Recent Developments (Review)

Journal of the University ofV. Dimitrov,Chemical M.Technology Kamenova-Nacheva and Metallurgy, 44, 4, 2009, 317-332

ENANTIOSELECTIVE ORGANOZINC-CATALYZED ADDITIONS TO CARBONYL COMPOUNDS – RECENT DEVELOPMENTS (REVIEW)

V. Dimitrov, M. Kamenova-Nacheva

(In memoriam Prof. D. Sc. Yuri Stefanovski)

Institute of Organic Chemistry Received 05 October 2009 with Centre of Phytochemistry Accepted 12 November 2009 Bulgarian Academy of Sciences Acad. G. Bonchev str. Bl. 9, 1113 Sofia, Bulgaria

ABSTRACT

The realization of enantioselective C-C-bond forming reactions is of immense importance in the modern organic synthesis. The global needs of pharmaceutical industry and the fast development of new technologies within the materials science are leading to a constant demand of enantiomerically pure compounds. Therefore the creation of enantioselective variants of well known or state-of-the-art chemical transformations is of permanent interest. In recent years, one of the most studied transformations in organic synthesis was the nucleophilic addition of dialkylzinc compounds to aldehydes, promoted by chiral aminoalcohols used as precatalysts. Impressive progress has been made in the design and synthesis of highly efficient aminoalcohols applied as ligands in metal-mediated asymmetric catalysis, and in understanding of mecha- nisms, and in particularly of the origin of enantioselection. The current report aims to present a short overview of the most important achievements and recent progress in this field. Keywords: asymmetric catalysis, enantioselective addition to aldehydes, organo-Zn-mediated catalysis.

INTRODUCTION existing drugs are compounds having at least one stereogenic centre. In nine of the top 10 drugs, the APIs In the recent decades one of the most important are chiral. The global sales of single enantiomer com- objectives of the synthetic organic chemistry is to modify pounds were expected by the end of 2004 to reach $8.57 the known chemical transformations of prostereogenic billion and $14.94 billion by the end of 2009 (annual starting compounds in asymmetric manner leading to growth of 11.4%). A survey by Frost & Sulivan [1] esti- enantiomerically pure (or at least enriched) products. mates a significant growth (Fig. 1) of the chemocatalytic Significant driving force for substantial achievements and biocatalytic methods for production of chiral prod- in the field of asymmetric synthesis is the pharmaceuti- ucts with lowering of the market importance of the tra- cal industry and the guidelines of the United States Food ditional technologies (utilization of substances from the and Drug Administration (FDA), and similar regulat- chiral pool and application of separation methods). ing agencies concerning the enantiomeric purity of ac- The trends in recent years are in directing the ef- tive pharmaceutical ingredients (APIs) possessing forts mainly in development of catalytic enantioselective chirality elements. At present more than 40% of the processes using both metal-mediated catalysis and

