Differentiating Catalysis in the Dearomative [4 + 2]-Cycloaddition Involving Enals and Heteroaromatic Aldehydes.

In this paper, the application of differentiating catalysis in the [4 + 2]-cycloaddition between 2-alkyl-3-formylheteroarenes and α,β-unsaturated aldehydes is described. Within the developed approach, the same aminocatalyst is employed for the independent activation of both starting materials, differentiating their properties via LUMO-lowering and HOMO-rising principles. By the combination of dearomative dienamine activation with iminium ion chemistry high enantio- and diastereoselectivity of the doubly asymmetric process was accomplished. Selected transformations of products were also demonstrated.

Stereocontrolled synthesis of specific structural motifs is one of the most important tasks in contemporary organic chemistry.[1] Within this area of research, double-asymmetric synthesis constitutes an interesting approach.[2] It leads to the formation of a new stereogenic center by the utilization of two enantiopure substrates bearing a chiral auxiliary unit. When appropriate enantiomers of substrates are employed (“match” case), the chirality of both reagents synergistically enhances the stereochemical reaction outcome (Scheme ). The main drawback of the approach concerns its atom- and step-economy as chiral auxiliaries are used in stoichiometric amounts and must be introduced and removed in additional, time-consuming procedures. A much easier strategy is based on the catalytic generation of chiral intermediates that participate in the reaction as no additional synthetic protocols are required. The main tool used for this type of asymmetric synthesis is synergistic catalysis where two different catalysts independently activate two substrates, thus providing chiral intermediates capable of participating in a given transformation.[3] On the contrary, the pathway relying on the activation of both substrates by two molecules of the same catalyst is much less explored.[4] In this type of approach, electronic properties of substrates are enhanced and at the same time differentiated via the formation of both LUMO-lowered and HOMO-raised reactive intermediates. Therefore, such catalytic activation can be referred to as differentiating catalysis. This strategy offers many benefits including operational simplicity, yet it is more challenging as substrates employed must possess functional groups of similar properties, thus resulting in competitive reaction pathways.

Scheme 1

Double Asymmetric Synthesis: Classical and Catalytic Approaches

Since the turn of the millennium, aminocatalysis has proven extremely useful in synthetic methodology, allowing for the stereoselective functionalization of numerous types of carbonyl compounds.[5] Among different strategies provided by this methodology, HOMO-raising enamine activation of aldehydes and ketones occupies a prominent position. Identification of polyenamine-mediated processes gave access to novel stereoselective methods of functionalization of unsaturated carbonyl compounds with dienamine and trienamine chemistry providing significant synthetic opportunities.[6] Over the past few years, novel approaches toward generation of polyenamines from (hetero)aromatic compounds have been identified with aminocatalytic dearomative strategies paving new directions in the development of the field. Interestingly, diverse heteroaromatic carbonyl compounds can be transformed with dearomatization into polyenamines under aminocatalytic conditions (Scheme , top).[7] Notably, dienamines derived from 2,3-disubstituted heteroaromatic compounds are prone to the reaction with electrophiles providing either alkylation products[7f,7i,7j] or more rarely undergoing cycloaddition[7e,7g] (Scheme , middle).

Scheme 2

Polyenamine Species Generated from Heteroaromatic Aldehydes and Their Functionalization

Given the interesting possibilities provided by differentiating catalysis, the task of development of dearomative dienamine-mediated [4 + 2]-cycloaddition was undertaken (Scheme , bottom). It was envisioned that catalytically generated iminium ions 6 derived from α,β-unsaturated aldehydes 2 might serve as an appropriate electron-poor dienophile for this reaction. It was anticipated that the utilization of selected aminocatalyst should be beneficial for two independent processes: formation of dearomatized dienamine 5 and the previously mentioned iminium ion 6. Chiral intermediates thus obtained should be prone to react in the Diels–Alder cycloaddition, and double-asymmetric catalysis concept should result in enhancement of stereoselectivity of the process.[8]

Herein, we present our studies on the aminocatalytic [4 + 2]-cycloaddition between dienamines 5 (generated from heteroaromatic aldehydes 1) and iminium ions 6 (derived from enals 2) realized according to differentiating catalysis principles. Dearomative Diels–Alder reaction proceeded efficiently, providing enantioenriched heteroaromatic derivatives 3. Utilization of the obtained product in selected transformations was also demonstrated.

