Regiochemical outcome

In polyhydroxylated systems the regiochemical outcome is determined by initial reaction at the sterically less hindered alcohol. ... 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

An unexpected varying regiochemistry in intramolecular benzannulation has also been observed in the synthesis of cyclophanes. As mentioned above, there are only two possible regiochemical outcomes in the benzannulation reaction, which differ in the direction of alkyne incorporation. / -Tethered vinyl-carbene chromium complexes undergo an intramolecular benzannulation reaction with incorporation of the tethered alkyne with normal regioselectivity to give meta-cyclophanes [28]. 

In this case, the Hofmann product is the major product, because a sterically hindered base was used. This case illustrates an important concept The regiochemical outcome of an E2 reaction can often be controlled by carefully choosing the base. Below are two examples of sterically hindered bases that will be encountered frequently throughout your organic chemistry course ... 

For the regiochemical outcome, we expect the Zaitsev product to be the major product, because the reaction does not utilize a sterically hindered base ... 

After forming the double bond, we must also carefully consider the regio-chemistry of how we add HBr across the double bond. Once again, by carefully choosing our reagents, we can control the regiochemical outcome. We can either use HBr to force a Markovnikov addition, or we can use HBr with peroxides to force an flnti-Markovnikov addition. Let s see an example ... 

The unexpected regiochemical outcome of the cycloaddition gave rise to a complete study of the factors influencing the regioselectivity, inasmuch as 4-spirocyclopropane isoxazolidines are unable to undergo the useful thermal rearrangement. 

A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of IV-substitution with bulky groups directing to C-3. The oxidative alkenylation of (V-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the (V-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. 

Theoretical calculations predict an asynchronous mechanism and suggest that the modification of the regiochemical outcome is related to the energies and hardness of the TS involved. Perhaps, in other words, the more polar TS are favored under the action of MW. 

For 1,2-disubstituted epoxides, the regiochemical outcome of nucleophilic attack becomes less predictable. However, in the case of epoxy ethers chelation control can be used to deliver the nucleophile preferentially to the epoxide carbon away from the ether moiety. Thus, treatment of epoxy ether 61 with an imido(halo)metal complex, such as [Cr(N-t-Bu)Cl3(dme)], leads to the clean and high-yielding production of the chlorohydrin 64. The regioselectivity is rationalized in terms of initial formation of a chelated species (62), followed by attack at C-3 to form the more stable 5-membered metallacyclic alkoxide 63 <00SL677>. 

A remarkable series of CH functionalizations has been described whereby the regiochemical outcome of the reaction is determined by the catalyst employed. Directed and nondirected C-H functionalizations on 2-phenylimi-dazole were observed. This orthogonal approach is excellent for introducing diversity and may have applications in library generation in areas including medicinal chemistry (Scheme 18). 

In rare cases, the Pd-catalyzed intramolecular allylic etherification has been extended to the construction of medium-sized rings. Both an 11-membered bis-ether ring (Equation (34))164 and an eight-membered ether ring (Equations (35) and (36))155 have been prepared in this fashion. In the latter case, the choice of ligand dictated the regiochemical outcome. 

Reactions with seven- to nine-membered cydic allylic carbonates or halides give the corresponding cydic allyltitanium compounds. These reagents add to aldehydes and imines with moderate to excellent diastereoselectivities [59]. The allyltitanium compound generated from 1-vinylcyclopropyl carbonate reacts regioselectively with aldehydes and ketones at the less substituted carbon atom to provide alkylidenecydopropane derivatives, as shown in Scheme 13.29 [60], The regiochemical outcome of the reaction can be rationalized by assuming an equilibrium between two allyltitanium spedes that favors the less strained tertiary structure. 

The a- and y-position activation has a remarkable impact on the regiochemical outcome for the Pd-catalyzed reaction of heterocycles. For example, the palladium-catalyzed reaction of 2,5-dibromopyridine takes place regioselectively at the C(2) position, although the halogen-metal exchange reaction takes place predominantly at C(5). Pd-catalyzed reactions of chloropyrimidines take place at C(4) and C(6) more readily than at C(2). 

To make tryptophan analogs, Gronowitz and coworkers conducted a pyrrole annulation from an aminoiodopyrimidine utilizing the Larock indole synthesis conditions (see Section 1.10.) [80]. They prepared heterocondensed pyrrole 115 by treating 4-amino-5-iodopyrimidine 114 with trimethylsilyl propargyl alcohol under the influence of a palladium catalyst The regiochemical outcome was governed by steric effects. 

Based on this model, the regiochemical outcome of both oxabicycHc alkenes and vinyl epoxides can be explained by the relative stability of the two cr-intermediates. With oxabicyclic alkenes intermediate 41 is generated directly and then goes on to give product, whereas with the vinyl epoxides a more highly strained intermediate 40 is first produced which must first isomerize to 41 prior to product formation. The regiochemical outcome with each substrate may therefore arise from the commonahty of a cr-in-termediate 41 to both reaction pathways (Scheme 9.13). 

More recently, Murakami and co-workers have developed a highly regioselechve method for the synthesis of substituted benzenes, which employs vinylallene derivatives and monosubshtuted alkynes (Eq. 2) [8]. Simple olefins, such as ethylene, are also applicable as dieneophile components, albeit with decreased efficiency (Eq. 3). A mechanistic raho-nale was presented for the proposed catalyhc cycle, which nicely explains the observed regioselectivity (Scheme 12.1). The regiochemical outcome was attributed to steric repulsion between the highly hindered metal center and the alkynyl substituent (20 versus 18). 

Feldman and Campbell, on the other hand, used hydrogen-bonding interactions to enforce a particular stereo- and regiochemical outcome of the sohd-state photocycloaddition of a naphthoic acid-derived cinnamic acid [45]. In a conceptually similar approach, Scheffer demonstrated that diamines can form double salts with a variety of trans-cinnamic acid derivatives. The locking in place of the double bonds steers the sohd-state [2+2] photodimerization [46]. 

The reaction of 5-alkylidene-l,3-dioxanes with electrophiles has been investigated in two different fields. Most importantly, additions of halogen and other electrophiles have been studied with respect to the stereo- and regiochemical outcome of the reaction and the role of the endocyclic heteroatoms <1998J(P2)1129, 1998J(P2)1139>. 

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