Direct (het)arylation of tetrahydroisoquinolines via a metal and oxidant free C(sp3)–H functionalization enabled three component reaction

Surajit Haldar and Chandan K. Jana *
Department of Chemistry, Indian Institute of Technology Guwahati, 781039, India. E-mail: ckjana@iitg.ac.in

Received 18th September 2018 , Accepted 24th November 2018

First published on 26th November 2018


An unprecedented method for the direct arylation and heteroarylation of tetrahydroisoquinolines under metal and oxidant free conditions is reported. The arylation reactions occurred via a C(sp3)–H functionalization enabled three component condensation of tetrahydroisoquinolines, 9-fluorenone imine, and arenes without involving a pre-functionalization/pre-derivatization step. A wide range of arenes and heteroarenes participated in the reaction to provide structurally diverse arylated tetrahydroisoquinolines with good to excellent yields.


Arylated and hetero-arylated tetrahydroisoquinolines (THIQs) are the key fragments of many natural products and bioactive molecules (Scheme 1a).1 The mostly used traditional reactions, namely the Pictet–Spengler reaction2 and the Bischler–Napieralski cyclization–reduction,3 for the synthesis of arylated THIQs involve the use of strong acid/dehydrating agents under harsh conditions. Therefore, different strategies using more advantageous direct arylation reactions of THIQs or their derivatives have been developed as the alternative to these classical methods (Scheme 1b). The direct C–H arylation of THIQ derivatives via a cross dehydrogenative coupling strategy has dominated the field (eqn (1)).4,5 This strategy required a stoichiometric amount of oxidants with or without the aid of a metallic reagent/catalyst to generate a reactive iminium ion that reacts further with an appropriate (pro)nucleophile. However, in the presence of an oxidant, facile oxidation of secondary amines could occur to provide stable and relatively unreactive imines which possibly restricted the direct functionalization of unprotected tetrahydroisoquinolines under this condition. Therefore, as the reaction necessitates the use of N-substituted (mostly N-arylated) substrates, an additional pre-functionalization step was required for this strategy. Similarly, N-arylated/protected substrates were also necessary for the desired C–H functionalization via photoredox reactions in the presence of metallic reagents/catalysts.6 Moreover, a difficult N-dearylation step is essential in order to further derivatize/use the functionalized tetrahydroisoquinolines which are formed via these two strategies.
image file: c8ob02309c-s1.tif
Scheme 1 (a) Examples of THIQs containing natural products and bioactive molecules. (b) Arylation reactions of THIQs.

The report on the arylation of unprotected THIQs necessitates the use of a tetra-arylborate based Lewis acid as the catalyst.7 Arylation reactions using pre-oxidized THIQs were also developed for the synthesis of the desired arylated THIQs (eqn (2)).8 Therefore, the involvement of metallic reagents and oxidants reduces the environmental viability of these functionalization reactions due to the possible generation of unwanted toxic waste. In contrast, incorporation of the functional group directly into the N-heterocycles via multicomponent reactions involving a C–H functionalization (CH-MCR) strategy that avoids the use of a metallic reagent/catalyst, oxidant, and pre-functionalization step is beneficial in this context.9–11 Direct C–H arylation of pyrrolidines and their derivatives was achieved efficiently using this strategy.11 However, although there are several reports on the C–H functionalization of THIQs,12 to the best of our knowledge, direct arylation of tetrahydroisoquinolines under metal and oxidant free conditions is not reported. Herein, we report the first example of direct arylation of unprotected tetrahydroisoquinolines using a CH-MCR strategy under conditions free of metallic reagents/catalysts, oxidants, and solvents (eqn (3)).

