The Piancatelli Rearrangement: New Applications for an Intriguing Reaction

Nearly forty years ago, at the University of Rome, Giovanni Piancatelli and co-workers discovered the acid-catalyzed water-mediated rearrangement of 2-furylcarbinols into 4-hydroxycyclopentenones. These motifs are core components of several pharmacologically active compounds and precursors of many natural products. The main features of this reaction are the simple experimental conditions, the stereochemical outcome and the generality of the procedure. Consequently, a re-emergence of this reaction has been seen recently, including developments of the Piancatelli rearrangement with some interesting inter- and intramolecular variants. This review will mainly focus on the general aspects of the reaction along with its more recent applications.


Introduction
In 1976, while studying the reactivity of heterocyclic steroids, Piancatelli and co-workers observed for the first time the rearrangement of a 2-furylcarbinol into a 4-hydroxycyclopent-2-enone in an acidic aqueous system. Following the original report on this transformation [1], the same group continued to systematically investigate the rearrangement [2]. In summary, the heating of 2-furylcarbinols (compounds 1a-c) in an acetone-water solvent system in the presence of strong acids (e.g., formic, polyphosphoric or p-toluenesulfonic acid) led to the formation of 4-hydroxy-5-substituted- The high level of stereochemical control inherent in the rearrangement delivered exclusively the trans isomer, as demonstrated by the 1 H-NMR coupling constant between the two vicinal hydrogens (J trans = 2.5 Hz). The proposed mechanism involves the formation of a carbocation driven by a protonation-dehydration sequence of the 2-furylcarbinol, the nucleophilic attack of a water molecule then generates intermediate A which undergoes ring opening (Scheme 2). The resulting 1,4-dihydroxypentadienyl cation B, that adopts a conformation in which the two hydroxy groups are anti, provides the trans-4-hydroxy-5-substituted-cyclopent-2-enone (2) as a racemate, through a 4π-conrotatory cyclization [2].

HO
The scope and limitations of the Piancatelli rearrangement were previously reviewed in 1982 and 1994 [12,13]. In this review the latest and most interesting features of the reaction, including its new applications will be described.

An Overview of the Piancatelli Rearrangement
Piancatelli observed that more reactive substrates like 5-methyl-2-furylcarbinols required milder conditions to rearrange in order to avoid side-products. In such cases, weak Lewis acids as ZnCl 2 could drive the reaction to the desired 4-hydroxy-4-methyl-5-substituted-cyclopent-2-enones, although an equimolar ratio of ZnCl 2 and substrate was required [14]. It was also noted that alkyl groups on the hydroxy-bearing carbon atom render the starting material more stable and less prone to dehydrate, thus resulting in longer reaction time. In addition the corresponding cationic intermediates are more reactive, consequentially leading to lower yields and the formation of side-products [14].
The corresponding 3-bromo (7a) and 4-bromo-2-furylcarbinols (7b) undergo a stereoselective rearrangement, although under more forcing conditions. The trans relationship between the substituents in the resulting cyclopenten-2-ones 8a and 8b is however maintained (Scheme 6) [15]. The same rearrangement was applied to 2-furyl-alkenyl carbinols 9 leading to 5-alkenyl-derivatives 10, useful intermediates for the synthesis of prostaglandin analogues as the upper side chain at C5 is suitable for further manipulations. Since these compound structures (9) are remarkably reactive, a simple solvolysis in an acetone/water mixture was sufficient for the rearrangement to occur (Scheme 7) [19].
Piancatelli's group also investigated the reactivity of 2-furyl-hydroxymethylphosphonates (11). In this case however, an acidic treatment of 11 led to levulinic acid derivatives 12 (Marckwald-type products) or to diethyl 2,5-dioxohex-3-enylphosphonate 13 according to the substitution pattern on the furan ring. However, in order to access compounds 15a-d, the hydroxy group had to be converted into a more reactive leaving moiety (e.g., chlorine, 14a-d, Scheme 8) [20]. During the 80s the rearrangement was widely studied by researchers at Sumitomo Chemical Company, Ltd. (Osaka, Japan), in collaboration with Prof. Piancatelli, resulting in several patent applications [21][22][23][24]. After an extensive experimentation, they found that treatment of 2-furylcarbinols (1) in an aqueous medium within a specific pH range (3.5-5.8) could afford 4-hydroxycyclopent-2-enones (2) in good yields, which also included the normally less reactive substrates (when R was an alkyl, alkenyl and alkynyl group). Furthermore, these experimental conditions increased the reaction rate and minimized the formation of by-products.
Recently, the rearrangement was also studied in a batch reactor under microwave irradiation (300 W), thus dramatically shortening the reaction time (minutes vs. several hours) and improving the yields (up to 95%). The scale-up of the rearrangement was optimized by employing a microreactor that allowed the development of a continuous flow process [25].
By extending this isomerization to a series of derivatives and after a careful examination of the mechanism, it was demonstrated that the reaction occurred via an intramolecular shift of the hydroxy group on the intermediate enolate 17 (Scheme 10) [28], thus ruling out a dehydration-hydration sequence involving the nucleophilic attack of an external water molecule, as previously supposed [29].

