Recent Developments in the Reformatsky-Claisen Rearrangement

The rearrangement of allyl α-bromoacetates with Zn dust is known as the Reformatsky-Claisen rearrangement. Whereas the Ireland-Claisen rearrangement has been widely used in the synthesis of a diverse range of natural products, the Zn-mediated Reformatsky-Claisen rearrangement has not been utilized so often. In this article, we will provide an overview of recent advances in the Reformatsky-Claisen rearrangement field, including the In-mediated Reformatsky-Claisen rearrangement we have recently developed.


Introduction
The development of new methods for stereoselective carbon-carbon bond formation has been important in the creation of useful molecules such as drugs and other chemical entities. [3,3]-Sigmatropic rearrangements are reliable reactions for selective carbon-carbon bond formation, in particular, the Claisen rearrangement is one of the most competent methods to provide useful building blocks for the synthesis of natural products [1][2][3][4]. The synthetic utility of this reaction has prompted the development of a considerable number of variants of the classical Claisen rearrangement [5][6][7][8][9]. For instance, zinc-mediated [3,3]-sigmatropic rearrangement of -haloesters, proceeding through Zn enolates, are referred to as the Reformatsky-Claisen rearrangement. Compared to the Ireland-Claisen rearrangement which was widely used in the synthesis of a diverse range of natural products [10][11][12][13][14], the Reformatsky-Claisen rearrangement has the advantage of being performed under non-basic conditions. This review article focuses on the chemistry of the Reformatsky-Claisen rearrangement and its applications, as well as the recent development of the In-mediated Reformatsky-Claisen rearrangement.

Pioneering Works of the Reformatsky-Claisen Rearrangement
In 1973, Baldwin and Walker reported a synthetically useful sigmatropic rearrangement of -halogenated allyl esters [15]. Zinc enolates, generated by Reformatsky-type reactions of -halogenated allyl esters with zinc dust, provided the corresponding rearranged products. For instance, when allyl -bromoisobutyrate 1a was added to a refluxing suspension of an excess amount of Zn dust it afforded acid 2a in excellent yield (Table 1). It should be noted that the rearrangement of 1a can readily install a quaternary center into the product. The reaction of -bromopropionate 1b also proceeded smoothly to give a rearranged product 2b. In contrast, the rearrangement of simple allyl ester 1c and secondary ester 1d were found to be fruitless. Baldwin stated that one of the reasons for the low yield would be the generation of 1,3-dicarbonyl products by intermolecular Claisen condensation, which had been known as byproducts of classical Reformatsky reactions. Another reason would arise from the decomposion of Zn enolate 4 to afford 5 and allyl bromide (Scheme 1). The resulting allyl bromide would undergo Friedel-Crafts reaction with the aromatic solvent catalyzed by the zinc bromide generated in the reaction.

Reformatsky-Claisen Rearrangement in the Presence of Zinc and a Silylating Reagent
The Reformatsky-Claisen rearrangement also proceeds in the presence of a silylating agent, in which a silyl ketene acetal is the most likely intermediate. Ireland and co-workers demonstrated that upon heating a mixture of -bromo ester 6, Zn dust, and TBSCl in THF and HMPA under reflux, the carboxylic acid 7 was obtained in 73% yield (Scheme 2) [11]. This reaction would be evaluated as a basefree reaction complementary to the ester enolate Claisen rearrangement.
An example of a reactions performed under these conditions was illustrated by Akiba, which involves preparation of a carboxylic acid bearing a silyl group [16]. A thermal reaction of -bromoacetate 8a with Zn and TBSCl in THF and HMPA provided carboxylic acid 9, LiAlH 4 reduction of which afforded alcohol 10 in 68% overall yield. On the other hand, application of the Ireland-Claisen protocol to acetate 8b resulted in the production of the same carboxylic acid 9 in lower yield (Scheme 3).

Scheme 3. Reformatsky-Claisen rearrangement of 8a.
Narasaka and co-workers employed the Reformatsky-Claisen rearrangement for the preparation of highly functionalized carboxylic acid 12. Exposure of -bromoisobutyrate 11 to Zn and TMSCl furnished branched acid 12, having a quaternary carbon. The product 12 was transformed to a dienyl oxime 13, which was a precursor in a palladium-catalyzed domino cyclization (Scheme 4) [17].

