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Challenging nickel-catalysed amine arylations enabled by tailored ancillary ligand design

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ABSTRACT

Palladium-catalysed C(sp2)–N cross-coupling (that is, Buchwald–Hartwig amination) is employed widely in synthetic chemistry, including in the pharmaceutical industry, for the synthesis of (hetero)aniline derivatives. However, the cost and relative scarcity of palladium provides motivation for the development of alternative, more Earth-abundant catalysts for such transformations. Here we disclose an operationally simple and air-stable ligand/nickel(II) pre-catalyst that accommodates the broadest combination of C(sp2)–N coupling partners reported to date for any single nickel catalyst, without the need for a precious-metal co-catalyst. Key to the unprecedented performance of this pre-catalyst is the application of the new, sterically demanding yet electron-poor bisphosphine PAd-DalPhos. Featured are the first reports of nickel-catalysed room temperature reactions involving challenging primary alkylamine and ammonia reaction partners employing an unprecedented scope of electrophiles, including transformations involving sought-after (hetero)aryl mesylates for which no capable catalyst system is known.

No MeSH data available.


Preliminary ligand screen in the nickel-catalysed monoarylation of ammonia.Reactions employed 4-chlorobiphenyl (0.12 mmol), 0.5 M stock solutions of ammonia in 1,4-dioxane (0.72 ml) and toluene (1.00 ml). Conversions estimated on the basis of gas chromatographic data, reported as % 4-aminobiphenyl (% 4-chlorobiphenyl unreacted); mass balance attributable to biphenyl and/or other unidentified products; COD, 1,5-cyclooctadiene.
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f3: Preliminary ligand screen in the nickel-catalysed monoarylation of ammonia.Reactions employed 4-chlorobiphenyl (0.12 mmol), 0.5 M stock solutions of ammonia in 1,4-dioxane (0.72 ml) and toluene (1.00 ml). Conversions estimated on the basis of gas chromatographic data, reported as % 4-aminobiphenyl (% 4-chlorobiphenyl unreacted); mass balance attributable to biphenyl and/or other unidentified products; COD, 1,5-cyclooctadiene.

Mentions: Against this background, we selected the monoarylation of ammonia with 4-chlorobiphenyl (1a) as a testing ground on which to evaluate the catalytic abilities of L1–L5 and related ligands (Fig. 3). Although Ni(COD)2/L2-L4 mixtures (COD=1,5-cyclooctadiene) performed poorly, use of Ni(COD)2/L1 afforded high conversion to the desired 4-aminobiphenyl (2a). These findings are in keeping with our view that sterically demanding yet relatively electron-poor bisphosphine ancillary ligands should support particularly effective nickel catalysts for such challenging cross-couplings (vide supra). Nonetheless, the competent performance of the P(tBu)2/P(o-tolyl)2 ancillary ligand L5, although inferior to the CgP/P(o-tolyl)2 variant L1 in the test reaction employed (Fig. 3), suggests that ancillary ligand sterics is particularly important in engendering useful catalytic behaviour within the nickel-catalysed C(sp2)–N cross-couplings under scrutiny herein. The poor performance of both CgPPh38 and P(o-tolyl)2Ph50, which did not vary when using Ni:L=1:1 or 1:2, confirms the benefit of bisphosphine ligation by L1. Finally, the observation that [Pd(cinnamyl)Cl]2/L1 mixtures afforded no conversion of 1a under analogous conditions underscores that the design of L1 (PAd-DalPhos) is particularly well-matched to the properties of nickel, rather than those of palladium, in this reaction setting.


Challenging nickel-catalysed amine arylations enabled by tailored ancillary ligand design
Preliminary ligand screen in the nickel-catalysed monoarylation of ammonia.Reactions employed 4-chlorobiphenyl (0.12 mmol), 0.5 M stock solutions of ammonia in 1,4-dioxane (0.72 ml) and toluene (1.00 ml). Conversions estimated on the basis of gas chromatographic data, reported as % 4-aminobiphenyl (% 4-chlorobiphenyl unreacted); mass balance attributable to biphenyl and/or other unidentified products; COD, 1,5-cyclooctadiene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814586&req=5

f3: Preliminary ligand screen in the nickel-catalysed monoarylation of ammonia.Reactions employed 4-chlorobiphenyl (0.12 mmol), 0.5 M stock solutions of ammonia in 1,4-dioxane (0.72 ml) and toluene (1.00 ml). Conversions estimated on the basis of gas chromatographic data, reported as % 4-aminobiphenyl (% 4-chlorobiphenyl unreacted); mass balance attributable to biphenyl and/or other unidentified products; COD, 1,5-cyclooctadiene.
Mentions: Against this background, we selected the monoarylation of ammonia with 4-chlorobiphenyl (1a) as a testing ground on which to evaluate the catalytic abilities of L1–L5 and related ligands (Fig. 3). Although Ni(COD)2/L2-L4 mixtures (COD=1,5-cyclooctadiene) performed poorly, use of Ni(COD)2/L1 afforded high conversion to the desired 4-aminobiphenyl (2a). These findings are in keeping with our view that sterically demanding yet relatively electron-poor bisphosphine ancillary ligands should support particularly effective nickel catalysts for such challenging cross-couplings (vide supra). Nonetheless, the competent performance of the P(tBu)2/P(o-tolyl)2 ancillary ligand L5, although inferior to the CgP/P(o-tolyl)2 variant L1 in the test reaction employed (Fig. 3), suggests that ancillary ligand sterics is particularly important in engendering useful catalytic behaviour within the nickel-catalysed C(sp2)–N cross-couplings under scrutiny herein. The poor performance of both CgPPh38 and P(o-tolyl)2Ph50, which did not vary when using Ni:L=1:1 or 1:2, confirms the benefit of bisphosphine ligation by L1. Finally, the observation that [Pd(cinnamyl)Cl]2/L1 mixtures afforded no conversion of 1a under analogous conditions underscores that the design of L1 (PAd-DalPhos) is particularly well-matched to the properties of nickel, rather than those of palladium, in this reaction setting.

View Article: PubMed Central - PubMed

ABSTRACT

Palladium-catalysed C(sp2)–N cross-coupling (that is, Buchwald–Hartwig amination) is employed widely in synthetic chemistry, including in the pharmaceutical industry, for the synthesis of (hetero)aniline derivatives. However, the cost and relative scarcity of palladium provides motivation for the development of alternative, more Earth-abundant catalysts for such transformations. Here we disclose an operationally simple and air-stable ligand/nickel(II) pre-catalyst that accommodates the broadest combination of C(sp2)–N coupling partners reported to date for any single nickel catalyst, without the need for a precious-metal co-catalyst. Key to the unprecedented performance of this pre-catalyst is the application of the new, sterically demanding yet electron-poor bisphosphine PAd-DalPhos. Featured are the first reports of nickel-catalysed room temperature reactions involving challenging primary alkylamine and ammonia reaction partners employing an unprecedented scope of electrophiles, including transformations involving sought-after (hetero)aryl mesylates for which no capable catalyst system is known.

No MeSH data available.