Oxidative alkenylation

A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of IV-substitution with bulky groups directing to C-3. The oxidative alkenylation of (V-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the (V-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. 

The C-H/olefin coupling of aryloxazolines proceeds with unusual product selectivity. In this case, alkylation products, i.e., formally dehydrogenation products, are obtained as a major product (Eq. 22) [11]. These types of dehydrogenation compounds are believed to be formed via a carbometalation pathway. The first example of this type of alkenylation of arenes with olefins using palladium(II) complexes via C-H bond cleavage was reported in 1967 [32]. Later, several efforts were made to perform this reaction in a catalytic manner [33]. In 2001, Milstein et al. [34] reported the oxidative alkenylation of arenes with olefins using a Ru/02/C0 catalyst system (Eq. 23). Details of the reaction mechanism have not been elucidated. 

In 2001, Mdstern reported on the oxidative alkenylation of arenes with olefins using a RU/O2/CO catalyst system (Eq. 9.12) [26], but details of the reaction mechanism have not been elucidated. Very recently, Gunnoe reported ethylation and propylation of ben-... 

Ruthenium-catalyzed direct oxidative alkenylation of arenes through twofold C—H bond functionalization 13CS886. 

Scheme 7.56 Oxidative alkenylation of a pyrrole en route to dragmacidin F.

Oxidative alkenylation directed by an amide group has also been developed [15]. de Vries, van Leeuwen, and coworkers [15a] reported the Pd-catalyzed ortho alkenylation of anilides (Scheme 18.15). The reaction can be conducted even at room temperature in the presence of benzoquinone and p-toluenesulfonic acid (TsOH) as oxidant and additive, respectively, in AcOH/toluene. 

The protocol was shown to be applicable to the alkenylation of halogenated acetoanilides by Prasad and coworkers [15b]. Amatore et al. [15c] succeeded in decreasing the amount of benzoquinone up to 10mol% by its electrochemical recycling. Liu, Guo, and coworkers [15d] reported aerobic oxidative alkenylation of anilides using Pd(OAc)2/Cu(OAc)2/TsOH. Recently, Lipshutz and Nishikata [15e] conducted the reaction in water in the presence of a surfactant polyoxyethanyl... 

Miura et al. also reported the oxidative alkenylation of phenylpyrazole derivatives." The same Ru(ii) precursor was employed and the main differences lay on the amount of Cu(OAc)2 H2O required (2 equivalents) and DMF was employed instead of AeOH. 

Alternatively, a ruthenium catalyst could be applied in phthalide preparation. In 2011, Ackermann s group developed a ruthenium-catalyzed cross-dehydrogenative C-H bond alkenylation reaction. The methodology used water as a solvent, benzoic acids and terminal alkenes as substrates good yields of the desired phthalides were isolated (Scheme 2.164). The reaction sequence consisted of cross-dehydrogenative alkenylation and a subsequent intramolecular oxa-Michael reaction. Mechanistic studies provided strong evidence that the oxidative alkenylation proceeds by an irreversible C-H bond metalation via acetate assistance. 

A 85% yield 146B 78% yield 146C 75% yield SCHEME 10.50 Miura s oxidative alkenylation of azoles. 

A unique rhodium-catalyzed oxidative alkenylation of diarylmethanols having a 2-(2-pyridyl) moiety with alkenes using silver carbonate as oxidant was reported (Scheme 4.99) [98]. The diarylmethanols also underwent a rhodium-catalyzed aldehyde-imine exchange reaction [99]. 

Other classes of direct functionalization of the 2-position pyridine JV-oxide have been described. For example, a Heck-like oxidative alkenylation of the title compound has been described (eq 29). Mechanistic studies elucidated that the Pd catalyst does not coordinate to the oxygen of thelV-oxide, although a KIE of 2.9 suggests that the C-H bond-breaking event is rate limiting. The substrate scope is largely limited to Heck acceptors, demonstrating the need for activated alkenes. 

In order to find alternative routes to functimial olefins via the very useful Heck reaction [52] oxidative dehydrogenative cross-coupling of sp C-H bonds with (alkene) C-H bond was first discovered using Pd(II) catalyst and an oxidant, by Moritani and Fujiwara [25,53], This oxidative alkenylation of aromatic C-H bonds profitably performed using cheap and stable mthenium(ll) catalysts was shown for the first time in 2011 successively by the groups of Satoh and Miura [54], Ackermann [55], Bruneau and Dixneuf [56], and Jegaiunohan [57] [(Eq. 2)]. This Ru(n)-catalysed alkenylation reaction offers a potential to reach a large variety of functional alkenes at low cost and has been extended to annulation reactions with alkynes for a fast access to heterocycles. 

