Br?nsted base-catalyzed three-component coupling reaction of α-ketoesters, imines, and diethyl phosphite utilizing [1,2]-phospha-Brook rearrangement

Article abstract of DOI:10.1039/c6ob00739b

A three-component coupling reaction of α-ketoesters, imines, and diethyl phosphite under Br?nsted base catalysis was developed by utilizing the [1,2]-phospha-Brook rearrangement. The reaction involves the generation of ester enolates via the umpolung proc

Full text of DOI:10.1039/c6ob00739b

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Brønsted Base-Catalyzed Three-Component Coupling Reaction of
α-Ketoesters, Imines, and Diethyl Phosphite Utilizing [1,2]-
Phospha-Brook Rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
Azusa Kondoha and Masahiro Terada*a,b
DOI: 10.1039/x0xx00000x
A three-component coupling reaction of α-ketoesters, imines, and diethyl phosphite under Brønsted base catalysis was
developed by utilizing the [1,2]-phospha-Brook rearrangement. The reaction involves the generation of ester enolates via
the umpolung process, i.e., the chemoselective addition of diethyl phosphite to α-ketoesters followed by the [1,2]-
phospha-Brook rearrangement, and the trapping of the resulting enolates by imines preferentially over α-ketoesters and
protons. This operationally simple reaction can provide densely functionalized β-amino acid derivatives including an
oxygen functionality at the α-position in good yields. The diastereoselectivity is highly dependent on the substrates and
reaction temperature, which is attributed to the reversibility of the addition of the ester enolates to the imines. The
methodology was further extended to the reaction of α-ketoesters, β-nitrostyrenes, and diethyl phosphite.
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aldehydes and dialkyl phosphites were achieved by using chiral
organobase catalysts, which can also be categorized as aldol-
type reactions.5 While the utility of the methodology has been
Introduction
The [1,2]-phospha-Brook rearrangement involves the
migration of the dialkoxyphosphoryl moiety of the alkoxide of
an α-hydroxyphosphonate from carbon to oxygen to generate
an α-oxygenated carbanion.1,2 This rearrangement proceeds
smoothly, especially with an alkoxide possessing an electron
stabilizing group at the α-position. Whereas the generation of
α-oxygenated carbanions using other methods requires several
preparative steps, the alkoxide that is the precursor for the
[1,2]-phospha-Brook rearrangement is easily accessible by
various methods, including the deprotonation of α-
hydroxyphosphonates, the addition of cyanide to
acylphosphonates, and the addition of the anion of secondary
phosphites to carbonyl compounds. Therefore, the generation
of the carbanion by using the [1,2]-phospha-Brook
gradually established, the types of reactions and the scope of
carbanion precursors and electrophiles applicable to the
reactions are still limited.
We have been focusing on the [1,2]-phospha-Brook
rearrangement as a useful tool for the development of novel
synthetic reactions under Brønsted base catalysis.6 Specifically,
our studies on new carbon-carbon bond forming reactions
utilizing the [1,2]-phospha-Brook rearrangement are
characterized by catalytic direct generation of enolates of less
acidic amides and esters from α-ketoamides and α-ketoesters
via the umpolung process, i.e., the addition of dialkyl
phosphite to a keto moiety followed by the [1,2]-phospha-
Brook rearrangement. Previously, we successfully utilized the
resulting enolates of such less acidic pronucleophiles for
intramolecular addition to alkynes to construct heterocyclic
and carbocyclic frameworks.6b,d As the next stage of our
studies, we envisioned the development of intermolecular
addition reactions of the enolates of less acidic
pronucleophiles to unsaturated compounds. During the course
of our studies on the α-oxygenation of carbonyl compounds
utilizing the [1,2]-phospha-Brook rearrangement, we
discovered the addition reaction of ester enolates to imines, in
rearrangement is potentially
a useful methodology for
developing new carbon-carbon bond forming reactions.
