Advances in Organic Synthesis: Volume 10

By Bentham Science Publishers

Advances in Organic Synthesis is a book series devoted to the latest advances in synthetic approaches towards challenging structures. The series presents comprehensive reviews written by eminent authorities on different synthetic approaches to selected ta

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Sep 25, 2018
• ISBN: 9781681087436

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Organocatalytic α-hydroxylation or α-aminoxylation of Carbonyl Compounds

Armando Talavera-Alemán¹, Rosa E. del Río¹, Christine Thomassigny*, ², Christine Greck²

¹ Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia, Michoacán, 58030, Mexico

² Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035Versailles, France

Abstract

α-Hydroxylation or α-aminoxylation of carbonyl compounds in the presence of an organocatalyst has become a significant method for the creation of asymmetric C-O bonds. From the first studies with the classical proline-type or Cinchona-derived organocatalysts, methods have evolved to more efficient systems. Phase-transfer organocatalysts, flow chemistry, ionic liquids, electrochemistry or photo-oxidation permit the reaction with a large range of substrate. While originally aldehydes and ketones were used in these reactions, it is now possible to extend the scope to amides or dicarbonyl compounds such as β-keto ester and β-keto amide. The present review aims to present a general overview of the evolution of these systems.

Keywords: Benzoyl peroxide, Carbonyl, Cinchona-based catalyst, Dicarbonyl, Flow chemistry, Ionic liquid, Nitrosobenzene, Organocatalysis, Organophotocatalysis, Phase-transfer, Photo-oxidation, Proline, Singlet oxygen, TEMPO, α-aminoxylation, α-hydroxylation, β-keto amide, β-keto ester, α-oxidation, α-oxybenzoylation.

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* Corresponding author Christine Thomassigny: Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035, Versailles, France; Tel: [phone]; Fax [phone]; E-mail: [e-mail]

INTRODUCTION

Chiral α-hydroxylated carbonyl compounds belong to a very important class of compounds in organic synthesis as intermediates for natural products or bioactive compounds. Their synthesis is of great interest, and the development of new methodologies to obtain them is still of significance.

Organocatalysis represents a very attractive pathway from the point of view of Green Chemistry. Many methods are known today for the α-hydroxylation of

carbonyl or dicarbonyl compounds, and these have been very well reviewed in 2010 by the group of Vilaivan [1] and in 2012 by the group of Momiyama [2]. The present review does not aim to make another systematic review of all these methods, but proposes an overview of recent advances, as most of the processes have evolved in the last decade.

The first part of the review is articulated around the four most widely used reagents for the asymmetric organocatalyzed α-oxidation of carbonyls, namely nitrosobenzene, benzoyl peroxide, TEMPO and O2. Other electrophiles have been used such as oxaziridines, H2O2, NaClO, meta-chloroperbenzoic acid, oxone or even ³O2, but will not be reviewed here, as they remain marginal methods. For the four most commonly used reagents, methods have greatly evolved as the classical protocol has given way to more modern or greener ones. Ionic or aqueous media, flow chemistry and photo-oxidation for instance have led to more powerful systems, and larger substrate scopes. The evolution of the use of these four oxidizing reagents will be detailed below, from their classical uses and facts about the reaction mechanism, up to the more modern protocols. The second part is focused on the α-oxidation of 1,3-dicarbonyl compounds.

FUNCTIONALISATION OF ALDEHYDES AND KETONES

α-Aminoxylation Reactions with Nitrosobenzene or Derivatives

First Publications: the Classical Method

The organocatalytic α-aminoxylation of aldehydes and ketones in the presence of nitrosobenzene (PhNO) has been one of the most studied reactions. The reasons for this are the accessibility of the reagents, the ease of following the reaction (the reaction mixture generally turns from light blue to blue-green then to yellow-orange when the reaction is finished), and the ease with which an alcohol can be obtained from an aminoxyl function.

