Trifluoromethyl ketones: properties, preparation, and application.

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FEATURE ARTICLE

Cite this: Chem. Commun., 2013, 49, 11133

Received 15th August 2013, Accepted 11th October 2013 DOI: 10.1039/c3cc46266h

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Trifluoromethyl ketones: properties, preparation, and application Christopher B. Kelly,a Michael A. Mercadantea and Nicholas E. Leadbeater*ab Trifluoromethyl ketones (TFMKs) are exceedingly valuable synthetic targets in their own right and as synthons in the construction of fluorinated pharmacons. This Feature Article provides an overview of the properties of TFMKs, an in-depth discussion of the methods available for their synthesis, and two illustrative examples of their application as key intermediates in medicinal chemistry.

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1. Introduction Much attention is currently being given to the development of methods to incorporate fluorine into organic molecules.1 The tremendous popularity of this area stems from the fact that the physiological and chemical properties of small molecules (for example chemical/metabolic stability, lipophilicity, and binding selectivity) are greatly altered by incorporation of fluorine atoms.1 Many drugs or drug candidates now feature fluorine for these reasons. While monofluoro- and difluoro-moieties are certainly of interest, the trifluoromethyl group (–CF3) has received significant attention, likely because of its ability to serve as a bioisostere.1 This can be used to adjust the steric and electronic properties of a compound, or to prevent metabolic degradation. One class of a

Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA. E-mail: [email protected] b Department of Community Medicine & Health Care, University of Connecticut Health Center, The Exchange, 263 Farmington Ave, Farmington, CT 06030, USA

Christopher B. Kelly

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Christopher Kelly studied chemistry at Stonehill College in Easton, Massachusetts, where he received his BS in Biochemistry in 2010. That same year, he joined the University of Connecticut in Storrs CT, where he is currently working towards his PhD under the supervision of Dr Nicholas Leadbeater. His research focuses on the development of new methods for incorporating fluorine into organic molecules as well as novel oxidation methods using oxoammonium ions.

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compounds containing the CF3 functionality that is of particular interest is the trifluoromethyl ketone (TFMK). TMFKs have proliferated through the literature in a wide range of fields. Not only have some been used as probes to obtain mechanistic information, but they themselves have been found to be potent enzyme inhibitors.2 Moreover these fluorinated motifs serve as critical intermediates in constructing trifluoromethylated heterocycles, medicinal compounds, and fluorinated analogues of natural products (Fig. 1).3 The importance of this motif is exemplified in the synthesis of one of the leading antiretroviral drugs in the treatment of HIV, Efavirenz (Sustivat).4 More recently, a potent glucocorticoid agonist has been prepared via a TFMK intermediate.5 The objective of this Feature Article is to provide a concise account of the progress made in the preparation and use of TFMKs. In view of a previous review article in 1991 focusing on the preparation of perfluoroalkyl ketones,6 this Feature Article will briefly outline classical strategies for the preparation of TFMKs but focus primarily on developments from 1992

Michael A. Mercadante

Michael Mercadante studied chemistry at Stonehill College in Easton, Massachusetts, where he received in BS in Chemistry with a minor in Physics in 2010. He also joined the University of Connecticut in Storrs CT, where he is currently working towards his PhD under the guidance of Dr Nicholas Leadbeater. His research focuses on the development of methods to access highly attractive fluorinated motifs and novel oxidative reactions.

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Fig. 2

Fig. 1

Applications of TFMKs as synthetic intermediates.

onwards. The advantages and limitations of the newer strategies will be discussed. A brief overview of the properties of TFMKs will precede the synthetic chemistry, to give an insight into the nuances of TFMKs. Finally, the application of TFMKs will be discussed in a chemical biology context and their application in several notable targeted syntheses of medicinally-relevant compounds highlighted.

2. Properties of TFMKs 2.1.

Chemical

The electronic characteristics of the trifluoromethyl group have significant implications on the carbonyl functionality of a TFMK. Due to the enhanced positive charge on the carbonyl carbon, TFMKs are far more prone to nucleophilic attack, such as in acyl addition reactions.6 While beneficial when performing an alkylation reaction (for example using an organolithium reagent) this property leads to complications, particularly with hydration. Depending on their structure, TFMKs readily form stable hydrates (Fig. 2).6,7 In certain cases, the equilibrium will

Dr Nicholas E. Leadbeater, is currently an Associate Professor at the University of Connecticut in the USA. The overarching theme of his research group is the development of new methods for synthetic organic chemistry. The group’s current hot topics are clean, green oxidation methods, the selective incorporation of fluorine into organic molecules and the application of flow processing in synthetic chemistry. Nicholas E. Leadbeater Allied to the preparative chemistry taking place within the group, they also use in situ reaction monitoring and computational chemistry to explore the mechanisms by which chemical reactions take place. 11134

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Equilibrium between TFMKs and their corresponding hydrates.

favour the keto-form but if the ketone is close in proximity to another electron-withdrawing group (EWG), the hydrate form will predominate.8 These hydrates inherently have enhanced water solubility. A consequence of this is that, when seeking to prepare TFMKs utilizing protocols involving aqueous reaction conditions or workups, care must be taken to avoid diminished yields. Stirring with drying salts or employing molecular sieves can typically resolve issues of partial hydration but, when the hydrate form predominates, a more rigorous dehydration method (P2O5 etc.) is required.9 As a consequence of the inductive power of the CF3 group, the carbonyl oxygen of a TFMK is far less prone to activation with Lewis acids and therefore less likely to participate in Lewis acid-mediated condensation processes.6,10 However, this also implies that the polarity of a TFMK is somewhat lower than its corresponding carbon analogue. Therefore, these compounds are often more volatile, have higher Rf values, and have an enhanced solubility in nonpolar solvents relative to their methyl or ethyl congeners.1 The powerful inductive effect of the CF3 group also has a dramatic effect on substituents in close proximity to the carbonyl group. For example, in the Diels–Alder reaction of benzylideneacetone (methyl styryl ketone) and its trifluoromethyl analogue with cyclopentadiene, only the a,b-unsaturated TFMK is dienophilic enough to react productively (Scheme 1).11 Moreover, in saturated TFMKs, a-protons are much more acidic than their aliphatic analogues. For example, the pKa of acetone in water is E19 vs. 10.5 for 1,1,1-trifluoromethylacetone.12 While this does enhance enol/ enolate formation, these are less prone to react with electrophilic species because of the inductive effects of the CF3 group.6,10 2.2.

