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Catalytic Arene meta-C–H Functionalization Exploiting a Quinoline Based Template Uttam Dutta, ATANU MODAK, Bangaru Bhaskararao, Milan Bera, Sukdev Bag, Anirban Mondal, David W. Lupton, Raghavan B. Sunoj, and Debabrata Maiti ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00247 • Publication Date (Web): 17 Mar 2017 Downloaded from http://pubs.acs.org on March 17, 2017
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Catalytic Arene meta-C–H Functionalization Exploiting a Quinoline Based Template Uttam Dutta,a,b,c Atanu Modak,a Bangaru Bhaskararao,a Milan Bera,a Sukdev Bag,a Anirban Mondal,a David W. Lupton,b,c,* Raghavan B. Sunoj,a,* and Debabrata Maiti a,b,* a
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India IITB-Monash Research Academy, IIT Bombay, Powai, Mumbai 400 076, India c School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
b
Supporting Information Placeholder Abstract: Strong s-coordination by a heteroatom containing directing group (DG) is one of the effective strategies for performing site selective C-H functionalization. Despite tremendous progress in directed ortho-C-H functionalization, selective meta-C-H functionalization using strong s-coordination remains extremely challenging. Herein, we introduce 8-nitroquinoline based DG to ensure the formation of a stable palladacycle which enables selective meta-alkenylation and acetoxylation of arenes. Kinetic experiments, ESIMS, NMR and DFT studies provided important information regarding the mechanism of the reaction. The scalability as well as diversification of the product have been examined and are expected to be beneficial in pharmaceutical and material sciences. KEYWORDS: meta-C-H Activation, Olefination, Acetoxylation, Palladium, DFT
INTRODUCTION Transformation of inert carbon-hydrogen (C-H) bonds into carbon-carbon (C-C) and/or carbon-heteroatom (C-X) bonds arguably defines one of the most concise approaches for the synthesis of functional group enriched arenes which are ubiquitous in pharmaceuticals, agrochemical, material science and complex natural products.1 Selective C-H functionalization posed the major challenge in this realm. In this context, DGassisted transition metal catalyzed C-H functionalization have been developed to discriminate energetically comparable C-H bonds in the arene. In case of ortho functionalization, chelation assistance by heteroatom bearing DGs successfully allow energetically favourable 5 or 6 membered metallacycle formation.2 In this regard, pioneering work has been carried out by Dauglish and co-workers for arylation using 8-aminoquinoline as directing group.3 Since then, pyridine and quinoline has been significantly utilized in directed ortho-C-H functionalization as well as aliphatic C-H activation.4 In sharp contrast, meta- and para-C-H activation remains much less explored.5 Nevertheless, such C-H activation can be achieved by exploiting non directed steric and electronic control.6 In addition, directed orthometallations can be exploited that either perturb electronic properties,7,8,9 or are coupled with Catelani-chemistry,10,11,12 to ultimately allow meta-functionalization. Recently, hydrogen bonding strategies have been developed by Kanai, to allow metaC-H activation via transiently formed intermediate.13 The capacity to form macrocyclic structures represents an alternative approach to the challenge of directed meta-C-H functionalization. Elegant approaches from Yu and co-workers using nitrile based templates for meta-C-H functionalization have been instrumental in the development of the field.5a-c,14 Extending this concept,
progress has been made, with one example from the Tan group,15 several examples from our group,16 as well as the Li group17 relying on the weak end-on coordination of the cyano group. This weak coordination is inherently competitive with solvents and other coordinating reagents, thus the efficacy of the DG can be undesirably affected. To address this limitation the Yu and our group demonstrated the use of pyridyl DGs which allow metaC-C bond and C-I bond formation.18 Herein, we wish to report the discovery of the sulfonate linked 8-nitroquinoline based strong σ donating DG for meta-C-H functionalization. The methodology used in C-C and C-O bond forming reactions as well as computational and mechanistic studies, derivatization and scale up are examined.
