An Alkyne Hydroacylation Route to Highly Substituted Furans

Abstract

Heterocyclic compounds, such as the bioactive natural products pukalide and nakadomarin A, and the hugely successful drug molecules ranitidine (Zantac) and atorvastatin (Lipitor) are of great importance in pharmaceutical, agrochemical, and other fine-chemical applications (Scheme 1).[1] While there exists a range of methods for transforming relatively complex starting materials into substituted heterocycles, and for the functionalization of existing heterocycles, there is less precedent for methodology which involves the direct, regiodefined synthesis of highly substituted heterocycles from simple starting materials.[2] As such, new methods for the synthesis of substituted heterocycles (or their precursors) are potentially of significant value. This is particularly true if such methods do not suffer from the same drawbacks as the traditional syntheses of 1,4-dicarbonyl compounds, the classic substrates for the preparation of furans, thiophenes, and pyrroles; these syntheses are often either step-or atom-inefficient. The recent advances achieved in intermolecular alkene and alkyne hydroacylation chemistry means that these transformations are now ideal methods to exploit for the synthesis of heterocyclic molecules, because they employ simple substrates and commercially available catalyst systems, and generate no by-products because of their 100 % atom-economy. [3][4][5] In addition, a broad range of aldehydes can now be employed, and particularly in the case of alkyne hydroacylation, significant substitution of the unsaturated component can be tolerated, thus allowing for the regioselective production of highly substituted complex molecules in one catalytic intermolecular carbon-carbon bond forming step. Herein, we demonstrate the utility of intermolecular alkyne hydroacylation in the efficient synthesis of di-and trisubstituted furans and related heterocycles.g-Hydroxy-a,b-enones are known to undergo acid-catalyzed dehydrative cyclization to form furans, and this transformation has been exploited by several research groups, [6] most notably in the recent work from Donohoe et al. [7] The intermolecular hydroacylation of an aldehyde with readily available propargylic alcohols would permit the synthesis of g-hydroxy-a,b-enones with 100 % atom efficiency; coupling this carbon-carbon bond formation with an acid-catalyzed dehydrative cyclization would allow for the regioselective synthesis of di-or trisubstituted furans. The associated disconnection is novel for this type of heterocycle (Scheme 2).Our initial investigations to realize the above route to furans focused on the combination of propargyl alcohol 1 a and the S-chelating alkyl aldehyde 2 a (Table 1). The hydroacylative union of these two substrates using a dppe-derived Rh catalyst proceeded without incident. However, attempts to achieve a dehydrative cyclization using TFA provided only a small amount of the desired furan 3 a (entry 1). Reducing the time for the cyclization event to 1 hour, and then to 10 minutes, increased the yield of furan up to 50 % (entrie...

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

“…This method is suitable for the preparation of furans bearing alkyl, alkenyl, or aryl substituents (Scheme 152). 262 …”

Synthesis of Pyridazine Derivatives by Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their Optical and Electronic Properties through Experimental and Theoretical Studies

“…This wide array of interesting applications has motivated the development of procedures for the preparation of differently substituted pyridazines. In general, two methods are reported which consist of: (i) Cyclisation reactions using 1,4-dicarbonilic precursors and hydrazine [26,27,28,29,30,31,32], in order to construct the pyridazine ring or (ii) by functionalization through nucleophilic substitution [33,34,35,36,37,38], ortho-metallation [39,40,41] and cross-couplings reactions (Suzuki, Stille, Sonogashira, etc.) [42,43,44,45,46,47,48,49,50] or a combination of cyclisation and cross-coupling reactions [51].…”

Substrate‐Directed Hydroacylation: Rhodium‐Catalyzed Coupling of Vinylphenols and Nonchelating Aldehydes

“…Vinylphenols with highly varied pK a values coupled with hydrocinnamaldehyde in 50-93 % yield with > 20:1 b/l regioselectivity (Table 3, entries 1-4). Transformations with benzaldehyde displayed varied regioselectivities (from 9:1 to > 20:1) depending on the electronic nature of the vinylphenol (Table 3, entries [16][17][18][19][20]. We predicted a concentration-dependent chemoselectivity for aldol condensation and hydroacylation as a result of the strong binding of the vinylphenol to Rh.…”

“…[15] On the basis of our double-chelation-assisted hydroacylations with salicylaldehydes, [5][6][7] we reasoned that an anionic group should promote binding of the alkene and guide the formation of the branched ketone. [17] Their method relied on the coupling of b-sulfur-substituted aldehydes with propargylic alcohols, and the sulfide directing group was retained in all of the furan products. [16] In principle, a wide range of acidic functional groups could be used to generate the requisite anionic directing group in the presence of a catalytic base.…”