Biochemical

As already mentioned, TFMKs can have dramatic effects on biological systems. They can act as reversible competitive inhibitors of several classes of enzymes.2 Due to their ability to form covalent bonds with key residues and also to fit into the active site of enzymes as well as their predisposition to nucleophilic attack, TFMKs are highly competitive inhibitors and thus potential

Scheme 1 The Diels–Alder reaction of benzylideneacetone and its CF3 analogue with cyclopentadiene.

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Scheme 2

Fig. 3 A serine proteases interacts with a TFMK to form a stable hemiacetals, this leading to enzyme inhibition.

drug candidates. They are particularly effective at inhibiting enzymes whose purpose is the degradation of biomolecules (e.g. proteases, esterases, lipases, and deacetylases).2,13 Not surprisingly, this capability stems both from the unique chemical properties of TFMKs and the mechanism by which these enzymes operate. For example, serine proteases interact with TFMKs to form stable hemiacetals.2,6 Interactions with serine proteases exemplify the inhibitory effects that TFMKs can have. The catalytic triad responsible for amide hydrolysis (and ultimately proteolytic activity) attempts to process a given TFMK but stalls because of the diminished net negative charge on the resulting alkoxide and the lack of a suitable leaving group (Fig. 3).2,6 This results in covalent, albeit reversible, inhibition of the enzyme.2,6

3. Classical routes for preparing TFMKs There are a number of well-established routes to the synthesis of TFMK’s, four of which are summarized in Fig. 4. 3.1.

Via oxidation of a-trifluoromethyl alcohols

One of the most successful strategies used for the preparation of TFMKs is a two-step protocol exploiting late stage trifluoromethylation. An aldehyde is first trifluoromethylated using a variety of CF3 sources, the Ruppert–Prakash reagent (TMS-CF3)14

Fig. 4

Four frequently-used classical routes to TFMKs.

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Preparation of TFMKs via oxidation using Dess–Martin periodinane.

being the most convenient. With the requisite a-trifluoromethyl alcohol (trifluoromethyl carbinol) in hand, oxidation provides the TFMK. However, such an oxidation is nontrivial.6,15 The inductive effect of the CF3 group raises the activation barrier for oxidation. This can likely be explained by either the diminished nucleophilicity of the OH group or through an increase in the bond enthalpy of the a-C–H bond. Since the majority of traditional oxidation protocols rely on attack of the oxygen on an activated complex, many well-known oxidants fail to oxidise trifluoromethyl carbinols.6 Attempts to perform such oxidations using ill-suited oxidants (metal or DMSO-based) result in failure or, if successful, require a large excess of the oxidant to ensure complete conversion thereby complicating scale-up.6 The most successful oxidant for oxidising perfluoroalcohols is the powerful, but costly, Dess–Martin periodinane (DMP).16 Utilisation of DMP provides the TFMK in a short period of time and in good yield (Scheme 2). Moreover, it is compatible with a broad range of substrates. However, even utilizing this oxidant, a 3.5- or 4-fold excess is sometimes required to ensure complete oxidation of some trifluoromethyl carbinols.16 3.2.

Via electrophilic addition of trifluoroacetic anhydride

Trifluoroacetic acid (TFA) represents an inexpensive source of a trifluoromethyl group. A logical approach would be to use an electrophilic addition strategy, especially in aromatic systems. However, this is complicated by two facts. Firstly, the strongly acidic nature of TFA makes in situ activation of this species difficult. Secondly, unlike acetic acid whose corresponding acid chloride is a liquid at 25 1C, trifluoroacetyl chloride is a gas with a boiling point of 27 1C.17 This likely explains the sparse reports of the use of this acid or its acid chloride for electrophilic aromatic substitution or related reactions. However, its anhydride, trifluoroacetic anhydride (TFAA), has been used frequently to accomplish trifluoroacetylation of aromatic systems (Scheme 3).18,19 For aromatic systems, activation via a Lewis-acid catalyst is still required unless the arene is very electron rich.18 Care needs to be taken when using more electron-rich arenes as many times the electron-donating group (EDG) is itself trifluoroacetylated.20 To overcome this problem, a pyridyl alternative to TFAA, 1, has been used (Scheme 4).21

Scheme 3 An example of the use of trifluoroacetic anhydride as a trifluoroacetylating agent.

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Scheme 4

The use of 1 as a trifluoroacetylating agent.

Scheme 5 chloride.

The trifluoroacetylation of alkenes using TFAA or trifluoroacetyl

Electron-poor arenes either fail to react or require significant heating to undergo trifluoroacetylation successfully.22 Similarly, unless highly activated, Lewis-acids are required to facilitate the reaction of alkenes with TFAA. (Scheme 5).23 The notable exceptions are electron-rich alkenes namely, vinyl ethers, vinyl thioethers, and enamines.24 These compounds react rapidly with TFAA under relatively mild conditions to generate b-alkoxy-, b-alkthioxy- and b-amino-trifluoromethyl butenones, respectively (Scheme 5).24,25

3.3.

Via organometallic compounds

Trifluoroacetylation can also be accomplished by employing organometallic reagents. Typically the ethyl ester of trifluoroacetic acid (EFTA) is used as the source of the trifluoroacetyl group26 in this process but various trifluoroacetate salts27 or trifluoroacetonitrile28 can also be used. When ETFA reacts with an organometallic species, the putative tetrahedral intermediate is stabilized, thereby preventing double-addition.29 The stability of the intermediate results from inductive effects of the CF3 group either raising the activation barrier to ethyl group displacement or diminishing the net negative charge on the oxyanion.29 Therefore, unlike the reaction of its non-fluorinated analogue, the mono-addition product is obtained in good yield (Scheme 6a). N,N-dialkyl amides, such as N,N-dimethyltrifluoroacetamide (DMTA) can also be used with virtually no risk of double addition (Scheme 6b), albeit at higher overall cost ($0.25 per gram for ETFA vs. $2.60 per gram for DMTA).8,30

