The effects of solvent on switchable stereoselectivity: Copper-catalyzed asymmetric conjugate additions using D2-symmetric biphenyl phosphoramidite ligands

Article abstract of DOI:10.1039/c2ob25730k

A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones was developed with phosphoramidite ligands bearing a D₂-symmetric biphenyl backbone. This type of reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield; R: 99% ee, 96% yield).

Full text of DOI:10.1039/c2ob25730k

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PAPER
The effects of solvent on switchable stereoselectivity: copper-catalyzed
asymmetric conjugate additions using D2-symmetric biphenyl
phosphoramidite ligands†
Han Yu, Fang Xie, Zhenni Ma, Yangang Liu and Wanbin Zhang*
Received 14th April 2012, Accepted 6th May 2012
DOI: 10.1039/c2ob25730k
A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones
was developed with phosphoramidite ligands bearing a D2-symmetric biphenyl backbone. This type of
reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of
the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield;
R: 99% ee, 96% yield).
Introduction
Catalytic asymmetric syntheses of both enantiomers of a chiral
compound are of significant interest to the chemical community.1
Commonly, in a catalytic asymmetric protocol, both isomers of a
chiral ligand are required to access each enantiomer of chiral
compounds. Alternatives include using different central metals
in the presence of an identical ligand2 or changing reaction para-
meters (temperature, additives, and solvents etc.).3,4
Fig. 1 Phosphoramidite ligands with
a D2-symmetric biphenyl
A number of effective chiral ligand systems have been devel-
oped for Cu-catalyzed enantioselective addition reactions of
diethylzinc to structurally diverse enones.5–8 Among the success-
ful chiral ligands, BINOL-,5 TADDOL-,6 and BIPOL-derived
phosphoramidites7 have shown remarkable enantioselectivities
in the reactions of diethylzinc to enones. Very recently, our
group reported new types of biphenyl phosphoramidite ligands
L1–5 (Fig. 1) containing a D2-symmetric backbone. These
ligands demonstrated excellent activity and selectivity in Cu-
catalyzed asymmetric 1,4-addition reactions of diethylzinc to
α,β-unsaturated ketones and nitroalkenes. Their excellent chiral
environment and their ability to be easily modified at the
3,3′,5,5′-position of the biphenyl backbone, makes them excel-
lent ligands.9 Interestingly, we found that the substituents at the
3,3′,5,5′-position of the biphenyl backbone of the ligands have a
dramatic effect on the stereocontrol in Cu-catalyzed asymmetric
1,4-addition reactions.9c,d
backbone.
valuable compounds for use as intermediates or building blocks
in organic chemistry.10 To explore the behaviour of the phosphor-
amidite ligands with a D2-symmetric biphenyl backbone, the
ligands were used in asymmetric conjugate additions of deithyl-
zinc to α,β-unsaturated acyclic aromatic enones. Both enantio-
meric products were obtained by changing reaction parameters, a
method of which has not been significantly reported.3
Results and discussion
Trans-L2 provided excellent enantioselectivities for the asym-
metric conjugate addition of diethylzinc to α,β-unsaturated car-
bonyl substrates and nitroalkenes.9a–c The conjugate addition of
diethylzinc to chalcone 1a was performed in the presence of
2 mol% of trans-L2 and 1 mol% of copper salt in toluene, at a
temperature of −40 °C (Table 1). Cu(OAc)2·H2O was found to
be the most suitable catalyst precursor because of its high reac-
tivity and enantioselectivity (entries 1–10). With Cu(OAc)2·H2O