In 2003, the groups of Hayashi [3], MacMillan [4] and Zhong [5] independently published the first publications on the asymmetric aminoxylation of aldehydes 1 in the presence of the catalyst L-proline and PhNO as the electrophilic agent, giving 2 that was reduced in situ to the corresponding primary alcohol 3 (Scheme 1). The three proposed systems lead to the expected products with good yields and ee. Hayashi and co-workers preferred reactions in acetonitrile at low temperatures (0 °C or -20 °C) to avoid side reactions such as the dimerization of PhNO or the self-aldol reaction of the aldehyde, known respectively to proceed at 0 °C and 4 °C. They needed to introduce an excess of aldehyde (3 equiv.). The group of MacMillan preferred reactions at 4 °C in chloroform and managed to decrease the catalyst loading to 0.5 mol% for the α-oxidation of propionaldehyde. Zhong and co-workers worked at room temperature in DMSO, which allowed them to decrease the ratio of aldehyde/PhNO to 1.2/1.

Scheme 1)

Asymmetric α-aminoxylation of aldehydes in the presence of proline.

In parallel, the reactivity of ketones 4 for the formation of the mono-adducts 5 briefly reported at that time by Hayashi and co-workers [3], was thoroughly studied the next year by the same group [6] and by the one of Córdova (Scheme 2) [7]. They demonstrated particularly the importance of the speed of addition of the PhNO reagent or the aldehyde to avoid α,α’-di-aminooxylation.

Scheme 2)

Asymmetric α-aminoxylation of ketones in the presence of proline.

Generalities

Several models have been proposed for the catalytic cycle of the reaction with proline, but the consensus today is for a standard cycle passing through an enamine transition state, accompanied by a possible autocatalytic route (Scheme 3) [8-11].

Scheme 3)

a) Catalytic cycle and b) transition state for the α-oxyamination of aldehydes with PhNO.

A proline-saturated solution would have a concentration inferior to 0.005 M in a nonpolar, aprotic solvent. The first step would be the slow formation of the (E)-anti-enamine B via the oxazolidinone A. Then the addition of the electrophile PhNO leads to the iminium C: this step is the key-point for both heteroatom selectivity and stereoselectivity. Indeed, the formation of the C-O bond in favor of the C-N one could be explained by the higher basicity of the nitrogen atom compared to the oxygen atom. In the presence of a catalyst which could form a hydrogen bond (e.g. proline: the hydrogen of the carboxylic function), this basicity induces a preferential protonation of the nitrogen, allowing the oxygen to become electrophilic and leading to the formation of the C-O bond. Consequently, a catalyst acting without a hydrogen bond should favor C-N bond formation. The hydrogen bond explains the stereoselectivity, as the approach of the PhNO would be on the same face as the carboxyl function. The corresponding transition state is represented in Scheme 3.b. Lastly, the hydrolysis of the iminium C gives the expected product E and proline that can be reused in a new cycle.

The autocatalytic route described by Blackmond and co-workers [8] is based on hydrogen bonds between the carboxylic oxygen atom of the catalyst and the NH of the product, giving the complex D from C. The lone pair of the proline nitrogen atom would then be accessible for the attack of a new substrate, giving B and an equivalent of the product E.

Taking into account the autocatalytic way and the studies of Seebach et al. [12] over the role of the oxazolidinone intermediate A for the formation of the enamine B, McQuade and coworkers in 2009 described the utility of introducing an urea co-catalyst in the reaction medium [13]. The bifunctional urea 6 (Fig. 1a) easily prepared from phenylisocyanate and N,N-dimethylethylenediamine has been tested for the α-aminoxylation of hexanal in the presence of 5 mol% of proline at 0 °C. The reaction rate was considerably accelerated, allowing the use of more eco-friendly solvents than normally used, namely ethyl acetate instead of chloroform. Substrate screening (Scheme 1: 5 mol% of both proline and 6) led to the expected products 2 with yields of 55-97% and ee of 98-99% (7 examples). The rate enhancement with conservation of the enantioselectivity led the authors to propose the formation of stabilizing hydrogen bonds between the urea and the oxazolidinone intermediate A (Fig. 1b). The corresponding enamine B would then be formed much faster.

Fig. (1))

a) Bifunctional urea 6 and b) proposed interactions with the oxazolidinone intermediate A.

After the firsts reports in 2003 of the α-aminoxylation of aldehydes or ketones, few developments have been reported to extend the system. Several modifications of the substrate or catalyst, including proline derivatives and non-proline catalysts, or studies of the mechanism have been reported [1, 14-20].

