Palladacycle-catalyzed asymmetric intermolecular construction of chiral tertiary P-heterocycles by stepwise addition of H-P-H bonds to bis(enones)

Article abstract of DOI:10.1021/om300405h

A palladacycle-catalyzed diastereo- and enantioselective stepwise double hydrophosphination of bis(enones) with PhPH₂ has been developed, allowing intermolecular construction of chiral tertiary bulky P-heterocycles in one pot in high yields. A catalytic cycle for the reaction is proposed as well.

Full text of DOI:10.1021/om300405h

Article
pubs.acs.org/Organometallics
Palladacycle-Catalyzed Asymmetric Intermolecular Construction of
Chiral Tertiary P-Heterocycles by Stepwise Addition of H−P−H Bonds
to Bis(enones)
Yinhua Huang, Sumod A. Pullarkat, Siewping Teong, Renta Jonathan Chew, Yongxin Li,
and Pak-Hing Leung*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A palladacycle-catalyzed diastereo- and enantio-
selective stepwise double hydrophosphination of bis(enones)
with PhPH2 has been developed, allowing intermolecular
construction of chiral tertiary bulky P-heterocycles in one pot
in high yields. A catalytic cycle for the reaction is proposed as
well.
catalyzed stepwise double hydrophosphination between a
primary phosphine and bis(enones) in one pot (eq 1).
INTRODUCTION
■
Chiral P-heterocycles containing phosphorus atom(s) in the
ring such as DuPhos,1 TangPhos,2 i-Pr-BeePhos,3 etc. have
played important roles in asymmetric transformations.4
However, most of these chiral P-heterocycles are predom-
inantly prepared either via a tedious resolution process or by
the synthetic manipulation of limited chiral pool starting
materials.5 Recently, a few efficient strategies for the catalytic
synthesis of chiral phosphines have emerged and attracted great
interest. These include the synthesis of P-stereogenic
phosphines via cross-coupling reactions6 and the synthesis of
C-stereogenic phosphines via allylic phosphination7 as well as
hydrophosphination of Michael acceptors such as conjugated
esters, nitriles,8 enones,9 enals,10 and nitroalkenes.11 Never-
theless, the products obtained via the aforementioned methods
are usually confined to chain phosphines (containing
phosphorus atom(s) in the chain). The methodology for
catalytic synthesis of chiral P-heterocycles, on the other hand,
remains a considerable challenge, especially when it involves
the generation of multiple chiral centers from achiral acyclic
substrates. Only Marks et al.12 and Glueck et al.13 have reported
metal-catalyzed intramolecular cyclization to generate chiral P-
heterocycles. Although syntheses of racemic P-heterocycles
have been reported by thermal-/acid-mediated addition
between primary phosphines and bis(enones) under high
temperature (>100 °C),14 the catalytic enantioselective
intermolecular construction of chiral P-hetereocycles, to the
best of our knowledge, has not been reported to date.
It is indeed noteworthy that chiral tertiary P-heterocycles
with sterically demanding groups are of interest as bulky ligands
for several reasons:14a (1) the 2,6-substituents are in close
proximity to the metal center, which may lead to unusual
coordination chemistry and catalytic activity; (2) tuning of the
2,6-substituents on the ring enables manipulation of the ligand
stereo- and electronic effects; (3) the carbonyl group allows
further elaboration of the ligand at a site remote from the donor
atom; (4) such ligands have been reported as efficient ligands
for metal-catalyzed asymmetric hydrogenation reactions.16
RESULTS AND DISCUSSION
■
On the basis of previous studies, we employed the chiral
palladacycles 1−3 (Figure 1) as catalysts toward the reaction of
a primary phosphine PhPH2 with dibenzylideneacetone (Table
1). Initially, the C,N-palladacycles (S)-1 and (S)-2 were used as
the catalysts. However, the results showed that they are not
efficient catalysts for this synthetic scenario. To our delight, the
C,P-palladacycle (S)-3 efficiently catalyzed the cyclization in
high yields when it was employed as the catalyst. Various
reaction conditions were subsequently screened, and the details
are given in Table 1. The results showed that the best ee was
achieved when THF was used as the solvent for the reaction. A
In connection with our continuous interest in the synthesis
of chiral tertiary phosphines and motivated by our previous
success in palladacycle-mediated15 and -catalyzed9b,e,g asym-
metric synthesis of chiral chain phosphines, herein we report
the first diastereo- and enantioselective intermolecular con-
struction of chiral P-heterocycles via a phosphapalladacycle-
Received: May 14, 2012
Published: June 19, 2012
© 2012 American Chemical Society
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Figure 1. Palladacycles used in the study.
