Cooperative Ligand-Promoted P(III)-Directed Ruthenium-Catalyzed Remote Meta-C-H Alkylation of Tertiary Phosphines

Article abstract of DOI:10.1021/acs.orglett.1c00237

Herein, we disclose a ruthenium-catalyzed meta-selective C-H activation of phosphines by using intrinsic P(III) as a directing group. 2,2,6,6-Tetramethylheptane-3,5-dione acts as the ligand and exhibits an excellent performance in boosting the meta-alkylation. The protocol allows an efficient and straightforward synthesis of meta-alkylated tertiary phosphines. Several meta-alkylated phosphines were evaluated for Pd-catalyzed Suzuki coupling and found to be superior to commercially available ortho-substituted phosphines. The practicability of this methodology is further demonstrated by the synthesis of difunctionalized phosphines.

Full text of DOI:10.1021/acs.orglett.1c00237

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Letter
Cooperative Ligand-Promoted P(III)-Directed Ruthenium-Catalyzed
Remote Meta-C−H Alkylation of Tertiary Phosphines
Zheng-Xin Zhou, Jia-Wei Li, Liang-Neng Wang, Ming Li, Yue-Jin Liu,* and Ming-Hua Zeng*
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ABSTRACT: Herein, we disclose a ruthenium-catalyzed meta-selective C−H activation of phosphines by using intrinsic P(III) as a
directing group. 2,2,6,6-Tetramethylheptane-3,5-dione acts as the ligand and exhibits an excellent performance in boosting the meta-
alkylation. The protocol allows an efficient and straightforward synthesis of meta-alkylated tertiary phosphines. Several meta-alkylated
phosphines were evaluated for Pd-catalyzed Suzuki coupling and found to be superior to commercially available ortho-substituted
phosphines. The practicability of this methodology is further demonstrated by the synthesis of difunctionalized phosphines.
Scheme 1. C−H Functionalizations of Phosphines
rganic phosphines constitute an important class of
Omolecules, which finds widespread applications in the
field of medicine, materials, organocatalysis, and particularly
metal catalysis as effective ligands.1 The importance of
phosphines provides a continuous driving force for the
development of more efficient synthetic methods. In recent
years, transition metal-catalyzed C(sp2)−H bond activation2
provides an efficient approach to functionalize phosphines.3
For instance, selective C−H functionalizations of phosphines
via O- or S directed C(sp2)−H activation were independently
developed by Miura, Glorius, and other groups.4 Recently,
P(III)-assisted ortho-C(sp2)−H functionalizations of phosphines
were accomplished by Clark, Shi, Soule, Takaya, and our
group, respectively (Scheme 1a).5 Compared with these
advances gained in ortho-C−H functionalization, selective
meta-C(sp2)−H functionalization of phosphines remains
unsolved and seems rather challenging, especially for tertiary
phosphines in virtue of its strong coordination ability.6 Herein,
we report a ruthenium-catalyzed meta-C(sp2)−H alkylation of
tertiary phosphines by using intrinsic PIII as a directing group
(Scheme 1c), which provides an efficient and rapid access to a
variety of synthetically useful phosphines from commercially
available precursors.
the difficulty in removal or derivatization of these directing
groups poses a fatal threat to its synthetic practicability.
Notably, Ackermann et al. designed a removable N-
(pyrimidine-2-yl) group for directing ruthenium-catalyzed
In recent years, meta-C(sp2)−H functionalization witnessed
rapid progress.7,8 In this area, several examples of meta-C−H
functionalization via ruthenium-catalyzed σ- activation were
independently reported by Ackermann, Frost, Greaney, et al.9
In those transformations, strongly N-based coordinating
groups including heteroaromatic pyridyl, pyrazolyl, imidazolyl,
and pyrimidyl are required as the directing groups. However,
Received: January 21, 2021
Published: February 25, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00237
© 2021 American Chemical Society
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meta-C−H alkylation of anilines.9b Recently, we reported the
ruthenium-catalyzed ortho-C−H functionalizations of phosphi-
nes5k,l in which a key six-membered ruthenacycle was
successfully isolated. Based on these results, we envisioned
that selective meta-C−H functionlization of tertiary phos-
phines could be achieved with the strategy of ruthenium-
catalyzed σ-activation. We hypothesized that a six-membered
ruthenacycle could be formed and might electronically
enhance the activation of para position and, hence, enable
para-functionalization to the ruthenium center. The success of
this strategy lies in the identification of an efficient catalytic
system, especially a suitable ligand to enhance the ruthenium
center electronically as well as promote the step of reductive
elimination.
