Domino cyclizations

Scheme 3.70. Examples for the 5-exo-dig-cyclization/1,5-hydrogen transfer/5-encfo-trig cyclization domino process.

Scheme 5.24 Proposed mechanism of the 5-exo/6-endo and 5-exo/5-exo cyclization domino process.

Metal-free iodine-promoted oxidative cyclization domino process was successfully utilized by Jiang et al. [15] to synthesize poly substituted oxazoles. Similarly, very efficient iodine-promoted oxidative cyclization domino process was reported by Wu et al. [16] for the synthesis of 2-acylbenzothiazoles 38 via a sp C-H functionalization (Scheme 9.8). 

Binder, J. T. and Kirseh, S. E. 2006. Synthesis of highly substituted pyrroles via a multi-metal-eatalyzed learrangement-eondensation-cyclization domino approaeh. Org. Lett. 8 2151-2153. 

Consult Ref [37] compare Ref [38], where a similar reaction principle is reported. (3-Alkylidene) THFs with a CH2CH=0 side chain in 4-position were obtained in anelegant PdCl2-catalyzed Heck carbopalladation/cyclization domino reaction of... 

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]. 

Scheme 1.8. Domino cyclization/rearrangements via iminium ions.

Scheme 1.11. Cationic domino poly-cyclization for the synthesis of 3-deoxyschweinfurthin B (1-42).

Scheme 1.24. Lewis acid-catalyzed cationic domino cyclization to give bicyclo[2.2.1]heptane derivatives.

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

Scheme 1.29. Domino acyliminium ion cyclization/Ritter reaction procedure in the synthesis of CPG 49823 (1-116).

As mentioned earlier, the McDonald group was able to extend their epoxide-domino-cyclization strategy to 1,5,9-triepoxides [10]. Indeed, they were successful in converting precursor 1-143 into the tricyclic product 1-146 in 52 % yield after hydrolysis (Scheme 1.36) [41]. As a possible mechanism of this polyoxacyclization it can be assumed that, after activation of the terminal epoxide by BF3, a sequence of intramolecular nucleophilic substitutions by the other epoxide oxygens takes place, which is induced by a nucleophilic attack of the carbonate oxygen, as indicated in 1-144 to give 1-145. 

Scheme 1.38. Domino epoxide-opening/rearrangemenl/cyclization reaction towards the total synthesis of (+)-stachyflin (1-152).

Scheme 1.44. Enantioselective synthesis of (-)-gilbertine (1-190) by a cationic domino cyclization.

A very impressive multiple cationic domino reaction was used in the enan-tioselective total synthesis of (-)-gilbertine (1-190), described by Blechert and coworkers [50]. When the tertiary alcohol 1-184 is treated with TFA, a carbocation is formed which undergoes a cascade of cyclizations to afford 1-190 in very good yield (61 %) (Scheme 1.44). The cations 1-185 to 1-189 can be assumed as intermediates. 

Scheme 1.48. Cationic domino cyclization/hetero-Diels-Alder procedure.

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

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. 

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. 

Recently, a further unique domino methodology has been reported by Lu and coworkers (Scheme 2.74) [173]. Herein, a triphenyl phosphine-catalyzed umpolung addition/cyclization of allenes and alkynes containing an electron-withdrawing group 2-316-2-318 followed by reaction with a double nucleophile 2-319 is assumed to account for the production of a broad palette of various heterocycles 2-321 and 2-323 via 2-320 and 2-322, respectively. Dihydrofurans, piperazines, morpholines and diazepanes were obtained during the process. 

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