ChemComm While certainly more long lived than standard tetrahedral intermediates, double-addition on ETFA can occur depending both on the reaction temperature and the organometallic reagent used. If conducted at 78 1C (or even at 40 1C) only trace amounts of the double addition adduct is formed when using either PhLi or PhMgBr.29 Many other organometallic species yield similar results. However, when a significantly electron-rich organometallic compound is used, double addition can occur even at lower temperatures. One could alternatively appeal to nucleophilic trifluoromethylation to accomplish acyl substitution rather than alkylation of TFA derivatives. Unfortunately, both CF3Li and CF3MgX are unstable,31 preventing this from being a suitable strategy for TFMK construction. These organometallic trifluoromethyl species readily decompose to give difluorocarbene and/or polymeric fluorinated materials, although a recent strategy involving fluoroform deprotonation may soon make this approach a viable alternative.32 3.4. Via alkylation and decarboxylation sequences using fluorinated b-ketoesters The final general approach to TFMK preparation involves another multistep sequence. Ethyl trifluoroacetoacetate (ETFAA), the typical starting material for this process, is an inexpensive source of the trifluoroacetyl functionality ($0.64 per gram).33 Unfortunately, while cost effective, this reagent is notoriously difficult to alkylate because of the diminished nucleophilicity of the requisite enolate and O-alkylation is commonly observed.34,35 However, conditions have been developed for successful C-alkylation, albeit with only modest to fair yields.34 For success, sodium hydride is necessary as the base and alkylation only occurs when activated and/or unhindered systems (benzyl, keto, methyl, or allyl halides) are used (Scheme 7).34 Moreover, this methodology seems to only be applicable to monoalkylation. Dialkylation requires even more rigorous reaction conditions (KH, refluxing HMPA/THF)34 and yields are fair to modest at best.34 As an alternative, imines of ETFAA can also be used but at the expense of additional steps.34 Unlike alkylation, decarboxylation of the alkylated ETFAA adducts occurs quite readily under standard Krapcho-like conditions conditions (LiCl, DMF at reflux). Yields of the TFMKs obtained are good to excellent but the diversity of this method is bottlenecked by the limited scope of the alkylation step. 3.5.

Other methods

Another very useful, non-traditional approach is to exploit Wittig-like chemistry. Amides of TFA can be reacted with phosphorous ylides to give enamines, hydrolysis of which yields the corresponding TFMK.36 Of these, the morpholinederived amides prove to be optimal. The two major advantages of this method are the variety in substitution pattern possible

Scheme 6 agents.

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Examples of the use of (a) ETFA and (b) DMTA as trifluoroacetylating Scheme 7

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Use of ETFAA as a trifluoroacetylating agent.

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Scheme 8

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A Wittig-type approach to the synthesis of TFMKs.

on the ylide and, although a two-step process, fair to good yields. Alternatively, phosphorous ylides can be reacted with TFAA in a similar strategy to that outlined in Section 3.2.37 The intermediate phosphonium salt can then be hydrolysed under basic conditions to give a variety of TFMKs (Scheme 8).37

4. Recent approaches to access TFMKs 4.1.

Oxidation of trifluoromethyl carbinols

The increasing interest in TFMKs has prompted new and improved synthetic strategies for their preparation. With the ease of accessing trifluoromethyl carbinols using TMS-CF3,38 a number of protocols specifically tackling the challenge of their oxidation to TFMKs have been published in the last two decades. These protocols have greatly supplemented the traditional DMP´gue ´ and co-workers disclosed the first based method. In 2000, Be catalytic oxidation of trifluoromethyl carbinols using the Ru(II) complex RuCl2(biox)2, 2 (Scheme 9).39 Prior to this, 2 was known to oxidise olefins to epoxides in good yields,40 indicating it could serve as a potent oxidation catalyst. Initial attempts to use oxygen as the terminal oxidant met with limited success. However, using dichloromethane as the solvent, employing 2.5 mol% of 2, and pivalaldehyde as a reductant, a 30% conversion of 5-phenyl-1,1,1-trifluoropentan-2-ol to the corresponding TFMK was obtained after 48 h. No additional conversion was observed even when the reaction mixture was brought to reflux. By using 1.5 equiv. of NaIO4 as a co-oxidant, complete conversion could be obtained after 32 h at reflux using 2.5 mol% of 2 as the catalyst. Control studies ruled out NaIO4 as the oxidant itself and hence demonstrated that the use of 2 was essential. A wide array of trifluoromethyl carbinols were converted to TFMKs using this protocol. In general, aromatic alcohols oxidised much faster (7–10 h) than aliphatic alcohols (22–50 h).

Scheme 9

Oxidation of trifluoromethyl carbinols using 2 as a catalyst.

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Scheme 10 Preparation and oxidation of trifluoromethyl carbinols using supported reagents.

Good to excellent yields of the corresponding TFMKs were obtained in all cases. The protocol was compatible with a representative pyridyl trifluoromethyl carbinol substrate. A few years later in 2002, Ley and co-workers investigated whether TFMKs could be could be accessed from CF3 alcohols via oxidation with polymer-supported permanganate (Scheme 10).41 Hoping to develop a scaleable, high-throughput method that minimized purification, they elected to prepare the requisite trifluoromethyl carbinols in a similar polymer-supported fashion by treating aldehydes with TMS-CF3 in the presence of a fluorideimpregnated Amberlyst A-27 resin. The crude material could be passed over an acidic ion-exchange resin followed by an aminomethylated polystyrene resin to remove any unreacted aldehyde or impurities. The carbinols were then oxidised using Amberlyst A-27 (MnO4 form) in refluxing dichloromethane. They also added 4 Å molecular sieves to sequester water, limiting hydrate formation and accelerating the oxidation. Using these conditions, only aryl-substituted trifluoromethyl carbinols were successfully oxidised. A decreased propensity for oxidation was noted for arenes bearing electron-withdrawing substituents and hence extended reaction times or elevated temperatures were required for these substrates. However, yields were good to excellent for these oxidations and no chromatography was required for purification. These conditions could be extended to commercially-available activated MnO2, enhancing the practicality of this method. This strategy has also been employed using continuous flow processing.42 More recently in 2012, as part of a broad program to enhance the profile of oxoammonium salt-based transformations, our group became interested in the possibility of utilizing 4-NHAc-TEMPO+ BF4, 3, as an oxidant for the preparation of TFMKs from trifluoromethyl carbinols.43 Oxoammonium salts such as 3 are environmentally benign, recyclable, metal-free, and air-stable oxidants that can facilitate oxidation under mild conditions. Moreover, 3 can be produced in-house on the multimole scale cheaply and efficiently, using water as the solvent.44 Initial studies employed the standard SiO2-assisted conditions for stoichiometric oxoammonium-mediated oxidations but failed, likely due to the high activation barrier of oxidation.43 Formation of the destabilized a-CF3 carbocationic intermediate Chem. Commun., 2013, 49, 11133--11148

