enantioselective organozinc-catalyzed additions to carbonyl compounds

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Nov 12, 2009 - compounds and reduction is the usual side reaction that could be observed. ... It has been demonstrated by Soai [16] that 5 mol % ofi N,N,N' ...

V. Dimitrov, Kamenova-Nacheva Journal of the University of Chemical M. Technology 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 with Centre of Phytochemistry Bulgarian Academy of Sciences Acad. G. Bonchev str. Bl. 9, 1113 Sofia, Bulgaria

Received 05 October 2009 Accepted 12 November 2009

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 mechanisms, 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 In the recent decades one of the most important objectives of the synthetic organic chemistry is to modify the known chemical transformations of prostereogenic starting compounds in asymmetric manner leading to enantiomerically pure (or at least enriched) products. Significant driving force for substantial achievements in the field of asymmetric synthesis is the pharmaceutical industry and the guidelines of the United States Food and Drug Administration (FDA), and similar regulating agencies concerning the enantiomeric purity of active pharmaceutical ingredients (APIs) possessing chirality elements. At present more than 40% of the

existing drugs are compounds having at least one stereogenic centre. In nine of the top 10 drugs, the APIs are chiral. The global sales of single enantiomer compounds were expected by the end of 2004 to reach $8.57 billion and $14.94 billion by the end of 2009 (annual growth of 11.4%). A survey by Frost & Sulivan [1] estimates a significant growth (Fig. 1) of the chemocatalytic and biocatalytic methods for production of chiral products with lowering of the market importance of the traditional technologies (utilization of substances from the chiral pool and application of separation methods). The trends in recent years are in directing the efforts mainly in development of catalytic enantioselective processes using both metal-mediated catalysis and

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Fig. 1. The worldwide production of chiral products in respect of the technology uses. organocatalysis. In both cases the application of a suitable chiral compound is decisively important and significant part of the synthetic community is involved in developing of new methods and technologies for synthesis of chiral auxiliaries and products. The number of the published chiral-technology-related papers is more than 24 000 in the period of ten years (1994-2003) and the overwhelming majority (ca. 72%) deals with stereoselective or enantioselective syntheses. Among the organic transformations the C-Cbond forming processes are of considerable importance. In particularly the nucleophilic addition reactions to carbonyl compounds offer elegant opportunities for synthesis of a variety of multifunctional compounds, many of them with therapeutic applications. Therefore, the enantioselective additions of dialkylzinc compounds to aldehydes catalyzed by chiral β-amino alcohols, discovered first by Oguni and Omi [2] , attracted great interest within the organic synthetic community [3] and still remains an object of intensive research [4]. The second variant of this reaction, catalysis by chiral diols in combination with Ti(OiPr)4, seems not to be competitive, since it needs larger catalyst loading (Fig. 2) [5, 6]. The optically active secondary alcohols resulting from the addition reaction are useful intermediates for preparation of biologically active compounds and often are components of natural products. In particular, the preparation of chiral diarylmethanols is of high practi-

Ti(OiPr)4

Fig. 2. Schematic presentation of dialkylzinc addition to aldehyde.

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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 has been changed recently by demonstration of highly efficient γ- and δ-aminoalcohols as catalysts [10]. In recent years the planar chirality of 1,2-disubstituted ferrocenes attracted significant interest in chiral catalysis leading to preparation of a number of ferrocene-based aminoalcohols showing excellent activity [11]. The preparation of new aminoalcohols able to serve as catalysts remains very important, justifying the synthetic efforts, since there is no universal ligand for addition of dialkylzincs to aldehydes synthesized yet. From theoretical point of view, the questions about how aminoalcohols facilitate the addition reaction of dialkylzincs, about the chirality transfer from catalyst to substrate and about the origin of nonlinear effects (asymmetric amplification) in the case of some catalysts has been extensively investigated [8, 12]. Recent theoretical studies allow new insights into the stereoselectivity trying to correlate structure with selectivity in the case of different kind of aminoalcohols used as catalysts [13]. In this paper the most important results published in recent years will be discussed aiming to describe the characteristic features of the zinc-mediated catalytic additions to carbonyl compounds and to outline the development in perspective. ADDITION OF DIALKYLZINK COMPOUNDS TO ALDEHYDES – LIGAND ACCELLERATION AND CHIRALITY AMPLIFICATION Although the first organozinc compound, the 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 could be observed. The low reactivity of R2Zn-compounds results from the low nucleophilicity of the organic group attached to the Zn-atom. The diorganozinc