317 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009

cal interest because of their utility as key intermediates for pharmaceutical products [7]. Over the past 20 years, a large number of chiral aminoalcohols have been synthesized and tested as catalysts [8, 9]. The initial opinion that only β-aminoalcohols are able to provide a high degree of enantioselectivity Fig. 1. The worldwide production of chiral products in has been changed recently by demonstration of highly respect of the technology uses. efficient γ- and δ-aminoalcohols as catalysts [10]. In recent years the planar chirality of 1,2-disubstituted fer- organocatalysis. In both cases the application of a suit- rocenes attracted significant interest in chiral catalysis able chiral compound is decisively important and sig- leading to preparation of a number of ferrocene-based nificant part of the synthetic community is involved in aminoalcohols showing excellent activity [11]. The prepa- developing of new methods and technologies for syn- ration of new aminoalcohols able to serve as catalysts thesis of chiral auxiliaries and products. The number of remains very important, justifying the synthetic efforts, the published chiral-technology-related papers is more since there is no universal ligand for addition of than 24 000 in the period of ten years (1994-2003) and dialkylzincs to aldehydes synthesized yet. the overwhelming majority (ca. 72%) deals with From theoretical point of view, the questions stereoselective or enantioselective syntheses. about how aminoalcohols facilitate the addition reac- Among the organic transformations the C-C- tion of dialkylzincs, about the chirality transfer from bond forming processes are of considerable importance. catalyst to substrate and about the origin of nonlinear In particularly the nucleophilic addition reactions to effects (asymmetric amplification) in the case of some carbonyl compounds offer elegant opportunities for syn- catalysts has been extensively investigated [8, 12]. Re- thesis of a variety of multifunctional compounds, many cent theoretical studies allow new insights into the of them with therapeutic applications. Therefore, the stereoselectivity trying to correlate structure with selec- enantioselective additions of dialkylzinc compounds to tivity in the case of different kind of aminoalcohols used aldehydes catalyzed by chiral β-amino alcohols, discov- as catalysts [13]. ered first by Oguni and Omi [2] , attracted great interest In this paper the most important results pub- within the organic synthetic community [3] and still lished in recent years will be discussed aiming to de- remains an object of intensive research [4]. The second scribe the characteristic features of the zinc-mediated variant of this reaction, catalysis by chiral diols in com- catalytic additions to carbonyl compounds and to out- bination with Ti(OiPr) , seems not to be competitive, line the development in perspective. 4 since it needs larger catalyst loading (Fig. 2) [5, 6]. The optically active secondary alcohols resulting ADDITION OF DIALKYLZINK COMPOUNDS TO from the addition reaction are useful intermediates for ALDEHYDES LIGAND ACCELLERATION AND preparation of biologically active compounds and often CHIRALITY AMPLIFICATION are components of natural products. In particular, the Although the first organozinc compound, the preparation of chiral diarylmethanols is of high practi- diethyl zinc (the first organometallic compound with ó-metal-carbon bond), has been obtained in 1849 by Frankland [14] the application of organozincs in organic synthesis has been developed only recently. The addition of dialkylzinc reagents to aldehydes is very slow compared with additions of organolithium or Grignard compounds and reduction is the usual side reaction that Ti(OiPr) 4 could be observed. The low reactivity of R Zn-com- 2 pounds results from the low nucleophilicity of the or- Fig. 2. Schematic presentation of dialkylzinc addition to ganic group attached to the Zn-atom. The diorganozinc aldehyde.

318 V. Dimitrov, M. Kamenova-Nacheva

Fig. 3. Structure change of R2Zn-compound by complexation with suitable ligand. compounds possess linear structure, a not very high elec- tronegativity difference between Zn- (EN=1.65) and C- atom (EN=2.55), and therefore relatively low polarity of the Zn-C-bond. However, through the complexation with a suitable ligand the linear structure of an R Zn- 2 compound change to a tetrahedral one and the Zn-C- bond becomes longer (Fig. 3). Therefore, the Zn-C-bond energy decreases, which results in an increase of the nucleophilicity of the carbanionic group [15]. It has been demonstrated by Soai [16] that 5 mol % of N,N,N,N-tetramethylethylenediamine catalyzes the quantitative addition of diethylzinc (Et Zn) to benzal- 2 dehyde. A variety of aprotic ligands and protic auxiliaries have been tested as catalysts showing results, which Fig. 4. Addition of Me2Zn to benzaldehyde – ligand leaded to the conclusion that â-dialkylamino alcohols acceleration through DAIB and catalyst formation. (in particularly sterically constrained á,β-disubstituted â-dialkylamino alcohols) are most effective additives [3a]. The merit of Oguni and Omi was the demonstration of the secondary alcohol 3 with high degree of tion that chiral â-dialkylamino alcohols are able to cata- enantioselectivity (95% ee). After adding the lyze the R Zn-addition to aldehydes enantioselectively aminoalcohol 4 which serves as precatalyst, the first step 2 (e.g. 2 mol % of (S)-leucinol catalyzed the addition of is the formation of the methylzinc alkoxide 5 as a result Et Zn to benzldehyde leading to (R)-1-phenyl-1-pro- of protolysis of one of the methyl-zinc groups by the 2 panol in 96% yield and 49% ee) [2]. The amino alcohol hydroxy proton of the aminoalcohol. In the Zn-alkoxide 5 there is an inner coordination by the Me N-group, catalyzed addition of organozinc compounds to alde- 2 hydes could be best described with the term ligand however the complex remains coordinatively unsatur- acceleration [17]. The first highly enantioselective cata- ated and thus readily forming in a course of an equilib- lytic addition of diorganozinc compound to aromatic rium reaction the dimer 6. The monomer Zn-akoxide 5 aldehydes was demonstrated by Noyori et al. [18] by is the real catalyst of the addition reaction able to coor- using (-)-3-exo-dimethylamino isoborneol (4, DAIB). dinate both the aldehyde 1 and the Zn-reagent 2 bring- The ligand acceleration phenomenon has been stud- ing them into reaction. If 100 mol % of the aminoalcohol ied in details by Noyori [3, 12] and is demonstrated 4 are used, no formation of product 3 occurs, because through the addition of dimethylzinc to benzaldehyde the organozinc reagent 2 is consumed quantitatively (Fig. 4). through the protolysis reaction. This was proved by de- In principle no reaction occurs between Me Zn tailed studies performed by Noyori et al. [3a, 12, 19], 2 (2) and benzaldehyde (1) in toluene or hexane as sol- The action of the methylzinc aminoalkoxide 5 as an vents at room temperature (the reasons have been dis- actual catalyst and the nature of the catalytic cycle were cussed above). However, the addition of only 2 mol % formulated by interpretation of the experimental data of aminoalcohol 4 leads to almost quantitative forma- and by performing of Ab Initio molecular orbital study