Indeed, in recent years, a few types of carbon-carbon bond
forming reactions utilizing the [1,2]-phospha-Brook
rearrangement have been developed, such as the benzoin-
type condensation of acylphosphonates3 and the aldol-type
reaction of α-hydroxyphosphonates.4 In addition, very
recently, the remarkable enantioselective three-component
coupling reactions of isatins or benzylidene pyruvates,
which
the
enolate
was
generated
from
diethylphosphonoacetate through α-oxidation followed by the
[1,2]-phospha-Brook rearrangement.6c Based on this result, we
proposed a new three-component coupling reaction of α-
ketoesters, imines, and diethyl phosphite under Brønsted base
catalysis, involving the Mannich-type process, i.e., the addition
of ester enolates to imines. Generally, in direct Mannich
reactions under Brønsted base catalysis, easily-enolizable
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enolate
basicity of
protonation of
B
, which is a competing side reaction arising from the
. Once the corresponding ester is formed by the
, it cannot re-enter the catalytic cycle via
B
5
B
deprotonation due to its low acidity. Indeed, the catalytic
three-component coupling reactions reported to date are
limited to those involving the generation of the enolates of
relatively acidic pronucleophiles probably because of avoiding
the protonation issue.5 Herein, we report the results of our
investigation on the challenging three-component coupling
reaction of α-ketoesters 1, imines 2, and diethyl phosphite (3)
Scheme 1 Proposed reaction system.
under Brønsted base catalysis,10 providing densely
functionalized β-amino acid derivatives including an oxygen
functionality at the α-position, which are important building
blocks for bioactive molecules.11
carbonyl compounds possessing a highly acidic α proton, such
as β-dicarbonyls and related compounds, are employed as
pronucleophiles, which facilitates the catalyst turnover by the
smooth protonation after the carbon-carbon bond forming
step.7 On the other hand, the catalytic reactions of less acidic
pronucleophiles, such as simple esters, are rather limited
because of the difficulty of the catalyst turnover,8,9 and a
stoichiometric amount of strong bases, such as LDA, are more
commonly used for the addition of those pronucloephiles.
Therefore, the present methodology could provide an
alternative approach toward the catalytic addition of the
enolate of less acidic pronucleophiles.
Results and Discussion
Investigation of reaction conditions
The initial study was conducted with benzyl phenylglyoxylate
(
1a), tosylimine 2a, and diethyl phosphite (
amounts of 1a 2a, and were treated with 10 mol% of tBuOLi
in THF at 20 °C. As a result, the desired three-component
3). Equimolar
,
3
—
coupling product 4aa was obtained as the major product in
50% yield with 86:14 dr along with by-products 5a (7%) and 6a
(42%). 5a was formed by the protonation of the enolate, while
6a was formed by the direct addition of diethyl phosphite to
imine 2a. This promising result prompted us to investigate the
reaction conditions further (Table 1). Brønsted bases were
screened first (entries 1-10). Surprisingly, the countercation of
t-butoxide dramatically influenced both the chemoselectivity
and diastereoselectivity (entries 1-3). Among alkaline metal t-
butoxides, tBuONa was the best and the desired product 4aa
was obtained in 81% yield with 83:17 dr along with 4% of 5a
and 15% of 6a (entry 2). LHMDS and NaHMDS provided almost
identical results to those obtained with tBuOLi and tBuONa,
indicating that the countercation of the reaction intermediates,
such as the anion of diethyl phosphite and the enolate, would
play a key role in determining the chemoselectivity, as well as
the diastereoselectivity, of the reaction (entries 4 and 5).
Several organic bases were also tested (entries 6-10).
Phosphazene bases, which are known as organosuperbases,
provided the desired three-component product. However,
significant amounts of by-products were formed in each case
(entries 6-8). Interestingly, the yield of the desired 4aa was
increased with decreased basicity of the phosphazene bases,
and thus the weakest P1-tBu provided the best result. On the
other hand, the use of organic bases weaker than
phosphazene bases, such as MTBD and DBU, facilitated the
protonation of the enolate and 5a was obtained as the major
product along with a trace amount of 4aa (entries 9 and 10).
Next, a variety of solvents were screened (entries 11-16).
