Solvent-free microwave-promoted Michael addition of aza-nucleophiles to benzo[ b ]thiophen-2-yl-2-propenone

A series of Michael adducts ( 5 - 11 ) have been synthesized with good yields under solvent-free microwave conditions. Aliphatic and aromatic amines utilized as Michael donors reacted with 1-(4,7-dimethoxybenzo[ b ]thiophen-2-yl)-2-propen-1-one ( 4 ), to produce β -aminoketones and azaheterocyclic compounds of potential biological interest.


Introduction
β-amino ketones are useful synthetic intermediates used in the synthesis of biologically active natural products and pharmaceuticals. 1,2Classical methods for the synthesis of β-aminoketones include the Mannich reaction of methylketones with amines in the presence of paraformaldehyde, alkylation of amines with β-haloalkyl ketones, and 1,4-conjugate addition reactions with vinyl ketones and amines. 3he Mannich reaction has serious disadvantages, including drastic reaction conditions and long reaction times.The Michael addition as one of the most important C-C bond-forming reactions, has attracted much attention toward the development of enantioselective catalytic procedures 4 .Aza-Michael addition of a nitrogen-centered nucleophile is a convenient way to introduce amine-based functionality to a β-carbon attached to an electron-withdrawing group, [5][6][7] although this route usually requires acid or base-catalyst to activate one of the substrates.Hetero-Michael addition of amines to α,β-unsaturated carbonyl compounds gives β-amino ketones, which are attractive for their use as synthetic intermediates of anticancer agents, and antibiotics. 8,9The addition of thiols to α,β-unsaturated carbonyl compounds results in the synthesis of biologically active compounds, such as the calcium antagonist diltiazem. 10,11omtsyan et-al 12,13 reported the synthesis of β-aminoketones from N-methoxy amides (Weinreb amides) through a novel sequential transformation consisting of nucleophilic substitution with vinyl-Grignard reagents, followed by a Michael-type reaction with a number of amines.The reaction proceeds in good yields for a variety of amides, vinyl Grignard reagents, and N-nucleophiles.It is interesting to note that aza-Michael reactions have also provided and easy and direct route to β-amino esters 14 and β-amino amides. 15any organic reactions proceed much faster and with higher yields under microwave irradiation compared to conventional heating.][18] In this paper we report the synthesis in good yield of a variety of β-aminoketones of potential biological interest under environmentally friendly conditions, using microwave-supported Michael-addition.This protocol includes reactions that can be conducted without solvent and in absence of metal catalysts, a highly desirable experimental condition.

Results and Discussion
In a previous communication 19 we described that 2-piperazinobenzothiophene derivatives (I) were allowed to react with benzothiophen-2-propenone (II) in a Michael reaction microwave supported under solventless conditions, to yield a series of benzothiophene (III) in the search for potential neurobioactive compounds, as shown in the retrosynthetic scheme 1. R 1 =OMe,H ; R 2 = H,OMe,NO 2
The synthesis of 2-propenone 4, was carried out 19 in three steps from the benzothiophene alcohol 1 which was oxidized with pyridinium chlorochromate (PCC) in CH 2 Cl 2 to give aldehyde 2 in good yield.Further reaction with vinyl magnesium bromide, afforded allyl alcohol 3 which was finally converted in the 2-propenone 4 (Scheme 2).

Scheme 2
In a model reaction, benzothiophen-2-propenone 4 and the corresponding aza-nucleophile were impregnated on a 95:5 mixture of silica gel-manganese dioxide as solid inorganic support, and irradiated in a microwave-assisted organic synthesizer during short periods of time (Scheme 3).

