Development and Studies of the Processes Involved in Minor Enantiomer Recycling. Anna Laurell Nash

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1 Development and Studies of the Processes Involved in Minor Enantiomer Recycling Anna Laurell Nash Doctoral Thesis Stockholm 2014 Akademisk avhandling som med tillstånd av Kungl Tekniska ögskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi med inriktning mot organisk kemi torsdagen den 18 december kl i sal F3, KT, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. pponent är Professor Karl Anker Jørgensen, Aarhus University.

2 ISBN ISSN TRITA-CE Report 2014:53 Anna Laurell Nash, 2014 Universitetsservice US AB, Stockholm

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4 Anna Laurell Nash, 2014: Development and Studies of the Processes Involved in Minor Enantiomer Recycling, KT Chemical Science and Engineering, Royal Institute of Technology, SE Stockholm, Sweden. Abstract This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling. The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen complex with a tertiary amine as a catalytic system in the enantioselective synthesis of -acylated cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step. The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of -acylated and -formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved. Keywords: asymmetric catalysis, biocatalysis, cyanohydrins, dual activation, Lewis acid, Lewis base, minor enantiomer recycling, recycling, titanium

5 Abbreviations Ac CA CALB CE CIAT CRL d DBU DKR DYKAT DIPT ee equiv. GC h PLC KR LA LB M MER Min n.d. NMR Nu PPL RDS TADDL TMS TMS Acetyl Carbonic anhydrase Candida antarctica lipase B Cholesterol esterase Crystallized induced asymmetric transformation Candida rugosa lipase Days 1,8-Diazabicyclo[5.4.8]octane Dynamic kinetic resolution Dynamic kinetic asymmetric transformation Diisopropyl tartrate Enantiomeric excess Equivalent Gas chromatography ours igh performance liquid chromatography Kinetic resolution Lewis acid Lewis base Metal Minor enantiomer recycling Minutes Not determined Nuclear magnetic resonance Nucleophile Porcine pancreatic lipase Rate-determining step Tetraaryl-1,3-dioxolane-4,5-dimethanol Trimethylsilyl Trimethylsilyl cyanide

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7 List of Publications This thesis is based on the following papers, referred to in the text by their Roman numerals I-V: I. Minor Enantiomer Recycling: Metal Catalyst, rganocatalyst and Biocatalyst Working in Concert Erica Wingstrand, Anna Laurell, Linda Fransson, Karl ult, and Christina Moberg Chem. Eur. J. 2009, 15, II. Minor Enantiomer Recycling-Effect of Two Reinforcing Catalysts on Product Yield and Enantiomeric Excess Linda Fransson, Anna Laurell, Khalid Widyan, Erica Wingstrand, Karl ult, and Christina Moberg ChemCatChem 2010, 2, III. pposite Enantiomers from Minor Enantiomer Recycling and Dynamic Kinetic Resolution Using a Single Biocatalyst Anna Laurell and Christina Moberg Eur. J. rg. Chem. 2011, IV. Recycling Powered by Release of Carbon Dioxide Anna Laurell Nash, Khalid Widyan, and Christina Moberg Accepted for publication in ChemCatChem V. Dual Lewis Acid-Lewis Base Catalyzed Acetylcyanation of Aldehydes. A Mechanistic Study Anna Laurell Nash, Robin ertzberg, Ye-Qian Wen, and Christina Moberg Manuscript

8 Table of Contents Abstract Abbreviations List of publications 1. Introduction Asymmetric Catalysis Resolution Coupled Processes Recycling Procedures Minor Enantiomer Recycling The Aim of This Thesis Mechanistic Studies of Enantioselective Dual Lewis Acid-Lewis Base Catalyzed Cyanohydrin Synthesis Introduction Mechanistic Investigations Kinetic Studies ammett Correlation Studies Role of the Lewis Acid and the Lewis Base NMR Study Conclusions Minor Enantiomer Recycling in Chiral Cyanohydrin Synthesis Introduction Synthesis of Chiral -Acylated Cyanohydrins Using Minor Enantiomer Recycling Conclusions Minor Enantiomer Recycling in Comparison with Dynamic Kinetic Resolution Sequential Catalysis Minor Enantiomer Recycling Dynamic Kinetic Resolution Conclusions Computer Simulations and Kinetics Computer Simulations Kinetics Conclusions Synthesis of Chiral -Formylated Cyanohydrins Using Minor Enantiomer Recycling Development of a New Model System Driving Force Combined Conclusions... 57

9 4. Summary and Concluding Remarks Acknowledgements Appendix References

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11 1. Introduction Chiral compounds have fascinated and intrigued scientists for decades. The task to chemically produce enantiomerically pure compounds has become a fundamental challenge in organic synthesis ever since Pasteur manually separated tartaric acid into its crystallized enantiomers. 1 Nature spent millions of years to develop perfect catalysts, the enzymes, for specific target molecules but in the chemistry lab there is still a great demand for new methodologies to satisfy the ever growing demand from industry of enantiopure compounds. In asymmetric synthesis, chiral molecules are produced starting from prochiral material. A high yield of enantiopure product with low waste production is the desired goal. Three main strategies to induce chirality from achiral starting material can be used: auxiliary control, reagent control and catalyst control. The following section will cover methodologies whereby catalyst control is used Asymmetric Catalysis In asymmetric catalysis only a small amount of chiral catalyst is used to produce large amounts of enantioenriched material. This type of strategy to form chiral compounds has been very important both in industry and academic research. Knowles, 2 Noyori, 3 and Sharpless 4 were together awarded the Nobel Price in chemistry 2001 for their development of catalytic asymmetric synthesis. A Cat* P S P R minor major Figure 1. Enantioenriched product P R can be obtained from achiral starting material, A, using a chiral catalyst, Cat* 1.2. Resolution Separation of enantiomers from a racemic mixture can be complicated and costly. Addition of an enantiopure resolving agent can form the corresponding pair of diastereomers, which can be separated via chromatography or crystallization. 1

