Direct enantioselective three-component kabachnik-fields reaction catalyzed by chiral bis(imidazoline)-zinc(II) catalysts

Article abstract of DOI:10.1002/adsc.201100482

A direct three-component reaction of aldehydes, amines and diaryl phosphites was catalyzed by a zinc(II) complex of 1,3-bis(imidazolin-2-ly) pyridine (pybim) giving the corresponding α-aminophosphonates in good yield with good enantioselectivity. The reac

Full text of DOI:10.1002/adsc.201100482

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DOI: 10.1002/adsc.201100482
Direct Enantioselective Three-Component Kabachnik–Fields
Reaction Catalyzed by Chiral Bis(imidazoline)-Zinc(II) Catalysts
Mutsuyo Ohara,a Shuichi Nakamura,a,* and Norio Shibataa,*
a
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-5245; e-mail: snakamur@nitech.ac.jp or nozshiba@nitech.ac.jp
Received: June 21, 2011; Revised: August 8, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100482.
Abstract: A direct three-component reaction of al-
dehydes, amines and diaryl phosphites was cata-
lyzed by a zinc(II) complex of 1,3-bis(imidazolin-2-
ly)pyridine (pybim) giving the corresponding a-ami-
nophosphonates in good yield with good enantiose-
lectivity. The reaction was applied to a wide variety
of aromatic aldehydes to give products with excel-
lent yields (up to 99%) and enantiomeric excesses
(up to 93% ee).
reaction, is highly desired. The pioneering work for
the highly enantioselective one-pot reaction of in situ
preformed imines and phosphites using a chiral sala-
len-aluminum catalyst was reported by Katsuki and
co-workers to give optically active a-aminophospho-
nates.[5] Feng and co-workers also reported the highly
enantioselective one-pot synthesis of a-aminophosph-
onates from in situ generated imines and phosphites
using a chiral scandium-N,N’-dioxide complex.[6] Al-
though remarkable progress has been made in one-
pot procedures for the synthesis of optically active a-
aminophosphonates, the development of a direct
three-component synthesis of chiral a-aminophospho-
nates is desired due to the more simple operation
(Figure 1). In this context, there is only one report on
the direct three-component enantioselective reaction
of aldehydes, amines, and phosphites. List and co-
Keywords: asymmetric catalysis; enantioselectivity;
hydrophosphonylation; imidazolines; three-compo-
nent synthesis
Optically active a-aminophosphonates are important workers reported the direct three-component reaction
synthetic intermediates for the preparation of various with a-branched aliphatic aldehydes using chiral
natural products and biologically active compounds.[1] phosphoric acids as an organocatalyst to furnish b-
Accordingly, their broad utility has prompted consid- branched a-aminophosphonates with high diastereo-
erable interest to develop asymmetric methods for and enantioselectivity by a dynamic kinetic resolu-
their preparation. One of the most efficient methods tion.[7] Therefore, expanding the scope of catalytic
for the preparation of chiral a-aminophosphonates is enantioselective three-component reactions with re-
the stereoselective addition of phosphites to imines. spect to both the chiral catalyst and the substrate
Since the pioneering work on the highly enantioselec-
tive hydrophosphonylation of imines reported by Shi-
basaki and co-workers,[2] there are many reports
about the catalytic enantioselective hydrophosphony-
lation of imines.[3] On the other hand, the strategy of
multicomponent synthesis has attracted more atten-
tion in the scientific community as an environmentally
friendly process which allows high levels of atom effi-
ciency to be obtained because only a single reaction
solvent, work-up procedure and purification step are
required to obtain a product.[4] Therefore, the devel-
opment of a three-component synthesis of a-amino-
phosphonates using a carbonyl compound, an amine,
and a phosphite, often called the Kabachnik–Fields synthesis of chiral a-aminophosphonates.
Figure 1. One-pot procedure and direct three-component
Adv. Synth. Catal. 2011, 353, 3285 – 3289
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Mutsuyo Ohara et al.
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Table 1. Enantioselective three-component reaction using
would be highly desirable. On the other hand, we re-
cently developed chiral bis(imidazoline)-metal cata-
lysts as highly tuneable chiral catalysts.[8,9] Further-
more, we reported the highly enantioselective hydro-
