Dearomatization–Rearomatization Strategy for Reductive Cross

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Dearomatization−Rearomatization Strategy for Reductive CrossCoupling of Indoles with Ketones in Water Zemin Wang,† Huiying Zeng,*,† and Chao-Jun Li*,‡ †

The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Road, Lanzhou 730000, People’s Republic of China ‡ Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada

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S Supporting Information *

ABSTRACT: N-Alkylation of indoles is one of the important pathways for the construction of various biologically active indole molecules. Using ketones as Nalkylation reagent for indoles has been a great challenge not only because of the competing alkylation reaction of C-3 position but also because of the poor nucleophilicity of the nitrogen atom of indole, in addition to the steric hindrance and lower electrophilicity of the ketones. A dearomatization−rearomatization strategy has been developed for reductive cross-coupling of indoles with ketones in water. Various functional groups and other heterocyclic compounds are tolerated.

I

Recently, our group has developed a dearomatization− rearomatization strategy for the cross-coupling of phenols11 or diaryl ethers12 with amines or ammonia (Scheme 1a). Inspired by those works, we posit that reductive dearomatization13 of an indole ring to form indoline can improve the nucleophilicity of nitrogen as well as avoid the C-3 alkylation

ndoles constitute important heterocyclic systems in many natural products, pharmaceuticals, dyes, and fine chemicals.1 Due to their biological activities, the functionalization of indoles has attracted significant interest for organic chemists.2 Among the indole derivatives, N-substituted indoles are of particular importance for the construction of various biologically active molecules.3 As the electron lone pair on the nitrogen atom has been delocalized to the indole ring, the C-3 position of indole has more nucleophilicity than the Nposition, which renders the N-selective alkylation of indoles difficult. The classical approach to tackle this problem is via the utilization of strong base to deprotonate the N−H bond in order to improve the nucleophilicity of nitrogen atom, which then reacts with alkyl halides. Besides the classical approach, new elegant methods for N-alkylation of indoles were developed recently, such as superbase-catalyzed Michael reactions with α,β-unsaturated compounds,4 hydroamination with alkenes,5 N-allylic alkylation with allyl esters,6 transitionmetal-catalyzed cross-coupling with boronic acid7 or bismuth reagent,8 “borrowing hydrogen” methodology with alcohols,9 and carbene insertion into the N−H bonds with methyl phenyldiazoacetate.10 The above alkylation reagents are often expensive or unstable, with the exception of the alcohols. However, only primary alkylation products are obtained when using primary alcohols as alkylation reagents, which limits the application of this method. Ketones are cheap, stable, and abundant commercial chemicals. If ketones are used as alkylation reagents of indoles, the secondary N-alkylation products will be generated to diversify their derivatives. However, such an approach is highly challenging not only because of the competing alkylation reaction of the C-3 position but also because of the poor nucleophilicity of the nitrogen atom of indole as well as the steric hindrance and lower electrophilicity of ketones, especially in aqueous solvent. © XXXX American Chemical Society

Scheme 1. Dearomatization−Rearomatization Strategies for Our Works

Received: February 16, 2019

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DOI: 10.1021/acs.orglett.9b00591 Org. Lett. XXXX, XXX, XXX−XXX

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(Table 1, entry 10). Different hydride sources were then examined (Table 1, entries 11−15), and 90% yield of Ncyclopentylindole was obtained by using potassium formate (Table 1, entry 15). The amount of cyclopentanone was also important for the reaction: a lower yield (65%) was achieved when 2.0 equiv of cyclopentanone was used in this reaction system (Table 1, entry 16), and further increasing the amount of cyclopentanone to 3 equiv improved the yield to 94% (Table 1, entry 17). Decreasing or increasing the reaction temperature lowered the yields (Table 1, entries 18 and 19). Adjusting the concentration to 0.1 M led to a lower yield (Table 1, entry 20). Nearly quantitative yield (99%) was obtained when the concentration was increased to 0.4 M (Table 1, entry 21). With the optimal reaction conditions in hand, we next proceeded to explore substituted indoles 1 to react with 3.0 equiv of cyclopentanone (2a) at 100 °C under argon atmosphere using 10 mol % of Pd(OH)2/C as the catalyst and 2.5 equiv of potassium formate in water (0.5 mL) for 24 h. A methyl substituent at the C-3 position had no effect on this transformation, and excellent yield was obtained (Scheme 2,

side reaction; upon reductive amination of indoline with ketone followed by oxidative rearomatization,14 N-alkylation indoles will be formed (Scheme 1b). Herein, we report such a dearomatization−rearomatization strategy for reductive crosscoupling of indoles with ketones in water, catalyzed by palladium. We commenced our initial investigation by reacting indole (1a) with cyclopentanone (2a) catalyzed by Pd/C15 (10 wt %, 10 mmol %) in aqueous solvent16 (1.0 mL) at 100 °C under an argon atmosphere for 24 h using sodium formate as hydride source. Fortunately, a moderate yield (44%) of N-cyclopentylindole was detected (Table 1, entry 1). Other palladium Table 1. Evaluation of Various Conditionsa

entry

catalyst

2a (mmol)

