Jun-An Ma

Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group from Prochiral Trifluoromethylated Substrates

Department of Chemistry, Tianjin University, Tianjin 300072, China; Department of Applied Chemistry, China Agricultural University, Beijing 100193, China; UMR 6014 CNRS, Laboratoire COBRA de l’IRCOF, Université et INSA de Rouen, Rue Tesniere, F-76130 Mont Saint Aignan, France; and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China

Silver-Mediated Cycloaddition of Alkynes with CF3CHN2: Highly Regioselective Synthesis of 3-Trifluoromethylpyrazoles†

immense usefulness of 3-trifluoromethylpyrazole derivatives, efficient construction of the 3-trifluoromethylpyrazole framework has become the subject of intensive research in the fields of synthetic and medicinal chemistry. Generally, 3-trifluoromethylpyrazoles can be accessed by cyclocondensations of an appropriate hydrazine with the corresponding 1,3-dicarbonyl compounds. However, these methods often suffer from the formation of regioisomeric mixtures with respect to substituents incorporated at the 3and 5-positions of the pyrazole ring. Recently, 2,2,2-trifluorodiazoethane has emerged as an attractive synthon in transition-metal-catalyzed/mediated and organocatalytic reactions for the construction of fluorinecontaining building blocks. In this regard, Morandi, Carreira, and co-workers disclosed a rhodium-catalyzed cyclopropenation of alkynes with CF3CHN2 generated in situ from CF3CH2NH2·HCl in aqueous media, [6b] and we developed the copper(I)-catalyzed cross-coupling of terminal alkynes and gaseous CF3CHN2, thus leading to the formation of C H insertion products (Scheme 1, top). These reactions

Hydrogen‐Bond‐Directed Enantioselective Decarboxylative Mannich Reaction of β‐Ketoacids with Ketimines: Application to the Synthesis of Anti‐HIV Drug DPC 083

The decarboxylative Mannich reaction (DMR) of b-ketoacids with imines has emerged as a very important tool for the synthesis of natural products and biologically active compounds. The elegant work of Robinson on the total synthesis of ( )-tropinone represents the first practical example of utilizing the DMR as a key step in organic synthesis. Herbert and co-workers and Mangla and Bhakuni then developed a similar decarboxylative Mannich condensations of b-ketoacids with D-pyrroline and D-piperideine for the synthesis of biologically relevant alkaloids, such as septicine, phenanthroindolizidines, and cryptopleurine. Despite these notable achievements, little progress has been made in the development of an asymmetric version for this important reaction. Recently, the group of Tian developed a chiralauxiliary-based method in which b-ketoacids undergo highly diastereoselective decarboxylative Mannich transformation with optically active 2-(tert-butanesulfinyl-imino)glyoxylates, and Lu and co-workers described a catalytic asymmetric DMR of b-ketoacids with aldimines to afford b-amino ketones with a maximum of ee value of 83%. However, all such studies have focused on the aldimine-based electrophiles. In contrast, the use of ketimines as the electrophilic acceptors for the decarboxylative Mannich reactions of bketoacids still remains a formidable challenge and there has been no report in the literature, to date, of such a potentially useful transformation. The obvious benefits that hydrogen-bonding catalysis can offer in asymmetric synthesis have been recognized in recent years. A unique characteristic of hydrogen-bonding catalysis is that the catalyst not only activates the reaction partners through hydrogen-bond interactions, but also positions them in close proximity with the desired relative geometry, and as such, the reaction is often facilitated in a synergistic manner, a manner similar to that of enzymatic catalysis. Herein, we report the results of our efforts in developing a hydrogenbond-directed enantioselective decarboxylative Mannich reaction of b-ketoacids by employing cyclic N-acyl ketimines as the electrophilic acceptor (Figure 1). This new reaction was cooperatively promoted by saccharide-based bifunctional organocatalysts. The catalysts contain a tertiary amine and thiourea moieties which simultaneously activate the substrates and are responsible for excellent overall stereochemical control. The potential application of this catalytic asymmetric decarboxylative Mannich reaction was further exemplified in a highly enantioselective synthesis of the antiHIV drug DPC 083.

Chiral bifunctional thiourea-catalyzed enantioselective Michael addition of ketones to nitrodienes.

Simple bifunctional thioureas, derived from the commercially available saccharides and chiral diamines, have been shown tunably to promote Michael-type addition of ketones to alpha,beta-gamma,delta-nitrodienes. The Michael adducts were obtained in good yields albeit with high enantioselectivites (84-99% ee). Furthermore, these products can be readily transformed into more useful molecules.

