A Simple and Efficient Protocol Using Acetone Cyanohydrin As Cyanide Source

Home , Acetone cyanohydrin, Benzylamine, Cyanohydrin, Hydrogen cyanide

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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.

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-phenylmethanamine. 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 carbonyl 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 aldehyde.

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

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. 7PhCH3CN 20 1 (36) A (64) 8BuCH3CN 20 2 (67) B (33) [b] 9 CH(CH3)Ph CH3CN 20 3 (68) B (11), C (12) 10 Ph Neat 0.5 1 (54) A (46) 11 Bu Neat 0.5 2 (30) n.d 12 CH(CH3)Ph Neat 0.5 3 (99) – 13 Ph tBuOMe/H2O2 1 (67) A (12), B (8), C (12) 14 Bu tBuOMe/H2O2 2 (90) B (5) 15 CH(CH3)Ph tBuOMe/H2O2 3 (87) B (4), C (9) 16 Ph CH3CN/H2O 0.5 1 (99) – 17 Bu CH3CN/H2O 0.5 2 (93) B (7) 18 CH(CH3)Ph CH3CN/H2O 0.5 3 (99) – 19 Ph H2O2 1 (96) – 20 Bu H2O 0.5 2 (90) B (10) [b] 21 CH(CH3)Ph H2O20 3 (90) – [c] 22 Ph H2O 2 1 (99) – [c] 23 Bu H2O 20 2 (99) – [c] [d] 24 CH(CH3)Ph H2O 20 3 (99) – [a] Reagents and conditions: aldehyde (1 mmol), benzylamine (1 mmol), acetone cyanohydrin (1.5 mmol), solvent (4 mL), room temp. See notes for exceptions. [b] Traces of acetophenone derived from decomposition of the starting aldehyde.[17a] [c] 1 mmol acetone cyanohydrin. [d] Diastereomeric ratio 65:35 determined by HPLC analysis on a chiral column of the trifluoroacetamide derivatives (IC, hexane/iPrOH, 85:15). with benzaldehyde (Table 1, Entries 13–15). However, the often used as a model aldehyde in nucleophilic addition re- amount of by-products A, B, and C were further reduced actions, did not work; however, arylaldehydes bearing elec- by using the homogeneous solvent mixture CH3CN/H2O tron-donating groups gave better results (Table 2, Entry 14 (1:1), in which the reaction was even faster (30 min for com- vs. Entries 9 and 12). Salicylaldehyde and 4-hydroxybenzal- plete conversion; Table 1, Entries 16–18). Finally, we tested dehyde gave interesting results under neat conditions with the reaction protocol in water alone and found that, al- 2 equiv. of acetone cyanohydrin (Table 2, Entries 8 and 11); though the reaction mixture was heterogeneous, it afforded however, better results were obtained when the phenol α-amino nitriles in high yields. Benzaldehyde and 2-phenyl- group was protected as the methoxy derivative (Table 2, En- propanal gave good results, whereas butanal gave a residual try 9). Aniline and 1,2-benzenediamine gave modest yields amount of the benzylamino nitrile of acetone, by-product with benzaldehyde and no reaction with butanal (Table 2, B (Table 1, Entries 19–21). By reducing the amount of acet- Entries 1, 2, and 19). When yields were not quantitative, no one cyanohydrin to 1 equiv., all three aldehydes were ef- traces of the amino nitrile B of acetone or cyanohydrines ficiently transformed into the corresponding α-amino ni- C were detected in the reaction mixtures. Recognized by- triles 1–3 in high overall yields and with the suppression of products included the starting aldehydes, unreacted inter- the by-product B (Table 1, Entries 22–24). mediate imines A, or autocondensation products of enoliz- The experimental conditions were thus standardized to able aldehydes. The reaction of 1,2-ethylenediamine was carbonyl compound, amine, and acetone cyanohydrin, successful with both benzaldehyde and butanal, giving the which were used in a 1:1:1 molar ratio, and the scope was corresponding diamino nitriles as a 1:1 diastereomeric mix- widened to include further amines, carbonyl components, ture (Table 2, Entries 3 and 16). Piperidine, as a model for aldehydes (Table 2) or ketones (Table 3). a secondary amine, gave excellent results (Entries 5 and 21), Benzylamine and allylamine gave excellent results with whereas morpholine and piperazine gave lower yields (En- benzaldehyde and aliphatic aldehydes (Table 1, Entries 22 tries 4, 6, 20, and 22). Remarkably, no traces of mono-α- and 23; Table 2, Entries 17, 23, and 24); in particular, pival- amino nitriles were detected in the reaction with diamines. aldehyde (Entry 24) is of great importance, because hydroly- It is noteworthy that the majority of substrates and prod- sis of its α-amino nitrile gives access to the non-natural ucts were not soluble in water. Complete reactions and ex- amino acid tert-leucine. p-Nitrobenzaldehyde, which is cellent yields of the desired products reflect the fact that the