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 electronegativity difference between Zn- (EN=1.65) and Catom (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 R2Zncompound change to a tetrahedral one and the Zn-Cbond 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 (Et2Zn) to benzaldehyde. A variety of aprotic ligands and protic auxiliaries have been tested as catalysts showing results, which leaded to the conclusion that â-dialkylamino alcohols (in particularly sterically constrained á,β-disubstituted â-dialkylamino alcohols) are most effective additives [3a]. The merit of Oguni and Omi was the demonstration that chiral â-dialkylamino alcohols are able to catalyze the R2Zn-addition to aldehydes enantioselectively (e.g. 2 mol % of (S)-leucinol catalyzed the addition of Et2Zn to benzldehyde leading to (R)-1-phenyl-1-propanol in 96% yield and 49% ee) [2]. The amino alcohol catalyzed addition of organozinc compounds to aldehydes could be best described with the term “ligand acceleration” [17]. The first highly enantioselective catalytic addition of diorganozinc compound to aromatic aldehydes was demonstrated by Noyori et al. [18] by using (-)-3-exo-dimethylamino isoborneol (4, DAIB). The “ligand acceleration” phenomenon has been studied in details by Noyori [3, 12] and is demonstrated through the addition of dimethylzinc to benzaldehyde (Fig. 4). In principle no reaction occurs between Me2Zn (2) and benzaldehyde (1) in toluene or hexane as solvents at room temperature (the reasons have been discussed above). However, the addition of only 2 mol % of aminoalcohol 4 leads to almost quantitative forma-

Fig. 4. Addition of Me 2Zn to benzaldehyde – ligand acceleration through DAIB and catalyst formation.

tion of the secondary alcohol 3 with high degree of enantioselectivity (95% ee). After adding the aminoalcohol 4 which serves as precatalyst, the first step is the formation of the methylzinc alkoxide 5 as a result of protolysis of one of the methyl-zinc groups by the hydroxy proton of the aminoalcohol. In the Zn-alkoxide 5 there is an inner coordination by the Me2N-group, however the complex remains coordinatively unsaturated and thus readily forming in a course of an equilibrium reaction the dimer 6. The monomer Zn-akoxide 5 is the real catalyst of the addition reaction able to coordinate both the aldehyde 1 and the Zn-reagent 2 bringing them into reaction. If 100 mol % of the aminoalcohol 4 are used, no formation of product 3 occurs, because the organozinc reagent 2 is consumed quantitatively through the protolysis reaction. This was proved by detailed studies performed by Noyori et al. [3a, 12, 19], The action of the methylzinc aminoalkoxide 5 as an actual catalyst and the nature of the catalytic cycle were formulated by interpretation of the experimental data and by performing of Ab Initio molecular orbital study

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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, dimethylzinc and formaldehyde (Fig. 5). The coordinatively unsaturated methylzinc aminoalkoxide complex 8 is acting as Lewis acid (the Zn-atom) and base (the O-atom), thus being able to coordinate dimethylzinc leading to 10 or formaldehyde to form 11. Intermediates 10 and 11 are able to coordinate formaldehyde and dimethylzinc, respectively, to form the mixed complex 12. The intramolecular alkyl transfer occurs within the intermediate 12 leading to the dinuclear complex 13, which contains the methylzinc alkoxide 14 as a product of the addition reaction. The presence of dimethylzinc and formaldehyde is causing displacement of the product alkoxide 14, which forms the dimmer 15 and finally the tetramer 16 as the more stable products of assotiation. The displacement of the product alkoxide 14 from the intermediate 13 by means of reactions with dimethyzinc or formaldehyde regen-

