FULL PAPER DOI: 10.1002/ejoc.201100089 Catalyst-Free Strecker Reaction in Water: A Simple and Efficient Protocol Using Acetone Cyanohydrin as Cyanide Source Paola Galletti,*[a] Matteo Pori,[a] and Daria Giacomini*[a] Keywords: Multicomponent reactions / Aldehydes / Ketones / Amines / Cyanides A simple, convenient, and practical method for the synthesis the expected α-amino nitrile pure after direct separation from of α-amino nitriles through a one-pot, three-component water. The protocol is particularly efficient for both aliphatic Strecker reaction of a carbonyl compound, amine, and acet- and aromatic aldehydes, and cyclic ketones, in combination one cyanohydrin in water has been developed. Reactions with primary and secondary amines. An unusual application proceed very efficiently without any catalyst at room tem- of the Strecker reaction to 1,2-diamines to obtain 1,2-diamino perature with high chemoselectivity and give, in some cases, nitriles, and to cyclic secondary amines is reported. Introduction ethylamine as catalyst.[11] Paraskar and Sudalai reported The Strecker reaction was a milestone in organic synthe- the use of acetone cyanohydrin in a one-pot amino nitrile sis and is still the classical method used to obtain α-amino synthesis in organic solvents with a base as catalyst.[15] nitriles,[1] which, in turn, are very important precursors of The original protocol developed by Strecker used water natural and non-natural α-amino acids,[2] 1,2-amino as reaction solvent, but, in modified Strecker protocols, alcohols, 1,2-diamines, and intermediates for several trans- water was replaced by organic solvents, such as toluene, formations.[3] The classical Strecker reaction is a three-com- dichloromethane, or acetonitrile, especially with TMSCN ponent reaction between a carbonyl compound, ammonia, as cyanide source, to improve the solubility of organic rea- and an alkaline cyanide, and is usually performed in aque- gents. As an example of the use of nonconventional sol- ous solution; in terms of atom economy the reaction is a vents, a Strecker reaction in ionic liquid was also re- model.[4] Several modifications of the original protocol have ported.[16] These modifications significantly improved the been reported, and these are referred to as modified performance of the reaction in terms of yields and reaction Strecker reactions. Such modifications concern the cyanide time, but, in some cases, the modified protocols required source, the presence of a catalyst, and the reaction solvent. tedious workup to separate toxic Lewis acids as well as their Hydrogen cyanide (HCN) is the most straightforward cy- hydrolysis products and organic solvents, leading to the anating agent, but its toxicity and volatility severely limits generation of a large amount of waste. Therefore, there was its widespread and practical application in organic synthe- scope to develop milder conditions to render the Strecker sis. To avoid the use of toxic HCN, a variety of cyanating reaction even more attractive. agents, such as trimethylsilyl cyanide (TMSCN),[5] (EtO) P- 2 As part of our interest in chemoenzymatic syntheses,[17] (O)CN,[6] Et AlCN,[7] Bu SnCN,[8] MeCOCN,[9] K [Fe- 2 3 4 we recognized the advantages of using acetone cyanohydrin (CN) ],[10] and acetone cyanohydrin,[11] have been used. 6 in water for a one-pot Strecker protocol under catalyst-free TMSCN is widely used in the Strecker reaction, but conditions, and here we report our results. We optimized Brönsted or Lewis acids or bases are often required as cata- the reaction protocol with three model aldehydes and lysts.[12] Interestingly, solvent- and/or catalyst-free condi- benzylamine, then explored the scope of the reaction with tions with TMSCN were recently reported.[13] Acetone a series of α-amino nitriles and with an unusual application cyanohydrin in water is frequently used in chemoenzymatic of the Strecker reaction on 1,2-diamines and secondary synthesis of cyanohydrines through transhydrocyanation,[14] amines (Scheme 1). but, surprisingly, it has found few applications in the Strecker reaction. A recent application in a synthesis of amino nitriles was reported starting from aldimine alanes generated in situ from diisobutylaluminium hydride and tri- [a] Department of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy Fax: +39-051-2099456 E-mail: [email protected] [email protected] Scheme 1. Three-component Strecker reaction. 3896 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 3896–3903 Catalyst-Free Strecker Reaction in Water Results and Discussion solution to give the amino nitrile B of acetone; (iii) it can react with the starting aldehyde to give the corresponding Acetone cyanohydrin is an important chemical interme- cyanohydrin C (Figure 2). The latter route can be regarded diate[18] for the manufacture of methacrylates; it is inexpen- as a competitive transcyanation reaction between acetone sive and is a large-scale, commercially available cyanide cyanohydrin and the aldehyde. We began our investigation source.