a

entry	NucH	yieldb	dr
1c	H2O	52%c	>10:1
2c	MeOH	86% c	>10:1
3	i-PrOH	88%	>10:1
4	t-BuOH	0%	n.d.
5	t-BuSH	99%	>10:1
6d	BnNH2	98%	>10:1
7d	pyrrolidine	75%	>10:1

^aUnless otherwise noted, cleavage of the imidazolium group was conducted using an excess of the nucleophile and 3.5 equiv of DBU in CH₂Cl₂.

^bIsolated yields.

^cCleavage conducted in Et₂O.

^dNo DBU added.

In conclusion, we have circumvented a limitation in the scope of the photocatalytic [2+2] cycloaddition developed in our laboratory by using unsaturated 2-acylimidazole groups as redox auxiliaries. These heteroaryl groups facilitate the reduction of the enone substrate to the key radical anion intermediate required for cycloaddition and are then susceptible to cleavage with a variety of nucleophiles under mild conditions. This redox auxiliary approach could be applied to other reactions that involve the reduction of carbonyl compounds to the corresponding radical anions. Continued studies in our laboratory will apply these concepts to other reactions of photogenerated radical ions.