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erates the complexes 10 and 11, respectively, and leads finally again to the dinuclear complex 12 that is responsible for the nucleophilic addition of the Me-Zngroup to the carbonyl C-atom. The alkyl transfer within complex 12 is the turnover limiting step of the reaction, which is also the stereodetermining step if chiral aminoalcohol is used as precatalyst. For explanation of the sense of the enantioselectivity of dialkylzinc additions to aldehydes promoted by chiral aminoalcohols the transition state structures in Fig. 6 that are possible to be formed within the dinuclear complex 12 have been proposed. Extensive investigations based on theoretical studies and experimental observations have been performed in recent years. Detailed discussion about this matter is outside the scope of the current article and should be referred to the published literature [4, 6, 12, 13]. It seems reasonable that in any case the structure of the chiral ligand used is respon-

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 stabilities of the postulated transition states (syn and anti) leading finally to formation of products with appropriate enantioselectivity and configuration. It should be pointed out that the data available do not allow making prediction concerning the structure of a possible successful ligand. Therefore the synthesis of new chiral aminoalcohols searching for more efficient ligands remains a challenging opportunity for the synthetic community. Another very important feature of the dialkylzinc addition reactions to aldehydes should also be treated within this review article. In some cases of ligands it has been observed a nonlinear relationship between the enantiomeric purity of the aminoalcohol used as precatalyst and the enantiomeric excess of the product obtained. This phenomenon is known as “chirality amplification” [3,

12]. In extensive studies of Noyori it has been shown that 8 mol % of DAIB used as precatalyst with only 15% enantiomeric excess was able to catalyze the addition of Et2Zn to benzaldehyde leading to formation of 1-phenyl1-propanol in 92% yield and enantiomeric excess of 95%. The origin of this nonlinear relationship was explained through the equilibrating interactions of alkyl-zincaminoalkoxide species of the type 5 and 6 (in Fig. 4), and 8 and 9 (in Fig. 5) respectively. In the first step of catalyst formation the aminoalcohol DAIB reacts with R2Zn to form the monomeric species of the type 5 (Fig. 7), 2S-5 being in excess in the case 2S-DAIB has 15% ee. The monomers of 5 (2S-5 and 2R-5) dimerize to form the dimeric species 6, which are in equilibrium. The mixed heterochiral dimer (2S, 2’R)-6 (meso form) is the most stable dimer in the mixture. In contrary the homochiral dimers pos-

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sess lower stability and can dissociate to give monomers 5, or upon action of dialkylzinc compound or aldehyde to form complex of the type 12 (Fig. 5) in which the alkyl transfer occurs. The meso compound 6 is not affected by the addition of R2Zn, benzaldehyde, or their mixtures [3, 12]. Therefore, through the formation of the meso compound (2S, 2’R)-6 equivalent amounts of 2S-5 and 2R-5 are “removed” from the catalytic cycle, allowing only those enantiomer of DAIB being in excess to act as catalyst.

Table 1. â-Aminoalcohols as precatalysts for R2Zn additions to aldehydes. No

Ligand

1. 17

2. 18

3.

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

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Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Me2Zn

Yield [%] 98 96 81 80 81 98 96 94 94 92 88

ee [%] (R/S) 99 (S) 93 (S) 96 (S) 90 (S) 61 (S) 98 (R) 91 (R) 99 (R) 99 (R) 99 (R) 95 (R)

Ph

Et2Zn

100

87 (S)

[23]

Ph

Me2Zn

87

94

[24]

Ph

Et2Zn

98

96 (R)

[25]

Ph

Et2Zn

94

99 (R)

[26]

Ph

Et2Zn

89

93 (S)

[27]

R2Zn

Ref.

