Enantioselective Synthesis of Chiral Phosphonates via Rh/f-spiroPhos Catalyzed Asymmetric Hydrogenation of β,β-Disubstituted Unsaturated Phosphonates

Article abstract of DOI:10.1021/acs.joc.1c01397

The first asymmetric hydrogenation of β,β-diaryl unsaturated phosphonates has been realized for synthesis of β,β-diaryl chiral phosphonates with excellent enantioselectivities (up to 99.9% ee) catalyzed by the Rh-(R,R)-f-spiroPhos complex. Furthermore, this catalyst also exhibits comparably excellent performance for β-aryl-β-alkyl unsaturated phosphonates providing the corresponding chiral phosphonates with up to 99.9% ee values. This methodology provides a straightforward access to asymmetric synthesis of chiral phosphonates.

Full text of DOI:10.1021/acs.joc.1c01397

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Article
Enantioselective Synthesis of Chiral Phosphonates via Rh/f-
spiroPhos Catalyzed Asymmetric Hydrogenation of β,β-
Disubstituted Unsaturated Phosphonates
Chaoqiong Wang,# Fang Xie,# Qianling Guo, Chaochao Xie, Guofu Zi, Weiping Ye, Zhangtao Zhou,
Guohua Hou,* and Zhanbin Zhang*
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ABSTRACT: The first asymmetric hydrogenation of β,β-diaryl
unsaturated phosphonates has been realized for synthesis of β,β-
diaryl chiral phosphonates with excellent enantioselectivities (up to
99.9% ee) catalyzed by the Rh-(R,R)-f-spiroPhos complex.
Furthermore, this catalyst also exhibits comparably excellent
performance for β-aryl-β-alkyl unsaturated phosphonates providing
the corresponding chiral phosphonates with up to 99.9% ee values.
This methodology provides a straightforward access to asymmetric
synthesis of chiral phosphonates.
acyloxy-, β-aryl-β-alkyl, or β-dialkyl unsaturated phosphonates,
and α,β-unsaturated γ-ketophosphonates has been reported
with satisfactory enantioselectivities by Hu et al., Zheng et al.,
Andersson et al., and other groups.5−9 Surprisingly, there has
been no example on the asymmetric hydrogenation of β-diaryl
unsaturated phosphonates explored so far. It can be
presumably attributed to the bigger aromatic conjugated
system and the much bulkier steric hindrance of this class of
substrates, which perhaps makes them more stable and
prevents the effective coordination of many catalysts with the
substrates resulting in relatively lower activity or enantiose-
lectivity.10
INTRODUCTION
■
Chiral phosphonates are important in organic chemistry and
medicinal chemistry and widely exist in natural products,
pharmaceuticals, pesticides, and biologically active compounds.
For example, chiral phosphonates can be used as antibacterial
agents,1 enzyme inhibitors,2 and intermediates in biosynthetic
processes3 (Figure 1). More significantly, chiral ligands and
catalysts containing phosphorus, such as chiral phosphorus
acids, play a crucial role in the field of asymmetric catalysis.4
Recently, a chiral ferrocenyl diphosphine ligand containing
the privileged spirobiindane skeleton,11 f-spiroPhos, was
developed by our group. It exhibited high efficiency and
enantioselectivity in the transition metal catalyzed asymmetric
hydrogenation of various prochiral substrates including α,β-
unsaturated nitriles, sulfones, and imines. All these substrates
were able to be successfully hydrogenated to produce the
desired chiral products in high yields with excellent
enantioselectivities achieved.12 Encouraged by these promising
results, we herein wish to tackle the unexplored β,β-diaryl
unsaturated phosphonate substrates in asymmetric hydro-
genation and report the first asymmetric hydrogenation of β,β-
Figure 1. Selected examples of natural and biologically active
phosphonates.
As a result, the synthesis of chiral phosphonates has attracted
increased attention due to its importance in pharmaceutical
and chemical synthesis and the catalysis field. Asymmetric
catalytic hydrogenation of α,β-unsaturated phosphonates
provides a convenient and efficient approach to the synthesis
of chiral phosphonates. To date, transition metal or
biocatalytic asymmetric hydrogenation of various α,β-unsatu-
rated phosphonates including α- or β-acylamino-, α- or β-
Received: June 12, 2021
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© XXXX American Chemical Society
A

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diaryl unsaturated phosphonates to provide chiral diaryl
phosphonates with excellent enantioselectivities of up to
99.9% ee, which affords a highly enantioselective and
straightforward approach to synthesis of both chiral diaryl
and β-aryl-β-alkyl phosphonates (Scheme 1).
Table 1, a significant counterion effect was observed in this
hydrogenation. The counterion structure, perhaps bulkier
steric hindrance, had an obvious influence on the catalyst
efficiency, which revealed the different interaction of counter-
ions with the metal center.13,14 Subsequently, a variety of chiral
electron-rich diphosphine ligands including JosiPhos, Duan-
Phos, Ph-BPE, and f-Binaphane were applied to the hydro-
genation in order to reach higher activity and enantioselectivity
(Figure 2). Although most of them could give good to high
conversions, the relatively lower enantioselectivities were
achieved with 85% ee at most (Table 1, entries 5−9). Finally,
this transformation was also evaluated in other solvents. It was
revealed that the hydrogenation was sensitive to the solvent
effect. Most of the solvents, such as toluene, THF, Et2O,
CH3OH, and 1,4-dioxane, only provided very poor conversions
(Table 1, entries 10−14).
Scheme 1. Rh-Catalyzed Asymmetric Hydrogenation of α,β-
Unsaturated Phosphonates
Encouraged by the promising result obtained in the
hydrogenation of diethyl (E)-(2-phenyl-2-(m-tolyl)vinyl)-
phosphonate 1a, we then prepared a variety of β,β-diaryl
unsaturated phosphonates 1 and applied them to the
asymmetric hydrogenation under the optimal reaction
conditions (Table 2). It was found that all of the substrates
examined (1a−1l) could be successfully hydrogenated to
produce the corresponding chiral phosphonates in high yields
with excellent enantioselectivities, 90−99.9% ee. As the results
revealed in Table 2, the electronic properties of the substituent
at the meta- or para- position of the aromatic ring had no
obvious influence on the enantioselectivity and reactivity. For
example, regardless of the electron-donating substituents (Me,
1a−1b and 1e) or electron-withdrawing substituents (F or Cl,
1c and 1f−1g), the substrates could be smoothly hydrogenated
to provide the corresponding products with full conversions
and high enantioselectivities, 91−94% ee. Notably, the
substrates with a Cl (1j) or F group (1k) at the ortho-
position as well as the 1-naphthyl substrate 1l could achieve
extremely high enantioselecitivities, up to 99.9% ee, albeit with
slightly lower conversions. The steric hindrance at the ortho-
position presumably could make it easier to distinguish the
relatively increased difference between two aryl groups for the
catalyst, which had a positive influence on much higher
enantioselectivity but with a negative effect on the reactivity.
Remarkably, this catalyst could also exhibit comparable
enantioselectivity in the hydrogenation of the corresponding
(Z)-isomers to afford the products with an opposite absolute
configuration in contrast to that obtained from (E)-isomers.
The substrates (Z)-1d and (Z)-1h were hydrogenated
providing the desired products 2d and 2h with 90% and
97% ee, respectively.
The absolute configuration of the hydrogenation product 2h
was determined and assigned to be the (R) configuration by X-
ray crystallographic analysis (Scheme 2). The absolute
configuration of product 2g could also be assigned to be (S)
by comparison with optical rotation data of the product 2h. On
the basis of the result, the enantio-determining transition
model for Rh-catalyzed asymmetric hydrogenation of β,β-
diaryl α,β-unsaturated phosphonates was proposed.
In addition, the asymmetric hydrogenation of β-aryl-β-alkyl
α,β-unsaturated phosphonates was also investigated using this
catalyst system. The diethyl (E)-(2-phenylprop-1-en-1-yl)-
phosphonate 3a was initially hydrogenated under the optimal
reaction conditions using 1.0 mol % catalyst loading. Likewise,
both full conversion and excellent enantioselectivity (94% ee)
were achieved. It was noteworthy that the substrate 3a could
RESULTS AND DISCUSSION
■
The investigation initially began with the hydrogenation of
diethyl (E)-(2-phenyl-2-(m-tolyl)vinyl)phosphonate 1a as the
model substrate under 80 atm of H2 in CH2Cl2 at room
temperature for 24 h using the complex generated in situ of
[Rh(COD)Cl]2 and (R,R)-f-spiroPhos. To our disappoint-
ment, only trace product was afforded (Table 1, entry 1).
Table 1. Asymmetric Hydrogenation of Diethyl (E)-(2-
Phenyl-2-(m-tolyl)vinyl)phosphonate 1a, Optimizing
a
Reaction Conditions
b
c
entry
precursor
L
solvent
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
[Rh(COD)Cl]2
[Rh(COD)2]BF4
[Rh(COD)2]OTf
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
[Rh(COD)2]PF6
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
trace
59
18
>99
>99
98
63
83
>99
18
13
ND
94
89
94
14
7
66
85
56
69
9
10
11
12
13
14
86
Et2O
CH3OH
1,4-dioxane
trace
5
4
ND
ND
ND
a
Unless otherwise mentioned, all reactions were carried out for 24 h
with a Rh/ligand/substrate 1a ratio of 1:1.1:100 under 80 atm of H2.
b
c
Determined by GC analysis. Determined by chiral supercritical fluid
chromatography (SFC).
However, when the metal precursor was replaced with cationic
[Rh(COD)2]BF4, the desired product 2a was afforded with
pretty high enantioselectivity (94% ee) albeit in a moderate
conversion (Table 1, entry 2). Inspired by the result, other
rhodium precursors with various counterions were evaluated.
