Constructing a quantitative correlation between N-substituent sizes of chiral ligands and enantioselectivities in asymmetric addition reactions of diethylzinc with benzaldehyde

Article abstract of DOI:10.1021/jo3016715

Using the asymmetric addition reaction of diethylzinc with benzylaldehyde as a model, we have demonstrated that excellent correlations exist between steric reference parameters (Charton and Sterimol values) for appropriate sets of substituents present on chiral 1,2-amino-phosphoramide ligands and the enantiomeric ratios of alcohol products produced in this process.

Full text of DOI:10.1021/jo3016715

Note
pubs.acs.org/joc
Constructing a Quantitative Correlation between N‑Substituent Sizes
of Chiral Ligands and Enantioselectivities in Asymmetric Addition
Reactions of Diethylzinc with Benzaldehyde
Huayin Huang, Hua Zong, Guangling Bian, 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: Using the asymmetric addition reaction of
diethylzinc with benzylaldehyde as a model, we have
demonstrated that excellent correlations exist between steric
reference parameters (Charton and Sterimol values) for
appropriate sets of substituents present on chiral 1,2-amino-
phosphoramide ligands and the enantiomeric ratios of alcohol
products produced in this process.
eveloping chiral ligands that promote formation of
used to develop a quantitative correlation between substituent
Dproducts with excellent levels of enantioselectivity has sizes and product enantiomeric ratios.
Compared to other classical steric parameters, such as A-
been the focus of intensive studies in the area of metal-
catalyzed asymmetric reactions.1−4 Despite the well-known
influence of steric factors on enantioselectivity, thus far ligand
optimization has for the most part focused on qualitative rather
than quantitative observations. The major reason for this lies in
the fact that most transition states for asymmetric catalytic
reactions involving metals are highly complicated and difficult
to analyze. Although significant progress has been made in the
design of ligands that optimize the stereochemical courses of
asymmetric reactions by using computational methods,5−20
further advances are made difficult because these methods
cannot be easily applied to metal-catalyzed reactions that
proceed via complicated or unidentified mechanisms.
Sigman and his co-workers have demonstrated that steric
parameters can be employed to quantitatively correlate
substituent sizes and enantiomeric ratios in cases where the
catalytic nature of an asymmetric reaction is not consid-
ered.21−26 Indeed, steric parameter based quantitative methods
targeted at optimizing chiral ligands are very attractive, and
some successful applications have been reported using this
approach.27−29 However, additional systematic studies aimed at
obtaining quantitative correlations between steric effects of
ligand-substituents and enantioselectivities of catalytic asym-
metric reactions are needed in order to develop a detailed
understanding of and predictive powers for these processes.
Herein, we report the results of an investigation in which steric
parameters are used to quantitatively analyze the steric effects
of the N-substituents of chiral phosphoramide ligands on the
enantioselectivities of catalytic asymmetric addition reactions of
diethylzinc with benzylaldehyde. The results of this effort show
that appropriately chosen substituent steric parameters can be
values30,31 and interference values,32 Charton values33,34 (ν),
which are derived from van der Waals radii and for which an
extensive library exists, have been widely used in QSAR
(quantitative structure−activity relationship) studies in both
the chemical and biological sciences. Consequently, we have
utilized Charton values as steric reference parameters in the
first phase of the investigation described below.
Although a long list of the Charton values for C-substituents
based on a modified Taft treatment35,36 (log kR = ψνR + h) of
the rate constants for ester hydrolysis (Figure 1a) exists, only a
very limited number of Charton values for N-substituents
1
2
(νNR R ) have come from studies of N-substituted amide
hydrolysis reactions (Figure 1b). However, Charton did
1
2
1 2
quantitatively correlate νNR R to νCHR R as a linear relationship
Figure 1. Charton steric parameters.
Received: August 6, 2012
Published: November 1, 2012
© 2012 American Chemical Society
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Note
Table 1. Charton Values Used in Our Investigation
2 a
2 b
b
NR1R2
NH2
νNR R
CHR1R2
CH3
νCHR R
R
νR
1
1
entry
1
0.47
0.51
0.63
0.63
0.63
0.68
0.94
0.96
0.71
1.49
1.54
0.66
0.83
0.52
0.56
0.68
0.68
0.68
0.73
0.98
1.00
0.76
1.28
1.56
0.71
H
0
2
NHMe
NHEt
CH2Me
Me
0.52
0.56
0.68
0.98
0.68
0.76
1.02
3
CH2Et
Et
4
NHBu
CH2Bu
Bu
5
NHCH2iPr
NHCH2Bu
NHiPr
CH2CH2iPr
CH2CH2Bu
CH2iPr
CH2iPr
CH2Bu
iPr
6
7
8
NHsBu
NMe2
CH2sBu
sBu
9
CHMe2
10
11
12
13
NEt2
CHEt2
NBu2
CHBu2
N(−C4H8−)
N(−C5H10−)
1
CH(−C4H8−)
CH(−C5H10−)
0.87
a
b
2
1
2
1 2
See ref 37. Calculated from νCHR R by using the equation of νNR R = 1.03(νCHR R ) − 0.0691. See refs 33, 34.
Table 2. Asymmetric Addition Reactions of Diethylzinc with Benzaldehyde Catalyzed by Chiral Phosphoramides 1
a
b
c
entry
ligand
NR1R2
NH2
CHR1R2
CH3
yield (%)
er (R/S)
ΔΔG‡ kcal/mol
1
1a
1b
1c
1d
1e
1f
72
71
76
99
99
90
99
99
95
98
99
99
95
73:27
0.589
0.820
1.152
1.300
1.334
1.487
2.057
2.303
0.406
0.650
0.277
1.027
0.474
2
NHMe
CH2Me
80:20
3
NHEt
CH2Et
87.5:12.5
90:10
4
NHBu
CH2Bu
5
NHCH2iPr
NHCH2Bu
NHiPr
CH2CH2iPr
CH2CH2Bu
CH2iPr
90.5:9.5
92.5:7.5
97:3
6
7
1g
1h
1i
8
NHsBu
CH2sBu
98:2
9
NMe2
CHMe2
66.5:33.5
75:25
10
11
12
13
1j
NEt2
CHEt2
1k
1l
NBu2
CHBu2
61.5:38.5
85:15
N(−C4H8−)
N(−C5H10−)
CH(−C4H8−)
CH(−C5H10−)
1m
69:31
a
b
c
Isolated yields. Determined by using chiral GC analysis. Estimated at 298 K (25 °C), ΔΔG‡ = −RT ln(S/R), R = 0.001986 kcal K−1 mol−1.