[18]

[22]

19

4.

For a long period of time the β-aminoalcohols have been thought as the most efficient ligands for enantioselective addition of R2Zn-compounds to aldehydes. This is probably a result of the relative ease to synthesize and modify β-aminoalcohols, since there is a variety of chiral precursors available from the “chiral pool” (e.g. aminoacids, alkaloids etc.). Undoubtedly the Noyori’s detailed studies in respect of the highly efficient DAIB-ligand have significantly contributed to the opinion that β-aminoalcohols should be the most suitable ligands (Table 1). However, in recent years series of new γ- and δ-aminoalcohols have been synthesized and shown to possess efficiency in providing high degree of enantioselectivity within variety of R2Zn-addition reactions. The selected examples presented in Tables 2 and 3 shows that there is definitely enough space for development of γ- and δ-aminoalcohols as ligands. Concerning the mechanism and the stereoselection some differences might occur in comparison with βaminoalcohols. Therefore the structural diversity of new ligands synthesized in recent years offer a challenging opportunity for mechanistic studies to obtain more close view in respect of the processes of enantioselection. The addition reaction catalyzed by γ- and δ-aminoalcohols are leading to more conformationally flexible six- and seven-member chelat species within the postulated catalyst-complex. It seems that the structural rigidity of the effective γ- and δ-aminoalcohols is significantly important for limitation of conformational flexibility close to the coordinating atoms (N- and O-atoms) binding the organo-Zn-species of the catalytic complex. The variety of structurally diverse ligands containing the bicycle

R-CHO R= Ph 4-MeOPh (E)-PhCH=CH PhCH2CH2 n-C6H13CHO Ph Hexanal i-Bu Cyclohexane 2-Ethylbutyraldehyde 3-MePhCHO

20

5. 21

6.

22 7. 23

[2.2.1]-heptane skeleton are suitable model compounds for comparative studies [20, 21]. Therefore the design and synthesis of structurally diverse aminoalcohols have importance in two general aspects, first to search for efficient ligands for practicable applications and second, to study the mechanism of the stereoselection that is still not fully understood. IMPORTANT TYPES OF CHIRAL LIGANDS FOR ADDITION OF DIALKYLZINK COMPOUNDS TO ALDEHYDES The number of the synthesized aminoalcohols has grown in recent decades to a dimensions that are difficult to be presented in details. In this article we are aiming to give only a general idea about the structural diversity of ligands used for enantioselective diorganoZn additions to aldehydes. The ligands presented are formally divided into groups, however there is no sharp border between these groups and in most cases a ligand could combine several attributes.

V. Dimitrov, M. Kamenova-Nacheva

Table 2. ã-Aminoalcohols as precatalysts for R2Zn additions to aldehydes.

No

R-CHO R=

L igand

R Zn

Ph 4-M ePh 4-ClPh 2-M ePh 1-Naphthaldehyde (E)-PhCH=CH PhCH CH

1.

24

2.

Et Et Et Et Et Et

Zn Zn Zn Zn Zn Zn

Yield [%]

AA [%] (4/5)

Ref.

91 99 99 99 94 86 82

94 (R) 93 (R) 92 (R) 95 (R) 91 (R) 79 (R) 84 (R)

[28]

Ph Ph Ph C#H  C$H ! Cyclohexane

Et Zn (n-C!H %) Zn (CH =CH ) Zn (CH =CH ) Zn (CH =CH ) Zn (CH =CH ) Zn

85 85 96 90 86 83

92 (S) 92 (S) 87 (S) >96 (R) 87 (R) 82 (S)

[29]

Ph

Et Zn

65

93 (R)

[30]

Ph

Et Zn

100

92 (S)

[31]

Ligands possessing chirality axis Chiral compounds possessing only symmetry elements of rotation and belonging to the symmetry groups Cn or Dn are of growing importance for asymmetric synthesis. The enantiomeric atropoisomers of 1,1’-binaphthyl-2,2’-diol (BINOL) have become among the most widely used ligands for C-C-bond forming reactions. The axially chiral BINOL has been utilized for preparation of structurally diverse ligands.

