First asymmetric Abramov-type phosphonylation of aldehydes with trialkyl phosphites catalyzed by chiral Lewis bases

Article abstract of DOI:10.1016/j.tet.2008.04.078

Chiral phosphine oxides (Lewis bases) catalyze silicon tetrachloride-mediated, enantioselective phosphonylation of aldehydes with trialkyl phosphites (Abramov-type reaction), which leads to optically active α-hydroxyphosphonates with moderate enantioselec

Full text of DOI:10.1016/j.tet.2008.04.078

Tetrahedron 64 (2008) 6415–6419
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First asymmetric Abramov-type phosphonylation of aldehydes
with trialkyl phosphites catalyzed by chiral Lewis bases
*
*
Kyoko Nakanishi, Shunsuke Kotani, Masaharu Sugiura , Makoto Nakajima
Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral phosphine oxides (Lewis bases) catalyze silicon tetrachloride-mediated, enantioselective phos-
phonylation of aldehydes with trialkyl phosphites (Abramov-type reaction), which leads to optically
active
Received 24 March 2008
Received in revised form 18 April 2008
Accepted 21 April 2008
a
-hydroxyphosphonates with moderate enantioselectivities. 31P NMR analysis of the phospho-
nylation of benzaldehyde with triethyl phosphite supports the assumed reaction mechanism.
Available online 24 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
BINAP dioxide (BINAPO) as a chiral Lewis base catalyst (Table 1). We
selected BINAPO catalyst because of its effectiveness in asymmetric
a
-Hydroxyphosphonates are an attractive class of biologically
aldol reactions,11e,f allylations,11c,f and epoxide ring-opening reac-
active compounds as well as useful synthetic intermediates of
tions.11d When SiCl4 was added dropwise to a solution of 1a, the
i
a
-substituted phosphonyl compounds.1 Because their biological
phosphite, and Pr2NEt13 in CH2Cl2 at ꢀ78 ꢁC, desired hydroxy-
activities usually depend on the absolute configuration, catalytic
enantioselective synthesis of these compounds has been explored.
Although a few successful asymmetric metal catalysts have been
developed for phosphonylation of aldehydes with dialkyl phos-
phites (Pudovik-type reaction2),3,4 asymmetric catalysis of the
alternative reaction with trialkyl phosphites (Abramov-type re-
action5) has yet to be achieved.
phosphonate 2a was obtained in a good yield with a moderate
enantioselectivity (entry 1). On the other hand, when the addition
order of the silane and the phosphite was reversed, enantiose-
lectivity was not observed (entry 2). We reasoned that SiCl4 itself
promoted the non-selective reaction. Therefore, the rate of silane
addition was investigated. It was found that adding the silane over
2 h improved the enantioselectivity (entry 3). In the absence of the
amine, both the yield and selectivity decreased (entry 4). Further-
more, the addition of 2-methyl-2-butene, a non-basic proton
scavenger did not improve the result (entry 5). This observation
implies that the role of the amine is not only to capture concomitant
acid, but also to promote the catalyst turnover. Next, the amount of
the amine was investigated (entries 6 and 7). A substoichiometric
amount (0.5 equiv) resulted in low yield, while an excess amount
(5.0 equiv) gave a result comparable to that using 1.5 equiv. In
addition, the loading of the BINAPO catalyst had a negligible effect
on the selectivity (entries 9 and 10). It should be noted that the
catalyst turnover of BINAPO was sufficient under the conditions,
considering the reaction proceeded even in the absence of the
catalyst (entry 8).
Recently, Denmerk et al. have reported that weakly Lewis acidic
silicon tetrachloride (SiCl4) can be activated by coordination of
Lewis bases and that the resulting Lewis base/SiCl4 complex pro-
motes ring-opening of epoxides6 or addition of nucleophiles (allyl/
propargyltin,7 enoxysilanes,8 isocyanides,9 or silyl ketene imines10
to aldehydes or ketones.
)
In our continuous efforts to develop chiral Lewis base-catalyzed
asymmetric reactions,11 we envisioned that a chiral Lewis base (LB
*
)/
SiCl4 complex could activate prochiral aldehydes and facilitate enan-
tioselective attack of trialkyl phosphites to yield trichlorosilylated
a
-hydroxyphosphonates after Arbuzov-type12 liberation of the
corresponding alkyl chloride (Fig. 1). Herein, we report first catalytic
enantioselective Abramov-type phosphonylation of aldehydes.
2. Results and discussion
LB*
SiCl4
LB*
SiCl3
At the onset, we investigated phosphonylation of benzaldehyde
(1a) with triethyl phosphite under various conditions using (S)-
O
Cl–
SiCl3
O
*
+
R
H
O
R'
OR'
OR'
SiCl3
Cl–
LB*
R
P
O
–LB*
R
H
P
O
OR'
OR'
* Corresponding authors. Tel.: þ81 96 371 4680; fax: þ81 96 362 7692.
E-mail addresses: msugiura@kumamoto-u.ac.jp (M. Sugiura), nakajima@gpo.
kumamoto-u.ac.jp (M. Nakajima).
LB* = chiral Lewis base
Figure 1. Assumed reaction mechanism.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.078

