Triethylborane-induced free radical reactions with benzylidene Meldrum’s acids. Simple and efficient synthesis of benzyl Meldrum’s acids

We have developed a simple aerobic synthesis of benzyl Meldrum’s acids from benzylidene Meldrum’s acids with Et 3 B or RI/Et 3 B. The reaction system has also been applied successfully to the synthesis of benzyl Meldrum’s acids in a one-pot procedure


Introduction
The conjugate addition reaction of organometallic reagents to α,β-unsaturated systems is one of the most widely used synthetic methods for carbon-carbon bond formation. 1Recently, reactions of α,βunsaturated systems with various kinds of organometallic reagents derived from lithium, 2 magnesium, 3 zinc, 4 aluminum, 5 copper, 6 and boronate 7 have been reported.Similarly, a catalytic asymmetric conjugate addition promoted by chiral metal complexes also has been shown to be an efficient method for enantioselective carbon-carbon bond formation. 6In the majority of these reactions, the carbon nucleophile is an ionic species and most often is an organocopper reagent.Despite extensive literature on the ionic reaction, comparatively little research has focused on the free radical variation.It is only quite recently that the conjugate addition of free radicals to α,βunsaturated systems has been successfully studied by using tin hydride as the radical initiator. 8arbon-carbon bond formation via a free radical-mediated reaction has led to a variety of useful applications in organic synthesis. 9In view of the excellent characteristics of triethylborane as a free radical initiator in aqueous solution and under aerobic conditions, we were prompted to examine the feasibility of Et 3 B-mediated free radical functionalized reactions of benzylidene Meldrum's acids prepared by Knoevenagel condensation of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and aldehydes under economical and eco-friendly conditions.Recently, Meldrum's acid derivatives have gained considerable attention not only from the novel chemistry they exhibit but also from the varied transformations they undergo. 10Meldrum's acid derivatives are key synthetic building blocks, with 5-alkylated, 11 5-acyl, 12 5-benzylidene, 13 and 5-benzyl derivatives 14 capable of subsequently useful transformations.In this paper, we wish to combine the feasibility of triethylborane with the synthetic utility of Meldrum's acid derivatives to develop a simple and effective procedure for the synthesis of various benzyl Meldrum's acid.

Results and Discussion
Based on our previous studies, 15  It is noteworthy to observe that corresponding benzyl Meldrum's acids 1b were obtained in excellent yield.Our previous studies found that the treatment of dimethyl benzylidenemalonate with RI/Et 3 B not only affords the β-monoalkylated but also the α,β-dialkylated product at the same time.15e Although the quantity of α,β-dialkylated product could been limited by using triethylaluminum, the air-sensitivity of this reagent makes it very difficult to handle and leads to a tedious to workup.The different results are explicable from the different coordination abilities of triethylborane and triethylaluminum.The size of the aluminum atom facilitates a tighter coordination to the oxygen of the dimethyl benzylidenemalonate than is the case for boron so that the substrates could be activated more efficiently and could be attacked by the nucleophilic alkyl radical easily.Comparatively, in the reaction of benzylidene Meldrum's acid 1 with RI/Et 3 B no α,βdialkylated product was observed.We proposed that the steric hindrance maybe plays an important role to restrict the formation of α,β-dialkylated products.As shown in Table 1, the free radical mediated-conjugate addition could be carried out with various benzylidene Meldrum's acids in 40-96% yields by using Et 3 B and various alkyl iodides.Both aromatic and aliphatic benzylidene Meldrum's acids reacted with various alkyl radicals, induced by triethylborane, and afford the corresponding benzyl Meldrum's acids in good to excellent yields.The yields of benzyl Meldrum's acid carrying electron-withdrawing groups were lower than those with electron-donating groups and this is ascribed to a poorer solubility under the reaction conditions.The reaction was performed using 1 mmol of benzylidene Meldrum's acid and 2.5 mmol of Et 3 B or 2.5 mmol of Et 3 B with RI (selected equiv) in 10 mL THF at 0 ºC.b Isolated yield.
The same reaction system has been extended efficiently to iodo-adamantane with triethylborane under similar conditions.Thus, the reaction of benzylidene Meldrum's acid 1 with the 1-adamantyl radical afforded the corresponding derivative 7 in 50% isolated yield (Scheme 2).The low yield of 7 could be due to steric hindrance of 1-adamantyl radical.
On the basis of literature results and our own studies, 15g the reaction system could be successfully applied to the one-pot synthesis of various benzyl Meldrum's acids from RI/Et 3 B and benzylidene derivatives prepared in situ from Meldrum's acids and aldehydes.The yields from the one-pot syntheses are shown in Scheme 3.
On the basis of our own studies on the triethylborane-induced free radical chemistry, the results show that oxygen is not only known to be a free radical scavenger but also to be a free radical initiator. 15A mechanism for the above reactions is proposed in Scheme 4. The synthetic utility of the benzyl Meldrum's acid preparations has been extended as shown in Scheme 5 through synthesis of the corresponding 1-indanone derivatives.Initially, the treatment of benzylidene Meldrum's acid with Et 3 B or i-PrI/Et 3 B at 0 ℃ for 3 min afforded benzyl Meldrum's acids 8a and 8b in 92% and 79% yields, respectively.These were converted into the corresponding 1-indanones 9a and 9b by Sc(OTf) 3 catalysis under reflux in 60% and 63% yields, respectively.or Et 3 B (2.5 eq.) i-PrI (9 eq.) Scheme 5.The synthesis of 1-indanones from benzylidene Meldrum's acids.

