Tartaric acid and its O -acyl derivatives. Part 8. Direct synthesis of novel N -substituted mono-and diacyltartrimides: unusual reaction course

Unexpected hydrolysis of diacyl tartaric acids during their reaction with primary amines yielded new monoacyl tartrimides.


Introduction
Tartrimides belong to the group of easy available tartaric acid derivatives.Two chiral carbons with hydroxyl substituent and rigid heterocyclic structure cause that tartrimides are excellent starting materials in asymmetric synthesis.So, diacetyl-N-p-methoxybenzyltartrimide is an intermediate in the diastereoselective synthesis of 3,4-dihydroxyglutamic acids, which can play agonists role of mGluR1. 1 It is also a precursor in the synthesis of 3-hydroxyoxiracetam, the API of a useful nootropic drug in treatment of dementia. 2Dicaffeoyl-and digalloyl-tartrimide derivatives were examined as inhibitors of the integrase of the HIV virus. 35][6][7] Lentiginosine itself was used as α-glucosidase and amyloglucosidase inhibitor a potential anticancer and antiviral agent.In the total synthesis of UCS1025A, which is an active agent against cancer human cells by the inhibition of telomerase, the starting materials were diacyl tartrimides (Figure 1).0][11] These valuable compounds were used as chiral ligands, for example, in the asymmetric epoxidation of allyl alcohols, 9,12 or the enantioselective addition of diethylzinc to aromatic aldehydes. 9,11e have found only two references regarding monoacyl tartrimides.A preparation of O-benzoyl-N-methyltartrimide raises doubts. 13Patent information concerns a rather specific N-substituent, 5-sulfamoyl-1,3,4-thiadiazol-2-yl, of O-acetyl-and O-pivaloyltartrimides; no spectroscopic data are given. 14

Results and Discussion
Motivated by the diverse and important applications of tartrimides, we sought an effective synthesis of this group of organic compounds.Our goal was to obtain various diacyltartrimides via the reaction of an appropriate acid 15 or anhydride 4 with a primary amine.
First, we examined the reaction of dibenzoyltartaric acid 1a, the most commonly used derivative of tartaric acid, with benzylamine 2f, refluxed in a few aromatic solvents with the azeotropic distillation of water.Unexpectedly, we isolated O-monobenzoyl-N-benzyltartrimide 3f (38% in toluene after 8 h, 42% in xylene after 12 h).Extending the reaction time beyond 12 h did not increase the yield.At lower temperatures the reaction did not proceed with the previously observed yield (Table 1).Similarly, in the reaction of dibenzoyltartaric anhydride and 2f monobenzoyltartrimide 3f was isolated with 41% yield.
Under optimal conditions we performed the reaction between three different diacyl tartaric acids and eight primary amines (1:1 mol/mol, azeotropic distillation of water, 12 h).Depending on the kind of substrates used, mono-or diacyltartrimides or mixtures thereof were obtained (Table 2).For comparison, we examined the reaction of N-benzyl-and N-phenyltartrimide with acyl chlorides (1:1 molar ratio) in pyridine.In spite of the low temperature, mixtures of mono-and diacylproducts were formed.The highest yield and selectivity was observed for monobenzoyl-N-phenyltartrimide (59%, according to HPLC, Table 3).However, due to the difficult resolution by crystallization and the necessity of column chromatography, this method is of little preparative importance as a source of monoacyl-N-substituted tartrimides.To check the reaction course of diacyltartaric acids with primary amines, we synthesized the compounds which may occur in the reaction system of dibenzoyltartaric acid 1a and benzyl amine 2f, i. e. dibenzoyl-N-benzyl-tartaric monoamide 7f 16 from dibenzoyltartaric anhydride, 17 dibenzoyl-N,N′-dibenzyltartaric diamide 8f 16 from 1a, 17 mixture of isomeric monobenzoyl-Nbenzyltartaric monoamides 10f′ and 10f″ 17 from monobenzoyltartaric anhydride, 18 and dibenzoyl-N-benzyltartrimide 4f 19 from N-benzyltartrimide.Then, we examined the reaction of dibenzoyltartaric acid with benzyl amine (1:1 molar ratio) (HPLC) under azeotropic distillation of water.Immediately after adding benzylamine 2f to the solution of dibenzoyl tartaric acid 1a in xylene a suspension appeared, most probably composed of mono-5 and/or diaminium salt 6 of dibenzoyltartaric acid, which dissolved after 2.5 h as the salts were converted to highly soluble in hot xylene amides and imides (Figure 2).Meanwhile, the evolution of water was observed.After 3 h 1a was totally consumed.It was converted mostly into dibenzoyl-N-benzyltartaric monoamide 7f, monobenzoyl-Nbenzyltartrimide 3f, dibenzoyl-N-benzyltartrimide 4f, and benzoic acid 9 as a byproduct.During further heating, the monoamide 7f vanished and there was a slow increase in the amount of tartrimide 4f present and a slightly faster increase in the amount of tartrimide 3f.Traces of isomeric monobenzoyl-N-benzyltartaric monoamide 10f′, 10f″ and of tartaric diamide 8f were also visible.To finally clarify the reaction course, some model reactions were performed under conditions of monobenzoyl-N-benzyltartrimide 3f synthesis (xylene, 140 °C, 8 h).The heating of 7f resulted in a mixture of mono-3f and di-4f benzoyltartrimides.Thus, the reaction of either dibenzoyltartaric acid or anhydride with benzylamine resulted in the same mixture of products.The hydrolysis of one benzoyl group of dibenzoyltartrimide 4f and of tartaric diamide (8f) proceeded slowly and with moderate or even small yield (30% and 15%, according to HPLC), respectively.No formation of 4f in the latter case was observed.In contrast, the cyclization of monobenzoyltartaric monoamides 10f′, 10f″ to monobenzoyltartrimide 3f proceeded quickly and with very high yield (>90% HPLC).This might be the reason why we did not isolate 10f′, 10f″ during heating of dibenzoyl-Nbenzyltartaric monoamide 7f, because the hydrolysis of 7f (synthesis of 10f′, 10f″) is much slower than the following cyclization (synthesis of 3f).Additionally, benzoic acid was found in the reaction mixture and N-benzyl benzamide was not detected (GC-MS, NMR).Thus, the formation of monobenzoyltartrimide proceeded via hydrolysis not aminolysis of one benzoyl group.Such a hydrolysis has not previously been reported, probably because diacyl imides were obtained from diacyl acids or anhydrides and amines under dehydration conditions caused by acetyl chloride, 20 acetyl anhydride, 21 or thionyl chloride. 13e assume that in the formation of monobenzoyltartrimide 3f in the early stages of the reaction the hydrolysis of dibenzoyltartaric monoamide 7f to monobenzoyltartaric monoamides 10f′, 10f″ is faster than the hydrolysis of dibenzoyltartrimide 4f.