Previously, we have developed a method for direct C–H arylation of pyrrolidines via a simple three component reaction under metal and oxidant free conditions.11a,b Thus, we wanted to use a similar strategy for the direct arylation of THIQs. Accordingly, 1,2,3,4-tetrahydroisoquinoline, 1,2-naphthol, and 9-fluorenone (2a) were reacted in refluxing benzene (Table 1, entry 1). Unfortunately, the desired arylated product 3 was not obtained under these reaction conditions. Variation of the reaction conditions such as reaction times, solvent, etc. also failed to provide the desired product 3 (Table 1, entries 2–5). Then 9-fluorenone imine (2b) in place of 9-fluorenone was tested as an activator for the direct arylation of tetrahydroisoquinoline. Interestingly, the desired arylated product 3 was isolated with 29% yield from the reaction which was carried out under a solvent free condition at 70 °C for 24 h (Table 1, entry 11). With this initial success, a number of reactions by varying the reaction time, temperature and activators have been performed to increase the yield of the desired product. The maximum yield (82%) of the desired product was obtained from the reaction which was carried out with 2b under a solvent free condition at 100 °C for 48 h (Table 1, entry 14).

 
image file: c8ob02309c-u1.tif(4)

Table 1 Optimization of reaction conditionsa

image file: c8ob02309c-u2.tif

Entry Activator Conditions Time Yieldb
a Reactions were carried out with 0.75 mmol of THIQ (1), 0.25 mmol of 2-naphthol and 0.3 mmol of carbonyl or imine derivatives (2a–2b). b Isolated yields. c Reactions were carried out in the presence of 20 mol% Sc(OTf)3.
1 2a Benzene, reflux 24 h
2 2a Benzene, reflux 36 h
3 2a Benzene, reflux 48 h
4 2a Toluene, reflux 48 h
5 2a Toluene, MW, 150 °C 45 min
6 2b Benzene, reflux 48 h
7 2b Toluene, reflux 48 h
8c 2b Toluene, reflux 48 h
9 2b Toluene, MW, 150 °C 45 min
10c 2b Toluene, MW, 150 °C 45 min
11 2b Neat, 60–70 °C 24 h 29%
12 2a Neat, 60–70 °C 48 h 56%
13 2b Neat, 60–70 °C 48 h 70%
14 2b Neat, 100 °C 48 h 82%


The reaction using benzaldehyde as an activator provided an inseparable mixture of regioisomers 3a and Betti product (1[thin space (1/6-em)]:[thin space (1/6-em)]2) with a poor combined yield (eqn (4)).13

Next, the substrate scope of the reaction was investigated using the optimized reaction conditions (Scheme 2). At first, different commercially available naphthol and phenol derivatives were used as potential nucleophiles. 7-Methoxy-, 7-bromo-, and 6-bromo-2-naphthols provided the desired arylated products 4a–c with very good yields. In addition to 2-naphthols, 1-naphthol also gave α-arylated product 4d (55%) with good yield. Catechol, 3,4-dimethoxy phenol, and sesamol produced the desired products 4e–g with moderate to good yields with exclusive ortho-selectivity. Other than phenol and naphthol derivatives, 6-hydroxyquinoline, 8-hydroxyquinoline, and 4-hydroxy coumarin also participated in this reaction to provide the desired products 4h–j with moderate to good yields.


image file: c8ob02309c-s2.tif
Scheme 2 Scope of the direct arylation of THIQs.

Then we turned our attention to different indole derivatives which can serve as potential nucleophiles for the arylation reaction of THIQs. Accordingly, the reactions of THIQs and indole derivatives in the presence of 9-fluorenone imine were carried out under the standard conditions to obtain the desired arylated products 5a–p with good to excellent yields. Both electron-rich and electron-poor indole derivatives produced the desired arylated products. Interestingly, 2-substituted indole derivatives, such as 2-methyl indole, ethyl indole 2-carboxylate and (1H-indol-2-yl) methanol acted as the effective nucleophiles to produce the corresponding arylated products 5b–d (60–72%) with very good yields. A sterically hindered substrate, 2-(3,4-dimethoxyphenyl)-1H-indole, also gave the desired product 5e (51%), however, with moderate yield. Halogenated indoles, such as 5-fluoro, 5-chloro, 5-bromo, and 6-bromo indoles gave the desired α-arylated products 5j–m with good to excellent yields.

