Efficient Synthesis of Isoquinoline Derivatives through Sequential Cyclization–Deoxygenation Reaction of 2-Alkynylbenzaldoximes

Dedicated to Professor Issa Yavari for his outstanding contributions to Chemistry in Iran

Abstract

We describe a novel, simple, robust, and efficient cyclization/deoxygenation approach for the synthesis of functionalized isoquinoline derivatives. Over the course of continued studies on o-alkynylbenzaldoxime cyclization reactions, the formation of cyclic nitrones through 6-endo-dig cyclization was achieved using silver triflate or bromine as an electrophile, and subsequently, the deoxygenation process was carried out in the presence of CS₂ in good to high yields.

Key words

2-alkynylbenzaldoxime - cyclization/deoxygenation - isoquinoline - silver triflate - bromine - carbon disulfide

In recent years, oxygen-atom-transfer reactions of heteroaromatic N-oxides have received much attention in modern chemistry due to their great potential in the synthesis of natural products, bioactive molecules, and applications in industrial processes.[1] As illustrated in Figure [1], deoxygenation of heteroaromatic N-oxides is the key step for the synthesis of a number of bioactive molecules such as p38 MAP kinase,[2] thrombin,[3] tyrosine kinase, and sodium channel[4] inhibitors.

Figure 1 Bioactive compounds containing deoxygenation step

Various procedures and conditions have been reported for the reduction of N-heteroarene N-oxides such as photocatalytic reactions,[5] electrochemical reactions,[6] sulfur sources,[7] trivalent phosphorus compounds,[8] hydride reagents,[9] and metal-catalyzed[10] reactions. Nevertheless, some of these processes have serious disadvantages such as utilizing expensive and complex metal catalysts and reagents, high reaction temperature, low yields, harsh reaction conditions, extended reaction times, and difficult workup.[11]

Due to the importance and broad application of the isoquinoline moiety in medicinal chemistry and materials science, numerous approaches such as the Bischler–Napieralski reaction[12] for the synthesis of substituted isoquinolones have been described and deoxygenation of isoquinoline N-oxides is an efficient way to achieve this core.[11e] On the other hand, the intramolecular annulation reaction of 2-alkynylbenzaldoximes with two active sites, which can be obtained by simple condensation of o-alkynylbenzaldehydes with hydroxylamine, is one of the most common methods among various strategies to access isoquinoline N-oxides (Scheme [1]).[13]

Scheme 1 Some strategies for the synthesis of isoquinolines via cyclization onto an alkyne

As part of our ongoing studies on the synthesis of functionalized 2-alkynylbenzaldoximes and their applications in a variety of tandem reactions,[14] we wish to report a novel and efficient method for the synthesis of isoquinolines via deoxygenation of in situ generated isoquinoline N-oxide using carbon disulfide as a reductant under mild reaction conditions (Scheme [2]).

Scheme 2 Representative sequential cyclization–deoxygenation reactions for the synthesis of isoquinoline derivatives

Initially, we investigated the cyclization–deoxygenation reactions of o-(phenylethynyl)benzaldoxime (1a) as a model substrate in the presence of a catalytic amount of AgNO₃ and CS₂ in DMF at 40 °C, which afforded the desired product 2a in 33% isolated yield (Table [1], entry 1). Subsequently, the influence of the various transition-metal catalysts on the cyclization reaction such as AgOTf, PPh₃AuCl, In(OTf)₃, and CuBr was screened, in which AgOTf (10 mol%) indicated the best catalytic activity (Table [1], entries 1–5). Then, solvent screening showed DMF to be the best choice (Table [1], entries 5–7). Next, several reaction temperatures were examied and showed that temperature had a significant effect on reaction yield (Table [1], entries 5 and 8–11) with a temperature of 60 °C giving the best results. Increasing the temperature up to 100 °C led to a slight decrease in the yield of the desired product. Screening of different amounts of carbon disulfide revealed that the 1.2 equivalents of CS₂ gave the best result (Table [1], entries 9 and 12–14).