Enantioselective Base‐Free Electrophilic Amination of Benzofuran‐2(3H)‐ones: Catalysis by Binol‐Derived P‐Spiro Quaternary Phosphonium Salts

However, enantioselective synthesis of such significant chiral benzofuran-2(3H)-ones remains a considerable challenge. Catalytic enantioselective introduction of substituents at the C3 position represents the most direct approach to chiral benzofuranones. For instance, Vedejs et al. and Hill and Fu have presented the asymmetric Black rearrangement of Oacylated benzofuranones by means of chiral derivatives of 4dimethylaminopyridine (DMAP) to afford enantioenriched C-acylated isomers with up to 98 % enantiomeric excess. Very recently, two other groups reported the enantioselective conjugate addition reactions of benzofuran-2(3H)-ones to a,b-unsaturated carbonyl compounds, in which chiral thioureas and amines were used as catalysts. Enantioselective introduction of a heteroatom group at the C3 position would substantially broaden the benzofuranone chemistry and offer more functionalized chiral products. Herein, we present a hitherto unknown catalytic enantioselective amination of benzofuranones by employing a new class of rigid chiral Pspiro quaternary phosphonium salts as organocatalysts. Over the past decades, organocatalysis that exploits the use of chiral quaternary ammonium salts has emerged as an area of intense interest in asymmetric synthesis owing to its operational simplicity and mild reaction conditions. 8] A number of quaternary ammonium salt catalysts have demonstrated useful levels of enantioselectivity in a wide range of asymmetric reactions. Furthermore, a recent breakthrough in this field involved the design and application of chiral quaternary phosphonium salts in catalytic asymmetric synthesis. For examples, the group of Ooi developed a series of P-spiro tetraaminophosphonium salts as chiral Brønsted acids for substrate recognition and functional-group activation through hydrogen bonding. Maruoka and co-workers reported other chiral quaternary tetraalkylphosphonium salts and their use in asymmetric phase-transfer catalysis. Despite the above mentioned progress, this field is still in its infancy and the construction of new phosphonium catalysts is still in great demand to meet the need of many challenging asymmetric reactions. Since 1,1’-binaphthyl-based enantiopure chiral materials are among the most readily available privileged sources of chirality, chemical modification of binaphthyls resulting in the formation of new modular structures for catalytic application has been a proven strategy for the development of novel chiral catalysts. We envisioned that the introduction of two chiral 2,2’-bis(methylene)-1,1’-binaphthyl moieties onto a phosphorus center would form a rigid P-spiro tetraalkylphosphonium framework, thus enabling a high level of asymmetric induction. A series of novel homochiral tetraalkylphosphonium bromides 1 possessing a [7.7] spirocyclic core were readily prepared by the reaction of (S)-4,5-dihydro-3Hdinaphtho[2,1-c :1’,2’-e]phosphepine with (S)-3,3’-disubstituted 2,2’-bis(bromomethyl)-1,1’-binaphthyls and purified in analytically pure form after one simple recrystallization. Crystals suitable for X-ray diffraction analysis were obtained for the quaternary phosphonium salt 1a. The ORTEP view of this structure is shown in Figure 2. As expected, the two binaphthylmethylene units are twisted at the phosphorus center. The dihedral angle between the planes of the two naphthyl units is 69.18. It was expected that the conformational rigidity imposed by the P-spiro scaffold could potenFigure 1. Examples of chiral benzofuran-2(3H)-ones.

