Correlating the effects of the N-substituent sizes of chiral 1,2-amino phosphinamide ligands on enantioselectivities in catalytic asymmetric Henry reaction using physical steric parameters

Article abstract of DOI:10.1021/jo500982j

In this study, a series of mono- and dialkylated chiral 1,2-amino phosphinamide ligands derived from modular (1R,2R)-diphenylethylenediamine were successfully applied in the chiral 1,2-amino phosphinamide-Zn(II) catalyzed asymmetric Henry reaction between benzaldehyde and nitromethane. Although the chiral N-monosubstituted and N,N-disubstituted 1,2-amino phosphinamide ligands gave the main alcohol products with opposite configurations, a validated quantitative structure - activity relationship (QSAR) mathematical model could be constructed between the physical Sterimol steric parameters of the N-substituents of the chiral ligands and the enantiomeric ratios of the alcohol products produced in the asymmetric Henry reaction. Since two sets of N-substituents are involved in the QSAR model construction, the key factor to succesfully construct a highly correlative and predictive model is to appropriately assign the N-substitutents. Ligand optimization based on the established QSAR model led to chiral 1,2-amino phosphinamide ligand 2r, which produced (R)-β-nitroalcohol in excellent yield and enantioselectivity (99% yield and 92% ee). In addition, a quantitative correlation could also be established with the use of subtractive Sterimol parameters.

Full text of DOI:10.1021/jo500982j

Article
pubs.acs.org/joc
Correlating the Effects of the N‑Substituent Sizes of Chiral 1,2-Amino
Phosphinamide Ligands on Enantioselectivities in Catalytic
Asymmetric Henry Reaction Using Physical Steric Parameters
Huayin Huang, Hua Zong, Guangling Bian, Huifeng Yue, and Ling Song*
The State Key Lab of Structural Chemistry, the Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
*
S Supporting Information
ABSTRACT: In this study, a series of mono- and dialkylated chiral 1,2-
amino phosphinamide ligands derived from modular (1R,2R)-
diphenylethylenediamine were successfully applied in the chiral 1,2-amino
phosphinamide-Zn(II) catalyzed asymmetric Henry reaction between
benzaldehyde and nitromethane. Although the chiral N-monosubstituted
and N,N-disubstituted 1,2-amino phosphinamide ligands gave the main
alcohol products with opposite configurations, a validated quantitative
structure−activity relationship (QSAR) mathematical model could be
constructed between the physical Sterimol steric parameters of the N-
substituents of the chiral ligands and the enantiomeric ratios of the alcohol
products produced in the asymmetric Henry reaction. Since two sets of N-
substituents are involved in the QSAR model construction, the key factor to
succesfully construct a highly correlative and predictive model is to
appropriately assign the N-substitutents. Ligand optimization based on the established QSAR model led to chiral 1,2-amino
phosphinamide ligand 2r, which produced (R)-β-nitroalcohol in excellent yield and enantioselectivity (99% yield and 92% ee). In
addition, a quantitative correlation could also be established with the use of subtractive Sterimol parameters.
63
64
65−70
1. INTRODUCTION
Mg, or Co ) and organocatalyzed reaction systems
were
developed. Some excellent results were obtained using metal-
based bifunctional chiral catalysts to doubly activate the
aldehyde and nitroalkane as reported by Shibasaki et
The development of highly efficient transformations for
catalytic asymmetric reactions relies on the identification and
optimization of chiral catalysts. Therefore, over the past three
decades, great effort was focused on the development of chiral
31,40−42,54
al.
In our previous investigations, a series of chiral
1
−4
1,2-diamino phosphinamide ligands based on (1R,2R)-1,2-
diphenylethylenediamine and (1R,2R)-1,2-diaminocyclohexane
were synthesized and applied in the ethylation reactions of
adehydes and ketones as conjugated Lewis acid−base catalysts,
catalysts;
however, most approaches are based on empirical
and qualitative observations despite the fact that great progress
5
−19
has been made by computer methods.
Sigman and co-
workers have made important advances in the design and
29,30
20−28
which afforded excellent yields and enantioselectivities.
As
optimization of chiral catalysts using quantitative methods.
part of a continuing effort to develop highly efficient
asymmetric reactions, the purpose of this investigation is to
explore the catalytic efficiency of (1R,2R)-1,2-diamino
phosphinamide-Zn(II) complexes as bifunctional catalysts in
the asymmetric Henry reaction and correlate the physical steric
parameters of the N-substituents of these chiral ligands to the
enantiomeric ratios of the outcome products. We found that N-
monosubstituted ligands gave (R)-alcohols and N,N-disubsti-
tuted ligands gave (S)-alcohols as the main products in the
Henry reaction despite that all of the chiral 1,2-diamino
phosphinamide ligands gave (R)-alcohols as the main products
in our previous studied ethylation reactions of aldehydes and
ketones. Successfully, by appropriately assigning the N-
substitutents of the ligands, a predictive QSAR model was
They demonstrated that a quantitative structure−activity
relationship (QSAR) model between steric parameters of chiral
ligand substituents and enantiomeric ratios of the outcome
products could be established, which could provide insight into
the transition state and be used to optimize the structure of
chiral catalysts. Inspired by their pioneer work, we
quantitatively evaluated the ligand substituent effect on
enantioselectivities in the asymmetric ethylation reactions of
aldehydes and ketones using physical parameters such as
29,30
Charton and Sterimol values.
The asymmetric Henry reaction is a very useful carbon−
31−34
carbon bond formation process in organic chemistry.
It
could provide β-hydroxy nitroalkanes, which are useful
intermediates for the syntheses of polyfunctionalized molecules
3
5−39
and biologically active compounds.
on the first asymmetric Henry reaction disclosed by Shibasaki
62
Since the pioneer work
Received: May 5, 2014
Published: September 15, 2014
4
0
41−52
53−61
in 1992, a variety of metal-catalyzed (Zn,
Cu,
Cr,
©
2014 American Chemical Society
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The Journal of Organic Chemistry
Article
Table 1. Evaluation of (1R,2R)-1,2-Diamino Phosphinamide Chiral Ligands 1 and 2a−2l in the Asymmetric Henry Reaction
between Benzaldehyde and Nitromethane
a
b
average ΔΔG‡
c
predicted ΔΔG‡
d
e
entry
ligand
X
Y
yield (%)
average er (%)
residual
1
2
3
4
5
6
7
8
9
1
H
i-Pr
H
70
23
15
39
76
81
80
81
52
65
95
98
85
73.5:26.5
70:30
0.513
0.426
−0.218
−0.107
1.071
1.163
1.016
1.188
1.156
1.045
1.535
1.571
1.323
2a
2b
2c
2d
2e
2f
H
Me
Et
H
H
H
H
H
H
H
H
H
0.625
−0.237
−0.087
0.948
0.948
1.168
1.203
1.124
1.057
1.359
1.546
1.527
−0.199
0.019
Me
Et
39.3:60.7
44.7:55.3
89.4:10.6
91:9
−0.02
0.123
Et
i-Pr
Bu
0.215
88.3:11.7
91.4:8.6
90.9:9.1
88.9:11.1
95.5:4.5
95.8:4.2
93.3:6.7
−0.152
−0.015
0.032
2g
2h
2i
CH Bu
2
c-Hex
CHEt2
Bn
10
11
12
13
−0.012
−0.176
0.025
2j
2k
CH (p-CH C H )
2 3 6 4
2l
CH (1-Nap)
−0.204
2
a
b
Isolated yields. er is R/S, which was determined by a chiral high performance liquid chromatography (HPLC) analysis, and each er was performed
twice and averaged. Estimated at 253 K (−20 °C), ΔΔG = RT ln(R/S), R = 0.001986 kcal K mol . Calculated by eq 2. Residual =
experimental ΔΔG − predicted ΔΔG .
c
‡
−1
−1
d
e
‡
‡
established to instruct the design and optimization of the chiral
ligands.
2. RESULTS AND DISCUSSION
With a variety of (1R,2R)-1,2-diamino phosphinamide ligands
in hand, we first examined the catalytic efficiencies of chiral
ligands 1 and 2e in the catalytic asymmetric addition of
nitromethane to benzaldehyde (Table 1, entries 1 and 6).
Chiral ligand 1, which was highly efficient in the asymmetric
addition reactions between diethylzinc and aldehyde,
afforded only 70% yield and 47% enantiomeric excess (ee) of
the alcohol product 3; however, chiral ligand 2e afforded 3 with
Figure 1. Verloop’s Sterimol parameters using ethyl group as an
example (L, length of the substituent measured along the axis of the
primary bond that joins the substituent to the parent molecule; B1,
2
9,71
minimum width orthogonal to the primary bond; B , maximum width
5
orthogonal to the primary bond).