1
2
1 2
on the basis of available νNR R and νCHR R values to lead the
As can be seen from viewing the data in Table 2 and the
corresponding plot in Figure 2a (plotted as ΔΔG‡, which is
derived from enantiomeric ratios), no LFER occurs between
the Charton values and enantiomeric ratios when all mono- and
disubstitued ligands are taken into account. However, a definite
LFER was found between the νNHR values of mono-N-
substituted ligands (Table 2, entry 1−8), which corresponds
to the equation ΔΔG‡ = 3.150(νNHR) − 0.766 with R2 = 0.963.
The large slope (Ψ = 3.15) seen in this correlation indicates
that enantioselectivities are highly sensitive to changes in the
nature of alkyl groups on the monosubstituted amino groups in
the 1,2-amino-phosphoramides. It should be noted that the lack
of an LFER that incorporates both mono- and di-N-
substituents may be a consequence of the limitations of
applying Charton parameters of sterically large groups.25,26
On the basis of the earlier observation that a linear
1
2
1 2
equation of νNR R = mνCHR R + c, where m = 1.03 and c =
−0.0691.37 As a result, νNR R can be directly calculated by using
1
2
1
2
the corresponding νCHR R values (see Table 1).
Our initial studies focused on an assessment of the possibility
that a linear free energy relationship (LFER) exists between
1
2
Charton values of N-substituents (νNR R ) on chiral 1,2-amino-
phosphoramide ligands and enantiomeric ratios in products of
the catalytic asymmetric addition of diethylzinc to benzylalde-
hyde. For this purpose five chiral 1,2-amino-phosphoramide
ligands, containing NH2, NEt2, N(−C5H10−), NHBu,
NHCH2Bu amine substituents with different Charton values,
were prepared. Although all of these ligands were observed to
catalyze enantioselective diethylzinc to benzaldehyde addition
reactions, no LFER was observed between the Charton values
and enantiomeric ratios. In order to further explore this issue, a
larger group of chiral phosphoramides, containing NMe2,
N(−C4H8−), NBu2, NHMe, NHEt, NHCH2iPr, NHiPr and
NHsBu substituted amine groups, was synthesized, and the
enantioselectivies of asymmetric diethylzinc to benzylaldehyde
addition reactions that they catalyze were determined (see
Table 2).
1
2
1 2
relationship exists between νCHR R and νNR R along with the
1
2
results of this study, which show that some of νNR R values
linearly correlate with ΔΔG‡ associated with the enantiose-
lectivities of diethylzinc additions to benzaldehyde, we expected
that ΔΔG‡ and Charton values of C-substituents (νCHR R ) that
1
2
correspond to those present on amino groups of 1,2-amino-
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Note
utilized, the one obtained using νR was poor (R2 = 0.557)
(Figure 3). Because ν values correspond to the influence of
Figure 3. LFERs between substituent sizes and enantiomeric ratios
1
2
using νNR R (red line) and νR (blue line) values.
substituents that are directly adjacent to the carbonyl carbon in
esters undergoing hydrolysis, we believed that the use of ν
values of the amino-groups (NHR) in the 1,2-amino-
phosphoramides that are directly adjacent to zinc in the
transition state of the addition reaction would lead to an even
more accurate correlation than one derived by employing ν
values of R groups that are one nitrogen atom away from the
zinc center. On the basis of this reasoning, ΔΔG‡ values were
calculated from the linear equation constructed using νNHR
values. The results along with experimental ΔΔG‡ values and
errors are tabulated in Table 3 and plotted in Figure 4.
Table 3. Comparison of Experimentally Determined and
Calculated ΔΔG‡ Values
Figure 2. Quantitative correlations between Charton N- and C-
1
2
1 2
substitutent size parameters, νNR R (a) and νCHR R (b), respectively,
and enantioselectivities of catalyzed diethylzinc addition reactions with
benzaldehyde.
a
b
entry
ligand
NH2
experimental ΔΔG‡ predicted ΔΔG‡
error
1
2
3
4
5
6
7
8
0.5886
0.8204
1.1516
1.3004
1.3340
1.4869
2.0573
2.3033
0.7145
0.8405
1.2185
1.2185
1.2185
1.3760
2.1950
2.2580
0.1762
0.0239
0.0549
0.0672
0.0948
0.0806
0.0627
0.0201
NHMe
NHEt
phosphoramides would be linearly correlated. This expectation
is a consequence of the fact that the two linear mathematical
expressions shown in eqs 1 and 2 can be combined to create
NHBu
NHCH2iPr
NHCH2Bu
NHiPr
the relationship between ΔΔG‡ and νCHR R shown in eq 3.
1
2
1
2
1
2
NHsBu
νNR R = 1.03(νCHR R ) − 0.0691
(1)
(2)
(3)
a
b
Calculated from ΔΔG‡ = 3.150(νNHR) − 0.766. Error = (|
ΔΔG‡ = 3.150(νNR R ) − 0.766 (R = H)
ΔΔG‡ = 3.245(νCHR R ) − 0.984 (R = H)
1
Experimental ΔΔG‡ − Predicted ΔΔG‡|)/Predicted ΔΔG‡.
1
2
1
1
2
Sigman pointed out earlier that identifying appropriate
reference parameters is an important component of a successful
quantitative correlation analysis of asymmetric catalyzed
processes.25,26 More recently, by using Verloop’s multidimen-
sional Sterimol parameters38−40 (B1, B5 and L) (Figure 5),
Sigman was able to demonstrate that quantitative correlations
exist between small and large substituents, located at various
distances from the reaction centers, and enantioselectivities of
asymmetric catalytic reactions. However, plots using Charton
parameters for both small and large substituents display only
partial linearity and breaks in linearity.
As inspection of this expectation, the plot in Figure 2b
demonstrates that an excellent linear relationship does indeed
exist (R2 = 0.966) between νCH R and enantiomeric ratios of the
2
catalyzed addition reactions. Therefore, this linear relationship
enables a LFER analysis to be carried out between N-
substituent sizes and enantioselectivities by simply using the
extensive list of Charton values of the corresponding C-
substituents.
