Straightforward Synthesis of 2(5h)-furanones as Promising Cross-coupling Partners: Direct Furanone Annulation Utilizing Ti-mediated Aldol Addition

Direct 2(5H)-furanone annulation produces promising cross-coupling partners incorporating m-or p-bromo-and p-tosyloxyphenyl groups into the 5-position of a notable 2(5H)-furanone pharmacore. The present one-pot annulation method involves two distinctive reactions: (i) a powerful and crossed Ti-direct aldol addition and (ii) an acid-induced characteristic cyclo-condensation, leading to 2(5H)-furanones. Suzuki-Miyaura cross-coupling of 5-(4-bromophenyl)-furan-2(5H)-ones, 5-(4-tosyloxyphenyl)-3,4-dimethylfuran-2(5H)-ones and a furan derivative successfully afforded the corresponding products with the 2(5H)-furanone skeleton.

Current drug discovery is considerably based on cross-coupling methodologies, especially Suzuki-Miyaura cross-couplings, because large boronic acid libraries are supplied in a commercial base.Because this privileged approach representatively requires aromatics with leaving groups (-Br and -OTs) as latent scaffolds in various organic molecules, this background led us to investigate the convenient synthesis of attractive cross-coupling partner, 2(5H)-furanones 4 bearing bromophenyl and tosyloxyphenyl leaving groups.
A literature survey using SciFinder ® revealed a two recent syntheses of 4a; (i) Ru-catalyzed CO insertion into the corresponding allenic alcohol [4]; and (ii) SeBr-resin-mediated lactonization of β,γ-unsaturated carboxylic acids, followed by three oxidation (H 2 O 2 )-elimination-methylation (MeI/LDA) reaction sequences [5].The first method requires three steps and special handling techniques and/or apparatuses using CO.The second synthetic method requires a less accessible SeBr-resin reagent and four steps.Other target molecules 4b-4f are novel compounds.

Results and Discussion
Crossed aldol reaction between acetophenones or propiophenones and carbonyl acceptors is pivotal in organic syntheses.Ti-direct aldol additions possess considerably powerful C-C bond forming ability allowing for the reaction between less reactive different ketones which would proceed with difficulty using other reaction systems [13].Mukaiyama, Iwasawa, and their coworkers disclosed direct crossed aldol addition between different ketones mediated by Sn(OTf) 2 /N-ethylpiperidine reagent, however, being limited to the reaction between both aromatic ketones [18].

Results and Discussion
Crossed aldol reaction between acetophenones or propiophenones and carbonyl acceptors is pivotal in organic syntheses.Ti-direct aldol additions possess considerably powerful C-C bond forming ability allowing for the reaction between less reactive different ketones which would proceed with difficulty using other reaction systems [13].Mukaiyama, Iwasawa, and their coworkers disclosed direct crossed aldol addition between different ketones mediated by Sn(OTf)2/Nethylpiperidine reagent, however, being limited to the reaction between both aromatic ketones [18].
On the other hand, Mehta and Ramesh applied the present method exquisitely for the total syntheses of a series of lindenane-type sesquiterpenoids [22] and atractylenolide-type Scheme 1. Crossed Ti-direct aldol addition and successive cyclo-condensation (furanone annulation) leading to 2(5H)-furanone 4.
The present direct annulation methods utilize commercially available, inexpensive substrates and reagents, under accessible reaction conditions without any use of special apparatus and technique with sufficient substrate-generality [16,17].Moreover, an application to the most straightforward total syntheses of (R)-mintlactone (a single step, 52%) and (R)-menthofuran (2 steps, overall 46%) was successfully performed [17].Since the publication of these reports, three subsequent syntheses of (R)-mintlactone have been presented; however, these methods require (i) 3 steps, overall 7% [19]; (ii) formal synthesis, over 3 steps, accurate overall yield is unknown [20]; and (iii) 10 steps, overall 22%, [21].The report [19] does not strictly evaluate our work [17], because it is categorized into racemic mintlactone synthesis in the authors' reference part.The other reports [20,21] fail to refer to our work [17].
On the other hand, Mehta and Ramesh applied the present method exquisitely for the total syntheses of a series of lindenane-type sesquiterpenoids [22] and atractylenolide-type eudesmanolides [23], wherein these key skeletons are smoothly constructed, utilizing this direct 2(5H)-furanone annulation.
A plausible mechanism for the reaction sequences is proposed, exemplified by the production of 4a (Scheme 2).The initially formed Ti-chelated cross aldol adduct 5 is transformed to dihydrofuran intermediate 6 with ring formation and elimination of MeOH.Intermediate 6 is converted to 4a through methoxyfuran 7 with elimination of Ti(OH)Cl 3 before H 2 O-workup.

General
All reactions were carried out in oven-dried glassware under an argon atmosphere.Flash column chromatography was performed with Silica Gel 60 (spherical) (63-210 µm, KANTO CHEMICAL, Tokyo, Japan).TLC analysis was performed on 0.25 mm Silicagel Merck 60 F254 plates.Melting points were determined on a hot stage microscope apparatus (ATM-01, AS ONE, Osaka, Japan) and were uncorrected.NMR spectra were recorded on a JEOLRESONANCE ECX-500II spectrometer (JEOL, Tokyo, Japan) operating at 500 MHz for 1 H-NMR and 125 MHz for 13 C-NMR.Chemical shifts (δ ppm) in CDCl 3 were reported downfield from TMS (= 0.00) for 1 H-NMR.For 13 C-NMR, chemical shifts were reported in the scale relative to CDCl 3 (77.0ppm) as an internal reference.IR Spectra were recorded on a SHIMADZU IRAffinity-1S spectrophotometer (SHIMADZU, Kyoto, Japan).Mass spectra were measured on a JEOL JMS-T100LCP spectrometer (JEOL, Tokyo, Japan).