Mechanistic Investigation of the Pd-Catalyzed Intermolecular

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Mechanistic Investigation of the Pd-Catalyzed Intermolecular Carboetherification and Carboamination of 2,3-Dihydrofuran: Similarities, Differences, and Evidence for Unusual Reaction Intermediates Gustavo M. Borrajo-Calleja,† Vincent Bizet,† Céline Besnard,‡ and Clément Mazet*,† †

Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland Laboratory of Crystallography, University of Geneva, 24 quai Ernest Ansermet, 1211 Geneva, Switzerland

‡

S Supporting Information *

ABSTRACT: The mechanism of the Pd-catalyzed intermolecular syn carboetherification and syn carboamination of 2,3dihydrofuran was investigated experimentally. Crystallographic, spectroscopic, and spectrometric methods have shed light on the nature of a number of catalytically competent palladium complexes. Several oxidative addition complexes as well as their cationic derivatives have been characterized by Xray diffraction analyses. In the latter, the complexes derived from 2-bromophenol displayed an unorthodox η6 binding mode of the privileged Buchwald-type dialkylbiarylphosphine ligands. The hemilabile character of this interaction was found to facilitate coordination of the polarized olefinic substrate, as evidenced by NMR spectroscopy. In contrast, coordination of the pendant sulfonyl group in the cationic complexes derived from 2-bromo-N-sulfonylated anilines prevented direct binding of 2,3-dihydrofuran. Deprotonation of these species induced aggregation of monomeric units through various weak noncovalent interactions to generate trinuclear palladium clusters. The reversibility of this process was probed by conducting crossover experiments. The nature of the alkali ion was found to strongly influence the selectivity of the assembly phenomenon. Examination of the importance of the nucleophilicity in these intermolecular reactions revealed that the switch between syn carbofunctionalization and Heck arylation of 2,3-dihydrofuran certainly arose from a zwitterionic intermediate common to both catalytic manifolds. The understanding of these reactions gained through this study should certainly favor the design of novel Pd-catalyzed transformations for related systems.

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INTRODUCTION The development of selective Pd-catalyzed intra- and intermolecular carboaminations and carboetherifications of alkenes has attracted increased interest in recent years.1 These methods enable the rapid elaboration of stereochemically complex heterocycles and provide access to structural motifs which are prevalent in numerous natural products and biologically relevant scaffolds. To date, most of the catalytic systems reported proceed by the cross-coupling of an aryl or alkenyl (pseudo)halide with an alkene equipped with a pendant N or O nucleophile (Figure 1A). The commonly accepted mechanism by which these carbofunctionalizations operate is disclosed in Figure 1B.2 After oxidative addition of the aryl halide into a Pd(0) intermediate, the resulting arylpalladium coordinates to the alkene while it undergoes ligand exchange with the deprotonated nucleophile to generate either a Pd alkoxide or a Pd amido complex. The high degree of preorganization provided by two-point binding of the olefinic substrate induces excellent stereocontrol in the subsequent syn heteropalladation step. The final product is generated upon a classical C−C bond-forming reductive elimination. A less © XXXX American Chemical Society

conventional alternative mechanism has been documented in certain occasions (Figure 1C).3 It distinguishes itself by an anti heteropalladation event after one-point binding of the alkene to the electrophilic palladium intermediate. The control of syn vs anti palladation in carbofunctionalization reactions typically depends on the nature of the ligand, the polarity of the solvent, and the coordinating nature of the counterion. We recently reported the Pd-catalyzed intermolecular syn carboetherification and syn carboamination of 2,3-dihydrofurans (2,3-dhf) using 2-halophenols and 2-halomesylated anilines (Figure 1D).4,5 The efficiency of both processes relies on the use of the privileged dialkylbiarylphosphines devised by Buchwald and co-workers.6 These reactions displayed a broad scope, and a wide spectrum of functional groups was tolerated, affording valuable tetrahydrofurobenzofuran and furoindoline derivatives. While a highly diastereo- and enantioselective variant of the carboetherification reaction was developed using in situ generated chiral bisphosphine monoxide ligands, Received: June 26, 2017

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DOI: 10.1021/acs.organomet.7b00483 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

Figure 1. (A) General equation for Pd-catalyzed carbofunctionalization of alkenes. (B) Accepted mechanism for carbofunctionalizations proceeding through syn heteropalladation of the alkene. (C) Accepted mechanism for carbofunctionalizations proceeding through anti heteropalladation of the alkene. (D) Pd-catalyzed syn carboetherification and syn carboamination of 2,3-dihydrofurans (2,3-dhf). (E) Initially proposed mechanistic hypothesis.

