Ru(II)-Catalyzed Amination of Aryl Fluorides via η6-Coordination

Article abstract of DOI:10.1021/jacs.9b13684

We developed a Ru/hemilabile-ligand-catalyzed nucleophilic aromatic substitution (S_NAr) of aryl fluorides as the limiting reagents. Significant ligand enhancement was demonstrated by the engagement of both electron-rich and neutral arenes in the S_NAr amination without using excess arenes. Preliminary mechanistic studies revealed that the nucleophilic substitution proceeds on a η⁶-complex of the Ru catalyst and the substrate, and the hemilabile ligand facilitates dissociation of products from the metal center.

Full text of DOI:10.1021/jacs.9b13684

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Ru(II)-Catalyzed Amination of Aryl Fluorides via #-Coordination
Qi-Kai Kang, Yunzhi Lin, Yuntong Li, and Hang Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13684 • Publication Date (Web): 10 Feb 2020
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Ru(II)-Catalyzed Amination of Aryl Fluorides via η6-Coordination
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Qi-Kai Kang,†,‡ Yunzhi Lin,†,‡ Yuntong Li†,‡ and Hang Shi*,†,‡
† Institute of Natural Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang
Province, China.
‡ Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake Univer-
sity, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.
Supporting Information Placeholder
temporarily may promote product dissociation through steric repul-
ABSTRACT: We developed a Ru/hemilabile-ligand catalyzed
sion; 2) the ligand’s hemilabile nature may provide flexibility to
stabilize reaction intermediates, as well as reduce steric effect in
the coordination of substrates to the catalyst. Herein, we present a
bisphosphine-Ru catalyzed SNAr amination that converts the inert
aryl C–F bond without the remnant of excessive arenes (Scheme
1d).8
nucleophilic aromatic substitution (SNAr) of aryl fluorides as the
limiting reagents. Significant ligand enhancement was demon-
strated by the engagement of both electron-rich and neutral arenes
in the SNAr amination without using excess arenes. Preliminary
mechanistic studies revealed that the nucleophilic substitution pro-
ceeds on a η6-complex of the Ru-catalyst and the substrate, and the
hemilabile ligand facilitates dissociation of products from the metal
center.
Scheme 1. SNAr reaction via η6-coordination
Nucleophilic aromatic substitution reactions of aryl halides with
external nucleophiles are among the most reliable transformations
for arene functionalization. In 2016, Brown analyzed reactions
used in medicinal chemistry research, and revealed that SNAr is the
most frequently transformation after amide bond formation.1 Alt-
hough various applications have been demonstrated, the classical
stepwise SNAr reaction, in general, is limited to the highly electron-
deficient arenes.2 In comparison, concerted protocols in part over-
come the above disadvantage by employing a stoichiometric
amount of activating reagents and/or strong bases.3 In addition, the
stepwise SNAr promoted by transition-metals (umpolung aromatic
substitution) is compatible with an array of unreactive aryl halides
by using the corresponding η6-arene-complexes as substrates
(Scheme 1a).4 In contrast to numerous stoichiometric reactions re-
ported to date, only a few catalytic examples that require large ex-
cess of aryl halides have been addressed.5 TM-catalyzed SNAr re-
action of electron-rich or neutral aryl fluorides as limiting reagents
remains to be demonstrated.
In general, umpolung aromatic substitution involves arene asso-
ciation, nucleophilic aromatic substitution of the resulting η6-com-
plex, and product dissociation.4 In a catalytic process, substrate as-
sociation and product dissociation merge as arene exchange, which
markedly affects the catalytic efficiency.5 A typical obstacle in
arene exchange is the detachment of one double bond from a rela-
tively stable η6-complex, which generates the corresponding η4-in-
termediate (Scheme 1b).6 Following an observation that donor mol-
ecules such as THF and cyclohexanone benefit arene exchange,
chemists introduced a coordinating group as a side chain on the lig-
ands to accelerate the exchange rate.5g,7 However, examples for the
ligand promoted SNAr by the strategy outlined above are absent. To
overcome the obstacle, we envisioned to utilize hemilabile, biden-
tate ligands, which could benefit catalytic SNAr reactions in two
ways (Scheme 1c): 1) a side chain group L’ that coordinates to TM
To execute this strategy, we selected fluorobenzene 1a as a lim-
iting reagent to explore the feasibility of SNAr amintion (Table 1).
