Ruthenium domino reaction

Within this chapter, two sections are devoted to rhodium and ruthenium. The two main procedures using rhodium are first, the formation of 1,3-dipoles from diazocompounds followed by a 1,3-dipolar cycloaddition [10] and second, hy-droformylation [11], The ruthenium-catalyzed domino reactions are mostly based on metathesis [12], with the overwhelming use of Grubbs I and Grubbs 11 catalysts. 

On the other hand, several groups have also recently developed asymmetric domino reactions through relay catalysis with combinations of organocatalysts with ruthenium catalysts. For example. You et al. demonstrated in 2009 that ruthenium catalyst could be compatible with Bronsted acid catalyst. They reported a practical and economical synthesis of chiral tetrahydropyrano[3,4-b]indols and tetrahydro-p-carbolines by the combination of ruthenium-catalysed olefin cross-metathesis and a chiral phosphoric acid-catalysed Friedel-Crafts alleviation reaction, as shown in Scheme 7.41. This domino reaction allowed the use of readily available materials to highly enantioselectively construct synthetically valuable polycyclic indole frameworks in enantioselectivity of up to 94% ee. 

On the other hand, Kita et al. reported a combination of the domino reaction concept and the DKR protocol, comprising the first lipase-catalysed domino process that combined the DKR of alcohols by using l-etho QAanyl esters and the Diels-Alder reaction of the intermediates. The finding that ruthenium catalysts produced a rapid racemisation of the slow-reacting (S)-enantiomers was the key to the success of this process, which provided useful chiral intermediates for natural products, such as compactin and forskolin (Scheme 8.28). 

Under ruthenium-catalyzed ortho-C-H activation and intramolecular C-N bond formation, the condensation of iminophosphoranes (in situ generated from acyl azides and triphenylphosphine) with internal alkynes afforded a variety of isoquinolinone derivatives (Eq. (7.43)) [53]. The regioselective insertion of unsymmetrical alkynes led to an (aryl)C-N bond formation. Thiophene and indole-based acyl azides were also compatible for this transformation. A domino reaction sequence via coordination of ruthenium with Af-atom of iminophosphoranes, ort/zo-cyclometalation, alkyne insertion, protonation, and reductive elimination was proposed for the catalytic cycle. Based on and NMR experiments, the involvement of benzamide during the reaction process was ruled out. 

The most important ruthenium-catalyzed domino process is based on a metathesis reaction. Nonetheless, a few other ruthenium-catalyzed processes have been employed for the synthesis of substituted 3,y-unsaturated ketones, as well as unsaturated y-lactams and allylic amines. 

The main reason for the rapid development of metathesis reactions on a laboratory scale (the reaction itself had been known for quite a long time) has been the development of active and robust second-generation ruthenium catalysts (6/3-14 to 6/3-16), which usually provide better yields than the first-generation Grubbs catalysts (6/3-9 or 6/3-13) (Scheme 6/3.2). This also reflects the huge number of domino processes based on ruthenium-catalyzed metathesis, which is usually followed by a second or even a third metathesis reaction. However, examples also exist where, after a metathesis, a second transition metal-catalyzed transformation or a pericyclic reaction takes place. 

A domino RCM of an ene-yne was also used by Granja and coworkers [250] for their synthesis of the B-bishomo-steroid analogue 6/3-70. Reaction of the substrate 6/3-69 with the ruthenium catalyst 6/3-13 led to 6/3-70 in 48% yield as a 6.5 l-mix-ture of the two C-10-epimers (Scheme 6/3.20). The aim of this study was to prepare haptenes for the production of catalytic monoclonal antibodies that could be used to study the mechanism of the physiologically important transformation of previtamin D3 into vitamin D3 [251]. 

Given the previous discussion on reductive amination, it is surprising that the potentially more complicated domino hydroformylation-reductive amination reactions have been more thoroughly developed. The first example of hydroaminomethylation was reported as early as 1943 [83]. The most synthetically useful procedures utilize rhodium [84-87], ruthenium [88], or dual-metal (Rh/Ir) catalysts [87, 89, 90]. This area was reviewed extensively by one of the leading research groups in 1999 [91], and so is only briefly outlined here as the second step in the domino process is reductive amination of aldehydes. Eilbrachfs group have shown that linear selective hydroaminomethylation of 1,2-disubstituted alkenes... 

Plumet et al. described domino metathesis of propargyl (2-endo-7-oxanorborn-5-enyl) ethers 62a-62c with allyl acetate in the presence of Grubbs ruthenium catalyst Ic (Scheme 22). The reaction proceeds stereoselectively to produce substituted m-fused bicyclic ethers 63a-63c. In a similar manner, indolizidinone derivative 64 is obtained from compound 62d instead of pyrrolizidine derivative 63d. ... 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

Nonstrained heterocyclic systems can also serve as suitable substrates for domino ROM/RCM processes [11]. Scheme 2.16 illustrates extended RRM transformations of the tetraenes 38 and 40 embedding two dihydropyran moieties, which proceed with remarkable eflBciency using the ruthenium complex 2 to give the rearranged products 39 and 41, respectively, without unwanted side reactions such as dimer or macrocycle formation [11a]. 

