From Ynimines to 2-imido-1,3-dienes and 2-amido-1,3-dienes:Three-component synthesis of 1-imido-trans-3,4-disubstituted cyclohex-1-enes. Both palladium-catalyzed (toluene, 70 °C)⁴³ and metal-free hydroacyloxylation (toluene, 100 °C) of ynamides to give α-acyloxyenamides are known^44–50. However, the multiple functional nature of ynimines raised concerns about competing side reactions, but also offered the opportunity to develop domino process inaccessible to ynamides. Gratifyingly, reaction of ynimine 4a with benzoic acid 5a at room temperature furnished the α-alkylidene imino enol ester 11a in 95% yield. The fact that this reaction occurred at room temperature is consistent with the higher reactivity of ynimines compared to ynamides. Heating 11a in DCE at reflux promoted a smooth Mumm rearrangement to deliver 2-imido-1,3-diene 6a in 90% yield, with no evidence for the competing 6π-electrocyclization to dihydropyridine 12 (Fig. 2a, inset)⁵¹. Finally, the Diels-Alder reaction of 6a with methyl vinyl ketone (MVK, 3a) in refluxing DCE provided the expected cycloadduct 7a in 83% isolated yield. To the best of knowledge, 2-imido-1,3-dienes have scarcely been reported³², and their Diels-Alder cycloaddition reactions remain unexplored.

Interestingly, the two acyl groups of the imido diene 6a can be selectively removed to access two distinct 2-amido-1,3-dienes. Thus, treatment of 6a with potassium carbonate (K₂CO₃) and methanol in DCE effected selective methanolysis of the phenylacetyl group, furnishing benzamide 8a (83% yield), whose structure was confirmed by X-ray crystallographic analysis. In contrast, reaction of 6a with pyrrolidine promoted selective aminolysis of the benzoic group, affording in 13a in 81% yield along with N-benzoyl pyrrolidine (80%).

The imido-1,3-diene 6a was stable and can be purified by conventional methods. The fact that no external reagent was required to promote the reaction of 4a, 5a and 3a prompted us to develop a one-pot three-component synthesis of 7a (Fig. 2b). Gratifyingly, stirring a DCE solution of the three reactants at room temperature until the complete consumption of 4a followed by heating to reflux the DCE solution afforded the 1-imido-trans 3,4-disubstituted cyclohex-1-ene 7a in 66% isolated yield. We have also briefly assessed the solvent effect. Whereas toluene was an efficient solvent affording 7a in a slight lower yield (60%) than DCE, others such as dioxane, MeCN, DMF, PhCF₃ and PhCl were far less good reaction media. Notably, six chemical bonds (one C_sp²-O, one C_sp²-N, two C_sp³- C_sp³ and two C_sp³-H) were formed in this operationally simple procedure. No external reagents, except for heating, is needed to drive this three-component reaction to completion⁵².

The scope of the three-component reaction was next examined (Fig. 3). The reaction tolerated a wide range of aryl groups at the β position of the conjugated ketimine motif. Both electron donating groups (OMe, Me) and electron-withdrawing groups (F, Cl, Br) at the para, meta, and ortho positions were well tolerated under the reaction conditions (7a-7i). Ynimines bearing a disubstituted phenyl (7j, 7k), a naphthyl (7 l), or a thiophene (7 m) also proved to be competent substrates. However, the ynimine bearing a 4-nitrophenyl group at its β position (Ar = 4-NO₂C₆H₄) led to an unstable cycloadduct that decomposed upon purification. Other dienophiles, such as ethyl vinyl ketone (EVK, 7n), ethyl acrylate (7o), 4-bromophenyl acrylate (7p) and 4-chlorophenyl acrylate (7q), successfully participated in this three-component reaction. However, no cycloaddition products were observed when acrylonitrile and nitroethylene were used as dienophiles, likely due to the facile polymerization of these highly active species. Finally, glycolic acid participated in this three-component reaction to afford cycloadduct 7r in 55% yield with diminished diastereoselectivity (dr 5:1).

The reaction of β-alkyl substituted ynimines with carboxylic acids was next examined. Not surprisingly, the reaction of 4 s with benzoic acid (5a) under refluxing in DCE afforded a roughly 1:1 mixture of two dienes: 2-imido-1,3-diene 6 s and 1-imido-1,3-diene 14 s (Fig. 4a). We note that no equilibrium was observed when either 6 s or 14 s was re-submitted to the reaction conditions (DCE, 100 °C).