12 Kinetic resolution, KR, is one of the most common methods for the separation of enantiomers from a racemate in industry. 5 The methodology takes advantage of the difference in rate with which the two enantiomers react with a stoichiometric chiral reagent or chiral catalyst (Figure 2a). 6 Starting from a racemic mixture, the catalyst reacts rapidly with enantiomer S S, and slowly with S R (k S >> k R ). Enantiomerically pure S R can be obtained in a uppermost yield of 50%. k S S S fast P S S S k S fast P S k rac fast S R k R P R S R k R slow slow a. b. P R Figure 2a. Kinetic Resolution b. Dynamic Kinetic Resolution To overcome the limitation of merely 50% yield, several methodologies have been developed. Dynamic kinetic resolution, DKR, utilizes the advantages of kinetic resolution to get enantioenriched compound via a chiral catalyst together with in situ racemization, leading to a theoretical possible yield of 100% of the desired product (Figure 2b). With a rapid racemization step between the two enantiomers S S and S R, the yield of P S depends on the selectivity of the resolution step by the chiral catalyst (k S >k R, k rac >> k S, k R ). 7 Since this strategy gives access to a potentially high yield of enantioenriched compound, it has become a useful approach in chemical research. DKR was recently used as a step in an improved procedure for the synthesis of chiral ligand QUINAP. 8 N PPh 2 (S)-QUINAP Crystallized induced asymmetric transformation, CIAT 9 explores the phenomenon that larger crystals will grow at the expense of smaller ones. An imbalance between enantiomers crystallizing as conglomerates, achieved for example by the addition of seeding crystals, can initiate the process and result in enantiopure crystals. A rapid racemization in solution is required for the process to work (Figure 3). 10 2

13 crystallization S S S S solution k rac crystals S R Figure 3. Crystallized induced asymmetric transformation Trost introduced dynamic kinetic asymmetric transformation, DYKAT. 11,12 The methodology is related to DKR but involves epimerization between diastereomers instead of racemization between enantiomers. The two enantiomers in a racemate are subjected to a chiral catalyst and forms diastereomeric complexes R-Cat* and S-Cat* (Figure 4a). Equilibration between the two complexes through intermediate I-Cat* makes the system dynamic and a theoretical yield of 100% of the S-product can be obtained. 7 The selectivity of the system depends on the ratio of k SC* /k RC* and the interconversion between the two diastereomeric complexes. 13 Several subclasses of DYKAT have been suggested where epimerization of the diastereomeric complexes plays an important role in the mechanism. 13 S S k SC* S-Cat* kc*s fast P S R RAc L* Pd + L*Pd Nu - Nu k SC*I I-Cat* PdL*AcR k RC*I S R k RC* R-Cat* k C*R slow P R R RAc L* Pd + L*Pd Nu - Nu a. b. Figure 4a. Schematic illustration of DYKAT b. Trost palladium catalyzed DYKAT in asymmetric allylic alkylation An enantioconvergent transformation is the independent conversion of two enantiomers into the same product enantiomer in the same reaction pot. 7 The S-enantiomer in a racemic mixture, S S, is transformed to S-product, P S, with retention of configuration, whereas the R-enantiomer, S R, proceeds with inversion of configuration to the same S-product simultaneously (Figure 5a). These transformations are usually catalyzed by two selective catalysts (Figure 3

14 5b), 14 but examples of enantioconvergent transformations of isomers using the same catalyst also exist. 15 k S S S P S Ph Epoxide ydrolase 1 Ph S R k SR Ph Epoxide ydrolase 2 a. b. Figure 5a. Enantioconvergent transformation b. Example of enantioconvergent transformation using two different enzymes to form the same product enantiomer from a racemic mixture 1.3. Coupled Processes Kinetic resolution performed on a scalemic mixture results in higher yield of the desired product enantiomer than if starting from a racemate. 16 Asymmetric transformation of prochiral starting material A, provides a scalemic mixture of R- and S-enantiomers. The minor enantiomer formed can then be resolved from its antipode by kinetic resolution (Figure 6). 17 k S A Cat*1 S R fast P R S S k R slow P S Figure 6. Sequential process consisting of asymmetric transformation of A into a scalemic mixture subsequentially subjected to kinetic resolution Belokon and North used a sequential procedure to improve the ee of the acylated cyanohydrins formed from aldehydes, acetic anhydride and K catalyzed by chiral Ti- complex (S,S)-1. By treating the product with an enzyme, ee:s of the product formed in the first reaction was improved by kinetic resolution of the scalemic mixture (Scheme 1). 18 4

15 tbu tbu R (S,S)-1 K + (R C) 2 R CALB CALB R N Ti N tbu tbu tbu tbu N Ti N R R tbu tbu Scheme 1. Sequential procedure by Belokon and North Sequential kinetic resolutions can be performed by the use of a single catalyst that can differentiate between enantiotopic groups. Starting from a prochiral compound, A, containing enantiotopic groups, the two enantiomers are first formed in different amounts. The difference in rate between the enantiomeric transformations provides an opportunity to obtain enantiomerically enriched product with the same catalyst (Figure 7a). The first example of this type of process was demonstrated by Sih who used PPL, porcein pancreatic lipase, in the two-step hydrolysis of R,S-1,5-diacetoxy-2,4-dimethylpentane. 19 Initial hydrolysis takes place with enantiotopic group selectivity by the enzyme to provide an enantiomerically enriched monoester; subsequent hydrolysis to the diol proceeds with the same enantiopreference to provide the R-monoester with increasing enantiomeric excess over time (Figure 7b). 1 A k S P S k' S fast slow P slow fast Ac S R k S Ac Ac k' S k R P R k' R k R Ac k' R a. b. Figure 7. Sequential kinetic resolution using a single catalyst for two subsequent steps a. P S can be isolated in enantioenriched form after further transformation of P R with the same enzyme. b. Sih s example of subsequent hydrolysis by the use of a single enzyme Two subsequent kinetic resolutions can give enhanced enantioselectivity of the desired product starting from a racemate if the catalyst has a preference for the same enantiomer in both steps (Figure 8a). An example of this procedure was demonstrated by treating a racemic binapthol ester derivate with cholestrol esterase, CE, to get the pure diol. The reaction involved two enzymatic steps; 5