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Fig. 5 Rationale for why trifluoromethyl carbinols cannot be oxidised by 3 under neutral/acidic conditions.

is too energetically unfavourable and deters the requisite hydride transfer (Fig. 5). Drawing analogies to a previous report involving b-oxygen alcohols,45 we attempted the oxidation in the presence of a pyridyl base and found success. While a number of pyridyl bases promoted oxidation, 2,6-lutidine (2,6-dimethylpyridine) proved to be the optimal base when taking into account the ease of purification of the TFMK product. An array of trifluoromethyl carbinols (aryl, alkenyl, alkynyl) could be oxidised to their corresponding TFMKs in good to excellent yield under very mild conditions (Scheme 11). Unfortunately, alkyl trifluoromethyl carbinols failed to oxidise under the standard conditions. However, utilization of 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) as an alternate base led to rapid oxidation of these systems, albeit at the expense of more extensive purification and hence somewhat diminished yield. The methodology was also found to be highly chemoselective (Scheme 12). Employing 4 as a substrate, the benzyl alcohol group could be selectively oxidised over the trifluoromethyl carbinol moiety using weakly acidic conditions. The trifluoromethyl carbinol could then be oxidised using basic conditions in similarly good yield. Also in 2012, another methodology for the oxidation of trifluoromethyl carbinols was disclosed (Scheme 13).46 Konno and co-workers explored whether a catalytic amount of sodium 2-iodobenzenesulfonate with Oxones (2KHSO5KHSO4K2SO4) as the terminal oxidant could affect oxidation. Initial screening using 1 mol% of the catalyst with 0.6 equiv. of Oxones in acetonitrile at 70 1C gave only 39% oxidation of a-(trifluoromethyl)benzyl alcohol after 3 h. Increasing the catalyst and Oxones loadings (5 mol% and 0.9 equiv., respectively) as well as the reaction time (18 h) afforded complete conversion. While these conditions were applicable to

Scheme 12

Scheme 13 Oxidation of trifluoromethyl carbinols using Oxones and catalytic sodium 2-iodobenzenesulfonate.

aryl-substituted trifluoromethyl carbinols, aliphatic substrates required an alternative approach. The solvent was changed to nitromethane, the catalyst loading increased to 10 mol%, and the reaction performed at 110 1C for 24 h. The fact that more rigorous conditions are required is in line with the observation that aliphaticsubstituted trifluoromethyl carbinols are very resistant to oxidation. Finally, the authors showed that scale up to a 25 mmol did not pose any issues (safety, cost, or otherwise) and gave excellent yield. 4.2.

Scheme 11

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Oxidation of trifluoromethyl carbinols using oxoammonium salt 4.

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Chemoselective oxidation of 4.

Nucleophilic acyl substitution using TMS-CF3

The advent of TMS-CF3 as a cost-effective, user-friendly method to access anionic ‘‘CF3’’14 has lent itself to the development of methods to convert carboxylic acid derivatives directly into TFMKs. The first successful use of this strategy was reported by Prakash and co-workers in 1998 (Scheme 14).47 Treatment of methyl benzoate in toluene with TMS-CF3 using tetrabutylammonium fluoride (TBAF) as an initiator gave the corresponding TFMK in 95% yield after acid hydrolysis to cleave the intermediate silyl ether. Using these conditions, a diverse range of TFMKs were prepared. The success of this reaction was highly dependent on two factors. This journal is

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Scheme 14

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Preparation of TFMKs from methyl esters.

Firstly, the water content of the reaction mixture had to be at a minimum. Rigorous drying of both the reaction solvent and TBAF was required to avoid failure due to quenching of the trifluoromethyl anion. To overcome this, and solubility issues, a variety of other nonpolar or polar aprotic solvents (pentane, benzene and dichloromethane) were also screened. Secondly, when adding the TBAF, the temperature of the reaction had to be maintained at 78 1C to avoid decomposition of the silylated tetrahedral intermediate and premature TFMK formation which would open up the avenue for potential double-addition. A year later in 1999, Shreeve and co-workers reported alternative conditions for the direct acyl substitution of esters using TMS-CF3 (Scheme 15).48 Among other innovations, their use of CsF as a initiator provided a new avenue for TMS-CF3 activation.49 The reaction could be conducted at room temperature without need for a solvent. The use of rigorously dry conditions was no longer necessary and double-addition was not observed, despite lack of cooling. Like before, acid hydrolysis to cleave the intermediate silyl ether was required to obtain the desired TFMKs. In some cases exotherms were observed, which could limit its scalability. However, the scope of this transformation was much broader with comparable or better yields than the method outlined by Prakash and reactions times were greatly diminished. Building on this success, Shreeve and co-workers were able to extend their protocol to esters of N-protected amino acids (Scheme 16).50 Reactions were carried out in glyme, again with CsF as an initiator. The final acid-mediated silyl ether cleavage with 6 M HCl allowed for the generation of the hydrated HCl salt product. The conditions were compatible with a variety of

Scheme 15

Preparation of TFMKs from esters using CsF as an initiator.

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Scheme 16

Preparation of TFMKs from N-protected amino esters.

esters, some of which gave enantiopure materials (depending on the amino acid ester used). In 2012, we became interested in the possibility of using Weinreb amides as viable candidates for the preparation TFMKs using TMS-CF3.51 We encountered a report of a synthesis of a TFMK via nucleophilic acyl substitution of the Weinreb amide of trifluoroacetic acid with a Grignard reagent.52 To us, this indicated that in an acyl substitution reaction, the N-methoxy-Nmethylamine group will be eliminated preferentially over the CF3 moiety. Upon treatment with TMSCF3, we obtained partial conversion of Weinreb amide 5 to the corresponding TMFK, 6, using CsF or TBAF as initiators in THF. Monitoring the reaction by NMR, intermediate 7 was observed but, over time, it reverted back to 5 with the liberation of CF3H gas. By altering the solvent polarity we were able to shift the reaction pathway to favour the formation of 7 as a stable, isolable species. Optimal conditions employed toluene as the solvent, 2 equivalents TMS-CF3 and 0.2 equivalents CsF. This was followed with a cleavage step by adding a stoichiometric equivalent of a 1 M TBAF in THF solution and an equal volume of H2O to the crude material, followed by heating to 50 1C for 2 h to furnish the TFMK (Scheme 17). With this protocol optimized, a variety of substrates were screened, most affording their corresponding TFMKs in fair to excellent yield (Scheme 18). However, arenes bearing orthosubstituents to the Weinreb functionality or alkyl systems with a-branching failed to generate the silyl ether intermediate. Removal of these components or distancing the amide from the area of steric congestion reverted to normal reactivity. We suggested this disparity in reactivity arises from a significant steric reaction component, possibly from the coordination of TMS-CF3 to the oxygenated groups of the amide. Additionally, the use of a,b-unsaturated Weinreb amides was complicated by the formation of the Michael adduct of the TFMK and N,O-dimethylhydroxylamine (Scheme 19). These two species were, however, easily separable. This method represented the first

Scheme 17

Conversion of 5 into TFMK 6 and reaction intermediate 7.

