One-pot synthesis of some N -benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinolines using benzotriazole-auxiliary

N -Benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinolines are prepared at room temperature from the reaction between 1-hydroxymethylbenzotriazole (1), a 2-phenylethylamine (2a-e) and AlCl 3 . This one-pot Friedel-Crafts reaction is a convenient improvement of the previously reported two-step procedure. The replacement of the benzotriazolyl moiety has often been demonstrated before; hence, the products of this reaction can be used as versatile, stable precursors for the preparation of various N -substituted 1,2,3,4-tetrahydroisoquinolines.


Introduction
Isoquinoline alkaloids form one of the largest groups of alkaloids in the plant kingdom and have generated intense research over the decades due to their potent biological activities.With more than 50 different compounds found in nature, 1,2,3,4-tetrahydroisoquinolines constitute the largest group within the simple isoquinoline alkaloids.A wide variety of methods are available for their synthesis in vitro and the preparation of derivatives with electron-donating substituents on the aromatic moiety is easily achieved with classic methods such as the Pictet-Spengler or Bischler-Napieralski cyclisations.The preparation of 1,2,3,4-tetrahydroisoquinolines with electron-withdrawing substituents, however, is more challenging due to a decreased activity of the aromatic ring in an intramolecular electrophilic cyclisation.Stokker introduced an interesting approach, which is exclusively applicable to the preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron-donating groups and therefore complementary to the Pictet-Spengler cyclisation.But there is still a need for more synthetic methods suitable for a wide variety of 1,2,3,4tetrahydroisoquinolines independent from the nature of the substituents on the aromatic moiety.The synthesis of some N-methyl-1,2,3,4-tetrahydroisoquinolines by Friedel-Crafts cyclisation using benzotriazole as auxiliary has recently been reported.This method is not only applicable to the preparation of 1,2,3,4-tetrahydroisoquinolines with activated aromatic systems, but also to structures lacking electron-donating groups.In this note an improvement to the above procedure is described using one-pot conditions which involve the simultaneous reaction between 1hydroxymethylbenzotriazole 1 and a phenylethylamine 2a-e facilitated by a Lewis acid.Reaction conditions are mild and yields generally high.

Results and Discussion
One-pot reactions have been reported before in benzotriazole chemistry.The simultaneous reaction between benzotriazole, various amines and formaldehyde or acetaldehyde in aqueous solution at 20 o C, for instance, yields 1-(α -aminoalkyl)-benzotriazoles.
The one-pot reaction also proceeds smoothly for N-benzotriazol-1-ylmethyl-5chlorophenylethylamine 3c, which had unveiled some difficulties in a two-step procedure with respect to crystallisation and purified yield.
The remaining benzotriazolyl moiety in compounds 3a-e can be replaced by a variety of nucleophiles.Katritzky and co-workers have reported its replacement by Grignard reagents, alcohols and thiols.Under acidic conditions it can also be replaced by a variety of electron-rich heterocycles, such as 2-naphthol, indoles or pyrroles and also by methoxy-substituted benzenes.A further option is the reduction with NaBH4, which leads to the corresponding N-methyl-1,2,3,4-tetrahydroisoquinolines.

Conclusions
In summary, the convenient one-pot reaction between 1-hydroxymethyl-benzotriazole 1, a phenylethylamine 2a-e and anhydrous AlCl 3 in CH 2 Cl 2 at room temperature yields the corresponding crystalline N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinoline 3a-e in good to excellent yields.This intra-molecular Friedel-Crafts cyclisation further improves the previously reported two-step reaction with respect to convenience and yields and allows the facile synthesis of compounds 3a-e as variable precursors for a variety of N-substituted 1,2,3,4tetrahydroisoquinolines.

Experimental Section
General Procedures.All reagents used were AR grade.Melting points were determined on a Gallenkamp Melting Point Apparatus and are uncorrected. 1H NMR spectra were recorded with a Varian Gemini 200 (200MHz) in deuteriochloroform (CDCl 3 ) using tetramethylsilane (TMS) as internal reference.Chemical shifts (δ) are reported in parts per million (ppm, δTMS = 0.00).

Table 1 .
N © ARKAT USA, Inc a Signal overlaps with those from -OCH3.