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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Comb Chem. Author manuscript; available in PMC 2010 November 1.
Published in final edited form as:
PMCID: PMC2783704

Palladium- and Copper-Catalyzed Solution Phase Synthesis of a Diverse Library of Isoquinolines


The solution phase synthesis of a 111 member isoquinoline library is described. The isoquinoline scaffold has been accessed through the palladium- and copper-catalyzed cyclization of iminoalkynes and the palladium-catalyzed iminoannulation of internal alkynes, followed by diversification of hydroxyl functionality where it is present.


The isoquinoline nucleus is one of the most abundant structural motifs found in natural products and biologically active molecules.1 Isoquinoline derivatives exhibit a broad range of pharmacological activity, including anti-tumor, anti-fungal, anti-malarial, anti-hypertensive and anti-histaminic activity.2,3 Some simple biologically active isoquinoline derivatives are shown in Figure 1. The opium alkaloid papaverine (1) has been found to be useful as a vasodilator.4 Decumbenine B (2) has been found to inhibit spontaneous contraction of the intestine.5 Simple isoquinolines, such as 3a and 3b, have been shown to be useful for the treatment and prevention of cardiovascular diseases.6 Similarly, isoquinolines 4a and 4b are potent anti-inflammatory agents.7 The isoquinoline backbone is also found in nitidine (5), pseudopalmitine (6) and related biologically active plant alkaloids.8 The tetrahydroisoquinoline 7, known as quinapril, is an angiotensin-converting enzyme (ACE) inhibitor and its hydrochloride salt is marketed under the brand name Accupril™ for the treatment of hypertension and congestive heart failure.9

Figure 1
Selected biologically active isoquinoline derivatives.

The immense biological importance of isoquinolines has led to extensive studies towards the synthesis of this ring system. Most of the classical methods, such as the Pomeranz-Fritsch,10 Bischler-Napieralski11 and Pictet-Spengler reactions,12 generally require either harsh conditions and/or tedious reaction procedures,13 which are not desirable for library synthesis. Several metal-mediated methods have been reported for the synthesis of the isoquinoline scaffold in recent years.14 Contrary to the classical methods, the mild metal-catalyzed methods developed earlier in our laboratory14a–e are well suited for library generation. These methods readily accommodate a wide variety of functionality, allowing one to dramatically increase molecular complexity in just a few synthetic steps starting from commercially available materials. In a continuation of our research efforts to adapt heterocyclization chemistry to a high-throughput synthesis format,15 we herein report the first solution phase synthesis of three combinatorial libraries I–III of isoquinolines using our Pd- and Cu-catalyzed alkyne annulations as the key step.16 The presence of the isoquinoline scaffold in numerous biologically active compounds justifies the generation of this discovery library of isoquinolines.17 Indeed, preliminary biological results from this library, which will be reported elsewhere, have proven quite interesting.

Results and Discussion

For generation of the first isoquinoline library, we have utilized the copper-catalyzed cyclization of iminoalkynes (Scheme 1).14d For this purpose, seven commercially available alkynes (10) and seven differentially substituted 2-bromobenzaldehydes (8) were chosen. These electron-rich and -deficient aldehydes and the variety of alkyne building blocks contribute substantially to the diversity of library I. Toward this goal, aldehydes 8 were first converted to their imine derivatives 9 (Figure 2), which were subsequently subjected to a Sonogashira reaction with the various alkynes 10 (Figure 3) to furnish the key N-tert-butyl-2-(1-alkynyl)benzaldimines 11. Gratifyingly, the final copper-catalyzed cyclization readily accommodated a wide variety of iminoalkynes and thus furnished the targeted 42 library I members. Due to the increasing importance of fluorine in pharmacologically active molecules,18 we have utilized several fluorinated building blocks to incorporate a fluorine atom in our library members. All of the isoquinolines 12 were isolated in >90% purity. As summarized in Table 1, modest yields (17–75%) of isoquinoline derivatives were obtained over the two steps from the 2-bromobenzaldimines 9.

Figure 2
Imine intermediates 9{1–7}.
Figure 3
Terminal alkynes 10{1–7}.
Scheme 1
Isoquinoline library I.
Table 1
Library data for compounds 12{1–42}.