Diethyl ether and aprotic polar solvents, such as DMF,
acetonitrile, and ethyl acetate, provided 4aa in similar yields,
albeit in significantly lower diastereoselectivities than that
obtained in THF (entries 11-14). In contrast, less polar solvents,
such as dichloromethane and toluene, were less effective and
Our proposed reaction system is shown in Scheme 1. First, the
deprotonation of diethyl phosphite (
followed by the addition of the resulting anion to a keto
moiety of α-ketoester provides alkoxide . Next, the [1,2]-
phospha-Brook rearrangement proceeds to generate ester
enolate . Finally, the addition of the enolate to an imine
3) by a Brønsted base
1
A
B
2
and the smooth protonation, which is the key step for
establishing the catalytic cycle, by the conjugated acid of the
Brønsted base or diethyl phosphite provides the desired
adduct
the anion of
issues of chemoselectivity must be overcome (Scheme 2). For
instance, the generation of the ester enolates requires the
chemoselective addition of diethyl phosphite ( ) to an α-
ketoester in the presence of an electrophilic imine (Scheme
2a). In contrast, the resulting enolate should react with an
imine in the presence of an α-ketoester for the formation
of (Scheme 2b). Furthermore, the carbon-carbon bond
4
along with the regeneration of the Brønsted base or
3. In order to achieve the designed reaction, some
B
3
1
2
B
2
1
4
formation should proceed in preference to the protonation of
a) chemoselective addition of anion of 3 to 1
Ts
N
BnO2C
R1
Ts
BnO2C
R1
HN
R2
R2
H
2
O
O
1
O
P(OEt)2
P(OEt)2
P(OEt)2
6
O
A
O
b) chemoselective addition of enolate B to 2
Ts
HN
R1
HO CO2Bn
BnO2C
BnO2C
R1
R2
1
2
BnO2C
R1
(EtO)2PO
O
R1
4
OP(OEt)2
O
(EtO)2PO
O
7
B
H
BnO2C
R1
OP(OEt)2
O
5
Scheme 2 Challenging issues of chemoselectivity. The normal arrows indicate the
desired reactions, while the dashed arrows indicate undesired side reactions.
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Table 1 Initial screening of reaction conditionsa
O
Ts
HN
HP(OEt)2 3 (1.0 eq.)
Ts
H
BnO2C
Ph
N
base (10 mol%)
BnO2C
Ph
+
O
Ph
solvent, 20 °C, 14 h
(EtO)2PO
Ph
1a
2a
1.0 eq.
O
4aa
yield (%)b
entry base
solvent
dr of
4aa
5a
6a
4aac
86:14
83:17
69:31
84:16
84:16
75:25
77:23
83:17
-
Scheme 3 Control experiments.
1
tBuOLi
tBuONa
THF
50
81
7
4
42
15
18
41
15
36
22
27
29
32
12
16
10
15
16
24
20e
2
THF
the enolate of less acidic pronucleophiles, such as esters, in
intermolecular carbon-carbon bond forming reactions. The
reversibility of the formation of 6a was also examined (Scheme
3
tBuOK
THF
74
6
4
LHMDS
NaHMDS
P4-tBu
P2-tBu
P1-tBu
MTBD
THF
50
4
5
THF
80
4
6
THF
10
50
25
8
3b). Treatment of 6a with tBuONa in THF at —20 °C in the
7
THF
48
presence of 1a resulted in no reaction. This result suggests that
6a cannot re-enter the catalytic cycle via a retro process once
it is formed.
8
THF
64
9
THF
5
63
68
8
10
11
12
13
14
15
16
17d
DBU
THF
<1
-
Scope of α-ketoesters and imines
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
Et2O
DMF
CH3CN
AcOEt
CH2Cl2
toluene
THF
80
59:41
64:36
56:44
69:31
50:50
46:54
79:21
80
2
The scope of α-ketoesters and imines was investigated under
the optimum reaction conditions (Table 2). First, the scope of
the α-ketoesters was examined (entries 1-9). In this reaction,
the substituents on the keto moiety significantly influenced
85
2
77
4
66
15
12
3
64
both chemical yield and diastereoselectivity of 4. A substrate
87 (77)
possessing an electron-donating group, such as a methoxy
group, at the para position of the benzene ring provided the
corresponding product 4ba in moderate yield with low
diastereoselectivity (entry 1). In this case, a significant amount
of 6a was formed. In contrast, the reaction of substrates
having electron-deficient aryl groups such as 1c and 1d
provided the corresponding products 4ca and 4da in high
yields with relatively good diastereoselectivities (entries 2 and
3). These results suggest that the chemoselectivity for the
generation of enolates, i.e., the addition of diethyl phosphite
a
Reaction conditions: 1a (0.10 mmol), 2a (0.10 mmol), 3 (0.10 mmol), base
(0.010 mmol), solvent (1.0 mL), —20 °C, 14 h. b NMR yields. Bn2O was used as the
internal standard. Isolated yield is shown in parentheses. Determined by 1H
c
NMR and 31P NMR analysis of the crude mixtures. 1.1 equivalents of 2a and 3
d
were used. e Based on the amount of 1a.
