Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

We have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel condensations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limitations were encountered. The synthetic modifications of some of the intermediates – using Suzuki–Miyaura coupling or cycloadditions – before undertaking the oximation step – provided accesses to further α-amino esters. Moreover, other pathways to α-hydroxyimino esters were explored including an attempt to improve the cycloadditions between ethyl β-bromo-α-hydroxyiminocarboxylate and various alkylfuranes.


Isolation of diethyl 2-(furan-2-ylmethyl)malonate (3ae):
In this specific case, the following protocol was used: The ethanol solution obtained as described above and containing compound 6ae was concentrated to dryness thoroughly. At 0 °C, under a calcium chlorideprotected atmosphere, the resulting oil (5.86 g, 0.0246 mol) was dissolved in dry THF (100 S22 mL) and sodium borohydride (0.65 g, 0.0172 mol) was added. This was stirred at 0 °C for 24 hours, diluted with water and ethyl acetate and made cautiously acidic with acetic acid. The resulting solution was extracted twice with ethyl acetate, the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography over silica gel (cyclohexanedichloromethane 2/3 to 1/4) to yield compound 3ae as an oil (2.91 g, 49%). 1

Preparations of oximes 23, 27 or 32:
The considered cyclopropyl-bearing arylidenemalonates 14, 18 or 30 were reduced using sodium borohydride overnight at 4 °C as described above and the resulting malonates 16, 20 or 31 were then used directly to S25 prepare the corresponding oxime as described above for the preparation of compounds 2 to give the target oximes which were purified and characterized as described below.

Diethyl 2-(1-(furan-2-yl)ethyl)malonate (34):
The ethanol solution containing compound 6ae and obtained as described above was concentrated to dryness thoroughly to give an oil (4.51 g, 0.0189 mol). This was dissolved under argon in dry THF (30 mL), cooled to 0 °C and a 3 M solution of methyl magnesium chloride in THF (16 mL, 0.0473 mol) was slowly added.

Ethyl 2-(hydroxyimino)-3-phenylbutanoate (37):
Step 1: preparation of diethyl 2-(1phenylethyl)malonate (36): under a calcium chloride guard, diethyl malonate (5.32 g, 0.033 mol) was dissolved in dry DMF (50 mL, dried over 4 Å molecular sieves) and 60% sodium hydride in mineral oil (1.39 g, 0.0348 mol) was added portion-wise while maintaining the solution temperature at 20 °C with a water bath. This was stirred until the end of hydrogen S28 evolution and (1-chloroethyl)benzene 4.8 mL, 0.036 mol) was added. This was stirred for 7 days, diluted in water and ethyl acetate, the organic layer was washed 5 times with water, brine, dried over magnesium sulfate and concentrated to dryness under high vacuum to remove most of the unreacted diethyl malonate and (1-chloroethyl)benzene to give an oil (6.22 g) pure enough for the next step.

S29
Ethyl 2-(hydroxyimino)-3-methyl-3-phenylbutanoate (40): Under an inert atmosphere, ethyl 3-methyl-3-phenylbutanoate [9,10] (1.38 g, 6.68 mmol) was dissolved in dry THF (20 mL). This solution was cooled to −78 °C and a 2 N solution of lithium diisopropylamide in THF (3.5 mL, 7.02 mmol) was added. This was stirred for 5 minutes and isoamylnitrite (1 mL, 7.35 mmol) was added. The solution was allowed to warm to room temperature and stirred for 24 hours. This was diluted in water, made acid with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to dryness. Under an inert atmosphere, this residue was diluted in dry ethanol (10 mL, dried over 4 Å molecular sieves), a 21% solution of sodium ethoxide in ethanol (1 mL) was added and this was heated to reflux for 7 hours. The resulting "transesterified" solution was diluted with water, made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to dryness and purified by a chromatography over silica gel (cyclohexaneethyl acetate 7/1 to 4/1) to yield the target oxime as an oil (0.24 g, 15%). 1 4, 158.6, 144.3, 128.2, 126.7, 126.4, 61.2, 42.9, 27.1, 13.7. HRMS (m/z): [M+H] + calcd for C 13 H 17 NO 3 Na, 258.1106, found, 258.1087.
To this was added an initial 2 equivalents of triethylsilane (0.15 mL, 0.965 mmol) and following the monitoring of the reaction by LC/MS, additional equivalent of triethylsilane were added to reach a sum of 6 equivalents on day six. Following another day of stirring, water and 1 N hydrochloric acid were added to the resulting solution. This was stirred for 15 minutes made basic by adding 1 N sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, brine, concentrated to dryness and purified by a chromatography over silica gel (dichloromethaneethanol 98/2, TLC detection using a KMnO 4 solution) to yield compound 42 as a film (0.07 g, 69%). 1 9,136.6,129.1,128.6,126.9,66.2,61.1,35.5,14.1. HRMS (m/z): [M+H] + calcd for C 11 H 16 NO 3 , 210.113011 H 16 NO 3 , 210. , found, 210.1136 H NMR data similar to the reported one [11].
Step 2: In a calcium chloride-protected atmosphere, the crude diethyl 2-(prop-2-yn-1-yl)malonate described above (15.5 g), the relevant nitroalkane (0.078 mol) and phenylisocyanate (15.3 mL, 0.14 mol) were dissolved in dichloromethane (200 mL). To this solution were added 10 drops of triethylamine and this was stirred for 48 hours at 20 °C. The S31 resulting suspension was filtered, the filtrate concentrate to dryness and the residue further purified as described below.

