Bis(oxazoline)-copper catalyzed enantioselective hydrophosphonylation of aldehydes

Article abstract of DOI:10.1039/c4ra03269a

A highly enantioselective copper-catalyzed hydrophosphonylation of aldehydes in the presence of bis(oxazoline) ligand is presented. The reaction proceeded smoothly under mild conditions. The resulting α- hydroxyphosphonates were obtained with high yields

Full text of DOI:10.1039/c4ra03269a

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Bis(oxazoline)-copper catalyzed enantioselective
hydrophosphonylation of aldehydes†
Cite this: RSC Adv., 2014, 4, 27853
Tao Deng and Chun Cai*
Received 11th April 2014
Accepted 9th June 2014
DOI: 10.1039/c4ra03269a
www.rsc.org/advances
A highly enantioselective copper-catalyzed hydrophosphonylation of enantioselective catalysts for the synthesis of chiral a-hydrox-
11
aldehydes in the presence of bis(oxazoline) ligand is presented. The yphosphonates. Chiral aluminium complexes (e.g. Al(salen)
reaction proceeded smoothly under mild conditions. The resulting a- and Al(salcyen) catalysts, Al-Schiff base) are the most successful
12
hydroxyphosphonates were obtained with high yields as well as among the chiral catalysts. During the last decade, Feng and
enantioselectivities (up to 98% ee).
co-workers reported the rst highly efficient Lewis-acid-cata-
lyzed hydrophosphonylations in the presence of Ti(OiPr) or
Et AlCl as catalysts. Then it was found that Ln(OTf) species
4
2
3
Chiral bis(oxazoline) (BOX) ligands were rst used in 1991 (ref. 1
(
Ln ¼ Sc, La, Yb) exhibited catalytic activities for hydro-
and 2) and since that time, a large number of such ligands have
13
phosphonylations of acetophenones. Very recently, Herrera
3
been reported. BOX ligands have been applied to the asym-
and co-workers reported the results concerning the rst asym-
metric catalysis of a wide variety of key organic reactions, such
14
metric squaramide-organocatalyzed Pudovik reaction.
4
5
as Friedel–Cras reaction, Mukaiyama–Michael reaction and
so on. In general, the BOX ligands reported to date are
predominantly based around the same ligand backbone with
variation in the pendant groups at the two available positions in
the oxazoline ring or on the bridgehead atom. Hence, a variety
of bisoxazoline derivatives have been prepared and extensively
utilized in asymmetric catalysis, in addition to other chiral
Although the asymmetric addition of dialkyl phosphites to
aldehydes has been successfully studied by different groups,
strong bases have been the most general reagents for the
synthesis of a-hydroxyphosphonates until now. However, the
yields were not always good and complex mixtures were some-
15
times obtained, due to side reactions. These results showed
that new and more effective catalysts need to be developed for
highly enantioselective dialkyl phosphite addition to aldehydes.
Following our interest in asymmetric synthesis using bis-oxa-
6
ligands.
Phosphonic acids and their phosphonate derivatives are of
immense interest in organic chemistry due to their biological
16
zoline ligands, we hypothesized that bis(oxazoline) ligand
7
activities. These molecules, such as a-aminophosphonates, a-
would afford a high level of chiral induction in the hydro-
phosphonylation reactions of aldehydes because of the pres-
ence of steric hindrance. Herein, we report the results of the
copper-catalyzed hydrophosphonylation of aldehydes in the
presence of bis(oxazoline) ligands.
hydroxyphosphonates, have been found a wide range of appli-
cations in the areas of ne chemical, biological, and medicinal
chemistry, as inhibitors of synthase, HIV protease, antibiotics,
enzyme inhibitors, anti-thrombotic agents, herbicides, fungi-
cides, insecticides, plant growth regulators and as substrates in
Firstly, a preliminary screening of different privileged
ligands (Fig. 1), such as L-proline (L1), quinine (L2), D-valine (L4)
8
the synthesis of phosphonopeptides. The addition of dialkyl
phosphites to carbonyl compounds, known as Pudovik reaction,
and bis(oxazoline) (L3 and L5), was carried out with CuBr
2
using
is a direct and atom-economical method for the synthesis of a-
methanol as solvent and K PO as base. Good enantioselectiv-
3
4
9
hydroxyphosphonates and for C–P bond formation. Since the
ities at room temperature were obtained only with the BOX-type
ligands (L3, L5), the best result being those obtained with Ph-
BOX (L3) (Table 1, entry 3). Copper complexes based on other
chiral ligands were found to catalyze the reaction in low yields
with moderate enantiomeric excess.