25

3. 26

4.

27



Table 3. ä-Aminoalcohols as precatalysts for R2Zn additions to aldehydes. No

Ligand

1.

R-CHO R=

R2Zn

Yield [%]

ee [%] (R/S)

Ref.

Ph

Et 2Zn

99

89 (S)

[10a]

Fig. 8. Ligands possessing chirality axis.

28

2.

Ph 2-MePh 2-Naphthyl

Et 2Zn Et 2Zn Et 2Zn

99 91 96

95 (S) 94 (S) 95 (S)

[10c, 32]

Ph

Et 2Zn

96

96 (R)

[33]

Ph

Et 2Zn

90

96 (R)

[34]

29

3. 30

4.

31

Ligands 32 and 33 (Fig. 8) have been prepared in several steps in good yields [35]. These were applied in 8 mol % as precatalysts for the addition of Et2Zn to series of substituted aromatic aldehydes with enantioselectivities of up to 97% ee. The aminoalcohols 34 showed high efficiency catalyzing (5 mol %) the addition of Et 2 Zn to aromatic aldehydes with enantioselectivity of up to 98% ee and also the addition to cinnamaldehydes (96% ee) [36]. A series of BINOL’s of the type of 35 has recently been synthesized and demonstrated to catalyze (5 mol %) the addition of Et2Zn to aldehydes without additives (e.g. Ti(O-i-Pr)4) and with an enantioselectivity of up to 95% ee [37].

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Ferrocenyl aminoalcohols and ligands possessing chirality plane The chirality plane realized as chirality element within ligand-structures provides significant advantages for asymmetric synthesis and catalysis and has attracted great interest in recent years. In most cases paracyclophanes or 1,2-disubstituted ferrocenes (or metallocenes) are the synthetically aimed structures (see 36 and 38 in Fig. 9) [11, 38]. A series of paracyclophanes of type 36 with different substituents at the C-atom bearing the hydroxy group have been synthesized and applied to catalyze the Et2Zn addition to aromatic aldehydes with up to 99% ee (97% ee for PhCHO) [39]. The ferrocene ligands

37 and 39-44 do not possess chirality plane, however are typical examples of highly efficient aminoalcohols incorporating the ferrocene core. The efficiency is obviously a result of the realized high substitution and hindrance of the stereogenic centers bearing the N, Oheteroatoms [40]. The substituted oxazolinyl ferrocenyl ligand 38 represents a group of highly active and efficient aminoalcohols possessing chirality plane and able to catalyze the R2Zn addition to aromatic aldehydes with high degree of enantioselectivity (see also next section of this article). Although the ligand example introduced in Fig. 9 gives only 23% ee for the addition of phenylacetylene to benzaldehyde, this is a case of very perspective application of Et2Zn-promoted additions of alkynes to aldehydes [40].

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

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V. Dimitrov, M. Kamenova-Nacheva

Ligands possessing the oxazoline structural motif Ligands containing the oxazolinyl structural motif have found application in different kind of asymmetric transformations.

series of N-sulfonated cis- and trans-aminocyclohexane oxazolines. These of ligands were effective for addition of Et2Zn to aromatic and aliphatic aldehydes, in the latter case with up to 98% ee (for cyclohexylcarbaldehyde) [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 Et2Zn to aromatic aldehydes [43]. Ligands containing diverse type of functionalities

Fig. 10. Ligands possessing the oxazoline structural motif. Ligand 45 is well suited for addition of R2Znreagents not only to aromatic aldehydes (Fig. 10) but in particularly for additions to aliphatic aldehydes (e.g. >99% ee have been realized for the addition of Et2Zn to hexanal) [41]. Ligand 46 is an example of a promising

The ligand accelerated R2Zn-addition to aldehydes is limited not only to the aminoalcohols used as precatalysts. Representative examples of different type of ligands, which are definitely very efficient precatalysts, are introduced in Fig. 11. Ligands of the type 48, containing imino functionality, are growing group with various asymmetric applications [44]. The chiral Schiff base catalyst 48 was very active in amounts

Fig. 11. Ligands containing diverse type of functionalities.

