Ferrier rearrangement

About: Ferrier rearrangement is a research topic. Over the lifetime, 321 publications have been published within this topic receiving 5524 citations.

Gold‐Catalyzed Tandem Intramolecular Heterocyclization/Petasis–Ferrier Rearrangement of 2‐(Prop‐2‐ynyloxy)benzaldehydes as an Expedient Route to Benzo[b]oxepin‐3(2 H)‐ones

Abstract: Partially or fully hydrogenated benzo[b]oxepines are common ring motifs found in many pharmaceutically interesting and potentially bioactive natural compounds. Representative examples range from the structurally simple and bioactive heliannuol A, pterulone, and radulanin A to the architecturally challenging compounds edulisone A and ovafolinin B. For this reason, the establishment of new synthetic methods to construct this biologically important class of compounds has received an immense amount of attention. The synthetic strategies toward functionalized benzo[b]oxepines can be divided into two groups: manipulation of a pre-existing oxygen-containing cyclic core or assembly from acyclic precursors. Despite the advances made through both these approaches, the development of new synthetic methods to prepare this class of oxygen heterocycles from readily available substrates and catalysts with selective control of substitution patterns under mild and operationally simplistic conditions remains desirable. The emergence of gold complexes as powerful and versatile Lewis acid catalysts that can mediate a plethora of C X (X=C, N, O, S) bond formations has been well documented in recent years. Among this myriad of works, one notable innovation has been the formation of carbocycles and heterocycles from cyclization of a carbonyl compound tethered to an alkyne in the presence of a gold catalyst. For example, Yamamoto and Jin recently reported an efficient synthetic route to fused triand tetracyclic enones based on the AuCl3/AgSbF6-catalyzed tandem heteroenyne metathesis/Nazarov cyclization of 1,3-enynyl ketones. On the basis of this and other previous studies on carbonyl metathesis, we reasoned that a strategy that made use of Opropargylated salicylaldehydes in the presence of a Lewis acid gold catalyst would hold promise as a new method for benzo[b]oxepin-3 ACHTUNGTRENNUNG(2H)-one synthesis. As part of an ongoing program exploring the scope of gold catalysis in heterocyclic synthesis, our discovery that Au complex 3 can effect tandem intramolecular heterocyclization/Petasis–Ferrier rearrangement of 2-(prop-2-ynyloxy)benzaldehydes is reported herein (Scheme 1). This process provides a convenient synthetic route to benzo[b]oxepin-3ACHTUNGTRENNUNG(2H)-ones in 21– 99% yield for a wide variety of substrates under mild and operationally simplistic conditions that did not require the exclusion of air or moisture. A study that delineates the influence on reactivity of a substituent at the ortho position to the ethereal moiety on the salicylaldehyde is also presented. To the best of our knowledge, synthetic methods involving metal-mediated cyclizations of propargylic aldehydes of type 1 have thus far been reported to typically give the benzopyran product. We began by examining the cyclization of 1a by a variety of Lewis and Bronsted acids to establish the optimal reaction conditions (Table 1 and Table S1 in the Supporting In[a] E. M. L. Sze, Dr. W. Rao, M. J. Koh, Prof. Dr. P. W. H. Chan Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 (Singapore) Fax: (+65)6791-1961 E-mail : waihong@ntu.edu.sg Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201003096. Scheme 1. Gold(I)-catalyzed synthesis of benzo[b]oxepin-3 ACHTUNGTRENNUNG(2H)-ones from 2-(prop-2-ynyloxy)benzaldehydes. R=H, alkyl, aryl, halide, or NO2; R , R=H or alkyl.

A modular, efficient, and stereoselective synthesis of substituted piperidin-4-ols.