Table 2. One-pot Strecker reaction in water with 1 equiv. of acetone cyanohydrin in combination with aliphatic and aromatic aldehydes and primary and secondary amines.[a]

[a] Reagents and conditions: aldehyde (1 mmol), amine (1 mmol) or diamine (0.5 mmol), acetone cyanohydrin (1 mmol), water (4 mL), room temp., 20 h. [b] For compounds 5, 6, 9, 17,and23 the diastereomeric ratio refers to the meso stereoisomer vs. the racemic pair; configurations were not assigned. [c] Neat conditions, 2 equiv. of acetone cyanohydrin.

substrates efficiently react without the aid of an organic co- Piperidin-4-one is a quite interesting bifunctional com- solvent. Enforced hydrophobic interactions could play a pound that, in the one-pot procedure, worked either as the significant role here.[22] amino component with butanal to afford α-amino nitrile Dialkyl and alkyl aryl ketones gave unsatisfactory results 26, or as the carbonyl component with benzylamine to give (Table 3 Entries 1–8), but cyclic ketones gave excellent 36 (Scheme 2; Table 2, Entry 25; Table 3, Entry 15). yields, which is in line with the reactivity and the internal With increasing concern for the environment, the need strain effect (I-strain) of linear versus cyclic ketones in nu- for more sustainable synthetic methods has become of sig- cleophilic addition reactions (Table 3, Entries 9, 10, and 12– nificant importance for reactions on any scale, from indus- 14).[23] Cyclohexenone did not react under these conditions, try to academia. Unquestionably, all cyanide sources are either in 1,2 or 1,4 reaction modes (Table 3, Entry 11). potentially noxious and must be used with precautions due

Table 3. One-pot Strecker reaction in water with 1 equiv. of acetone absence of catalysts, the use of water, and the straightfor- cyanohydrin in combination with ketones and benzylamine.[a] ward procedure. In particular, the use of 1 equiv. of acetone cyanohydrin to obtain α-amino nitriles in high to optimum yields with acetone as the unique by-product makes this protocol more competitive from the atom economy point of view than any other cyanide source, including TMSCN, which is also much more expensive. HCN would be more favorable but, unquestionably, liquid acetone cyanohydrin is easier to quantify and handle than gaseous HCN. In or- der to reduce the environmental impact of the overall process as much as possible, another important favorable as- pect of the protocol is the possibility to completely avoid the use of organic solvents, even in the workup and isola- tion of the products. The heterogeneous reaction conditions used in this procedure have the additional advantage that, at the end of reaction, the product can be removed by a simple phase separation. When the one-pot reaction in water is scaled up to 4 mmol, extraction with an organic solvent was no longer necessary because the hydrophobic nature of the liquid products allowed them to be separated from the water and dried under reduced pressure; solid products were simply filtered off and dried (Figure 3). Scal- ing up with no workup was tested with a number of substrates to give the expected products with unaltered yields (Table 1, Entry 24; Table 2, Entries 2, 16, 19, 20, 22; Table 3, Entry 13).

[a] Reagents and conditions: ketone (1 mmol), benzylamine (1 mmol), acetone cyanohydrin (1 mmol), H2O (4 mL). [b] For Figure 3. Examples of heterogeneous reaction conditions for the compounds 33, 34 and 35, diastereomeric ratio refers to trans vs. scaled-up, one-pot Strecker synthesis with acetone cyanohydrin in cis stereoisomers. [c] 1.5 equiv. of acetone cyanohydrin. water; reaction product 3 (left); 34 (centre), and 16 (right).

