Pd(II)-catalyzed P(O)R1R2-directed asymmetric C-H activation and dynamic kinetic resolution for the synthesis of chiral biaryl phosphates

Article abstract of DOI:10.1021/acs.orglett.5b00844

An efficient method of Pd(II)-catalyzed P(O)R¹R²-directed asymmetric C-H activation and dynamic kinetic resolution for synthesis of chiral phosphinate ligands has been performed and exhibits a wide scope of substrates and an excellen

Full text of DOI:10.1021/acs.orglett.5b00844

Letter
pubs.acs.org/OrgLett
1
2
Pd(II)-Catalyzed P(O)R R ‑Directed Asymmetric C−H Activation and
Dynamic Kinetic Resolution for the Synthesis of Chiral Biaryl
Phosphates
†
†
,†,‡
Yan-Na Ma, Hong-Yu Zhang, and Shang-Dong Yang*
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory of Elemento-Organic Chemistry, NanKai University, Tianjin 300071, P. R. China
*
S Supporting Information
ABSTRACT: An efficient method of Pd(II)-catalyzed P(O)-
1
2
R R -directed asymmetric C−H activation and dynamic kinetic
resolution for synthesis of chiral phosphinate ligands has been
performed and exhibits a wide scope of substrates and an
excellent diastereomeric ratio (>95:5).
n many transition metal-catalyzed asymmetric transforma-
formation of the racemic prefunctionalized (naphthyl)quinoline
6d,e
I
tions, axially chiral phosphine-based ligands play indispen-
derivatives.
Very recently, Colobert first reported the
1
sable roles. The extent to which they can be utilized in these
endeavors depends on the efficient and selective chemical
methods for their construction. Consequently, researchers have
devoted tremendous efforts over the past decades to synthesize
these kinds of chiral auxiliaries that possess novel electronic,
synthesis of axially chiral biaryls through sulfoxide-directed
6f−h
asymmetric C−H activation and dynamic kinetic resolution.
Here in, we disclose the first example of Pd(II)-catalyzed
1
2
P(O)R R -directed asymmetric C−H alkenylation, acetoxyla-
tion, and iodization through dynamic kinetic resolution for the
synthesis of various axially chiral phosphine oxide compounds
2
steric properties, as well as functional groups. The most
commonly used method involves optically pure substrates such3
as binaphthol and others afforded directly by phosphorization.
Transition metal-catalyzed asymmetric cross-coupling with two
(
Scheme 1), which proved easier when converting the
corresponding axially chiral phosphine auxiliary by hydrogen
reduction of silicide. Compared with our previous reports of
Pd(II)-catalyzed the optically pure chiral [1,1′-binaphthalen]-2-
yldiphenylphosphine oxide directed C−H functionalization to
4
aryl compounds also provides an efficient pathway. Moreover,
the kinetic resolution is also the main route for preparation of
5
axially chiral phosphine-based ligands. However, this proce-
dure is limited to a maximum theoretical yield of 50%. Many
efforts have been devoted to overcome this limitation and to
afford compounds with the same high enantiomeric purity but
with much improved yields. Recently, a new method of
dynamic kinetic resolution (DKR) of biaryl atropisomers,
which occur in tandem with in situ racemization and resolution,
provides one of the most convenient and efficient approaches
Scheme 1. Pd(II)-Catalyzed C−H Activation/Dynamic
Kinetic Resolution for Synthesis Chiral Biaryl Phosphates
6
to a wide range of enantiomerically enriched molecules. The
dynamic kinetic resolution of biaryl atropisomers through
rhodium-catalyzed atropoenantioselective alkylation of 2-(1-
naphthyl)-3-methylpyridine was first applied in 2000 by the
6
b
Murai group. Ten years later, Miller developed a dynamic
kinetic resolution of biaryl atropisomers via peptide-catalyzed
asymmetric bromination and delivered chiral nonracemic biaryl
6c
compounds with excellent enantioselectivity and good yields.
In 2013, two groups of Stoltz and Lassaletta achieved
simultaneous but independent asymmetric synthesis of axially
chiral heterobiaryls via dynamic kinetic asymmetric trans-
Received: March 22, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00844
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
a
synthesize different axially chiral phosphine-based ligands. This
method demonstrated a wide substrate scope and the excellent
diastereomeric ratio (>95:5) under higher reaction temper-
atures. The products contained both the axially chirality and P-
stereogenic center, which are difficult to obtain in former
P(O)R2-directed C−H activation reactions. Furthermore,
Table 1. Pd(II)-Catalyzed C−H Activation/DKR
1
2
chiral P(O)R R acts not only as the directing group but also
serves to facilitate the composition of the product in a useful
manner.
