Asymmetric Synthesis of Highly Functionalized Cyclohexa-1,3-dienes via Organocatalyzed One-Pot Three-Component Domino Reaction of Malononitrile with α,β-Unsaturated Imines

4a was obtained as a yellow solid in 42% yield after flash chromatography and the enan t iomer ic excess was determined to be 89% by HPLC analysis on Chiralcel OD column (20% 2-propanol/n-hexane, 1 mL min), UV 254 nm, tRmajor 10.259 min, tRminor 14.758 min; [α]D –12.9 (c 0.233, CHCl3); m.p. 191-193 C; IR (KBr) nmax/cm 3396, 2217, 1643, 1606, 1553, 1508, 827; H NMR (400 MHz, DMSO) d 7.91 (s, 2H), 7.43-7.39 (m, 7H), 6.99 (d, 2H, J 8.7 Hz), 5.66 (d, 1H, J 4.1 Hz), 4.77 (d, 1H, J 4.0 Hz), 3.77 (s, 3H); C NMR (100 MHz, DMSO) d 160.3, 149.1, 135.5, 131.3, 130.7, 130.5, 129.3, 129.2, 128.9, 127.9, 127.8, 127.0, 117.2, 116.5, 115.9, 115.1, 114.7, 114.6, 77.3, 55.8, 47.2, 44.3; HRMS (ESI) C22H16N4O+Na [M+Na] + calcd.: 375.1216; found 375.1217.


Introduction
Regio-, chemo-, and enantioselective construction of six-membered carbocycles is one of the most fundamental and important issues in synthetic organic chemistry because of the importance and prevalence of these motifs in many biologically active natural products and drug molecules. 1ntermolecular annulation reaction is one of the most ideal processes for the rapid and selective construction of complex cyclic structures in a one-pot manner from relatively simple building blocks. 2,3While the annulation approaches to construct six-membered carbocycles have typically relied on the [4 + 2] and [5 + 1]-modes 4,5 and to the best of our knowledge, there is no report on the direct enantioselective organocatalytic [1 + 3 + 2]-processes for the synthesis of chiral six-membered carbocycles.7][8] First, multicomponent domino reactions allow construction of complex structures in as few steps as possible.In theory, they also eliminate the need for a purification step (or steps).Since the intermediates are not isolated it becomes easier to work with sensitive or unstable intermediates.Finally, employing multicomponent domino reactions will reduce the amount of waste formed and save on cost and amounts of reagents, solvents, time.In connection with our continuous interest in organocatalysis, and on the basis of our recent achievement, 9 we report herein an alternative approach to the synthesis of highly functionalized cyclohexa-1,3-dienes by an enantioselective organocatalytic one-pot threecomponent domino [1 + 3 + 2] pathway using commercially available, low cost quinidine as the organocatalyst.