Conclusions We have demonstrated a simple, convenient, and practical method for the synthesis of racemic α-amino nitriles through a one-pot, three-component Strecker reaction of a carbonyl compound, an amine, and acetone cyanohydrin in water. Reactions proceeded very efficiently at room tem- perature with high selectivity and gave, in some cases, the expected α-amino nitrile pure by direct separation from Scheme 2. Reaction with piperidin-4-one. water. The mild reaction conditions and the operational simplicity make this atom-economic cyanation process ex- to the high toxicity of HCN that can be released. However, tremely attractive to the development of cleaner and envi- the protocol developed here has several favorable aspects ronmentally more friendly processes for the synthesis of α- concerning the atom economy of the reaction as well the amino nitriles of synthetic importance. Moreover, in view

of the importance of natural and unnatural α-amino acids 2.98 (m, 4 H, NCH2CH2N), 4.76 (s, 2 H, 2 CHCN), 7.33–7.45 (m, 13 in the fine chemicals and pharmaceutical industries, the 10 H, ArH) ppm. C NMR (50 MHz, CDCl3): δ = 46.0, 46.2 (2nd current methodology offers the possibility of utilizing the diastereoisomer), 54.1, 54.2 (2nd diastereoisomer), 118.7, 127.2, –1 Strecker reaction economically for large-scale syntheses. 129.0, 129.1, 134.5 ppm. IR: ν˜ = 3330, 2223 cm . {4-[(Cyano)(phenyl)methyl]piperazin-1-yl}(phenyl)acetonitrile (9): 1 Yield: 70%; major stereoisomer; oil. H NMR (400 MHz, CDCl3): Experimental Section δ = 2.60–2.70 (m, 8 H, 2 NCH2CH2), 4.88 (s, 1 H, CHCN), 4.90 (s, 1 H, CHCN), 7.35–7.45 (m, 6 H, ArH), 7.52–7.57 (m, 4 H, ArH) 13 General: Commercial reagents were used as received without ad- ppm. C NMR (100 MHz, CDCl3): δ = 49.3 (broad signal), 61.9, ditional purification, N-benzyl-4-piperidone was prepared accord- 115.2, 127.7, 128.7, 128.9, 132.6 ppm. IR: ν˜ = 2224, 1600 cm–1. [24] 1 13 ing to the literature. Hand C NMR spectra were recorded C20H20N4 (316.40): calcd. C 75.92, H 6.37, N 17.71; found C 76.03, + with an INOVA 400 or a GEMINI 200 instrument with a 5 mm H 6.44, N 17.74. GC-MS: m/z (tr = 25.6 min) = 316 [M] , 290 + probe. All chemical shifts are quoted relative to deuterated solvent [M – CN], 200, 116. HPLC-MS: m/z (tr = 10.55 min) = 339 [M + signals (δ in ppm and J in Hz). FTIR spectra were recorded with Na]+, 317 [M + 1]+. a Thermo Nicolet 380 instrument and measured as films between (Benzylamino)(2-hydroxyphenyl)acetonitrile (10): Yield: 65%; oil. –1 NaCl plates; wave numbers are reported in cm . TLC was con- 1 H NMR (400 MHz, CDCl3): δ = 2.78 (br. s, 1 H, NH), 3.94 (d, ducted with Merck 