as the catalyst precursor and trans-L2 as the ligand, we investi-
gated the solvent effect (entries 10–16) and discovered that
toluene provided the most promising results. When Et2O, methyl
t-butyl ether (MTBE) or diisopropyl ether (DIPE) were used as
In addition, Cu-catalyzed asymmetric additions to acyclic aro-
matic α,β-unsaturated enones such as chalcone, can provide
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
E-mail: wanbin@sjtu.edu.cn; Fax: +86-21-5474-3265;
Tel: +86-21-5474-3265
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25730k
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Table 1 Screening of reaction conditionsa
Table 2 Screening of ligandsa
Solvent T (°C) Yieldb (%) eec (%)
Entry
L
Solvent
Yieldb (%)
eec (%)
Entry Cu salt
1
2
3
4
5
6
7
8
cis-L1
cis-L1
trans-L1
trans-L1
cis-L2
cis-L2
trans-L2
trans-L2
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
92
91
93
94
96
93
96
92
77 (R)
52 (R)
79 (R)
57 (R)
93 (R)
86 (S)
99 (R)
92 (S)
1
2
3
4
5
6
7
8
Cu(I)(MeCN)4PF6 Toluene −40
96
95
98
95
93
90
91
99
94
96
95
99
97
97
93
96
97
95
93
93
98
96
92
68 (R)
78 (R)
65 (R)
53 (R)
79 (R)
76 (R)
73 (R)
67 (R)
66 (R)
92 (R)
73 (R)
39 (R)
42 (R)
43 (R)
70 (R)
81 (S)
75 (S)
92 (S)
91 (S)
82 (S)
81 (R)
99 (R)
83 (R)
Cu(II)(OTf)2
Cu(II)(acac)2
Cu(II)Br2
Toluene −40
Toluene −40
Toluene −40
Toluene −40
Cu(II)ClO4·6H2O
Cu(I)(MeCN)4BF4 Toluene −40
Cu(I)(MeCN)4PF6 Toluene −40
Cu(I)TC
Toluene −40
Toluene −40
Toluene −40
9
Cu(I)(C6H6)OTf
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
Cu(II)(OAc)2·H2O
a 1 mol% Cu salt, 2 mol% L, 1.5 eq. ZnEt2. b Yield of the isolated
product. c Determined by HPLC, Chiralcel AD-H column. The absolute
configuration was determined by comparison with literature data.
10
11
12
13
14
15
16
17
18
19
20d
21e
22
23d
PhCF3
Et2O
MTBE
DIPE
DCM
THF
−40
−40
−40
−40
−40
−40
−30
−50
−60
−78
lacking substituents at the 3,3′,5,5′-position, gave R configuration
products (entries 1–4). Substituents at the 3,3′,5,5′-position of
the biphenyl backbone of the ligands showed significant
influence on catalysis. No matter whether the 3,3′,5,5′-position
contained substituents or not, both cis- and trans-L provided
R configuration product when using toluene as the solvent.
Trans-L gave higher enantioselectivity compared to its cis-L
counterpart (entries 1, 3, 5 and 7), and up to 99% ee was
obtained with methyl-substituted trans-L2 (entries 1, 3, 5 and 7).
When THF was used as the reaction solvent, ligands cis-L2 and
trans-L2, containing substituents on the biphenyl backbone, all
provided S configuration product (entries 6 and 8). Up to 92% ee
was obtained with methyl-substituted trans-L2 (entry 8). Trans-
L3–5 were also examined, however no improvement was
observed with these ligands (ESI†).
THF
THF
THF
THF
Toluene −30
Toluene −50
Toluene −78
a 1 mol% Cu salt, 2 mol% trans-L2, 1.5 eq. ZnEt2. b Yield of the
isolated product. c Determined by HPLC, Chiralcel AD-H column. The
absolute configuration was determined by comparison with literature
data. d The reaction was stirred for 20 h. e The reaction was stirred for
12 h.
the reaction solvent, excellent reactivity but low enantioselecti-
vities for the conjugate addition reactions were obtained
(Table 1, entries 12–14). To our surprise, when THF was
employed as the reaction solvent, the other enantiomer was
obtained in excellent yield and enantioselectivity (entry 16),
most probably due to THF’s strong coordinating ability. These
results indicated that the ether solvent possessed appropriate
coordinating ability to be involved in the catalytic cycle, acting
as a hemilabile ligand and altering the structure of the catalyst.