Figure 2. (A) Synthesis of oxidative addition complexes 4a−d using CPhos. (B) Notable crystallographic bond lengths and angles. (C) CYLview representations of 4a−c.16

C(sp2)−C(sp3) bond for the carbofunctionalizations and the related intermolecular Heck reaction is equally intriguing.9,10 Guided by the notion that gaining insight into the factors that govern the reactivity and selectivity of these transformations will be beneficial for further developments, we decided to

moderate levels of enantioselectivity were achieved in the carboamination reaction using MOP-type ligands. 7,8 Of important note, opposite diastereoselective outcomes were obtained for the syn carboetherification and syn carboamination when racemic 2-substituted 2,3-dhf was employed. The opposite selectivity observed for the formation of the new B


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Organometallics

tion of 2,3-dhf was clearly established by subjecting 4b,c (5 mol %) to the model cross-coupling reactions with 2-bromophenol (2b) and 2-bromo-N-mesylaniline (2c) (Figure 3). While the yield remained identical for 3b (94%), a notable improvement was noticed for 3a (88% vs 56% with the original procedure).4

embark on a comparative mechanistic study of the two carbofunctionalization reactions. Herein we report the results of our investigations, which provide evidence on several productive palladium complexes involved in both carbofunctionalizations. Crystallographic and spectroscopic analyses have revealed notable structural similarities and differences. Unusual coordination of the privileged dialkylbiarylphosphine ligands employed and unexpected self-aggregation of catalytically competent intermediates have been identified. Our studies also enabled us to propose a rationale for the different selectivities of C−C bond formation between the two carbofunctionalization reactions and the related intermolecular Heck process.

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RESULTS AND DISCUSSION Synthesis, Characterization, and Reactivity Study of Oxidative Addition Complexes. On the basis of our experimental results and data available in the literature, we drafted a hypothetical but plausible catalytic cycle that could account for both the carboetherification and carboamination of 2,3-dhf (Figure 1E). We believed that the reaction commenced by a classical oxidative addition into the C(sp2)−Br bond of the 2-halophenol of 2-halomesitylaniline derivatives (I → II). Subsequently, the well-documented ligand exchange using alkoxide bases was expected to generate the corresponding palladium alkoxo intermediate III, which would be followed by deprotonation of the neighboring nucleophilic site to yield complex IV.11 Although the proposed zwitterionic structure is necessarily speculative, on the basis of steric arguments, we felt that formation of neutral four-membered oxa- or azapalladacycles was less likely to occur.12 Initial deprotonation prior to ionization of the halide was also envisaged as a viable alternative to the sequence II → III → IV.13 Finally, coordination of the olefinic substrate (V) and syn heteropalladation (VI) were hypothesized to take place upstream from the more conventional C−C bond-forming reductive elimination step that delivers the cyclized product and regenerates the active Pd(0) species (VI → I). We began our study by focusing on the synthesis of oxidative addition complexes 4a−d, which were prepared following literature procedures (Figure 2A).14 In order to directly compare potential intermediates involved in both carbofunctionalization reactions, all experiments were conducted using CPhos. This ligand was found to be the best candidate for the carboamination of 2,3-dhf and the second best in the related carboetherification.4,15 These compounds were isolated in good yield as air-stable white (4a) or brown-orange (4b−d) solids. Consistent with literature precedents, their 31P{1H} NMR spectra revealed the coexistence of two isomeric structures in a ratio of typically >9:1 (4a, δ 29.9 ppm; 4b, δ 36.2 ppm; 4c, δ 34.6 ppm; 4d, δ 34.3 ppm).17 Single crystals of sufficient quality for X-ray diffraction analyses were obtained for 4a−c (Figure 2B,C). All three complexes exhibit a distorted-square-planar geometry around the palladium atom with a typical Cipso coordination of the lower ring of the dialkylbiarylphosphine ligand.17 This interatomic distance decreases gradually from 4a to 4c, while the trans-disposed Pd−Ar bond length increases proportionally. Similarly, the lower aryl ring of the biaryl ligand is bent farther away from the palladium atom as the Pd−Cipso distance shortens (18.2 < |α| < 22.5 in Figure 2). These slight structural changes may result from increased steric effects of the ortho substituents in 4b,c. The relevance of the oxidative addition complexes in the carboetherification and carboamina-