THF, rt, 2 h
We propose the following formation course of N-substituted mono-and diacyltartrimides in the reaction of diacyltartaric acids with primary amines (1:1) (Scheme 1).In the first step mono- Scheme 1.The routes of the reaction of diacyltartaric acid 1 with primary amine 2

Conclusions
In conclusion, the results show that the reaction of diacyltartaric acids 1 with primary amines to give the corresponding N-substituted monoacyltartrimides 3 and diacyltartrimides 4 is of practical importance.It was found that the diacylimide 4 occurs together with the monoacylimide 3, which shows that the reaction proceeds via two routes (Scheme 1).After its formation, the monoamide 7 undergoes two competitive reactions, a hydrolysis of one acyl group with the formation of previously unknown isomeric monoacyltartaric monoamides 10′, 10″ and a cyclization to the imide 4. Both the following cyclization of 10′ and 10″ and the hydrolysis of 4 result in the formation of monoacyltartrimide 3.
Depending on the kind of substrates used and the solubility of the products, N-substituted mono-3 or diacyltartrimides 4 can be efficiently obtained and isolated.Thus, we supplied the chiral pool with six mono-and 10 diacyltartrimides, novel buildings blocks for organic chemistry.Both the presence of carboxylic acid 9 and the absence of carboxylic acid amide confirmed our earlier assumptions that the monoacyl derivatives are formed as a sequence of the hydrolysis not aminolysis of one of two acyl groups of the tartaric skeleton.

Experimental Section
General.Dibenzoyltartaric acid and dibenzoyltartaric anhydride were obtained from our pilot plant.All other reagents were obtained from commercial sources and were used without further purification.Solvents were dried over 4Å molecular sieves.HPLC was carried out with an HP 1100 (Agilent Technologies) on an RP column, using a UV-Vis detector (at 230 nm).NMR spectra were recorded with a Varian Gemini 2000 spectrometer (200 MHz for 1 H NMR, 50 MHz for 13 C NMR) or a Varian Mercury 400 (400 MHz for 1 H NMR, 100 MHz for 13 C NMR) and measured in CDCl3 with TMS as the internal standard.IR spectra were recorded on a Specord M80 spectrometers using KBr pellets.The optical rotations were measured with a PolAAr 32 (Optical Activity Ltd).All the elemental analysis were measured with a Perkin Elmer 2400 Series II CHNS/O Elemental Analyzer.

General procedure for the synthesis of N-substituted mono-and diacyltartimides
The appropriate diacyl acid (15 mmol) was dissolved in 50 ml xylene and placed in a threenecked flask equipped with a Dean-Stark trap and refluxed until the azeotropic distillation of crystalline water was completed.The appropriate amine (15 mmol) was added and reaction mixture refluxed for 12 h under azeotropic distillation of water.After cooling to r. t., the reaction mixture was filtered under reduced pressure.Crude products were crystallized from methanol and dried (60°C, 6 h).4H), 1.36 (dt, J = 2.9 Hz, J = 7.2 Hz, 3H). 13