One-pot nickel-catalyzed cross-coupling of (Het)arylammonium salts prepared in situ and organozinc reagents

Abstract

A nickel-catalyzed arylation of aromatic amines using arylzinc reagents with trimethylammonium salts formed in situ is developed. Compared with previous systems using ammonium salts as the starting materials and complexes of pre-prepared nickel catalysts, this reaction directly employed an N,N-dimethyl(het)arylamine as the coupling partner and commercial Ni(COD)₂/TMEDA as the catalyst, greatly simplifying the experimental procedure, decreasing the cost, and being especially suitable for scale-up production processes.

Introduction

Transition metal–catalyzed cross-coupling reactions have become an extremely versatile tool in organic synthesis for the connection of electrophilic and organometallic fragments by the formation of either carbon-carbon or carbon-heteroatom bonds. ¹ Examples include Kumada, Negishi, Suzuki, and Stille cross-couplings and, among these coupling reactions, the Negishi coupling is one of the most powerful owing to the widespread availability and high functional group tolerance of organozinc reagents.^2,3 In addition to aryl iodides, bromides, and chlorides, ⁴ more recently, triflates and other O-based substrates, such as tosylates, mesylates, and carboxylates, are useful alternative electrophiles for cross-coupling reactions.^5,6 Reactions through C–N bond cleavage of the electrophilic substrates are scarce, although Wenkert and co-workers carried out the nickel-catalyzed reaction of aryltrimethylammonium iodides with Grignard reagents in the early stage of cross-coupling studies. ⁷ On the other hand, nitrogen-containing compounds such as aryl- and alkyl-amines are very important and widely available in the natural world and in industry. A tactic is to convert arylamines to triazenes ⁸ or arylammonium salts ⁹ to weaken the C–N bonds before cleavage. Wang and other groups have performed some transition metal–catalyzed cross-coupling reactions using aryltrimethylammonium salts as the electrophilic partners in the past few years. ¹⁰ Recently, Wang and co-workers developed a pincer nickel complex–catalyzed Negishi coupling reaction of aryltrimethylammonium triflate with arylzinc reagents (Scheme 1). Despite the fact that long reaction times were required, this reaction provided an efficient method for using tertiary aromatic amines in aromatic couplings for the first time.

Scheme 1.

Ni-catalyzed arylation of arylammonium.

We recently became interested in using aryltrimethylammonium salts in cross-coupling reactions with organozinc reagents. As aryltrimethylammonium triflates were prepared by reactions of aromatic amines, lithium chloride, and Methyl trifluoromethanesulfonate (MeOTf), we assumed that the aromatic amines might be used directly as the starting materials, if the quaternization process would take place in situ. ¹¹ Herein, we report such an arylation reaction in one step using aromatic amines (Scheme 1). It is worth mentioning that it was also not necessary to pre-synthesize the catalyst as the common Ni(COD)₂/L2 served well under the reaction conditions. These measures simplified the experimental manipulation, making the reaction more practical for organic synthesis.

Results and discussion

In this communication, we report our findings on the subsequent development of conditions which allow, for the first time, nickel-catalyzed cross-couplings using aromatic amines and arylzinc reagents. By heating a mixture of 4-(dimethylamino) toluene (1a, 0.2 mol), LiCl (2.0 equiv.), and MeOTf (2.0 equiv.) with stirring at 25 °C in tetrahydrofuran (THF) (3 mL) for 2 h, then adding Ni(COD)₂/L1 (1 mol%) phenylzinc (2a, 1.5 equiv.) to the reaction system, and heating to 80° for 3 h under the Ar gas, the corresponding arylated product (3aa) was produced in a 52% GC yield (Table 1, entry 1). When the reaction was carried out in the absence of any catalyst, none of the desired product was detected (Table 1, entry 2), indicating that this transformation proceeded via a transition metal–catalyzed process rather than a simple nucleophilic substitution. ¹² Other nickel catalysts such as Ni(dppp)Cl₂, Ni(dppf)Cl₂, NiCl₂(Pph₃)₂, NiCl₂, and Ni(acac)₂ could also promote this reaction, furnishing 3aa in <5%–43% yields (Table 1, entries 3–7). The ligand was also crucial to this reaction since nearly no 3aa was detected in its absence (Table 1, entry 8). Bidentate nitrogen ligands proved to be more effective than bidentate phosphine ligands, as exemplified by 1,2-bis(dimethylamino)ethane (TMEDA) L2 and 1,2-bis(dimethylamino)cyclohexane L3 (Table 1, entries 1, 7−15). The best result (70% assay yield) was obtained with L2 (Table 1, entry 9). 1.5, 1.0, and 1.3 equiv. of MeOTf and LiCl (1:1) were tested and 1.3 equiv. of MeOTf and LiCl (1:1) were demonstrated to be the most suitable amount (Table 1, entries 16–18). When the reaction was run in different solvents, the results varied greatly. Toluene was demonstrated to be ineffective (Table 1, entry 19). The use of either 1,4-dioxane or a 1:1 mixture of THF/toluene led to desired product and N-methylpyrrolidone (NMP) gave a high yield (Table 1, entries 19–21). The 1:1 mixture of THF/NMP behaved better than a single solvent and led to a slightly higher yield (Table 1, entry 23). A higher proportion of THF in the mixture of THF and NMP was more effective than 1:1 THF/NMP (Table 1, entries 24–25); hence, we chose 2:1 THF/NMP as the solvent.

