Reductive amination

The direct reductive amination (DRA) is a reaction of great importance in organic chemistry not only for the formation of compounds with the CN bond, but also due to the formation of alkylated amine in a single step, that is, without prior isolation of the intermediates (imines or iminium ion). Compared to methods that use organic halides, DRA has the advantage of allowing a reaction to minimize formation of significant waste and a reduction of unwanted polyalkylation methods such as Leuckart-Wallach reaction [1], borohydrides [2] and catalytic hydrogenation [3]. These methods are efficient at producing alkylated amines, but entail some limitations from the industrial and environmental standpoint. A major limitation is the sensitivity of the reaction water in the reaction process. NaBH 3 CN is toxic and not all hydrides are consumed in the reaction. Hydrogenation requires a strict control of pressure and equipment with high costs.. It is therefore important that new strategies could be developed to reduce the cost of obtaining products and minimize the environmental impact. Furthermore, electrochemical methods provide an alternative to standard procedures in organic synthesis [4] as the electron is an inexpensive reagent, and its availability is fully exploited since their reactivity can be controlled by electronic devices. The first reports of reductive amination emerged from early 20th century when methylamine was obtained from the electrolysis of ammonia with formaldehyde, but with low yield and poor selectivity in the formation of the product out of amino [5] . After decades, N-methyl-cyclohexylamine was obtained from the electrolysis of cyclohexanone with methylamine, but with low yield [6]. In the 80's, Schafer Pienemann studied eletroreductive amination of ketones and aldehydes by electrolysis; result of a mixture of amino / carbonyl compound with a ratio of 15:1 (amine / carbonyl compound) in the presence of mercury (cathode) in pH between 10-11 and controlled by constant potential between -1.55 to -1.90 versus SCE specifically to each "mixture". Years later Sminorv Tomilov studied the electroreductive amination alkyl ketones with aqueous methylamine in ratio 6:5 (amine / ketone). They realized that lead electrodes (cathode and anode) led to obtaining good yields of secondary amines by applying a constant current. An efficient application of electroreductive amination was developed by Cvetovich and employees in the instant of 4''-epi-(N-methylamino)-5-O-(tert-butyldimethylsilyl) -4''deoxiavermectina a macrolactone pertaining to the group of avermectins with fungicidal properties, was synthesized from the electrolysis of methylamine with 4 "-Oxo-5-O-(tertbutyldimethylsilyl) avermectin B1 in CH 3 CN to afford the desired amine product with 65% yield [10]. In this sense, motivated by the good results of our reaction of reductive methylation with formaldehyde promoted by zinc [11] and few reports in the literature [12, 13], then it was developed a new methodology that uses electrosynthetic graphite electrodes in undivided cell and aqueous electrolyte and an aqueous acid, unique in the literature, as if only an alkaline medium and divided cells were used for this type of yet DRA. Here we report a new elelectrosynthetic approach of electroreductive methylation that is a reproducible method and follows several principles of green chemistry and uses materials easy to handle and it is available in the market.