81% yield and 82% ee. Therefore, a series of chiral 1,2-diamino
phosphinamide ligands 2a−2l derived from (1R,2R)-1,2-
diphenylethylenediamine with systematically modified N-alkyl
groups were applied in the catalytic asymmetric Henry reaction,
which provided 12 enantiomeric ratios (Table 1, entries 2−13).
Equation 1 included all of the Sterimol subparameters of the X
substituent (B , B , and L ) and Y substituent (B , B , and
1X
5X
X
1Y
5Y
L ) of chiral ligands 2a−2l.
Y
72−74
As one of the most classical and commonly used statistical
methods for the construction of QSAR models, a multiple
linear regression was applied in our investigation. To avoid the
chance correlations among terms, exclude the terms that
destabilize regression models, and keep the significance of the
models, a stepwise regression was introduced in the process of
multiple linear regression. By performing a forward stepwise
regression analysis on the system by adding one term in each
step and optimizing the generated model based on F-tests of
statistical significance for the model and p-tests for the
individual coefficients, three models were generated with
three steps. The corresponding statistical parameters of each
model generated in each step, such as the correlation coefficient
Then, Verloop’s Sterimol parameters
(B , B , and L) were
1 5
used to quantitatively correlate the steric effect of the N-
substituent sizes of the chiral ligands on the enantioselectivities
(
Figure 1).
The Sterimol parameters used in our investigation are listed
in Table 2. The Sterimol parameters of the X and Y
substituents attached on the N atom of (1R,2R)-1,2-diamino
phosphinamide ligands 2a−2l were used, and two sets of three-
dimensional Sterimol parameters were evaluated simultane-
ously using eq 1 as the pool of terms from which all models
could be constructed:
‡
ΔΔG = z0 + aB + bB5X + cL + dB + eB5Y + f LY
1X
X
1Y
2
2
(1)
(R ), cross-validated correlation coefficient (q ), root−mean−
square error (RMSE), and F-test value, which could be used to
evaluate the robustness of a QSAR model, are listed in Table 3.
(
z, a, b, c......f are coefficients of the equation)
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Table 2. Calculated Sterimol Parameters (B , B , L) of R-Groups
Article
a
1
5
entry
R-group
B1
B5
L
entry
R-group
CHEt2
B1
B5
L
1
2
3
4
5
6
7
8
9
H
1.17
1.70
1.71
2.10
1.71
1.71
2.12
1.71
2.08
1.17
2.22
3.38
3.38
4.89
4.65
3.91
5.13
4.59
2.20
3.04
4.33
4.27
6.39
5.21
5.30
7.26
5.46
10
11
12
13
14
15
16
17
18
2.26
1.70
1.72
1.71
1.70
1.70
1.70
1.70
4.13
6.20
7.52
8.01
7.48
8.65
7.35
7.09
5.41
5.44
5.07
5.74
5.73
4.90
4.23
4.65
Me
Et
Bn
CH (p-ClC H )
2
6
4
i-Pr
Bu
CH (p-CF C H )
2 3 6 4
CH (p-CH C H )
2
3
6
4
CH i-Pr
CH (p-CH OC H )
2 3 6 4
2
s-Bu
CH (1-Nap)
2
CH Bu
CH (p-FC H )
2
2
6
4
c-C H
6
11
a
Sterimol parameters of R-groups used in this investigation were calculated using Molecular Modeling Pro software available from ChemSW.
Table 3. Results of Forward Stepwise Regression Analysis
step
added term
R2
RMSE
F
q2
1
2
3
B1X
0.756
0.947
0.960
0.304
0.149
0.137
30.957
80.951
64.212
0.692
0.896
0.890
B , B
5Y
1X
B , B , B
1Y
1X
5Y
2
In step one, B1X was introduced and a model with R = 0.756
and RMSE = 0.304 was generated. In step two, B1X and B5Y
were used as the terms, the corresponding model was obtained
2
with much better values of R = 0.947 and RMSE = 0.149,
which indicates the improvement of the model’s fitting ability.
2
The addition of B1Y in step three only improved the R and
2
RMSE values slightly. Since the R value is necessary but not
sufficient to evaluate a QSAR model, the best model was also
2
evaluated based on the q value and the F-test value. In the
2
process of a leave-one-out cross validation, the q value with B1
X
in step one increased from 0.692 to 0.896 with the addition of
B5Y in step two and then decreased to 0.890 with the further
addition of B1Y in step three, which indicates that the model
with B1X and B5Y as terms has the best predictive ability. In
addition, the model with B1X and B5Y as terms also has the
largest F value. As a result, the corresponding eq 2, based on
‡
Figure 2. Plot of experimentally determined versus predicted ΔΔG
values based on a Sterimol analysis.
≤ 1.15 (see the Supporting Information for the definitions of
2
R
and k as described by Tropsha). Our model well satisfies
0
2
2
2
2
0
2
B1X and B , was chosen as the best fitted model:
these criteria with q = 0.896; R = 0.947; (R − R )/R =
0.056; and k = 0.999. The result indicates that eq 2 is a well-
5Y
−
‡
ΔΔG = 2.696 − 1.916B + 0.146B5Y
(2)
1
X
accepted predictive model.
2
2
−6
Eq 2 reveals that B1X and B5Y are the key terms for the model
construction; however, when B1X was plotted on one axis and
B5Y was plotted along another axis, we found that the B1X and
B5Y parameters of ligands 2a−2l are unevenly spread as shown
in Figure 3. We wondered if the removal of the chiral ligands
2e, 2f and 2l from eq 2 to make these ligands spread more
evenly in B5Y dimension would have a positive effect on the
predictive ability of the model. As shown below, the generated
new eq 3 is different from eq 2 only in the values of the
R = 0.947, q = 0.896, F = 80.951, RMSE = 0.149, p = 1.76 × 10
‡
Equation 2 shows that the ΔΔG value strongly depends on
the B1 term because of its big coefficient compared to that of
B5Y (for details, see the Supporting Information). Therefore, a
smaller proximal steric bulk of the X group will lead to a larger
X
‡
increase of the ΔΔG value. Obviously, a more positive value of
‡
ΔΔG indicates a higher enantioselectivity of the asymmetric
Henry reaction for the (R)-alcohol product, and a more
‡
2
2
negative value of ΔΔG indicates a higher enantioselectivity of
the asymmetric Henry reaction for the (S)-alcohol product.
Therefore, the NHCH (p-MeC H ) group of the chiral 1,2-
amino phosphinamide ligand 2k with the smallest B1X value and
the largest B5Y value gave the (R)-alcohol product with the
highest optical purity in the reaction among the 12 chiral
ligands 2a−2l. A plot of the predicted and experimentally
determined ΔΔG values (Figure 2) is linear with a slope =
.948, an intercept = 0.050, and R = 0.942.
coefficients and constant with q = 0.953 > 0.5; R = 0.984 >
2
2
2
0.6; (R − R )/R = −0.016 < 0.1; and 0.85 ≤ k ≈ 1.00 ≤ 1.15.
0
2
6
4
The above statistic paremeters are even better than those of eq
2, which implies that the omission of the uneven data may lead
to better predictive model.
‡
ΔΔG = 2.468 − 1.839B + 0.180B5Y
(3)
1X
‡
2
2
−6
R = 0.984, q = 0.953, F = 183.036, RMSE = 0.097, p = 4.19 × 10
2
0
A leave-one-out cross-validation was performed to examine
To develop an even more efficient chiral ligand other than 2k
and at the same time to further evaluate the predictive power of
eq 2, an additional seven chiral 1,2-diamino phosphinamide
ligands 2m−2s were synthesized and used in the asymmetric
Henry reaction between benzaldehyde and nitromethane, and
the predictive power of eq 2. The results are listed in Table 4,
2
75,76
and the obtained q value is 0.896. Tropsha
pointed out
that an acceptable predictive model should satisfy the following
2
2
2
2
0
2
criteria: q > 0.5; R > 0.6; [(R − R )/R ] < 0.1; and 0.85 ≤ k
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Table 4. Leave-One-out Cross-Validation Results for Eq 2
entry
ligand
measured ΔΔG‡
predicted ΔΔG‡
entry
ligand
measured ΔΔG‡
predicted ΔΔG‡
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
0.426
−0.218
−0.107
1.071
0.807
−0.257
−0.067
0.924
7
2g
2h
2i
1.188
1.156
1.045
1.535
1.571
1.323
1.203
1.119
1.058
1.324
1.532
1.610
8
9
10
11
12
2j
1.163
0.907
2k
2l
1.016
1.184
small alkyl group should be assigned to Y to give a negative
‡
ΔΔG value to show the higher enantioselectivitity of the
asymmetric Henry reaction to the (S)-alcohol. As shown in
Table 5, just as predicted by eq 2, the chiral ligand 2r, with the
smallest B1X value and largest B5Y value, is the most efficient
‡
chiral ligand, which give the largest positive ΔΔG value and
could promote the asymmetric Henry reaction to afford the
(
2
R)-alcohol product with 92% ee. In addition, the chiral ligand
m gives the largest negative ΔΔG value and could promote
‡
the asymmetric Henry reaction to afford the (S)-alcohol
product with 32% ee.
