P(O)R2-directed Pd-catalyzed C-H functionalization of biaryl derivatives to synthesize chiral phosphorous ligands

Article abstract of DOI:10.3762/bjoc.10.215

Chiral phosphorus ligands have been widely used in transition metal-catalyzed asymmetric reactions. Herein, we report a new synthesis approach of chiral biaryls containing a phosphorus moiety using P(O)R ₂-directed Pd-catalyzed C-H activation; the functionalized products are produced with good enantioselectivity.

Full text of DOI:10.3762/bjoc.10.215

P(O)R2-directed Pd-catalyzed C–H functionalization of biaryl
derivatives to synthesize chiral phosphorous ligands
Rong-Bin Hu1, Hong-Li Wang1, Hong-Yu Zhang1, Heng Zhang1, Yan-Na Ma1
and Shang-dong Yang*1,2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2071–2076.
1State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P. R. China and 2State Key Laboratory
for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Lanzhou 730000, P. R. China
doi:10.3762/bjoc.10.215
Received: 28 April 2014
Accepted: 15 August 2014
Published: 02 September 2014
Email:
Shang-dong Yang* - yangshd@lzu.edu.cn
This article is part of the Thematic Series "Organophosphorus chemistry".
Guest Editor: P. R. Hanson
* Corresponding author
Keywords:
© 2014 Hu et al; licensee Beilstein-Institut.
License and terms: see end of document.
chiral synthesis; Pd-catalysis; organophosphorus; phosphorus
ligands; P(O)R2-directing
Abstract
Chiral phosphorus ligands have been widely used in transition metal-catalyzed asymmetric reactions. Herein, we report a new syn-
thesis approach of chiral biaryls containing a phosphorus moiety using P(O)R2-directed Pd-catalyzed C–H activation; the function-
alized products are produced with good enantioselectivity.
Introduction
In the past decades, phosphorus ligands have been demon- However, these methods are not compatible for some activated
strated to be efficient ligands in many metal-catalyzed organic functional groups in precursor compounds. Over the past
reactions [1-4]. In particular, their special effects of enhancing several years, we have achieved reactions of C–P bond forma-
the metal-catalyst efficiency and of controlling chiral induction tion with new and efficient protocols via transition metal-catal-
has continually prompted synthetic chemists to probe efficient ysis [11-16]. Despite the progress in this area, only limited
methods generating access to chiral, enantiomerically pure development has been accomplished through metal-catalyzed
phosphorus compounds used in pharmaceutical, agrochemical C–H activation to build C–P bonds [17,18]. As an alternative,
and perfume industries [5-10]. However, the difficulty of we disclosed a novel protocol of palladium-catalyzed C–H
synthesizing such ligands hampered their wide application, functionalization by using the P(O)R2 moiety as a new directing
mainly due to the challenging formation of P–X (X = N, O, group to synthesize a series of phosphorus-containing com-
C…), especially C–P bond formation.
pounds in a straightforward and atom-efficient way (Scheme 1)
[19-23]. In our system, we proposed a seven-membered cyclo-
At present, the traditional strategy to introduce phosphorus palladium transition state instead of the common five or six-
atoms requires prefunctionalization or lithiation of substrate. membered transition state [24-30]. The P(O)R2 group not only
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Scheme 1: C–H functionalization of P(O)R2 directed through a seven-membered cyclopalladium transition state.
achieved the directing role but also acts as an important compo- the axial chirality within the substrates, a steric hindrance effect
nent unit of the C–H functionalized products. In this paper, we at the ortho position of phenylboronic acids was required,
use the axially chiral biaryl phosphine oxides as substrates and rendering the non-ortho substituted-phenylboronic acid that is
report the synthesis of various chiral phosphorus ligands with not applicable in these reactions. As the P(O)Ar2 group showed
high enantiomeric selectivity using palladium-catalyzed C–H a better directing ability in the process of C–H activation, the
functionalization.
axial chiral P(O)(OEt)2 4a was transformed into P(O)Ar2 by
reacting with an arylgrignard reagent (Scheme 2) [32]. At the
same time, the racemic substrates were produced using the non-
Results and Discussion
To obtain the axially chiral phosphorus compounds, we first chiral S-phos ligand. By using 2-chlorophenylboronic acid as
synthesized the special chiral-bridged atropisomeric monophos- coupling component, we demonstrated that we could obtain the
phorus ligand L-1 through an eight-step reaction sequence phosphate compound, but it failed to yield the P(O)Ph2 group in
starting from 1,3-dimethoxybenzene. According to the reported the arylation step. In addition, in the processes of hydroxylation,
operation, the substrates of biaryl derivatives that contained arylation, alkenylation, the P(O)(iPr)2 group showed a good
phosphate with axial chirality were obtained in high yields guiding ability, but the corresponding substrates could not be
using the Suzuki–Miyaura coupling reaction with the assistance obtained because the phosphate moiety did not react with the
