Csp3âCsp3 Cleavage in

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

pubs.acs.org/Organometallics

Tandem Remote Csp3−H Activation/Csp3−Csp3 Cleavage in Unstrained Aliphatic Chains Assisted by Palladium(II) ́ ez,†,# Hamid Azizollahi,†,‡,# Ivan Franzoni,§ Egor M. Larin,§ Mark Lautens,*,§ Marta Peŕ ez-Gom and Jose-́ Antonio García-Loṕ ez*,† †

Grupo de Química Organometálica, Departamento de Química Inorgánica, Universidad de Murcia, Murcia 30100, Spain Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran § Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada ‡

Organometallics Downloaded from pubs.acs.org by IOWA STATE UNIV on 02/06/19. For personal use only.

S Supporting Information *

ABSTRACT: We report here a proof-of-concept for the cleavage of unstrained remote Csp3−Csp3 bonds at room temperature assisted by a directing group, opening up new possibilities to use aliphatic carboxylic acids as suitable alkenyl coupling partners. This strategy involves the Pdmediated Csp3−H activation directed by a tethered 8-aminoquinoline group, followed by a concerted asynchronous carbene insertion into the Pd−C bond, and an unexpected β-carbon−carbon bond splitting. The insertion of a coupling partner into a Pd−C bond is a novel route to promote C−C bond cleavage, which in contrast to most common methodologies does not rely on the use of strained carbocycles.

■

INTRODUCTION The study of transition metal mediated reactions has boosted the possibilities to functionalize unreactive C−H and C−C bonds, allowing their consideration as suitable functional groups when tackling complex molecular design challenges.1,2 While the activation of remote Csp2−H and Csp3−H moieties has been made widely accessible with the help of directing groups1,3 (such as 8-aminoquinoline),4 the cleavage of C−C bonds is mainly restricted to (a) the oxidative addition of C− CN groups5 or C−C bonds present in strained cycloalkyl substrates6 to transition metals in low oxidation state (Scheme 1a); (b) chelation-assisted activation of unstrained C−Csp2 bonds5b,7 (Scheme 1b); (c) processes involving a β-carbon elimination in systems bearing a strained cycloalkyl group6 (Scheme 1c); or (d) decarboxylation or decarbonylation reactions.2j The methods dealing with unstrained Csp3−Csp3 cleavage are less common,2j,8−10 and they are related to specific moieties which, upon splitting of the Csp3−Csp3 bond, lead to cyclopentadienyl rings9 or substrates where at least one of the Csp3 atoms is bound to either a heteroatom or two carbonyl groups. Moreover, although some β-carbon elimination reactions in unstrained Csp3−Csp3 systems have been reported, they involve σ-alkyl complexes of early transition metals such as Lu, Sc, Zr, or Ti, among others.10 Nevertheless, in spite of the impressive developments achieved in the activation of C−H and C−C bonds, the synthetic methods merging the functionalization of both types of bond are still in their infancy.8i,11−14 Significantly, most of them rely on intramolecular processes taking place on conveniently designed substrates, which typically include a strained cycloalkyl moiety in order to promote the C−C cleavage step.13 With the exception of decarboxylative or decarbonylative methods, the © XXXX American Chemical Society

Scheme 1. Reported (a−c) and Novel (d) Routes for C−C Bond Cleavage Assisted by Transition Metals

limited examples of intermolecular reactions encompassing C− H/C−C activations also involve the use of a strained Received: December 17, 2018

A

DOI: 10.1021/acs.organomet.8b00920 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics cycloalkane as a coupling partner.14 Recently, Engle and coworkers found a catalytic procedure for unstrained Csp3−H/ Csp3−Csp3 cleavage where one of the Csp3 forms part of a 1,3dicarbonyl leaving group.8i Hence, further development of strategies merging Csp3−H and Csp3−Csp3 bond activations in ubiquitous unstrained aliphatic moieties remains a challenging and appealing goal. In the course of our investigations devoted to the use of Pd in organic synthesis,15 we uncovered a new path to promote the Csp3−Csp3 bond cleavage based on the Csp3−H palladation of acyclic alkyl chains, followed by the insertion of an unstrained molecule, a carbene in this case (Scheme 1d).

yield of alkene 6a was obtained, which corresponded to a stoichiometric transformation. The likely reason underlying the inability of Pd to restart the catalytic cycle relies on the nature of the proposed Pd species 5, generated upon the C−C bond cleavage. We have isolated the Pd species arising from the stoichiometric reaction, finding that it did not further react with ligands such as PPh3, picoline, t-BuNC, phenanthroline, or diphenylphosphinoethane (DPPE). Solid 5 was partially soluble in common organic solvents, and its 1H NMR spectrum in CDCl3 showed multiple overlapped signals in the aromatic region (see the Supporting Information). The spectrum did not change in more polar solvents such as d6-DMSO. The mass spectrometry + ESI of a sample of 5 in CH2Cl2 showed a broad range of peaks up to more than 1000 m/z ratio. The spectrum showed an intense peak at 145.070 m/z, which could correspond to the 8aminoquinoline moiety (M + H+ = 145.076) generated upon fragmentation of species 5. The IR spectrum of 5 showed an intense band at 1733 cm−1, presumably corresponding to the stretching of the CO bond present in the amide moiety attached to the quinoline ring. With these data in hand, we tentatively propose that the solid 5 might be composed by a mixture of Pd-coordination oligomers containing N-(quinolin8-yl) acetamide units. In addition, we performed the reaction of species 5 with CO in MeOH at 70 °C for 16 h (Scheme 3) and observed the