‡
The comparison between the measured ΔΔG and predicted
‡
ΔΔG values for 2m−2s is depicted in Figure 4 with a slope =
0
predictive model. For these testing sets, the corresponding
statistical parameters are listed as follows: q = 0.978 > 0.5; R
=
1
.995 between 0.6 and 1.4, which indicates that eq 2 is a highly
27
2
ext
2
2
2
2
0.978 > 0.6; (R − R )/R = −0.02 < 0.1; 0.85 ≤ k = 0.968 ≤
0
.15. These parameters further demonstrate that eq 2 has good
stability and predictive power. In addition, all of the residuals of
the 19 chiral ligands in Table 1 and Table 5 distribute between
Figure 3. B1X and B5Y values for ligands 2a−2l.
−
2RMSE and +2RMSE, which implies that no outlier exists in
the model.
their measured enantioselectivities were compared to the values
predicted by eq 2 and listed in Table 5.
Moreover, as shown in Table 5, entries 4−6, CF
-, Cl-, and
3
Notably, the appropriate assignment of the two different
alkyl groups of the asymmetric N,N-disubstituted ligands 2m
and 2s (Table 5, entries 1 and 7) to X and Y in Table 5 is
important for a correct prediction. The predictive model of eq 2
was established on the basis of Y as the big alkyl group and X as
CH O- substituted ligands gave 45%, 80%, and 99% yields of
3
the corresponding alcohol products with similar ee values,
respectively. This result indicates that the electronic effect
affects the reaction activity dramatically but has little influence
on the reaction enantioselectivity. Therefore, it is steric
hindrance that plays a key role for the enantioselectivity of
the asymmetric reaction.
Obviously, the steric differentiation between the X and Y
groups is very important for the chiral ligands. For example, the
catalytic efficiency of the chiral ligand 2m with an N(Me)Et
‡
the small alkyl group and gave a positive ΔΔG value to show
the higher enantioselectivity of the asymmetric Henry reaction
to the (R)-alcohol (Table 1). Therefore, for the N,N-
disubstituted ligands that offered the (S)-alcohol as the main
product, the big alkyl group should be assigned to X and the
Table 5. Experimental and Predicted ee Values of the Asymmetric Henry Reaction Catalyzed by Chiral Phosphinamide Ligands
2m−2s
a
b
measured ΔΔG‡
c
predicted ΔΔG‡
d
e
entry
ligand
X
Y
yield (%)
er (%)
residual
1
2
3
4
5
6
7
2m
2n
2o
2p
2q
2r
Et
H
H
H
H
H
Me
31
85
76
80
45
99
33
34:66
89.3:10.7
92.1:7.9
95.3:4.7
95.1:4.9
95.9:4.1
35:65
−0.332
1.066
1.234
1.512
1.490
1.584
−0.311
−0.256
1.133
1.025
1.552
1.624
1.717
−0.256
−0.076
−0.067
0.209
CH i-Pr
2
s-Bu
CH (p-ClC H )
−0.04
2
6
4
CH (p-CF C H )
−0.134
−0.133
−0.055
2
3
6
4
CH (p-MeOC H )
2
6
4
2s
CH Bu
Me
2
a
b
c
‡
Isolated yields. er is R/S, which was determined by a chiral HPLC analysis. Estimated at 253 K (−20 °C); ΔΔG = RT ln(R/S); R = 0.001986
−1
−1
d
‡
e
‡
‡
kcal K mol . Predicted ΔΔG was calculated by eq 2. Residual = experimental ΔΔG − predicted ΔΔG .
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Article
‡
ΔΔG = 0.112 + 0.631B + 0.165B5S
(4)
1
S
2
2
−8
R = 0.934, q = 0.886, F = 92.493, RMSE = 0.160, p = 2.05 × 10
A plot of the predicted and experimentally determined ΔΔG‡
values (Figure 5) is linear with a slope = 0.935, an intercept =
2
0
.071, and R = 0.930.
To evaluate the predictive power of eq 4, two chiral 1,2-
diamino phosphinamide ligands 2t and 2u containing two
different X and Y groups were synthesized and used in the
asymmetric Henry reaction between benzaldehyde and nitro-
methane. Their measured enantioselectivities were compared to
the values predicted by eq 4 and listed in Table 7. The
‡
predicted ΔΔG values are in good agreement with the
‡
measured ΔΔG values, which indicates that eq 4 is also reliable
and powerful in prediction. Mechanistically, the validation of
the subtracted Sterimol-based mathematical model of eq 4
indicates that a bigger steric differentiation between the X and
Y groups could result in a better asymmetric environment of
the transition state for a higher enantioselectivity.
‡
‡
Figure 4. Plot of experimental ΔΔG values versus predicted ΔΔG
values from eq 2 for ligands 2m−2s in the asymmetric Henry reaction.
3
. CONCLUSION
group is better than those of 2b and 2c with NMe and NEt2
In conclusion, we successfully developed a novel chiral 1,2-
diamino phosphinamide-Zn(II) catalyzed asymmetric Henry
reaction. The effects of the N-substituent sizes of chiral ligands
on the enantioselectivities in the asymmetric Henry reaction
were correlated using physical steric Sterimol parameters and a
predictive QSAR model, which was constructed to guide the
ligand optimization. For N,N-disubstituted ligands with two
different alkyl groups, the appropriate assignment of the two
different alkyl groups is important for a correct prediction. A
highly correlated model was also established based on
subtractive Sterimol parameters. In addition, the electronic
effect of the substituent on the reaction activity is dramatic, but
it has little influence on the enantioselectivity. An investigation
is currently under way to apply the quantitative methodology of
2
groups, respectively. To evaluate the differential effect of X- and
Y-substituted ligands 2d−2s with different X and Y
substituents, a new model of eq 4 was obtained (for details,
see the Supporting Information) using subtractive Sterimol
parameters (Table 6).
The subtracted Sterimol-based mathematical model of eq 4
‡
shows that the ΔΔG value strongly depends on the B and
1S
B terms. The positive coefficients of B and B indicate that
5S
1S
5S
the larger the difference between B and B parameters of the X
1
5
and Y substituents, the higher the enantioselectivity of the
alcohol product would be observed. Eq 4 is also stable and
2
2
2
2
2
predictive with q = 0.886; R = 0.934; (R − R )/R = −0.071;
0
and k = 0.999.
Table 6. Calculated Subtractive Sterimol Parameters (B , B , L )
1
S
5S
S
entry
ligand
X
Y
B1S
B5S
LS
1
2
3
4
5
6
7
8
9
2d
2e
2f
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
Et
0.54
0.93
0.54
0.54
0.91
1.09
0.53
0.53
0.53
−0.01
0.54
0.95
0.55
0.54
0.53
−0.01
0.53
−0.01
2.21
2.21
3.72
3.96
3.42
2.96
5.03
6.31
6.18
−1.16
3.48
2.74
6.35
6.84
7.48
−2.91
5.92
−2.43
2.13
2.07
4.19
5.06
3.26
3.21
3.24
3.53
2.03
−1.29
3.01
3.10
2.87
3.54
2.70
−4.22
2.45
−2.17
i-Pr
Bu
2g
2h
2i
CH Bu
2
c-Hex
CHEt2
Bn
2j
2k
2l
CH (p-CH C H )
2 3 6 4
CH (1-NapCH )
2
2
10
11
12
13
14
15
16
17
18
2m
2n
2o
2p
2q
2r
2s
2t
Me
CH i-Pr
2
s-Bu
CH (p-ClC H )
2
6
4
CH (p-CF C H )
2
3
6
4
CH (p-CH OC H )
2
3
6
4
CH Bu
Me
CH (p-FC H )
2
H
2
6
4
2u
CH i-Pr
Me
2
9
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dx.doi.org/10.1021/jo500982j | J. Org. Chem. 2014, 79, 9455−9464

The Journal of Organic Chemistry
Article
1
1
28.4, 128.5, 131.52, 131.54, 131.62, 131.7, 132.0, 132.1, 133.1, 133.3,
34.3, 134.6.
