A Novel Three‐Component [3+2] Cycloannulation Process for the Rapid and Highly Stereoselective Synthesis of Pyrrolobenzoxazoles

Abstract

Four new σ bonds and two chiral centers are formed in a novel three‐component, one‐pot [3+2] cycloannulation process, which gives pyrrolobenzoxazoles directly in good yields and with excellent diastereoselectivity (see scheme, TMS=trimethylsilyl). The products could be converted into proline derivatives with full stereochemical control. A chiral scandium complex catalyzed the formation of the products with up to 83 % ee.

A Complex Catalytic Reaction Caught in the Act: Intermediates and Products Sampling Online by Liquid μ‐Beam Mass Spectrometry and Theoretical Modeling

“…Reaction (1) in Equation (1) produces af irst intermediate IIa.A fter the addition of the third reagent IIb,t hese react furthert ot he second detected intermediate, the d-amino-a-silyloxy-a,b-unsaturated ester IV.T hese first reaction steps are relatively fast and lead to IV being the dominant species in the mass spectra already 2.5 minutes after the addition of IIb.D uring the following measurements the intensities of IIa and IV slowly decay,w hilet he measured mass peak intensity of the final product VII increases. The reaction to VII took aboutf our hours to complete in our measurements,i na greement with the recent results of Boomhoff et al [21] After four hours, the concentration of pyrrolobenzoxazole VII was so high that it exceeded itss olubility and some precipitation was visible. To keep the product in solution and to avoid clogging of the liquid-beam nozzle the solutionw as diluted in the last measurement (4 ).…”

“…Three-dimensional structures of complexes optimized in acetonitrile accordingt ot his pathway are showni n the SupportingI nformation in Figure X2. We want to emphasize here that we experimentally conducted the reaction with differentc atalysts, namely,Y b(OTf) 3 , Zn(OTf) 2 ,a nd ZnCl 2 .I na greement with the literature, [21] when utilizing Yb(OTf) 3 the reactionw as completed much faster, whereas when using Zn(OTf) 2 and ZnCl 2 the reactionw as not only slower but also precipitation problems occurred. Therefore, the experimental results presentedh ere were achieved using Yb(OTf) 3 as ac atalyst.…”

“…[8] We reportedanovel [3+ +2] cycloannulation reaction to produce pyrrolo [2,1-b]benzoxazoles in ad omino fashion in 2012. [21] Under Lewis acid catalysis, bissilyl-dienediolate IIa was treated with imines in av inylogous Mannich reaction to generate a d-amino-a-silyloxy-a,b-unsaturated ester,w hich subsequently hydrolyzed to the corresponding a-keto ester.T his highly reactive intermediate spontaneously reactedi na[3+ +2] cycloannulation to the final pyrrolo [2,1-b]benzoxazole. For the proof-of-principlem easurements described here the reaction was simply probed in ab atch experiment next to the mass spectrometer setup and samples were taken at predefined time steps and injected manually into the MS high-pressure line.…”

“…In the currents tudy we highlight the first application of the approach on an important typeo f modularm ulticomponent reaction as at est case for the technique. [21][22][23][24] We have recently studied some details of the overall reactiond isplayed in Scheme 1, which belongs to af amily of recently developedr eaction schemes to efficiently build up complexo rganic structures. The products and intermediates, as well as the reaction mechanisms are investigatedh ereb y means of laser desorption liquid m-beam mass spectrometry supported by quantum chemical calculations.…”

Chip‐Based Free‐Flow Electrophoresis with Integrated Nanospray Mass‐Spectrometry

“…We chose a multicomponent [3+2]-cycloannulation of anthranilic acid (1), benzaldehyde (2), and a bis(silyl)dienediolate 3 as a model reaction. This reaction forms a pyrrolobenzoxazinone 4 ( Figure 3) and expands our previously described synthesis for pyrrolobenzoxazoles [23] to another group of substances. Preliminary batch synthesis with varying reaction conditions revealed a possible formation of side product 5 by "aaddition".…”