16 hydrolysis of the diester to the monoester and hydrolysis of the monoester to the diol. In both steps the enzyme was selective for the S-enantiomer (Figure 8b). 20 k S k' S k S R k' S S S fast k R P S fast k' R P S' R R S R slow P R slow P R' k R R k' R a. b. Figure 8a. Two selective transformations, starting from a racemic mixture, by a single catalyst, leading to enantioenrichment of the product, P S b. Two-step resolution of a binapthol derivate The use of two catalysts instead of one can be advantageous when reactions are optimized. By varying the ratio of the catalyst concentrations individually the different rates of the catalytic reactions can be controled. 21,22 Sequential kinetic resolution using two different selective catalysts (Figure 9a) can give the product formed in the first step, P S, in high ee after resolution of the minor enantiomer. This strategy was used to transform nitriles into the corresponding enantioenriched amides by the use of nitrile hydratase; the enantiomeric excess was improved by a second resolution using an amidase for the further transformation of the minor enantiomer into carboxylic acid (Figure 9b). 21 S S k R fast P S k' R slow P S' k R Ar 2 k' R Ar C Ar S R k S slow P R k' S fast P R' k S Ar 2 k' S Ar C a. b. Figure 9. Sequential kinetic resolution; two enantioselective catalysts with different enantiopreference give enrichment of the major product, P S, formed in the first transformation 6

17 Recycling Procedures Although impressive results for methodologies using destruction or further transformation of the undesired enantiomer in order to get enantiopure products have been achieved, these types of approaches lead to a loss of yield due to the unproductive pathway of the unwanted enantiomer. Recycling procedures can circumvent the problem with separation of waste and low yields by transformation of the unwanted enantiomer back into starting material. In autocatalytic reactions the initially formed product acts as a catalyst for the amplification of the enantiomeric excess (Figure 10). The product, P S, is first formed with low ee by the reaction between achiral reagents X and S. P S then acts as a chiral catalyst for its own formation, creating amplification of the ee. S X X P S P S X P S low ee high ee X S Figure 10. Autocatalytic reaction. S S-X formed in a first step acts as an autocatalyst that amplifies the enantiomeric excess of the product This type of chiral amplification, first considered by Frank, 23 starting from a small chemical imbalance forming large enantiomeric excess, has been implicated as the reason for the emergence of biological homochirality Soai has to date the most striking examples of autocatalysis. 27,28 Starting from achiral reagents with the product in very small ( %) enantiomeric excess present as a catalyst generated the product in a final 99.5% ee (Scheme 2). The mechanism has been thoroughly investigated and debated. The catalytically active monomeric species is in equilibrium with homochiral (2a) and heterochiral (2b) dimers. The asymmetric amplification is a result of the inactivity of the heterodimer. 29,30 t Bu N N Zn t Bu N N R Zn N N A B N N Zn R 2a: A=, B=Pr i 2b: A=Pr i, B= Scheme 2. Autocatalytic reaction 7

18 Cyclic deracemization can be accomplished by selective transformation of one enantiomer in a racemic mixture to prochiral molecule A. Further reaction of A with a stoichiometric amount of X back into the two enantiomers is a successful way of generating enantioenriched products in high yield (Figure 11a). Most cases of this type of transformations include one selective catalyst in combination with stoichiometric amount of reagent X, but the use of two selective catalysts also exists The final ee of the product depends on the selectivity of the catalyst, Cat*, thus the relative rates of reaction of S R and S S. 34 Several elegant examples of this type of recycling have been demonstrated. 32,33,35,36 S R Cat* Ph N 2 enzyme N X A Ph N 2 N 3 B 3 S S Ph a. b. Figure 11a. Cyclic deracemization b. Example of cyclic deracemization of secondary amine using an enzyme to selectively transform one enantiomer back into staritng material Models for recycling procedures include both forward and reverse reactions and may exist in systems open to energy flow The energy released from a sacrificial reagent in a reaction coupled to the cycle is a reasonable way to provide the energy needed to force recycling in one direction. 40, Minor Enantiomer Recycling The concept of minor enantiomer recycling, MER, 42 was developed in our group to optimize the enantiomeric purity of the product without sacrificing the yield of the reaction. The methodology includes two steps where at least one step has to be enantioselective. Using two chiral catalysts simultaneously in the recycling procedure has a reinforcing effect where the total selectivity E of the system is a product of the individual selectivities E 1 and E 2 for the catalysts, E=E 1 E 2. 43,44 The process is coupled to a thermodynamically downhill reaction that feeds the system with the energy needed for recycling (Figure 12a). 43 In a first step the product enantiomers are formed by reaction between prochiral starting material A and X, catalysed by a chiral catalyst, Cat*1. The initial ee of the product is corrected by the presence of the second chiral catalyst, Cat*2, that selectively transforms the minor enantiomer formed in the 8

19 first step back into starting material. By the continuous addition of reagent X, new product is generated and potentially 100% yield of enantiomerically pure product can be obtained. The formation of energetically stable product Y, derived from the second step serves as the thermodynamic driving force for the cycle. A X Cat*1 Cat*2 P S P R Ph (S,S)-1 CALB Ph Ac Ph Ac Y C 3 C - a. b. Figure 12 a. Minor enantiomer recycling b. MER in enantioselective cyanohydrin synthesis 1.4. The Aim of This Thesis The aim of this thesis was to further develop the concept of minor enantiomer recycling and to gain deeper understanding of the processes involved. 9