Scheme 3
In general, the reactions proceeded efficiently with relatively good yields of the desired products (Table 1, entries 1-7).Michael addition and cyclodehydratation in a single synthetic step occurred for compound 9.An interesting reaction was carried out using the carbonucleophile 1(H)-indole as a Michael-donnor.The product was the 3-indolyl adduct 11 because of the known electron-rich nature of the C-3 position of 1(H)-indoles In table 1 it is seen that products were obtained in relatively good yields (63-90%) and with short reaction times.The bis -adduct 6 needed the longest time, which may be due to a major steric hinderance present in the second addition step.It is important to note that when the reaction of thiophene 4, with the azanucleophiles was carried out under conventional heating conditions, long times (over 7h ) were required and the reactions did not go to completion, which may be attributed to the high stability of propenone 4, due to the great aromatic character of the π-donor benzothiophene moiety.
We next moved to binucleophiles by reaction of 1-(4,7-Dimethoxy benzo[b]thiophen-2-yl)-2propen-1-one 4 with 1,2-diaminobencene.The solid mixture was irradiated at 600W for 7 min, to give an orange solid characterized as 1,5-benzodiazepine 9.The reaction takes place in two steps involving the previous formation of the Michael Adduct as an intermediate, which readily undergoes a dehydrative cyclization to give 9 as described in Scheme 3.

Scheme 3
The 1 H NMR spectrum of 9 was clean and exhibited two triplets at δ: 3.22 and 3.78 ppm derived from methylene groups.The IR (KBr) spectrum exhibited absorptions at 3386 cm -1 (N-H), and a weak band at 1611 cm -1 (C=N), along with the dissapearence of the strong carbonylic absorption at 1665 cm -1 , which indicated the nature of the cyclization.The final confirmation came with the HRMS analysis M + ( Theoric / Experimental ) (338.10890 / 338.10868).
The bis-aza-Michael reaction between piperazine and Michael acceptor 4, followed a similar procedure, although in this case a 2:1 mole ratio of piperazine (1 mmol), and 2-propenone (2 mmol) was used forming a bis-addition product, leading to dimeric benzothiophene piperazine 10 in 78% yield.The 1 H NMR displayed a singlet at δ: 2.73 ppm, for the eight equivalent piperazine hydrogens, along with two triplets at δ: 2.97 and 3.29 ppm for the methylene protons.The homo bis -adducts have been recognized in medicinal chemistry as compounds which usually enhance the potency and selectivity relative to their monomeric lead, through a more thermodynamically favourable binding interaction with a biological receptor 23 .
Finally, we were interested in the reaction of 4 with 1(H)-indole since it often gives raise to rather complicated reactions (e.g., dimerization and polimerization).As stated previously, the C-3 alkylation proceeded regioselectively (N-alkylation product was not observed), giving the adduct 11 in relatively good yield.The IR band at 3414 cm -1 (N-H), along with singlets in 1 H NMR at δ: 7.96 (s, 1H, NH) ppm, and δ: 8.06 (s,1H, 2'-H) ppm for the C-2 indole position confirmed this addition.

Conclusions
The procedure presented here provides a simple, efficient and rapid method for the preparation of β-aminoketones and benzothiophene propenone bis-adducts of biological interest using an aza-Michael microwave-assisted protocol.Further efforts focused on the synthesis of new skeletons with potential biological relevance, along with a neurobiological screening of the synthesized compounds are in progress.

Experimental Section
General.Melting points were determined on a hot-stage apparatus and are uncorrected.The IR spectra were recorded, on a FT-IR Bruker IFS 55 spectrophotometer for KBr disc and wave numbers are reported in cm -1 .The 1 H NMR and 13 C NMR spectra were performed on a Bruker DRX-300 spectrometer (300 and 75 MHz) in deuterochloroform, or DMSO-d 6 .Chemical shifts were recorded in ppm (δ) relative to TMS as an internal standard.J values are given in Hz.
Microanalyses were carried out on a Fisons EA 1108 analizer.High resolution mass spectrum were recorded on a Thermo Finnigan model MAT 95XP Mass Spectrometer.The microwaveassisted procedures were carried out in a Milestone, Lavis 1000.Multiquant ® , operating at 600watts.Manganese (IV) dioxide was obtained by our reported procedure 14 .The solid support was prepared by heating a 4:1 mixture of silica gel (70-230mesh) and manganese (IV) dioxide at 300 °C for 2h.Silica gel Merck 60 (70-230mesh) and DC-alufolien 60 F 254 were used for column and TLC chromatography respectively.