Microwave Activation: Solventless Catalysed Synthesis of Cross Conjugated Dienones of Tropinone ^†

Abstract

Cross-conjugated dienones are very important biologically active products. The condensation of N-methyl-8-azabicyclo[3.2.1]-bicyclo[3.2.1]octan-3-one (tropinone) with aromatic aldehydes takes place in the presence of acidic (K10 clay, silica) or basic catalysts (alumina, KF-alumina). The best yields of (2E,4E)-2,4-bis-arylmethylene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones were obtained with the K10 clay under microwave irradiation without solvent. New dienones derived from tropinone will be tested in various biological assays.

1. Introduction

Cross-conjugated dienones exhibit important biologically activities [1]. Furthermore, tropane derivatives are very known class of bioactive alkaloids [2] (atropine, cocaine, …).

In the course of our ongoing research on Knoevenagel condensation in the dry condition under microwave activation [3], we are interested in performing condensation of tropinone 1 with aromatic aldehydes in order to prepare potentially active precursors (Scheme 1). We described herein the solventless synthesis of 2,4-bis(arylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-ones, only some derivatives were described more than one century ago [4].

2. Results and Discussion

In a preliminary experiment, we have studied the reaction of condensation of tropinone with piperonal 2a (Scheme 2) in order to optimize the experimental conditions. First, we have investigated the non-catalytic reaction by simply grinding the two solids at room temperature [5]. Within a few minutes, an eutectic liquid (tropinone/piperonal stoichiometry: 1/1 or 1/2) was formed, but no reaction took place after ten days.

For the second time, we chose to explore the abilities of various catalysts with different acid-base properties (

Table 1. Catalysts and experimental conditions for condensation of tropinone 1 with piperonal 2a.

Catalysts	RT conditions	Microwave
Piperidine	Very partial reaction	partial reaction
Neutral alumina	no reaction	partial reaction
KF on alumina	reaction	reaction with by-products
Silica	no reaction	partial reaction
K10	complete after 3 days	complete within 4 min

). The progress of the reactions was monitored by TLC.

The progress of the reactions was monitored by TLC [6]. Firstly, we have performed the condensation of tropinone and piperonal in the presence of few drops of piperidine, as a base, but unfortunately, an incomplete condensation took place even under microwave irradiation.

Next, we focussed on several solid catalysts, two with basic properties, such as alumina and KF on alumina, and two with acidic properties, such as silica and K10 clay. With neutral alumina (Woelm 2087), a poorly basic catalyst, no reaction was observed at room temperature, whereas the reaction took place under microwave irradiation but ungratifyingly, the reaction was not completed. With the very basic catalyst KF on alumina, the solid became rapidly yellow, even at room temperature. Nevertheless, in the case of alumina/KF (and unlike alumina), the products remain adsorbed to the support and are very difficult to recover using a solvent. Moreover, by-products were detected as a result of microwave irradiation.

With silica, a poorly acidic catalyst, no reaction was observed at room temperature after 24 h. With the more acidic clay K10, the reaction occurred and was completed after more than 3 days, but under the influence of microwave irradiation (50 W, 4 min, 2450 MHz), the condensation was very rapid and efficient.

It is worth mentioning that with piperonal, under basic or acidic conditions, the bicondensation product was accompanied by only a small amount of the monocondensation product. By varying the stoichiometry of the reactants, it was not possible to prepare a pure monocondensation product, whereas the bicondensation product can be obtained with excellent purity with an excess of piperonal (piperonal/tropinone equal or superior to 2).

Based on these results and by taking into consideration both the purity of the product and yield of the reaction, we have chosen to conduct the condensations of tropinone with K10 clay under microwave irradiation to recover using a solvent. Moreover, by-products were detected under microwave irradiation along with other aromatic aldehydes in a stoichiometry of 1/1. The products were eluted with acetonitrile and purified by flash chromatography on silica column. The monocondensation products can be isolated in very small amount as oil, and the bicondensation products are recovered as crystallized solids. In one case, the monocondensation product was obtained in significant amount with the hindered 2,6-dichlorobenzaldehyde.

All products were characterized by ¹H and ¹³C NMR, elemental analysis, and ESI mass spectroscopy. The stereochemistry of double bonds (2E,4E) was attributed by NOE experiments, according to the method described [7] for the nortropinone derivatives. The products of condensation are reported in

Table 2. Condensation products 3a–g obtained from tropinone 1 and aromatic aldehydes with K10 clay under microwave irradiation (2450 MHz, 4 min, 50 W).

Product	Aldehyde	Yield (%)	mp (mp lit.)	Mol Formula	Found (Required) %
					C	H
2a	piperonal	96	214	C24H21NO5	71.37 (71.45)	5.34 (5.25)
2b	benzaldehyde	77	152 (1534)	C22H21NO	83.63 (83.78)	6.76 (6.71)
2c	2,4-dichlorobenzaldehyde	88	222	C22H17NOCl4	58.10 (58.31)	3.75 (3.78)
2d	2,4,6-trimethoxybenzaldehyde	85	215	C28H33NO7	67.75 (67.86)	6.82 (6.71)
2e	3-phenoxybenzaldehyde	92	114	C34H29NO3	81.83 (81.74)	5.95 (5.85)
2f	furaldehyde	81	145 (1454)	C18H17NO3	73.17 (73.20)	5.86 (5.80)
2g	cinnaldehyde	98	149	C26H25NO	84.95 (84.98)	6.90 (6.86)

.

3. Conclusions

New (2,4-bis-arylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-ones can be conveniently prepared by the reaction of tropinone with various aromatic aldehydes without solvent on K10 clay under microwave irradiation.

4. Experimental

The reactions were conducted with the monomode resonance cavity Prolabo Synthewave 402 (2450 MHz) piloted by a microcomputer. ¹H and ¹³C NMR (reference from internal Me₄Si) were recorded on a Brucker AC 250 instrument from solution in CDCl₃ with TMS as the internal reference. FT IR spectra were recorded on a PerkinElmer Spectrum One spectrometer. Elemental analyses were recorded on a CE Instrument NA 2500. Melting points were determined with a Kofler bench. KF on alumina was prepared according to the literature.

General procedure for the preparation of (2E,4E)-2,4-bis-benzo[1,3]dioxol-5-ylmethylene-8-methyl-8-aza-bicyclo[3.2.1]octan-3-one:

In a typical experiment, a mixture of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (600 mg, 4.3 mmol) and piperonal (1.3 g, 8.6 mmol) was ground and a liquid was obtained. The liquid was adsorbed on clay K10 (2 g), and the solid mixture was irradiated at 50 W for 4 min. The yellow solid was extracted with acetonitrile (3 × 20 mL). After evaporation of solvent, the residue was chromatographed on silica with AcOEt—n-hexane (30:70) and then with pure AcOEt. (2E,4E)-2,4-bis-benzo[1,3]dioxol-5-ylmethylene-8-methyl-8-aza-bicyclo[3.2.1]octan-3-one. The yellow solid was recrystallized in ethyl acetate. (mp = 214 °C; lit 214 °C). C₂₄H₂₁NO₅; IR = 1680 cm⁻¹ (νCO). PMR: δ = 1.50–1.55 (m, 4H, CH₂-CH₂); 2.30 (s, 3H, N-CH₃); 3.50 (m, 2H, 2xCH-N); 6.0 (s, 4H, 2X-O-CH₂-O-); 6.90–7.0 (m, 6H, 2X 3Harom).