Since both enantiomers could be obtained by using toluene
and THF as solvents, different temperatures were screened to
optimize the reaction conditions. Reducing the reaction tempera-
ture from −30 °C to −50 °C provided excellent yields and
increased enantioselectivity (entries 18 and 22). The highest
enantioselectivity was observed at −50 °C in both toluene and
THF. Furthermore, decreasing the temperature to −78 °C resulted
in a slight decrease in yield, and an obvious drop in enantio-
selectivity in toluene or THF at this temperature (entries 20
and 23).
With toluene and THF used as a reversal solvent pair, we
expected to induce the formation of both absolute configurations
in the products. A wide range of aromatic enones were examined
to investigate substrate scope and the reversal in stereoselectivity
(Table 3).
To our delight, a complete switch in stereoselectivity was
observed for all of the substrates. The introduction of a methyl
group at the ortho-, meta- and para-position on the phenyl ring
R1 or R2 of substrate 1, led to a drop in enantioselectivity when
using both solvents, which may be a result of steric hindrance
(entries 1–4 and 8–10). When a methoxy group was introduced
at the para-position of the phenyl ring R1 or R2, decreased
enantioselectivity was observed with the exception of substrate
1e, whose enantioselectivity was similar to that of substrate 1a
(entries 1, 5 and 11). Addition of an electron-withdrawing substi-
tuent (such as para-bromo group) to the phenyl ring R1 or
addition of a para-chloro group to the phenyl ring R2, was detri-
mental to enantioselectivity when compared to substrates lacking
substituted groups on the phenyl ring (entries 1, 6 and 12).
Neither the electron-donating nor the electron-withdrawing
groups at the para-position of the phenyl ring of R1 or R2
improved the enantioselectivity of this reaction. Furthermore,
replacement of R1 or R2 with 2-naphthyl groups resulted in a
decrease in enantioselectivity when the reaction was performed
Encouraged by the results described above, reactions invol-
ving several phosphoramidite ligands containing a D2-symmetric
biphenyl backbone were investigated to identify the most
efficient ligand for use in toluene and THF (Table 2).
Ligand screening revealed that the phosphoramidite ligands
L1–2 in Fig. 1 were effective for this transformation (91–96%
yield, R-2a: 52–99% ee, S-2a: 86–92%). Both cis- and trans-L1
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Table 3 Substrate scopea
Entry
1
Substrate
1a
R1
R2
Solvent
Yieldb (%)
eec (%)
Ph
Ph
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
THF
94
96
91
92
92
94
93
95
93
96
95
96
90
92
90
91
92
93
91
95
93
97
92
93
93
94
93
90
92 (S)
99 (R)
80 (S)
71 (R)
78 (S)
85 (R)
86 (S)
86 (R)
92 (S)
90 (R)
86 (S)
96 (R)
87 (S)
91 (R)
60 (S)
79 (R)
90 (S)
75 (R)
83 (S)
91 (R)
65 (S)
92 (R)
81 (S)
92 (R)
87 (S)
92 (R)
86 (S)
97 (R)
2
1b
1c
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-BrC6H4
2-naphthyl
Ph
Ph
3
Ph
4
1d
1e
Ph
5
Ph
6
1f
Ph
7
1g
Ph
8
1h
1i
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-ClC6H4
2-Naphthyl
Me
9
Ph
10
11
12
13
14d
1j
Ph
1k
1l
Ph
Ph
1m
1n
Ph
Ph
Toluene
a 1 mol% Cu salt, 2 mol% trans-L2, 1.5 eq. ZnEt2. b Yield of the isolated product. c Determined by HPLC, Chiralcel AD-H column. The absolute
configuration was determined by comparison with literature data. d The ee value (toluene as solvent) is cited from our previous report for
comparison.9a
in THF or toluene (entries 1, 7 and 13). The above results
suggested that the effect of steric hindrance and the electron-
donating/withdrawing properties of the para-position substituent
on the phenyl ring R1 or R2, decreased enantioselectivity.
We also performed the reaction using a typical acyclic enone,
benzalacetone (1n). Using toluene and THF as a solvent pair,
products were obtained with high enantioselectivities and
reversed absolute configurations (entry 14).