Ethyl 3-bromo-2-(hydroxyimino)propanoate (47):
Two preparations were used to synthesize compound 47. The first one is very much the protocol described in a patent [12]: 75% pure ethyl bromopyruvate (5 mL, 0.0299 mol) was dissolved in water (10 mL) and chloroform (10 mL). To this was added hydroxylamine hydrochloride (2.52 g, 0.036 mol) and this was stirred in a closed vessel overnight. The resulting solution was diluted in dichloromethane, the organic layer was washed with water, brine, dried over magnesium sulfate, concentrated to dryness and recrystallized from n-heptane to yield compound 47 (still containing traces of ethyl 2-(hydroxyimino)propanoate;  = 2.12 ppm) as white needles (5.43 g, 64%). Note: an improved yield (19.74 g, 77%) was obtained when following the same procedure but using 90% pure ethyl bromopyruvate. Alternatively, we used the following original protocol (very much inspired by a report [13] mentioning a one pot synthesis of ethyl 2-(hydroxyimino)acetate from glyoxylic acid): 3-bromo-2-oxopropanoic acid (5.85 g, 0.0316 S33 mol), hydroxylamine hydrochloride (2.2 g, 0.0316 mol) and sodium bromide (6.5 g, 0.063 mol) were stirred overnight at 20 °C in dry ethanol (60 mL) and then heated to reflux for 30 minutes. This was dispersed in water and ethyl acetate, the organic layer was washed with water, brine, concentrated to dryness and the residue recrystallized from n-heptane to yield compound 47 (4.67 g, 70%) still containing some amount of its (oily) chlorinated homolog. 1 H NMR data similar to the reported one [12].

3-Ethyl-2-methylfuran (48ao):
In a 500 mL flask fitted with a condenser and a dropping funnel, lithium aluminium hydride (0.91 g, 0.024 mol) was weighted. Under an argon atmosphere, dry ether (20 mL) was added and the suspension stirred. In another flask, dry aluminium trichloride (3.2 g, 0.024 mol) was dissolved in dry ether (25 mL); note: a slight heating can be observed. This solution was then added to the suspension described above (no or little heating occurred). To this suspension 1-(2-methylfuran-3-yl)ethan-1-one, prepared from acetylacetone and chloroacetaldehyde as described below for the preparation of 6,7-dihydrobenzofuran-4(5H)-one (2.97 g, 0.024 mol) dissolved in dry ether (50 mL) was added drop-wise, slowly enough to avoid too much reflux. The resulting solution was stirred for 2 hours, cautiously quenched with water, and cautiously diluted with a 3 N solution of sulfuric acid. This was diluted in water and ether, the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated at atmospheric pressure to yield an oil containing compound 48ao and some ether which was directly used for the cycloaddition reaction as described below.
Step 2, reduction with AlLiH 4 /AlCl 3 : from 6,7-dihydrobenzofuran-4(5H)-one (3.62 g, 0.026 mol) the procedure is identical to the one described above for the preparation of 48ao. Note: but for the purification, this reduction protocol is pretty much identical to the one reported previously [15]. Again the oil containing 48ap and some ether was used directly for the cycloaddition reaction as described below.
Step 2, reduction with AlLiH 4 /AlCl 3 : the procedure is identical to the one described above for the preparation of 3-ethyl-2-methylfuran (48ao) but for the differences that two equivalent of AlCl 3 and two equivalent of AlLiH 4 were used and that the reaction was left to stir for 50 hours before undertaking the work up procedure described above. This gave the volatile compound 48aq as an oil still containing ether and cyclohexane which was used directly for the cycloaddition reaction as described below.
Step 2, reduction with AlLiH 4 /AlCl 3 : the procedure is identical to the one described above for the preparation of 3-ethyl-2-methylfuran (48ao) but for the differences that 2 equivalent of AlCl 3 and two equivalent of AlLiH 4 were used and that the reaction was left to stir for 50 hours before undertaking the work up procedure described above. This gave the volatile S35 compound 48ar as an oil still containing ether and cyclohexane which was used directly for the cycloaddition reaction as described below.
Protocols for the synthesis of furan-bearing -hydroxyimino esters by [2 + 4] cycloaddition Protocol b: The considered furan (0.013 mol), compound 47 (2.75 g, 0.013 mol) and sodium carbonate (1.5 g, 0.0144 mol) were dispersed in toluene (15 mL) before adding tetrabutylammonium bromide (0.042 g, 13 mmol). This was stirred for 1 hour, diluted in water and ethyl acetate, the organic layer was washed with water, brine, dried over magnesium sulfate, concentrated to dryness and further purified as described below.
Protocol c: The considered furan (0.01 mol), compound 47 (2.10 g, 0.01 mol) and ammonium bicarbonate (0.86 g, 0.011 mol) were dispersed in ethyl acetate (10 mL) before adding water (2 mL). This was stirred for 1 hour, diluted in water and ethyl acetate, the organic layer was washed with water, brine, dried over magnesium sulfate, concentrated to dryness and further purified as described below. Protocol d: The considered furan (6.09 mmol), compound 47 (1.28 g, 6.09 mmol) and lithium carbonate (0.49 g, 6.69 mmol) were dispersed in ethyl acetate (10 mL) before adding water (2 mL). This was stirred for 1 hour, diluted in water and ethyl acetate made, the organic layer was washed with water, brine, dried over magnesium sulfate, concentrated to dryness and the residue further purified as described below. Protocol e: The considered furan (0.0117 mol), compound 47 (2.56 g, 0.0117 mol) and sodium carbonate (1.42 g, 0.0129 mol) were dispersed in ethyl acetate (6 mL) and water (3 mL).
This was stirred for 1 hour, diluted in water and ethyl acetate, the organic layer was washed with water, brine, dried over magnesium sulfate, concentrated to dryness and further purified as described below.