319 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009

Fig. 5. The catalytic cycle of the reaction of dimethylzinc and formaldehyde promoted by catalyst formed from aminoalcohol and dimethylzinc.

[12] of the model reaction system of aminoethanol, erates the complexes 10 and 11, respectively, and leads dimethylzinc and formaldehyde (Fig. 5). finally again to the dinuclear complex 12 that is re- The coordinatively unsaturated methylzinc sponsible for the nucleophilic addition of the Me-Zn- aminoalkoxide complex 8 is acting as Lewis acid (the group to the carbonyl C-atom. The alkyl transfer within Zn-atom) and base (the O-atom), thus being able to complex 12 is the turnover limiting step of the reac- coordinate dimethylzinc leading to 10 or formaldehyde tion, which is also the stereodetermining step if chiral to form 11. Intermediates 10 and 11 are able to coordi- aminoalcohol is used as precatalyst. nate formaldehyde and dimethylzinc, respectively, to For explanation of the sense of the enantioselectivity form the mixed complex 12. The intramolecular alkyl of dialkylzinc additions to aldehydes promoted by chiral transfer occurs within the intermediate 12 leading to aminoalcohols the transition state structures in Fig. 6 that the dinuclear complex 13, which contains the methylzinc are possible to be formed within the dinuclear complex alkoxide 14 as a product of the addition reaction. The 12 have been proposed. Extensive investigations based presence of dimethylzinc and formaldehyde is causing on theoretical studies and experimental observations displacement of the product alkoxide 14, which forms have been performed in recent years. Detailed discus- the dimmer 15 and finally the tetramer 16 as the more sion about this matter is outside the scope of the cur- stable products of assotiation. The displacement of the rent article and should be referred to the published lit- product alkoxide 14 from the intermediate 13 by means erature [4, 6, 12, 13]. It seems reasonable that in any of reactions with dimethyzinc or formaldehyde regen- case the structure of the chiral ligand used is respon-

320 V. Dimitrov, M. Kamenova-Nacheva

Fig. 6. Possible syn- or anti-transition state structures within the dinuclear complex of the type 12.

Fig. 7. Formation of homo- and heterochiral dimers of 6. sible for the fine changes in the steric demand and the 12]. In extensive studies of Noyori it has been shown that stabilities of the postulated transition states (syn and 8 mol % of DAIB used as precatalyst with only 15% anti) leading finally to formation of products with ap- enantiomeric excess was able to catalyze the addition of propriate enantioselectivity and configuration. It should Et Zn to benzaldehyde leading to formation of 1-phenyl- 2 be pointed out that the data available do not allow making 1-propanol in 92% yield and enantiomeric excess of 95%. prediction concerning the structure of a possible suc- The origin of this nonlinear relationship was explained cessful ligand. Therefore the synthesis of new chiral through the equilibrating interactions of alkyl-zinc- aminoalcohols searching for more efficient ligands re- aminoalkoxide species of the type 5 and 6 (in Fig. 4), mains a challenging opportunity for the synthetic com- and 8 and 9 (in Fig. 5) respectively. munity. In the first step of catalyst formation the Another very important feature of the dialkylzinc aminoalcohol DAIB reacts with R Zn to form the mo- 2 addition reactions to aldehydes should also be treated nomeric species of the type 5 (Fig. 7), 2S-5 being in within this review article. In some cases of ligands it has excess in the case 2S-DAIB has 15% ee. The monomers been observed a nonlinear relationship between the enan- of 5 (2S-5 and 2R-5) dimerize to form the dimeric spe- tiomeric purity of the aminoalcohol used as precatalyst cies 6, which are in equilibrium. The mixed heterochiral and the enantiomeric excess of the product obtained. This dimer (2S, 2R)-6 (meso form) is the most stable dimer phenomenon is known as chirality amplification [3, in the mixture. In contrary the homochiral dimers pos-

