Domino sequence

Besides the numerous examples of anionic/anionic processes, anionic/pericydic domino reactions have become increasingly important and present the second largest group of anionically induced sequences. In contrast, there are only a few examples of anionic/radical, anionic/transition metal-mediated, as well as anionic/re-ductive or anionic/oxidative domino reactions. Anionic/photochemically induced and anionic/enzyme-mediated domino sequences have not been found in the literature during the past few decades. It should be noted that, as a consequence of our definition, anionic/cationic domino processes are not listed, as already stated for cationic/anionic domino processes. Thus, these reactions would require an oxidative and reductive step, respectively, which would be discussed under oxidative or reductive processes. 

Further investigations in this field revealed that the described domino sequence can also be performed in an intramolecular mode to afford to 2-acyl-3-halocyclohex-anols 2-78 from 2-77 (Scheme 2.17) [24e],... 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

Another domino cuprate 1,4-addition-initiated threefold anionic domino sequence was developed by Chemla and coworkers (Scheme 2.93) [214]. Michael addition of the a, 3-unsaturated ester 2-387 with PhCu(CN)ZnBr was followed by a carbocyclization to give the zinc species 2-388 which can be intercepted by iodine or an allyl bromide affording substituted pyrrolidines 2-389 and 2-390, respectively. 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

A very attractive anionic/anionic/pericyclic/anionic fourfold domino sequence was developed by Kuehne s group, as illustrated in Scheme 2.147 [336]. Herein, on treatment of the enantiopure tryptophane-derived diester 2-644 with a, 3-unsatu-rated aldehydes 2-645 at 70 °C in benzene with benzoic acid and freshly activated... 

Recent reports have shown that this highly efficient domino sequence can also be employed for the synthesis of (-)-strychnine [337] and (-)-lochneridine [338]. 

Besides morefold anionic domino processes with one pericyclic reaction, domino sequences combining two initiating anionic with two pericyclic steps have also been developed. For example, the group of Nesi and Turchi reported on the synthe-... 

There are also some rare domino sequences where two anionic and two radical reactions are combined (Scheme 2.152) [347]. According to a report of the Wang group, thionyl chloride is able to promote a succession of reactions by an initial formation of a chlorosulfite 2-673 of the tertiary alcohol 2-672, followed by an SN-type reaction to produce the chloroallene 2-674. A Schmittel cyclization reaction [348] then generates... 

It is also worth emphasizing that the initiation and termination steps are not included in the central chain process. For instance, in metal hydride-promoted domino reactions the initial halogen abstraction (or SePh displacement, etc.) and the final hydrogen abstraction from R MH are not classified as part of the domino sequence. More precisely, only the propagation steps within the mechanism of this process will be considered as a strict integral part of the domino reaction. 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

In their studies, Takasu, Ihara and coworkers used a new methodology based on a boomerang-type radical domino sequence [51], in which an iodoalkenyl can act as both radical donor and acceptor providing [4+2] or [4+1] cyclization products [52]. 

Scheme 5.25. Proposed mechanism of the Pd/light-induced domino sequence.

During the past few years, increasing numbers of reports have been published on the subject of domino reactions initiated by oxidation or reduction processes. This was in stark contrast to the period before our first comprehensive review of this topic was published in 1993 [1], when the use of this type of transformation was indeed rare. The benefits of employing oxidation or reduction processes in domino sequences are clear, as they offer easy access to reactive functionalities such as nucleophiles (e. g., alcohols and amines) or electrophiles (e. g., aldehydes or ketones), with their ability to participate in further reactions. For that reason, apart from combinations with photochemically induced, transition metal-catalyzed and enzymatically induced processes, all other possible constellations have been embedded in the concept of domino synthesis. 

Examples of the oxidative cleavage/bis-hetero-Diels-Alder domino sequence of compounds of type 7-124 to give acetals of type 7-125 are listed in Scheme 7.34. This shows that the reaction is high-yielding and can be carried out under rather mild conditions. 

