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483One-pot synthesis of enaminones using Gold's reagent

Letters in Organic Chemistry, 2010, 7, 483-486 483

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? 2010 Bentham Science Publishers Ltd.

One-Pot Synthesis of Enaminones Using Gold's Reagent

Tamer S. Saleh*,a , Mohamed A. Al-Omar b and Hatem A. Abdel-Aziz b

a Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

Received December 16, 2009: Revised March 13, 2010: Accepted March 20, 2010

Abstract:

Enaminones were efficiently prepared via modification for Gupton method, which depends on carrying out the latter procedure in one step reaction, avoiding the isolation of [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethylammonium chloride (Gold's reagent) (5) which is prepared in situ from cyanuric chloride (4) then it reacts successfully with ketone 1a-j to produce the enaminones 3a-j in suitable yields. The modified method overcomes the drawbacks of the known methods for preparation of enaminones.

Keywords: Enaminone, cyanuric chloride, gold's reagent, DMF-DMA , Ketone. Enaminones have proven to be valuable synthons for a wide variety of biologically active heterocyclic ring system [1-5]. Several methods for the preparation of enaminones have been reported [6-10], since the preparation of dimethylformamide-dimethylacetal (DMF-DMA ) first repor-ted by Meerwin et al. [11,12], a plethora of transformations has appeared in the literature employing formamide acetals and their derivatives.

A Large number of articles were reported for the synthesis of enaminones by using the commercially available and the most effective -dimethylamino methylenating agent dimethylformamide-dimethylacetal (DMF-DMA ) (Scheme 1) [6-9] but it is relatively expensive, moisture and heat sensitive reagent [13,14].

On the other hand, although, the preparation of enaminones has been prepared by the Gupton method using Gold's reagent in a good yields, this method has some limitations due to the difficulties of the isolation of Gold's reagent 5, where it is very hygroscopic and should be handled under a moisture-free condition (Scheme 2) [10]. Thus, this is necessary to develop a more effective synthetic procedure for enaminone.

As an extension of our continuous efforts directed towards the development of convenient synthetic approaches

*Address correspondence to this author at the Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt; Tel: +20 101978724; Fax: +202 333 70931; E-mail: tamsaid@https://www.wendangku.net/doc/a617660328.html, for the construction of some biologically active heterocyclic compounds [15-19].

We report herein the synthesis of enaminones 3a-j as important starting materials by using Gold's reagent 5 instead of DMF-DMA , we modified the Gupton method to become more simple, faster, efficient and economical method for obtaining such class of compounds and to be a promising excellent strategy for the synthesis of enaminones for incoming studies (Scheme 3).

[3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethyl ammonium chloride (Gold's reagent) (5) was prepared in situ from cyanuric chloride (4) in the presence of 6 equivalent of dimethylformamide under reflux in dry dioxane for 1 h followed by addition of ketone 1a-j in sodium methoxide to

produce the enaminones 3a-j in excellent yields (Scheme 3). Our modification for Gupton method depends on carrying out the latter procedure in one step reaction avoiding the isolation of Gold's reagent 5 prepared, in our procedure , in situ where it is very hygroscopic and should be handled under a moisture-free environment in addition to reducing working up time used in the isolation of this intermediate also, we found that yield of enamiones produced 3 affected with molar ratio of cyanuric chloride to the ketone used. Table 1 shows the effect of using different molar ratio of cyanuric chloride on yield of enaminones of ketone 1a , 1b ,1i or 1j which are taken as representative examples. The reaction time, for each compound, was examined by TLC and it was the same in the different ratios.

Method A

Me Me +

N Me

O O Me

1a-j

3a-j 2

(DMF-DMA)

Scheme 1.

484 Letters in Organic Chemistry, 2010, Vol. 7, No. 6 Saleh et al.

From these results, it is obvious that molar ratio of ketone

to cyanuric chloride 1:0.7 is the most adaptable ratio for one step synthesis of enaminones, since comparatively higher yields are achieved and when the molar ratio of ketone to cyanuric chloride increased (more than 1:0.7) no noticeable change in the yield of enaminone. Table 2 shows the yield and time of the mentioned reaction (method C). EXPERIMENTAL

Melting points were measured with a Gallenkamp apparatus and are uncorrected. IR spectra were recorded on Shimadzu FT-IR 8101 PC infrared spectrophotometer. The

NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer. 1H spectra were run at 300 MHz in deuterated dimethylsulphoxide (DMSO-d 6). Chemical shifts were quoted in and were related to that of the solvents. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 e.V. Elemental analyses were carried out at the Microanalytical center of Cairo University, their results were found to be in good agreement (±0.2%) with the calculated values.” 2-acetyl benzothiazole (1i) [25] 2-Acetyl benzofuran (1h) [23] and 2-acetyl-1-methy benzimidazole (1j) [26] were prepared by the reported methods. Cyanuric chloride (4), acetophenone, 4-bromoacetophenone, 4-nitroacetophenone, 2-acetyl furan, 2-acetyl thiophene, 2-

N Me

Me Me

6 DMF

Me Me

N Me

Method B (Gupton method)

3 CO 2

Step 1

Step 2

1a-j

53a-j

(Gold's reagent)

Scheme 2.

N Me

Method C

1a-j

3a-j

MeONa

Scheme 3. Table 1. Yields of Enaminones 3a, 3b, 3i and 3j for 0.1 mol of Ketones 1a, 1b, 1i and 1j, Respectively with Different Molar Ratios of Cyanuric Chloride (4)

Yield%

1a, 1b, 1d or 1h

Cyanuric Chloride (4)a

3a 3b 3i 3j 0.035 mol 83 74 85 75 0.05 mol

0.07 mol 0.08 mol 0.1 mol

0.09 mol

95 98 96 89

The molar equivalent of DMF was used in each time 6 moles of cyanuric chloride (4).

One-Pot Synthesis of Enaminones Using Gold's Reagent Letters in Organic Chemistry, 2010, Vol. 7, No. 6 485

acetyl pyrrole and 3-acetyl pyridine were used as obtained commercially.

Table 2. Yields and Time of Reaction (Method C)

Modified Method for the Synthesis of Enaminones; General Procedure

To a mixture of cyanuric chloride (4) (12.77 g, 0.07 mol) in dry 1,4-dioxane (15 mL), N,N-dimethylformamide (30.7 g, 0.42 mol) was add. The resulting solution was refluxed gently for 1 h, while a considerable amount of carbon dioxide was evolved, the [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]-dimethylammonium chloride (5) rapidly solidified, the reaction mixture was allowed to cool to room temperature. A mixture of sodium metal (4.6 g, 0.2 mol) dissolved in absolute methanol (200 mL) was added in small portions followed by the addition of appropriate ketone (1a-j) (0.1 mol) and the resulting mixture was refluxed for 3-4 h (as examined by TLC) through which the non-isolable salt and the ketone were dissolved (in case of solid ketones) and sodium chloride was formed. The reaction mixture is cooled to room temperature; ethanol (25 ml) was added. The resulting solid was collected by filtration, washed thoroughly with ethanol, dried and finally crystallized from the proper solvent to afford the enaminones 3a-j.

All the products are known and the data are found to be identical with those that reported in the literature (Table 1) [27].

In conclusion, we have uncovered a facile reaction for the preparation of enaminones. The experimental simplicity of the reaction is especially noteworthy.

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[27] Selective data of compounds: (3a) Yield 95%; mp 86–88 0C; 1H

NMR (300 MHz, CDCl3, TMS) 2.85–3.22 (6H, 2br s, N(Me)2),

5.78 (1H, d, J =12.8 Hz), 7.40 (3H, m), 7.70 (1H, d, J =12.8 Hz),

7.85 (2H, m) IR (KBr) v max 1649 (CO); MS (EI) m/z 175 (M+,

37%), 158 (84), 98 (100), 55 (55), 51 (55). (3f) Yield 96%; mp

106-108 0C; 1H NMR (300 MHz, CDCl3, TMS) 3.15–3.29 (6H, 2br

s, N(Me)2), 5.92 (1H, d, J =12.7 Hz), 7.70 (1H, d, J =12.7 Hz), 7.86

(3H, m), , 8.05 (2H, m) IR (KBr) v max 1680 (CO); MS (EI) m/z 225

(M+, 62%).(3J) Yield 89%; mp 150-151 0C; 1H NMR (300 MHz,

CDCl3, TMS) 3.08 (6H, s, N(Me)2), 6.37 (1H, d, J =12.3 Hz),

7.82-7.89 (4H, m), 7.92 (1H, d, J =12.3 Hz), IR (KBr)vmax 1648

(C=O), 1601 (C=N); MS (EI) m/z 229 (M+, 58%).