Double Ligands Enabled Ruthenium Catalyzed ortho-C?H Arylation of Dialkyl Biarylphosphines: Straight and Economic Synthesis of Highly Steric and Electron-Rich Aryl-Substituted Buchwald-Type Phosphines

Article abstract of DOI:10.1002/adsc.202100283

A double-ligands enabled ruthenium catalyzed C(sp²)?H arylation of dialkyl phosphines is described, which provides a straight access to aryl-substituted dialkyl phosphine ligands. The combination of 1,3-diketone and amino acid ligands is essential for this transformation. An important six-membered cycloruthenium intermediate was successfully isolated and characterized by X-ray diffraction. Mechanistic studies showed that the 1,3-diketone promoted the process of oxidative addition of cycloruthenium intermediate. Some of modified CyJohnPhos ligands exhibited highly catalytic activity in palladium catalyzed C?N bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.202100283

FULL PAPER
DOI: 10.1002/adsc.202100283
Double Ligands Enabled Ruthenium Catalyzed ortho-CÀ H
Arylation of Dialkyl Biarylphosphines: Straight and Economic
Synthesis of Highly Steric and Electron-Rich Aryl-Substituted
Buchwald-Type Phosphines
a
a
a
a
a,
Liang-Neng Wang, Pan-Ting Tang, Ming Li, Jia-Wei Li, Yue-Jin Liu, * and
a, b,
Ming-Hua Zeng *
a
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, People’s Republic of China
E-mail: liuyuejin@hubu.edu.cn
b
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical
Sciences, Guangxi Normal University, Guilin, 541004, People’s Republic of China
E-mail: zmh@mailbox.gxnu.edu.cn
Manuscript received: March 4, 2021; Revised manuscript received: April 1, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100283
2
Abstract: A double-ligands enabled ruthenium catalyzed C(sp )À H arylation of dialkyl phosphines is
described, which provides a straight access to aryl-substituted dialkyl phosphine ligands. The combination of
1
,3-diketone and amino acid ligands is essential for this transformation. An important six-membered
cycloruthenium intermediate was successfully isolated and characterized by X-ray diffraction. Mechanistic
studies showed that the 1,3-diketone promoted the process of oxidative addition of cycloruthenium
intermediate. Some of modified CyJohnPhos ligands exhibited highly catalytic activity in palladium catalyzed
CÀ N bond formation.
Keywords: double ligands; ruthenium catalysis; tertiary phosphines; CÀ H arylation
Introduction
Recently, late-stage diversification via CÀ H bond
activation and functionalization has been employed for
Tertiary phosphines are commonly and widely used efficient construction of natural products and pharma-
[5,6]
ligands in the field of metal catalysis due to their ceutical compounds, but it is few applied to directly
[1]
[7]
excellent tunable electronic and steric properties.
prepare tertiary phosphines. In 2014, Clark discov-
Among them, dialkyl biarylphosphines such as John- ered the regioselective CÀ H functionalization of
Phos, CyJohnPhos, MePhos and XPhos are demon- phosphines assisted by intrinsic tertiary phosphine
[7a]
strated as the most effective ligands in the transition- groups,
this strategy has been further applied to
metal catalyzed construction of CÀ C and CÀ X bonds, modification of phosphines by CÀ H bond functionali-
as their unique structural feature of highly steric zation. In 2017, Shi group disclosed the first direct
[2]
hindrance and electronic abundance(Scheme 1a). The functionalization of dialkyl biarylphosphines via Rh-
(III)
[7b]
presence of bulky substituents at ortho-position can catalyzed, P -assisted CÀ H arylation. Then, alkyla-
further improve the catalytic activity by avoiding tion and alkenylation of dialkyl phosphines were
[
7g–i]
cyclometallation and promoting reductive elimination realized by Shi and Soulé groups, respectively.
of metal catalysts. However, the traditional methods
[3]
Despite of high efficiency and usefulness, highly
for the synthesis of dialkyl biarylphosphines involving active and expensive rhodium catalysts are required for
multiple steps with organometallic reagents under these transformations, which limits their wide applica-
harsh conditions, making it challenging to efficiently tion in synthesis of phosphine ligands. With the higher
[4]
and diversified prepare and discovery new ligands.
