Palladium-catalyzed R2(O)P directed C(sp2)-H acetoxylation

Article abstract of DOI:10.1039/c4cc01238k

A novel and efficient Pd-catalyzed C-H acetoxylation is described. The approach uses R₂(O)P as a directing group to synthesize various substituted 2′-phosphorylbiphenyl-2-OAc compounds. Notably, the reaction exhibits smooth operation under mild conditions and shows good functional group tolerance. Products are obtained with high selectivity and yields. This journal is the Partner Organisations 2014.

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Palladium-Catalyzed R2(O)P Directed C(sp2)-H
Acetoxylation
Cite this: DOI: 10.1039/x0xx00000x
Heng Zhang,a Rong-Bin Hu,a Xiao-Yu Zhang,a Shi-Xia Li,a Shang-Dong
Yang*a.b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org
A novel and efficient Pd-catalyzed C-H acetoxylation is example, these compounds will act as ligands in asymmetric
described. The approach uses R2(O)P as directing group to catalysis and in transition-metal-catalyzed cross-coupling
synthesize various substituted 2’-phosphorylbiphenyl-2-OAc reactions.12 On the basis of these comprehensions, we wished to
compounds. Notably, the reaction exhibits smooth operation use the R2(O)P as directing group in order to achieve the C-H
under mild conditions and shows good functional group acetoxylation
and
afford
various
substituted
2’-
tolerance. Products are obtained with high selectivity and phosphorylbiphenyl-2-OAc compounds, which serve as a kind
yields.
The development of a catalytic method for the transition-
of P, O-ligands precursor. Our endeavors have resulted in the
development of a new method of Pd(OAc)2-catalyzed R2(O)P-
directed C-H acetoxylation (Scheme 1). Furthermore, the
R2(O)P and OAc groups can be transferred into trivalent
phosphorus and –OH easily, which lead to the synthesis of the
important chiral P, O-ligand of (R)-MeO-MOP.
metal-catalyzed oxidation of unactivated C-H bonds represents
a considerable research goal to the chemical industry and to
synthetic chemists more generally.1,2 In the past few years, the
method of C-H oxidation by transition-metal-catalyzed ortho-
functional groups has been applied as a powerful weapon to
transform arenes and alkanes directly into new products in
catalytic reactions.3 Among the efficient directing groups that
have been developed, nitrogen-containing directing groups such
as amides,4 imines,5 and N-heterocycles,6 carboxyl and
hydroxyl directing groups7,8 contribute to C-H acetoxylation.
Furthermore, this strategy has also been applied to the synthesis
of several natural products and to the functionalization of other
steroids.9 Despite good progress so far, the application of
innovative directing groups with improved directing qualities,
such as tunable functional groups with increased levels of
reactivity and selectivity, remains an important challenge. Very
recently, we selected diphenylphosphine oxide [Ph2(O)P] as a
directing group and have succeeded in applying it to the
palladium-catalyzed C-H olefination, hydroxylation, and
arylation.10 In our transformations, the R2(O)P not only acts as
a directing group, but also as a useful composition of product.
In contrast to the phosphonic acid or phosphate ester directed
C-H functionalizations,11 our reactions featured an unique
seven-membered cyclopalladium intermediate. We all know
that organphosphorus compounds are most famous for their
unusual roles in various aspects of organic synthetic areas. For
Scheme 1. P=O directed C-H acetoxylation through seven–membered
cyclopalladium intermediate
Our first study in this area focused on the Pd (
2-diphenylphosphino-2’-methylbiphenyl 1a).
Ⅱ
)-catalyzed
(
A
possible
acetate source, (Diacetoxyiodo)- benzene was selected as the
oxidant at the same time. We discovered that the combination
of 1.0 equiv of substrate 2-diphenylphosphino-2’-
methylbiphenyl (1a) with 10 mol% Pd(OAc)2 and PhI(OAc)2
(2.0 equiv) in ClCH2CH2Cl (DCE) at 90
℃ for 16 h produced
the desired product 2a in 44% isolated yield (Table 1, entry 1).