Application of Reformatsky-Claisen Rearrangement with Zinc and a Silylating Reagent
The most frequently reported Reformatsky-Claisen protocol involves heating a substrate with Zn dust and a silylating reagent in an aprotic polar solvent. Several additional applications are described below.

Preparation of -Fluorocarboxylic Acid by Reformatsky-Claisen Rearrangement
Fluorinated ketones have been successfully employed as enzyme inhibitors in modern bioorganic chemistry. Therefore, the synthesis of selectively fluorinated molecules which have fluorine substituents adjacent to a carbonyl group became a major target in fluoroorganic chemistry. One of the earliest applications of Reformatsky-Claisen rearrangement of fluorinated substrates, reported by Lang and co-workers, was the conversion of allyl chlorodifluoroacetate 14 to difluoroacid 15 (Scheme 5). Various allyl chlorodifluoroacetates can undergo a Reformatsky-Claisen protocol to give 2,2-difluoro-4-pentenoic acid derivatives [18].

Application of -Fluorocarboxylic Acid Induced by Reformatsky-Claisen Rearrangement to Biological Active Compounds
An intriguing extension of this methodology would be found in the synthesis of a key building block for a number of second-generation HIV protease inhibitors reported by Chen's group at Pfizer. They performed the reaction of chlorodifluoro derivative 16 with Zn and TMSCl in 1,3-dimethylimidazolidin-2-one (DMI) for the preparation of difluorocarboxylic acid 17. The product 17 was then converted to amide 18, from which 4,4-difluoro-3,3-dimethylproline derivative 19, a core part of HIV protease inhibitors such as 20 and 21 was synthesized (Scheme 6) [19]. Qing and co-workers employed a Reformatsky-Claisen rearrangement to synthesize fluorinated thionucleosides. The replacement of a carbohydrate moiety of naturally occurring nucleosides with other five membered rings is one of the promising approaches for exerting a significant effect on the biologic activity. In the course of the studies of nucleoside analogues, they targeted difluoromethylene containing thionucleosides, such as 22 and 23, which were the modified analogs of highly bioactive (−)-2'-deoxy-3'-thiacytidine (3TC) and (+)-2'-deoxy-3'-oxacytidine (L-OddC) (Scheme 7) [20]. When Reformatsky-Claisen rearrangement of 24 was carried out under conventional conditions (Zn, and TMSCl), none of desired product was obtained. On the other hand, the addition of pyridine promoted this rearrangement effectively. Thus, treatment of 24 with Zn and TMSCl in the presence of pyridine at 120 °C in a sealed tube afforded the desired product 25 in 43% yield. Compound 25 was then transformed to thiofuranose 26 in 4 steps, which was condensed with pyrimidine bases by regioselective Pummerer reaction to afford nucleosides 27a and 27b (Scheme 7).

Scheme 7. Synthesis of thionucleosides through Reformatsky-Claisen Rearrangement by Qing.
Qing's group further targeted fluorinated carbocyclic nucleosides based on the similar strategy. Upon treatment of 28 with Zn and TMSCl at 105 °C in MeCN, the rearrangement took place to deliver difluorinated acids, esterification of which afforded ethyl ester 29 as a mixture (syn:anti = 3:1) in 72% yield [21]. On the other hand, the reaction of monofluoro ester 31 provided four isomers (dr = 8.7:3.4:1.8:1), major component of which was syn-anti-product 32. The resulting esters 29 and 32 were convertible to cyclopentenes 30a,b, and 33a-c after installation of nucleobases, respectively (Scheme 8) [22].

Indium-Mediated Reformatsky-Claisen Rearrangement
Recently Ishihara and Hatakeyama reported the In-mediated Reformatsky-Claisen rearrangement, which is feasible for various -bromoisobutyrate derivatives [23,24]. Initially, -bromocyclohexanecarboxylate 34 was subjected to the conventional rearrangement conditions. However, when 34 was treated with Zn and TMSCl-Et 3 N in boiling THF, the protonated product 35 was obtained exclusively (Scheme 9). The scope of the Reformatsky reaction has been considerably extended by the use of metals other than Zn. For instance, in is known to react readily with -halo esters to induce the Reformatsky-type reaction [25]. Recently Baba and co-workers demonstrated that In(I)X is effective for the Reformatsky-type reactions of ketones and esters to afford -hydroxyketones and -hydroxyesters diastereoselectively [26][27][28]. Gratifyingly, we found that treatment of 34 with In-InCl 3 in the presence of TMSCl and Et 3 N in MeCN under ultrasonication conditions at 10-30 °C furnished 36 in 88% yield.