Chiral ligands 2a−2h and 2m−2o were synthesized according to
3
0
31.1
the reported procedure. Chiral ligand 2a: Mp, 217−218 °C; [α]
,
D
1
−
48.2 (c 0.50, CH Cl ); H NMR (400 MHz, CDCl ): δ 1.72 (s, 2H),
2
2
3
4
.23−4.32 (m, 1H), 4.33−4.37 (m, 1H), 4.43−4.54 (m, 1H), 7.11−7.6
13
(m, 18H), 7.62−7.86 (m, 2H); C NMR (100 MHz, CDCl ): δ 61.3,
3
6
1
1
1.4, 126.8, 127.1, 127.2, 127.5, 128.1, 128.18, 128.23, 131.2, 131.32,
31.34, 131.49, 131.52, 132.0, 132.13, 132.17, 132.28, 132.5, 133.6,
41.5, 142.4.
3
1.4
Chiral ligand 2b: Mp, 197−198 °C; [α] , 48.1 (c 0.50, CH Cl );
D
2
2
1
H NMR (400 MHz, CDCl ): δ 2.24 (s, 6H), 3.72 (d, J = 10.7 Hz,
3
1
H), 4.84 (t, J = 10.9 Hz, 1H), 5.37 (s, 1H), 6.79−6.91 (m, 3H),
6
7
4
1
1
.92−6.99 (m, 2H), 7.01−7.11 (m, 4H), 7.12−7.25 (m, 4H), 7.39−
13
.64 (m, 5H), 7.86−7.98 (m, 2H); C NMR (100 MHz, CDCl ): δ
3
0.5, 54.7 (d, J = 2.0 Hz), 74.5, 74.6, 126.5, 127.3, 127.37, 127.39,
27.49, 127.52, 128.3, 128.5, 128.6, 129.9, 130.69, 130.72, 131.2,
31.3, 131.4, 131.47, 132.5, 133.5, 134.8, 140.8.
3
1.4
Chiral ligand 2c: Mp, 167−168 °C; [α] , 68.1 (c 1.00, CH Cl );
D
2
2
1
H NMR (400 MHz, CDCl ): δ 1.12 (t, J = 7.0 Hz, 6H), 2.09−2.24
3
(
m, 2H), 2.78−2.98 (m, 2H), 3.97 (d, J = 10.7 Hz, 1H), 4.91 (t, J =
10.7 Hz, 1H), 5.65 (s, 1H), 6.79−6.90 (m, 3H), 6.94−7.01 (m, 2H),
7.03−7.26 (m, 8H), 7.40−7.53 (m, 3H), 7.54−7.64 (m, 2H), 7.84−
‡
‡
Figure 5. Plot of experimental ΔΔG values versus predicted ΔΔG
values from eq 4 for ligands 2d−2s in the asymmetric Henry reaction.
8
.00 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 14.0, 42.7, 54.5, 69.8
3
(
1
d, J = 9.0 Hz), 126.6, 127.2, 127.4, 127.5, 127.6, 128.3, 128.4, 128.6,
28.8, 130.62, 130.65, 131.1, 131.2, 131.39, 131.42, 131.7, 132.3,
132.4, 133.0, 133.6, 134.6, 134.9, 140.9.
the design and optimization of catalysts in other catalytic
asymmetric reaction systems.
30.8
Chiral ligand 2d: Mp, 202−203 °C; [α] , −55.9 (c 1.00, CH Cl );
D
2
2
1
4. EXPERIMENTAL SECTION
H NMR (400 MHz, CDCl ): δ 0.98 (t, J = 7.1 Hz, 3H), 1.56−2.20
3
(
br, 1H), 2.27−2.40 (m, 1H), 2.44−2.57 (m, 1H), 3.97 (d, J = 6.0 Hz,
4.1. General Methods. All of the experiments were carried out in
1
7
7
H), 4.26−4.41 (m, 1H), 4.47−4.60 (m, 1H), 7.06−7.20 (m, 5H),
dried glassware with magnetic stirring under an atmosphere of dry
1
13
31
.21−7.33 (m, 9H), 7.34−7.43 (m, 2H), 7.46−7.56 (m, 2H), 7.67−
nitrogen. H NMR (400 MHz), C NMR (100 MHz), P NMR (162
MHz), and 19F NMR (376 MHz) spectra were recorded in CDCl3
.78 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 15.0, 41.4, 60.8, 68.6
3
(d, J = 6.5 Hz), 126.8, 127.1, 127.75, 127.8, 127.9, 128.0, 128.1, 131.2,
solutions using a 400 MHz spectrometer. Chemical shifts were
1
1
1
31.5, 131.68, 131.73, 131.77, 132.0, 132.1, 132.8, 133.0, 140.3,
40.76, 140.78.
reported in parts per million (ppm, δ) relative to CDCl (δ 7.26 for H
3
13
NMR) or CDCl (δ 77.0 for C NMR). Multiplicities are indicated as
3
2
9.9
Chiral ligand 2e: Mp, 206−207 °C; [α] , −19.6 (c 1.00, CH Cl );
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br
D
2
2
1
H NMR (400 MHz, CDCl ): δ 0.88 (d, J = 6.2 Hz, 3H), 0.96 (d, J =
(
broad). Commercial reagents were used as received unless otherwise
3
indicated. All of the solvents were purified and dried prior to use
6.4 Hz, 3H), 1.32−1.87 (br, 1H), 2.52−2.67 (m, 1H), 4.02 (d, J = 6.3
Hz, 1H), 4.29−4.38 (m, 1H), 4.48−4.65 (m, 1H), 7.05−7.17 (m, 5H),
7.17−7.22 (m, 2H), 7.22−7.34 (m, 7H), 7.34−7.45 (m, 2H), 7.50−
77
according to standard methods. Optical rotations were measured on
a polarimeter and reported as follows: [α]T (c g/100 mL, solvent).
D
13
The high performance liquid chromatography (HPLC) analysis was
performed using Chiralcel columns. High resolution mass spectra
7.60 (m, 2H), 7.63−7.76 (m, 2H); C NMR (100 MHz, CDCl ): δ
3
21.7, 24.3, 45.5, 61.0, 66.1 (d, J = 6.9 Hz), 127.0, 127.3, 127.4, 127.9,
128.0, 128.1, 128.2, 128.3, 128.4, 131.38, 131.40, 131.49, 131.52,
131.8, 131.9, 132.3, 132.4, 133.21, 133.25, 140.80, 140.82, 140.88.
(
HRMS) were obtained by electrospray ionization (ESI) sources using
the time-of-flight mass spectrometry (TOF MS) technique.
