Nitroalkanes and Dimethyl Maleate as Source of 3-Alkyl Succinic Anhydrides and (E)-3-Alkylidene Succinic Anhydrides

Abstract

Nitroalkanes react with dimethyl maleate giving a tandem Michael addition/elimination of nitrous acid. The obtained (E)-2-alkylidene dimethyl succinates are: (i) reduced to the corresponding 2-alkyl dimethyl succinates which after hydrolysis produce 1,4-dicarboxylic acids that are prone to convert into the corresponding 3-alkyl succinic anhydrides or (ii) hydrolysed to (E)-2-alkylidenesuccinic acids that are easily cyclised to (E)-3-alkylidene succinic anhydrides.3-Alkyl-dihydro-furan-2,5-diones (3-alkyl succinic anhydrides) and (E)-3-alkylidene-dihydro-furan-2,5-diones [(E)-3-alkylidene succinic anhydrides] are both important class of compounds due to their utility as intermediates in the synthesis of important targets such as natural antibiotics, 1,2 pyrrolidines, 3 metalloproteinase inhibitors, 4 inhibitors towards human leukocytes, 5 cephalotaxine, 6 and monoesters of alkylated succinic acids. 7 Although several methods have been reported 3-7,8-12 for the preparation of the title compounds, they seem not of general applicability.Recently, an interesting methodology for the preparation of 3-alkyl succinic anhydrides has been published. 7d However, a more efficient procedure for the synthesis of both the anhydrides is still desirable.Over the last decade aliphatic nitro compounds have demonstrated to be a valuable source for the preparation of alkylated heterocyclic derivatives. 13 In continuation of our studies we wish to report here a general synthesis of both 3-alkyl succinic anhydrides 6 and (E)-3-alkylidene succinic anhydrides 8, using nitroalkanes 1 and dimethyl maleate 2 as common starting materials. Conjugate addition (Scheme) of the nitronate, derived from the nitro compound 1, to 2 in acetonitrile with DBU as base allows the formation of the product 3, essentially as single stereoisomer of E configuration. 13a,14 The adduct 3 is obtained pure enough and can be directly used without purification as the key building block for the synthesis of the anhydrides 6 or 8 by two different synthetic sequences.Scheme Synthesis of compounds 6a-k and 8a-e.Thus, chemoselective hydrogenation (10% Pd/C as catalyst) of the C=C double bond of the crude compound 3 yields the saturated diester 4 (80-98% from 1). Saturated diester 4 after hydrolysis with aqueous 2% sodium hydroxide and ethanol at reflux temperature provides the dicarboxylic acid 5 (63-90%).Although several methods are available for the conversion of 1,4-dicarboxylic acids into the corresponding anhydrides, we chose acetyl chloride 15 as a dehydrating agent for the preparation of 6 in high yields (85-98%, Table 1). On the other hand, the basic hydrolysis of the crude adduct 3 (2% sodium hydroxide solution) allows the formation of the 2-alkylidene succinic acid 7 (71-95%). The 2-alkylidene succinic acids 7 are converted to the (E)-2-alkylidene succinic anhydrides 8 in excellent yield (87-98%) following the previous procedure for the anhydrides 6. R R 1 NO 2 COOMe COOMe COOMe COOMe R R 1 COOH COOH R R 1 O R 1 R O O COOMe COOMe R R 1 COOH COOH R R 1 O R 1 R O...

An Easy Access to (E)-Alkylidenesuccinic Acids

“…14,17 The analytical and spectral data obtained for 1a-e were in complete agreement with the reported data. [4][5][6][7][8][9][10][11][12][13][14] The reduction of alkylidenesuccinic acids 1 to alkylsuccinic acids using palladium/charcoal and ring-closure of both the alkyl and alkylidenesuccinic acids to the corresponding alkyl and alkylidenesuccinic anhydrides using acetyl chloride as a dehydrating agent is well established. 14 In summary, we have demonstrated an efficient two-step easy approach to (E)-alkylidenesuccinic acids.…”

“…[2][3][4][5][6][7][8] Several methods have been reported [4][5][6][7][8][9][10][11][12][13] for the preparation of these acids/anhydrides but they do not seem to be of general nature. Very recently Ballini et al have demonstrated 14 an elegant 1,8diazabicyclo [5.4.0]undec-7-ene (DBU)-induced general coupling of nitroalkanes with dimethyl maleate to obtain these acids/anhydrides. Barrett et al have successfully condensed 15 the maleimide-triphenylphosphine adduct with D-ribose to complete the synthesis of showdomycin and epishowdomycin.…”

Total Synthesis of (+)‐Brefeldin C, (+)‐nor‐Me Brefeldin A and (+)‐4‐epi‐nor‐Me Brefeldin A

“…however, we recorded only a modest 60 % ee for the formation of acid 17. [22] In a search for more efficient conditions we then discovered that a patent [23] reported the preparation of 17 in up to 84 % ee through desymmetrization of the anhydride 11 in the presence of methanol and a catalytic amount of hydroquinidine anthraquinone-1,4-diyl diether [(DHQD) 2 AQN]. Attempts to reproduce these conditions did not at first lead us to record such a high ee, but we became aware that the enantioselectivity of the reaction was highly dependent on the anhydride concentration.…”

“…[20] Acidic hydrolysis of 15 [21] afforded the keto-diacid 16, which was next cyclized into the anhydride 11 in acetyl chloride at reflux. [22] By this five-step sequence of reactions, the anhydride 11 could be prepared on a 100 g scale in 66 % overall yield. The anhydride 11 was next subjected to Bolm's conditions as described previously for anhydride 10.…”

Self‐Supported and Clean One‐Step Cathodic Coupling of Activated Olefins with Benzyl Bromide Derivatives in a Micro Flow Reactor

“…The coupling products such as 2‐benzyl succinic acid dimethyl ester are important classes of compounds owing to their utility as intermediates in the synthesis of important targets such as natural antibiotics,5a pyrrolidines,5b metalloproteinase inhibitors,5c inhibitors towards human leukocytes,5d cephalotaxine,5e and monoesters of alkylated succinic acids 5f. Several methods have been reported5b,g,h for this class of compounds, most of which involve multi‐step processes and require the presence of metal catalysts. Alternatively, a photochemical procedure based on electron transfer to a photo‐sensitizer has been proposed for the coupling of methylbenzene and dimethylsuccinate,5i but the method resulted in a complex mixture of reaction products.…”