K2CO3 and NaOAc were also tested but did not give better
results (entries 6 and 7). Control experiments indicated that
ruthenium catalyst is essential to this reaction, and L6 is rather
crucial to achieve a high catalytic efficiency (entries 8 and 9).
The high efficiency of 1,3-dione ligands may result from the
strong coordination of the dioxygen atom to the ruthenium
center.10 Other 1,3-dione compounds were also investigated.
In comparison to L6, less steric symmetric or unsymmetric
dialkyl-substituted 1,3-diones such as L1−L4 as well as less
electron-withdrawing and less sterically hindered diaryl 1,3-
diones such as L5 and L7, unfortunately, did not afford a
higher yield.
With the optimized conditions in hand, we first investigated
the scope of phosphines (Scheme 2). A broad range of
To test our hypothesis, we chose the [1,1′-biphenyl]-2-
yldiphenylphosphane 1a with 2a as the model reactants (Table
1). After extensive investigations of various reaction parame-
a
Scheme 2. Scope of Phosphines
a
Table 1. Optimization of the Reaction Conditions
a
All of the reactions were performed on a 0.3 mmol scale in 2 mL of
b
toluene at 140 °C under argon, 24 h, isolated yields. L3 used as
ligand at 160 °C.
Buchwald-type biaryl monophosphines bearing electron-rich
and electron-deficient substituents at both phenyl rings
coupling with 2a could afford the corresponding meta-alkylated
products in moderate to high yields (3b−3o, 61−94%). Most
common and widely used functional groups, such as OMe (3i),
SMe (3k), F (3b and 3f), Cl (3c and 3g), and CO2Me (3m),
were all tolerant. Substrates with a strongly electron-with-
drawing CF3 substituent (1d, 1h and 1n) could undergo an
organometallic C−H activation by base assistance, generating
the corresponding product in high yields. Notably, the active
Br group could also survive, delivering the desired product 3k
in 89% yield, which can be used for further diversification.
Phosphine-containing naphthyl group (1o) was also compat-
ible, affording the meta-alkylated product 3o in 62% yield with
high regioselectivity. Besides Ph2P-based monophosphines,
dialkylphosphine such as CyJohnPhos with PCy2 substituent
1p could also afford the desired product 3p in moderate yield
by using a less sterically hindered 1-cyclopropylbutane-1,3-
dione ligand L3. Unfortunately, phosphines with substituents
at ortho- and meta-positions had low activities probably due to
challenges in ortho-C−H bond metalation.
a
Reaction conditions: 1a (0.20 mmol), 2a (0.60 mmol), 5 mol %
[RuCl2(p-cymene)]2, 30 mol % L6, KOAc (2 equiv), 1 mL of toluene,
at 140 °C, 24 h, under argon. Yields determined by H NMR using
CH2Br2 as the internal standard. Isolated yield.
b
1
c
ters, the desired meta-C(sp2)−H-alkylated product 3a was
obtained in 93% yield with excellent regioselectivity under the
conditions of [RuCl2(p-cymene)]2 as the catalyst, highly
sterically hindered bidentate 2,2,6,6-tetramethylheptane-3,5-
dione L6 as the ligand and KOAc as the base, in toluene under
argon (see the Supporting Information for details). Further
investigations showed that organic acids, such as 1-AdCO2H,
MesCO2H, and monoprotected amino acids, were not
beneficial for the transformation, probably due to their lower
steric hindrance (Table 1, entries 2−5). Other bases such as
Next, we performed the meta-alkylation of 1a with various
alkyl bromides 2 (Scheme 3). Diverse secondary alkyl
bromides such esters, amides, and ketone could be used as
meta-alkylating reagents. Ester substrates with primary alkyl
and tertiaryl alkyl group deriving from alcohols could react
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a
viable for meta-alkylation, generating the corresponding meta-
alkylated phosphines in moderate to high yields (4m−4r). In
addition, ketone substrate (2s) was suitable for this meta-
alkylation reaction, giving the alkylated phosphine (4s) in a
lower yield, maybe due to the strong electron-withdrawing
property of carbonyl group. Notably, unactivated alkylating
reagent such as 2-bromooctane also worked, affording the
desired meta-alkylation product (4t) in an acceptable yield at a
higher temperature, in which a large proportion of the
phosphine (1a) were retained due to the low reactivity of 2t.