■

RESULTS AND DISCUSSION We were interested in the reactivity of palladacycle 2a, arising from the Csp3−H activation of alkyl-substituted 8-aminoquinoline 1a, toward carbene precursors such as diazo compound 3a (Scheme 2).16 Thus, we started our study by Scheme 2. Reactivity of Palladacycles 2a and 2b toward Diazocompound 3a

Scheme 3. Reactivity of Species 5 toward CO

reacting complex 2a with compound 3a in toluene at 90 °C under inert atmosphere. The reaction was repeated in MeCN at 80 °C and in CH2Cl2 at room temperature finding similar results. To our surprise, no alkenylated derivative arising from a possible β-hydrogen elimination (Scheme 1d) was detected in the reaction mixture. Instead, terminal alkene 6a (Scheme 2) was the main produced product. Apparently, plausible intermediate 4a, arising from the carbene insertion into the Pd−C bond present in palladacycle 2a, did not evolve through the expected β-hydrogen but through a β-carbon elimination, affording alkene 6a. To further confirm the origin of the coupled moieties in this transformation, we performed the reaction of palladacycle 2b, bearing a methyl group on the palladated carbon. Indeed, the reaction generated a mixture of E/Z isomers of alkenes 6b in a 7:1 ratio (Scheme 2). The unexpected coupling of alkyl substituted 8-aminoquinoline amides 1 with the diazocompound 3 represents a novel entry to the synthesis of alkenes. Furthermore, this process encompasses a) a remote Csp3−H activation, and b) a carbene insertion and Csp3−Csp3 cleavage at room temperature. In contrast to other approaches merging C−H and C−C bond cleavage reported to date,13 none of the coupling partners bear a strained cycloalkyl moiety to promote the C−C bond splitting step. We tried to perform the coupling reaction of amide 1a and diazo compound 3a in a catalytic fashion by using a 10 mol % of a Pd(II) source under a wide range of conditions (see the Supporting Information). Unfortunately, a maximum of 10%

formation of palladium black. From the crude reaction mixture we could isolate and characterize the methyl ester 10, likely arising form methoxycarbonylation of the 8-amidoquinolinePd unit contained in 5, along with N-(quinolin-8-yl)acetamide 11, formed upon protodepalladation of the Pd−CH2 bond in that unit. It is likely that the stability of species 5 prevents the coordination of a new molecule of substrate 1a, a key step to allow the catalytic cycle to proceed. We decided to continue investigating this novel transformation since the Csp3−Csp3 cleavage is an underexplored research area, where stoichiometric organometallic chemistry can shed light and set the basis for future catalytic developments. In addition, stoichiometric organometallic studies have made possible challenging coupling reactions, finding applications in the synthesis of natural products and pharmaceuticals.17 We then performed the reaction of substrate 1a with diazo compound 3a in a one-pot, two-step procedure, thus avoiding the isolation of the palladacycle intermediate. No significant differences were found in the yield (Scheme 4). With these conditions in hand, we explored the scope of the reaction. First, we tested several diazo compounds with different substitution patterns. We found that aryl substituted αdiazocarbonyl compounds were well-tolerated, providing good yields (measured by NMR) for aryl rings containing either electron-withdrawing or -donating groups (6c and 6d, Scheme 4). When a more stabilized diazocompound bearing B


Article

Organometallics

sensitive to the bulkiness of the ester group, as observed by comparison of the outcome of the reactions of substrate 1b and methyl- or benzyl-diazocarbonyl esters (E/Z ratio, 7:1 and 9:1 respectively, for products 6b and 6h, Scheme 5). The reactions of standard phenyl diazocarbonyl ester 3a with substrates 1f and 1g, bearing a phenyl group either in the 3- or 4-position of the alkyl chain, gave none or traces of the expected coupling products, even when the second step of the reaction was carried out in MeCN at 80 °C. Nevertheless, these substrates did produce coupling products 6k and 6l when they reacted with the less sterically hindered ethyl 2diazoacetate. Curiously, in these reactions only the E isomer could be detected in the crude reaction mixture. The behavior of substrate 1h, containing a phenyl substituent in C5-position of the alkyl chain, was similar to simple alkyl substituted substrates 1b−e, affording the alkene 6m in 52% isolated yield, although only the E isomer could be observed in the crude reaction mixture. When the Ph group was located at remote positions there was no influence in the outcome of the reaction, with 1i giving a 57% isolated yield of product 6n as a E/Z mixture in a ratio >95:5 (Scheme 5). Aliphatic carboxylic acids are important moieties present in natural products, such as fatty acids, and biologically active compounds and pharmaceuticals, like biotin, ibuprofen, or gemfibrozil to name a few. Hence, we extended our study to 8aminoquinoline amide derivatives of oleic and linoleic acids 1j and 1k. The reactions of these starting materials with the diazocarbonyl coupling partner 3a led to the expected diene 6o and triene 6p, respectively, in good isolated yields (Scheme 6).