10
pioneering chiral organocatalytic example appeared in 1983,
in which a limited number of aldehydes (only two) was dis-
closed, much attention has been paid to developing
Chemical Engineering College, Nanjing University of Science &Technology, Nanjing,
Jiangsu 210094, P. R. China. E-mail: c.cai@mail.njust.edu.cn
Next, solvents were evaluated for this reaction (Table 1,
entries 6–14). Tetrahydrofuran gave the best result in terms of
both yield and enantioselectivity (76% yield, 96% ee, Table 1,
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c4ra03269a
1
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basicity and a low solubility in THF. The results of the base
screening (Table 1, entries 14–21) showed that 0.1 equivalent of
inorganic bases, such as Na CO , K CO , K PO , produced
2
3
2
3
3
4
hydroxyphosphonates with higher ee values (84%, 94% and
6%, respectively) than that of organic bases, such as TEA, DBU
9
and DABCO. NaOEt and t-BuOK afford only traces of product,
and the non-nucleophilic organic base DBU affords almost
racemic phosphonate (only 28% ee).
Additionally, we explored other copper sources, such as
Cu(TFA) , Cu(OTf) , CuCl , Cu(OAc) , and Cu(OAc) was found
2
2
2
2
2
to be the best choice for the hydrophosphonylation of benzal-
dehyde to obtain good yield and enantioselectivity (Table 1,
Fig. 1 Selected examples of chiral ligands examined.
entry 25). In the case of using Cu(TFA)
2 2
or Cu(OTf) , low
conversion and enantioselectivity were obtained (Table 1,
entries 22, 23). The reaction did not occur with CuCl
source (Table 1, entry 24).
2
as copper
Table 1 Optimization of the conditions for the hydrophosphonylation
of benzaldehyde
a
Table 2 shows the result of the hydrophosphonylation of
various aldehydes under the optimal conditions. Most of the
aldehydes rendered moderate to excellent yields (up to 91%)
and ee values (up to 98%) of a-hydroxyphosphonates. The
aromatic aldehydes possessing a strong electron-donating
group at the para-position showed a high enantioselectivity; for
instance, 4-methoxybenzaldehyde and 4-methylbenzaldehyde
formed 2a and 4a with 98% ee and 97% ee, respectively (Table 2,
entries 2 and 4). Electron-withdrawing halogen substituent
slightly reduced the enantioselectivity (Table 2, entry 5). With
b
c
Entry
L
Cu source
Base
Solvent
Yield /%
ee /%
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
K PO
4
4
4
4
4
4
4
4
4
4
4
4
4
MeOH
MeOH
MeOH
MeOH
MeOH
Hexane
Toluene
DMSO
MeCN
37
53
41
48
45
nr
nr
nr
nr
71
33
67
49
76
67
53
33
38
29
nr
nr
63
37
nr
81
58
64
94
76
88
—
—
—
—
86
64
90
92
96
84
94
28
72
66
—
—
94
82
—
96
Table
aldehydes
2 Enantioselective hydrophosphonylation of various
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH
DMF
Et
2
Cl
2
2
O
Dioxane
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
4
Na
2
CO
3
2
K CO
3
b
c
Entry
R1
R2
Product
Yield /%
ee /%
DBU
DABCO
TEA
NaOEt
t-BuOK
d
1
2
3
4
5
6
7
8
9
Ph
4-MeOC
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
iPr
Et
Et
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
—
—
11a
—
81
75
67
76
73
91
86
83
69
42
nr
nr
71
nr
84
53
96(S)d
98(S)
6
H
4
d
3-NO
4-MeC
4-ClC
4-CF
3-CF
2-CF
4-CNC
2-NO C H
2-Furyl
2-Thienyl
2
C
6
H
4
96(S)d
6
H
4
97(S)
94(S)
Cu(TFA)
Cu(OTf)
CuCl
Cu(OAc)
2
3
K PO
3
K PO
3
K PO
3
K PO
4
4
4
4
d
6
H
4
2
3
3
3
C
6
C
6
C
6
H
H
H
4
74
2
d
4
4
95(S)
2
88
a
d
Unless otherwise specied, all reactions were carried out at room
6
H
4
91(S)
temperature with benzaldehyde (1.0 mmol), diethyl phosphite (1.2 10
96
—
—
79
—
2
6
4
mmol), base (0.2 mmol), Cu source (0.1 mmol) and ligand (0.1 mmol)
in the solvent (1 mL) for 24 hours. Isolated yields aer column
chromatography. The ee values were determined by chiral HPLC
11
12
13
14
15
16
b
c
2-Pyridinyl
Ph
1-Naphthyl
using a Ultron ES-OVM column.