Enyne RCM reactions have been successfully coupled with a CM event [16]. Thus, a domino enyne RCM/CM process with enyne 65 and methyl vinyl ketone was used as the final step in a concise total synthesis of the bioactive sesquiterpene lactone (+)-8-epi-xanthatin (66) (Scheme 2.25) [16a,b. Using the phosphine-free ruthenium catalyst 4, an efHcient transformation was achieved with the required electron-deficient co-olefin. 

In the reaction of the a-amino acid derivative 73 with 1,5-cyclooctadiene catalyzed by ruthenium complex 2 depicted in Scheme 2.29, an enyne CM followed by an RCM was coupled in a domino manner with an initial ROM of the cyclic diene [17b,cj. The resulting enantiomericaUy pure 1,3-cyclohexadiene 74 was then used to construct the diketopiperazine core of the scabrosin epidithiodiketopiperazine antibiotics [17cj. 

Domino metathesis reactions of the dienynes 97 and 99 catalyzed by the phosphine-free ruthenium catalyst 4 in the presence of ethylene allowed a rapid access to the naturally occurring marine trisnorsesquiterpenes (—)-clavukerin A (98) and (—)-isoclavukerin A (100), respectively, by preferential initiation at the disubstituted alkene (Scheme 2.36) [18i]. As the dienyne substrates 97 and 99 were easily available from (S)- and (J )-citronellal, respectively, in only three high yielding operations, the 1,3-dienes 98 and 100 now offer themselves as enantiopure building blocks for the preparation of structurally more complex hydroazulene targets. 

Already in the absence of ethylene, the oxanorbornene propargyl ethers 125 and 126 bearing an internal or terminal alkyne readily participated in a domino ROM/enyne RCM process catalyzed by ruthenium complex 1 as well to give the heterobicycles 127 and 128, respectively, in high yields (Scheme 2.46) [23]. An efficient domino ROM/double enyne RCM transformation of the bis-propargyl ethers 129 and 130 likewise furnished the bis-dienes 131 and 132, respectively, under similar reaction conditions. 

Enyne metathesis/metallotropic [l,3]-shift domino processes are also valuable for natural product synthesis [33c,d]. Reaction of substrate 168 with cis-l,4-diacetoxy-2-butene in the presence of Grubbs catalyst 2 generated the intermediate ruthenium alkinyl carbene through a relay RCM with the hberation of 2,5-dihydrofuran followed by metallotropic [l,3]-shift and terminating (Z)-selective CM with the co-olefin to yield the conjugated enediyne 169 (Scheme 2.58) [33c]. The antitumor active Panax ginseng constituent (3R,9R,10R)-panaxytriol was readily synthesized from 169 in six steps. 

Metathesis events and substitution reactions can be readily combined in attractive domino processes. Thus, a dual catalysis with palladium and ruthenium complexes... 

Coupling of CM and intramolecular substitution to domino processes leading to tetrahydrofurans is feasible as well [38]. However, a corresponding combination to give tetrahydropyrans is better carried out as a sequential process [38d]. Reaction of the terminal olefin 184 with allyl chloride catalyzed by ruthenium complex 2 led to tetrahydrofuran 185 by a completely diastereoseleclive cyclization of the intermediate CM product (Scieme 2.65) [38a,b]. Compound 185 was then successfully advanced to the immunosuppressive diterpenoid pyrone subglutinol B. 

A tandem (domino) cross-metathesis reaction between an enyne and 3 equivalents of a conjugated alkene proceeds in dichloromethane at 40 °C for 12 h with a high yield in the presence of the same ruthenium-carbene flve-membered ring compound 8.53, as shown in Eq. (8.21) [54, 55]. 

Scheme 3.4 Domino double hydrogenation reaction catalysed by a combination of chiral rhodium catalysis and chiral ruthenium catalysis.

Scheme 7.41 Domino cross-metathesis-Friedel-Crafts reaction catalysed by chiral phosphoric acid catalysis and ruthenium catalysis.

Later, You et al. investigated relay catalysis consisting of a combination of the same ruthenium catalyst and a closely related chiral BINOL-derived phosphoric acid. As shown in Scheme 7.42, the use of this catalyst system in an asymmetric domino intramolecular Friedel-Crafts-type-aza-Michael reaction allowed a range of chiral fused indoles to be achieved in high yields and moderate to high enantioselectivities from the corresponding enones and indolyl olefins. 

Scheme 7.44 Domino oxidation-Michael-intramolecular alkylation reaction, domino oxidation-Michael-hemiacetalisation reaction, and domino oxidation-oxa-Michael-Michael reaction catalysed by chiral amine catalysis and ruthenium catalysis.

---