Synthesis of fused isoquinolines via gold-catalyzed tandem alkyne amination/intramolecular O–H insertion

Abstract

A novel gold-catalyzed tandem alkyne amination/intramolecular O–H insertion has been developed. A variety of [1,4]oxazino[3,2-c]isoquinolines are readily accessed under mild reaction conditions by utilizing this strategy, thereby providing an efficient and practical route for the construction of synthetically useful fused isoquinolines.

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Isoquinolines are a commonly encountered structural motif in many natural products and bioactive compounds.¹ Consequently, the development of new synthetic methodologies for their preparation remains an active research area.² In recent years, transition metal- or iodine-promoted cyclization of readily available 2-alkynyl benzyl azides has emerged as one of the most efficient tools available for the construction of isoquinoline derivatives.^3–6 For example, Yamamoto and co-workers reported a gold-catalyzed intramolecular cyclization of 2-alkynyl benzyl azides, allowing the facile synthesis of isoquinolines (Scheme 1a).³ Later, Liang and co-workers also described a general route for the construction of various isoquinolines via Ag-catalyzed cyclization of 2-alkynylbenzyl azides (Scheme 1b).⁴ Recently, elegant studies about the synthesis of isoquinolines from 2-alkynyl benzyl azides were reported by Yamamoto and co-workers by an iodine-mediated electrophilic cyclization reaction (Scheme 1c).⁵ Despite these significant achievements, the above cyclization has to be quenched by an electrophile, that is, the position 4 of the produced isoquinoline is limited to a hydrogen or halogen. Therefore, the exploration of novel and general methods for such a cyclization is highly desirable.

Scheme 1 Synthesis of isoquinoline derivatives by cyclization of 2-alkynyl benzyl azides.

In our recent study on the ynamide chemistry,^7–9 we disclosed that benzyl azides could serve as efficient nitrene-transfer reagents to react with ynamides for the generation of α-imino gold carbenes,^10,11 leading to the highly site-selective synthesis of versatile 2-aminoindoles and 3-amino-β-carbolines.^9a With these in mind, we envisioned that the above cyclization of 2-alkynylbenzyl azide might be trapped by a nucleophile through a gold-catalyzed amination-initiated tandem reaction involving an α-imino gold carbene as the intermediate (Scheme 1d). In this communication, we describe herein the realization of such a gold-catalyzed tandem alkyne amination/intramolecular O–H insertion, which provides ready access to valuable [1,4]oxazino[3,2-c]isoquinolines in generally good to excellent yields. Importantly, two fused six-membered rings have been built in one step.

To test our hypothesis, (azido)ynamide 1a was prepared and treated with IPrAuNTf₂ (5 mol%) in 1,2-dichloroethane (DCE) at 80 °C for 6 h. To our delight, 62% yield of the desired [1,4]oxazino[3,2-c]isoquinoline 2a was obtained, albeit with a minor isoquinoline 3a, which was formed similar to Yamamoto's protocol (Table 1, entry 1). Importantly, no Huisgen 1,3-dipolar cycloaddition product was observed in this case.^3,4,5a,12 Subsequently, the influence of various gold catalysts bearing different ligands was examined (Table 1, entries 2–6), and BrettPhosAuNTf₂ gave a slightly improved yield (Table 1, entry 5). PtCl₂ was not effective in promoting this reaction (Table 1, entry 7) while no trace of the desired product 2a was detected by employing Zn(OTf)₂ or Cu(OTf)₂ as the catalyst (Table 1, entries 8 and 9). In addition, the use of other solvents, including toluene, PhCl and THF, led to a significantly decreased yield (Table 1, entries 10–12). Of note, the amount of byproduct 3a increased when the reaction was performed at a reduced temperature (Table 1, entry 13). Finally, different types of external oxidants, including O₂, oxone, AgOAc and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), were investigated (Table 1, entries 14–17) and it was found that the use of DDQ gave the best result, which minimized the formation of the byproduct 3a (Table 1, entry 17).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Conditions	Yield^b (%)
			2a	3a
a Reaction conditions: [1a] = 0.05 M. b Estimated by ^1H NMR using diethyl phthalate as an internal reference. c Ar = 2,4-di-tert-butylphenyl. d >90% of 1a remained unreacted. e Using O2 (1 atm) as the oxidant. f Using oxone (2.0 equiv.) as the oxidant. g Using AgOAc (1.1 equiv.) as the oxidant. h Using DDQ (1.1 equiv.) as the oxidant.
1	IPrAuNTf2	DCE, 80 °C, 6 h	62	25
2	Ph3PAuNTf2	DCE, 80 °C, 6 h	49	19
3	(4-CF3C6H4)3PAuNTf2	DCE, 80 °C, 6 h	56	38
4	Cy-JohnPhosAuNTf2	DCE, 80 °C, 6 h	44	37
5	BrettPhosAuNTf2	DCE, 80 °C, 6 h	68	<10
6	(ArO)3PAuNTf2^c	DCE, 80 °C, 6 h	51	36
7	PtCl2	Toluene, 80 °C, 6 h	18	27
8^d	Zn(OTf)2 (10 mol %)	DCE, 80 °C, 6 h	<5	<5
9^d	Cu(OTf)2 (10 mol %)	DCE, 80 °C, 6 h	<5	<5
10	BrettPhosAuNTf2	Toluene, 80 °C, 6 h	38	23
11	BrettPhosAuNTf2	PhCl, 80 °C, 6 h	50	13
12	BrettPhosAuNTf2	THF, 80 °C, 6 h	21	64
13	BrettPhosAuNTf2	DCE, 40 °C, 8 h	40	25
14^e	BrettPhosAuNTf2	DCE, 80 °C, 6 h	65	11
15^f	BrettPhosAuNTf2	DCE, 80 °C, 6 h	51	13
16^g	BrettPhosAuNTf2	DCE, 80 °C, 6 h	72	<10
17^h	BrettPhosAuNTf2	DCE, 80 °C, 6 h	91	<5

