Comparison of metal-carbenoid reactions of β-2-five-membered heteroaryl substituted α,β-unsaturated ketones

In this study, β-2-heteroaryl substituted (N-methyl 2-pyrrolyl, 2-thiophenyl, 2-furyl) α,β-unsaturated ketones were reacted with two α-diazo carbonyl compounds that had different characteristics (dimethyl diazo malonate and 1-diazo-1-phenyl-propane-2-one) in the presence of both copper and rhodium catalysts. In the case of reactions with N-methyl 2-pyrrolyl α,β-unsaturated ketones, the major product was the insertion derivative. However, in the reactions of 2-thiophenyl and 2-furyl α,β-unsaturated ketones with dimethyl diazomalonate (acceptor-acceptor disubstituted), only dihydrofuran products were formed over carbonyl ylides. When 2-thiophenyl and 2-furyl α,β-unsaturated ketones were reacted with 1-diazo-1-phenyl-propane-2-one (donor-acceptor disubstituted), 1-phenylpropane-1,2-dione was obtained under our reaction conditions.

(Agilent Technologies, Santa Clara, CA, USA) at 500 and 125 MHz, respectively.Chemical shifts (δ) are reported in ppm downfield from tetramethyl silane at ambient temperature.GC-MS analyses were performed on a Thermo Finnigan trace DSQ instrument (Thermo Fisher, Waltham, MA, USA) equipped with a flame ionization detector.A 5% phenyl polyphenylene-siloxane capillary column (TR-5MS, Thermo Fisher) was used with helium as the carrier gas.The temperature program was as follows: start at 100 °C, then 5 min isothermal, ramp at 20 °C/min; final 290 °C, and then 10 min isothermal.Retention times (t R ) are given in minutes.HR-MS: Agilent 6230-B TOF LC/MS in m/z.

Reactions of substrates and diazo compounds
For condition x, to a solution of CuCl (0.15 mmol), AgSbF 6 (0.15 mmol), (-)-2,2'-isopropylidene bis[(4S)-4-phenyl-2oxazoline] (0.15 mmol), and a molecular sieve (4 Å) were added and the mixture was refluxed for 1 h.A heteroaryl carbonyl compound (1-3) (1.7 mmol) was added to the reaction mixture and the mixture was stirred for 5 min.A solution of diazo compound (1.7 mmol) in benzene (3 mL) was added to this mixture over 2.5 h under N 2 atmosphere.When the IR spectrum of the reaction mixture indicated the total consumption of the diazo compound (absence of the characteristic diazo band), the mixture was filtered, evaporated, and purified by column chromatography or preparative thin-layer chromatography.
For condition y, to a solution of the heteroaryl carbonyl compound (1-3) (2 mmol) in solvent (benzene if the diazo compound was dimethyl diazomalonate or CH 2 Cl 2 if the diazo compound was 1-diazo-1-phenylpropane-2-one) (20 mL) was added Rh 2 (OAc) 4 (0.01 mmol), and the mixture was heated at reflux.A solution of diazo compound (1.4 mmol) in solvent (2 mL) was added to this solution over 2.5 h under N 2 atmosphere.When the IR spectrum of the reaction mixture indicated the total consumption of the diazo compound (absence of the characteristic diazo band), the mixture was filtered, evaporated, and purified by column chromatography or preparative thin-layer chromatography.
Zhou et al. reported that [1,5]-or [1,7]-ring closure products can be obtained from ylide intermediate under CuCl/ AgSbF 6 /ligand catalytic conditions in a diastereo-controlled way [30].Accordingly, we tried to use CuCl/AgSbF 6 /ligand as a catalyst (condition x) in the reaction of 1 and 4. In this attempt, we obtained an insertion product to the pyrrole ring as a major product and a dihydrofuran derivative as a minor product (Table 1, entry i).
As is known, Rh-complexes have become the most common catalysts in diazo reactions, especially C-H insertion reactions [31][32][33][34][35]. Therefore, we needed to repeat the same reaction of 1 and 4 with Rh 2 (OAc) 4 (condition y) to search for the probable change in the product distribution.It was observed that the yield of dihydrofuran (6 1-4 ) decreased.As expected, insertion products (7 1-4 , 8 1-4 ) to the pyrrole ring were formed mainly depending on the decreasing steric probabilities.In our previous study (Scheme 1B) [24], only the dihydrofuran product was obtained from the reaction of N-methyl 2-pyrrolylmethylydene malonate and dimethyl diazomalonate (2) with the Rh 2 (OAc) 4 catalyst.The mechanism of formation of dihydrofuran is initiated by the [1,5]-electrocyclic ring closure of the corresponding carbonyl ylide intermediate, derived from the electron-deficient metal-carbenoid and one of the ester carbonyl oxygens of the malonate function (Scheme 1B) or the α,β-unsaturated keto carbonyl oxygen function (Table 1, compound 6).However, the main insertion mechanism (in Table 1, compounds 7 and 8) preferred the attack of the frontier metal-carbenoid to the pyrrole ring instead of the carbonyl oxygen under the same conditions.
All products were obtained by two general mechanism pathways over the heteroaryl function (path a)/carbonyl oxygen (paths b 1 and b 2 ) (Scheme 2).
As is known, the pyrrole ring is the most reactive species in electrophilic substitution according to thiophene and furan.Recent studies [38][39][40] have shown that the relative reactivities and regioselectivities of heteroaryl derivatives towards electrophiles are mostly variable, depending on the positions and nature of the substituents and also the types of electrophiles.When we performed the reactions of the N-methyl 2-pyrrolyl derivative (1) and diazo compounds (4, 5), insertion products (7, 8) to the pyrrole core were dominant (Table 1; Scheme 2, path a).The reactivity of the pyrrole core of 1 was effective for this chemoselective reaction.On the contrary, a 2-thiophenyl or 2-furyl-insertion product was not observed in the reactions with 2 and 3 (Table 2; Scheme 2, path b).The sole products from 2 and 3 with dimethyl diazomalonate (4) were dihydrofurans (6) formed via [1,5]-ring closure reactions over carbonyl ylide-intermediates (chemoselective reactions) (Scheme 2, path b 1 ).