Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Copper-Catalyzed C4‑H Regioselective Phosphorylation/ Trifluoromethylation of Free 1‑Naphthylamines Chunfeng Jing,† Xiaolan Chen,*,†,‡ Kai Sun,† Yongkang Yang,† Tong Chen,§ Yan Liu,† Lingbo Qu,† Yufen Zhao,†,‡ and Bing Yu*,† †
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China § High and New Technology Research Center of Henan Academy of Sciences, Zhengzhou 450001, China Downloaded via HONG KONG UNIV SCIENCE TECHLGY on January 2, 2019 at 13:42:55 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: A novel and facile copper-catalyzed synthetic methodology was developed to access a large variety of 4-phosphoryl-substituted 1naphthylamines by reacting various 1-naphthylamines with different diarylphosphine oxides in the presence of Cu(OAc)2 and Ag2CO3 in one pot under mild reaction conditions. This copper-catalyzed synthetic system was also suitable for being employed to synthesize 4-trifluoromethylsubstituted 1-naphthylamines by reacting various 1-naphthylamines with Togni’s reagent in the presence of CuI and NaOAc in DMSO in one pot under mild reaction conditions.
P
catalyzed C8 amination of with aliphatic amines,9 as well as direct Pd-catalyzed C8 cyanation with TMSCN.10 Over the past two years, much progress has also been achieved in metalcatalyzed remote C4−H functionalization of 1-naphthylamides via a single-electron-transfer (SET) mechanism as illustrated in Scheme 1B. Such achievements include direct metal (Cu, Cu/ Ru, or Cu/Ag) catalyzed C4 sulfonation of 1-naphthylamides with sulfonyl chlorides and sulfinate salts, developed by the groups of Weng,11 Manolikakes,12 and Wu,13 respectively, direct Cu-catalyzed C4 nitration with AgNO3 and direct azidation with TMSN3,14 direct Ag-catalyzed C4 amination with azodicarboxylates,15 and also direct Ag-catalyzed C4 phosphorylation with diarylphosphine oxides.16 It can be seen that all of those regioselective C−H functionalization reactions started with the use of 1-naphthylamides as the starting reactants, in which amide groups, picolinamide (PA) and quinolinamide moieties, acted as directing groups of the metalcatalyzed transformations, as illustrated in Scheme 1A,B. Organophosphorus compounds occupy an essential position in biochemistry, pharmaceutical chemistry, material chemistry, and organic synthesis, where phosphorus moieties modify biological responses, material functions, and medicinal properties or act as ligands of metals.17 As part of our continuing efforts in the development of novel phosphorus-radicalinvolved reactions,18 herein we report a facile synthetic methodology for construction of various biologically important 4-phosphoryl-substituted 1-naphthylamines by reaction of 1naphthylamines with various diarylphosphine oxides in the presence of Cu(OAc)2 and Ag2CO3 in one pot under mild
rimary arylamines are important intermediates for the synthesis of numerous organic chemicals such as pharmaceuticals, agrochemicals, dyestuffs, and rubber.1 As one of the most widely used starting reactants, primary arylamines routinely need to be acylated to their corresponding arylamides before major chemical transformations are carried out.2 The reason is that the very powerful activating amino group often causes the aromatic ring to be highly reactive so that undesirable reactions take place. The amino group through its electron-donating ability makes the ring electron rich and, thus, especially susceptible to oxidation. Oxidation of aromatic amines is not only confined to the amino group but also frequently occurs in the ring. Meanwhile, the high contribution of electron density to the aromatic ring through resonance also makes arylamines highly susceptible to electrophilic aromatic substitutions, rendering unwanted multiple substituted aromatic products. In fact, the routine operations of the initial acylation as well as the later deprotection, when arylamines are used as starting reactants, always make the related synthesis less atom- and stepeconomical.3 Naphthalene is a privileged structural motif that widely exists in pharmaceuticals, agrochemicals, and many biologically active synthetic compounds.4 Notable progress has been achieved over the past five years in bidentate-chelation controlled C8-H functionalization of 1-naphthylamides, as illustrated in Scheme 1A. There are numerous such examples, such as direct metal (Pd, Rh or Fe) catalyzed C8 alkylation of 1-naphthylamides with alkyl halides, alkenes, and trimethylaluminum,5 direct Pd/Cu-catalyzed C8 arylation with aryl iodides and 1,3-azoles,6 direct Co/Cu-catalyzed C8 alkoxylation with carboxylic acids and arylboronic acids,7 direct Pdcatalyzed C8 thiolation with diaryl disulfides,8 direct Pd© XXXX American Chemical Society
Received: November 25, 2018
A
DOI: 10.1021/acs.orglett.8b03768 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. 4-Phosphorylation of 1-Naphthylaminesa,b
Scheme 1. Transition-Metal-Catalyzed Regioselective C−H Functionalization of Naphthalene
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2· H2O (20 mol %), and Ag2CO3 (2 equiv) in DMSO (1 mL) at 80 °C for 6 h. bIsolated yield based on 1a.