Because the mono-N-substituted ligands employed in the
above analysis contain only one R-group, we determined if a
correlation would occur between enantioselectivities and the
Charton νR values (see Table 1).33,34 However, compared with
the excellent linear correlation seen when νNHR values were
Inspired by Sigman’s observations, we engaged in an effort to
determine if a quantitative correlation occurs between N-
substituent sizes and enantioselectivities by using the Steimol
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Note
Figure 6. Substituent assignment for phosphoramide ligand.
ΔΔG‡ = 0.163 − 1.678XB1 + 1.867YB1
(4)
Analysis of the Sterimol-based model shows that ΔΔG‡
strongly depends on the XB1 terms for both the R1 and R2
substituents (see the Supporting Information for details). The
negative coefficient relating the XB1 term indicates that a larger
proximal steric bulk of the R1 group will lead to an increase in
the transition state bond distance between the carbonyl and the
zinc active center and a corresponding decrease in the level of
enantioselectivity. In contrast, the positive coefficient related to
the YB1 term indicates that a large proximal steric bulk of the R2
group is required to generate higher enantioselectivities. As
predicted, the NHsBu group, which has the largest calculated
Figure 4. Plot of experimentally determined vs predicted ΔΔG‡ values
(Table 3).
Y
B1 value and the smallest calculated XB1 value, is present in the
ligand that promotes the highest enantioselectivity for the
catalyzed addition reaction. Indeed, a plot of the predicted and
experimentally determined ΔΔG‡ values (Figure 7) is linear
Figure 5. Sterimol parameters: B1 (minimal width of substituent), B5
(maximal width of substituent), and L (maximal length of substituent).
parameters listed in Table 4. In this treatment, it is possible to
use Sterimol parameters for either the NR1R2 groups or the
individual R1 and R2 substiuents of NR1R2 in the phosphor-
amide ligands (see Figure 6). When Sterimol parameters of
NR1R2 groups were used, no quantitative relationship was
observed in the case (see the Supporting Information for
details). Therefore, our attention turned to utilizing Sterimol
parameters of the individual R1 and R2 groups. Because two sets
of three-dimensional Sterimol parameters should be evaluated
simultaneously, the base model included all Sterimol
subparameters of substituents (R1, R2) and cross-terms relating
each R1-Sterimol subparameter to the R2-Sterimol subpara-
meter. A stepwise regression analysis was then performed on
the system to generate the correlation represented by eq 4, in
which X and Y represent the respective R1 and R2 substituents.
Figure 7. Plot of experimentally determined vs predicted ΔΔG‡ values
based on a Sterimol analysis.
with R2 = 0.885. Because the N atom of the NR1R2 amino
substituent in the 1,2-amino-phosphoramides directly coor-
dinates with zinc, the steric repulsive effect of NR1R2 on the
degree of enantioselectivity is mainly contributed by the R1 and
a
Table 4. Sterimol Parameters (B1, B5, L) of NR1R2 and R Groups
entry
substituent
B1
B5
L
entry
substituent
B1
B5
L
1
NH2
1.35
1.35
1.35
1.35
1.35
1.35
1.35
1.35
1.35
1.35
1.97
3.08
3.42
4.87
4.47
5.89
4.13
4.47
2.56
4.39
2.78
3.53
4.83
6.88
6.07
8.13
4.83
6.07
3.53
4.83
11
12
13
14
15
16
17
18
19
20
N(−C4H8−)
N(−C5H10−)
H
1.90
1.91
1
4.09
3.49
1
4.90
6.17
2.06
2.87
4.11
6.17
4.92
6.97
4.11
4.92
2
NHMe
NHEt
3
4
NHBu
NHCH2iPr
NHCH2Bu
NHiPr
NHsBu
NMe2
Me
1.52
1.52
1.52
1.52
1.52
1.90
1.90
2.04
3.17
4.54
4.45
4.94
3.17
3.49
5
Et
6
Bu
7
CH2iPr
CH2Bu
iPr
8
9
10
NEt2
sBu
a
See refs 38−40.
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Note
R2 groups. Thus, using the Sterimol parameters of R1 and R2
groups for quantitative correlation analysis leads to a more
accurate prediction of the levels of enantioselectivity of the
catalyzed asymmetric addition reaction than using those of
NR1R2 groups.
column chromatography (EtOAc/hexane = 1/1), which afforded 11.33
g (85%) of 4 as a white solid: mp 193−194 °C; [α]2D2.0 −41.5 (c 2.00,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.20−1.40 (m, 3H), 1.65−
1.85 (m, 3H), 2.26−2.42 (m, 2H), 2.90−3.00 (m, 1H), 3.50−3.68 (m,
1H), 3.85−4.00 (m, 1H), 7.00−7.13 (m, 2H), 7.23−7.31 (m, 1H),
7.32−7.39 (m, 2H), 7.40−7.53 (m, 3H), 7.65−7.75 (m, 4H), 7.75−
7.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.8, 25.2, 28.7, 37.0
(d, J = 2.5 Hz), 51.6, 56.2 (d, J = 5.9 Hz), 122.9, 128.0 (d, J = 12.8
Hz), 128.2 (d, J = 12.6 Hz), 131.4 (d, J = 38.4 Hz), 131.5 (d, J = 9.5
Hz), 131.7 (d, J = 7.6 Hz), 131.8 (d, J = 9.1 Hz), 133.0 (d, J = 5.8 Hz),
133.6, 168.3, 168.6; 31P NMR (162 MHz, CDCl3) δ 22.0. Elemental
Analysis, Anal. Calcd. for C26H25N2O3P: C 70.26, H 5.67, N 6.30
Found: C 70.15, H 5.77, N 6.25.
In summary, in the effort described above, we have
thoroughly investigated quantitative correlations between
Charton and Sterimol steric parameters associated with steric
sizes of N-substituents in the amino groups of chiral
phosphoramide ligands and the levels of enantioselectivity in
asymmetric catalytic addition reactions of diethylzinc to
benzaldehyde. When Charton values of NR1R2 groups were
employed, a LFER was found to exist only between the size of
the N-substituent in chiral mono-N-substituted ligands and
enantioselectivity. In contrast, Sterimol parameters of R1 and R2
groups of all N-substituents were observed to quantitatively
correlate with enantiomeric ratios. The different quantitative
relationships obtained by using the Charton and Sterimol
analytical methods can perhaps be attributed to the different
nature of these steric reference parameters. Significantly, this
investigation has demonstrated that choosing appropriate sets
of substituents in chiral ligands and reference parameters is
important for successfully constructing quantitative steric
correlations between ligand substituents and enantioselectivities
of catalytic asymmetric reactions.
