Attempting to use chloroketones 36 and 37 as cross-coupling electrophiles revealed that these chloroketones are challenging to use in the presence of organometallic species and common catalytically active metals such as Ni, Pd or Cu. Hence, oxidative homocoupling of organozinc
225 a) A. Ayati, S. Emami, A. Asadipour, A. Shafiee, A. Foroumadi, Eur. J. Med. Chem. 2015, 97, 699; d) A. C.
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reagents typically accounted for the formation of the major products in presence of chloroketones.
This problem has been observed and partly solved in prior reports of related cross-couplings,
especially if secondary chloroketones were used.226 In the course of this work, it was found, that acetophenone-derived zinc enolates of type 41 selectively underwent chloride substitution in the absence of catalysts with primary chloroketones 37, i.e. the products obtained by CAC reaction (Table 17).227 Thus, valuable 1,4-diketones 42 were accessed under mild conditions (25 °C, 5 – 12 h).
An initial screening identified zinc enolates derived from either electron-rich and -poor acetophenones and furanyl actate as suited electrophiles, furnishing asymmetic diketones 42a – d in 63 – 90% yield with chloroacetophenone. Zinc enolates with sensitive functionalities were obtained by using TMPZnCl·LiCl as base. Using either of the two methods, a variety of polyfunctional 1,4-diketones (42e – i) were further obtained in 54 – 82% yield using CAC reaction products 37c and 37j. As expected for zinc enolates, various functionalities like a nitrile, an ester, a triflate, and halogens are tolerated by this protocol. This method constitutes a straightforward and to date unexplored, transition-metal-free synthesis of important precursors to Paal-Knorr chemistry.226d
Table 17: Substitution reaction of chloroketones 37 with zinc enolates of type 41 leading to functionalized 1,4-diketones 42.
a Isolated yield with respect to chloroketone. Reactions performed on a 0.5 mmol scale. Method indicated in brackets.
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227 See Experimental part for reaction optimization of the reaction conditions.
6 Summary
Microflow setups offer enhanced residence time control, mixing, and heat transfer compared to batch chemistry. These features make them ideal for reactions employing unstable, highly reactive reagents.
This work focused on applying these features of continuous flow setups to metalation, halogen-metal exchange and enolate chemistry. Additionally, the synthesis and derivatization of a novel heterocyclic scaffold by batch methods was described.
First, the metalation of acrylonitriles, acrylates and nitroolefins with TMPZnCl·LiCl and TMPMgCl·LiCl in continuous flow was investigated. For the metalation and subsequent in-line quenches of various substrates, conditions were achieved, which are hardly accessible with batch reactors. These special operation windows include intense mixing regimes as well as scale-independent high-temperature (> 60 °C) reactions above the boiling point of THF. Furthermore, a new subclass of acrylate starting materials was shown to undergo efficient metalation with TMPMgCl·LiCl. Finally, the scope of accessible furanones via metalation chemistry was exhaustively explored due to the biological relevance of this compound class.
Second, the lithiation of (thio)formamides by LDA in presence of electrophiles was revisited due to the relevance of nucleophilic amidation, which typically gives access to α-hydroxy and α-keto amides.
While cryogenic conditions are usually applied in batch, the newly developed Barbier flow procedure proceeds at ambient temperature with economic reagent stoichiometries. The reaction was combined with the prior in-line generation of LDA at −10 °C. The favorization of formamide lithiation even in the presence of well-known C-H acids was systematically investigated with the aid of competition experiments, which allowed a placement of the lithiation enthalpy of diethylformamide among well-known C-H acids. The combination of these results with ab initio studies provided further insights regarding these difficult to characterize intermediates.
Furthermore, a novel in situ trapping halogen-lithium exchange was developed. This method combines the generality of halogen-lithium exchange with the functional group tolerance exhibited by organomagnesium-, zinc- and copper-compounds. Intense mixing flow conditions at temperatures up to 0 °C enabled the performance of this exchange/in situ transmetalation sequence, which furnished bis(hetero)aryl organometallics bearing highly sensitive moieties such as esters, ketones, isothiocyanates, azides and nitro groups. Quenching in semi-batch mode gave access to functionalized aryl and heteroaryl alcohols, ketones, biaryls, iodides and allylation products.
Finally, the last two methods describe transition-metal free syntheses for aryl-heteroaryl and heteroaryl-heteroaryl units. First, a simple batch method for regioselective addition of organolithium reagents to a novel fused N-heterocycle, followed by reoxidation, was described, which led to an array of modified triazaphenantrenes with varying optical properties. Second, the development of an ester chloromethylation to the corresponding mono- and bis-chloroketone derivatives was described. The reaction can be telescoped into subsequent cyclocondensations, furnishing aryl-heteroaryl products.
Handling the unstable dianions of chloroacids in continuous flow with improved control of exothermy, the mono- and bis-chloromethylations proceeded under practical conditions and thus offers an alternative to hazardous, unsustainable and less selective chloroketones synthesis routes.
6.1 Continuous Flow Magnesiation or Zincation of Acrylonitriles, Acrylates and Nitroolefins