We initially chose the easily available enantiopure menthyl
phenylphosphate group as the directing group for C−H
olefination. We synthesized the axially racemic substrate (S)-
(
−)-menthyl (2′-methyl-[1,1′-biphenyl]-2-yl)(phenyl)-
8
phosphinate 1a (see the Supporting Information) and
examined the asymmetric C−H olefination between 1a and
ethyl acrylate (2a). To our delight, the desired product 3a was
9
obtained in 58% yield with an excellent diastereomeric ratio
(
>95:5) under our previous conditions (entry 1; for detailed
studies, see the Supporting Information). Encouraged by this
result, we further optimized the reaction conditions. Solvents
screening showed that the CF CH OH is still the best choice.
3
2
The influence of the oxidants was further examined; Cu(OAc)2,
Ag CO , AgNO , and PhI(OAc) could effectively promote the
2
3
3
2
reaction and Cu(OAc) shows the best results. Finally, the
2
combination of Ag CO (1.0 equiv) and Cu(OAc) (20 mol %)
2
3
2
was found optimal and gave 3a in 73% yield and >95:5 dr.
Subsequently, we carried out evaluations of other amino acids,
but relatively lower yields were obtained. Other Pd sources,
such as Pd(TFA) , PdCl , Pd(PPh ) Cl , Pd(NO ) , and
2
2
3 2
2
3 2
Pd(acac) , could also promote this reaction, and when
2
Pd(acac) was used, the desired product 3a was also obtained
2
with the best result. Finally, when we selected the relatively
cheaper Pd(OAc) as the catalyst, the optimized reaction
2
a
Reaction conditions: 0.2 mmol of 1, 0.6 mmol of 2, 10 mol %
conditions are as follows: Pd(OAc) (10 mol %) as the catalyst,
2
Pd(OAc) , 20 mol % Ac-Gly-OH, 20 mol % Cu(OAc) , and 0.2 mmol
of Ag CO in CF CH OH (2.0 mL) under air atmosphere. Isolated
yields. Determined by H NMR and P NMR.
2
2
Ac-Gly-OH (20 mol %) as the ligand, and Ag CO (1.0 equiv)
b
2
3
2
3
3
2
and Cu(OAc) (20 mol %) as the oxidants in CF CH OH at
c
1
31
2
3
2
1
00 °C for 16 h.
With the optimized reaction conditions in hand, we
synthesize axially racemic ortho trisubstituted substrates, but we
produced the chiral ones.
examined the scope of different substituted axially racemic
(
S)-(−)-menthyl phenylphosphinate derivatives and various
Next, we turned our attention to asymmetric C−H
acrylates (Table 1). We focused first on the investigation of
various acrylates using (S)-(−)-menthyl (2′-methyl-[1,1′-
biphenyl]-2-yl)(phenyl)phosphinate 1a as a substrate (Table
1
1,12
functionalization with other reagents. (Scheme 2)
When
(
S)-(−)-menthyl (2′-methyl-[1,1′-biphenyl]-2-yl)(phenyl)
phosphinate 1a was subjected to the C−H acetoxylation with
PhI(OAc) under 10 mol % Pd(OAc) in CF CH OH at 100
1, entries 1−8). We were pleased to find that different olefins
such as methyl, butyl, and benzyl acrylates, phenyl vinyl sulfone,
alkenyl phosphate, and acrolein were compatible with the
reaction and the corresponding products were afforded in
moderate to good yields with excellent diastereomeric ratios
2
2
3
2
°
C for 16 h, the desired acetoxylated product 4a was obtained
in 46% yield with excellent diastereomeric ratio (dr >95:5).
(
(
all >95:5). Furthermore, a variety of axially racemic (S)-
−)-menthyl phenylphosphinate derivatives bearing substitu-
Scheme 2. Asymmetric C−H Acetoxylation and Iodization/
KDR
10
ents in position 2′ were taken into the reaction (Table 1, entries
9
alkenylation with ethyl acrylate and the corresponding coupling
products 3ba−3da were isolated in moderate to good yields
showing excellent diastereoselectivity. The axially racemic (S)-
−11). All the substrates were subjected to the C−H
(
−)-menthyl (2′,3′-dimethyl-[1,1′-biphenyl]-2-yl)(phenyl)-
phosphinate 1e was also examined and gave the alkenylation
product 3ea in 60% yield and excellent diastereoselectivity (dr
>
95:5). Finally, the substrates with a substituent at position 6
could also go through C−H alkenylation with good yield and
show excellent diastereoselectivity, a little of di-ortho-
alkenylated products were also observed in these reactions
(
Table 1, entries 13 and 14). Moreover, we also tried to
B
DOI: 10.1021/acs.orglett.5b00844
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Organic Letters
Letter
a
Moreover, the product can be further transformed into the
chiral P,O-ligand. Delightedly the iodization also carried out
smoothly in this transformation, and the desired product of 5a
could be acquired in 54% yield with excellent diastereomeric
ratio (dr >95:5).
