Carbonylative cascade

An allene moiety can serve as a nucleophile vis-a-vis a 7r-allylpalladium species generated from an allylic acetate moiety in substrates such as 495 (Scheme 124). The cyclization involving these two moieties generates another 7r-allyl intermediate, and the stage is set for the subsequent carbonylative cascade process as demonstrated by the transformation of 495 to 496.402... 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

Even more impressive is the carbonylative cascade starting from the trienyliodobenzene derivative 153 (Scheme 3-40) [1 0b]. Under appropriate conditions even the tetracycle 155 was formed, albeit in low yield. This is quite remarkable, as it involves the formation of seven new carbon-carbon bonds in a single operation. 

Scheme 3-39 Heck-carbonylation cascades [110a]. A = [PdCPPhjljClJ, 40 atm CO, NEtj, C HeMeCN/MeOH, 100°C, 24h. B = [PdCPPhjlJ, l.l atm CO, KEt3, THE, 60°C, 24h.

Oppolzer, W., Robyr, C. Synthesis of ( )-hirsutene by a catalytic allylpalladium-alkyne cyclization/carbonylation cascade. Tetrahedron 1994, 50, 415 24. 

Sugihara, T., Coperet, C., Owczarczyk, Z. et al. (1994) Deferred carbonylative esterification in the Pd-catalyzed cyclic carbometalation-carbonylation cascade. J. Am. Chem. Soc., 116, 7923-4. 

A facile and selective palladium-catalyzed carbonylative domino synthesis of benzothiophenes was developed by Alper and Zeng in 2011 [273]. 2-Carbon-ylbenzo[Z ] thiophene derivatives were produced from 2-gem-dihalovinylthiophe-nols in 24-73 % yields (Scheme 2.39). This protocol involved an intramolecular C-S coupling/intermolecular carbonylation cascade sequence and allowed for access to various highly functionalized benzo[h]thiophenes. 

X = O, OCH2, NC02Me, NSO2PI1, Bn Y = CH2, CO) Scheme 28. Carbonylation cascade reaction on solid support.P 1... 

Carbonylation Cascades. The norbornene enamide shown underwent a palladium-catalyzed 5-g o-trig cyclization followed by carbonylation (1 atm) to give a spirocyclic product as a single di-astereoisomer (eq 84). In this case ring strain prevents the competing /3-hydride elimination pathway. Similar diastereoselective three-component cascade processes proceed smoothly in excellent yield (eq 85). ... 

In 2002, Aggarwal et al. developed an efficient route to unsaturated carboxylic acid 44 by a palladium-catalyzed Heck cyclization/carbonylation cascade of vinylic bromide 43 [18a] (Scheme 6.9). By choosing the appropriate phosphine ligand and intensive optimization, the formation of linear carboxylic acid 45 and the direct Heck-type product can be restricted. Recently, the same group applied this cascade transformation as the key step to the total synthesis of avenaciolide [18bJ. 

SCHEME 6.9 Palladium-catalyzed Heck cyclization/carbonylation cascade. 

SCHEME 6.58 Palladium-catalyzed ring opening/heterocycUzation/carbonylation cascade. 

In another interesting application of this procedure, the acid-mediated cascade cyclization of (3-diketone diepoxide 73 involves the participation not only of the two oxirane rings and of the secondary alcoholic group, but also of one of the two carbonyl groups. In this way, besides the two adjacent C and D THF rings, the simultaneous construction of the spiroketal function between the B and C rings of etheromycin is obtained (compound 74, in a 70 30 mixture with 12 -epi compound Scheme 8.19) [37]. 

Radical-based carbonylation procedures can be advantageously mediated by (TMSlsSiH. Examples of three-component coupling reactions are given in Reactions (74) and (75). The cascade proceeds by the addition of an alkyl or vinyl radical onto carbon monoxide with formation of an acyl radical intermediate, which can further react with electron-deficient olefins to lead to the polyfunctionalized compounds. ... 

In addition, Wu and Li recently have developed an efficient rhodium-catalyzed cascade hydrostannation/conjugate addition of terminal alkynes and unsaturated carbonyl compounds in water stereoselectively (Scheme 4.5).88... 

Later, a nickel-catalyzed cascade conversion of propargyl halides and propargyl alcohol into a pyrone in water was reported. The reaction involved a carbonylation by CO and a cyanation by KCN (Eq. 4.55).96 Recently, Gabriele et al. explored a facile synthesis of maleic acids by palladium catalyzed-oxidative carbonylation of terminal alkynes in aqueous DME (1,2-dimethoxyethane) (Eq. 4.56).97... 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

A cascade process involving a Ni-catalysed coupling, carbonylation, cyanation and heterocyclisation results in the rapid, efficient conversion of propynyl halides and alcohols into 5-cyanopyran-2-ones in aqueous conditions (Scheme 37) <00JCS(P1)1493>. 

The objective was to engineer a catalytic carbonylation-amination-Michael addition cascade employing carbon monoxide (1 atm). This cascade, if viable, could, conceptually, proceed via either of two pathways (Scheme 9). 

Grigg expanded his Pd-catalyzed cascade cyclization reactions to include carbonylation as the termination step [427]. Thus, indoline 329 is obtained in excellent yield and the spiroindoline 330 is secured as a single diastereomer. Thallium acetate results in significant improvement in these reactions by allowing for low-pressure carbonylation. 

Abstract The use of Co building block in presence of water or an alcohol to functionalise alkenes by hydroxycarbonylation or alkoxycarbonylation reactions is reviewed in this chapter. The hydroxyl groups can be present in the substrate itself so cascade reactions can occur. Palladium precursors are largely involved in these reactions and this analysis of the literature focuses on the mechanisms involving Pd(0), Pd(H)(X)L2, PdX2 and an oxidant like CuCl systems. Introduction of chiral L or L2 ligands or even the presence of chiral carbon atoms in the substrate lead to asymmetric carbonylation reactions. 

It is worth mentioning that some precursors easily catalyze the reductive carbonylation of alkynes from the C0/H20 couple. Here, the main role of water is to furnish hydrogen through the water-gas-shift reaction, as evidenced by the co-production of CO2. In the presence of Pd /KI terminal alkynes have been selectively converted into furan-2-(5H)-ones or anhydrides when a high concentration in CO2 is maintained. Two CO building blocks are incorporated and the cascade reactions that occur on palladium result in a cyclization together with the formation of an oxygen-carbon bond [37,38]. Two examples are shown in Scheme 4. 

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