In order to explain the reversal phenomenon, a stereochemical
pathway has been proposed according to our experimental
results (Fig. 2). As a copper ion coordinates to one phosphorus
on the ligand,11 the other phosphorus remains relatively far away
from the reaction center. Both the cis and trans configurations of
the ligands therefore have little effect on the absolute configur-
Fig. 2 Proposed stereochemical pathway showing the facial coordi-
nation of the copper atom with the enone substrate.
ation of the products. The steric repulsion between the substitu-
ents at the 3,3′- or 5,5′-position of the biphenyl backbone with
the aryl groups of the substrate or THF, may determine the
stereochemical outcome of the 1,4-addition. For the transition
states involving THF as a solvent in this reaction, the oxygen
atom of THF coordinates with the zinc ion. Steric repulsion
between the substituent at the 3,3′,5,5′-position of the biphenyl
backbone of ligand L2 and THF in L2-THF-TS2, is larger than
that in L2-THF-TS1 between the substituent at the 3,3′,5,5′-
position of the biphenyl backbone of ligand L2 and the aryl
group of the substrate. This leads to the 1,4-adduct with a S
isomer configuration. However, when toluene is used as a
solvent, there are no coordination effects. The steric repulsion
between the aryl group of ligand L2 and the aryl group of the
substrate in transition state L2-TS2, is smaller than that between
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the substituent at the 3,3′,5,5′-position of the biphenyl backbone,
and the aryl group of the substrate in L2-TS1. This leads to the
1,4-adduct with the R isomer configuration.
7.55–7.50 (m, 1H), 7.45–7.40 (m, 2H), 7.31–7.15 (m, 5H),
3.31–3.22 (m, 3H), 1.85–1.74 (m, 1H), 1.70–1.57 (m, 1H), 0.80
(t, J = 7.4 Hz, 3H). HPLC conditions: Chiralcel AD-H column,
i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1, UV detection at
254 nm, ts = 13.1 min, tR = 15.1 min.
Conclusions
In summary, we have developed a highly enantioselective
copper-catalyzed conjugate addition of diethylzinc to acyclic
aromatic enones with phosphoramidite ligands bearing a D2-
symmetric biphenyl backbone. These types of reactions demon-
strated that toluene and THF solvents can be used to completely
reverse the absolute configuration of the products, thus simplify-
ing the process of accessing either enantiomer (S: 92% ee, 94%
yield; R: 99% ee, 96% yield).
1-Phenyl-3-o-tolylpentan-1-one (2b)
A white solid, mp: 56–57 °C; using THF as solvent: S-2b,
80% ee, 91% yield; using toluene as solvent: R-2b, 71% ee,
1
92% yield; H NMR (400 MHz, CDCl3) δ 7.92–7.88 (m, 2H),
7.55–7.50 (m, 1H), 7.45–7.40 (m, 2H), 7.22–7.05 (m, 4H),
3.66–3.55 (m, 1H), 3.30–3.20 (m, 2H), 2.38 (s, 3H), 1.85–1.57
(m, 2H), 0.80 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 198.2, 163.5, 145.0, 130.6, 128.5, 127.8, 126.4, 113.8,
55.7, 45.5, 43.4, 29.5, 12.3. HRMS calcd for C17H19O [M +
Na]+ 253.1592, found 253.1599. ESI-MS: 253. HPLC con-
ditions: Chiralcel OJ-H column, i-PrOH–hexane 2 : 98, flow
rate: 1.0 mL min−1, UV detection at 254 nm, ts = 14.4 min, tR =
16.8 min.
Experimental section
General details
Commercially available reagents were used without further
purification other than those described below. Substrates 1 were
prepared according to modified methods of reported pro-
cedures.10 All air- and moisture-sensitive manipulations were
carried out with standard Schlenk techniques under nitrogen.
