Xinwei
He
*a,
Ruxue
Li
a,
Pui Ying
Choy
bc,
Jiahui
Duan
a,
Zhenzhen
Yin
a,
Keke
Xu
a,
Qiang
Tang
a,
Rong-Lin
Zhong
b,
Yongjia
Shang
*a and
Fuk Yee
Kwong
*bc
aKey Laboratory of Functional Molecular Solids, Ministry of Education, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, P. R. China. E-mail: xinweihe@mail.ahnu.edu.cn; shyj@mail.ahnu.edu.cn
bState Key Laboratory of Synthetic Chemistry and Department of Chemistry, The Chinese University of Hong Kong, New Territories, Shatin, Hong Kong SAR, P. R. China. E-mail: fykwong@cuhk.edu.hk
cShenzhen Center of Novel Functional Molecules, Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules, CUHK Shenzhen Research Institute, No. 10. Second Yuexing Road, Shenzhen 518507, P. R. China
First published on 3rd November 2022
ortho-Alkynyl quinone methides are well-known four-atom synthons for direct [4 + n] cycloaddition in constructing useful oxa-heterocyclic compounds owing to their high reactivity as well as the thermodynamically favored aromatization nature of this process. Herein we report an operationally simple and eco-friendly protocol for the modular and regioselective access of (E)-4-(vinyl or aryl or alkynyl)iminochromenes from propargylamines and S-methylated β-ketothioamides in the presence of FeCl3, and particularly under undried acetonitrile and air atmosphere conditions. This method exhibits a broad substrate scope and displays nice functional group compatibility, thus providing an efficient access of 3,4-disubstituted iminochromenes.
Scheme 1 Selected applications of multi-functionalized iminochromenes, previous methods and our design for the synthesis of such compounds. |
Classical methods for constructing useful iminochromenes often employ salicylaldehyde as a typical synthon. Previous investigations showed the possible multicomponent reactions between terminal alkynes, sulfonyl azides and salicylaldehydes for affording 2,3-functionalized-2H-chromene using CuI as the catalyst (Scheme 1b(i)).11 Recently, Li introduced a synthetic method to obtain 2,3-disubstituted-2H-chromene using a cascade three-component coupling of arynes, dimethylformamide and N,S-keteneacetals (Scheme 1b(i)).12 In 2011, Liu and Wang reported the synthesis of 2-iminocoumarin-3-carboxamide from methyl cyanoacetate, aryl amines and salicylaldehydes via amidation and Knoevenagel condensation under microwave heating (Scheme 1b(i)).13 Remarkably, this skeleton displayed good photophysical properties for application in fluorescent intracellular imaging. Later, a modified multicomponent reaction of 4-methoxy-1-naphthol, substituted benzaldehyde and ethyl cyanoacetate allowed the formation of 2,3-functionalized-4-aryl-4H-chromenes (Scheme 1b(ii)).14 Certainly, the aforementioned methods have considerable merits in the assembly of multi-substituted iminochromenes. Nevertheless, the examples of all-pyran-functionalized iminochromenes were very limited. Only 5 relevant examples were reported. In fact, they are notable for having therapeutic potential as highlighted in Scheme 1a. Inspired by our pioneering results, in which highly reactive ortho-alkynyl quinone methide (o-AQM)15 displays the unique feature of cyclization,16 and in continuation of our interest in investigating the polyarene assembly,17 we herein report a new cascade reaction between alkylaminophenols and N,S-keteneacetals catalysed by FeCl3 (Scheme 1c). This process provides a simple, rapid, and direct approach to access alkenyl-, aryl- and alkynyl-iminochromene skeletons.