Table 1. Catalyst, Solvent, and Temperature Effects on the
a
Reaction of PhPH2 and Dibenzylideneacetone
b
d
temp
(°C)
yield
ee(R,R)
(%)
c
entry
cat.
solvent
(%)
dr
1
2
3
4
(S)-1
(S)-2
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(R)-3
THF
80, 20
80, 20
80, 20
20
trace
trace
98
THF
THF
78:22
95
THF
messy
81
e
5
acetone
CH2Cl2
CHCl3
NCMe
benzene
THF
80, 20
80, 20
40, 20
40, 20
20
82:18
83:17
83:17
66:14
70:30
78:22
47
56
Figure 2. Molecular structure and absolute stereochemistry of (S,R,R)-
8a with 50% probability thermal ellipsoids shown. Hydrogen atoms,
except those on the chiral center, are omitted for clarity.
6
7
8
93
93
72
97
35
e
9
99
41
f
Table 2. Substrate Scope of the (S)-3-Catalyzed Asymmetric
10
80, 20
98
95
a
Hydrophosphination of Bis(enones) with PhPH2
a
Conditions: 0.35 mmol of PhPH2, 15 mol % of cat., 1.0 equiv of
bis(enone), 4 mL of solvent, 2.0 equiv of Et3N. Reactions were started
at the given low temperature for 12 h, and then the mixture was
b
warmed to 20 °C with stirring for 24 h, unless otherwise noted. Yield
c
was calculated from 31P{1H} NMR of the crude product. dr was
d
calculated from 31P{1H} NMR of the crude product. The ee (of the
major product) was determined by 31P{1H} NMR; see the Supporting
e
f
Information for details. Stirring at 20 °C for 24 h. (R)-3 was used as
the catalyst.
Scheme 1. Protocol Adopted for the Determination of ee by
Coordination of the P-Heterocycles to (S)-4
a
Conditions: 0.35 mmol of PhPH2, 15 mol % of (S)-3, 4 mL of THF,
1.0 equiv of bis(enone), 2.0 equiv of Et3N. The reactions were started
at 80 °C for 12 h, and then the mixtures were warmed to 20 °C with
b
stirring for another 24 h, unless otherwise noted. Yield was calculated
c
from 31P{1H} NMR of the crude product. dr was calculated from
d
31P{1H} NMR of the crude product. The ee (of the major product)
was determined by 31P{1H} NMR: see the Supporting Information for
e
details. Stirring at 80 °C for 16 h and then at 20 °C for 3 days.
The reaction was conveniently monitored by 31P{1H} NMR
spectroscopy. The diastereomeric ratio (dr = rac/meso) was
determined from the 31P{1H} NMR spectrum of the crude
better dr with lower ee was observed when other solvents such
CH2Cl2, acetone, CHCl3, and NCMe were used.
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Scheme 2. Proposed Catalytic Cycle
product, and the enantiomeric excess (ee) of the rac isomers
was determined from 31P{1H} NMR spectra of the derivatives 8
formed by treating the corresponding enantiomerically
enriched 7 with the enantiopure palladacyclic complex (S)-/
(R)-4 (Scheme 1).8f,g Though meso and rac isomers involving
two chiral centers were formed during the reaction, the
corresponding derivatives for determination of ee could be
conveniently and efficiently identified in 31P{1H} NMR
spectroscopy by the use of a combination of (R)- and (S)-4.17
The single-crystal X-ray diffraction analysis of one such major
derivative, 8a (R = Ph), revealed that the absolute configuration
at both chiral carbon centers of the major product is R (Figure
2).
With the optimal conditions established, a range of aromatic
bis(enones) were screened for the asymmetric stepwise
hydrophosphination reaction catalyzed by (S)-3. The results
are presented in Table 2 and showed that the reaction
proceeded to full conversion of PhPH2 under the given
conditions, allowing the intermolecular construction of a series
of air-sensitive P-heterocyclic products. The process also
tolerates a range of functional groups such as halogens (F,
Cl, Br). Bis(enones) with electron-withdrawing substituents
showed good reactivities with excellent enantioselectivities and
concomitant high yields. However, those bearing electron-
donating groups (such as MeO−) and more steric substituents
(such as o-ClC6H4, 3,5-Cl2C6H3) showed less reactivity and
failed to give the expected products under the same conditions.