Gratifyingly, the precursor [Rh(COD)2]PF6 could achieve not
only comparably high enantioselectivity (95% ee) but
complete conversion (Table 1, entry 4). As illustrated in
B
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Figure 2. Structures of the phosphine ligands screened for hydrogenation of 1a.
a
Table 2. Rh-Catalyzed Asymmetric Hydrogenation of β,β-Diaryl α,β-Unsaturated Phosphonates 1
a
Unless otherwise mentioned, all reactions were carried out with a [Rh(COD)2]PF6/(R,R)-f-spiroPhos/substrate ratio of 2.0:2.2:100, CH2Cl2, 80
1
atm H2, rt, 24 h. The conversion was determined by H NMR spectroscopy or GC analysis; the enantioselectivity was determined by SFC or
HPLC analysis using a chiral stationary phase. 1.0 mol % [Rh(COD)2]PF6.
b
be completely hydrogenated in an hour under 1.0 atm
hydrogen pressure to produce the desired 4a with remained
enantioselectivity, 94% ee. Moreover, besides the precursor
[Rh(COD)2]PF6, [Rh(COD)2]BF4 was also proven as an
efficient alternative precursor for this hydrogenation, and
comparably excellent enantioselectivity with complete con-
version was achieved. Subsequently, a series of (E)-β-aryl-β-
alkyl α,β-unsaturated phosphonates 3a−k were prepared and
successfully hydrogenated to afford the desired products 4a−k
with full conversion and excellent enantioselectivities, 92−
99.9% ee (Table 3). The electron property and position of the
substituents at the phenyl ring of the substrates had no obvious
influence on both the reactivity and the enantioselectivity.
Generally, the substrates with electron-withdrawing substitu-
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Scheme 2. X-ray Crystal Structure of the Product (R)-2h, and the Proposed Enantio-Determining Transition Model for Rh-
Catalyzed Asymmetric Hydrogenation of β,β-Diaryl α,β-Unsaturated Phosphonates
a
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of β-Aryl-β-alkyl α,β-Unsaturated Phosphonates 3
a
Unless otherwise mentioned, all reactions were carried out with a [Rh(COD)2]BF4/(R,R)-f-spiroPhos/substrate ratio of 1.0:1.1:100, CH2Cl2, 10
1
atm H2, rt, 1.0 h. The conversion was determined by H NMR spectroscopy or GC analysis; the enantioselectivity was determined by SFC or
HPLC analysis using a chiral stationary phase. 1.0 atm H2, 1.0 h.
b
D
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cooled and a solution of tetraethyl methylenedisphosphonate (1.2
equiv, 12.0 mmol) in THF (0.4 mL/mmol) was slowly added, and the
resulting mixture was stirred at room temperature for 30 min. A
solution of ketone (1.0 equiv, 10.0 mmol) in THF (1.42 mL/mmol)
was then added to the reaction. The solution was stirred at room
temperature until no starting material was detected by TLC. The
reaction mixture was quenched with saturated aqueous NH4Cl
solution and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, and distilled to
dryness in vacuo. The residue was purified by chromatography giving
1 and 3.8b
General Procedure B. The dialkyl phosphite (1.4 equiv, 14.0
mmol) was added to a brown suspension of Cu2O (0.14 equiv, 1.4
mmol) in acetonitrile (28.6 mL/mmol). Then, the corresponding
alkyne (1.0 equiv, 10.0 mmol) was added, and the reaction mixture
was warmed to 70 °C and stirred overnight under air. The reaction
mixture turned a pale-green clear solution. The solvent was
evaporated in vacuo, and the crude product was purified by flash
column chromatography (silica gel, EtOAc/PE) to give diethyl
(phenylethynyl)phosphonate.12d,15
CuBr (1.28 equiv, 12.8 mmol) was added to an oven-dried 250 mL
three-neck round-bottom flask under nitrogen, THF (4.0 mL/mmol)
was added, and the reaction mixture was cooled to −20 °C. Then,
LiBr (1.3 equiv, 13.0 mmol) in THF (0.8 mL/mmol) was added,
followed by stirring for 10 min. The RMgBr (1.3 equiv, 13.0 mmol)
was added dropwise at −20 °C, followed by stirring for 15 min. After
that, the solution was cooled to −78 °C, and a solution of the diethyl
(phenylethynyl)phosphonate (1.0 equiv, 10.0 mmol) in THF (4.0
mL/mmol) was added dropwise and stirred at −78 °C for 1 h. The
reaction was quenched with MeOH, and the reaction mixture was
washed with saturated aqueous NH4Cl solution and extracted with
CH2Cl2. The combined organic extracts were washed with water and
brine and then dried over Na2SO4 and concentrated in vacuo. The
residue was purified by chromatography giving 1b, 1e, 1f, 1g, and
1h.2a,b
ents on the phenyl ring gave higher enantioselectivities than
those with electron-donating substituents. For example,
substrates 3b and 3g with a meta-methoxy or a para-methyl
substituent gave 96% ee and 92% ee, while substrates 3c and 3f
bearing a fluoro substituent at meta- or para- position of the
phenyl ring provided enantioselectivities as high as 99.9% and
97% ee, respectively. Significantly, the catalyst could still
maintain excellent activity and enantioselectivity for the
subtrates with steric hindrance. The ortho-substituted
substrates 3d and 3e exhibited similar reactivity and were
also completely hydrogenated under low hydrogen pressure in
an hour with comparable enantioselectivities of up to 99.7% ee.
When the R group was changed to bulkier ethyl or isopropyl
(3j and 3k), both the reactivity and the enantioselectivity were
not decreased. The desired products 4j and 4k were obtained
with full conversion and excellent enantioselectivities, 99.2%
and 99.9% ee, respectively. However, the dialkyl substrate 3l
only achieved 75% ee albeit with a full conversion, which could
perhaps be attributed to the flexibility of the alkyl group. When
the phenyl was replaced with a 2-pyridyl group (3m), both the
reactivity and the enantioselectivity were decreased.
Finally, the hydrogenation on a gram-scale was evaluated
using one of the substrates. The full conversion was still
achieved in an hour providing the desired product 4d with
excellent enantioselectivity of 98% ee (Scheme 3).
Scheme 3. Asymmetric Hydrogenation of β,β-Disubstituted
Unsaturated Phosphonate 3d on Gram Scale
(E)-Diethyl-(2-phenyl-2-(m-tolyl)vinyl)phosphonate (1a). Purifi-
cation by column chromatography (silica gel, PE:EA = 2:1) afforded
1
the product as yellow oil; 2.50 g, yield: 42%. H NMR (400 MHz,
CDCl3): δ (ppm) 7.36 (s, 5H), 7.25−7.14 (m, 2 H), 7.09 (s, 1H),
7.04 (d, J = 7.2 Hz, 1H), 6.14 (d, J = 15.7 Hz, 1H), 3.95−3.75 (m,
4H), 2.30 (s, 3H), 1.11 (t, J = 7.1 Hz, 6H); 13C{1H}NMR (101 MHz,
CDCl3): δ (ppm) 160.4 (d, J = 5.9 Hz), 141.7 (d, J = 22.4 Hz), 139.1
(d, J = 7.4 Hz), 138.1, 130.3, 129.8, 128.9, 128.7, 128.3, 127.9, 125.6,
114.7 (d, J = 192.9 Hz), 61.6 (d, J = 6.1 Hz), 21.5, 16.2 (d, J = 6.7
Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 17.4; TOF-HRMS
Calculated for C19H24O3P ([M + H]+): 331.1457, found 331.1460.
(E)-Diethyl-(2-phenyl-2-(p-tolyl)vinyl)phosphonate (1b). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil; 0.50 g, yield: 92%. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.36 (s, 5H), 7.25−7.10 (m, 4H), 6.14 (d, J = 15.6
Hz, 1H), 3.94−3.74 (m, 4H), 2.34 (s, 3H), 1.11 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 160.1 (d, J = 6.1 Hz),
139.7, 139.2 (d, J = 7.5 Hz), 138.8 (d, J = 22.3 Hz), 130.2−129.5
(m), 129.1, 128.6, 128.2, 127.9, 113.8 (d, J = 193.6 Hz), 61.6 (d, J =
6.0 Hz), 21.3, 16.2 (d, J = 6.8 Hz); 31P NMR (162 MHz, CDCl3) δ
(ppm) 17.6; TOF-HRMS Calculated for C19H24O3P ([M + H]+):
331.1457, found 331.1460.
CONCLUSIONS
■
In summary, we have developed a highly efficient method for
enantioselective synthesis of various chiral phosphonates. By
employing a Rh-(R,R)-f-spiroPhos complex, a wide range of
α,β-unsaturated phosphonates including the (E)- and (Z)-
isomers of β,β-diaryl and β-aryl-β-alkyl α,β-unsaturated
phosphonates were smoothly transformed into chiral phos-
phonates in high yields and excellent enantioselectivities of up
to 99.9% ee. This methodology provides a straightforward
access to asymmetric synthesis of chiral phosphonates.
EXPERIMENTAL SECTION
■
General Information. All the air- or moisture-sensitive reactions
and manipulations were performed by using standard Schlenk
techniques and in a nitrogen-filled glovebox. 1H NMR and 13C
NMR spectra were recorded on Bruker AV (400 MHz) spectrometers
and JEOL JNM-ECX600P and JNM-ECS600 (400 or 600 MHz)
spectrometers. (CDCl3 was the solvent used for the NMR analysis,
with TMS as the internal standard.) Optical rotation was determined
using an Autopol III Automatic polarimeter (Rudolph research
Analyical). HPLC analysis was conducted on an Agilent 1260 series
instrument. SFC analysis was conducted on an Agilent 1260 series
instrument. HRMS were recorded on a Waters LCT Premier XE mass
spectrometer with TOF.
