Asymmetric organocatalytic conjugate addition of diarylphosphane oxides to chalcones

Article abstract of DOI:10.1002/ejoc.201001308

The first example of a convenient and enantioselective asymmetric conjugate addition of diarylphosphane oxides to chalcones is reported. By using commercially available dihydroquinine as the organocatalyst and diphenylphosphane oxide as the nucleophile, t

Full text of DOI:10.1002/ejoc.201001308

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001308
Asymmetric Organocatalytic Conjugate Addition of Diarylphosphane Oxides
to Chalcones
Alessio Russo[a] and Alessandra Lattanzi*[a]
Keywords: Michael addition / Alkaloids / Organocatalysis / Phosphorus / Enones
The first example of a convenient and enantioselective asym-
metric conjugate addition of diarylphosphane oxides to chal-
cones is reported. By using commercially available dihy-
droquinine as the organocatalyst and diphenylphosphane
oxide as the nucleophile, the adducts were isolated in high
yield and up to 89%ee. The final adducts can be easily
recrystallized to enantiopure material.
phane oxides in good to high yield and excellent enantio-
selectivity.[9] A few studies have been focused on secondary
aryl or alkylphosphane oxides as the donors to develop di-
rect enantioselective approaches to phosphane oxide deriva-
tives through conjugate addition to α,β-unsaturated car-
bonyl compounds. A metal-catalyzed highly enantioselec-
tive conjugate addition of dialkylphosphane oxides to α,β-
unsaturated N-acylpyrroles has been reported by Wang and
co-workers.[10] An organocatalytic Michael addition of di-
arylphosphane oxides to cyclic and aliphatic enones has
been disclosed by Ye and co-workers employing diamino
cinchona alkaloid derived thioureas.[11] These multifunc-
tional catalysts enabled the formation of the adducts in high
yield and enantioselectivity. Iminium ion/Brønsted base bi-
functional activation of the reagents by the catalyst has
been postulated to explain the stereochemical outcome of
the reaction.
With the aim of enlarging the scope of relatively underex-
plored enantioselective phospha-Michael addition reac-
tions, we undertook an investigation on easily accessible
trans-chalcones as the acceptors and diarylphosphane ox-
ides as the donors. Secondary phosphane oxides are known
to equilibrate with the tautomer phosphinous acid
(R2POH), which is the nucleophilic form, although the
phosphane oxide is almost exclusively prevalent under neu-
tral conditions (Scheme 1).[12]
Introduction
Enantiomerically enriched organophosphorus com-
pounds play a dominant role in organic synthesis as attested
by the importance of chiral phosphanes and phosphane ox-
ides as ligands or preligands in metal-catalyzed transforma-
tions.[1] Moreover, the wide structural diversity and proper-
ties of phosphorus compounds make them not only a valu-
able class of building blocks, but also products of interest-
ing biological activities witnessed by their naturally occur-
ring representatives.[2] For example, α- and β-aminophos-
phonic acids are isosteric or bioisosteric analogues of the
corresponding amino acids showing antibacterial and anti-
fungal activities.[3] Moreover, they behave as enzyme inhibi-
tors,[4] including HIV protease.[5] Consequently, increasing
research efforts have been focused on the development of
stereoselective approaches for the synthesis of organophos-
phorus compounds through metal-catalyzed protocols[1]
and more recently by organocatalytic approaches.[6] The
formation of a P–C bond can be straightforwardly achieved
by a Michael addition reaction of trivalent and pentavalent
phosphorus species to an electron-poor alkene.[7] In the
area of organocatalytic phospha-Michael addition, a few
successful achievements have been reported by using α,β-
unsaturated aldehydes and nitroalkenes as the acceptors
with different organic promoters mainly by using dialkyl
phosphites.[8] Nevertheless, only very recently, enones have
been investigated as acceptors by using trivalent and penta-
valent phosphorus nucleophiles. Duan and co-workers de-
veloped a pincer-palladium-catalyzed Michael addition of
diarylphosphanes to chalcones, whose adducts were in situ
oxidized with hydrogen peroxide to the more stable phos-
Scheme 1. Phosphane oxide–phosphinous acid equilibrium under
neutral conditions.
[a] Dipartimento di Chimica, Università di Salerno,
via Ponte don Melilllo, 84084 Fisciano, Italy
Fax: +39-089-969603
The equilibrium shift toward the active phosphinous acid
form is likely to be effected by the presence of a base.[13]
Moreover, taking into consideration that chalcones gen-
erally require harsher conditions to proceed via iminium
E-mail: lattanzi@unisa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001308.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6736–6739