In recent years, many novel MCRs - including Michael addition-initiated three-component domino sequences [10], Knoevenagel/hetero-Diels-Alder-based MCRs [11], radical chain MCRs [12], transition metal-catalyzed Pauson-Khand MCRs [13], as well as Petasis MCRs [14], have been added to the chemisf s armamentarium and successfully applied to all fields of organic synthesis. 

As shown in Scheme 14, a sulfuric acid-catalyzed dehydration-cyclization-elimination domino sequence starting from protonation of the secondary hydroxy group of the indolo[2,3- ]quinolizidine 112 led to the isolation of the pentacyclic compound 113 in good yield <1999EJ03429>. 

This theory led to the Updated Domino Theory by Kuhlmann, Seven-Domino Sequence by Marcum, Relabeled Five-Domino Sequence by Bird, Modified Domino by Weaver, and Relabeled Five-Domino Sequence by Adams. 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

The domino sequence leading to the conversion of 30 to 31 was performed without isolation of the intermediates. The sequence is thought to proceed as shown in Scheme 7.6. Treatment of 30 with benzaldehyde with azeotropic removal of water led to the protection of the amine as the benzaldehyde imine 33, which was directly mesylated to give 34. The solution of 34 was treated with allylamine (4 equiv.) and autoclaved at 112°C for 15 h to provide 31 in 80% yield after acidic hydrolysis. It is assumed that the benzaldehyde imine of 33 is exchanged with allyl amine to form the aminomesylate 35, which undergoes fast ring closure to the aziridine 36. Then allylamine adds to the... 

The N-alkylation of amines with alcohols [63] can also be carried out with Ir catalysts through a similar domino sequence reaction. In this case, the aldehyde/ketone resulting from oxidation is condensed with an amine to the corresponding imine, which is hydrogenated to the alkylated amine [63]. By way of example, the reaction of benzyl alcohol with aniline in toluene afforded benzylaniline in a 88% isolated yield by using catalytic amounts of [ lr(/z-Cl)Cp Cl 2]/K2C03. 

The hitherto unknown oxazolo[4,5-f]isoxazole system has been synthesized by Nesi et al. in their studies on isoxazoles and their reactions. Oxazole 118 reacts with 1-dimethylaminopropyne through, what the authors describe as a four-step hetero-domino sequence, which they postulate includes a 1,3-dipolar cycloaddition of intermediate nitrile oxide 122 (Scheme 13) <1999T13809>. 

A novel one-pot synthesis of various fused lactones has been achieved via a domino sequence of Knoevenagel/ hetero-Diels-Alder/elimination reactions of N- and 0-prenyl aryl aldehyde derivatives with Meldrum s acid in the presence of D- or L-proline with high diastereoselectivity (Scheme 68) <2005MI1353>. 

Scheme 25 Formation of three new rings from 2-bromoalka-1, m-dien-n-ynes in a domino sequence of two intramolecular Heck-type reactions and 67r-electrocyclization...

Chemla, Normant and coworkers also reported a one-pot 1,4-addition/carbocyclization domino sequence as a new access to 3-carbomethoxypyrrolidines. Conjugate addition of the mixed organocopper-zinc reagent n-BuCu(CN)ZnBr LiBr to the Michael acceptor 427 in ether at room temperature directly led after hydrolysis to the 3-carbomethoxypyr-rolidine 428 as a 84/16 diastereomeric mixture, the trans disubstituted isomer being predominant (equation 185). A similar explanation as described above was proposed for the stereochemical outcome264. 

The formation of spirolactams 47-49 could be rationalized in terms of a sequence domino cyclization of a-allenols-cross coupling reactions. A palladium (Il)-catalyzed mechanism for the domino sequence leading to spiranic adducts 47-49 is proposed in Scheme 17. It could be presumed that the initially formed allenepalladium complex 50 undergoes an intramolecular attack by the hydroxyl group (oxypalladation), giving rise to the spirocyclic vinylic palladium species 51. 

Alder reaction [89]. The latter compounds can be submitted again to a Diels-Alder reaction by treatment with maleimide and the resulting oxa-bridged intermediates, obtained as a mixture of diastereoisomers, can be transformed into hexasubstituted benzenes by thermal treatment. In these cases however, the possible asymmetric induction obtained during the cydoaddition is lost in the final part of the domino sequence. 

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