Table 1 Optimization of Reaction Conditions for the Synthesis of 2a in the Presence of AgNO₃ and CS₂ ^a

Entry	Metal catalyst (10 mol%)	CS2 (equiv)	Solvent (2 mL)	Temp (℃)	Yield (%)b
1	AgNO3	1.2	DMF	40	33
2	PPh3AuCl	1.2	DMF	40	29
3	In(OTf)3	1.2	DMF	40	35
4	CuBr	1.2	DMF	40	33
5	AgOTf	1.2	DMF	40	49
6	AgOTf	1.2	toluene	40	28
7	AgOTf	1.2	DCE	40	31
8	AgOTf	1.2	DMF	50	63
9	AgOTf	1.2	DMF	60	97
10	AgOTf	1.2	DMF	80	95
11	AgOTf	1.2	DMF	100	92
12	AgOTf	0.8	DMF	60	70
13	AgOTf	1	DMF	60	86
14	AgOTf	1.5	DMF	60	97

^a Reaction conditions: 1a (0.2 mmol), CS₂ (1.2 equiv), AgOTf (10 mol%), solvent (2 mL) for 6 h.

^b Isolated yields.

With optimal reaction conditions in hand, the scope of the reaction was surveyed. To expand the diversity of the starting materials, a wide range of o-alkynylbenzaldoxime derivatives containing electron-withdrawing, electron-donating, and halogen groups substituted on the phenyl ring, as well as aliphatic and aromatic alkynes was synthesized in excellent yields. Subsequently, under optimized reaction conditions, the annulation–deoxygenation reaction of various substituted o-alkynylbenzaldoximes was examined and afforded the corresponding substituted isoquinolines in good to high yields. The observed results are shown in Scheme [3], and all structures were confirmed by ¹H and ¹³C NMR and HRMS spectral analysis (see the Supporting Information).

Scheme 3 Substrate scope for the isoquinoline skeletons 2a–i. Reagents­ and conditions: 2a–i (0.2 mmol), CS₂ (1.2 equiv), AgOTf (10 mol%), DMF (2 mL) at 60 °C. All products were characterized by ¹H and ¹³C NMR spectroscopy and HRMS analysis.

In the second part of the work, activation of the alkyne moiety in the 2-alkynylbenzaldoxime skeleton was investigated employing Br₂ instead of a transition-metal catalyst, and subsequent deoxygenation of isoquinoline N-oxides was carried out in the presence of the carbon disulfide. After some screening and trials, the best results were obtained using Br₂ (1.2 equiv) and NaHCO₃ (1.2 equiv) in DMF at room temperature and carbon disulfide (1.2 equiv) in DMF at 60 °C.

The generality of the approach to produce the 4-bromo-3-alkylisoquinoline derivatives was studied under these optimum reaction conditions. As illustrated in Scheme [4, a] wide range of substituted 4-bromo-3-alkylisoquinolines bearing electron-donating and electron-withdrawing groups was synthesized in good to high yields.

Scheme 4 Substrate scope for the 4-bromo-3-alkylisoquinoline skeletons 3a–g. Reagents and conditions: 3a–g (0.2 mmol), Br₂ (1.2 equiv), NaHCO₃ (1.2 equiv), CS₂ (1.2 equiv), DMF (2 mL) for 3.5 h. In all cases, the reported yields are isolated yields.

According to the literature,[15] the proposed reaction mechanism is as depicted in Scheme [5]. In the presence of an electrophile, 6-endo-dig cyclization of the 2-alkynylbenzaldoxime by π-activation of alkyne moiety leads to the formation of the isoquinoline-N-oxides I. Then, [3+2] dipolar cycloaddition of the isoquinoline N-oxide with CS₂ results in intermediate II. By homolytic cleavage of N–O and C–S bonds, the desired isoquinoline is obtained with COS and S as byproducts, according to the literature.

Scheme 5 A plausible reaction mechanism for the synthesis of 2a–i and 3a–g

To confirm the radical pathway, the deoxygenation reaction was examined by adding the TEMPO as a radical scavenger and neither of the products was obtained. These results demonstrate the reaction does proceed through radical deoxygenation (Scheme [6]).

Scheme 6 Control experiment for the deoxygenation reaction process

In conclusion, we have opened a novel class of cyclization–deoxygenation reactions through the introduction of a CS₂ as an efficient reagent for the synthesis of isoquinoline derivatives using 2-alkynylbenzaldoximes.[16] [17] [18] Furthermore, in comparison to existing approaches in the literature, the use of cheap, commercially available carbon disulfide under mild reaction conditions are some advantages of this reported work.

Conflict of Interest

The authors declare no conflict of interest.

