Copper(I)-Catalyzed [ 3+ 2] Cycloaddition of 3-Azidoquinoline-2,4(1H,3H)-diones with Terminal Alkynes †

3-Azidoquinoline-2,4(1H,3H)-diones 1, which are readily available from 4-hydroxyquinolin-2(1H)-ones 4 via 3-chloroquinoline-2,4(1H,3H)-diones 5, afford, in copper(I)-catalyzed [3 + 2] cycloaddition reaction with terminal acetylenes, 1,4-disubstituted 1,2,3-triazoles 3 in moderate to excellent yields. The structures of compounds 3 were confirmed by 1H and 13C-NMR spectroscopy, combustion analyses and mass spectrometry.

3-Azidoquinoline-2,4(1H,3H)-diones 1 were examined as partners in copper(I) catalyzed [3 + 2] cycloaddition (Scheme 2). Three different terminal acetylenes 2 were chosen; phenylacetylene (2a), propargyl alcohol (2b) and 3-ethynylaniline (2c). When screening for the optimal reaction conditions, we initially tested the most commonly used system, copper(II) sulphate pentahydrate and ascorbic acid as a source of copper(I) in tert-BuOH/H 2 O as a solvent [6]. Interestingly, no reaction could be detected by thin-layer chromatography (TLC) analysis after 24 h and the starting azides 1 were recovered nearly quantitatively from the reaction mixtures. Similarly unsuccessful were attempts to use a combination of copper(II) acetate and elemental copper in acetonitrile. We assumed that the prime reasons for the failure of these reactions were the extremely low solubilities of azides 1 in the reaction media used. Similar difficulties were previously encountered by some of us in attempts at using sparingly soluble propargyl functionalized diazenecarboxamides [11] or azido-appended platinum(II) complexes [12] as click components. In those instances the use of dimethyl sulfoxide (DMSO) as a reaction solvent and a combination of copper(II) sulphate pentahydrate and elemental copper (CuSO 4 /Cu (0) ) provided results that were superior to other combinations. Conducting the cycloadditions between azides 1 and acetylenes 2 in DMSO, in the presence of CuSO 4 /Cu (0) couple afforded the expected 1,4-disubstituted 1,2,3-triazoles 3 in moderate to excellent yields, as shown in Table 1.
The structures of triazoles 3 were confirmed by 1 H-and 13 C-NMR spectroscopy, combustion analyses and mass spectrometry on the crystallized compounds. In one instance, that of 3Cb, the expected 1,4-regiochemistry at the 1,2,3-triazole ring was confirmed by a NOESY experiment. As demonstrated in Figure 1, the triazole hydrogen atom (H triazole ) displays five NOE cross peaks; three to the propyl group bound to C3 of the quinolinedione core and two to the hydroxymethyl group, attached to C4' of the triazole ring. The most important for the assigned regiochemistry is the cross peak of H triazole to the C3-CH 2 protons, which would not be possible for the isomeric 1,5-disubstituted product. The absence of a cross peak between the hydroxymethyl group and C3-CH 2 further corroborates the structure of 3Cb. In one instance, that of 3-phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (3Aa), the preparation of 3-azido-3-phenylsquinoline-2,4(1H,3H)-dione (1A) and its cycloaddition with phenylacetylene were conducted as a one-pot multicomponent reaction, i.e., by mixing the corresponding 3-bromoquinolinedione substrate 6A, sodium azide and alkyne (2a) in the presence of Cu (II) /Cu (0) (Experimental section). Similar one-pot azidation-cycloaddition procedures are described in the literature [13,14] This protocol afforded the desired product (3Aa) in modest 43% yield.