On the basis of the experimental results, a mechanism was
proposed for the (S)-3-catalyzed asymmetric stepwise double
hydrophosphination reaction (Scheme 2). Free PhPH2 has a
high affinity for palladium, and this leads to the facile
displacement of the relatively weakly coordinated NCMe of
the palladacycle and allows the formation of a bis(phosphine)
complex. However, due to the strong π-accepting properties of
the aromatic carbon donor, the P−Pd bond in the trans P−Pd−
C moiety is labile and readily undergoes the ligand
redistribution process, which provides the opportunity for the
bis(enone) to coordinate to palladium. In comparison, the trans
P−Pd−P moiety in the catalytic intermediate is more stable and
allows the subsequent acidification of the P−H bond of the
coordinated PPh(R′)H. In the presence of Et3N as the external
base, the coordinated PPh(R′)H is thus readily deprotonated to
form the corresponding reactive phosphido species, which
undergoes 1,4-addition with the coordinated bis(enone). The
31P{1H} NMR study of the reaction revealed that (S)-3 can
indeed catalyze the first addition of a P−H bond to bis(enone)
at −80 °C quantitatively to give the secondary phosphine
intermediate (A or B) with chiral centers at both carbon and
phosphorus. Only one isomer was observed (31P NMR δ
−23.0), which means that the first addition indeed proceeds
with excellent diastereoselectivity. However, the addition of
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challenging in terms of both electronic factors and stereo-
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°C). It is important to note that racemization at phosphorus
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CONCLUSIONS
■
In summary, we have developed a novel method for the
diastereo- and enantioselective intermolecular construction of
tertiary P-heterocycles by a palladacycle-catalyzed stepwise
double hydrophosphination of bis(enones) with a primary
phosphine in high yields. A mechanism has been proposed for
the reaction. We are currently investigating the applications of
the chiral tertiary P-heterocycles in asymmetric transformations.
EXPERIMENTAL SECTION
■
General Procedure for Asymmetric Synthesis of P-Hetero-
cycles. To a solution of PhPH2 6 (38.5 mg, 0.35 mmol, 1.0 equiv) in
THF (4 mL) was added (S)-3 (32.9 mg, 0.053 mmol, 15 mol %). The
solution was stirred at room temperature for 5 min and then was
cooled to −80 °C. Subsequently, the bis(enone) 5 (0.35 mmol, 1.0
equiv) was added. Et3N (70.8 mg, 0.70 mmol, 2.0 equiv) in THF (0.5
mL) was then added dropwise. The solution was subsequently stirred
at −80 °C for 12 h. Then, the mixture was warmed to room
temperature (20 °C) gradually and stirred for 24 h. The reaction was
monitored by 31P{1H} NMR. After the reaction was complete, the
solvent (THF) was evaporated by vacuum pump to give the crude P-
heterocyclic products. The diastereomeric ratio (dr) was measured by
the 31P{1H} NMR spectrum of the crude products. For determination
of the ee, the enantiopure dimeric palladacycle (R)-/(S)-4 (in slight
excess) was dissolved in the corresponding ligand solution, leading to
the coordinated derivatives quantitatively. The ee was calculated from
the 31P{1H} NMR spectra of the derivatives.17
Caution! Perchlorate salts of metal complexes are potentially explosive
compounds and should be handled with care.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and a CIF file giving experimental
procedures, characterization data, and single crystal X-ray
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Douglass, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc.
2001, 123, 10221. (b) Douglass, M. R.; Ogasawara, M.; Hong, S.;
Metz, M. V.; Marks, T. J. Organometallics 2002, 21, 283.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pakhing@ntu.edu.sg.
■
(13) Brunker, T. J.; Anderson, B. J.; Blank, N. F.; Glueck, D. S.;
Rheingold, A. L. Org. Lett. 2007, 9, 1109.
Notes
(14) (a) Doherty, R.; Haddow, M. F.; Harrison, Z. A.; Orpen, A. G.;
Pringle, P. G.; Turner, A.; Wingad, R. L. Dalton Trans. 2006, 4310.
(b) Welcher, R. P.; Day, N. E. J. Org. Chem. 1962, 27, 1824.
(15) For recent selected examples, see: (a) Huang, Y. H.; Pullarkat, S.
A.; Yuan, M. J.; Ding, Y.; Li, Y. X.; Leung, P. H. Organometallics 2010,
29, 536. (b) Yuan, M. J.; Zhang, N.; Pullarkat, S. A.; Li, Y. X.; Liu, F.
L.; Pham, P. T.; Leung, P. H. Inorg. Chem. 2010, 49, 989. (c) Yuan, M.
J.; Pullarkat, S. A.; Ma, M. T.; Zhang, Y.; Huang, Y. H.; Li, Y. X.; Goel,
A.; Leung, P. H. Organometallics 2009, 28, 780. (d) Liu, F. L.;
Pullarkat, S. A.; Li, Y. X.; Chen, S. L.; Yuan, M. J.; Lee, Z. Y.; Leung, P.
H. Organometallics 2009, 28, 3941.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Nanyang Technological University for supporting
this research.
■
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(17) For more details, see the Supporting Information.
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