Scheme 4. Scope of the Coupling Reaction of 1a with Different Diazocompounds

two ester groups was used, the reaction afforded a poor yield of the alkene (6e, 23% NMR yield, Scheme 3). The use of the monosubstituted ethyl 2-diazoacetate rendered a 60% yield of corresponding ethyl acrylate 6f. Diphenyl diazomethane proved unproductive under these reaction conditions, rendering intermediate complex 2a as the main reaction product. Next, we moved to evaluate the Csp3−Csp3 cleavage of 8aminoquinoline amides containing longer alkyl chains (Scheme 5). We observed that the reaction proceeded smoothly with Scheme 5. Scope of Substrates 1 and Diazocompounds

Scheme 6. Use of Oleic and Linoleic Acid Derivatives

To evaluate the factors governing this transformation, we performed the reaction of pivalic acid derivative 1c and found that α-disubstitution on the amide hampered the reaction, giving a 34% yield of 6a (Scheme 5). We also tested the reaction of diazocompound 3a and other σ-alkyl palladacycles arising from other ligands such as 2-pivaloylpyridine or 8methylquinoline. In those cases, no alkene 6a was produced. These results point to the strong chelation of the 8aminoquinoline as a key factor that enables the C−C bond splitting to proceed smoothly. When the reaction of palladacycle 2a with 3a was carried out in the presence of PMe3, the replacement of MeCN by the PMe3 ligand in 2a took place leading to complex 2c (see the Supporting Information), avoiding the formation of 6a, which may discard outersphere mechanisms in the reaction with the diazocompound. We monitored the reaction of complex 2a with an excess of diazocompound 3a in an NMR tube under nitrogen atmosphere (Figure 1) to check the possible existence of intermediate 4a. Nevertheless, although we could observe the progressive conversion of starting materials 2a and 3a into alkene 6a, we detected only the signals corresponding to these species. Noteworthy, the reaction starts immediately upon mixture of the reagents, reaching a 30% conversion of 2a in the

derivatives arising from butyric, caproic, and capric carboxylic acids, yielding corresponding alkenes 6b, 6i, and 6j in good yields. The E/Z ratio of the products increased with the length of the alkyl chain, rising form 7:1 to >95:5 (measured by 1H NMR) when passing from 4 to 9 carbons in the aliphatic moiety of the starting materials. The E/Z ratio was also slightly C


Article

Organometallics

Figure 1. 1H NMR monitoring of the reaction of 2a and 3a in an NMR tube under N2 atmosphere at 20 °C. Species are marked with color dots as follows: complex 2a (red); diazocompound 3a (blue); alkene 6a (green); free MeCN (black).

Figure 2. Key modeled structures and computed concerted asynchronous mechanism for the formation of 6a.

first 2 min. This experiment suggests that either intermediate 4a has a very short lifetime or that the reaction proceeds in a concerted asynchronous fashion where there is no such an intermediate, as pointed out by DFT calculations (see below). Furthermore, we observed that the excess of diazocompound 3a was fully consumed after 8 h, with the appearance of a range of multiple peaks in the 3.5−4.0 ppm region, attributed to the methoxy group in a plausible polymeric material formed by reaction of the excess of diazocompound with the Pdacetamide fragment present in the reaction mixture. Moreover, when a second batch of diazocompound 3a was added to the NMR tube, it was also consumed (see the monitoring data in the Supporting Information), explaining in part why no clear signals can be identified in the NMR spectra of species 5 and

why some excess of the diazocompound is necessary to reach the full conversion of starting complex 2a into alkene 6a. In order to gain a better understanding of the underlying mechanism for this transformation, a computational study was carried out.18 We first studied the reactivity of postulated palladacycle intermediate 4a toward either β-hydride or -carbon elimination processes (Scheme 1d). The first mechanism is precluded by an unfavorable Pd−C1−C2−H dihedral angle (63−83°) and by a poor orientation of the orbitals imposed by the cyclic nature of this intermediate. The same structural features were also at the origin of the unrealistic activation energies computed for the β-carbon elimination process (Figure 1, TS_4a_8a, ΔG⧧ = 49.5 kcal mol−1). D