321 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009 sess lower stability and can dissociate to give mono- Table 1. â-Aminoalcohols as precatalysts for R Zn ad- 2 mers 5, or upon action of dialkylzinc compound or al- ditions to aldehydes. dehyde to form complex of the type 12 (Fig. 5) in which R-CHO Yield ee [%] No Ligand R Zn Ref. the alkyl transfer occurs. The meso compound 6 is not R= 2 [%] (R/S) Ph Et2Zn 98 99 (S) affected by the addition of R Zn, benzaldehyde, or their 4-MeOPh Et2Zn 96 93 (S) 2 1. (E)-PhCH=CH Et2Zn 81 96 (S) [18] mixtures [3, 12]. Therefore, through the formation of PhCH2CH2 Et2Zn 80 90 (S) 17 n-C6H13CHO Et2Zn 81 61 (S) the meso compound (2S, 2R)-6 equivalent amounts of Ph Et2Zn 98 98 (R) Hexanal Et2Zn 96 91 (R) 2S-5 and 2R-5 are removed from the catalytic cycle, i-Bu Et Zn 94 99 (R) 2. 2 [22] Cyclohexane Et2Zn 94 99 (R) allowing only those enantiomer of DAIB being in ex- 2-Ethylbutyraldehyde Et Zn 92 99 (R) 18 2 3-MePhCHO Me Zn 88 95 (R) cess to act as catalyst. 2

3. Ph Et2Zn 100 87 (S) [23]

â-, ã- AND ä-AMINOALCOHOLS USED WHAT 19 IS THE BEST

4. Ph Me2Zn 87 94 [24] For a long period of time the β-aminoalcohols have been thought as the most efficient ligands for 20 enantioselective addition of R Zn-compounds to alde- 2 5. Ph Et Zn 98 96 (R) [25] hydes. This is probably a result of the relative ease to 2 synthesize and modify β-aminoalcohols, since there is a 21 variety of chiral precursors available from the chiral pool (e.g. aminoacids, alkaloids etc.). Undoubtedly the 6. Ph Et2Zn 94 99 (R) [26] Noyoris detailed studies in respect of the highly efficient DAIB-ligand have significantly contributed to the 22 opinion that β-aminoalcohols should be the most suit- 7. Ph Et2Zn 89 93 (S) [27] able ligands (Table 1). However, in recent years series 23 of new γ- and δ-aminoalcohols have been synthesized [2.2.1]-heptane skeleton are suitable model compounds and shown to possess efficiency in providing high de- for comparative studies [20, 21]. Therefore the design gree of enantioselectivity within variety of R Zn-addi- 2 and synthesis of structurally diverse aminoalcohols have tion reactions. The selected examples presented in Tables importance in two general aspects, first to search for 2 and 3 shows that there is definitely enough space for efficient ligands for practicable applications and sec- development of γ- and δ-aminoalcohols as ligands. Con- ond, to study the mechanism of the stereoselection that cerning the mechanism and the stereoselection some is still not fully understood. differences might occur in comparison with β- aminoalcohols. Therefore the structural diversity of new IMPORTANT TYPES OF CHIRAL LIGANDS FOR ligands synthesized in recent years offer a challenging ADDITION OF DIALKYLZINK COMPOUNDS TO opportunity for mechanistic studies to obtain more close ALDEHYDES view in respect of the processes of enantioselection. The addition reaction catalyzed by γ- and δ-aminoalcohols The number of the synthesized aminoalcohols are leading to more conformationally flexible six- and has grown in recent decades to a dimensions that are seven-member chelat species within the postulated cata- difficult to be presented in details. In this article we are lyst-complex. It seems that the structural rigidity of the aiming to give only a general idea about the structural effective γ- and δ-aminoalcohols is significantly impor- diversity of ligands used for enantioselective diorgano- tant for limitation of conformational flexibility close to Zn additions to aldehydes. The ligands presented are the coordinating atoms (N- and O-atoms) binding the formally divided into groups, however there is no sharp organo-Zn-species of the catalytic complex. The variety border between these groups and in most cases a ligand of structurally diverse ligands containing the bicycle could combine several attributes.

322 V. Dimitrov, M. Kamenova-Nacheva

Table 2. ã-Aminoalcohols as precatalysts for R Zn ad- Ligands possessing chirality axis 2 ditions to aldehydes. Chiral compounds possessing only symmetry elements of rotation and belonging to the symmetry R-CHO Yield ee [%] No L igand R Zn Ref. R= 2 [%] (4/5) groups C or D are of growing importance for asym- n n

Ph 91 94 (R) metric synthesis. The enantiomeric atropoisomers of Et Zn 4-MePh 2 99 93 (R) Et Zn 4-ClPh 2 99 92 (R) 1,1-binaphthyl-2,2-diol (BINOL) have become among Et Zn 1. 2-MePh 2 99 95 (R) [28] Et Zn 1-Naphthaldehyde 2 94 91 (R) the most widely used ligands for C-C-bond forming re- Et Zn (E)-PhCH=CH 2 86 79 (R) Et Zn PhCH CH 2 82 84 (R) actions. The axially chiral BINOL has been utilized for 24 2 2 preparation of structurally diverse ligands.

