Evaluación de los resultados de la Matriz de Cumplimiento Ambiental

The catalytic hydroalkylation of alkenes is a valuable, atom-economical approach for the synthesis of C–C bonds from readily available starting materials.17

It is formally defined as the addition of an alkyl nucleophile across a C-C π-system to form a new C-C and C-H σ-bond (Scheme 3.1.1-1), which differs from hydroarylation in that the bond formed is between two sp3

- hybridized carbon atoms. The carbon nucleophiles used are usually derived from nucleophilic π- bonds of an sp2

carbon center (ie: silyl enol ethers18

being an atom-economical process, however hydroalkylation can be the exception to this rule as protected enolate nucleophiles generate byproducts. For the purposes of this section, any carbon nucleophile that adds across a C-C π-system to install an adjacent C-C sp3

-sp3

linkage and C-H bond will qualify as a hydroalkylation.

H + _R catalyst 1 _R 1 C-C π-system Alkyl Nucleophile R' X or R' sp3_-sp3 hybridized C-C bond

Scheme 3.1.1-1: Defining hydroalkylation as a subset of hydrofunctionalization.

3.1.1.1 Classifying Hydroalkylation Reactions by π-Electrophile

Pioneering studies have led to the development of intermolecular processes that employ styrenes,19–21

unactivated alkenes,22–25

allenes,26–28

and alkynes18,29,30,30–32

as effective substrates that can react with appropriate C-based nucleophiles. These studies will focus on diene electrophiles for the practical reason that they react efficiently with the developed CDC-Rh(I) catalysts1,2 _and

because such reactions convert readily available unsaturated hydrocarbons into versatile allyl- containing building blocks. Only a limited number of catalytic intermolecular hydroalkylations of dienes have been reported, with none able to effectively promote the diastereoselective addition of C-based nucleophiles to terminal dienes. Catalytic intermolecular diene hydroalkylation was first accomplished with a Pd catalyst by Takahashi33 _{and subsequent Pd}

catalyzed hydroalkylations have introduced a variety of enolizable nucleophiles.34–36

These reactions selectively generate linear products via 1,4-addition with modest to excellent site- selectivity. Such reactions work well with small 2,3-substituted dienes, but are limited to methyl- substituted or cyclic substrates for 1,4-substituted dienes (e.g., cyclohexadiene).39

3.1.1.2 Classifying Hydroalkylation Reactions by Nucleophile

The type of carbon nucleophile employed can also be used to classify hydroalkylation reactions. The majority of carbon nucleophiles36–38

can be categorized as enols, enolates, or organometallic reagents. Neutral enol nucleophiles form from in situ tautomerization of carbonyl species, either thermally39

or with the assistance of an acidic40

or basic41

promoter. The equilibrium between the enol and carbonyl form must be favorable enough to generate a sufficient concentration of the π-nucleophile to react with an electrophilic π-system. The necessity of this equilibrium limits enol nucleophiles to acidic carbon atoms alpha to a carbonyl or similar π-system. Although many useful products can be formed with readily enolizable C-C π-systems, this curtails the range of nucleophiles that could be utilized. This class of carbon nucleophiles is the most prevalent in the hydroalkylation literature and has been shown with Cu,39 Ag,42 Au,41,43–48 Pd,22,23,27,28,49–54 Pt,22,23,55 Rh,24,25,32 Ru,56

and Lewis acid20,40,57–67

catalysts. It is also important to note that the majority of these methods employ 1,3-diketo or malonate nucleophiles and there is a distinct lack of nucleophile diversity in the reported literature.

