Three-Component Catalytic Carboxygenation of Activated Alkenes

Oct 19, 2017 - A novel cascade Cp*Rh(III)-catalyzed C–H alkylation/Cu(II)-promoted α-oxygenation which enabled a three-component carboxygenation of...
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Letter Cite This: Org. Lett. 2017, 19, 5868-5871

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Three-Component Catalytic Carboxygenation of Activated Alkenes Enabled by Bimetallic Rh(III)/Cu(II) Catalysis Shang-Shi Zhang,† Jie Xia,† Jia-Qiang Wu, Xu-Ge Liu, Chu-Jun Zhou, E. Lin, Qingjiang Li, Shi-Liang Huang,* and Honggen Wang* School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China S Supporting Information *

ABSTRACT: A novel cascade Cp*Rh(III)-catalyzed C−H alkylation/Cu(II)-promoted α-oxygenation which enabled a three-component carboxygenation of activated alkene is reported. Mild reaction conditions, broad substrate scope, and good functional group tolerance were observed. The synthetic utility of the protocol was showcased by the facile transformations of the product to a variety of structurally diverse molecules. Preliminary mechanistic studies were conducted.

T

pioneered a three-component difunctionalization of alkenes using two different coupling partners, thereby leading to rapid construction of complex products in a single reaction (path e).6 We have long been interested in relay catalysis combining C− H activation and other catalytic reactions for efficient multibond-forming reactions.7 The high atom economy8 and pot economy9 associated with these reactions render them highly appealing in organic synthesis. In view of the recent advances in copper-catalyzed α-oxygenation of carbonyl compound with TEMPO,10 we thus envisioned whether we could realize a Rh(III)/Cu(II) relay catalysis to achieve a one-pot carboxygenation of α,β-unsaturated carbonyl compounds. In this reaction design, the organometallic species Int-1 derived from C−H activation/migratory insertion sequence is expected to undergo transmetalation to generate an organocopper Int-2, which could then react with free radical TEMPO to deliver the α-oxygenated carbonyl compound (path f). To test the feasibility of our working hypothesis, the reaction of 1-(pyrimidin-2-yl)-1H-indole 1a, acrolein 2a, and TEMPO was chosen as the model reaction. By using [Cp*RhCl2]2 (2.5 mol %) as catalyst in the presence of 1.0 equiv of Cu(OAc)2·H2O in DCE at 60 °C under air, the desired carboxygenation product 4aa was formed in 56% yield, together with significant amount of alkylation (5) and alkenylation (6) side products, that arose from protonation and β-H elimination, respectively (Table 1, entry 1). The structure of 4aa was unambiguously confirmed by X-ray crystallographic analysis.11 Whereas the switch of solvent to DMF led to the predominant formation of alkenylation product 6 (entry 2), the use of protic solvent MeOH gave mainly the alkylation product 5 (entry 3). Further screening showed that CH3CN was the solvent of choice, in which the competing protonation and β-H elimination pathways could be largely suppressed (entry 4). A moderate yield of 4aa was obtained when lowering the loading of Cu(OAc)2·H2O to 0.2 equiv (entry 5).

ransition-metal-catalyzed direct C−H bond functionalization has proven to be a powerful strategy for the rapid and efficient construction of diverse C−C and C−X bonds.1 In this regard, alkenes, for their versatile reactivities in metal catalysis, have been frequently employed as a coupling partner to effect straightforward C−C bond formation reactions. Mechanistically, several different reaction modes were feasible. After the metalcatalyzed C−H activation and alkene migratory insertion, the formed organometallic species Int-1 would typically undergo βH elimination to provide the oxidative Heck reaction product (Scheme 1, path a).2 With judicious selection of a directing Scheme 1. Reaction Modes with Alkene as Coupling Partner in Transition-Metal-Catalyzed C−H Activation Reaction

group, coupling partner, or metal catalyst, direct alkylation was realizable upon protonation of the carbon metal bond (path b).3 On the other hand, with specific oxidative directing groups installed, the formal carboamination reactions of alkene were observed via either intramolecular reductive elimination4 (path c) or directing group transfer5 (path d). Very recently, by taking advantage of the high nucleophilicity of C−Co bond, Ellman © 2017 American Chemical Society