Ph Et2Zn 85 92 (S) Ph (n-C3H7)2Zn 85 92 (S) Ph (CH =CH ) Zn 96 87 (S) 2. 2 2 2 [29] C5H11 (CH2=CH2)2Zn 90 >96 (R) C6H13 (CH2=CH2)2Zn 86 87 (R) Cyclohexane (CH2=CH2)2Zn 83 82 (S) 25

3. Ph Et 2Zn 65 93 (R) [30]

4. Ph Et 2Zn 100 92 (S) [31]

Table 3. ä-Aminoalcohols as precatalysts for R Zn ad- 2 ditions to aldehydes.

R-CHO Yield ee [%] No Ligand R Zn Ref. R= 2 [%] (R/S)

1. Ph Et Zn 99 89 (S) [10a] 2 Fig. 8. Ligands possessing chirality axis.

28 Ligands 32 and 33 (Fig. 8) have been prepared in several steps in good yields [35]. These were applied Ph Et2Zn 99 95 (S) 2. 2-MePh Et2Zn 91 94 (S) [10c, 32] in 8 mol % as precatalysts for the addition of Et Zn to 2-Naphthyl Et Zn 96 95 (S) 2 2 series of substituted aromatic aldehydes with

29 enantioselectivities of up to 97% ee. The aminoalcohols 34 showed high efficiency catalyzing (5 mol %) the addition of Et Zn to aromatic aldehydes with 3. Ph Et2Zn 96 96 (R) [33] 2 enantioselectivity of up to 98% ee and also the addition 30 to cinnamaldehydes (96% ee) [36]. A series of BINOLs of the type of 35 has recently been synthesized and dem- 4. Ph Et2Zn 90 96 (R) [34] onstrated to catalyze (5 mol %) the addition of Et Zn to 2 aldehydes without additives (e.g. Ti(O-i-Pr) ) and with 4 31 an enantioselectivity of up to 95% ee [37].

323 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009

Ferrocenyl aminoalcohols and ligands possessing 37 and 39-44 do not possess chirality plane, however chirality plane are typical examples of highly efficient aminoalcohols incorporating the ferrocene core. The efficiency is ob- The chirality plane realized as chirality element viously a result of the realized high substitution and within ligand-structures provides significant advantages hindrance of the stereogenic centers bearing the N, O- for asymmetric synthesis and catalysis and has attracted heteroatoms [40]. The substituted oxazolinyl ferrocenyl great interest in recent years. In most cases ligand 38 represents a group of highly active and effi- paracyclophanes or 1,2-disubstituted ferrocenes (or cient aminoalcohols possessing chirality plane and able metallocenes) are the synthetically aimed structures (see to catalyze the R Zn addition to aromatic aldehydes with 2 36 and 38 in Fig. 9) [11, 38]. high degree of enantioselectivity (see also next section A series of paracyclophanes of type 36 with dif- of this article). Although the ligand example introduced ferent substituents at the C-atom bearing the hydroxy in Fig. 9 gives only 23% ee for the addition of group have been synthesized and applied to catalyze phenylacetylene to benzaldehyde, this is a case of very the Et Zn addition to aromatic aldehydes with up to perspective application of Et Zn-promoted additions of 2 2 99% ee (97% ee for PhCHO) [39]. The ferrocene ligands alkynes to aldehydes [40].

Fig. 9. Ferrocenyl aminoalcohols and ligands possessing chirality plane.

