Silica-Supported Polyphosphoric Acid in the Synthesis of 4-Substituted Tetrahydroisoquinoline Derivatives

We report herein an application of an α-amidoalkylation reaction, as an alternative efficient synthesis of 4-aryl- and 4-methyl-1,2,3,4-tetrahydroisoquinoline derivatives. The amides required for this purpose would result from reaction of aminoacetaldehyde dimethylacetal with different substituted benzenes in polyphosphoric acid, followed by acylation of the obtained amines with different acid chlorides or sulfochlorides. We compared the cyclisation step using conventional (milieu of acetic-trifluoracetic acid = 4:1) and solid supported reagents (SiO2/PPA), as recovered, regenerated and reused without loss of its activity catalyst. We found that in comparison to conventional methods, the yields of the reaction are greater and the reaction time is shorter.

In our previous investigations we report application of polyphosphoric acid (PPA) as a cyclisation agent for the construction of tetrahydroisoquinoline ring systems. Polyphosphoric acid is a strong mineral acid which has powerful dehydrating properties and is widely used for intramolecular and intermolecular acylations, heterocyclic synthesis, and acid-catalyzed reactions. For instance, in recent reports the cyclization reactions of N,N'-bis(oxotrifluoroalkenyl)-1,3-phenylenediamines in PPA medium [43], the acylation of benzene and its derivatives with 2-, 3-, 4-aminobenzoic and 4-aminophenylacetic acid in PPA to aminobenzophenones [44], and the reaction of tryptamine with carboxylic acid in PPA to afford 1-substitued-3,4-dihydro-9H--carboline derivatives [45], etc, were described. However, the use of PPA has several drawbacks: since 10-to 50-fold excess is generally employed, it is difficult to pour and stir at room temperature, and it is necessary to carefully neutralize the reaction mixtures before the product extraction.
Recently, PPA/SiO 2 has been used as an efficient heterogeneous catalyst for many organic transformations. PPA/SiO 2 has some advantages including its low cost, ease of preparation, and ease of handling. In addition, the catalyst can be easily separated from the reaction mixtures by simple filtration and is reusable. Previously [46], the conversion of carbonyl compounds into oxathioacetals or dithioacetals using PPA/SiO 2 and a convenient method for the synthesis of isoxazole derivatives using PPA/SiO 2 as a reusable catalyst have been reported [47]. In the last several years the development of non-toxic, low cost, eco-friendly, recycable catalyst systems which give high productivity under mild reaction conditions has received much attention in organic synthesis [48]. Solid supported catalysts [49,50] have gained much prominence due to their inherent economic and environmental benefits, ease of handling, easy catalyst separation and regeneration, thermal stability and long catalytic life [51]. Since the activity and selectivity of a reagent dispersed on the surface of the support is improved as the effective surface area of reagent can be increased manifold, they are expected to perform better than the individual reagents [52]. Low toxicity, moisture, air tolerance and low price are other common features that make the use of solid supported reagents attractive alternative to the conventional catalysts.

Results and Discussion
Our retrosynthetic analysis of 4-substituted 1,2,3,4-tetrahydroisoquinolines is depicted in Scheme 1. We anticipated that 5 could be constructed from amides 4 via an α-amidoalkylation reaction. The required amides 4 can be prepared from the amines 3 via acylation with different acid chlorides. The amines 3 would arise from reaction [53] of aminoacetaldehyde dimethylacetal (1) with benzene or substituted benzenes 2 (Scheme 2).

PPA
For the synthesis of the required starting materials Klumpp's [53] protocol using amino acetals and benzene in TfOH to give the corresponding products with good yields can be used. We carried out the same reaction in polyphosphoric acid instead of TfOH. We found that aminoacetaldehyde dimethylacetal reacts with excess of 1,2-dimethoxybenzene (veratrol) in PPA at rt for 5 to 10 min to give a good (82%) yield of the corresponding product 3. The same product with unsubstituted benzene was obtained after 30 min at 80 °C with 42% yield (Scheme 2, Table 1). The amides 4 required for the next step of our synthesis, were prepared by acylation of the amines 3 with different acid chlorides or sulfochlorides. The next step was cyclization of the newly synthesized amides (Scheme 3, Table 2).  We compared the cyclisation step using either mixture of acetic-trifluoracetic acid = 4:1 or silica-supported PPA (SiO 2 -PPA). We found that with SiO 2 -PPA the reaction yields are greater and the reaction times are shorter ( Table 3). The shortest time and best yield were achieved at 80 °C, using 0.06 g of catalyst and 1 h reflux. As described earlier [54] the catalyst was recovered quantitatively and used in the reaction three times. The recovered catalyst did not show any significant loss of activity. Table 3. Comparative yields of the compounds 5 synthesized through two conventional methods. The same protocol was applied for the synthesis of 4-methyl-1,2,3,4-tetrahydroisoquinoline derivatives which are interesting as potential anaesthetics and antispasmodics [55] (Scheme 4, Table 4).

