Efficient Preparation of α-Ketoacetals

The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a–j in 70–99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.


Introduction
The α-ketoacetals constitute a strategic array of functional groups of great value in synthetic organic chemistry. They offer the possibility of performing the selective functionalization of a keto group over the more reactive aldehyde, as the latter is protected as an acetal. For instance, α-ketoacetals are key intermediates in the preparation of chiral cyanohydrins [1], nicotine derivatives [2], chiral sulfoxides [3], α-hydroxy acetals [4][5][6], chiral 1,2-diols [7] and, of particular importance for our research group, of several myrtenal-derived chiral auxiliaries [8][9][10]. A number of methods have been described for the preparation of α-ketoacetals, including the classic acetalization of monoalkyl-substituted glyoxals with trialkylorthoformate [1], treatment of α,α-dichloroketones with MeONa [11], selenium-catalyzed conversion of terminal alkynes [12] and methyl aryl ketones [13] in the presence of MeOH, transformation of methoxystyrenes with Ce(IV) ammonium nitrate [14], treatment of methylketones OPEN ACCESS with alkylnitrite [15], rearrangement of 1,3-dimethoxy-2-alkanones [16], oxidation of arylketones by thallium(III) and halogens [17], nucleophilic addition to α,α-dialkoxyacetyl chlorides [18] as well as addition of RMgX and RLi to ethyl α,α-diethoxyacetate [19]. From our own experience, direct treatment of either α,α-dialkoxyacetates 1a or 1b with Grignard reagents [19] gave the desired α-ketoacetals invariably accompanied by the corresponding tertiary alcohols. Hence, a protocol for the separation of the latter must be implemented in order to obtain pure α-ketoacetals. While some methods lack generality because they need specific substrates, others involve elaborate protocols or the formation of byproducts which are hard to separate from the reaction mixture. In addition, there is a scarcity of commercially available α-ketoacetals, which is essentially limited to the existence of 2,2-diethoxyacetophenone and 1,1-dialkoxyacetone [20]. These facts prompted us to develop a general, easy, and efficient procedure to prepare a wide variety of α-keto-acetals. Therefore, we describe herein the preparation of Weinreb amides [21] (WAs) 2a,b (Scheme 1) as key reagents for the synthesis of a wide range of α-ketoacetals through the addition of nucleophiles such as Grignard reagents or alkyllithiums. The synthetic versatility of α-ketoacetals is demonstrated in the synthesis of rac-salbutamol.
Thus, using triphosgene in CH 2 Cl 2 at 0 °C, followed by the treatment of the carboxylic acid chloride intermediate with MeO(Me)NH-HCl and TEA [25], these compounds were readily converted to their respective WAs 2a and 2b in 88 and 75% yield, respectively (ii pathway, Scheme 2). The WAs 2a and 2b are stable enough to be freely handled without any decomposition under the experimental procedure. Their purification was achieved by distillation using a Kugelrohr apparatus at 40 °C and 0.5 mmHg, or by column chromatography on silica gel. A representative series of nucleophilic additions performed on WA 2a yielded only the corresponding α-ketoacetals 3a-j, with yields ranging from good to excellent (Table 1). Both Grignard reagents and alkyllithiums led to essentially the same results, as revealed through trials 1 and 6, and 4 and 8, where these different pairs of nucleophiles gave the same product in very similar yields. The α-ketoacetals were obtained in excellent yields and no further purification was required. In the same sense, no substantial differences in the reactivity of WAs 2a and 2b were observed, as the latter gave essentially the same result as the former under nucleophilic addition conditions (see entries 1 and 2, 3 and 4, as well as 6 and 7) giving compounds 4a and 4b. Although some WAs suffer demethoxylation under the action of LDA or some alkyllithiums (via an E2 reaction) [27], with the concomitant loss of formaldehyde and formation of the corresponding N-alkylamide, no such behaviour was observed in this case.
In order to illustrate the synthetic utility of α-ketoacetals they were used for the synthesis of 1,2-aminoalcohols in a protocol similar to that previously described (Scheme 3) [28], a method which represents a synthetic alternative to that described by using addition of amines to epoxides [29].
For instance, α-ketoacetal 3c was reduced in quantitative yield to the corresponding secondary carbinol, which was hydrolyzed to the cyclic dimer of the corresponding α-hydroxyaldehyde 6. The latter was directly treated, without isolation, with primary amines followed by reduction of the imine intermediate 6 with NaBH 4 to afford the corresponding 1,2-aminoalcohols 7a-d in 82-93% yield. This protocol was then successfully implemented for the total synthesis of (±)-salbutamol, a β2-adrenergic receptor agonist used for the treatment of chronic obstructive pulmonary disease. Thus, starting from 6-bromosalicylic acid (8), bromobenzodioxane 9 was obtained after reduction of the carboxyl group of 8 and after the successive formation of the dioxane functionality (Scheme 4). Treatment of 9 with Li in dry THF gave the corresponding organolithium which was subsequently added to Weinreb amide 2a affording the new α-ketoacetal 10 in 55% global yield from salicylic acid 8. Then, 10 was converted to carbinol 11 with NaBH 4 in MeOH. Finally, after hydrolysis of 11 and successive treatment of the α-hydroxyaldehyde intermediate with tBuNH 2 and reduction of the corresponding ketoimine with NaBH 4 , (±)-salbutamol was obtained in 81% yield.   High Resolution Mass Spectra (HRMS) were determined with a JEOL GCmate spectrometer by Electronic Impact (EI) ionization. Thin-layer chromatograms (TLC) were done on precoated TLC sheets of silica gel Merck 60F-254. Spots on TLC were revealed by using UV lamp, ceric sulfate, iodine chamber or 2,4-dinitrophenylhydrazine. Purification of compounds was performed by column chromatography on silica gel (Merck 230-400 mesh). A Kugelrohr SEV 200 apparatus was also used for liquid samples. THF was freshly distilled from a purple solution of sodium and benzophenone under nitrogen atmosphere. Some reagents were purchased from Sigma-Aldrich Chemical Co. and used without further purification.