EXPERIMENTS All reagents that were used came from Aldrich and they all had high purity. Voltammetry and the electrolysis were carried out using a potentiostat / galvanostat Autolab PGSTAT 30. In cyclic voltammetry experiments, we used a single glass cell compartment, solution of KBr 0.1 mol L-1 as the supporting electrolyte, glassy carbon ( ... = cm2) working electrode, platinum wire auxiliary electrode and saturated calomel electrode (SCE) as reference. We used a scan rate of 50 mV s-1. The electrolyses were carried out in a Teflon cell, a single compartment, and the bottom area 4.7cm2 graphite serving as a cathode, a graphite rod as the anode and saturated calomel electrode (SCE) as the reference. Figure 3. All electrolyses were carried out at constant potential of -1.6 V for 4 h. Cyclic voltammetry: three aqueous solutions, 10 ml of morpholine (1.0x10-3 mol L1), formaldehyde (2.0 10 -3 mol-1 L) and acetic acid (2.0x10-3 mol L-1) were prepared using bromide potassium 0.1 mol L-1 as the supporting electrolyte and subjected to a sweep potential between 0 and -2.2 V at a speed of 50 mV s-1 in a single compartment electrolytic cell using glassy carbon electrode (working electrode) , platinum (counter electrode) and ECS (reference electrode) without agitation. Next, an experiment was conducted in the presence of the mixture (morpholine, formaldehyde, acetic acid) in the same proportions of the previous example and subjected to a potential sweep from 0 to -2.2 V. Morpholine Electroreductive Methylation: 2 ml of 37% formaldehyde (x mmol), 0.44 mL (5 mmol) of morpholine, 1.2 ml of acetic acid were added to 10 mL KBr 1 mol-1 L (supporting electrolyte) in a cell single compartment electrolytic bottom graphite (cathode), graphite rod (anode) and reference electrode SCE. After stirring for 2 min a constant potential of -1.6 V was applied to the passage of charge needed concerning two electrons / mol amine which took 4 h. After electrolysis, the aqueous mixture was basified with aqueous ammonium hydroxide and then the product was extracted with chloroform. It was added an ethanolic solution of picric acid to the filtrate and after 24 h yellow precipitate was recrystallized. The yield obtained in the picrate of N-methylmorpholine was 80%. To the procedure was also applied piperidine, diethylamine and benzylamine.

After the electrolysis products were treated with NH4OH and extracted with CHCl3. The products were identified by gas chromatography coupled with mass spectrometry GC / MS (Varian CP-3380, Chrompack CP-SPL5CB), capillary column 30 m, with a ramp (heating rate) 10 C min-1 between 60 C and 220 C . After structural confirmation methylated products were isolated as picrate salts. Mass and NMR data for each reaction followed yield

N-methylmorpholine: ...........

Results and Discussion

The morpholine electroreductive methylation reaction with formaldehyde was investigated using cyclic voltammetry to determine the behavior of the electroactive substances involved and thus define the potential suitable for carrying out the electrolysis. Thus, aqueous solutions of morpholine (1.0 x 10-3 mol L-1), formaldehyde (2.0 x 10-3 mol1 L) and acetic acid (2.0 x 10-3 mol L-1 in 0.1 mol KBr L-1 (supporting electrolyte) were subjected to scanning the potential between 0 and -2.2 V, the discharge only regarding water reduction and a small shoulder in the range of -1.2 to -1.4 V were observed on the voltammetry of morpholine

0,0001 0,0000 -0,0001

intensidade de corrente (A)

-0,0002 -0,0003 -0,0004 -0,0005 -0,0006 -0,0007 -0,0008 -2,0

formaldedo AcO H Morfolina

-1,8

-1,6

-1,4

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

Potencial(V)

figure 1.

Figure 1. Voltammograms in aqueous KBr (0.1 mol L-1): formaldehyde (black), AcOH (red), morpholine (green). Speed: 50 mVs-1. Working electrode: glassy carbon. Auxiliary electrode: platinum. Reference electrode: SCE. However, in the presence of the mixture of reactants (morpholine, formaldehyde and acetic acid), the cyclic voltammogram (Fig. 2) presents a shoulder between -1.7 and -1.3 V, which may correspond to the reduction of the iminium ion at the surface of the glassy carbon electrode.

Figure 2. Voltammogram of the aqueous mixture of morpholine (1 x 10-3 mol L-1), formaldehyde (2 x 10-3 mol L-1), AcOH (2 x 10-3 mol L-1) in KBr (0.1 mol L-1). Speed: 50 mVs-1. Working electrode: glassy carbon. Auxiliary electrode: platinum. Reference electrode: SCE. Then, electrolysis of an aqueous solution of morpholine (1 mol-1 L), formaldehyde (2 mol L-1), AcOH (2 mol L-1) and KBr (1 mol-1 L) was performed on a potential of - 1.6 V (potential shoulder in Figure 2) vs SCE for 4 h, the total charge required for the passage of two electrons / mole of amine and as the result of methylation product was obtained in 80% yield (Table 1, entry 1). A new electrolysis was carried out by reproducing the previous conditions, but this time with piperidine leading to 70% yield (entry 2). Another non-cyclic secondary amine, diethylamine, was also tested under the same conditions already standardized for the previous reactions and positive results have been obtained to achieve a 92% yield (entry 3). To our surprise benzylamine had suffered demethylation and no monomethylation product was detected, indicating that secondary amines are more reactive to acidic medium (entry 4). No dimerization. product was detected

