tert-Butyl Nitrite Mediated Synthesis of Fluorinated O

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

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tert-Butyl Nitrite Mediated Synthesis of Fluorinated O‑Alkyloxime Ether Derivatives Xingxing Ma† and Qiuling Song*,†,‡,§ †

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Institute of Next Generation Matter Transformation, College of Materials Science & Engineering, Huaqiao University, 668 Jimei Blvd, Xiamen, Fujian 361021, China ‡ Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108, China § State Key Laboratroy of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai, 200032, China S Supporting Information *

ABSTRACT: A tert-butyl nitrite (TBN)-mediated synthesis of fluorinated O-alkyloxime ether derivatives with bromodifluoroalkyl reagents as the fluorine sources has been developed. A variety of halodifluorinated compounds were found compatible, delivering the desired products in moderate to excellent yields. This transformation features a simple operation, can be done in air, and found to involve radicals. This protocol represents a straightforward approach to access various fluorinated O-alkyloxime ether derivatives.

F

It is well-known that indole and its derivatives are vital building blocks due to their wide occurrence in natural products and pharmaceutical molecules.8 Moreover, indoles are π electron excessive aromatic heterocyclic compounds in which there are multiple reaction sites including N-1, C-2, and C-3; among them, C-3 is nucleophilic and is the most reactive position.8d,e In addition, our group has reported myriad protocols for halodifluoroalkyl compounds (BrCF2COOEt, BrCF2CONRR′, ClCF2COONa, and ClCF2H) in multiple roles,4 such as difluoroalkylating reagents,4a−e difluorocarbene precursors,4f and the C1 synthon via quadruple cleavage4g−j and C2 source in triple cleavage transformation very recently.4k Herein, we disclosed an efficient and practical approach to access the fluorinated O-alkyloxime ethers at the C-3 position of indoles with TBN and difluoroalkyl reagents under mild reaction conditions. Of note, the products have the potential to provide the −OCF2− scaffold attributing to N−O bond cleavage in the presence of Lewis acid or oxidant (Scheme 1). Moreover, it is a challenge to obtain target products in high yields under competition of two electrophiles in the same system. Our initial efforts toward the formation of C−N and C−O bonds to generate ethyl (E)-2,2-difluoro-2-(((2-phenyl-3Hindol-3-ylidene)amino)oxy)acetate (3a) commenced with the treatment of 2-phenyl-1H-indole (1a), ethyl bromodifluoroacetate (BrCF2COOEt), TBN as mediator, and K2CO3 as base in MeCN at 80 °C, a 73% yield of the desired product 3a was obtained. Whereafter we examined several bases including Na2CO3, NaHCO3, Cs2CO3, and NaOH for improving the

luorinated compounds have found widespread applications in organic synthesis, pharmaceuticals, agrochemicals, and materials science, due to their unique and intriguing properties.1 And there are great variations regarding their physicochemical properties and bioactivities when a fluorine atom or fluorine-containing groups are incorporated into the parent molecules.2 It is therefore very significant for researchers to pursue facile and efficient tactics for the synthesis of fluorine-containing compounds. Among all of the organofluorine molecules, the fluorinated O-alkyloxime ethers are attractive synthetic targets because of their significant application potential in medicinal and bioorganic chemistry, such as monoamine oxidase, benzisoxazole derivatives, which exhibit preferable cytokinin-like and neuroleptic activities.3 Although abundant reliable processes have been developed to construct the C−C(F) bond with halodifluoroalkyl reagents as a fluorine source,4−6 direct construction of OCF2R along with C−N bond formation has not been reported yet. To our knowledge, t-BuONO (tert-butyl nitrite, TBN) has been deemed a good nitrating agent and a radical precursor in recent decades, in which elegant work utilizing TBN as a nitrogen source to assemble nitrogen-containing molecules has been reported.7 Among them, TBN could readily generate a NO radical to form a C−NO bond which will be further tautomerized into ketoximes. Inspired by this transformation, we envision that the newly formed OH might have an opportunity to be captured by in situ generated CF2R species from BrCF2COR (R = OR1 and NR2R3); thus, fluorinated oxime derivatives could be afforded. In order to validate our hypothesis, a suitable parent molecule should be selected. In this context, indole and its derivatives arouse our interest. © XXXX American Chemical Society

Received: July 31, 2019

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DOI: 10.1021/acs.orglett.9b02689 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of 2-Phenyl Indole Derivativesa

Scheme 1. Synthesis of Fluorinated Products via TBNMediation

yield of this reaction (entries 2−5), among them, Na2CO3 demonstrated to be the optimal one under the above conditions (Table 1, entry 2). The yields of desired product Table 1. Identification of Reaction Conditions for the Product 3a

entry

base

time (h)

solvent

temp (°C)

yield (%)a

1 2 3 4 5 6 7 8 9 10 11 12

K2CO3 Na2CO3 NaHCO3 Cs2CO3 NaOH Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3