The development of sequences including this reaction leads to compounds with two consecutive stereogenic centers. As examples, chiral 1,2-diols have been obtained by O-nitrosoaldol/Grignard addition [21] or chiral 1,2,3-triols by a α-hydroxylation of protected β-hydroxyaldehydes/reduction process [22].

Today, the organocatalyzed α-aminoxylation of carbonyls is used in total synthesis as a key-step for the formation of a stereocontrolled C-O bond. The protocol is generally based on the use of nitrosobenzene or nitrosotoluene in the presence of a proline catalyst. Numerous examples have been cited in the both reviews of the groups of Vilaivan in 2010 [1] and of Kumar for the synthesis of biologically active compounds in 2012 [23]. More recent total syntheses led to the targets represented in Fig. (2): (-)-cleistenolide 7 [24], (+)-trans cognac lactone 8 and analogues [25], oxylipids 9 [26], xyolide 10 [27], (+)-duryne 11 [28], hydroxylated piperidines 12 or 3-hydroxypipecolic acid 13 [29], and vinyl sulfone derivatives 14 [30].

Fig. (2))

Target molecules obtained via α-aminoxylation of carbonyls.

Even if the method using PhNO has been studied in depth, some problems remain with its use. The first concerns the generally large quantities of carbonyl substrate needed, generating evident limitations for multistep syntheses. Effectively, the syntheses generally used this reaction as a key-step when it can be introduced at the very beginning of the synthesis. A second inconvenience is the non-ecofriendly solvent usually encountered in the protocols: acetonitrile, chloroform, dichloromethane, dimethylformamide or dimethylsulfoxide. Finally, another problem is the possibility of oxyamination in parallel to the expected aminoxylation. This point was particularly significant in the case of α-branched aldehydes. These facts explain the development of supplementary methods for the oxidation of carbonyls with PhNO. Performing the reaction in water, the introduction of ionic liquids or the use of continuous flow techniques are some of the modifications that have been explored, and will be discussed below.

α-Aminoxylation Reactions in Aqueous Media

The advantages of the use of water in organocatalysis are well described now, namely acceleration of the reaction rates and enhancement of the stereoselectivity. Zhong demonstrated the possibility of running the reaction in aqueous medium by using L-thiaproline and tetrabutyl ammonium bromide as a phase-transfer catalyst (Scheme 4) [31]. The reaction with aldehydes led to the expected products with good yields (74-88%) and ee (93-99%). Replacing PhNO by nitrosotoluene (p-TolNO) in the optimized conditions for propanal led to the corresponding product in a good yield of 83% and enantioselectivity of 97%.

Scheme 4)

α-Aminoxylation reaction in aqueous media.

α-Aminoxylation Reactions in Ionic Liquids

As catalyst recycling is an important aspect of Green Chemistry, ionic liquids represent a good solution as the mixture of catalyst/ionic liquid can be recovered easily. The first examples with 1-butyl-3-methyl imidazolium tetrafluoroborate [bmim][BF4], known to be a room temperature ionic liquid (RTIL) and used as a solvent, were reported independently by the groups of Huang [32] and Guo [33] in 2006.

The system for the direct α-aminoxylation in the presence of PhNO and 20 mol% of proline was efficient for aldehydes or ketones 15 (Scheme 5). Huang and co-workers noted short reaction times (10-30 min) giving high yields after in situ reduction of 17 (68-94%) and ee (95-99%), whereas the team of Guo noted similar values with longer times (3-4 h) to obtain the compound 16. Recycling was possible taking advantage of the solubility of each partner, as the catalyst was retained by the RTIL after extraction of the product with diethyl ether. The proline/RTIL mixture could then be reused. Huang described little or no decrease in yield and ee after 6 batches with propanal or cyclohexanone as substrates. Guo remarked good yields from cyclohexanone for 4 batches (74-73%) then a drastic decrease for the fifth one (50%), pointing perhaps to a failure in the system.

Scheme 5)

L-Proline catalyzed α-aminoxylation of carbonyls in [bmim][BF4].

The first polymer-supported catalyst for the α-aminoxylation of ketones was made possible by fixing 4-trans-hydroxyproline onto Merrifield-type resins through click chemistry [34]. The resulting resin 18 (Fig. 3) remained very enantioselective for ketones and aldehydes. A very slow introduction of PhNO (3 h) to a mixture of carbonyl/catalyst in DMF provided the desired product with modest to good yields (ketones, 5 ex: 43-60%; aldehydes, 8 ex: 35-86%) and excellent ee (ketones: 97-99%; aldehydes: 96-99%).

