Synthesis of 1,2,3,4-substituted spiroheterocyclic tetrahydroisoquinoline-1-ones and their structural similarity in water solution and in crystallohydrate solid state

The title compounds were synthesized starting from homophthalic anhydride and a ketimine. The structure of 1'-methyl-1-oxo-2-(pyridine-3-yl-methyl)-2,4-dihydro-1 H -spiro[isoquinoline-3,4'- piperidine]-4-carboxylic acid was studied by X-ray analysis, ab initio and DFT calculations and the similarity between the conformation in crystalline hydrate state and in water solution was inferred. Derivatives of the parent compound were synthesized and studied by means of theoretical calculations.


Introduction
Tetrahydroisoquinolines are a wide class of compounds with a broad range of biological activities including antitumor, 1 antibacterial, antiallergic, and psychotropic. 2The tetrahydroisoquinoline fragment is present in a number of plant alkaloids. 3In addition these compounds are also attractive objects for stereochemical studies, since they display variable conformational behavior depending on the substituents that are introduced. 4Their synthesis is a field of ongoing interest for synthetic organic chemistry because of their properties and for elucidation of the structure-activity relationship. 5Various methods for the synthesis of tertrahydroisoquinolines are known; amongst them is the reaction of homophthalic anhydride with imines. 6This method has the advantage of constructing the tetrahydroisoquinoline fragment and introducing three substituents in a single step.
The water molecules play a crucial role for the stabilization of the crystal structure.They are responsible for the formation of an extensive three-dimensional hydrogen bonding network between themselves and the tetrahydroisoquinoline-1-one molecules (Table 1).This arrangement suggests similarity between the conformation in crystalline hydrate state and in water solution, which can correlate with an in vivo conformation of the molecule.The obtained structural data can provide insight for similar isoquinolinones, for which the structures in solution are not known.
To further study the structure of acid 1, ab initio and DFT calculations were performed using the GAUSSIAN 03 suite of programs. 11The geometry of 1 was elucidated by calculations at HF/6-31+G** and B3LYP/6-31+G** levels.The B3LYP/6-31+G** optimized geometry of zwitterionic form of acid 1 is presented on Figure 3. Selected interatomic distances are collected in Table 2 (the X-Ray numbering scheme is used).The obtained ab initio and DFT results for the geometry of zwitterionic form of 1 are in agreement with the X-ray data.In the course of the present investigation derivatives of acid 1 were synthesized and studied as well (Scheme 2).Аcid chloride 4 was synthesized in a separate step and subsequently reacted with MeOH to the ester 5. Different reaction conditions were tested to increase the yield of acid chloride and thence -of 5.The best achieved yield was 53% after purification by column chromatography.Attempts to prepare the same compound by esterification with methanol/H2SO4 were unsuccessful.When the reaction was carried out in methanol in the presence of thionyl chloride, only a small amount of the ester 5 (5%) was isolated.

Experimental Section
General.All new synthesized compounds were purified by column chromatography and characterized on the basis of NMR and microanalytical data.NMR spectra were recorded on DRX Bruker Avance-250 ( 1 H at 250.1 MHz; 13 C at 62.9 MHz) and Bruker Avance II+ 600 ( 1 H at 600.1 MHz; 13 C at 150.9 MHz) spectrometer, with TMS as the internal standard; J values are given in Hertz.Flash chromatography was performed on Silica Gel 60 (0.040-0.063 nm, Merck).Elemental analyses were performed by the Microanalytical Service Laboratory of Faculty of Chemistry, University of Sofia, using Vario EL3 CHNS(O).Melting points were determined on a Kofler hot stage.For description of the NMR spectral data the arbitrary numbering given in formula of amide 6c is used (Figure 4).

General procedure for the preparation of amides 6a-e
To the solution of acid chloride 4 (0.0013 mol) in dry THF and dry CHCl3 (1:1) 4.5 eq. of the corresponding secondary amine were added at 10C and the mixture was stirred at this temperature for 1 h.Then was poured into CH2Cl2 (70ml), washed with brine and dried over MgSO4.After evaporation of the solvent the crude product was purified by flash chromatography.

Figure 1 .
Figure 1.(A) ORTEP drawing of the basic crystallographic unit of acid 1 (S-enantiomer is shown), the hydrogen atoms are shown as small sphere of arbitrary radii.(B) A view of the molecular packing in 1 x 4H2O.All hydrogen atoms have been omitted for clarity.

Figure 3 .
Figure 3. (A) Comparison of the X-ray determined structure of zwitterionic form of acid 1 (green) and the optimized one.(B) Comparison of the X-ray determined structure of 1 (green) and optimized structure of amide ap-6a.

Table 2 .
Selected experimental and calculated distances (Å) and bond angles (degrees) of the zwitterionic form of 1 and ap-6a