(E)-Diethyl-(2-(4-fluorophenyl)-2-phenylvinyl)phosphonate (1c).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow solid; 0.60 g, yield: 25%; MP: 48−50
1
°C; H NMR (400 MHz, CDCl3): δ (ppm) 7.37−7.28 (m, 5H),
7.25−7.23 (m, 2H), 7.05 (t, J = 8.2 Hz, 2H), 6.14 (d, J = 15.2 Hz,
1H), 3.95−3.80 (m, 4H), 1.16−1.12 (m, 6H); 13C{1H}NMR (101
MHz, CDCl3): δ (ppm) 163.1 (d, J = 248.4 Hz), 159.2 (d, J = 5.8
Hz), 141.5 (d, J = 22.1 Hz), 135.1−134.9 (m), 131.8 (d, J = 8.1 Hz),
123.0−129.2 (m), 128.5, 128.3, 115.2 (d, J = 192.91), 114.9 (d, J =
21.5 Hz), 61.7 (d, J = 6.1 Hz), 16.3 (d, J = 6.6 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 17.0; TOF-HRMS Calculated for
C18H21O3FP ([M + H]+): 335.1206, found 335.1205.
General Procedures for the Synthesis of Substrates 1 and 3.
General Procedure A. NaH (1.3 equiv, 13.0 mmol, 60% in oil) was
placed in an oven-dried 250 mL, three-neck round-bottom flask. THF
(1.8 mL/mmol) was added under nitrogen. The reaction mixture was
E
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(Z)-Diethyl (2-(4-fluorophenyl)-2-phenylvinyl)phosphonate (1d).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 0.85 g, yield: 36%; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.38−7.24 (m, 7H), 7.07 (t, J = 8.7 Hz, 2H),
6.16 (d, J = 15.2 Hz, 1H), 3.97−3.83 (m, 4H), 1.16 (t, J = 7.1 Hz,
6H); 13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 163.6 (d, J = 250.2
Hz), 159.2 (d, J = 7.3 Hz), 138.9, 138.4−137.37 (m), 135.9 (d, J =
7.9 Hz), 130.2 (d, J = 9.0 Hz), 129.8, 128.7, 115.3 (d, J = 22.0 Hz),
114.4 (d, J = 192.4 Hz), 61.6 (d, J = 6.7 Hz), 16.2 (d, J = 7.5 Hz); 31P
NMR (162 MHz, CDCl3): δ (ppm) 17.0; TOF-HRMS Calculated for
C18H21O3FP ([M + H]+): 335.1206, found 335.1205.
(E)-Diethyl (2-(2-fluorophenyl)-2-phenylvinyl)phosphonate (1j).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as a white solid; 0.90 g, yield: 20%; MP: 52−54
1
°C. H NMR (400 MHz, CDCl3): δ (ppm) 7.41−7.39 (m, 2H),
7.34−7.32 (m, 3H), 7.29−7.27 (m, 1H), 7.13−7.00 (m, 3H), 6.12 (d,
J = 15.4 Hz, 1H), 3.93−3.83 (m, 4H), 1.11 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 160.0 (d, J = 250.9 Hz),
154.7 (d, J = 6.3 Hz), 139.1 (d, J = 7.5 Hz), 131.3 (d, J = 2.5 Hz),
130.7 (d, J = 8.5 Hz), 130.1 (dd, J = 22.7, 12.1 Hz), 129.3, 128.9,
127.9, 124.1 (d, J = 3.8 Hz), 119.2 (dd, J = 189.3, 4.3 Hz), 116.3 (d, J
= 22.4 Hz), 61.8 (d, J = 6.1 Hz), 16.2 (d, J = 6.7 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 15.1; TOF-HRMS Calculated for
C18H21O3FP ([M + H]+): 335.1206, found 335.1205.
(E)-Diethyl-(2-(3,5-dimethylphenyl)-2-phenylvinyl)phosphonate
(1e). Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow solid; 1.20 g, yield: 93%; MP: 60−62
(E)-Diethyl (2-(2-chlorophenyl)-2-phenylvinyl)phosphonate (1k).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 1.20 g, yield: 42%; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.46−7.43 (m, 2H), 7.38−7.35 (m, 1H),
7.31 (dt, J = 3.5, 1.4 Hz, 3H), 7.28−7.22 (m, 3H), 5.92 (d, J = 15.3
Hz, 1H), 3.99−3.86 (m, 4H), 1.12 (t, J = 7.1 Hz, 6H); 13C{1H}NMR
(101 MHz, CDCl3): δ (ppm) 158.07 (d, J = 5.9 Hz), 141.78 (d, J =
22.8 Hz), 138.53 (d, J = 7.1 Hz), 132.48, 130.89, 130.21, 129.63,
129.45, 129.02, 127.86, 126.74, 61.85 (d, J = 6.0 Hz), 16.18 (d, J = 6.7
Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 17.4; TOF-HRMS
Calculated for C18H21O3PCl ([M + H]+): 351.0911, found 351.0908.
(E)-Diethyl (2-(naphthalen-1-yl)-2-phenylvinyl)phosphonate
(1l). Purification by column chromatography (silica gel, PE:EA =
1
°C; H NMR (400 MHz, CDCl3): δ (ppm) 7.36 (s, 5H), 6.98 (s,
1H), 6.87 (s, 2H), 6.12 (d, J = 15.8 Hz, 1H), 4.03−3.41 (m, 4H),
2.26 (s, 6H), 1.11 (t, J = 7.1 Hz, 6H); 13C{1H}NMR (101 MHz,
CDCl3): δ (ppm) 160.57 (d, J = 5.8 Hz), 141.75 (d, J = 22.1 Hz),
139.23, 137.92, 129.90 (d, J = 254.9 Hz), 129.84, 127.02 (d, J = 164.3
Hz), 114.50 (d, J = 192.5 Hz), 61.55 (d, J = 6.0 Hz), 21.32, 16.23 (d,
J = 6.8 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 17.5; TOF-
HRMS Calculated for C20H26O3P ([M + H]+): 345.1614, found
345.1610.
(E)-Diethyl (2-(3,5-difluorophenyl)-2-phenylvinyl)phosphonate
(1f). Purification by column chromatography (silica gel, PE:EA =
1
2:1) afforded the product as yellow oil; 0.70 g, yield: 40%; H NMR
1
(400 MHz, CDCl3): δ (ppm) 7.37−7.29 (m, 3H), 7.23 (d, J = 1.9 Hz,
2H), 6.91−6.80 (m, 3H), 6.22 (d, J = 14.5 Hz, 1H), 4.00−3.88 (m,
4H), 1.19 (t, J = 7.1 Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ
(ppm) 163.8 (d, J = 12.6 Hz), 161.3 (d, J = 12.8 Hz), 157.5 (dd, J =
4.8, 2.1 Hz), 143.0−141.5 (m), 140.2 (d, J = 21.7 Hz), 129.9, 128.3
(d, J = 64.0 Hz), 116.5 (d, J = 192.6 Hz), 113.0 (d, J = 25.9 Hz),
104.0 (t, J = 25.2 Hz), 61.8 (d, J = 6.0 Hz), 16.3 (d, J = 6.7 Hz); 31P
NMR (162 MHz, CDCl3): δ (ppm) 16.0; TOF-HRMS Calculated for
C18H20O3F2P ([M + H]+): 353.1112, found 353.1110.
2:1) afforded the product as yellow oil; 0.75 g, yield: 32%; H NMR
(400 MHz, CDCl3): δ (ppm) 7.86−7.81 (m, 3H), 7.54 (dd, J = 6.6,
3.0 Hz, 2H), 7.46−7.36 (m, 4H), 7.31−7.25 (m, 3H), 6.04 (d, J =
16.3 Hz, 1H), 4.03−3.91 (m, 4H), 1.15 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 160.1 (d, J = 5.2 Hz),
141.0, 140.8, 139.8 (d, J = 7.2 Hz), 133.9, 131.0, 129.3, 129.1 (d, J =
3.1 Hz), 128.4, 128.1, 127.1, 126.6, 126.0, 125.9, 125.1, 118.8 (d, J =
186.3 Hz), 61.9 (d, J = 6.0 Hz), 16.2 (d, J = 6.7 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 16.5; TOF-HRMS Calculated for C22H24O3P
([M + H]+): 367.1457, found 367.1460.
(E)-Diethyl (2-phenylprop-1-en-1-yl)phosphonate (3a). Purifica-
tion by column chromatography (silica gel, PE:EA = 1:1) afforded the
product as yellow oil; 0.50 g, yield: 64%; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.47−7.45 (m, 2H), 7.36−7.34 (m, 3H), 5.89 (d, J
= 16.5 Hz, 1H), 4.11 (dtd, J = 8.1, 7.1, 1.0 Hz, 4H), 2.49 (d, J = 3.3
Hz, 3H), 1.34 (t, J = 7.0 Hz, 6H); The analytical data are consistent
with the literature.8b
(E)-Diethyl (2-(3,5-dichlorophenyl)-2-phenylvinyl)phosphonate
(1g). Purification by column chromatography (silica gel, PE:EA =
1
2:1) afforded the product as yellow oil; 0.66 g, yield: 41%; H NMR
(400 MHz, CDCl3): δ (ppm) 7.39−7.31 (m, 3H), 7.25−7.23 (m,
5H), 6.24 (d, J = 14.6 Hz, 1H), 4.03−3.87 (m, 4H), 1.20 (t, J = 7.1
Hz, 6H); 13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 157.1 (d, J =
5.9 Hz), 141.8 (d, J = 8.2 Hz), 140.1 (d, J = 21.6 Hz), 134.6, 130.0,
128.7, 128.6, 128.2, 128.1, 116.9 (d, J = 193.1 Hz), 61.9 (d, J = 6.9
Hz), 16.3 (d, J = 7.2 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm)
15.9; TOF-HRMS Calculated for C18H20O3PCl2 ([M + H]+):
385.0521, found 385.0520.