[19] Acetone cyanohydrin is highly soluble in water, by studying the multicomponent reaction with acetone where its dissociation to give acetone and hydrogen cyanide cyanohydrin under catalyst-free conditions with benzyl- reaches equilibrium in 18 h.[20] In the presence of an amine, amine and tested three aldehydes: benzaldehyde, butanal, establishment of the equilibrium is almost instantaneous.[21] and racemic 2-phenylpropanal (a model for a chiral compo- In an attempt to reproduce one-pot Strecker reaction condi- nent). tions and to study the influence of the parent amine and of the corresponding imine intermediate, we monitored the 1 dissociation of acetone cyanohydrin in D2Oby H NMR analysis following the formation of acetone, and tested the effect of additives such as benzylamine and its imine with benzaldehyde (N-benzylidene-1-phenylmethanamine). In an NMR tube, acetone cyanohydrin (10 μL) was added to D2O (0.7 mL), and a 1H NMR spectrum was quickly recorded. The reaction time course was sampled every 5 min for a total time of 35 min. The same conditions were used with 5 mol-% benzylamine or the imine N-benzylidene-1-phenyl- methanamine. The data were obtained by digital integration of the acetone signal (Ia at δ = 2.11 ppm), which was com- pared to the integration of the acetone cyanohydrin signal Figure 2. Competitive reactions in a one-pot Strecker synthesis (Iac at δ = 1.51 ppm) and were plotted as the ratio Ia/Iac against time (Figure 1). The data clearly showed that the with acetone cyanohydrin in water. equilibrium conditions were established more rapidly in the presence of additives than in D2O alone. The presence of The reaction was tested in a series of solvents, binary either benzylamine or imine facilitated rapid acetone cya- aqueous mixtures, and neat conditions. Reactions were car- nohydryn decomposition in situ, thus establishing suitable ried out in closed vials to minimize the loss of volatiles and conditions for an efficient one-pot Strecker reaction. stirred in an orbital shaker. The crude reaction mixtures from reactions carried out in organic solvents were directly concentrated and analyzed; those in water were extracted into ethyl acetate. In Table 1, Entries 1–20, the amount of acetone cyanohydrin was 1.5 equiv. with respect to the car- bonyl compound, whereas it was reduced to 1 equiv. in En- tries 22–24. Reactions were monitored by either HPLC or NMR analysis, and the reaction times reported in Table 1 correspond to a maximum conversion of the starting alde- hyde. In the organic solvents (CH2Cl2, tBuOMe, and CH3CN), the yields of amino nitriles 1–3 ranged from moderate to poor (Table 1, Entries 1–9). With benzaldehyde, the imine intermediate A (see Figure 2) was recovered in a significant amount and, in the case of tBuOMe, it was the only product (Table 1, Entry 4). With butanal and 2-phenylpropanal, the Figure 1. Effect of additives on the decomposition of acetone by-products B and C were also recovered (Table 1, En- cyanohydrin in D2O. Dependence of the ratio of integrals for the tries 2, 3, 5, 8, and 9). Under neat conditions without any resonance lines of acetone Ia and acetone cyanohydrin Iac over time. solvent, the reactions were very fast, but only 2-phenyl- Data in D2O (dots), D2O and 5 mol-% BnNH2 (triangles), D2O propanal gave the α-amino nitrile 3 in almost quantitative and 5 mol-% N-benzylidene-1-phenylmethanamine (squares). yield; benzaldehyde gave 1 in 53% yield with 46% recovery of the unreacted imine. Butanal gave 2 in 30 % yield to- Decomposition of acetone cyanohydrin in water gives gether with a series of unidentified by-products, perhaps HCN, which, in a one-pot procedure, can participate in due to aldehyde polymerization (Table 1, Entries 10–12). three concurrent and competitive reaction pathways: (i) it Better results were obtained with homogeneous or biphasic can react with the imine intermediate A (Figure 2) to give solvent mixtures composed of an organic solvent and water. the expected Strecker amino nitrile; (ii) it can react with The biphasic mixture tBuOMe/H2O (1:1) gave good results, the ketimine derived from acetone and the amine present in with lower amounts of by-product, except for the reaction Eur. J. Org. Chem. 2011, 3896–3903 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3897 FULL PAPER P. Galletti, M. Pori, D. Giacomini Table 1. Optimization of reaction conditions for the one-pot Strecker reaction with acetone cyanohydrin.[a] Entry R Solvent Time [h] Product (yield [%]) By-product (yield [%]) 1PhCH2Cl2 20 1 (76) A (24) 2BuCH2Cl2 20 2 (76) B (20) [b] 3 CH(CH3)Ph CH2Cl2 20 3 (76) B (10) 4Ph tBuOMe 20 1 (0) A (99) 5Bu tBuOMe 20 2 (33) B (33), C (33) 6 CH(CH3)Ph tBuOMe 20 3 (20) n.d.