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• 16 General Procedure for the Synthesis of 2-Alkynylbenzaldoximes 1a–i2-Alkynylbenzaldehyde (2.0 mmol) (synthesized following previously reported procedures¹⁴), hydroxylamine hydrochloride (3 mmol, 1.5 equiv), sodium acetate (4.0 mmol, 2.0 equiv), and CH₃CN (10 mL) were added sequentially into a 25 mL flask and the mixture stirred at room temperature for 12 h (monitored by TLC). After completion of reaction, the solvent was evaporated to afford the crude product. Finally, the pure corresponding 2-alkynylbenzaldoximes 1a–i were obtained by flash chromatography (silica gel, eluent: n-hexane/EtOAc, 4:1).
• 17 General Procedure for the Synthesis of Isoquinolines 2a–i in the Presence of AgOTf and CS₂ To a solution of 2-alkynylbenzaldoximes (0.2 mmol) in DMF (2 mL) was added AgOTf (10 mol%), and the mixture was stirred at 60 ℃ in an oil bath for 30 min, leading to the isoquinolines N-oxide (monitored by TLC). Then CS₂ (1.2 equiv) was added, and the reaction mixture was stirred at 60 ℃ for 6 h. Upon completion of the reaction (as indicated by TLC), the reaction mixture was extracted with H₂O (10 mL) and EtOAc (3 × 10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified using column chromatography (silica gel, eluent: n-hexane/EtOAc, 5:1) to afford the corresponding isoquinolines 2a–i (70–95%). 3-Phenylisoquinoline (2a) Yellow solid (39 mg, yield 95%, mp 48–49 °C), R_f = 0.35 (n-hexane/EtOAc, 5:1). ¹H NMR (300 MHz, CDCl₃): δ = 9.35 (s, 1 H, H-1 isoquinoline), 8.15 (d, J = 7.2 Hz, 2 H, HAr), 8.06 (s, 1 H, HAr), 7.98 (d, J = 8.0 Hz, 1 H, HAr), 7.86 (d, J = 8.0 Hz, 1 H, HAr), 7.68 (t, J = 7.2 Hz, 1 H, HAr), 7.57 (t, J = 7.3 Hz, 1 H, HAr), 7.53 (t, J = 7.3 Hz, 2 H, HAr), 7.43 (t, J = 7.3 Hz, 1 H, HAr). ¹³C {¹H} NMR (75 MHz, CDCl₃): δ = 152.4, 151.2, 139.6, 136.6, 130.5, 128.8, 128.5, 127.7, 127.5, 127.1, 127.0, 126.9, 116.5. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₂N: 206.0957; found: 206.0961.
• 18 General Procedure for the Synthesis of 4-Bromo-3-aryl(alkyl)isoquinolines 3a–g Using Br₂and CS₂ A mixture of 2-alkynylbenzaldoxime (0.2 mmol), NaHCO₃ (1.2 equiv), and Br₂ (1.2 equiv) in DMF (2 mL) was stirred at room temperature for 30 min. After preparation of the 4-bromo-3- aryl(alkyl)isoquinoline N-oxide (monitored by TLC), CS₂ (1.2 equiv) was added, and the reaction mixture was allowed to stir at 60 ℃ until the reaction was complete (TLC monitoring, about 3.5 h). The crude mixture was extracted with H₂O (10 mL) and EtOAc (3 × 10 mL), and the combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/EtOAc, 5:1) to give the corresponding 4-bromo-3-aryl(alkyl)isoquinoline 3a–g (65–89%). 4-Bromo-3-phenylisoquinoline (3a) Brown solid (50 mg, yield 89%, mp 47 °C); R_f = 0.30 (n-hexane/EtOAc, 5:1). 1H NMR (300 MHz, CDCl₃): δ = 9.25 (s, 1 H, H-1 isoquinoline), 8.35 (d, J = 8.6 Hz, 1 H, HAr), 8.02 (d, J = 8.1 Hz, 1 H, HAr), 7.75 (d, J = 6.4 Hz, 1 H, HAr), 7.56–7.48 (m, 3 H, HAr), 7.39–7.32 (m, 3 H, HAr). ¹³C{¹H}NMR (75 MHz, CDCl₃): δ = 151.1, 148.8, 132.5, 132.0, 131.6, 129.9, 129.5, 128.7, 128.4, 128.0, 127.0, 125.2, 118.4. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₁ ⁷⁹BrN: 284.0738; found: 284.0741.

Publication History

Received: 14 November 2021

Accepted after revision: 30 November 2021

Article published online:
13 January 2022