Figure 3. Evaluation of the oxidative addition complexes 4b,c in the model carboetherification and carboamination of 2,3-dhf (1a) with 2b,c.

Sodium, lithium, and potassium tert-alkoxides have established themselves as privileged bases in a number of C−C, C− O, and C−N bond-forming cross-coupling processes. The synthesis of well-defined palladium alkoxo complexes finds several precedents in the literature and often proceeds by quantitative halogen metathesis of the corresponding [LnPd(Ar)(X)] complexes,11 themselves resulting from oxidative addition of Pd(0) precursors into aryl halides. Unfortunately, all our attempts to react 4b,c with alkoxide bases under a variety of reaction conditions proved unfruitful. Monitoring of these reactions by 1H and 31P{1H} NMR spectroscopy at low temperature systematically revealed the formation of multiple unidentified species along with the formation of a black precipitate attributed to decomposition into Pd(0) aggregates. These results questioned either our ability to identify transient intermediates such as III and IV or simply determine their existence in the catalytic reactions. Synthesis, Characterization, and Reactivity Study of Putative Reaction Intermediates. To circumvent this issue, an indirect route consisting of abstracting the bromide ion with a halide scavenger associated with a weakly basic and noncoordinating ion was pursued (Figure 4).10h,18 Thus, the oxidative addition complexes 4a−d were reacted with 1.2 equiv of NaBArF in dichloromethane at room temperature. After filtration and evaporation of the solvent, four new complexes were isolated quantitatively as yellow (5a,b) or bright-orange (5c,d) solids. Their 31P{1H} NMR spectra in CD2Cl2 revealed a sharp and unique singlet resonating downfield with respect to the oxidative addition precursors. Of important note, the deshielding of the signal was more pronounced for 5a,b (5a, δ 64.3 ppm; 5b, δ 68.6 ppm) than for 5c,d (5c, δ 51.3 ppm; 5d, δ 51.0 ppm). Single-crystal analyses were obtained for 5a−c, and CYLview representations of their molecular structures are depicted in Figure 4.16 As a direct consequence of bromide abstraction, the cationic complexes 5a,b exhibit an unusual η6 coordination of the lower ring of the dialkylbiarylphosphine ligand with a particularly short Pd−Cipso interatomic distance (Pd−C1 2.29 Å). The five other carbon atoms are all at a distance that is much shorter than the Pd−Cipso distance in the parent oxidative addition complexes, and overall, the aromatic ring is now bent toward the metal ion (α = +13.4°). Finally, C


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Figure 4. (A,C) Synthesis of oxidative addition complexes 5a−d using CPhos. (B,D) CYLview representations of 5a−d along with relevant crystallographic bond lengths and angles.16