demands in phosphine ligands, developing a new and
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Results and Discussion
We commenced our studies with commercially avail-
able and widely utilized CyJohnPhos (1a) as substrate,
1-iodo-4-methoxybenzene (2a) as coupling reagent
and [RuCl (p-cymene)] as catalyst (Table 1). Based on
2
2
the previous studies, we believe that the key to achieve
this reaction is to select the appropriate ligand, so a
series of different ligands were investigated. The
simple acid ligands such as MesCO H (L ) and 1-
2
A1
AdCO H (L ), which are widely used in ruthenium
2
A2
catalytic CÀ H activation had little activity for this
transformation. Then, we tuned to investigate amino
acid ligands. To our disappointment, most of the amino
acid ligands including protected and unprotected amino
acids had no promoting effect (L –L ).
A3
A7
[a]
Table 1. Optimization of the reaction conditions.
Scheme 1. Significant dialkyl biarylphosphine compounds and
their synthesis by late-stage modification strategy.
inexpensive catalytic system to late-stage modification
of dialkyl phosphines is necessary.
Ruthenium catalysis has received tremendous atten-
tion owing to its advantage of inexpensive and
[8]
catalytic diversity. Although N or O coordination
assisted CÀ H functionalization has achieved significant
[9]
progress, the methods of strongly coordinated P-
directed CÀ H activation is less developed. Only two
examples of P-directed ruthenium catalyzed CÀ H
functionalization of triphenylphosphine were recently
reported by Takaya and Shi respectively-
[10]
(Scheme 1b).
However, these methods are not
suitable to synthesis of Buchwald-type biarylphos-
phines.
Our group has been focused on developing new
[11]
methods of CÀ H activation. We recently explored
late-stage modification of biarylphosphines via Ph P-
2
directed ruthenium catalyzed ortho-CÀ H arylation and
[11a–c]
alkylation reactions,
but these catalytic systems
were ineffective to highly sterically hinderded dialkyl-
based biarylphosphines. Herein, we report a double-
ligands enabled ruthenium-catalyzed ortho-CÀ H aryla-
tion of dialkyl phosphines(Scheme 1c). The combina-
tion of amino acid and acetylacetone ligands is the key
for achieving this transformation. This protocol pro-
vides a new and practical approach for the synthesis of
aryl-substituted dialkyl biarylphosphines with inexpen-
sive ruthenium catalyst. A series of mono-arylated
dialkyl biarylphosphines with a variety of functional
groups can be obtained in high yields and with
excellent chemoselectivity.
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [RuCl2
p-cymene)]2 (5 mol%), Ligand A (30 mol%), Ligand B
(40 mol%) and KOAc (3 equiv) in 1 mL cyclohexane at
(
160°C under argon, 12 h. Yield of product was determined by
1
H NMR using dibromomethane as an internal standard.
[b]
[c]
[d]
Without LA8.
Using K CO instead of KOAc.
2
3
Using 4-bromoanisole instead of 2a.
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The cyclolencine (L ) could improve the activity
A8
of ruthenium catalyst, giving the arylated product in
1
5% yield. To further improve the efficiency of the
reaction, second ligand of 2,2,6,6-tetrameth-
a
ylheptane-3,5-dione (L ) was added to the reaction,
B1
which has been used as an effective ligand in
ruthenium catalyzed meta-alkylation of tertiary
[11d]
phosphines.
To our delight, a high yield (32%) of
the product 3aa was obtained, indicating the 1,3-dione
ligand could promoted the arylation of CyJohnPhos.
After screening of a series of 1,3-diones with different
steric and electronic properties, we found that the less
steric acetylacetone (L ) gave the best result (93%).
B5
Other 1,3-diones with alkyl (L –L ) and phenyl
B2
B4
(
L –L ) groups had lower activity for this reaction
B6 B7
likely due to their higher steric hindrances. 1,3-diones
with electron-withdrawing CF groups (L ) also had a
3
B8
lower promotion for the arylation. Other type of 1,3-
dione such as ethyl acetoacetate (L ) had a little effect
B9
on the arylation of dialkyl biarylphosphines, high-
lighting the importance of 1,3-dione motif in secondary
ligand. A low yield of product (18%) was observed in
the absence of L , proving the importance of amino
A8
acid ligand (L ) in this transformation. Other bases
A
such as K CO , had a lower activity for this reaction,
2
3
affording the product in 46% yield. Notably, aryl
bromide such as 4-bromoanisole was effective for this
double-ligands catalytic system, generating the ary-
lated phosphine products 3aa in 67% yields.
