Cross-Cyclotrimerization with Two Nitriles as a Synthetic Pathway to Unsymmetrically 3,3’-Disubstituted bis(Tetrahydroisoquinolines)

Microwave assisted CpCo(CO)2 catalyzed cross-cyclotrimerizations of 1,7,9,15-hexadecatetrayne with two different nitriles to give unsymmetrically substituted bis(tetrahydroisoquinolines) was studied. The reaction proceeded with a range of alkyl and aryl nitriles with reasonable isolated yields.


Results and Discussion
The microwave assisted cyclotrimerization of alkynes with nitriles offers several advantages in comparison with standard thermal conditions. Among these are, for example, reduced reaction times from hours to minutes, reactants are thus exposed to high reaction temperatures for shorter periods of time reducing possibility of thermal decomposition, and also the use of lower boiling point solvents such as THF, which allows easier separation of products [35][36][37][38][39][40].
For the study of cross-cyclotrimerization of 1,7,9,15-hexadecatetrayne (1) with various nitriles the previously used conditions were applied: CpCo(CO) 2 (20 mol%), nitrile R 1 -CN (1 equiv.), nitrile R 2 -CN (1-20 equiv.), THF as solvent. The reactions were carried out in microwave reactor (microwave irradiation 300 W, reaction time 25 min). A series of cross-cyclotrimerization reactions between two different nitriles with 1,7,9,15-hexadecatetrayne (1) in various molar ratios was carried out with varied success (Scheme 1). Scheme 1. Co-cyclotrimerization of tetrayne 1 with nitriles 2 and 3. In all cases the desired products of cross-cyclotrimerization of 1 with two different nitriles 2 and 3unsymmetrically substituted bis(tetrahydroisoquinolines) 4 -were formed. The reaction was always accompanied by the formation of varying amounts of symmetrically substituted bis(tetrahydroisoquinolines) 5 and/or 6, the products of cyclotrimerization of 1 with 2 or 3. Some of the most representative examples are given in Table 1. Thus the cross-cyclotrimerization of benzonitrile (2) with acetonitrile (3a, 1/1 2/3a ratio) gave preferentially symmetrical product 5a (Entry 1), the change of the nitrile ratio to 1/10 resulted in the preferential formation of 4a (25% isolated yield) which was accompanied by a small amount of 5a (10%) (Entry 2). The formation of 6a was not detected. Further change of the nitrile ratio did not affect the reaction outcome (Entry 3). The analogical results were obtained also in other cases. Thus cross-cyclotrimerization of benzonitrile (2) and 4-methoxybenzonitrile (3b, 1/10 2/3b ratio) gave 4b in 28% isolated yield along with 10% of 5a (Entry 5). The formation of 4c was achieved in 28% isolated yield (1/5 2/3c ratio) and 5a was formed in just 2% yield (Entry 7). Finally benzonitrile (2) and (R)tetrahydrofurancarbonitrile (2d) were cross-cyclotrimerized to yield the corresponding 4d in 28% isolated yield. Unlike in the previous cases, the best result was obtained when both nitriles were used in 1/1 molar ratio (compare Entries 8 and 9). In none of the cases was the formation of 6a-6d detected.
It should be emphasized that the cross-cyclotrimerization proceeded only under microwave irradiation. Carrying out the reaction under standard thermal condition (130 °C, 24-48 h) or attempts to facilitate the cyclotrimerization by visible light irradiation gave rise to intractable reaction mixtures.
Attempts to carry out the cyclotrimerization sequentially, i.e. to cyclotrimerize tetrayne 1 with one nitrile, isolate the expected intermediate (1-diynyltetrahydroisoquinoline), and then to carry out the second cyclotrimerization with another nitrile, also failed. The first reaction under the above mentioned conditions usually proceeded with low selectivity for the monocyclotrimerization (only up to 30%) and low yields (~10%), regardless of the nitrile used, making the whole process uneconomical. Carrying out the monocyclotrimerization under less forcing conditions by using another catalytic system, e.g. CoCl 2 ·6H 2 O, Zn, dppe [41,42], did not meet the expectations either. Although the reaction proceeded exclusively to yield 1-diynyltetrahydroisoquinolines, the yields did not exceed in 10%. The use of catalysts based on other transition metals (Rh, Ru) did not promote the cyclotrimerization.

General
All solvents, unless otherwise stated, were used as obtained. THF was distilled from sodium and benzophenone under Ar. All other reagents were obtained from commercial sources. 1 H-and 13 C-NMR spectra were recorded on a Varian UNITY 300 ( 1 H at 300 MHz, 13 C at 75 MHz) as solutions in C 6 D 6 . Chemical shifts are given in δ-scale, coupling constants J are given in Hz. Mass spectra were recorded on a LTQ Orbitrap XL. Infrared spectra were recorded on a FTIR Nicolet avatar Drift KBr and are reported in wave numbers (cm -1 ). Fluka 60 silica gel was used for flash chromatography. TLC was performed on silica gel 60 F 254 -coated aluminum sheets (Merck). All reactions were carried out under an argon atmosphere using flasks or in microwave reactor Biotage Initiator. Hexadeca-1,7,9,15tetrayne (1) was prepared according to the previously reported method [43].

Conclusions
In conclusion, we have demonstrated that CpCo(CO) 2 catalyzed cross-cyclotrimerization of 1,7,9,15-hexadecatetrayne with two different nitriles under microwave irradiation can be a convenient method for synthesis of unsymmetrically substituted bis(tetrahydroisoquinolines). Although the isolated yields of the unsymmetrical products did not exceed 30%, this shortcoming is counterweighed by the simplicity and expeditiousness of the cross-cyclotrimerization method and also by the fact that sequential two step cyclotrimerization cannot be applied due to low selectivity and thermal instability of the starting tetrayne. Last but not least, it also should taken into the account that during two catalytic cycles six new bonds are formed.