Enantioselective Cu-Catalyzed Arylation of Secondary Phosphine Oxides with Diaryliodonium Salts toward the Synthesis of P-Chiral Phosphines

Article abstract of DOI:10.1021/jacs.6b09334

Catalytic synthesis of nonracemic P-chiral phosphine derivatives remains a significant challenge. Here we report Cu-catalyzed enantioselective arylation of secondary phosphine oxides with diaryliodonium salts for the synthesis of tertiary phosphine oxides

Full text of DOI:10.1021/jacs.6b09334

Communication
pubs.acs.org/JACS
Enantioselective Cu-Catalyzed Arylation of Secondary Phosphine
Oxides with Diaryliodonium Salts toward the Synthesis of P‑Chiral
Phosphines
Rodolphe Beaud, Robert J. Phipps, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
Scheme 1. New Synthesis of P-Chiral Phosphines
ABSTRACT: Catalytic synthesis of nonracemic P-chiral
phosphine derivatives remains a significant challenge. Here
we report Cu-catalyzed enantioselective arylation of
secondary phosphine oxides with diaryliodonium salts for
the synthesis of tertiary phosphine oxides with high
enantiomeric excess. The new process is demonstrated on
a wide range of substrates and leads to products that are
well-established P-chiral catalysts and ligands.
hiral phosphines are essential ligands for enantioselective
C
metal-catalyzed reactions.1 Most of the chiral phosphines
commonly used today display planar or point chirality where the
asymmetric feature is presented in the carbon framework of the
ligand. Although P-stereogenic phosphines have been known as
effective ligands for enantioselective catalysis for over 40 years,2
they are less frequently utilized compared with more readily
available planar- and point-chiral phosphines. Classical methods
for the synthesis of P-stereogenic phosphines usually rely on
auxiliary-based or resolution processes.3 Recently, however,
advances in asymmetric catalysis have provided alternative
methods to access these chiral phosphorus compounds via
methods based on alkene phosphination,4a arylation4c or
alkylation4d of secondary phosphines, and C(sp2)−H activation
of aryl phosphine derivatives.4e−h Despite these advances, the
development of distinct strategies that provide convenient access
to a broad range of P-stereogenic phosphines remains an ongoing
challenge in chemical synthesis. Herein we report a new method
to form P-stereogenic organophosphorous compounds via
enantioselective Cu-catalyzed arylation of secondary phosphine
oxides (SPOs) using diaryliodonium salts (DAISs).
nucleophiles, whose arylation would lead to tertiary phosphine
oxides (TPOs), precursors to P-chiral phosphines as well as
useful asymmetric catalysts in their own right.
An SPO exists in equilibrium with its phosphinous acid form
when in solution, with the latter recognized as a competent
ligand for a range of transition metals (Scheme 1b).7 Therefore,
we envisioned that a simple SPO would bind to a high-oxidation-
state chiral Cu(III)−aryl complex, formed through the action of a
DAIS on the starting Cu catalyst, through the P atom, resulting in
a square-pyramidal complex (Scheme 1c). The aromatic group
would be transferred to the substrate as part of a stereocontrolled
reductive elimination process to form the enantioenriched TPO.
At the outset of our studies, we were aware of a report by Zhao
that racemic arylation of SPOs can be achieved with diaryliodium
salts and simple Cu catalysts.8 By applying the knowledge
accrued from our enantioselective arylation studies with C2-
symmetric bisoxazoline ligands, we began our studies with the
straightforward merger of these sets of reaction conditions
toward the development of a catalytic enantioselective arylation
process (Scheme 1d).