Article

Organometallics

For full experimental procedures and characterization data of starting materials 1a−k, palladacycles 2a−c, and alkenes 6a−p, see the Supporting Information. Representative Procedure A: Synthesis of Starting Material 1a. Propionyl chloride (1.5 mL, 16.8 mmol) was added to a solution of 8-aminoquinoline 1 (2.0 g, 14.0 mmol) and triethylamine (2 mL) in dry CH2Cl2 (30 mL) under N2 atmosphere. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with Na2CO3 aq. (2 × 40 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed to dryness. The crude was purified by column chromatography (silica-gel, petroleum ether/EtOAc, gradient from 0 to 15% EtOAc) to afford 1a as a dense yellow oil that solidified slowly (2150 mg, 10.7 mmol, 76% yield). Mp: 30 °C. IR (cm−1) υ (CO) 1690 (s). 1H NMR (400 MHz, CDCl3) δ = 9.82 (br s, 1 H), 8.78− 8.80 (m, 2 H), 8.15 (dd, J = 8.4, 1.7 Hz, 1 H), 7.43−7.55 (m, 3 H), 2.60 (q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ = 172.4 (s, Cq), 148.0 (s, CH), 138.2 (s, Cq), 136.2 (s, CH), 134.5 (s, Cq), 127.8 (s, Cq), 127.3 (s, CH), 121.5 (s, CH), 121.2 (s, CH), 116.2 (s, CH), 31.1 (s, CH2), 9.7 (s, CH3). HR-MS (+ESI) m/z calcd for C12H13N2O [M + H]+ 201.1022, found 201.1030. These data are in agreement with the data reported in the literature.4b Representative Procedure B: Synthesis of Complex 2a. Pd(OAc)2 (448 mg, 2 mmol) and K2CO3 (553 mg, 4 mmol) were added to a solution of 1a (400 mg, 2 mmol) in CH3CN (15 mL). The resulting suspension was stirred at reflux for 16 h. The suspension was filtered through a Celite pad, the filtrate concentrated to ca. 2 mL, and Et2O (15 mL) added. The resulting suspension was filtered, and the solid was washed with Et2O (2 × 5 mL) and air-dried to give complex 2a as a yellow solid (618 mg, 2.03 mmol, 89% yield). Dec. point: 170 °C. IR (Nujol, cm−1) υ (CO) 1722 (s). 1H NMR (400.9 MHz, CDCl3) δ = 9.02 (dd, J = 8.0, 1.2 Hz, 1 H), 8.27 (dd, J = 4.5, 1.6 Hz, 1 H), 8.13 (dd, J = 8.6, 1.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.33− 7.17 (m, 2 H), 2.79 (t, J = 7.3 Hz, 2 H), 2.35 (s, 3 H), 1.77 (t, J = 7.3 Hz, 2 H). 13C NMR (100.1 MHz, CDCl3) δ = 187.0 (s, Cq), 146.7 (s, Cq), 145.7 (s, CH), 145.0 (s, Cq), 137.7 (s, CH), 129.7 (s, Cq), 129.0 (s, CH), 120.4 (s, 2 × CH), 118.3 (s, Cq), 118.1 (s, CH), 43.1 (s, CH2), 4.1 (s, CH2), 3.5 (s, CH3). Elemental analysis calcd (%) for C14H13N3OPd: C: 48.64, H: 3.79, N: 12.15. Found: C: 48.55, H: 3.74, N: 12.03. Synthesis of Complex 2b. Prepared according to the procedure B from substrates N-(quinolin-8-yl)butyramide (400 mg, 1.87 mmol) and Pd(OAc)2 (419 mg, 1.87 mmol). Data for compound 2b: yellow solid (481 mg, 1.34 mmol, 72% yield). Mp: 200 °C. IR (Nujol, cm−1) υ (CO) 1722 (s). 1H NMR (300 MHz, CDCl3) δ = 9.02 (dd, J = 7.9, 1.2 Hz, 1 H), 8.29 (dd, J = 4.7, 1.6 Hz, 1 H), 8.13 (dd, J = 8.4, 1.7 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.35−7.15 (m, 2 H), 2.97−2.82 (m, 1 H), 2.61−2.45 (m, 2 H), 2.34 (s, 3 H), 1.10 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ = 185.2 (s, Cq), 146.5 (s, Cq), 145.8 (s, CH), 144.5 (s, Cq), 137.5 (s, CH), 129.5 (s, Cq), 128.8 (s, CH), 120.4 (s, CH), 119.9 (s, CH), 118.1 (s, CH), 117.8 (s, Cq), 52.8 (s, CH2), 24.9 (s, CH3), 19.3 (s, CH), 3.3 (s, CH3). Elemental analysis calcd (%) for C15H15N3OPd·1/2 H2O: C: 48.80, H: 4.37, N: 11.40. Found: C: 48.74, H: 4.13, N: 11.16. Representative Procedure C: Synthesis of Alkene 6a from Palladacycle 2a. A 50 mL Schlenck was charged with 2a (50 mg, 0.15 mmol) and dry dichloromethane (5 mL) under N2 atmosphere, and 3a (51 μL, 0.33 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. After this period, the reaction mixture was diluted with dichloromethane (10 mL) and filtered through a Celite pad. Diethyl ether (15 mL) was added. The resulting suspension was filtered and the brown solid was air-dried to give the solid 5, containing unidentified Pd-species (see the Supporting Information). The filtrate was concentrated to dryness. The crude contained a 95% yield determined from the 1H NMR spectrum of the crude reaction mixture using 1,3,5-trimethoxycarbonyl benzene as standard. The crude was purified by preparative TLC (silica gel, 10:1 petroleum ether/EtOAc), affording compound 6a as an oil (18 mg, 0.11 mmol, 73% isolated yield). IR (cm−1) υ (CO) 1721 (s). 1H

We next studied the reactivity of the thermodynamically favored intermediate generated by reaction of palladacycle 2 with diazocompound 3a, namely, 7a (Figure 2). Our attempts to locate the transition state for the carbene insertion process connecting 2a to 4a were unsuccessful. Relaxed scans analysis of the potential energy surface by shortening of the distance between C1 (red) and C2 (blue) in 7a suggest a highly concerted asynchronous insertion/elimination process leading to olefin 6a without the intermediacy of 4a. The corresponding transition state models the formation of the C1C2 and the Pd−C3 bonds while breaking the C2−C3 bond (Figure 2). The computed activation energy for this concerted asynchronous mechanism is 17.5 kcal mol−1, a value consistent with a reaction carried out at room temperature. Corresponding product 8a undergoes ligand exchange to release the final product and the palladacycle 9. This intermediate may represent unidentified unreactive species 5 or (one of) its precursor(s). Extension of this mechanism in the case of methyl-substituted intermediate 7b was considered. Comparison of the activation energies for the two possible pathways leading to either E or Z isomer of 6b provides a theoretical ratio of 8:1 in favor of the former (ΔΔG⧧ = 1.2 kcal mol−1). This result is in remarkable agreement with the experimental 7:1 E/Z ratio obtained in the reaction between palladacycle 2b and diazocompound 3a, thus lending support for our mechanistic model for this transformation. Unfortunately, for the reasons explained above, we were unable to fully characterize proposed species 5 or 9, which would have further supported experimentally the plausible mechanism found by DFT. Hence alternative stepwise reaction pathways can not be discarded for this process, for instance involving bimetallic intermediates.

■

CONCLUSION In summary, we have discovered a new path to promote the cleavage of Csp3−Csp3 bonds present in unstrained alkyl chains by exploiting several reactivity modes of Pd(II): directed Csp3−H activation, concerted migratory insertion of a carbene moiety, and β-carbon−carbon bond cleavage. This route allows the use of aliphatic carboxylic acids as alkenyl synthons and represents a new case of study for directed C−C activation. This work may serve as a proof of concept to inspire future catalytic developments. Further studies on the reaction mechanism will be necessary to gain a deeper understanding on this transformation.