Table 1.

Optimization of the reaction conditions ^a .

Entry	Cat.	Ligand	MeOTf + LiCl (equiv.)	Solvent	Yield (%) b
1	Ni(COD)2	L1	2.0 + 2.0	THF	52
2	–	L1	2.0 + 2.0	THF	–
3	Ni(dppp)Cl2	L1	2.0 + 2.0	THF	32
4	Ni(dppf)Cl2	L1	2.0 + 2.0	THF	26
5	NiCl2	L1	2.0 + 2.0	THF	<5%
6	NiCl2(Pph3)2	L1	2.0 + 2.0	THF	<5%
7	Ni(acac)2	L1	2.0 + 2.0	THF	43%
8	Ni(COD)2	–	2.0 + 2.0	THF	<5%
9	Ni(COD)2	L2	2.0 + 2.0	THF	70%
10	Ni(COD)2	L3	2.0 + 2.0	THF	59%
11	Ni(COD)2	L4	2.0 + 2.0	THF	35%
12	Ni(COD)2	L5	2.0 + 2.0	THF	11%
13	Ni(COD)2	L6	2.0 + 2.0	THF	–
14	Ni(COD)2	L7	2.0 + 2.0	THF	23%
15	Ni(COD)2	L8	2.0 + 2.0	THF	17%
16	Ni(COD)2	L2	1.5 + 1.5	THF	73%
17	Ni(COD)2	L2	1.0 + 1.0	THF	55%
18	Ni(COD)2	L2	1.3 + 1.3	THF	78%
19	Ni(COD)2	L2	1.3 + 1.3	Toluene	<5%
20	Ni(COD)2	L2	1.3 + 1.3	1,4-dioxane	56%
21	Ni(COD)2	L2	1.3 + 1.3	THF/Toluene (1:1)	32%
22	Ni(COD)2	L2	1.3 + 1.3	NMP	83%
23	Ni(COD)2	L2	1.3 + 1.3	THF/NMP (1:1)	88%
24 c	Ni(COD)2	L2	1.3 + 1.3	THF/NMP (2:1)	92% (90%)
25	Ni(COD)2	L2	1.3 + 1.3	THF/NMP (1:2)	85%

NMP: N-methylpyrrolidone, THF: tetrahydrofuran.

a

Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv.), MeOTf/LiCl (2 equiv.), catalyst 0.5 mol%, bisdentate ligand 0.5 mol%, solvent (3 mL), Ar, 80 °C, 3–5 h. ^bGC yield using tridecane as an internal standard. ^cIsolated yields are given in parentheses.

We next evaluated the substrate scope under the optimized conditions. The reaction of various aromatic amines with p-methoxyphenylzinc reagent was first examined (Table 2). Electron-deficient aromatic amines such as p-fluoro- and p-trifluoro-N,N-dimethylaniline exhibited high reactivity in the reactions with the p-methoxyphenylzinc reagent, affording the corresponding products in excellent yields (Table 2, entries 3ca and 3da). The reactions of p-chloro- and p-bromo-N,N-dimethylaniline with p-methoxyphenylzinc reagent gave relatively high yields of products (Table 2, entries 3ea and 3fa) and small amounts of 4′-methoxy-N,N-dimethyl[1,1′-biphenyl]-4-amine and 1,4-bis(4-methoxyphenyl)benzene as by-products. Electron-rich aromatic amines, such as p-methyl-N,N-dimethylaniline, also reacted smoothly with p-methoxyphenylzinc reagent under the same reaction conditions (Table 2, entry 3aa). The steric hindrance of the o-ethoxycarbonyl group in o-ethoxycarbonyl-N,N-dimethylaniline did not affect the reaction significantly (Table 2, entry 3ha). However, the more sterically hindered 2,6-dimethyl-N,N-dimethylaniline showed lower reactivity in comparison to o-ethoxycarbonyl-N,N-dimethylaniline. Its reaction with p-methoxyphenylzinc gave only a 55% yield of the cross-coupled product, although a higher yield of 3ga was obtained by increasing the reaction temperature (Table 2, entry 3ga). N,N-dimethylaniline, 4-(dimethylamino)-N,N-dimethylbenzamide, and 2-(dimethylamino)pyridine also exhibited useful reactivity and good yields were obtained (Table 2, entries 3ba, 3ia, and 3ja). The reaction of p-methyl-N,N-dimethylaniline with p-trifluoro- and p-fluorophenyl-zinc gave the desired products in 93% and 75% yields (Table 2, entries 3kb and 3kc). When p-dimethylaminophenylzinc was used as the coupling partner, only a 41% yield was obtained under similar reaction conditions. This may be due to the in situ formation of the ammonium salt from the starting arylzinc reagent with MeOTf, which leads to a complicated reaction system (Table 2, entry 3ld). The functional group compatibility of the reaction was extended to an alkyl ester (Table 2, entry 3ha), an amide (Table 2, entry 3ia), a ketone (Table 2, entries 3op and 3qi), an aldehyde (Table 2, entry 3ph), and nitriles (Table 2, entries 3rj); all coupled with (het)arylzinc reagents in excellent yields. Even p-methoxy- and o-methoxy-N,N-dimethylaniline reacted with 4-cyanophenyl- and 4-(ethoxycarbonyl)phenyl-zinc reagents resulting in satisfactory 81% and 75% yields (Table 2, entries 3me and 3nf). It appeared that no matter whether electron-rich or electron-deficient heteroarylzinc reagents were used, the reactions showed high efficiency (Table 2, entries 3op and 3sk). To show the practicability of this reaction, a gram-scale reaction of p-chloro-N,N-dimethylaniline with p-methoxyphenylzinc reagent was performed giving an 86% isolated yield of the product (Scheme 2).

