Four-component Domino Reaction Providing an Easy Access to Multifunctionalized Tricyclo[6.2.2.0^1,6]dodecane Derivatives

Abstract

A novel four-component domino reaction has been discovered. The reaction is easy to perform simply by mixing four common reactants and Cs₂CO₃ in ethylene glycol under microwave heating. The reaction proceeds at fast rates and can be finished within 15–24 min, which makes work-up convenient. Four stereogenic centers with one quaternary carbon-amino function have been controlled completely. The stereochemistry has been unequivocally determined by X-ray structural analysis. The resulting tricyclo[6.2.2.0^1,6]dodecane derivatives are of importance for organic and medicinal research.

Introduction

Efficient and elegant assembly of complex structures with multiple stereocenters has become an important topic in chemical sciences.^1–4 Multi-component domino reaction has thus emerged as a powerful tool for this purpose in which a series of chemical processes can be controlled in a one-pot operation; it can avoid time-consuming and costly syntheses, tedious work-up and purifications of precursors as well as protection/deprotection of functional groups.^5–6

In the past several years, we have been engaging in the development of multi-component domino reactions that can provide easy accesses to useful core structures of chemical and pharmaceutical interests.^7–8 Very recently, we discovered a new four-component domino reaction for the synthesis of multifunctionalized quinazoline derivatives.^7a The reaction is easy to perform simply by mixing readily available starting materials, aromatic aldehyde, cyclopentanone and cyanoacetamide with K₂CO₃ in ethylene glycol under microwave (MW) irradiation. This reaction is believed to undergo the tandem formations of two different Knoevenagel intermediates followed by C=C bond rearrangement, [4+2] cycloaddition, intramolecular Michael-type addition and carbonyl addition/elimination reactions.

During continuing this project, we found that when aromatic aldehydes employed in our previous system were replaced by their aliphatic counterparts, the quinazoline derivatives were not generated. Instead, the reaction occurred to another direction to form multi-functionalized tricyclo[6.2.2.0^1,6]dodecanes that belong to another family of important scaffolds for organic synthesis and drug design in pharmaceutical sciences.⁹ In this communication, we would like to disclose the discovery of this novel four-component domino reaction (Scheme 1).

Scheme 1.

The four-component domino reaction

Results and Discussion

We started this study by subjecting iso-butyraldehyde and cycloketones 2a to the reactions with cyanoacetamide 3 in the presence of K₂CO₃ under microwave (MW) irradiation (Scheme 2).^7a As described in our previous communication, the original reaction worked best in ethylene glycol at 120 °C. However, in the current aliphatic aldehyde-based system, the product 4a was only obtained in a yield of 42%. We then decreased the temperature to 80 °C and found the yield can be enhanced to 51% (a similar yield was obtained at 100 °C). Pleasingly, when we utilized one equiv. of Cs₂CO₃ to replace K₂CO₃ as the base additive at this temperature, the yield can be further increased to 73% (Table 1, entry 3).

Scheme 2.

The four-component domino reaction of 1 with 2a and 3

Table 1.

Optimization of reaction conditions

Entry	Base	T / °C	Time / min	Yield /%a
1	K2CO3	120	20	47
2	K2CO3	80	16	51
3	Cs2CO3	80	15	73

^aIsolated yield

Under the above optimized conditions, the substrate scope of this reaction was examined by using readily available starting materials. As revealed in Table 1, a range of aliphatic aldehydes are suitable for reacting with various cyclic cycloketones 2 and cyanoacetamide 3 under microwave heating. In addition, the scope of cycloketones 2 was also proven to be remarkable, which include normal cycloketones (2a and 2b) and heteroatom (O, S, and N)-attached cycloketones, such as tetrahydropyran-4-one 2c, tetrahydrothiopyran-4-one 2d, N-t-Boc and N-Bn-piperidin-4-one 2e–f. Particularly, the N-t-Boc-amino cycloketone substrate (2d) led to cycloamino products 4l–4o in which N-t-Boc functionality was found to be stable under microwave irradiation at 80 °C.

Most functionalities of resulting tricyclo[5.2.2.0^1,5]undecane products offer a great flexibility for further structural modifications. These products are indeed lactam analogs that are directly useful for drug design; their rings can be opened for peptide/protein mimetic studies. In fact, after careful hydrolysis of cyano group, a series of special dehydro β-amino acids can be obtained.¹⁰

Similar to our previous four-component domino process,^7a the present reaction also showed the following attractive characteristics: (1) fast reaction rates which enable the reaction to be completed within 15–24 min, which can save energy and manpower for future industrial production; (2) the environmentally friendly process in which water is the major by-product; (3) the convenient work-up which only needs simple filtration since the products directly precipitate out after the reaction is finished and when its mixtures are diluted with cold water; (4) readily available starting materials of aldehydes, cycloketones and cyanoacetamide. Moreover, all stereogenetic centers and geometry have been completely controlled including a quaternary amino center attached on the lactam ring. The present reaction is among a very few cases in organic chemistry in which multiple-rings, four stereocenters and geometry can be controlled in a one-pot intermolecular manner.