With the optimal conditions in hands, we first
studied the scope of dialkyl biarylphosphine
(
Scheme 2). A series of CyJohnPhos analogues with
[a]
Scheme 2. Scope of phosphines.
(
(
Reaction conditions: 1
various functional groups including MeO, MeS, F and
Cl at ortho, meta, and para positions could be coupling
0.2 mmol), 2a (0.4 mmol), [RuCl (p-cymene)] (5 mol%), L
30 mol%), LB5 (40 mol%) and KOAc (3 equiv) in 1 mL
2
2
A8
[b]
in good to excellent yields (3aa–3ja). Notably, cyclohexane at 160°C under argon, 16 h; isolated yield.
naphthalene-containing phosphine (1k) could exhibit 180°C, 30 h.
high activity, affording the corresponding product
(3ka) in 91% yield. Moreover, heterobiarylphosphine
(1l) with pyrrole also underwent the arylation, giving under reaction conditions, generating the correspond-
the product (3la) in medium yield. In addition, other ing arylated phosphines. Disubstituted aryl iodides
i
dialkylated substrate such as ( Pr) P-based biarylphos- with same and different functional groups were
2
phine successfully went through this transformation, efficiently coupled (3ao–3aq). The naphthalene-con-
affording the product (3ma) in 87% yield. Unfortu- taining substrates (2n) also reacted with CyJohnPhos.
nately, the JohnPhos (1n) did not undergo the arylation In addition, hereroaryl substrates such as thiophene
reaction, probably due to the highly steric hindrance of (2r), pyridine (2s) and quinoline (2t) were found
t
P( Bu) group. These results show the efficiently and tolerable, affording the desired heteroarylated products
2
rapidly construct a library of different steric and in acceptable yields. These results show that this
electronic dialkyl biarylphosphines.
protocol could efficiently and rapidly construct a
We next investigated the scope of aryl iodides library of different steric and electronic (hetero)aryl
coupling with CyJohnPhos (2a) (Scheme 3). Aromatic substituted CyJohnPhos analogues.
iodides with a variety of functional groups such as
To demonstrate the practicability of this protocol,
MeO (2b, 2c), Me (2d, 2h), Ph (2i), F (2k), Cl (2j), gram-scale reaction of CyJohnPhos (1a) and aryl
CF (2m), CO Me (2e, 2l) and CN (2q) groups at iodide (2a) was performed under standard conditions
3
2
ortho, meta and para positions underwent facile trans- (Scheme 4a). The product 3aa was obtained with
formation to afford the desired products in medium to 1.13 g in 83% yield. With rapidly constructed aryl-
high yields. Notably, active Br (2p), OH (2g) and OTf substituted CyJohnPhos library in hand, we then tested
(2f) substituents on the aryl groups could survive it in palladium-catalyzed Buchwald-Hartwig amination
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[a]
Scheme 3. Scope of aryl iodines.
Reaction conditions: 1a
(0.2 mmol), 2 (0.4 mmol), [RuCl (p-cymene)] (5 mol%), L
2 2 A8
(30 mol%), LB5 (40 mol%) and KOAc (3 equiv) in 1 mL
cyclohexane at 160°C under argon, 16 h; isolated yield.
Scheme 4. Synthetic application.
(Scheme 4b), which is widely applied in the synthesis
of natrual products and drug molecules. We selected
inactive phenyl chloride (5a) and common N-methey- intermediate Ru(II) Int A was prepared
To gain insight into the reaction mechanism, an
[11b]
and the
laniline (4a) as substates with 0.05 mol% Pd(dba) . To structure of Int A was confirmed by X-ray crystallo-
2
our delight, our arylated CyJohnPhoses (3aa, 3ac, graphic analysis (Scheme 5a). When the Int A was
3
aq) exhibited excellent catalytic activity, giving the used as catalyst, the reaction could take place smoothly
desired amination product (6a) in almost quantitive under standard conditions. However, trace amount of
yields (96%–99%). Medium yields of products were product was detected without the addition of LB5
obtained with CyJohnPhos (64%) and JohnPhos (Scheme 5b). The comparative experiments demon-
(19%), which indicated the imortance of ortho-sub- strated the importance of LB5 in this transformation.