■

EXPERIMENTAL SECTION

General Considerations, Materials, and Instrumentation. 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 or 400 MHz Bruker NMR spectrometers in CDCl3 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 1H NMR and the CDCl3 solvent peak for 13C{1H} NMR. Anhydrous MeCN, CH2Cl2 and toluene 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 or neutral alumina. For those compounds where no elemental analysis is provided, clean NMR spectra are provided as a proof of bulk purity. E


Article

Organometallics NMR (300 MHz, CDCl3) δ = 7.43−7.38 (m, 2 H), 7.37−7.32 (m, 3 H), 6.35 (d, J = 1.2 Hz, 1 H), 5.88 (d, J = 1.2 Hz, 1 H), 3.82 (s, 3 H). 13 C NMR (75 MHz, CDCl3) δ = 167.3 (s, Cq), 141.3 (s, Cq), 136.7 (s, Cq), 128.3 (s, CH), 128.2 (s, CH), 128.1 (s, CH), 126.9 (s, CH2), 52.2 (s, CH3). GC-MS (+EI) m/z calcd for C10H10O2, 162.07. Found, 162.10. These data are in agreement with the data reported in the literature.19 Representative Procedure D: One-Pot Two-Step Synthesis of Alkene 6a from 8-Aminoquinolin amide 1a and Diazocompounds 3a. Step 1: A Schlenck tube was charged with corresponding substrate N-(quinolin-8-yl)propionamide 1a (100 mg, 0.5 mmol), Pd(OAc)2 (112 mg, 0.5 mmol), and K2CO3 (138 mg, 1 mmol) in MeCN (7 mL). The suspension was stirred at reflux for 16 h. Step 2: The solvent of the suspension was taken to dryness. The tube was set under nitrogen atmosphere, dry CH2Cl2 (5 mL) added, and diazocompond 3a (176 μL, 1.1 mmol) added to the reaction mixture. The mixture was stirred at room temperature for 16 h. The crude was diluted with CH2Cl2 (15 mL) and filtered through a Celite pad. The filtrate was concentrated to dryness and the crude was purified by preparative TLC (silica gel, petroleum ether/EtOAc (9:1)) to afford product 6a. Yield: 62 mg, 0.38 mmol, 76% isolated yield.

■

rapid construction and late-stage diversification of functional molecules. Nat. Chem. 2013, 5, 369−375. (c) Yang, L.; Huang, H. Transition-Metal-Catalyzed Direct Addition of Unactivated C−H Bonds to Polar Unsaturated Bonds. Chem. Rev. 2015, 115, 3468− 3517. (d) Hartwig, J. F. Evolution of C−H Bond Functionalization from Methane to Methodology. J. Am. Chem. Soc. 2016, 138, 2−24. (e) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild metal-catalyzed C−H activation: examples and concepts. Chem. Soc. Rev. 2016, 45, 2900−2936. (f) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C−H Bond Activation. Acc. Chem. Res. 2016, 49, 1389−1400. (g) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C− H Bonds. Chem. Rev. 2017, 117, 8754−8786. (h) Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnürch, M. A comprehensive overview of directing groups applied in metal-catalysed C−H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603−6743. (2) For reviews on C−C activation: (a) Jun, C.-H. Transition metalcatalyzed carbon−carbon bond activation. Chem. Soc. Rev. 2004, 33, 610−618. (b) Murakami, M.; Matsuda, T. Metal-catalysed cleavage of carbon−carbon bonds. Chem. Commun. 2011, 47, 1100−1105. (c) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Cyclobutanes in Catalysis. Angew. Chem., Int. Ed. 2011, 50, 7740−7752. (d) Ruhland, K. Transition-Metal-Mediated Cleavage and Activation of C−C Single Bonds. Eur. J. Org. Chem. 2012, 2012, 2683−2706. (e) Xu, T.; Dermenci, A.; Dong, G. Transition Metal-Catalyzed C−C Bond Activation of Four-Membered Cyclic Ketones. Top. Curr. Chem. 2014, 346, 233−257. (f) Liu, H.; Feng, M.; Jiang, X. Unstrained carboncarbon bond cleavage. Chem. - Asian J. 2014, 9, 3360−3389. (g) Souillart, L.; Cramer, N. Catalytic C−C Bond Activations via Oxidative Addition to Transition Metals. Chem. Rev. 2015, 115, 9410−9464. (h) Kondo, T. Ruthenium- and Rhodium-Catalyzed Strain-Driven Cleavage and Reconstruction of the C−C Bond. Eur. J. Org. Chem. 2016, 2016, 1232−1242. (i) Murakami, M.; Ishida, N. Potential of Metal-Catalyzed C−C Single Bond Cleavage for Organic Synthesis. J. Am. Chem. Soc. 2016, 138, 13759−13769. (j) Song, F.; Gou, T.; Wang, B.-Q.; Shi, Z.-J. Catalytic activations of unstrained CC bond involving organometallic intermediates. Chem. Soc. Rev. 2018, 47, 7078−7115. (3) (a) Topczewski, J. T.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. Palladium-catalysed transannular C−H functionalization of alicyclic amines. Nature 2016, 531, 220−224. (b) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Ligand-accelerated enantioselective methylene C(sp3)-H bond activation. Science 2016, 353, 1023−1027. (c) Liu, Y.; Ge, H. Site-selective C−H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat. Chem. 2017, 9, 1037−1038. (d) Xu, Y.; Dong, G. sp3 C−H activation via exo-type directing groups. Chem. Sci. 2018, 9, 1424−1432. (4) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regioselective Arylation of sp3 C−H Bonds Catalyzed by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154−13155. (b) Shabashov, D.; Daugulis, O. Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3 Carbon−Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 3965−3972. (c) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon−Hydrogen Bonds. Acc. Chem. Res. 2015, 48, 1053−1064. (5) (a) Tobisu, M.; Chatani, N. Catalytic reactions involving the cleavage of carbon−cyano and carbon−carbon triple bonds. Chem. Soc. Rev. 2008, 37, 300−307. (b) Chen, F.; Wang, T.; Jiao, N. Recent Advances in Transition-Metal-Catalyzed Functionalization of Unstrained Carbon−Carbon Bonds. Chem. Rev. 2014, 114, 8613−8661. (c) Xia, Y.; Wang, J.; Dong, G. Suzuki−Miyaura Coupling of Simple Ketones via Activation of Unstrained Carbon−Carbon Bonds. J. Am. Chem. Soc. 2018, 140, 5347−5351. (6) (a) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent Methodologies That Exploit C−C Single-Bond Cleavage of Strained Ring