6416
K. Nakanishi et al. / Tetrahedron 64 (2008) 6415–6419
Table 1
Table 2
Phosphonylation of benzaldehyde catalyzed by (S)-BINAPO
BINAPO-catalyzed reaction of 1a with various phosphitesa
(S)-BINAPO (10 mol %)
O
O
P
OH
SiCl4 (1.5 equiv)
Ph
Ph
Ph
Ph
i
Pr2NEt (1.5 equiv)
(S)-BINAPO (10 mol %)
OR
OR
1a
Ph
H
+
phosphite
(1.5 equiv)
Ph
P
O
OH
SiCl4 (1.5 equiv)
additive
CH2Cl2, –78 °C, 2 h
1a
OEt
OEt
P
O
+
Ph
P
O
(R)-2a
CH2Cl2, –78 °C
P(OEt)3
(1.5 equiv)
Entry
Phosphite
R
Yield (%)
% ee (config.)
(S)-BINAPO
1
2
3
4
5
P(OR)3
Me
Et
97
91
84
84
0
28 (R)
41 (R)
40 (R)
33
iPr
Bu
Ph
Entry
Additive (equiv)
Methoda
2a (%)
% ee (config.)
d
1
2
3
4
5
6
7
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
d
A
B
C
C
C
C
C
C
C
C
73
57
91
30
18
28
86
75
67
60
31 (R)
0
6
7
8
9
HP(O)(OR)2
Me
Et
57
82
72
51
27 (R)
18 (R)
19 (R)
8 (R)
41 (R)
15 (R)
29 (R)
37 (R)
41 (R)
d
iPr
Bn
2-Methyl-2-butene (1.5)
iPr2NEt (0.5)
iPr2NEt (5.0)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
a
All reactions were carried out using 1a (0.5 mmol), (S)-BINAPO (10 mol %),
a phosphite (1.5 equiv), Pr2NEt (1.5 equiv), and SiCl4 (1.5 equiv slowly added over
i
8b
9c
10d
2 h) at ꢀ78 ꢁC.
40 (R)
40 (R)
a
(A) Addition of SiCl4 at usual rate to a solution of 1a, (S)-BINAPO (10 mol %),
P(OEt)3, and additive in CH2Cl2 at ꢀ78 ꢁC. (B) Addition of P(OEt)3 over 5 h to a so-
lution of 1a, (S)-BINAPO (10 mol %), SiCl4, and additive in CH2Cl2 at ꢀ78 ꢁC. (C) Ad-
dition of SiCl4 over 2 h to a solution of 1a, (S)-BINAPO (10 mol %), P(OEt)3, and
additive in CH2Cl2 at ꢀ78 ꢁC.
6–9). However, the selectivities were lower than those with trialkyl
phosphites.
Then the scope and limitations of aldehyde substrates were
examined (Table 3). The reactions were performed under optimized
conditions using triethyl phosphite. p-Anisaldehyde, an electron-
donating benzaldehyde derivative, and benzaldehyde provided
comparable results (entry 1), but that with p-bromobenzaldehyde
gave a lower selectivity (entry 2). Aldehydes with a low Lewis
basicity may loosen the transition state structure for the enantio-
determining step (vide infra), leading to a decreased selectivity.
b
Without BINAPO.
c
(S)-BINAPO (30 mol %).
(S)-BINAPO (5 mol %).
d
Using toluene or THF instead of dichloromethane afforded re-
actionswith inferiorresults. Althougha highreactivitywas observed
in propionitrile (90% yield), the enantioselectivity decreased to 7%
ee, presumablybecausepropionitrile served asanachiralLewisbase.