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Scheme 20 Scheme 18

Scheme 19

Preparation of TFMKs from Weinreb amides.

Reaction of a,b-unsaturated Weinreb amides with TMSCF3.

documented case of TMS-CF3 reacting in a constructive manner with an amide to yield a TMFK. In addition, this reaction could be performed without risk of over-trifluoromethylation. 4.3.

Ketene-based strategies

A somewhat unusual approach to TFMKs involving ketene intermediates was first reported by Zard and co-workers in 1992 and fully elaborated in 1995.53 Realizing that TFMKs are difficult to alkylate using traditional enolate chemistry, they hoped to exploit ketenes as nucleophiles. While this is a less common strategy for a-functionalization chemistry, it was a well-precedented occurrence.54 The objective was to generate trifluoromethyl ketenes by deprotonation of an acyl chloride using a weak base. This species could then feasibly be trapped with TFAA, generating an intermediate acylium ion. To expedite this process, they judiciously elected to use pyridine as a base since it would both react with the TFAA to yield N-trifluoroacetylpyridinium trifluoroacetate which is a much more active 11140

Synthetic strategy for preparing TFMKs from ketenes.

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trifluoroacetylating reagent and also would react with the ketene to generate a more nucleophilic adduct. Trifluoroacetylation of the ketene or the ketene-pyridine adduct would yield the desired pyridinium ion. Treatment of this reactive species with water would result in rapid decarboxylation to yield the TFMK. The synthetic strategy is shown in Scheme 20. With this paradigm in mind, the Zard group developed conditions that successfully accomplished this process. Treatment of an acid chloride bearing an a-hydrogen with trifluoroacetic anhydride at room temperature in dichloromethane gave the desired intermediate which, when subjected to an aqueous workup yielded the corresponding hydrated TFMK. By using either toluene or ether as solvents as opposed to dichloromethane, the crude product yield was substantially higher (86% vs. 60%) because silica gel-based purification (which leads to TFMK hydration) could be avoided. Exploring the scope of the reaction, a range of acid chlorides were found to be compatible with the optimized conditions. However, only those chlorides possessing two a-hydrogens (‘‘primary acid chlorides’’) reacted productively, presumably for steric reasons. To further elaborate this methodology, the group found that treatment with alcohols, such as MeOH, trapped the acylated intermediate, giving b-trifluoromethylketoesters (Scheme 21). They also found that the ketene intermediates could be used to prepare a variety of heterocyclic species by trapping with olefinic nucleophiles (e.g. vinyl ethers, N,N-dimethylcyanamide, enamines etc.).55 In 2007, seeking to solve the problems encountered with sterically encumbered acid chlorides and the lack of reactivity with

Scheme 21

Preparation of b-trifluoromethylketoesters from acid chlorides.

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Scheme 22

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Preparation of TFMK 9 from carboxylic acid 8.

Scheme 24

Scheme 23

Preparation of TFMKs from carboxylic acids.

secondary acid chlorides, Reeves and co-workers at BoehringerIngelheim Pharmaceuticals initially attempted heating the reaction to drive both the trifluoroacetylation step and the decarboxylation process.56 Using 1-adamantaneacetyl chloride, 8, as a representative sterically-hindered acid chloride and performing the reaction at 40 1C for 48 h, they obtained an improved yield (31%) of the adamantyl-substituted TFMK 9 after hydrolysis (also at 40 1C) as compared to control runs using Zard’s conditions (o5%). By switching the solvent to toluene and performing the reaction at 60 1C for 2 h it was possible to obtain 9 in 80% yield (Scheme 22). Wondering whether the ketene-derived pyridinium intermediate posited by Zard could be generated from a carboxylic acid rather than an acid chloride, Reeves and co-workers subjected 1-adamantane acetic acid to the optimized conditions. They met with success and re-optimized conditions for this process to then prepare a more diverse array of TFMK ketones from these simpler, more stable starting materials (Scheme 23). Secondary carboxylic acids could also be used, albeit taking substantially longer to be converted to their corresponding TFMKs relative to their primary congeners (24–48 h vs. 6–8 h). 4.4.

Decarboxylative and related approaches

The notable ease in which ETFAA or related species can be decarboxylated to give TFMKs has drawn chemists to develop creative methods to exploit this property. In 2002, Pedro and co-workers reported an oxidative decarboxylation strategy to convert a-trifluoromethyl-a-hydroxy acids to TFMKs (Scheme 24).57 The approach first requires the reaction of a Grignard reagent (which will serve as the point of attachment of the trifluoroacetyl group) with ethyl trifluoropyruvate. This generates an a-hydroxy ester which, upon saponification, yields the requisite a-trifluoromethyla-hydroxy acid. In the presence of 10, a cobalt catalyst initially This journal is

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Preparation of TFMKs from carboxylic acids.