Abstract: Piperidine is a key structural motif in various alkaloids and a variety of compounds studied in medicinal chemistry. Though many methods have been developed for their construction, there is still a need for noval approaches, especially those with high efficiency, good modularity and excellent stereoselectivity. Recent intense research in gold catalysis[1] has provided several novel methods of piperidine synthesis.[2,3] For example, we reported earlier that piperidin-4-ones could be prepared in a two-step, [4+2] manner;[2a] however, the products are limited to those with ring nitrogen substituted with hard-to-remove aliphatic groups or benzyl groups suffering from low regioselectivities. To address this deficiency and develop a generally effective and modular synthesis of N-unsubstituted piperidines, we envisioned, as shown in Scheme 1, that a gold-catalyzed cyclization of N-homopropargyl amide 2 would offer cyclic imidate 3, which could be chemoselectively reduced to afford α-amino ether A. We anticipated that A would undergo spontaneous Ferrier rearrangement to furnish piperidin-4-one B, which might be further reduced in situ to the corresponding alcohol (i.e. 4). Several aspects of this design are noteworthy: 1) the sequence is highly modular and flexible; it is an overall {[2+3]+1} annulation from readily available imines, propargyl Grignard, and carboxylic acids or their derivatives; 2) enantiomeric synthesis is readily achievable as chiral amine 1 would be easily prepared from chiral sulfinyl imines;[4] 3) it constitutes an alternative to an aza-Petasis-Ferrier rearrangement, which has not been realized.[5,6] This is a surprising void as the Petasis-Ferrier rearrangement[7] has been applied with much success in total synthesis of complex natural products.[8] 4) the piperidine nitrogen is free and could be readily derivatized; 5) the gold catalysis is not the key transformation but instead employed to deliver requisite intermediates for subsequent processes. This sequential combination of gold catalysis and other distinctively different transformations in a one-pot process offer new opportunities to develop versatile synthetic methods with high efficiency. (1) Scheme 1 Modular synthesis of N-unsubstituted piperidines: design We began the implementation of the design by examining the feasibility of the gold catalysis[9] using amide 5 as the substrate. To our delight, the gold-catalyzed cyclization proceeded quantitatively in either CH2Cl2 or THF at ambient temperature (Eq 1). The keys to this reaction were the addition of MsOH (1.2 equiv) to prevent the nitrogen of imidate 6 from coordinating to and thus deactivating the gold catalyst[10] and the use of molecular sieves to minimize hydrolysis. Due to the sensitivity of imidate 6 to hydrolysis, we decided to study its reduction in a one-pot process. Hence, upon the complete consumption of amide 3 in the gold catalysis, various reductants were added. To our delight, with borane the all cis-isomer (i.e., 7) was indeed formed. Screening other reductants especially boron-based ones revealed that catecholborane (5 equiv) worked the best (entries 5-9), and an 80% isolated yield was achieved in CH2Cl2 and at -78 °C. Notable is that 7 was formed with excellent diastereoselectivity, and other potential diastereomers were formed in negligible amounts. The relative stereochemistry of 7 was initially established via NMR studies and later corroborated by the structure of 9p (vide infra) established by X-ray crystallography (see SI). We then tested a range of secondary amides as substrates following the optimized one-pot sequence with some fine tunings of reaction temperatures and the amount of the borane. As shown in Table 2, different acyl groups including aliphatic (entries 1-7) and aromatic ones (entries 8-11) were readily allowed. Steric bulk was well tolerated although the reduction was slower (entry 4). Different functional groups including a non-conjugated C-C double bond (entry 6), fluoro groups (entries 7 and 9), a carboxylate (entry 11) and a naphthyl group (entry 10) were tolerated. However, (2) (3) trifluoroacetamide 8 (R = CF3, R = Cy) was not a suitable substrate as its weakly nucleophilic carbonyl group failed to undergo gold-catalyzed cyclization. Notably, high to excellent diastereoselectivities were observed in the cases of aliphatic amides. However, the catecholborane reduction in the cases of aromatic amides (entries 8-11) was very slow at -40 °C, and the reactions were run at ambient temperature in order to achieve completion in 24 h; low diastereoselectivities were observed in most of these cases. To our delight, while the major isomers were the expected all-cis ones, the minor component in each case appeared to be the 4-OH epimer, which was confirmed via oxidation of the separated isomers of 9j to a common piperidin-4-one.[11] These results indicated that the piperidine ring-forming step was highly diastereoselective even at room temperature. In contrast to entry 6, the vinyl group in acrylamide 8l (entry 11) was reduced during the reaction, and piperidine 9l with an ethyl group instead was isolated in 47% yield. Substrates with an aryl group at the homopropargylic position worked equally well in this one-pot process (entries 13-18), and at -40 °C the diastereoselectivities were mostly excellent. Again, steric bulk (entries 15 and 17) were readily tolerated. Table 2 One-pot sequential gold catalysis, chemoselective reduction, and Ferrier rearrangement: scope study.[a] A key feature in these piperidin-4-ol products is that the ring nitrogen is free and could be readily derivatized. For example, subsequent one-pot intramolecular alkylations (Eq. 2 and 3) provided quick access to quinolizidine and indolizidine skeletons, respectively, which can be found in the structures of a range of alkaloids.[12] As a demonstration of the synthetic utility of this chemistry, an enantioselective synthesis of (+)-subcosine II[13,14] was achieved in 6 steps in an overall 22% yield (Scheme 2). Notably, homopropargyl amine 10 was easily prepared in >94% ee using Ellman's sulfinyl imine chemistry,[4a] and neither the gold catalysis nor the reduction/Ferrier rearrangement compromised the stereochemistry integrity of the original chiral carbon center. Scheme 2 Six-step, enantioselective total synthesis of (+)-subcosine II. In conclusion, we have developed a one-pot synthesis of piperidin-4-ols v i a sequential gold-catalyzed cyclization, chemoselective reduction and spontaneous Ferrier rearrangement. This reaction has a broad substrate scope and shows excellent diastereoselectivities in the ring formation step; in combination with a routine amide formation, it constitutes a highly flexible and diastereoselective [5+1] cycloaddition approach to piperidines. Since homopropargylic amines could be readily prepared with excellent e.e. from chiral sulfinyl imines and propargylmagnesium bromide, this overall {[2+3]+1} modular approach offers an ideal solution to enantioselective synthesis of various substituted piperidine. Importantly, the piperidine nitrogen is free and can be readily derivatized. By coupling with one-pot intramolecular alkylations, this chemistry provides a rapid access to quinolizidines and indolizidines and allows a succinct enantioselective synthesis of (+)-subcosine II.

Synthesis of optically active substituted cyclohexenones from carbohydrates by catalytic Ferrier rearrangement

Abstract: Conversion of hex-5-enopyranosides into substituted cyclohexanones (Ferrier rearrangement) was found to proceed efficiently with a catalytic amount of various mercury(II) salts at room temperature in a neutral solvent system. Among the mercury(II) salts tested, mercury(II) trifluoroacetate showed the highest activity. Four optically active cyclohexenones were prepared from hex-5-enopyranosides utilizing this method.