substituents (−OMe, −Me) at the para position of benzene rings, reacted with 1-naphthylamine (1a) smoothly under the optimized reaction conditions, giving the resulting 4phosphoryl-substituted 1-naphthylamines 3a−e in moderate to good yields (3a−e). In contrast, diphenylphosphine oxides bearing both electron-withdrawing groups (−Cl, −F) and electron-donating substituents (−OMe, −Me) at the meta position of the benzene rings gave the corresponding 4phosphoryl-substituted 1-naphthylamines (3f−i) in relatively low yields (3b−e). Further experiments proved that the positions of substituents attached to the benzene rings in diphenylphosphine oxides could pose remarkably different steric hindrances to their reacting sites and thus notably influence the final yields of the corresponding products (for details, see the Supporting Information). It also can be seen that no obvious electronic effects of the substituents were observed from these cases (3a−i). Afterward, 1-naphthylamines bearing different substituents were employed to react with diphenylphosphine oxide itself (2a), affording the resulting 4-phosphoryl-substituted 1-naphthylamines in moderate to good yields (3j−m). As can be seen from the case of 3j, owing to the mildness of the reaction conditions employed, the vinyloxyl group, an unstable functional group, survived the reaction unchanged. At last, two 1-naphthylamines, 2-methyl1-naphthylamine and 7-methoxyl-1-naphthylamine, reacted with various diarylphosphine oxides under the optimized conditions, giving the resulting 4-phosphoryl-substituted 1naphthylamines in moderate to good yields (3n−r). Moreover, diethyl H-phosphonate was employed to react with 1naphthylamine, yielding the corresponding product 3s in 22% yield. This relatively low yield might be due to the higher theoretical bond dissociation energies of the P−H bonds.19 Among the products, the structure of 3a was further confirmed by X-ray crystallography (CCDC 1879938). Following this, we performed a scale-up reaction (gram level) with the desired product (3a) being obtained in 58% yield (see the Supporting Information). We then carried out two control experiments and online mass spectrometry detection to gain mechanistic insight of the phosphorylation reaction (Scheme 3). When the model
reaction conditions as shown in Scheme 1C. This coppercatalyzed synthetic system was also suitable for being employed to synthesize 4-trifluoromethylated 1-naphthylamines by reacting various 1-naphthylamines with Togni’s reagent in the presence of CuI and NaOAc in DMSO in one pot under mild reaction conditions (Scheme 1C). Compared with the previously reported methodologies mentioned above, our newly developed methodology, for the first time, realized copper-catalyzed direct and regioselective C4-H phosphorylation/trifluoromethylation of 1-naphthylamines by directly using 1-naphthylamines rather than 1-naphthylamides as the starting reactants. The unprotected amino group in the starting 1-naphthylamines survived well in the standard experimental procedure, exhibiting unexpected efficiency and high atomand step-economy. We initiated the study by establishing optimal experimental conditions of the regioselective C4-phosphorylation of 1naphthylamine using the model reactions of 1-naphthylamine (1a) with diphenylphosphine oxide (2a) in the presence of different metal catalysts and silver salts under open-air conditions for 6 h, as summarized in Table S1. After intensive experimentation, the optimized reaction conditions were established as follows: 1a (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2 (20 mol %), and Ag2CO3 (2 equiv) were mixed in DMSO at 80 °C for 6 h under open air conditions. With the optimized conditions in hand, we then explored the substrate scope by examining various 1-naphthylamines 1 and diarylphosphine oxides 2, and the results are illustrated in Scheme 2. As can be seen from cases 3a−e, a group of diphenylphosphine oxides, mainly including those bearing electron-withdrawing groups (−Cl, −F) and electron-donating B
DOI: 10.1021/acs.orglett.8b03768 Org. Lett. XXXX, XXX, XXX−XXX
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helps to stabilize the unprotected amino group in the reaction process and prevents it, to a great extent, from occurrence of the possible side reactions, such as unwanted oxidation reactions. Trifluoromethylated compounds have been targeted increasingly in the fields of pharmaceuticals, agrochemicals, and organic materials during recent decades. The trifluoromethyl moiety is often present in agrochemicals and synthetic drugs, leading to altered physical and physiological behavior of those compounds with respect of uptake and metabolism. Within this family, compounds bearing the CF3 group on the aromatic rings compose an important part of pharmaceuticals.22 Therefore, the strategic introduction of a CF3 group into arenes is a highly desirable synthetic goal. Much to our delight, this newly developed copper-catalyzed synthetic system could be extended to the preparation 4-trifluoromethyl-substituted 1naphthylamines by the reaction of various 1-naphthylamines with Togni’s reagent 5 in the presence of CuI and NaOAc in DMSO in one pot under mild reaction conditions, as illustrated in Scheme 5. As can be seen, the target products
Scheme 3. Control Experiments
reaction was performed in the presence of two commonly used radical scavengers, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), respectively, no desired product 3a was obtained in either case, indicating that this transformation might involve a radical process. It is worth pointing out that when the control reaction was performed with BHT under standard reaction conditions (Scheme 3b), product 4 was detected by high-resolution mass spectrometry (HRMS), suggesting that diphenylphosphoryl radical (·P(O)Ph2) was produced from diphenylphosphine oxide and trapped by BHT. The related mechanism is proposed on the basis of the experimental outcomes and previous reports,11,13,16,20 as shown in Scheme 4 (i). Initially, the amino group in 1-
Scheme 5. 4-Trifluoromethylation of 1-Naphthylaminesa
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1a (0.2 mmol), 5a (0.24 mmol), CuI (10 mol %), and NaOAc (3 equiv) in DMSO (1 mL) at 50 °C for 3 h. Isolated yields are given. *New compound.
