Iminoiodane- and Brønsted Base-Mediated Cross Dehydrogenative Coupling of Cyclic Ethers with 1,3-Dicarbonyl Compounds

A one-pot, two-step approach to prepare 2-tetrahydrofuran and -pyran substituted 1,3-dicarbonyl compounds by PhI=NTs-mediated amination/Brønsted base-catalyzed cross dehydrogenative coupling (CDC) reaction of the cyclic ether and 1,3-dicarbonyl derivative under mild conditions is reported. The reaction is compatible with a variety of cyclic ethers and 1,3-dicarbonyl compounds, affording the corresponding coupled products in moderate to good yields of up to 80% over two steps.


Introduction
Recently, there has been an increasing amount of attention toward the ultimate goal of the establishment of more sustainable organic transformations, owing to increased concerns over the impact of present chemical methods and processes on the living environment [1][2][3][4]. In this regard, the direct activation of carbon-hydrogen bonds in carbon-carbon bond forming CDC reactions has emerged as one of the most powerful and atom-economical methods in modern organic chemistry [5][6][7][8][9]. A number of transition metal salts, mainly those of Pd, Rh, Ru and Cu, in the presence of an oxidant, to effect these transformations at a variety of C-H bonds such as those at the benzylic, aryl, and alkyl C(sp 3 )-H positions have often been targeted . In the case of the latter, this has included CDC reactions at the α-C-H bond of the heteroatom in ethers, amines, and sulfides with nucleophiles catalyzed by Fe or Cu salts . More recently, the development of these reactions mediated by non-metal based catalysts has come under increasing scrutiny [62][63][64][65][66][67][68][69][70][71]. In the presence of an oxidant such as a peroxide, DDQ, TEMPO, dioxygen or hypervalent iodide reagent, a variety of carbon nucleophiles were shown to functionalize the α-carbon position of the heteroatom in amines and ethers [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. As part of our interest in the chemistry of iminoiodanes, we wondered whether this class of I(III) compounds could mediate the α-functionalization of cyclic ethers by a carbon nucleophile under basic conditions. In doing so, we discovered THF, 2-methyl tetrahydrofuran and THP shown in Scheme 1 to undergo α-C-H bond amination by PhI=NTs . This was followed by substitution at the aminal carbon center by 1,3-dicarbonyl compounds under the basic conditions. Herein, we report the details, this chemistry that provides access to 2-tetrahydrofuran and -pyran substituted 1,3-dicarbonyl compounds in up to 80% yield over two steps. Scheme 1. Iminoiodane-mediated CDC reaction of cyclic ethers with 1,3-dicarbonyl compounds.

Results and Discussion
Our investigations began with the in situ generation of 2-tosylaminotetrahydrofuran 2a from THF 1a and PhI=NTs, which was obtained in 90% yield based on 1 H-NMR measurements [95]. Subsequent treatment of this adduct with 3 equiv of ethyl benzoylacetate 3a and 10 mol % of DBU as the catalyst in THF at room temperature for 18 h gave ethyl 3-oxo-3-phenyl-2-(tetrahydrofuran-2-yl)propanoate 4a in 41% yield (Table 1, entry 1) [103,[110][111][112]. Changing the solvent from THF to diethyl ether in the second step gave a comparable product yield (Table 1, entry 2). Our subsequent studies found that the use of dichloromethane and toluene in place of THF led to higher product yields of 79% and 78%, respectively (Table 1, entries 3 and 4). However, other bases, such as Et3N, DABCO, and MTBD, in place of DBU as the catalyst, afforded lower product yields of 61% or no reaction ( With DBU as the base and toluene as the solvent, decreasing the amount of 3a from 3 to 2 or 1 equiv led to comparable product yields of 80% and 73%, respectively (Table 1, entries 8 and 9). On the other hand, a lower product yield of 67% was observed on lowering the catalyst loading of DBU from 10 to 5 mol % (Table 1, entry 10). From these results, the one-pot reaction of 1a and PhI=NTs at room temperature for 50 min followed by treating with 2 equiv of 3a in the presence of 10 mol % of DBU catalyst in toluene at room temperature for 18 h was deemed to provide the optimal reaction conditions. To define the generality of the present procedure, a series of cyclic ethers 1 and 1,3-dicarbonyl compounds 3 were tested and the results are summarized in Figure 1. These experiments revealed that reaction of 1a with a range of aryl-substituted β-ketoesters bearing electron-donating (3b-d) and electron-withdrawing (3e-h) groups proceeded well to afford the corresponding adducts 4b-h in good yields of 40%-78%. Likewise, aliphatic-substituted β-ketoesters (3i-k) were well tolerated, furnishing the corresponding targets 4i-k in yields of 32%-63%. The present methodology was also applicable to dialkyl malonates (3l-o), as well as the 1,3-dimethyl dione 3p with the corresponding products 4l-p provided in good yields of 42%-71%. This is notable, as existing transition metal-catalyzed CDC reactions of these types of 1,3-dicarbonyl compounds have been previously reported to be incompatible [60].
The influence of the cyclic ether coupling partner on the efficiency of the reaction was then assessed. For 2-methyltetrahydrofuran 1b and THP 1c, the reaction of these cyclic ethers with 3a gave the corresponding adducts 4q and 4r in 43% and 57% yield, respectively. However, no reaction was observed when either 2,3-dihydrobenzofuran 1s or dibutyl ether 1t was treated with 3a, under the standard conditions, with PhI=NTs and DBU. In the case of 1t, decomposition of the α-aminated ether intermediate was observed by both TLC and 1 H-NMR analysis of the crude reaction mixture.   At room temperature, reaction of 1a with diisopropyl malonate 3n was found to lead to 5n being isolated in 25% yield (Scheme 2). The structure of compound 5n was confirmed by single crystal X-ray analysis ( Figure 2). The isolation of this acyclic adduct led us to speculate its possible involvement as an intermediate in the α-functionalization reaction. This was further supported by re-subjecting 5n to 10 mol % of DBU under the standard conditions at 40 °C (Scheme 3, eq. 1). This test gave 4n along with a 1:1 mixture of 2a and 3n in 35% and 43% yield, respectively, with the latter two adducts being obtained, presumably, from a competitive retro-Mannich-type pathway [113][114][115][116][117][118] On-Bu n-Pr in mediating the cyclization of the 1,4 amino aldol was also supported by our findings showing the recovery of the substrate on treating it to the standard conditions in the absence of the Schiff base (Scheme 3, Equation (2)).

