M. N. Elinson*a,
A. N. Vereshchagina,
R. F. Nasybullina,
S. I. Bobrovskya,
A. I. Ilovaiskya,
V. M. Merkulovaa,
I. S. Bushmarinovb and
M. P. Egorova
aN. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia. E-mail: elinson@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Vavilova str. 28, 119991 Moscow, Russia
First published on 1st June 2015
A new type of catalytic stereoselective cascade pseudo four-component reaction was discovered. The simple and facile pseudo four-component reaction of isatins, cyclic ketones with two molecules of malononitrile catalyzed by triethylamine at ambient temperature stereoselectively results in the formation of tetracyclic spirooxindoles in 60–90% yields. Thus, a new simple and efficient ‘one-pot’ method to synthesize substituted spirooxindoles was found directly from reasonable starting compounds. Unique stereoselectivety was achieved on two or three centers in this pseudo four-component reaction.
MCRs are also convenient processes for the rapid generation of complex molecules with biologically relevant scaffold structures from three or more simple starting molecules.2
The MCRs protocol has significant advantages compare to conventional reactions in several aspects including lower costs, shorter reaction times, high degree of atom economy, and environmental friendliness. Therefore, the exploration of new MCRs is of a substantial interest in organic, combinatorial and medicinal chemistry.3–5
The heterocyclic spirooxindole ring system is a widely distributed structural framework in a number of pharmaceuticals and natural products,6 including cytostatic alkaloids such as spirotryprostatins A,7 B8 and stychnophylline.9 The unique molecular architecture and remarkable pharmacological activity have claimed the spirooxindoles and their derivatives attractive synthetic targets.10–13
Among either carbocycles or heterocycles fused with a spirooxindole moiety, the spiro[indole-3,1′-naphthalene]s are of particular interest, as they are an inhibitors of histone methyltransferase Pr-Set7 and applied in prevention and treatment of cancers and lifestyle-related diseases.14
To the best of our knowledge, only two methods of synthesis of spirooxindoles with fused cyclohexane ring have been reported so far.15,16 Both of them employ two-component condensation of isatylidene malononitriles and α,α-dicyanocycloalkenes catalyzed by various organic bases. Although it proceeds in one reaction step, the preliminary synthesis of Knoevenagel adducts is still required, which implies two extra steps in preparation of target spirooxindoles. Moreover, flash chromatography is needed for purification of desired products.16 In addition, the techniques mentioned above utilize only carbocyclic ketones, which markedly limit the scope of the reaction. Thus, the known procedures have their merits, but the essence of facile and convenient pseudo four-component methodology of synthesis of spirooxindoles from isatins and cyclic ketones and two molecules of malononitrile should be developed.
![]() | ||
Scheme 1 One-pot multicomponent transformation of isatins 1a–j, cyclic ketones 2a–g and two equivalents of malononitrile into spirooxindoles 3a–p. |
Entry | Solvent | Base | Quantity of base (mmol) | Time (h) | Yield of 3ab (%) |
---|---|---|---|---|---|
a Isatin 1a (1 mmol), cyclohexanone 2a (1 mmol), malononitrile (2 mmol), EtOH (3 mL), 20 °C.b Isolated yield.c 60 °C. | |||||
1 | MeOH | NaOAc | 0.1 | 1.5 | — |
2 | MeOH | NaOAc | 0.1 | 3 | 45 |
3 | EtOH | NaOAc | 0.1 | 3 | 53 |
4 | EtOH | NaOAc | 0.2 | 3 | 61 |
5 | EtOH | NaOAc | 0.2 | 12 | 63 |
6 | EtOH | NH4OAc | 0.2 | 3 | 59 |
7 | EtOH | NaOH | 0.1 | 3 | 30 |
8 | EtOH | DBU | 0.1 | 3 | 35 |
9 | EtOH | NEt3 | 0.1 | 1.5 | 65 |
10 | EtOH | NEt3 | 0.2 | 1.5 | 85 |
11 | EtOHc | NEt3 | 0.2 | 1.5 | 41 |
12 | n-PrOH | NEt3 | 0.2 | 1.5 | 73 |
Entry | Isatin | Cyclic ketone | Time (h) | Product, yieldb (%) |
---|---|---|---|---|
a Isatin 1 (1 mmol), cyclic ketone 2 (1 mmol), malononitrile (2 mmol), NEt3 (0.2 mmol), EtOH (3 mL), 20 °C.b Isolated yield. | ||||
1 | 1a | 2a | 1.5 | 3a, 85 |
2 | 1b | 2a | 1.5 | 3b, 86 |
3 | 1c | 2a | 1.5 | 3c, 90 |
4 | 1d | 2a | 1.5 | 3d, 65 |
5 | 1e | 2a | 1.5 | 3e, 62 |
6 | 1f | 2a | 1.5 | 3f, 68 |
7 | 1g | 2a | 2 | 3g, 61 |
8 | 1h | 2a | 2 | 3h, 63 |
9 | 1i | 2a | 2 | 3i, 60 |
10 | 1j | 2a | 2 | 3j, 81 |
11 | 1a | 2b | 2 | 3k, 68 |
12 | 1a | 2c | 1.5 | 3l, 72 |
13 | 1a | 2d | 1.5 | 3m, 66 |
14 | 1a | 2e | 1.5 | 3n, 60 |
15 | 1a | 2f | 2 | 3o, 73 |
16 | 1a | 2g | 2 | 3p, 77 |
In order to find optimal conditions, the one-pot pseudo four-component transformation of isatin 1a, cyclohexanone 2a and two equivalents of malononitrile was selected as a model reaction. The results are summarized in Table 1.