(1R,2R)-1-N-(Diphenylphosphoroso)cyclohexane-1,2-diamide
(1a, Entry 1 in Table 2).43 A solution of 4 (11.33 g, 25.5 mmol) in
ethanol (5 mL) containing hydrazine monohydrate (1.0 mL) was
stirred at reflux for 2 h. The mixture was then cooled to room
temperature and diluted with diethyl ether, forming a precipitate that
was removed by filtration. The filtrate was dried over MgSO4 and
concentrated in vacuo to afford 7.62 g (95%) 1a as a light yellow solid,
which was used in the following step without further purification: mp
152−153 °C; [α]2D1.3 −5.8 (c 2.00, CH2Cl2); H NMR (400 MHz,
1
CDCl3) δ 0.80−0.95 (m, 1H), 0.95−1.22 (m, 3H), 1.44−1.55 (m,
2H), 1.62−1.74 (br, 2H), 1.74−1.85 (m, 1H), 1.87−2.02 (m, 1H),
2.18−2.31 (m, 1H), 2.36−2.52 (m, 1H), 3.40−3.52 (m, 1H), 7.22−
7.42 (m, 6H), 7.70−7.89 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
24.6, 25.0, 34.6, 34.8 (d, J = 4.5 Hz), 56.4 (d, J = 4.0 Hz), 58.6 (d, J =
2.0 Hz), 128.3 (d, J = 12.5 Hz), 131.6 (d, J = 2.4 Hz), 131.8, 131.9,
132.2 (d, J = 9.4 Hz), 132.8 (d, J = 129.9 Hz), 133.4 (d, J = 128.0 Hz);
31P NMR (162 MHz, CDCl3) δ 22.2. Elemental Analysis, Anal. Calcd.
EXPERIMENTAL SECTION
■
General Methods. All experiments were carried out in dried
glassware with magnetic stirring under an atmosphere of dry nitrogen.
1H NMR (400 MHz), 13C NMR (100 MHz) and 31P NMR (162
MHz) spectra were recorded in CDCl3 solutions using a 400 MHz
spectrometer. Chemical shifts were reported in parts per million (ppm,
for C18H23N2OP: C 68.77, H 7.37, N 8.91 Found: C 68.92, H 7.54, N
8.64.
(1R,2R)-1-N-(Diphenylphosphoroso)-2-N-(2-methyl)cyclohexane-
1,2-diamine (1b, Entry 2 in Table 2). To a solution of 1a (314 mg, 1.0
mmol) in dry CH2Cl2 (5 mL) at room temperature was added Et3N
(202 mg, 2.0 mmol). After being stirred for 10 min, di-tert-butyl
dicarbonate (262 mg, 1.2 mmol) in dry CH2Cl2 (4 mL) was added
dropwise to the solution at 0 °C, and then the reaction mixture was
stirred at room temperature for 12 h and concentrated in vacuo to give
an oil. To a solution of the oil in THF (4 mL) was added LiAlH4 (156
mg, 4.0 mmol) in THF (5 mL). The mixture was stirred at reflux for 4
h, cooled to 0 °C, diluted with 15 mL ice water and extracted with
CH2Cl2. The combined organic layers were washed with brine, dried
over MgSO4 and concentrated in vacuo, giving a residue that was
subjected to silica gel column chromatography (MeOH/CH2Cl2 = 1/
20), which afforded 253 mg (77%) of 1b as a white solid: mp 171−172
δ) relative to CDCl3 (δ 7.26 for 1H NMR), or CDCl3 (δ 77.0 for 13
C
NMR). Multiplicities are indicated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) and br (broad). Commercial
reagents were used as received unless otherwise indicated. All solvents
were purified and dried prior to use according to standard methods.41
Optical rotations were measured on a polarimeter and reported as
follows: [α]TD (c g/100 mL, solvent). GC analysis was performed on a
gas chromatograph with a FID detector on fused silica chiral capillary
column (Chirasil Dex CB column, 25 m length × 0.32 mm ID × 0.25
mm film thickness).
Representative Procedure for Preparing Chiral Ligands 1a−
1m. (1R,2R)-N-Phthaloyl-1,2-diaminocyclohexane (3). Prepared
following the procedure described previously.42
°C; [α]2D9.8 −21.3 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ
1
0.92−1.06 (m, 1H), 1.09−1.23 (m, 2H), 1.27−1.36 (m, 1H), 1.55−
1.76 (m, 2H), 2.05−2.15 (m, 2H), 2.16−2.24 (m, 1H), 2.24−2.28 (br,
1H), 2.41 (s, 3H), 2.76−2.93 (m, 1H), 3.33−3.47 (m, 1H), 7.38−7.56
(m, 6H), 7.86−7.98 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 24.5,
25.0, 30.4, 33.3, 35.0, 55.3 (d, J = 1.9 Hz), 64.4 (d, J = 5.0 Hz), 128.3,
128.5, 128.6, 131.7, 131.8, 131.9, 132.1, 132.2, 132.4, 132.6, 133.7,
133.9; 31P NMR (162 MHz, CDCl3) δ 22.6. Elemental Analysis, Anal.
Calcd. for C19H25N2OP: C 69.49, H 7.67, N 8.53 Found: C 69.69, H
7.70, N 8.55.
