Enantioselective phospha-Michael addition of diarylphosphines to β,γ-unsaturated α-ketoesters and amides

Article abstract of DOI:10.1039/c4cc01610f

An enantioselective hydrophosphination of β,γ-unsaturated α-ketoesters and amides has been developed using a chiral palladacycle catalyst. Adducts can be obtained in excellent yields and enantioselectivities, providing direct access to chiral tertiary phosphines which are synthetically useful intermediates in the preparation of bidentate ligands.

Full text of DOI:10.1039/c4cc01610f

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Enantioselective phospha-Michael addition of
diarylphosphines to b,c-unsaturated a-ketoesters
and amides†
Cite this: Chem. Commun., 2014,
50, 8768
Received 4th March 2014,
Accepted 19th May 2014
Renta Jonathan Chew, Kai Yuan Teo, Yinhua Huang, Bin-Bin Li, Yongxin Li,
Sumod A. Pullarkat and Pak-Hing Leung*
DOI: 10.1039/c4cc01610f
www.rsc.org/chemcomm
An enantioselective hydrophosphination of b,c-unsaturated a-ketoesters can be further converted into other synthetically and biologically
and amides has been developed using a chiral palladacycle catalyst. useful compounds.13
Adducts can be obtained in excellent yields and enantioselectivities,
To the best of our knowledge, there have been no known reports
providing direct access to chiral tertiary phosphines which are synthe- on the enantioselective addition of phosphorus nucleophiles
tically useful intermediates in the preparation of bidentate ligands.
amongst the diverse reactions associated with b,g-unsaturated
a-ketoesters. An added advantage is that desired adducts can be
readily transformed into corresponding alkoxyphosphines14a
/
The ability to fine-tune chiral phosphines to achieve varying steric
and electronic properties has resulted in their widespread utiliza-
tion as ligands in metal-mediated asymmetric transformations1 as
well as in organocatalysis.2 Despite their importance, the prepara-
tion of chiral phosphines has traditionally been a cumbersome
and wasteful affair.3 Since Glueck pioneered the Pt(0)-catalyzed
addition of secondary phosphines to alkenes,4 it has sparked
interest as a powerful method for the direct generation of chiral
phosphines from prochiral reactants.5 Up to this date, there have
been a considerable number of reports involving the enantio-
selective addition of secondary phosphines to Michael acceptors.6
In spite of these reports, the majority of the protocols usually
require the protection of the phosphine products for ease of
handling and characterization. However, in the context of in situ
complexation or direct organocatalyst preparation, such protocols
render the phosphine dysfunctional since the electron pair
on phosphorus, which is critical for its purported function, is no
longer available. Furthermore, deprotection protocols are usually
plagued with problems such as racemisation.7
Literature review revealed that over the past decade,
b,g-unsaturated a-ketoesters have served as excellent substrates
for a myriad of reactions due to their superior reactivities versus
typical a,b-unsaturated carbonyls. They are valuable electro-
philes in conjugate additions,8 including less commonly
reported sulfa-,9 oxy-10 and aza-Michael additions.11 Other than
1,4-additions, they also participate readily in other classes of
reactions.12 It should be noted that the resultant products
phosphine-amino acid esters,14b providing rapid access to a
library of versatile chiral P,O and P,N-ligands. Inspired by the
potential of the targeted phospha-Michael adducts, we hereby
disclose the first enantioselective addition of diarylphosphines
to b,g-unsaturated a-ketoesters and amides.
Using (E)-2-methyl-2-oxo-4-phenylbut-3-enoate 1a as the model
substrate, we attempted the hydrophosphination with diphenyl-
phosphine (Ph2PH). While it was expected for 1a to have an improved
reactivity over chalcones and their analogues, we were intrigued to
find that the reaction proceeded even in the absence of any catalyst at
room temperature (Table 1, entry 1). It should be highlighted that the
uncatalyzed hydrophosphination of Michael acceptors under mild
conditions is rare in recent literature. As such, this finding made our
desired asymmetric transformation considerably more challenging.
In order to circumvent the problem at hand, it was imperative to
suppress the uncatalyzed pathway in the hope of achieving enantio-
selectivity control. It was fortuitous to find that when a temperature
of ꢀ80 1C was utilized, the rate of the uncatalyzed reaction was
significantly suppressed (Table 1, entry 2). To our delight, the use of
(R)-4 as the catalyst produced commendable results when coupled
with reduced temperature and base loading (Table 1, entry 3).
