Synthesis of N -substituted-3,4,5,6-tetrachlorophthalimide using trichloroacetimidate C-C bond formation method

A series of N -substituted-3,4,5,6-tetrachlorophthalimides were prepared by a novel sequential reaction of trichloroacetimidate 3 with C-nucleophiles in the presence of TMSOTf. The nucleophiles include arenes, alkenes and active methylene to give the imidomethylation product of 3,4,5,6-tetrachlorophthalimide 5 , 7 , 9 and 11 , respectively.


Introduction
α-Glucosidase catalyzes the final step in the digestive process of carbohydrates and the biosynthesis of the N-linked oligosaccharides on the envelope glycoprotein. 1,2onsiderable attention was directed to the design and synthesis of α-glucosidase inhibitors.Phthalimides, 3 tetrachlorophthalimides, and N-substituted phthalimides [4][5][6] are well known αglucosidase inhibitors.Inhibition of this enzyme retard the uptake of dietary carbohydrates to absorbable monosaccharides, 4 and due to that tetrachlorophthalimides can be potentially valuable for various diseases treatment as antiviral, 5 diabetes, certain forms of hyperlipoteinemia, and obesity. 6,7Structural development studies showed that the hydrophobic groups at the N atom are of crucial effect. 8][11]  Tetrachlorophthalimide system is a valuable amine-protecting group that can be cleaved under neutral or mild conditions. 12The use of trichloroacetimidates method is well recognized. 13- 14Trichloroacetimidates method have been widely used to activate the anomeric oxygen exchange reactions with the consequent glycosidec bond formation; useful in the glycoside synthesis area. 15,16Ibrahim A. I. Ali, et al, 17 reported the reaction of O-phthalimidomethyl trichloroacetimidate with C-nucleophiles to afford N-substituted phthalimides.We have extended the scope of this process enabling the efficient and selective carbon-carbon bond formation via N-substituted alcohol conversion into N-substituted alkanes.This research offers the development of a series of N-substituted-3,4,5,6-tetrachloro-phthalimide via C-C bond formation using trichloroacetimidate method as potent α-glucosidase inhibitors and anti-viral agents.

Results and Discussion
The base catalyzed addition reaction of trichloroacetonitrile to N-hydroxymethyl-3,4,5,6tetrachlorophthalimide hydroxyl group afforded the trichloroacetimidate 3 in 91 % yield.The reaction of 3 with C-nucleophiles in the presence of catalytic amount of TMSOTf at room temperature gave readily the imidomethylation product in high yield.Thus, trichloroacetimidate 3 was reacted with a series of substituted benzenes derivatives 4a-d in the presence of TMSOTf to give 2-substituted benzyl-3,4,5,6-tetrachlorophthalimides 5a-d, respectively in good to moderate yield, scheme1.][11] The structure assignment of the 2-substituted benzyl-3,4,5,6-tetrachlorophthalimides 5a-d is based on 1 H and 13 C NMR spectral and physicochemical analysis.The 1 H NMR spectra clearly confirm the selective aromatic electrophilic substitution site.Thus, the 1 H NMR spectrum of 5b gave a doublet and a multiplet signals at δ 7.19 and 6.41-6.37 ppm associated with the three aromatic protons. 1 H NMR spectrum also reveals a singlet signal at δ 4.80 ppm typically associated with NCH 2 , which confirms the generated C-C linkage.The 13 C NMR spectrum of 5b displays signals at δ 55.8, 55.75 and 37.8 ppm associated with 2OCH 3 and NCH 2 , respectively.
2-(3-Phenyl-allyl)-3,4,5,6-tetrachlorophthalimide 7a was characterized by 1 H, 13 C NMR and elemental analysis.The 1 H NMR spectrum exhibits the presence of NCH 2 as a doublet signal at δ 4.43 ppm confirming the C-C linkage that are common for all compounds.The 1 H NMR spectrum also displayed a doublet signal at δ 6.67 ppm typically associated with (CH=CHC 6 H 5 ) and a multiplet at δ 6.27-6.14ppm due to CH=CHC 6 H 5 .On the other hand, the 13 C NMR spectrum of 7a shows characteristic signals at δ 128.1 and 121.4 ppm corresponding to two CH groups (CH=CHC 6 H 5 ) while a signal at δ 40.4 ppm was assigned to the NCH 2 group.The chemical shifts of the remaining 1 H, 13 C NMR signals correlated with the proposed structure as reported in the experimental section.

Scheme 2
The structure of ketone 11 was established through 1 H NMR spectrum which reveal the presence of NCH 2 generated from the C-C linkage as a triplet at 4.11 ppm.On the other hand, the 1 H NMR of cyclohexanone 9 gave two doublet of doublets signals at δ 4.11 and 3.74 attributed to NCH 2 .

Conclusions
A general method has been developed for formation of N-substituted-3,4,5,6tetrachlorophthalimides by a novel sequential reaction of trichloroacetimidate 3 with Cnucleophiles.The prepared compounds might act as novel α-glucosidase inhibitors.

Experimental Section
General.Solvents were purified and dried in the usual way.The boiling range of the petroleum ether used was 40-60 o C. Analysis of the reaction mixtures and purity control of the products were carried out by TLC on Silufole UV-254.Elemental analyses were performed on a Flash EA-1112 instrument at the Microanalytical laboratory, Faculty of Science, Suez Canal University, Ismailia, Egypt.Melting points were determined on a Buchi 510 melting-point apparatus. 1H NMR spectra were recorded at 250 MHz (Bruker AC 250) in CDCl 3 solution with tetramethylsilane as an internal standard. General procedure for the preparation of 3,4,5,6-tetrachloro-O-phthalimido-methyl trichloroacetimidate 3 A stirred solution of N-hydroxymethyl-3,4,5,6-tetrachlorophthalimide 2 (1.58 g, 5 mmol) in dry dichloromethane (30 mL) and trichloroacetonitrile (1.5 mL, 10 mmol) was treated with DBU (71 µL) at room temperature and then left for 2 h.The solvent was evaporated under reduced pressure and the product was purified by column chromatography 5 % triethylamine in toluene/ethylacetate, 25:1 to give 3 as white powder.Colorless crystals (2.1 g, 91 %); mp 145-146 °C.