Chemoselective Homologation–Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into (n+1)-Halomethyl-Alkanes

Abstract

The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp 3 -type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanionlike species can act as nucleophiles, thus making it of general applicability. E mbodying a halogen-containing functionality within a carbon skeleton profoundly influences the physicochemical features, thus properly modulating the reactivity profile of the array. 1 Accordingly, solid synthetic methodologies levered on different logics (e.g., radical, electrophilic, and nucleophilic) have been designed and thoroughly applied. 2 In this sense, the introduction of metalated α-halogenated carbon species (MCR 1 R 2 Hal, i.e., the so-called carbenoid reagents) reacting under a nucleophilic or electrophilic regime (Scheme 1, path a), depending on the nature of the metal, has emerged as a valuable tool for delivering synthons featuring the exact degree of functionalization requested (i.e., halogen loading). 3 As a result, common downsides associated with the use of conceptually different approaches, such as polyhalogenations, can be conveniently skipped. The initial installation of the CR 1 R 2 Hal unit, that is, a homologative event, is later exploited en route to the construction of more complex molecular architectures accessible through a single synthetic operation, as, for example, illustrated in the versatile Matteson homologation of sp 3 -hybridized boron electrophiles, elegantly adapted by Aggarwal to the assembly line concept. 4 Regrettably, carbon-based platforms suitable for homologations with halocarbenoids are restricted to sp 2 -type systems: For example, our group demonstrated that homologations of carbonyl-type derivatives conduct, through a single operation, to more sophisticated architectures (quaternary aldehydes 5 and aziridines). 6 Also, olefins are amenable substrates for C1 insertions into cyclopropanes. 7 In this scenario, the endeavored homologations of (primary) sp 3 -carbon platforms resulted in uncontrollable multi-insertion phenomena (up to four consecutive homologations) of questionable synthetic value,

Modular and Chemoselective Strategy for Accessing (Distinct) α,α‐Dihaloketones from Weinreb Amides and Dihalomethyllithiums

“…The synthesis of gem-dibromoketones further expanded the potentiality of the method, confirming the genuine chemoselectivity pattern previously discussed (Scheme 4). A series of aromatic functionalized analogues were uniformly prepared in high yield, regardless the modulating effect displayed by the substituents on the ring (33). In this sense, we appreciated once more the high chemoselective profile of the acylic substitution on a nitrile bearing material (34), as well as, on ether, thioether, alkyl or aryl presenting species (35)(36)(37)(38).…”

“…It is interesting to note that the more sterically hindered bromoiodomethane could be efficiently deprotonated only with with LiNEt 2 , thus giving the mixed bromoiodo carbenoid for preparing the unprecedented chiral (and racemic) ketone 7 in high yield and excellent enantiopurity. The methodology was flexible for preparing diversely functionalized mixed dihaloketones from both aromatic and aliphatic Weinreb amides such as the bromoiodo (8,14), bromochloro (9-13) and iodochloro (15) [33] derivatives. It is worth noting that no concomitant attack of LiCHBrCl on the sensitive aromatic nitrile was observed.…”

Fluoroiodomethane: A CH2F‐Moiety‐Delivering Agent Suitable for Nucleophilic‐, Electrophilic‐, and Radical‐Harnessed Operations

“…Cognizant of the reluctance of carbenoids in homologating C‐ sp 3 ‐hybridized platforms, [51] Pace and coworkers reported the sequential installation of a carbenoid and a hydride – released by Lewis acid activation of a silane – into carbonyls [52] . Although most of the reported experiments employ different dihalomethanes for the generation of carbenoid, the group reported one flurormethylated example.…”

“…Cognizant of the reluctance of carbenoids in homologating C-sp 3 -hybridized platforms, [51] Pace and coworkers reported the sequential installation of a carbenoid and a hydride -released by Lewis acid activation of a silane -into carbonyls. [52] Although most of the reported experiments employ different dihalomethanes for the generation of carbenoid, the group reported one flurormethylated example. Using fluoiodomethane as the carbenoid precursor, they prepared a fluoromethyl alkyl derivative, resulting from the addition of LiCH 2 F to benzophenone, followed by hydride-mediated reduction of the fluorohydrine intermediate (Scheme 7).…”

Straightforward synthesis of bench-stable heteroatom-centered difluoromethylated entities via controlled nucleophilic transfer from activated TMSCHF2

“…10 Compared to the Ruppert–Prakash reagent, the reactivity of TMSCHF 2 is tamed 11 and its proper activation under Lewis basic conditions is essential, as demonstrated by Hu in 2011 in the course of difluoromethylations of ketones and imines, 12 and later extended also to other sp 2 -hybridized carbon electrophiles by our group. 13 Collectively, these precedents showcase that replacing a putative ionic ( e.g. Li) M-CHF 2 bond with a covalent one ( e.g.…”