Toluene, PhCF3, DMF, THF, Et2O, DIPE, MTBE, and dichloro-
methane were dried according to published procedures. Column
chromatography was run on silica gel (100–200 mesh). 1H NMR
(400 MHz) spectra and 13C NMR (100 MHz) spectra were
obtained on a Varian MERCURY plus-400 spectrometer. HRMS
was performed on a Micromass LCT TM at the Instrumental
Analysis Center of Shanghai Jiao Tong University.
1-Phenyl-3-m-tolylpentan-1-one (2c)10
A white solid, mp: 57–58 °C; using THF as solvent: S-2c, 78%
ee, 92% yield; using toluene as solvent: R-2c, 85% ee, 94%
yield; 1H NMR (400 MHz, CDCl3) δ 7.93–7.90 (m, 2H),
7.56–7.50 (m, 1H), 7.46–7.40 (m, 2H), 7.21–6.80 (m, 4H),
3.31–3.15 (m, 3H), 2.34 (s, 3H), 1.84–1.60 (m, 2H), 0.80 (t, J =
7.4 Hz, 3H). HPLC conditions: Chiralcel AD-H column,
i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1, UV detection at
254 nm, ts = 16.6 min, tR = 18.2 min.
1-Phenyl-3-p-tolylpentan-1-one (2d)10
General procedures for conjugate addition
A white solid, mp: 59–60 °C; using THF as solvent: S-2d, 86%
ee, 93% yield; using toluene as solvent: R-2d, 86% ee, 95%
yield; 1H NMR (400 MHz, CDCl3) δ 7.93–7.88 (m, 2H),
7.56–7.51 (m, 1H), 7.46–7.40 (m, 2H), 7.16–7.05 (m, 4H),
3.30–3.15 (m, 3H), 2.34 (s, 3H), 1.84–1.60 (m, 2H), 0.80 (t, J =
7.4 Hz, 3H). HPLC conditions: Chiralcel AD-H column,
i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1, UV detection at
254 nm, ts = 18.0 min, tR = 23.1 min.
A flame dried Schlenk tube was charged with Cu(OAc)2·H2O
1.0 mg (0.005 mmol) and two equivalents of ligand
(0.010 mmol) under nitrogen, and the mixture was dissolved in
dry toluene (1.5 mL), resulting in a colorless solution. The solu-
tion was stirred at 25 °C for 2 h and then cooled to −50 °C. The
substrate 1 (0.50 mmol dissolved in 1.0 mL dry toluene) was
then added dropwise over 3 min. The solution was stirred for
5 min at −50 °C and gradually turned to light yellow. Diethyl-
zinc (0.75 mmol, 0.75 mL of 1 M sol. in hexane) was added
dropwise over 3 min. The reaction mixture was stirred at −50 °C
for 16 h and monitored by TLC until full conversion of product
was observed. The reaction mixture was quenched with aqueous
saturated NH4Cl and extracted with ethyl acetate (5 mL × 2).
The organic extracts were combined, concentrated and the
residue was purified by silica gel column chromatography to
afford the product 2. Enantiomeric excess was determined by
chiral HPLC. Melting points of racemic product 2 was measured
with SGW X-4 micro melting point apparatus.
3-(4-Methoxyphenyl)-1-phenylpentan-1-one (2e)10
A white solid, mp: 62–63 °C; using THF as solvent: S-2e, 92%
ee, 93% yield; using toluene as solvent: R-2e, 90% ee, 96%
yield; 1H NMR (400 MHz, CDCl3) δ 7.90–7.86 (m, 2H),
7.57–7.51 (m, 1H), 7.46–7.39 (m, 2H), 7.15–7.11 (m, 2H),
6.85–6.80 (m, 2H), 3.77 (s, 3H), 3.30–3.17 (m, 3H), 1.83–1.58
(m, 2H), 0.80 (t, J = 7.4 Hz, 3H). HPLC conditions: Chiralcel
AD-H column, i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1
UV detection at 254 nm, ts = 39.6 min, tR = 65.3 min.