to α-ketoester
1
,
is highly sensitive to the relative
to imine , and electron-
electrophilicity of α-ketoester
1
2
deficient α-ketoesters are more suitable than electron-rich
ones for this three-component reaction. Meta-methoxy-
phenyl-substituted 1e underwent the reaction without any
problems to afford 4ea in good yield (entry 4). However,
ortho-tolyl-substituted 1f resulted in low yield of 4fa along
with the formation of considerable amounts of 5f and 6a
(entry 5). This result indicates that the steric hindrance of the
substituent detrimentally affected not only the addition of
diethyl phosphite to 1f but also the addition of the enolate to
imine 2a. 2-Naphthyl and 2-thienyl groups were applicable to
the reaction (entries 6 and 7). The reactions of substrates
the yield of by-product 5a was increased (entries 15 and 16).
Finally, the use of a slight excess of the imine and diethyl
phosphite improved the yield of 4aa to 87%, although the
diastereoselectivity was slightly decreased (entry 17). The
structure of the major diastereomer of 4aa was confirmed by
single-crystal X-ray diffraction analysis.12
At this point, control experiments shown in Scheme 3 were
conducted. In order to clarify whether 5a was the intermediate
for the formation of 4aa
,
5a was treated with tBuONa in the
20 °C (Scheme 3a). Only a
having primary and secondary alkyl substituents, 1i and 1j
,
presence of imine 2a in THF at
—
were also attempted. In these cases, however, the protonation
of the enolates proceeded preferentially to afford 5a as the
major product (54% and 58%, respectively), and the desired
4ia and 4ja were formed only in modest yields (entries 8 and
9).
trace amount of 4aa was detected in the crude reaction
mixture and most of 5a was recovered. This result clearly
indicates that the carbon-carbon bond formation that provides
4aa occurred directly between the enolate generated via the
[1,2]-phospha-Brook rearrangement and imine 2a, and 5a was
not the intermediate for the formation of 4aa presumably due
to the difficulty of the deprotonation of less acidic 5a by
NaOtBu. Thus, this experiment demonstrates the usability of
the [1,2]-phospha-Brook rearrangement for the generation of
Next, the scope of imines
2 was examined (entries 10-21). The
substituents of the imines also strongly affected the chemical
yield and diastereoselectivity. For instance, the reaction with
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2b, which has an electron-donating methoxy group at the para increased (entries 14 and 15). Heteroaryl groups, such as 2-
position of the benzene ring, afforded the desired product 4ab furyl and 3-pyridyl groups, were compatible under the reaction
conditions to provide the corresponding products 4ai and 4aj
,
Table 2 Scope of α-ketoesters and iminesa
Table 3 Temperature effect
yield (%)b
entry R1
R2
4
4
dr of 4c
5
2
6d
44
12
17
24
44
21
15
19
19
5
yield (%)a
1
4-MeO-C6H4 Ph
4ba 62 (52) 56:44
4ca 84 (82) 79:21
4da 91 (80) 74:26
4ea 80 (77) 79:21
4fa 40 (27e) 68:32
4ga 74 (62) 82:18
4ha 88 (88) 72:28
entry
temp.
4aa
81
72
0
dr of 4aab
83:17
83:17
-
5a
4
6a
15
15
19
13
2
4-Cl-C6H4
4-F-C6H4
Ph
Ph
3
1
2
3
4
—20 °C
0 °C
3
2
10
78
3
4
3-MeO-C6H4 Ph
2
rt
5
2-Me-C6H4
Ph
Ph
Ph
Ph
Ph
19
2
—40 °C
83
47:53
6
2-naphthyl
7
2-thienyl
PhCH2CH2
cC6H11
Ph
2
a
b
NMR yields. Bn2O was used as the internal standard. Determined by 1H NMR
and 31P NMR analysis of the crude mixtures.
8
4ia
4ja
32 (32) 73:27
30 (26) 77:23
54
58
5
9
10
11
12
13
14
15
16
17
18
19
20
21
4-MeO-C6H4 4ab 93 (93) 83:17
4-Cl-C6H4 4ac 67 (56) 61:39
respectively, the yields of which were highly dependent on the
electronic nature of those groups (entries 17 and 18).