324 V. Dimitrov, M. Kamenova-Nacheva

Ligands possessing the oxazoline structural motif series of N-sulfonated cis- and trans-aminocyclohexane oxazolines. These of ligands were effective for addition Ligands containing the oxazolinyl structural motif of Et Zn to aromatic and aliphatic aldehydes, in the lat- 2 have found application in different kind of asymmetric ter case with up to 98% ee (for cyclohexylcarbaldehyde) transformations. [42]. The oxazolinyl aminoalcohol 47 is representing a group of ligands combining both the oxazoline motif and the planar chiral paracyclophane core. The ligands of this type were highly effective for the addition of Et Zn to aromatic aldehydes [43]. 2

Ligands containing diverse type of functionalities

The ligand accelerated R Zn-addition to alde- 2 Fig. 10. Ligands possessing the oxazoline structural motif. hydes is limited not only to the aminoalcohols used as precatalysts. Representative examples of different type Ligand 45 is well suited for addition of R Zn- of ligands, which are definitely very efficient 2 reagents not only to aromatic aldehydes (Fig. 10) but in precatalysts, are introduced in Fig. 11. Ligands of the particularly for additions to aliphatic aldehydes (e.g. type 48, containing imino functionality, are growing >99% ee have been realized for the addition of Et Zn to group with various asymmetric applications [44]. The 2 hexanal) [41]. Ligand 46 is an example of a promising chiral Schiff base catalyst 48 was very active in amounts

Fig. 11. Ligands containing diverse type of functionalities.

325 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009 of 1 mol % promoting the enantioselective addition of Et Zn to benzaldehyde with enantioselectivity of 96% 2 ee. Ligands of the type 49 have been synthesized have been synthesized by condensation of substituted benzaldehydes and (S)-tert-butanesulfinamide followed by NaBH reduction [45] and were found to be very effi- 4 cient for addition of Et Zn to benzaldehyde. Starting from 2 (S)-valine a series of amino thiol derivatives of type 50 have been prepared promoting the Et Zn addition to al- 2 dehydes with 99% enantioselectivity by catalyst loading of only 0.02 mol % [46]. Hydroxyalkyl thiazoline ligands of the structure of 51 have been synthesized and used with excellent results in respect of the addition of alkyl- and arylzinc compounds to aldehydes [47]. Several different chiral imidazolidine disulfides Fig. 12. Diphenylzinc addition to aromatic aldehydes. of type 52 have been obtained using L-cystine. These of diaryl ketones because of the large electronic and compounds have been found to be active precatalysts steric differences between the aryl group and the hy- for enantioselective Et Zn addition to aldehydes with 2 drogen atom in a case of an aromatic aldehyde. For the up to 91% ee [48]. Chiral aziridine sulfides and disul- arylzinc additions two major aspects are object of in- fides (structure 53) have been prepared by using (R)- creased interest and preparative efforts the process cysteine. The addition of Et Zn to aldehydes catalyzed 2 development and the preparation of new more effective by this kind of ligands provides secondary alcohols with catalysts. up to 99% ee [49]. From (R)-cysteine have been syn- The first diphenylzinc addition (Fig. 12) was thesized also several oxazolidine type of ligands 54, which realized with 3 mol % of the planar chiral compound were efficient precatalysts [50]. Diselenide and disul- 59 to 4-chlorobenzaldehyde providing the correspond- fide ligand structures similar to 55 and 56 have been ing alcohol 58 with 57% ee [54]. Soon after this report, prepared recently and have show high efficiency by the Pu [55] and Bolm [56] could achieve better results by addition of Et Zn to aldehydes [51]. 2 using ligands 60 and 61 correspondingly, and by in- creasing the catalyst loading (Table 4). In the case of THE Zn-MEDIATED ADDITIONS OF ARYL-RE- ligand 60 pretreatment with Et Zn has been carried out 2 AGENTS TO ALDEHYDES THE PRACTICABLE for the formation of the catalyst. The arylation proce- DEVELOPMENT dure was improved by Bolm applying the combination It should be pointed out that the enantioselective Ph Zn/Et Zn as necessary to achieve high 2 2 addition of dialkylzincs to aldehydes is limited mainly to enantioselectivity [57]. In contrast to the diethylzinc a several organic groups (Et, Me, i-Pr, Ph) due to the low addition to aldehydes, which is extremely slow reaction number of zinc compounds commercially available [52]. in the absence of a catalyst, the phenylzinc addition can There are several methods to synthesize organozinc proceed even without catalyst [57a]. Therefore the com- (RZnX and R Zn) compounds, also such containing func- peting uncatalyzed Ph Zn-addition is a process lower- 2 2 tional groups [53]. However, their use can be carried out ing the enantioselectivity. only on a small preparative scale. Extensive studies suggested that the arylating In 1997, Fu reported the first catalytic enantio- agents are mixed PhZnEt-species, which are less active selective addition of Ph Zn to aldehydes [54]. Since then, than Ph Zn itself being thus more selective [58]. Be- 2 2 significant progress has been made in understanding of sides, the procedure using 1:2-mixture of Ph Zn/Et Zn 2 2 this addition reaction and in developing of practicable allows efficient use of all phenyl groups in the addition procedures. The enantioselective addition of aryl reagents reaction [58a-d]. Very efficient ligands have been de- to aryl aldehydes for preparation of diarylmethanols is veloped (Fig. 13, Table 4) producing pharmaceutically more suitable pathway than the asymmetric reduction relevant diarylmethanols starting from 2- and 4-Me-

326 V. Dimitrov, M. Kamenova-Nacheva

Fig. 13. Ligands for diphenylzinc additions (see Table 4).

