(E)‐Dimethyl 2‐Oxopent‐3‐enylphosphonate: An Excellent Substrate for Cross‐Metathesis – Easy Access to Functionalized Heterocycles

Abstract

Simple and efficient access to tetrahydrofurans, tetrahydropyrans, and pyrrolidines through a tandem cross‐metathesis/1,4‐addition process from (E)‐dimethyl 2‐oxopent‐3‐enylphosphonate and N‐protected ω‐unsaturated amines or alcohols under microwave irradiation is described. As the Grubbs–Hoveyda catalyst is highly chemoselective, a diversity of functionalized heterocycles were synthesized. Furthermore, an additional functionalization can be performed due to the presence of a side chain that possesses a ketophosphonate at the C2 position of the heterocycle.

Decomposition of a Phosphine-Free Metathesis Catalyst by Amines and Other Bronsted Bases: Metallacyclobutane Deprotonation as a Major Deactivation Pathway

“…[5][6][7] The Cossy group recently extended the latter strategy to metathesis of N-heteroaromatic compounds. 12 For protected amines, a survey of recent examples [13][14][15][16][17][18][19][20][21] illustrates moderate to excellent metathesis yields. Reaction is relatively slow even at high catalyst loadings, however, suggesting competing catalyst deactivation.…”

“…Reports from pharma highlight the destructive effect on metathesis of even traces of morpholine, DBU (1,8-diazabicyclo[5.4.0]-undec-7-ene), and other nitrogen bases. − Likewise, metathesis of amine-bearing substrates has long been known to require either N-protection, or an adjacent substituent to block access to and/or withdraw electron density from the nitrogen site. − The Cossy group recently extended the latter strategy to metathesis of N-heteroaromatic compounds . For protected amines, a survey of recent examples − illustrates moderate to excellent metathesis yields. The reaction is relatively slow even at high catalyst loadings, however, suggesting competing catalyst deactivation.…”

Cross-Metathesis/Intramolecular (Hetero-)Michael Addition: A Convenient Sequence for the Generation of Carbo- and Heterocycles

“…Cossy and Bellosta demonstrated that β-ketophosphonate 22 could be combined with ω-unsaturated protected amines 23 in a CM/IMAMR sequence. 17 Under optimized conditions, reaction of phosphonate 22 with tosyl-or Bocprotected amines 23 (n = 1) took place in dichloromethane at 100 °C under microwave irradiation after two additions of second-generation Hoveyda-Grubbs complex I. In this manner, pyrrolidines 24 were obtained in generally good yields with moderate diastereoselectivity.…”

“…The synergistic combination of Brønsted acids with ruthenium complexes was also evaluated, exploiting the concept of orthogonal domino-catalysis. 34 After screening several combinations, the authors found that the use of a catalytic amount of camphorsulfonic acid (CSA) 35 in dichloromethane at 25-35 °C (method C) provided the best results in terms of yields and diastereoselectivity with both enal 17b and unsaturated amide 39, leading to the domino products 41 and 44 in a very efficient manner (entries [12][13][14][15][16][17][18][19]. As mentioned above, it seems that a ruthenium hydride species, generated by thermal degradation of the methylidene ruthenium complex, might also be the active catalytic species for the IMOMR.…”

“…The CM/IMAMR sequence developed by Cossy and Bellosta in 2012 with β-keto phosphonate 22 and ω-unsaturated amines 23 (see Scheme 9) was also suitable for ω-unsaturated alcohols 47, yielding the corresponding tetrahydrofurans 48a and tetrahydropyrans 48b (Scheme 18). 17 It is important to point out that the domino protocol was more efficient with alcohols than with amines. Therefore, the formation of tetrahydropyrans 48b took place in moderate to good yields with high levels of diastereoselectivity, whereas the corresponding piperidine derivatives could not be obtained through this methodology (see Scheme 9).…”