60 F254 plates. Column chromatography was JAB = 12.8 Hz, 1 H, CHHPh), 4.12 (d, JAB = 12.8 Hz, 1 H, conducted with Merck silica gel 200–300 mesh. GC-MS was con- CHHPh), 5.02 (s, 1 H, CHCN), 6.83–6.89 (m, 2 H, ArH), 7.19– ducted with an Agilent Technologies MSD1100 single-quadrupole 13 7.37 (m, 7 H, ArH) ppm. C NMR (100 MHz, CDCl3): δ = 50.6, mass spectrometer, EI voltage 70 eV, gradient from 50 to 280 °C in 51.5, 117.6, 120.2, 125.7, 127.5, 128.2, 128.5, 128.6, 131.0, 30 min, column HP5 5% Ph-Me Silicon. HPLC-MS was conducted –1 156.3 ppm. IR: ν˜ = 3350, 2221, 1620 cm .C15H14N2O (238.28): with an Agilent Technologies HP1100 instrument, with a ZOB- calcd. C 75.61, H 5.92, N 11.76; found C 75.58, H 5.86, N 11.83. RAX-Eclipse XDB-C8 Agilent Technologies column; mobile phase: H O/CH CN, gradient from 30 to 80% of CH CN in 8 min, (Benzylamino)(4-hydroxyphenyl)acetonitrile (12): Yield: 75%; 2 3 3 1 orange solid; m.p. 79 °C. H NMR (400 MHz, CDCl3): δ = 1.82 80% of CH3CN until 25 min, 0.4 mL/min, coupled with an Agilent Technologies MSD1100 single-quadrupole mass spectrometer, full- (br. s, 1 H, NH), 3.86 (d, JAB = 12.8 Hz, 1 H, CHHPh), 3.97 (d, scan mode from m/z = 50 to 2600, scan time 0.1 s in positive ion JAB = 12.8 Hz, 1 H, CHHPh), 4.61 (s, 1 H, CHCN), 6.76 (m, 2 H, 13 mode, ESI spray voltage 4500 V, nitrogen gas 35 psi, drying gas ArH), 7.26–7.33 (m, 7 H, ArH) ppm. C NMR (100 MHz, flow 11.5 mL/min, fragmentor voltage 20 V. Elemental analyses CDCl3): δ = 50.9, 52.6, 115.8, 118.9, 125.7, 127.5, 128.2, 128.5, –1 were carried out with a Thermo Flash 2000 CHNS/O Analyzer. 128.6, 137.6, 156.7 ppm. IR: ν˜ = 3300, 2200, 1654, 1612, 1465 cm . C15H14N2O (238.28): calcd. C 75.61, H 5.92, N 11.76; found C General Procedure for the Synthesis of Amino Nitriles 1–37: The 75.48, H 5.83, N 11.72. chosen aldehyde (or ketone) (1 mmol) and amine (1 mmol, (Benzylamino)(pyridin-2-yl)acetonitrile (16): Yield: 98%; oil. 1H 0.5 mmol in the case of diamines) were mixed in an orbital shaker NMR (400 MHz, CDCl ): δ = 2.75 (br. s, 1 H, NH), 3.97 (d, J at room temp. in a 5 mL vial equipped with a screw cap. After 3 AB = 12.8 Hz, 1 H, CHHPh), 4.04 (d, J = 12.8 Hz, 1 H, CHHPh), 10 min, water (4 mL) and acetone cyanohydrin (1 mmol) were AB 4.79 (s, 1 H, CHCN), 7.25–7.48 (m, 7 H, ArH), 7.76 (dd, J = 10.0, added, and the cap was closed. The mixture was stirred in an or- 10 Hz, 1 H, ArH), 8.60 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR bital shaker for 20 h or until the reaction was complete (TLC moni- (100 MHz, CDCl ): δ = 51.4, 54.9, 122.0, 123.9, 127.7, 128.5, 128.6, toring). The reaction mixture was poured into brine (5 mL) and 3 