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21 2. Mechanistic Studies of Enantioselective Dual Lewis Acid-Lewis Base Catalyzed Cyanohydrin Synthesis (Paper V) 2.1. Introduction Chiral cyanohydrins are important building blocks in organic synthesis. 45 Due to the two functional groups attached to the chiral center, a range of transformations to valuable compounds can be made. 46 The reversible formation of cyanohydrin by addition of to carbonyl compounds, reported over 100 years ago, 47 is catalyzed by the presence of base. The active nucleophile in the reaction has been identified as the cyanide ion. 48 The first enantioselective route to chiral cyanohydrin was reported by Rosenthaler 49 who used an enzyme, found in almond extract, to catalyze the enantioselective addition of to a prochiral aldehyde (Scheme 3). R enzyme R Scheme 3. Formation of enantioenriched cyanohydrin using enzyme extract by Rosenthaler is toxic and volatile, which is why other cyanide sources are preferably used today. Direct access to -functionalized cyanohydrins by the use of alternative cyanide sources (Figure 13) circumvents the problems of the reverse reaction and racemization of the free cyanohydrin, by trapping the oxygen with a functional group. M TMS R R R P R Figure 13. Cyanide sources in cyanohydrin synthesis A large number of Lewis acid metal complexes have been used in enantioselective cyanohydrin synthesis. 50 Reetz reported the first example by using boron-containing heterocycle 3 to catalyze the reaction between isobutanal and TMS, to yield the corresponding cyanohydrin in enantioenriched form. 51 Narasaka and co-workers reported the first example of 11

22 titanium catalysis in cyanohydrin synthesis. They used a stoichiometric amount of a complex formed in situ from TiCl 2 ( i Pr) 2 and TADDL (4) to get enantioenriched cyanohydrins from the reaction between aromatic or aliphatic aldehydes and TMS. 52 guni and co-workers first reported the use of catalytic amounts of titanium catalyst in the reaction between TMS and aromatic aldehydes. The catalyst used was formed in situ from DIPT and Ti( i Pr) 4 (5). 53 Titanium complexes have since then been the most extensively studied metal catalysts in the field. 54 Ar Ar N B NTf 2 Ph Ph Ph Ph R i Pr i Pr i Pr Ti i Pr Salen-based titanium complex (S,S)-1 has been widely used in the synthesis of chiral -functionalized cyanohydrins using various cyanide sources. The dimeric complex (R,R)-1 was first used by the groups of Belokon and North in the silylcyanation of aldehydes providing -TMS-protected cyanohydrins in high yields and with high enantiomeric excess (Scheme 4) TMS (R,R)-1 TMS C 2 Cl 2 Scheme 4. Silylcyanation of benzaldehyde by the use of (R,R)-1 Zhang et al. 59 modified (R,R)-1 by connecting two salen ligands with a linker providing the more efficient catalyst 1a. Superior conversion rates and higher ee of the products formed in silylcyantation of aldehydes were observed by the use of 1a instead of (R,R)-1. tbu tbu Linker N Ti N tbu tbu tbu tbu N Ti N N Ti N tbu tbu tbu tbu N Ti N tbu tbu tbu tbu (R,R)-1 Efficient catalytic systems can be achieved by dual activation of electrophiles and nucleophiles by the combined use of Lewis acids and Lewis bases. Two 1a 12

23 main approaches for dual Lewis acid-lewis base catalysis exist: either a bifunctional catalyst containing both a Lewis acidic and a Lewis basic site is used, or two separate catalysts (Figure 14). Nu E Nu E LB catalyst LA LB catalyst LA catalyst a. b. Figure 14. a. Bifunctional catalyst, b. two separate catalysts Successful use of bifunctional catalyst 6 in highly selective silylcyanation of aldehydes was first demonstrated by Shibasaki and co-workers. 60 The group of Nájera and Saá later designed an analogous catalyst (7) for the preparation of enantioenriched cyanohydrins from aldehydes and TMS. This catalyst gave similar results, but had the advantage that chiral ligand 7a easily could be recovered. 61 When catalyst 7 was used for the synthesis of -benzylated cyanohydrins, it was proposed that the reaction between aldehyde and benzoyl cyanide was initiated by free cyanide ions, present in commercially available ketonitrile. The role of the diethylaminomethyl arm was later suggested to be that of a Brønstedt base, used to deprotonate. 62,63 Ph Ph P Cl Al P Ph Ph 6 Cl Et 2 N Et 2 N Al 7 Et 2 N Et 2 N 7a Previous work in our group reported access to acylated cyanohydrins from aldehydes and ketonitriles using dual Lewis acid-lewis base activation. igh yields and enantiomeric excess were obtained when dual activation by (S,S)-1 in combination with tertiary amine was used to catalyze the reactions (Scheme 5). 64,65 13

24 1, NR 3 Ac Ac R C 2 Cl 2 40 C R R Scheme 5. Direct acylcyanation of aldehydes by dual Lewis acid Lewis base catalyzed procedure Extensive mechanistic studies of cyanation reactions between aldehydes and different cyanide sources (TMS, cyanocarbonates and K in combination with anhydrides) catalyzed by (S,S)-1 performed in the groups of Belokon and North have given valuable information about the behavior of the Ti complex It was shown that binuclear catalyst (R,R)-1 exists in equilibrium with the monomer 1b (Scheme 6). In chloroform the dissociation of (R,R)-1 to 1b was found to be concentration dependent where higher concentration favors the dimer. In dichloromethane the equilibrium is shifted more towards (R,R)-1 and in benzene, only the undissociated form (R,R)-1 was found. 56 tbu tbu tbu N Ti N tbu tbu tbu tbu N Ti N 2 x tbu tbu N Ti N tbu tbu tbu (R,R)-1 1b Scheme 6. Equilibrium between dimeric Ti-salen complex (R,R)-1 and its monomeric species 1b By following the evolution of the enantiomeric excess over time while running the addition of potassium cyanide to aldehydes catalyzed by (R,R)-1 in the presence of anhydride, Belokon and North observed that the ee of the product increased during the course of the reaction. Based on this observation they proposed that (R,R)-1 has to convert into a species with higher catalytic activity and that other, less enantioselective catalysts were present in the initial part of the reaction. 56 Thorough kinetic investigations followed by ammett correlation studies of the addition of TMS to aldehydes catalyzed by (R,R)- 1 resulted in large positive ammett constants. 66 The results implied as expected that Lewis acid catalysis is dominating the reaction. Coordination of the aldehyde to the metal complex could however not be observed by 1 NMR spectroscopy when a 30-fold excess of benzaldehyde was added to the Lewis acid in chloroform at room temperature. 57 The result could be explained by the fact that titanium is six-coordinated. For the aldehyde to coordinate to (R,R)-1 14

