CO2-Enabled Cyanohydrin Synthesis and Facile Homologation Reactions Martin Juhl†, Allan R

CO2-Enabled Cyanohydrin Synthesis and Facile Homologation Reactions Martin Juhl†, Allan R. Petersen†, Ji-Woong Lee*,† †Department of Chemistry, Nano-Science Center, University of Copenhagen, Universitetsparken 5, Copenhagen Ø, 2100, Denmark KEYWORDS: Carbon Dioxide, Cyanohydrin, Xanthate, Homologation ABSTRACT: Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when desired product is not accessible; one may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to direct reaction pathways in order to selectively afford desired products in high reaction rates while avoiding the formation of byproducts. The utility of CO2-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani-Fischer synthesis to offer an easy access to variety of polyols, cyanohydrins, linear al- kylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and atmospheric pressure of CO2. 9 A chemical reaction is governed by kinetics and ther- investigated the role of CO2 in a cyanation reaction, where CO2 modynamics, and a simultaneous control of both parameters is can be used in catalytic amounts to facilitate the stereoselective a common practice in designing and optimizing chemical reac- transformation of activated electrophiles via 1,4-conjugate ad- tions. The manipulation of thermodynamic stability of reactants dition reactions. Cyanohydrin synthesis - 1,2-cyanide addition and products will decide the outcome of a chemical process, reactions to carbonyls - is one of the oldest C-C bond-forming while various reaction pathways can lead to undesired products reactions, reported in 1832 by Winkler using HCN as a cyanide thus reducing overall efficiency of the process.1 To circumvent source.10 Despite the high utility of cyanohydrins in organic unwanted reaction pathways, chemists have developed selec- synthesis11-14 the use of HCN may reduce its application poten- tive catalysis, protecting groups (P in Figure 1), trapping rea- tial due to its volatile nature and health risks. Recent activities gents and reactivity-altered reactants (A’ and B’), which in turn in cyanohydrin synthesis are mainly performed by using can limit the scope and generality of the original reaction. In our TMSCN15 and cyanoformate16 as an HCN surrogate.11,12,17 ongoing pursuit to implement CO2 in the core of organic syn- These reagents suffer from poor atom economy when un-pro- thesis, we sought out ways in which equilibria can be controlled tected cyanohydrins are desired. Furthermore, the cyanation re- by the presence and the absence of CO2 – a mild Lewis and po- actions with in-situ generated HCN (from mixture of TMSCN tentially Brønsted acid. Here we demonstrate our strategy by and an alcohol) are limited by the instability of the cyanide accelerating an organic reaction; nucleophilic 1,2-addition of a sources thereby limiting the solvent compatibility. 11,18 carbon nucleophile to carbonyl compounds, namely cyanohydrin formation reaction promoted by CO2. Facile homologation It has been a common knowledge that cyanohydrin formation of aldehydes with cyanide was realized expanding the scope be- can not be “catalyzed” due to the high nucleophilicity of cya- yond Killiani-Fischer synthesis, under practical reaction condi- nides although the reaction undergoes strong backward reaction -8 -1 -1 -10 -1 tions, accessing variety of compounds in a modular fashion. (kforward = 1.96 x 10 sec M , kbackward = = 0.87 x 10 sec , in RCHO +HCN ó RC(OH)CN).19 Whilst Brønsted acids can generate volatile yet nucleophilic HCN from solid cyanide sources (NaCN or KCN), general and specific acid catalysis can only be operative at exceedingly low concentration of an acid catalyst.20 This has been manifested in total synthesis, which O RCHO R O OK OH R KCN OK Figure 1. A comparison of traditional reaction optimization and our R H R CN R CN O CO CO2-approach. (P = catalysts, protecting groups or trapping reagents) CO2 2 + R CO H then H3O OH HO R 2 2-3 OH R' Carbon dioxide is intrinsically stable molecule, however, it H O O2 O 2,4 R' can readily and reversibility react with various nucleophiles. R CN R OH Recent applications of carbon dioxide in organic synthesis no HCN generation potential by products from benzoin reaction 5 carboxylation, oxidation, aldol reaction and condensation showed fruitful success particularly in CO2-incorporation, CO2 higher reaction rate 6 as a temporal protecting group for C-H activation, CO2 for Scheme 1. Cyanohydrin synthesis enabled by CO2/KCN and side reac- asymmetric catalysis7 and oxidation reactions8. We recently tion pathways. requires sophisticated cyanide sources and reagents. For exam- ple, high selectivity towards cyanohydrin formation was realized assisted by an activating reagent, i.e. Al-based cyanide 21,22 sources (AlEt2CN, Nagata’s reagent). Entry Deviation from standard reaction conditions Yieldb At this juncture, the lack