128.8, 137.4, 138.0, 149.9, 153.7 ppm. IR: ν˜ = 3300, 2228, extracted with EtOAc (2ϫ10 mL), dried with Na SO , and concen- 2 4 1673 cm–1.C H N (223.27): calcd. C 75.31, H 5.87, N 18.82; trated. When necessary, products were purified by flash chromatog- 14 13 3 found C 75.44, H 5.94, N 18.98. HPLC-MS: m/z (t = 7.1 min) = raphy. When the reaction was performed on a higher scale, the r 224 [M + 1]+. workup was not necessary; the product separated from the aqueous phase when liquid or could be recovered by filtration when solid. 2-({2-[(1-Cyanobutyl)amino]ethyl}amino)pentanenitrile (17): Yield: Spectra of amino nitriles 1,[25] 2,[25] 3,[27] 4,[13a] 7,[28] 8,[29] 11,[30] 65%; mixture of diastereoisomers, dr = 50:50 (determined by GC- 13,[30] 14,[26] 19,[26] 24,[28] 25,[30] 27,[31] 30,[13b] 31,[32] 34 (trans/cis, MS analysis of trifluoroacetamide derivatives), diastereoisomers 88:12),[13b] and 37[33] were consistent with data reported in the lit- separated by flash chromatography. 1st diastereoisomer: Oil. 1H erature. NMR (400 MHz, CDCl3): δ = 0.97 (t, J =7.2Hz,6H,CH3), 1.47– 1.59 (m, 6 H, NH, CH ), 1.70–1.76 (m, 4 H, CHCH ), 2.72–2.81 [(2-{[(Cyano)(phenyl)methyl]amino}phenyl)amino](phenyl)aceto- 2 2 (m, 2 H, NCHHCHHN), 2.97–3.05 (m, 2 H, NCHHCHHN), 3.51– nitrile (5): Yield: 33%; mixture of diastereoisomers, dr = 95:5 (de- 3.56 (m, 2 H, CHCN) ppm. 13C NMR (100 MHz, CDCl ): δ = termined by NMR spectroscopy on crude material). Major stereo- 3 13.4, 18.9, 35.3, 35.4, 46.2, 46.8, 50.0, 50.4, 120.1, 120.2 ppm. IR: isomer: pale-yellow solid; m.p. 98 °C. 1H NMR (400 MHz, CDCl ): 3 ν˜ = 3316, 2225, 1464 cm–1.C H N (222.23): calcd. C 64.83, H δ = 3.07 (br. s, 2 H, NH), 5.39 (s, 2 H, CHCN), 7.02–7.05 (m, 2 12 22 4 9.97, N 25.20; found C 64.91, H 10.02, N 25.28. HPLC-MS: m/z H, ArH), 7.13–7.29 (m, 6 H, ArH), 7.36–7.42 (m, 3 H, ArH), 7.60– (t = 7.02 min) = 245 [M + Na]+, 223 [M + 1]+, 196 [M – HCN]+. 7.63 (m, 2 H, ArH), 7.80–7.82 (m, 1 H, ArH) ppm. 13C NMR r 2nd diastereoisomer: Oil. 1H NMR (400 MHz, CDCl ): δ = 0.98 (100 MHz, CDCl ): δ = 48.1, 110.5, 119.3, 122.8, 123.1, 125.7, 3 3 (t, J =7.6Hz,6H,CH), 1.51–1.64 (m, 6 H, NH, CH ), 1.72–1.78 127.6, 128.6, 128.8, 129.2, 130.0, 135.4, 135.9, 142.1, 153.9 ppm. 3 2 (m, 4 H, CHCH ), 2.74–2.82 (m, 2 H, NCHHCHHN), 3.07–3.00 IR: ν˜ = 3400, 2232, 1605, 1453 cm–1.C H N (338.41): calcd. C 2 22 18 4 (m,2H,NCHHCHHN), 3.53–3.60 (m, 2 H, CHCN) ppm. 13C 78.08, H 5.36, N 16.56; found C 77.92, H 5.32, N 16.41. NMR (100 MHz, CDCl3): δ = 13.5, 19.0, 35.4, 35.5, 46.3, 46.9, [(2-{[(Cyano)(phenyl)methyl]amino}ethyl)amino](phenyl)acetonitrile 50.1, 50.5, 120.2, 120.3 ppm. IR: ν˜ = 3312, 2224, 1464 cm–1.

