Download Author Version (PDF)

Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 8 Journal Name Organic & Biomolecular Chemistry Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Reductive Alkylation of Active Methylene Compounds with Carbonyl Derivatives, Calcium Hydride and a Heterogeneous Catalyst Carole Guyon, Marie-Christine Duclos, Marc Sutter, Estelle Métay* and Marc Lemaire* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX Manuscript 5 DOI: 10.1039/b000000x A one-pot two-step reaction (Knoevenagel condensation - reduction of the double bond) has been developed using calcium hydride as a reductant in the presence of a supported noble metal catalyst. The reaction between carbonyl compounds and active methylene compounds such as methylcyanoacetate, 1,3-dimethylbarbituric acid, dimedone and the more challenging dimethylmalonate, affords the 10 corresponding monoalkylated products in moderate to good yields (up to 83%) with minimal reduction of the starting carbonyl compounds. reductive alkylation of Meldrum’s acid with amino-boranes has Accepted Introduction 50 been successfully applied to a number of challenging aliphatic aldehydes. 3 On the contrary, the stepwise addition of the reagents The development of methodologies to create C-C bonds remains led to a predominant formation of the Michael adduct (by the an important research area. Active methylene compounds such as reaction with a second Meldrum’s acid).3,10 15 malonates, malononitrile, 1,3-diketones, Meldrum acid or A limited number of direct reductive alkylation methods with barbituric acid are useful starting materials due to the low p Ka of 55 various combinations of Knoevenagel catalysts and reductants are 11 12 the methylene protons. The corresponding mono-alkylated already known in the literature: NaBH 4, H2/Pd/C, 13 compounds are useful synthetic intermediates, for example, for piperidinium acetate/H 2/rhodium, proline/Hantzsch the preparation of pharmaceutical and agrochemical compounds.1 ester 1,14,15,16,17 , triethylammonium formate/rhodium complex 18 19 20 However, a selective mono-alkylation of an active methylene and tetracarbonylhydridoferrate. More recently, it has been compound with an electrophilic alkylating reagent in the presence 60 shown that the reductive alkylation can be carried out with Chemistry of a base is often challenging to achieve, as such compounds are alcohols by using “hydrogen borrowing” strategy with generally prone to a second addition of the electrophile; as a homogeneous 20 or heterogeneous catalysts. 21,8a result, the reaction gives a mixture of mono- and di-alkylated However, there is no general reductive alkylation method 25 products which are often difficult to separate. applicable to all the active methylene compounds today. In 1,12e,f,13 One way to selectively prepare the mono-alkylated product is the 65 particular, dialkylmalonates remain challenging substrates. reduction of the alkene isolated from a Knoevenagel The direct reductive alkylation is often limited by an undesirable condensation. The reaction sequence of a Knoevenagel reduction of the starting carbonyl 11 and a Michael addition of the condensation and a subsequent reduction can be performed in one active methylene on the Knoevenagel adduct.14 Furthermore in 30 pot, and it is often referred to as the reductive alkylation for a C- the context of green chemistry, the use of a heterogeneous C bond formation, which is less widespread than the formation of 70 catalyst and an easily separable reductant is desirable. a C-N bond by a reductive amination. 2 The reductive alkylation In our laboratory, we have a long standing interest in the can be carried out by a sequential addition of a base then a development of new methodologies in reduction. We have been reductant to avoid the undesired reduction of the starting carbonyl exploring the use of poorly reactive reductants in economical and 3 35 compound (indirect reductive alkylation). This sequential two- eco-friendly reducing systems. Amongst alternatives, we have 22 23 step procedure has been described with different base/reductant 75 studied hydrosiloxanes, hypophosphite derivatives and Biomolecular 4 5 24 combinations, such as K 3PO 4/NaBH 4, alumina/NaBH 4, calcium hydride. piperidinium acetate/NaBH CN, 6 ruthenium-amido complex/ 3 Calcium hydride, compared to other hydrides, has the advantage & 7 8 NEt 3·HCO 2H and Pd or Rh/basic support/H 2. of being stable under air and inexpensive. In addition, by- 40 As an alternative and analogous to the direct reductive products from calcium hydride are non-toxic solids and easy to 9 25 26 amination, the procedure can be simplified by the 80 separate. However, without a physical or chemical activation, simultaneously addition of a reductant at the beginning of the it is unreactive as a reductant in organic chemistry. 