Thiocarbamate-Directed Tandem Olefination–Intramolecular

Letter Cite This: Org. Lett. 2018, 20, 1162−1166

pubs.acs.org/OrgLett

Thiocarbamate-Directed Tandem Olefination−Intramolecular Sulfuration of Two Ortho C−H Bonds: Application to Synthesis of a COX‑2 Inhibitor Wendong Li,† Yingwei Zhao,† Shaoyu Mai, and Qiuling Song* Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Boulevard, Xiamen 361021, P. R. China S Supporting Information *

ABSTRACT: A palladium-catalyzed dual ortho C−H bond activation of aryl thiocarbamates is developed. This tandem reaction initiates by thiocarbamate-directed ortho C−H palladation, which leads to favorable olefin insertion rather than reductive elimination. The oxidative Heck reaction followed by another C−H activation and sulfuration affords the dual-functionalized products. This reaction provides a concise route to the S,O,C multisubstituted benzene skeleton which could be successfully applied for the synthesis of a COX-2 inhibitor.

I

two-step processes3 are usually required to achieve this goal (Scheme 1A, right). The realization of a tandem, unsymmetrical, 2-fold C−H bond functionalization in one pot with only one catalyst would be more attractive, as this step-efficient strategy makes the creation of novel molecular scaffolds concise and efficient. However, because of the unique reaction condition for each C−H functionalization step, the cooperation of the relay catalysis is usually inefficient, and this ideal fashion therefore has rarely been achieved. Only one unprecedented example was developed by Sahoo and co-workers, who used a rationally designed olefin tethered substrate with an additional directing group in which intramolecular C−H bond activation occurred first.4 The intramolecular mode of aromatic C−H bond functionalization directed by a tethered heteroatom such as N,5 O,6 and S7 often leads to an oxidative annulation, affording benzoheterocycles (Scheme 1B, left).8 In this type of C−H activation, heteroatom not only plays the role of ligand to chelate a transition metal but is also incorporated into the final heterocycle product. The last but essential step of such a reaction is the reductive elimination of palladacycle intermediate which contains a Pd−Het covalent bond to release the product. If this process is interrupted, the combination of this intramolecular reaction with another intermolecular C−H functionalization would be possible. In contrast to this assumption, thus far, most tethered heteroatom-containing groups with suitable length act as directing groups to lead to single ortho functionalization, and no further cyclization occurred (Scheme 1B, right).9 Huang and Xia and our group had reported a readily prepared and robust thiocarbamate directing group10 which caused intramolecular C−H bond sulfuration to form benzo[d][1,3]oxathiol-2-ones. The electron-donating property of this

n recent years, directing group (DG) aided activation of aromatic C−H bond became an economic method to introduce functional groups to the aromatic rings.1 By using a single directing group, a dual C−H bond functionalization can lead to the formation of 1,2,3-trisubstituted benzenes. For this mode, symmetrical dual functionalization using an excess amount of reactant has been considerably studied2 (Scheme 1A, left). On the contrary, an unsymmetrical pattern has the problems of low reactivity and poor selectivity, and sequential, Scheme 1. Directed Dual C−H Functionalization

Received: January 9, 2018 Published: February 8, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b00089 Org. Lett. 2018, 20, 1162−1166

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Organic Letters

outcome, indicating that oxygen might not participate in the catalytic cycle (entries 10 and 11, Table 1). Having the optimized reaction conditions, we then continued to explore the substrate scope of this reaction. First, various aryl thiocarbamates were submitted to the reaction with butyl acrylate (2a). As shown in Scheme 2, the thiocarbamates with

group results in the formation of stable Pd−S covalent bond (Scheme 1C), which demonstrates a strong trend of cyclization. We envisioned that reaction of another cross-coupling reagent with this palladacycle species might make a tandem, unsymmetrical, 2-fold C−H functionalization feasible. If this is true, the one-pot, 2-fold C−H functionalization could lead to a novel and concise route for the synthesis of the valuable S,O,Cmultisubstituted benzene skeleton (Scheme 1C, right), which is widely found in many pharmacologically active molecules.11 Oxidative Heck-type olefination is probably the most widely studied reaction used in C−H bond activation to introduce a carbon chain on the aromatic ring,12 which represents an attractive strategy to access a variety of functionalized aromatic rings. We decided to choose this oxidative Heck olefination to test its compatibility with our previous intramolecular C−H bond sulfuration. Initially, O-phenyl N,N-dimethylthiocarbamate (1a) and butyl acrylate (2a) were submitted to this reaction by using Pd(OAc)2 as the catalyst, BQ as the oxidant, and AcOH/ toluene mixture as the solvent. Under these conditions, which were established in our previous C−H sulfuration, 25% of the desired dual functionalization product 3aa (butyl (E)-3-(2oxobenzo[d][1,3]oxathiol-7-yl)acrylate) was obtained (entry 1, Table 1).

