Copper-catalyzed selective C_O bond formation by oxidative α-C(sp3)_H/O_H coupling between ethers and salicylaldehydes
Graphical abstract
Introduction
Cyclic ethers are important constituents of several natural products and biologically active compounds.1 The development of an efficient methodology for the introduction of ether rings in complex organic molecules is still a challenging goal due to the substantial stability of ethers under different reaction conditions. The direct functionalization of ethers has emerged as an attractive strategy to tackle this problem.2 However, the introduction of cyclic ethers into organic molecules carrying sensitive functionalities such as an aldehyde represents a stimulating task.3 Aldehydes with their high degree of reactivity play an important role in synthetic and medicinal chemistry as key building blocks for bioactive compounds.4
Metal catalyzed coupling reactions have been successfully employed in constructing carbon–carbon and carbon–heteroatom bonds as well as for the synthesis of natural products and medicinally important molecules.5, 6
Among the developed strategies in the last decades, cross-dehydrogenative coupling (CDC) has showed significant potential applications. They have emerged as effective techniques for C–C bond formation through the direct α-C(sp3)–H bond activation/functionalization adjacent to heteroatoms.7 However, the α-C(sp3)–H bond activation of ethers for the construction of C–O bonds has been less explored.8 Recently, our group developed an efficient protocol for the selective C–O bond formation utilizing iron catalyzed reaction of salicylaldehydes with cyclic ethers.9, 9(a) Within the same field, the Phan and Corma group reported independently the application of the copper based metal–organic frameworks, while the Reddy group utilized Cu(OAc)2 catalyst for the formation of C–O bonds by the oxidative coupling of ethers with 2-carbonyl substituted phenols.9, 9(b), 9(c), 9(d) Despite these successful examples, the reported protocols suffered from certain drawbacks such as the use of an expensive and less stable iron catalyst (associated with toxic CO ligand), excess oxidant (TBHP in decane is relatively expensive in comparison with other oxidants) and limited substrate scope (applied only to cyclic ethers).9a
Furthermore, Reddy and Kappe protocol was applied only to 2-keto substituted phenols and the compatibility of 2-formyl substituted phenols under such oxidative condition was not explored.9c Aiming to overcome these drawbacks and to check the compatibility of 2-formyl group of phenols under oxidative condition, we report here a copper-catalyzed oxidative coupling reaction of ethers and salicylaldehydes. The reaction led to the formation of a diverse library of acetals without affecting the adjacent sensitive formyl group (Scheme 1).
Recent reports have demonstrated the peculiar behavior of the formyl group toward different oxidants and catalysts.10, 11 In general, aldehydes are reactive compounds, which are utilized as important building blocks for the preparation of carboxylic acids.10 Different catalysts, oxidants, and solvents have been utilized in this valuable transformation reaction (Scheme 2, Eq. 1).
The aldehyde susceptibility to oxidation led to their exploitation as starting materials for a wide array of compounds under different catalytic and oxidant conditions (Scheme 2, Eqs. 2–6).11 However, the generally accepted concept of aldehydes sensitivity toward different oxidants has been challenged with the recent results reported by our group as well as by the Patel group describing the selective synthesis of acetals, carbamates, and O-aroylation of phenols, while selectively preserving the formyl group under oxidative condition (Scheme 3, a–c).9(a), 12, 12(a), 12(b)
The inertness of the aldehyde group under these protocols will open a new avenue for the utilization of compounds carrying formyl functionality in multistep synthetic procedures under oxidative conditions.
