Access to Isoquinolin-2(1H)-yl-acetamides and Isoindolin-2-yl-acetamides from a Common MCR Precursor

We achieved a divergent synthesis of isoquinolin-2(1H)-yl-acetamides (16 examples, up to 90% yields) and regioselective isoindolin-2-yl-acetamides (14 examples, up to 93% yields) in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi-4CR/Copper(I)-catalyzed annulation sequence reaction. The same intermediate thus gives 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor. The scopes and limitations of these efficient sequence reactions are described, as well as gram-scale synthesis.


■ INTRODUCTION
Multicomponent reactions (MCRs) and post transformations of MCR products have become progressively popular, which has made them some of the most successful methods leading to the rapid generation of small-molecule library of high structural diversity and molecular complexity. 1 The Ugi reaction, one of the best-known MCRs, with the advantage of atom economy and environmental benefit, could typically afford a linear bis amide backbone. 2 However, linear bis amides often have issues with stability, solubility, and distribution− metabolism−pharmacokinetic (DMPK) and are not a preferred scaffold in medicinal chemistry. 3 Therefore, Ugi-4CR and its post-amide-cyclization reactions are widely used in medicinal chemistry research due to the diversity of scope and ability to improve the metabolic stability of final products. 4,5 Isoquinolin-2(1H)-yl-acetamide and isoindolin-2-yl-acetamide have attracted increasing attention due to their possible diverse biological activities. The isoquinolin-2(1H)-yl-acetamide scaffold, for example, was found in P2X7 inhibitors I, proteasome inhibitors II or TLR agonists III ( Figure 1A). 6−8 Likewise, the isoindolin-2-yl-acetamide also appears in the FDA-proved anticancer drug Lenalidomide, 9 as well as the antimicrobial compound IV or the EGFR inhibitor EAI045 ( Figure  1B). 10−12 Not surprisingly, new and superior ways to construct the isoquinolin-2(1H)-yl-acetamide scaffold or isoindolin-2-ylacetamide skeleton are in high demand. Yang's group published a Ugi-4CR/Pd-catalyzed intramolecular arylation reaction to efficiently afford the tricyclic isoquinolin-2(1H)-ylacetamides. 13 Recently, our group reported a two-step synthesis of privileged tetracyclic isoquinolin-2(1H)-yl-acetamide scaffold via an ammonia-Ugi-4CR/copper-catalyzed annulation sequence (Scheme 1A). 14 As for the isoindolin-2-yl-acetamides (Scheme 1B), Ibrahim synthesized a series of (1-benzylidene-3-oxoisoindolin-2-yl)-acetamide derivatives from 3-benzalphthalide and the corresponding amino acids. 10 Most recently, Li's group developed an efficient protocol to construct a DNA-encoded, isoindolin-2-yl-acetamide-based chemical library with potential lenalidomide-like pharmacological properties. 15 However, to date, no article has achieved the fast synthesis of both isoquinolin-2(1H)-yl-acetamide and isoindolin-2-ylacetamide derivatives from a common Ugi MCR-based precursor.
Based on previous works on copper-catalyzed cyclization reactions 16 and our ongoing experience in MCR chemistry and post-MCR modifications, 17 we hypothesized that two different polycyclic heterocycles could be accessed by a Ugi/Cucatalyzed annulation sequence reaction between Ugi adducts and different corresponding reagents. Hence, we report herein the synthesis of either isoquinolin-2(1H)-yl-acetamides or isoindolin-2-yl-acetamides in moderate to good yields by adopting Cu(I)-catalyzed C−C coupling/annulation reaction of the C(sp 2 )−I/Br bond of Ugi-4CR adducts with substituted ethanones or terminal alkynes, respectively (Scheme 1C).
Aside from Ugi intermediates based on tert-butyl isocyanide, the Ugi adducts generated from other alkyl isonitriles like tertoctyl-isocyanide and cyclohexyl isocyanide afforded final products 5g−5m in moderate to excellent yields.
Gratifyingly, Ugi synthons from two aryl nitriles, phenylethyl isocyanide and 2-methoxyphenyl isocyanide could also result in corresponding isoindolin-2-yl-acetamides (5n−5o) in good yield, thus widely broadening the scope of the reaction. It should be noted that when the Ugi product from cyclohexyl isonitrile reacted with 2-pyridineacetylene, we could obtain a product (5k, Z/E = 51/49) with almost equal amounts of Z and E forms in 73% yield, which was further purified to give 5l (Z/E = 96/4) and 5m (Z/E = 9/91) with better regioselectivity. The 2D NMR correlations were done to assign the structure of 5a which was subsequently unambiguously determined by X-ray ( Figure S5).
To support the preparative usefulness of our method, gramscale experiments were carried out for the synthesis of isoquinolin-2(1H)-yl-acetamide 3a and isoindolin-2-yl-acetamide 5a in moderate yields (Scheme 5A). Two CuBrpromoted cyclization reactions of Ugi-4CR-based 2-iodobenzamide 1a with acetophenone and phenylethyne were conducted on an 8 mmol scale, producing 3a (1,14 g) and 5a (1,74g) in 43% and 64% yield, respectively. To further evaluate the potential of the above-described two scaffolds, we performed the Suzuki coupling late-stage functionalization. 3b and 5b were coupled with phenylboronic acid and 4methoxyphenyl boronic acid separately, giving the corresponding products 6a and 6b in good yields via Pd-catalyzed Suzuki reaction (Scheme 5B). We also applied our method to synthesize antibacterial compound IV (Scheme 5C); however, instead of obtaining the normal cyclization product IV directly, we obtained the carboxylic acid 6c, which may be due to the similar hydrolysis of the methyl ester occurring in the process as in our previous work. 4 Then, we reacted 6c with MeOH and SOCl 2 to realize product IV (6d, Z/E = 26/74) in 53% yield.
The herein-reported two complementary syntheses of two related scaffolds are based on a common Ugi-4CR intermediate. Switching between two related scaffolds is often applied in medicinal chemistry and sometimes called "scaffold hopping". It is of high importance during lead optimization as the two related scaffolds might bind similarly into the same receptor site but might have different pharmacokinetic/pharmacodynamic (PKPD) parameters. Clearly, the two scaffolds align well in 3D ( Figure 2) and are therefore potential bioisosteres.