(E)-Diethyl (2-(3-methoxyphenyl)prop-1-en-1-yl)phosphonate
(3b). Purification by column chromatography (silica gel, PE:EA =
1
2:1) afforded the product as yellow oil; 1.50 g, yield: 58%; H NMR
(Z)-Diethyl (2-(3,5-dichlorophenyl)-2-phenylvinyl)phosphonate
(1h). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as white solid; 1.00 g, yield: 53%; MP: 68−
(400 MHz, CDCl3): δ (ppm) 7.24−7.20 (m, 1H), 6.99 (d, J = 7.4 Hz,
1H), 6.93−6.92 (m, 1H), 6.85−6.83 (m, 1H), 6.01−5.50 (m, 1H),
4.07 (dd, J = 8.5, 6.4 Hz, 4H), 3.76 (s, 3H), 2.43 (d, J = 2.0 Hz, 3H),
1.30 (t, J = 7.1 Hz, 6H); The analytical data are consistent with the
literature.8b
1
70 °C; H NMR (400 MHz, CDCl3): δ (ppm) 7.39 (dt, J = 3.8, 2.7
Hz, 3H), 7.35−7.32 (m, 3H), 7.13 (d, J = 1.9 Hz, 2H), 6.15 (d, J =
14.2 Hz, 1H), 3.93−3.77 (m, 4H), 1.12 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 157.2 (d, J = 7.8 Hz),
144.7 (d, J = 23.4 Hz), 137.7 (d, J = 8.3 Hz), 135.2, 129.7, 129.3,
129.2, 128.3, 126.7, 117.7 (d, J = 193.4 Hz), 61.8 (d, J = 6.7 Hz), 16.2
(d, J = 7.4 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 15.7; TOF-
HRMS Calculated for C18H20O3PCl2 ([M + H]+): 385.0521, found
385.0520.
(E)-Diethyl (2-(3-fluorophenyl)prop-1-en-1-yl)phosphonate (3c).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 0.75 g, yield: 59%; 1H NMR (600
MHz, CDCl3): δ (ppm) 7.30 (td, J = 8.0, 6.0 Hz, 1H), 7.21 (d, J = 7.9
Hz, 1H), 7.12 (dt, J = 10.2, 2.1 Hz, 1H), 7.01 (td, J = 8.2, 2.2 Hz,
1H), 5.88 (d, J = 15.9 Hz, 1H), 4.10 (m, 4H), 2.45 (d, J = 3.2 Hz,
3H), 1.32 (t, J = 7.1 Hz, 6H); 13C{1H}NMR (151 MHz, CDCl3): δ
(ppm) 162.9 (d, J = 246.3 Hz), 156.6 (d, J = 8.4 Hz), 144.1 (d, J =
23.7 Hz), 130.1 (d, J = 8.3 Hz), 121.7 (d, J = 2.9 Hz), 116.0 (d, J =
21.3 Hz), 114.9 (d, J = 190.3 Hz), 113.2 (d, J = 22.3 Hz), 61.7 (d, J =
5.7 Hz), 19.3 (d, J = 7.1 Hz), 16.5 (d, J = 6.5 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 17.1; TOF-HRMS Calculated for
C13H19O3FP ([M + H]+): 273.1050, found 273.1048.
(E)-Diethyl (2-(2-fluorophenyl)prop-1-en-1-yl)phosphonate (3d).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 0.50 g, yield: 46%; 1H NMR (600
MHz, CDCl3): δ (ppm) 7.29−7.25 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H),
7.05 (dd, J = 10.9, 8.3 Hz, 1H), 5.77 (d, J = 17.0 Hz, 1H), 4.14−4.10
(m, 4H), 2.46−2.45 (m, 3H), 1.35 (t, J = 7.1 Hz, 6H); 13C{1H}NMR
(Z)-Diethyl (2-(4-fluorophenyl)-2-(p-tolyl)vinyl)phosphonate (1i).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as white solid; 1.20 g, yield: 30%; MP: 94−96
°C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.35 (dd, J = 8.0, 5.5 Hz,
2H), 7.15−7.10 (m, 4H), 7.06 (t, J = 8.3 Hz, 2H), 6.13 (d, J = 15.3
Hz, 1H), 3.97−3.80 (m, 4H), 2.35 (s, 3H), 1.15 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 163.3−157.6 (m), 139.9,
138.8, 138.6, 135.1 (dd, J = 7.8, 2.7 Hz), 131.8 (d, J = 8.0 Hz), 129.2,
128.2, 114.9 (d, J = 21.5 Hz), 114.2 (d, J = 188.6), 61.6 (d, J = 6.0
Hz), 21.3, 16.3 (d, J = 6.7 Hz); 31P NMR (162 MHz, CDCl3): δ
(ppm) 17.4; TOF-HRMS Calculated for C19H23O3FP ([M + H]+):
349.1363, found 349.1360.
F
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(151 MHz, CDCl3): δ (ppm) 159.3 (d, J = 249.3 Hz), 154.8 (d, J =
10.2 Hz), 130.9 (dd, J = 24.8, 13.4 Hz), 130.2 (d, J = 9.1 Hz), 126.6
(dd, J = 720.0, 4.1 Hz), 120.9−116.8 (m), 116.1 (d, J = 23.2 Hz); 31P
NMR (162 MHz, CDCl3): δ (ppm) 17.4; TOF-HRMS Calculated for
C13H19O3FP ([M + H]+): 273.1050, found 373.1048.
(E)-Diethyl (2-(o-tolyl)prop-1-en-1-yl)phosphonate (3e). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil; 0.60 g, yield: 40%; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.19−7.05 (m, 3H), 7.05 (d, J = 6.9 Hz, 1H), 5.49
(dd, J = 18.7, 1.3 Hz, 1H), 4.12 (p, J = 7.1 Hz, 4H), 2.37 (dd, J = 3.4,
1.2 Hz, 3H), 2.28 (s, 3H), 1.35 (t, J = 7.1 Hz, 6H); The analytical
data are consistent with the literature.8b
(E)-Diethyl (2-(4-fluorophenyl)prop-1-en-1-yl)phosphonate (3f).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 0.75 g, yield: 40%; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.40−7.37 (m, 2H), 7.34−7.30 (m, 2H),
5.87 (dd, J = 15.9, 1.0 Hz, 1H), 4.11 (dd, J = 7.9, 7.1 Hz, 4H), 2.46
(dd, J = 3.3, 1.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 6H); The analytical data
are consistent with the literature.8b
(E)-Diethyl (2-(p-tolyl)prop-1-en-1-yl)phosphonate (3g). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil; 0.80 g, yield: 60%; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.37 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H),
5.87 (dd, J = 16.6, 1.0 Hz, 1H), 4.15−4.07 (m, 4H), 2.47 (dd, J = 3.3,
1.0 Hz, 3H), 2.35 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H); The analytical
data are consistent with the literature.8b
126.8, 126.0 (d, J = 23.0 Hz), 61.8, 34.6, 30.9, 30.1, 25.0, 16.5. The
analytical data are consistent with the literature.8b
(E)-Diethyl (2-(pyridin-2-yl)prop-1-en-1-yl)phosphonate (3m).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 1.45 g, yield: 58%; 1H NMR (400
MHz, CDCl3): δ (ppm) 8.59 (d, J = 4.7 Hz, 1H), 7.71−7.63 (t, J =
8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.24−7.20 (m, 1H), 6.56 (d, J
= 15.0 Hz, 1H), 4.14−4.06 (q, J = 8.8 Hz 4H), 2.52 (d, J = 1.9 Hz,
3H), 1.31 (t, J = 7.1 Hz, 6H). 13C{1H}NMR (151 MHz, CDCl3): δ
(ppm) 157.1 (d, J = 98.4 Hz), 155.7 (d, J = 33.6 Hz), 149.2, 136.8,
123.7, 120.6, 115.9 (d, J = 756.0 Hz), 61.6 (d, J = 19.8 Hz), 17.6 (d, J
= 28.2 Hz), 16.4 (d, J = 28.8 Hz) The analytical data are consistent
with the literature.8b
General Procedure for Asymmetric Hydrogenation of Com-
pound 1. A stock solution was made by mixing [Rh(COD)2]PF6 with
(R,R)-f-spiroPhos in a 1:1.1 molar ratio in solvent (CH2Cl2) at room
temperature for 20 min in a nitrogen-filled glovebox. An aliquot of the
catalyst solution (1.0 mL, 0.02 equiv, 0.0025 mmol) was transferred
by syringe into the vials charged with different substrates 1 (1.0 equiv,
0.125 mmol for each) in anhydrous solvent (CH2Cl2) (2.0 mL). The
vials were subsequently transferred into an autoclave and then
hydrogen gas was charged. The reaction was then stirred under H2
(80 atm) at r.t. for 24 h. The hydrogen gas was released slowly and
carefully. The solution was passed through a short column of silica gel
to remove the metal complex. The conversion of products was
1
determined by GC or H NMR analysis. The crude products were
concentrated and purified by column chromatography, and the ee
values were determined by HPLC or SFC analysis on a chiral
stationary phase.12d
(E)-Diethyl (2-(4-isobutylphenyl)prop-1-en-1-yl)phosphonate
(3h). Purification by column chromatography (silica gel, PE:EA =
1
2:1) afforded the product as yellow oil; 0.90 g, yield: 46%; H NMR
General Procedure for Asymmetric Hydrogenation of Com-
pound 3. A stock solution was made by mixing [Rh(COD)2]BF4 with
(R,R)-f-spiroPhos in a 1:1.1 molar ratio in solvent (CH2Cl2) at room
temperature for 20 min in a nitrogen-filled glovebox. An aliquot of the
catalyst solution (1.0 mL, 0.01 equiv, 0.00125 mmol) was transferred
by syringe into the vials charged with different substrates 3 (1.0 equiv,
0.125 mmol for each) in anhydrous solvent (CH2Cl2) (2.0 mL). The
vials were subsequently transferred into an autoclave and then
hydrogen gas was charged. The reaction was then stirred under H2
(10 atm) at r.t. for 1 h. The hydrogen gas was released slowly and
carefully. The solution was passed through a short column of silica gel
to remove the metal complex. The conversion of products was
(600 MHz, CDCl3): δ (ppm) 7.39 (d, J = 8.2 Hz, 2H), 7.13 (d, J =
8.2 Hz, 2H), 5.89 (dt, J = 16.6, 1.0 Hz, 1H), 4.11 (p, J = 7.1 Hz, 4H),
2.49−2.46 (m, 5H), 1.85 (dt, J = 13.5, 6.8 Hz, 1H), 1.34 (t, J = 7.1
Hz, 6H), 0.89 (d, J = 6.6 Hz, 6H); 13C{1H}NMR (151 MHz, CDCl3)
δ (ppm) 158.1 (d, J = 9.3 Hz), 143.2, 139.1 (d, J = 24.0 Hz), 129.3,
125.9, 112.5 (d, J = 190.7 Hz), 61.5 (d, J = 6.1 Hz), 45.1, 30.2, 22.4,
19.2 (d, J = 7.5 Hz), 16.5 (d, J = 7.2 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 19.3; TOF-HRMS Calculated for C17H28O3P ([M
+ H]+): 311.1770, found 311.1773.
