Synthesis of Benzofused O- and N-Heterocycles through Cascade Carbopalladation/Cross-Alkylation of Alkynes Involving the C–C Cleavage of Cyclobutanols

We report a Pd-catalyzed route to heterocycles bearing a tetrasubstituted alkene fragment. Our approach merges the intramolecular carbopalladation of tethered alkynes with an alkylation step produced by the C–C cleavage of cyclobutanol derivatives. An alkenyl-Pd(II) intermediate has been isolated and characterized by X-ray diffraction studies. Interestingly, the nature of the tethering alkynyl chain influences the E/Z stereochemistry of the alkenyl fragment in the functionalized heterocycles.


■ INTRODUCTION
The development of Pd-catalyzed cascade reactions based on the carbopalladation of alkynes has become a direct entry to the synthesis of substituted alkenes. 1−9 Such reactions have been performed in either intra-or intermolecular fashion, with the resulting alkenyl-Pd intermediate being coupled afterward with different species, such as boronic acids, 10−12 organotin reagents, 13−18 and C-, 19 N-, 20,21 and O-nucleophiles, 22 among many others (a, Scheme 1). 23−28 Parallel studies have demonstrated the ability of Pd to perform the opening of strained cycloalkanols through βcarbon elimination (b, Scheme 1). 29,30 This process leads to a σ-alkyl-Pd(II) intermediate, which can evolve in different manners, depending on the substitution pattern of the cycloalkanol. 31−37 For instance, they can participate in further intramolecular steps, or be cross-coupled with aryl-, 38−42 alkenyl-, 43,44 and alkynylhalides, 45 or propargylcarbonates, 46 among others. 29,47,48 Therefore, cyclopropyl-or cyclobutyl alcohols can behave as alkylating reagents under the appropriate conditions.
The merging of both aspects of palladium chemistry (carbopalladation/alkylation via opening of cycloalkanols) has rarely been reported in the literature. Werz et al. disclosed an interesting cascade reaction relying on the formal anticarbopalladation of an internal alkyne, evolving through further intramolecular trapping of the alkenyl-Pd(II) intermediate by a tethered cyclopropanol moiety (c, Scheme 1). 49 Very recently, Murakami, Chen, and co-workers reported the synthesis of 2,3dihydrobenzofurans through the use of alkenyl-tethered aryliodides and benzocyclobutanols (d, Scheme 1). 50,51 With these precedents in mind, and given our interest in the topics of Pd chemistry and the processes related to C−C cleavage, 52−57 we aimed to extend the applicability of these types of cascades to the synthesis of heterocycles bearing an alkylated olefine moiety (Scheme 1).