Dichloro(cymene)ruthenium dimer was used as a precursor of the
real catalyst, cationic Ru(II)-ligand complex, which was formed
through a Ag-promoted dechlorination and subsequent ligand co-
ordination. We firstly investigated the reaction conditions with sev-
eral representative ligands such as cyclopentadienyl anion (Cp, L1),
N-heterocyclic carbene (NHC, L2), and bipyridine (L3). However,
none of them gave any observable amination product 2a. We then
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turned to test phosphine ligands, and detected a trace amount of 2a
The optimized amination conditions proved effective for intro-
duction of the morpholine motif on a wide range of aromatics. (Ta-
ble 2). Both electron-rich (2b, 2c) and deficient (2d, 2e) ortho-sub-
stituted aryl fluorides were compatible, giving more than 50%
yields. Notably, the C–Cl bond (2e), which is more reactive than a
C–F bond in both Hartwig-Buchwald9 and Ullmann aminations10,
survived under the conditions. A broad range of substituents at the
meta-position, including strongly electron-donating groups such as
-OMe (2f), -SMe (2g), -NH2 (2h) and alkene (2i), as well as elec-
tron-neutral methyl (2j) and benzyl (2k) groups, were all tolerated,
providing desired products in good yields. The free hydroxyl group
did not inhibit the reaction (2l, 2m), while the primary alcohol was
converted to the amine 2m under the conditions. Para-substituted
aryl fluorides bearing various functional groups (2n-2u) showed
good reactivity in the reactions. An array of active motifs were tol-
erated, for example: amine (2o), amide (2r), sulfamide (2s), borate
(2t), and carboamide (2u). Multi-substituted aryl fluorides also
gave desired products in good yields (2v-2y). Notably, exclusive
regio-selectivity was observed in the aminations of difluoroaniline
(2w) and difluorophenol (2x). For substrate 1z, which bears two
aromatic fluoride motifs, the nucleophilic substitution predomi-
nantly happened on the more electron-rich arene (2z), giving com-
plete opposite selectivity with classical SNAr reactions (2z’).
by utilizing monodentate triphenylphosphine (L4) or diphenyl-
butylphosphine (L5). Notably, following our design, when a
hemilabile phosphine ligand (L6) bearing a methoxyl side chain
was used, a dramatic improvement of the yield (42%) was obtained.
Changing either the flexibility of the side chain (L7, L8, L9) or the
steric environment around the chelating atom oxygen (L10, L11,
L12) reduced the yield or even inhibited the reaction. An array of
stronger donating groups, thioether (L13), amine (L14), phosphine
(L15), and pyridine (L16), were examined and proved ineffective,
demonstrating the importance of matching the two chelating groups
on the hemilabile ligand. Tridentate ligand L17 bearing two meth-
oxyl groups reduced the yield of 2a to 13%, while L18 did not af-
ford any desired product, which is consistent with the above obser-
vation that using a strongly coordinating group instead of the OMe
suppressed the reaction. We then evaluated aryl groups of phos-
phines: 1) both the steric hindrance of an ortho substituent (L19)
and electron-deficient arenes (L20, L21) decreased the yield; 2) in-
troducing an electron-donating group (L22) slightly improved the
yield to 45%, but further increasing the electron-density of the
arene (L23) only resulted in 35% yield. Further optimization of the
conditions, including solvent and temperature, enhanced the yield
to 95% with L22 as the ligand (for more details of optimization,
see Supporting Information).
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We next examined the scope of amines by using 3,4-difluoroan-
iline as the limiting reagent (Table 3). Piperidine (3a) and its ana-
logues (3b to 3e), including hydroisoquinoline and N-methylpiper-
azine, turned out to be suitable nucleophiles, giving the yield up to
98%. The 4-membered amine, azetidine, was not stable under the
conditions, and only a trace amount of product was observed. In
comparison, both 5- and 7-membered amines gave the desired
products in good yields, respectively (3g, 3h). Other than cyclic
amines, linear secondary and primary amines were all compatible,
affording products in moderate yields (3i-3l). Notably, a high meta-
selectivity was observed in each of the above case.