27 We have reaction along with the substrates and optionally a base (direct previously developed the reductive amination of carbonyl reductive alkylation).3 This convenient (non-sequential) one-pot derivatives with calcium hydride and platinum on charcoal as a 24 45 procedure can give access to products often difficult to obtain by catalyst. We proposed that calcium hydride was activated by the aforementioned sequential process, since the condensation 85 water during the imine formation and it generated a product can be reduced as soon as it is formed by the reductant stoichiometric amount of hydrogen used for the following Organic already present in the reaction mixture. 3 For example, the one-pot reduction. Because hydrogen is released only after the This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 Organic & Biomolecular Chemistry Page 2 of 8 condensation step in a stoichiometric amount, by-products from 40 However, benzyl alcohol 3 was formed as a major side product the reduction of the starting aldehyde or ketone might be avoided. when the reaction was carried out in the presence of palladium Therefore, we decided to investigate the potential applicability of and platinum but not in the presence of rhodium. calcium hydride to more challenging reactions such as the Palladium and platinum on silica gave better GC yields for alkane 5 reductive C-alkylation of active methylene compounds. 4b . The best results were obtained when palladium and platinum 45 were supported on silica, giving alkane 4b in 68 and 86% GC Reductive alkylation of methylcyanoacetate yields, respectively (Table 1, entries 8 and 10). Furthermore, To validate the possibility of the C-C bond formation in the platinum on silica did not reduce the starting benzaldehyde to presence of CaH 2, the reaction of benzaldehyde 1 and benzyl alcohol, and for this reason, it was selected as the catalyst methylcyanoacetate 2 was carried out with calcium hydride (1.2 for further investigation. 10 equiv.) and palladium on carbon (2 mol%) at 60 °C for 15 h in a 50 Table 1 Influence of the catalyst pressure tube. Benzyl alcohol 3, alkene 4a and alkane 4b were obtained in 12, 8 and 65% GC yields, respectively (Scheme 1). This preliminary result showed that calcium hydride was Manuscript effective in the reductive alkylation. Presumably, calcium hydride 15 was activated by the water formed during the condensation (Figure 1). Then, the liberated hydrogen absorbed on the Pd/C Entry Catalyst GC yield (%) a reduced the double bond. Under the reaction conditions, we 1 3b 4a 4b noticed also the undesired reduction of benzaldehyde. 1 Ru/C 5% (60 °C) 0 0 95 0 2 Ru/C 5% (130 °C) 0 0 48 9 3 Ru/Al 2O3 5% 0 0 >95 0 4 Ni SiO 2/Al 2O3 65% 90 0 9 0 5 Ni-SiO 2 65% 5249P 75 0 23 0 Accepted 6 Pd/C 5% 1 12 8 65 20 Scheme 1 Reaction of benzaldehyde and methylcyanoacetate with CaH 2 and Pd/C (GC yields were determined by the use of dodecane as an 7 Pd/Al 2O3 5% 8 8 51 30 internal standard.) 8 Pd/SiO 2 5% 0 11 5 68 9 Pt/C 5% 0 15 50 12 10 Pt/SiO 2 5% 0 0 2 86 11 Pt/Al 2O3 5% 0 7 23 45 12 Rh/C 5% 0 0 66 29 13 Rh/Al 2O3 5% 0 0 37 54 a GC yields were determined by the use of dodecane as an internal standard. b Benzyl alcohol. Chemistry The influence of the solvent was evaluated in the presence of 1.2 mol of calcium hydride per mol of benzaldehyde (Table 2). 55 Changing the solvent from toluene to another unpolar solvent, cyclohexane, led to a comparable GC yield of alkane 4b (Table 2, entries 1 and 2). The reactions in THF, 2-MeTHF and CPME (cyclopentylmethyl ether) gave 4b in 65, 53 and 13% yields, respectively (Table 2, entries 3-5). Under neat conditions, 49% of Figure 1 A proposed mechanism 60 alkene 4a remained unreduced (Table 2, entry 6).

Load more