Fig. (3))

Polymer supported organocatalyst 18.

The imidazolium ion-tagged 19 has been prepared in 3 steps from protected proline by Cheng and co-workers [35]. They then studied the α-oxyamination of aldehydes or ketones 20 in the presence of PhNO in ionic liquid medium (Scheme 6). The catalyst loading (5-20 mol%) had no significant effect on enantioselectivity as the corresponding products 21 (ketones) or 22 (reduction of the aldehydes) were always obtained with an ee of 99%. The authors assumed a synergistic effect of the catalyst and the ionic liquid media ([bmim][BF4]) that would stabilize the enamine intermediate.

Scheme 6)

Imidazolium ion-tagged proline catalyzed α-aminoxylation of carbonyls in ionic liquid.

The proline or lysine derivatives tagged with several triazolium or guanidinium salts 23-28 in [bmim][BF4] (Fig. 4) were efficient catalysts for the aminoxylation of cyclohexanone with PhNO in short times (15-35 min) [36]. The protocol was extended to isobutyraldehyde and 3-phenylpropionaldehyde with 23a, giving the corresponding products with good yields (83 and 89% respectively) and ee (96 and 98% respectively). Recycling of 23a lead to a notable decrease of enantioselectivity and yield in each cycle, linked to a need to increase the reaction time to complete the reaction.

Based on the observation that the oxazolidinone 29 (detected by HPLC-MS) was present in equilibrium with the enamine 30 in the reaction with cyclohexanone, the authors assumed that the addition of a small amount of water favors catalyst recycling by facilitating the hydrolysis of 29 or 30 (Fig. 5).

α-Aminoxylation Reactions in Continuous Flow Systems

The main problem for α-aminoxylation under flow chemistry is the use of a catalyst that is known to only partially or slowly dissolve in the reaction medium, such as the proline catalyst. One answer to override this problem would be to limit the solubility of the catalyst by immobilizing it on a resin or polymer. This was the solution envisaged by Pericàs and co-workers [37] in 2011 who used a combination of flow chemistry and the polymer-supported catalyst 18 linked to 1,4-divinylbenzene (DVB) with various degrees of functionalization. The system with low cross-linked polystyrene (18a: 1% DVB; functionalization f = 0.48 mmol.g-1) was described as a microporous system giving a gel that could ensure contact of the reactants, showing high activity. Another system (18b: 8% DVB; f = 0.74 mmol.g-1) had behavior between a micro- and macroporous system. Both catalysts have been tested for the α-aminoxylation of aldehydes 31 with PhNO followed by reduction to the corresponding alcohol 32 (Scheme 7). Excellent enantioselectivities were obtained by both catalysts in 1 h. In terms of activities, the catalyst 18a was more efficient than 18b and was not dependent on chain length, as opposed to 18b that worked better with propanal than with longer-chain or branched aldehydes.

Fig. (4))

Catalysts 23-28 used for the α-aminoxylation of cyclohexanone with PhNO.

Fig. (5))

Equilibrium between oxazolidinone 29 and enamine 30.

Scheme 7)

Continuous flow α-aminoxylation of aldehydes with immobilized catalysts.

The same year, McQuade and co-workers [38] proposed a system where a mixture of aldehyde 33/thiourea 34 was passed through a packed-bed of solid proline before reacting with the PhNO reagent (Scheme 8). They particularly demonstrated that one of the more important parameters was the temperature of both the column and coil. Their adjustment allowed good yields and enantioselectivities from hexanal, 3-phenylpropionaldehyde or isovaleraldehyde.

Scheme 8)

Continuous flow α-aminoxylation of aldehydes with thiourea 34.

Oxidative α-C-H N,O-ketalization of Ketone

As a last example, the α-oxidation reaction of carbonyls by a primary amine catalyst has been described recently [39]. The group of Luo demonstrated that the action of N-hydroxycarbamate on β-keto esters or ketones led to a duality for C-N and C-O bond formation, introducing both bonds in the α,α’-position. Several cyclic ketones 36 were tested for α,α’-bis-functionalization in the presence of the catalyst 37 (20 mol%), the chiral additive 38 (20 mol%) and CuCl (15 mol%) (Scheme 9). The corresponding N,O-ketals 39 were obtained with yields and ee up to 78%, although the determination of their absolute configuration was not possible. Five or seven membered-ring, or acyclic ketones were unreactive under these conditions.