Other alkyl halides such as alkyl iodide, primary alkyl bromide,
and tertiary alkyl bromide were also investigated. Alkyl iodide
could react with phosphine, giving the desired product in a low
yield. Primary and tertiary alkyl bromides were not suitable for
this reaction. Pleasingly, substrates derived from natural
products and drug molecules, such as cholesterol (2u),
piperitol (2v), estrone (2w), camphorsultam (2x), and
tocopherol (2y) also tolerated the reaction, affording the
corresponding products in 50−81% yields.
Scheme 3. Scope of the Alkyl Bromides
To demonstrate the practicability of this protocol, a gram-
scale reaction of 1a and 2a was conducted, giving the mono-
and di-meta-alkylation products 3a and 3a′ (1.3 g) in 73%
yield (Scheme 4a). Next, the catalytic activity of meta-alkylated
phosphines was evaluated in the palladium-catalyzed Suzuki
coupling reaction (Scheme 4b). Aryl chlorides act as promising
arylating reagents in Suzuki coupling reactions owing to its low
cost and easily available property. However, due to high
dissociation energy of C−Cl bond, they show low activities.
Scheme 4. Synthetic Applications
a
Reactions were performed on a 0.3 mmol scale in 2 mL of toluene at
b
c
140 °C under argon, 24 h, isolated yields. oxidized by H2O2. at 160
d
°C. reactions were performed on a 0.20 mmol scale. NP = no
product.
with 1a, affording the corresponding products in 69−91%
yields (4a−4g). Cyclic substrates from cyclopentanol, cyclo-
hexanol, and adamantyl alcohol could be installed at the meta-
position of arenes in good yields (4d−4f). Besides alkyl esters,
phenyl ester from phenol (2h) could be tolerated as well.
Notably, other α-substituted substrates with Et, nPr, nHex, and
Bn groups were suitable for this meta-functionalization, giving
the desired products in 81−90% yields (4i−4l). Apart from
esters, secondary and tertiary amides were also found to be
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Buchwald et al. explored that bulky monobiarylphosphine can
effectively improve the reaction activity of aryl chlorides. We
believed that the introduction of alkyl groups into the meta
position of biarylphosphines can increase their electron density
and steric hindrance, thus promoting the oxidative addition
and reduction elimination steps of palladium catalyst. There-
fore, we evaluated the potential of CyJohnPhos congeners in
the cross-coupling of 4-methyl-phenyl chloride 5 and phenyl-
boronic acid 6. A series of commercially available CyJohnPhos
ligands (L8) bearing othro-substituents, such as Me (L9),
OMe (L10), and NMe2 (L11) groups, associated with PdOAc2
gave the biaryl product 7 in low yields (18−35%). The ortho-
alkylated CyJohnPhos (L12) prepared via hydroarylation of
alkene and CyJohnPhos proved a higher activity, giving the
product in 48% yield. To our delight, up to 98% yield was
obtained when the meta-alkylated CyJohnPhos (3p) was used,
probably owing to its unique meta-effect in electronic and
steric properties. These results demonstrated the potential
synthetic utilizations of meta-alkylated phosphines in metal
catalysis. Interestingly, the product 3a could be further
transformed into ortho- and meta-difunctionalized phosphines
(8, 72%) and (9, 80%) in high yields with our previous ortho-
alkylation and arylation of biaryphosphines (Scheme 4c).
To gain insight into this transformation, radical-trapping
experiments were performed. No desired product 3a was
obtained in the presence of TEMPO or 1,1-diphenylethylene,
indicating the reaction may undergo a radical process (Table
S4). To further explore the mechanism, control experiments
were conducted (Schemes S6−S10). The possible cyclo-
ruthenated intermediate Int A was prepared (Scheme S6).
