Anion ligand promoted selective C-F bond reductive elimination enables C(sp2)-H fluorination

Article abstract of DOI:10.1039/c9cc07726j

A detailed mechanism study on the anion ligand promoted selective C-H bond fluorination is reported. The role of the anion ligand has been clarified by experimental evidence and DFT calculations. Moreover, the nitrate promoted C-F bond reductive elimination enabled a selective C-H bond fluorination of various symmetric and asymmetric azobenzenes to access diverse o-fluoroanilines.

Full text of DOI:10.1039/c9cc07726j

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Anion ligand promoted selective C–F bond
reductive elimination enables C(sp2)–H
fluorination†
Cite this: Chem. Commun., 2019,
55, 14458
Received 2nd October 2019,
Accepted 4th November 2019
a
Yang-Jie Mao,
Gen Luo, *b Hong-Yan Hao,a Zhen-Yuan Xu,a
Shao-Jie Lou *a and Dan-Qian Xu
*
a
DOI: 10.1039/c9cc07726j
rsc.li/chemcomm
A detailed mechanism study on the anion ligand promoted selective
C–H bond fluorination is reported. The role of the anion ligand has
been clarified by experimental evidence and DFT calculations.
Moreover, the nitrate promoted C–F bond reductive elimination
enabled a selective C–H bond fluorination of various symmetric
and asymmetric azobenzenes to access diverse o-fluoroanilines.
The strategies to incorporate fluorine into organic molecules have
long been explored due to the unique properties of fluorinated
motifs.1 Pd catalysis plays an important role in this field.
However, given the low nucleophilicity of the fluorine anion,
C–F bond reductive elimination from aryl-Pd(II)–F species is
usually challenging.2 Metals in higher oxidation states are more
favorable to undergo reductive eliminations and facilitate the con-
Scheme 1 Selective reductive elimination from Pd(IV).
struction of new chemical bonds,3 thus a high-valent aryl-Pd(IV)–F group studied the selective C(sp3)–F reductive elimination of Pd(IV)
species has emerged as a useful alternative for the synthesis of aryl with diverse oxygen nucleophiles. Interestingly, a special cation
fluorides via C–H bond activation.4 Despite the advances, the effect was observed to enable the disfavored C(sp3)–F coupling.5b
selective reductive elimination from octahedral Pd(IV) intermediates Very recently, Yu’s group exhibited a selective benzylic C–H fluori-
remains the central goal of this chemistry. Owing to the sluggish C–F nation controlled by adjusting the ligand environment of Pd(IV)
reductive elimination, a number of different anion ligands such as fluoride species.6 Another practical and efficient pathway to achieve
acetoxyl, halo or N-anions adopted at high-valent Pd(IV)–F species selective C–F bond reductive eliminations is to replace the
will participate in the competing reductive elimination (RE) to afford competing nucleophilic anions with less nucleophilic anion ligands
diverse products other than fluorides, which renders F+ reagents as especially in a catalytic fashion. For instance, Yu previously used
so-called bystanding oxidants (Scheme 1, a).3e,5 Therefore, general palladium triflates to avoid the side C–H acetoxylation in their C–H
strategies to control the selectivity of RE from high-valent Pd(IV) bond fluorination.4e,7 Our group developed a Pd–nitrate catalytic
fluorides are highly desirable in developing reliable procedures for system for the selective C(sp2)–H bond fluorination of diverse
C–F bond formation.
fundamental substrates, albeit with a deficient understanding of
Several strategies have been developed to control the selective the mechanism.8 Herein, we report detailed mechanism studies on
C–F bond RE from Pd(IV)–F intermediates. In 2014, Sanford’s the role of anionic NOx additives in C–H bond fluorination. Two
well-defined aryl-Pd(II)–NOx complexes were obtained and studied
for the first time (Scheme 1, b). NOx anions such as nitrate or nitrite
have received increasing attention due to their unique reactivity in
several palladium-catalyzed reactions.9 However, the catalytic
behavior of putative Pd(II)–NOx complexes in catalytic processes
is somehow elusive.
At the outset of the project, the preliminary reaction conditions
were screened for the C–H bond fluorination of azobenzene 1a.
As anticipated, the Pd catalyst and nitrate are indispensable in
a College of Chemical Engineering, Catalytic Hydrogenation Research Center, State
Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang
University of Technology, Hangzhou 310014, P. R. China.
E-mail: loushaojie@zjut.edu.cn, chrc@zjut.edu.cn
b State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian
University of Technology, Dalian 116024, P. R. China. E-mail: luogen@dlut.edu.cn
† Electronic supplementary information (ESI) available. CCDC 1853333,
1949005–1949006. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c9cc07726j
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Fig. 1 Catalytic activity of [Pd] complexes with varying equivalents of
AgNO3.