(1R,2R)-N-[2-(N′-Phthaloyl)cyclohexyl]diphenylphosphinic amide
(4). To a solution of 3 (7.33 g, 30 mmol) in dry CH2Cl2 (100 mL),
Et3N (7.58 g, 75 mmol) was added at room temperature. After being
stirred for 10 min, diphenylphosphinic chloride (10.64 g, 45 mmol) in
dry CH2Cl2 (50 mL) was added dropwise to the solution at 0 °C. The
mixture was stirred for 4 h at room temperature, cooled in ice bath and
diluted with water (20 mL). Extraction with CH2Cl2 gave combined
organic layers that were washed with brine, dried over MgSO4 and
concentrated in vacuo to give a residue that was subjected to silica gel
10431
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The Journal of Organic Chemistry
Note
(1R,2R)-1-N-(Diphenylphosphoroso)-2-N-(2-ethyl)cyclohexane-
1,2-diamine (1c, Entry 3 in Table 2). To a solution of 1a (314 mg, 1.0
mmol) in dry CH2Cl2 (5 mL) at room temperature was added Et3N
(253 mg, 2.5 mmol). After being stirred for 10 min, acetyl chloride
(118 mg, 1.5 mmol) in dry CH2Cl2 (4 mL) was added dropwise to the
solution at 0 °C, and the resulting mixture was stirred for 2 h, diluted
with water (20 mL), and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated in vacuo to give 320 mg of a yellow solid. To a solution
of this solid in THF (4 mL) was added LiAlH4 (117 mg, 3.0 mmol) in
THF (5 mL). The mixture was stirred at reflux for 4 h, cooled to 0 °C,
diluted with 15 mL of ice water and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over MgSO4
and concentrated in vacuo to give a residue that was subjected to silica
gel column chromatography (MeOH/CH2Cl2 = 1/30), which afforded
287 mg (84%) of 1c as a white solid: mp 123−125 °C; [α]2D7.6 −30.9 (c
6H), 1.48−1.63 (m, 3H), 1.64−1.72 (m, 1H), 2.03−2.14 (m, 2H),
2.33−2.44 (m, 1H), 2.45−2.55 (m, 1H), 2.69−2.84 (m, 2H), 3.67−
3.81 (m, 1H), 7.36−7.56 (m, 6H), 7.82−7.95 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 22.6, 24.7, 24.9, 29.6, 29.9, 31.1, 34.8 (d, J
= 2.9 Hz), 46.6, 55.5, 62.8 (d, J = 6.1 Hz), 128.4 (d, J = 12.6 Hz),
128.5 (d, J = 12.4 Hz), 131.6 (d, J = 2.7 Hz), 131.7, 131.7, 132.1(d, J =
9.5 Hz), 133.3 (d, J = 127.2 Hz), 133.4 (d, J = 129.9 Hz); 31P NMR
(162 MHz, CDCl3) δ 23.3. Elemental Analysis, Anal. Calcd. for
C23H33N2OP: C 71.85, H 8.65, N 7.29 Found: C 71.77, H 8.52, N
7.16.
(1R,2R)-1-N-(Diphenylphosphoroso)-2-N-(propan-2-yl)-
cyclohexane-1,2-diamine (1g, Entry 7 in Table 2). The title
compound was prepared following the general procedure described
for 1d on the same scale and was obtained as a white solid with the
yield of 303 mg (85%): mp 113−114 °C; [α]2D2.0 −42.4 (c 1.00,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.91−1.00 (m, 1H), 1.02−
1
1.06 (d, J = 6.1 Hz, 3H), 1.06−1.11 (d, J = 6.3 Hz, 3H), 1.16−1.30 (m,
3H), 1.54−1.72 (m, 3H), 2.01−2.11 (m, 2H), 2.27−2.38 (m, 1H),
2.77−2.88 (m, 1H), 2.88−3.00 (septet, J = 6.2, 1H), 3.83−4.08 (br,
1H), 7.39−7.56 (m, 6H), 7.80−8.00 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 22.8, 24.5, 24.8, 24.9, 32.4, 34.4, 45.7, 56.0, 60.0 (d, J = 6.8
Hz), 128.3 (d, J = 12.8 Hz), 128.5 (d, J = 12.5 Hz), 131.5 (d, J = 2.7
Hz), 131.6, 131.7, 132.0 (d, J = 9.5 Hz), 133.7 (d, J = 125.7 Hz), 134.0
(d, J = 130.0 Hz); 31P NMR (162 MHz, CDCl3) δ 22.4. Elemental
Analysis, Anal. Calcd. for C21H29N2OP: C 70.76, H 8.20, N 7.86
Found: C 70.80, H 8.03, N 7.86.
1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.03−1.11 (m, 1H),
1.15−1.20 (m, 3H), 1.21−1.36 (m, 2H),1.59−1.73 (m, 2H), 2.02−
2.17 (m, 2H), 2.30−2.49 (m, 2H), 2.49−2.62 (m, 2H), 2.74−2.97 (m,
2H), 3.51−3.65 (m, 1H), 7.41−7.60 (m, 6H), 7.80−8.00 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 15.3, 24.6, 24.9, 31.1, 35.0 (d, J = 3.43
Hz), 40.9, 55.4, 62.8 (d, J = 5.29 Hz), 128.5 (q, J = 6.35 Hz), 131.7,
131.8, 132.1, 132.2,132.4, 132.6, 133.7, 133.8; 31P NMR (162 MHz,
CDCl3) δ 26.6. Elemental Analysis, Anal. Calcd. for C20H27N2OP: C
70.15, H 7.95, N 8.18 Found: C 70.12, H 7.99, N 8.20.
(1R,2R)-1-N-Butyl-2-N-(diphenylphosphoroso)cyclohexane-1,2-
diamine (1d, Entry 4 in Table 2). To a solution of 1a (314 mg, 1.0
mmol) in CH3CN (5 mL) at room temperature was added K2CO3
(276 mg, 2.0 mmol) and butyl iodide (239 mg, 1.3 mmol). The
resulting mixture was stirred at reflux overnight, cooled to room
temperature and concentrated in vacuo to give an oil. The residue oil
was diluted with CH2Cl2 (20 mL) and water (20 mL). The organic
layer was separated, and the aqueous layer (pH ∼ 10) was extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with brine, dried over MgSO4 and concentrated in vacuo, giving a
residue that subjected to silica gel column chromatography (MeOH/
CH2Cl2 = 1/40), which afforded 274 mg (74%) of 1d as a white solid:
mp 133−134 °C; [α]2D0 −16.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 0.91 (d, J = 7.4 Hz; 3H), 1.10−1.29 (m, 4H), 1.30−1.43 (m,
3H), 1.57−1.72 (m, 4H), 2.02−2.09 (m, 1H), 2.10−2.8 (m, 1H),
2.54−2.71 (m, 2H), 2.78−2.87 (m, 1H), 2.92−3.06 (m, 1H), 3.96−
4.11 (br, 1H), 7.40−7.55 (m, 6H), 7.82−7.94 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 13.8, 20.3, 24.4, 24.8, 30.2, 31.2, 34.6 (d, J = 3.4
Hz), 46.0, 54.6, 62.6 (d, J = 4.8 Hz), 128.4 (d, J = 12.6 Hz), 131.5,
131.6, 131.7, 132.0 (d, J = 9.8 Hz), 132.7 (d, J = 130.0 Hz), 133.3; 31P
NMR (162 MHz, CDCl3) δ 24.1. Elemental Analysis, Anal. Calcd. for
C22H31N2OP: C 71.32, H 8.43, N 7.56 Found: C 71.16, H 8.18, N
7.36.