It should be highlighted that few catalysts are able to achieve a fine
balance between reactivity and stereoselectivity when subjected to
low operating temperatures. The choice of catalyst here was based on
reports demonstrating the effectiveness and versatility of (R)-4 and its
analogues as catalysts in cycloaddition,15 hydroamination16 and
hydrophosphination6e–g reactions.
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: pakhing@ntu.edu.sg; Fax: +65-67911961; Tel: +65-67903749
† Electronic supplementary information (ESI) available. CCDC 988281. For ESI and
Encouraged by the results, we performed a systematic
screening of reaction conditions (Table 1). A mixture of chloro-
form and dichloromethane turned out to be the ideal solvent
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc01610f system (Table 1, entry 9). In addition, our studies also revealed
8768 | Chem. Commun., 2014, 50, 8768--8770
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Table 1 Optimization of reaction conditions for the asymmetric hydrophosphination of (E)-2-methyl-2-oxo-4-phenylbut-3-enoate 1a with diphenylphosphinea
Entry
Catalyst/loading [mol%]
Solvent
Temperature [1C]
Base [equiv.]
Time [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
—/0%
—/0%
CHCl3
DCM
DCM
DCM
Acetone
THF
CHCl3
CHCl3–DCM (5%)
CHCl3–DCM (10%)
CHCl3–DCM (10%)
DCE–DCM (25%)
CHCl3–DCM (10%)
CHCl3–DCM (10%)
21 (rt)
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ50
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
Et3N (1.0 eq.)
Et3N (0.2 eq.)
Et3N (0.5 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Et3N (0.2 eq.)
Piperidine (0.2 eq.)
Et3N (0.2 eq.)
42
415
2
41.5
o2.5
2
99
16
99
99
99
99
99
98
98
98
99
55
20
0
0
(R)-4/5%
(R)-4/5%
(R)-4/5%
(R)-4/5%
(R)-4/5%
(R)-4/5%
(R)-4/5%
(S)-4/5%
(R)-4/5%
(R)-4/5%
(R)-5/5%
70
80
70
71
70
76
81
ꢀ77
68
52
29
2
4
9
2.5
2.5
43
2.5
31
10
11
12
13
a
b
Reaction was carried out with Ph2PH (0.1–0.15 mmol) and 1a (0.1–0.15 mmol) in 4 mL of degassed solvent(s). Yield is derived from the 31P{1H}
NMR spectrum of the crude product. Enantiomeric excess (ee) is calculated from the 31P{1H} NMR integration of signals of diastereomers arising
c
from the treatment of 2a and 3a with (R)-6.
that while the amount of base employed did not significantly changing the substitution from the para to the meta position
impact yields, a reduction in base loading did produce better (Table 2, entries 4 and 5). However, for heterocycles, substandard
selectivities (Table 1, entries 3 and 4). Triethylamine was the results were observed for ortho-substituted moieties as compared to
base of choice due to its suitable basicity as well as its ease of meta-substituted ones (Table 2, entries 11 and 12).
removal. Nevertheless, we attempted the reaction with a weaker
In addition to Ph2PH, we also examined di(p-tolyl)phosphine
amine but unfortunately this gave poor results (Table 1, entry 12). (( p-Tol)2PH) to study the applicability of various secondary
Lastly, we employed an amine analog of (R)-4, (R)-5, as the catalyst phosphines in our protocol. While ( p-Tol)2PH also afforded
but it was disappointing as it produced poor results even with excellent yields, only moderate ee values were obtained, with
prolonged reaction times (Table 1, entry 13).
comparatively longer reaction times (Table 2, entries 13–16).
The enantiomeric excess (ee) of the adducts was determined We believe that the reduced reactivity of ( p-Tol)2PH ensured
from the integration of 31P{1H} NMR signals arising from that the uncatalyzed reaction was marginally more dominant,
diastereomers formed upon treatment of 2a and 3a with (R)-6, thus accounting for the reduced selectivities. In general, regard-
an effective resolving agent for both phosphines and arsines.17 less of the phosphinating agents employed, electron-deficient
Enantioselectivities were readily established with adducts showing substrates produced superior enantioselectivities compared to
signals at d 49.22 (R,S)-7a, 45.78 (R,S)-8a and 44.04 (R,R)-7a.18 more electron-rich moieties (Table 2, entries 3–10 and 13–15).
