Substitution 1,3-disubstituted allenes

Allenes add nitrile oxides either to one or two double bonds. For mono- and 1,1-disubstituted allenes, relative activity of the two bonds depends on the nature of substituents. The reaction (Scheme 1.18) of N-propadienylanilines 54 with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide proceeds site- and regioselectively to give 5-substituted 4-methylene-4,5-dihydroisoxazoles 55, which add a second molecule of nitrile oxide to afford 4,5/-spirobi-(4,5-dihydroisoxazoles) 56. Dihy-droisoxazoles 55 isomerize to 4-(2-aminobenzyl)isoxazoles 57 via a Claisen-type rearrangement (224). 

Even the reaction with 1,1-disubstituted allenes delivered 2-chloroallyl alcohols 16 with the hydroxyl group connected to the more substituted terminus [15]. 

Marks et al. s organolanthanide catalysts show a strong dependence on the substitution of the allene [99]. Terminal allenes 144 with three carbons in the tether deliver the tetrahydropyridines 145. 1,2-Disubstituted allenes with the same length of the tether lead to the vinylpyrrolines 146 (Scheme 15.45). 

Monomers with cumulated double bonds, such as substituted allenes and ketenes, produce a great variety of structures. Stereoisomerism is found both at the saturated (iso- or syndiotacticity) and at the unsaturated carbons where the substituents in the plane of the chain can be oriented in either direction (forward or backward). With regard to 1,3-disubstituted allenes, four stereoregular strac-tures, 43-46 (Scheme 10), are predicted. Porri, Rossi, and Ingrosso succeeded in polymerizing 2,3-pentadiene (1,3-dimethylallene) samples of different optical purity (87). In their experiments they recognized the existence of sequences 43. 

Another reactive ketene which undergoes efficient cycloaddition with allenes is tert-butyl-cyanoketene (TBCK). Again mixtures of isomeric cycloadducts are obtained when unsymmet-rically substituted or 1,3-disubstituted allenes are employed.10-12... 

Allenes The reaction of 1 with a 1,1 -disubstituted allene liberates a new titanacycle considered to have structure 2. Addition of a ketone to 2 results in a new substituted allene 3. 

In general, 1,1-disubstituted allenes form the adducts from addition of dichlorocarbene to the more highly substituted double bond, and mixtures of monoadducts occasionally result from addition to both double bonds by the chloroform/base/phase-transfer catalyst method. For example, 18 19 and 20 i 21, 22 and 23 ° 24 and 25. ° ... 

It has been found that 1-substituted (trimeLhylsilyl)allenes are more efficient as the three-carbon component than the corresponding unsubstiluted allene and further substitution of the allene at the terminus allows a direct and stereoselective route to highly substituted cyclopentanes. However, for a sterically demanding acceptor such as /i./f-disubstituted enones. terminally substituted allenes fail to react. 

For some selected ketenes the CNDO/S electron densities are summarized in the Appendix (Part A). The CNDO/S carbon and oxygen electron densities in ketenes exhibit the linear correlations (83a)-(83c) with those in correspondingly substituted mono- and 1,1-disubstituted allenes, which reflect the close similarities of both these three-atomic cumulenic functionalities. 

The situation for 1,3-disubstituted allenes with different ligands becomes complex and is discussed, for instance, for 7-substituted phenylallenes in Ref. c. Symmetry arguments lead to the expectation that in such 1,3-disubstituted allenes the x-o separability breaks down. But, symmetry does not allow any statement about the extent of the breakdown. For 7-substituted phenylallenes PhHC=C=CHX it has been shown (Ic) that the orbitals correlating with the x(a") orbitals in phenylallene (16) retain to a good approximation their nodal planes and thus may be treated and classified (with respect to their nodal plane symmetry) like x orbitals. The question about the extent of the possibility for a quasi x-quantitative treatment of the circular dichroism of chiral allenes (16,73). 

The first examples of a Pd-catalyzed addition of terminal alkynes to allenes have been reported by Trost and Kottirsch (Scheme They observed that different palladium complexes efficiently catalyze the addition of terminal alkynes I to 3-substituted allenecarboxylates 23 to produce a mixture of the a,)8-unsaturated ester 24 and the two isomeric /S.-y-unsaturated esters (Z)- and (E)-25 (Scheme 9). Remarkably, the type of Pd catalyst used played a crucial role in determining the regiochemistry of addition to the 1,3-disubstituted allenes 23. Thus, with the Pd(OAc)2 TDMPP system (cat. A) a 76 24 ratio of 24 and E/Z)-25 was produced, whereas with a combination of tetrakis(carbo-methoxy)palladacyclopentadiene (TCPC) and TDMPP (cat. B) these products were obtained in a ratio of 9 91 (Scheme 9). ° ... 

In 2008, Willis and co-workers developed a highly enantioselective inter-molecular hydroacylation reaction employing ortfto-S-substituted benzal-dehydes 51 and 1,3-disubstituted allenes 52 (Scheme 8.25). When using a (7 ,/ )-Me-DuPhos-derived cationie rhodium catalyst, excellent yields and ee were obtained. Extension of the substrate scope to a trisubstituted allene led to the product with high ee, but in a disappointingly low yield. It was revealed that the reaction was not a simple kinetic resolution of the racemic allene but rather proceeded by dynamie kinetie asymmetric transformation. 

