TBAHS Catalyzed Synthesis of β-Acetamido Ketones/ Esters

 

Narasimha Murthy Kotra¹*, Buchi Reddy Reguri²  , Mukkanti Khagga³

^1,3Center for Chemical Science and Technology, JNT University, Kukatpally, Hyderabad

²PCA Laboratories Ltd, Kandivali, Industrial Estate, Mumbai, India

*Corresponding Author E-mail: kotramurthy@hotmail.com

An alternative synthesis of amidoalkyl naphthols, employing a four-component  reaction of aryl aldehydes, enolisable ketones, acetyl chloride and acetonitrile to form the corresponding β-acetylamino ketones at room temperature in the presence of a catalytic amount of tetrabutyl ammonium hydrogen sulphate (TBAHS) has been described. The present procedure offers advantages such as shorter reaction time, simple workup with excellent yields. This simple procedure combined with the easy recovery and reuse of the catalyst makes this method economic, benign and a greener chemical process for the synthesis of β-acetamido ketones.

 

 

INTRODUCTION:

β-Acetamido ketones are versatile intermediates in that their skeletons exist in a number of biologically or pharmacologically important compounds. The best known route for the synthesis of these compounds is the Dakin-West reaction¹, which involves the condensation of α-amino acid with acetic anhydride in the presence of a base via an intermediate azalactone to give α-acetamido ketones.

 

EXPERIMENTAL

All the commercial reagents and solvents were used without further purification unless otherwise stated. Melting points were recorded on a Buchi 535 melting point apparatus and are uncorrected. All the reactions were monitored by thin layer chromatography performed on precoated silica gel 60F₂₅₄ plates (Merck). Compounds were visualized with UV light at 254 nm and 365 nm, I₂ and heating plates after dipping in 2% phosphomolybdic acid in 15% aq. H₂SO₄ soln. IR spectra were recorded on a Perkin-Elmer 683 or a 1310 FT-IR spectrometers with KBr pellets. NMR spectra were recorded on a Varian Unity-400 MHz and BRUKER AMX 300 spectrometers using TMS as an internal standard. Mass spectra were recorded on a VG. Micromass 7070H and a Finnigan Mat 1020B mass spectrometers operating at 70eV.

 

Typical procedure:

To a stirred mixture of TBAHS (15 mg) in acetonitrile (2.5 mL), an aldehyde (106 mg), an enolisable ketone (120 mg), and acetyl chloride (5.0 mL) were added. The reaction mixture was stirred at room temperature for 2-3 h. The mixture was filtered to remove the catalyst, and the filtrate was poured in to ice-cold water. The precipitated solid was filtered, dried, washed with petroleum ether 60-80 ⁰C to remove any residual starting material, and dried. All products were characterized by their physical constants and spectra data compared with those for authentic samples.

 

Representative Spectral data:

Compound3a:

Mp 101-103 ⁰C, IR (KBr, cm^-1): 3281, 3060, 1646, 1688, 1557, 1262, 989, 751, 586; ¹H NMR (300 MHz, CDCl₃), δ: 2.09 (s, 3H, Ac), 3.32 (dd, 1H, J= 6.0 and 9.8 Hz), 3.78 (dd, 1H, J=6.0 and 9.8 Hz), 5.54 (m, 1H), 6.74 (brs, 1H), 7.35 (d, 5H, J= 9.6 Hz), 7.56 (d, 3H, J=9.0Hz), 7.89 (d, 2H, J=9.0Hz); . MS (ESI) m/z 268 ([M+H])⁺.

 

Compound 3d:

Mp156.2-158.5 ⁰C, IR (KBr, cm^-1): 3250, 3030, 1662, 1635, 1574, 1265, 1085; ¹H NMR (200MHz, CDCl₃), δ: 2.01 (s, 3H, Ac), 3.44(dd, 1H, J= 5.46 and 9.8 Hz), 3.88 (dd, 1H, J=5.46 and 9.8 Hz), 5.78 (m, 1H), 6.74 (brs, 1H), 7.35 (d, 2H, J= 9.6 Hz), 7.56 (d, 4H, J=9.0Hz), 7.89 (d, 2H, J=9.0Hz); MS (ESI) m/z 336 ([M+H])⁺.

 

Compound 3g:

Mp 176.9-178.1 ⁰C, IR (KBr, cm^-1): 3215, 3062, 1690, 1642, 1551, 1362, 1092, 992, 776; ¹H NMR (200MHz, CDCl₃), δ: 2.02 (s, 3H, Ac), 3.60(dd, 1H, J= 6.59 and 16.11 Hz), 3.89 (dd, 1H, J=5.12 and 16.11 Hz), 6.33 (m, 1H), 6.48 (brs, 1H), 7.34-7.56 (m, 4H,), 7.72-7.86 (m, 4H,), 8.08 (d, 2H, J=8.0Hz); . MS (ESI) m/z 302 ([M+H])⁺ .

