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

Abstract

The enantioselective synthesis of highly functionalized cyclohexa-1,3-dienes was achieved via an organocatalytic one-pot three-component domino reaction. In addition, a possible mechanism accounting for the reaction was proposed.

organocatalytic; domino reactions; quinidine; cyclohexa-1,3-dienes

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.¹ Intermolecular 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.^2,3 While 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. In addition, multicomponent domino reactions (MDRs), in which more than one bond is being formed in a multistep one-pot reaction sequence are of great importance in organic chemistry because they have several advantages over a series of individual reactions.^6-8 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 three-component 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.¹¹ Many 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-1,3-dienes. We envisioned the reaction sequence involving Michael addition of N-sulfonyl-1-aza-1,3-dienes 1 to malononitrile2 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.

Scheme 1
Potential strategies for the cyclization of α,β-unsaturated imines with malononitrile.

Figure 1
Structures of organocatalysts I-VI.

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).

Table 1
Screening of the reaction conditions of malononitrile 3 with N-sulfonyl-1-aza-1,3-diene 2a catalyzed by 1ª

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 (CHCl₃) 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 ºC, 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 ºC were established.

Table 2
Quinidine-catalyzed reaction of N-sulfonyl-1-aza-1,3-dienes 1 with malononitrile 2ª

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 electron-withdrawing or electron-donating substituents proceeded without noticeable changes in yield or stereoselectivity. N-sulfonyl-1-aza-1,3-dienes with electron withdrawing 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 (TsNH₂) 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-1,3-dienes1 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.

Scheme 2

Scheme 3
Plausible mechanism.

Figure 2
Molecular structure of enantiopure 4l (ellipsoids with 50% probability).

Crystallographic data

Crystal data for 4l: C₂₁H₁₄N₄ (322.36); monoclinic; P2(1)/c; a = 7.995(10) Å, b = 13.031(16) Å, c = 16.63(2) Å; V= 1733(4) ų; Z = 12; specimen 0.326 × 0.312 × 0.218 mm³; T= 296(2) K; SIEMENS P4 diffractometer; absorption coefficient 0.076 mm^-1; reflections collected 9576; independent 3046 [R(int) = 0.0272]; refinement by full-matrix least-squares on F², data/restraints/parameters 3046/0/227; goodness-of-fit on F²= 1.026; final R indices [I > 2σ(I)] R1 = 0.0380, wR2 = 0.0905; R indices (all data) R1 = 0.0602, wR2 = 0.1016; largest diff. peak and hole 0.166 and –0.123 e Å^-3. CCDC 1035842 contains the supplementary crystallographic data for the structure of 4l. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: (+44)‑1223/336-033; e-mail: [e-mail]].

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.

Experimental

Nuclear magnetic resonance (NMR) spectra were recorded with tetramethylsilane as the internal standard. Thin-layer chromatography (TLC) was performed on glass-backed silica plates. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether. ¹H NMR spectra were recorded at 400 MHz, and ¹³C NMR spectra were recorded at 100 MHz. Chemical shifts were reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: proton (chloroform ∂ 7.26, DMSO ∂ 2.50), carbon (chloroform ∂ 77.0, DMSO ∂ 39.5). Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), bs (broad singlet). Coupling constants were reported in Hertz (Hz). Optical rotations were measured in CHCl₃ solution at 589 nm and 20 ºC. Enantiomeric excess was determined by high-performance liquid chromatography (HPLC) analysis on Chiralcel IC, OD and Chiralpak AD columns. Infrared (IR) spectra were recorded using a Perkin-Elmer 1600 Series FTIR. Electrospray ionization-high resolution mass spectrometry (ESI‑HRMS) was measured with a Finnigan LCQ^DECA ion trap mass spectrometer. Chloroform was distilled from CaH₂. The N-sulfonyl-1-aza-1,3-dienes were easily prepared according to Carretero and co-workers' procedure.¹²

General procedure for the one-pot domino reaction of N-tosyl-1-aza-1,3-dienes and malononitrile

To a solution of N-sulfonyl-1-aza-1,3-dienes 1a (0.10 mmol) in CHCl₃ (0.5 mL) was added catalyst II (6.5 mg, 20 mol%) at –50 ºC under N₂. Then, a solution of malononitrile 2 (42 µL, 0.25 mmol) in anhydrous CHCl₃(1.5 mL) was added. Subsequently, CHCl₃ (0.5 mL) was also added. The mixture was kept at the temperature until the reaction was completed. Then the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give 4.

Acknowledgements

The authors gratefully acknowledge financial support from the Zhejiang Provincial Natural Science Foundation of China (LQ13B020005), Ningbo Natural Science Foundation (2012A610175), the Foundation of Zhejiang Educational Committee (Y201226178), Zhejiang Pharmaceutical Association (2011ZYY 18 and 2014ZYY 34) and Ningbo No. 2 Hospital.

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• Supplementary Information
  Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

Data availability

https://minio.scielo.br/documentstore/1678-4790/hZmYJ4ptQ4v4FdG3tJdxXGL/0f30ca991773c0abedda0e7cc52d47b8cb798292.pdf

Publication Dates

• Publication in this collection
  Mar 2015

History

• Received
  23 Oct 2014
• Accepted
  16 Dec 2014