Encouraged by this result, we attempted to further optimize the
reaction conditions. Different solvents were tested first, and the
expected product (2
a
) was obtained in a low yield when
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CH3NO2 was used as solvent (Table 1, entry 2). When the were also involved in the smooth direction of the C-H
reaction proceeded in CF3CH2OH (TFE), the product was acetoxylation. Corresponding products were afforded in 80%
obtained in 52% yield (Table 1, entry 5). Similar result was and 42% yields, respectively (Table 2, 2b and 2c). However,
obtained when HOAc was used as the solvent, giving 50% other phosphorus compounds, such as triphenylphosphine oxide
yield (Table 1, entry 6). We hypothesized that Ac2O would and α-diethyl naphthalenyl phosphine oxides, were entirely
acetylate the Pd–OR complex and regenerate Pd(OAc)2
thereby complying with this reaction catalytic. Different mixed directed C-H acetoxylation undergoes
，
inactive, implying first that this palladium-catalyzed R2(O)P
seven-member
a
solvents were also tested, and the desired products were cyclopalladium intermediate in the procedure, and second that
obtained in a moderate yield when HOAc + Ac2O and palladium should be coordinated with the oxygen of the R2(O)P
CF3CH2OH + Ac2O were used as solvents (Table 1, entries 7-8). group.
Further studies indicated that higher reaction temperature gave
Table 2. Evaluation of Different Directing Groupsa,b
a better result in 59% yield (Table 1, entry 9). Significant
improvement was achieved when 3.0 equiv of PhI(OAc)2 was
o
used at 100 C for 7 h, giving an 86% yield of the product
(Table 1, entry 10). These results seemed to suggest that higher
temperatures and more PhI(OAc)2 were advantageous to both
the rate of the reaction and its yield. Furthermore, conducting
the reaction at 110 oC showed similar results (Table 1, entry 11).
Further increasing temperatures provided moderate yield,
however, indicating that perhaps the starting materials or the
product decomposed at a high temperature (Table 1, entries 12-
13). Some other Pd (
Ⅱ ) catalysts, such as PdCl2, PdBr2,
Pd(TFA)2, PdCl2(PPh3)2, and PdCl2(CH3CN3)2, could also
produce good results (Table 1, entries 14-18). No product was
detected in the absence of Pd(OAc)2.
Table 1. Screening for Reaction Conditions a,b
a
Reaction conditions :1a-1e (0.2 mmol), PhI(OAc)2 (3.0 equiv), Pd(OAc)2 (10
mol %), CF3CH2OH (2.0 mL), air atmosphere, 100 oC. bIsolated yields of products.
Next,
we
investigated
different
substituted
2-
(diphenylphosphine) biphenyl derivatives (Table 3). When 2-
(diphenylphosphine) biphenyl was used as the substrate, the
reaction occurred very smoothly and the product of 2f was
obtained in 92% highest yield with a mixture of acetoxylated
and diacetoxylated product. Following this result, we focused
our investigation on various substituted 2-(diphenylphosphine)
biphenyls. Although methyl or dimethyl groups lie on the Ar2
aromatic ring, the reaction proceeded smoothly and the
corresponding product was obtained in good yields (2a, 2g-2k).
However, the substituent at the ortho-position was changed into
the methoxyl group; the desired product of 2l was afforded in
only 46% yield. When the methoxyl group lay on the meta-
position, however, the mixture of acetoxylated and
diacetoxylated products (2m) was obtained in 53% and 43%
yields. These results indicate that the steric effect is the main
factor leading to lower yields. This reaction displayed good
functional group tolerance, but the electronic effect was also
quite evident. When the electron-withdrawing groups ester,
ketone, fluoride, bromide, and chloride were located in the Ar2
aromatic ring, the corresponding product was generally
a
All reactions were carried out in the presence of 0.2 mmol of 1a in 2.0 mL
different solvents under air atmosphere. b Yield of isolated product. c HOAc (1 mL)
+Ac2O (1 mL). d CF3CH2OH (1 mL) + Ac2O (1 mL).