Conjugate Addition of Diarylphosphane Oxides to Chalcones
ion catalysis,[14] we devised an organocatalytic approach Table 1. Michael addition of diphenylphosphane oxide to trans-
chalcone promoted by catalysts 1–11.[a]
based on the use of noncovalent promoters such as cin-
chona alkaloids and their derivatives (Figure 1). We specu-
lated that the tertiary base and an acidic group would pro-
vide bifunctional activation of the phosphane oxide and
chalcone, respectively.[15] Herein, we wish to describe the
first enantioselective direct phospha-Michael addition of di-
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
arylphosphane oxides to chalcones catalyzed by cinchona
alkaloids.
1
2
3
4
5
6
7
8
9
1
2
24
22
48
39
39
39
45
44
69
65
48
99
66
99
78
95
88
99
52
72
79
82
47 (R)
16 (R)
64 (R)
23 (R)
44 (S)
4 (S)
62 (S)
12 (S)
3 (S)
3
4
5
6
7
8
9
10
11
10
11
4 (R)
rac
[a] Reaction conditions: 12a (0.2 mmol), 13a (0.2 mmol), and cata-
lyst (0.02 mmol) in toluene (1.0 mL). [b] Isolated yield after flash
chromatography. [c] Determined by chiral HPLC. Absolute config-
uration determined by comparison with the optical rotation value
given in the literature.[9]
tion and conversion were observed when using aromatic
solvents (Table 2, Entries 4–7), with chlorobenzene as the
best medium (Table 2, Entry 5).[16] Differently substituted
Table 2. Screening of solvents and diarylphosphane oxides in the
Michael addition to trans-chalcone promoted by compound 3.[a]
Figure 1. Cinchona alkaloids and their derivatives screened in the
phospha-Michael addition.
Results and Discussion
In a preliminary investigation, commercially available
trans-chalcone 12a and diphenylphosphane oxide 13a were
reacted at room temperature in toluene with a variety of
catalysts 1–11 (Table 1).
As highlighted in Table 1, adduct 14a was obtained in
good to high yield but with a variable level of enantio-
selectivity, showing the relevant role played by structural
features on catalytic efficiency. Dihydroquinine 3 and dihy-
droquinidine 7 afforded both enantiomerically enriched
products with an acceptable ee value and in high yield
(Table 1, Entries 3 and 7).
Cinchona alkaloids with additional or stronger Brønsted
acidic moieties such as cupreine 4, cupreidine 8, and thio-
urea derivatives 9 and 10 proved to be among the worst
promoters. Finally, dimeric ligand 11 led to racemic prod-
uct. Having established dihydroquinine 3 as the most effec-
tive catalyst for the reaction, the influence of solvent and
the nature of the phosphane oxides were next studied
(Table 2). Polar or coordinating solvents were less suitable
media for the phospha-Michael addition of compound 13a
Entry
Solvent
13
t [h]
Yield [%][b] ee [%][c]
1
2
3
4
5
THF
CHCl3
13a
13a
13a
13a
13a
13a
13a
13b
13c
13d
13e
13f
63
48
48
39
48
64
39
71
48
46
72
48
67
67
67
80
90
79
99
99
99
99
83
99
88
95
52
35
77
56
49
65
41
65
69
63
56
73
45
75
65
54
51
78
80
CH3CN
m-xylene
ClC6H5
1,3-Cl2C6H4
CF3C6H5
ClC6H5
ClC6H5
ClC6H5
ClC6H5
ClC6H5
ClC6H5
ClC6H5
ClC6H5
6
7
8[d]
9[d]
10[d]
11[d]
12[d]
13[d,e]
14[d,e,f]
15[d,f,g]
13d
13a
13a
[a] Reaction conditions: 12a (0.2 mmol), 13 (0.2 mmol), and 3
(0.02 mmol) in toluene (1.0 mL). [b] Isolated yield after flash
chromatography. [c] Determined by chiral HPLC. Absolute config-
uration determined by comparison with the optical rotation value
given in the literature.[9] [d] Using 30 mol-% of 3. [e] Reaction per-
formed at –20 °C. [f] Reaction performed at c = 0.1 m with respect
to 12a, whereas, as expected, the highest asymmetric induc- to 12a. [g] Reaction performed at –30 °C.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6737