Single crystal X-ray diffraction analysis of 9a, a phosphine–enolate
In addition to b,g-unsaturated a-ketoesters, we were curious as
chelate, revealed that the absolute configuration of the newly to whether the protocol would also be pertinent for b,g-unsaturated
generated chiral centre was S.18,19 A subsequent reaction carried a-ketoamides 1aa. Owing to the Lewis basicity of nitrogen, the
out using (S)-4 as the catalyst generated the R isomer with ketone carbonyl was activated to a lesser extent, thus accounting for
comparable results (Table 1, entry 10).
the longer reaction time required (Table 2, entry 17).
With the optimal conditions thus established, the substrate scope
Drawing upon previously reported experimental results,6e
a
for the asymmetric phospha-Michael addition of b,g-unsaturated catalytic cycle for the asymmetric phospha-Michael addition of 1 is
a-ketoesters was examined and our findings are summarised in proposed. Relative to the phosphorus atom in metallacycle 4, the
Table 2. Our protocol can tolerate a wide range of functional groups naphthyl ring exerts a stronger trans effect, thereby labilizing the
including halo, nitro, alkyl, and alkoxy chains as well as heterocycles. bound diarylphosphine trans to the aromatic ring. Its departure
Generally, reactions proceeded smoothly to give excellent yields of up generates a vacant site, allowing 1 to bind via its keto oxygen due to
to 499%. However, it should be noted that when an electronically the pronounced oxophilicity of that particular site.20 The remaining
richer and bulkier isopropyl ester was employed, the ee improved bound phosphine then undergoes deprotonation in the presence of
slightly (Table 2, entry 2). Excellent results were also obtained by base to give a phosphido species, which attacks the electrophilic
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Table 2 Substrate scope for the (R)-4 catalyzed enantioselective phospha-Michael addition of b,g-unsaturated a-ketoesters and amides 1 with
diarylphosphinesa
Entry
Substrate
R
R0
Ar
Time [h]
Product
Yieldb,c [%]
eed [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1a
1d
1i
1k
1aa
Ph
Ph
OMe
OiPr
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NEt2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
Ph
2.5
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
98 (93)
98 (94)
98 (93)
98 (94)
98 (90)
99 (95)
98 (90)
98 (94)
98 (91)
93 (95)
90 (93)
94 (95)
98 (96)
499 (96)
98 (94)
499 (90)
95 (499)
81
83
83
85
85
87
90
89
71
78
84
65
66
71
70
75
70
p-FC6H4
p-ClC6H4
m-ClC6H4
p-BrC6H4
p-CF3C6H4
p-NO2C6H4
p-MeC6H4
p-MeOC6H4
m-Pyridyl
2-Thienyl
Ph
2.5
2.5
2.5
2.5
2.5
4
5
5
2
4
3.5
3.5
6
3.5
23
9
10
11
12
13
14
15
16
17
2j
2k
2l
2a0
2d0
2i0
2k0
2aa
p-ClC6H4
p-MeC6H4
m-Pyridyl
Ph
a
Reaction was carried out with Ar2PH (0.1 mmol) and 1 (0.1 mmol) in 3.6 mL of chloroform and 0.4 mL of dichloromethane. Solvents were degassed
prior to use. Yield is derived from the 31P{1H} NMR spectrum of the product. Values in parentheses indicate the abundance of keto tautomer 2
b
c
which is determined from the 31P{1H} NMR spectrum of the product. Enantiomeric excess (ee) is calculated from the 31P{1H} NMR integration
d
signals of diastereomers arising from the treatment of 2 and 3 with (R)-6.
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product from the catalyst then completes the catalytic cycle. It
should be highlighted that 4 behaves purely as a Lewis acid catalyst
and thus palladium does not undergo any change in oxidation state
throughout the cycle. It is noteworthy that similar catalytic cycles
have recently been reported, resembling our proposed system.5
In conclusion, we have developed the first protocol involving
the catalytic enantioselective phospha-Michael addition of b,g-
unsaturated a-ketoesters and amides. Excellent yields of up
to 499% and enantioselectivities of up to 90% can be achieved
when coupled with low temperatures, which suppress the undesired
uncatalyzed pathway. The ease of access to such synthetically
important chiral tertiary phosphines greatly facilitates the prepara-
tion of catalytically versatile P,O and P,N bidentate ligands.
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8770 | Chem. Commun., 2014, 50, 8768--8770
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