25 a bond in the Ti-complex would first have to be broken. Controlled addition of one equivalent of acetic anhydride to (R,R)-1 gave the mono-bridged binuclear titanium 1c; further attempts to form the mononuclear species by addition of additional anhydride failed (Scheme 7). 55 Ti Ti Ti Ac Ti Ac 1 1c Scheme 7. Schematic picture of the formation of mono-bridged titanium complex 1c by controlled addition of anhydride to 1 In line with the results of Belokon and North, previous members of our group observed that the product ee increased when the reaction progressed in the dual Lewis acid-lewis base catalyzed acylcyanation of aldehydes. A reaction consisting of (R,R)-1 in dichloromethane together with triethylamine, benzaldehyde, and acetyl cyanide at -40 C gave ee:s starting at 78% and increasing to a final 95% ee. When the Ti-complex was cooled down to -40 C for three hours in the presence of the Lewis base and ketonitrile before the addition of aldehyde, the ee of the product remained constant at 95% ee. 65 NMR studies of the Ti-complex showed that the monomer to dimer ratio was higher at -40 C than at room temperature. By mixing acetyl cyanide with (R,R)-1 in chloroform, a change in the shift of the carbonyl peak was observed by 13 C NMR. 65 To investigate the possibility of Brønstedt base catalysis in our procedure, as suggested by Baeza et al., 63 two equivalents of 13 C-labelled were bubbled through a solution of (R,R)-1 in C 2 Cl 2 before addition of the reactants. A mass spectrum recorded after 5% conversion showed no incorporation of 13 C into the product, indicating that free was not present in the reaction solution, thus excluding the role of the tertiary amine to be that of a Brønstedt base. 65 In addition, commercial acetyl cyanide was not used in the experiments but freshly made from the corresponding acetyl bromide using a previously published procedure Mechanistic Investigations Despite previous knowledge from experimental data, the mechanism of dual Lewis acid-lewis base acetylcyanation of aldehydes was still unclear. Therefore we decided to investigate it further. 15

26 2.3. Kinetic Studies To get a better insight into the mechanism we decided to study the initial part of the reaction more closely. The aim of the study was to elucidate the influence of the different components in the reaction and the importance of the addition order. Experiments were prepared in the glovebox by mixing (S,S)-1 with benzaldehyde and triethylamine in C 2 Cl 2. The mixture was cooled to -40 C for two hours before cold acetyl cyanide was added. The development of product formation and enantiomeric excess was followed by chiral GC. Product formation, preceded by an induction period, was a characteristic pattern for these experiments. In order to explore this phenomenon better we decided to use the more slowly reacting 4-methoxybenzaldehyde and only half the amounts of the two catalysts (2.5 mol % Ti-complex and 5 mol % triethylamine instead of 5 mol % and 10 mol %, respectively) to truly enable the study at the initial part of the reaction. The new experiment resulted in a longer induction period before product started to evolve. This result was compared to experiments where the order of addition of the reactants was varied. When triethylamine was added last, only a short induction period proceeded before the rate of the reaction increased. When aldehyde was added as the final ingredient the reaction started almost immediately (Figure 15). In experiments performed without precooling of the reaction mixture, the addition order did not matter; all experiments showed the same pattern of low conversion before the product started to evolve. 16

27 yield / % time / min Figure 15. Kinetic experiments following the development of product over time varying the addition order. (n ) NEt 3 added last (o) aldehyde added last and (w ) acetyl cyanide added last The kinetic experiments indicate that catalyst 1 reacts with acetyl cyanide in a first step before product can be formed ammett Correlation Studies A ammett plot can provide valuable information about the mechanism of a reaction. The equation used, originally developed by ammett, describes the influence of meta and para substituents on the reactivity of the reaction center in benzene derivates: log(kx/k )=ρσ or log(kx/k )=ρσ K or k is the equilibrium or rate constant for a reaction of unsubstituted benzoic acid and K X or k the equilibrium or rate constant for the corresponding X-substituted benzoic acid. The ammett constant, σ, describes how electron-donating or electron-withdrawing the substituent -X is compared to -. ammett originally defined the constant from the ionization of benzoic acids in water: σx = logkx - logk Efforts have been made to find more accurate values of σ taking electronic effects of individual substituents into account. These constants are tabulated and can be used to get a better fit to the ammett plot