phosphonylation reaction of phosphites with aldi-
mines or ketimines.[10] Herein, our ongoing interest
was extended to a direct enantioselective three-com-
ponent reaction of aldehydes, amines, and phosphites
using a chiral bis(imidazoline)-metal catalyst.
various chiral ligands and metal salts.[a]
We first examined the reaction of benzaldehyde, p-
anisidine, and diphenyl phosphite using 10 mol% of
chiral Lewis acid catalysts including bis(imidazoline)s
1a–f. The reaction was carried out as follows: benzal-
dehyde, p-anisidine, and diphenyl phosphite were suc-
cessively added to the solution of chiral Lewis acids
in CH2Cl2. The results are shown in Table 1.
Although the reaction using various metal salts,
such as AlCl3, Sc
almost racemic product 3 in high yield, the reaction
using 1a-Zn(OTf)2 gave product 3 in 99% yield with
45% ee (entries 1–4). When the reaction was carried
out at À508C, the enantioselectivity was improved
slightly over that at À208C (entry 5). After optimiza-
tion of the anion part of the zinc salts, such as NTf2
and SbF6, the best enantioselectivity was obtained in
ACHTUNGTRENNUN(G OTf)3, and MgHCATUNGTREN(NUNG OTf)2, afforded the
ACHTUNGTRENNUNG
Entry Metal salt Ligand Temp.
Time Yield
ee
[8C]
[h]
[%]
[%][b]
1
2
3
4
5
6
7
8
AlCl3
Sc(OTf)3 1a
Mg(OTf)2 1a
(OTf)2 1a
(OTf)2 1a
(NTf2)2 1a
(SbF6)2 1a
(NTf2)2 1b
(NTf2)2 1c
(NTf2)2 1d
(NTf2)2 1e
(NTf2)2 1f
(NTf2)2
(NTf2)2 1d
(NTf2)2 1d
1a
0
48
3
18
4
6
6
48
30
12
12
6
48
30
6
94
97
88
99
93
99
95
99
95
99
99
84
99
99
99
0
0
0
N
À20
G
0
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
A
E
N
R
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
N
AHCTUNGTRENNUNG
N
À20
À50
À50
À50
À50
À50
À50
À50
À50
À50
À50
À50
45
53
59
45
6
56
62
49
3
the reaction using ZnACHTNUGTRNEUG(N NTf2)2 (entries 5–7). To im-
prove the enantioselectivity, we next optimized the
structure of bis(imidazoline). After fine-tuning vari-
ous substitutions on nitrogen in imidazolines, the 2-
methylpropionyl group was found to be the best sub-
stitution to obtain a high yield with high enantioselec-
tivity (entries 8–11). On the other hand, a product
was formed in low enantioselectivity by using the bi-
dentate phenylenebis(imidazoline) (phebim) 1f with
ZnACHTUNGTRENNUNG(NTf2)2 in CH2Cl2 (entry 12). Interestingly, the re-
action using chiral Lewis acid prepared from pybox 2,
which has oxygens instead of the N-CO-i-Pr group in
1d, and ZnACHTUNGTRENNUNG(NTf2)2 afforded product 3 with low enan-
tioselectivity (entry 13). It should be noted that an
electron-rich phosphite such as bis(o-methoxyphenyl)
phosphite enhanced the reactivity of the reaction and
enantioselectivity of product 3 (entry 14).[11,12] Catalyst
loading was successfully reduced to 5 mol% without
loss of enantioselectivity (entry 15).
9
10
11
12
13
14[c]
2
À2
90
90
15[c,d] Zn
24
[a]
Reaction conditions: PhCHO (0.10 mmol), p-anisidine
(0.12 mmol), diphenyl phosphite (0.15 mmol), metal salt
(0.01 mmol), and 1 (0.01 mmol).
[b]
The ee was determined by HPLC analysis using chiral
columns.
[c]
[d]
Bis(ortho-methoxyphenyl) phosphite was used.
1d (5 mol%) was used.
Under the optimized reaction conditions, a variety enantioselectivity (entries 13 and 14), however the re-
of aldehydes was examined by using the combination action with 3-methylbutanal afforded the product 18
of 1d with ZnACHTUNGTRENNUNG(NTf2)2, the results of which are sum- with low enantioselectivity (entry 15). Although the
marized in Table 2. The reaction of imines derived reaction with cyclohexanecarbaldehyde afforded
from various substituted benzaldehydes afforded product 19 with low enantioselectivity, the slow addi-
products 4–11 with high enantioselectivity, although tion of phosphite could improve the enantioselectivity
the reaction with ortho-substituted aldehydes de- of 19 (entries 16 and 17).
creased the enantioselectivity (entries 1–8). 2-Naph-
We next examined the synthesis of optically active
thaldehyde and heteroatom-containing aldehydes also a-aminophosphoric acid 21 from N-PMP protected a-
resulted in high enantioselectivity (entries 9–12). The aminophosphonate 4 (Scheme 1). Deprotection of the
reaction with a,b-unsaturated aldehydes such as phe- PMP group from 90% ee of 4 using NBS afforded a-
nylpropargyl aldehyde and trans-cinnamaldehyde af- aminophosphonate 20,[13] which can be converted to
forded products 16 and 17 in high yield with good optically active a-aminophosphoric acid 21 without a
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Adv. Synth. Catal. 2011, 353, 3285 – 3289