N-Trimethoxy-N-methyl-acetamide (2a):
Method A N,O-Dimethylhydroxylamine hydrochloride (6.70 g, 68.6 mmol) in THF (60 mL) was cooled for 10 min. at −78 °C in a bath of acetone-dry ice. A freshly prepared solution of isopropylmagnesium chloride (14.12g, 137.28 mmol) was slowly added to the above solution, maintaining a vigorous stirring for 30 min under nitrogen atmosphere. To the resulting reaction mixture, methyl dimethoxyacetate (1a, 6 mL, 6.58 g, 49.03 mmol) was added dropwise and the reaction mixture was stirred for 1h at −78 °C, then quenched with 20 wt % NH 4 Cl. The reaction was extracted with dichloromethane (3 × 30 mL) and the organic layer was dried over anhydrous Na 2 SO 4 and evaporated to dryness. The product was purified using a Kugelrohr apparatus at 40 °C (0.5 mmHg), obtaining amide 2a (2.39 g, 30%) as a pale yellow oil. The same procedure was followed to prepare amide 2b, starting from ethyl diethoxyacetate (1b).

Method B
To a stirred solution of the carboxylic acid 1c (58 mg; 0.48 mmol) in CH 2 Cl 2 (10 mL) at 0 °C; triphosgene (71.1 mg; 0.24 mmol) and triethylamine (0.334 mL; 2.398 mmol) were added. Then N,O-dimethylhydroxylamine hydrochloride (51 mg; 0.52 mmol) was added to the solution and the ice bath removed. The reaction mixture was stirred at room temperature for 1h. The reaction was extracted with EtOAc (3 × 10 mL). Then; the organic phase was dried with anhydrous Na 2 SO 4 and concentrated in vacuum. The product was purified by column chromatography on silica gel using EtOAc-n-hexane

General Procedure for the Preparation of α-Ketoacetals
To a solution of amide 2a (100 mg, 0.61 mmol) in THF (6 mL), cooled at −78 °C, the organometallic reagents (1.5-2.0 eq.) were slowly added, maintaining vigorous stirring under nitrogen atmosphere for 1 h. Then, the reaction was quenched with a saturated solution of NH 4 Cl. The reaction was extracted with dichloromethane (3 × 4 mL). The organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness. The crude reaction was flash chromatographed (silica gel) using a mixture of n-hexane-EtOAc (8:2) as eluent.