Scheme 2. Substrate Scopea,b

Table 1. Effect of Reaction Parametersa

entry

catalyst

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10c 11d

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd(TFA)2 Pd2(dba)3 Pd(PPh3)4 Pd(OAc)2 Pd(OAc)2

AcOH/toluene AcOH AcOH/TFE AcOH/DMF AcOH/HFIP AcOH/HFIP AcOH/HFIP AcOH/HFIP AcOH/HFIP AcOH/HFIP AcOH/HFIP

25 22 55 trace 62 0 40 55 50 59 61

a

Reaction conditions: 0.2 mmol of 1a, 1 mmol of 2a, 0.02 mmol of Pd(OAc)2, 0.4 mmol of BQ, AcOH/HFIP (1 mL, 1:1), the reaction is carried out under air atmosphere. b1.0 mmol of 3h, 5 mmol of 2a, 0.1 mmol of Pd(OAc)2, 2 mmol of BQ, AcOH/HFIP (5 mL, 1:1) at 80 °C for 18 h.

a

Reaction conditions: 0.2 mmol of 1a, 1 mmol of 2a, 0.02 mol of Pd catalyst, 0.4 mmol of BQ, 1 mL of solvent (the volume ratio of two components is 1:1); the reaction is carried out under air atmosphere. BQ = 1,4-benzoquinone; TFE = trifluoroethanol; HFIP = hexafluoroisopropanol; TFA = trifluoroacetic acid. bIsolated yield. cUnder N2 atmosphere. dUnder 1 atm of O2.

electron-donating groups, such as alkyl (3ba and 3ca), aryl (3da), methoxyl (3ea), and methylthio (3fa) on the para position of the phenyl ring, afforded the corresponding tandem olefination−sulfuration products in moderate yields. For the aryl thiocarbamates containing electron-withdrawing groups on the para position, such as halogen (3ga−ia), acyl (3ja−la), and trifluoromethyl (3ma), satisfactory yields were also obtained. This electronic effect is quite different from the results obtained in the previous single C−H sulfuration, where electrondeficient thiocarbamates exhibited lower activity compared to electron-rich ones. The substitution on the meta position of the phenyl ring might lead to a mixture of isomers. To our delight, excellent regioselectivity was observed with these substrates, and the

Acetic acid not only leads to the C−N bond cleavage of iminium salt intermediate but also plays an important role in the C−H bond cleavage; thus, it is indispensable for the success of annulation. The cosolvents were screened first to enhance the catalytic efficiency. Removal of toluene did not give positive results (entry 2, Table 1). When the solvent combination of AcOH/HFIP was used instead of AcOH/toluene, a satisfactory yield of 62% was achieved (entry 5, Table 1). The performance of other common palladium catalysts for this reaction was also tested. These Pd(II) salts and Pd(0) complexes mostly exhibited comparable activities, except for PdCl2 (entry 6, Table 1). Reaction atmosphere did not affect the reaction 1163

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Organic Letters products with C−H sulfuration occurring adjacent to the substitute group were dominant (3na−qa). The structures of the products were unambiguously confirmed by NOESY and single-crystal X-ray analyses (see the Supporting Information). Other olefin candidates were also examined. Gratifyingly, various acrylate esters were transformed smoothly into the corresponding 7-vinylbenzo[d][1,3]oxathiol-2-ones (3ab−ad). Remarkably, unactivated styrene was also tolerated for this reaction, albeit with relatively low yield (3ae). To gain insights into the mechanism, we have to figure out which step occurs first between intramolecular sulfuration and intermolecular olefination. Starting from phenyl thiocarbamate 1a, we synthesized benzo[d][1,3]oxathiol-2-one (4a) and then subjected this sulfuration product to the reaction with butyl acrylate (2a) under the standard conditions. However, no reaction occurred (Scheme 3, eq 1). This phenomenon