 

Compound 3l:

Mp 92.8-94.0 ⁰C, IR (KBr, cm^-1): 3299, 3062, 1689, 1644, 1587, 1296, 1085; ¹H NMR (200MHz, CDCl₃), δ: 1.94 (s, 3H, Ac), 3.33(dd, 1H, J= 5.95 and 16.38 Hz), 3.72 (dd, 1H, J=3.72 and 16.38 Hz), 5.45 (m, 1H), 6.61 (brs, 1H), 7.13-7.35(m, 6H), 7.38 (d, 2H, J=8.19Hz), 7.91 (d, 2H, J=8.19Hz); . MS (ESI) m/z 352 ([M+H])⁺ 

 

RESULTS AND DISCUSSION:

β-Acetylamino ketones are usually prepared through acylation of β-amino ketones², Michael addition to α, β-unsaturated ketones³, or photo-isomerization of phthalimides⁴. The most interesting reaction for the synthesis of these compounds is multicomponent coupling involving aldehyde, enolisable ketone, acetyl chloride and acetonitrile as first reported by Bahulayan and coworkers^5a. The multicomponent reactions leading to the formation of β-acetylamino ketones can be catalyzed by CoCl₂^5b, cobalt(II) acetate supported on polyaniline^5c, monmorillonite K10^5a, and bismuth oxychloride^5d. β-Acetylamino ketones have also been synthesized using Cu(OTf)₂, Zn(II), Bi(II), Sn(II), Sc(III), triflates, BF₃, CuCl₂, BiCl₃, LaCl₃,  LiClO₄, InCl₃^5a, H₂SO₄/SiO₂^5b, zeolite Hβ⁶ and silica-supported sodium hydrogen sulfate (NaHSO4-SiO₂)⁷. In view of the above and taking in to the account of modern paradigm shift towards greener chemistries using catalysis, our studies were directed towards the development of practical and yet environmental friendly procedures for understanding some important transformations.  In the process we developed for the first time the applicability of novel phase transfer catalyst, TBAHS for efficient, convenient and facile one-pot reaction for the synthesis of β-Acetylamino ketones using aryl aldehydes, enolisable ketones, acetyl chloride and acetonitrile in the presence of TBAHS as a phase transfer catalyst at room temperature (Scheme 1).TBAHS as the phase transfer catalyst, being acidic in nature and it performs many organic transformations under mild conditions. It has been used for dehydration and cyclisation step in Hantzsh dihydropyridine synthesis and it is easy to handle, inexpensive, water soluble and thermally stable.^{8, 9}

 

Initially 4-chlorobenzaldehyde was selected as a representative aldehyde in order to optimize the reaction conditions and it was found that the reaction in the presence catalytic amount of TBAHS needs shorter reaction time than that without any catalyst at room temperature. So the best condition was that the reaction was catalyzed by TBAHS at room temperature using the best conditions reported in table, we continued to investigate the reaction at room temperature under solvent free media with 15mg of TBAHS, the desired product was obtained in satisfactory yields. Encouraged by these results, to explore the catalytic potential of TBAHS for the above reaction, we then continued to study the reaction using various aldehydes in the presence of TBAHS. The results were summarized in table indicating different aromatic aldehydes, underwent smooth reaction with acetonitrile and acetophenone to give high yields of products. The presence of acetyl chloride is necessary for the transformation and in its absence gave none of the desired product even after 20 h.

 

 

Scheme 1

 

Table 1: One pot condensation of aryl aldehydes, aryl ketones, acetyl chloride and acetonitrile to give corresponding β-acetamido ketones catalyzed by TBAHS

 

 

The reaction was extended to other aryl aldehydes and ketones as substrate under the optimum conditions. As shown in above Table 1, aromatic aldehydes or acetophenones with electron-donating substitution performed to afford the β-acetamido ketones without the formation of any side products, in excellent yields and in relatively short reaction times at room temperature. The reaction was extended to a variety of aldehydes with β-ketoesters using as catalyst and the results are summarized in Table-2. In all cases mixtures of syn- and anti-diastereomers were obtained, whilst the diastereoselectivity depended upon the nature of the reactants. The regioselectivity was determined by ¹H NMR spectroscopy and by comparison with known compounds in the literature. In general syn and anti selectivity was observed in the reactions of metyl acetoaetate or ethyl acetoacetate (Scheme -2)

 

The reactions with benzaldehyde and 4-substituted benzaldehydes (4-chloro, 4-bromo) were diastereoselective leading to the formation of one diastereomer as the major product (Table-2). It is interesting to note that the opposite diastereoselctivity was observed between 4-chlorobenzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde and 2, 4-dichlorobenzaldehyde. For example, the reaction with 4-chlorobenzaldehyde or 3-chlorobenzaldehyde gives the anti diastereomer as the major product whereas in case of 2-chlorobenzaldehyde the corresponding syn diastereomer predominates and in case of 2, 4-dichlorobenzaldehyde the corresponding syn and anti diastereomers afforded an equal mixtures.

 

Our protocol is advantageous as it does not need an inert atmosphere or a high temperature, involves an aqueous workup and above all short reaction times (2-3 h). The reaction involving acetophenone and substituted acetophenone gave products with only one asymmetric centre. The reaction involving substituted benzaldehydes and methylacetoacetate however, led to diastereomeric mixtures. The ratio of these diastereomers was determined by ¹H NMR spectroscopy.

 

CONCLUSION:

In conclusion, this work describes a convenient and efficient process for the synthesis of β-acetamido ketones through the three-components coupling of various aromatic aldehydes, acetophenone, acetyl chloride and acetonitrile using TBAHSas phase transfer catalyst at room temperature. Present methodology offers very attractive features such as reduced reaction times higher yields and economic viability of the catalyst when compared with conventional method as well as with other catalyst and will have wide scope in organic synthesis. This simple procedure combined with the easy recovery and reuse of the catalyst makes this method economic, benign and a greener chemical process for the synthesis of β-acetamido ketones. We believe that this procedure is convenient, economic and a user-friendly alternative process for the synthesis of β-amino ketones.

 

Scheme 2

 

Table 2: One pot condensation of aryl aldehydes, methyl acetoacetate, acetyl chloride and acetonitrile to β-ketoesters catalyzed by TBAHS.

^a Isolated yields

^b Ratio obtained from ¹H NMR of the Crude reaction mixture

 

 

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Received on 06.02.2015         Modified on 25.02.2015

Accepted on 08.03.2015         © AJRC All right reserved