Table 1. Electroreductive methylation.a

R1 N H

R2 + H

R1 H+ H H

+ N

R2 + H H2O E = -1.6 V vs. ECS grap hite, H2O, H

+

R1 N CH3

R2

Entry 1

amina
O

Product metilated
O

Yield (%) 80

references X

N H

N CH3

2
N H

70
N CH3

3
N H
N CH3

92

NH2

N CH3

CH3

60

a.. general reaction conditions: 5 mmol of amine, 2 ml formaldehyde (37%) and 20 mmol of acetic acid dissolved in 10 mL of 0.1 mol KBr L-1. Pontencial applied: -1.6 V; electrodes: cathode (graphite), anode (graphite), reference (ECS), electrolysis time: 4 h. b. demethylation. For a more detailed explanation 3 shows the electrochemical cell in which the experiments were performed. The reduction process involves receiving electroreduction of an electron to the iminium ion formed in situ from the condensation of the amine with formaldehyde, thereby forming a free radical species which then receives another electron together with a proton. .

(a)

(b)

Figure 3. a) electrochemical system with three components: the cathode (bottom graphite), anode (graphite rod) and reference electrode (SCE), (b) Reduction of the iminium ion at the surface of the graphite electrode. Conclusion The electroreductive amination can be considered as a good and inexpensive clean alternative to the preparation of N-methylamines in good yields. This method unlike the others uses a single compartment cell, an acidic medium and graphite electrodes that are inexpensive, nontoxic and inert. Dimerization products found in other methodologies were not detected. Our method is simple, reproducible and presents low toxicity, besides it can be applied at room temperature without the need for an inert atmosphere. References 1. Moore, M. L. Org. React. 1949, 5, 301303. 2. Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1714. 3. Emerson, W. S. Org. React. 1948, 4, 174255. 4. Lund, H.; Baizer, M. M., Organic Electrochemistry an Introduction and a Guide. 4th Ed.: New York, 2001. 5- Mesister, Lucius e Bruning Ger. pat. 148.054 [Frdl. 1, 26 (1905)]. 6-Lund, H. Acta Chem. Scand. 1959, 13, 249. 7-Pienemann, T.; Schafer, H.-J. Synthesis 1987, 1005-1007. 8-Smirnov, Y. ; Tomilov, A. P. Zhurnal Organicheskoi Khimmi 1992, 28 (1), 51-58. 9-Cvetovich, R. J.; Amato, J. S.; DiMichele, L.; Weinstock, L.; Hazen, G. J. Org. Chem. 1997, 62, 6697-6698. 10-Silva, R. A.; Estevam, I. H. S.; Bieber, L. W. Tetrahedron Lett. 2007, 48, 7680 7682.

X1. Alinezhad Heshmatollah; Tajbakhsh Mahmood; Zamani Reza (Efficient and mild procedure for reductive Methylation of amines using N-methylpiperidine zinc borohydride) SYNTHETIC COMMUNICATIONS 2006, 36 (23), 3609-3615. (Rendimento da metilmorfolina 80%) X2. Sukanta Bhattacharyya, (Titanium(IV) isopropoxide and sodium borohydride: a reagent of choice for reductive amination) TETRAHEDRON LETTERS 1994, 35 (15), 2401-2404. (Rendimento da metilmorfolina 82%) X3. Ref. 10 . (Rendimento da metilpiperidina 80%) X4. Torchy, Sverine; Barbry, Didier (N-alkylation of amines under microwave irradiation: modified Eschweiler-Clarke reaction) Journal of Chemical Research, 2001, 7, 292-293. (Rendimento da dimetilbenzilamina 66%)