With optimized conditions (Table 1, entry 10) in hand, we
examined the scope of substrates first by varying the phosphate
directing group (Table 2). Beside the diphenylphosphine oxide,
diisopropylphosphine oxide and di-tert-butylphosphine oxide
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obtained in lower yields (2n-2r). The chloride group in
Phosphorus-based ligands play an important role in many
particular at the meta- and para-position gave the desired metal-catalyzed organic reactions, including various
product of 2s 25% and 2t 43% yields and a low conversion led asymmetric transformations.13 To demonstrate the potential
to the recovery of the remaining starting material (1s-
1t). synthetic utility of the Ph2(O)P directed C(sp2)-H activation to
Furthermore, we also found that the reaction was sensitive to form C-O bond, we selected the acetoxylation product of 2'-
substituents on the Ar1 aromatic ring. For example, the electron- (diphenylphosphoryl)-1,1'-binaphthyl-2-yl acetate (R)-2v as
neutral group of methyl achieved the product with higher yield starting material to synthesize the chiral ligand of (R)-Meo-
than electron-withdrawing group of CF3 (2j-2k). Finally, the MOP. According to pioneering reports, acetoxylation can be
reaction saw a smooth execution with naphthalene derivatives. hydrolyzed in order to afford the (2'-hydroxy-[1, 1’-
When the optically pure 2- diphenylphosphine oxide-1,1'- binaphthalen])-2-yl)diphenylphosphine oxide (R)-2va in 73%
binaphthyl was used as the substrate, the R- and S-configuration yield with 99% ee.13e Then, under basic conditions the
products were obtained in 75% yields, respectively and methylation of hydroxyl group is formed using the methyl
accompanied by excellent ee values (2v
-
2w).
iodide; (R)-2vb is thus obtained in 95% yield. Finally,
deoxidation of (R)-2vb is carried out in the presence of Cl3SiH
and Et3N under inert gas and the chiral ligand of (R)-MeO-
MOP is obtained in a 77% yield.14 To our delight, the excellent
ee value persisted throughout the conversion process.
Table 3. The investigation of different substituted (2-
biphenyl)diphenyl phosphine oxide derivatives a,b
Scheme 2. The utility for the synthesis Chiral Ligand (R)-MeO-
MOP
In summary, we have developed a novel R2(O)P-directed Pd (Ⅱ)
–catalyzed C-H acetoxylation of diphenyl phosphine oxide
compounds. Notably, the reaction is easy to handle, shows good
functional group tolerance, and generates high yields with high
selectivity. Various diphenyl phosphine oxide compounds could be
synthesized under standard conditions. Further applications based on
this research to synthesize biologically active compounds as well as
detailed mechanism studies are currently in progress.
Acknowledgement
We are grateful to the NSFC (Nos. 21272100), Program for
Changjiang Scholars, the Innovative Research Team in University
(PCSIRT: IRT1138), and the Program for New Century Excellent
Talents in University (NCET-11-0215 and lzujbky-2013-k07) for
financial support.
aState Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P. R. China. E-mail: yangshd@lzu.edu.cn;
Fax: +86-931-8912859; Tel: +86-931-8912859
a Reaction conditions:1a, 2f-2w (0.2 mmol), PhI(OAc)2 (3.0 equiv), Pd(OAc)2 (10
mol %), CF3CH2OH (2.0 mL), air atmosphere, 100 oC. bIsolated yields of products.
cYield of diacetoxylated product. dThe reaction was carried out at 110 oC.
eRecovery yield of staring material.
bState Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China
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