Kesari Lakshmi Manasa*
Department of Pharmaceutical Chemistry, Malla Reddy Pharmacy College, Hyderabad-500037, India.
*Corresponding Author E-mail: manasa.kesari@gmail.com
ABSTRACT:
It is easy and effective to obtain a range of isoquinolines and β-carbolines and their natural derivatives, including 3,4-dihydropapaverine, Harmane, and Eudistomin U, via β-elimination and aromatization. Additionally, this protocol works well in the synthesis of partially dehydrogenated isoquinolines at a good yield.
KEYWORDS: Isoquinoline, β-carboline, Dehydrogenation, Eudistomin, Iodobenzene diacetate.
INTRODUCTION:
Many natural alkaloids, manufactured medicines, and other fine chemicals with a variety of biological properties contain isoquinoline and β-carboline scaffolds, which are of great importance in medical and organic chemistry.1-5 In nature, there are two kinds of isoquinoline alkaloids: 1-benzoylisoquinoline and 1-benzylisoquinoline alkaloids. Many natural products, including nigellimine,6 papaverine,7 refescine,8 harmine, eudistomin U, N, and harmane,9 as illustrated in Fig. 1, are synthesized using functionalized isoquinolines and β-carbolines, which are common scaffolds. Tetrahydroisoquinolines (THIQs) and tetrahydro-β-carbolines (THBCs) alkaloids can be synthesized by pictet-Spengler reaction using 2-aryl (or 2-indolyl) ethylamines and aldehydes.10
Isoquinolines and β-carbolines have been developed by various synthetic methods due to its wide application.11 Strong oxidants, toxic reagents, noble metal catalysts, SeO2, MnO2, and mild oxidants such toxic sulfur and palladium on carbon over an extended period of time with surplus equivalents of the oxidants have all been used in the usual procedures for this transformation.12-16
Figure 1. Biologically active isoquinoline (A, B & C) and β-carboline derivatives (D, 5, 2n & E).
Nevertheless, the majority of these techniques frequently have one or more disadvantages, such as harsher reaction conditions like temperature, usuage of poisonous metal reagents that cause environmental issues when disposed of, less yield, and longer reaction periods that is not acceptable from ecological and economic point of view.17-20 Therefore, we expected a modified and workable approach for the conversion of N-tosyl-THIQs and N-tosyl-THBCs were utilized as starting materials, in order to solve the drawbacks of earlier methods.
In light of these findings and as part of our ongoing research on a variety of heterocyclic scaffolds, we would like to create effective protocol for the synthesis of isoquinolines.21-25 β-carbolines were selected as target scaffolds due to their distinct structural characteristics and biological properties. N-tosyl-THIQs and N-tosyl-THBCs were aromatized in a single pot using Iodobenzene diacetate and potassium carbonate were used as a base.
RESULTS AND DISCUSSION:
Our first efforts were concentrated on investigating how base and iodobenzene diacetate affected N-tosyl-THIQs and N-tosyl-THBCs in different solvents under reflux conditions to produce isoquinolines and β-carbolines. The reaction of substrate 1 with excess K2CO3 as a base and PhI(OAc)2 in DMSO as a solvent at room temperature was the first step in our inquiry (entry 1, Table 1). Even after stirring for 24 hours, the reaction doesn't continue. Unexpectedly, reacting 1 with K2CO3 as the base and PhI(OAc)2 at a high temperature formed the desirable product 2 in good yield (entry 2, Table 1). When the amount of PhI(OAc)2 was increased to 3 equiv., there was a further minor rise in the yield of product 2 (entry 3, Table 1). Even after stirring for more than 12 hours, there was a detrimental influence on the conversion of the reaction, as proved by a reduction in the percentage yield and a decrease in the amount of PhI(OAc)2 (1.5 equiv) (entry 4, Table 1). The reaction was conducted using a wide collection of solvents, including THF, Chloroform, DMF, Acetonitrile, 1,4-dioxane, Toluene in an attempt to increase the product yield. The results showed that DMSO was the most effective solvent for this transformation (entry 5-10, Table 1). In order to synthesize isoquinolines and β-carbolines, the best conditions were determined to be using 1 and PhI(OAc)2 (2 equiv.) in DMSO as a solvent and K2CO3 (10 equiv.) as a base at 125oC for 12 hours.
In order to assess the extent of methodology, a collection of N-tosyl-THIQs and N-tosyl-THBCs produced by the Pictet-Spengler reaction of 3,4-dimethoxy phenylethylamine and tryptamine were treated with various aldehydes. This initial reaction gave THIQs and THBCs, subsequently converted into N-tosyl-THIQs and N-tosyl-THBCs in good yield upon reacting p-toluenesulfonyl chloride with triethylamine acting as a base in CH2Cl2 as a solvent.
Table 1. Development of reaction parameters for the synthesis of substituted isoquinolinesa.
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Entry |
Base [equiv.] |
PhI(OAc)2 [equiv.] |
Solvent |
Temp [ ºC] |
Time [h] |
Yieldb [%] |
|
1 |
K2CO3 (10) |
2 |
DMSO |
r.t |
24 |
0 |
|
2 |
K2CO3 (10) |
2 |
DMSO |
125 |
12 |
78 |
|
3 |
K2CO3 (10) |
3 |
DMSO |
125 |
12 |
79 |
|
4 |
K2CO3 (10) |
1.5 |
DMSO |
125 |
16 |
38 |
|
5 |
K2CO3 (10) |
3 |
DMF |
125 |
12 |
40 |
|
6 |
K2CO3 (10) |
3 |
ACN |
125 |
12 |
36 |
|
7 |
K2CO3 (10) |
3 |
1,4-dioxane |
125 |
14 |
32 |
|
8 |
K2CO3 (10) |
3 |
DCM |
125 |
14 |
28 |
|
9 |
K2CO3 (10) |
3 |
Toluene |
125 |
12 |
34 |
|
10 |
K2CO3 (10) |
3 |
THF |
125 |
12 |
36 |
a Reaction conditions: 1 (1 equiv.), K2CO3 (10 equiv.), PhI(OAc)2 (2 equiv.); bIsolated yields.