A Facile Parallel Synthesis of Trifluoroethyl-Substituted Alkynes†

The physicochemical and biological properties of an organic compound are profoundly modified by the presence of fluorine functional groups, which alter the steric, electronic, lipophilic, and metabolic characteristics of the compound. The incorporation of fluorinated moieties into organic molecules has captured the attention of synthetic chemists over the past decades. As a reactive intermediate, 2,2,2trifluorodiazoethane is an attractive C2 synthon for the construction of fluorine-containing building blocks. The earlier studies involving this reagent primarily focused on noncatalytic reactions. These methods usually suffer from relatively harsh reaction conditions and limited substrate scope. To overcome these problems, recent research has paid more attention to metal-catalyzed transformations of 2,2,2trifluorodiazoethane. For instance, the Simonneaux and Komarov groups reported metal-catalyzed cyclopropanation reactions of gaseous F3CCHN2 with various olefins. [3] Carreira and co-workers demonstrated the catalytic generation of 2,2,2-trifluorodiazoethane in situ from CF3CH2NH2·HCl. [4] Several metal catalysts have been found to be compatible with the diazotization reaction, allowing a tandem transformation to take place in aqueous media. However, the generation of Csp3 CH2CF3 or Csp2 CH2CF3 bonds has been the focus of nearly all such studies. In sharp contrast, the formation of Csp CH2CF3 bonds through simple trifluoroethylation of terminal alkynes has not been reported to date, and still remains an interesting challenge. A survey of the literature reveals that the use and preparation of trifluoroethyl-substituted alkynes is extremely rare, which likely correlates with the absence of practical general methods for their synthesis. Only one recent report by Shibata and co-workers has addressed the trifluoromethylation of 3-(4’-nitrophenyl)propargyl bromide with [CuCF3] species, which were generated in situ from an electrophilic trifluoromethylating reagent and a stoichiometric amount of copper, but the desired product was obtained in only 36% yield (Scheme 1a). Herein, we report our efforts in developing a direct catalytic trifluoroethylation of terminal alkynes by using 2,2,2-trifluorodiazoethane (Scheme 1 b). This crosscoupling reaction can be conducted under mild conditions without the need for additional base or ligands. Furthermore, the ease of preparation and workup allows for the quick and efficient parallel synthesis of a broad variety of trifluoroethylated alkynes. These products, which bear a CH2CF3 group in the propargyl position, are versatile precursors for the synthesis of other types of fluorinated molecules. Additionally, both experimental and theoretical analyses indicate that this trifluoroethylation could proceed by a concerted Csp H insertion process. In general, reactions of terminal alkynes with diazo compounds lead to cyclopropenation or Csp H insertion. The reaction course strongly depends on the nature of the metal and the catalyst structure. For example, the groups of P rez and Doyle described cyclopropenation reactions of alkynes with diazoesters catalyzed by Cu or Rh complexes, whereas the groups of Fu, Fox, and Wang reported the cross-coupling of alkynes with diazo compounds catalyzed by Cu or Pd to afford the corresponding products. Very recently, Morandi and Carreira disclosed a rhodium-catalyzed cyclopropenation of alkynes by CF3CHN2 generated in situ from CF3CH2NH2·HCl in aqueous media. [4b] Based on these important precedents, we examined the ability of various Cu and Cu salts to catalyze the trifluoroethylation of phenylacetylene 1a using gaseous CF3CHN2. A preliminary result was obtained using CuI as a catalyst under mild conditions to provide the corresponding trifluoroethylated product 2 a in 63% yield without the use of extra base or ligands. However, a disadvantage of this method is that it requires the use of a large excess of CF3CH2NH2·HCl (5–8 equiv). In order to use gaseous CF3CHN2 more efficiently, we needed to set up a recycling system. After the reactor, a storage balloon was placed to trap and reuse the escaping gaseous CF3CHN2. Gratifyingly, examination of the same test reaction with the recycling system in place revealed that the yield can be significantly improved to 85 % and that the amount of CF3CH2NH2·HCl can be lowered to three equivalents. Furthermore, a multireactor setup has been designed to provide an integrated system for simultaneously running Scheme 1. Synthesis of trifluoroethyl-substituted alkynes. NMP = N-methyl-2-pyrrolidone, OTf = trifluoromethanesulfonate.

Catalytic Enantioselective Alkynylation of Trifluoromethyl Ketones: Pronounced Metal Fluoride Effects and Implications of Zinc-to-Titanium Transmetallation†