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of 1 mol % promoting the enantioselective addition of Et2Zn to benzaldehyde with enantioselectivity of 96% ee. Ligands of the type 49 have been synthesized have been synthesized by condensation of substituted benzaldehydes and (S)-tert-butanesulfinamide followed by NaBH4 reduction [45] and were found to be very efficient for addition of Et2Zn to benzaldehyde. Starting from (S)-valine a series of amino thiol derivatives of type 50 have been prepared promoting the Et2Zn addition to aldehydes 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 alkyland arylzinc compounds to aldehydes [47]. Several different chiral imidazolidine disulfides of type 52 have been obtained using L-cystine. These compounds have been found to be active precatalysts for enantioselective Et2Zn addition to aldehydes with up to 91% ee [48]. Chiral aziridine sulfides and disulfides (structure 53) have been prepared by using (R)cysteine. The addition of Et2Zn to aldehydes catalyzed by this kind of ligands provides secondary alcohols with up to 99% ee [49]. From (R)-cysteine have been synthesized also several oxazolidine type of ligands 54, which were efficient precatalysts [50]. Diselenide and disulfide ligand structures similar to 55 and 56 have been prepared recently and have show high efficiency by the addition of Et2Zn to aldehydes [51]. THE Zn-MEDIATED ADDITIONS OF ARYL-REAGENTS TO ALDEHYDES – THE PRACTICABLE DEVELOPMENT It should be pointed out that the enantioselective addition of dialkylzincs to aldehydes is limited mainly to a several organic groups (Et, Me, i-Pr, Ph) due to the low number of zinc compounds commercially available [52]. There are several methods to synthesize organozinc (RZnX and R2Zn) compounds, also such containing functional groups [53]. However, their use can be carried out only on a small preparative scale. In 1997, Fu reported the first catalytic enantioselective addition of Ph2Zn to aldehydes [54]. Since then, significant progress has been made in understanding of this addition reaction and in developing of practicable procedures. The enantioselective addition of aryl reagents to aryl aldehydes for preparation of diarylmethanols is more suitable pathway than the asymmetric reduction

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Fig. 12. Diphenylzinc addition to aromatic aldehydes. of diaryl ketones because of the large electronic and steric differences between the aryl group and the hydrogen atom in a case of an aromatic aldehyde. For the arylzinc additions two major aspects are object of increased interest and preparative efforts – the process development and the preparation of new more effective catalysts. The first diphenylzinc addition (Fig. 12) was realized with 3 mol % of the planar chiral compound 59 to 4-chlorobenzaldehyde providing the corresponding alcohol 58 with 57% ee [54]. Soon after this report, Pu [55] and Bolm [56] could achieve better results by using ligands 60 and 61 correspondingly, and by increasing the catalyst loading (Table 4). In the case of ligand 60 pretreatment with Et2Zn has been carried out for the formation of the catalyst. The arylation procedure was improved by Bolm applying the combination Ph 2 Zn/Et 2 Zn as necessary to achieve high enantioselectivity [57]. In contrast to the diethylzinc addition to aldehydes, which is extremely slow reaction in the absence of a catalyst, the phenylzinc addition can proceed even without catalyst [57a]. Therefore the competing uncatalyzed Ph2Zn-addition is a process lowering the enantioselectivity. Extensive studies suggested that the arylating agents are mixed PhZnEt-species, which are less active than Ph2Zn itself being thus more selective [58]. Besides, the procedure using 1:2-mixture of Ph2Zn/Et2Zn allows efficient use of all phenyl groups in the addition reaction [58a-d]. Very efficient ligands have been developed (Fig. 13, Table 4) producing pharmaceutically relevant diarylmethanols starting from 2- and 4-Me-

