Domino initiated

Domino effeets eliminated so that adverse events are self-terminated and do not initiate new events. 

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bis-diQnQ 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

An enzyme-initiated hydroxylation-oxidation carbo-Diels-Alder domino reaction [82]... 

Besides these special physical properties, hydrogen-bonded liquid water also has unique solvent and solution properties. One feature is high proton (H ) mobility due to the ability of individual hydrogen nuclei to jump from one water molecule to the next. Recalling that at temperatures of about 300 K, the molar concentration in pure water of H3O ions is ca. 10 M, the "extra" proton can come from either of two water molecules. This freedom of to transfer from one to an adjacent "parent" molecule allows relatively high electrical conductivity. A proton added at one point in an aqueous solution causes a domino effect, because the initiating proton has only a short distance to travel to cause one to pop out somewhere else. 

In our opinion, this approach provides not only a clear overview of the existing domino reactions, but also helps to develop new domino reactions and to initiate ingenious independent research projects in this important field of synthetic organic chemistry. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

Scheme 1.28. Acyliminium ion-initiated domino cyclization in the synthesis of azasteroids.

As an alternative mechanistic assumption the initiation of the domino process by one molecule of water could be considered. However, this would lead to the corresponding enantiomer mt-1-146, which was excluded by crystallographic structure determination. 

As discussed previously, West and coworkers developed a two-step domino process, which is initiated by a Nazarov reaction. This can be extended by an electrophilic substitution. Thus, reaction of 1-179 with TiCl4 led to 1-182 via the intermediate cations 1-180 and 1-181. The final product 1-183 is obtained after aqueous workup in 99% yield (Scheme 1.43) [23]. It is important to mention here that all six stereocenters were built up in a single process with complete diastereoselectivity hence, the procedure was highly efficient. 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Scheme 2.1. Twofold anionic domino reaction initiated by a Michael addition.

Scheme 2.16. Intermolecular domino Michael/aldol process initiated by the addition of...

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

An unusual two-component domino Michael/aldol process was described by Tomioka and coworkers in which the initiating step is the formation of an a-lithiated vinyl-phosphine oxide [28] or vinyl phosphate [29]. 

Besides this unique above-described process, there a numerous examples of inter- and intramolecular domino Michael/aldol processes in which the sequence is initiated by the addition of a metalorganic compound to an enone moiety. The Kamimura group [30] synthesized several five- to seven-membered thio- and hy-... 

Similarly, the addition of an amine to the enone moiety can initiate a domino process leading to substituted diaminocyclohexanes [34]. In this transformation an imino aldol reaction occurs. The observed stereoselectivity was again >95 5, and the yield between 51 % and 69% in all cases. 

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

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. 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

Leaving the (retro-)aldol addition-initiated threefold anionic domino processes, we are now describing sequences which are initiated by a SN-type transformation. In particular, domino reactions based on SN/1,4-Brook rearrangement/SN reactions are well known. For example, the group of Schaumann obtained functionalized cyclopentanols of type 2-461 by addition of lithiated silyldithioacetals 2-458 to epoxy-homoallyl tosylates 2-459 in 41-75% yield (Scheme 2.106) [248]. 

The domino reaction is initiated by the chemoselective attack of the carbanion 2-458 on the terminal ring carbon atom of epoxyhomoallyl tosylate 2-459 to give the alkoxides 2-460 after a 1,4-carbon-oxygen shift of the silyl group. The final step to give the cyclopentane derivates 2-461 is a nucleophilic substitution. In some cases, using the TBS group and primary tosylates, oxetanes are formed as byproducts. 

The following example completes the section of threefold anionic domino processes initiated by a SN-type reaction. As discussed earlier in Section 2.2, the reaction of a five-membered cyclic phosphonium ylide with enones, a, 3-unsaturated esters, and a, 3-unsaturated thioesters provides cycloheptene or hydroazulene derivatives in a domino Michael/intramolecular Wittig reaction. This sequence... 

The final group of threefold anionic domino processes described here includes transformations with an initiating elimination step which is either followed by two Michael additions or by substitutions. Thus, reaction of protected nitro alcohol 2-... 

Another example belonging to the class of domino processes initiated by an elimination was described by Gurjar and coworkers in their synthesis of the 2,4-dis-ubshtuted tetrahydrofuran 2-554 [288] this compound is a potent anti-asthmatic drug lead (Scheme 2.125) [289]. 

The final example in this section is the synthesis of a tristetrahydrofuran 2-606 described by the group of Rychnovsky [313]. Here, the tris(sulfate) 2-605 was converted into 2-606 by simply heating it in a mixture of MeCN and H20 (Scheme 2.138). The domino reaction is most likely initiated by deprotection of the primary alcohol, which then attacks the adjacent sulfonate unit in a SN2-type manner to afford the first furan moiety. Under the reaction conditions the formed acyclic sulfate is hydrolyzed affording a free secondary alcohol which then attacks the next adjacent cyclic sulfate unit. Overall, the SN2/hydrolyzation sequence proceeds three times to finally provide the poly(tetrahydrofuran) 2-606 as a single isomer in 93 % yield. 

The present section describes domino processes which combine two or three initiating anionic reaction steps with a following nonanionic transformation. 

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... 

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