.2. Synthesis of Chiral Ligands 1, 2a−2h, and 2m−2o. Chiral
3
1.3
4
Chiral ligand 2f: Mp, 201−202 °C; [α]
D
, −48.6 (c 1.00, CH
H NMR (400 MHz, CDCl ): δ 0.81 (t, J = 7.3 Hz, 3H), 1.12−1.25
3
2 2
Cl );
2
9
1
ligand 1 was synthesized according to the reported procedure. Mp,
1
CDCl ): δ 0.89−0.98 (m, 1H), 1.02 (d, J = 6.1 Hz, 3H), 1.06 (d, J =
2
2.0
1
13−114 °C; [α] , −41.2 (c 1.00, CH Cl ); H NMR (400 MHz,
(m, 2H), 1.29−1.42 (m, 2H), 1.61−2.11 (br, 1H), 2.26−2.35 (m, 1H),
2.40−2.55 (m, 1H), 3.92 (d, J = 5.8 Hz, 1H), 4.24−4.41 (m, 1H),
4.44−4.55 (m, 1H), 7.10−7.22 (m, 5H), 7.22−7.26 (m, 2H), 7.26−
D
2
2
3
6
2
.3 Hz, 3H), 1.12−1.27 (m, 3H), 1.49−1.76 (m, 3H), 1.97−2.10 (m,
H), 2.22−2.37 (m, 1H), 2.73−3.00 (m, 2H), 3.90 (s, 1H), 7.33−7.55
7.36 (m, 7H), 7.36−7.44 (m, 2H), 7.44−7.55 (m, 2H), 7.65−7.77 (m,
13
13
(
m, 6H), 7.79−8.01 (m, 4H); C NMR (100 MHz, CDCl ): δ 22.8,
2H); C NMR (100 MHz, CDCl ): δ 13.9, 20.2, 32.0, 47.0, 61.1, 68.9
3
3
2
4.5, 24.8, 25.0, 32.4, 34.4, 45.7, 56.0, 60.0 (d, J = 6.8 Hz), 128.3,
(d, J = 6.7 Hz), 127.1, 127.28, 127.33, 128.0, 128.14, 128.19, 128.21,
Table 7. Experimental and Predicted ee Values of the Asymmetric Henry Reaction Catalyzed by Chiral Phosphinamide Ligands
2t and 2u
a
b
measured ΔΔG‡
c
predicted ΔΔG‡
d
e
entry
ligand
X
Y
yield (%)
er (%)
residual
1
2
2t
H
CH (p-FC H )
81
52
95.0:5.0
1.479
1.423
0.056
0.021
2
6
4
2u
CH i-Pr
Me
36.7:63.3
−0.274
−0.295
2
a
b
c
‡
Isolated yields. er is R/S, which was determined by a chiral HPLC analysis. Estimated at 253 K (−20 °C); ΔΔG = RT ln(R/S); R = 0.001986
−1
−1
d
‡
e
‡
‡
kcal K mol . Predicted ΔΔG was calculated by eq 4. Residual = experimental ΔΔG − predicted ΔΔG .
9
460
dx.doi.org/10.1021/jo500982j | J. Org. Chem. 2014, 79, 9455−9464

The Journal of Organic Chemistry
Article
1
1
28.26, 128.4, 131.5, 131.7, 131.9, 132.0, 132.2, 132.3, 132.9, 133.3,
40.6, 140.96, 140.98.
removed to give the crude product, which was subjected to silica gel
column chromatography (EtOAc/hexane = 1/2) and afforded 314 mg
31.5
24.8
Chiral ligand 2g: Mp, 176−177 °C; [α] , −73.4 (c 1.00, CH Cl );
(65%) of 2i as a white solid. Mp, 188−189 °C; [α] , −40.5 (c 1.00,
D
2
2
D
1
1
H NMR (400 MHz, CDCl ): δ 0.82 (t, J = 7.3 Hz, 3H), 1.11−1.24
CH Cl ); H NMR (400 MHz, CDCl ): δ 0.53 (t, J = 7.4 Hz, 3H),
3
2
2
3
(
2
m, 4H), 1.31−1.41 (m, 2H), 1.56−1.71 (br, 1H), 2.18−2.37 (m, 1H),
0.77 (t, J = 7.4 Hz, 3H), 1.21−1.30 (m, 5H), 2.18−2.30 (m, 1H), 3.96
.37−2.52 (m, 1H), 3.92 (d, J = 5.3 Hz, 1H), 4.25−4.52 (m, 2H),
(d, J = 5.9 Hz, 1H), 4.27−4.33 (m, 1H), 4.55−4.58 (m, 1H), 7.06−
7
7
4
1
1
.11−7.26 (m, 7H), 7.28−7.36 (m, 7H), 7.37−7.52 (m, 4H), 7.65−
7.17 (m, 5H), 7.20−7.32 (m, 9H), 7.33−7.50 (m, 4H), 7.62−7.71 (m,
.76 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 14.0, 22.5, 29.3, 29.5,
13
2H); C NMR (100 MHz, CDCl
): δ 7.8, 10.4, 23.8, 26.6, 55.5, 61.3,
3
3
7.2, 61.0, 68.8 (d, J = 6.8 Hz), 127.1, 127.29, 127.34, 128.01, 128.03,
28.14, 128.76, 128.22, 128.4, 131.5, 131.7, 131.9, 132.0, 132.1,
32.25, 132.35, 133.0, 133.4, 140.6, 140.93.
65.8 (d, J = 7.2 Hz), 127.0, 127.2, 127.3, 127.9, 128.0, 128.07, 128.1,
128.2, 128.25, 128.3, 131.3, 131.36, 131.4, 131.43, 131.8, 132.0, 132.1,
132.2, 133.1, 133.6, 140.9, 141.1; 31P NMR (162 MHz, CDCl
): δ
OP,
3
1.6
D
+
Chiral ligand 2h: Mp, 204−205 °C; [α] , −51.4 (c 1.00, CH Cl );
22.0; HRMS (ESI): (m/z) [M + H] calcd for C31
H
N
36
2
2
2
1
H NMR (400 MHz, CDCl ): δ 0.78−0.89 (m, 1H), 0.96−1.20 (m,
483.2560; found, 483.2560.
3
4
.3.2. Benzyl[(1R,2R)-2-[(diphenylphosphoroso)amino]-1,2-
4
H), 1.40−1.70 (m, 5H), 1.73−1.85 (m, 1H), 2.16−2.32 (m, 1H),
.07 (d, J = 6.1 Hz, 1H), 4.25−4.35 (m, 1H), 4.48−4.60 (m, 1H),
.08−7.19 (m, 5H), 7.19−7.25 (m, 2H), 7.25−7.35 (m, 7H), 7.36−
diphenylethyl]amine (2j). Following the general procedure described
for 2i on the same scale, benzaldehyde (117 mg, 1.1 mmol) was used
to replace 3-pentanone and 2j was obtained as a white solid with the
4
7
7
13
.46 (m, 2H), 7.46−7.54 (m, 2H), 7.64−7.75 (m, 2H); C NMR
2
0.8
yield of 427 mg (85%). Mp, 204−205 °C; [α] , −54.2 (c 1.00,
(
100 MHz, CDCl ): δ 24.3, 24.9, 26.0, 32.2, 34.6, 52.8, 61.1, 65.4 (d, J
D
3
1
CH Cl ); H NMR (400 MHz, CDCl ): δ 2.20−2.32 (s, 1H), 3.42 (d,
=
1
1
7.1 Hz), 127.0, 127.2, 127.3, 127.9, 128.0, 128.1, 128.12, 128.14,
2
2
3
J = 13.7 Hz, 1H), 3.74 (d, J = 13.7 Hz, 1H), 3.91 (d, J = 6.1 Hz, 1H),
28.3, 128.4, 131.4, 131.5, 131.8, 131.9, 132.0, 132.1, 132.2, 132.3,
33.1, 133.4, 140.9, 141.2.
4
.23−4.43 (m, 2H), 7.07−7.18 (m, 7H), 7.22−7.35 (m, 12H), 7.37−
13
2
8.9
7.45 (m, 2H), 7.53−7.60 (m, 2H), 7.71−7.80 (m, 2H); C NMR
(100 MHz, CDCl ): δ 50.7, 60.8, 67.6 (d, J = 6.5 Hz), 126.7, 127.1,
Chiral ligand 2m: Mp, 177−178 °C; [α] , 96.4 (c 1.00, CH Cl );
D
2
2
1
H NMR (400 MHz, CDCl ): δ 1.09 (t, J = 7.1 Hz, 3H), 2.24 (s, 3H),
3
3
1
1
1
27.3, 127.8, 127.86, 127.91, 128.0, 128.07, 128.11, 128.15, 128.20,
28.24, 131.4, 131.5, 131.6, 131.7, 131.8, 132.1, 132.2, 132.8, 132.9,
2
.25−2.34 (m, 1H), 2.49−2.62 (m, 1H), 3.82 (d, J = 10.8 Hz, 1H),
4
.87 (t, J = 10.8 Hz, 1H), 5.52 (s, 1H), 6.79−6.86 (m, 3H), 6.91−6.98
39.9, 140.1, 140.59, 140.61; 31P NMR (162 MHz, CDCl ): δ 22.6;
3
(
m, 2H), 6.99−7.10 (m, 4H), 7.10−7.21 (m, 4H), 7.39−7.61 (m, 5H),
+
13
HRMS (ESI): (m/z) [M + H] calcd for C H N OP, 503.2240;
33
32
2
7
5
1
1
.82−7.92 (m, 2H); C NMR (100 MHz, CDCl ): δ 13.6, 36.1, 47.3,
3
found, 503.2247.
.3.3. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
4.5, 73.6 (d, J = 8.8 Hz), 126.6, 127.3, 127.4, 127.5, 127.6, 128.3,
28.5, 128.6, 129.8, 130.7, 130.73, 131.2, 131.3, 131.36, 131.44, 131.5,
32.4, 132.5, 132.7, 133.3, 133.6, 134.9, 140.8.