With the Int A as catalyst, 80% yield of 3a was obtained
(Scheme S7). When the Int A was used as the substrate,
product 3a was also isolated in 20% yield (Scheme S8),
suggesting that the cycloruthenated intermediate Int A may be
an intermediate in this catalytic cycle. Next, the H/D exchange
experiment was conducted under the standard conditions in
the presence of methanol-d4 (Scheme S9), 86% and 52%
deuterium substitutions were observed at both ortho and
ortho′-C−H bonds. However, no H/D exchange happened at
the meta-C−H bond which implied that activations of ortho-
and ortho′-C−H bonds are reversible while the cleavage of
meta-C−H bond is irreversible. At last, the KIE value of ortho-
C−H activation in meta-alkylation of 1a and D5−1a with
phosphine 2a was 4.6:1 (Scheme S10), revealing that the meta-
C−H cleavage is the rate-determining step.11 On the basis of
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00237.
Detailed experimental procedures and compound
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Yue-Jin Liu − Collaborative Innovation Center for Advanced
Organic Chemical Materials Co-constructed by the Province
and Ministry, Ministry of Education Key Laboratory for the
Synthesis and Application of Organic Functional Molecules.
College of Chemistry and Chemical Engineering, Hubei
University, Wuhan 430062, P.R. China; orcid.org/0000-
0003-4226-0890; Email: liuyuejin@hubu.edu.cn
Ming-Hua Zeng − Collaborative Innovation Center for
Advanced Organic Chemical Materials Co-constructed by the
Province and Ministry, Ministry of Education Key Laboratory
for the Synthesis and Application of Organic Functional
Molecules. College of Chemistry and Chemical Engineering,
Hubei University, Wuhan 430062, P.R. China; Key
Laboratory for the Chemistry and Molecular Engineering of
Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, P.R. China; orcid.org/0000-0002-7227-7688;
Email: zmh@mailbox.gxnu.edu.cn
Authors
Zheng-Xin Zhou − Collaborative Innovation Center for
Advanced Organic Chemical Materials Co-constructed by the
Province and Ministry, Ministry of Education Key Laboratory
for the Synthesis and Application of Organic Functional
Molecules. College of Chemistry and Chemical Engineering,
Hubei University, Wuhan 430062, P.R. China
Jia-Wei Li − Collaborative Innovation Center for Advanced
Organic Chemical Materials Co-constructed by the Province
and Ministry, Ministry of Education Key Laboratory for the
Synthesis and Application of Organic Functional Molecules.
College of Chemistry and Chemical Engineering, Hubei
University, Wuhan 430062, P.R. China
Liang-Neng Wang − Collaborative Innovation Center for
Advanced Organic Chemical Materials Co-constructed by the
Province and Ministry, Ministry of Education Key Laboratory
for the Synthesis and Application of Organic Functional
Molecules. College of Chemistry and Chemical Engineering,
Hubei University, Wuhan 430062, P.R. China
Ming Li − Collaborative Innovation Center for Advanced
Organic Chemical Materials Co-constructed by the Province
and Ministry, Ministry of Education Key Laboratory for the
Synthesis and Application of Organic Functional Molecules.
College of Chemistry and Chemical Engineering, Hubei
University, Wuhan 430062, P.R. China
these experimental results and previous literatures,9,11
plausible catalytic cycle is proposed (Scheme S11).
a
In summary, we developed a novel meta-C−H functionaliza-
tion of phosphines by using the intrinsic P(III) as the directing
group via ruthenium-catalyzed σ-activation, which provides a
straightforward and efficient access to meta-alkylated phos-
phines. This protocol features a broad scope of alkyl bromide
such as esters, amides, ketone, and alkane, including
complicated natural product derivatives. The choice of a
bulky bidentate 1,3-dione ligand is crucial for the improvement
of catalytic efficiency. Mechanistic investigations suggest the
reaction may undergo a radical pathway involving the
formation of six-membered cycloruthenium intermediate.
This work paves a new way to the synthesis of remote-
substituted phosphines. Further applications of phosphines and
more detailed mechanistic investigations are ongoing in our
lab.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00237
Notes
The authors declare no competing financial interest.
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Dixneuf, P. H.; Soulé, J. F. RhI-Catalyzed PIII-Directed C−H Bond
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L.-N.; Li, M.; Tang, P.-T.; Luo, X.-P.; Kurmoo, M.; Liu, Y.-J.; Zeng,
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ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of Guangxi Province (No. 2017GXNSFDA198040) and the
BAGUI talent program of Guangxi Province (2019AC26001).
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