V. Dimitrov, M. Kamenova-Nacheva

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

Table 4. Representative examples for enantioselective Ph2Zn-additions to aldehydes. No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

R-CHO Catalyst Reagent Solvent Temp. Yield (%) R= (mol %) (equiv.) (oC) 4-MeO-C6H4- 60 (20) + Et2Zn (40) Ph2Zn (1) toluene -30 84 4-Cl-C6H460 (20) + Et2Zn (40) Ph2Zn (1) Et2O r.t. 86 4-Cl-C6H461 (5) Ph2Zn (1.5) toluene 0 99 4-Cl-C6H461 (10) Ph2Zn (1.5) toluene -20 92 4-Cl-C6H461 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 89 4-Cl-C6H461 (5) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 92 4-Cl-C6H461 (5) Ph2Zn toluene 10 4-Cl-C6H461 (2.5) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 86 2-Br-C6H461 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 64 2-Br-C6H461 (10) Ph2Zn toluene 10 4-Me-C6H461 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 86 j 4-Cl-C6H462 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 j 4-Cl-C6H463 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 4-Cl-C6H464 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 85 j 4-Cl-C6H465(10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 j 2-Br-C6H465 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 4-Cl-C6H466 (10) Ph2Zn (0.65) / Et2Zn (1.3) toluene 10 quant. 4-MeO-C6H467e (10) Ph2Zn (2) toluene 0 97 4-Me-C6H468 (10) Ph2Zn (0.64) / Et2Zn (1.32) hexane 0 90 2-Me-C6H468 (10) Ph2Zn (0.64) / Et2Zn (1.32) hexane 0 84 a [55]. b[56]. c[57]. d[58a]. e[58b]. f[58c]. g[58d]. h[58e]. i[58f]. jYields good to quantitative.

ee (%) 93 (R)a 94 (R)a 82 (R)b 90 (R)b 97 (R)c 95 (R)c 82 (R)c 93 (R)c 91 (R)c 73 (R)c 98 (R)c 96 (R)d 96 (R)d 84 (R)e 98 (R)f 96 (R)f 97g 98 (R)h 98 (R)i 98 (R)i

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substituted benzaldehydes (Table 4, entries 11, 19 and 20) [57, 58f]. It is difficult to make conclusions about the catalyst species in the reaction mixtures, since there is difficult to monitor the interchange of phenyl and ethyl groups. However, an experimental evidence has been provided recently in favour of the EtZnPh as the predominating species formed after mixing Ph2Zn and Et2Zn (1:2) [58f]. Experiments have shown that the active catalytic complex is predominantly A (Fig. 14), due to the faster protolysis of the phenyl groups.

Fig. 14. Catalytic complexes within the Ph 2Zn/Et 2Zn additions. Although efficient protocols for phenylzinc addition and highly active ligands have been developed [56-58], the disadvantage in price and availability of aryl-Zn-sources remains the main drawback of this method. However, there is new development consisting

in application of aryl boronic acids as a source of transferable aryl groups [59]. Large variety of phenyl boronic acids are commercially available at appropriate prices thus offering a cheaper alternative to the expensive diphenyl zinc. The protocol developed by Bolm [59] required first of all transmetalation by mixing PhB(OH)2 with 3fold excess of Et2Zn at 60oC for 12 h prior to the catalytic reaction. The additions to 4-Cl-, 4-biphenyl-, 4Me- 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 enantioselectivity at low catalyst loading. The application of additives has been previously tested [55a] and now the concept has been further developed as demonstrated by Bolm [60a] and Chan [60b] (Table 5, entries 7-15). The introduction of 10 mol % of dimethoxy polyethyleneglycol (DiMPEG) allowed carrying out highly efficient large-scale additions, as well as recov-