(E)-Diethyl (2-(3,4-dimethylphenyl)prop-1-en-1-yl)phosphonate
(3i). Purification by column chromatography (silica gel, PE:EA =
1
2:1) afforded the product as yellow oil; 0.50 g, yield: 42%; H NMR
1
determined by GC or H NMR analysis. The crude products were
(400 MHz, CDCl3): δ (ppm) 7.23 (s, 1H), 7.20 (dd, J = 7.9, 1.9 Hz,
1H), 7.10 (d, J = 7.9 Hz, 1H), 5.89−5.84 (m, 1H), 4.14−4.07 (m,
4H), 2.46 (dd, J = 3.2, 0.8 Hz, 3H), 2.26 (d, J = 3.5 Hz, 6H), 1.33 (t, J
= 7.1 Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 158.3 (d,
J = 8.0 Hz), 139.4 (d, J = 23.5 Hz), 138.1, 136.7, 129.8, 127.3, 123.5,
112.3 (d, J = 190.5 Hz), 61.5 (d, J = 5.6 Hz), 19.9, 19.6, 19.3 (d, J =
7.0 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 19.3; TOF-HRMS
Calculated for C15H24O3P ([M + H]+): 283.1457, found 283.1460.
(E)-Diethyl (2-phenylbut-1-en-1-yl)phosphonate (3j). Purification
by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil; 0.50 g, yield: 30%; 1H NMR (400 MHz,
CDCl3): δ (ppm) δ 7.41−7.39 (m, 2H), 7.36−7.33 (m, 3H), 5.74 (d,
J = 17.2 Hz, 1H), 4.11 (m, 4H), 2.99 (qd, J = 7.5, 2.3 Hz, 2H), 1.34
(t, J = 7.1 Hz, 6H), 1.02 (t, J = 7.5 Hz, 3H); The analytical data are
consistent with the literature.8b
(E)-Diethyl (3-methyl-2-phenylbut-1-en-1-yl)phosphonate (3k).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil; 0.65 g, yield: 25%; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.30 (dd, J = 5.1, 1.8 Hz, 3H), 7.16−7.15 (m,
2H), 5.42 (d, J = 18.8 Hz, 1H), 4.11 (m, 4H), 3.73 (m, 1H), 1.34 (t, J
= 7.0 Hz, 6H), 1.07 (d, J = 6.9 Hz, 6H); The analytical data are
consistent with the literature.8b
concentrated and purified by column chromatography and the ee
values were determined by HPLC or SFC analysis on a chiral
stationary phase.12d
(+)-Diethyl (2-phenyl-2-(m-tolyl)ethyl)phosphonate (2a). Purifi-
cation by column chromatography (silica gel, PE:EA = 2:1) afforded
the product as yellow oil, 40.7 mg, yield: 98%; 95% ee; [α]D20 = +0.8
(c = 0.6, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/CO2 = 10/90,
flow rate = 3.0 mL/min, l = 210 nm) tR = 2.9 min (major), tR = 2.5
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.27−7.24 (m,
4H), 7.18−7.13 (m, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 7.7
Hz, 1H), 4.39 (dt, J = 11.7, 7.5 Hz, 1H), 3.90−3.67 (m, 4H), 2.55
(dd, J = 18.2, 7.6 Hz, 2H), 2.29 (s, 3H), 1.09 (t, J = 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 144.3, 144.2, 144.1,
138.1, 128.6, 128.5, 127.8, 127.4, 126.6, 124.7, 61.4 (d, J = 6.5 Hz),
45.8−21.1 (m), 32.5 (d, J = 140.6 Hz), 29.8, 16.3 (d, J = 6.4 Hz); 31
P
NMR (162 MHz, CDCl3): δ (ppm) 30.0; TOF-HRMS Calculated for
C19H26O3P ([M + H]+): 333.1614, found 333.1611.
(−)-Diethyl (2-phenyl-2-(p-tolyl)ethyl)phosphonate (2b). Purifi-
cation by column chromatography (silica gel, PE:EA = 2:1) afforded
the product as yellow oil, 40.3 mg, yield: 97%; 94% ee; [α]D20 = −2.2
(c = 0.6, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/CO2 = 5/95,
flow rate = 3.0 mL/min, l = 210 nm) tR = 6.5 min (major), tR = 6.1
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.27−7.25 (m,
4H), 7.16 (d, J = 8.0 Hz, 3H), 7.07 (d, J = 7.9 Hz, 2H), 4.40 (dt, J =
11.6, 7.5 Hz, 1H), 3.89−3.68 (m, 4H), 2.55 (ddd, J = 18.4, 7.5, 1.1
Hz, 2H), 2.27 (s, 3H), 1.09 (td, J = 7.1, 2.4 Hz, 6H); 13C{1H}NMR
(101 MHz, CDCl3): δ (ppm) 144.4 (d, J = 9.7 Hz), 141.3 (d, J = 10.9
Hz), 136.1, 129.3, 128.6, 127.7, 127.5, 126.5, 61.4 (d, J = 6.5 Hz),
(E)-Diethyl (2-methyl-4-phenylbut-1-en-1-yl)phosphonate (3l).
Purification by column chromatography (silica gel, PE:EA = 2:1)
1
afforded the product as a colorless oil; 1.44 g, yield: 51%. H NMR
(600 MHz, CDCl3): δ (ppm) 7.27−7.25 (m, 2H), 7.15−7.20 (m,
3H), 5.37 (d, 1H, J = 18.2 Hz, 1H), 3.95−4.02 (m, 4H), 2.77−2.81
(m, 2H), 2.45−2.49 (m, 2H), 2.11 (s, 3H), 1.28 (t, J = 7.0 Hz, 6H).
13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 141.0, 128.6, 128.1,
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45.1, 32.5 (d, J = 140.1 Hz), 21.0, 16.3 (d, J = 6.4 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 30.1; TOF-HRMS Calculated for C19H26O3P
([M + H]+): 333.1614, found 333.1611.
= 1.9 Hz, 1H), 7.15 (d, J = 1.8 Hz, 2H), 4.38 (dt, J = 11.4, 7.5 Hz,
1H), 4.07−3.76 (m, 4H), 2.49 (ddd, J = 18.4, 7.5, 1.9 Hz, 2H), 1.13
(dt, J = 15.4, 7.1 Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ
(ppm) 147.5 (d, J = 9.7 Hz), 142.7 (d, J = 11.0 Hz), 135.0, 128.9,
127.6, 127.2, 126.9, 126.5, 62.8−58.5 (m), 39.0 (d, J = 1243.5 Hz),
30.6 (d, J = 163.3 Hz), 16.3 (d, J = 6.3 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 28.7; TOF-HRMS Calculated for C18H21O3NaPCl2
([M + Na]+): 409.0497, found 409.0501.
(−)-Diethyl (2-(4-fluorophenyl)-2-phenylethyl)phosphonate (2c).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil, 40.3 mg, yield: 96%; 94% ee;
20
[α]D = −1.4 (c = 0.4, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/
CO2 = 10/90, flow rate = 3.0 mL/min, l = 230 nm) tR = 2.4 min
(major), tR = 2.6 min (minor); 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.27−7.17 (m, 7H), 6.95 (t, J = 8.7 Hz, 2H), 4.43 (dt, J = 11.5,
7.6 Hz, 1H), 3.90−3.72 (m, 4H), 2.56−2.49 (m, 2H), 1.10 (t, J = 7.1
Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 161.6 (d, J =
244.8 Hz), 144.1 (d, J = 10.8 Hz), 139.9 (d, J = 10.1 Hz), 129.3 (d, J
= 8.0 Hz), 128.7, 127.6, 126.8, 115.4 (d, J = 21.3 Hz), 61.4 (d, J = 5.6
Hz), 44.8 (d, J = 2.7 Hz), 32.6 (d, J = 140.8 Hz), 16.3 (d, J = 6.4 Hz);
31P NMR (162 MHz, CDCl3): δ (ppm) 29.6; TOF-HRMS Calculated
for C18H23O3FP ([M + H]+): 337.1363, found 337.1360.