stituents. Other common ortho-substituted CyJohnPho- When using Int A as substrate, 87% yield of product
ses with Me (MePhos) and Me N (DavePhos) groups was obtained in the presence of LB5 and L , but only
2
A8
were also investigated, but low yields (32% and 46%) trace amount of product was detected in the absence of
of product were observed. This result highlighted the LB5 (Scheme 5c). These experimental results suggested
importance of aryl group in enhancing the activity of the Int A may be an intermediate involving in the
CyJohnPhos. Arylated PhJohnPhos (Lp) with Ph2P catalytic cycle, and the LB5 played a key role in
group gave only 25% yield of amination product, promoting the oxidative addition of the cycloruthenium
showing the importance of dialkyl group. Using the intermediate. Considering that ruthenium-catalyzed
most active arylated CyJohnPhos (3aa) with low Pd CÀ H activation can be promoted by tertiary phosphine
[9c,d,11b]
catalyst loading, a series of significant bioactive ligands,
30 mol% of 3aa was added to the
compounds (6a–6h) including indole (6b), dihydroin- standard conditions to test the effect of the formed
dole (6c) and tetrahydroquinoline (6d) are isolated in phosphine products. However, a lower yield of product
8
7%–99% yields. These results proved the efficiency 3aa (27%) was observed (Scheme 5d). This result
and generality of the arylated-substituted dialkylbiar- showed that the formed product did not serve as an
ylphosphine ligands in the synthesis of amine com- effective ligand to accelerate the reaction.
pounds.
According to these experimental results and pre-
[12]
vious reports,
a plausible process of this double
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Scheme 6. Proposed mechanism for double ligands promoted
ruthenium CÀ H arylation.
plex with single crystal diffraction for the first time.
Mechanism studies demonstrated that the 1,3-
dicarbonyl ligand played a crucial role in acceleration
of oxidative addition of aryl iodides. The potential
application of aryl-substituted dialkyl biarylphosphines
was demonstrated in highly efficient Pd-catalyzed
Scheme 5. Mechanistic studies.
ligand enabled CÀ H arylation of dialkyl biarylphos- Buchwald-Hartwig cross-coupling reaction. Detailed
phines is proposed (scheme 6). In the presence of base, mechanistic investigations are undergoing in our
the [RuCl (p-cymene)] reacted with L and LB5, group.
2
2
A8
generating active complex I in which the p-cymene
dissociates from ruthenium centre. Next, the phosphine
Experimental Section
1
a coordinates to the complex I to form complex II.
Then, the six-membered cyclometalated Ru-complex General procedures for synthesis of arylated dialkyl biar-
III generates via amino acid assisted ortho-CÀ H ylphosphines: To a 25 mL Schlenk tube was added tertiary
phosphine 1 (0.2 mmol, 1.0 equiv.), aryl iodine 2 (0.4 mmol,
cleavage. Oxidative addition of aryl iodide to the thus-
2
.0 equiv.), [RuCl (p-cymene)]2 (6.1 mg, 5.0 mol%), LA8
2
formed Ru-species III and formation of the complex
IV, followed by reductive elimination to generate
complex V, which releases the product 3 and regener-
ates the active Ru(II)-catalyst in the presence of amino
acid ligand (LA8).
(
3
7.8 mg, 30 mol%), LB5 (8.0 mg, 40 mol%), KOAc (58.9 mg,
.0 equiv.). The tube was purged with Ar three times, followed
by addition of cyclohexane (1 mL). The mixture was stirred at
1
60°C for 16 h. The solution was then cooled to room
temperature and the solvent was removed under vacuum
directly. The crude product was purified by column chromatog-
raphy on silica gel affording the arylated products 3.
Conclusion
In summary, we have developed a ruthenium-catalyzed
system for the late-stage modification of highly steri-
cally hindered dialkyl biarylphosphines via CÀ H
Acknowledgements
arylation, which provides a straight and efficient access This work was supported by the NSF of Guangxi Province (No.
2
017GXNSFDA198040) and the BAGUI talent program
to aryl-substituted dialkyl biarylphosphines. The effec-
tive combination of 1,3-dione and amino acid ligands
is the key to realize this transformation. We separated
and characterized the important cycloruthenium com-
(2019AC26001).
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