With the optimised reaction conditions, we next explored the substrate scope (Scheme 2). Given the unique feature of halogen-containing arene systems in halogen-bonding medicinal chemistry and chemical biology18 and the possibility of further functionalization using coupling technology,19 the substituents, e.g. –Br, –Cl and –F on the phenolic moiety and alkynyl arene moiety at the propargylic scaffold were therefore investigated. In contrast to the common Fe-catalysed coupling reaction where the halo groups would react, the present reaction system showed a halo moiety which remained intact under the stated reaction conditions (Scheme 2a, products 3ba, 3ca, 3ea, 3ha and 3qa). In addition to halo-substituents, the steric bulky tert-butyl group at the ortho-phenolic-position of propargylamine was found to be a feasible reaction partner towards the ring-forming process (product 3ga). Substrates with an ortho-hindered-substituent at the alkynyl arene moiety were also cyclised successfully to afford target iminochromenes (products 3na and 3oa). The alkenyl or alkyl unit located at propargylic amines furnished the products 3ra and 3sa in both 72% yield. Next, the reaction scope was further tested using various N,S-keteneacetal derivatives (Scheme 2b). The reactions were found to proceed smoothly and the functional groups of –Br and –Cl again were well tolerated (products 3ab–3ak). Strongly electron-withdrawing –CN and –CF3 positioned at the para-position of the arene moiety of 2 did not affect the annulation process (products 3ac and 3ae). Particularly noteworthy is that this method was found even able to accommodate ortho-substituted substrates, e.g. a chloro-substituent at the ortho-position of the arene moiety close to the carbonyl group and bromo-substituent at the ortho-position of the arene moiety near the imine group, in accessing 3ak (78%) and 3am (65%), respectively. These outcomes showed the suitability of this approach for further transformation of a π-extended system using an intramolecular annulation pathway.20
Considering the prevalence of the 4-arylchromene skeleton in drug discovery,21 we attempted to conduct the reaction using arene-containing aminoalkylphenols 4 (Scheme 3a). In fact, common modular assembly of chromene, which consists of aryl units, relies on the palladium-catalysed Suzuki–Miyaura coupling of its sulfonates/bromides with arylboronic acids in which the reaction scope is often limited by the incompatibility of –Br or –Cl groups.22Scheme 3a shows that various halogen-bearing aminophenols were tested in delivering products 5ca–5ga. Indeed, these resulting compounds exhibit rich potential for further functionalization using well-established cross-coupling technology.23 Product 5ga was unambiguously confirmed by single crystal X-ray crystallography (CCDC 2184625†). Steric bulky product 5ba was obtained in 82% yield. 4-Alkynyl-chromenes 6aq and 6ia were also afforded successfully (Scheme 3b). These products offer a high opportunity for further functionalization and thus allows new entities for material investigations.24
To gain more insight on this transformation, control experiments were carried out (Scheme 4a). Propargylamine 7 without a hydroxyl group did not react with 2a which indicates that the hydroxyl group plays a crucial role in the initial stage of this reaction (Scheme 4a(i)). Further attempts of 2s and 2t revealed that the –NH and –S–R groups in N,S-keteneacetals are essential for the reaction while the latter showed that the S-substituent did not affect the reaction (Scheme 4a(i) to (iii)). We were intrigued that 6ia is a probable intermediate before achieving product 3 (Scheme 4a(iv)). Yet, investigation showed that the in situ cyclisation does not occur. Furthermore, a deuterium-labelling experiment was performed, and compound 3aa–d was obtained with 85% of the deuterium atoms at the alkenyl group (Scheme 4a(v)). A mechanistic proposal is illustrated in Scheme 4b. Initially, the ortho-alkynyl quinone methide (o-AQM) intermediate is formed in the presence of Lewis acid (FeCl3), as proposed in the literature.25 Meanwhile, 2 coordinates with Lewis acid to form intermediate A with higher nucleophilicity. Intermediate B is then generated via the 1,4-conjugate addition between intermediate A and o-AQM, followed by alkyne–allene isomerization to give the intermediate C. Finally, a proton transfer followed by an intramolecular nucleophilic attack of the oxygen anion of the intermediate C yields the intermediate D,26 which further transforms to desired product 3via 1,5-H shift and releases the Lewis acid. In order to further elucidate the reaction mechanism, we also carried out theoretical investigations. Detailed information is presented in ESI Fig. S4.†26
To demonstrate the synthetic versatility of 2,3,4-multi-functionalized iminochromene in resembling biological frameworks27 as well as photosensitive molecular assemblies,28 further pursuit of organic transformations was performed to show the accomplishment of multi-functionalized coumarins (Scheme 5). An iodine-promoted hydrolysis allowed the formation of coumarin 8 in 92% yield (Scheme 5a). Alternatively, the same product was able to be obtained in 78% yield when 1a was treated with 2r under standard reaction conditions. A method of accessing 1,5-dihydro-2H,4H-pyrano[3,4-c]iminochromenes is also shown in Scheme 5b (products 9aa, 9na and 9qa). The pyrano-embedded product 9aa was unambiguously confirmed by single crystal X-ray crystallography (CCDC 2184629†).
Footnote |
† Electronic supplementary information (ESI) available: Detailed experimental procedures, characterization data and copies of the NMR spectra. CCDC 2184624, 2184625 and 2184629. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2sc04431e |
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