Received: September 13, 2017 Published: October 19, 2017 5868

DOI: 10.1021/acs.orglett.7b02846 Org. Lett. 2017, 19, 5868−5871

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10 11 12b 13 14

Scheme 2. Substrate Scope

additives (equiv)

solvent

4aa

5

6

Cu(OAc)2·H2O (1.0) Cu(OAc)2·H2O (1.0) Cu(OAc)2·H2O (1.0) Cu(OAc)2·H2O (1.0) Cu(OAc)2·H2O (0.2) Cu(OAc)2·H2O (0.2) + MnO2 (1.0) CuBr2 (1.0) Cu(acac)2 (1.0) CuSO4 (1.0) Cu(CH3CN)4BF6 (1.0)

DCE DMF MeOH CH3CN CH3CN CH3CN

56 27 11 78 (75)c 58 60

21 10 74 8 13 16

8 62 12 9 10 15

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

0 9 41 8 0 0 0 0

0 20 18 4 0 0 4 0

0 11 16 53 0 0 3 0

Cu(OAc)2·H2O (1.0) CsOAc (1.0) PivOH (1.0)

a

Conditions: 1a (0.2 mmol), 2a (1.5 equiv), TEMPO (1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), additive (1.0 equiv), solvent (0.1 M), at 60 °C under air for 2 h. Yield was determined by 1H NMR using 1-iodo4-methoxybenzene as internal standard. bWithout [Cp*RhCl2]2. c Isolated yield.

The use of MnO2 as co-oxidant did not improve the yield (entry 6).12 Other copper salts, such as CuBr2, Cu(acac)2, CuSO4, and Cu(CH3CN)4BF6, showed diminished reactivity (entries 7−10). Control experiments demonstrated that both the rhodium catalyst and copper salt were essential for the reaction (entries 11 and 12). Surprisingly, the replacement of Cu(OAc)2·H2O with either CsOAc or PivOH also retarded the alkylation and alkenylation reaction (entries 13 and 14), indicating the crucial role of copper salt for C−H activation or catalyst regeneration. With the optimized conditions established (Table 1, entry 4), we next investigated the generality and limitation of reaction (Scheme 2). With acrolein 2a as coupling partner, a wide variety of substituted indoles reacted smoothly to give the corresponding products in moderate to good yields. Functional groups, regardless of their electronic properties, such as methyl (4ea, 4na), alkoxy (4ca, 4ia, 4la), ester (4ba), formyl (4da), fluoro (4fa, 4ja), chloro (4ga, 4ka, 4ma), and bromo (4ha) were all well-tolerated. Importantly, substituents residing at the C3 (4na, 4oa) and C7 (4ma) positions, which could potentially retard the reaction for steric reasons, were compatible, as well. Not unexpectedly, the reaction was also effective for pyrroles (4pa− 4ra). In addition, 2-phenylpyridines (4sa, 4ta) and 1-phenyl-1Hpyrazoles (4ua−4wa) were also suitable substrates. Encouraged by these results, we sought to further explore the scope on the alkenes. Unfortunately, but-2-enal 7 and methacrylaldehyde 8, with additional substituent on the CC bond, failed to undergo any functionalization reactions, probably for steric reactions. The reaction of α,β-unsaturated ketones did provide the desired carboxygenation product, but a significant amount of alkenylation products was also produced (4ab−4ai). The use of methyl acrylate 9, N,N-dimethylacrylamide 10, and α,β-unsaturated acyl pyrrole 11 as coupling partners, however, led to only the formation of alkenylation product. α,β-Unsaturated acyl pyrazole 12 shut down the reactivity completely, probably due to the coordination property of the pyrazole moiety with rhodium catalyst. A 5 mmol scale reaction was conducted with a

a

Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), 3 (1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H2O (1.0 equiv), CH3CN (0.1 M), 60 °C, 0.5−8 h. b1a (5.0 mmol). cIn 9:1 DCE/CH3CN. dYield of alkenylation product.

comparable yield of 70% being obtained for compound 4aa, demonstrating the practicability of the reaction. The value of the formed product was demonstrated by its ready conversions to a variety of densely functionalized molecules. As shown in Scheme 3, upon Pinnick oxidation, the formyl group in 4aa could be converted to the corresponding αhydroxy carboxylic acid derivative 13 in good efficiency. On the other hand, the formyl group could be chemoselectively reduced with NaBH4 to give alcohol 14. Diol 15 was obtained by full reduction of the N−O bond and the carbonyl group with Zn in AcOH, under which reaction conditions the directing 2pyrimidyl group was cleaved, as well. The reductive amination produced the 1,2-aminoalcohol derivative 16 in good yield. Besides, the Wittig olefination of the carbonyl group provided the allylic alcohol derivative 17 in 92% yield. The carbonyl addition using MeMgCl furnished a substituted diol 18 with excellent efficiency and diastereoselectivity (20:1 dr). 5869