d
12a
13a
69(S)d
(E)-PhCH]CH
67(S)
entry 14). In the case of using hexane, toluene, dimethyl sulf-
oxide and acetonitrile as solvent, no reaction occured.
Subsequently, we focused on optimizing the base for the
hydrophosphonylation. Inorganic bases have been considered
to facilitate the hydrophosphonylation reaction without eroding
a
Unless otherwise specied, all reactions were carried out at room
temperature with aldehyde (1.0 mmol), diethyl phosphite (1.2 mmol),
PO (0.2 mmol), Cu(OAc) (0.1 mmol) and L3 (0.1 mmol) in the THF
K
3
4
2
b
(1 mL) for 24 hours. Isolated yields aer column chromatography.
c
The ee values were determined by chiral HPLC using a Ultron ES-
d
OVM column. The absolute congurations were determined by
the enantioselectivity because they exhibit a relatively weak comparison with literature data.
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strong electron-withdrawing groups on the phenyl ring led to
lower yields and enantioselectivities (Table 2, entries 3, 6–10).
Regardless of the electronic nature of the substituents on the
aryl groups, it was also found that the steric hindrance of the
substrates had an effect on the reactivities of hydro-
phosphonylation of aldehydes, with the corresponding prod-
ucts being obtained in higher yields but with obvious loss of ee
values (Table 2, entries 6–8). The addition of diethyl phosphite
to 4-triuoromethyl benzaldehyde, for example, afforded the
product 6a in 91% yield and 74% ee (Table 2, entry 6), the
addition to 2-triuoromethyl benzaldehyde gave 8a in 83% yield
and 88% ee (Table 2, entry 8). However, the addition to 3-tri-
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
uoromethyl benzaldehyde afforded 7a in an excellent ee of
95% (Table 2, entry 7). For heterocyclic aldehydes, 2-pyr-
idinecarboxaldehyde was also converted to the a-hydrox-
yphosphonate 11a with 79% ee in 71% yield (Table 2, entry 13),
while no desired a-hydroxyphosphonates were obtained for
furfural and 2-thienaldehyde (Table 2, entries 11 and 12).
Unfortunately, we found that no desired product was obtained
with bulky diisopropyl phosphite due to side reaction (Table 2,
entry 14). While the condensed-ring aldehydes (1-naph-
thaldehyde) reacted smoothly with diethyl phosphite, giving the
product with 69% ee (Table 2, entry 15), the a,b-unsaturated
aldehyde (cinnamaldehyde) showed a slightly reduced reactivity
and enantioselectivity (Table 2, entry 16).
Conclusions
8
In summary, we have demonstrated for the rst time that
Cu(OAc) paired with Ph-BOX (L3) turned out to be a good
2
catalytic system to accomplish the asymmetric hydro-
phosphonylation of aldehydes with diethyl phosphite. This
process was applied to a wide variety of aldehydes and in most
of the cases good yields and enantioselectivities were achieved.
Our work in this area is currently ongoing particularly in the
application of metal complexes of the bis(oxazoline) ligands to
the catalysis of different reactions.
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