To favour the formation of 6 s, various bases were screened and 2,2,6,6-tetramethylpiperidine (TMP), was identified as optimal (See Supplementary Information, page S18, Table S4). Experimentally, heating a DCE solution of 4 s, 5a and TMP (1.3 equiv) furnished 6 s and 14 s in yields of 83% and 8%, respectively. Finally, the three-component reaction of 4 s, 5a, and phenyl vinyl ketone (3 f) in the presence of TMP afforded directly the 3,4-disubstituted 1-imidocyclohex-1-ene 7 s in 73% isolated yield (Fig. 4b).

As shown in Fig. 4b, a variety of dienophiles, including 4-methoxy, 4-chloro, 4-bromo and 4-cyanophenyl and thiophenyl vinyl ketones, readily participated in this reaction to afford the three-component adducts (7t-7x) in good yields with excellent diastereoselectivity. Moreover, ynimines containing functional groups such as silyl ether and cyano substituents also proved to be competent substrates, delivering the corresponding cyclohexene derivatives 7 y and 7z.

The 3,4-trans relative stereochemistry of 7k (Fig. 3) was unambiguously determined by X-ray crystallographic analysis. For all compounds depicted in Fig. 3 and Fig. 4, the coupling constants J_H3-H4 and J_H2-H3 were found to be in the range of 8.4-8.9 Hz and 2.3-3.2 Hz, respectively. Accordingly, a 3,4-trans stereochemistry was assigned for all these cyclohexenes.

Organocatalytic enantioselective Diels-Alder reaction of 2-amido-1,3-dienes

We previously reported a chiral phosphoric acid-catalyzed enantioselctive cycloaddition of 2-trifluoroacetamido-1,3-dienes with electron-deficient dienophiles²⁸. However, these conditions proved unsuitable for other 2-acylamino-1,3-dienes due to the decomposition of these more nucleophilic dienes. With ready access to 2-amido-1,3-dienes from ynimines, we thought to develop a more general catalytic enantioselective protocol for this family of 1,3-dienes. Using ynimine 4a (R = Ph) as a model substrate, its catalytic enantioselective transformation was investigated as follows. A solution of ynimine 4a (R = Ph) and benzoic acid 5a (R¹ = Ph) in DCE was heated to reflux for 15 h, then cooled to room temperature, diluted with MeOH, and treated with K₂CO₃. After aqueous work-up, the crude 2-amido-1,3-diene (8a, R = R¹ = Ph) was directly subjected to a D-A reaction with 4-chlorophenyl vinyl ketone (3 h) at room temperature in the presence of organocatalysts (Fig. 5). Consistent with our previous report, decomposition of 8a was observed in the presence of chiral phosphoric acids (CPA)^53–56 and N-triflyl phosphoramides⁵⁷.

We therefore turned our attention to other H-bonding organocatalysis (See Supplementary Information, page S18-20, Tables S5 and S6). Screening sixteen chiral squaramides^58–62, three thioureas^63–65 and two ureas bearing a single H-bond donor⁶⁶ revealed squaramide 10a as the most effective catalyst^67,68, affording the cycloadduct 9a with 67% ee. Gratifyingly, conducting the same reaction at -20 °C furnished 9a in 48% isolated yield with 93% ee.

The generality of this catalytic enantioselective cycloaddition of 2-amido-1,3-dienes, generated from ynimines without purification, was next explored, with particular attention being paid on the structural diversity of the carboxylic acids. As shown in Fig. 5, benzoic acids bearing either electron-donating or electron-withdrawing substituents were well tolerated, affording adducts 9a-9f. Both 2-naphthoic acid and biphenyl-4-benzoic acid also participated in the reaction, delivering the corresponding adducts 9 g and 9 h, respectively, in good yields with high ees. An ynimine bearing a β-alkyl substituent was converted to cyclohexene 9i in 43% yield with 88% ee. In addition to α,β-unsaturated ketones, methyl acrylate underwent cycloaddition but provided the cycloadduct with low ee. The absolute and relative stereochemistry of compound 9 h was determined by X-ray crystallographic analysis. For all compounds listed in Fig. 5, the coupling constants J_H3-H4 and J_H2-H3 are found in the ranges of 5.1-5.6 Hz and 4.0-5.4 Hz, respectively, supporting the assignment of a 3,4-cis stereochemistry for all cyclohexenes.

Intramolecular Diels-Alder reaction of in situ generated 2-imido-1,3-dienes

The observation that the presence of dienophiles did not interfere with the generation of 2-imido-1,3-dienes from the reaction of ynimines with carboxylic acid prompted us to explore an intramolecular variant of the D-A cycloaddition reaction. Ynimine 15a (R = Cl) was accordingly selected as a model substrate for this study (Fig. 6). Gratifyingly, heating a DCE solution of 15a (R = Cl) and benzoic acid (5a) at 100 °C furnished the trans-fused tricyclic compound 16a in 45% isolated yield. The reaction is proposed to proceed through the imido-diene intermediate 17, which undergoes an intramolecular D-A reaction to deliver the observed cycloadduct. Analogous compounds 16b-16d were obtained in comparable yields. The structure of 16b was confirmed by X-ray crystallographic analysis. Although the overall yield appears to be moderate, it should be noted that the conversion of 15 and 5a to 16 involves at least five individual bond-forming events, including the formation of two C-C, one C-N, one C = O, and two C-H bonds. On this basis, the effective yield per bond formation is comparatively high.