Table 4. Representative examples for enantioselective Ph Zn-additions to aldehydes. 2

No R-CHO Catalyst Reagent Solvent Temp. Yield ee R = (mol %) (equiv.) (oC) (%) (%) a 1 4-MeO-C6H4- 60 (20) + Et2Zn (40) Ph2Zn (1) toluene -30 84 93 (R) a 2 4-Cl-C6H4- 60 (20) + Et2Zn (40) Ph2Zn (1) Et2O r.t. 86 94 (R) b 3 4-Cl-C6H4- 61 (5) Ph2Zn (1.5) toluene 0 99 82 (R) b 4 4-Cl-C6H4- 61 (10) Ph2Zn (1.5) toluene -20 92 90 (R) c 5 4-Cl-C6H4- 61 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 89 97 (R) c 6 4-Cl-C6H4- 61 (5) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 92 95 (R) c 7 4-Cl-C6H4- 61 (5) Ph2Zn toluene 10 82 (R) c 8 4-Cl-C6H4- 61 (2.5) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 86 93 (R) c 9 2-Br-C6H4- 61 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 64 91 (R) c 10 2-Br-C6H4- 61 (10) Ph2Zn toluene 10 73 (R) c 11 4-Me-C6H4- 61 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 86 98 (R) j d 12 4-Cl-C6H4- 62 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 96 (R) j d 13 4-Cl-C6H4- 63 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 96 (R) e 14 4-Cl-C6H4- 64 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 85 84 (R) j f 15 4-Cl-C6H4- 65(10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 98 (R) j f 16 2-Br-C6H4- 65 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 96 (R) g 17 4-Cl-C6H4- 66 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 quant. 97 h 18 4-MeO-C6H4- 67e (10) Ph2Zn (2) toluene 0 97 98 (R) i 19 4-Me-C6H4- 68 (10) Ph2Zn (0.64) / Et2Zn (1.32) hexane 0 90 98 (R) i 20 2-Me-C6H4- 68 (10) Ph2Zn (0.64) / Et2Zn (1.32) hexane 0 84 98 (R) a[55]. b[56]. c[57]. d[58a]. e[58b]. f[58c]. g[58d]. h[58e]. i[58f]. jYields good to quantitative.

327 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009 substituted benzaldehydes (Table 4, entries 11, 19 and in application of aryl boronic acids as a source of trans- 20) [57, 58f]. It is difficult to make conclusions about ferable aryl groups [59]. Large variety of phenyl bo- the catalyst species in the reaction mixtures, since there ronic acids are commercially available at appropriate is difficult to monitor the interchange of phenyl and prices thus offering a cheaper alternative to the expen- ethyl groups. However, an experimental evidence has sive diphenyl zinc. been provided recently in favour of the EtZnPh as the The protocol developed by Bolm [59] required predominating species formed after mixing Ph Zn and first of all transmetalation by mixing PhB(OH) with 3- 2 2 Et Zn (1:2) [58f]. Experiments have shown that the ac- fold excess of Et Zn at 60oC for 12 h prior to the cata- 2 2 tive catalytic complex is predominantly A (Fig. 14), due lytic reaction. The additions to 4-Cl-, 4-biphenyl-, 4- to the faster protolysis of the phenyl groups. Me- and 2-MeO-benzaldehyde, correspondingly, catalyzed by ligand 61 (10 mol %) provided diaryl methanols within 12 h at 10oC in high yields and high degree of enantioselectivity (90-95% ee). The most important results realized in the Zn-mediated aryl boronic acid additions to aldehydes are summarized in Fig. 15 and Table 5. New efficient ligands for arylation of aldehydes have been applied, which should be marked as very important, since there are a relatively low number of catalysts able to provide high ee values in phenyl transfer reactions [60, 61]. Of a particular importance has been the finding that the presence of polyethers can increase the Fig. 14. Catalytic complexes within the Ph2Zn/Et2Zn additions. enantioselectivity at low catalyst loading. The application of additives has been previously tested [55a] and Although efficient protocols for phenylzinc ad- now the concept has been further developed as demon- dition and highly active ligands have been developed strated by Bolm [60a] and Chan [60b] (Table 5, entries [56-58], the disadvantage in price and availability of 7-15). The introduction of 10 mol % of dimethoxy aryl-Zn-sources remains the main drawback of this polyethyleneglycol (DiMPEG) allowed carrying out method. However, there is new development consisting highly efficient large-scale additions, as well as recov-

Fig. 15. Et2Zn-Assisted addition of aryl-boronic acids to aromatic aldehydes.

