Intramolecular reactions domino

The intramolecular version presents a very useful synthetic route to various polycyclic compounds. Even terminal alkenes give cyclopentenones in good yields, assisted by the addition of /V-methylmorpholine N-oxide (NMO) [85], The addition of trimethylamine A -oxidc also dramatically accelerates the reaction in the presence of oxygen, and both inter- and intramolecular reactions proceed at 0°C to room temperature [86]. The reaction was found to proceed rapidly at 25 °C by the addition of aqueous NH4OH [87]. Numerous applications to natural product syntheses have been reported. The tri- and tetracyclic skeletons 214 for crinipellin B, from 213 [88], and the triquinacene derivative 216, from 215, have been constructed [89,90], These results show that internal alkynes and terminal alkenes react smoothly in the intramolecular reactions. Domino reaction of the endiyne 217 produced the strained molecule of oxa[5.5.5.5]fenestrenedione (219) via 218 [91]. 

On the other hand, many reactions are known where in a first intermolecular step a functionality is introduced which than can undergo an intramolecular reaction. A nice example is the reaction of dienone 0-34 with methyl acrylate in the presence of diethylaluminum chloride to give the bridged compound 0-35 (Scheme 0-11). The first step is an intermolecular Michael addition, which is followed by an intramolecular Michael addition. This domino process is the key step of the total synthesis of valeriananoid A, as described by Hagiwara and coworkers [21]. 

The cyclic ylide intermediate 366, as a 1,3-dipole, is generated by intramolecular reaction of Rh-carbene with the ketone in 365, and undergoes cycloaddition with n-bonds to give the adduct 367 [121]. When a-diazocarbonyls have additional unsaturation, domino cyclizations occur to produce polycyclic compounds. The Rh-carbene method offers a powerful tool for the construction of complex polycyclic molecules in short steps, and has been applied to elegant syntheses of a number of complex natural products. 

The decomposition of 368 catalysed by Rh perfluorobutyrate and subsequent intramolecular cycloaddition give 370 in high yield (93%) as the key step in the total synthesis of lysergic acid (371), and is believed to involve the intramolecular reaction of the ylide intermediate 369 at the alkene. No C—H insertion takes place [122], Another elegant example is the efficient construction of the aspidosperma alkaloid skeleton 374. The Rh-catalysed domino cyclization cycloaddition of diazo irnide 372 afforded cycloadduct 374 in 95% yield as a single diastereomer via the dipole 373, and desacetoxy-4-oxo-6,7-dihydrovindorosine (375) has been synthesized from 374 [123]. 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

An interesting variation in this reaction combined an intermolecular Mukaiyama aldol followed by an intramolecular reaction (a domino Mukaiyama aldol) that gave cyclic conjugated ketone products.Borane derivatives such as C=C—OB(NMe2)2 react with aldehydes to give p-amino ketones. ... 

Scandium triflate catalyzed the intramolecular redox reaction from yne-enones to ring-fused tetrahydroquinolines (eq 28). This Lewis acid-catalyzed intramolecular redox domino reaction occurs via domino 1,5-hydride shift and cycUzation to afford tetrahydroquinolines in moderate to excellent yields and with high diastereoselectivity. A similar Sc(OTf)3-catalyzed tandem 1,5-hydride transfer cyclization process was applied in the construction of 3-amino-3-carboxy-tetrahydroquinoline derivatives (eq 29). ... 

In the reaction of allylic ethers with aryl halides, elimination of /t-alkoxy group occurs in some cases. Intramolecular reaction of the glycal 127 afforded the cis-fused pyrano[2,3-c]pyran 129 via deoxypalladation as shown by 128 [74]. On the other hand, ring cleavage of 130 occurs by deoxypalladation to give 132 via 131 [75]. Furthermore, the fcjiy-annulated pyranoside 134 was obtained by domino HR without elimination of the allyl ether group in 133 [76]. 

Domino or cascade reactions are particularly valuable for the construction of various carbo- and heterooligocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades. In this section, such processes with a termination by attack of various nucleophiles will be described. 

In 2013, Enders and co-workers reported a kinetically controlled asymmetric organocatalytic Michael addition/intramolecular Henry domino reaction, providing a facile access to enantioenriched cis-nitroindanol products 164 in excellent yields (61->99%) with up to 97% ee and 17 1 dr (Scheme 6.77). ... 

A flexible diversity-oriented synthesis (DOS) approach to a collection of tricyclic sultams is depicted in Scheme 2.21 [13f. The functionalized sultam scaffolds 52 and 55 embedding oxanorbornene units are readily derived by intramolecular Diels-Alder (IMDA) reactions. Domino ROM/RCM/CM transformations of these substrates using the Grubbs catalyst 2 with a set of co-olefins 53 gave rise to the desired heterocyclic systems 54 and 56, respectively, in good to very good yields. Interestingly, only one of the two epimers 55 participated in the RRM process. 

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.

Domino or cascade reactions provide valuable approaches, especially to various carbo- and heterocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades, hi this section, the termination of these processes by alkenes, arenes, and related ir-bond systems such as alkynes and allenes will be described. A cascade Heck reaction is considered to consist of an oxidative addition of a heteroatom-carbon bond to palladium (starter), carbopalladation of a nonaromatic carbon-carbon double or triple bond without immediate dehydropalladation (relay), one, two, or more fimher car-bopalladation(s) of a carbon-carbon double or triple bond, and eventually ensuing dehydropalladation. Crucial for a cascade reaction of this kind to occur is the blockage or retardation of a dehydropalladation at one of the intermediate stages by using 1,1-disubsti-tuted alkenes and appropriately substimted cycloalkenes, bicycloalkenes, or alkynes as relays since they give kinetically stable alkyl- or alkenylpalladium intermediates, respectively. 

Remarkably, only a small number of intramolecular reactions utilize Barton esters " - likewise, the use of the Barton chemistry in making CC bonds in tandem or domino reactions is far less exploited compared to the tin-hydride-mediated free-radical sequences. The following example is taken from the biomimetic conversion of isoflavone to the rotenoid, where the reaction affords the 6-endo product (Scheme 24). ... 

The domino processes discussed so far concern intramolecular reactions. Extension of the intramolecular domino metathesis processes described in previous sections to an intermolecular reaction, namely, CM, was also successfully applied in organic synthesis (Scheme 11.22). Although CM is afflicted with difficulties in E/Z selectivity and chemoselectivity (three different products are possible in a reaction with two different olefins), the choice of suitable substrates and catalysts alleviates the limitation of these problems. Both mono- and bicycles are suitable substrates. In this case, however, the loss of ring strain, which usually shifts the domino metathesis process toward the desired product in RRM of bicycUc structures, does not guarantee a successful reaction, as CM displays the main origin of side reactions. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

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 ... 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

Kita et al. have made use of the structure of the acyl donor to develop a domino transformation, a DKR followed by an intramolecular Diels-Alder reaction [32]. They... 

Figure 6.54 A domino DKR-intramolecular 1,3-dipolar cycloaddition reaction.

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

Alkenones were used by Rao and coworkers [40] to prepare cyclohexane derivatives which, for example, can be transformed into substituted arenes in a single step. Another interesting intermolecular Michael/intramolecular aldol reaction sequence for the construction of the highly substituted 2-hydroxybicy-clo[3.2.1]octan-8-one framework has been described by Rodriguez group [41]. This process can be extended to a three- and even a fourfold domino reaction [41a, 42, 43],... 

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