Ackermann reported the second general example of oxidative alkenylation with Ru(ll) catalyst by reaction of benzoic acid derivatives with acrylonitrile or alkyl acrylates. The alkenylation this time was performed in water under mild conditions. Further oxa-Michael reaction occurred leading to lactones in good yields [(Eq. 54)] [55]. 

The Ru(II) catalysed arylation of 0-protected phenols by 2-pyridyl group was already performed under efficient conditions [(Eq. 28)] [101]. Ackermann has now succeeded to perform their oxidative alkenylation with alkyl acrylates and Ru(II)/ AgSbFg catalytic system with Cu(0Ac)2-H20 as oxidant in aerobic atmosphere at orf/to-position of the (7-Py group [(Eq. 74)] [158]. The ortho C-H bond activation of these substrates is providing a 6-membered metallacycle intermediate by contrast to all the previous examples of alkenylation taking place via a 5-membered metallacycle. The phenol can be obtained from the alkenylated O-2-Py product by successive treatment with MeOTf and sodium in methanol without transformation of the alkenyl ester group and with tolerance of p-C, p-COR, p-CO, or P-NO2 arene substituent. 

Most of the above oxidative alkenylations take place with 2-5 mol% of a Ru (11) species and excess of silver salt, usually 20 mol%, and 1 equiv of Cu(ll) unless the reaction can be performed in air. As [RuCl2(p-cymene)]2 leads to partial formation of Ru(OAc)2(p-cymene) with Cu(0Ac)2.H20 [160], AgSbFg by abstracting the chlorides is expected to increase the formation of Ru (OAc)2(p-cymene). The Ru-OAc bond of the latter dissociates easily [49, 91] to allow the coordination of the heterocycle Directing Group (D=G) to the Ru (II) centre (Scheme 16). The interaction of the Ru(II) site with the ortho carbon atom (A) is expected to favour the deprotonation of its C-H bond by the external... 

Recently, Kim and coworkers developed an efficient strategy for the construction of isoindolines 10 via Rh(III)-catalyzed oxidative alkenylation and subsequent intramolecular cyclization ofAf-benzyltriflamides with olefins. Under these reaction conditions, various substituted electron-deficient alkenes were successfully employed in good product yields [8]. The authors proposed a mechanism to account for the catalytic reaction (Eq. (5.10)). 

During the investigation of the ruthenium(II)-catalyzed or / o-alkenylation of arylpyrazoles with acrylates, Satoh and Miura found that benzanilide reacted with -butyl acrylate in o-xylene to deliver lactam via oxidative alkenylation and subsequent intramolecular aza-Michael addition (Eq. (7.46)) [56]. 

In 2014, Ackermann and coworkers reported the oxidative C-H alkenylation of sulfonamides. After ruthenium(II) catalyst enabled oxidative alkenylation of sulfonamides with acrylates at 120 °C for 18 h, the resulting ort/zo-alkenylated products underwent a chemoselective intramolecular aza-Michael reaction to yield the sultams by heating the reaction mbcture at 150 C for 5h (Eq. (7.49)) [59]. 

Scheme 7.11 Proposed mechanism for ruthenium-catalyzed oxidative alkenylation and cyclization of N-methoxybenzamides.

By using ruthenium complexes derived from [RuCl2(p-cymene)]2/AgOAc, oxidative alkenylations of amidines with substituted acrylates provided diversely substituted 1-iminoisoindolines (Eq. (7.52)) [48]. The resulting product was proposed to form in a process of oxidative alkenylation, intramolecular aza-Michael addition, and dehydrogenation. 

Functionalization of the C-5 position of triazoles is not limited to arylation. A direct oxidative alkenylation of 1,4 triazoles has been reported (Scheme 41) [96]. Two mechanisms have been proposed. The first one involves an electrophilic attack of Pd° on the triazole, followed by coupling with the alkene partner. The second one starts with a vinylpalladium species, followed by a vinylpalladation step. In both mechanisms, Pd reoxidation by Cu and O2 finally closes the catalytic cycle. 

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