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With the optimal conditions in hand, we next investigated the substrate scope of this transformation. As shown in Table 2, the reaction exhibited good functional group compatibility. 2-Alkynyl benzyl azides with different N-protecting groups, such as benzenesulfonyl, Ts, Bs (p-bromobenzenesulfonyl) and Ms, were well tolerated and the corresponding products 2a–2d were isolated in good to excellent yields (Table 2, entries 1–4). Attempts to prepare ynamides with other electron withdrawing protecting groups such as Boc and Ac were not successful probably due to the fact that these kinds of protecting groups are too labile. In addition, electron-withdrawing and electron-donating substituents at the m- and p-positions on the phenyl ring of aromatic alkynes all underwent tandem alkyne amination/O–H insertion smoothly to produce the desired products 2e–2h in 71–95% yields (Table 2, entries 5–8). Furthermore, N-Ms (azido)ynamides were also effective substrates and provided the desired products 2i–2j in good yields (Table 2, entries 9 and 10). Once again, no triazole formation was observed in all cases. Thus, this cascade cyclization provides a highly efficient and convenient route for the preparation of fused isoquinoline derivatives, which may have applications in drug development and chemical biology.¹³

Table 2 Reaction scope study^a

Entry	Substrate	1	Product	2	Yield (%)
a Reactions run in vials; [1] = 0.05 M; isolated yields are reported.
1		1a		2a	88
2		1b		2b	68
3		1c		2c	78
4		1d		2d	85
5		1e		2e	82
6		1f		2f	95
7		1g		2g	75
8		1h		2h	71
9		1i		2i	76
10		1j		2j	80

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The reaction could also be extended to secondary alcohol-tethered ynamide 1k, derived from the commercially available (S)-(+)-1-amino-2-propanol, leading to the efficient formation of the corresponding optically active fused isoquinoline 2k in 93% yield (eqn (1)). In addition, (azido)ynamide 1l was also a suitable substrate for this tandem alkyne amination/O–H insertion reaction to furnish the corresponding isoquinoline fused with a seven membered ring, albeit with isoquinoline 3l as a significant byproduct (eqn (2)). Of note, our attempts to extend the reaction to tandem alkyne amination/intramolecular N–H insertion only gave a complicated mixture of products and no desired 2m was obtained (eqn (3)).

Finally, a plausible mechanism to rationalize this gold-catalyzed cascade reaction is presented in Scheme 2. Taking substrate 1a for example, an initial Au-catalyzed nucleophilic addition of the azide nitrogen onto the alkyne moiety in 1a, followed by extrusion of molecular nitrogen, generates the key α-imino gold carbene intermediate B. A subsequent intramolecular trapping of the α-imino gold carbenoid by the OH moiety affords the intermediate C, which undergoes further proton transfer/deauration/dehydrogenative oxidation to deliver the target fused isoquinoline 2a.

Scheme 2 Plausible reaction mechanism.

In summary, we have developed an efficient and practical method for the preparation of structurally diverse fused isoquinolines via an α-imino gold carbene intermediate. Importantly, fused six-membered rings have been built in one step, highlighting the power of this gold-catalyzed tandem sequence. Other notable features of this approach include readily available starting materials, high flexibility, the simple procedure and mild reaction conditions. Further investigations of this gold-catalyzed amination-initiated tandem reaction will be pursued in our laboratory.¹⁴

We are grateful for financial support from the National Natural Science Foundation of China (no. 21272191, 21302048 and 21572186), the Natural Science Foundation of Fujian Province for Distinguished Young Scholars (no. 2015J06003), the Fundamental Research Funds for the Central Universities (no. 20720150045), NFFTBS (no. J1310024) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00033a

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