(6): Yield: 99%; mixture of diastereoisomers, dr = 50:50 (deter- C12H22N4 (222.23): calcd. C 64.83, H 9.97, N 25.20; found C 64.76, + mined by GC-MS analysis on trifluoroacetamide derivatives); oil. H 9.92, N 25.18. HPLC-MS: m/z (tr = 7.05 min) = 223 [M + 1] , 1 + H NMR (400 MHz, CDCl3): δ = 1.80 (br. s, 2 H, 2 NH), 2.83– 196 [M – HCN] .

2-(Allylamino)pentanenitrile (18): Yield: 99 %; yellow oil. 1H NMR 7.6, 29.0, 48.9, 60.5, 121.8, 127.3, 128.3, 128.5, 139.4 ppm. IR: ν˜ = –1 (400 MHz, CDCl3): δ = 0.90 (t, J = 7.6 Hz, 3 H, CH3), 1.40 (br. s, 3320, 2218, 1457 cm .C13H18N2 (202.30): calcd. C 77.18, H 8.97, 1 H, NH), 1.44–1.51 (m, 2 H, CH2CH3), 1.68 (dt, J = 7.2, 7.6 Hz, N 13.85; found C 77.17, H 8.91, N 13.78. HPLC-MS: m/z (tr = + + 2H,CH2CH2CH), 3.23 (ddt, J = 1.2, 6.4, 13.6 Hz, 1 H, 9.8 min) = 203 [M + 1] , 176 [M – HCN] . CH2CHCN), 3.43–3.49 (m, 2 H, NHCH2), 5.10 (m, 1 H, 1 CH=CHH), 5.21 (m, 1 H, CH=CHH), 5.79 (m, 1 H, CH=CHH) 2-(Benzylamino)-2-methylhexanenitrile (29): Yield: 47%; oil. H 13 NMR (400 MHz, CDCl3): δ = 0.95 (t, J =7.2Hz,3H,CH3), 1.39 ppm. C NMR (100 MHz, CDCl3): δ = 13.3, 18.8, 35.3, 49.3, 50.1, 117.3, 120.1, 134.9 ppm. IR: ν˜ = 3321, 2220, 1644, 1465 cm–1. (quint, J =7.2Hz,2H,CH2CH2CH2), 1.44–1.57 (m, 6 H, NH, CH2,CH3), 1.67–1.82 (m, 2 H, CH2), 3.90 (s, 2 H, CH2Ph), 7.27– C8H14N2 (138.21): calcd. C 69.52, H 10.21, N 20.27; found C 69.44, 13 H 10.16, N 20.26. 7.40 (m, 5 H, ArH) ppm. C NMR (100 MHz, CDCl3): δ = 13.7, 22.5, 24.6, 25.8, 39.5, 49.0, 55.6, 122.1, 127.2, 128.1, 128.3, 2-(Morpholin-4-yl)pentanenitrile (21): Yield: 30%; yellow solid; 139.1 ppm. IR: ν˜ = 3318, 2219, 1455 cm–1.C H N (216.32): 1 14 20 2 m.p. 159 °C. H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, calcd. C 77.73, H 9.32, N 12.95; found C 77.82, H 9.41, N 12.91. 3H,CH3), 1.41–1.56 (m, 2 H, CH2), 1.65–1.79 (m, 2 H, CH2), 2.43–2.48 (m, 2 H, 2 NCHH), 2.62–2.68 (m, 2 H, NCHH), 3.37 (t, 1-(Benzylamino)-4-methylcyclohexanecarbonitrile (33): Yield: 99%; 13 J = 7.6 Hz, 1 H, CHCN), 3.66–3.76 (m, 4 H, CH2OCH2) ppm. C mixture of diastereoisomers, dr = 72:28 (determined by HPLC 1 NMR (50 MHz, CDCl3): δ = 13.4, 19.2, 32.5, 50.0, 33.0, 57.9, 66.6, analysis of the crude product). H NMR (400 MHz, CDCl3): δ = –1 116.9 ppm. IR: ν˜ = 2223, 1455 cm .C9H16N2O (168.24): calcd. C 0.86 (d, J = 6.0 Hz, 3 H, CH3, minor diast.), 0.88 (d, J = 6.0 Hz, 64.25, H 9.59, N 16.65; found C 64.39, H 9.67, N 16.47. GC-MS: 3H,CH3, major diast.), 1.23–1.50 (m, 6 H, NH, CH, + + m/z (tr = 11.7 min) (%) = 168 (2) [M] , 153 (1) [M – 15] , 125 (100) CH2CHCH2), 1.66–1.69 (m, 2 H, CHH, CHH, major diast.), 1.69– [M – 43]+. 