Conclusions
In comparison with our previous study 15e , we have now found that the formation of the α,βdialkylated products cannot only be avoided by using a strong coordinative reagent such as triethylaluminum but also by using sterically hindered benzylidene Meldrum's acids.Herein, we have developed a simple procedure for the synthesis of benzyl Meldrum's acids, which are key building blocks for synthesis.The reaction system was successfully applied to a variety of benzylidene Meldrum's acids as well as alkyl radicals generated by triethylborane.Various benzyl Meldrum's acids have been prepared in a one-pot procedure.

Experimental Section
General.All reagents and chemicals were purchased from Sigma-Aldrich Chemical Company, Acros organics, Alfa Aesar or Merck and were used as received.Analytical thin layer chromatography was performed with Merck silica gel 60F glass plates and flash chromatography by the use of Merck silica gel 60 (230-400 mesh).Melting points were determined on a microscope hot-stage apparatus and are uncorrected. 1H-NMR and 13 C-NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker Avance 400 FT-NMR instrument.Chloroform-d was used as the solvent and TMS (δ = 0.00) as an internal standard.Chemical shift values are reported in ppm relative to TMS.Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), br (broadened), m (multiplet).Coupling constants (J) are in Hz.MS and HRMS were measured on JEOL JMS-D300 and JEOL JMS-HX110 spectrometers, respectively.

Typical experimental procedures for the synthesis of benzyl Meldrum's acids from benzylidene Meldrum's acids (Table 1)
In a pyrex test tube with a magnetic stirrer were placed benzylidene Meldrum's acid (1 mmol) alone or with alkyl iodide (selected equiv) in THF (10 mL) at 0 ºC.Triethylborane (2.5 mmol) was added dropwise into the mixture solution, into which was bubbled air from air pump at 0 ºC.After 3 min the reaction mixture was poured into ice cold water and then extracted with CH 2 Cl 2 (3 × 25 mL).The combined CH 2 Cl 2 layers were washed with brine, dried over anhydrous MgSO 4 , and the solvents removed.The crude product was purified by flash column chromatography to obtain benzyl Meldrum's acids 1.

Typical experimental procedures for the one-pot synthesis of benzyl Meldrum's acids (Scheme 3)
In a pyrex test tube with a magnetic stirrer were placed aldehyde (1.1 mmol) and Meldrum's acid (1 mmol) in water (3 mL) and the whole heated to 75 ℃ for 2 h.After cooling to room temperature, THF (10 mL) alone or containing alkyl iodide (selected equiv) was added to the aqueous solution.Triethylborane (2.5 mmol) was added dropwise into the THF-water biphasic solution, into which was bubbled air from air pump at 0 ºC.After 3 min the reaction mixture was poured into ice cold water and then extracted with CH 2 Cl 2 (3 × 25 mL).The combined CH 2 Cl 2 layers were washed with brine, dried over anhydrous MgSO 4 , and the solvents removed.The crude product was purified by flash column chromatography to obtain benzyl Meldrum's acids 1.  (100), 57 (28); HRMS (EI) m/z calcd for C 18 H 24 O 5 (M + ) 320.1624, found 320.1621.

Scheme 1 .
Scheme 1. Reaction of benzylidene Meldrum's acid with Et 3 B and RI.

Scheme 4 .
Scheme 4. Proposed mechanism for the synthesis of benzyl Meldrum's acid.

Table 1 .
The synthesis of benzyl Meldrum's acids from benzylidene Meldrum's acid and Et 3 B or RI/Et 3 B a