HO
In fact, when adsorbed on methanol-deactivated alumina under anhydrous conditions, 2 delivered isomer 16 quantitatively, with no detectable amounts of the 4-methoxy derivative. On the other hand, 4-acetoxy-5-phenylcyclopent-2-enone isomerizes to 4-acetoxy-2-phenylcyclopent-2-enone after adsorption on neutral alumina and elution with a mixture of benzene and diethyl ether, thus confirming the proposed mechanism. With aromatic R groups, neutral alumina was sufficient for the isomerization to occur, while with aliphatic substituents the employment of basic alumina was necessary to promote the hydroxy shift [28].

Applications of the Original Piancatelli Rearrangement
One of the most important applications of the Piancatelli rearrangement is in the synthesis of prostaglandins and their derivatives. Demonstration of the versatility of the domino sequence "2-furylcarbinol rearrangement/isomerization" was shown by Piancatelli himself, who synthesized key intermediates for the preparation of the prostanoic acid skeleton starting from 2-furylcarbinols bearing a second functional group in the side chain [29].

Recent Versions of the Piancatelli Rearrangement
Several new and efficient applications of this rearrangement have recently appeared in the literature utilizing alternative nucleophiles to water, and the synthetic utility of this reaction has been widely developed. Pharmacologically valuable scaffolds, which were usually prepared via multi-step sequences, can be synthesized in very mild conditions, directly and smartly, in only one step.

Intermolecular Aza-Piancatelli Rearrangement
Recently Read de Alaniz's group employed 2-furylcarbinols and a series of anilines to access trans-4-amino-5-substituted-cyclopent-2-enones (35), appealing structures for the synthesis of biologically active compounds [44]  This was allowed thanks to the identification of catalysts such as lanthanoid salts which were able to selectively activate 2-furaldehydes in the presence of an excess of nucleophilic amines [45]. Under optimized conditions, the aza-version of the Piancatelli rearrangement was carried out in acetonitrile at 80 °C, together with a catalytic amount (5 mol %) of Dy(OTf) 3 [46], preferred over Sc(OTf) 3 which gave similar results, but it is more expensive.
The mechanism is proposed to involve the elimination of the hydroxy-group through coordination and activation by the Lewis acid. The resulting furylcation undergoes nucleophilic attack by the aniline at the 5 position of the ring, thus starting the cascade reaction that forms the product (Scheme 15). The 1-amino-4-hydroxy pentadienyl cation F is analogous to B (Scheme 2) and it is supposed to undergo the 4π-conrotatory electrocyclization, thus explaining the high trans-diasteroselectivity of the reaction.
A further advance in the aza-Piancatelli rearrangement has been recently published and allowed the synthesis of cyclopent-2-enones with a quaternary carbon atom at the 5 position in high diasteroselectivity [50]. Taking advantage of the reactivity of polarized donor-acceptor (D-A) cyclopropanes (40) [51,52] due to ring strain [53] and their behavior as carbocation upon Lewis acid activation, the Read de Alaniz group found an alternative method to trigger the rearrangement and obtain highly functionalized cyclopent-2-enones (41) (Scheme 18, A). The protocol obviated the problems that Piancatelli and D'Auria [15] encountered when they tried to prepare cyclopent-2-enones with a quaternary carbon through the Piancatelli rearrangement starting from a furan with a tertiary carbinol side chain (42) and a large amount of dehydrated compound was found together with the rearranged product (Scheme 18, B). The best results in terms of yields (57%-89%), diasteroselectivity (6:1 up to 60:1) and reaction times (5-60 min) were found with 10 mol % Dy(OTf) 3 in acetonitrile at room temperature. The influence of R 1 and R 2 was investigated ( Table 2).
Para-substituted anilines with electron-withdrawing groups led to higher diastereoselectivities (41c vs. 41a, 41i vs. 41h) than the corresponding anilines bearing electron-donating groups (41b vs. 41a, 41g  vs. 41h). But when R 1 was a methoxy moiety, good yields and diasteroselectivities (41d-f) were observed with anilines possessing either an electron-donating or electron-withdrawing group. When R 1 was an electron-withdrawing group (e.g., CN, CF 3 ), diasteroselectivities were poor (41g-i) and the resulting products were less stable. In fact an intramolecular Michael addition frequently occurred, even during column chromatography, delivering bicyclic compounds that could not be isolated from the reaction mixture. With R 1 = R 2 = CF 3 , compound 43 was obtained in high yield (83%) , by forcing this side-reaction under basic conditions. The X-ray crystal structure analysis demonstrated that only the major diastereomer deriving from the rearrangement underwent cyclization [50] (Figure 2). Diastereoselectivity was observed to be dependent on the reaction temperature. In fact, when the rearrangement was carried out at 80 °C, the diastereomeric ratio improved to 30:1 for 41a, to 16:1 for 41b and to 22:1 for 41i.

