Center quaternary

In addition to direct attack on the nitrogen atom which finally becomes the quaternary center, it is possible for the electrophile to attack elsewhere in the heterocyclic molecule and for a mesomeric shift to proceed to completion to give a salt. 

The action of methyl iodide on chloro-substituted heterocychcs usually results, in addition to quatemization, in the replacement of the chlorine by iodine if the halogen is in a position alpha or gamma to the quaternary center, particularly so in the former case. This type of replacement is less likely if dimethyl sulfate is used but may still occur to give a sulfate betaine (see Section IV, C). An easy method to obtain a-halogeno-quatemary salts has recently been discovered by Balli and Kersting who reacted the readily accessible triethyloxonium borofluoride 12 with a variety of bases. The very... 

Quaternary salts have been prepared from a number of these bases. 7-(Dialkylaminoalkyl)amino-l,2,3a,4-tetraazaindenes (132) were prepared and converted into mono-quaternary salts, but no structures were assigned to the salts and the quaternary center may well be in the side-chain. When this ring system carries 3-methyl and 5-alkyl or... 

The key step in this sequence, achieved by exposure of 46 lo a mixture of sulfuric acid and acetic anhydride, involves opening of the cyclopropane ring by migration of a sigma bond from the quaternary center to one terminus of the former cyclo-l>ropane. This complex rearrangement, rather reminiscent of the i enone-phenol reaction, serves to both build the proper carbon. keleton and to provide ring C in the proper oxidation state. 

Treatment of an ethylidene malonic ester such as (a) with strong bases results in loss of a proton from the allylic position to produce the ambident ion fb). Alkylation of such carban-ions usually occurs at the carbon bearing the carbonyl groups, resulting in the establishment of a quaternary center and deconjugation of the double bond fc). 

Recendy, the VNS intermediates have beo) used for further introducing electrophiles For example, reacdon of the enolate of ethyl 3-chloroptDpionate v/ith nitrobenzene followed by subsequent reacdon v/ith an alkylating agent gives a series of esters bearing a quaternary center fEq 9 36,... 

Quaternary centers have also been generated, often with good to excellent stereoselectivity, by the addition of y.y-disubstituted allylboranes or y,) -disubstituted aiiylboronates to aldehydes 50,97. 

The utility of this method becomes apparent in a synthesis of 6, a precursor of pinguisone. This demonstrates that sterically hindered compounds can be easily synthesized in one step by a cis annulation, i.e., even those that have two adjacent quaternary centers, and three adjacent methyl groups41. The structure of 6 was confirmed by X-ray analysis46. 

Despite the favorable thermodynamics associated with the cyclization of unsaturated organolithiums, the isomerization is often sluggish when the ring closure involves generation of a quaternary center or formation of a strained framework. In such cases it has been found that addition of lithiophilic Lewis bases such as THF or TMEDA facilitate the reaction.7 9 The preparation of cuparene, a sterically congested sesquiterpene possessing two adjacent quaternary centers, illustrates the methodology.11... 

IH of hindered aminoalkenes has been developed as a route to heterocycles containing quaternary centers a to the nitrogen atom (Eq. 4.21) [134]. For these reactions, the easy-to-prepare catalyst precursors [(MejSiCpljLnMejj prove very efficient. 

The compact bicyclic lactams 15 and 16 are examples of chiral systems that show high facial selectivity. Interestingly, 15 is alkylated from the convex face. When two successive alkylations are done, both groups are added from the endo face, so the configuration of the newly formed quaternary center can be controlled. The closely related 16 shows exo stereoselectivity. 100... 

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments.208 Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the kcto-fi-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionalized hydroxy-ji-lactams (Eq. 8.82). 

For most dienes, 7r-bonds adjacent to quaternary centers do not undergo insertion reactions. One notable exception is 1,5-diene (75) (Scheme 17) [44], For this substrate, the observed selectivity is inconsistent with a chair-like (in this case a trans decalin-like) transition structure (76 top) leading to the insertion product, which is typically seen in diene cyclizations with 70 [36]. 

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). 

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

In a similar way, carbocycles having a quaternary center could be obtained from acyclic unsaturated 1,3-dicarbonyl compounds [206]. Other combinations are the domino hydroformylation/Wittig olefmation/hydrogenation described by Breit and coworkers [207]. The same group also developed the useful domino hydroformyla-tion/Knoevenagel/hydrogenation/decarboxylation process (Scheme 6/2.14) [208] a typical example is the reaction of 6/2-66 in the presence of a monoester of malonic acid to give 6/2-67 in 41 % yield in a syn anti-ratio of 96 4. Compounds 6/2-68 and 6/2-69 can be assumed as intermediates. 

Scheme 4.3 Formation of the C7 quaternary center by C7-C3 bond formation by Woodward and...

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