(+)-Diethyl (2-(3,5-dichlorophenyl)-2-phenylethyl)phosphonate
(2h). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as yellow solid, 44.4 mg, yield: 92%; MP:
20
88−90 °C; 97% ee; [α]D = +10.1 (c = 0.7, CH2Cl2); SFC (Lux 5u
Amylose-2, MeOH/CO2 = 10/90, flow rate = 3.0 mL/min, l = 230
nm) tR = 3.9 min (major), tR = 3.0 min (minor); 1H NMR (600 MHz,
CDCl3): δ (ppm) 7.30−7.29 (m, 2H), 7.25−7.22 (m, 3H), 7.17 (d, J
= 1.9 Hz, 1H), 7.15 (d, J = 1.8 Hz, 2H), 4.38 (dt, J = 11.4, 7.5 Hz,
1H), 4.07−3.76 (m, 4H), 2.49 (ddd, J = 18.4, 7.5, 1.9 Hz, 2H), 1.13
(dt, J = 15.4, 7.1 Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ
(ppm) 147.5 (d, J = 9.7 Hz), 142.7 (d, J = 11.0 Hz), 135.0, 128.9,
127.6, 127.2, 126.9, 126.5, 62.8−58.5 (m), 39.0 (d, J = 1243.5 Hz),
30.6 (d, J = 163.3 Hz), 16.3 (d, J = 6.3 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 28.7; TOF-HRMS Calculated for C18H21O3NaPCl2
([M + Na]+): 409.0497, found 409.0501.
(+)-Diethyl (2-(4-fluorophenyl)-2-phenylethyl)phosphonate (2d).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil, 26.1 mg, yield: 62%; 90% ee;
20
[α]D = +0.1 (c = 3.8, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/
CO2 = 10/90, flow rate = 3.0 mL/min, l = 210 nm) tR = 2.6 min
(major), tR = 2.4 min (minor); 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.27−7.17 (m, 7H), 6.95 (t, J = 8.7 Hz, 2H), 4.43 (dt, J = 11.5,
7.6 Hz, 1H), 3.90−3.72 (m, 4H), 2.56−2.49 (m, 2H), 1.10 (t, J = 7.1
Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 161.62 (d, J =
244.8 Hz), 144.05 (d, J = 10.8 Hz), 139.89 (d, J = 10.1 Hz), 129.26
(d, J = 8.0 Hz), 128.71, 127.59, 126.76, 115.35 (d, J = 21.3 Hz), 61.43
(d, J = 5.6 Hz), 44.82 (d, J = 2.7 Hz), 32.58 (d, J = 140.8 Hz), 16.28
(d, J = 6.4 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 29.6; TOF-
HRMS Calculated for C18H23O3FP ([M + H]+): 337.1363, found
337.1360.
(−)-Diethyl (2-(4-fluorophenyl)-2-(p-tolyl)ethyl)phosphonate
(2i). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as yellow oil, 40.7 mg, yield: 93%; 90% ee;
[α]D20 = −24.2 (c = 0.5, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/
CO2 = 5/95, flow rate = 3.0 mL/min, l = 230 nm) tR = 4.7 min
1
(major), tR = 5.2 min (minor); H NMR (400 MHz, CDCl3): δ
(ppm) 7.24−7.20 (m, 2H), 7.13−7.06 (m, 4H), 6.96−6.92 (m, 2H),
4.39 (dt, J = 11.4, 7.6 Hz, 1H), 4.91−3.71 (m, 4H), 2.50 (dd, J = 18.4,
7.6 Hz, 2H), 2.27 (s, 3H), 1.11 (td, J = 7.1, 2.0 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 161.6 (d, J = 244.7 Hz),
141.1 (d, J = 11.4 Hz), 140.1 (dd, J = 9.4, 3.1 Hz), 136.3, 129.4, 129.2
(d, J = 7.9 Hz), 127.4, 115.3 (d, J = 21.2 Hz), 61.5, 44.4 (d, J = 2.6
Hz), 32.6 (d, J = 140.5 Hz), 21.0, 16.3 (d, J = 6.3 Hz); 31P NMR (162
MHz, CDCl3): δ (ppm) 29.8; TOF-HRMS Calculated for
C19H25O3FP ([M + H]+): 351.1519, found 351.1521.
(+)-Diethyl (2-(3,5-dimethylphenyl)-2-phenylethyl)phosphonate
(2e). Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil, 41.1 mg, yield: 95%; 92% ee;
20
[α]D = +0.8 (c = 0.6, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/
CO2 = 15/85, flow rate = 3.0 mL/min, l = 230 nm) tR = 2.0 min
(major), tR = 1.7 min (minor); 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.30−7.24 (m, 5H), 7.17−7.13 (m, 1H), 6.88 (s, 2H), 6.80 (s,
1H), 4.36 (dt, J = 11.8, 7.5 Hz, 1H), 3.91−3.68 (m, 4H), 2.55 (ddd, J
= 18.4, 7.5, 2.8 Hz, 2H), 2.25 (s, 6H), 1.09 (td, J = 7.1, 2.0 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 144.3 (d, J = 9.4 Hz),
144.1 (d, J = 11.0 Hz), 138.0, 128.6, 128.3, 127.8, 126.5, 125.5, 61.4
(d, J = 6.4 Hz), 45.4 (d, J = 2.6 Hz), 32.5 (d, J = 140.3 Hz), 21.4, 16.3
(d, J = 6.4 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 30.2; TOF-
HRMS Calculated for C20H28O3P ([M + H]+): 347.177, found
347.1775.
(+)-Diethyl (2-(3,5-difluorophenyl)-2-phenylethyl)phosphonate
(2f). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as white solid, 41.6 mg, yield: 94%; MP:
62−64 °C; 92% ee; [α]D20 = +4.5 (c = 0.2, CH2Cl2); HPLC (Lux 5u
Amylose-1, isopropanol/hexane = 20/80, flow rate = 1.0 mL/min, l =
254 nm) tR = 5.6 min (major), tR = 6.4 min (minor); 1H NMR (600
MHz, CDCl3): δ (ppm) 7.29−7.28 (m, 2H), 7.25−7.23 (m, 3H),
6.80−6.78 (m, 2H), 6.61−6.59 (m, 1H), 4.40 (dt, J = 11.4, 7.5 Hz,
1H), 3.93−3.72 (m, 4H), 2.50 (ddd, J = 18.5, 7.5, 2.5 Hz, 2H), 1.14−
1.09 (m, 6H); 13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 163.9 (d,
J = 13.5 Hz), 162.2 (d, J = 13.6 Hz), 148.2 (d, J = 10.5 Hz), 142.8 (d,
J = 10.8 Hz), 128.3 (d, J = 186.4 Hz), 127.2, 111.2−109.1 (m), 102.1
(t, J = 25.7 Hz), 61.6 (dd, J = 15.0, 7.0 Hz), 45.3, 32.1 (d, J = 141.8
Hz), 16.3 (d, J = 6.9 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm)
28.88; TOF-HRMS Calculated for C18H22O3F2P ([M + H]+):
355.1269, found 355.1270.
(−)-Diethyl (2-(3,5-dichlorophenyl)-2-phenylethyl)phosphonate
(2g). Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow solid, 45.8 mg, yield: 95%; MP: 88−90
°C; 91% ee; [α]D20 = −9.3 (c = 1.0, CH2Cl2); SFC (Lux 5u Amylose-
2, MeOH/CO2 = 10/90, flow rate = 3.0 mL/min, l = 230 nm) tR =
3.1 min (major), tR = 4.2 min (minor); 1H NMR: (600 MHz,
CDCl3): δ (ppm) 7.30−7.29 (m, 2H), 7.25−7.22 (m, 3H), 7.17 (d, J
(−)-Diethyl (2-(2-fluorophenyl)-2-phenylethyl)phosphonate (2j).
Purification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil, 38.3 mg, yield: 91%; 99% ee;
20
[α]D = −4.4 (c = 0.5, CH2Cl2); SFC (Lux 5u Cellulose-4, MeOH/
CO2 = 10/90, flow rate = 3.0 mL/min, l = 210 nm) tR = 3.3 min
1
(major), tR = 3.1 min (minor); H NMR (400 MHz, CDCl3): δ
(ppm) 7.31−7.24 (m, 5H), 7.19−7.05 (m, 2H), 7.07 (td, J = 7.5, 1.4
Hz, 1H), 6.97 (ddd, J = 10.7, 8.1, 1.3 Hz, 1H), 4.70 (dt, J = 11.7, 7.6
Hz, 1H), 3.93−3.74 (m, 4H), 2.69−2.51 (m, 2H), 1.13−1.09 (m,
6H); 13C{1H}NMR (101 MHz, CDCl3) δ (ppm) 161.8, 143.0 (d, J =
10.9 Hz), 129.3, 129.1 (d, J = 4.3 Hz), 128.6, 128.3 (d, J = 8.4 Hz),
127.7, 126.8, 124.2, 115.8 (d, J = 22.5 Hz), 85.3−71.3 (m), 61.5 (dd,
J = 9.3, 6.5 Hz), 39.3, 33.0−28.3 (m), 16.3 (d, J = 6.4 Hz); 31P NMR
(162 MHz, CDCl3): δ (ppm) 29.4; TOF-HRMS Calculated for
C18H23O3FP ([M + H]+): 337.1363, found 337.1360.
