Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Domino Reaction between Nitrosoarenes and Ynenones for Catalyst-Free Preparation of Indanone-Fused Tetrahydroisoxazoles Shaotong Qiu,† Renxiao Liang,† Yongdong Wang,‡ and Shifa Zhu*,†,‡ †
Key Laboratory of Functional Molecular Engineering of Guangdong Province and Guangdong Engineering Research Center for Green Fine Chemicals, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China ‡ Singfar Laboratories, Guangzhou, 510670, China Org. Lett. Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 03/08/19. For personal use only.
S Supporting Information *
ABSTRACT: A catalyst-free domino reaction to synthesize highly functionalized indanone-fused tetrahydroisoxazole from easily accessed nitrosoarene and 1,6-ynenone with good chemo- and regioselectivity was disclosed. This unprecedented domino reaction represents a new strategy for multifunctionalization of an internal alkyne with nitrosoarene by formation of two rings and four bonds in a single operation.
N
Scheme 2. Overview of Multifunctionalization of Alkyne with Nitrosoarene
itroxy containing compounds are widely accepted as powerful building blocks since these N−O containing species can be transformed into important precursors for agrochemical, pharmaceutical, and fine chemical industries. Particularly nitroso species may be regarded as nucleophiles,1 electrophiles,2 and even radical precursors3 in some cases (Scheme 1). Scheme 1. Versatile Reactivity of Nitrosoarene
Recently, much attention has been drawn to multifuntionalization of alkynes with nitrosoarenes to synthesize various molecules. For example, terminal alkynes reacted with nitrosoarenes to afford indole derivatives via 1,4 diradical intermediates.4 When a bulky 2,6-dihalonitrosoarene is used, an α-styryl cation is produced, which is attacked by another nitrosoarene to provide a dinitrone (Scheme 2a).5 Beside terminal alkynes, the Liu group found that ynamide and propiolate could also react with nitrosoarene to give 2oxoiminylamide and α-imidoyl nitrone with gold salt as the catalyst (Scheme 2b−c).6,7 As for the common internal alkyne, fewer examples have been reported due to its relatively lower reactivity compared with the terminal alkyne, ynamide and propiolate. In 1922, Alessandri reported a solvent-evaporated method to achieve dinitrones for 2 months. A higher reaction temperature was tried to shorten the conversion time, while the desired product was obtained in a decreased yield with a large quantity of azoxyarenes detected,8 which indicated nitrosoarene has a strong tendency to react with itself to form the undesired byproduct (Scheme 2d).9 To our knowledge, the multifunctionalization of common internal © XXXX American Chemical Society
alkynes with nitroarenes still remains unsolved due to its inherent low reactivity and undesired side reaction. As part of our continuous efforts in developing highly efficient tandem reactions based on alkyne chemistry,10 here, we devised a new kind of substrate of 1 with both an internal alkyne and deficient CC bifunctional groups, in which the internal alkyne was first attacked by two nitrosobenzenes to form dinitrone dipoles, and triggered the subsequent [3 + 2] Received: January 31, 2019
A
DOI: 10.1021/acs.orglett.9b00426 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters domino reaction11,12 with the deficient alkene; thus, two rings with four new bonds were built up rapidly in a single operation (Scheme 3). It was noted that in this process a highly functionalized tetrahydroisoxazole13 was furnished.
tetrahydroisoxazole 4a was also detected (entries 7 to 12). Both structures of 3a and 4a were confirmed by X-ray diffraction analysis (see the Supporting Information). Based on the optimized reaction condition (Table 1, entry 10), the substrate scope of this protocol was examined. As shown in Scheme 4, the reaction could be scaled up to 10 mmol, giving the product 3a in 60% yield. 1,6-Ynenones with different substituent groups at R1 gave the desired products 3b−i in good yields (60−80%). The reaction seemed insensitive to both the electron property and steric hindrance of the R1 group. An attempt to extend this reaction to heterocycles also succeeded (3j), albeit the terminal alkenyl failed to give the desired product (3k). When ynenones with different capping aryl groups on the CC triple bond were tested, they all gave the corresponding products smoothly (3l− p, 52−74%). Besides, the substrate with a cyclopropyl capping group also successfully gave the desired product in 41% yield (3q), while linear hexyl substituted 1r resulted in a sharp decrease in reaction yield (3r). Furthermore, ynenones bearing different R3 substituents at the phenylene ring could also be effectively converted into the target products (3s−u, 59− 75%). To further study the robustness of this reaction system, nitrosobenzenes containing different functionalized groups were also investigated. As our expectation, nitrosobenzenes with both electronic-withdrawing and -donating groups were all compatible with our protocol (3v−x). Additionally, it was found that electronic-deficient nitrosobenzene performed slightly better than the electron-rich one. To broaden the generality of this transformation, electrondeficient alkenes were tested to conduct the intermolecular reactions. As shown in Scheme 5, neither isoxazole 7 nor 8 was detected in the standard condition. Major azoxybenzene 5a was furnished, which was consistent with the previous results mentioned above (Scheme 2d). To better understand the reaction mechanism, control reactions were then carried out (Scheme 6). Initially, azoxybenzene 5a was isolated and added into the reaction system under standard conditions to test whether 5a was involved as an intermediate. However, no desired product was detected even after 24 h of heating (eq 1). When 1.5 equiv of TEMPO was added, the reaction seemed to be depressed partially. The desired product 3a was isolated only in 17% yield, which indicated that a radical process might be involved (eq 2). Based on the results in hand, a possible reaction mechanism was proposed (Scheme 7). First, the internal alkyne of the ynenone was attacked by two nitrosobenzenes to form dinitrone intermediate A, which underwent [2 + 3] dipolar cycloaddition to give the final product 3 or 4. There might exist two reaction pathways (paths a and b), as either nitrone in intermediate A could react with the CC double bond. For path a, indanone-fused tetrahydroisoxazole 3 was formed preferably due to less steric hindrance in the cycloaddition process. As for path b, naphthalenone-fused tetrahydroisoxazole B was produced. Furthermore, with the attack of an external nitrosobenzene, an O-bridged intermediate C might be generated, followed by release of one nitrosoarene molecule to furnish the desired product 4. With the tetrahydroisoxazoles 3 in hand, further chemical transformations were performed to demonstrate the potential applications of these molecules (Scheme 8). Taking 3a as an example, the nitrone of 3a could be easily trapped by in situ generated benzyne, giving [2 + 3] annulation product 9 in 52%
Scheme 3. New Strategy for Multifunctionalization of Internal Alkyne with Nitrosoarene
With this design in mind, the easily accessed 1,6-ynenone 1a was selected as a model substrate. Initial efforts were made to systematically screen the suitable conditions to convert alkyne 1a and nitrosobenzene 2a into the target product (Table 1). Table 1. Optimization of Reaction Conditionsa
yield (%)c b
entry
catalyst
1 2 3 4 5 6 7 8 9 10d 11d,f 12d,g
IPrAuNTf2 AgNTf2 Pd(OAc)2 PtCl2 Rh2(OAc)4 CuCl2 − − − − − −
solvent
T (°C)
3a
4a
5a
DCE DCE DCE DCE DCE DCE DCE MeCN CHCl3 CHCl3 CHCl3 CHCl3
80 80 80 80 80 80 80 80 80 80 100 60
15 nd nd 20 30 32 36 62 66 69e 56 40h
nd nd nd nd nd nd
