Palladium‐Catalyzed Intramolecular Coupling of Amino‐Tethered Vinyl Halides with Ketones, Esters, and Nitriles Using Potassium Phenoxide as the Base

Abstract

Vinyl halides undergo intramolecular coupling with amino-tethered ketones, esters, and nitriles in the presence of a palladium catalyst and potassium phenoxide as the base. This reaction constitutes a useful methodology for the synthesis of monocyclic, bridged, and spirocyclic nitrogen-containing compounds.Keywords: alkenylation; enolates; homogeneous catalysis; nitrogen heterocycles; palladium During the past decade there has been a growing interest in the palladium-catalyzed coupling reactions of aryl and vinyl halides with enolates and related anions. However, while the reactions of aryl halides have been extensively studied, and it is now possible to introduce an aromatic unit to a broad range of enolate-type nucleophiles, [1] the coupling reactions involving vinyl halides have received little attention and deal almost exclusively with the a-alkenylation of ketone enolates.The first examples of such palladium-catalyzed coupling reactions involving vinyl halides were reported by Piers at the beginning of the 1990s, when he described the intramolecular alkenylation of ketone enolates and then applied the reaction to the synthesis of the diterpenoid crinipellin B.[2] Some years later, another example of this coupling process was reported by Cook in the context of the total synthesis of the alkaloid (þ)-vellosimine, [3] and we reported our studies on the synthesis of nitrogen heterocycles by the Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates.[4] Later on, Buchwald described the intermolecular vinylation of ketone enolates. [5] Finally, it is worth mentioning that isolated examples of the alkenylation reaction have also been reported in the studies of the Pd(0)-catalyzed intermolecular arylation of ester [6] and alanine-derived azlactone [7] enolates.In our previous work, we established that the use of Pd(PPh 3 ) 4 (0.2 equivs.) and KO-t-Bu (1.5 equivs.) in THF at reflux effectively promotes the intramolecular coupling of amino-tethered vinyl halides and ketones to afford bridged, condensed, and monocyclic nitrogen-containing compounds.[4] However, for some substrates side reactions such as the elimination of HX leading to alkynes which may undergo subsequent coupling with the starting vinyl halides to afford dimeric compounds, and dealkylation at the nitrogen, resulted in low or moderate yields of the cyclization products.[4b]As these side reactions can mainly be attributed to the use of a strong base, a more general protocol for the intramolecular a-alkenylation of ketones could be found if, instead of KO-t-Bu, a milder base was used. In this context, it should be noted that the intramolecular coupling of amino-tethered vinyl halides and ketones was also accomplished in some cases by using Cs 2 CO 3 as the base, although these reaction conditions were only suitable for the construction of five-membered ring systems and afforded moderate or low yields. [4b] Continuing our studies on this palladium chemistry, [8] we have recently reported that both vinyl an...

First stereospecific total synthesis of (−)-affinisine oxindole as well as facile entry into the C(7)-diastereomeric chitosenine stereochemistry

“…The structures of both oxindoles, 5 and 14, were now unequivocally confirmed by X-ray crystallography and were diastereomeric at C(7) as expected. 7,13 To complete the synthesis of (À)-affinisine oxindole 1, ketone 5 was converted into the desired pentacyclic ketone 17 in 65% yield (Scheme 6) via an intramolecular palladium-catalyzed (enolate mediated) cross-coupling reaction with (10 mol %) Pd(PPh 3 ) 4 / PhONaÁ3H 2 O (2.5 equiv)/THF/reflux/2 h. 15 The steric outcome of this reaction for 17 was again confirmed by X-ray analysis. The Wittig reaction with (methoxymethyl)triphenyl-phosphonium chloride and anhydrous tBuOK in benzene with oxindole 17 provided a mixture of enol ethers represented by 18.…”

“…5 The original structure and relative configuration of this alkaloid were established via analysis by IR, UV/VIS, NMR, and mass spectroscopy. 5 The configuration of the spirocyclic center was determined to be (R) from the NOE interaction observed between H(9) and H (16) and the geometry of the C(19),C(20)-double bond was determined to be (E) from the NOE interaction observed between H(18) (methyl group) and H (15). 5 Herein we report the first enantiospecific total synthesis of (À)-affinisine oxindole 1, which confirmed the absolute configuration at C(7) and C(16) proposed by Kam et al 5 This stereospecific approach will provide entry into either the spirocyclic oxindole of the chitosenine-series 3 or the opposite configuration at C (7) in the alstonisine-series 4 ( Fig.…”

Sarpagine and Related Alkaloids

“…105 Martin reported the total synthesis of geissoschizine with stereoselective establishment of the E -ethylidene double bond by an elimination process. 112 Furthermore Rawal 113 and Bosch 114 reported the total synthesis of Strychnos alkaloids with stereocontrolled establishment of the double bond by a Heck coupling reaction.…”

“…Alkylation of the secondary amine in 164 with ( Z )-1-bromo-2-iodo-2-butene ( 165 ), a unit prepared by Ensley et al 116 and employed by Rawal, 113 Bosch 114 and Kuehne 117 provided the N b -( Z )-2′-iodo-2′-butenyl-substituted tetracyclic ketone 166 in 87% yield. The ( Z )-olefin unit 165 can now be prepared in 500 gram scale regiospecifically and setereoselectively in a 2 pot process in high yield combining the chemistry of Kraft et al with Cook et al 118 The iodo olefin 166 was subjected to the optimized conditions of the intramolecular palladium-catalyzed cross coupling reaction (3 mol% Pd(OAc) 2 , 30 mol% PPh 3 ) to furnish the cyclized product 167 stereospecifically in 80% yield.…”

“…119 Later in the same year Bonjoch et al executed a similar process in a different system. 114 Piers et al had run this type of coupling a few years earlier in an aliphatic system. 120 …”