Table 2. Pd(II)-Catalyzed C−H Acylation/KR
Encouraged by the efficiency of this diastereoselective
alkenylation, acetoxylation, and iodization reactions, we
subsequently focused on proving a more general character of
such an original asymmetric C−H activation. Aiming to
construct synthetically useful axially chiral scaffolds, we wished
9
chiral-8
b
b
c
c
entry
R
yield
dr
yield
dr
t
1
2
3
4
R = Bu
9a, 36%
9b, 22%
9c, 20%
9d,18%
>95.5
>95.5
>95.5
>95.5
8a, 25%
8b, 55%
8c, 56%
8d, 52%
>95:5
>95:5
80:20
80:20
13
i
to extend this methodology to the hydroxylation reaction.
R = Pr
n
However, our efforts produced only trace amounts of the
hydroxylation product under our previous hydroxylation
reaction conditions when 1a was used as the substrate. Then,
we tried to replace the menthyl group by alkyl with alkyl
lithium in order to synthesize axially racemic (R)-alkyl (2′-
methyl-[1,1′-biphenyl]-2-yl)(phenyl)phosphine oxides but
failed. This impelled us to speculate on the possibility that
conditions could be developed to acquire the chiral
hydroxylation product. Combing the axially chiral substrates
induced the kinetic resolution with C−H activation provided a
conceivable alternative, because we could obtain different two
axially chiral phosphine oxide ligands via one step. To the best
of our knowledge, this strategy has never been demonstrated.
Indeed, when we used the axially chiral substrates (R)-isopropyl
R = Bu
R = Et
a
Reaction conditions: 0.3 mmol of 5, 0.75 mmol of PhCH OH, 10
2
mol % Pd(TFA) , 1.2 mmol of TBHP (70% aqueous solution) in DCE
2
b
c
1
(1.5 mL) under air atmosphere. Isolated yields. Determined by H
NMR and 31P NMR.
additional key advantage the strategy presented herein relies on
1
2
the character of the P(O)R R directing group, which paves the
way toward a general application of the transformation to
phosphine-based ligands (for example, alkene-phosphine
hybride ligands, P,O-ligands).
Summit
In summary, a novel atroposelective mild C−H activation
occurring through dynamic kinetic resolution and kinetic
resolution toward the synthesis of alkenylation, acetoxylation,
iodization, hydroxylation, and acylation atropisomeric biaryls or
chiral phosphine oxides isomers represents a rare example of a
C−H activation-based asymmetric strategy enabling axial
stereocontrol or formation of central chirality on the
phosphorus atom.
(
2′-methyl-[1,1′-biphenyl]-2-yl)(phenyl)phosphine oxide (6a)
and (R)-ethyl (2′-methyl-[1,1′-biphenyl]-2-yl)(phenyl)-
phosphine oxide (6b) to the C−H hydroxylation, the
corresponding products of 7a and 7b were obtained with
good yields and excellent diastereoselectivity, but the starting
material disappeared under the reaction conditions (Scheme 3).
Scheme 3. Asymmetric C−H Hydroxylation/KR
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental details and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: yangshd@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
In addition to the hydroxylation, we attempted to extend the
ACKNOWLEDGMENTS
We are grateful for the NSFC (Grants 21272100 and
1472076) and Program for New Century Excellent Talents
in University (Grants NCET-11-0215 and lzujbky-2013-k07)
kinetic resolution (R)-alkyl (2′-methyl-[1,1′-biphenyl]-2-yl)-
■
1
4
(
phenyl)phosphine oxides through C−H acylation (Table 2).
2
As we expected, reactions were carried out smoothly in terms of
highest diastereoselectivity and good yields for both of the
products (9a, 9b) and recovered starting materials (8a, 8b)
notably, the dr of substrate 8b is 1:1.7, so the yield of product
b is lower and the yield of recovered starting material 8b is
1
5
for financial support.
(
8
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