■ RESULTS AND DISCUSSION
We studied the feasibility to perform the envisioned carbopalladation/alkylation cascade reaction employing the 2-bromoarylether 1a and the cyclobutanol derivative 2a (Table  1). Initial screening of experimental conditions revealed the formation of some amounts of the byproduct 4a, likely arising from the protodepalladation of the plausible alkenyl-Pd(II) intermediate generated upon the carbopalladation of the internal alkyne moiety. The use of 10 mol% of [Pd(dba) 2 ] along with 20 mol% of PPh 3 showed good selectivity to give the desired compound 3a in THF or toluene as solvents (entries 3 and 4, Table 1). Replacing PPh 3 by other ligands such as JohnPhos, PCy 3 , or Xantphos did not improve the yields of 3a (entries 5−7, Table 1). The increase of the amount of Cs 2 CO 3 in the reaction mixture could not suppress the protodepalladation process leading to the byproduct 4a, and other organic bases like NEt 3 precluded the formation of 3a. We tested Pd sources like Pd(OAc) 2  With the optimized conditions in hand, we proceeded to study the scope and limitations of the reaction. Several aspects were assessed: the presence of electron-donating/withdrawing groups in the haloaryl moiety, the nature and length of the chain tethering the internal alkyne, and the use of different substituted cyclobutanols.
The reactions of haloaryl ethers bearing methyl, methoxy, fluoro, or trifluoromethyl substituents with the 3,3-substituted cyclobutanol 2a afforded good yields of the expected dihydrobenzofuran derivatives 3b−3e (Scheme 2). The pyridine derivative 1g gave rise to the heterocycle 3f, albeit in moderate yield, perhaps due to competing coordination of the pyridine moiety to Pd(II). C3-unsubstituted cyclobutanol derivatives 2 were also productive in the cascade reaction, giving the functionalized dihydrobenzofuran derivatives 3g−j in comparable yields to those obtained with 2a (Scheme 2); therefore, the possible byproduct formation arising from β-H elimination processes seem to be overridden. The cyclobutanol derivative bearing a mesityl group in α-position led to mixtures where the desired compound 3k could not be identified. The compound 3l could be isolated in 44% yield from the reaction carried out employing the tertiary cyclobutanol bearing an i-Pr group.
Finally, the cross-coupling reactions of 2b and Me-or TMSsubstituted alkynyl substrates were tested. We observed that among such substrates, only the silylated alkyne was competent to deliver the desired product 3m in 56% yield (Scheme 2). Possibly, the substrate leading to 3n could experience a β-H elimination upon the carbopalladation step to render an allenyl moiety, as described in other Pd-catalyzed reactions dealing with alkyl-substituted alkynes. 58,59 In order to assess the stereochemistry of the exocyclic double bond present in the dihydrobenzofuran cores, a NOESY NMR experiment was carried out for compound 3d. The NOE contacts between the methylene group CH 2c and the o-H atoms from the Ph ring, as well as the H a of the heterocycle with the CH 2b group of the aliphatic chain, pointed out the Z-stereochemistry for these compounds (Scheme 3).
As a general feature of compounds 3a−3m, we observed their relative sensitivity to chromatography purification in either silica gel or alumina. The decomposition of the compounds could be minored by using silica gel previously deactivated with Et 3 N, and Et 3 N/hexane/EtOAc mixtures as eluents. Solutions of these compounds in CDCl 3 also evolved to more complex mixtures over time (see the Supporting Information). The instability of these compounds might be due to the migration of the exocyclic double bond to form benzofuran derivatives, a process that could be catalyzed by Lewis acids. 60 We examined the influence of the length and nature of the chain linking the 2-haloryl and alkyne fragments. The alkenylated indoline derivative 3o was obtained in good yield from the corresponding amine precursor (Scheme 4). Nevertheless, no desired product 3p was produced from the related ester starting material. Substrates with one extra carbon atom in the chain reacted smoothly under the optimized conditions to produce the six-membered heterocycles 3q and 3r. The 1 H NMR of the crude reaction mixture arising from N-  the formation of the corresponding coupling product 3s as the main component, which could be isolated in 58% yield (Scheme 5). Similarly, the oxindole derivatives 3t and 3u could be isolated in moderate yields from the reactions of the corresponding propiolamides and the C3-unsubstituted cyclobutanol 2b. The 1 H NMR spectra of compounds 3s−u showed an aromatic signal belonging to the oxindole core at a relatively low chemical shift (5.8−6.0 ppm). This shielding on H a (compound 3u, Scheme 3) is provoked by the phenyl ring on the exocyclic olefine moiety, as observed in related structures reported in the literature. 23,61,62 In addition, the NOESY NMR analysis of 3u also confirmed the E-stereo-chemistry of the exocyclic double bond. The presence of minor Z-stereoisomers in the reaction mixtures leading to 3s−u cannot be discarded; however, we were unable to isolate such minor components of the crude mixtures and identify their nature unambiguously. The plausible mechanistic pathway for this reaction is depicted in Scheme 6. The aryl-Pd species A would form upon oxidative addition of the C−Br bond present in the starting material 1a to Pd(0) (Chart 1). Next, the intramolecular syn carbopalladation of the tethered alkyne would render the intermediate B. At this stage, Cs 2 CO 3 would assist the deprotonation of the cycloalkanol, along with the removal of the halogen ligand from the coordination sphere, allowing the formation of the alkoxide complex C. The opening of the strained cycloalkanol through β-C cleavage would render the σ-alkyl-Pd(II) intermediate D, from which reductive elimination could take place to deliver the substituted olefin 3a upon C(sp 2 )−C(sp 3 ) bond formation.
The fact that propiolamide substrates afford the Ealkenylated oxindoles 3s−u as main coupling products reveals that in those cases the alkenyl-Pd(II) intermediate, arising from the syn carbopalladation step, could undergo an isomerization process. There are several precedents in the literature of related Pd-catalyzed cascade reactions involving the syn carbopalladation of alkynes and subsequent isomerization prior to the final C−Pd bond functionalization. 14,22,25,63−67 Generally, the isomerization of the alkenyl-Pd intermediates is driven by steric factors. Nevertheless, αalkyl-substituted alkynyl substrates, such as 1a, require the use of bulky phosphine ligands (Q-Phos, X-Phos, or P t Bu 3 among others) to increase the steric hindrance around the Pd center and therefore promote the isomerization. 25,63,64 In the case of α-acyl-substituted alkynyl substrates, such as propiolamides 1m−o, the isomerization is a frequent feature in a range of different conditions, probably due to the conjugation of the alkenyl-Pd moiety and the carbonyl group, which might lower the energy barrier for the C−C rotation process (Scheme 6). 28,62,68,69 Likely the coordination of the carbonyl moiety might facilitate such processes. Nevertheless, the opposite isomerization has been observed in related systems (that is, the steric factors seemed to predominate over the possible coordination of the carbonyl group in intermediates such as E). 68,69 We carried out the reaction of substrate 1b with a stoichiometric amount of [Pd(PPh 3 ) 4 ] in CH 2 Cl 2 at 50°C for 18 h under N 2 atmosphere (Scheme 7). From the reaction mixture, the vinyl-Pd(II) complex 4 (analogous to the intermediate B) could be isolated in 84% yield. The complex 4 was subsequently heated in toluene at 100°C in the presence of cyclobutanol 2a and Cs 2 CO 3 . The 1 H NMR spectra of the crude reaction mixture confirmed the formation of the functionalized dihydrobenzofuran 3a in 70% yield.
The crystal structure of complex 4 was solved by X-ray diffraction studies (Figure 1, Chart 2). The PPh 3 ligands adopted a trans disposition. The palladium atom was in a slightly distorted square-planar environment, with a mean deviation of the Pd(II) coordination plane of 0.088 Å. The exocyclic double bond exhibited a E geometry, with the phenyl