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

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Table 5. Enantioselective Zn-mediated addition of arylboronic acids catalyzed by chiral ligands (see Fig. 15). Aldehyde Ligand R2-PhB(OH)2 Yield ee 1 R = R2 = (mol %) (%) (%) 1 4-MeH 97a 97 (4) 69 (20) 2 4-MeH 98a 91 (4) 70 (20) 3 4-MeH 88a 91 (4) 71 (20) 4 2-MeH 93a 97 (4) 69 (20) 5 H 4-MeO98a 94 (5) 69 (20) 6 H 4-Cl97a 94 (5) 69 (20) 7 4-ClH 93b 96 (4) 61 (10) 8 4-MeH 94b 96 (4) 61 (10) 9 H 4-Me95b 94 (5) 61 (10) 93 (4) 10 2-BrH 99b 61 (10) 11 2-ClH 91c 97 (5) 72 (8) 12 2-FH 93c 97 (5) 72 (8) 13 2-BrH 90c 97 (5) 72 (8) 14 2-MeOH 93c 96 (5) 72 (8) 15 2-MeH 94c 98 (5) 72 (8) a Reactions were performed with 2.4 equiv. R2-PhB(OH)2 and 7.2 equiv. Et2Zn at r.t. for 24 h without additive [61]. bReactions were performed with 2.4 equiv. R2-PhB(OH)2 and 7.2 equiv. Et2Zn at 10oC for 12 h with additive DiMPEG (10 mol %) [60a]. cReactions were performed with 2.0 equiv. R2-PhB(OH)2 and 6.0 equiv. Et2Zn at -15oC for 15 h with additive DiMPEG (10 mol %) [60b].

Entry

ery and reuse of catalyst [60]. The MPEG-concept has been introduced within the polymer supported ferrocene ligand 66 (MeO-PEG-OH, MW=5000 and trityl chloride resin have been used) obtaining excellent catalytic activity and possibility for the catalyst to be recovered and reused [58d]. In contrast, 20 mol % of chiral catalyst was necessary to be used without application of additive for achieving of high degree of enantioselectivity (Table 5, entries 1-6). Interestingly, by using the appropriate combination of aldehyde and arylboronic acid, it was possible to obtain the both enantiomers of one diaryl methanol with a single catalyst (Table 5, entries 8 and 9) – PhB(OH)2 and 4-Me-C6H4CHO gave the R-enantiomer (96% ee), and 4-Me-PhB(OH)2 and C6H5CHO gave the S-enantiomer (94% ee). Remarkably, ligand 72 catalyzed with high selectivity the arylation of ortho-substituted aromatic aldehydes, which is in generally difficult to achieve (Table 5, entries 11-15). Ligand 72 and the procedure described [60b] have been tested on a 20 g scale with up to 4-fold higher concentrations and 1 mol % catalyst loading providing excellent results, thus promising possible application in industry. However, the use of a large amount of Et2Zn and relatively drastic conditions for the transmetalation reaction is undoubtedly disadvantage of the method.

CONCLUSIONS The enantioselective addition of dialkylzinc compounds and in particular the Zn-mediated aryl-additions catalyzed by chiral aminoalcohols have been significantly developed in recent years. The principle elucidation of the mechanism and the origin of nonlinear phenomena (chirality amplification) offer fundamentals for better understanding of catalytic asymmetric processes. The large-scale protocols developed [60] will give probably rise to interest for practical applications. The utilization of aryl boronic acids offers promising opportunity for practicable synthesis of diarylcarbinols, particularly since a large number of such boronic acids are commercially available. The continuous growth in the synthesis of new ligands should be pointed out as very important, because a “made-to-measure”-catalyst will be rather necessary and possible to develop than a universal one. REFERENCES 1. Data analysis based on a survey by the Company Frost & Sullivan published in Chen. Eng. News 82 (24), 2004, 47.

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