developed for oxidative decarboxylation,58 an oxygen atmosphere, and pivalaldehyde (likely as a co-reductant), the aryl a-trifluoromethyl-a-hydroxy acids could be readily converted to TFMKs in 4–5 h. Aliphatic a-trifluoromethyl-a-hydroxy acids required longer reaction times to react completely (>7 h) and gave diminished yields compared to their aryl-functionalized counterparts. Removal of pivalaldehyde proved problematic when attempting purification. To overcome this hurdle, the pivalaldehyde was allowed to oxidise to its corresponding carboxylic acid under the reaction conditions. An aqueous bicarbonate wash of the organic solution then allowed for removal of this byproduct. The scope of this protocol proved to be quite broad and the catalyst did not cause any appreciable oxidation of other functionalities, such as double bonds. Several years later in 2008, the Boehringer-Ingelheim team of Reeves and co-workers developed a rapid route to TFMKs from enolizable carboxylic acids.59 Inspired by a report of a onestep synthesis of aldehydes from carboxylic acids via an enediolate dianion intermediate and ethyl formate,60 they hoped to employ ETFA in a similar protocol (Scheme 25). Preparation of the enediolates was quite simple and could be accomplished by treatment of carboxylic acids with 2.2 equiv. of lithium diisopropylamide (LDA). The carboxylic acid dianion was trapped with ETFA to give an intermediate a-trifluoroacetyl carboxylate. Acidification facilitated rapid decarboxylation to give the TFMK product. Of note, is that an inverse quench (adding the enediolate to a chilled solution of ETFA) substantially improved yields and control over the reaction. As a matter of convenience and practicality, carboxylate salts could also be used thereby reducing the amount of LDA required for the reaction to 1.1 equiv. A range of both primary (unsubstituted) and secondary (mono-a-substituted) acids were explored and in general they gave fair to good yields of the corresponding TFMKs using this procedure. Very recently, in 2013, a tandem Claisen condensation–retroClaisen process for accessing TFMKs was reported (Scheme 26).61 Following the serendipitous formation of the TFMK when conducting a Claisen condensation of 1,3-diphenyl-1-propanone with ETFA and inspired by Reeves’ strategy, Qu and co-workers Chem. Commun., 2013, 49, 11133--11148

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Scheme 25

Scheme 26

Preparation of TFMKs via a Claisen–retro-Claisen process.

Other approaches

Several notable synthetic routes to TFMKs have been reported that do not fall into the categories already discussed. In 1997, a strategy to convert methyl esters into TFMKs via nucleophilic acyl substitution was reported by Mochida and co-workers (Scheme 28).62 Rather than using TMS-CF3, the same group had previously developed a system using Et3GeNa and PhSCF3 to accomplish trifluoromethylation of aldehydes to furnish trifluoromethyl carbinols.63 Wondering if this reaction could be used to access TFMKs, they exposed methyl-1-naphthoate to their optimized conditions. After obtaining the corresponding TFMK in 95% isolated yield, they moved to explore 11142

Scheme 27

Anomalies seen with acetophenone and tetralone.

Scheme 28

Preparation of TFMKs from methyl esters.

TFMKs from carboxylic acids.

sought to convert enolizable alkyl phenyl ketones to alkyl phenyl trifluoromethyl ketones. Initial screening of conditions demonstrated that the reaction was highly dependent on the base used, with strong bases producing the best results. Ultimately sodium hydride was chosen due to cost and convenience of operation. In general, aprotic solvents were better for this reaction, with THF being the ideal solvent. The reaction tolerated a wide array of functional groups (aryl, alkenyl, and heteroaryl) and allowed access to the more difficult to synthesize alkyl TFMKs. Yields of the TFMK products in most cases were quite high. Not surprisingly, nonenolizable phenyl ketones were unreactive. Interestingly, acetophenone and tetralone gave the corresponding b-keto TFMKs instead of the desired TFMK under the same reaction conditions (Scheme 27). 4.5.

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the scope, finding that a wide array of alkyl and aryl TFMKs could be prepared in excellent yield. Importantly, only methyl esters were suitable starting materials in this reaction and other more bulky esters could not be used successfully. Exploiting this fact, it was possible to trifluoromethylate methyl esters chemoselectively in the presence of sterically hindered esters (e.g. cyclohexyl, i-propyl, t-butyl) or various protecting groups without decomposition of these other functionalities. In 2001, Yamamoto and co-workers disclosed the first catalytic route to install a trifluoroacetyl group onto aryl rings using a palladium catalyst (Scheme 29).64 A previous study by the group explored the ability to cleave the CF3C(O)–OPh bond of phenyl trifluoroacetate to generate a trifluoroacetyl palladium complex.65 Using this isolable complex, they were able to convert phenylboronic acid into trifluoromethylacetophenone stoichiometrically at room temperature in 1.5 h in N-methylpyrrolidine (NMP) as the solvent. Wanting to develop a more practical, catalytic process to convert boronic acids to TFMKs, they screened a variety of conditions including palladium source, ligands, and solvents. The ideal Pd source and ligand combination was found to be Pd(OAc)2 and tributylphosphine. Highly polar solvents (DMF and NMP) gave the highest yields as compared to less polar solvents (dioxane and toluene). After establishing optimal conditions, the substrate scope was probed. Electron-rich aryl boronic acids gave, in general, good yields of their corresponding TFMKs. Electron-poor aryl boronic acids gave much lower yields. Interestingly, ortho substitution by any substituent was not tolerated under the reaction conditions, indicating that there is a significant steric component to the reaction. Heteroaryl boronic acids were also not tolerated. This journal is

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Scheme 29 Preparation of TFMKs by palladium-catalyzed reaction of phenyl trifluoroacetate with boronic acids.

Boronates, specifically those with a sodium counterion, underwent trifluoroacetylation readily. In a somewhat esoteric route to access TFMKs,66 Kim and co-workers sought to develop a route involving a free-radicalapproach akin to that they had used previously to prepare oxime ethers from alkyl iodides and phenylsulfonyl oxime ethers.67 Attempts to accomplish direct trifluoroacetylation of alkyl iodides using trifluoromethyl thiol ester in the presence of (Me3Sn)2 by photolysis at 300 nm gave only polymeric material. Turning to an indirect strategy, they first tried to prepare the trifluoromethyl sulfonyl oxime ether from an alkyl iodide, 2,2,2-trifluoro-1-(phenylsulfonyl)ethanone O-benzyl oxime, and (Me3Sn)2, again irradiating at 300 nm. Having proven successful, they then turned attention to converting this oxime to the TFMK but this proved fruitless. However, using a two-step reduction (LiAlH4)/deamination (N-bromosuccinimide/DBU) approach, they were able to readily convert the oxime into the corresponding TFMK in good yield (Scheme 30). One major limitation of this work is the use of organotin species which are known to be highly toxic although several structurally unique TFMKs could be accessed via this method. Another route to effect trifluoroacetylation was reported by Guerrero and co-workers in 2005.68 Seeking a new route to access inhibitors of insect antennal esterases, they sought to develop a practical and efficient method to make long chain saturated and unsaturated TFMKs. Wondering if Julia-like sulfones could serve as viable candidates for trifluoroacetylation, they prepared a range of aliphatic and olefinic sulfones

Scheme 30

Radical-mediated synthesis of TFMKs.

