Carboxylate Catalysis: A Catalytic O-Silylative Aldol Reaction of Aldehydes and Ethyl Diazoacetate

A mild catalytic variant of the aldol reaction between ethyl diazoacetate and aldehydes is described using a combination of N,O-bis(trimethylsilyl)acetamide and catalytic tetramethylammonium pivalate as catalyst. The reaction proceeds rapidly at ambient temperature to afford the O-silylated aldol products in good to excellent yield, and the acetamide byproducts can be removed by simple filtration.


Introduction
Synthetic reactions involving catalytic bases are sometimes sensitive to water or unprotected hydroxy groups in the substrate as they are rapidly deprotonated to potential nucleophiles by the catalyst.In addition, unprotected hydroxyl groups in the product could also present problems.For example, the aldol addition and related reactions give rise to unprotected aldolates, which may render the reaction reversible and result in incomplete conversions.
To overcome these limitations, reactions involving catalytic bases are sometimes assisted by auxiliary hard acid reagents, such as magnesium ions or silylating agents.
2 Herein we describe a particularly mild combination of a carboxylate salt and N,O-bis(trimethylsilyl)acetamide (BSA) 3 as a catalyst/silyl reagent combination as traces of reagent and catalyst can be removed by simple trituration, filtration and concentration.
We have selected the aldol reaction between ethyl diazoacetate and aldehydes to illustrate the benefits of the catalytic system.The first published variant of the reaction, catalysed by KOH in methanol, resulted in an equilibrium that favoured the starting materials. 4To overcome this limitation, milder catalytic methods and other variants have been published.In 1976, Evans and co-workers described a mild Osilylative variant which required the use of TMS-activated diazoacetate and catalytic KCN/18-cr-6. 5Even milder methods employing, among others, DBU , or benzoic acid 9 as catalysts have been disclosed.With metal phenolates or organometallic bases, the reaction has also been rendered enantioselective.
Typically, the reactions have been restricted to simple aryl or alkyl aldehydes, and chromatographic purification has been required for the products.Based on our previous work on carboxylate catalysis in the enolization of thioesters with simple carboxylate catalysts such as tetramethylammonium pivalate (TMAP) , we hypothesized that the diazoacetate aldol reaction should also be amenable to carboxylate catalysis.Herein we describe a particularly mild method for the one-pot diazoacetate aldol under silylative conditions with a mild silylating agent (N,Obis(trimethylsilyl)acetamide, BSA) that gives the O-silylated products in good yields even without any chromatographic purification.

Results and discussion
Tetramethylammonium pivalate (TMAP, 3) was chosen as the carboxylate catalyst for our test reactions since it is soluble in acetonitrile.With catalytic amount of TMAP (Table 1, entry 1), only traces alcohol 4 could be obtained.We hypothesized that the catalytic cycle did not turn over due to deactivation of the catalyst by the product 4 by protonation.Indeed, with a stoichiometric amount (1.2 equiv) of TMAP, the reaction reached 41% conversion (Table 1, entry 2).To tackle this problem, a silylating agent -N,O-bis(trimethylsilyl)acetamide (BSA) -was added to the reaction (entry 3), this resulted in full conversion to O-silylated product 5a in under 3 hours.Encouraged by this success, we moved to preparative scale in optimizing the reaction conditions.The present variant of the diazoacetate aldol reaction involves two steps, the C-C bond formation and silylation step.To provide insight into which of these steps might be turnover-determining, we examined the relative rates of the formation of 5a-d via competition experiments (see the Supporting Information). 13While a reliable  value could not be established from these experiments alone, the reaction was found to be accelerated by electron-withdrawing and decelerated by electrondonating groups (p-OMe, k rel ≈ 0.11; p-Me, k rel ≈ 0.12; and p-Cl, k rel ≈ 4 compared to 5a).These data are consistent with a turnover-limiting nucleophilic addition to the aldehyde carbonyl, and the aldolate O-silylation event is unlikely to limit the overall rate.However, we cannot rule out the possibility that the carboxylate anion is Osilylated by BSA to generate the actual catalyst via a probase mechanism. 14 In conclusion, we have established a mild carboxylate catalysed silylative diazoaldol reaction that proceeds rapidly at rt with a range of substrates and provides products in minutes, generally without the need of any chromatographic purification.
Studies of the applications of the present catalytic system in other reactions are in progress.

General procedure A (GP A):
To a solution of aldehyde (limiting reagent, typically 0.98 mmol, 1.0 equiv.),ethyl diazoacetate (1.03 mmol, 1.1 equiv.)and N,O-bis(trimethylsilyl)acetamide (1.96 mmol, 2.0 equiv.) in dry MeCN was added a freshly prepared solution of tetramethylammonium pivalate (TMAP) (57.3 mM in MeCN, 0.001-0.10equiv).The reaction progress by taking small aliquots which were analyzed by 1 H NMR. After no aldehyde remained in the reaction mixture (typically after 5-25 min), the NMR sample solution combined with reaction mixture, EtOAc (10 mL) and water (15 mL) were added, and the layers were separated.The organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give the crude product as a tan/orange oil, and the side product N-trimethylsilylacetamide as white crystals.Repeated trituration with EtOAc/hexanes (5:95, ca 25 mL total), and filtration provided the pure products (typically 2-3 times was sufficient).
The enantiomeric purity of 5n was determined from the corresponding desilylated derivatives 6 (see below).

Note 1:
The desilylation and purification protocol results enriches the diastereomeric ratio of the compound from ca 91:9 to ca. 97:3, depending on the rigorousness of the purification.The reduction reaction was carried out using a followed modified literature procedure 16 .To a degassed solution of 5n (160 mg, 0.35 mmol, 1 equiv) in EtOAc       = 7.1 Hz, 3H), 0.12 (s, 9H). 13 Another batch of (±)-5n was prepared following GP A at 0 °C.NMR spectra of this batch correspond to those obtained for the batch obtained at r.t.

Note 2 :
The same procedure was applied to the batch of 6 obtained at 0 °C.

Table 1 :
Optimization of the TMAP-catalyzed diazoaldol-type reaction *Conversion to product, determined by 1 H NMRIn dry acetonitrile, the reaction is generally over in 5-10 min after adding 1-10 mol% of the catalyst (Table1, entries 4-8).Only with very low catalyst loading (0.1 mol%, see entry 9), the reaction takes 24 h to reach completion.The reaction proved to be very high yielding, with over 90% yield in every optimization test (en-