DBU-catalyzed Michael addition of bulky glycine imine to α,β-unsaturated isoxazoles and pyrazolamides

A DBU-catalyzed Michael additions of several pronucleophiles with high pKa values including bulky glycine imines, α-tetra-lone, 1-methyl-2-indolone and nitroalkanes to α,β-unsaturated isoxazoles and pyrazolamides have been realized in THF with 1.0 eq. LiBr as a additive at room temperature within 3 h to provide Michael adducts in excellent yields (up to 97%) and diastereoselectivities (> 20:1).

Li and coworkers [47] have reported a highly enantioselective Michael addition of αnitroacetate to activated α,β-unsaturated pyrazolamide catalyzed by a bifunctional 4 squaramide to produce Michael adducts with excellent yields but without diastereoselectivties (dr = 1:1 for all cases), and the reaction is very sluggish (up to 168 h). Recently, we have developed tandem grinding reactions involving aldol condensation and Michael addition in sequence for preparation of 3,4,5-trisubstituted isoxazoles [48]. For our continue effort to introduce heterocyclic rings to linear organic molecules, herein, we have reported DBU-catalyzed highly diastereoselective

Results and Discussion
Initially, glycine imine 1a and styrylisoxazole 2b were used as substrates for the reaction conditions optimization of Michael addition, and the results are shown in Table 1. When the reactions of 1a and 2b were performed in CH2Cl2 at room temperature in the presence of Et3N or i Pr2NEt, no Michael adduct 4ab was found within 24 h ( Table 1, entries 1-5). The product 4ab was obtained by using 1.0 eq. Cs2CO3 as base but with very low yield (11%, entry 6). No product was obtained when DABCO as a stronger base than Et3N was used in the reaction (entries 7 and 8). The combination of catalytic amount of DABCO (10 mol%) and Cs2CO3 (10 mol%) has still given a disappointed result even with a long reaction time (entry 9). To our delight, 4ab was obtained in 62% yield when the increase of Cs2CO3 from 0.1 eq. to 1.0 eq., but with 16% yield of a accompanied [3+2] cyclo-addition product Cyc-4ab (entry 10). Both the yields of Michael adduct 4ab and cyclization adduct Cyc-4ab were increased with the increased use of DABCO from 0.1 eq. to 1.0 eq. (entry 11, 75% and 18%). By replacing DABCO and Cs2CO3 with 10 mol% of DBU, 4ab and Cyc-4ab were obtained in 71% and 14% yields, respectively (entry 12). The yields of 4ab and Cyc-4ab were promoted with the increase use of DBU in a short reaction time (entry 13 vs entry 12). In order to improve the yield of cyclization adduct Cyc-4ab, 2.5 eq. of DBU was used, but no significant change of the yields of 4ab and Cyc-4ab was found (entry 14 vs entries 12 and13). Du and co-workers have reported a DBU-catalyzed Michael reaction of glycine imine 1a and trans-β-nitrostyrene in the presence of LiOTf to provide Michael adducts in high yields and good diastereoselective ratios (up to 99% yield and 10.4:1 dr) [31,46]. Inspired by their research, 10 mol% LiBr was used as a addictive to afford 4ab in 69% yield with trace of cyclization product Cyc-4ab (entry 15). It was found that the addition of LiBr can 6 suppress [3+2] cyclo-addition of two substrates 1a and 2b. This pheromone is very different to metal-catalyzed [3+2] cyclo-addition of nitroolefins with glycine imines [49,50]. When the amount of LiBr was increased from 0.1 eq. to 1.0 eq., the yield of 4ab was up to 81% in CH2Cl2 (entry 16). Switching CH2Cl2 to THF, the Michael adduct 4ab was formed almost in quantitative yield (95%) within half an hour (entry 17) under room temperature. The yield of 4ab was decreased by using 1.0 eq. LiCl as a additive (entry 18). LiOTf can furnish 4ab in a comparable yield with LiBr as a additive (entry 19), however, LiBr is cheaper and more moisture-stable than LiOTf.
Due to a very bulky hinderance of tert-butyl group in 1a, the above-obtained distereoratios of 4ab are beyond 20:1. Therefore, the optimal reaction conditions for the Michael addition of 1a and 2b were established as follows: 10 mol% DBU, 1.0 eq. LiBr, THF, room temperature and proper reaction time.  c. The diastereo-ratio of 4ab is up to 20:1 which was determined by 1 HNMR.
With the optimal conditions in hand, various α,β-unsaturated isoxazoles 2a-s as substrates were used in the Michael addition of 1a to provide 4a-s in moderate to excellent yields (45~95%) and distereo-ratios (> 20:1), and the results were listed in Figure 3. From Figure 3, it was found that α,β-unsaturated isoxazoles with an aromatic ring at β-position to give Michael products in higher yields than substrates with one alkyl substituent at β-position (for example, 4ab vs 4aq, 95% vs 65%) within 3 h. Substrates containing one hetero-aromatic ring such as pyridine (2m), pyrrole (2n), furan (2o) and thiophene (2p) are also suitable to this reaction to afford products in good to high yields (74-89%). Substrates 2q-s are less active than 2b and the other α,β-unsaturated isoxazoles in this Michael reaction, and they need relative long reaction time to give the corresponding products (up to 24 h). When the R group in glycine imine 1a was changed from tert-butyl to methyl (1b), the diastereoratio of product is dramatically decreased from 20:1 to 1:1 but with excellent yield (4bb, 94%). Some challenging substrates including nitroalkanes 1c and 1d, α-nitro ethyl acetate 1e, N-methylindolin-2-one 1f and 1-tetralone 1g were also used in this DBU-catalyzed Michael addition to provide the corresponding products in high yields except 4eb (19%) and 4gb (11%).