Yamamoto has also demonstrated the intermolecular hydroamination of mono-substituted arylallenes with morpholine [40]. For example, treatment of l-p-tolyl-1,2-propadiene with morpholine and a catalytic 1 1 mixture of [PPh2(o-tolyl)]AuCl and AgOTf in toluene at 80 °C for 24h led to isolation of the allylic amine 56 in 83% yield as a single regio- and stereo-isomer (Eq. (11.31)). 1-Alkylallenes, 1,1-, and 1,3-disubstituted allenes also underwent gold(I)hydroamination with morpholine, albeit with diminished efficiency and/or regioselectivity. 

The potential of allenes in stereoselective synthesis was reported by Barlan and Micalizio [126] who studied the reductive cross-coupling reaction of alkenyl-silanes and styrene with a range of disubstituted allenes bearing a proximal hthiated alkoxide. When allenes 448 were treated with the preformed Ti complex of vinyltrimethylsilane or styrene, the substituted 1,3-dienes 449 were obtained (Scheme 10.153). 

Recently, the reaction of polymer-bound aryl halides with 2,4-disubstituted allene-carboxyUc acids leading to polymer-bound butenolides was reported (Scheme 7). After removal from the polymer, the substituted butenolides can serve as important building blocks for natural product synthesis. ... 

Mono- and asymmetrically-substituted allenes absorb strongly at 875-840cm (11.43-11.90pm) due to the out-of-plane deformation vibrations of the =CH2 group. The overtone of this band occurs near 1700 cm (5.88 pm). Symmetrically-disubstituted allenes absorb near... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

The reaction is versatile and proceeds with a variety of cyclic and acylic alkenes substituted with alkyl, aryl, vinyl and heteroatom substituents. Allene derivatives also undergo cycloaddition with nitrones ". A variety of cyclic and acyclic aliphatic nitrones bearing aliphatic and aromatic substituents has been tested. The reaction is, however, relatively sensitive to steric constraints and proceeds easily only for mono- and disubstituted alkenes. Steric requirements for a nitrone molecule are similar and, although several reactions with R, R2 are known, good yield has been achieved only with R = H (equation 105). 

Efforts have been made to find stereoselective routes which provide disubstituted azetidines. Palladium catalysed cyclization of an enantiomer of allene-substituted amines and amino acids gives the azetidine ester 2 and a tetrahydropyridine in variable yield and ratio, depending on the substituents and conditions <990L717>. The (TRIS)- and (253I )-isomeis of the substituted azetidine-2-carboxylic acids 3 (R = COjH) are obtained in several steps from the corresponding 3 (R = CHjOSiMejBu ) which, in turn, is produced in high yield by photochemical intramolecular cyclization <98HCA1803>. 

Shibata and co-workers have reported an effective protocol for the cyclization/hydrosilylation of functionalized eneallenes catalyzed by mononuclear rhodium carbonyl complexes.For example, reaction of tosylamide 13 (X = NTs, R = Me) with triethoxysilane catalyzed by Rh(acac)(GO)2 in toluene at 60 °G gave protected pyrrolidine 14 in 82% yield with >20 1 diastereoselectivity and with exclusive delivery of the silane to the G=G bond of the eneallene (Equation (10)). Whereas trimethoxysilane gave results comparable to those obtained with triethoxysilane, employment of dimethylphenylsilane or a trialkylsilane led to significantly diminished yields of 14. Although effective rhodium-catalyzed cyclization/hydrosilylation was restricted to eneallenes that possessed terminal disubstitution of the allene moiety, the protocol tolerated both alkyl and aryl substitution on the terminal alkyne carbon atom and was applicable to the synthesis of cyclopentanes, pyrrolidines, and tetrahydrofurans (Equation (10)). 

Chiral separations are concerned with separating molecules that can exist as nonsuperimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers, are illustrated in Figure 1. Although chirality is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphorus or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahelicene, tetrasubstituted adamantanes, and substituted allenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

A new type of triaryl phosphine-functionalized imidazolium salt containing cations such as (6) has been prepared. Palladium complexes of (6) generated in situ have been used successfully in Heck-type reactions of aryl halides with acrylates and of 4-bromotoluene with styrene derivatives.34 The first Heck-type reaction of aryl halides with allenes has been reported. 1,3-Double arylations were observed with 3-substituted-l,2-allenyl sulfones, while 1-monoarylation was favoured with 3,3-disubstituted-l,2-allenyl sulfones.35 It has been shown that the a-arylation of methane-sulfonamides (7) may be achieved using palladium catalysis reaction proceeds through the sulfonamide enolates.36 It is also reported that palladium cross-coupling of alkynes with /V - (3 - i odophe n y I an i I i ncs) may lead to the formation of substituted carbazoles.37... 

Higher-order zinc cyanocuprates react in a similar manner with propargyl chlorides and bromides46. Allenes are the result (S 2 substitution), except in the case of l,4-dihalo-2-butynes, which undergo two successive S 2 substitutions to afford 2,3-disubstituted butadienes (equations 33 and 34)47. 

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