■ CONCLUSIONS
In summary, we developed an efficient Ugi-4CR/copper(I) catalytic system for the synthesis of two different bioactive potential scaffolds: isoquinolin-2(1H)-yl-acetamide and isoindolin-2-yl-acetamide, with the advantages of atom economy, good yields and absence of ligands. Additionally, product diversity can be achieved not only through the Ugi starting materials aldehydes, isocyanides, and 2-halogene benzoic acids but also by different substituted ethanones and terminal alkynes. The proposed two different reaction mechanisms were also discussed in the Supporting Information. Having access to two different scaffolds from a common MCR precursor potentially facilitates structure−activity relationship (SAR) enormously, while allowing optimization of "druglike" properties through scaffold hopping. ■ EXPERIMENTAL SECTION General Information. Nuclear magnetic resonance spectra were recorded on a Bruker Avance 500 spectrometer. Chemical shifts for 1 H NMR were reported relative to TMS (δ 0 ppm) or internal solvent peak (CDCl 3 δ 7.26 ppm, CD 3 OD δ 3.31 ppm or D 2 O δ 4.79 ppm) and coupling constants were in hertz (Hz). The following abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dt = double triplet, ddd = doublet of double doublet, m = multiplet, and br = broad. Chemical shifts for 13 C NMR reported in ppm relative to the solvent peak (CDCl 3 δ 77.23 ppm, DMSO δ 39.52 ppm, CD 3 OD δ 49.00 ppm). Flash chromatography was performed on a Grace Reveleris X2 using Grace Reveleris Silica columns (12 g) and a gradient of petroleum ether/ethyl acetate (0−100%) or dichloromethane/methanol (0−20%) was applied. Thin layer chromatography was performed on Fluka precoated silica gel plates (0.20 mm thick, particle size 25 μm). All isocyanides were made inhouse via the Ugi procedure. 18 Benzoic acids, ethanones (2), terminal alkynes (4), and other reagents were purchased from Sigma Aldrich, ABCR, Acros, Fluorochem, AK Scientific, Combiblocks, or A2B and were used without further purification. Mass spectra were measured on a Waters Investigator Supercritical Fluid Chromatograph with a 3100 MS Detector (ESI) using a solvent system of methanol and CO 2 on a Viridis silica gel column (4.6 × 250 mm 2 , 5 μm particle size) and reported as (m/z). High-resolution mass spectra (HRMS) were recorded using an LTQ-Orbitrap-XL (Thermo Fisher Scientific; ESI pos. mode) at a resolution of 60000@m/z400. Melting points were obtained on a melting point apparatus and were uncorrected. Yields given refer to chromatographically purified compounds unless otherwise stated. Compounds 1a, 1d, 1f, and 1j were all prepared following our reported literature 4,14 (Table S3).
General Experimental Procedure and Characterization. General Procedure for Ugi-4CR Products. To a stirred solution of the carboxylic acid (2 mmol, 1.0 equiv) in 2,2,2-trifluoroethanol (2 mL) in a 5 mL vial, 0.3 mL of 25% ammonia solution (2.4 mmol, 1.2 equiv) was added. Aldehyde (2 mmol, 1.0 equiv) and isocyanide (2 mmol, 1.0 equiv) were then introduced into the mixture, the vial was capped, and then the reaction mixture was placed in a heated metal block and stirred at 60°C overnight. After the completion of the reaction, the solvent was removed in vacuo and the crude products were purified by column chromatography to give the desired products 1b, 1c, 1e, and 1g−1i (Table S3).
Procedure C. Compound 3b or 5b (0.15 mmol, 1.0 equiv) and the corresponding phenylboronic acid (0.225 mmol, 1.5 equiv) were placed in a 10 mL tube, and toluene/ethanol (v/v = 5:1) (3 mL) and sat. NaHCO 3 (3 mL) were added. The tube was flushed with N 2 for 10 min, then Pd(dppf)Cl 2 (0.015 mmol, 0.1 equiv) was added, and the tube was sealed. The mixture was allowed to react at 90°C in an oil bath for 12 h. Then, the reaction mixture was cooled to room temperature and treated with H 2 O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After the removal of EtOAc, the residues were purified by silica gel column chromatography to afford Suzuki coupling products 6a and 6b.  13 163.7, 142.6, 135.5, 132.7, 128.8, 125.8, 124.3, 123.1, 116.0 13  The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c01905.