X-ray diffraction of single crystals of tricyclo[5.2.2.0^1,5]undecanes 4a has been unambiguously determined.¹¹ The structural elucidation and attribution of relative stereochemistry of all products have been fully characterized by ¹H- and ¹³C-NMR and other analyses.

The mechanism of this domino reaction is proposed as shown in Scheme 3. Similar to the aromatic aldehyde-based reaction, the initial steps involve Knoevenagel condensations to generate two individual Knoevenagel intermediates A and B. However, these two intermediates do not occur through [4+2] cyclic addition. Instead, they undergo α,β-unsaturated addition in which A is added onto B to give intermediate C; this would be attributed to the fact that β-alkyl intermediates B are less stable (more partially separated charges exist) than its β-aryl counterparts, which favors Michael-type addition by enolate anion under the basic condition. The next step involves an intramolecular tandem process of another Michael-type addition and carbonyl addition to form intermediate D to form the key tricyclic skeleton. The subsequent amide hydrolysis and decarboxylation result in the final product 4. It seems that Cs₂CO₃ is more effective than K₂CO₃ by acting as the base for dehydration and decarboxylation during this domino process to drive the reaction toward the formation of tricyclo[5.2.2.0^1,5]undecane product.

Scheme 3.

The reasonable mechanism of formation of tricyclo[5.2.2.0^1,5]undecanes

In conclusion, a novel four-component domino reaction and the unprecedented challenging mechanism have been discovered and proposed, respectively. This reaction is very simple and easy to perform simply by mixing four common reactants and Cs₂CO₃ in ethylene glycol under microwave irradiation. A wide range of readily available commercial chemicals of aliphatic aldehydes, cycloketones and cyanoacetamide can be employed as substrates. This domino method provides a rapid access to highly functionalized tricyclo[5.2.2.0^1,5]undecanes (tricyclic lactams) with the complete control of stereo and regiochemistry in which four stereogenic centers with one quaternary carbon-amino attachment. The stereochemistry has been unequivocally determined by X-ray structural analysis. The asymmetric versions of the present and previous new domino reactions are being studied in our laboratories.

Experimental Section

General

Microwave irradiation was carried out with microwave oven Emrys Creator from Personal Chemistry, Uppsala, Sweden.

Example for the synthesis of 4a: 11-Amino-6-isopropyl-8-oxo-9-azatricyclo[5.2.2.0^1,5] undec-10-ene-10-carbonitrile (4a)

Microwave Heating

i-Butyraldehyde (1a, 2.2 mmol, 0.16 g, 1.1 equiv.) was introduced in a 10-mL Emrys™ reaction vial, cyclopentanone (2a, 2.0 mmol, 0.17 g, 1.0 equiv.) and cyanoacetamide (3, 4.0 mmol, 0.34g, 2.0 equiv.) were then successively added, followed by the catalyst Cs₂CO₃ (2 mmol, 0.65g, 2 equiv.) and ethylene glycol (1.5 mL). Subsequently, the reaction vial was capped and then pre-stiring for 20 second. The mixture was irradiated (initial power 50 W and maximum power 100 W) at 80 °C until TLC (petroleum ether: acetone 3:1) revealed that conversion of the starting material 1a was complete (15 min). The reaction mixture was then cooled to room temperature and then diluted with cold water (40 ml). The solid product was collected by Büchner filtration and was purified by flash column chromatography (silica gel, mixtures of petroleum ether / acetone, 10:1, v/v) to afford the desired pure products 4a as white solid (Mp: > 300 °C).

Table 2.

Domino Synthesis of Tricyclo[6.2.2.0^1,6]dodecane Derivatives 4^a

Entry	2		Product 4b	R =	Time / min	Yieldb /%
1		2a		4a, i-Propyl	15	73
2		2a		4b, sec-Butyl	16	65
3		2a		4c, i-Butyl	22	61
4		2b		4d, i-Propyl	16	67
5		2b		4e, Cyclohexyl	24	49
6		2c		4f, i-Propyl	20	74
7		2c		4g, i-Butyl	22	58
8		2d		4h, i-Propyl	18	70
9		2d		4i, sec-Butyl	18	65
10		2d		4j, n-Propyl	22	50
11		2d		4k, Cyclohexyl	24	52
12		2e		4l, i-Propyl	18	67
13		2e		4m, sec-Butyl	20	63
14		2e		4n, i-Butyl	20	60
15		2e		4o, i-Pentyl	24	54
16		2f		4p, i-Propyl	18	66
17		2g		4q, i-Propyl	18	70
18		2g		4r, sec-Butyl	20	63
19		2g		4s, i-Pentyl	22	58

^aReagents and conditions: Cs₂CO₃ (1.0 equiv), 80 °C, ethylene glycol, microwave heating.

^bIsolated yield..