while the Pd−Ar bond length is nearly identical with that measured in 4a,b, the P−Pd distance is slightly contracted. The molecular structure of 5c reveals coordination of one of the two oxygen atoms of the mesylsufonyl group to the metal center (P−O = 2.202 Å) and a more conventional but significantly shorterPd−Cipso interaction (2.348 Å vs 2.496 Å in 4c). In the infrared spectrum, the marked shift of the antisymmetric stretching frequency of the sulfonyl group between the neutral and cationic complexes is also consistent with oxygen coordination (2c, νas 1310 cm−1; 4c, νas 1322 cm−1; 4d, νas 1328 cm−1; 5c, νas 1273 cm−1; 5d, νas 1273 cm−1). Remarkably, complexes 5a−d were all found to be air-stable and could be perfectly handled under a standard laboratory atmosphere. In line with recent reports from the Buchwald group, we noted that when NMR spectra of 4a,b were recorded in more coordinating solvents such as THF-d8 and CD3CN, their resonance in 31P NMR was shifted markedly upfield (THF-d8: 5a, δ 42.7 ppm; 5b, δ 47.0 ppm; CD3CN: 5a, δ 36.6 ppm; 5b, δ 40.6 ppm), suggesting that solvent binding might prevail over η6 interaction.19 The ability of 5b,c to act as competent precatalysts for the carbofunctionalization of 2,3-dhf was evaluated in test reactions between 1a and 2b,c (Figure 5). Gratifyingly, both products were obtained in excellent yield (94% of 3a with 5b; 84% of 3b with 5c), lending credence to the ability of the cationic complexes to effect the carbofunctionalization of 2,3-dhf. Supporting Organometallic Chemistry. Reactivity toward NaOtBu. In order to further investigate the fate of 5b,c in the catalytic reactions, their reactivity with an alkoxy base was monitored by NMR spectroscopy (Figure 6). While all experiments with 5b led to complex mixtures of unidentified

Figure 5. Evaluation of the cationic complexes 5b,c in the model carboetherification and carboamination of 2,3-dhf (1a) with 2b,c.

products, when 5c was reacted with 2.2 equiv of NaOtBu, a single species (6c) was generated quantitatively within minutes at room temperature. A complex (6d) with similar spectroscopic signatures was generated by starting from 5d, and 6c,d were both isolated as beige solids after filtration. These compounds could be stored in solid form under an inert atmosphere for a few days without noticeable decomposition.20 Collectively, the analytical data accumulated and the experiments disclosed in Figure 6 provide evidence for the formation of polynuclear aggregates consisting of three units of general formula [(Na)(CPhos)Pd(2-N(SO 2 R)-C 6 H 4 )(tBuOH)(BArF)]; units were held together through weak supramolecular interactions (6c, R = Me, 6d, R = Ph). Because the spectroscopic features of 6c,d are essentially identical, for the sake of clarity, the following discussion is limited to 6c. First, upon addition of NaOtBu to 5c, a significant upfield shift of the singlet was noted by 31P{1H} NMR (5c, δ 51.3 ppm; 6c, δ 33.6 ppm). In the 1 H NMR spectrum, disappearance of the broad signal at 6.72 ppmwhich supports D


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Organometallics

Figure 6. (A) Deprotonation of 5c,d using NaOtBu. (B) Representative 1H NMR spectrum of 6c (CD2Cl2, 500 MHz, 300 K). (C) 31P{1H} NMR of 5c and 6c (CD2Cl2, 162 MHz, 300 K).

distinguishing whether this is with palladium or sodium (νas 1273 cm−1). Finally, the peaks observed at m/z 962 and 1212 by mass spectrometric analysis (MALDI-TOF) are consistent with a certain degree of aggregation in 6c (molecular ion for 5c, m/z 712). To further probe the polynuclear nature of 6c,d, two complementary experiments were carried out (Figure 7). First, after their independent preparation in two separate NMR tubes, 6c and 6d were mixed together and analyzed by 1H and 31P spectroscopy. After 15 min, an apparent triplet resonating at −3.43 ppm was detected by 1H NMR and four distinct signals in a 1:1:1:1 ratio were observed by 31P{1H} NMR. After 24 h, no change was noted. In a second experiment, equimolar amounts of 5c and 5d were mixed together and reacted with NaOtBu (2.2 equiv per Pd), leading to the exact same product distribution (Figure 7C,D). Taken together, these results support the notion that 6c and 6b are indeed oligomeric species of high symmetry. Moreover, these palladium clusters are certainly in rapid equilibrium with monomeric units which recombine into mixed species (noted 6c/d in Figure 7). Interestingly, attempts to deprotonate 5c using NaH or an organic base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) did not lead to the formation of 6c; instead, complex mixtures were observed. When KOtBu was employed, a particularly broad signal characteristic of a highly fluxional system was visible at 32.1 ppm by 31P{1H} NMR (v1/2 = 248 Hz) and four broad signals of similar intensity were detected at higher field in comparison to the TMS reference in 1H NMR (from −1.39 to −3.16 ppm). In contrast, with LiOtBu 11 and 5 sharp signals were seen by 1H and 31P NMR spectroscopy, respectively (1H