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00920. Full experimental procedures, spectral data, DFT energy profiles (PDF) Cartesian coordinates of the optimized structures (XYZ)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ivan Franzoni: 0000-0001-8110-6218 Mark Lautens: 0000-0002-0179-2914 José-Antonio García-López: 0000-0002-8143-7081 Author Contributions #

M.P.-G. and H.A. contributed equally to this work.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Financial support from MINECO (grant CTQ2015-69568-P) and Fundación Séneca (grant 19890/GERM/15) is gratefully acknowledged. M.L. thanks the University of Toronto, Alphora Research Inc., and the Natural Sciences and Engineering Research Council (NSERC) for financial support. E.M.L thanks NSERC for a postgraduate scholarship (CGS-D). I.F. thanks the Collaborative Research and Training Experience (Create ChemNET) program for a postdoctoral fellowship. H.A. thanks Ministry of Science, Research and Technology of Iran for a Ph.D. stay fellowship. The computational studies reported herein were carried out at the Centre for Advanced Computing (https://cac.queensu.ca).

■

REFERENCES

(1) For reviews on C−H activation: (a) Alberico, D.; Scott, M. E.; Lautens, M. Aryl−Aryl Bond Formation by Transition-MetalCatalyzed Direct Arylation. Chem. Rev. 2007, 107, 174−238. (b) Wencel-Delord, J.; Glorius, F. C-H Bond Activation enables the F


Article

Organometallics Systems by Transition Metal Complexes. Chem. Rev. 2017, 117, 9404−9432. (b) Chen, P.-H.; Billett, B. A.; Tsukamoto, T.; Dong, G. Cut and Sew” Transformations via Transition-Metal-Catalyzed Carbon−Carbon Bond Activation. ACS Catal. 2017, 7, 1340−1360. (c) For an alternative example of C−C cleavage driven by strain, see Fawcett, A.; Biberger, T.; Aggarwal, V. K. Carbopalladation of C−C σ-bonds enabled by strained boronate complexes. Nat. Chem. 2019, 11, 117. (7) (a) Suggs, J. W.; Jun, C.-H. Directed cleavage of carbon-carbon bonds by transition metals: the α-bonds of ketones. J. Am. Chem. Soc. 1984, 106, 3054. (b) Jun, C.-H.; Lee, H. Catalytic Carbon−Carbon Bond Activation of Unstrained Ketone by Soluble Transition-Metal Complex. J. Am. Chem. Soc. 1999, 121, 880. (c) Xia, Y.; Wang, J.; Dong, G. Suzuki−Miyaura Coupling of Simple Ketones via Activation of Unstrained Carbon−Carbon Bonds. J. Am. Chem. Soc. 2018, 140, 5347−5351. (d) Just-Baringo, X.; Larrosa, I. Ketone C−C Bond Activation Meets the Suzuki-Miyaura Cross-coupling. Chem. 2018, 4, 1203. (e) Zhu, J.; Wang, J.; Dong, G. Catalytic activation of unstrained C(aryl)−C(aryl) bonds in 2,2′-biphenols. Nat. Chem. 2019, 11, 45−51. (8) (a) Kondo, T.; Kodoi, K.; Nishinaga, E.; Okada, T.; Morisaki, Y.; Watanabe, Y.; Mitsudo, T.-A. Ruthenium-Catalyzed β-Allyl Elimination Leading to Selective Cleavage of a Carbon−Carbon Bond in Homoallyl Alcohols. J. Am. Chem. Soc. 1998, 120, 5587−5588. (b) Niwa, T.; Yorimitsu, H.; Oshima, K. Palladium-Catalyzed 2Pyridylmethyl Transfer from 2-(2-Pyridyl)-ethanol Derivatives to Organic Halides by Chelation-Assisted Cleavage of Unstrained Csp3Csp3 Bonds. Angew. Chem., Int. Ed. 2007, 46, 2643−2645. (c) Li, H.; Li, W.; Liu, W.; He, Z.; Li, Z. An Efficient and General Iron-Catalyzed C-C Bond Activation with 1,3-Dicarbonyl Units as a Leaving Groups. Angew. Chem., Int. Ed. 2011, 50, 2975−2978. (d) Liu, Z.-Q.; Zhao, L.; Shang, X.; Cui, Z. Unexpected Copper-Catalyzed Aerobic Oxidative Cleavage of C(sp3)−C(sp3) Bond of Glycol Ethers. Org. Lett. 2012, 14, 3218−3221. (e) Cooke, H. A.; Peck, S. C.; Evans, B. S.; van der Donk, W. A. Mechanistic Investigation of Methylphosphonate Synthase, a Non-Heme Iron-Dependent Oxygenase. J. Am. Chem. Soc. 2012, 134, 15660−15663. (f) Zhao, Y.; Cai, S.; Li, J.; Wang, D. Z. Visible-light photo-catalytic C−C bond cleavages: preparations of N,N-dialkylformamides from 1,2-vicinal diamines. Tetrahedron 2013, 69, 8129−8131. (g) Chen, Y.-C.; Zhu, M.-K.; Loh, T.-P. Csp3−Csp3 Bond Cleavage in the Palladium-Catalyzed Aminohydroxylation of Allylic Hydrazones Using Atmospheric Oxygen as the Sole Oxidant. Org. Lett. 2015, 17, 2712−2715. (h) Wang, D.; Mao, J.; Zhu, C. Visible light-promoted ring-opening functionalization of unstrained cycloalkanols via inert C−C bond scission. Chem. Sci. 2018, 9, 5805− 5809. (i) Tran, V. T.; Gurak, J. J. A.; Yang, K. S.; Engle, K. M. Activation of diverse carbon−heteroatom and carbon−carbon bonds via palladium(II)-catalysed β-X elimination. Nat. Chem. 2018, 10, 1126−1133. (9) (a) Benfield, F. W. S.; Green, M. L. H. Alkyl, alkynyl, and olefin complexes of bis(π-cyclopentadienyl)-molybdenum or -tungsten: a reversible metal-to-ring transfer of an ethyl group. J. Chem. Soc., Dalton Trans. 1974, 1324−1331. (b) Eilbracht, P.; Dahler, P. Die Spaltung nichtgespannter CC-Einfachbindungen in Tricarbonyleisenkomplexen 5,5-dialkylsubstituierter Cyclopentadiene. Chem. Ber. 1980, 113, 542−554. (c) Hemond, R. C.; Hughes, R. P.; Locker, H. B. Competitive C-H and C-C Activation In the Reaction of Pentamethylcyclopentadiene with Decacarbonyldimanganese. Organometallics 1986, 5, 2391−2392. (d) Jones, W. D.; Maguire, J. A. Preparation, dynamic behavior, and C-H and C-C cleavage reactions of (.eta.4-C5H 6)Re(PPh3)2H3. Structures of (.eta.4-C5H 6)Re(PPh3)2H3, CpRe(PPh3)2H2, and CpRe(PPh3)H4. Organometallics 1987, 6, 1301−1311. (e) Crabtree, R. H.; Dion, R. P.; Gibboni, D. J.; McGrath, D. V.; Holt, E. M. Carbon-carbon bond cleavage in hydrocarbons by iridium complexes. J. Am. Chem. Soc. 1986, 108, 7222−7227. (f) Crabtree, R. H.; Dion, R. P. Selective alkane C−C bond cleavage via prior dehydrogenation by a transition metal complex. J. Chem. Soc., Chem. Commun. 1984, 1260−1261.