Over the past 8 years, our laboratory has developed a new
reactivity platform based on the combination of DAISs and Cu
catalysts to generate an aromatic electrophile equivalent in the
form of a putative Cu(III)−aryl intermediate (Scheme 1a).5 As a
result, the arylation of carbon-centered neutral nucleophiles,
including arenes,5a,b alkenes,5c and alkynes,5d has led to the
realization of many distinct transformations. Furthermore, we
and others have translated this novel activation mode to
asymmetric catalysis using chiral bisoxazoline ligands to achieve
the enantioselective C-arylation of enol silanes,6a,b allylic
amides,6c and tryptamine derivatives.6d,e In further expanding
the scope of this asymmetric arylation platform, we questioned
whether certain heteroatom nucleophiles could engage the
catalytically generated aromatic electrophile to form configura-
tionally stable products. To test this, we selected SPOs as suitable
We began by attempting the asymmetric arylation of SPO 1a
with substituted DAIS 2a using (S,S)-diphenylbisoxazoline 4a as
the chiral ligand, copper(II) triflate as the catalyst, and Et3N as
the base in CH2Cl2 solution at room temperature (Table 1).
Received: September 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b09334
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Cu(OTf)2, 12 mol % pybox ligand 4d, 2 equiv of K2HPO4, and 2
equiv of water in MeCN with stirring for 12 h at room
temperature, which gave 3a in 96% yield with 96% ee after
purification by silica gel chromatography.
Table 1. Optimization of Enantioselective Arylation
With an optimal process in hand, we next investigated the
scope of the SPO component in this transformation (Table 2).
Simple SPOs bearing methyl and n-alkyl substituents were
arylated to give the desired TPOs 3b−d with excellent ee and
yield. SPOs with secondary branched alkyl groups also were
excellent substrates for the arylation and gave high yields of 3e
and 3f with excellent ee. Substrates with branching adjacent to
the P atom gave mixed results. While arylation of t-Bu- and
cyclohexyl-derived SPOs resulted in good yields of 3g and 3h,
respectively, the enantioselectivities were moderate. However,
cyclopropyl- and isopropyl-substituted SPOs underwent aryla-
tion in excellent yields to give 3i and 3j, respectively, with high ee
using slightly modified conditions. More functionalized sub-
stituents, including benzyl and CH2SiMe3 groups, also gave the
desired products (3k, 3l) in comparably high yields and ee.
We next investigated different DAISs displaying a variety of
electronic and steric properties (Table 3). Electron-withdrawing
groups at the para position were well-tolerated, and enantioen-
riched TPOs 3m−o were obtained in excellent yields and ee.
Halogenated arenes were also transferred smoothly to afford 3p
and 3q in good yields and enantioselectivities. Finally, more
electron-rich aryls delivered 3r and 3s with remarkably high
enantiomeric excess. After recrystallization, 3r was obtained as a
single enantiomer, and its X-ray structure confirmed the absolute
stereochemistry of the enantioenriched TPOs.9 DAISs display-
ing p-OMe or p-NO2 substituents were unsuccessful in this
reaction. However, we found that other substituted arenes are
transferred effectively; meta-substituted DIASs are effective in
this process. For example, electron-deficient arenes (3v−x),
halogenated arenes (3y, 3z), and simple alkyl-substituted arenes
(3ab, 3ac) were transferred to form TPOs in excellent yields and
ee. Conducting the reaction with disubstituted DAISs also led to
the formation of the arylated TPOs 3ad−af with enantiose-
lectivities of over 90% ee in excellent yields.
a
Yields based on 1H NMR analysis using 1,2-DME as an internal
b
c
standard. 2 equiv was added. Average yield over 3 runs.
Unfortunately, only traces of 3a were observed under these
conditions (entry 1). However, we found that using the hindered
base di-tert-butylpyridine (dtbpy) afforded the arylated TPO 3a
with low conversion but importantly with modest enantiomeric
excess (56% ee) (entry 3). A survey of readily available ligands
showed that changing substituents on the oxazoline moieties or
using the corresponding tridentate pyridinebisoxazoline (pybox)
catalysts led to no improvement using dtbpy as the base (entries
4 and 5). However, we were delighted to find that changing the
solvent to MeCN while retaining (S,S)-diphenylpybox 4d as the
ligand and dtbpy as the base resulted in a dramatic increase in the
ee of 3a, but only a modest yield. Moreover, changing the base to
NaHCO3 resulted in a significant increase in conversion, with 3a
isolated in 99% yield (with respect to DAIS 2a) and high ee.