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Scheme 31

Preparation of TFMKs from sulfones.

from the corresponding bromides and sodium phenyl sulfinate. Deprotonation of these sulfones with n-BuLi at 78 1C followed by treatment with 10 equiv. ETFA gave the desired TFMK-sulfone adducts. While most substrates succeeded at this stage, allylic and propargylic substrates did not react under these or other conditions screened. To accomplish sulfone removal, either an aluminum amalgam or samarium iodide could be employed. While a three-step process from the starting bromide, yields of each of the individual reactions were generally good to excellent (Scheme 31).

5. Recent applications of TFMKs 5.1.

Overview

Trifluoromethyl ketones are versatile materials which have been used as synthons in a range of fields (Fig. 6). For example, they have been employed in the construction of various fluorinated heterocycles including pyrroles,69 furans,70 pyridines,71 and pyrazoles.72 They also find application in the synthesis of trifluoromethylbearing carbocycles73 and various-sized lactones.74 Other avenues include the preparation of chiral amines75 and carbinols76 as well as trifluoromethyl olefins.77,78

Fig. 6

Application of TFMKs in synthetic chemistry.

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5.2.

Key intermediates for medicinally-relevant molecules

TFMKs have recently appeared as critical intermediates in the syntheses of some therapeutic or potentially therapeutic molecules. Two specific examples will be discussed in detail here. 5.2.1 Efavirenz. HIV-1 (Human immunodeficiency virus type 1), a single stranded RNA retrovirus, is the causative agent of AIDS. Over the past 20 years, there has been an intense interest in the development of therapeutic compounds to combat HIV-1.4a Common targets for such compounds are reverse transcriptase and viral proteases.4a Developing nonnucleoside reverse transcriptase inhibitors (NNRTIs) provides another option. One highly successful NNRTI, Efavirenz (11), was first patented by DuPont Pharm (now Bristol-Myers-Squibb). It is marketed under the trade name Sustiva in the US and Europe.79 It has substantially improved antiviral activity and an enhanced pharmacokinetic profile compared to previous NNRTIs.4a,80

An early synthesis of 11 is outlined in Scheme 32.80 Starting from inexpensive p-chloroaniline, the system was quickly set up for directed ortho-metalation (DoM) by acetylation of the nitrogen using pivaloyl chloride yielding 12. Treatment with n-BuLi gave the desired organolithium which was reacted with ETFA at low temperature followed by acid-mediated pivaloyl deprotection to yield the aryl TFMK 13, a key intermediate for future steps.80 This preparation capitalized on the lack of double addition when using aryl organolithiums with ETFA at low temperature.29 The TFMK moiety was next alkynylated with 1-lithio-2-cyclopropylacetylene to give a racemic mixture of the resulting tertiary trifluoromethyl carbinol, 14. Treatment with 1,10 -carbonyldiimidazole (CDI) allowed for carbamate construction. To resolve the product mixture to give only the (S) enantiomer of 11, (–)-camphanoyl chloride was utilised followed by a recrystallization

Scheme 32

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Scheme 33

Enantioselective synthesis of acetylide 17.

and deprotection. The TFMK intermediate was critical in this synthesis both as an electrophilic centre and as a trifluoromethyl source.80 Rather than resolving a racemic mixture, a collaborative team of chemists from DuPont Pharma and Merck sought to perform the alkynylation of the TFMK in an enantioselective manner (Scheme 33).4a To accomplish this, the researchers drew on reports that, by using (1R,2S)-N-pyrrolidinylnorephedrine (15) as a ligand, asymmetric alkylations were possible using organolithiums.4a In a preceding report they focused both on ligand loading and the influence of the requisite protecting group on the nitrogen of 13. Ultimately, it was found that the combination of p-methoxybenzylation of the nitrogen, conducting the reaction below 50 1C, and utilization of 2 equivalents each of 15 and lithium acetylide maximized enantioselectivity and conversion to 17.81 Also, the ligand–acetylide mixture is best generated between 25 to 0 1C in order to establish aggregate equilibration of aggregate 16 prior to reaction with the TFMK.4a Carbamate construction and deprotection afforded Efavirenz.4a In 2009, Nicolaou and co-workers developed another approach to the preparation of 11 (Scheme 34).4b Rather than undertake an alkynylation of the aryl TFMK 13 with a lithium acetylide, they sought to perform the alkylation of an alkynyl TFMK, 18.4b Boc protection of the nitrogen of p-chloroaniline again enabled DoM. The lithiated arene could then be reacted with 18, which could be readily prepared by treatment of ETFA

Early synthesis of 11.

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Scheme 36

Scheme 34

Alternative synthesis of 11.

Preparation of TFMK 23.

In 2013, chemists at Boehringer-Ingelheim reported a scaleable route to access BI 653048 BS H3PO4 (19), a candidate for the treatment of rheumatoid arthritis.5 Current treatments such as Prednisolone and Dexamethasone, while effective, can cause undesirable side effects due to nonspecific activation of the glucocorticoid receptor.5 The medicinal chemistry route to 19 was deemed problematic for scale up since it was far too lengthy with low overall yield (17 steps, 0.07% overall yield).5 Notable features in this route, however, include the installation of the TFMK using the TFAA route56 (see Section 4.3) and the subsequent diastereoselective addition of a lithiated chiral sulfoxide to this TFMK (Scheme 35). Design of a more efficient and scalable route incorporating these concepts was therefore attempted. Fortuitously for this Feature Article, many of the problems encountered by the chemists during this process illustrate the complexity of working with TFMKs. The first challenge to the development of a scaleable route to 19 was the preparation of TFMK 23.5 A simple a,b-unsaturated TFMK precursor material could be accessed from commercially

available 2-methyl-1-propenylmagnesium bromide and the Weinreb amide of trifluoroacetic acid.5 While successful, this amide was deemed to be a high-energy compound and thus unsuitable for scale-up.5 Using the corresponding morpholine amide (20) the same yield and purity could be attained as with the Weinreb amide. Not surprisingly, isolation of the enone product was complicated by its low boiling point and appreciable solubility in water. A special isolation protocol involving distillation from dodecane was employed and allowed for the successful preparation of 10 kg of TFMK 21. Conjugate addition of a Grignard reagent derived from commercially available 2-bromo-4-fluoro-1-iodobenzene, 22, proceeded quite readily allowing access to pure 23 on the kilo scale after vacuum distillation (Scheme 36).5 A subsequent synthetic step towards 19 involved an aminocarbonylation and this ultimately required protection of the TFMK due its incompatibility with the reaction conditions. Initially, the chemists turned to protecting it as its dioxolane. However, deprotection of the TFMK after successful aminocarbonylation was found to be very difficult and, when successful, undesired dimethylation the aryl methoxy group occurred. To resolve this, a very unusual protecting group strategy was adopted (Scheme 37). By capitalizing on the acidity of the a-hydrogen atoms of TFMKs, and poor nucleophilicity of their deprotonated form, 23 could be ‘‘protected’’ as its sodium enolate through deprotonation using NaH.5 Subsequent bromine–metal exchange and isocyanate quench gave 24, the desired

Scheme 35

Scheme 37

with lithio-5-chloropropyl acetylide. With the success of this strategy (following subsequent cyclopropanation and carbamate formation), the group transitioned this approach to a one pot protocol for the synthesis of 11.4b 5.3.