Table 1. Catalyst Development for SNAr Aminationa
Given the limited knowledge on phosphine-supported Ru-
fluoroarene complex,5d,5e,11 we synthesized a Ru-fluoroarene η6-
complex 4 to gain insights into the reaction process (Scheme 2a).
The proposed SNAr amination precursor 5, bisphosphine-Ru arene
η6-complex, was synthesized from complex 4 and characterized by
NMR spectroscopy. According to the 1H and 31P NMR spectra, we
propose that the two hemilabile ligands on intermediate 5 are asym-
metric: one chelates the Ru by the phosphine and oxygen simulta-
neously, while the other is mono-coordinated. Unexpectedly, the
fluorine peak disappeared instantly after adding morpholine, which
suggests the amination proceeds fast even at room temperature. Fi-
nally, heating the reaction mixture released the free aniline product
in 65% yield based on the starting complex 4. During the above
investigations, no signal of free fluoroarene was detected by 19F
NMR. The experiments support that the amination proceeds on a
η6-complex of the Ru-catalyst and fluoroarene. Furthermore, we
compared diphenylbutylphosphine L5 that possesses a non-coordi-
nating, linear group with the hemilabile ligand L6 in the arene dis-
sociation (Scheme 2b). The hemilabile ligand coordinated Ru com-
plex 8 released the aniline completely in a half hour under heating
conditions. In comparison, only a trace amount of the free aniline
was detected by using ligand L5, which revealed that the weakly
coordinating group facilitates dissociation of product arenes from
the Ru center.
aConditions: 1a (0.40 mmol), morpholine (0.44 mmol), [Ru(cy-
mene)Cl2]2 (0.010 mmol), AgPF6 (0.042 mmol), Ligand (0.048
mmol), 4Å MS (20 mg), 1,4-dioxane (0.10 mL), N2, 100 °C. Yield
was determined by 1H NMR using 1,1,2,2-tetrachloroethane as the
b
c
internal standard. Ligand (0.024 mmol). Ligand (0.040 mmol),
morpholine (1.2 mmol), THF (0.10 mL), 120 °C.
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Table 2. Scope of Aryl Fluoridesa
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aConditions: 1 (0.40 mmol), [Ru(cymene)Cl2]2 (0.010 mmol), AgPF6 (0.042 mmol), Ligand (0.040 mmol), morpholine (1.2 mmol), 4Å MS
(20 mg), THF (0.10 mL), N2, 120 °C.b2-(4-Fluorophenyl)ethanol was used as the substrate. c[Ru(cymene)Cl2]2 (0.040 mmol), AgPF6 (0.168
d
mmol), Ligand (0.16 mmol). [Ru(cymene)Cl2]2 (0.020 mmol), AgPF6 (0.084 mmol), Ligand (0.080 mmol). Data are reported as isolated
yield of purified compound.
Table 3. Scope of Aminesa
Scheme 2. Mechanistic Studies
aConditions: 1w (0.40 mmol), amine (1.20 mmol), [Ru(cy-
mene)Cl2]2 (0.010 mmol), AgPF6 (0.042 mmol), L22 (0.040 mmol),
b
4Å MS (20 mg), THF (0.10 mL), 120 °C. L6 (0.040 mmol).
c[Ru(cymene)Cl2]2 (0.020 mmol), AgPF6 (0.084 mmol), L22
(0.080 mmol). Data are reported as isolated yield of purified com-
pound.
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has been developed. The mild reaction conditions, as well as broad
substrate scope, make this protocol attractive for synthesis and
functionalization of bioactive compounds. Preliminary mechanistic
studies reveal that the substitution proceeds via η6-coordination,
and the weakly coordinating group on the hemilabile ligand pro-
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, characterization of new compounds and
spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*shihang@westlake.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This project was supported by Foundation of Westlake University,
and China Postdoctoral Science Foundation (2019M662118). We
thank Instrumentation and Service Center for Physical Sciences at
Westlake University for the assistance work in measurement/data
interpretation.
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