Direct Enantioselective Three-Component Kabachnik–Fields Reaction
Table 2. Enantioselective three-component reaction of various aldehydes and phosphites using 1d-Zn(II).[a]
Entry
Aldehyde [R]
Product
Time [h]
Yield [%]
ee [%]
1
2
3
4
Ph
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
19
6
6
1
3
4
24
4
18
96
48
6
1
1
36
0.5
1
99
99
99
99
86
99
99
99
99
90
99
99
85
92
99
85
98
90
91
68
90
90
84
76
80
82
89
93
82
68
76
31
45
61
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
4-HO-C6H4
4-Cl-C6H4
4-MeO2C-C6H4
2-naphthyl
2-thienyl
5
6[b]
7
8[b]
9[c]
10
11
12
13
14[d]
15
16
17[e]
2-furyl
2-benzofuryl
trans-cinnamyl
ꢀ À
PhC C
À
AHCTNURTGEG(NNNU CH3)2CHCH2
cyclohexyl
cyclohexyl
2
[a]
Reaction conditions: RCHO (0.10 mmol), p-anisidine (0.12 mmol), bis(ortho-methoxyphenyl) phosphite (0.15 mmol),
metal salt (0.01 mmol), and 1d (0.01 mmol).
Carried out at À408C.
[b]
[c]
[d]
[e]
Carried out at À808C.
Reaction mixture was warmed to À408C from À508C.
Phosphite was added dropwise for 2 h.
loss of enantioselectivity. The absolute configuration three-component reaction (Scheme 2). Although the
of 21 was assigned to be S after conversion to N-Cbz- addition of 0.2 equivalents of p-methoxyaniline or
dimethyl phosphonate,[14] and the stereochemistry of 1.0 equivalent of water slightly improved the yield
other products was tentatively assumed by analogy.
and enantioselectivity, the addition of p-methoxyani-
In order to clarify the reaction mechanism, we ex- line and water afforded (S)-4 with a similar enantiose-
amined the enantioselective reaction of isolated lectivity as that in Table 1 entry 14. This result implies
imines with bis(o-methoxyphenyl) phosphite using 1d- that amine and water play an important role for the
ZnACHTUNGTRENNUNG(NTf2)2, which gave product 4 in poor yield with
lower enantioselectivity than that from the direct
Scheme 2. Enantioselective reaction of isolated imine with
phosphite.
Scheme 1. Synthesis of chiral a-aminophosphoric acid 21.
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Mutsuyo Ohara et al.
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Figure 2. Assumed transition state for the hydrophosphonylation of imine with (ArO)2POH using 1d-Zn(II).
transition state, although the presence of amine and component reactions. Further studies are in progress
water in the reaction mixture generally decomposes to study the potential of these catalytic systems to
or deactivates chiral Lewis acids.
other process.
On the other hand, the enantioselective hydrophos-
phonylation with TBSOPACHTNUGRTENUNG(OPh)2 did not afford a
product, although the enantioselective hydrophospho- Experimental Section
nylation with diphenyl phosphite gave products in
good yield with moderate enantioselectivity (Table 1, General Procedure for the Enantioselective Three-
entry 10). This result shows that the tautomerization Component Synthesis of a-Aminophosphonates
of phosphite [(RO)2POH] to the phosphonate Catalyzed by the 1d-Zn(II) Complex
[(RO)2P(=O)H] and the deprotonation of phospho-
nate is a key factor for the hydrophosphonylation. Al-
A solution of ligand 1d (0.01 mmol, 10 mol%) and Zn-
AHCTNURTGEG(NNNU NTf2)2 (0.01 mmol, 10 mol%) in dry CH2Cl2 (0.55 mL) was
though the detailed reaction mechanism remains un-
clear, the proposed transition state for the reaction of
imines with phosphites using 1d-Zn(II) as the catalyst
is shown in Figure 2.[15]
Imines formed in situ coordinated to the chiral
Zn(II) catalysts in the equatorial position by avoiding
the steric repulsion of bis(imidazoline). Coordination
of oxygen in phosphite to Zn(II) and the deprotona-
tion of phosphite affords the phosphonate, which at-
tacks to the imine in the coordination sphere of chiral
bis(imidazoline)-Zn salt and leads to chiral addition
stirred at room temperature for 1 h. An aldehyde
(0.10 mmol), p-anisidine (0.12 mmol) and bis(o-methoxy-
phenyl) phosphite (0.15 mmol) were added, and the whole
mixture was stirred at À508C. After completion of the reac-
tion as monitored by TLC, the mixture was concentrated
and purified over silica gel by column chromatography (ben-
zene/EtOAc=80:20) yielding the a-aminophosphonates.
Acknowledgements
products. The phosphonate approaches imines avoid- This work was partly supported by Teijin Pharma Award in
Synthetic Organic Chemistry, Japan and Commons from JST.
ing steric repulsion with phenyl groups in 1d, there-
fore the (S)-isomer is preferably formed. Further
studies are required to fully elucidate the mechanistic
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Adv. Synth. Catal. 2011, 353, 3285 – 3289
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