The presence of aryl halide functions in compounds 16a-16b provides useful handles for further diversification through transition metal catalyzed cross-coupling reactions. Notably, compounds 16 can be viewed as structural analogues of trans ∆⁹-tetrahydrocannabinol 18 (Fig. 6 inset), the principal psychoactive constituent of marijuana and an FDA-approved drug (dronabinol) for the treatment of HIV/AIDS-induced anoxia⁶⁹ and chemotherapy-induced nausea and vomiting⁷⁰.

Stereochemical outcomes

The stereodivergence observed in the cycloaddition of dienophile 3 with 2-imido-1,3-dienes 6 versus 2-amido-1,3-dienes 8 is of synthetic significance and warrants further discussion. Control experiments showed that the 3,4-trans diastereomer 7a was formed in the reaction of 6a with 3a, regardless of the reaction temperature (20 °C to 100 °C). Monitoring the reaction progress under standard conditions revealed that 7a remained the sole cycloadduct at different conversion levels. In contrast, the cycloaddition of 2-amido-1,3-diene 8a with 4-chlorophenyl vinyl ketone (3 h) proceeded readily at room temperature to afford two diastereomers, the cis-9a and trans-9a in 85% yield with a dr of 5:1 (Fig. 7). No epimerization was observed when a solution of diastereomerically pure cis-9a or trans-9a was heated to reflux for 5 h.

The results of these control experiments suggested that a) both trans-7 and cis-9, obtained from the cycloaddition of imidodiene 6 and amidodiene 8, respectively, are kinetic products, and no epimerization took place under reaction conditions; b) amidodiene 8 is significantly more reactive than imidodiene 6 towards electron-poor dienophiles, likely because the nitrogen in 6 bears two acyl groups, reducing thereby the nucleophilicity of the enamide unit; c) the presence of chiral catalyst 10a significantly enhanced the diastereoselectivity of the cycloaddition of 8. In the absence of the catalyst, the racemic cyclohexene 9a was formed as a mixture of cis/trans diastereomers in 5 to 1 ratio, whereas in the presence of chiral squaramide 10a, the enantioenriched 9a was formed with a dr > 20:1 (Fig. 7).

Based on the aforementioned results, we hypothesized that the Diels-Ader reaction of 6 with 3 proceeded via a concerted mechanism, with the exo-TS favoured over the alternative endo-TS. In the endo-TS, any stabilizing secondary orbital interaction between the carbonyl group and the π* of diene is offset by the sever steric repulsion. In addition, the 2-imido function in the exo-TS may engage with the π* of the diene, lowering thereby the activation energy. Moreover, the 3,4-trans-7 was expected to be thermodynamically more stable than the cis-isomer, as the latter suffered from the steric clash between the C4 substituent and one of the N-acyl groups (Fig. 8a).

For the intramolecular D-A reaction of imido-diene 17, generated in situ from ynimine 15, the exo-TS would also be favoured for the same reasons as in the intermolecular version (Fig. 8b). Interestingly, the benzo-tethered, ester-linked 1,3,9-decatriene also afforded the trans-fused tricycle as a major product, albeit with lower trans/cis selectivity (dr 3:1)⁷¹. Therefore, the presence of a 2-imido function in the 1,3-diene system of 18 improved significantly the diastereoselectivity of the cycloaddition reaction.

Finally, we propose a stepwise mechanism for the squaramide 10a-catalyzed enantioselective cycloaddition of 2-amido-1,3-dienes 8 with α,β-unsaturated carbonyl compounds 3. Indeed, most cycloadditions involving enamides are known to proceed through a stepwise pathway^{22–24,72–80}. The reaction likely began with a Michael addition of the enamide moiety of 8 to 3 in the presence of 10a, generating intermediate 19. This is followed by an intramolecular 1,4-addition of the resulting enolate to the α,β-unsaturated N-acyliminium ion via a synclinal TS, yielding the cis-adduct 9. In this TS, both the nucleophile and electrophile are activated through multiple hydrogen bonding interactions with the squaramide catalyst, lowering the activation barrier for C-C bond formation. Notably, no reaction occurred at -20 °C without catalyst 10a, underscoring its crucial role in both activating the reactants and facilitating the enantio-determining C-C bond forming step in the proposed stepwise pathway.