Pd-catalyzed intramolecular addition of active methylene compounds to alkynes with subsequent cross-coupling with (hetero)aryl halides

We report an efficient protocol for tandem Pd-catalyzed intramolecular addition of active methylene compounds to alkynes, followed by subsequent cross-coupling with (hetero)aryl bromides and chlorides. The reaction proceeds under mild conditions, providing excellent functional group tolerance, including unprotected OH, NH2 groups, enolizable ketones, or a variety of heterocycles. Mechanistic studies point towards a catalytic cycle involving oxidative addition, intramolecular nucleophilic addition to the Pd(ii)-activated alkyne, and reductive elimination, with 5-exo-dig cyclization being the rate limiting step.


Introduction
Palladium complexes emerge as some of the most versatile homogenous catalysts with a myriad of applications in both academic and industrial research. The most prominent area of palladium catalysis, awarded with the 2010 Nobel Price to R. Heck, A. Suzuki, and E. Negishi, 1 covers cross-couplings of (hetero)aryl or vinyl(pseudo)halides with nucleophilic or organometallic partners. High efficiency of these and many other processes (e.g. Wacker oxidation) arises from the facile interconversion of palladium oxidation states through twoelectron redox chemistry. Besides the most widespread Pd(0)/ Pd(II) cycle, palladium is also able to enter radical processes or to serve as a carbophilic Lewis acid in redox-neutral transformations. The ability to mediate mechanistically distinct transformations makes palladium the catalyst of choice for the design of tandem reactions in which a single metal complex catalyzes a sequence of transformations. 2 In our research, we are focused on the development of tandem processes combining the nucleophilic addition to alkynes and subsequent cross-coupling, which give the access to a wide set of carbo-and heterocyclic systems. 3 In contrast to cross-coupling reactions, these transformations are highly underdeveloped and suffer from harsh reaction conditions (e.g. the use of strong bases), narrow substrate scope (usually limited to active aryl iodides), and poor functional group tolerance, as well as insufficient mechanistic understanding.
In the late 1980s, Gore disclosed seminal works on a novel Pd-catalyzed dicarbofunctionalization of unsaturated C-C systems through arylation with iodobenzene and intramolecular nucleophilic additions of malonates to alkylidenecyclopropanes or alkenes. 4 In subsequent accounts, the authors reported a sequential 5-exo-dig cyclization of malonates and bketoesters tethered to the alkyne moiety, followed by coupling with aryl iodides. 5 The scope of the methodology was further extended to the use of haloalkynes, 6 allyl halides and acetates 7 as coupling partners. Recently, we have developed a protocol enabling the effective reaction of much less active aryl bromides with acetylenic b-ketoesters. 8 A similar strategy, utilizing a 5endo-dig cyclization has also been applied to the synthesis of cyclopentenes 9 and indenes. 10 Propargylmalonates led to substituted cyclopropanes via analogous cyclization/coupling protocol. 11 On the other hand, propargyl-b-ketoesters underwent 5-exo-dig oxocyclization/coupling, leading to the formation of substituted furan systems due to ambident nature of enolates of b-ketoesters. 12 Interestingly, the analogous transformation involving homopropargyl-b-ketoesters possessing an internal or terminal alkyne motif clearly led to either cyclopentenes 9 or dihydropyranes, 13 respectively.
The vast majority of the known methodologies utilizing sequential Pd-catalyzed nucleophilic cyclization and cross coupling are limited to aryl iodides. Moreover, the functional group compatibility appeared very narrow, which could possibly arise from the use of a strong base. Recently, we have addressed these challenges in a transformation involving acetylenic bketoesters which readily undergo cyclization. Extension of the scope with respect to activated methylene compounds still awaits investigation. Although there are examples of such transformations involving derivatives of ketoesters and malonates (with active aryl iodides), to the best of our knowledge, cyclization/coupling of haloarenes with acetylenic derivatives of Here, we report an efficient protocol for tandem Pd-catalyzed intramolecular addition of active methylene compounds to alkynes and subsequent cross-coupling with (hetero)aryl bromides and chlorides. The methodology features excellent tolerance for functionalities present in either reaction partner.