effective deprotonation of the mesylated aniline moietyis accompanied by appearance of a new singlet resonating at −3.51 ppm and integrating for ca. one proton (relative to welldefined aromatic signals, for instance).21 The formation of a [Pd−H] moiety seems to be excluded because no spin−spin coupling was observed by 31P NMR and no characteristic stretching frequency was detected by IR at around 1950 cm−1. Two-dimensional NMR analyses (COSY, HMQC, HMBC) suggest a direct connectivity with a heteroatomitself connected to a quaternary carbon atom. Taken together with the relative integrations in 1H NMR, we attribute the signal at −3.51 ppm to the H atom of the hydroxyl group of a molecule of tBuOH.22 This was further convincingly established when gradual disappearance of this resonance occurred upon addition of a 10-fold excess of tBuOD while all other signals were unaffected in 1H and 31P NMR. We tentatively ascribe the unusual shielding to pronounced ring current effects induced by neighboring aromatics and/or to intermolecular H bonding.23 Recent computational investigations by Norrby and co-workers on the role of alkoxy bases in the Buchwald−Hartwig amination are in support of this hypothesis.24 In their study, amidopalladium intermediates with hydrogen-bonded tBuOH were located at lower energy levels in comparison to the known Tshaped oxidative addition precursor [(tBu3P)Pd(Br)(Ph)].11c,25 Importantly, the inclusion of sodium in the structure of 6c was unequivocally demonstrated with the detection of a single resonance at 7.7 ppm by 23Na NMR spectroscopy (NaBArF, δ −4.3 ppm) and by the fact that addition of 15-crown-5 led to rapid decomposition of 6c. Infrared spectroscopy reveals oxygen coordination of the sulfonyl group but does not allow E


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Organometallics

Table 1. Molecular Volume of 5c and of Its Individual Componentsa entry

entity +

[(CPhos)Pd(2-NH(Ms)-C6H4)]

1 2 3

BArF−

[(CPhos)Pd(2-NH(Ms)-C6H4)]BArF

V (Å3)

rX‑ray (Å)

1090 758 1848

6.38 5.65 7.61 (7.55)b

a

Connolly surfaces assessed using OLEX2.31 The volume of 5c was obtained by adding the individual volumes of the anionic and cationic fragments. bValue in parentheses obtained by dividing the volume of the unit cell by the chemical formula unit Z.

Table 2. 1H and 19F DOSY NMR Experiments for Complex 5c in CD2Cl2 and CDCl3a entry

solvent

1 2 3 4

CD2Cl2

nucleus

D (10−10 m2/s)

rH (Å)b

8.281 7.368 5.335 5.495

6.42 7.22 7.52 7.30

1

H F 1 H 19 F 19

CDCl3

a

The samples were prepared in 5 mm Young-valve NMR tubes using CD2Cl2 or CDCl3 (0.02 M). 1H and 19F DOSY experiments were run in triplicate at 298 K using 500 and 300 MHz spectrometers, respectively. bThe hydrodynamic radius (rH) was directly calculated using the Stokes−Einstein equation (rH = KBT/6πηD).29

Figure 7. (A) Crossover experiment between 6c and 6d. (B) Simultaneous deprotonation of 5c,d. Both experiments give the same NMR spectra, which are displayed in (C) and (D). (C) Expansion of the high-field 1H NMR region. (D) 31P{1H} NMR.

As a control, the molecular weight of CPhos and four different mononuclear palladium complexes was assessed using Morris’ correlation from the diffusion coefficient measured in CDCl3 (Table 3; entries 1−5). While the estimated MWMorris values for the free ligand CPhos and the neutral oxidative addition complex 4a differed substantially from the theoretical MW, the deviation for the cationic complexes 5b−d was only minimal (

Mechanistic Investigation of the Pd-Catalyzed Intermolecular

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