The Ru3(CO)12-Catalyzed Intermolecular [2 + 2 + 1] Cyclocoupling of Imines, Alkenes or Alkynes, and Carbon Monoxide: A New Synthesis of Functionalized γ-Lactams

Abstract

The reaction of imines which contain N-heterocycles or an ester group with alkenes or alkynes and carbon monoxide in the presence of a catalytic amount of a ruthenium carbonyl results in [2+2+1] cyclocoupling to give g-butyrolactams in good yields.A [2+2+1] cycloaddition represents one of the most direct and convenient strategies for the construction of fivemembered carbocyclic and heterocyclic carbonyl compounds from simple acyclic building blocks. 1 In particular, the Pauson-Khand reaction, in which an alkyne, an alkene, and carbon monoxide are assembled into cyclopentenones, mediated by Co 2 (CO) 8 (Scheme 1, a), has been a subject of great interest. 2[2+2+1] Cycloaddition approaches to the construction of five-membered carbonyl compounds Scheme 1It should be noted, however, that the application of the [2+2+1] cycloaddition to the synthesis of heterocycles, such as g-lactone and g-lactam derivatives (Scheme 1, b), has met with limited success. In 1996, Crowe and Buchwald independently reported on the cyclocarbonylation of olefinic aldehydes and ketones leading to bicyclic g-butyrolactones, mediated 3,4 or catalyzed 4 by a titanocene complex. Subsequently, we reported on the Ru 3 (CO) 12 -catalyzed cyclocarbonylation of yne-aldehydes 5 and yneimines 6 to give bicyclic g-lactones and g-lactams, respectively. In these cases, a C=X moiety (X = O, N) and an alkene or alkyne are incorporated in an intramolecular manner. Quite recently, we reported the first example of the intermolecular [2+2+1] cyclocoupling of ketones, olefins, and CO catalyzed by Ru 3 (CO) 12 , a reaction which leads to the formation of g-butyrolactones bearing carbonyl or N-heterocyclic groups at the g-position. 7 This finding prompted us to examine the possibility of using imines in place of ketones for the synthesis of g-lactams, which are of importance for use as pharmaceutical agents. 8 Herein, we wish to report that the intermolecular [2+2+1] cyclocoupling of imines, alkene or alkynes, and CO can be achieved catalytically, using Ru 3 (CO) 12 as the catalyst.We initially examined the reaction of an imine which contained a 2-pyridyl group, since it has been reported that such a group, when adjacent to a carbonyl group has an accelerating effect in the ketone cycloadditions. 7 We were pleased to observe that the reaction proceeded smoothly and efficiently. The reaction of imine 1a (1 mmol) with ethylene (3 atmospheres) at 5 atmospheres of CO in toluene (3 mL) in the presence of Ru 3 (CO) 12 (0.025 mmol) at 160°C for 20 hours furnished the expected g-lactam 2a in 97% isolated yield, based on 1a (eq 1). The yields were lower when a tert-butyl group (38%), or a benzyl group (57%), or a p-toluenesulfonyl group (0%) were used as the N-protecting groups of the imine moiety. The introduction of an additional 2-pyridyl group at the imino carbon (i.e. 1b) resulted in the formation of the corresponding g-lactam 2b in quantitative yield. Imine 1c (E-isomer only) also underwent cycloaddition to give lactam 2c in a good yield. In contrast, the use of benzo...

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

“…They also reported that the reaction of the imines 394, which contain a nitrogen heterocycle or an ester as the R group, with ethylene or diphenylacetylene and carbon monoxide in the presence of catalytic amounts of ruthenium carbonyl gave the γ-butyrolactams 395 or 396 in good yields (Schemes 125 and 126). 188 …”

Regioselectivity, Stereoselectivity and Catalysis in Intermolecular Pauson-Khand Reactions: Teaching an Old Dog New Tricks

“…The conversion of the corresponding imine 150 with alkyne 1p afforded under similar conditions the unsaturated g-lactam 151. 103 Scheme 60 Reagents and conditions: (a) Ru 3 (CO) 12 (2.5 mol%), P(4-CF 3 C 6 H 4 ) 3 (7.5 mol%), 5 atm CO, toluene, 160°C, 20 h According to Mitsudo Ru 3 (CO) 12 could also be employed in the catalytic cocondensation of squaric acid derivatives such as 152 and norbornene (20) to yield the cyclopentenone 153 as a single regioisomer (Scheme 61). 104…”

Ruthenium‐catalyzed carbonylative cycloaddition reactions involving carbonyl and imino groups as assembling units

“…10). 24 The reaction of an aldimine 21a (1 mmol), with ethylene (3 atm) at 5 atm of CO in toluene (3 mL) in the presence of Ru 3 (CO) 12 (0.025 mmol) at 160°C for 20 h, gave the expected γ‐lactam 22a in 97% isolated yield, based on 21a (Eq. 10).…”