First, this process was performed in alcohols at ambient temperature in the presence of NaOAc as catalyst (Table 1, entries 1–5). Only Knoevenagel adducts were observed in the reaction mixture within 1.5 h (Table 1, entry 1). After doubling the reaction time (3 h) we obtained the spiro[indole-3,1′-naphthalene]-2′,2′,4′-tricarbonitrile 3a in moderate 45% yield (Table 1, entry 2). Replacement of MeOH with much more appropriate EtOH allowed us to afford 3a in 53% yield (Table 1, entry 3), so the latter turned out to be the solvent of choice and was further used for catalyst screening. We examined various bases, such as NH4OAc, NaOH, and DBU (Table 1, entries 6–8). It was found that NH4OAc had no significant influence on outcome of the reaction, while in the case of NaOH and DBU the process performed poorly. Nevertheless, the most dramatic improvement was achieved when the catalyst was switched to NEt3 (Table 1, entries 8,9). The one-pot multicomponent transformation of isatin 1a, cyclohexanone 2a and malononitrile proceeded smoothly and 3a was obtained in good 82% yield (Table 1, entry 9).
Under the optimal catalytic conditions [i.e. ethanol as solvent, NEt3 as catalyst 20 °C and 1.5 h reaction time] isatins 1a–j, cyclic ketones 2a–g and two equivalents of malononitrile were transformed into corresponding substituted tetracyclic spirooxindoles 3a–p in 60–90% yields (Table 2).
The developed multicomponent technique proved to be general, since good to excellent yields (60–90%) of tetracyclic spirooxindoles 3a–p were observed in all the cases. The reaction proceeded smoothly with cyclohexanone and substituted cyclohexanones. N-substituted piperidin-4-ones reacted properly as well (Table 2, entries 11–14). Further involving of tetrahydro-4H-pyran-4-one 2f and tetrahydro-4H-thiopyran-4-one 2g into the process allowed to afford corresponding spiro compounds 3o and 3p in 73% and 77% yield respectively (Table 1, entries 15–16).
Spirooxindoles 3a–j, m–p have two and spiroxindoles 3k,l three asymmetric centers, but in the NMR spectra of all these compounds only a single set of signals was identified. Thus, in all cases the individual diastereoisomer was isolated.
The cis relationship of the carbonyl group and proton at tert-C atom in bicyclic system is characteristic and preferable for the compounds of such type as was established earlier.15,17 Thus, (3R*,8a′R*)-configuration was assigned for spirooxindoles 3a–j, m–p. To confirm the suggested structure for spirooxindoles, single crystals of 3a were crystallized from ethanol. X-Ray diffraction analysis unambiguously supports outlined on Fig. 1 (3R*,8a′R*)-configuration.
![]() | ||
Fig. 1 The general view of 3a in crystal. Atoms are represented by thermal displacement ellipsoids (p = 50%). |
The cis position of two protons at tert-C atoms between CH2 fragment in bicyclic system for spiroxindoles 3k,l was assigned based on the NOESY correlation of these protons (Fig. 2).
Thus, (3R*,7′R*,8a′R*) configuration was assigned for spiroxindoles 3k,l.
With the above results taken into account and the mechanistic data on multicomponent transformations of isatins and C–H acids,18–23 the following mechanism for the one-pot pseudo four component condensation of isatins 1, cyclic ketones 2 and two equivalents of malononitrile in the presence of triethylamine at ambient temperature was proposed (Scheme 2).
![]() | ||
Scheme 2 Mechanism of multicomponent transformation of isatins 1, cyclic ketones 2 and two equivalents of malononitrile into spirooxindoles 3. |
The first step of this multicomponent process begins with base induced Knoevenagel condensation of isatin 1 and malononitrile with the formation of isatilidenemalononitrile 4 (Scheme 2). Another equivalent of malononitrile simultaneously reacts with cyclic ketone affording adduct 5 (Scheme 2). Then, by the action of NEt3 cyclic adduct 5 forms anion A, which attacks activated double bond of isatilidenemalononitrile 4 with further cyclization into anion C. The latter interacts with malononitrile providing spirooxindole 3 with the regeneration of malononitrile anion to continue the catalytic cycle.
Footnote |
† Electronic supplementary information (ESI) available: Full characteristics of the new compounds, copies of 1H, 13C, IR-spectra for selected compounds, and X-ray details. CCDC 1050772. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra03452c |
This journal is © The Royal Society of Chemistry 2015 |