General
Reagents and solvents were commercially sourced (Fluka, Aldrich, Alfa Aesar) and used as purchased. Granular copper (particle size 0.2-0.7 mm), coating quality (99.9%, Fluka #61144) was used. For column chromatography, Fluka Silica gel 60, 220-440 mesh was used. The course of separation and also the purity of substances were monitored by TLC on Alugram® SIL G/UV254 foils (Macherey-Nagel). NMR spectra were recorded at 302 K on a Bruker Avance DPX 300 spectrometer operating at 300 MHz ( 1 H) and 75 MHz ( 13 C), and Bruker Avance III 500 MHz NMR instrument operating at 500 MHz ( 1 H) and 125 MHz ( 13 C). Proton spectra were referenced to TMS as internal standard. Carbon chemical shifts were determined relative to the 13 C signal of DMSO-d 6 (39.5 ppm). Chemical shifts are given on the δ scale (ppm). Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broadened). Phase sensitive NOESY with gradient pulses in mixing time, of 3Cb, was recorded in DMSO-d 6 (c = 21 mM) using standard pulse sequence from the Bruker pulse library (noesygpphpp in the Bruker software) at 296 K, with mixing time of 300 ms and relaxation delay of 2 s. Mass spectra and high-resolution mass spectra were obtained with a VG-Analytical AutospecQ instrument and Q-TOF Premier instrument. Data are reported as m/z (relative intensity). The IR spectra were recorded on a Perkin-Elmer 421 and 1310 and Mattson 3000 spectrophotometers using samples in potassium bromide disks. Elemental analyses (C, H, N) were performed with FlashEA1112 Automatic Elemental Analyzer (Thermo Fisher Scientific Inc.). The melting points were determined on a Kofler block or Gallenkamp apparatus and are uncorrected. Starting compounds 1, 4-6 were prepared by known procedures as shown in Scheme 3 and described below.

Scheme 3. Preparation of starting compounds 4-6.
For key to substituents, please see Table 1.

4-Hydroxy-6-methoxy-3-propylquinolin-2(1H)-one (4C)
A mixture of 4-methoxyaniline (6.16 g, 50 mmol) and diethyl propylmalonate (10.52 g, 52 mmol) was heated on a metal bath at 220-230 °C for 1 h and then at 260-280 °C for 3 h (the reaction was complete when the distillation of ethanol stopped). After cooling, the solid product was crushed, suspended in aqueous sodium hydroxide solution (0.5 M, 125 mL) and after filtration the filtrate was washed with toluene (3 × 20 mL). The aqueous phase was filtered and acidified by concentrated hydrochloric acid. The precipitated crude product was filtered, washed with water, air dried and crystallized from ethanol affording white solid of 4C, yield 5.
The precipitated solid was filtered, washed with water, dried on the air and crystallized from benzene (1.3 L) affording compound 5D. The mother liquor was concentrated in vacuo to approximately 380 mL. The precipitated solid was filtered and recrystallized from benzene to give compound 5F.

General Procedure for the Preparation of 1,2,3-Triazoles 3
A mixture of 3-azidoquinoline-2,4(1H,3H)-dione (1, 2.00 mmol), terminal alkyne (2, 2.02 mmol), CuSO 4 ⋅5H 2 O (0.2 mmol, 10 mol%), granular copper (8.8 mmol), and DMSO (6 mL) was stirred at room temperature in darkness until the starting compound 1 became undetectable by TLC (The reaction times are indicated in Table 1). Then the reaction mixture was diluted with CH 2 Cl 2 (160-250 mL) and filtered. The filtrate was washed with saturated aqueous NH 4 Cl (3 × 80 mL) until the aqueous layer remained colourless (concentrated aqueous ammonia (0.25 mL) was added to the saturated aqueous NH 4 Cl for the isolation of 3Ac. Each time the product was back-extracted from the water layer with few millilitres of CH 2 Cl 2 . The combined organic layers were shortly dried over Na 2 SO 4 , filtered, and the solvents were evaporated in vacuo. Residual DMSO was removed by several consecutive co-distillations in vacuo with toluene and then ethanol. The product was suspended in boiling cyclohexane (20 mL), cooled down to room temperature, filtered and dried to give the corresponding triazole 3. For analyses the products were crystallized from the solvent indicated below. Reaction times along with the yields of crude and crystallized products are indicated in Table 1.    79.2, 100.0, 112.4, 116.7, 123.2, 125.1, 127.8, 128.3, 128.7, 128.8, 129.5,