Table 2.

Coupling of various arylammonium with arylzinc reagents^ab.

Ar1-NMe2	Ar2-ZnCl	Ar1-Ar2	Yield
1a	2a	3aa	90%
1b	2a	3ba	89%
1c	2a	3ca	95%
1d	2a	3da	93%
1e	2a	3ea	91%
1f	2a	3fa	73%
1g	2a	3ga	55% (83%)c
1h	2a	3ha	85%
1i	2a	3ia	91%
1j	2a	3ja	85%
1k	2b	3kb	93%
1k	2c	3kc	75%
1l	2d	3ld	41%
1m	2e	3me	81%
1n	2f	3nf	75%
1o	2g	3og	91%
1P	2h	3ph	90%
1q	2i	3qi	89%
1r	2j	3rj	89%
1s	2k	3sk	88%

a

Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv.), MeOTf/LiCl (1.3 equiv.), catalyst 0.5 mol%, ligand L2 0.5 mol%, THF/NMP (2:1) (3 mL), under Ar at 80 °C for 3–5 h. ^bIsolated yields for all products. ^cIsolated yields are given in parentheses Stirred at 100 °C.

Scheme 2.

A gram scale of reaction.

Conclusion

In conclusion, the reaction reported here is applicable to simple (het)arylammonium salts prepared in situ as the coupling partners, avoiding the synthesis and isolation of these ammonium salts. In addition, commercially available Ni(COD)₂ was used as the catalyst instead of pre-prepared Ni complexes, making the experimental procedure simpler, and excellent for laboratory and large-scale synthesis. Finally, the reaction provides an alternative method converting carbon-nitrogen bonds into carbon-carbon bonds.

Experimental

General information

Ni(acac)₂, Ni(cod)₂, NiCl₂(dppf), NiCl₂(dppp), and all ligands were purchased from Aldrich. NiCl₂, LiCl, and Ni(Pph₃)₂Cl₂ were purchased from Alfa Aesar. Other reagents are available commercially and were used without further purification, unless otherwise indicated. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. THF was dried over alumina under N₂ using a Grubbs-type solvent purification system. All arylzinc chlorides were prepared from the corresponding arylmagnesium bromides and ZnCl₂. All aromatic amines were purchased from Alfa Aesar. Spectroscopic data of the known compounds matched the published data. Reactions were monitored by Agilent GC Series 6890N and GCMS 7890A GC. All compounds were characterized by 1H NMR spectra measured on a Bruker 400 M spectrometer. 1H NMR were recorded using tetramethylsilane (TMS) in deuterated chloroform (CDCl₃) using deuterium oxide as the internal standard. Chemical shifts are reported in parts per million (d). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets; and m, multiplet. The coupling constant, J, is reported in Hertz (Hz). The products were purified by column chromatography on silica gel 300–400 mesh under an argon atmosphere.

Experimental procedures

An oven dried 25-mL Schlenk tube was charged with the amine 1 (0.2 mmol), LiCl/MeOTf (1.3 equiv.), and THF (2 mL) and was flushed with Ar 3 times. After stirring at 25 °C for 2 h, Ni(COD)₂/L2 (0.5 mol%) and the arylzinc reagent^13–15 (2a, 1.5 equiv.) in NMP (1 mL) were added to the reaction mixture. The reaction mixture was then heated to 80 °C and stirred for 3 h under Ar. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Saturated aqueous NH₄Cl was added and the mixture was extracted with CH₂Cl₂ several times. The combined organic extracts were dried over anhydrous MgSO₄, concentrated under reduced pressure, and the resulting crude mixture was purified by silica gel column chromatography on silica gel 300–400 mesh by mixed solvents of different proportions of ethyl acetate and hexane.

Supplemental Material

sj-doc-1-chl-10.1177_17475198211063806 – Supplemental material for One-pot nickel-catalyzed cross-coupling of (Het)arylammonium salts prepared in situ and organozinc reagents

Supplemental material, sj-doc-1-chl-10.1177_17475198211063806 for One-pot nickel-catalyzed cross-coupling of (Het)arylammonium salts prepared in situ and organozinc reagents by Yong-Mao Huang in Journal of Chemical Research