Diastereomeric Amides Derived from Malonic Acid : the Role of Chiral Auxiliaries and of the Nature of Co-Acids in the Mixed Kolbe Electrolyses

Experimentos visando o acoplamento diastereosseletivo de mono-amidas do ácido metilmalônico, sintetizadas a partir de aminas quirais comerciais [S-(+)-1-ciclo-hexiletilamina e (R)-(+)1-feniletilamina] foram realizados, utilizando-se oxidação anódica de Kolbe [cela não dividida, Pt (ânodo e cátodo), MeOH, neutralização de 5% a 10% com solução metanólica de KOH (1 M), 200 a 250 mA/cm], usando diferentes co-ácidos (ácidos hexanóico, trimetilsililacético, dietilfosfonoacético e ftaloilglicina). Amidas de cadeia longa ou sililadas (dímeros mistos de Kolbe) foram obtidas com bom rendimento (56 a 63%) e baixa diastereosseletividade, na presença de excesso de co-ácidos, em conjunto com produtos derivados de caminhos alternativos, principalmente produtos de desproporcionamento e derivados metoxilados. O acoplamento radicalar mostrou-se altamente sensível à natureza dos radicais envolvidos, sendo mais efetivo entre radicais de reatividade oposta. Radicais eletrofílicos acoplam entre si em muito pequena extensão. Acoplamentos diastereosseletivos, na presença dos auxiliares quirais acíclicos, não foram expressivos. Eletrólise de Kolbe realizada com a ftaloilglicina forneceu dímeros simétricos, N-metoximetilhidroxilactama e N-metoxiftalimida. Na presença de ácido hexanóico, além dos produtos já citados, foram obtidas uma imida alquilada e a hidroxilactama correspondente.


Introduction
Radical chemistry provides mild reaction conditions for the formation of C-C bonds.Anodic decarboxylation of carboxylic acids is an useful synthetic method for generating radicals (Kolbe electrolysis) or carbocations (non-Kolbe electrolysis) (Scheme 1).The generated radicals can be used in homo-and heterocouplings or in addition to double bonds 1 , being a powerful synthetic tool [2][3][4] .Yields and selectivities of the Kolbe synthesis are strongly dependent on the structure of the acid and on reaction conditions 1 .High current densities and high carboxylate concentrations favour the formation of dimers, as well as weakly acidic medium.Platinum and methanol are, respectively, the electrode and solvent of choice.Methanol oxidation is inhibited by the formation of the carboxylate layer 1,2 .An important advantage of this method is that functional groups in the carboxylic acid components are tolerated, so there is no need for protection-deprotection reactions.In the presence of co-acid, as the intermediate radicals combine statistically, besides the expected mixed Kolbe dimer, two homocoupling products are also generated.If the less costly acid is used in excess, the number of major products is reduced to two, simplifying the isolation of the cross-coupled compound.Besides Kolbe products, disproportionation of the generated radicals together with reactions from the non-Kolbe pathway (extended oxidation leading to the carbocation) are expected (Scheme 1).It is useful to report that the maximum yield of mixed dimer for Kolbe eletrolysis in the presence of co-acid, in a concentration 10 times greater, is 91% 1 .To calculate maximum yield, on use n.100/1 + n where n = [co-acid]/[acid] 1 .As reported, the yields of Kolbe electrolysis are considered good, even in the range of 34% 4 -43% 2 .In spite of the relatively low yield, it has important synthetic and industrial applications 5 .Similar radicals produced homogeneously do not couple with useful yields and there is only one example of a metal-based oxidant (OsCl6 -) which gives comparable coupling 6 .
Radical reactions and their stereochemical aspects are of fundamental importance in organic chemistry, and have been exhaustibly studied and are fairly well understood 7 .Control of acyclic stereochemistry of intermolecular radical reactions was recently reviewed 8 .Diastereoselective coupling derived from Kolbe electrolysis is far less studied.High diastereoselectivity was obtained only recently 9 , through the use of 1,4-induction by chiral cyclic amide auxiliaries.
This paper reports an extension of this approach using new derivatives of methylmalonic acids, half substituted with readily available amines with an acyclic stereogenic center.For this study, the chiral auxiliaries were chosen based on their availability and inactivity in electrochemical terms.Earlier studies showed that the easily available, commodity chemicals, (R)-(+)-and (S)-( _ )-1-phenylethylamine used as chiral auxiliaries are very valuable in asymmetric synthesis 10,11 and led to high yield asymmetric reductive amination 12 .Comprehension of the factors governing the stereoselectivity of intermolecular electrogenerated radical coupling of acyclic systems is of further importance.
It is useful to report that few examples of Kolbe electrolysis of amides and imides have been available in the literature, most of them leading to non-Kolbe products 1,9,13 .Anodic methoxylative decarboxylations (Hofer-Moest reaction), related to the non-Kolbe pathway, have been used to generate several interesting nitrogen heterocycles, key intermediates for stereoselective syntheses 14 .