4
diphenylethyl][(4-methylphenyl)methyl]amine (2k). The general
procedure described for 2i was followed on the same scale; p-
tolualdehyde (132 mg, 1.1 mmol) was used to replace 3-pentanone,
and 2k was obtained as a white solid with a yield of 413 mg (80%).
3
1.3
Chiral ligand 2n: Mp, 214−215 °C; [α] , −26.6 (c 0.50, CH Cl );
D
2
2
1
H NMR (400 MHz, CDCl ): δ 0.76 (d, J = 6.6 Hz, 6H), 1.55−1.68
3
(
1
(
m, 2H), 2.06−2.16 (m, 1H), 2.18−2.28 (m, 1H), 3.86 (d, J = 5.8 Hz,
H), 4.26−4.48 (m, 1H), 5.52 (s, 1H), 7.08−7.24 (m, 7H), 7.24−7.33
26.0
1
Mp, 198−199 °C; [α]D , −57.2 (c 1.00, CH Cl ); H NMR (400
2
2
MHz, CDCl ): δ 2.31 (s, 3H), 2.37 (d, J = 8.8 Hz, 1H), 3.36 (d, J =
13
3
m, 7H), 7.35−7.49 (m, 4H), 7.62−7.73 (m, 2H); C NMR (100
1
4
7
2
3.6 Hz, 1H), 3.68 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 5.8 Hz, 1H),
MHz, CDCl ): δ 20.4, 20.6, 28.3, 55.3, 61.1, 68.9 (d, J = 7.0 Hz),
3
.20−4.38 (m, 2H), 6.93−7.00 (m, 2H), 7.01−7.09 (m, 4H), 7.10−
1
1
27.1, 127.26, 127.30, 128.0, 128.03, 128.13, 128.16, 128.2, 128.3,
31.4, 131.9, 132.0, 132.3, 140.7, 140.9.
.17 (m, 3H), 7.21−7.35 (m, 9H), 7.37−7.50 (m, 4H), 7.64−7.72 (m,
13
H); C NMR (100 MHz, CDCl ): δ 21.1, 50.6, 61.0, 67.7 (d, J = 6.3
2
6.0
3
Chiral ligand 2o: Mp, 203−204 °C; [α] , −56.9 (c 1.00, CH Cl );
D
2
2
Hz), 127.0, 127.1, 127.3, 127.5, 127.9, 128.0, 128.1, 128.2, 128.4,
1
H NMR (400 MHz, CDCl ): δ 0.55−0.84 (m, 3H), 0.84−0.92 (m,
3
1
1
29.0, 131.5, 131.7, 131.9, 132.0, 132.3, 132.4, 133.0, 133.2, 136.4,
3
H), 1.07−1.45 (m, 3H), 2.20−2.58 (m, 1H), 3.96−4.10 (m, 1H),
.27−4.39 (m, 1H), 4.54−4.68 (m, 1H), 7.07−7.17 (m, 5H), 7.17−
.21 (m, 1H), 7.21−7.33 (m, 8H), 7.33−7.44 (m, 2H), 7.44−7.61 (m,
31
37.0, 140.3, 140.8; P NMR (162 MHz, CDCl ): δ 22.3; HRMS
3
4
7
2
1
+
(ESI): (m/z) [M + H] calcd for C H N OP, 517.2402; found,
34
34
2
5
17.2403.
.3.4. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
13
H), 7.62−7.75 (m, 2H); C NMR (100 MHz, CDCl ): δ 8.7, 10.4,
3
4
9.0, 20.7, 27.3, 30.8, 50.8, 61.1, 65.8 (d, J = 7.2 Hz), 66.2 (d, J = 7.1
diphenylethyl](naphthalen-1-ylmethyl)amine (2l). The general
procedure described for 2i was followed on the same scale; 1-
naphthaldehyde (172 mg, 1.1 mmol) was used to replace 3-pentanone,
and 2l was obtained as a white solid with a yield of 414 mg (75%). Mp,
Hz), 127.0, 127.3, 127.4, 127.43, 127.87, 127.91, 128.0, 128.07, 128.12,
1
1
1
28.14, 128.26, 128.38, 128.4, 131.4, 131.5 (m), 131.8 (m), 131.9 (m),
32.1, 132.2, 132.22, 132.3, 133.1, 133.2, 133.3, 133.4, 140.7, 140.8,
40.9, 141.2.
30.1
1
2
48−249 °C; [α]D , −39.4 (c 1.00, CH Cl ); H NMR (400 MHz,
2
2
4
.3. General Procedure for Preparing Chiral Ligands 2i−2l,
CDCl ): δ 1.69 (br, 1H), 3.80−4.04 (m, 2H), 4.10−4.46 (m, 3H),
3
2
1
p−2r, and 2t. 4.3.1. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-
6
7
4
1
1
1
.94−7.14 (m, 5H), 7.20−7.55 (m, 17H), 7.58−7.69 (m, 2H), 7.71−
,2-diphenylethyl](pentan-3-yl)amine (2i). To a stirred solution of 2a
13
.79 (m, 1H), 7.80−7.91 (m, 2H); C NMR (100 MHz, CDCl ):
3
(
412 mg, 1.0 mmol) in dried methanol (10 mL) and 4 Å molecular
9.0, 61.0, 68.4 (d, J = 6.8 Hz), 123.6, 125.3, 125.5, 126.1, 126.2, 127.1,
sieves (1g), 3-pentanone (94 mg, 1.1 mmol) was added followed by 3
drops of glacial acetic acid. The reaction mixture was monitored by
thin-layer chromatography (TLC) until the imine was formed, then
27.3, 127.5, 127.8, 127.95, 128.0, 128.1, 128.25, 128.3, 128.4, 128.6,
31.5, 131.7, 131.8, 131.9, 132.2, 132.4, 132.97, 133.0, 133.8, 135.4,
40.2, 140.7; P NMR (162 MHz, CDCl ): δ 22.6; HRMS (ESI):
m/z) [M + H] calcd for C H N OP, 553.2405; found, 553.2403.
31
3
NaBH CN (189 mg, 3.0 mmol) was added at 0 °C. The reaction
+
3
(
37
34
2
mixture was allowed to warm to room temperature and was stirred
overnight. The molecular sieves were filtered through filter paper, and
the solution was evaporated under reduced pressure. The residue was
dissolved in CH Cl (20 mL), washed by saturated Na CO solution
4
.3.5. [(4-Chlorophenyl)methyl][(1R,2R)-2-[(diphenyl-
phosphoroso)amino]-1,2-diphenylethyl]amine (2p). The general
procedure described for 2i was followed on the same scale; p-
chlorobenzaldehyde (154 mg, 1.1 mmol) was used to replace 3-
pentanone, and 2p was obtained as a white solid with a yield of 311
2
2
2
3
(
20 mL), and then dried over anhydrous Na SO . The solvent was
2 4
2
6.0
1
mg (58%). Mp, 215−217 °C; [α] , −45.6 (c 1.00, CH Cl ); H
D
2
2
NMR (400 MHz, CDCl ): δ 1.97 (br, 1H), 3.38 (d, J = 14.0 Hz, 1H),
3
3
1
7
.68 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 6.4 Hz, 1H), 4.05−4.21 (m,
H), 4.25−4.38 (m, 1H), 6.95−7.08 (m, 4H), 7.10−7.22 (m, 7H),
13
.27−7.35 (m, 5H), 7.37−7.76 (m, 8H); C NMR (100 MHz,
CDCl ): δ 50.1, 61.1, 67.8 (d, J = 6.0 Hz), 127.19, 127.23, 127.5,
3
1
28.07, 128.13, 128.3, 128.35, 128.43, 128.48, 129.3, 131.5, 131.6,
9
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1
1
31.66, 131.68, 131.7, 131.8, 131.9, 132.3, 132.4, 132.5, 132.8, 133.0,
27.5, 29.3, 36.5, 53.7, 54.8, 66.2, 123.0, 127.1, 127.5, 127.7, 128.2,
129.3, 129.6, 132.5, 133.5, 133.8, 137.4, 168.5, 168.7.