Scheme 9)

Oxidative α-C-H N,O-ketalization of ketones.

The proposed catalytic cycle from a β-keto ester 40 assumed the formation of the enamine 41 after reaction with 37 (Scheme 10). Addition to the nitroso derivative 42 led to the intermediate 43, that can easily lose a molecule of water due to the strong acidity of the H-N. The corresponding compound 44 can react with another equivalent of the N-hydroxycarbamate to produce the intermediate 45, whose hydrolysis gave the product 46 and the catalyst 37.

Scheme 10)

Catalytic cycle for the oxidative α-C-H N,O-ketalization of a ketone.

α-Oxybenzoylation Reactions

Benzoyl peroxide (BPO) has long been known as a readily available oxidative reagent. In 2009, the groups of Hayashi [40], Maruoka [41] and Tomkinson [42] simultaneously used this reagent for the organocatalyzed α-oxybenzoylation of several aldehydes 47 (Scheme 11). Bulky catalysts need to be introduced in the reaction to avoid the reaction of BPO with the secondary amine, that would lead to N-benzoyloxy or amide side-products. The three authors used respectively the prolinol derivative 50, 51 and the imidazolidinone 52. Hydroquinone may be used as a radical scavenger to increase the yield. In all cases, the aldehyde 48 or the corresponding alcohol 49 were obtained with medium to acceptable yields and good enantioselectivities.

Scheme 11)

α-Oxybenzoylation of aldehydes.

The authors agree on two plausible mechanisms as represented in Scheme 12 with the catalyst 52. The first one would be the direct approach of BPO to the enamine 53 formed by the condensation of aldehyde 47 (R = Me) with 52, leading to the iminium 54 (path A). The second would concern a N-oxybenzoylation of the enamine 53 followed by a [3, 3]-sigmatropic rearrangement of the intermediate 55, giving 54. The hydrolysis of this last would give the product 48 and recovery of the catalyst 52.

Scheme 12)

Proposed mechanisms for the α-oxybenzoylation of aldehydes.

The α-oxybenzoylation of cyclic ketones was described in 2011 by List and co-workers [43], becoming the first example of the use of a primary amine as a catalyst for the α-oxidation of carbonyl compounds (Scheme 13). With the aim to avoid the decomposition of the secondary amine used as catalyst with aldehydes as substrates, the authors used the Cinchona derivative 56 in the presence of an acid and 2,6-di-tert-butyl-4-methylphenol (BHT). The reaction was possible with diversely substituted and functionalized cyclohexanones 57 including acetal, olefin and carbamate, and can be extended to cyclohepta- and cyclooctanones. Larger rings or acyclic ketones were not reactive enough under these reaction conditions.

Scheme 13)

α-Oxybenzoylation of ketones.

The group of Bencivenni described three years later a similar system, composed of 9-amino-(9-deoxy)epi-dihydroquinidine 59 and salicylic acid in the presence of a base [44]. The scope of cyclic ketones used was fairly large, giving the products with yields of up to 96% and ee up to 99% (13 examples). In particular, the reaction was extended to 1-indanones 60 and showed low to good yields (30-82%) with ee from 40 to 89% (Scheme 14).

Scheme 14)

α-Oxybenzoylation of 1-indanones.

The benzoylation of 3-aryloxindole 62 in the presence of several chiral phosphoric acids has been tested [45]. In particular, 63 was very efficient to obtain 64 with a yield of 81% and an ee of 99% when used in ether at 5 mol% (Scheme 15). Interestingly, the use of DCM as solvent induced a reverse in selectivity (yield 56%; ee (-)-64 36%). A systematic study of the salts of 63 allowed a decrease in catalytic charge to 2.5 mol% to reach a yield of 83% and an ee of 99% when the catalyst was used as its calcium salt.

Scheme 15)

α-Oxybenzoylation of 3-aryloxindoles.

α-Aminoxylation Reactions with TEMPO

First Publications: the Classical Method

The introduction of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)