Scheme 4. Proposed Mechanism

Scheme 3. Control Experiments

Scheme 5. Ortho Effect

indicated that oxathiol-2-one group could not act as a directing group for oxidative Heck olefination. Next, ortho-olefinated phenyl thiocarbamate 5ab was synthesized, and it successfully cyclized to afford 3ab in 85% yield (Scheme 3, eq 2). These two experiments clearly illustrated that the thiocarbamatedirected oxidative olefination occurred first, followed by intramolecular sulfuration. We also monitored this reaction profile by GC under standard conditions (see SI, Figure S1). The curves obtained further proved the cascade character of this reaction: the concentration of the intermediate 5aa reached to the summit (red curve in Figure S1) when the reaction proceeded 1 h and then was followed by the formation of intramolecular sulfuration product 3aa. Based on these observations and mechanistic studies in our previous work, two connected Pd0/PdII redox catalytic cycles are proposed as shown in Scheme 4. In cycle 1, the thioenolate form of 1a reacts with Pd(OAc)2 followed by ortho C−H activation to give cyclopalladium species I, which has been confirmed by HRMS. Migrative insertion of butyl acrylate into the C−Pd bond affords a Pd-containing eight-membered ring II. Subsequent β-H elimination and reductive elimination releases the intermediate product 5aa, which then participated in cycle 2. Again, another C−H palladation occurs to form complex III. Direct reductive elimination leads to the formation of the iminium salt, which reacts with acetic acid to afford the final product 3aa. The Pd0 species formed in the processes is reoxidized to PdII by BQ in the presence of acetic acid to furnish the catalytic cycles. It would be interesting to discover what would happen if one ortho position of phenyl thiocarbamate was occupied13 (Scheme 5). Cyclized benzo[d][1,3]oxathiol-2-one (4b) was obtained as the sole product. This result indicated that the ortho substituent makes the migratory insertion difficult, which transfers the reaction pathway into reductive elimination. These cases, as well as 3na−qa in Scheme 1, implied oxidative

Heck reaction is quite sensitive to steric hindrance. 2-Phenylsubstituted starting material 3c also transformed to the product 4c with the C−H activation taking place on the phenyl ring connecting to thiocarbamate, rather than the further 2-phenyl group. To further demonstrate the utility of this dual C−H activation strategy, we made some transformations on the functional groups (Scheme 6). Nucleophilic attack of an amine Scheme 6. Synthetic Transformations

led to the ring-opening of the oxathiol-2-one structure, giving omercaptophenyl carbamate 6e. Saponification also took place facilely to afford 2-hydoxyl-3-mercaptocinnamic acid 7e. SN2 reaction with methylene bromide under basic conditions could give benzo[d][1,3]oxathiole structure 8h, which can be found in some potential drugs with cytotoxic activity.11d Compound 11, which possesses an ortho S,O,C-skeleton, exhibits the highest COX-2 inhibiting activity in more than 1164

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Organic Letters Notes

1000 chromen derivative candidates that have been screened.11b Typical synthesis includes an ortho formylation followed by sulfonylation to introduce the C and S groups with tedious processes. We decided to apply our strategy to the synthesis of this potential drug molecule. Starting from 4-chlorophenol, double C−H activations directly gave 3ha (see Scheme 1). The oxidative cleavage then led to the formation of aldehyde 9. Further nucleophilic attack on the oxathiol-2-one ring with Et2NH opened the thiocarbamate ring, and subsequent methylation selectively afforded 10 in a one-pot synthesis. Final deprotection of carbamate group under basic conditions, condensation with ethyl trifluorocrotonate, and saponification eventually rendered the target molecule 11 (Scheme 7).

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We appreciate the financial support from “Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University (600005Z15J0027)”, the Natural Science Foundation of Fujian Province (2016J01064), the Recruitment Program of Global Experts (1000 Talents Plan), and the Program of Innovative Research Team of Huaqiao University (Z14X0047). We also thank the Instrumental Analysis Center of Huaqiao University for analysis support.

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Scheme 7. Application for Synthesis of COX-2 Inhibitor

In summary, we have developed a novel dual unsymmetric C−H bond activation strategy directed by a thiocarbamate group. The tandem oxidative Heck-intramolecular sulfuration realized a concise construction of an S,O,C-trisubstituted benzene skeleton with a wide substrate scope. Moreover, it could be applied to COX-2 inhibitor synthesis. Mechanistic studies showed that oxidative Heck reaction occurred first if no steric hindrance existed. Further expansion of this strategy and optimization of the reaction conditions for the application in synthesis of other useful molecules are underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00089. General procedures, product characterization, 1H and 13 C NMR spectra, and X-ray data (PDF) Accession Codes

CCDC 1574429 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Qiuling Song: 0000-0002-9836-8860 Author Contributions †

W. Li and Y. Zhou contributed equally. 1165

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