of a general and practical method for cyanohydrin formation reaction under neutral conditions led us 1 None 99% (97%)c to investigate the potential utility of CO2 in cyanohydrin syn- 2 No CO2 (under N2) 7% thesis with alkaline metal cyanides. Under mild conditions, CO2 can generate slightly acidic medium thus enabling catalysis, 3 HCN (2 equiv) instead of KCN 21% while exhibiting Lewis acidic character at the central carbon for trapping and stabilizing anionic species. However, another 4 30 min of reaction time 91% challenge lays on the side reactions: benzoin- and self-aldol reactions from KCN and aldehydes, generating numerous byprod- 5 H2O as a solvent 95% ucts (Scheme 1). Based on our previous work, we sought that 6 n-heptane as a solvent 87% the use of CO2 in principle provide a practical method by min- imzing side products, while overcoming the limit of Kiliani- 7 toluene as a solvent 9% Fischer synthesis beyond carbohydrate modification via selective cyanohydrin synthesis.23 8 DCM as a solvent 22% We have recently shown the applicability cyanohydrins as a nu- 9 DCM as a solvent + DBU (1 eq) 97% cleophile via an umpolung strategy (Scheme 1, a-keto acid syn- 11 NaCN, 30 min 57% thesis).24 In the absence of Ti(IV) and DBU, we observed facile formation of cyanohydrin in pseudo first order of the aldehyde 12 NEt4CN, 30 min 97% with KCN under CO2 atmosphere (1 atm) in ethanol (k = 2.50 x 10-3). This is approximately 105-folds rate acceleration com- 13 NEt4CN, 30 min, under N2 33% pared to the reported values,19 which is surprising considering 14 aq. 5M HCl (4 eq.) instead of CO2 24% that the reaction requires the solubilization of KCN in the organic solvent. We verified that the solubility of KCN was in- 15 AcOH (4 eq.) instead of CO2 95% creased in the presence of CO2 (Figure S6), which can be as- cribed to the formation of cyanoformate in solution liberating a4-fluorobenzaldehyde (1 mmol) and KCN (2 mmol) were mixed solubilized cyanide nucleophiles.25 Therefore, we performed in EtOH (2 mL). The reaction mixture was stirred under CO2 (1 various control experiments as summarized in Table 1. Under atm) for 18 h. bYield was determined by 19F nuclear magnetic res- onance spectroscopy (NMR) (D1; relaxation time = 2 s) of the CO2 atmosphere (1 atm), full conversion of the starting material c (1a) was observed to the desired cyanohydrin affording quanti- crude mixture. Isolated yield. tative isolated yield (99% conversion, 97% yield). When per- forming the cyanation under a N2 atmosphere, low conversion to cyanohydrin (7%) was detected within 10 min with no increase in yield of the product after prolonged reaction time (up to 18 h), indicating the reaction reached fast equilibrium in fa- vor of starting materials. More importantly, in situ generated HCN gave inferior result, (entry 3, 21% yield), while quantita- tive yield was obtained with KCN/CO2 combination within 30 minutes (entry 4, 91%). Variety of solvents were found to be compatible to induce desired product (i.e. ethanol, heptane, ac- etonitrile and water, see supporting information for full optimization, Table S1-13) showing the generality of the use of CO2 to accelerate cyanohydrin synthesis. The solubility of cyanide is important – a soluble cyanide source, ammonium cyanide, showed good conversion to the product however, the reaction was not efficient under inert N2 atmosphere (entries 12 and 13). Therefore, we concluded that CO2 is not innocent in this reaction, and it was evident that the reaction can be promoted by Figure 2. Cyanohydrin formation using stoichiometric amounts of carbon dioxide whereas a strong acid (e.g. HCl) afforded only CO . After 10 min was added CO (20 mol%) every 20 min. Cross low yield of the product since HCN (a “slower” nucleophile) 2 2 (X) marks the addition of catalytic amounts of CO2 (20 mol%). generation is favored (entry 14). The use of acetic acid26 showed compatible result (entry 15) confirming that weak acid can in- The role of CO2 in the cyanohydrin synthesis was further veri- deed catalyze the reaction, by prohibiting the complete proto- fied by adding catalytic amounts of CO2 (20 mol%) to a reaction nation of KCN. mixture repeatedly (Figure 2). A sharp increase of product formation was immediately observed followed by the addition of Table 1. Optimizing CO2 Mediated Cyanation CO2. A near stoichiometric relationship between product formation and the amounts of added CO2 indicates the added CO2 was quantitatively consumed as a stoichiometric reagent. Having demonstrated the feasibility of the CO2 promoted cyanohydrin formation, we explored the scope of the reaction with respect to both aryl and alkyl aldehydes and ketones (Scheme 2). A variety of aryl aldehydes was tested and provided the cor- responding cyanohydrin in excellent yields regardless their sub- stitution in terms of electron donating and withdrawing proper- ties.

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