Propargylic alcohols are valuable intermediates in organic synthesis and pharmaceutical science. Metal-catalyzed direct asymmetric addition of alkyne nucleophiles to aldehydes and prochiral ketones represents the most convergent and efficient approach to the synthesis of optically active propargylic alcohols. The asymmetric titanium-catalyzed zinc alkynylide addition to carbonyl substrates has been extensively studied in the past decade, and numerous chiral ligands have been developed to give the desired propargylic alcohols in excellent enantioselectivity. In spite of the importance of this practical transformation, some challenging problems remain unsolved. These problems include the stereochemical control for reactions involving challenging substrates as well as the mechanism of the putative zinc-totitanium transmetallation, a key process in this type of asymmetric addition that has been reasonably implicated but remains largely unproven. Trifluoromethyl ketones are a class of particularly challenging substrates for this asymmetric transformation because of the presence of the strongly electron-withdrawing fluorine atoms. The activating trifluoromethyl group renders the ketone functionality highly reactive and has a detrimental effect on the control of facial selectivity. Although the asymmetric additions of alkyne nucleophiles to trifluoromethyl ketones have been well studied using stoichiometric chiral-auxiliary-based methods to control the absolute configuration, to the best of our knowledge, there are no effective methods for catalyzing the asymmetric addition of alkynes to trifluoromethyl ketones. 7] We report herein a catalytic enantioselective addition of zinc alkynylides to various trifluoromethyl ketones with selectivities that surpass 94% ee. We demonstrate that with the application of pseudoenantiomeric cinchona alkaloids as chiral ligands, the synthesis of both enantiomers of the trifluoromethylated products is possible. Additionally, we provide the first experimental and computational evidence that the alkynyl group is bound to the titanium catalyst through transmetallation, and the organotitanium complex is responsible for the addition to trifluoromethyl ketones. In an initial investigation, we conducted the reaction of the alkynylzinc, which was generated in situ from alkyne 4a (see Table 1 for structure) and Et2Zn, with 2,2,2-trifluoroacetophenone 3a by employing (S)-3,3’-disubstituted binol (binol = 1,1 -bi-2-naphthol) ligands and (S,S)-taddol (taddol = tetraaryl-1,3-dioxolane-4,5-dimethanol) ligands to afford the desired adduct 5a in quantitative yields and poor enantioselectivities (< 20% ee). Next, a large number of chiral amino alcohol ligands, which included DAIB [(2S)-( )3-exo-(dimethylamino)isoborneol], salen (N,N -bis(salicylidene)ethylenediamine), cinchona alkaloids, ephedrine, prolinol, and some of their derivatives, were screened for the Ti(OR)4-catalyzed alkynylation of 3a. It was found that the pseudoenantiomeric cinchona alkaloids 1b and 2b were the most promising ligands for the test reaction (Table 1, entries 1–6), whereas all the other chiral ligands tested resulted in poor yields or enantioselectivities (not listed in Table 1). Interestingly, the introduction of CaH2 as a base was found to significantly increase the conversion and selectivity for the reaction catalyzed by quinine 1b (entry 7). The replacement of diethylzinc with dimethylzinc further improved the result (81 % yield and 80% ee ; entry 8). By using the same reaction conditions as used in entry 8, chiral alkaloid ligands such as DHQD (1c), CPN (1d), and BnOPN (1e) showed lower conversion and diminished enantioselectivity (entries 9–11). The superior level of asymmetric induction and reaction efficiency exhibited by the Ti(OiPr)4/ cinchona alkaloid catalyst upon addition of CaH2 prompted us to examine the effect of various other additives. In view of the similarity in the nature of the hydride and the fluoride anions, we expected that the use of a fluoride salt could have a comparable effect on the selectivity. Therefore a number of metal fluorides were subsequently examined (entries 12–17). Pleasingly, the use of BaF2 led to a 90% yield of the isolated adduct (R)-5 a with 87% ee. This beneficial effect was found to be sensitive to the metal center because metal ions of different sizes and Lewis acidity relative to barium imparted a deleterious impact on the enantioselectivity. Other barium salts including BaCl2 and BaBr2 were found to exhibit low levels of conversion and selectivity (entries 18 and 19). The pronounced rate and selectivity enhancement obtained when using BaF2 probably stems from the good p-donating properties of fluoride, which could coordinate to titanium(IV) to [*] G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang, Prof. J.-A. Ma Department of Chemistry, Tianjin University Tianjin 300072 (China) Fax: (+ 86)22-2740-3475 E-mail: majun_an68@tju.edu.cn

Regioselective Cycloaddition of Trifluorodiazoethane with Electron-Deficient Allenic Esters and Ketones: Access to CF3-Substituted Pyrazolines and Pyrazoles

A highly regioselective cycloaddition procedure of electron-deficient allenes with trifluorodiazoethane (CF3CHN2) is described. In absence of bases, the reaction proceeded smoothly to give 5-(trifluoromethyl)pyrazolines, whereas the utility of Et3N led to the formation of 3-(trifluoromethyl)pyrazoles.

Cyclic aldimines as superior electrophiles for Cu-catalyzed decarboxylative Mannich reaction of β-ketoacids with a broad scope and high enantioselectivity.

A novel Cu-catalyzed enantioselective decarboxylative Mannich reaction of cyclic aldimines with β-ketoacids is described. The cyclic structure of these aldimines, in which the C═N bond is constrained in the Z geometry, appears to be important, allowing Mannich condensation to proceed in high yields with excellent enantioselectivities. A chiral chroman-4-amine was synthesized from the decarboxylative Mannich product in several steps without loss of enantioselectivity.