38.6, 139.9, 140.7; 31P NMR (162 MHz, CDCl ): δ 22.9; HRMS
3
+
(
ESI): (m/z) [M + H] calcd for C H ClN OP, 537.1859; found,
Compound 5u was synthesized according to the reported
33
31
2
3
0
28.9
1
5
37.1853.
procedure. Mp, 116−117 °C; [α]D , 10.1 (c 1.00, CH Cl ); H
2
2
4
.3.6. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
NMR (400 MHz, CDCl ): δ 0.69 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7
3
diphenylethyl]({[4-(trifluoromethyl)phenyl]methyl})amine (2q). The
general procedure described for 2i was followed on the same scale; 4-
trifluoromethylbenzaldehyde (192 mg, 1.1 mmol) was used to replace
Hz, 3H), 1.33−1.59 (m, 2H), 2.17−2.24 (m, 1H), 2.24−2.31 (m, 1H),
5.01 (d, J = 11.5 Hz, 1H), 5.48 (d, J = 11.5 Hz, 1H), 7.09−7.20 (m,
4H), 7.20−7.30 (m, 4H), 7.41−7.52 (m, 2H), 7.66−7.73 (m, 2H),
13
3
-pentanone, and 2q was obtained as a white solid with a yield of 354
7.82−7.89 (m, 2H); C NMR (100 MHz, CDCl ): δ 20.4, 28.4, 55.1,
3
26.2
1
mg (62%). Mp, 220−222 °C; [α] , −37.3 (c 1.00, CH Cl ); H
NMR (400 MHz, CDCl ): δ 2.46 (br, 1H), 3.49 (d, J = 14.3 Hz, 1H),
61.1, 62.2, 123.1, 127.1, 127.5, 127.8, 128.1, 128.2, 129.3, 132.0, 133.8,
137.7, 141.2, 168.8.
D
2
2
3
3
1
7
7
5
1
1
.76 (d, J = 14.4 Hz, 1H), 3.87 (d, J = 6.6 Hz, 1H), 4.10−4.20 (m,
H), 4.22−4.35 (m, 1H), 6.95−7.06 (m, 2H), 7.09−7.16 (m, 3H),
.16−7.21 (m, 2H), 7.21−7.36 (m, 9H), 7.37−7.64 (m, 6H), 7.64−
2-[(1R,2R)-2-[Methyl(2-methylpropyl)amino]-1,2-diphenylethyl]-
2,3-dihydro-1H-isoindole-1,3-dione (4u). A mixture of 5u (1.20 g, 3
mmol), 98% formic acid (1.38 g, 30 mmol), and 36% formaldehyde
solution (2.31 mL, 30 mmol) was stirred under reflux (oil bath, 90 °C)
overnight. The solvent was removed under reduced pressure followed
.75 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 50.4, 61.2, 68.0 (d, J =
3
.7 Hz), 125.2 (q, J = 3.6 Hz), 127.21, 127.23, 127.6, 128.1, 128.2,
28.27, 128.3, 128.35, 128.4, 128.5, 128.9, 129.2, 131.4, 131.7, 131.8,
by the addition of saturated K
with CH Cl (15 mL × 3). Then, the organic layer was dried over
anhydrous MgSO and concentrated in vacuo to give the crude
2 3
CO (50 mL) solution and extracted
31
31.9, 132.4, 132.5, 132.7, 133.0, 139.8, 140.7, 144.3; P NMR (162
2
2
1
9
MHz, CDCl ): δ 23.1; F NMR (376 MHz, CDCl ): δ −62.3; HRMS
4
3
3
+
(
ESI): (m/z) [M + H] calcd for C H F N OP, 571.2119; found,
product, which was subjected to silica gel column chromatography
34
31
3
2
571.2121.
(EtOAc/hexane = 1/30) to afford 977 mg (79%) of 4u as a white
2
9.2
1
4
.3.7. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
solid. Mp, 151−152 °C; [α]
D
, −75.4 (c 1.00, CH Cl ); H NMR
2 2
diphenylethyl][(4-methyloxyphenyl)methyl]amine (2r). The general
procedure described for 2i was followed on the same scale; p-
methoxylbenzaldehyde (150 mg, 1.1 mmol) was used to replace 3-
pentanone, and 2r was obtained as a white solid with a yield of 431 mg
(400 MHz, CDCl ): δ 0.55−0.69 (m, 6H), 1.49−1.68 (m, 1H), 2.05
3
(s, 3H), 2.06−2.16 (m, 2H), 5.28 (d, J = 12.3 Hz, 1H), 6.04 (d, J =
12.3 Hz, 1H), 7.05−7.13 (m, 1H), 7.14−7.22 (m, 3H), 7.22−7.30 (m,
1
3
4H), 7.52−7.62 (m, 2H), 7.65−7.73 (m, 2H), 7.76−7.91 (m, 2H);
C
2
5.6
1
(
(
(
(
7
7
81%). Mp, 223−225 °C; [α] , −49.7 (c 1.00, CH Cl ); H NMR
NMR (100 MHz, CDCl ): δ 20.2, 20.4, 25.4, 36.2, 54.8, 62.6, 66.7,
3
D
2
2
400 MHz, CDCl ): δ 1.89 (br, 1H), 3.34 (d, J = 13.4 Hz, 1H), 3.65
122.9, 123.1, 127.1, 127.6, 127.7, 128.2, 129.4, 129.7, 131.8, 132.6,
3
+
d, J = 13.4 Hz, 1H), 3.78 (s, 3H), 3.87 (d, J = 6.1 Hz, 1H), 4.18−4.38
133.6, 133.8, 137.5, 168.6, 168.8; HRMS (ESI): (m/z) [M + H] calcd
m, 2H), 6.68−6.81 (m, 2H), 6.97−7.08 (m, 4H), 7.09−7.18 (m, 3H),
for C27H N O , 413.2220; found, 413.2223.
29 2 2
.19−7.25 (m, 2H), 7.27−7.32 (m, 6H), 7.34−7.52 (m, 5H), 7.63−
(Diphenylphosphoroso)[(1R,2R)-2-[methyl(pentyl)amino]-1,2-
diphenylethyl]amine (2s). To a solution of 4s (853.1 mg, 2.0 mmol)
in ethanol (2 mL), hydrazine monohydrate (0.97 mL, 20 mmol) was
added, and the reaction mixture was stirred at reflux (oil bath, 80 °C)
for 4 h. After the resultant mixture was cooled to room temperature,
diethyl ether (20 mL) and CH Cl (20 mL) were added to form
.75 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 50.2, 55.3, 61.0, 67.6
3
(
d, J = 6.5 Hz), 113.7, 127.1, 127.3, 127.4, 128.0, 128.1, 128.19,
1
1
28.22, 128.3, 128.4, 129.1, 131.5, 131.7, 131.9, 132.0, 132.1, 132.3,
32.4, 133.0, 133.1, 140.2, 140.8, 158.5; 31P NMR (162 MHz, CDCl ):
3
+
δ 22.3; HRMS (ESI): (m/z) [M + H] calcd for C H N O P,
2
2
34
34
2
2
precipitates, which were removed by filtration. The filtrate was dried
533.2352; found, 533.2352.
