Toshifumi
Morioka
,
Syun
Nakatani
,
Yuki
Sakamoto
,
Takuya
Kodama
,
Sensuke
Ogoshi
,
Naoto
Chatani
* and
Mamoru
Tobisu
*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan. E-mail: tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.osaka-u.ac.jp
First published on 29th May 2019
Nickel-catalyzed decarbonylation of N-acylated N-heteroarenes is developed. This method can be used to produce a variety of N-aryl heteroarenes, including pyrroles, indoles, carbazoles and phenoxazines, using benzoic acid derivatives as arylating reagents. Arylnickelamide intermediates that are relevant to the catalytic reaction were characterized by X-ray crystallography. When N-acylated benzimidazoles are used as substrates, decarbonylation accompanied 1,2-migration to form 2-arylated benzimidazoles.
Entry | Ligandb | GC yields (%) | |
---|---|---|---|
2a | 1a | ||
a Reaction conditions: 1a (0.25 mmol), Ni(cod)2 (0.050 mmol), ligand (0.050 mmol), in toluene (1.0 mL) for 18 h at 120 °C. b N-Heterocyclic carbene ligands were generated in situ from the corresponding imidazolium salts by treatment with NaOtBu (25 mol%). c Ni(cod)2 (0.25 mmol) and the ligand (0.25 mmol) were used at 80 °C. d Run at 180 °C. e Isolated yield. | |||
1 | PPh3 | 0 | 71 |
2 | PCy3 | 31 | 60 |
3 | dcype | 16 | 52 |
4 | ICy | 0 | 46 |
5 | IMes | 28 | 29 |
6 | IMesMe | 27 | 27 |
7 | IPr | 12 | 25 |
8c | PCy3 | >99 (88)e | 0 |
9d | PCy3 | 19 | 65 |
10c | dcype | 4 | 86 |
11d | dcype | 93 (84)e | 0 |
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The scope of the N-acyl group was initially investigated to identify the electronic requirement for this nickel-catalyzed decarbonylation reaction (Table 2). Under the catalytic conditions (condition A), N-acylindoles bearing an electron-withdrawing group (i.e., 1a and 1b) readily underwent decarbonylation, while electron-neutral (1c and 1d) and electron-rich (1e and 1f) amides were much less reactive.11 The yields of these less reactive amides could be improved by using condition B, in which Ni(cod)2/PCy3 (1 equiv. each) was used.
R | σ p | Isolated yield [%] | |
---|---|---|---|
A | B | ||
a Condition A: amide (0.25 mmol), Ni(cod)2 (0.050 mmol), dcype (0.050 mmol) in toluene (1.0 mL) for 18 h at 180 °C; condition B: amide (0.25 mmol), Ni(cod)2 (0.25 mmol), PCy3 (0.25 mmol) in toluene (1.0 mL) for 18 h at 80 °C. b Substituent constants from ref. 11. c GC yield. d NMR yield. e 3,4-Bis(dicyclohexylphosphino)thiophene (100 mol%) was used instead of PCy3 and run at 180 °C. | |||
CF3 (1a) | 0.54 | 84 | — |
CO2Me (1b) | 0.45 | 85 | — |
Ph (1c) | −0.01 | 30c | 79 |
H (1d) | 0 | 23c | 71 |
Me (1e) | −0.17 | 18c | 63 |
OMe (1f) | −0.27 | 8c | 14d (33)c,e |
A diverse array of N-acylated N-heteroarenes could be decarbonylated using our nickel-mediated protocol (Table 3). Although a methoxy group can be activated by Ni(0) catalysis,12 it was compatible with this decarbonylation reaction, as exemplified by efficient reactions when 1i and 1j were used. Several other common functional groups, including esters 1g, amides 1k, ketones 1l, nitriles 1m, and fluorides 1n, were found to be tolerated and decarbonylation occurred chemoselectively at the indole amide moiety. In addition to benzoic acid derivatives, π-extended analogues, such as 1o and 1p, also served as good substrates for forming N-arylated products. The alkenyl amide 1q could be used to produce N-alkenylindole 2q in excellent yield under condition B. Heteroarene-based carboxylic acids can also be used in this decarbonylation reaction, as demonstrated in the reaction of 1r. The scope of the N-heteroarene moiety was also investigated. Substituents on the indole ring had no significant effect on the efficiency of the reaction, thus permitting a variety of indole derivatives to be produced via decarbonylation (1s–1ab). This decarbonylation is not limited to indole derivatives and pyrroles 1x, carbazoles 1y and azaindoles 1z also participated in this decarbonylation reaction, allowing rapid access to a diverse array of arylated heteroarenes from the corresponding carboxylic acids. Moreover, the non-aromatic six-membered phenoxazine derivative 1aa was decarbonylated successfully, whereas the N,N-diphenyl amide was much less reactive (10% yield, see ESI† for details). These results indicate that there is a threshold for the pKa value of the parent amine in determining whether or not the reaction will proceed (pKa in DMSO: pyrrole 23, indole 21, carbazole 20, phenoxazine 22, and diphenylamine 25).13 This seems to be reasonable since the C(O)–N bond becomes stronger as the parent amine becomes more basic, leading to a lower reactivity in this decarbonylation reaction. In agreement with this conclusion, a substrate derived from an electron-deficient diphenylamine (i.e., 1ab) exhibited a significantly improved reactivity for this decarbonylation reaction.
a Condition A: amide (0.25 mmol), Ni(cod)2 (0.050 mmol), dcype (0.050 mmol) in toluene (1.0 mL) for 18 h at 180 °C; condition B: amide (0.25 mmol), Ni(cod)2 (0.25 mmol), PCy3 (0.25 mmol) in toluene (1.0 mL) for 18 h at 80 °C. b 1,3-Bis(dicyclohexylphosphino)propane (0.050 mmol) was used instead of dcype. c Run for 48 h. d Ni(cod)2 (0.25 mmol) and dcype (0.25 mmol) were used. |
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This decarbonylative N-arylation allows for the orthogonal introduction of azoles into halogen and carboxylic acid functionalities. For example, the N-arylation of carbazole using ethyl 3-iodobenzoate (3) occurs at the iodide site when the common copper-catalyzed method is used,2 and the resulting carboxylic acid moiety can be converted to another azole ring through an amidation/decarbonylation protocol (Scheme 2).
