In the realm of organocatalysis1 there are some quests for glory. As the knights of Camelot dreamt of finding the Holy Grail,2 many organocatalytic chemists have long sought methodologies to enable α-alkylation of aldehydes, with simple amines catalyzing this process.
The α-alkylation of simple aldehydes constitutes a cornerstone in CC forming reactions. In organometallic chemistry, Evans,3 Helmchen,4 Oppolzer,5 and others developed powerful strategies based on the formation of metal enolates and treatment with different alkyl halides by an SN2 mechanism. This strategy was rendered asymmetric by using stoichiometric amounts of chiral auxiliaries.
After the development of enamine catalysis6 by secondary amines, it was easy to assume that α-alkylation represented an obvious and easily accessible target. However, little progress was made towards this goal prior to 2009, despite the enormous efforts of many research groups.
In 2004, Vignola and List developed a powerful reaction for the intramolecular α-alkylation of halo-aldehydes (Scheme 1), catalyzed by proline or proline derivatives.7 The results of this method were excellent in terms of yield and enantioselectivity and it allowed the synthesis of carbocycles, such as cyclopropanes or cyclopentanes, in a simple asymmetric fashion. The addition of 1 equivalent of base was mandatory, probably in order to trap the resulting hydrogen halide obtained as a secondary product in the reaction. However, when the corresponding intermolecular reaction was attempted, the desired adducts were not obtained at all due to side reactions that removed the catalyst from the system.
The presumption of an easy transition proved erroneous, which led to much wasted effort for several research groups. This struggle was what induced us to refer to this reaction as the Holy Grail for organocatalytic chemists. Why α-alkylation of aldehydes is such a challenging task is exemplified by the multitude of possible side reactions, including the Canizzaro and Tischenko reactions,8 and N- and O-alkylation of the catalyst by the alkyl halide.
In 2007, Nicewitz and MacMillan avoided these problems by making use of SOMO activation of aldehydes (Scheme 2). In this case, they merged organocatalysis with metal catalysis, by using a combination of photoredox catalysis and amine catalysis.9, 10 Although it is true that Nicewitz and MacMillan solved the problem of α-alkylation of aldehydes, this methodology could not be regarded as purely organocatalytic.
Several research groups, inspired by the previous work by List and co-workers, developed new and powerful cascade reactions with intramolecular α-alkylation as a key step. For example, in 2007, the groups of Córdova and, soon after, Wang developed a cyclopropanation reaction between halomalonates and unsaturated aldehydes (Scheme 3 a).11 After the initial Michael addition of the malonate, an irreversible α-alkylation took place. In the same year, Córdova developed the synthesis of cyclopentanones by making use of a similar approach, with 1-bromo-2-keto-4-esters being used instead of 2-halomalonates.12 In 2008, Enders reported a powerful cascade reaction between aldehydes and halonitroalkenes (Scheme 3 b). In this case, the aldehyde reacted with the secondary amine catalyst to form an enamine, which underwent a Michael addition to the nitroalkene.13 Next, a second enamine was formed and underwent an intramolecular α-alkylation to afford the desired carbocycle.
Despite the efforts of these research groups and the utility of these methodologies, the challenge remained open: no methods existed for the organocatalytic intermolecular α-alkylation of simple aldehydes. The quest for the Holy Grail still occupied the mind of chemists around the world.
In the mythology of Camelot, the Holy Grail was found by Percival, a humble knight from Wales. In the case of α-alkylation, two Italian research groups developed the long-awaited intermolecular organocatalytic α-alkylation of aldehydes. Both groups based their methodologies on the use of stable carbocations, in order to achieve an SN1 mechanism. With this strategy, they managed to avoid most of the problems associated with SN2 reactions.
In 2008, Melchiorre, Petrini, and co-workers reported the first intermolecular organocatalytic α-alkylation of aldehydes (Scheme 4).14 In this work, the authors disclosed that highly stabilized carbocations, such as 3-(1-arylsulfonylalkyl)indoles,15 can trap an enamine intermediate (Scheme 5). The process could be catalyzed by simple proline. The nature of the alkylating agent was the crucial point for this strategy.
The sulfonyl moiety at the benzylic position of 3-substituted indoles constitutes a good leaving group, which allowed the generation of electrophilic species that are able to react with electrophiles, such as enamines, under either basic or acidic conditions. Even so, only potassium fluoride supported on basic alumina was able to promote the carbocation formation. After further optimization, they tested the scope of the reaction by using a range of aldehydes and 3-(1-arylsulfonylalkyl)indoles as substrates (Scheme 4). The results were excellent in terms of yield and enantioselectivity; diastereoselectivities, however, were moderate in some cases. Wide-ranging investigations into the scope of the reaction indicate that it the process can be applied for almost any aliphatic aldehyde.
In 2009, Cozzi and co-workers used a similar approach that made use of stabilized carbocations, such as ferrocenyl and diaryl methanol derivatives (Scheme 6).16 As the catalyst for the enamine formation, they tested several secondary amines, such as proline, diphenylprolinol derivatives, and MacMillan’s catalysts. The authors disclosed that the addition of a strong acid such as trifluoroacetic acid was key to the successful reaction, being crucial to the formation of the carbocation. As stated by Melchiorre, the use of stabilized carbocations allowed the α-alkylation of aldehydes avoiding all of the aforementioned problems.
MacMillan’s catalysts had high efficiency and gave the final alkylated products in moderate to high enantiomeric excesses. This methodology allowed the enantioselective direct alkylation of aldehydes with unfunctionalized alcohols, only limited by the nature of the alcohol, which must stabilize the formed carbocation in order to obtain the alkylated products.
In summary, the organocatalytic intermolecular α-alkylation of aldehydes has been accomplished. The groups of Melchiorre and Cozzi demonstrated that the attack of stabilized carbocations on an enamine intermediate affords the desired alkylated adducts in good to excellent enantioselectivities. However, there are some drawbacks and issues that must be solved. Both methods required special constructs to stabilize the carbocations, which constitutes a clear limitation. Taking the impressive expansion of organocatalysis into account, we certainly foresee a continuous improvement in the topic in question. The quest remains open, since the use of alkyl halides in cooperation with enamines is still an incredible challenge for organocatalytic chemists. A general methodology for the intermolecular organocatalytic α-alkylation needs still to be found.