Results and Discussion
N-Sulfonyl-1-aza-1,3-dienes, which were found by Boger et al. 10 to participate as a 4π component in organic synthesis, have been well demonstrated as versatile electrophiles in cycloaddition reactions such as [4 + 2], [3 + 2], [2 + 2], etc., as well as 1,2-and 1,4-addition reactions. 11Many nucleophiles have been reported in the addition reactions involving N-sulfonyl-1-aza-1,3-dienes. 10 However, to the best of our knowledge, malononitriles have never been reported to date as nucleophiles for the asymmetric addition to N-sulfonyl-1-aza-1,3dienes.We envisioned the reaction sequence involving Michael addition of N-sulfonyl-1-aza-1,3-dienes 1 to malononitrile 2 by using H-bonding activation, followed by subsequent intramolecular cyclization of the resulting adducts as a facile and efficient approach to the piperidine derivatives (Scheme 1, path a), which may be useful in the total synthesis of natural products and medicinal chemistry (Scheme 1).To our surprise, no desired product 3a was observed, but cyclohexa-1,3-diene 4a, which was isolated in the presence of the organocatalysts I-VI (Figure 1) in dichloromethane (DCM) at -40 °C (Scheme 1, path b).Notably, 5a was also isolated as a byproduct in low yield.
Subsequently, investigations were carried out in order to find the optimal reaction conditions for the formation of enantiomeric piperidine derivatives 3 and the N-sulfonyl-1-aza-1,3-diene 1a was chosen as a model substrate.The reaction was first carried out in the presence of the organocatalysts I-VI in DCM at -40 °C.We first investigated the catalytic activity of organocatalysts for the multicomponent domino annulation of N-sulfonyl-1-aza-1,3-diene 1a with malononitrile 2. A few representative results are shown in Table 1.We tended to activate both donors and acceptors to promote this transformation and the multicomponent domino annulation was first catalyzed by thiourea-tertiary amine I.The reaction proceeded smoothly and cyclohexa-1,3-diene 4a was obtained in moderate yield, while the enantiomeric excess (ee) was very low (Table 1, entry 1).Cinchona alkaloids have appeared to be efficient organocatalysts in asymmetric transformations since the basic tertiary nitrogen of cinchona alkaloids could activate nucleophiles by deprotonation, whereas the secondary hydroxyl group would serve as hydrogen-bonding donor in the activation of electrophiles such as α,β-unsaturated carbonyl compounds or nitroalkenes.As such, quinidine II and cinchonine III were screened and better results were obtained (Table 1, entries 2-3).
Especially, quinidine II exhibited excellent catalytic activity and even much higher enanotioselectivity (72% ee) was obtained (Table 1, entry 2).Catalysts IV-VI derived from cinchona alkaloids were also found to be highly active catalysts, product 4a was obtained in moderate yield, while the ee was very low (Table 1, entries 4-6).In the next stage of the studies, different solvents and temperatures were screened.The reaction proceeded smoothly and afforded moderate yields (10-44%) and varied enantioselectivities (Table 2, entries 7-13) in different solvents.However, chlorinated solvents were the most useful in terms of enantioselectivities and yields (Table 1, entries 2 and 14).Notably, the multicomponent domino annulation worked very well in chloroform (CHCl 3 ) to afford 4a with high enantioselectivity in 46% yield (Table 1, entry 14) and chloroform turned out to be the solvent of choice and was used for temperature screening.By lowering the reaction temperature to -50 o C, high enantioselectivity (89% ee) and a moderate yield (42%) were obtained in the presence of quinidine II (Table 1, entry 15).Based on the above screened results, the optimal reaction conditions of 1 eq. 1 and 2.5 eq. 2 in chloroform with 20 mol% quinidine II at -50 o C were established.
With the optimized conditions in hand, we investigated the scope of the reaction.The results are summarized in Table 2. Various substituted N-sulfonyl-1-aza-1,3-dienes 1a-l were treated with malononitrile 2. The reaction proved to be general, since moderate yields (31-53%) and high enantioselectivities (81-91% ee) were observed in all cases.The position of the substituent on the aromatic ring had no significant influence on the stereochemical outcome of the reaction.Moreover, the multicomponent domino annulation with N-sulfonyl-1-aza-1,3-dienes bearing either electronwithdrawing or electron-donating substituents proceeded without noticeable changes in yield or stereoselectivity.N-sulfonyl-1-aza-1,3-dienes with electron withdrawing  Vol. 26, No. 3, 2015   substituents on the ortho, meta or para positions afford cyclohexa-1,3-dienes 4 with slightly inferior yields and enantioselectivities (Table 2, entries 7-9).The opposite configuration of cyclohexa-1,3-diene 4a was obtained with slightly inferior enantioselectivity when the multicomponent domino annulation was catalyzed by quinine.
This catalytic cascade is a three-component annulation comprising a N-sulfonyl-1-aza-1,3-diene, two malononitriles and a simple chiral tertiary amine, which is capable of catalyzing each step of this triple cascade.To obtain mechanistic information about the enantioselective multicomponent domino annulation, several control experiments were conducted.The reaction proceeded smoothly between 6l and malononitrile 2 in good yield under the same reaction conditions, while the enantioselectivity is very low (Scheme 2).Even when p-toluenesulfonamide (TsNH 2 ) was added as an additive, the enantioselectivity is very poor (Scheme 2).The sulfonyl group proved to be a key group in the N-sulfonyl-1-aza-1,3-dienes 1 in the enantioselective multicomponent domino annulation.On the basis of the above observations and previous studies, 3 a possible mechanism for the present tertiary amine-catalyzed three-component cascade annulation was proposed (Scheme 3).We propose a stepwise mechanism in which the rate-determining step consists of a dual Brønsted base/hydrogen-bonding activation step involving both the N-sulfonyl-1-aza-1,3-dienes 1 and malononitrile 2. First, malononitrile 2 was deprotonated by the quinidine nitrogen atom to generate an ion pair, while the hydroxyl group coordinates to the oxygen atom of the sulfonyl group, bringing the two reactants into close proximity.Next, attack of the nucleophile on the N-sulfonyl-1-aza-1,3dienes 1 generates intermediate A followed by Knoevenagel condensation to produce intermediate B. Then, further intramolecular cyclization reactions occurred, followed by proton transfer of the resulting adducts as a facile and efficient approach to the target compounds 4 (Scheme 2).In addition, the molecular structure of enantiopure 4l has been firmly determined by X-ray (Figure 2).The enantiopure crystals of 4 suitable for determination of the absolute configuration were not obtained in our lab.

Conclusions
In summary, a concise and stereoselective methodology for the synthesis of highly substituted carbocycles has been developed.Further investigation on the application of the present strategy to construct complex organic molecules is currently underway.
a Reactions performed with 0.1 mmol of 1a, 0