Scheme 1. Overview of present work
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RESULT AND DISCUSSION Design of the quinoline scaffold for meta-C-H activation builds upon our, and others, earlier studies exploiting ester linked nitrile materials.12-15 While linking the pyridyl DG via an ester was examined, we observed the formation of meta-alkenylated products with very low selectivity and transesterification caused premature removal of the DG. As a replacement; we envisaged the incorporation of a sulfonyl linker. It was postulated that steric and electronic repulsion between the two oxygen atoms, and the sp3 nature of the sulfur should enhance meta-projection and establish close vicinity between the donor atom and the phenyl ring. To our delight, a remarkable improvement in metaselectivity was obtained using the sulfonyl linker, allowing a 56% yield of meta-olefinated product.
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Encouraged by this finding, we examined substituted pyridyl DGs DG2-DG4 (Table 1). Switching to quinoline directing group DG5 gave good yields and selectivity. Finally, introduction of 8substituents, in the form of either a methoxy or nitro group enhanced the yield to 81% and 86%, respectively. It was reasoned that the secondary assistance by the oxygen atom of the nitro or the methoxy group can help metal binding and hence facilitate the formation of meta-olefinated product. Finally, the importance of connectivity was examined with 1,3- and 1,4- linked substrates (DG8 and DG9) proving inadequate for the reaction.
Table 3. Scope of Benzyl Sulfonate Ester
Table 1. DG and Connectivity Optimization
Yields in parenthesis are based on recovered starting material; mono:di ratio determined by 1H-NMR Yields and ratio determined by 1H-NMR using trimethoxybenzene as internal standard
Table 4. Scope with Appended Complex Molecule
Subsequent optimization was performed with the 8nitroquinoline DG (i.e. DG7). Changing the standard conditions (eq. 1) to room temperature with a decrease in silver acetate (2 equiv.) as oxidant and exploiting a mixture of HFIP and DCE as the solvent (See supporting information; Table S1 to S8) were required to achieve the desired functionalization of 1a in synthetically useful yields and selectivity.19 Various terminal olefins and internal olefins (Table 2) were successfully employed with excellent selectivity for meta-olefination using the present scaffold.
Table 2. Olefination Scope
Table 5. Scope of Homo- and Hetero-Diolefination
yields in paranthesis are based on recovered starting material, a. 80 °C, b. 120 °C in HFIP, mono:di ratio determined by 1H-NMR
The scope with substituted arenes was examined to probe the electronic and/or steric influence on the product distribution (Table 3). A gram scale reaction was performed with 3-methyl sulfonate ester moiety (4c) to demonstrate the scalability of the method. The compatibility of the protocol with substrates bearing complex partner such as acrylic ester of a-tocoferol, thymol
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acrylate, isoboronyl acrylate and dicyclopentanyl acrylate provided the olefinated product in good to excellent yields (Table 4) and with complete meta selectivity. The mono olefinated products were further treated with olefins and produced the desired meta-diolefinated product with exclusive meta-selectivity (Table 5).
MECHANISTIC STUDY 3000 2500
Table 6. Scope of Acetoxylation Intensity
O S O O
H3 C N
2000
O
O N
Pd
565.9875
567.9876
N
564.9890
566.9897 568.9904
m/ Z 566
1500
563.9838
569.9893
1000 500
a
540
reaction performed at 100 °C, breaction run for 36 h
Scheme 2. Utility of meta-functionalized products
550
m/Z
560
570
Figure 1. ESI-MS study to detect Pd-arene complex with substrate 1a in CH3CN 0.10
Substrate Conc. (mM)
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0.05 mmol 0.1 mmol
0.08
0.06
0.04
0.02 0
5
10 15 Time (h)
20
25
Figure 2. Order determination with respect to substrate
Scheme 3. Intermolecular labelling experiment
D
condition a: Pd(PPh3)2Cl2, PPh3, K2CO3, toluene, 100 °C; condition b: Pd2(dba)3, DPPF, tBuONa, toluene, 100 °C; condition c: Pd(OAc)2, PPh3, K3PO4, DMSO, 80 °C
phenyl methane sulphonate and 75% acetoxylated product was isolated with excellent meta-selectivity using PhI(OAc)2 After succeeding in olefination reaction we examined the versatility of the scaffold and successfully achieved the metaacetoxylation products in useful yields. Initial study was carried out with unsubstituted as the acetoxylating reagent. Under the optimized conditions, the substrate scope with differently substituted arenes were explored (Table 6). Utilization of the meta-functionalized products generated from this protocol can be further demonstrated by converting the olefinated and acetoxylated intermediates to synthetically versatile compounds (Scheme 2).