Results and discussion
The reaction of dimethyl pent-4-yn-1-ylmalonate 1 with bromobenzene was chosen as a model transformation for the development of the reaction conditions. First, a range of Pdcomplexes of mono-and diphosphine ligands were examined using 3rd-generation Buchwald-type palladacyclic system as a platform in order to identify an active catalyst system. Optimization revealed XPhos Pd G3 as the pre-catalyst of choice. Then, the benchmark reaction was evaluated against various reaction conditions, including base, solvent, catalyst loading, temperature, and time, among others (Table 1). 14 A polar aprotic solvent appeared to be crucial for the efficiency of the cyclization. Reactions carried out in moderately polar, or nonpolar solvents (e.g. dioxane, THF, toluene) failed to proceed at all, or competitive Sonogashira coupling was observed. The best results were achieved for the reaction run for 24 h at 50 C in DMF with potassium phosphate as the base. 2 mol% of palladium complex was necessary to achieve a high yield of desired product 2.
Next, we investigated various phosphorus-substituted acetylenes as potential reaction partners. We were pleased to nd that esters, ketones, and nitriles bearing phosphoryl or phosphinoyl functions entered the reaction with bromobenzene, affording the target cyclopentanes (49-54) with moderate to good yields and complete diastereoselectivity. Compound 49 was isolated with a low yield due to difficulties in the isolation and purication.
Finally, we were pleased to nd that the developed protocol is also applicable to the remarkably less active aryl chlorides (Table 4). Both electron-rich and electron-decient chloroarenes, as well as heteroaryl chlorides (2-chloropyridine) entered the reaction, yielding the expected products in moderate to good yields (39-69%). Interestingly, electron-decient chloroarenes gave products with low diastereoselectivity, in contrast to their corresponding aryl bromides which provided the products as single isomers (except 4-nitrobromobenzene).
The postulated mechanism, based on the observations of the reaction outcome, several control experiments, and literature data, is depicted in Scheme 1. First, the bromoarene undergoes fast oxidative addition to Pd(0) complex 57 (formed upon the activation of the precatalyst with a base) 15 leading to the Table 3 Substrate scope: acetylenic active methylene compounds a a Reaction conditions: acetylenic active methylene compound (0.400 mmol), aryl bromide (0.500 mmol), K 3 PO 4 (0.600 mmol), XPhos Pd G3 (8.0 mmol, 2 mol%), DMF (1 ml), 50 C, 24 h. b Run for 4 h. c Run at 80 C for 24 h. d Run at 50 C for 2 h. Table 4 Substrate scope: aryl chlorides a a Reaction conditions: dimethyl pent-4-yn-1-ylmalonate 1 (0.400 mmol), aryl chloride (0.500 mmol), K 3 PO 4 (0.600 mmol), XPhos Pd G3 (8.0 mmol, 2 mol%), DMF (1 ml), 80 C, 24 h. formation of aryl-Pd(II) species 58 which coordinates to the alkyne moiety. Then, intramolecular nucleophilic addition to the activated unsaturated system occurs, providing vinyl-Pd(II) species 60 which undergoes facile reductive elimination affording the expected product 61 and reconstituting the Pd(0) complex 57. Although the above mechanism seems viable for the majority of the investigated reactions, for some specic combinations of substrates, alternative scenarios should also be considered. For instance, the formation of chelate 62 (possibly being in equilibrium with 59), in which palladium is bound by both alkyne and active methylene moieties, could facilitate the insertion of the Pd-arene to the alkyne (syn-carbometallation), and thus rationalize the formation of some amount of another diastereoisomer of the product with altered conguration at the exocyclic double bond (64).
Oxidative addition to Pd(0) ligated to a single electron-rich monophosphine is fast. In fact, oxidative addition of bromoarene to XPhos-Pd(0) complex proceeds within minutes at room temperature, as observed by 31 P NMR spectroscopy. Reductive elimination from Pd complexes of sterically demanding ligands is also facile. In particular, we have recently shown that the reductive elimination is not a rate-limiting step in the XPhos-Pd-catalyzed tandem cyclization/coupling of 3acetylenic b-ketoesters with aryl bromides (Scheme 2a). 8 The tandem reaction of ketoester 65 with bromobenzene is much slower than Negishi coupling of compound 66 with diphenylzinc, both proceeding through reductive elimination from a common intermediate 67. This points towards the conclusion that the cyclization step is a bottleneck of the transformation. In order to shed more light on the inuence of the structure of reagents on the reaction outcome, we compared the rate of reactions of bromobenzene with three acetylenic substratesderivatives of malonate 1, b-ketoester 65, and b-diketone 68 (Scheme 2b). As expected, malonate 1 reacted signicantly slower than ketoester 65, providing the corresponding product in only 21% yield aer 1 h, compared to 90% for 65. This is due to considerably lower C-H acidity of the malonate. Surprisingly, under identical conditions, the more C-H acidic b-diketone 68 delivered the product with only 14% yield. Competition experiments, involving pairs of acetylenic substrates (1 equiv. of each) and bromobenzene (1 equiv.) were also conducted (Scheme 2c). A reaction involving ketoester 65 and malonate 1 delivered only the product of the cyclization/coupling of 65, demonstrating the huge difference in their reactivity. Despite diketone 68 reacting slower than malonate in a parallel experiment (see: Scheme 2b), in the competition experiment it provided higher yield of the corresponding product (60% and 31%, respectively). Similarly, the cyclization of ketoester and diketone occurred at comparable rates under the competition conditions (42% and 27%, respectively), in contrast to the parallel experiment (90% vs. 14%). The remarkably slow reaction of diketone 68 could be attributed either to the lower nucleophilicity of its enolate due to extended resonance stabilization, or the capability for the formation of stable complexes with palladium. 16 The relatively stable palladium complex with diketone (or its anion) could possibly be in tautomeric equilibrium with Pd-alkyne complex suitable for intramolecular nucleophilic addition leading to 61. Thus, the involvement of arylpalladium 58 in complexation with diketone 68 could make it less available for the catalytic transformation of the more reactive ketoester 65 in the competition experiment.
