Yuan
Pan
a,
Gui-Wei
Chen
b,
Cang-Hai
Shen
b,
Weimin
He
*a and
Long-Wu
Ye
*bc
aState Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
bState Key Laboratory of Physical Chemistry of Solid Surfaces & The Key Laboratory for Chemical Biology of Fujian Province, Department of Chemistry, Xiamen University, Xiamen 361005, China. E-mail: longwuye@xmu.edu.cn
cState Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
First published on 12th February 2016
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.
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).
Entry | Catalyst | Conditions | Yieldb (%) | |
---|---|---|---|---|
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)3PAuNTf2c | DCE, 80 °C, 6 h | 51 | 36 |
7 | PtCl2 | Toluene, 80 °C, 6 h | 18 | 27 |
8d | Zn(OTf)2 (10 mol %) | DCE, 80 °C, 6 h | <5 | <5 |
9d | 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 |
14e | BrettPhosAuNTf2 | DCE, 80 °C, 6 h | 65 | 11 |
15f | BrettPhosAuNTf2 | DCE, 80 °C, 6 h | 51 | 13 |
16g | BrettPhosAuNTf2 | DCE, 80 °C, 6 h | 72 | <10 |
17h | BrettPhosAuNTf2 | DCE, 80 °C, 6 h | 91 | <5 |
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 |
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)).
![]() | (1) |
![]() | (2) |
![]() | (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.
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).
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00033a |
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