A diverse range of N-tosyl-THIQs substituted with various groups like aromatic, aliphatic moieties at position-1 were reacted to achieve the desired product in good yield (Table 2). Further, when electron withdrawing substituents like nitro, trifluoromethoxy (2f-g, Table 2) were substituted on the aromatic ring gave the desired product in moderate yield. However, when halogen substituents like fluoro, difluoro (2b & 2c, Table 2) present on the aromatic ring, were well compatible for this transformation and the desired product were isolated in 75% and 74% yield respectively. But when electron rich substituents like phenyl, methyl, methoxy, dimethoxy (2a, 2d, 2e and 2h, Table 2) show the corresponding products in good yield. Even cyclopropane ring (2i, Table 2) were well reacted to furnish the final product in good yield.
Table 2. Scope of substrate for the synthesis of isoquinolines from various N-tosyl-THIQs using PhI(OAc)2a
aReaction conditions: All the reactions were performed with 1(0.1 mmol), K2CO3 (1.0 mmol) and PhI(OAc)2 (0.2 mmol) in DMSO at 125oC for 12h.
To further extend the synthetic applicability of this protocol we examined the reaction with N-tosyl-THBCs as well. A series of reactions have been carried under optimized reaction conditions gave desired product in moderate to good yield. Various N-tosyl-THBCs having different substitution pattern at position 1 were well tolerated. Interestingly, when the aromatic ring possesses electron donating groups (2j-m & 2o, Table 3) gave good yield compared to electron withdrawing substituents (2p, Table 3) regardless of position on the aromatic ring. Later when the aromatic ring possesses halogens such as fluoro and chloro (2q-r, Table 3) gave the desired product in moderate yield. Moreover, heteroaromatic substituents like 3-pyridyl (2s, Table 3) and the aliphatic moiety propyl (2t, Table 3) gave the final product in less yield. Furthermore, this method utilized in the synthesis of natural alkaloid Harmane considerably gave good yield (2n, Table 3).
Table 3. Scope of substrate using PhI(OAc)2a for the synthesis of β-carbolines
aReaction conditions: All the reactions were carried with 1 (0.1 mmol), K2CO3 (1.0 mmol) and PhI(OAc)2 (0.2 mmol) in DMSO at 125 oC for 12 h.
Furthermore, decreasing the stiochiometric amount of PhI(OAc)2 to 0.1 mmol partial dehydrogenation has been taken place and resulted in 3,4-dihydroisoquinolines. In this context, the yield of product was slightly depending on electronic nature of substituents on position-1. Moreover, this method utilized in the synthesis of 3,4-dihydropapaverine (2ad, Table 4) considerably gave 75% yield.
Table 4. Scope of substrate for the synthesis of dihydroisoquinoline from various N-tosyl-THIQs using PhI(OAc)2a
aReaction conditions: All the reactions were carried with 1 (0.1 mmol), K2CO3 (1.0 mmol) and PhI(OAc)2 (0.1 mmol) in DMSO at 125 oC for 7 h.
By the above results, we further extended the synthetic applicability of this strategy in the total synthesis of eudistomin U. Commercially available stating material i.e, tryptamine was used in order to synthesize eudistomin U undergoes pictet splenger reaction with indole-3-carboxaldehyde gave the desired THBC which was further treated with p-toluenesulfonyl chloride to give N-tosyl-THBCs which undergoes β-tosyl-elimination followed by aromatization to give eudistomin U in presence of base K2CO3 and PhI(OAc)2.
Scheme 1. Total synthesis of eudistomin U
Plausible Mechanism:
Based on a literature report and from the results obtained, a plausible mechanism for N-tosyl-THIQs and N-tosyl-THBCs is outlined in scheme 1. Intially the N-tosyl-THIQs and N-tosyl-THBCs 1 undergoes β-tosyl-elimination at the reflux temperature of solvent, to afford intermediate A which might inturn undergoes elimination of hydrogen and OAc group in presence of base to furnish the final product 2. 26, 27
Scheme 1. Probable reaction mechanism for the aromatization of N-tosyl-THIQs and N-tosyl-THBCs.
CONCLUSION:
In outline, created a straightforward and effective one-step approach that uses PhI(OAc)2 in a single operation under basic conditions to achieve isoquinolines and β-carbolines. This protocol is an replacement to the traditional methods. Additionally, this procedure was used to synthesize partly dehydrogenated isoquinolines, which can be further developed in the complete synthesis of eudistomin U.
ACKNOWLEDGEMENTS:
The authors thank the Principal of Malla Reddy Pharmacy College for the continuous support.
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Received on 21.08.2023 Revised on 15.11.2024 Accepted on 06.11.2025 Published on 13.01.2026 Available online from January 17, 2026 Research J. Pharmacy and Technology. 2026;19(1):137-140. DOI: 10.52711/0974-360X.2026.00021 © RJPT All right reserved
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