12 12 12 12 12 8 3 3 3 3 3 3

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF dioxane CH3CN CH3CN CH3CN

80 80 80 80 80 80 80 80 80 100 60 40

73 81 68 66 53 83 88(82)b 79 69 71 53 trace

a

Reaction condition:Indole (1) (0.2 mmol), ethyl bromodifluoroacetate (BrCF2COOEt) (1.5 equiv), TBN (1.2 equiv), Na2CO3 (1.8 equiv) in MeCN at 80 °C for 3 h, isolated yield, TBN = tert-Butyl nitrite.

product 3a′ was obtained when unsubstituted indole was employed as a substrate. Halo-substituted 2-(4-bromophenyl)1H-indole (1g) and trifluoromethyl (−CF3, 1h) were well compatible, rendering the anticipated product (3g and 3h) in 80% and 72% yield accordingly. When the meta-bromocontaining substrate 1i was employed, the target product 3i was isolated in 77% yield. Subsequently, the substituents on Ar1 rings were investigated under optimized reaction conditions as well. Thereby 5-methyl-2-phenyl-1H-indole (1j), 5-fluoro-2-phenyl-1H-indole (1k), and 2-phenyl-5-(trifluoromethyl)-1H-indole (1l) proceeded under the viable reaction conditions to afford the desired corresponding products 3j, 3k, and 3l in 86%, 74%, and 62% yield, respectively. It was noteworthy that the fused ring compound 1H-benzo[f ]indole 1m was tested under optimum reaction conditions as well, leading to the desired product 3m in excellent yield (92%). Encouraged by the above successful results, we wonder whether this transformation could be employed into other bromodifluoroalkyl compounds. But low yields of the corresponding products were obtained with the above optimized reaction conditions with a significant amount of starting materials remaining. We then screened the reaction conditions and found that prolonging the reaction time to 8 h led to a better result (see Supporting Information (SI) for details). With these optimal reaction conditions in hand, various bromodifluoroalkyl reagents, such as 2-bromo-2,2difluoro-N-phenylacetamide and its derivatives, were subjected to 2-phenyl indole (1a) (Scheme 3). Various 2-bromo-2,2difluoro-N-phenylacetamides (4a−4e) which bear electrondonating and -withdrawing groups or disubstituted on an aromatic ring and a heterocycle were well-tolerated, rendering the corresponding products in moderate to good yields (5a− 5e). The crystal structures of 5b were determined by X-ray crystallography (CCDC: 1935697) (Scheme 3; see SI for

a

Reaction condition: 2-phenylindole (1a, 0.2 mmol), ethyl bromodifluoroacetate (2a, 1.8 equiv), TBN = tert-Butyl nitrite (1.8 equiv), base (1.8 equiv), solvent (2.0 mL) under air at 40−100 °C for 3−12 h, GC yields bIsolatded yield.

were raised to 83% and 88% yields respectively when the reaction time was shortened to 8 and 3 h (entries 6−7). It did not significantly improve the efficiency of this transformation while solvents tetrahydrofuran (THF) and 1,4-dioxane took the place of acetonitrile (MeCN) (entries 8−9). Finally, the temperature of this transformation was investigated (entries 10−12). To our surprise, the observed reaction efficacy was poor at both 100 and 60 °C. When the temperature was reduced to 40 °C, only a trace amount of fluorinated product 3a was detected (entry 12). Eventually, the optimized conditions were obtained: 2-phenyl-1H-indole (1a, 1 equiv) reacted with BrCF2COOEt (2, 1.5 equiv) with TBN (1.2 equiv) at 80 °C using Na2CO3 as base in MeCN for 3 h. Having the optimized reaction conditions in hand, we next explored the scope of the indole derivatives for investigating the generality of this reaction, which are summarized in Scheme 2. In general, this transformation revealed a high reaction efficiency with diverse functional groups ranging from electron-donating to electron-withdrawing ones, thus obtaining the target fluorinated compounds in good to excellent yield. Specifically, electron-releasing groups such as methoxy (1b) and alkyl (1c−1f) on the Ar2 ring of 4-substituted were performed under standard reaction conditions to afford the expected products in 83%−95% yield. However, no desired B

DOI: 10.1021/acs.orglett.9b02689 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of Bromodifluoroalkyl Compoundsa

Scheme 4. Gram-Scale Reaction and Transformation of Product 3a

Scheme 5. Direct Synthesis of Compound 8

a Reaction conditions: Indole (1) (0.2 mmol), ethyl bromodifluoroamide (BrCF2COR) (1.5 equiv), TBN (1.2 equiv), Na2CO3 (1.8 equiv) in MeCN at 80 °C for 8 h, isolated yield, TBN = tert-Butyl nitrite.