(10) (a) Watson, P. L.; Roe, D. C. beta.-Alkyl transfer in a lanthanide model for chain termination. J. Am. Chem. Soc. 1982, 104, 6471−6473. (b) Hajela, S.; Bercaw, J. E. Competitive Chain Transfer by.beta.-Hydrogen and.beta.-Methyl Elimination for a Model ZieglerNatta Olefin Polymerization System [Me2Si(.eta.5-C5Me4)2]Sc{CH2CH(CH3)2}(PMe3). Organometallics 1994, 13, 1147−1154. (c) Horton, A. D. Direct Observation of β-Methyl Elimination in Cationic Neopentyl Complexes: Ligand Effects on the Reversible Elimination of Isobutene. Organometallics 1996, 15, 2675−2677. (d) O’Reilly, M. E.; Dutta, S.; Veige, A. S. β-Alkyl Elimination: Fundamental Principles and Some Applications. Chem. Rev. 2016, 116, 8105−8145. (11) (a) Nairoukh, Z.; Cormier, M.; Marek, I. Merging C−H and C−C bond cleavage in organic synthesis. Nat. Rev. Chem. 2017, 1, 0035. (b) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Remote C−H alkylation and C−C bond cleavage enabled by an in situ generated palladacycle. Nat. Chem. 2017, 9, 361−368. (12) Schwarz, H. Remote functionalization of C-H and C-C bonds by ″naked″ transition-metal ions (Cosi Fan Tutte). Acc. Chem. Res. 1989, 22, 282−287. (13) (a) Aïssa, C.; Fürstner, A. A Rhodium-Catalyzed C−H Activation/Cycloisomerization Tandem. J. Am. Chem. Soc. 2007, 129, 14836−14837. (b) Seiser, T.; Roth, O. A.; Cramer, N. Enantioselective Synthesis of Indanols from tert-Cyclobutanols Using a Rhodium-Catalyzed C-C/C-H Activation Sequence. Angew. Chem., Int. Ed. 2009, 48, 6320−6323. (c) Crépin, D.; Tugny, C.; Murray, J.-H.; Aïssa, C. Facile and chemoselective rhodium-catalysed intramolecular hydroacylation of α,α-disubstituted 4-alkylidenecyclopropanals. Chem. Commun. 2011, 47, 10957−10959. (d) Masarwa, A.; Didier, D.; Zabrodski, T.; Schinkel, M.; Ackermann, L.; Marek, I. Merging allylic carbon−hydrogen and selective carbon−carbon bond activation. Nature 2014, 505, 199−203. (e) Masarwa, A.; Weber, M.; Sarpong, R. Selective C−C and C−H Bond Activation/Cleavage of Pinene Derivatives: Synthesis of Enantiopure Cyclohexenone Scaffolds and Mechanistic Insights. J. Am. Chem. Soc. 2015, 137, 6327−6334. (f) Xia, Y.; Lu, G.; Liu, P.; Dong, G. Catalytic activation of carbon−carbon bonds in cyclopentanones. Nature 2016, 539, 546− 550. (g) Wang, G.-W.; Bower, J. F. Modular Access to Azepines by Directed Carbonylative C−C Bond Activation of Aminocyclopropanes. J. Am. Chem. Soc. 2018, 140, 2743−2747. (14) (a) Cui, S.; Zhang, Y.; Wu, Q. Rh(III)-catalyzed C−H activation/cycloaddition of benzamides and methylenecyclopropanes: divergence in ring formation. Chem. Sci. 2013, 4, 3421−3426. (b) Wu, J.-Q.; Qiu, Z.-P.; Zhang, S.-S.; Liu, J.−G.; Lao, Y.-X.; Gu, L.-Q.; Huang, Z. S.; Li, J.; Wang, H. Rhodium(III)-catalyzed C−H/C−C activation sequence: vinylcyclopropanes as versatile synthons in direct C−H allylation reactions. Chem. Commun. 2015, 51, 77−80. (c) Zell, D.; Bu, Q.; Feldt, M.; Ackermann, L. Mild C−H/C−C Activation by Z-Selective Cobalt Catalysis. Angew. Chem., Int. Ed. 2016, 55, 7408− 7412. (d) Meyer, T. H.; Liu, W.; Feldt, M.; Wuttke, A.; Mata, R. A.; Ackermann, L. Manganese(I)-Catalyzed Dispersion-Enabled C−H/ C−C Activation. Chem. - Eur. J. 2017, 23, 5443−5447. (e) Liang, Y.F.; Müller, V.; Liu, W.; Münch, A.; Stalke, D.; Ackermann, L. Methylenecyclopropane Annulation by Manganese(I)-Catalyzed Stereoselective C-H/C-C Activation. Angew. Chem., Int. Ed. 2017, 56, 9415−9419. (f) Lu, Q.; Klauck, F. J. R.; Glorius, F. Manganesecatalyzed allylation via sequential C−H and C−C/C−Het bond activation. Chem. Sci. 2017, 8, 3379−3383. (g) Li, M.; Kwong, F. Y. Cobalt-Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes. Angew. Chem., Int. Ed. 2018, 57, 6512−6516. (15) For recent works see (a) Yoon, H.; Rölz, M.; Landau, F.; Lautens, M. Palladium-Catalyzed Spirocyclization through C-H Activation and Regioselective Alkyne Insertion. Angew. Chem., Int. Ed. 2017, 56, 10920−10923. (b) Pérez-Gómez, M.; HernándezPonte, S.; Bautista, D.; García-López, J.-A. Synthesis of spirooxoindoles through Pd-catalyzed remote C−H alkylation using αdiazocarbonyl compounds. Chem. Commun. 2017, 53, 2842−2845. G