General Procedure for the Synthesis of β-Aminoalcohols
To a cooled (0 °C) solution of α,α-dimethoxyacetophenone (3c, 2 g, 11.09 mmol) in EtOH (100 mL) 839.3 mg (22.18 mmol) of NaBH 4 were added and the resulting mixture was stirred for 30 min. The reaction was quenched with acetone, the solvent was evaporated and 100 mL of hot water was added to the crude reaction. The latter was extracted with dichloromethane (3 × 5 mL), the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness giving the corresponding carbinol (1.98 g, 96%). This compound (500 mg, 2.74 mmol) was treated with 0.2 mL of HCl 37% diluted in 2 mL of THF and stirred for 15 min. The reaction mixture was washed with a sat. solution of NaHCO 3 (3 × 10 mL), extracted with dichloromethane (3 × 15 mL) and the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness, giving 285.9 mg (74%) of 5 as a white solid.
The amine (7.34 mmol) was added to a solution of α-hydroxyaldehyde 5 (200 mg, 1.49 mmol) in THF and the resulting mixture was stirred for 30 min. The crude reaction was dissolved in 3 mL of ethanol and treated with NaBH 4 (2.94 mmol) under vigorous stirring for 30 min. After this time, the reaction was quenched with acetone and the solvent was evaporated. The crude syrup was treated with 5 mL of hot water, extracted with dichloromethane and (3 × 5 mL), the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness giving the corresponding β-aminoalcohol.  Bromo-2-(hydroxymethyl)phenol (8a). A solution of LiAlH 4 (3.5 g, 90 mmol) in 50 mL of ether was cooled for 30 min. at −78 °C in a bath of acetone-dry ice. After that, a solution of 5-bromosalicylic acid (8, 16 g, 0.078 mmol) in ether (20 mL) was added dropwise and the reaction mixture was stirred for 2.5 h under nitrogen atmosphere and was quenched with EtOAc and water (ice). Then, to the reaction mixture a solution of hydrochloric acid 50% v/v (200 mL) was added. The reaction was extracted with dichloromethane (3 × 20 mL) and washed with sat. NaHCO 3 (3 × 30 mL) and the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness. The crude was dissolved in EtOAc and n-hexane was added to obtain a precipitate, obtaining 8a (8.6 g, 57%) as a white solid. 1 [1,3]dioxane (9). To a stirred solution of 8a (5 g, 24.62 mmol), p-TsOH (450 mg, 0.24 mmol) and sodium sulfate (9.6 g) in acetone (95 mL) 2,2-dimethoxypropane (121 mmol) were added. The reaction was maintained with a vigorous stirring for 72 h at 40 °C. After that, the reaction was extracted with CH 2 Cl 2 (120 mL) and washed with sat. NaHCO 3 (3 × 30 mL). The organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness giving 9 (5.65 g, quantitative yield) as an amber liquid. 1 [1,3]dioxin-6-yl)-2,2-dimethoxyethanol (11). To a cooled solution (0 °C) of 10 (161 mg, 0.6 mmol) in ethanol (10 mL) NaBH 4 (46 mg, 1.22 mmol) was added. The reaction mixture was stirred for 30 min. Then it was quenched with acetone, the solvent was evaporated and 5 mL of hot water was added to the reaction crude. The reaction was extracted with dichloromethane (3 × 5 mL), the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness giving 11 (160 mg, quantitative yield) as a yellow and viscous liquid. 1  (±)-Salbutamol. To a solution of hydroxyacetal 11 (160 mg, 0.59 mmol) 37% HCl (0.16 mL) diluted in THF (1 mL) was added. After 15 min the reaction finished and the reaction mixture was washed with a solution of NaHCO 3 sat (3 × 2 mL). The reaction was extracted with dichloromethane and (3 × 3 mL) the organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness, giving the corresponding α-hydroxyaldehyde (80 mg as crude). To this crude t-BuNH 2 (0.76 mL, 7.3 mmol) was added and the reaction mixture was stirred for 30 min. The reaction crude was dissolved in ethanol (3 mL) and treated with NaBH 4 (109.7 mg, 2.9 mmol) under vigorous stirring for 30 min. The reaction was then quenched with acetone and the solvent was evaporated. After this, hot water (5 mL) was added to the crude. The reaction was extracted with dichloromethane and (3 × 5 mL). The organic layer was dried over anh. Na 2 SO 4 and evaporated to dryness giving (rac)-salbutamol (85.3 mg, 81% yield).

Conclusions
In conclusion, it has been shown that WAs 2a,b represent an efficient and practical alternative for obtaining a wide variety of α-ketoacetals, which in turn represent an array of functional groups in high demand in synthetic organic chemistry. A practical synthetic application of α-ketoacetals was developed for the synthesis of some 1,2-aminoalcohols, including the total synthesis of (±)-salbutamol.