Heteroatom containing 7-aza indoles also participated in the arylation reaction to provide the desired product 5n with very good yield (82%). In addition, THIQs having an electron withdrawing group (NO2) and an electron donating group (OMe) have been reacted under standard conditions. The desired arylated products 5o and 5p were isolated with very good yields. Unfortunately, 1-methyl and 3-methyl indoles did not produce the desired arylated products under these conditions. Besides the indole derivatives, pyrrole has also been successfully used as a nucleophile to afford the desired product 5q (53%).

A probable mechanism of the direct arylation of free tetrahydroisoquinolines, which occurred under metal, oxidant, and solvent free conditions, is shown in Scheme 3. THIQs condensed with 9-fluorenone or its imine derivative to provide the corresponding iminium ion 6a which was isomerized readily to produce the regioisomeric iminium ion 6b. The iminium ion 6b then participated in the electrophilic aromatic substitution reaction with the aromatic nucleophile to provide the observed arylated tetrahydroisoquinoline 7.


image file: c8ob02309c-s3.tif
Scheme 3 Proposed mechanism for direct arylation of THIQs.

To demonstrate the synthetic utility of our methodology, arylated compounds were further derivatized using selected reactions. The 6-bromo functionality of 4c was utilized for the Suzuki coupling reaction with phenylboronic acid 8 to obtain the corresponding phenyl substituted arylated THIQ derivative 9 with an excellent yield (82%) (Scheme 4, eqn (5)).


image file: c8ob02309c-s4.tif
Scheme 4 Synthetic transformations of arylated THIQ derivatives.

The removal of the N-fluorenyl group of arylated compounds was achieved under standard hydrogenolysis conditions. Accordingly, secondary amines 10 (55%) and 11 (57%) were formed from the reactions of N-fluorenyl amines 5a and 5b, respectively, under standard hydrogenolysis conditions in the presence of Pd/C and hydrogen (Scheme 4, eqn (6)). Next, the removal of an N-fluorenyl group and aromatization of arylated compounds 3 and 4a were achieved under dehydrogenation conditions to obtain the 1-(isoquinolin-1-yl)naphthalen-2-ol derivatives 12 (96%) and 13 (84%) (Scheme 4, eqn (7)) with excellent yields. These aryl isoquinoline derivatives are an important class of compounds which are found as the core moiety of chiral ligands and fluorescence imaging agents.14 This class of compounds is generally synthesized via metal mediated cross-coupling reactions of pre-functionalized starting materials.14

Conclusions

In summary, we have developed the first example of direct arylation and heteroarylation of tetrahydroisoquinolines under conditions free of metallic reagents/catalyst, hazardous oxidants and pre-functionalization/derivatization steps. A wide range of aromatic and heteroaromatic nucleophiles, such as naphthols, phenols, indoles, and pyrroles participated in the reaction to provide the structurally diverse arylated tetrahydroisoquinolines with good to excellent yields. We have also shown that the fluorenyl moiety which was introduced during the C–H arylation reaction can easily be cleaved to provide the valuable saturated amine derivatives or aryl isoquinoline derivatives.

Experimental

General experimental procedure for C–H arylation

In a reaction tube, a nucleophile (0.25 mmol, 1.0 equiv.) was added to the mixture of aldehydes, ketones or imines (0.30 mmol, 1.2 equiv.) and 1,2,3,4-tetrahydroisoquinoline (0.75 mmol, 3 equiv.). The tube was closed and the mixture was stirred at 100 °C (oil bath temperature) for 18–48 h. After completion of the reaction, the product was purified either via precipitation or column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]hexane) to obtain an analytically pure product.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge financial support from the SERB and the MHRD.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. CCDC 1868392. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob02309c

This journal is © The Royal Society of Chemistry 2019