Enolates are a separate class of carbon nucleophiles that are derived from the anionic form of the enol nucleophiles discussed above. These reagents are prepared by deprotonating alpha to a carbonyl and then trapping the resulting enolate through protection of the anionic oxygen, usually with a silyl group.18,26,31,68–70 _{The formed silyl enol ethers can be deprotected in} situ to form a reactive charged nucleophile either concurrently or prior to addition to the olefin. A proton source, such as an alcohol, is commonly necessary to turn over the reaction and to trap silyl byproducts. The use of enolates significantly increases the scope of carbon nucleophiles available from neutral enols since there is no need for in situ equilibrium between the carbonyl and enol tautomers. This has been extensively applied in Mukaiyama-Aldol71–75

additions,76,77

where the variety and synthetic utility of enolate nucleophiles has been extensively demonstrated. However, far fewer hydroalkylation reactions have been studied with enolates. Examples of silyl enol ether additions to activated carbon π-systems exist (eg: additions to α,β- unsaturated carbonyls), but there are no prior examples of intermolecular enolate additions to unactivated olefins.

The final class of carbon nucleophiles utilized in hydroalkylation is organometallic reagents such as grignards and alkyl-zincs. These more reactive species behave as carbon anions rather than carbon π-nucleophiles. Although there are relatively few publications in this area, Sigman et al. has introduced several impressive transformations to this rapidly developing field.78–81

The increased reactivity of organometallic reagents is both a strength and weakness of this nucleophile class, as the increased nucleophilicity can allow for difficult additions, but the reagents are unstable and must be synthesized rather than purchased. These nucleophiles also trade reactivity for atom economy as they produce metal salts as byproducts (ie: Mg2+

or Zn2+

).

3.1.1.3 Current Limitations in Hydroalkylation

Although it was discovered as early as 1972 by Takahashi,33 _{relatively few methods for}

hydroalkylation exist. This is mirrored in the limited application of hydroalkylation in synthesis; the only synthetic use for hydroalkylation was in a formal synthesis of KRN7000.79

Despite the advances in olefin hydroalkylation discussed above, intramolecular41,45,49,52,82–90 _examples

predominate. The rarity of intermolecular transformations has been a trend common to all the classes of hydrofunctionalization reviewed in this dissertation and is likely caused by the increased entropic penalty associated with intermolecular reactions. Intermolecular processes can be more generally applied to the synthesis of natural products without the need for the preparation of specific intramolecular substrates. One of the goals of our research program is to

develop intermolecular transformations that bridge the gap between methods development and the application of hydrofunctionalization in total synthesis.

The types of nucleophiles applied to hydroalkylation reactions highlight the lack of diversity in hydroalkylation methods; the majority of examples utilize 1,3-diketone or malonate derived nucleophiles and do not stray from established enols. This is evidenced in the literature in that the number of publications that utilize enols dwarfs those with either enolate or organometallic nucleophiles. Even thermally enolizable nucleophiles other than 1,3-diketones are comparatively uncommon (ie: oxazolones,26

oxindoles,28

β-keto amides,44

etc.). The development of methods for the general addition of multiple carbon π-systems would significantly expand the utility of hydroalkylation.

One of the advantages of hydroalkylation over hydroarylation is that it is capable of forming two adjacent stereocenters in a single step. Limited examples of enantioselective transformations exist for intramolecular reactions18,31,41,43

and intermolecular reactions26–28,91

with the majority of the work accomplished by the Trost lab. Diastereoselective transformations are more common, although few are highly diastereoselective (>90% dr).37,44,45,47,48,68,70,87

Almost all of these diastereoselective reactions are from intramolecular cyclizations, and exhibit selectivities that vary dramatically depending on the substrate. The potential to form two stereocenters enantioselectively has attracted significant attention, but is still an unsolved challenge.

Hydroalkylation is capable of forming exceptionally useful C-C sp3

-sp3

hybridized bonds and installing two stereocenters, however current methods are not general enough to be used in synthesis. While this reaction is often applied to the transformation of alkenes, the intermolecular hydroalkylation of dienes remains relatively unexplored. This was particularly encouraging as

catalysis with CDC-Rh(I) complexes would be a novel addition to the field. A logical first step would be to establish that Ph_{CDC-Rh-styrene could catalyze the intermolecular hydroalkylation}

of a diene. Starting with an intermolecular reaction would ensure that these studies will impact the field. After establishing proof-of-concept we could look towards expanding the nucleophile scope to include carbon nucleophiles with more varied functionality.