(+)-Diethyl (2-(2-chlorophenyl)-2-phenylethyl)phosphonate
(2k). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as yellow oil, 38.8 mg, yield: 88%; 99% ee;
[α]D20 = +19.0 (c = 0.4, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/
CO2 = 10/90, flow rate = 3.0 mL/min, l = 210 nm) tR = 3.3 min
1
(major), tR = 3.6 min (minor); H NMR: (400 MHz, CDCl3): δ
(ppm) 7.35−7.10 (m, 9H), 4.98 (dt, J = 11.7, 7.5 Hz, 1H), 3.95−3.76
(m, 4H), 2.56 (dd, J = 18.3, 7.5 Hz, 2H), 1.12 (ddd, J = 10.3, 7.5, 6.6
Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 142.6 (d, J =
10.1 Hz), 141.4 (d, J = 10.4 Hz), 133.9, 130.0, 128.6, 128.5, 128.1,
127.8, 127.0, 126.8, 61.5 (t, J = 7.3 Hz), 41.4 (d, J = 2.4 Hz), 31.9 (d,
J = 140.8 Hz), 16.3 (dd, J = 6.4, 2.8 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 29.0; TOF-HRMS Calculated for C18H23O3PCl
([M + H]+): 353.1067, found 353.1066.
(+)-Diethyl (2-(naphthalen-1-yl)-2-phenylethyl)phosphonate
(2l). Purification by column chromatography (silica gel, PE:EA =
2:1) afforded the product as yellow oil, 41.4 mg, yield: 90%; >99.9%
H
https://doi.org/10.1021/acs.joc.1c01397
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
20
ee; [α]D = +46.1 (c = 0.8, CH2Cl2); SFC (Lux 5u Amylose-2,
flow rate = 3.0 mL/min, l = 210 nm) tR = 3.8 min (major), tR = 4.0
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.17−7.04 (m,
4H), 4.02−3.83 (m, 4H), 3.51−3.40 (m, 1H), 2.35 (d, J = 4.0 Hz,
3H), 2.09−1.94 (m, 2H), 1.35−1.31 (m, 3H), 1.20 (ddt, J = 11.3, 7.1,
3.5 Hz, 6H); The analytical data are consistent with the literature.8b
(R)-Diethyl (2-(4-fluorophenyl)propyl)phosphonate (4f). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 32.3 mg, yield: 95%; 97% ee; [α]D20 = +5.2 (c =
6.6, CH2Cl2); HPLC (Lux 5u Cellulose-2, isopropanol/hexane = 5/
95, flow rate = 1.0 mL/min, l = 254 nm) tR = 12.4 min (major), tR =
11.5 min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.29−7.16
(m, 4H), 3.95 (dq, J = 21.0, 7.1 Hz, 4H), 3.23−3.13 (m, 1H), 2.06
(ddd, J = 25.8, 17.4, 8.4 Hz, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.26−1.17
(m, 6H); The analytical data are consistent with the literature.8b
(R)-Diethyl (2-(p-tolyl)propyl)phosphonate (4g). Purification by
column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 30.5 mg, yield: 91%; 92% ee; [α]D20 = +0.5 (c =
1.2, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 = 10/90, flow
rate = 3.0 mL/min, l = 210 nm) tR = 3.7 min (major), tR = 3.5 min
(minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.10 (s, 4H), 4.47−
3.86 (m, 4H), 3.21−3.11 (m, 1H), 2.30 (s, 3H), 2.13−1.94 (m, 2H),
1.36 (dd, J = 6.9, 0.6 Hz, 3H), 1.27−1.19 (m, 6H).The analytical data
are consistent with the literature.8b
(+)-Diethyl (2-(4-isobutylphenyl)propyl)phosphonate (4h). Puri-
fication by column chromatography (silica gel, PE:EA = 2:1) afforded
the product as yellow oil, 35.7 mg, yield: 92%; 95% ee; [α]D20 = +21.8
(c = 1.0, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 = 5/95,
flow rate = 3.0 mL/min, l = 230 nm) tR = 4.0 min (major), tR = 3.7
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.11 (d, J = 8.1
Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 4.02−3.82 (m, 4H), 3.17 (dq, J =
14.0, 7.0 Hz, 1H), 2.42 (d, J = 7.1 Hz, 1H), 2.14−1.97 (m, 2H), 1.82
(dt, J = 13.5, 6.7 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H), 1.21 (dt, J = 15.8,
7.0 Hz, 6H), 0.87 (dd, J = 6.6, 0.7 Hz, 6H); 13C{1H}NMR (151
MHz, CDCl3): δ (ppm) 144.1 (d, J = 11.8 Hz), 139.8, 129.3, 126.5,
61.4 (dd, J = 29.9, 6.4 Hz), 45.1, 34.9, 34.7−33.6 (m), 30.3, 29.8, 23.7
(d, J = 9.4 Hz), 22.4, 16.4 (d, J = 6.2 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 31.0; TOF-HRMS Calculated for C17H30O3P ([M
+ H]+): 313.1927, found 313.1925.
MeOH/CO2 = 3/97, flow rate = 3.0 mL/min, l = 230 nm) tR = 27.8
min (major); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.23 (d, J = 8.0
Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.72 (d, J = 9.4 Hz, 1H),
7.51−7.42 (m, 4H), 7.37−7.35 (m, 2H), 7.25 (d, J = 3.2 Hz, 2H),
7.18−7.11 (m, 1H), 5.29 (ddd, J = 12.2, 8.2, 6.5 Hz, 1H), 3.88−3.70
(m, 4H), 2.71−2.65 (m, 2H), 1.06 (dtd, J = 11.0, 7.1, 0.5 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 143.5 (d, J = 7.8 Hz),
140.0 (d, J = 11.9 Hz), 134.2, 131.3, 128.9, 128.5, 128.2, 127.5, 126.7,
126.3, 125.6, 125.3, 124.7, 123.8, 61.5 (d, J = 5.7 Hz), 40.7, 32.9 (d, J
= 140.1 Hz), 16.2; 31P NMR (162 MHz, CDCl3): δ (ppm) 29.8;
TOF-HRMS Calculated for C22H26O3P ([M + H]+): 369.1614, found
369.1617.
(R)-Diethyl (2-phenylpropyl)phosphonate (4a). Purification by
column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 30.8 mg, yield: 97%; 94% ee; [α]D20 = +18.6 (c
= 0.5, CH2Cl2); HPLC (Lux 5u Amylose-1, isopropanol/hexane = 3/
97, flow rate = 1.0 mL/min, l = 210 nm) tR = 15.8 min (major), tR =
17.1 min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34−7.26
(m, 2H), 7.22−7.16 (m, 3H), 4.03−3.83 (m, 4H), 3.23−3.13 (m,
1H), 2.11−1.95 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.26−1.17 (m,
6H); The analytical data are consistent with the literature.8b
(R)-Diethyl (2-(3-methoxyphenyl)propyl)phosphonate (4b). Pu-
rification by column chromatography (silica gel, PE:EA = 2:1)
20
afforded the product as yellow oil, 3.1 mg, yield: 96%; 96% ee; [α]D
= +22.6 (c = 0.7, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 =
10/90, flow rate = 3.0 mL/min, l = 230 nm) tR = 2.4 min (major), tR
1
= 2.3 min (minor); H NMR (600 MHz, CDCl3): δ (ppm) 7.20−
7.17 (m, 1H), 6.81−6.70 (m, 3H), 4.01−3.89 (m, 4H), 3.78 (d, J =
10.9 Hz, 3H), 3.16 (dq, J = 14.6, 7.4 Hz, 1H), 2.12−1.95 (m, 2H),
1.38−1.35 (m, 3H), 1.25−1.19 (m, 6H); The analytical data are
consistent with the literature.8c
(+)-Diethyl (2-(3-fluorophenyl)propyl)phosphonate (4c). Purifi-
cation by column chromatography (silica gel, PE:EA = 2:1) afforded
the product as yellow oil, 32.0 mg, yield: 94%; >99.9% ee; [α]D
+26.5 (c = 0.4, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 = 2/
20
=
1
98, flow rate = 2.0 mL/min, l = 254 nm) tR = 13.6 min (major); H
NMR (600 MHz, CDCl3): δ (ppm) 7.25−7.22 (m, 1H), 6.99 (d, J =
7.7 Hz, 1H), 6.92−6.86 (m, 2H), 4.02−3.89 (m, 4H), 3.23−3.18 (m,
1H), 2.10−1.96 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H), 1.22 (dt, J = 21.9,
7.0 Hz, 6H); 13C{1H}NMR (151 MHz, CDCl3): δ (ppm) 163.0 (d, J
= 245.3 Hz), 149.4 (dd, J = 12.7, 7.2 Hz), 130.1 (d, J = 8.9 Hz), 122.5
(d, J = 3.4 Hz), 113.7 (d, J = 21.7 Hz), 113.3 (d, J = 21.5 Hz), δ 61.5
(dd, J = 17.7, 7.2 Hz), 35.9−34.0 (m), 33.8, 23.5 (d, J = 10.4 Hz),
16.4 (t, J = 5.6 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm) 30.3;
TOF-HRMS Calculated for C13H21O3FP ([M + H]+): 275.1206,
found 275.1210.