,
1,3-Diphenylpentan-1-one (2a)10
3-(4-Bromophenyl)-1-phenylpentan-1-one (2f)10
A white solid, mp: 55–56 °C; using THF as solvent: S-2a,
92% ee, 94% yield; using toluene as solvent: R-2a, 99% ee,
A white solid, mp: 65–66 °C; using THF as solvent: S-2f,
86% ee, 95% yield; using toluene as solvent: R-2f, 96% ee,
1
96% yield; H NMR (400 MHz, CDCl3) δ 7.92–7.87 (m, 2H),
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1-(4-Methoxyphenyl)-3-phenylpentan-1-one (2k)10
1
96% yield; H NMR (400 MHz, CDCl3) δ 7.93–7.88 (m, 2H),
7.55–7.50 (m, 1H), 7.45–7.39 (m, 4H), 7.13–7.08 (m, 2H),
3.26–3.18 (s, 3H), 1.82–1.70 (m, 1H), 1.66–1.54 (m, 1H), 0.79
(t, J = 7.2 Hz, 3H). HPLC conditions: Chiralcel AD-H column,
i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1, UV detection at
254 nm, ts = 25.3 min, tR = 35.3 min.
A white solid, mp: 60–62 °C; using THF as solvent: S-2k,
65% ee, 93% yield; using toluene as solvent: R-2k, 92% ee,
97% yield; H NMR (400 MHz, CDCl3) δ 7.90–7.87 (d, J = 12
Hz, 2H), 7.31–7.14 (m, 5H), 6.92–6.87 (m, 2H), 3.85 (s, 3H),
3.26–3.17 (m, 3H), 1.82–1.56 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H).
HPLC conditions: Chiralcel AD-H column, i-PrOH–hexane
2 : 98, flow rate: 1.0 mL min−1, UV detection at 254 nm, ts =
57.2 min, tR = 77.6 min.
1
3-(Naphthalen-2-yl)-1-phenylpentan-1-one (2g)10
A white solid, mp: 55–56 °C; using THF as solvent: S-2g,
87% ee, 90% yield; using toluene as solvent: R-2g, 91% ee,
92% yield; H NMR (400 MHz, CDCl3) δ 7.93–7.89 (m, 2H),
1-(4-Chlorophenyl)-3-phenylpentan-1-one (2l)10
1
A white solid, mp: 65–67 °C; using THF as solvent: S-2l,
81% ee, 92% yield; using toulene as solvent: R-2l, 92% ee,
93% yield; H NMR (400 MHz, CDCl3) δ 7.85–7.80 (m, 2H),
7.41–7.37 (m, 2H), 7.31–7.25 (m, 2H), 7.23–7.15 (m, 3H),
3.27–3.17 (m, 3H), 1.81–1.60 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H).
HPLC conditions: Chiralcel AD-H column, i-PrOH–hexane
2 : 98, flow rate: 1.0 mL min−1, UV detection at 254 nm, ts =
24.3 min, tR = 29.1 min.
7.80–7.76 (m, 3H), 7.66 (s, 1H) 7.56–7.50 (m, 1H), 7.47–7.38
(m, 5H), 3.45–3.10 (m, 3H), 1.95–1.64 (m, 2H), 0.80 (t, J = 7.4
Hz, 3H). HPLC conditions: Chiralcel AD-H column, i-PrOH–
hexane 2 : 98, flow rate: 1.0 mL min−1, UV detection at 254 nm,
ts = 28.1 min, tR = 38.9 min.
1
3-Phenyl-1-o-tolylpentan-1-one (2h)
A white solid, mp: 57–58 °C; using THF as solvent: S-2h,
60% ee, 90% yield; using toluene as solvent: R-2h, 79% ee,
91% yield; H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz,
1-(Naphthalen-2-yl)-3-phenylpentan-1-one (2m)10
1
A white solid, mp: 58–60 °C; using THF as solvent: S-2m,
87% ee, 93% yield; using toluene as solvent: R-2m, 92% ee,
1H), 7.35–7.14 (m, 8H), 3.21–3.12 (m, 3H), 2.27 (s, 3H),
1.82–1.56 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 204.2, 144.5, 138.8, 137.7, 131.9, 131.1,
128.6, 128.2, 127.9, 126.5, 125.7, 48.8, 43.6, 29.6, 20.9, 12.3.