(1R,2R)-1-N-(Butan-2-yl)-2-N-(diphenylphosphoroso)-
cyclohexane-1,2-diamine (1h, Entry 8 in Table 2). The title
compound was prepared following the general procedure described
for 1d on the same scale and was obtained as a white solid with the
yield of 252 mg (68%): mp 97−99 °C; [α]2D3.0 −41.4 (c 1.00, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 0.80−0.95 (m, 3H), 0.95−1.15 (m,
4H), 1.15−1.33 (m, 4H), 1.34−1.74 (m, 4H), 1.97−2.13 (m, 2H),
2.27−2.45 (m, 1H), 2.65−2.79 (m, 1H), 2.80−2.97 (m, 1H), 3.98−
4.14 (m, 1H), 7.36−7.54 (m, 6H), 7.82−7.98 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 9.7, 10.4, 20.1, 21.2, 24.6, 24.7, 24.9, 25.0, 28.9,
30.9, 32.1, 32.5, 34.2, 34.3, 51.3, 51.7, 56.1, 56.2, 59.7, 59.8, 60.3, 60.4,
128.2 (d, J = 13.0 Hz), 128.3 (d, J = 12.8 Hz), 131.5, 131.6, 131.7,
132.0 (d, J = 9.5 Hz), 133.3 (d, J = 125.7 Hz), 134.0 (d, J = 129.4 Hz);
31P NMR (162 MHz, CDCl3) δ 22.3. Elemental Analysis, Anal. Calcd.
for C22H31N2OP: C 71.32, H 8.43, N 7.56 Found: C 71.36, H 8.41, N
7.44.
(1R,2R)-2-N-(Diphenylphosphoroso)-1-N,1-N-dimethylcyclohex-
ane-1,2-diamine (1i, Entry 9 in Table 2). To a solution of 1a (314
mg, 1.0 mmol) in CH3CN (5 mL) at room temperature was added
K2CO3 (690 mg, 5.0 mmol) and methyl iodide (710 mg, 5.0 mmol).
The resulting mixture was stirred at reflux overnight, cooled to room
temperature and concentrated in vacuo to give an oil. The residue oil
was diluted with CH2Cl2 (20 mL) and water (20 mL). The organic
layer was separated, and the aqueous layer (pH ∼ 10) was extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with brine, dried over MgSO4 and concentrated in vacuo, giving a
residue that subjected to silica gel column chromatography (MeOH/
CH2Cl2 = 1/40), which afforded 277 mg (81%) of 1i as a white solid:
mp 103−105 °C; [α]D23.0 −36.6 (c 1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.00−1.25 (m, 4H), 1.44−1.54 (m, 1H), 1.68−1.80 (m,
2H), 1.89−1.99 (m, 1H), 2.21 (s, 6H), 2.23−2.31 (m, 1H), 3.07−3.19
(m, 1H), 4.73 (d, J = 6.8 Hz, 1H), 7.38−7.50 (m, 6H), 7.75−7.95 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 20.7, 24.5, 25.3, 34.2, 39.9, 52.3
(d, J = 1.9 Hz), 68.0 (d, J = 8.4 Hz), 128.2 (d, J = 12.5 Hz), 128.4 (d, J
= 12.5 Hz), 131.3 (d, J = 3.3 Hz), 131.4, 131.5, 132.1 (d, J = 9.5 Hz),
134.4 (d, J = 123.2 Hz), 134.8 (d, J = 130.4 Hz); 31P NMR (162 MHz,
CDCl3) δ 22.3. Elemental Analysis, Anal. Calcd. for C20H27N2OP: C
70.15, H 7.95, N 8.18 Found: C 70.08, H 7.86, N 8.14.
(1R,2R)-1-N-(Diphenylphosphoroso)-2-N-(2-methylpropyl)-
cyclohexane-1,2-diamine (1e, Entry 5 in Table 2). The title
compound was prepared following the general procedure described
for 1d on the same scale and was obtained as a white solid with the
yield of 289 mg (78%): mp 116−117 °C; [α]2D3.0 −19.7 (c 1.00,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 6.6 Hz, 3H),
0.91 (d, J = 6.6 Hz, 3H), 0.94−1.04 (m, 1H), 1.08−1.30 (m, 4H),
1.52−1.59 (m, 3H), 2.00−2.10 (m, 2H), 2.19−2.27(m, 2H), 2.52−
2.60 (m, 1H), 2.80−2.93 (m, 1H), 3.78−3.96 (m, 1H), 7.36−7.50 (m,
6H), 7.80- 7.95 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 20.7 (d, J =
4.0 Hz), 24.8 (d, J = 6.2 Hz), 28.7, 31.2, 34.6, 34.7, 54.8, 55.6 (d, J =
1.9 Hz), 63.0 (d, J = 6.6 Hz), 128.2 (d, J = 10.7 Hz), 128.4 (d, J = 10.5
Hz), 131.5 (d, J = 2.5 Hz), 131.6, 131.7, 132.0 (d, J = 9.5 Hz), 133.5
(d, J = 126.9 Hz), 133.6 (d, J = 130.0 Hz); 31P NMR (162 MHz,
CDCl3) δ 22.6. Elemental Analysis, Anal. Calcd. for C22H31N2OP: C
71.32, H 8.43, N 7.56 Found: C 71.14, H 8.30, N 7.38.