Scheme 6. Control Experiments

details). The substrates 4f and 4g were examined under the same reaction conditions to afford the desired products (5f and 5g) in 74% and 78% yield, respectively. Finally, when reactant 2-bromo-2,2-difluoro-N-(3-methylbenzyl)acetamide (4h) was subjected to the reaction conditions, the corresponding desired (Z)-2,2-difluoro-N-(3-methylbenzyl)-2-(((2-phenyl-3H-indol3-ylidene)amino)oxy) acetamide (5h) was obtained in 82% yield. It is very easy to convert products 3 into valuable compounds due to the low bond energy of the N−O bond.9 To further indicate the synthetic potential of our strategy, we undertook a gram-scale synthesis of ethyl (E)-2,2-difluoro-2(((2-phenyl-3H-indol-3-ylidene)amino)oxy)acetate (3a); to our delight, the efficiency of this transformation was well maintained (2.7 g, 78% yield) (Scheme 4, eq 1). Subsequently, further transformations of 3a were carried out. First, the compound N-(2-cyanophenyl)-N-pivaloylbenzamide (6) was prepared using 1.2 equiv of pivalic acid under air at 80 °C for 1 h in MeCN (Scheme 4, eq 2). The 3a could undergo a ringopening reaction catalyzed by TsOH to lead to N-(2cyanophenyl)benzamide (7) in 90% yield (Scheme 4, eq 3), which is one of the most important building blocks due to their anti-inflammatory effects, such as DPP-IV inhibitors.10 The ester group of 3a was hydrolyzed under basic conditions to access (Z)-2-phenyl-3H-indol-3-one O-difluoromethyl oxime (8), which has an intriguing potential to provide −OCF2H construction that can serve as a bioisostere of hydroxyl and thiol groups, in 83% yield (Scheme 4, eq 4). In addition, we found that the use of excessive Na2CO3 in the model reaction could furnish the compound 8 directly (Scheme 5). To gain further insights into the reaction mechanism, several control experiments were performed (Scheme 6). Addition of radical scavengers TEMPO or BHT dramatically reduced the

efficiency of this transformation, resulting in the desired product 3a in trace yields (Scheme 6, eq 5), which suggests that a single electron transfer (SET) process may be involved in this transformation. We then carried out a simple experiment to capture possible radical species in the system in the absence of 2-phenyl indole and BrCF2COOEt (Scheme 6, eq 6). The mass of the species NO radical was trapped by TEMPO via GC-MS. Since this is a cascade reaction, we decided to carry out the three-compoment reaction in a stepwise manner: (1) only 2-phenyl-1H-indole 1a and TBN were subjected to the standard reaction conditions for 1 h, without further purification, rendering a reaction mixture N; (2) by direct addition of Na2CO3 and BrCF2COOEt to the above reaction mixture N, the target product 3a was obtained in 73% yield (Scheme 6, eq 7). Based on the above-mentioned experiment evidence and previous work,4 a possible mechanism for this cascade reaction is described in Scheme 7. The C-3 position of indole in the presence of base attacks the NO radical generated in situ from TBN, leading to an intermediate species M. Subsequently, M goes through a 1,3-H shift to deliver the reaction intermediate P. Finally, the desired products 3 and 5 are acquired when exposed to base and bromodifluoroalkyl reagents. C

DOI: 10.1021/acs.orglett.9b02689 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Scheme 7. Mechanism Proposal

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02689. Experimental details, characterization data of compounds, NMR, and X-ray crystallographic data (PDF) Accession Codes

CCDC 1935697 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 [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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REFERENCES

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In summary, we have developed an approach to access various brand-new fluorinated O-alkyloxime ether derivatives which might have significant potential due to the low bond dessociation energy of the N−O band. This transformation involved an SET and a 1,3-H shift under a transition-metal-free protocol. This transformation features mild reaction conditions, high efficiency, good functional group tolerance, and compatibility. In addition, this process allows the efficient construction of the C−N bond and C−O bond simultaneously. Efforts toward further transformation and application of fluorinated O-alkyloxime ether derivatives are currently underway in our laboratory.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Qiuling Song: 0000-0002-9836-8860 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21772046) and the Natural Science Foundation of Fujian Province (2016J01064) is gratefully acknowledged. We also thank the Instrumental Analysis Center of Huaqiao University for analysis support. X.M. thanks the Subsidized Project for Cultivating Postgraduates’ Innovative Ability in Scientific Research of Huaqiao University. Finally, we thank Jianke Su in this group (Institute of Next Generation Matter Transformation, College of Materials Science & Engineering Huaqiao University) for reproducing the preparation of compounds 3a, 3e, and 5f. D

DOI: 10.1021/acs.orglett.9b02689 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b02689 Org. Lett. XXXX, XXX, XXX−XXX