Finally,aliphatic imines were tested (entries 19-21). The
primary and secondary alkyl-substituted imines provided the
corresponding products in moderate yields (entries 19 and 20)
while tBu-substituted imines only afforded by-products 5a and
6m (entry 21).
Ph
2
36
54
20
14
29
12
14
49
15
25
31
Ph
4-NO2-C6H4 4ad 50 (42) 50:50
3-MeO-C6H4 4ae 83 (82) 83:17
6
Ph
5
Ph
2-MeO-C6H4 4af
84 (84) 83:17
12
12
5
Ph
1-naphthyl
2-naphthyl
2-furyl
4ag 65 (62) 74:26
4ah 86 (76) 74:26
Ph
Ph
4ai
4aj
91 (81) 53:47
48 (48) 50:50
3
Ph
3-pyridyl
nC6H13
7
Temperature effect
Ph
4ak 60 (58) 50:50
33
22
75
In the course of investigating the reaction conditions, a
remarkable temperature effect was observed. When the
reaction temperature was increased to 0 °C, the yield of 4aa
was decreased, and instead, the yield of 5a was increased
(entry 2). Furthermore, when the reaction was conducted at
room temperature, the desired 4aa was not observed and 5a
was obtained as the major product in high yield (entry 3). In
Ph
cC6H11
4al
60 (57) 80:20
<1
Ph
tBu
4am
-
a
Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), 3 (0.11 mmol), tBuONa
b
(0.010 mmol), THF (1.0 mL), —20 °C, 14 h. NMR yields. Bn2O was used as the
internal standard. Isolated yields are shown in parentheses. Determined by 1H
c
NMR and 31P NMR analysis of the crude mixtures. d Based on the amount of 1a.
e
Isolated yield of the major diastereomer.
contrast, when the reaction temperature was decreased to
40 °C, 4aa 5a, and 6a were obtained in yields similar to those
obtained at 20 °C. However, the diastereoselectivity of 4aa
was dramatically reduced to 47:53 (entry 4). Our previous
study suggested that the formation of through the addition
—
,
—
4
in high yield with good diastereoselectivity (entry 10). In
contrast, employment of imines possessing electron-deficient
aryl groups, such as 2c and 2d, resulted in the formation of 4ac
and 4ad in only moderate yields with low diastereoselectivities
of the ester enolate to the imine followed by protonation
could be reversible under Brønsted base catalysis.6c Therefore,
in order to clarify the origin of the temperature effect, the
reversibility of the formation of
coupling conditions and
4
under the three-component
its influence on the
along with the formation of
corresponding (entries 11 and 12). These differences in the
yields of can also be rationalized by considering the relative
electrophilicity of α-ketoester to imine . Thus, electron-rich
a significant amount of
6
diastereoselectivity were investigated by conducting several
control experiments (Scheme 4). First, the major diastereomer
of 4aa was treated with 10 mol% of tBuONa in THF at room
temperature for 14 h (Scheme 4a). As a result, 5a was
obtained in 83% yield along with 13% recovery of the starting
4aa. This result suggested that the irreversible retro-Mannich-
type reaction of 4aa would dominate at room temperature,
and therefore 4aa was not observed when the reaction was
performed at room temperature (Table 3, entry 3). Next, the
major diastereomer of 4aa was treated with 10 mol% of
4
1
2
imines, which facilitate the chemoselective addition of diethyl
phosphite to α-ketoesters, were more suitable than electron-
deficient imines for this reaction. The reaction with meta-
methoxyphenyl- and 2-naphthyl-substituted imines proceeded
without any problem to provide the products 4ae and 4ah
,
respectively, in good yields with good diastereoselectivities
(entries 13 and 16). Sterically hindered imines, such as 2f and
2g, slightly retarded the carbon-carbon bond formation with
the enolate and as a result, the yield of by-product 5a was
tBuONa in the presence of imine 2c at
—20 °C (Scheme 4b). As
a
result, three-component products 4aa and 4ac were
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obtained as a mixture of diastereomers. Interestingly, 5a was reaching full conversion (after 1.5 h, Scheme 4e), the
not obtained at all in this case, in contrast to the reaction at diastereomeric ratio was 50:50, which is similar to that
room temperature. This result indicates that the formation of
obtained in the reaction at —40 °C. In contrast, increasing the
reaction time to 48 h did not change the diastereomeric ratio
from that obtained after 14 h (Scheme 4e). These results
a)
Ts
HN
Ph
BnO2C
Ph
tBuONa (10 mol%)
BnO2C
Ph
provide a tentative profile of the formation of 4aa at —20 °C. At
OP(OEt)2
O
(EtO)2PO
O
THF, rt, 14 h
the beginning of the reaction, the addition of the enolate
generated by the [1,2]-phospha-Brook rearrangement to the
imine proceeded with low diastereoselectivity under kinetic
control, and then the diastereomeric ratio was gradually
improved through the reversible process aforementioned
under thermodynamic control.