[H]

[H] (mmol)

3ab (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18f 19g 20h 21i

Pd/C Pd(OH)2/Cc PdCl2 Pd(OAc)2 Pd(OH)2 Pd(PPh3)4 Pd(OH)2/Cd Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce Pd(OH)2/Ce

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.6 0.6 0.6 0.6 0.6

HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Na HCO2Li·H2O HCO2Cs HCO2NH4 HCO2H HCO2K HCO2K HCO2K HCO2K HCO2K HCO2K HCO2K

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.5 0.4 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

44 48 9 6 8 np 59 84 87 81 68 80 83 71 90 65 94 73 51 92 99 (97)

Scheme 2. N-Alkylation of Different Indoles with Cyclopentanonea

a

General conditions: indole 1a (0.2 mmol), 2a (0.5 mmol), [Pd] (10 mol %), H2O (1.0 mL) under an argon atmosphere at 100 °C for 24 h. bYields were determined by 1H NMR with nitromethane as internal standard; isolated yield is given in parentheses. cPd(OH)2/C (20 wt %). dPd(OH)2/C (10 wt %). ePd(OH)2/C (5 wt %). f70 °C. g130 °C. hH2O (2.0 mL). iH2O (0.5 mL).

catalysts, such as Pd(OH)2/C (20 wt %), PdCl2, Pd(OAc)2, Pd(OH)2, and Pd(PPh3)4, gave lower yields (Table 1, entries 2−6). Interestingly, when Pd(OH)2/C was used as catalyst, 48% yield of product was detected (Table 1, entry 2), whereas only 8% yield of the desired product was formed with Pd(OH)2 (Table 1, entry 5). This information illustrated the importance of the active carbon to this transformation. Lowering the loading of palladium hydroxide on active carbon (10 wt %) increased the yield of 3a to 59% (Table 1, entry 7). Further decreasing the loading of palladium hydroxide on active carbon to 5 wt % gave 84% yield (Table 1, entry 8). Decreasing the amount of sodium formate to 2.5 equiv increased the yield to 87% (Table 1, entry 9). Further decreasing the amount to 2.0 equiv lowered the yield to 81%

a Reaction conditions: indole 1 (0.2 mmol), ketone 2a (0.6 mmol), Pd(OH)2/C (5 wt %) (10 mol %), and HCO2K (0.5 mmol) in water (0.5 mL) under Ar at 100 °C for 24 h; yields of isolated products are provided. bHCO2H (0.4 mmol) instead of HCO2K. cHCO2H (0.6 mmol) instead of HCO2K.

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DOI: 10.1021/acs.orglett.9b00591 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 3. N-Alkylation of Indole with Different Ketonesa

3b). The yield was decreased to 53% with a methyl at C-2 due to the increased steric hindrance of the reactive center (Scheme 2, 3c). The corresponding products were isolated in good to excellent yields with a methyl substituted at other positions of indole (C-4, C-5, and C-6 positions) (Scheme 2, 3d−f). Electron-donating substituents on the indole ring also had no effect, and high to excellent yields were obtained (Scheme 2, 3g,h). It is interesting to note that the hydroxyl group was tolerated in this system, generating the corresponding product in 93% yield (Scheme 2, 3i). Electron-withdrawing groups were also well tolerated in our system (Scheme 2, 4j). When 1H-indole-6-carboxylic acid, 1H-indole-5-carboxylic acid, and 4-(1H-indol-3-yl)butanoic acid were used as substrates, the corresponding products were formed with good to high yields without interfering by the free acids (Scheme 2, 3k−m). 2,3-Disubstituted indole substrate, 2,3,4,9tetrahydro-1H-carbazole, was successfully cross-coupled with cyclopentanone in good yield (Scheme 2, 3n). We subsequently proceeded to investigate the generality of this system with a wide range of ketones. As shown in Scheme 3, various N-alkylated indoles were obtained with moderate to excellent yields (Scheme 3, 3o−af). With increasing ring size, the yields of the corresponding N-alkylation products declined gradually due to the increased steric hindrance of cycloketones (Scheme 3, 3o,p). When the C-4 position of cyclohexanone bears a bulky tert-butyl group, a pair of geometric isomers (2:1) were obtained with excellent yield (95%) (Scheme 3, 3q). The ketal group was tolerated in this system with 92% yield (Scheme 3, 3r). Heterocyclic ketones also reacted smoothly with indole to give the corresponding N-alkylated indoles with high to excellent yields (Scheme 3, 3s−u). 2Indanone and the sterically hindered 2-adamantanone also reacted smoothly in good yields (Scheme 3, 3v−w). Fluorinecontaining cyclohexanone was also tolerated to generate product 3x efficiently (Scheme 3, 3x). Linear ketone was also explored, and the N-alkylation product 3y was generated in excellent yield (96%) (Scheme 3, 3y). Levulinic acid, bearing a free acid group at the terminal position, also successfully reacted with indole (Scheme 3, 3z). Product 3aa was obtained with moderate yield, tolerating a free hydroxyl group (Scheme 3, 3aa). Ethyl 5-oxohexanoate and ethyl 3oxobutanoate also gave high yields (Scheme 3, 3ab−ac). Good to high yields were obtained when aryl groups substituted at the terminal position (Scheme 3, 3ad−ae). 3,4-Hexanedione was also explored under the standard conditions to generate 4(indol-1-yl)hexan-3-one (3af) efficiently (Scheme 3, 3af). To investigate the reaction mechanism, several control experiments were carried out. No product was detected when the reaction was explored in the absence of Pd(OH)2/C or potassium formate (Scheme 4a). Indole (1a) was investigated under the standard reaction conditions in absence of cyclopentanone, and indoline (4) was detected in 30% yield within 5 min (Scheme 4b). Conversely, a 41% yield of indole (1a) was obtained when indoline (4) was explored under standard conditions without cyclopentanone (Scheme 4c). Those results illustrated that indole and indoline were easily reduced or oxidized in this system, and indoline might be the intermediate for this transformation. When indoline (4) and cyclopentanone (2a) were reacted under standard conditions, 80% yield of 3a was generated (Scheme 4d). No such product was obtained in the absence of palladium catalyst or both Pd(OH)2/C and potassium formate. In the absence of HCO2K alone, the N-alkylation product 3a was also formed in 60%