(1R,2R)-1-N-(Diphenylphosphoroso)-2-N-pentylcyclohexane-1,2-
diamine (1f, Entry 6 in Table 2). The title compound was prepared
following the general procedure described for 1d on the same scale
and was obtained as a white solid with the yield of 315 mg (82%): mp
(1R,2R)-2-N-(Diphenylphosphoroso)-1-N,1-N-diethylcyclohex-
ane-1,2-diamine (1j, Entry 10 in Table 2). The title compound was
prepared following the general procedure described for 1i on the same
scale and was obtained as a white solid with the yield of 293 mg
1
1
146−147 °C; [α]2D0.9 −33.3 (c 1.00, CH2Cl2); H NMR (400 MHz,
(79%): mp 112−113 °C; [α]2D3.0 −62.5 (c 1.00, CH2Cl2); H NMR
CDCl3) δ 0.88 (t, J = 6.4 Hz; 3H), 1.01−1.20 (m, 3H), 1.21−1.41 (m,
(400 MHz, CDCl3) δ 1.00 (t, J = 7.0 Hz, 6H), 1.06−1.26 (m, 4H),
10432
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The Journal of Organic Chemistry
Note
1.45−1.53 (m, 1H), 1.68−1.81 (m, 2H), 1.92−2.03 (m, 1H), 2.26−
2.44 (m, 3H), 2.53−2.68 (m, 2H), 3.11−3.22 (m, 1H), 4.97 (d, J = 7.6
Hz, 1H), 7.35−7.52 (m, 6H), 7.72−7.83 (m, 2H), 7.86−7.98 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 14.8, 23.2, 24.5, 25.8, 34.0, 42.9, 52.0,
64.6 (d, J = 8.9 Hz), 128.1 (d, J = 12.6 Hz), 128.3 (d, J = 12.2 Hz),
131.1, 131.2, 132.0 (d, J = 9.4 Hz), 134.5 (d, J = 123.0 Hz), 135.0 (d, J
= 130.5 Hz); 31P NMR (162 MHz, CDCl3) δ 21.6. Elemental Analysis,
Anal. Calcd. for C22H31N2OP: C 71.32, H 8.43, N 7.56 Found: C
71.54, H 8.28, N 7.49.
(1R,2R)-2-N-(Diphenylphosphoroso)-1-N,1-N- dibutylcyclohex-
ane-1,2-diamine (1k, Entry 11 in Table 2). The title compound
was prepared following the general procedure described for 1i on the
same scale and was obtained as a white solid with the yield of 332 mg
(78%): mp 82−83 °C; [α]2D3.0 −81.2 (c 0.50, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 0.82 (t, J = 7.2 Hz, 6H), 1.06−1.38 (m, 12H), 1.46−
1.49 (m, 1H), 1.68−1.77 (m, 2H), 1.95−1.98 (m, 1H), 2.27−2.34 (m,
3H), 2.41−2.48 (m, 2H), 3.12−3.23 (m, 1H), 4.94 (d, J = 8.0 Hz,
1H), 7.37−7.45 (m, 6H), 7.76−7.81 (m, 2H), 7.88−7.93 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 13.9, 20.5, 22.7, 24.3, 25.6, 29.5, 31.2,
33.6, 52.0, 65.0 (d, J = 8.9 Hz), 128.1 (d, J = 12.7 Hz), 128.2 (d, J =
12.5 Hz), 131.0, 131.1, 131.7 (d, J = 9.5 Hz), 134.2 (d, J = 123.0 Hz),
134.9 (d, J = 131.0 Hz); 31P NMR (162 MHz, CDCl3) δ 21.5.
Elemental Analysis, Anal. Calcd. for C26H39N2OP: C 73.21, H 9.22, N
6.57 Found: C 73.34, H 9.18, N 6.50.
with brine (10 mL), dried over MgSO4 and concentrated in vacuo to
give a residue that was subjected to silica gel column chromatography
(EtOAc/hexane = 1/10), which afforded 135 mg (99%, 96% ee) of
(R)-1-phenylpropan-1-ol as a colorless oil: [α]2D0.9 +20.3 (c 1.00,
CHCl3) (Lit.44 [α]D26.0 +40.3 (c 1.21, CHCl3) for 96% ee (R); 1H NMR
(400 MHz, CDCl3) δ 0.90 (t, 3H), 1.71−1.92 (m, 2H), 1.96 (br, 1H),
4.51−4.72 (m, 1H), 7.25−7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 10.1, 31.8, 75.9, 125.9, 127.4, 128.4, 144.6. The ee value was
determined by Chiral GC Chirasil Dex CB [Inlet temperature: 130 °C,
tR = 6.9 min (major, R), tR = 7.2 min (minor, S)].
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed information of the Sterimol analysis, copies of 1H and
13C NMR spectra of products, and GC data of chiral 1-
phenylpropan-1-ol are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: +86-591-83722697. Tel: + 86-591-83720913. E-mail:
songling@fjirsm.ac.cn.
■
1-[(1R,2R)-2-[(Diphenylphosphoroso)amino]cyclohexyl]-
pyrrolidine (1l, Entry 12 in Table 2). The title compound was
prepared following the general procedure described for 1i on the same
scale and was obtained as a white solid with the yield of 262 mg
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(71%): mp 99−101 °C; [α]2D3.0 −31.8 (c 1.00, CH2Cl2); H NMR
1
■
The authors would like to thank State Key Lab of Structural
Chemistry, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences; the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry; and Natural Science Foundation of Fujian
Province, China (Grant No. 2010J01055).
(400 MHz, CDCl3) δ 0.91−1.41 (m, 5H), 1.44−1.60 (m, 1H), 1.63−
1.88 (m, 6H), 1.92−2.06 (m, 1H), 2.44−2.84 (m, 4H), 3.11−3.29 (m,
1H), 4.62−4.98 (br, 1H), 7.36−7.62 (m, 6H), 7.72−8.02 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 21.8, 23.6, 24.1, 24.8, 33.8, 47.1, 53.0,
63.3 (d, J = 8.1 Hz), 128.1 (d, J = 12.7 Hz), 128.3 (d, J = 12.4 Hz),
131.2 (d, J = 9.7 Hz), 131.3 (d, J = 5.7 Hz), 131.4 (d, J = 11.1 Hz),
132.1(d, J = 9.4 Hz), 134.2 (d, J = 124.2 Hz), 134.4 (d, J = 130.2 Hz);
31P NMR (162 MHz, CDCl3) δ 22.7. Elemental Analysis, Anal. Calcd.
REFERENCES
■
for C22H29N2OP: C 71.71, H 7.93, N 7.60 Found: C 71.81, H 7.73, N
7.93.
(1) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: Sausalito, CA, 2009.
(2) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Comprehensive
Asymmetric Catalysis I-III; Springer Verlag: New York, 1999; Vols. 1−
3.
1-[(1R,2R)-2-[(Diphenylphosphoroso)amino]cyclohexyl]-
piperidine (1m, Entry 13 in Table 2). The title compound was
prepared following the general procedure described for 1i on the same
scale and was obtained as a white solid with the yield of 294 mg
(77%): mp 117−118 °C; [α]2D2.0 −36.8 (c 1.00, CH2Cl2); H NMR
1
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley-
Interscience: New York, 1994.