Reversal of Enantioselectivity by Tuning the Conformational Flexibility of Phase‐Transfer Catalysts

Catalytic asymmetric synthesis provides one of the most powerful and economical approaches for the preparation of a variety of enantiomerically enriched compounds that are critical to developments in medicine, biology, and materials science. In this scenario, the development of environmentally friendly, highly efficient, and selective chiral catalysts is important. Therefore, one crucial objective is the design and synthesis of new chiral catalysts, which enable challenging and/or previously unknown asymmetric transformations to occur in a highly efficient way. The requirement of maximum conformational rigidity is central to the design of a chiral catalyst. The rigid structure of the catalyst would enhance the enantiofacial differentiation by minimizing the possibilities of different conformers available to the coupling partners, and thus, deliver the maximum asymmetric induction from the chiral catalyst. These semiempirical criteria have been applied to the creation of thousands of chiral catalysts in accord with the increasing need for enantiopure medicinal agents and the rapid advancement of the field of asymmetric synthesis. Furthermore, most efficient catalysts with rigid structures, such as cinchona alkaloids, salen complexes, and binol (1,1’-bi-2-naphthol) derivatives, have demonstrated useful levels of enantioselectivity for a wide range of different asymmetric reactions. On the other hand, the conformational flexibility is another fundamental characteristic of a chiral catalyst. Keeping the conformational flexibility at an optimal level is also essential to the catalyst reactivity and stereoselectivity. However, the effect of an appropriate balance between the conformational rigidity and flexibility in asymmetric catalysis has largely been ignored. Herein we report the development of new chiral quaternary ammonium salts as phase-transfer catalysts (PTC) based on the concept of a linker-dictated structure that tunes rigidity and flexibility. This strategy led to the discovery of two catalysts that give access to both enantiomeric products of a catalyzed addition reaction from a common chirality source. In recent years, chiral phase-transfer catalysis has emerged as an area of intense interest in asymmetric synthesis owing to its operational simplicity and mild reaction conditions. Although impressive new advances have been made, there appears a growing number of challenging substrates and difficult transformations that cannot be promoted by existing phase-transfer catalysts. One such instance involves the conjugate addition of nitroalkanes to enones to give products that are useful and versatile precursors for a variety of structures such as aminocarbonyl compounds, aminoalkanes, and pyrrolidines. Although the reactions can be successfully carried out with simple, unhindered linear nitroalkanes in high enantioselectivity, utilization of sterically more demanding nitroalkanes for the reaction of bulky b-aryl-substituted enones such as the chalcones can be less rewarding. Variable levels of asymmetric induction with unpredictable stereoselectivity were obtained when cinchona-alkaloid-derived quaternary ammonium salt 3 and the sugar-based azacrown ether 4 were used as chiral catalysts (Scheme 1). The structurally rigid and highly reactive chiral phase-transfer catalysts based on the binaphthyl scaffold, such as the N-spiroammonium salts 5 and 6, which were recently developed by Maruoka et al., and the analogous phosphonium salt 7, gave poor performance for the addition of 2-nitropropane to chalcone. The reactions were plagued with extremely low yield and disappointing ee values (< 10%) as indicated by the results shown in Scheme 1. We surmised that dual activation of both the nucleophile and the electrophile is necessary for this particularly challenging reaction. As depicted in Scheme 2, the modular dimeric structure 8 was anticipated to provide a potential entry into a chiral catalyst to fulfill such a goal. It is further expected that the key to creating a positive synergy between the two chiral fragments is the choice of a flexible linker. The linker we have chosen to explore can provide us with the following opportunities for the fine-tuning of the reactivity and stereoselectivity of the catalysts: 1) to regulate the distance between the quaternary ammonium centers by varying the chain length, so that the reactants can be synergistically stabilized and/or activated; 2) to maintain an optimal relative orientation of the two chiral binaphthyl moieties, by virtue of the flexibility of the -(CH2)nchain through C C bond rotation, to achieve a high level of enantioselectivity. The latter requires the nitronate nucleophile to be delivered to either the Re or the Si face of the enone. The use of the piperidine rings for the construction of the dimeric structure was based on the anticipation that the resulting N-spiroammonium centers, which bear the binaphthyl chiral elements, help preserve the rigidity of the [*] M.-Q. Hua, H.-F. Cui, L. Wang, J. Nie, Prof. J.-A. Ma Department of Chemistry, Tianjin University Tianjin 300072 (China) Fax: (+ 86)22-2740-3475 E-mail: majun_an68@tju.edu.cn