a Reaction conditions: indole 1a (0.2 mmol), ketone 2 (0.6 mmol), Pd(OH)2/C (5 wt %) (10 mol %), and HCO2H (0.4 mmol) in water (0.5 mL) under Ar at 100 °C for 24 h; yields of isolated products are provided.

yield (Scheme 4d). It is possible that indoline intermediate condenses with cyclopentanone to form an iminium intermediate, which undergoes hydrogen transfer via an azomethine ylide intermediate17 to form a new iminium on the pyrrolidine ring and then tautomerizes to form product 3a. To investigate this possibility, indoline (4) and cyclopentanone (2a) were explored under various acid conditions (such as 0.5 equiv of AcOH, TFA, benzoic acid, or scandium(III) triflate) in water at 100 °C for 24 h; however, it proved otherwise (Scheme 4e). The N-cyclopentylindoline (5) was also explored under the standard conditions, and a 73% yield of oxidized product N-cyclopentylindole (3a) was detected, together with 27% of compound 5. In the absence of potassium formate, the yield of compound 3a reached 92% (Scheme 4f). Competing experiments showed that, when indole (1a) and methyl 1HC

DOI: 10.1021/acs.orglett.9b00591 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 5. Tentative Mechanism

of pyrrole ring generates indoline B, which condenses with cyclopentanone C to form iminium D. Then intermediate D is further reduced to form N-alkylated indoline E. Indoline E then oxidatively rearomatizes to form the N-alkylated indole F as well as regenerates HPdIIH. In conclusion, we have successfully developed a palladiumcatalyzed synthesis of N-alkylation indole from N−H indoles and ketones via a novel dearomatization−rearomatization strategy. This strategy successfully elevated the nitrogen nucleophilic ability of indole via dearomatization and avoided a competing alkylation reaction of the C-3 position of indole. Notably, the reaction system also exhibited high chemoselectivity: various functional groups including acids, esters, alcohols, phenols, ethers, and heterocyclic compounds were tolerated, thereby providing handles for further product diversifications, especially for N-secondary alkyl derivatives. Further application of such a dearomatization−rearomatization strategy is 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.9b00591. Experimental procedures, additional experimental data, and compound characterization data (PDF)

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indole-5-carboxylate (1j) were reacted with cyclopentanone, 28% of 3a and 13% of 3j were formed, respectively (Scheme 4g). This result illustrated that an electron-withdrawing group at the C-5 position can reduce the nucleophilicity of nitrogen, resulting in a lower yield for product 3j. On the basis of these experimental results, a plausible mechanism was proposed for this N-alkylation reaction (Scheme 5). The HPdIIH species is formed by reacting Pd(OH)2/C with potassium formate and water. Then reduction of the indole A by the HPdIIH via dearomatization

AUTHOR INFORMATION

Corresponding Authors

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

Huiying Zeng: 0000-0002-2535-111X Chao-Jun Li: 0000-0002-3859-8824 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.9b00591 Org. Lett. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS We thank Fundamental Research Funds for the Central Universities (lzujbky-2018-62), the International Joint Research Centre for Green Catalysis and Synthesis, Gansu Provincial Sci. & Tech. Department (Nos. 2016B01017, 18JR3RA284, and 18JR4RA003), and Lanzhou University for support of our research. We also thank the Canada Research Chair (Tier I) foundation, the E.B. Eddy endowment fund, CFI, NSERC, and FQRNT (C.-J.L.). We thank Mr. Jianjin Yu in this group (Lanzhou University) for reproducing compound 3i in Scheme 2 and compounds 3o, 3s, and 3ab in Scheme 3.

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