Indium-Mediated Reformatsky-Claisen Rearrangement of -Bromopropionates
To probe the generality of the In-mediated reaction, -bromoesters 37a-c were subjected to the optimized reaction conditions (Scheme 10). The benzyl and TBS ethers were also not affected at all under the conditions; however the THP group was susceptible owing to the Lewis acidity of InCl 3 .
The aromatic compounds 39, 41, and 43 underwent rearrangement to carboxylic acids 40, 42, and 44 in moderate to excellent yields, although the diastereoselectivities were poor. In the case of 39a, 41a, and 43a, the rearrangement took place in MeCN rather smoothly, whereas the rearrangement of 39b, 41b, and 43b proceeded in THF-DMPU (1:1) but not in MeCN. On the other hand, the reactions of aliphatic substrates 45 and 47 brought about the Reformatsky-Claisen rearrangement successfully to give highly functionalized carboxylic acids 46 and 48. In fact, when the In-mediated reaction of bulky 2-methylbut-3-en-2-yl esters 45a and 45b were performed, compounds 46a and 46b were obtained in 63% and 62% yields, respectively. Notably, the rearrangement of 47a can install contiguous quaternary centers, giving compound 48a in 91% yield.

The Reaction of Base-Sensitive Compounds
The most intriguing feature of the Reformatsky-Claisen rearrangement is the feasibility of utilizing base-sensitive substrates. The reactions of -bromoisobutyrates E-49 and Z-49 under the optimized conditions proceeded smoothly to afford 50 in 80% and 53% yields, respectively (Scheme 11). In the case of -bromopropionate 51, a moderate diastereoselectivity was observed, although the yield was not satisfying. On the other hand, the reaction of 53 afforded carboxylic acid 54 having contiguous quaternary carbons in 66% yield. It should be noted that the acetoxy group could survive under the reaction conditions in stark contrast to the Ireland-Claisen rearrangement.
The results shown in Scheme 12 reveals a marked advantage over the Ireland-Claisen rearrangement. Thus, when the reaction of 55 was performed under the above mentioned In-mediated rearrangement conditions, the rearranged product 56 was obtained in 64% yield. In contrast, the reaction of 57 with KHMDS in the presence of TMSCl and Et 3 N afforded isomer 58 in place of 56 [29][30][31].

Proposed Mechanism of the Indium-Mediated Reformatsky-Claisen Rearrangement
As illustrated in Scheme 13, it has been reported that a mixture of In and InCl 3 generates InCl (I) in situ, which readily reacts with -bromoacetate 59 to afford -In(III) intermediate 60 or -In(I) 61 [27]. Both -indium intermediates can be transformed to the In enolate 62, which is converted to silyl ketene acetal 63 by silylation. Since no rearrangement was observed without TMSCl and Et 3 N, the direct rearrangement of In enolates seems unlikely. Finally, the rearrangement of 63 proceeds to generate the corresponding carboxylic acid 64. The rearrangement of -bromoisobutyrate derivatives (R 3 , R 4 = Me) smoothly proceeded in MeCN, whereas the reaction of -bromopropionates (R 3 = Me, R 4 = H) in MeCN afforded only the protonated products. These results can be rationalized as follows: compared to enolate 62 (R 3 , R 4 = Me) derived from isobutyrate, the enolate 62 derived from the propionate derivative (R 3 = Me, R 4 = H) is more nucleophilic, so it easily undergoes protonation with MeCN to form a protonated product. The deuteration experiment in MeCN-d 3 clearly supported that the rearrangement would proceed, provided that the protonation of an enolate is relatively slow. Scheme 13. Proposed mechanism of Reformatsky-Claisen rearrangement.

Conclusions
The recent studies show that Zn-and In-mediated Reformatsky-Claisen rearrangements of -haloacetate derivatives are regarded as a useful variant of the classical Ireland-Claisen rearranegements. The feasibility of these methods for base-sensitive substrates makes it complementary to the Ireland-Claisen rearrangement, and allows simple access to valuable building blocks for the synthesis of complex natural products.