Equipments
Melting points are uncorrected.Mass spectra were obtained by using an A.E.I.MAT-312, Finnigan and CH-7A, Varian, in conjunction with an SS200 Data Acquisition, Varian; for GC/MS, a GC 1400, Varian and a CH-7A with data system SS200, Teknivent and/or Shimadzu GC 8A. 1 H and 13 C-NMR spectra were measured at a WM 300, Bruker.NMR spectra were obtained by using CDCl3 solvent with TMS reference, unless otherwise stated.IR spectra were measured in cm -1 at an IR-408, Shimadzu and FT-IR, Nicolet.Elemental analyses were performed at M. Beller -CO 2 alcohol, ethers and esters Microanalysis Laboratory, in Göttingen.For GC analyses, GC-9A, with Shimadzu C-R3A integrator were used, with the following columns: •FS-HP1-CB, 25 m, 0.32 mm internal diameter, 0.25 m film thickness; •FS-SE54-CB, 50 m, 0.32 mm internal diameter, 0.25 m film thickness.

Synthesis of N-substituted-2-methylmalonamic acids
The syntheses followed the general scheme: The following procedure is typical for synthesis of the substrates.The amounts are expressed in mol or mmol.
Diethyl methylmalonate (34.8 g, 0.20 mol) in 100 mL abs.ethanol was added, with stirring, to a solution of of KOH (11.7 g, 0.21 mol) in 150 mL abs.ethanol.The solution was left overnight, and the pH measured (7-8).The white precipitate (di-potassium salt) was filtrated (2.94 g, 0.015 mol, 7.5%) and the resulting solution evaporated under reduced pressure.The semisolid opaque residue was dissolved in 20 mL of water and extracted twice with 20 mL of petroleum ether.The organic phase was concentrated, leading to colourless oil (3.13 g, 0.017 mol), the starting ester.Acidification with HCl until pH 2 and extraction with ether, followed by vacuum distillation and drying with MgSO4, furnished a colourless oil, the half ethylester of methyl malonic acid [(CO2H)CHMeCO2Et] (24.8 g, 0.17 mol, 84%).This latter product (5.8 g, 0.040 mol) was dissolved in 15 mL of dry ether and freshly distilled thionyl chloride was slowly added to it.Reflux for 2 h and elimination of the excess of SOCl2 and ether, under vacuum, furnished a clear yellow oil [(CO2Et)CHMeCOCl], used without further purification in the following procedure.The production of the acid chloride was followed by TLC (CH2Cl2/MeOH 9:1).

Kolbe electrolysis
The following description is typical for Kolbe electrolysis and methods for work-up and isolation of products.After partial neutralisation (methanolic KOH, 5 to 10%), 1a-b (0.5 to 1 mmol) were submitted to Kolbe oxidations [undivided jacketed cell, Pt (anode, cathode), MeOH, 200 to 250 mA/cm 2 , 1.3-1.5 F mol -1 , co-acid in excess (10x)], with a temperature range between 10 and 60 °C.To get this temperature inside the cell, it is necessary to use a cooling device and the cryostat was cooled earlier to -40 °C.The electrolyses were always carried out with the diastereomeric mixture of the carboxylic acids 1a or 1b.The end of the reaction was monitored by pH measurement (acid to neutral).When passivation or coverage of electrodes were noticed, the technique of polarity inversion was used.Adequate work up and fractionation, through flash chromatography, furnished products from Kolbe (K) and non-Kolbe (nK) pathways.The yields in Table 1 are related to the main acid (1a, 1b or 2e) present.Homocoupling of the co-acids was not quantified.The absolute configurations of the purified reaction products were not determined.Relevant data from the main products of Kolbe electrolyses (Table 1, Fig. 2), mainly mixed Kolbe dimers (MKD), are included.

Results and Discussion
Two new N-substituted-2-methylmalonamic acids (1ab), with a chiral auxiliary linked through the amide function were synthesised in ca 45%, non-optimised yields.They were prepared by substitution of the mono-acyl chloride derived from ethyl methylmalonic acid, with commercially available amines [(S)-(+)-1-cyclohexylethylamine and