1.79 (m, 2 H, CHH, CHH, minor diast.), 1.86–1.93 (m, 2 H, CHH, 2-(Piperidin-1-yl)pentanenitrile (22): Yield: 99%; oil. 1H NMR CHH, minor diast.), 2.01–2.01 (m, 2 H, CHH,CHH), 3.76 (s, 2 H, CH2Ph, minor diast), 3.84 (s, 2 H, CH2Ph, major diast), 7.19–7.28 (400 MHz, CDCl3): δ = 0.89 (t, J =7.6Hz,3H,CH3), 1.36–1.76 13 (m, 5 H, ArH) ppm. C NMR (100 MHz, CDCl3): δ = 21.7, 28.0 (m,10H,5CH2), 2.29–2.34 (m, 2 H, 2 NCHH), 2.53–2.59 (m, 2 H, NCHH), 3.37 (dd, J = 6.8, 8.8 Hz, 1 H, CHCN) ppm. 13C NMR (minor diast.), 31.1 (major diast.), 31.8, 34.0 (minor diast.), 36.2 (major diast.), 48.5 (minor diast.), 48.7 (major diast.), 57.7, 121.9 (50 MHz, CDCl3): δ = 13.3, 19.2, 23.9, 25.7, 33.0, 50.8, 58.3, 117.3 ppm. IR: ν˜ = 2220, 1465 cm–1.C H N (166.26): calcd. C (major diast.), 123.0 (minor diast.), 127.2, 128.3, 128.4, 139.3 ppm. 10 18 2 –1 72.24, H 10.91, N 16.85; found C 72.35, H 10.96, N 16.80. HPLC- IR: ν˜ = 3313, 2218, 1453 cm . HPLC-MS: m/z [tr = 10.4 min + MS: m/z (t = 8.8 min) = 189 [M + H O]+, 167 [M + 1]+, 140 [M – (major diast.), 11.1 min (minor diast.)] = 229 [M + 1] , 202 [M – r 2 + HCN]+. HCN] . 2-[4-(1-Cyanobutyl)piperazin-1-yl]pentanenitrile (23): Yield: 50%; 1-(Benzylamino)-2-methoxycyclohexanecarbonitrile (35): Yield: mixture of diastereoisomers, dr = 80:20. Diastereoisomers were sep- 61%; mixture of diastereoisomers, dr = 57:43 (separated by flash arated by flash chromatography. Major diastereoisomer: White so- chromatography). Major diastereoisomer: Oil. 1H NMR 1 lid; m.p. 153 °C. H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = (400 MHz, CDCl3): δ = 1.20–1.30 (m, 1 H, CH2CHH), 1.35–1.38 7.2Hz,6H,2CH3), 1.41–1.54 (m, 4 H, 2 CH2CH), 1.65–1.80 (m, (m,1H,CH2CHH), 1.48 (br. s, 1 H, NH), 1.53–1.76 (m, 5 H, 4H,2CH2CH2), 2.50–2.55 (m, 4 H, 2 NCHHCHHN), 2.62–2.72 CHHCH2CH2), 2.10–2.14 (m, 1 H, CHCHH), 3.38 (s, 3 H, OCH3), (m,4H,2NCHHCHHN), 3.49 (t, J = 7.6 Hz, 2 H, 2 CHCN) 3.39 (dd, J = 4.4, 9.6 Hz, 1 H, CHOCH3), 3.73 (d, JAB = 12.0 Hz, 13 ppm. C NMR (100 MHz, CDCl3): δ = 13.4, 19.2, 32.8, 49.2, 57.3, 1H,CHHPh), 3.79 (d, JAB = 12.0 Hz, 1 H, CHHPh), 7.18–7.32 –1 13 116.9 ppm. IR: ν˜ = 3344, 2222 cm .C14H24N4 (248.37): calcd. C (m, 5 H, ArH) ppm. C NMR (100 MHz, CDCl3): δ = 19.2, 23.0, 67.70, H 9.74, N 22.56; found C 67.82, H 9.77, N 22.58. HPLC- 24.8, 32.3, 48.0, 57.5, 59.4, 81.8, 121.9, 127.2, 128.3, 128.4, + + –1 MS: m/z (tr = 9.4 min) = 271 [M + Na] , 249 [M + 1] , 222 [M – 139.5 ppm. IR: ν˜ = 3334, 2210, 1454 cm .C15H20N2O (244.33): + + HCN] . GC-MS: m/z (tr = 18.9 min) = 248 [M] , 221 [M – calcd. C 73.74, H 8.25, N 11.47; found C 73.64, H 8.12, N 11.31. + 1 + + HCN] . Minor diastereoisomer: H NMR (400 MHz, CDCl3): δ = HPLC-MS: m/z (tr = 10.6 min) = 245 [M + 1] , 218 [M – HCN] . 