A. Russo, A. Lattanzi
SHORT COMMUNICATION
diarylphosphane oxides slightly affected the conversion and
On the basis of the absolute configuration of adducts 14,
the enantioselectivity (Table 2, Entries 8–12). 2-Naphthyl a transition-state proposal for the dihydroquinine-catalyzed
derivative 13d furnished the adduct in up to 75%ee phospha-Michael addition is shown in Figure 2. The nature
(Table 2, Entry 10), but when performing the reaction at of the acidic moiety in the catalyst was found to be crucial
–20 °C the enantioselectivity decreased (Table 2, Entry 13). for the activation, as attested by findings reported in
Nevertheless, the use of commercially available phosphane Table 1. Indeed, thiourea derivatives 9 and 10 gave racemic
oxide 13a at lower temperature afforded good results in adduct, whereas the hydroxy group of dihydroquinine
terms of asymmetric induction and conversion (Table 2, En- proved to be superior in establishing a hydrogen-bonding
tries 14 and 15).
interaction with the oxygen of the carbonyl moiety of trans-
With optimized conditions in hands, the scope and chalcone.
limitations of the dihydroquinine-catalyzed Michael ad-
dition of diphenylphosphane oxide to a variety of chalcones
was investigated (Table 3).
Table 3. Asymmetric phospha-Michael addition of diphenylphos-
phane oxide to trans-chalcones promoted by dihydroquinine 3.[a]
Figure 2. Postulated transition state for dihydroquinine-catalyzed
phospha-Michael addition.
The diarylphosphane oxide is expected to be activated by
the quinuclidine nitrogen atom by shifting the equilibrium
toward the reactive phosphinous acid form (Scheme 1). The
preferential attack of the activated nucleophile toward the
Re face of chalcone would lead to the R-configured prod-
uct.
Entry
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph (a)
Ph (a)
Ph (g)
Ph (h)
Ph (i)
Ph (j)
Ph (k)
Ph (k)
91 (60)
85
75
98 (58)
99
87 (64)
99
80
99
95
85
80 (Ͼ99)
81[d]
78
76 (Ͼ99)
65
4-MeC6H4
3-BrC6H4
4-NO2C6H4
2-MeOC6H4
2-ClC6H4
2-ClC6H4
Ph
89 (Ͼ99)
86
79[d]
77
4-MeOC6H4 (l)
4-BrC6H4 (m)
4-ClC6H4 (n)
3-BrC6H4 (o)
Ph (p)
Conclusions
Ph
Ph
Ph
82
79
76
60
In conclusion, we have developed the first enantioselec-
tive direct phospha-Michael addition of diarylphosphane
oxides to trans-chalcones. The adducts are generally ob-
tained in high yield and good to high enantioselectivity
when using commercially available diphenylphosphane ox-
ide and dihydroquinine as the catalyst. The final adducts
can be easily recrystallized to enantiopure material. Chiral
phosphane oxides and phosphanes are typically prepared
using enantiopure starting materials, chiral auxiliaries, or
by recrystallization of racemic compounds.[1,18] The present
methodology provides simple and convenient access to both
enantiomerically enriched phosphane oxides 14, potentially
useful ligands and building blocks for asymmetric synthesis.
99
30
cyclohexyl
[a] Reaction conditions: 12 (0.2 mmol), 13a (0.2 mmol),
3
(0.06 mmol) in solvent (2 mL). [b] Isolated yield after flash
chromatography. Yield after crystallization is given in parentheses.
[c] Determined by chiral HPLC. The ee value after crystallization
is given in parentheses. [d] Dihydroquinidine 7 was used as the cata-
lyst to give the opposite enantiomer.
trans-Chalcones bearing electron-donating or electron-
withdrawing groups at both the aromatic rings were
smoothly converted into the final adducts in high yield. R-
Configured adducts 14 were obtained with fairly good level
of asymmetric induction. Strong electron-withdrawing
groups slightly decreased the enantioselectivity, as observed
with the nitrophenyl-substituted enone (Table 3, Entry 5).
The ortho-substitution on the β-phenyl ring was found to
Experimental Section
be beneficial for stereocontrol, as the adducts were isolated General Procedure for the Phospha-Michael Addition of Diphenyl-
phosphane Oxide to trans-Chalcones: trans-Chalcone (12; 0.2 mmol)
and dihydroquinine (0.06 mmol) were dissolved in anhydrous chlo-
robenzene (2 mL). Diphenylphosphane oxide (13a; 0.2 mmol) was
added, and the reaction was stirred at –22 °C until completion as
monitored by TLC. A white precipitate was formed. The mixture
was directly purified by flash chromatography (pure chloroform) to
give adducts 14 contaminated by residual 13a (13a has the same
TLC mobility of products 14).[19] Compound 13a could be removed
by washing the mixture with warm hexane and collecting solid 14
as a pure compound. For recrystallization of adducts 14, mixtures
of CHCl3/EtOH were used.
with up to 89%ee (Table 3, Entries 6 and 7). Dihydroquin-
idine 7 afforded the S-configured adducts with almost com-
parable efficiency (Table 3, Entries 2 and 8). Although we
have not fully explored the dihydroquinine-catalyzed phos-
pha-Michael addition to β-alkyl-substituted enones, a pre-
liminary study with a cyclohexyl derivative showed a de-
creased conversion to the product obtained with somewhat
lower ee (Table 3, Entry 13).[17] Compounds 14 are solids
and they can be recrystallized in enantiopure form (Table 3,
Entries 1, 4, and 6).
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Conjugate Addition of Diarylphosphane Oxides to Chalcones
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cle): General experimental methods, experimental procedures, char-
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Acknowledgments
Ministero Italiano Università e Ricerca (MIUR) and University of
Salerno are acknowledged for financial support. Dr. P. Iannece is
thanked for MS analyses.
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Received: September 20, 2010
Published Online: November 5, 2010
Eur. J. Org. Chem. 2010, 6736–6739
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6739