(6a−c, 6d/d′, 6e/e′) were obtained in moderate to good yields. The result from the case 6d/d′ showed a high para regioselectivity, rendering a good overall yield of 6d + 6d′ (63%) with two regioisomers in a ratio of 2.6:1. This was also the case with 6e/e′ (57% overall yield with two regioisomers in a ratio of 2:1). The mechanism concerning this regioselective trifluoromethylation is given in Scheme 4 (ii). CuI initially reacts with Togni’s reagent to generate iodine radical intermediate G via a SET process. Then, radical G homolytically cleaves the I−CF3 bond to give trifluoromethyl radical I along with Cu(II) complex H. Meanwhile, the amino group in 1a coordinates with Cu(II) to form metal complex A′. Following that, trifluoromethyl radical I added regioselectively to the C-4 of complex A′ to generate radical B′. A SET from radical B′ to Cu(II) then takes place to give a resonance-stable arenium ion C′ along with Cu(I). Afterward, a proton is removed from the carbon atom bearing the trifluoromethyl group in C′, rendering 4-trifluoromethyl-substituted intermediate D′, which immediately dissociates to the desired product 6d with participation of a proton, along with the regeneration of Cu(II) to fulfill the catalytic cycle. A related control experiment with TEMPO was further performed, and no desired 4-trifluoromethylation product was obtained (see the Supporting Information), suggesting that this copper-
naphthylamine 1a coordinates with Cu(II) to form metal complex A. Meanwhile, Ag2CO3 reacts with diphenylphosphine oxide to generate diphenylphosphoryl silver E,21 which then homolytically cleaves the Ag−P bond to produce diphenylphosphoryl radical F along with Ag(0) metal. Subsequently, diphenylphosphoryl radical F adds regioselectively to the C-4 of complex A to generate radical B. Then SET from radical B to Ag+ takes place to give a resonance-stable arenium ion C. After that, a proton is removed from the carbon atom bearing a diphenylphosphoryl group in C and the aromatic system is regenerated, rendering 4-phosphorylsubstituted intermediate D, which immediately dissociates to the desired product 3a with participation of a proton, along with the regeneration of Cu(II) to fulfill the catalytic cycle. It has been observed from entry 17 of Table S1 that only trace target product 3a was obtained without participation of Cu(OAc)2, making the indispensable role of the copper catalyst in the phosphorylation reaction clear. It can be seen from the proposed mechanism that the free amino group in starting 1-naphthylamine 1a initially coordinates Cu(II) ion to form complex A, in which the aminocopper coordination moiety acts as the directing group (DG) in the following regioselective phosphorylation reaction. Meanwhile, the formation of the aminocopper coordination moiety also C
DOI: 10.1021/acs.orglett.8b03768 Org. Lett. XXXX, XXX, XXX−XXX
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catalyzed trifluoromethylation underwent a radical-involved reaction process. In conclusion, we report a novel and facile copper-catalyzed synthetic methodology to access a large variety of 4phosphoryl-substituted 1-naphthylamines by reacting various 1-naphthylamines with different diarylphosphine oxides in the presence of Cu(OAc)2 and Ag2CO3 in one pot under mild reaction conditions. In this way, this copper-catalyzed synthetic system could well be expanded to access 4-trifluoromethylsubstituted 1-naphthylamines starting from 1-naphthylamines and Togni’s reagent. To the best of our knowledge, this is the first example of realizing Cu-catalyzed direct and regioselective C4-H phosphorylation/trifluoromethylation of 1-naphthylamines by directly using 1-naphthylamines as the starting reactants. The newly developed syntheses avoided the trouble of the routine operations of the initial acylation and the later deprotection, showing much higher atom- and step-economy.
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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.8b03768. Experimental details and characterization data (PDF) Accession Codes
CCDC 1879938 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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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xiaolan Chen: 0000-0002-3061-8456 Kai Sun: 0000-0003-2135-0838 Yufen Zhao: 0000-0002-8513-1354 Bing Yu: 0000-0002-2423-1212 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the National Natural Science Foundation of China (21501010) and the 2017 Science and Technology Innovation Team in Henan Province (22120001).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03768 Org. Lett. XXXX, XXX, XXX−XXX