1 0.94 (t, J =6.8Hz,6H,2CH3), 1.44–1.52 (m, 4 H, 2 CH2CH), Minor diastereoisomer: White solid; m.p. 69 °C. H NMR 1.69–1.74 (m, 4 H, 2 CH2CH2), 2.50–2.55 (m, 4 H, 2 (400 MHz, CDCl3): δ = 1.15–1.27 (m, 1 H, CH2CHH), 1.29–1.42 NCHHCHHN), 2.65–2.72 (m, 4 H, 2 NCHHCHHN), 3.48 (t, J = (m,1H,CH2CHH), 1.53–1.76 (m, 2 H, CHHCH2CH2), 1.64–1.70 13 7.6 Hz, 2 H, 2 CHCN) ppm. C NMR (100 MHz, CDCl3): δ = (m, 1 H, CHCHH), 1.76–1.81 (m, 1 H, CHCHH), 2.08–2.13 (m, 1 13.4, 19.1, 32.8, 49.3, 57.3, 116.9 ppm. HPLC-MS: m/z (tr = H, CHCHH), 2.18–2.22 (m, 1 H, CHCHH), 2.48 (br. s, 1 H, NH), + 9.2 min) = 249 [M + 1] . 3.08 (dd, J = 4.4, 10.8 Hz, 1 H, CHOCH3), 3.31 (s, 3 H, OCH3), 2-(4-Oxopiperidin-1-yl)pentanenitrile (26): Yield: 30%; oil. 1H 3.77 (d, JAB = 12.0 Hz, 1 H, CHHPh), 3.84 (d, JAB = 12.0 Hz, 1 H, CHHPh), 7.19–7.32 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, NMR (400 MHz, CDCl3): δ = 0.93 (t, J =7.2Hz,3H,CH3), 1.44– CDCl3): δ = 22.0, 23.3, 26.5, 33.6, 48.4, 56.7, 62.8, 83.4, 120.0, 1.51 (m, 2 H, CH2), 1.71–1.78 (m, 2 H, CH2), 2.38–2.51 (m, 4 H, 127.3, 128.4, 128.5, 139.5 ppm. IR: ν˜ = 3319, 2219, 1456 cm–1. CH2COCH2), 2.66–2.72 (m, 2 H, CHHNCHH), 2.89–2.95 (m, 2 H, CHHNCHH), 3.58 (t, J = 7.6 Hz, 1 H, CHCN) ppm. 13C NMR C15H20N2O (244.33): calcd. C 73.74, H 8.25, N 11.47; found C (50 MHz, CDCl ): δ = 13.3, 19.2, 33.3, 40.8, 49.4, 56.9, 116.6, 73.58, H 8.14, N 11.27. HPLC-MS: m/z (tr = 9.5 min) = 267 [M + 3 + + –1 Na] , 245 [M + 1] . 207.2. IR: ν˜ = 2223, 1780, 1720 cm .C10H16N2O (180.25): calcd. C 66.63, H 8.95, N 15.54; found C 66.58, H 8.94, N 15.67. GC- 4-(Benzylamino)piperidine-4-carbonitrile (36): Yield: 50%; m.p. + MS: m/z (tr = 14.0 min) (%) = 180 (5) [M] , 153 (100) [M – 1 70 °C. H NMR (400 MHz, CDCl3): δ = 1.61 (ddd, J = 4.0, 11.2, HCN]+, 137. 13.2 Hz, 2 H, 2 CHHCH2N), 1.72 (br. s, 2 H, 2 NH), 1.94–2.00 1 2-(Benzylamino)-2-ethylbutyronitrile (28): Yield: 48%; oil. H NMR (m,2H,2CHHCH2N), 2.82 (ddd, J = 2.8, 10.8, 13.6 Hz, 2 H, (400 MHz, CDCl3): δ = 1.04 (t, J = 7.2 Hz, 6 H, CH3), 1.43 (br. s, NCHHCH2), 3.04 (ddd, J = 4.0, 4.4, 13.6 Hz, 2 H, NCHHCH2), 13 1 H, NH), 1.77 (non, J = 7.2 Hz, 4 H, CH2), 3.81 (s, 2 H, CH2Ph), 3.85 (s, 2 H, PhCH2), 7.23–7.37 (m, 5 H, ArH) ppm. C NMR 13 7.19–7.33 (m, 5 H, ArH) ppm. C NMR (100 MHz, CDCl3): δ = (100 MHz, CDCl3): δ = 36.4, 42.6, 48.2, 56.3, 121.5, 127.4, 128.3,

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Received: January 20, 2011 Sharma, N. N. Sharma, T. C. Bhalla, Enzyme Microb. Technol. Published Online: April 5, 2011