Competition experiments of malonate 1 with pairs of electronically divergent bromoarenes revealed the preference for the reaction with the more electron-decient substrate (Scheme 2e). This stays in contrast with the outcome of the parallel experiments of 1 with each of the above bromoarenes showing comparable rates (Scheme 2d). Apparently, oxidative addition is not a rate limiting step, although in control experiments it determines the ratio of aryl-Pd(II) intermediates, which in turn dictates the nal product distribution.
Another factor used for better understanding the reaction mechanism is the stereochemical outcome of the transformation. All of the reactions with malonates proceeded with complete diastereoselectivity, arising from anti-carbopalladation of the alkyne moiety. Similarly, other acetylenic active methylene compounds delivered the corresponding products as single isomers, unless electron-decient bromoarenes (e.g. pbromobenzonitrile) were used as coupling partners. In this case, the isomer with the alternate conguration on the double bond was formed to some extent, suggesting an alternative pathway for these sets of substrates (Scheme 1, dashed lines).
of reaction mixtures was performed on Merck silica gel 60 F254 TLC plates and visualized with cerium molybdate stain (Hanessian's stain). 1 H, 13 C{1H}, and 19 F NMR spectra were recorded with a Bruker AV 400 spectrometer. 1 H and 13 C chemical shis are given in ppm relative to TMS. Solvent signals were used as references (CDCl 3 d H ¼ 7.26 ppm, d C ¼ 77.0 ppm) and the chemical shi converted to the TMS scale. Coupling constants (J) are reported in Hz, and the following abbreviations were used to denote multiplets: (denotes a complex pattern), dd ¼ doublet of doublets, dt ¼ doublet of triplets and br ¼ broad signal. Infrared spectra were recorded with a Jasco FTIR-6200 spectrometer. Electron ionization high-resolution mass spectra (EI-HR) were recorded with an Autospec Premier (Waters Inc) mass spectrometer using the narrow-range high-voltage scan technique with lowboiling peruorokerosene (PFK) as internal standard. Samples were introduced by using a heated direct insertion probe. Electrospray ionization high-resolution mass spectra (ESI-HR) were recorded with MALDISynapt G2-S HDMS (Waters Inc) mass spectrometer equipped with an electrospray ion source and q-TOF type mass analyzer. ESI-MS spectra were recorded in the positive ion mode (source parameters: capillary voltage 3.15 kV, sampling cone 25 V, source temperature 120 C, desolvation temperature 150 C).
Unless otherwise noted, all commercially available compounds (ABCR, Acros, Fluorochem, TCI, Sigma-Aldrich, Strem) were used as received. Phosphine ligands were purchased from Aldrich or Fluorochem, Pd(OAc) 2 was purchased from Strem. Buchwald-type 3rd-generation palladacyclic precatalysts (Ligand Pd G3) were prepared following literature procedures, 15 and showed similar reactivity to the commercial samples (XPhos Pd G3 was compared with commercial samples). Dimethyl pent-4-yn-1-ylmalonate 1 and other acetylenic active methylene compounds were synthesized by alkylation of dimethyl malonate or other C-H acids with 1iodo-pentyne, according to typical literature procedures.
General procedure A for Pd-catalyzed carbocyclizationcoupling of aryl bromides with acetylenic active methylene compounds In a drybox, a 4 ml screw-cap vial was charged with XPhos Pd G3 (6.8 mg, 8 mmol), aryl halide (0.5 mmol), K 3 PO 4 (127.2 mg, 0.6 mmol), DMF (1 ml), and a magnetic stirring bar. Then, acetylenic active methylene compound (e.g. dimethyl pent-4-yn-1ylmalonate 1) was added (0.4 mmol), the vial was tightly sealed and removed from drybox. The reaction mixture was stirred for 24 h at 50 C in a heating block, then cooled to room temperature, quenched with 20 ml of an NH 4 Cl solution, added to 10 ml of water, and extracted with MTBE (3 Â 10 ml). The combined organic phases were dried with Na 2 SO 4 , ltered, and concentrated. The crude product was puried by column chromatography on silica gel.

Conclusions
In summary, we developed an efficient protocol for tandem Pdcatalyzed intramolecular addition of active methylene compounds to alkynes, followed by subsequent cross-coupling with (hetero)aryl bromides and chlorides. The methodology features exceptional tolerance to functional groups (including unprotected OH, NH 2 , or enolizable ketones), broad applicability of aryl and heteroaryl bromides of different electronic properties, as well as a range of active methylene partners, including acetylenic derivatives of malonates, cyanomalonates, b-ketoesters, b-diketones, cyanoacetates, and organophosphorus compounds. Mechanistic studies revealed a plausible mechanism comprising oxidative addition of haloarene, nucleophilic addition to alkyne activated by coordination to aryl-Pd(II), and reductive elimination. However, for the transformations of less C-H acidic substrates (e.g. b-ketoesters, bdiketones) and electron-decient haloarenes, an alternative path involving syn-carbometallation may operate in parallel.

Conflicts of interest
There are no conicts to declare.