DOI: 10.1021/acs.orglett.7b02846 Org. Lett. 2017, 19, 5868−5871

Letter

Organic Letters

On the basis of the above observations and literature precedents, a reaction mechanism was proposed and outlined in Scheme 5. Initially, the coordination of substrate 1a to

Scheme 3. Synthetic Elaboration of Product 4aa

Scheme 5. Proposed Mechanism

To gain insight into the mechanism of this protocol, experimental mechanistic studies were carried out (Scheme 4). Scheme 4. Mechanistic Studies

[Cp*Rh] species is followed by a C−H activation to afford rhodacycle A, which would then undergo alkene insertion, leading to intermediate B. Thereafter, a Rh to Cu transmetalation generates a copper(II) species C. Homolysis of C results in the formation of alkyl radical D, which is trapped by TEMPO to deliver the α-oxygenated product 4aa.10 On the other hand, the β-H elimination from intermediate B, competing with the transmetalation process, gives the alkenylation product 6. With α,β-unsaturated ketone or methyl acrylate as coupling partner, the corresponding rhodacycle B is less stable due to the stronger basicity of the C−Rh bond, which renders the unimolecular β-H elimination more favorable than the bimolecular transmetalation process. Therefore, in these cases, the alkenylation dominates. The protonation of B or C is also feasible, especially in protic solvent (Table 1, entry 3), resulting in the formation of alkylation product 5. In summary, using a Rh(III)-catalyzed C−H alkylation/ Cu(II)-promoted α-oxygenation cascade, we have accomplished an efficient three-component carboxygenation of activated alkenes. The substrate scope was extensively explored and found to be broad. Mild reaction conditions, remarkable functional group tolerance, and moderate to good efficiency were observed. Derivatization of the product led to the fast synthesis of structurally diverse molecules. Preliminary mechanistic studies were conducted, and a rational mechanistic scenario was proposed.

First, the five-membered cyclometalated complex 19 was synthesized,2g which was found to be reactive as a catalyst for the title reaction (eq 1), indicating that complex 19 was likely involved in this catalytic cycle. The kinetic isotope effect (KIE) experiments gave a small KIE value of KH/KD = 1.1 (eq 2). Therefore, the cleavage of the C−H bond might not be turnoverlimiting.13 One would assume that the protonation product 5 might be the intermediate for the α-oxygenation reaction. To verify this possibility, 5 was subjected to the standard condition in the presence of 1.2 equiv of TEMPO. After 1 h, only a trace amount of α-oxygenated 4aa was detected, with the majority of 5 being recovered (eq 4). The omission of rhodium catalyst resulted in the formation of 4aa in 17% yield, which is also far less than the yield from the standard reaction (75% in 1 h, eq 4 vs eq 3). We noted that when pent-1-en-3-one 2c was used as coupling partner, the oxygenation only took place at the α position of ketone proximal to the indole moiety (4ac), with no formation of 20 being observed (eq 5). These results suggested that the protonation product was less likely the intermediate for oxygenation.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02846. Crystallographic data of 4aa (CIF) Detailed experimental procedures, characterization of all reported compounds, and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 5870

DOI: 10.1021/acs.orglett.7b02846 Org. Lett. 2017, 19, 5868−5871

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Organic Letters ORCID

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Shang-Shi Zhang: 0000-0002-9247-1373 Jie Xia: 0000-0002-5005-3069 Jia-Qiang Wu: 0000-0001-5067-7616 Xu-Ge Liu: 0000-0003-1878-2525 Chu-Jun Zhou: 0000-0003-0759-3219 E. Lin: 0000-0002-8557-9159 Qingjiang Li: 0000-0001-5535-6993 Shi-Liang Huang: 0000-0003-0878-5503 Honggen Wang: 0000-0002-9648-6759 Author Contributions †

S.-S.Z. and J.X. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the support of this work by the Key Project of Chinese National Programs for Fundamental Research and Development (2016YFA0602900), “1000-Youth Talents Plan”, the National Natural Science Foundation of China (Nos. 81402794, 21502242, and 21472250), and the Natural Science Foundation of Guangdong Province (2015A030313120).

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DOI: 10.1021/acs.orglett.7b02846 Org. Lett. 2017, 19, 5868−5871