Scheme 2 Preparation and transformation of Pd(II) complexes.
complexes should be the key reactive species. In addition, the
this reaction. 1a was largely converted into the desired product 1-(2- kinetic experiment displayed a lack of induction period, indicating
fluorophenyl)-2-phenyldiazene 2a when a catalytic amount of that the cyclopalladatation complexes might be involved in the
AgNO3 or AgNO2 was used as an additive in EtOAc. The reaction catalytic cycle (see the ESI,† S6).10
efficiency decreased sharply when the nitrate additive was replaced
These stoichiometric and catalytic reactions showed a great
ligand effect of NOx additives in the fluorination. We proposed
by other anion ligands (see the ESI,† S4).10
The unique anionic effect encouraged us to prepare aryl-Pd–NOx that the NOx ligands might promote the fluorination by the
complexes to get further insight into the mechanism. Firstly, a well- following two pathways: (1) control the selective C–F bond
established Cl-bridged dinuclear Pd(II) complex Int-I was prepared reductive elimination from high-valent Pd(IV) due to their poor
(Scheme 2).11 Treating Int-I with AgNOx could quantitatively give nucleophilicity; (2) make the Pd metal center more electrophilic
Pd(II)–NOx complexes Int-II and Int-III smoothly (see the ESI†).12 and attenuate the polarization of the Pd(IV)–F bond due to the
X-ray analysis of Int-II revealed that the NO3 ligand is trans to the coordination of the highly electron-withdrawing NOx ligand.
sp2-carbon center and possesses O-bound to the Pd center. In HRMS analysis and 19F NMR experiments were then conducted
contrast, complex Int-III has cis-configuration and an N-bound in order to capture the putative Pd(IV) species.13 A m/z value
nitrite ligand. Our initial study commenced on evaluating the of 601.9837 was detected when the reaction mixture of Int-II
fluorination of the Pd(II) complexes with NFSI and diverse anion with NFSI was subjected to HRMS (ESI-TOF), which was con-
additives. As shown in Scheme 2, treating Int-I with NFSI and sistent with the m/z value of the Pd(IV) fluoride intermediate
different additives afforded a mixture of 1a, 2a and 2-Cl. Notably, [azobenzene–PdIV(F)–N(SO2Ph)2]+. And a fluorine resonance at
anion additives had a profound influence on the transformation À180 ppm was monitored by 19F NMR from the reaction
of Int-I. Chlorinated azobenzene 2-Cl was detected as the sole mixture of Int-II with NFSI in CD3CN, the pivotal signal of
product in the absence of any additives. Nitrate additives such as which might be the fluorine resonance of the key [azobenzene–
KNO3, CsNO3, and AgNO3 significantly promoted the fluorina- PdIV–F] intermediate according to the previous reports.8d,13
tion. Moreover, 2-Cl was not observed in the absence of nitrate After 30 min and heating at 55 1C for another 25 min, the
and NFSI, which suggested that an oxidative induced C(sp2)–Cl fluorine resonance of the o-fluoroazobenzene emerged, indicating
bond reductive elimination from a high-valent Pd(IV) chloride that the reductive elimination of the [azobenzene–PdIVÀF] inter-
intermediate might be involved in this chlorination. In addition, mediate might take place to give the fluorinated azobenzene.
both the Pd(II)–NOx complexes transformed smoothly into fluori- However, probably due to their high reactivity, an attempt to
nation product 2a even at room temperature within 2 hours in obtain the high-valent aryl-Pd(IV)–NOx complexes failed. Thus, as
À
the absence of extra anion ligands, which further implied the an alternative, the reductive elimination processes of ClÀ, NO3
,
À
pivotal role of NOx in the selective C–F bond formation. Next, an and NO2 substituted Pd(IV) species were investigated by DFT
assessment of diverse Pd(II) complexes for the catalytic fluorina- calculations.13 As shown in Fig. 2, the Pd(IV) species (A, B, and C)
tion of 1a was done as shown in Fig. 1. In all cases, the addition adopt an octahedron form, in which the azobenzene and
of a catalytic amount of nitrate could dramatically promote the N(SO2Ph)2 anionic ligands occupied the equatorial positions
fluorination of 1a. Pd(dba)2, PdCl2, and Int-I showed negativÀe and the F and Cl (or NO3/NO2) anionic ligands were located at
catalytic reactivity in the absence of AgNO3. In sharp contrast, NOx
the axial positions. It was obvious that the equatorial N(SO2Ph)2
containing complexes, especially the aryl-Pd(II)–NO3 complex Int-II, ligand in Pd(IV) species was bound to the Pd center in Z2-form and
gave much better results, which suggested that the aryl-Pd(II)–NOx thus less available to undergo the reductive elimination process
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Table
1
C–H Fluorination of symmetrical and unsymmetrical
azobenzenesab
Fig. 2 Computed reductive elimination processes of the species A, B, and C.