HRMS calcd for C17H19O [M + Na]+ 253.1592, found
253.1586. ESI-MS: 253. HPLC conditions: Chiralcel AD-H
column, i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1, UV
detection at 254 nm, ts = 13.0 min, tR = 16.5 min.
1
94% yield; H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.00 (d,
J = 8.6, 1H), 7.95 (d, J = 8.0, 1H), 7.87 (d, J = 8.6, 2H), 7.60 (t,
J = 7.9, 1H), 7.55 (t, J = 7.4, 1H), 7.34–7.28 (m, 5H), 3.42 (t,
J = 6.9, 2H), 3.38–3.29 (m, 1H), 1.92–1.82 (m, 1H), 1.77–1.66
(m, 1H), 0.86 (t, J = 7.4, 3H). HPLC conditions: Chiralcel
AD-H column, i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1
UV detection at 254 nm, ts = 33.4 min, tR = 41.6 min.
,
4-Phenylhexan-2-one (2n)10
3-Phenyl-1-m-tolylpentan-1-one (2i)
Colorless oil; using THF as solvent: S-2n, 85% ee, 80% yield;
using toulene as solvent: R-2n, 98% ee, 82% yield; H NMR
A white solid, mp: 60–61 °C; using THF as solvent: S-2i,
90% ee, 92% yield; using toluene as solvent: R-2i, 75% ee,
93% yield; H NMR (400 MHz, CDCl3) δ 7.72–7.68 (m, 2H),
1
1
(400 MHz, CDCl3) δ 7.33–7. 15 (m, 5H), 3.05–3.00 (m, 1H),
2.72 (d, J = 7.2 Hz, 2H), 2.03 (s, 3H), 1.69–1.58 (m, 2H),
0.78 (t, J = 7.4 Hz, 3H). GC, Supelco γ-DEX-120 column
(30 m × 0.25 mm, ID): 115 °C; Retention time: ts = 29 min,
tR = 30 min.
7.36–7.15 (m, 7H), 3.30–3.20 (m, 3H), 2.38 (s, 3H), 1.84–1.56
(m, 2H), 0.80 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.7, 145.1, 138.4, 137.5, 133.8, 128.8, 128.3, 127.8, 126.4,
125.4, 45.6, 43.2, 29.3, 21.5, 12.3. HRMS calcd for C17H19O
[M + Na]+ 253.1592, found 253.1588. ESI-MS: 253. HPLC
conditions: Chiralcel AD-H column, i-PrOH–hexane 2 : 98,
flow rate: 1.0 mL min−1, UV detection at 254 nm, ts = 15.6 min,
tR = 18.4 min.
Acknowledgements
This work was supported by the National Nature Science Foun-
dation of China (No. 20872091 and 20972095), Science
and Technology Commission of Shanghai Municipality
(No. 10dz1910105), Nippon Chemical Industrial Co., Ltd and
Shanghai Jiao Tong University. We thank Professor T. Imamoto
and Dr M. Sugiya for helpful discussions and the Instrumental
Analysis Center of Shanghai Jiao Tong University.
3-Phenyl-1-p-tolylpentan-1-one (2j)10
A white solid, mp: 59–60 °C; using THF as solvent: S-2j,
83% ee, 91% yield; using toluene as solvent: R-2j, 91% ee, 95%
1
yield; H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H),
7.31–7.15 (m, 7H), 3.27–3.19 (m, 3H), 2.39 (s, 3H), 1.84–1.55
(m, 2H), 0.80 (t, J = 7.4 Hz, 3H). HPLC conditions: Chiralcel
Notes and references
AD-H column, i-PrOH–hexane 2 : 98, flow rate: 1.0 mL min−1
UV detection at 254 nm, ts = 26.6 min, tR = 35.2 min.
,
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5142 | Org. Biomol. Chem., 2012, 10, 5137–5142
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