Scheme 2.
Reaction of 3n under optimum conditions at room temperature.
A tentative mechanism for the present iminoidane-mediated transformation under basic conditions is illustrated in Scheme 4. Using the reaction 1a with 3a as a representative example, this could involve formation of 2a on treating the cyclic ether with the PhI=NTs [95,96]. While the possible amination pathway of this step remains presently unclear, the basic conditions provided by DBU may promote ring-opening of the adduct to give the 1,4-imino alcohol intermediate Aa. Nucleophilic attack at the imino carbon center of this substrate by the enolate of 3a would deliver the amino alcohol 5a. On base-mediated deamination, the ensuing 3-methylene β-keto ester Ba might undergo 5-exo-trig cyclization involving addition of the hydroxyl moiety to the alkene bond in the adduct to provide the product 4a. Scheme 4. Proposed mechanism of CDC of cyclic ethers 1a and 1,3-dicarbonyl compounds 3a.

General Information
All reactions were performed in oven-dried glassware, under a N2(g) atmosphere at ambient temperatures, unless otherwise stated. Unless specified, all reagents and starting materials were purchased from commercial sources and used as received. PhI=NTs was prepared following literature procedures [120]. Toluene and THF were distilled over sodium/benzophenone, and 2-methyltetrahydrofuran, tetrahydropyran, CH2Cl2 and MeCN were purified prior to use by distilling over CaH2. Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 pre-coated silica gel plates (Merck, Darmstadt, Germany). Visualization was achieved by UV-Vis light (254 nm) followed by treatment with ninhydrin stain and heating. Flash chromatography was performed using Merck silica gel 60 and a gradient solvent system (EtOAc/n-hexane as eluent). Unless otherwise stated, 1 H-and 13 C-NMR spectra were measured on a Bruker AV300 or AV400 NMR spectrometer (Bruker, Fällanden, Switzerland), and chemical shifts (ppm) were recorded in CDCl3 solution with tetramethylsilane (TMS) as the internal reference standard. 1 H-NMR product yields were determined with CH2Br2 as the internal reference standard. Multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet), dt (doublet of triplets), or m (multiplet). The number of protons (n) for a given resonance is indicated by nH, and coupling constants are reported as a J value in Hz. Infrared spectra were recorded on a Shimadzu IR Prestige-21 FTIR spectrometer (Shimadzu, Kyoto, Japan). Solid samples were examined as a thin film between NaCl salt plates. Low resolution mass spectra were determined on a LCQ XP MAX mass spectrometer (ThermoFisher Scientific, San Jose, CA, USA) and reported as a ratio of mass to charge (m/z). High resolution mass spectra (HRMS) were obtained using a Finnigan MAT95XP LC/HRMS Q-TOF mass spectrometer (Waters, Manchester, UK). The 1 H-and 13 C-NMR spectra of products 4a-r and compound 5n is available in the Supplementary Materials.

Conclusions
In summary, a mild transition metal-free cross dehydrogenative coupling (CDC) synthetic route to 2-tetrahydrofuran and -pyran substituted 1,3-carbonyl compounds from commercially available cyclic ethers and 1,3-dicarbonyl derivatives has been developed. Achieved in moderate to excellent yields of 32%-80%, the synthetic method was shown to tolerate β-ketoesters, dialkyl malonates and 1,3-diones, which complements and supplements the existing transition metal approaches. The present method also shows the promising utility of other hypervalent iodine reagents other than diaryliodonium salts for transition metal-free CDC reactions. Further exploration on the utility of iminoiodanes is currently underway.