Cyclopropanation of 5-(1-bromo-2-phenyl-vinyl)-3-methyl-4- Nitro-isoxazoles under Phase Transfer Catalysis (ptc) Conditions

Heavily substituted cyclopropane esters were prepared in high yields, complete diastereoselection and average (up to 58%) enantioselectivity. The reaction described herein entailed reacting 4-nitro-5-bromostyrylisoxazoles, a class of powerful Michael acceptors with malonate esters under the catalysis of 5 mol% of a chincona derived phase-transfer catalyst.

Interestingly, isoxazoles 2 (Figure 1), in which a halide is introduced on the exocyclic alkene, hold an additional electrophilic center E3 that increases the number of their possible synthetic applications [3].
The first type involves formation of cyclopropanes such as 7 (Scheme 1) via Michael addition of a nucleophile containing a leaving group to an activated alkene.For example, our group has recently reported a highly enantioselective cyclopropanation of 3-methyl-4-nitro-5-styrylisoxazoles 1 that reacted with bromomalonate 6 under the catalysis of Cinchona based phase transfer catalysts [43].The second type of MIRC processes involves the formation of cyclopropanes by nucleophilic addition to electrophilic substrates containing a leaving group, for example a bromide as in compound 2. Herein we report the results of our studies on the reaction of bromostyreneisoxazoles 2 and malonate 5 under the catalysis of Cinchona based phase transfer catalysts.

Results and Discussion
We first investigated the addition of dimethyl malonate 5a to 2a in the presence of K3PO4 50% w/w as inorganic base, toluene as organic solvent and quaternary ammonium salts derived from Cinchona alkaloids as catalysts (Table 1).The choice of toluene and phosphate arose from a preliminary screening which identified these as the most suitable condition to obtain desired cyclopropane 7 in high yields.
These experiments afforded cyclopropane 7a with in high conversion even with only 0.05 equiv. of catalyst loading, but with enantioselectivity up to a maximum of 42%.Importantly, cyclopropane 7a was always obtained as a single diastereoisomer.The higher enantiomeric excess was obtained with catalyst N-benzylquininium chloride (Table 1, entry 1).The second generation catalyst O-Allyl-N-9anthracenylmethylcinchonidinium bromide, provided high yields of desired 7a, but in an almost racemic form (Table 2, entry 5).The reason for this may lay in the peculiar mode of action of these catalytic species (see Figure 2) in which a free OH is required to provide a key H-bond with the enolate.[43] Based on the results collected on N-benzylquininium catalyst series, a series of Nbenzylquininium salts was prepared containing various functional groups at the benzyl ortho-position and employed as catalysts to promote the Michael addition.These catalysts provided cyclopropane 7a in similar enantiopurity as commercially available N-benzylquininium chloride (Table 1, entries 6-9).
In order to increase the enantioselectivity of this reaction, compound 2a was reacted with malonates bearing alkyl groups of increasing steric hindrance (  The scope of reaction was shown by reacting styryilisoxazoles 2a-1 with methyl malonate 5a under the catalysis of 14 (Table 3).The results collected pointed out the following facts: (i) compounds containing either electron withdrawing or electron donating groups were equally good substrates; (ii) substrates containing aromatic heterocycles were also good substrates giving products 7e in excellent yields and similar enantiomeric excess (Table 3, entries 7); (iii) alkyl substituted isoxazole 1i reacted equally well giving aliphatic cyclopropane 7i in comparable yield and ee.[a] Reaction Conditions: bromostyrylisoxazole 2a-i (0.1 mmol), toluene (5.0 mL), cat.14 (0.005mmol), dimethyl malonate 5a (0.2 mmol), K 3 PO 4 50% w/w (1 mmol).[b] Isolated yields after flash column chromatography.
[c] The enantiomeric excess (ee) of the product was determined by chiral stationary phase HPLC.
We have compared the data collected for the reaction of 1 and 6 [14] with those for the reaction of 2 and malonate 5 and explained the observed difference in enantioselectivity as follows (Figure 2).Firstly, the requirement for a free -OH on the phase transfer catalyst indicates the interaction of this group with one of the two reagents involved, presumably the enolate.It is well known that + N-CαH behaves as strong hydrogen bond donors.[44] Therefore, it is possible that in apolar media such as toluene an interaction could take place between the catalyst + N-CαH and the nitro group of the styrylisoxazole.According to this rationale, the bromine in compounds 2 shielded the NO2, limiting its interaction with the PTC as it may occur for compounds 1, hence justifying the lower enantioselectivity observed.

Experimental Section
General procedure for the preparation of compounds 7a-i: To a test tube equipped with a magnetic stirring bar were sequentially added the bromostyrylisoxazole 2a-1 (0.1 mmol), toluene (1.0 mL), catalyst 14 (5 mol%) and malonate 5a-e (0.2 mmol).The test tube was placed at the stated temperature, then K3PO4 50% w/w was added in one portion (0.28 mL, 1.0 mmol).The mixture was then vigorously stirred at the same temperature, with no precautions to exclude moisture or air.After the stated reaction time, the reaction was then quenched with sat.NH4Cl (4 mL) and the product extracted with toluene (3 × 1 mL).The combined organic phases were evaporated and the product was then purified by chromatography on silica gel (petroleum ether/EtOAc mixtures).

Figure 2 .
Figure 2. Proposed transition states for the cyclopropanation of 1 and 2.