Further improvement was achieved by changing the base to
K2HPO4, and we found that the presence of 2 equiv of water was
important in securing a reproducible and robust reaction. Thus,
the optimal conditions involved treatment of 2 equiv of SPO 1a
with DAIS 2a as the limiting reagent in the presence of 10 mol %
Finally, we sought to access P-stereogenic compounds bearing
three groups of differing steric properties, namely alkyl, aryl, and
ortho-substituted aryl. To achieve this goal, we reacted SPO 1b
with ortho-substituted DAISs. The reaction occurred smoothly
with o-trifluoromethoxy iodonium salt to form the electron-
Table 2. Enantioselective Arylation of SPOs: Scope of the SPO Component
a
b
Yields of isolated products based on 2a as the limiting reagent are shown. Reaction with degassed MeCN.
B
DOI: 10.1021/jacs.6b09334
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Journal of the American Chemical Society
Communication
Table 3. Enantioselective Arylation of SPOs: Scope of Aryl Transfer
a
Yields of isolated products based on 2 as the limiting reagent are shown.
deficient PAMP10 analogue 3ag in excellent yield with very good
ee. An o-tolyl iodonium salt reacted in almost quantitative yield
to afford 3ah, again with excellent ee. We were also pleased to
find that ortho-halogenated iodonium salts reacted smoothly to
produce TPOs with a convenient handle for further function-
alization (3ai−3ak) in high yields and ee.
Scheme 2. Control Experiments
Reflecting on a possible mechanism for this enantioselective
arylation process, our first impressions were that the reaction
would operate as an arylative kinetic resolution process. On the
basis of the formation of TPO 3a, its enantioselectivity, and the
assumption of first-order kinetics, this arylative kinetic resolution
displays a selectivity factor of 148. Although in principle the
starting material should be produced with enantiomeric excess,
we found that isolating the remaining starting material was not
trivial. A deleterious oxidation process transforms the remaining
SPO into the corresponding phosphinic acid derivative, which
undergoes O-arylation to give the phosphinate. However, it was
possible to isolate the small quantities of the remaining SPO, and
we were surprised that this material was either racemic or
displayed very low enantiomeric excess and hence was not
consistent with a classical kinetic resolution. To probe this
unusual finding, we conducted a series of control reactions. We
tested the stability of enantioenriched SPO (−)-1c under a
number of conditions related to the optimal process and were
surprised to find that in all cases the remaining SPO was partially
or fully racemized in the presence of any of the reaction
components (Scheme 2a) and accompanied by significant
amount of the corresponding of aryl phosphinate. While this
configurational instability of the SPO is contrary to most reports
in the literature, we believe that racemization is the result of acid
generated as a result of the deleterious oxidation pathway.
We also showed that the reaction of enantioenriched (−)-1c
under standard conditions but without the chiral ligand gave a
stereospecific arylation in moderate yield accompanied by
oxidative arylation to racemic phosphinate 5a (Scheme 2b).
Reaction of (−)-1c with (S,S)-4d·Cu(OTf)2 leads to the
productive, matched formation of the arylation product in high
er. However, we were surprised to find that the supposed
mismatched experiment (with (R,R)-4d·Cu(OTf)2) gave a
similar yield and high er of the opposite enantiomer of the
product, accompanied by the corresponding arylated phosphi-
nate in low yield and enantioselectivity (Scheme 2c). We
rationalize this observation on the basis that the starting
enantioenriched SPO must be racemizing during the reaction11
to form quantities of the enantiomer that is matched to the
catalyst being used, resulting in arylation to give the observed
TPO enantiomer. Taken together, these experiments hinted at
the opportunity for a dynamic kinetic resolution arylation of a
racemic SPO, but all attempts to secure such a transformation
have failed; clearly, the mechanism of this enantioselective
arylation process is more complex than simply a kinetic
resolution. Despite this, it is clear that the distinct Cu-catalyzed
C
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Journal of the American Chemical Society
Communication
Chem. Rev. 2011, 111, 2119. (c) Phosphorus(III) Ligands in Homogeneous
Catalysis: Design and Synthesis; Kamer, P. C. J., van Leeuwen, P. W. N.