328 V. Dimitrov, M. Kamenova-Nacheva

Table 5. Enantioselective Zn-mediated addition of arylboronic acids catalyzed by chiral ligands (see Fig. 15).

2 Entry Aldehyde Ligand R -PhB(OH)2 Yield ee R1 = (mol %) R2 = (%) (%) 1 4-Me- 69 (20) H 97a 97 (R) 2 4-Me- 70 (20) H 98a 91( R) 3 4-Me- 71 (20) H 88a 91( R) 4 2-Me- 69 (20) H 93a 97 (R) 5 H 69 (20) 4-MeO- 98a 94 (S) 6 H 69 (20) 4-Cl- 97a 94 (S) 7 4-Cl- 61 (10) H 93b 96 (R) 8 4-Me- 61 (10) H 94b 96 (R) 9 H 61 (10) 4-Me- 95b 94 (S) 10 2-Br- 61 (10) H 99b 93 (R) 11 2-Cl- 72 (8) H 91c 97 (S) 12 2-F- 72 (8) H 93c 97 (S) 13 2-Br- 72 (8) H 90c 97 (S) 14 2-MeO- 72 (8) H 93c 96 (S) 15 2-Me- 72 (8) H 94c 98 (S) a 2 Reactions were performed with 2.4 equiv. R -PhB(OH)2 and 7.2 equiv. Et2Zn at r.t. for 24 h b 2 without additive [61]. Reactions were performed with 2.4 equiv. R -PhB(OH)2 and 7.2 equiv. o c Et2Zn at 10 C for 12 h with additive DiMPEG (10 mol %) [60a]. Reactions were performed 2 o with 2.0 equiv. R -PhB(OH)2 and 6.0 equiv. Et2Zn at -15 C for 15 h with additive DiMPEG (10 mol %) [60b]. ery and reuse of catalyst [60]. The MPEG-concept has CONCLUSIONS been introduced within the polymer supported ferrocene ligand 66 (MeO-PEG-OH, MW=5000 and trityl chlo- The enantioselective addition of dialkylzinc com- ride resin have been used) obtaining excellent catalytic pounds and in particular the Zn-mediated aryl-addi- activity and possibility for the catalyst to be recovered tions catalyzed by chiral aminoalcohols have been sig- and reused [58d]. In contrast, 20 mol % of chiral cata- nificantly developed in recent years. The principle elu- lyst was necessary to be used without application of cidation of the mechanism and the origin of nonlinear additive for achieving of high degree of enantioselectivity phenomena (chirality amplification) offer fundamen- (Table 5, entries 1-6). Interestingly, by using the appro- tals for better understanding of catalytic asymmetric priate combination of aldehyde and arylboronic acid, it processes. The large-scale protocols developed [60] will was possible to obtain the both enantiomers of one diaryl give probably rise to interest for practical applications. methanol with a single catalyst (Table 5, entries 8 and The utilization of aryl boronic acids offers promising 9) PhB(OH) and 4-Me-C H CHO gave the R-enanti- opportunity for practicable synthesis of diarylcarbinols, 2 6 4 omer (96% ee), and 4-Me-PhB(OH) and C H CHO gave particularly since a large number of such boronic acids 2 6 5 the S-enantiomer (94% ee). Remarkably, ligand 72 cata- are commercially available. The continuous growth in lyzed with high selectivity the arylation of ortho-substi- the synthesis of new ligands should be pointed out as tuted aromatic aldehydes, which is in generally difficult very important, because a made-to-measure-catalyst to achieve (Table 5, entries 11-15). Ligand 72 and the will be rather necessary and possible to develop than a procedure described [60b] have been tested on a 20 g universal one. scale with up to 4-fold higher concentrations and 1 mol % catalyst loading providing excellent results, thus prom- REFERENCES ising possible application in industry. However, the use of a large amount of Et Zn and relatively drastic condi- 1. Data analysis based on a survey by the Company Frost 2 tions for the transmetalation reaction is undoubtedly & Sullivan published in Chen. Eng. News 82 (24), disadvantage of the method. 2004, 47.

329 Journal of the University of Chemical Technology and Metallurgy, 44, 4, 2009

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