The relative free energy barriers (DG‡) are given in kcal molÀ1
.
compared with the axial Z1-coordinated F or Cl (NO3/NO2) anionic
ligands. In Cl-containing species A (Fig. 2a), the reductive elimina-
tion of C–Cl via TS-ACl (DG‡ = 12.6 kcal molÀ1) was more favorable
than that of C–F via TS-AF (DG‡ = 14.6 kcal molÀ1). This is in good
agreement with the experimental observation that a chlorinated
product was obtained rather than a fluorinated product. In contrast
to A, in the cases of B and C, the reductive elimination processes of
C–F were favored compared to those of C–ONO2 or C–NO2, thus
leading to fluorinated product (Fig. 2b and c). The computational
results clearly suggested that the introduction of NO3 or NO2 anions
could reduce the energy barrier of C–F reductive elimination and
increase the energy barrier of reductive elimination of the other
À
anion (NO3 or NO2À) in comparison with the Cl-containing case.
Therefore, the synthesis of the fluorinated product could be achieved
by regulating the anions.
Guided by this mechanistic blueprint, we commenced to
carry out the catalytic C–H bond fluorination of azobenzenes.
Though azobenzenes are widely found as substrates in various C–H
bond transformations as aniline surrogates, no C–H fluorination
has been reported to date.14 Further detailed screening of the
catalytic conditions was conducted (see the ESI†).10 The substrate
scope of symmetrical azobenzenes was then explored under the
optimal conditions. Considering the inseparable mixture of mono-
and difluorinated arenes, we proposed to eliminate the NQN
framework by restoring the azo double bond to the corresponding
anilines, which is present widely in various pharmaceuticals and
medical intermediates (i.e. Cobimetinib, Regorafenib and Finaflox-
a
Conditions: 1 or 3 (0.30 mmol), Pd(dba)2 (10 mol%), NFSI (0.60 mmol),
KNO3 (30 mol%) in 1.5 mL of EtOAc under air at the indicated oil bath
temperature for 12 h. Yield of the mono-fluorination was determined by
GC-MS using biphenyl as an internal standard as shown in parentheses.
b
Azobenzene reduction procedure: NaBH4 (7.0 equiv.), CuCl (6.0 equiv.),
anhydrous ethanol (0.1 M), RT, air, 5–30 min, unless otherwise noted.
Isolated yields of o-fluoroanilines over two steps were given, see the ESI
for the detailed reaction information of each entry from different starting
materials. Reduction process was under reflux. RA = recovered 2,4,6-
trimethylaniline. Using 4.0 equiv. NFSI.
c
d
e
acin, see the ESI†).15,16 Pleasingly, under the efficient NaBH4–CuCl with more electron-withdrawing groups required more harsh condi-
reductive system,17 the desired fluorinated anilines could be tions at temperatures ranging from 75 1C to 105 1C. Halo groups
obtained in moderate to good yields (Table 1).
such as chloro (4h and 4p) and bromo (4i and 4q) remained intact
Various symmetrical para- (4a–d and 4f–k), meta (4m and under the fluorination conditions. Fluorination of meta-substituted
4o–r) or ortho (4s)-substituted azobenzenes were tested in this substrates took place at the less sterically hindered para-sites of the
fluorination. In general, both electron-donating (4b–d, 4m, and 4t) functional groups (4m and 4o–r).
and electron-withdrawing (4f–k and 4o–s) groups were well tolerated
Next, we turned our attention to the scope of diverse unsym-
under the fluorination conditions at indicated temperatures. metrical azobenzenes. We envisaged that the inactive aniline
Electron-rich azobenzenes were more prone to undergo fluorination moiety in unsymmetrical azobenzene could serve as a removable
in good yields under mild conditions at 55 1C. In contrast, substrates directing group, which would be utmost practical for the C–H
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In conclusion, a nitrate-promoted selective C–H fluorination
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corresponding fluorinated anilines by further reduction. More
importantly, the ligand effect of NOx additives was studied in
detail by employing well-defined aryl-Pd(II)–NOx intermediates.
In addition, DFT calculations showcased that utilizing simple
nitrate/nitrite as an anion ligand significantly decreased the
energy barrier of the C–F bond reductive elimination pathway
from the Pd(IV) intermediate. Utilizing this distinct strategy for
the selective reductive elimination of other challenging
chemical bonds could also be expected in the near future.
G. L. thanks the Fundamental Research Funds for the
Central Universities (DUT18RC(3)002) and the Network and
Information Center of Dalian University of Technology for
computational resources.
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Conflicts of interest
9 I. J. S. Fairlamb, Angew. Chem., Int. Ed., 2015, 54, 10415.
10 For detailed information, see the ESI†.
The authors declare no competing financial interests.
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