4aa
5a 83%
dr > 99:1
+ 4aa (13% recovery)
b)
Ts
Ar
Ts
H
HN
N
tBuONa (10 mol%)
BnO2C
4aa
dr > 99:1
+
+
4aa
56%
Ar
1.0 eq.
2c
THF, 20 °C, 20 h
Ph
4ac
43%
dr = 74:26
(EtO)2PO
dr = 95:5
O
Ar = 4-Cl-C6H4
During the examination of the substrate scope, the
diastereoselectivity was found to be highly dependent on the
choice of α-ketoesters and imines, which is now attributed to
the difference in the rate of the reversible retro-Mannich-type
c)
Ts
N
tBuONa (10 mol%)
4aa
+
4aa
Ar
H
2c
dr > 99:1
THF, 40 °C, 20 h
>99% recovery
dr > 99:1
1.0 eq.
Ar = 4-Cl-C6H4
process among the corresponding products 4. Therefore, if this
O
process could be accelerated, the diastereoselectivity would
be improved. Based on this idea, the reaction conditions were
modified in two ways: by increasing the catalyst loading and by
increasing the reaction temperature. The results are
summarized in Table 4. As the initial attempt for improvement
in diastereoselectivity, the amount of tBuONa was increased
from 10 mol% to 20 mol% in the reaction of 1a with 2a (entry
1). As we expected, the diastereoselectivity was improved
from 79:21 to 84:16 without loss of the yield (entry 1 vs Table
1, entry 17). This strategy was also applied to the reaction of
1a with 2c, in which the original diastereomeric ratio was
61:39 (entries 2 and 3 vs Table 2, entry 11). In this case, while
20 mol% of tBuONa improved the diastereomeric ratio to
72:28, the employment of 30 mol% of tBuONa further
accelerated the reversible process and provided the product
with 81:19 dr. Increasing the reaction temperature to 0 °C was
also found to be an efficient strategy to improve the
diastereoselectivity; the reaction with 20 mol% of tBuONa at
0 °C gave a comparable result to that with 30 mol% of tBuONa
d)
HP(OEt)2 3 (1.0 eq.)
Ts
H
BnO2C
Ph
N
tBuONa (10 mol%)
4aa
+ 5a + 6a
+
(removed)
dr = 47:53
O
THF, 40 °C, 14 h
Ph
1a
2a
1.0 eq.
Ts
HN
BnO2C
tBuONa (10 mol%)
Ph
+
5a
Ph
4aa
(EtO)2PO
O
THF, 20 °C, 24 h
75% (2 steps)
dr = 85:15
O
e)
Ts
HN
Ph
HP(OEt)2 3 (1.0 eq.)
tBuONa (10 mol%)
Ts
BnO2C
Ph
N
BnO2C
Ph
+
O
(EtO)2PO
O
THF, 20 °C, time
Ph
H
2a
1.0 eq.
1a
4aa
1.5 h, 70%, dr = 50:50
14 h, 81%, dr = 83:17
48 h, 77%, dr = 84:16
Scheme 4 Control experiments.
4
under the three-component coupling conditions is reversible
even at —20 °C, whereas the protonation of the enolate
at
—20 °C (entry 4). Next, the reaction of 1a with 2d was
intermediate is rather slow compared to the carbon-carbon
bond formation at that temperature. In other words, the effect
of decreasing the reaction temperature from room
examined (entries 5 and 6). In this case, employment of an
increased amount of tBuONa did not improve the
diastereomeric ratio, indicating the retro-Mannich-type
temperature to —20 °C is the suppression of the competing
Table 4 Investigation toward improvement of the diastereomeric ratio
side reaction, the protonation of the enolate intermediate,
against the desired carbon-carbon bond formation reaction. A
similar experiment was also conducted at
In this case, 4aa was fully recovered as a single diastereomer,
which showed that the formation of is nearly irreversible at
that temperature. The difference between the results
obtained at 20 °C and 40 °C suggests that the reversibility of
the formation of is responsible for the diastereoselectivity.