over anhydrous MgSO , and the solvent was removed under reduced
4
.3.8. [(1R,2R)-2-[(Diphenylphosphoroso)amino]-1,2-
4
diphenylethyl][(4-fluorophenyl)methyl]amine (2t). The general
procedure described for 2i was followed on the same scale; p-
fluorobenzaldehyde (136.5 mg, 1.1 mmol) was used to replace 3-
pentanone, and 2t was obtained as a white solid with a yield of 266 mg
pressure to afford 533 mg of white solid, which was used in the next
step without further purification. A reaction mixture of the white solid
in CH Cl (10 mL) with Et N (545 mg, 5.4 mmol) was stirred at
2 2 3
room temperature for 10 min. After being cooled to 0 °C, it was added
the solution of diphenylphosphinic chloride (1.06 g, 4.5 mmol) in dry
2
9.1
1
(
(
(
4
7
2
6
1
1
51%). Mp, 216−217 °C; [α] , −39.2 (c 1.00, CH Cl ); H NMR
D
2
2
400 MHz, CDCl ): δ 2.20 (br, 1H), 3.41 (d, J = 13.6 Hz, 1H), 3.70
CH Cl (10 mL) dropwise and was stirred for 30 min at 0 °C. Then,
2 2
3
d, J = 13.6 Hz, 1H), 3.87 (d, J = 6.3 Hz, 1H), 4.10−4.29 (m, 1H),
the temperature was allowed to warm to room temperature and was
kept at room temperature for about 4 h. After the reaction mixture was
.30−4.45 (m, 1H), 6.85−7.00 (m, 2H), 7.01−7.13 (m, 4H), 7.13−
cooled to 0 °C, water (20 mL) and CH Cl (20 mL) were added. The
.27 (m, 5H), 7.28−7.38 (m, 7H), 7.39−7.48 (m, 2H), 7.49−7.60 (m,
2
2
13
organic layer was dried over anhydrous MgSO and concentrated. The
H), 7.63−7.82 (m, 2H); C NMR (100 MHz, CDCl ): δ 50.1, 61.1,
4
3
crude product was subjected to silica gel column chromatography
7.8 (d, J = 6.2 Hz), 115.0, 115.2, 127.2, 127.3, 127.5, 128.1, 128.13,
(
EtOAc/hexane = 1/1), which afforded 616.8 mg (62%) of 2s as a
28.3, 128.4, 128.5, 129.46, 129.54, 131.7, 131.8, 131.9, 132.38,
32.45, 132.9, 133.0, 135.8, 140.1, 140.8; P NMR (162 MHz,
30.4
1
31
white solid. Mp, 168−169 °C; [α] , 79.5 (c 1.00, CH Cl ); H NMR
D
2
2
19
(400 MHz, CDCl ): δ 0.84 (t, J = 6.7 Hz, 3H), 1.26−1.35 (m, 4H),
CDCl ): δ 22.6; F NMR (376 MHz, CDCl ): δ −116.2; HRMS
3
3
3
+
1
1
6
7
.41−1.55 (m, 2H), 2.25 (s, 3H), 2.27−2.36 (m, 1H), 2.38−2.48 (m,
H), 3.83 (d, J = 10.7 Hz, 1H), 4.91 (t, J = 10.9 Hz, 1H), 5.59 (s, 1H),
.77−6.89 (m, 3H), 6.94−7.42 (m, 10H), 7.40−7.64 (m, 5H), 7.81−
(
ESI): (m/z) [M + H] calcd for C H FN OP, 521.2153; found,
33 31 2
521.2154.
4
.4. Synthesis of Chiral Ligands 2s and 2u. Compound 4s was
.97 (m, 2H); 13C NMR (100 MHz, CDCl ): δ 14.1, 22.7, 27.5, 29.4,
78
synthesized according to the reported procedure. 4s: Mp, 129−130
3
C; [α]2 , −105.6 (c 1.00, CH Cl ); H NMR (400 MHz, CDCl ): δ
9.0
D
1
35.9, 53.6, 54.5, 73.9 (d, J = 8.9 Hz), 126.6, 127.3, 127.4, 127.5, 127.6,
°
0
2
2
3
1
1
2
28.3, 128.5, 128.7, 129.8, 130.7, 131.2, 132.24, 131.5, 132.3, 132.4,
.63 (t, J = 7.3 Hz, 3H), 0.91−1.37 (m, 6H), 2.07 (s, 3H), 2.20−2.30
32.8, 133.2, 133.6, 134.9, 140.7; 31P NMR (162 MHz, CDCl ): δ
(
1
2
m, 1H), 2.32−2.42 (m, 1H), 5.27 (d, J = 12.3 Hz, 1H), 6.04 (d, J =
3
+
3.7; HRMS (ESI): (m/z) [M + H] calcd for C H N OP,
2.3 Hz, 1H), 7.06−7.29 (m, 8H), 7.52−7.62 (m, 2H), 7.65−7.73 (m,
32 38
2
13
497.2701; found, 497.2716.
H), 7.79−7.91 (m, 2H); C NMR (100 MHz, CDCl ): δ 13.9, 22.5,
3
(
Diphenylphosphoroso)[(1R,2R)-2-[methyl(2-methylpropyl)-
amino]-1,2-diphenylethyl]amine (2u). The same procedure de-
scribed for 2s was followed on the same scale; 4u (824 mg, 2
mmol) was used to replace 4s, and 2u was obtained as a white solid
2
9.1
with a yield of 771 mg (80%). Mp, 206−208 °C; [α] , 64.9 (c 1.00,
D
1
CH Cl ); H NMR (400 MHz, CDCl ): δ 0.83 (d, J = 3.9 Hz, 3H),
2
2
3
0
.85 (d, J = 3.9 Hz, 3H), 1.70−1.86 (m, 1H), 2.11 (d, J = 7.4 Hz, 3H),
2
.21 (s, 1H), 3.80 (d, J = 10.8 Hz, 1H), 4.92 (t, J = 10.7 Hz, 3H), 5.63
(s, 1H), 6.74−6.85 (m, 3H), 6.93−7.07 (m, 6H), 7.07−7.18 (m, 4H),
9
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The Journal of Organic Chemistry
Article
7
.37−7.49 (m, 3H), 7.49−7.61 (m, 2H), 7.83−7.96 (m, 2H); 13C
NMR (100 MHz, CDCl ): δ 20.56, 20.64, 25.7, 35.6, 54.5, 62.6, 74.2
(3) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
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(4) Ojima, I. Catalytic Asymmetric Synthesis, 3rd ed.; Wiley-VCH:
Winheim, Germany, 2010.
3
(
1
1
d, J = 9.2 Hz), 126.6, 127.27, 127.34, 127.38, 127.47, 127.57, 128.3,
28.4, 128.7, 129.9, 130.59, 130.61, 131.1, 131.2, 131.4, 131.5, 131.6,
32.3, 132.4, 132.9, 133.1, 133.7, 134.9, 140.5; 31P NMR (162 MHz,
(5) Oslob, J. D.; Akermark, B.; Helquist, P.; Norrby, P. O.
+
CDCl ): δ 23.4; HRMS (ESI): (m/z) [M + H] calcd for
C H N OP, 483.2552; found, 483.2557.
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3
31
36
2
4.5. Typical Procedure for the Catalytic Asymmetric Henry
Reaction between Benzaldehyde and Nitromethane.
(
(
(
7) Lipkowitz, K. B.; Kozlowski, M. C. Synlett 2003, 1547−1565.
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(
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2
(12) Chen, J.; Wen, J. W.; Li, M. Z.; Tianpa, Y. P. J. Mol. Catal. A:
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min at −50 °C under an atmosphere of nitrogen. Then,
nitromethane (0.54 mL, 10 mmol) was added in one portion,
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temperature was allowed to warm to −20 °C, and the mixture
was stirred for 48 h. The reaction was quenched by the addition
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(
(
14) Houk, K. N.; Cheong, P. H. Y. Nature 2008, 455, 309−313.
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5358−15374.
of a saturated NH Cl solution (15 mL), and the mixture was
4
(16) Donoghue, P. J.; Helquist, P.; Norrby, P. O.; Wiest, O. J. Am.
extracted with EtOAc (15 mL × 3). The combined organic
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2
4
removed under reduced pressure. The crude product was
purified by flash column chromatography on silica gel (hexane/
EtOAc = 8/1) to give 166 mg of the corresponding product 3
of (R)-2-nitro-1-phenylethanol (99% yield, 92% ee). The ee
value was determined by HPLC analysis with a Chiralcel OD-H
column (Hexane/2-propanol = 90/10, 1.0 mL/min, 230 nm).
The major enantiomer tR = 11.7 min, and the minor
(18) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011,
7
(
7
(
7
(
6, 4260−4336.
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1
7.6
enantiomer t = 12.5 min. [α] , −30.40 (c 1.00, CH Cl )
R
D
2
2
6
1
16.0
[
Literature [α]D , −40.16 (c 1.00, CH Cl ) for 93% ee (R)];
H NMR (400 MHz, CDCl ): δ 3.11 (s, 1H), 4.48 (dd, J = 4.8
2
2
108, 2179−2183.
1
3
(23) Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875−1878.
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3
2
(
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MHz, CDCl ): δ 70.8, 81.1, 125.8, 128.7, 128.8, 138.1.
3
3
(
(
66−374.
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ASSOCIATED CONTENT
Supporting Information
Asymmetric Henry reaction of benzaldehyde, the Sterimol
■
27) Harper, K. C.; Vilardi, S. C.; Sigman, M. S. J. Am. Chem. Soc.
*
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(
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analysis, Tropsha’s criteria on evaluating the constructed model,
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13
copies of H and C NMR spectra of products, and HPLC
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(
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AUTHOR INFORMATION
Corresponding Author
E-mail: songling@fjirsm.ac.cn. Phone: + 86-591-83720913.
Fax: +86-591-83722697.
■
*
2
(
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(36) Narayana, C.; Reddy, N. K.; Kabalka, G. W. Synth. Commun.
The authors would like to thank the State Key Lab of Structural
Chemistry, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences for the financial support.
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