28 The value of the reaction constant, ρ, is a measure of the change in charge of the reaction relative to the dissociation of benzoic acid, where ρ = 1. The sign of the reaction constant therefore gives information of the electronic properties of the reaction center in the rate-determining step of a reaction. If ρ > 1 the reaction is more sensitive to substituents than benzoic acid and a negative charge is built up during the course of the reaction (or positive charge lost). If 0 < ρ < 1 the reaction is less sensitive to substituents than benzoic acids and a negative charge is built up (or positive charge lost), if ρ = 0 there is no sensitivity towards substituents, and if ρ < 0 a positive charge is built up during the reaction (or negative charge is lost). 72 The ratio of the products formed from competing substrates in the same reaction flask can be used in order to get information about the mechanism without having to rely on absolute kinetics. Instead, two or more substrates compete in the same reaction vessel and the relative rates of the reactions are compared and used in a ammett plot. 73 The assumptions that the competing substrates do not react with each other or with the products formed and that they do not alter the reactivity of one another have to be made. 74 The ratio of the products formed in two competing reactions equals the ratio of their rates, i.e. the relative rates. This assumption is only valid if equimolar amounts of the competing starting materials are used and if they are present in large excess compared to the common reagent. 74,75 ammett correlation studies using actual rates derived from absolute kinetic studies give information about the rate-determining step whereas ammett correlations derived from competitive experiments give information about the selectivity-determining step. These are not always the same and depend on the substrates ability to compete. owever ammett plots made from competition experiments still give good indications of the mechanism. 76 A competitive ammett study was designed for the dual Lewis acid-lewis base acetylcyanation of aldehydes. The relative rates of competing reactions between benzaldehyde and nine different meta- and para-substituted benzaldehydes with acetyl cyanide were determined. The aldehydes were added in equimolar ratios and in large excess to acetyl cyanide so that no reaction could go to completion (Scheme 8). The experiments were set up in the glovebox by mixing (S,S)-1 with the two competing aldehydes and triethylamine in C 2 Cl 2. Acetyl cyanide was added after cooling the reaction mixture to -35 C for 90 minutes. The relative rates of the competing aldehydes were determined as the ratio of the products formed analyzed by 1 NMR spectroscopy. 18

29 X 1, NEt 3 C 2 Cl 2 35 C X Ac Ac 1 equiv 1 equiv 0.5 equiv Scheme 8. Competeive experiment setup; equimolar ratio of aldehydes and substoichiometric amount of acetyl cyanide to measure the relative rates of the product formed All competition experiments were repeated three times to get accurate values. The logarithms of the relative rates were plotted against the ammett constant σ, listed in the literature. 71,77 The resulting ammett plot (Figure 16) gave a good linear fit for six out of the nine substrates. 4-Cyanobenzaldehyde, 3,5- dichlorobenzaldehyde, and 4-nitrobenzaldehyde deflected from the straight line that could be drawn for the other aldehydes. Deviation from the ammett plot is commonly due to a change in the mechanism or bad selection of the ammett constant, σ. 78 To investigate this, several different σ values were tested but none was found with a better fit than the standard values. σ 1 p-cf 3 m-n 2 0,8 3,5-Cl 2 0,6 pcl p- 0,4 p-br 0,2 0 m-me -0,4-0,2-0,2 0 0,2 0,4 0,6 0,8 1 p-me -0,4 p-n 2 p-me 1,2-0,6-0,8-1 log(k X / k ) Figure 16. ammett plot for competing reactions using the relative rates and standard σ values The enantiomeric excess for the products was measured for each experiment when possible and listed in Table 1. Reactions with four aldehydes with strongly electron-withdrawing groups, 4-nitrobenzaldehyde, 4-19

30 cyanobenzaldehyde, 4-trifluoromethylbenzaldehyde, and 3-nitrobenzaldehyde, showed no or very little enantiomeric excess. Table 1. Relative rate of the products formed and %ee of the product determined by chiral GC. X σ k X/k % ee of product 4-Me Me Me Br Cl CF n.d 3-N * 3,5-Cl n.d 4-N n.d *Bad peak separation Linear regression derived from the ammett plot (excluding the three aldehydes assumed to react via a different mechanism) gave the reaction constant ρ = 1.63 (Figure 17). The results of the competitive ammett study thus indicate that a negative charge is built up during the course of the reaction for these aldehydes. 1,5 1 0,5 σ 0-0,4-0,2 0 0,2 0,4 0,6 0,8-0,5-1 log(k X / k ) Figure 17. Linear regression of the aldehydes assumed to proceed by the same mechanism 20

31 In the initially proposed mechanism the reaction was assumed to proceed while both aldehyde and acetyl cyanide were coordinated to the Ti-complex (Scheme 9). After coordination to the Lewis acid, nucleophilic attack of the Lewis base on acetyl cyanide to form a more potent acylation reagent was presumed. The liberated cyanide ion could then in turn undergo rate-determining attack on the aldehyde to form cyanohydrin, followed by rapid acylation. Ti R Ti R N Scheme 9. Initially proposed mechanism for LA-LB dual activation of -acylated cyanohydrins using 1 as the chiral Lewis acid and triethylamine as the Lewis base Comparing the suggested mechanism to the ammett plot, this assumption fits well in for the electron-rich aldehydes but not for the more electron-poor aldehydes. The three substrates that deviated from the straight line in the ammett plot were assumed to react with a different mechanism Role of the Lewis Acid and the Lewis Base The aim of the study was to identify the mode of activation for the electronpoor aldehydes that deviated from the ammett curve. Tian and Deng have previously shown that when cyanoformate is added to ketones in the presence of a chiral Lewis base, the corresponding carbonate is formed in enantioenriched form. 79 Similarly, the asymmetric acetylcyanation of α-ketoesters gives the enantioenriched product in the presence of a chiral Lewis base. 80 The cyanohydrin is in equilibrium with the α-ketoester and acetylation thus proceeds through dynamic kinetic resolution catalyzed by a chiral Lewis base. The reactive ketoesters were not influenced by the chirality of Ti-salen complex; when (S,S) or (R,R)-1 was used as a catalyst together with achiral base for the cyanoacylation of ketoesters, only racemic product was obtained (Scheme 10). 21

32 + LB + LB R - R + NC - R NC R Scheme 10. Mechanism of Lewis base catalyzed acylcyanation of α-ketoester If the more electron-poor aldehydes follow the same reaction mechanism as the α-ketoesters it would be in good agreement with the ammett correlation studies. Lewis base catalyzed reaction of benzaldehyde using cinchonidine at -40 C provided enantioenriched product with very low conversion rate in earlier studies. 64 Subjecting the most electron-poor aldehydes in the study to the same reaction conditions gave the product in low yield and low ee (Scheme 11). The results indicate that dual activation is required even for the electron-poor aldehydes in order to get an efficient reaction. - NR 3 + Ar Ar Ar Ar Scheme 11. Possible mechanism for Lewis base catalysis via dynamic kinetic resolution To explore the role the Lewis acid and the Lewis base for the different aldehydes, experiments with different combinations of enantiopure or racemic Lewis acid with chiral or achiral Lewis base were designed. Enantiopure Lewis acid in combination with achiral Lewis base should generate enantioenriched product if the first step is rate-determining (Scheme 12) and a racemate, or a product with low ee, if the acylation step is rate-determining (Scheme 13). 22