Section snippets
Results and discussion
We started our investigation by studying the reaction between salicylaldehyde (1a) and 1,4-dioxane (2a) utilizing tert-butyl hydroperoxide (TBHP, 70 wt % in water, 3.0 equiv) as the oxidant. Initially the reaction was performed under metal free condition (Table 1, entry 1). Also the use of different commercially available inexpensive catalysts (5.0 mol %) was evaluated (Table 1, entries 2–4). Unfortunately, the reaction failed to proceed under metal free condition and no product was detected
Conclusions
A selective C–O bond formation reaction for the preparation of acetals was developed. The presented copper-catalyzed protocol differs from the previously reported methodologies by its compatibility with substrates carrying a susceptible formyl group. Functionalization of the stable α-C(sp3)–H bonds of ethers was successfully investigated utilizing a commercially available and inexpensive copper salt. Furthermore, the methodology can be applied to the selective protection of phenolic hydroxy
General procedure for the synthesis of acetals, preparation of 3a as representative example
To a flask charged with a stir bar, 1a (25.0 mg, 0.20 mmol, 1.0 equiv), CuCl (1.0 mg, 0.01 mmol, 0.05 equiv), TBHP (0.059 mL, 0.61 mmol, 70 wt % in water, 3.0 equiv), and 1,4-dioxane as ether (2.0 mL, 22.8 mmol, 112.0 equiv) were mixed at room temperature. The reaction temperature was increased to 100 °C and the reaction mixture was stirred for 15–90 min. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum yielding the crude product, which was purified
Acknowledgements
This project received generous support from the National Science Council Taiwan (NSC 99-2628-B-037-003-MY3) and the Ministry of Health and Welfare of Taiwan (MOHW103-TD-B-111-05). The authors would like to thank the Centre for Research Resources and Development (CRRD), Kaohsiung Medical University for the technical support and services in LC–MS and NMR analysis.
References and notes (14)
- et al.
Chem. Commun.
(2014)et al.Angew. Chem., Int. Ed.
(2013)et al.Angew. Chem., Int. Ed.
(2013)et al.Org. Biomol. Chem.
(2012)et al.Chem. Commun.
(2011)et al.Chem. Commun.
(2014)et al.Chem. Commun.
(2014) - et al.
J. Org. Chem.
(2013)et al.Eur. J. Med. Chem.
(2013)et al.Org. Biomol. Chem.
(2011)et al.J. Med. Chem.
(2013) - et al.
J. Org. Chem.
(2008)et al.J. Org. Chem.
(2004)et al.Org. Lett.
(2003) - et al.
Angew. Chem., Int. Ed.
(2013)et al.Chem. Rev.
(2013)et al.ACS Med. Chem. Lett.
(2013)et al.Chem. Commun.
(2013)et al.J. Am. Chem. Soc.
(2012)et al.Chem.—Eur. J.
(2012)et al.J. Chem. Soc., Perkin Trans. 1
(1997) - et al.
Chem. Soc. Rev.
(2013)et al.Chem. Rev.
(2013)et al.Angew. Chem., Int. Ed.
(2013)et al.Chem. Rev.
(2013) - et al.
Chem. Soc. Rev.
(2014)et al.Chem. Soc. Rev.
(2013)et al.Chem. Soc. Rev.
(2013)et al.Angew. Chem., Int. Ed.
(2012)et al.Chem.—Eur. J.
(2012)et al.Acc. Chem. Res.
(2012) - et al.
Org. Chem. Front.
(2014)et al.Tetrahedron
(2013)et al.Org. Lett.
(2013)et al.J. Org. Chem.
(2012)et al.Angew. Chem., Int. Ed.
(2012)et al.Chem. Soc. Rev.
(2011)et al.Proc. Natl. Acad. Sci. U.S.A.
(2006)
Cited by (16)
Construction of C–O bond via cross-dehydrogenative coupling of sp [ 3] C–H bond with phenols catalyzed by copper porphyrin
2020, TetrahedronCitation Excerpt :With the optimized conditions in hand, we explored the scope of phenol substrates with 1,4-dioxane subsequently. It was reported that 29% yield could be obtained by coupling p-methylphenol with tetrahydrofuran [19]. In our cases, the target products could not be obtained when the phenols bear electron-donating groups (EDG) such as methyl, methoxy, hydroxyl, tertiary butyl and amino in current system (Scheme S1).
Recent Progress in the Synthetic Methods of Pyrazoloquinoline Derivatives
2024, Current Organic ChemistryPhotochemical C–H acetalization of O-heterocycles utilizing phenylglyoxylic acid as the photoinitiator
2022, Photochemical and Photobiological SciencesPd-Catalyzed and ligand-enabled alkene difunctionalization: Via unactivated C-H bond functionalization
2021, Chemical Communications