Optimization studies were performed using 2-benzylfuran-3-carbaldehyde 1a and trans-cinnamaldehyde 2a as model reactants (Table ). The initial experiment, performed with Hayashi–Jørgensen catalyst 4a in dichloromethane, showed that the desired enantioenriched product 3a was formed; nevertheless, the conversion and diastereoselectivity of the reaction were unsatisfactory (Table , entry 1). Utilization of amine 4b provided only traces of cycloadduct 3a; therefore, further organocatalyst screening proved necessary (Table , entry 2). Inspired by our previous work,[4f] (R)-2-benzhydrylpyrrolidine 4c was used as catalyst, which gave similar results as 4a, but with enhancement of diastereoselectivity (Table , entry 3). Therefore, 4c was chosen as the most suited catalyst, and subsequent optimization studies were focused on the influence of the relative ratio of substrates on the cycloaddition outcome (Table , entries 3–5). The best results were obtained when 1.2-fold excess of 2a was used, providing 43% conversion within 24 h (Table , entry 5). Therefore, the additive screening covering the effect of basic, acidic, or amphiprotic additives was carried out (Table , entries 6–8). The highest reaction enhancement was observed when benzoic acid was used as cocatalyst, providing the desired product in 80% yield after 24 h (Table , entry 6). Further optimization studies were devoted to the choice of the most suited solvent for the studied cycloaddition (Table , entry 9–11). Et2O proved the best as it afforded the product 3a in high chemical yield and with excellent stereoselectivity, thus determining the final reaction conditions (Table , entry 11). It is worth mentioning that the developed reaction was readily realized in a 20-fold higher scale, providing cycloadduct 3a with similar results (Table , entry 12).

Table 1

Differentiating Catalysis in the [4 + 2]-Cycloaddition Optimization Studiesa

entry	cat.	solvent	convb (%)	drc	erd
1	4a	CH2Cl2	34	12:1	>99:1
2	4b	CH2Cl2	trace
3	4c	CH2Cl2	32	>20:1	>99:1
4e	4c	CH2Cl2	25	>20:1
5f	4c	CH2Cl2	43	>20:1
6f,g	4c	CH2Cl2	92 (80)	>20:1	>99:1
7f,h	4c	CH2Cl2	32	>20:1
8f,i	4c	CH2Cl2	85	>20:1
9f,g	4c	CHCl3	39	>20:1
10f,g	4c	toluene	30	>20:1
11f,g	4c	Et2O	94 (95)	>20:1	>99:1
12f,g,j	4c	Et2O	96 (91)	>20:1	>99:1

The reactions were performed in 0.05 mmol scale using equimolar amounts of 1a and 2a in 0.2 mL of the solvent.

Determined by 1H NMR spectroscopy of a crude reaction mixture after 24 h. The isolated yield is shown in parentheses.

Determined by 1H NMR spectroscopy of a crude reaction mixture.

Determined by chiral stationary phase UPC.[2]

Reaction performed using 1a (1.2 equiv) and 2a (1.0 equiv).

Reaction performed using 1a (1.0 equiv) and 2a (1.2 equiv).

Reaction performed with PhCO2H (40 mol %) as additive.

Reaction performed with triethylamine (40 mol %) as additive.

Reaction performed with 4-dimethylaminobenzoic acid (40 mol %) as additive.

Reaction performed on a 1 mmol scale.

With the optimized reaction conditions in hand, studies on the scope and limitations of the method were undertaken. In the first part, the influence of the substitution pattern of α,β-unsaturated aldehydes 2 on the developed cycloaddition was investigated (Scheme ). Transformation was unbiased toward the presence of both electron-withdrawing and electron-donating substituents on the aromatic ring in 2 (Scheme , compounds 3b–d). Interestingly, aldehyde 2b bearing a nitro group in the para position gave access to cycloadduct 3b in good yield and with excellent enantioselectivity, but with diminished diastereoselection. Substitution of the aromatic ring in 2c with the chlorine atom and in 2d with methyl group was also well-tolerated in the transformation affording product 3c and 3d with satisfactory results. Further examples showed that the stereoselectivity of the method is not influenced by the position of substituents on the aromatic ring in enals 2 (Scheme , products 3e–g) as various methoxy-functionalized aldehydes 2e–g reacted smoothly, providing cycloadducts 3e–g with excellent enantio- and diastereocontrol. It is worth noting that introduction of the double substitution pattern on the aryl ring in 2h was also possible, but product 3h was obtained with lower enantioselectivity. Furthermore, the trans-3-(2-furyl)acrolein 2i was also utilized in this transformation, yielding product 3i decorated with a heteroaryl substituent. Unfortunately, hex-2-enal did not participate in the reaction, indicating that aliphatic α,β-unsaturated aldehydes were difficult substrates for the process.