Article

Organometallics (c) Franzoni, I.; Yoon, H.; García-López, J.-A.; Poblador-Bahamonde, A. I.; Lautens, M. Exploring the mechanism of the Pd-catalyzed spirocyclization reaction: a combined DFT and experimental study. Chem. Sci. 2018, 9, 1496−1509. (16) For migratory insertion of carbenes see Xia, J.; Qiu, D.; Wang, J. Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion. Chem. Rev. 2017, 117, 13810−13889. (17) (a) Brown, J. M.; Gouverneur, V. Transition-Metal-Mediated Reactions for C−F Bond Construction: The State of Play. Angew. Chem., Int. Ed. 2009, 48, 8610−8614. (b) Trzupek, J. D.; Lee, D.; Crowley, B. M.; Marathias, V. M.; Danishefsky, S. J. Total Synthesis of Enantiopure Phalarine via a Stereospecific Pictet−Spengler Reaction: Traceless Transfer of Chirality from l-Tryptophan. J. Am. Chem. Soc. 2010, 132, 8506−8512. (c) Kamlet, A. S.; Neumann, C. N.; Lee, E.; Carlin, S. M.; Moseley, C. K.; Stephenson, N.; Hooker, J. M.; Ritter, T. Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation. PLoS One 2013, 8, No. e59187. (d) Peacock, D. M.; Jiang, Q.; Hanley, P. S.; Cundari, T. R.; Hartwig, J. F. Reductive Elimination from Phosphine-Ligated Alkylpalladium(II) Amido Complexes To Form sp3 Carbon−Nitrogen Bonds. J. Am. Chem. Soc. 2018, 140, 4893−4904. (e) Messina, M. S.; Stauber, J. M.; Waddington, M. A.; Rheingold, A. L.; Maynard, H. D.; Spokoyny, A. M. Organometallic Gold(III) Reagents for Cysteine Arylation. J. Am. Chem. Soc. 2018, 140, 7065−7069. (18) The computational details and a more comprehensive discussion on the theoretical results can be found in the Supporting Information. (19) Gualandi, A.; Mazzarella, D.; Ortega-Martínez, A.; Mengozzi, L.; Calcinelli, F.; Matteucci, E.; Monti, F.; Armaroli, N.; Sambri, L.; Cozzi, P. G. Photocatalytic Radical Alkylation of Electrophilic Olefins by Benzylic and Alkylic Zinc-Sulfinates. ACS Catal. 2017, 7, 5357− 5362.

H


Csp3âCsp3 Cleavage in

Recommend Documents

Csp3âCsp3 Cleavage in