Thus, we conducted the experiment shown in Scheme 4d. First,
the reaction was conducted at 40 °C to provide 4aa in a 47:53
diastereomeric ratio. After removing the by-product 6a 4aa
with a tiny amount of 5a thus obtained was re-subjected to
the reaction conditions at 20 °C. As result, the
diastereomeric ratio of 4aa was increased to 85:15, which is
almost the same ratio as that obtained in the reaction at
—40 °C (Scheme 4c).
4
—
—
4
—
,
—
a
—
20 °C. Furthermore, when the reaction was quenched before
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DOI: 10.1039/C6OB00739B
ARTICLE
Journal Name
reaction of 1a, β-nitrostyrene (8a), and diethyl phosphite (3)
tBuONa temp.
yield
(%)a
entry R1
R2
4
drb
(mol%)
20
(°C)
under the optimum conditions for the previous reaction
provided the desired adduct 9aa in 28% yield with 79:21 dr
along with the formation of 5% of 5a. In this reaction, the
compound formed by the direct addition of diethyl phosphite
to β-nitrostyrene was not observed. While substantial
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
—20 4aa
—20 4ac
—20 4ac
85 84:16
67 72:28
67 81:19
65 82:18
47 55:45
38 79:21
78 78:22
75 83:17
57 56:44
48 85:15
2
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-NO2-C6H4
2-furyl
20
3
30
4
20
0
4ac
—20 4ad
4ad
—20 4ai
4ai
—20 4ba
4ba
5
30
amounts of 1a and
3 remained after 14 h, β-nitrostyrene was
6
20
0
fully consumed, probably because the polymerization of β-
nitrostyrene is initiated by basic species. When the reaction
was conducted at room temperature, the yield of 9aa was
improved to 57% (Table 5, entry 1). Based on this result, the
screening of bases and solvents was carried out at room
temperature (Table 5). Screening of the bases showed that
tBuONa and tBuOLi were the most suitable bases for this
7
30
8
2-furyl
20
0
9
4-MeO-C6H4 Ph
4-MeO-C6H4 Ph
30
10
30
0
a
b
NMR yields. Bn2O was used as the internal standard. Determined by 1H NMR
and 31P NMR analysis of the crude mixtures.
Table 5 Screening of reaction conditionsa
yield (%)b
dr of 9aac
80:20
74:26
74:26
80:20
50:50
50:50
73:27
85:15
-
entry base
solvent
9aa
57
5a
40
46
10
38
50
77
53
33
12
14
19
5
Scheme 5 Three-component reaction with β-nitrostyrene derivatives 8. Yields are NMR
1
tBuONa
THF
yields. Isolated yields of the major diastereomers are shown in parentheses.
2
tBuOLi
THF
54
3
tBuOK
THF
19
reaction (entries 1-6). Again, NaHMDS provided almost
identical results to that obtained with tBuONa (entry 1 vs entry
4). Screening of solvents with tBuONa was then carried out
(entries 7-10). As a result, ethereal solvents were the solvents
of choice. In particular, the reaction in 1,4-dioxane resulted in
good diastereoselectivity. Employment of 2.0 equivalents of 8a
improved the ratio of 9aa and 5a (entries 11 and 12). However,
4
NaHMDS
P2-tBu
THF
59
5
THF
33
6
P1-tBu
THF
18
7
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuOLi
Et2O
31
8
1,4-dioxane
DMF
55
9
1
10
11d
12d
13d
14d
CH3CN
THF
6
-
61
80:20
85:15
73:27
81:19
a substantial amount of 1a remained (12% and 27%,
1,4-dioxane
THF
54
respectively). Finally, the combination of tBuOLi with 1,4-
dioxane as a solvent was found to be the optimum reaction
conditions (entry 14). The structure of the major diastereomer
of 9aa was confirmed by single-crystal X-ray diffraction
analysis.13 With these reaction conditions in hand, β-
nitrostyrene derivatives having a substituent at the para
position of the benzene ring were examined (Scheme 5). The
reaction with para-methoxy-substituted β-nitrostyrene 8b
provided the product 9ab in moderate yield. In this case, a
significant amount of by-product 5a was formed. On the other
hand, β-nitrostyrene 8c having an electron-deficient para-
chlorophenyl group provided the product 9ac in good yield. As
a control experiment, the treatment of 5a with 8a in the
presence of a catalytic amount of tBuOLi did not provide
three-component coupling product 9aa and 5a was fully
recovered, clearly indicating that the enolate generated via the
[1,2]-phospha-Brook rearrangement directly underwent the
addition reaction to β-nitrostyrene as was the case in the
reaction with imines.