of this versatile chiral ligand [31-34]. We used substituted naph- (iPr)MgBr.
thylboronic acid or ortho-substituted-phenylboronic acid to
synthesize the corresponding substituted binaphthyl or phenyl- Under the optimized conditions, we started to investigate the
naphthyl skeleton substrates with axial chirality. To maintain scope and applicability of our strategies. Initially, we used
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Scheme 2: Synthesis of chiral and racemic substrates.
chiral [1,1'-binaphthalen]-2-yldiphenylphosphine oxide as a Next, the substrates of the phenyl-naphthyl framework were
substrate [35]. In the process of alkenylation and acetoxylation, examined. For the ortho-OMe substituted substrate, we
the corresponding products 2a and 2b were obtained in achieved the products of alkenylation, acetoxylation and
moderate yields and high enantioselectivities. Next, we exam- hydroxylation. The OMe group is a relatively small group, so
ined the substituent effect with P(O)(p-Tol)2 as a directing the ee was not very high. If the substituent was OEt, the prod-
group: The reactions of alkenylation, acetoxylation, hydroxyla- ucts of alkenylation and acetoxylation (Figure 1, 2m and 2n)
tion and acylation occurred smoothly. Even if the products were were obtained in moderate yield and the results showed good
obtained in low to moderate yields, they were optically pure enantioselectivities. Although the yields were not very high in
(Figure 1, 2c–f). For the substrate of 4-methoxy substituted these processes, the starting materials were completely
binaphthyl, we could achieve the alkenylation product 2g in converted except for the acylation reaction, presumably due to
moderate yield and with high ee. When a fluorine substituent partial decomposition of the starting materials. These function-
was used, the acetoxylated product 2h was obtained in moderate alized products showed that the axially chiral substrates could
yield and high ee. Even if the alkenylation product 2i was be well maintained in our system of P(O)R2-directed
obtained when the substituent was methyl, we failed to produce Pd-catalyzed C–H activation. These compounds could be trans-
the desired chromatogram; however, it did exhibit a good formed to trivalent phosphorus compounds by silane to obtain
optical rotation. Those results showed that the products of C–H the corresponding phosphorous ligands.
functionalization were maintained with high enantio-
selectivities when the substrates were optically pure, even when Conclusion
these reactions were carried out in air atmosphere and at high In summary, a series of substrates with axially chiral biaryl
temperature. Herein, we provided a method to synthesize the compounds containing a P(O)Ar2 directing group were success-
substituted axially chiral binaphthyl compounds with a phos- fully synthesized using the Suzuki–Miyaura coupling reaction
phorus moiety. Moreover, these products can be further trans- under the assistance of a chiral ligand. Moreover, the substrates
formed into other functional groups.
were further C–H functionalized using the P(O)Ar2 directing
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Figure 1: C–H functionalization of axially chiral phosphorus substrates. The yields are isolated yields and the ee values are determind by HPLC.
aReaction conditions: substrate (0.3 mmol), ethyl acrylate (1.5 mmol), Pd(OAc)2 (10 mol %), Ac-Gly-OH (20 mol %), AgOAc (1.5 mmol), TFE
(3.0 mL), 100 °C, 24 h, air atmosphere; bSubstrate (0.3 mmol), PhI(OAc)2 (0.9 mmol), Pd(OAc)2 (10 mol %), TFE (3.0 mL), 100 °C, 24 h, air atmos-
phere; cSubstrate (0.3 mmol), TBHP (1.2 mmol), benzyl alcohol (0.75 mmol), Pd(TFA)2 (10 mol %), DCE (3.0 mL), 60 °C, air atmosphere; dSubstrate
(0.3 mmol), PhI(TFA)2 (0.45 mmol), Pd(OAc)2 (10 mol %), MeNO2 (3.0 mL), 60 °C, 24 h, air atmosphere.
role with Pd salt as catalyst. Notably, the reactions took palladium transition state for this transformation and provide
place in air atmosphere and at high temperature and the a new and efficient route to synthesize the substituted axially-
corresponding functionalized products exhibited good enantio- chiral oxygen–phosphine or alkene–phosphine ligand
selectivities. We propose a unique seven-membered cyclo- analogues.
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17.Feng, C.-G.; Ye, M.; Xiao, K.-J.; Li, S.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 9322–9325. doi:10.1021/ja404526x
Experimental
See Supporting Information File 1.
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Supporting Information File 1
Experimental details, characterization data (1H, 13C, 31P
spectra) of products.
21.Hu, R.-B.; Zhang, H.; Zhang, X.-Y.; Yang, S.-D. Chem. Commun. 2014,
50, 2193–2195. doi:10.1039/C3CC49050E
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
We are grateful to the NSFC (No. 21272100), Program for
Changjiang Scholars and Innovative Research Team in Univer-
sity (PCSIRT: IRT1138) and Research Fund for the Doctoral
Program of Higher Education of China (No. 20100211120014)
for financial support.
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