Intramolecular Aza-Piancatelli Rearrangement
In 2011 Read de Alaniz published the first example of an intramolecular version of the aza-Piancatelli rearrangement [54]. This approach was based upon Piancatelli's observation that suitable 5-substituted-2-furylcarbinols could rearrange under certain conditions [14] and upon the protocol of Yin on the synthesis of oxabicyclic cyclopentenones (6) starting from 2-furylcarbinols (3) bearing a hydroxyalkyl side chain at the 5 position of the furan ring (Scheme 5) [8,11].
The authors worked with 2-furylcarbinols bearing an aminoalkyl chain at the 5 position of the furan ring (44)(45) and generated azaspirocyclic scaffolds (46)(47)Scheme 19) [54]. This densely functionalized framework was obtained in only one step, as a single diastereomer, with high efficiency and in high yield, differently from the known procedures that require several synthetic steps for the construction of the tertiary carbon center bearing the nitrogen atom, and the formation of the spirocyclic ring [55,56]. The optimized conditions for the intermolecular rearrangement (Dy(OTf) 3 5 mol % in refluxing acetonitrile) [44] turned out to be suitable also for the intramolecular version, and the mechanism previously hypothesized was also assumed to be in action (Scheme 15). As shown in Table 3 for the formation of 5-azaspirocycles 46 (n = 1), the rearrangement worked equally well for most common substituents, but the nature of R 2 had a significant impact on the outcome of the reaction, both in terms of yield and reaction rate. When R 2 was an electron-rich group, as in the case of PMP-cleavable N-protecting group, yields were lower and longer reaction times were required (46a vs. 46b, 46e vs. 46f), while the presence of CF 3 -or Ion the aryl at R 2 led to faster rearrangement (46g and 46h). NO 2 -or Br-substituted aryl groups at R 1 increased the reaction times (46c and 46d). Furthermore, a methyl group at R 1 was very well tolerated (46i). A similar effect of the R1 and R2 substitution occurred in the synthesis of 6-azaspirocycles 47 (n = 2). Electron-rich anilines required longer reaction times than unsubstituted ones (47a vs. 47b; 47d vs. 47f, Table 4), and in the case of 47f a 20 mol % catalyst was required to achieve a modest yield. On the contrary, the presence of a halogen had a beneficial effect on the reaction rate (47c, 47e and 47h).

Intramolecular Oxa-Piancatelli Rearrangement
Read de Alaniz also explored the oxa-Piancatelli version of the rearrangement on substrates bearing a hydroxy-alkyl moiety at the 5 position of the furan ring (3, see Scheme 5, and 48) [57] and thereby accessing oxaspirocycles (49 and 50) (Scheme 20) in only one step and in a highly diasteroselective manner, thus avoiding the usually performed multistep procedures [58][59][60]. According to Scheme 20, 2-furylcarbinols 3 and 48 lead to the formation of spiroketal enol ether 4 and 51 upon acidic catalysis. The coordination of Dy(OTf) 3 delivers intermediate G which, according to the canonical 4π-conrotatory cyclization, affords spirocyclic ethers 49 and 50. The optimized conditions required 5 mol % Dy(OTf) 3 in toluene at 80 °C. It has to be mentioned that the use of refluxing acetonitrile, the best solvent for the aza-Piancatelli rearrangement, in this case led to decomposition.