63
36
22
tBuOLi
1,4-dioxane
78 (59)
a
Reaction conditions: 1a (0.10 mmol), 8a (0.11 mmol), 3 (0.11 mmol), base
(0.010 mmol), solvent (1.0 mL), rt, 14 h. Yields based on 31P NMR analysis of
b
crude reaction mixture. P(O)(OMe)3 was used as the internal standard. Isolated
c
yield of the major diastereomer is shown in parentheses. Determined by 1H
NMR and 31P NMR analysis of the crude mixtures. 2.0 equivalents of 8a were
d
used.
process does not occur at —20 °C (entry 5 vs Table 2, entry 12).
However, upon increasing the reaction temperature to 0 °C
with 20 mol% of tBuONa, the product was obtained with 79:21
dr (entry 6). The yield was slightly decreased due to the
competing protonation of the enolate intermediate. The
diastereomeric ratios of the reactions of 1a with 2i and 1b with
2a were also substantially improved by employing the same
strategies (entries 7-10 vs Table 2, entries 1 and 17).
Investigation of three-component coupling reaction of α-
ketoesters, β-nitrostyrenes, and diethyl phosphite
In order to expand the scope of the newly developed
methodology, alternative electrophiles to imines were
explored. After screening of a variety of electrophiles, β-
nitrostyrene was found to be a suitable candidate. The
Conclusions
In conclusion, we have developed a three-component coupling
reaction of α-ketoesters, imines, and diethyl phosphite under
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00739B
Journal Name
ARTICLE
7
For selected reviews, see: (a) S. Kobayashi, Y. Mori, J. S.
Fossey and M. M. Salter, Chem. Rev., 2011, 111, 2626-2704;
(b) S. Kobayashi and H. Ishitani, Chem. Rev., 1999, 99, 1069-
1094; (c) J. M. M. Verkade, L. J. C. Van Hemert, P. J. L.
Brønsted base catalysis by utilizing the [1,2]-phospha-Brook
rearrangement. This reaction involves the generation of an
ester enolate via the umpolung process, i.e., the
chemoselective addition of diethyl phosphite to α-ketoesters
followed by the [1,2]-phospha-Brook rearrangement, and the
trapping of the resulting enolates by imines preferentially over
α-ketoesters and protons. This operationally simple reaction
can provide densely functionalized β-amino acid derivatives
including an oxygen functionality at the α-position in good
yields. The diastereoselectivities are highly dependent on the
substrates, as well as the reaction temperature, which is
attributed to the reversibility of the addition of the enolates to
imines. In addition, the methodology was extended to the
reaction of α-ketoesters, β-nitrostyrenes, and diethyl
phosphite. Further investigation of this methodology, including
the development of an enantioselective version, is in progress.
Quaedflieg and F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37
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8
9
Takeda and M. Terada, Angew. Chem. Int. Ed., 2015, 54
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,
The reaction of ester equivalents under Brønsted base
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10 During the preparation of this manuscript, the related
stoichiometric reaction was reported. The reaction involves
the generation of ester enolates by treating α-ketoesters
with diethyl phosphite in the presence of a stoichiometric
amount of NaHDMS or LHDMS and the subsequent
entrapment of the generated enolates by adding imines in a
one-pot fashion. See: J. Jiang, H. Liu, C.-D. Lu and Y.-J. Xu,
Org. Lett., 2016, 18, 880-883.
11 For selected synthetic study of α-hydroxy-β-amino acid
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Chem., 2005, 70, 4174-4176; (b) A. Guerrini, G. Varchi and A.
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Y.-M. Zeng, C.-D. Lu and Y.-J. Xu, Org. Lett., 2016, 18, 620-
623, and references cited therein.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (Japan) and a
Grant-in-Aid for Scientific Research from the JSPS.
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