Scheme 3

Differentiating Catalysis in the [4 + 2]-Cycloaddition: α,β-Unsaturated Aldehyde 2 Scope

The next step of scope studies was focused on the utilization of structurally diversified heteroaryl aldehydes 1 (Scheme ). Aldehyde 1b, containing an electron-acceptor substituent at the para position of the phenyl ring, led to the product 3j with satisfactory yield, diastereoselectivity, and very good enantioselectivity. In the case of aldehydes 3k and 3m bearing methyl groups on the phenyl ring, the substituent position had a slight effect on the reaction results - for both 2- and 4-substituted substrates 1c and 1e, a significant decrease in the diastereoselectivity and yield was observed, while the enantioselectivity was not affected. Nevertheless, substrate 1d with a strongly electron-donating methoxy group at the meta-position of the phenyl ring gave access to product 3l with decreased enantioselectivity. It is worth noting that allyl-substituted aldehyde 1f was also employed in the cycloaddition providing 3n as a single diastereoisomer in high yield. To our delight, further scope expansion was possible by the utilization of benzofuran-based aldehyde 1g, which reacted smoothly to give cycloadduct 3o with good enantioselectivity. Unfortunately 2-butyl-3-furfural and 2-methyl-3-formylbenzofuran were not reactive under the optimal reaction conditions. Moreover, attempts toward utilization of Boc-protected 2-methylindole-3-carbaldehyde and 2-benzylindole-3-carbaldehyde as dienamine precursors were undertaken, but no reactivity was observed in these cases.

Scheme 4

Differentiating Catalysis in the [4 + 2]-Cycloaddition: Heteroaromatic Aldehyde 1 Scope

Subsequent investigations were focused on the synthetic applications of the obtained product 3a (Scheme ). Reduction using NaBH4 provided alcohol 7 in 78% yield. Moreover, cerium chloride promoted the reaction with o-phenylenediamine, affording chiral diazepine 8. In these two cases, reactions proceeded with full preserevation of the stereochemical composition of 3a, as products 7 and 8 were obtained as single diastereomers. It was also demonstrated that cycloadduct 3a can be transformed using DDQ as an oxidant into a highly functionalized benzofuran-5-carbaldehyde 9 with loss of all stereogenic centers.

Scheme 5

Selected Transformations of the Product 3a

The absolute configuration of 3a was determined by the X-ray analysis of a single crystal as (6S,7S) (see the Supporting Information for further details). The stereochemistry of products 3b–o was assigned by analogy given the assumption that changes in the substitution pattern of products do not have any impact on the mechanism of the cycloaddition. With the knowledge of the stereochemical reaction outcome, the possible reaction mechanism was proposed (Scheme ).

Scheme 6

Differentiating Catalysis in the [4 + 2]-Cycloaddition: Mechanistic Considerations

The main role is played by the aminocatalyst 4c which is responsible for the activation and differentiation of both substrates: (1) it forms the dienamine 5 by dearomatization of heteroaryl aldehyde 1 (HOMO-rising differention) and (2) it independently activates α,β-unsaturated aldehyde 2 through LUMO-lowering iminium ion differentiation. Intermediates 5 and 6 subsequently participate in the endo-selective Diels–Alder cycloaddition with the steric interactions between bulky groups in the 2-position of the pyrrolidine units present in both diene 5 and dienophile 6 governing the approach. In the next step, after aromative cycloaddition, iminium ion 11 undergoes eliminative cleavage of catalyst and hydrolysis to obtain target product 3. Moreover, the postulated mechanism involving two molecules of the catalyst was confirmed by the nonlinear effects studies, which indicated the positive nonlinear effect (for more information, see the Supporting Information).

In conclusion, we demonstrated that differentiating catalysis constitutes a powerful tool for the stereoselective synthesis functionalization of carbonyl compounds. The cycloaddition reaction between 1 and α,β-unsaturated aldehydes 2 was realized through the combination of dearomative dienamine 5 and iminium ion activations, thus providing high enantio- and diastereoselectivity of the transformation. The scope and limitations of the process were carefully studied and the stereochemical model of the reaction was proposed. Moreover, useful synthetic transformations of product 3a were elaborated.