■ CONCLUSION
In summary, we have expanded the versatility of Pd cascades relying on intramolecular carbopalladation processes through its merging with the opening of strained cycloalkanols. Thus, the carbopalladation of tethered alkynes followed by an alkylation process delivers interesting O-and N-heterocyclic cores bearing a fully substituted exocyclic double bond. In addition, we observed a different behavior of haloarylether and propiolamide substrates, being the last ones prone to afford the coupling products arising from isomerization of the alkenyl-Pd(II) intermediate.

■ EXPERIMENTAL SECTION
General Remarks. Infrared spectra were recorded on a PerkinElmer spectrum 100 spectrophotometer. High-resolution ESI mass spectra were recorded on an Agilent 6220 Accurate Mass TOF LC-MS spectrometer. Melting points were determined using a Reichert apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded on a 300, 400, or 600 MHz Bruker NMR spectrometers in CDCl 3 at 298 K (unless stated otherwise). All chemical shift values are reported in parts per million (ppm) with coupling constant (J) values reported in Hz. All spectra were referenced to TMS for 1 H NMR and the CDCl 3 solvent peak for 13 C{ 1 H} NMR. The anhydrous solvents were purchased from commercial sources and used as received. TLC tests were run on TLC Alugram Sil G plates and visualized under UV light at 254 nm. Chromatography: Separations were carried out on silica gel. The general procedures and characterization for the substrates 1a−o are included in the Supporting Information.
Representative Procedure A for the Synthesis of the Carbopalladation/Alkylation Cascade Products 3. A Carius tube equipped with a magnetic stirrer was charged with [Pd(PPh 3 ) 4 ] (16 mg, 10 mol %), Cs 2 CO 3 (51 mg, 0.17 mmol, 1.2 equiv), 3methyl,-1,3-diphenylcyclobutan-1-ol (40 mg, 0.17 mmol, 1.2 equiv), and the corresponding substrate (1a) (40 mg, 0.14 mmol). The tube was set under a nitrogen atmosphere, and dry toluene (4 mL) was added. The tube was sealed, and the reaction mixture was stirred for 16 h at 100°C. After cooling the tube, the crude was diluted with CH 2 Cl 2 (50 mL) and filtered through a plug of Celite. The filtrate was concentrated under a vacuum, and the crude mixture was purified by column chromatography to afford the desired cascade product (3a). Compounds 3a−o are sensitive to purification in silica gel chromatography; therefore, the silica gel was previously deactivated with Et 3 N. In addition, n-hexane containing 1% Et 3 N and EtOAc mixtures were used as eluents.