33 LA* RDS - LA* LB + Ar Ar Ar Scheme 12. Suggested rate-detemining step for the electron-rich aldehydes Racemic Lewis acid in combination with chiral Lewis base should give enantioenriched product if instead the acylation step is rate-determining whereas racemic product is expected if the first step is rate-determining. A combination of enantiopure Lewis acid and chiral Lewis base should give enantioenriched product for both scenarios. RDS - LB + Ar Ar Ar Scheme 13.Proposed rate-determining step for electron-poor aldehydes Three different catalyst combinations were compared I. Enantiopure Lewis acid (R,R)-1 and the achiral Lewis base triethylamine, II. (R,R)-1 and the chiral Lewis base cinchonidine (10). III. Racemic mixture of (S,S)- and (R,R)-1 combined with cinchonidine (Scheme 14). X LA-LB C 2 Cl 2 40 C X Scheme 14. Setup for the reactions using different combinations of Lewis acid and Lewis base Experiments were prepared in the glovebox by mixing Lewis acid, Lewis base, and aldehyde in C 2 Cl 2. The reaction mixture was kept at -40 C for one hour before addition of acetyl cyanide to start the reaction. The ee:s of the products, analyzed by chiral GC or PLC, are presented in Table 2. Ac X Ac N 10 N 23

34 Table 2. Enantiomeric excess derived from acetylcyanation of aldehydes catalyzed by combining enantiopure Lewis acid achiral Lewis base, enantiopure Lewis acidchiral Lewis base, racemic Lewis acid-chiral Lewis base or only chiral Lewis base entry X LA LB %ee (S) σ 1 a 4-C 3 2 a 4-3 a 4-Cl 4 b 4-CF 3 5 b 4-6 b,d 3-N 2 7 c 3,5-Cl 2 (R,R)-1 NEt 3 79 (R,R)-1 cinchonidine 83 (S,S)+ (R,R)-1 cinchonidine 6 (R,R)-1 NEt 3 82 (R,R)-1 cinchonidine 84 (S,S)+(R,R)-1 cinchonidine 6 (R,R)-1 NEt 3 79 (R,R)-1 cinchonidine 81 (S,S)+(R,R)-1 cinchonidine 4 (R,R)-1 NEt 3 43 (R,R)-1 cinchonidine 42 (S,S)+(R,R)-1 cinchonidine 7 - cinchonidine 26 (R,R)-1 NEt 3 5 (R,R)-1 cinchonidine 41 (S,S)-1 cinchonidine -61 (S,S)+(R,R)-1 cinchonidine 2 - cinchonidine 32 (S,S)-1 NEt 3-14 (S,S)-1 cinchonidine -40 (S,S)+(R,R)-1 cinchonidine -13 (R,R)-1 NEt 3 27 (R,R)-1 cinchonidine 74 (S,S)+(R,R)-1 cinchonidine 10 (S,S)-1 cinchonidine cinchonidine 23 a Determined by chiral GC. b Determined by chiral PLC. c Determined by PLC; abs. config not known. d Bad peak separation. The results from the study reveal that the aldehydes that followed the straight line of the ammett plot (entries 1-4) also followed the expected reaction pattern where chirality is transferred from the Ti-complex. The presence of chiral base 10 affected the final ee to a very small extent. In contrast, starting from 4-cyanobenzaldehyde (entry 5), the enantiopure Ti-complex did not seem to influence the enantiomeric excess when used in combination with achiral base; in combination with chiral base 10, enantioenriched product was formed,

35 but the use of chiral base in combination with a racemic mixture of (S,S)-1 and (R,R)-1 gave the product as a racemate. Starting from 3-nitrobenzaldehyde and 3,5-dichlorobenzaldehyde resulted in a similar pattern (entries 6-7). Changing the configuration of the Ti-complex to (S,S)-1 gave the opposite configuration of the product. The results imply that the cyanohydrin is coordinated to the titanium complex in the acylation step. With this assumption, the results could then be explained by looking at the formation of the different chiral species in the reaction mixtures. In the first scenario, I., enantiopure Lewis acid was combined with achiral Lewis base. For electron-rich aldehydes, such as 4- methoxybenzaldehyde, the presence of (R,R)-1 favored the formation of S- cyanohydrin. Acylation of the enantioenriched cyanohydrin proceeded with achiral base to give enantioenriched product (Scheme 15). I. electron-rich aldehydes RDS LA R LA R - LA R R LA R S Me Me Me Me NEt 3 Ac Ac R S Me Me 79% ee Scheme 15. Dual catalysis using enantiopure Lewis acid and achiral Lewis base gave the product in enantioenriched form for the electron-rich aldehydes 25

36 When instead electron-poor 4-cyanobenzaldehyde was used, combining the same catalysts, the product appeared in low enantiomeric excess. The reason was probably due to the different rate-determining step. The energy barrier for the formation of the Ti-bound cyanohydrins is most certainly lower from electron-poor aldehydes, which is why the two enantiomers were formed in similar amounts. Acylation by achiral Lewis base gave the product in merely 5% ee (Scheme 16). I. electron-poor aldehydes LA R LA R - LA R R LA R S NC NC NC NC RDS NEt 3 Ac Ac R S NC NC 5% ee Scheme 16. Dual catalysis using enantiopurel Lewis acid and achiral Lewis base gave the product in low ee for the electron-poor aldehydes 26