SO 2 DG7 1 D D D
D
D D
SO2 DG7
SO 2 DG7
CO2Et olef ination reaction condition
D-1
pH/ pD - 2.9
CO2Et 2a
+
D D
D D
D
D
SO2 DG7
CO 2Et D-2a
In order to gain mechanistic insight, the reaction progress was monitored by NMR.19 Stoichiometric addition of palladium acetate and ligand to the model substrate 1a resulted in a downfield shift of 8-nitroquinoline protons indicating the involvement of quinoline group in the coordination to the metal. ESI-MS study reveals the formation of C-H activated complex, [CH3CN-Pd-1a] with palladium acetate, ligand and model substrate 1a in CH3CN (Figure 1). Observation was further confirmed by solvated Pd(OAc)2 in CD3CN with 1a as well as with m-tolylmethanesulfonate ester substrate (3c) in CH3CN.19 Kinetic studies revealed the first order rate dependency on substrate (Figure 2) and zero order dependency with respect to the olefin.19-20 From intermolecular competition experiment, pH/pD is found to be 2.9 (Scheme 3) and KH/KD is 1.9. The mechanistic investigations on the catalytic cycle (Scheme 4 and Figure 3) was carried out by using DFT method with the M06 functional.21 In line with earlier reports on Pd-catalyzed meta-C–H activation, we have examined the role of the N-
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protected amino acid by computing the energies of various intermediates and transition states involved in the catalytic cycle.14b,c As noted earlier, the solvent HFIP is considered as a coordinating ligand in the early states of the reaction.16d While the mechanism of the reaction can be broadly viewed as consisting of three major steps such as the C-H activation, olefin insertion and b-hydride elimination, other elementary steps are equally important to develop a comprehensive view of the actual catalytic event. The combination of palladium acetate and N-acyl amino acid is considered first toward the formation of a chelated species I (Scheme 4).19 Species I can undergo a ligand exchange wherein the AcOH is displaced by a molecule of HFIP. The uptake of a molecule of substrate by the resulting intermediate II can then be accomplished through the exchange of the second molecule of bound AcOH. The resulting catalyst-substrate complex III can now create an open coordination site by the expulsion of the weakly bound HFIP. This will enable the Pd center to develop a desirable and vital interaction with the aryl C-H bond, as shown in intermediate IV. In the next step, meta-C-H activation gives a palladated intermediate b, with weakly chelating iminol nitrogen.
Scheme 4. A plausible catalytic cycle
Figure 3: (a) Detailed mechanism of olefination using the metaC–H bond activation, and (b) the corresponding Gibbs free energy profile (kcal/mol) obtained at the SMD/M06/631G**,SDD(Pd)//M06/6-31G**,SDD(Pd) level of theory (The structures shown using the Roman numbers are described in Scheme 4) It can be noticed that in the ligand assisted C-H activation transition state [IV-b]‡, the abstraction of the meta-Caryl–H proton is facilitated by the carbonyl group of the amido moeity of the amino acid ligand.22 We note that the order of preference, based on the relative energies of the transition states, is meta > para > ortho.22 Computed relative Gibbs free energy barriers (in kcal/mol) follows the trend, meta(0.0) < para(1.0)