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Ligands in Asymmetric Catalysis; Wiley-VCH: Weinheim, 2008.
arylation process provides an effective way to produce
enantioenriched TPOs in excellent yield with very high
enantiomeric excess.
We demonstrated the utility of these enantioenriched TPOs
through further transformations of the P-chiral scaffold (Scheme
3). We carried out Suzuki cross-coupling of 3ak to form a chiral
(2) (a) Horner, L.; Siegel, H.; Buthe, H. Angew. Chem., Int. Ed. Engl.
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Scheme 3. Transformations of TPOs
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overview, see ref 1c.
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phosphine oxide analogue of the S/X-Phos-type ligands that are
ubiquitous in Pd-catalyzed transformations.12 Although P-chiral
TPOs are also effective ligands in a range of asymmetric
reactions,13 the corresponding phosphines are more widely used
in chemical synthesis. Therefore, we were pleased to find that
reduction to the corresponding P-chiral phosphines can be
achieved by treating the enantioenriched TPOs with a
combination of MeOTf and LiAlH4 to form the P-chiral
phosphine−BH3 adducts, providing potential opportunities for
asymmetric metal-catalyzed transformations.
In summary, we have described a general and highly
enantioselective route to access P-chiral tertiary phosphine
oxides via a Cu-catalyzed arylation process using readily available
diaryliodonium salts. Although its mechanism remains unclear,
this arylation process provides rapid access to a range of P-chiral
phosphines that have great potential as ligands in catalytic
enantioselective processes. Current studies are focused on
elucidating the mechanism of this reaction and exploring the
applications of the new ligand scaffolds.
(7) Shaikh, T. M.; Weng, C.-M.; Hong, F.-E. Coord. Chem. Rev. 2012,
256, 771.
(8) Xu, J.; Zhang, P.; Gao, Y.; Chen, Y.; Tang, G.; Zhao, Y. J. Org. Chem.
2013, 78, 8176.
(9) The X-ray structure of 3r confirmed the absolute stereochemistry.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b09334.
■
S
Procedures and spectral data (PDF)
Crystallographic data for 3r (CIF)
AUTHOR INFORMATION
Corresponding Author
*mjg32@cam.ac.uk
Notes
■
(10) (a) Vedejs, E.; Donde, Y. J. Am. Chem. Soc. 1997, 119, 9293.
(b) Moncarz, J. R.; Brunker, T. J.; Jewett, J. C.; Orchowski, M.; Glueck,
D. S.; Sommer, R. D.; Lam, K.-C.; Incarvito, C. D.; Concolino, T. E.;
Ceccarelli, C.; Zakharov, L. N.; Rheingold, A. L. Organometallics 2003,
22, 3205. Also see ref 2c.
The authors declare no competing financial interest.
(11) A similar acid-promoted racemization has been reported. See: Xu,
Q.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2008, 130, 12648.
(12) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338. (b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(13) Benaglia, M.; Rossi, S. Org. Biomol. Chem. 2010, 8, 3824.
ACKNOWLEDGMENTS
■
We are grateful to the European Commission for a Marie Curie
International Outgoing Fellowship (R.J.P.), the ERC (R.B.), the
EPSRC, and the Royal Society (M.J.G.) for fellowships. Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
REFERENCES
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DOI: 10.1021/jacs.6b09334
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX