Cu(I)-catalyzed one-pot decarboxylation-alkynylation reactions on 1,2,3,4-tetrahydroisoquinolines and one-pot synthesis of triazolyl-1,2,3,4-tetrahydroisoquinolines

Dedicated to Professor Georgiy B. Shul'pin on the occasion of his 70th birthday.
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Highlights

  • Short chained alkynes can be introduced without the need for gaseous reagents by using the corresponding alkynoic acids.

  • Alkynylations with alkynoic acids work in good yields independent of the chain length and protecting group of the substrate.

  • A three step cascade of decarboxylation, alkynylation, and click reaction was developed using the same catalyst, namely CuCl.

Abstract

A facile and efficient method to introduce alkyne groups to the C-1 position of biologically interesting 1,2,3,4-tetrahydroisoquinolines via direct Csingle bondH-functionalization is reported. Various alkynylated N-substituted 1,2,3,4-tetrahydroisoquinolines could be obtained by using copper(I)-chloride as catalyst, alkynoic acids as alkyne source and t-BuOOH as oxidant, in a one-pot two-step decarboxylation- alkynylation reaction in moderate to high yields. Furthermore, a one-pot protocol of a three-step decarboxylation-alkynylation-1,3-dipolar cycloaddition reaction leading to 1-triazolyl-tetrahydroisoquinolines was developed, a hitherto unknown reaction cascade.

Introduction

The structural motif of 1,2,3,4-tetrahydroisoquinoline (TIQ) is present in many natural products, such as in mammalian alkaloids (e.g. salsoline carboxylic acid) [1], [2], the ecteinascidin family [3], [4], [5], [6], spiro-benzoisoquinoline alkaloids (parfumine) [7], and cactus alkaloids [8]. Some derivatives have been determined as pharmacologically active, showing antitumor [9] or anti-HIV activities [10], [11], as well as playing an important role in the research to find a treatment for Parkinson ’s disease [12], [13]. More specifically, in recent years, examples of in position 1 alkynylated TIQs displaying biological activity have been reported repeatedly (Fig. 1). For example, compound I was synthesized to target microtubule polymerization [14] and compounds II and III have been reported as sirtuin inhibitors for treating viral infections [15], [16].

Since the biologically and pharmaceutically interesting TIQ derivatives mostly carry a substituent in C1-position, it is of high interest to introduce various functional groups into this position. Classical synthetic routes, such as the Pictet-Spengler, Bischler-Napieralski and Pommeranz-Fritsch reactions [17] have been successful in the synthesis of TIQs for many years. However, the trend in synthetic chemistry goes into the direction of functionalizing simple scaffolds to get to the desired (hetero)cyclic compounds rather than building up the ring system for each compound separately. Furthermore, due to the trend to increase atom efficiency in synthetic processes, direct functionalization reactions of Csingle bondH bonds manifested themselves as highly desirable transformations [18], [19], [20]. One such method is cross-dehydrogenative-coupling [21], [22] which stirred a lot of attention in recent years. Various methods such as alkynylation [23], indolation [24], arylation [25], methoxylation [26], phosphonation [27], cyanation [27], [28], and introduction of nitroalkanes [27], [29], or malonic esters [30] to the C-1 position of N-substituted TIQs have been reported. The alkyne functionality is here of special interest since the triple bond can be further transformed to other functional groups. Although good results have been reported in all cases, alkynylation reactions on TIQ (Scheme 1, upper part) have only been performed with long alkyl chains (C > 6) or aromatic or bulky substituents, and the substrate scope is limited to N-phenyl-, N-4-methoxyphenyl- (PMP), and N-2-methoxyphenyl-TIQs (OMP) [23]. One reason for that is for sure the fact that shorter chain alkynes are quite volatile and hence difficult to handle (1-pentyne is the shortest 1-alkyne which is liquid at room temperature with a boiling point of 40 °C). However, especially a terminal alkyne functionality would be of high interest for further transformations, such as Huisgen 1,3-dipolar cycloadditions (click reactions) [31], [32], [33], leading to triazolyl-derivatives. Decarboxylative coupling methods were also developed in recent years and interesting results have been reported [34], [35], [36], especially also using copper catalysis [37], [38], [39]. Hence, we hypothesized that a combination of decarboxylative coupling and cross-dehydrogenative coupling could solve the problem of introducing short chained alkynes onto TIQ since the corresponding alkyne-acids are either liquid or solid at room temperature and handling of these compounds is not a problem (Scheme 1, lower part). In fact, the shortest chain representative, propiolic acid, has a boiling point of 102 °C at 200 mmHg and a melting point just below room temperature of 16–18 °C. Herein we report our efforts in this direction.

Section snippets

Materials and methods

Unless otherwise noted, chemicals were purchased from commercial suppliers and used without further purification.

Flash column chromatography was performed on silica gel 60 from Merck (40–63 μm) whereas separations were carried out using a Büchi SepacoreTM MPLC system. For TLC aluminum coated silica gel was used and signals were visualized with UV light (254 nm). GC–MS runs were performed on a Thermo Finnigan Focus GC/DSQ II using a standard capillary column BGB 5 (30 m × 0.32 mm ID) and the following

Results and discussion

Starting point for our investigations was a protocol published by Kolarovic and coworkers in 2009, which reported copper-catalyzed decarboxylation of 2-alkynoic acids (Scheme 2, upper left) [39]. Since this decarboxylation reaction and the C1-alkynylation reaction on TIQ reported by Li et al. (Scheme 2 upper right) [23] are both copper catalyzed, it was tried to investigate a one-pot protocol, where the alkyne source first undergoes decarboxylation and then couples with the

Conclusions

In conclusion, we have developed a protocol for alkynylation of N-phenyl-, N-PMP- and N-benzyl-1,2,3,4-tetrahydroisoquinolines in the C1-position, using alkynoic acids as alkyne source. Hence, short chain alkynes can be introduced without the need for gaseous reagents, enabling an operationally very simple protocol. In addition, a three-step one-pot-procedure leading to triazolyl-1,2,3,4-tetrahydroisoquinolines was elaborated, when using propiolic acid as the alkyne source. In this cascade

Acknowledgement

We acknowledge the Austrian Science Foundation (FWF, Project P21202-N17) for financial support of this work.

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