(+)-Diethyl (2-(2-fluorophenyl)propyl)phosphonate (4d). Purifi-
cation by column chromatography (silica gel, PE:EA = 2:1) afforded
the product as yellow oil, 33.0 mg, yield: 97%; 99% ee; [α]D20 = +1.6
(c = 0.1, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/CO2 = 10/90,
flow rate = 3.0 mL/min, l = 254 nm) tR = 1.5 min (major), tR = 1.6
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.23−7.12 (m,
2H), 7.08−7.03 (m, 1H), 7.00−6.95 (m, 1H), 4.01−3.90 (m, 4H),
3.45 (dq, J = 14.1, 7.1 Hz, 1H), 2.23−1.98 (m, 1H), 1.40−1.37 (m,
3H), 1.23−1.19 (m, 6H); 13C{1H}NMR (151 MHz, CDCl3): δ
(ppm) 160.7 (d, J = 245.9 Hz), 133.1 (dd, J = 14.2, 11.3 Hz), 128.5
(d, J = 5.9 Hz), 128.0 (d, J = 9.0 Hz), 124.2 (d, J = 4.5 Hz), 115.6 (d,
J = 22.8 Hz), 61.5 (dd, J = 11.9, 7.0 Hz), 32.8 (d, J = 139.4 Hz), 29.2,
22.1 (d, J = 10.5 Hz), 16.4 (d, J = 6.3 Hz); 31P NMR (162 MHz,
CDCl3): δ (ppm) 30.5; TOF-HRMS Calculated for C13H21O3FP ([M
+ H]+): 275.1206, found 275.1210.
(+)-Diethyl (2-(3,4-dimethylphenyl)propyl)phosphonate (4i). Pu-
rification by column chromatography (silica gel, PE:EA = 2:1)
afforded the product as yellow oil, 33.9 mg, yield: 96%; 94% ee;
20
[α]D = +20.5 (c = 0.8, CH2Cl2); HPLC (Lux 5u Amylose-2,
isopropanol/hexane = 5/95, flow rate = 1.0 mL/min, l = 230 nm) tR =
8.5 min (major), tR = 9.1 min (minor); 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.04 (d, J = 7.7 Hz, 1H), 6.95−6.92 (m, 2H), 4.04−3.89 (m,
4H), 3.19−3.07 (m, 1H), 2.21 (d, J = 8.2 Hz, 6H), 2.14−1.92 (m,
2H), 1.35 (d, J = 7.0 Hz, 3H), 1.23 (dt, J = 15.6, 7.1 Hz, 6H);
13C{1H}NMR (101 MHz, CDCl3): δ (ppm) 144.4 (d, J = 13.1 Hz),
136.6, 134.6, 129.8, 128.1, 123.9, 61.4 (dd, J = 19.5, 6.5 Hz), 35.1,
34.3 (d, J = 3.5 Hz), 33.7, 23.5 (d, J = 8.4 Hz), 19.6 (d, J = 52.0 Hz),
16.4 (dd, J = 6.3, 2.9 Hz); 31P NMR (162 MHz, CDCl3): δ (ppm)
31.2; TOF-HRMS Calculated for C15H26O3P ([M + H]+): 285.1614,
found 285.1612.
(R)-Diethyl (2-phenylbutyl)phosphonate (4j). Purification by
column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 31.5 mg, yield: 94%; 99.2% ee; [α]D20 = +2.9 (c
= 1.3, CH2Cl2); SFC (Lux 5u Cellulose-1, MeOH/CO2 = 3/97, flow
rate = 2.5 mL/min, l = 210 nm) tR = 7.9 min (major), tR = 8.6 min
(minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.29−7.25 (m, 2H),
7.19−7.15 (m, 3H), 3.97−3.70 (m, 4H), 2.95−2.84 (m, 1H), 2.15−
2.00 (m, 2H), 1.88−1.78 (m, 1H), 1.66−1.55 (m, 1H), 1.15 (dt, J =
25.1, 7.1 Hz, 6H), 0.73 (t, J = 7.3 Hz, 3H); The analytical data are
consistent with the literature.8b
The gram scale hydrogenation of 3d was performed according to
the general procedure for asymmetric hydrogenation of 3 previously
mentioned. The product 4d was obtained as yellow oil in 97% yield,
0.98 g.
(+)-Diethyl (3-methyl-2-phenylbutyl)phosphonate (4k). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
20
product as yellow oil, 33.2 mg, yield: 94%; >99.9% ee; [α]D = +2.5
(R)-Diethyl (2-(o-tolyl)propyl)phosphonate (4e). Purification by
column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 31.2 mg, yield: 93%; 99.7% ee; [α]D = +13.8
(c = 2.2, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 = 3/97,
flow rate = 2.0 mL/min, l = 210 nm) tR = 9.4 min (major), tR = 10.2
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.31−7.23 (m,
3H), 7.18−7.13 (m, 2H), 3.89−3.56 (m, 2H), 2.80 (dd, J = 11.6, 5.9
20
(c = 0.6, CH2Cl2); SFC (Lux 5u Cellulose-2, MeOH/CO2 = 5/95,
I
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Article
Hz, 1H), 2.37−1.97 (m, 2H), 1.97−1.76 (m, 1H), 1.12 (t, J = 7.0 Hz,
3H), 1.03 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.9 Hz, 3H), 0.71 (d, J = 6.7
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 142.76,
128.70, 128.02, 126.42, 61.24 (d, J = 29.4 Hz), 46.76, 34.31 (d, J =
15.7 Hz), 29.76 (d, J = 141.4 Hz), 20.77, 19.76, 16.27 (d, J = 6.1 Hz);
31P NMR (162 MHz, CDCl3): δ (ppm) 32.0; TOF-HRMS Calculated
for C15H26O3P ([M + H]+): 285.1614, found 285.1612.
Authors
Chaoqiong Wang − Key Laboratory of Radiopharmaceuticals,
College of Chemistry, Beijing Normal University, Beijing
100875, China
Fang Xie − Key Laboratory of Radiopharmaceuticals, College
of Chemistry, Beijing Normal University, Beijing 100875,
China
Qianling Guo − Key Laboratory of Radiopharmaceuticals,
College of Chemistry, Beijing Normal University, Beijing
100875, China
Chaochao Xie − Key Laboratory of Radiopharmaceuticals,
College of Chemistry, Beijing Normal University, Beijing
100875, China
Guofu Zi − Key Laboratory of Radiopharmaceuticals, College
of Chemistry, Beijing Normal University, Beijing 100875,
China; orcid.org/0000-0002-7455-460X
Weiping Ye − HwaGen Pharma, Shenzhen 518122, China
Zhangtao Zhou − HwaGen Pharma, Shenzhen 518122,
China
(R)-Diethyl (2-methyl-4-phenylbutyl)phosphonate (4l). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as colorless oil; 35.5 mg, yield: 99%; 75% ee; [α]D20 = +7.20
(c = 1.0, CH2Cl2); HPLC (Lux 5u Cellulose-3, isopropanol/hexane =
1/99, flow rate = 0.5 mL/min, l = 210 nm) tR = 14.684 min (major),
1
tR = 14.122 min (minor); H NMR (600 MHz, CDCl3) δ (ppm)
7.28−7.24 (m, 2H), 7.18−7.14 (m, 3H), 4.04−4.00 (m, 4H), 2.64−
2.52 (m, 2H), 1.93−1.83 (m, 1H), 1.79−1.73 (m, 2H), 1.67−1.56
(m, 2H), 1.25 (t, J = 7.1 Hz, 6H), 1.08 (d, J = 6.6 Hz, 3H). 13C{1H}
NMR (150 MHz, CDCl3): δ (ppm) 142.3, 128.4, 125.8, 61.4, 40.0 (d,
J = 4.0 Hz), 33.3, 33.1, 32.4, 28.0, 20.8, 17.0. The analytical data are
consistent with the literature.8b
(R)-Diethyl (2-(pyridin-2-yl)propyl)phosphonate (4m). Purifica-
tion by column chromatography (silica gel, PE:EA = 2:1) afforded the
product as yellow oil, 27.1 mg, yield: 85%; 66% ee; [α]D20 = +18.4 (c
= 1.0, CH2Cl2); SFC (Lux 5u Amylose-1, MeOH/CO2 = 10/90, flow
rate = 3.0 mL/min, l = 210 nm) tR = 2.084 min (major), tR = 2.734
min (minor); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.50 (d, J = 4.0
Hz, 1H), 7.56 (t, J = 8.0 Hz 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.07 (t, J =
8.1 Hz, 1H), 3.91 (q, J = 14.4 Hz, 4H), 3.39−3.19 (m, 1H), 2.40 (dd,
J = 25.2, 8.2 Hz, 1H), 2.01 (dd, J = 25.2, 8.2 Hz, 1H), 1.37 (d, J = 6.9
Hz, 3H), 1.14 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ (ppm)
164.9 (d, J = 96.0 Hz), 149.3, 136.5, 122.1, 121.6, 61.4, 36.6, 32.2 (d,
J = 553.8 Hz), 22.7 (d, J = 38.4 Hz), 16.4 (d, J = 24.0 Hz). The
analytical data are consistent with the literature.8b
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01397
Author Contributions
#C.W. and F.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Method for Crystal Growth of the Product 2h. The crystal of
enantiomerically enriched 2h was obtained by diffusion from the
mixture solvent of CH2Cl2 and hexane. The product 2h was dissolved
in CH2Cl2 followed by an addition of 1.0 mL hexane, and then placed
in the refrigerator (about −4 °C) carefully.
We thank the National Natural Science Foundation of China
(Grant Nos. 21672024, 21272026, and 21871029), Beijing
Natural Science Foundation (2182025), and Beijing Municipal
Commission of Education for generous financial support.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01397.
NMR, SFC, and HPLC spectra PDF)
Accession Codes
CCDC 2089539 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Guohua Hou − Key Laboratory of Radiopharmaceuticals,
College of Chemistry, Beijing Normal University, Beijing
100875, China; Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, China; HwaGen Pharma, Shenzhen
518122, China; orcid.org/0000-0002-3571-456X;
Email: ghhou@bnu.edu.cn
Zhanbin Zhang − Key Laboratory of Radiopharmaceuticals,
College of Chemistry, Beijing Normal University, Beijing
100875, China; Email: 92045@bnu.edu.cn
J
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