General
Reagents and chemicals were purchased from commercial sources (Sigma-Aldrich S.A. and Riedel-de Haën) and used as received. Melting points were determined on a Boetius hot stage apparatus and are uncorrected. Spectra were recorded on a Bruker Avance DRX250 spectrometer (BAS-IOCCP, Sofia). 1 H-NMR and 13 C-NMR spectra were taken in CDCl 3 (unless otherwise specified) at 250 MHz and 62.5 MHz respectively. Chemical shifts were given in part per million (ppm) relative and were referenced to TMS ( = 0.00 ppm) as an internal standard and coupling constants are indicated in Hz. All the NMR spectra were taken at rt (ac. 295 K). Elemental analyses were performed with a vario EL III. TLC was carried out on precoated 0.2 mm Fluka silica gel 60 plates, using diethyl ether/n-hexane = 1:1 as chromatographic system. Merck silica gel 60 (0.063-0.2 mm) was used for column chromatographic separation. Polyphosphoric acid was obtained from 85% phosphoric acid and P 2 O 5 (1:1 w/w).

Preparation of PPA/SiO 2 Catalyst General Procedure
PPA (4.0 g) was charged in the round-bottom flask, and CHCl 3 (100 mL) was added. After the mixture was stirred at 50 °C for 1 h, followed by SiO 2 (16.0 g, 70-230 mesh) was added to the solution, and the mixture was stirred for another 1 h. CHCl 3 was removed by evaporation, and the resulting solid was dried in vacuo at room temperature for 3 h. Used PPA/SiO 2 was regenerated as follows: PPA/SiO 2 was recovered by filtration from the reaction mixture, and then it was put in the 50 mL round-bottom flask and dried in vacuum at 100 °C for 2 h.

Typical Procedure for the Synthesis of 2-Amino-1,1-diphenylethanes 3
Aminoacetaldehyde dimethylacetal (1, 0,210 g, 2 mmol) was dissolved in the corresponding benzene (22.47 mmol) in an open flask and polyphosphoric acid (3 g) was added. The reaction mixture was stirred for 20 min at rt. After completion of the reaction, the mixture was poured over ice. The organic layer was removed and after that the water layer the solution was neutralized with sodium hydroxide, then extracted with CH 2 Cl 2 (3 × 20 mL). Combined extracts were dried (Na 2 SO 4 ) and concentrated. The products, after evaporation of the solvent, were purified by column chromatography on silica gel using Et 2 O as eluent.

Acylation of Amines 3: Typical Procedure for the Synthesis of Amides 4 and 6
To solution of amine 3 (1 mmol) in dichloromethane (15 mL) equal amount of acetyl chloride, methanesulfonyl chloride or biphenyl-4-carbonyl chloride was added. After 10 min a little excess of triethylamine was added. After 30 min the solution was washed with diluted hydrochloric acid, saturated solution of Na 2 CO 3 and water. The organic layer was dried (Na 2 SO 4 ), concentrated and filtered on short column with neutral Al 2 O 3 .

Cyclization of Amides 4 and 6 in SiO 2 -Supported Milieu: Typical Procedure
2-Phenylethylamides (3 mmol) and paraformaldehyde (5 mmol) were dissolved in a C 2 H 4 Cl 2 (10 mL) at 80 °C, 0.06 g of catalyst (SiO 2 /PPA) and 1h reflux. After the completion of the reaction the reaction mixture was cooled and the catalyst was separated by simple filtration.

Conclusions
In conclusion, we have developed a highly efficient SiO 2 -PPA catalyzed method for the construction of 4-aryl-or 4-methyl-1,2,3,4-tetrahydroisoquinoline ring systems, as analogues of biologically-active compounds. The catalyst is completely recoverable and the efficiency of the catalyst remains unaltered even after three to four cycles. It is also noticed that the cyclisation using PPA-SiO 2 proceeds rapidly and is superior to the reported procedures with respect to yield and amount of the catalyst employed.