Glucocorticoid agonist BI 653048

Key steps from the medicinal chemistry route to 19.

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Production of 24 by ‘‘protecting’’ 23 as its sodium enolate.

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Feature Article product needed for the subsequent chiral propargylation step without any formal deprotection step. Later it was found that addition of sub-stoichiometric amounts of water greatly accelerated enolization, which became a necessary additive upon scale-up.5 Even after screening many conditions for a subsequent propargylation step, a better than a 1 : 1 diastereomeric ratio could not be obtained.5 Ultimately it was decided that resolution of this mixture by recrystallization was acceptable, giving 99 : 1 dr of intermediate 25, albeit at 33% yield.5 This material was carried through several more steps (totaling seven) to give 19 in 6.8% overall yield.5

In order to scale-up this route to 19 further, several steps still required adjustment; namely the preparation of the TFMK intermediate 23 and its carboxylic acid precursor as well as the subsequent amidation to yield 24 (Scheme 38). Distillation on large scale is undesirable and hence an alternative route to 23 was pursued. The chemists opted to perform the conjugate addition of 22 to isopropylene Meldrum’s acid, 26, which, upon heating, decomposed to the corresponding carboxylic acid 27.5 Using their previously developed methodology for converting carboxylic acids to TFMKs,56 23 was prepared. Next, while the enolate protection strategy was retained, amide construction via an isocyanate intermediate was deemed impractical. Amide installation to prepare 24 was instead accomplished by treatment of 23 with CO2 followed by acid chloride formation and subsequent acylation of the chiral benzyl amine 29. Of note is that intermediate TFMK 28 underwent reversible lactol formation (64 : 36 mixture of 28 to lactol) which likely stems from the combined conformational rigidity evoked by the gem-dimethyl moiety and the electrophilic nature of TFMKs. The final challenge relating to the TFMK was to revisit the synthesis of 25 in a diastereoselective manner from 24. By using

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Scheme 39

Diastereoselective propargylation of 24 to yield 25.

a propargyl borolane, diethyl zinc, and N-isopropyl-L-proline as a ligand, the dr of the propargylation reaction was improved substantially from 1 : 1 to 4 : 1 (Scheme 39).5 A further exploration of this reaction was released concurrently with disclosure of the route to 19.82 The enriched material was carried on through several more steps (totaling eight) to again give 19 in significantly improved overall yield (17.6%).5

6. Summary This Feature Article has highlighted the significant advances in the preparation of TFMKs by an array of research groups over the past 21 years. While the classical methods discussed in the beginning are the typical ‘‘go-to’’ approaches for TFMK preparation, the new developments, particularly those employing TFAA or TMS-CF3, are gaining significant popularity because of their operational simplicity. In addition, many of the classical approaches have been greatly expanded by more recent modifications. This is particularly the case for the oxidation of trifluoromethyl carbinols where new routes have enhanced the practicality, scope, and scalability of the reaction. An underlying theme of this Article is to demonstrate that, despite being a structurally simple moiety, the peculiar properties of TFMKs often complicate preparation. As such, a diverse portfolio of methods is thereby necessary for the synthetic organic chemist seeking to prepare them in the event that the first selected synthetic route fails. The developments discussed here have certainly bolstered this portfolio. With TFMKs being important compounds themselves as well as serving as key intermediates to medicinally-relevant compounds, demand for new routes for their preparation will likely precipitate further innovation. Future work by our laboratory and others will endeavour to meet this demand.

Acknowledgements Our work in organofluorine chemistry has been funded by National Science Foundation (CAREER award CHE-0847262) and the University of Connecticut.

Notes and references

Scheme 38

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Scalable route to 24.

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This journal is

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A Convergent Radical Based Route to Trifluoromethyl Ketones and to α,β-Unsaturated Trifluoromethyl Ketones.

NHCs catalyzed hydrophosphonylation of α-ketoesters and α-trifluoromethyl ketones.

Characterization of neuropathy target esterase using trifluoromethyl ketones.

Poly(trifluoromethyl)azulenes: structures and acceptor properties.

cyclization of propargylic alcohols with trifluoromethyl ketones.

Synthesis and evaluation of phenylalanine-derived trifluoromethyl ketones for peptide-based oxidation catalysis.

Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to α,β-unsaturated trifluoromethyl ketones.

Simple access to β-trifluoromethyl-substituted ketones via copper-catalyzed ring-opening trifluoromethylation of substituted cyclopropanols.

copper system.

Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones.

A new preparation of acetylenic ketones and application to the synthesis of exo-brevicomin, the pheromone from Dendroctonus brevicomis.

Anodic Cu₂S and CuS nanorod and nanowall arrays: preparation, properties and application in CO₂ photoreduction.

Application of the Wittig-Horner reaction to steroid ketones.

Influence of ketones on selected mechanical properties of resin composites.

Rapid access to β-trifluoromethyl-substituted ketones: harnessing inductive effects in Wacker-type oxidations of internal alkenes.

Synthesis of α-trifluoromethyl ketones via the Cu-catalyzed trifluoromethylation of silyl enol ethers using an electrophilic trifluoromethylating agent.

Anticonvulsant properties of some Mannich bases of conjugated arylidene ketones.

Preparation of unsymmetrical ketones from tosylhydrazones and aromatic aldehydes via formyl C-H bond insertion.

Nickel-Catalyzed Synthesis of Ketones from Alkyl Halides and Acid Chlorides: Preparation of Ethyl 4-Oxododecanoate.

Preparation and properties of bilirubin photoisomers.

Preparation of hydroxypropyl agars and their properties.

Preparation and Electrical Properties of La0.9Sr0.1TiO3+δ.

Preparation and properties of fluorescein-labelled hyaluronate.

The preparation and properties of bromoacetylphosphonic acid.