(400 MHz, CDCl3) δ 1.03−1.25 (m, 4H), 1.37−1.63 (m, 7H), 1.70−
1.76 (m, 1H), 1.80−1.87 (m, 1H), 1.96−2.05 (m, 1H), 2.19−2.39 (m,
3H), 2.60−2.75 (m, 2H), 3.14−3.28 (m, 1H), 4.96−5.04 (d, J = 7.6
Hz, 1H), 7.34−7.59 (m, 6H), 7.72−7.86 (m, 2H), 7.88−8.00 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 22.7, 24.4, 24.8, 25.6, 26.9, 34.2, 51.6,
(4) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106−112.
(5) Oslob, J. D.; Akermark, B.; Helquist, P.; Norrby, P. O.
Organometallics 1997, 16, 3015−3021.
(6) Lipkowitz, K. B.; D’Hue, C. A.; Sakamoto, T.; Stack, J. N. J. Am.
Chem. Soc. 2002, 124, 14255−14267.
(7) Lipkowitz, K. B.; Kozlowski, M. C. Synlett 2003, 1547−1565.
(8) Kozlowski, M. C.; Panda, M. J. Org. Chem. 2003, 68, 2061−2076.
(9) Alvarez, S.; Schefzick, S.; Lipkowitz, K.; Avnir, D. Chem.Eur. J.
2003, 9, 5832−5837.
(10) Kozlowski, M. C.; Dixon, S. L.; Panda, M.; Lauri, G. J. Am.
Chem. Soc. 2003, 125, 6614−6615.
69.3, 69.4, 128.2 (d, J = 12.6 Hz), 128.3 (d, J = 12.5 Hz), 131.1, 131.2,
131.3 (d, J = 9.0 Hz), 132.1 (d, J = 9.4 Hz), 134.5 (d, J = 122.6 Hz),
134.7 (d, J = 144.7 Hz); 31P NMR (162 MHz, CDCl3) δ 22.1.
Elemental Analysis, Anal. Calcd. for C23H31N2OP: C 72.23, H 8.17, N
7.32 Found: C 72.40, H 8.15, N 7.31.
General Procedure for the Enantioselective Addition of
Diethylzinc to Benzaldehyde. To a solution of the chiral ligand 1h
(11) Lipkowitz, K. B.; Kozlowski, M. C. Synlett 2003, 1547−1565.
(12) Ianni, J. C.; Annamalai, V.; Phuan, P. W.; Panda, M.; Kozlowski,
M. C. Angew. Chem., Int. Ed. 2006, 45, 5502−5505.
(13) Chen, J.; Wen, J. W.; Li, M. Z.; Tianpa, Y. P. J. Mol. Catal. A:
Chem. 2006, 258, 191−197.
(14) Urbano-Cuadrado, M.; Carbo, J. J.; Maldonado, A. G.; Bo, C. J.
Chem. Inf. Model. 2007, 47, 2228−2234.
(15) Houk, K. N.; Cheong, P. H. Y. Nature 2008, 455, 309−313.
(16) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131,
15358−15374.
(37 mg, 0.10 mmol) in toluene (0.5 mL), diethylzinc (2.0 mL of 1.5 M
solution in toluene, 3.0 mmol) was slowly added at 0 °C under
nitrogen atmosphere and stirred for 30 min, and then benzaldehyde
(106 mg, 1.0 mmol) in toluene (0.5 mL) was added dropwise. The
mixture was stirred for 12 h at room temperature, cooled in ice bath
and quenched with aqueous HCl (10%, 10 mL). Extraction with
EtOAc (10 mL × 3) gave combined organic layers, which were washed
(17) Donoghue, P. J.; Helquist, P.; Norrby, P. O.; Wiest, O. J. Am.
Chem. Soc. 2009, 131, 410−411.
(18) Maldonado, A. G.; Rothenberg, G. Chem. Soc. Rev. 2010, 39,
1891−1902.
10433
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The Journal of Organic Chemistry
Note
(19) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011,
76, 4260−4336.
(20) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011,
76, 4337−4357.
(21) Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 771−
774.
(22) Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7633−7643.
(23) Harper, K. C.; Sigman, M. S. Proc. Natl. Acad. Sci. U. S. A. 2011,
108, 2179−2183.
(24) Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875−1878.
(25) Gustafson, J. L.; Sigman, M. S.; Miller, S. J. Org. Lett. 2010, 12,
2794−2797.
(26) Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4,
366−374.
(27) Quintard, A.; Alexakis, A. Org. Biomol. Chem. 2011, 9, 1407−
1418.
(28) Mantilli, L.; Gerard, D.; Torche, S.; Besnard, C.; Mazet, C.
Chem.Eur. J. 2010, 16, 12736−12745.
(29) Quintard, A.; Alexakis, A.; Mazet, C. Angew. Chem., Int. Ed.
2011, 50, 2354−2358.
(30) Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562−
5578.
(31) Eliel, E. L., Wilen, S. H., Mander, L. N., Ed.; Stereochemistry of
Organic Compounds; Wiley: New York, 1994.
(32) Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102,
5618−5626.
(33) Charton, M. J. Am. Chem. Soc. 1975, 97, 1552−1556.
(34) Charton, M. J. Org. Chem. 1976, 41, 2217−2220.
(35) Taft, R. W. J. Am. Chem. Soc. 1952, 74, 2729−2732.
(36) Taft, R. W. J. Am. Chem. Soc. 1953, 75, 4538−4539.
(37) Charton, M. J. Org. Chem. 1977, 42, 3535−3538.
(38) Verloop, A.; Tipker, J. In QSAR in Drug Design and Toxicology;
Hadzi, D., Borka, J. B., Eds.; Elsevier: Amsterdam, 1987.
(39) Hansch, C.; Leo, A. Exploring QSAR: Fundamentals and
Applications in Chemistry and Biology; American Chemical Society:
Washington, D.C., 1995.
(40) Hansch, C.; Leo, A., Hoekma, D. Exploring QSAR: Hydrophobic,
Electronic, and Steric Constants; American Chemical Society:
Washington, D.C., 1995.
(41) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 5th ed.; Butterworth Heinemann: Oxford, 2003.
(42) Kaik, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14,
1559−1563.
(43) Tan, K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46,
1315−1317.
(44) Zhong, J. C.; Guo, H. C.; Wang, M. A.; Yin, M. M.; Wang, M.
Tetrahedron: Asymmetry 2007, 18, 734−741.
10434
dx.doi.org/10.1021/jo3016715 | J. Org. Chem. 2012, 77, 10427−10434