37 The second scenario included two chiral catalysts and gave enantioenriched product for both types of aldehydes. Starting from 4-methoxybenzaldehyde resulted in a slightly higher ee (83% instead of 79%) than when enantiopure Lewis acid was used in combination with achiral Lewis base, demonstrating that the chiral base also influences the enantioselectivity, although only to a small extent (Scheme 17). II. electron-rich aldehydes RDS LA R LA R - LA R R LA R S Me Me Me Me NR 3 * Ac Ac R S Me Me 83% ee Scheme 17. Dual catalysis using enantiopure Lewis acid and chiral Lewis base gave the product in enantioenriched form for the electron-rich aldehydes 27

38 When instead 4-cyanobenzaldehyde was used, the cyanohydrin diastereomers were assumed to be formed in close to equal amounts in the first step followed by resolution of the diastereomers by the chiral Lewis base-activated acylation reagent. The product was formed in 41% ee (Scheme 18). II. electron-poor aldehydes LA R LA R - LA R R LA R S NC NC NC NC RDS NR 3 * Ac Ac R S NC NC 41% ee Scheme 18. Dual catalysis using enantiopure Lewis acid and chiral Lewis base gave the product in enantioenriched form for the electron-poor aldehydes 28

39 Starting form 4-methoxybenzaldehyde and a racemic mixture of (S,S)- and (R,R)-Ti complex was assumed to yield two favored opposite cyanohydrin enantiomers in the first step due to the presence of both enantiomers of the chiral catalyst. Acylation by chiral Lewis base then gave the product in close to a racemate (Scheme 19). III. electron-rich aldehydes LA S LA R Me Me LA R LA S RDS - Me LA R R LA S Me LA R S LA S Me R S Me Me NR 3 * Ac Ac R S Me Me 6% ee Scheme 19. Dual catalysis using racemic Lewis acid and chiral Lewis base gave the product in racemic form for the electron-rich aldehydes 29

40 Subjecting 4-cyanobenzaldehyde to the same combination of catalysts also resulted in a racemic product (Scheme 20). Following the same reasoning as before the cyanohydrin diastereomers would form in close to equal amounts in the first step. Use of chiral Lewis base in the acylation step formed the product as a racemate. III. electron-poor aldehydes LA S LA R NC NC LA R LA S - NC LA R R LA S NC LA R S LA S NC R S NC NC RDS NR 3 * Ac Ac R S NC NC 2% ee Scheme 20. Dual catalysis using racemic Lewis acid and chiral Lewis base gave the product in racemic form for the electron-poor aldehydes The results from the reactions would have differed if the cyanohydrins were not coordinated to the Ti-complex for the electron-poor aldehydes. This can be explained by going back to the different scenarios again. In the first scenario, I., Scheme 16, the same result for coordinated and decoordinated cyanohydrin could be expected due to unselective acylation of the cyanohydrin by triethylamine (still assuming unselective formation of R- and S-cyanohydrins from electron-poor aldehydes due to the lower energy barriers, and rapid interconversion back to aldehyde). Reactions according to scenarios II. (Scheme 18) and III. Scheme 20, would have been expected to yield products with similar enantiomeric excess if the cyanohydrin was not coordinated to the Ti-complex. These two reactions 30

41 would have proceeded through dynamic kinetic resolution due to the presence of chiral base. This was clearly not the case, which is why it was concluded that cyanohydrin was coordinated to the Ti-complex in the acylation step. By using different combination of enantiopure and racemic Lewis acid together with chiral or achiral Lewis base it was found that the ratedetermining step differs depending on the properties of the starting aldehyde. For electron-rich aldehydes the formation of cyanohydrin was found to be ratedetermining whereas the acylation step was presumed to be rate-determining for the electron-poor aldehydes. The results provide strong support for the assumption that cyanohydrin is formed and acylated while coordinated to the Ti-complex NMR Study The aim of the study was to identify possible intermediates in the reaction, in particular to investigate if free cyanohydrin was formed, and to detect coordination of aldehyde to the Lewis acid. The reaction of benzaldehyde with acetyl cyanide, catalyzed by (S,S)-1 and triethylamine in CD 2 Cl 2, was followed by low temperature NMR. Yields of the species formed in the reaction were calculated using an internal standard. (S,S)-1 and CD 2 Cl 2 were mixed in the glovebox and then cooled to -40 C for 2 hours. Addition of aldehyde, Lewis base, acetyl cyanide, and internal standard was made at -78 C. 1 NMR spectra were recorded every 10 minutes for 15 hours (Figure 18) yield / % time / min Figure 18. Development of % yield cyanohydrin (w ) and % yield acylated product (o) over time 31

42 Interpreting the result from the kinetic study it could clearly be seen that cyanohydrin was formed. Zooming in on the initial part of the plot (Figure 19) it was noted that both development of product and free cyanohydrin followed after an induction period. This indicated that both species are formed while coordinated to the Ti-complex. Formation of cyanohydrin could be due to the presence of water that would hydrolyze the Ti-cyanohydrin complex. The constant amount of the cyanohydrin present in the reaction mixture indicates that it is not an intermediate but a by-product, although further studies are needed in order to confirm this conclusion. yield / % time / min Figure 19. Enlarged part of Figure 18. Development of % yield cyanohydrin (w ) and % yield acylated product (o) over time Attempts to detect what happens with the Ti-complex in the presence of acetyl cyanide did not give any clear results. When one equivalent of acetyl cyanide was added to one equivalent of Ti-complex in CD 2 Cl 2 at -40 C, acetyl cyanide was slowly consumed over 90 minutes and formed acetyl cyanide dimer 11. The dimer is previously known to form by the addition of base to acetyl cyanide (Scheme 21). 81 Very small changes in chemical shifts (< 0.1 ppm) were detected for the Ti-complex. NMR spectra recorded after the addition of one equivalent of benzaldehyde again revealed marginal changes in chemical shifts both for the aldehyde and the Ti-complex. Addition of one equivalent of triethylamine to the NMR tube did not change the appearance of the spectra. 32