For the second isoquinoline library, we have used the palladium-catalyzed cyclization of the iminoalkynes 11 in the presence of aryl iodides (Scheme 2).14a,b These functionally substituted aryl groups provide an additional element of diversity in library II members. For this purpose, three commercially available 2-bromobenzaldehydes were subjected to a Sonogashira reaction with phenyl acetylene to synthesize the corresponding 2-(phenylethynyl)benzaldehydes 13, which were subsequently converted to the key o-(1-alkynyl)benzaldimine intermediates 11. The palladium-catalyzed cyclization of these iminoalkynes 11 in the presence of various commercially available aryl iodides furnished the targeted isoquinoline library II. Based on our previous results with this cyclization,14a aryl iodides bearing an electron-withdrawing group or groups were mostly chosen for this reaction. The carbonylative version of this reaction with selected iodides also gave the targeted isoquinoline derivatives.14b However, lower compound purities were obtained using this carbonylative process. The results for the synthesis of library II members obtained in 11–72% yields are summarized in Table 2.

Scheme 2
Isoquinoline library II.
Table 2
Library data for compounds 15{1–31}.

It is worth mentioning that the attempted cyclization of 16 with the aryl iodides 14{2, 3, 4, 6, 7, 11} gave complex mixtures containing the bis-arylated product 18 (as determined by LC-MS) as one of the major by-products (Scheme 3). Similar C-H arylation chemistry for thiophene derivatives has been previously reported.19 Only in one case (14{3}) have we been able to isolate the desired mono-arylated product 17 (R = 4-F) in good purity (92%) and 18% yield.

Scheme 3
Attempted synthesis of 3-(3-thienyl)isoquinolines.

Our strategy for the construction of a third library of isoquinolines is outlined in Scheme 4. We planned to exploit the palladium-catalyzed iminoannulation14e of suitably functionalized internal alkynes to provide diversification. We speculated that the presence of alcohol functionality in the key intermediates 22 would be an ideal point for further diversification, because such alcohols could be readily elaborated to more complex isoquinolines using a wide variety of commercially available carboxylic acid derivatives. Toward this goal, N-tert-butyl-2-iodobenzaldimine (20), prepared in two steps from commercially available 2-iodobenzyl alcohol (19), was treated with the appropriate internal alkynes 21 to furnish the targeted isoquinoline intermediates. These hydroxyl-bearing isoquinolines 22 were subsequently treated with a variety of acid chlorides, acid anhydrides and carbamoyl chlorides to furnish a diverse 38 member library of isoquinolines. The cyclic anhydrides 24{1–3} were chosen in order to have a polar carboxylic acid functionality in the final molecules. The acylation reaction with acid chlorides and acid anhydrides proceeded smoothly. However, the reactions with carbamoyl chlorides were less efficient. For the reactions with acyl chlorides and anhydrides, the yields were 18–82% and 31–67%, respectively, while the yields for the carbamoyl chloride reactions were in the range of 13–42%. Among the 38 library members, 36 compounds have greater than 95% purity. The results for the library III members are summarized in Table 3.

Scheme 4
Isoquinoline library III.
Table 3
Library data for compounds 26{1–38}.

Most of the desired isoquinoline library members were highly Lipinski compliant.20 Overall, 55% of the library members are entirely compliant with Lipinski’s rules and 45% had one violation. The most common violation was clog P (calculated by EPI Suite)21 for which the average value for the entire library was 4.95. The molecular weight distribution, shown in Figure 6, indicates that all members of the library reside in the desirable molecular weight range (<500).20

Figure 6Figure 6
Acid chlorides, acid anhydrides and carbamoyl chlorides.

In conclusion, a 111 member isoquinoline library has rapidly been constructed utilizing palladium- and copper-catalyzed reactions. Variation of the substituents on the isoquinoline scaffold has been achieved by the choice of the commercially available building blocks. These isoquinoline library members will be evaluated against various biological screens by the National Institutes of Health Molecular Library Screening Center Network.

Figure 4
Iminoalkyne intermediates 11{1–3}.
Figure 5Figure 5
Aryl iodides 14{1–15}.
Figure 7
Molecular weight distribution for members of libraries I–III.

Supplementary Material



We would like to thank Dr. Jesse P. Waldo of Iowa State University and Dr. Frank Schoenen of Kansas University for helpful discussions. We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Chemical Methodologies and Library Development Center of Excellence (GM069663) for support of this research and Johnson Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for donating the palladium catalysts.


Supporting Information Available. Experimental details and characterization of a representative 20 library members, including full 1H and 13C NMR spectra and conditions for the high throughput liquid chromatography purification.

References and Notes

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