Several mechanistic experiments were conducted. A nickel-catalyzed reaction using a mixture of 1a and 1ac provided the corresponding decarbonylation products 2a and 2ac without the formation of any crossover products, indicating that this reaction proceeds via an intramolecular pathway (Scheme 3a). The reaction of amide 1a with 1 equivalent of Ni(cod)2 and dcype was monitored by 31P NMR, which revealed that a signal derived from the Ni(CO)2(dcype) (64.0 ppm, singlet) and two sets of doublets (57.9 ppm and 60.7 ppm, J = 13.1 Hz) appeared upon heating the mixture at 80 °C.14 These results indicate that a relatively stable organometallic intermediate is formed. Additional stoichiometric experiments resulted in the isolation of the arylnickelamide complex 6a, the structure of which was unambiguously determined by X-ray crystallography (Scheme 3b).15 Interestingly, the corresponding arylnickelamide complex 6f can also be formed from a methoxy-substituted amide 1f under similar conditions, although the amide 6f was much less reactive under the catalytic conditions used. These results indicate that, the reductive elimination from the arylnickelamide species to form a C–N bond has higher activation barrier than the prior C–N and C–C(O) bond cleavage processes. Indeed, a higher temperature (>120 °C) was required for this reductive elimination to occur to form an N-arylated product.16 Since Ni(CO)2(dcype) is also formed as the decarbonylation reaction proceeds, its catalytic activity was investigated (Scheme 3c). The Ni(CO)2(dcype) was found to catalyze the decarbonylation of 1a at 180 °C, whereas only a trace amount of the product was formed at 120 °C. These results suggest that heating at 180 °C is necessary for the dissociation of a CO ligand to occur to generate a catalytically active nickel species.
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Scheme 3 Mechanistic Studies. aThermal ellipsoids set at the 50% probability level. All hydrogen atoms are omitted for clarity.15 |
Based on the mechanistic studies described in Scheme 3, we propose a catalytic cycle shown in Scheme 4. In situ generated Ni(dcype) A17 serves as the catalytically active species, which initially activates a C(acyl)–N bond of the amide 1dvia oxidative addition18 to form an acylnickelamide intermediate B. The subsequent extrusion of CO from the acyl ligand in B leads to the formation of the carbonylnickel species C, in which one of the phosphorus atoms of dcype is dissociated. The dissociation of the CO ligand in C is facilitated by the recovery of the bidentate coordination of dcype to form the arylnickelamide complex D, which is one of the resting states of the catalyst. C–N bond forming reductive elimination from D is one of the difficult steps of this catalytic cycle. The higher reactivity of electron deficient amides is in agreement with the general trend in which C(aryl)–N bond reductive elimination proceeds more efficiently with an aryl ligand bearing an electron-withdrawing group.19 The dissociated CO is captured by A to form Ni(CO)2(dcype), which is catalytically inactive but can regenerate A upon heating to temperatures over 180 °C. The use of a PCy3 ligand instead of dcype generates a more active complex that can more easily mediate all the elementary steps required for the conversion of the amide 1d to the amine 2d (i.e., oxidative addition, extrusion of CO, and reductive elimination). However, unlike the case of dcype, there is no driving force available for the CO dissociation step, which hampers catalyst turnover when PCy3 is used. A similar contrast between PCy3 and dcype was also reported in the catalytic decarbonylative cross-coupling of phenyl esters.20
During the course of our investigations into the decarbonylation of N-acylated N-heteroarenes, we examined the benzimidazole derivative 7a. To our surprise, an N-arylation product was not formed in the Ni/dcype-catalyzed reaction of 7a but rather, C2-arylation occurred to afford 8a (Table 4). The overall reaction involves decarbonylation and 1,2-migration of the N-substituent.21,22 Although the detailed mechanism for this intriguing transformation remains elusive at present, the results of several preliminary mechanistic studies are noteworthy. First, a crossover experiment using two different N-acylated benzimidazole derivatives resulted in the formation of crossover products, suggesting that, unlike the decarbonylation of N-acylated indoles shown in Scheme 3a, an intermolecular pathway is likely to be operative. Second, when benzimidazoles bearing a para-substituted benzoyl group on the nitrogen atom, such as 8b, 8c and 8d, were used as substrates, small amounts of meta isomers were also formed in addition to the expected para-substituted 2-arylbenzimidazoles.23 This type of rearrangement was not observed in the case of the other heteroarene-based substrates shown in Table 3. Third, neither N-phenylbenzimidazole (S17) nor 2-benzoylbenzimidazole (S18) were converted into the 2-phenylbenzimidazole (8a) under these nickel-catalyzed conditions, excluding the intermediacy of these compounds in this migrative decarbonylation reaction. Finally, labelling experiments using a substrate having deuterium at the 2-position of a benzimidazole ring revealed that the cleavage of the C(2)–H bond is not involved in a turnover-limiting step.24meta-Disubstituted substrates 8e–8h underwent this decarbonylation to form the corresponding 2-arylated products without forming regioisomers. The reaction can also be applied to N-acylimidazole 8i, albeit in a lower yield.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1901697 and 1901702. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9sc02035g |
This journal is © The Royal Society of Chemistry 2019 |