Figure 4:
The X-ray structure of syn-4ab.
In order to know the relative configuration of Michael adducts, the single crystal of 4ab was cultivated from the mixed solvent of petroleum ether and CH2Cl2 which is suitable for X-ray diffraction analysis [51]. Owing to the poor quality of single crystal, some disorder was found during the analysis process, however, the X-ray single crystal diffraction diagram obviously indicated that the syn-addition is predominated in this LiBr-assisted DBU-catalyzed Michael reaction (Figure 4). This phenomena is contrary to previous reports by Du's group and Kyungsoo with colleagues [45,49], in their researches, the reactions of trans-nitrostyrenes with glycine imine 1a exclusively provide anti-adducts. The reason to syn-addition may due to the dynamic control in the reaction process with a relative short reaction time (0.25~3 h for most cases). Pyrazole and derivatives have presented many types of bioactivities, and α,βunsaturated pyrazolamides 3 have been used as substrates for construction of molecules with pyrazole core. Encouraged by the above success of Michael additions between bulky glycine imine 1a and α,β-unsaturated isoxazoles 2, α,β-unsaturated pyrazolamides 3 were used as Michael acceptors under the optimal reaction conditions, 5a-k ( Figure 5) were obtained in excellent yields (93~97%) and diastereoratios (> 20:1), and no cyclization product was found in all cases. Substrates (3b-g) with electron-withdrawing groups on their aromatic ring have furnished corresponding products (5b-g) in excellent yields within 0.5 h, but substrate 3h with an electron-donating group (4-OMe) is less active than 3b-g to give Michael adduct 5h in three hours. Substrates with one furan (3j) or thiophene (3k) are tolerated in this reaction to provide 5j and 5k in good yields within two hours.

Experimental
To a solution of glycine imine 1a (0.5 mmol) and α,β-unsaturated isoxazoles 2b (0.5 mmol) in 5.0 mL of THF, 7.5 uL of DBU (10 mol%, 0.1 eq.) and LiBr (44 mg, 1.0 eq., 0.5 mmol) were added successively. The mixture is stirred at room temperature for 0.5 h, and the reaction was monitored by TLC. When TLC indicates that starting materials were consumed, the solvent was evaporated under reduced pressure and the residue was purified through a flash column chromatography (petroether/ethyl acetate = 10:1 to 5: 1, v/v). The pure product 4ab was obtained as a white foam.

Supporting Information
Supporting information text Supporting Information File 1: Characterization data and copies of 1H, 13C, 19F NMR spectra and HRMS for all new compounds, X-ray crystal structure data of 4ab.

File Format: Word
Supporting Information File 2: Checkcif files of 4ab File Format: PDF