Scheme 20. Intramolecular oxa-Piancatelli rearrangement and proposed mechanism
In most cases the products were isolated in reasonable to excellent yields and with the expected high trans-selectivity ( Table 5). The reaction proceeded efficiently (compounds 49a-c), but in the case of strong electron-withdrawing groups as R 1 , harsher conditions (higher temperature and longer reaction time) were required in respect to the aza-rearrangement (compare 49d and 46c, Table 3). The presence of a heterocycle was also tolerated (49e). In contrast to the aza-Piancatelli reaction, aliphatic R 1 groups delivered complex reaction mixtures (49g and 49i), except in the case where a gem-dimethyl moiety was present in position γ (Scheme 20). The beneficial effect of this substitution is not clear, but the Authors hypothesize a more favoured formation of intermediate G because the gem-dimethyl group prevents Lewis acid from coordinating the vicinal oxygen atom. The gem-dimethyl effect is pronounced also in the formation of the 6-oxaspirocycles (50a and 50b).
Further investigations of the effects of substituents along the aliphatic chain (α, β and γ positions, Scheme 20) were carried out revealing that only groups in the γ or β were tolerated, while the presence of a α substitution hampered the rearrangement.
The initial steps of the mechanism are the same as proposed for the aza-Piancatelli (see Scheme 15). Then after the 4π-conrotatory cyclization which leads to intermediate H, a thia/oxa-conjugate addition finally gives compounds 51 or 52, that show a trans relationship between R 1 and N, resulting from the aza-Piancatelli rearrangement, and a cis orientation between N and X (O or S) arising from the conjugate addition (Scheme 21).
In Table 6, some compounds obtained with the domino approach are illustrated. The isolated yields were high both with 2-aminothiophenols and 2-aminophenols, although 2-aminophenols required slightly longer reaction times, being less reactive. Curiously, nearly two months later, another group published [66] the same reaction sequence shown in Scheme 21 using La(OTf) 3 (5 mol %) as the catalyst and acetonitrile at reflux as the solvent. For the same substrates, yields were lower if compared with those obtained with In(OTf) 3 and reaction times were longer (Table 7). Moreover 2-aminothiophenols failed to react under these conditions. Complex mixtures or no reaction were observed in the attempts of building [1,4]heterocycles different from benzoxazine, starting from building blocks such as o-phenylenediamines, pyrocatechols or 2-aminopyridin-3-ol. The introduction of an electron-withdrawing group (e.g., methanesulfonyl, tosyl) on one of the nitrogens of o-phenylenediamines proved beneficial for the isolation of the desired products (Scheme 22, 53a-d). On the other hand, despite the electron-withdrawing group in R 2 , the presence of an electron-poor moiety in R 1 hampered the reaction to occur (53e). (53)

Intramolecular C-Piancatelli Rearrangements
A very recent variant of this transformation, which is also the first example of an intramolecular C-Piancatelli rearrangement, has been reported by Yin and co-workers [67]. When treating 2-furylcarbinols functionalized with an electron-rich aromatic tertiary amide (54) in the presence of acidic catalysts, a nucleophilic Friedel-Craft attack from the ortho position onto the oxa-carbenium intermediate occurs, forming the spirofurooxindole derivative (55) (Scheme 23) [68,69]. Since these compounds are structurally similar to intermediate A (Scheme 2) in the proposed Piancatelli rearrangement mechanism, the authors envisioned the possibility to promote the rearrangement through ring opening and cyclization under suitable reaction conditions, thus accessing the novel core scaffold spirocyclopenten-2-oneoxindoles (56) as a mixture of cis/trans isomers [67]. The use of a catalyst (Pd II complexes or Lewis acids) led to a mere 40% yield, while a simple solvolysis without the use of a catalyst proved to be more successful. The influence of substituents R 1 and R 2 on diasteroselectivity is highlighted in Table 8. The lack of a methoxy group at the 3-position of R 2 leads to a lower diasteroselectivity (56a-b vs. 56c, 56e vs. 56f, 56g vs. 56h), while an increase is seen if an ortho-substituent is present at R 1 (56d vs. 56g). 3,4,5-Trimethoxy derivatives combined with an o-substituent enabled almost exclusively cis-isomer isolation (56e, 56g and 56i).

Conclusions
Since its discovery in 1976, the Piancatelli rearrangement has appeared as a versatile reaction for the construction of substituted cyclopent-2-enones convenient for the synthesis of prostaglandin derivatives. Several groups have been investigating new applications of the reaction that culminated in the recent publication of a number of fascinating papers. The use of alternative nucleophiles to water in both interand intramolecular reactions has allowed access to several attractive and complex chemotypes, such as azaspirocycles and spirocyclic ethers. Moreover, the combination with a subsequent intramolecular conjugate addition permits the synthesis of thiazines and oxazines in a straightforward manner. These are promising scaffolds for the synthesis of complex natural products and biologically active compounds.
In summary, the Piancatelli rearrangement turned out to be an elegant approach for the stereoselective construction of complex scaffolds that traditional methods would generate via multistep processes and with limited diversity on the substituents. Thanks to the use of milder reaction conditions, this recently re-discovered rearrangement holds promises for a number of new applications. An enantioselective version would represent a further progress in the field, for instance in the synthesis of oxaspirocycles with the use of chiral Lewis acids.