Microwave Accelerated Aza-Claisen Rearrangement

A study of microwave-induced and standard thermal Overman rearrangement of selected allylic trichloroacetimidates 1a-1f, 6-8 to the corresponding acetamides 2a-2f, 9- 11 is reported. The microwave-assisted rearrangement of trifluoroacetimidate 13 is also described. Using this methodology, an efficient access to versatile allylic trihaloacetamides building synthons was established.


OPEN ACCESS
A significant acceleration of aza-Claisen rearrangements was observed using microwave irradiation [15]. This fact eliminated problems with previously required high temperatures and extended reaction times, and also reduced decomposition of the starting materials and products.

Results and Discussion
In this communication, we wish to report on microwave-assisted thermal Overman rearrangement of some selected allylic trihaloacetimidates 1a-f, 6-8, 13 that are derived either from simple allylic alcohols, amino acids or the modified sugars, respectively, and thus illustrate the potential of microwave irradiation to accelerate this reaction.  Thermally driven [3,3]-sigmatropic rearrangements (Scheme 1) were carried out according to the procedure described by Overman [10]. In the microwave-assisted thermal aza-Claisen rearrangement, the imidate was dissolved in o-xylene, powdered anhydrous K 2 CO 3 [17] (2 mg/mL) was added, and the solution was heated under sealed vessel conditions. The scope of this method was investigated and all synthesized imidates (only imidates 1e and 1f were not characterized and used immediately to avoid problems connected with their instability) in Table 1 were converted to the corresponding trichloroacetamides 2a-2f in considerably shorter reaction times, compared to the conventional thermal rearrangement. We have observed that the use of microwave irradiation lead to a substantial reduction of the reaction times (from hours to minutes, Table 1, Entry 1-5). On the other hand, the conversion of 1f to compound 2f was achieved at the same reaction time in the both cases (the microwave-assisted and standard thermal conditions, Table 1, Entry 6).

Scheme 2.
Microwave accelerated Overman rearrangement of the chiral imidates. In earlier studies was found that Pd(II)-catalyzed Overman rearrangement of trichloroacetimidates 6, 7 derived from primary allylic alcohols with an adjacent centre of chirality proceeded with an excellent diastereoselectivity (de ≥ 98%) [12]. In the next phase of our work we decided to study whether the described microwave-assisted Overman rearrangement could lead to a certain degree of diastereoselection. The conversion of known allylic alcohols [12,14] into trichloroacetimidates 6-8 was achieved using trichloroacetonitrile and DBU as a base in dichloromethane (Scheme 2). The results of the thermal and microwave induced Overman rearrangements of imidates 6-8 are summarized in Table  2. We have found that microwave irradiation of 6-8 led to the rearranged products 9, 10 [12] and 11 [14] (as the mixtures of diastereoisomers) with substantial shortening of the reaction times (from 24 h to 5 min) with good yields (Table 2), however, it has shown that in these cases microwave-induced rearrangement had practically no influence on the diastereoselectivity of aza-Claisen rearrangement ( Table 2).
Finally, we have investigated Overman rearrangement of the sugar allylic trifluoroacetimidate 13 under microwave irradiation. Trifluoroacetimidate 13 was prepared from the corresponding allylic alcohol 12 derived from D-glucose [19] by reaction with CF 3 CN in THF (Scheme 3). Rearrangement of 13 afforded trifluoroacetamide 14 as the mixture of diastereoizomers (de=19%) (Scheme 3). In order to determine the best reaction conditions, a series of the thermally and microwave accelerated rearrangements of imidate 13 was performed. Studies showed that microwave irradiation accelerated of the rearrangement 13→14a,b (24 times) in comparison with conventional thermal conditions ( Table  2, entry 4) without any improvement in the stereoselectivity. Extension of the reaction time led to the decomposition of product 14.

Conclusions
In summary, a remarkable acceleration of the Overman rearrangemet of allylic trihaloimidates to the corresponding allylic trihaloamides was observed using microwave irradiation conditions. The [3,3]-sigmatropic rearrangement carried out under conventional conditions (reflux temperature of the solvent) required long reaction times and produced moderate yields, usually a result of connected with the decomposition of starting materials. This paper demonstrates the practical usability of microwave acceterated thermal Overman rearrangement for the synthesis of various amides.

Experimental
All commercially available reagents were used without further purification and solvents were dried according to standard procedures. Column chromatography was carried out on Silica Gel 60 (Merck, 0.040-0.063 mm, 230-400 mesh). Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F 254 analytical plates; detection was carried out with either UV (254 nm), or spraying with a solution of phosphomolybdic acid, and with a basic solution of KMnO 4 , with subsequent heating. NMR spectra were recorded at room temperature on a Varian Mercury Plus 400 FT NMR spectrometer ( 1 H at 400.13 MHz and 13 C at 100.6 MHz), in CDCl 3 as the solvent (unless otherwise noted) with tetramethylsilane as internal reference. For those fully assigned 1 H-and 13 C-NMR spectra standard NMR (COSY, DEPT, HSQC) experiments were conducted. Optical rotations were measured with a P3002 Krüss polarimeter in chloroform at 25 o C. All moisture-sensitive reactions were performed under a nitrogen atmosphere. Microwave experiments were conducted using a focused microwave system (CEM Discover). Reactions were performed in a glass vessel (10 mL) sealed with a septum. At the end of the reaction the vessels together with their contents were cooled rapidly using a stream of compressed air. The melting points were determined on the Kofler block and are uncorrected.

General procedure for Overman rearrangement
Conventional method (Procedure A): To a solution of imidates in dry solvent (see Tables 1, 2) was added anhydrous K 2 CO 3 (1.1 eq). The reaction mixture was heated (for temperatures see Tables 1, 2). The solvent was evaporated under reduced pressure and chromatography of the residue on the silica gel (cyclohexane-ethyl acetate) afforded corresponding amides 2a-2f, 9-11, 14 (Tables 1, 2). (B1) Microwave-assisted synthesis (Procedure B): To a solution of the corresponding imidate in o-xylene in a 10 mL glass pressure microwave tube equipped with a magnetic stirrer bar was added anhydrous K 2 CO 3 (1.1 eq) and the tube was closed with a silicon septum. The reaction mixture was subjected to microwave irradiation (power: 300W; for temperatures, reaction times and yields see Tables 1, 2). The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane-ethyl acetate) to give amides 2a-2f, 9-11, 14 (Tables 1, 2 [10]. 13 C-NMR data have not previously been reported [10].  [10]. 13 C-NMR data have not previously been reported [10].