Entry
Subst (mM) (R)-(+)-1-phenylethylamine)], in the presence of triethylamine in absolute ether.This reaction was followed by hydrolysis of the ester group from 1c and 1d, leading to 1a-b, as diastereomeric mixtures (Figs. 1 and 2).They were submitted as such to mixed Kolbe electrolyses, using several co-acids 2c-f (Fig. 1) (Table 1).The results from the several performed electrolyses are shown in Table 1 and summarised in Scheme 2. Figure 2 shows the structures of the starting materials and final compounds.Mixed Kolbe dimers (MKD) (3a-b) were obtained in good yields (56 to 63%), in the presence of hexanoic acid (2c), together with non Kolbe (nK) products, mainly from disproportionation (5a-b, 6a-b) and solvolysis (4a-b) (Table 1, entries 2, 3).Hexanoate derivatives (7a-b), evidenced by GC/MS techniques, were also present in minute amounts (not included in Table 1).Symmetrical dimers (K) (8a-b), expected Kolbe products from electrolysis in the absence of co-acids 1 (Scheme 3) (Table 1, entry 1), and oxidation on the nitrogen of the amide, furnishing the corresponding N-alkylated products were also observed in a very small proportion ( < 3%) (not included in Table 1).
The diastereomeric excesses (de), determined by gas chromatography and isolation of both diastereomers (Table 1), showed that the stereoselective induction was not high (Table 1, entries 2, 3), but acceptable and encourages further investigations with other families of acyclic chiral auxiliaries.Experiments in the presence of co-acids 2c-f were performed not only to verify the stereochemical profile of the reactions but to get useful synthetic intermediates (Table 1, entries 4-8).They were chosen due to the presence of a bulky group (2d) or to promote hydrogen bonding formation between the co-acid and the chiral amide, during the coupling step (2e-f).A new amide was obtained (3a, R = CH2SiMe3), with a very impressive ratio between products from Kolbe and non-Kolbe pathways (K/nK = 2.7), but without any de improvements (Table 1, entry 4).
The coupling of the methyl malonamic acid derived radicals with the electrophilic radicals derived from 2e-f did not succeed, giving, predominantly, homocoupling from the less valuable acids present in larger amounts with traces of mixed Kolbe dimers 17 [3b, R=CH2PO(OEt)2], characterised only by MS (Table 1, entry 5).
The unexpected presence of 11 can be explained by cathodic reduction of 10, a consequence of polarity inversion to avoid electrode passivation.Reduction of the imide carbonyl to hydroxylactams has also been accomplished in the presence of metal hydrides and amalgams 19,20 .
Results from the mixed Kolbe reaction of 2e and 1b (Table 1, entry 6) as well as with 1a (not shown) showed complete absence of MKD (3), the malonamic acids (1a and 1b) being recovered unchanged.The reason for the failure of the above mentioned radical coupling could be the similar nature of the radicals, both electrophilic, due to the presence of electron-withdrawing substituents.Differences in the acidity of the original acids as well as Pt electrode preferential adsorption of the more abundant carboxylate could be also used to explain the experimental behaviour.The malonamides, present in smaller quantities in relation to the less valuable co-acids, might have been kept far from the electrode surface.Their oxidative decarboxylation would be avoided and homocoupling of co-acids would predominate.In cases where the values of pka differ strongly, a complete neutralisation is recommended, in spite of the expected lower selectivity 1 .Alternatively, sequential and continuous addition of one of the acids (more acidic over an excess of the weaker acid) may lead to successful cross-coupling 1 .Preferential adsorption of one of the carboxylates, especially the less-valuable one, onto the electrode can also be avoided by a similar strategy.Attempts (not shown in Table 1) in those directions were tried in the case of 1a/1b with 2e, but in no circumstance, was an increase of the expected MKD evidenced.
To allow comparison, mainly with respect to reactivity and differences of acidity, 2e was electrolysed in the presence of 2c (Table 1, entry 8).The expected mixed Kolbe dimer (10a) was present, as well as an N-hexylhydroxylactam (11a), along with 9 and 11b.In spite of the low K/nK, there was an expressive increase on Kolbe pathway.This result also shows that the electrophilic imide-derived radical reacts easier with the nucleophilic pentyl radical.The presence of the mixed Kolbe dimer (10a, 11a), in spite of the low yield, is interesting and demonstrated the feasibility of the use of phthalic anhydride to protect the N functions, decreasing the amount of non-Kolbe products.Hydroxylactams obtained probably through reduction of adsorbed species due to the applied technique of reversal of polarity are useful intermediates in organic synthesis 19,21 .
The combined results showed that mixed Kolbe dimers are favourably obtained when the radicals have opposite reactivity (Table 1, entries 2, 3, 4), for instance, the high yield coupling of the highly nucleophilic pentyl or silylsubstituted radicals (derived from 2c and 2d, respectively), used in excess, with the electrophilic amide-substituted ones.In this case, yields closer to the statistical ones can be obtained.Electrophilic radicals can couple between themselves, but, to a much lower extent.
Concerning the stereochemical course of the reactions, the low observed diastereoselectivity can be explained by the not yet optimal chiral auxiliaries, by their secondary amide nature and the early transition state of the coupling reaction.Increase of the volume of the malonic acid substituent, use of bulkier nucleophilic co-acids, as tried before 9 and amide N-alkylation would be relevant for the improvement in mixed Kolbe electrolysis using 1a and 1b.

Figure 2 .
Figure 2. Structures of starting materials and reaction products.

Table 1 .
Results from Kolbe and mixed Kolbe electrolyses.