As summarized in Figure 2, chiral Lewis bases other than
BINAPO were examined for the phosphonylation of benzaldehyde
(1a) with triethyl phosphite under optimized conditions (Table 1,
entry 3). Triarylphosphine oxides showed high activities, whereas
alkylarylphosphine oxides or bisquinoline N,N0-dioxides provided
inferior results.
Next, the effect of varying the phosphites on reaction of 1a was
investigated (Table 2). For trialkyl phosphites, smaller alkyl groups
tended to give higher yields (entries 1–4), whereas triphenyl
phosphite did not react at all (entry 5). These findings are consis-
tent with the assumed mechanism, which involves an Arbuzov-
type attack of the chloride anion on the alkyl group of phosphite.
Among the trialkyl phosphites tested, triethyl phosphite gave the
highest enantioselectivity. On the other hand, it was found that
Pudovik-type reactions with dialkyl phosphites were also pro-
moted by silicon tetrachloride and the BINAPO catalyst (entries
Although sterically congested 1-naphthaldehyde gave
a low
selectivity (entry 3), 2-naphthaldehyde afforded a moderate se-
lectivity (entry 4). Cinnamaldehyde, an even less congested con-
jugate aldehyde, afforded an improved enantioselectivity (entry 5),
and the 1,4-adduct was not observed. The enantioselectivity was
slightly improved by using (S)-PHANEPHOS dioxide as a catalyst,
but the yield remained moderate (entry 6). Aliphatic aldehydes
exhibited good reactivities, albeit with their low selectivities,
despite low reactivity due to chlorohydrin formation with chloro-
silane reagents14 (entries 7 and 8).
Table 3
Asymmetric phosphonylation of various aldehydes with triethyl phosphite cata-
lyzed by BINAPOa
(S)-BINAPO (10 mol %)
OH
SiCl4 (1.5 equiv)
O
i
Pr2NEt (1.5 equiv)
OEt
OEt
+
P(OEt)3
(1.5 equiv)
R
P
O
R
H
CH2Cl2, –78 °C
1
O
O
P
O
P
O
P
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Entry
R
Product
Yield (%)
% ee (config.)
Ph
Ph
P
O
P
O
1
2
p-MeOC6H4
p-BrC6H4
2b
2c
2d
2e
2f
2f
2g
2h
90
87
83
98
89
64
65
49
40 (R)
22
9
P
O
Ph
O
3
1-Naphthyl
2-Naphthyl
(E)-PhCH]CH
(E)-PhCH]CH
PhCH2CH2
95% yield
31% ee (R)
94% yield
44% ee (S)
57% yield
10% ee (R)
4b
5
33
49 (R)
52 (S)
17f
6c
7d
8e
P
N
N
Cyclohexyl
23f
O
O
O
O
a
N
O
N
O
Reactions were carried out using an aldehyde (0.5 mmol), (S)-BINAPO
(10 mol %), P(OEt)3 (1.5 equiv), iPr2NEt (1.5 equiv), and SiCl4 (1.5 equiv slowly added
over 2 h) at ꢀ78 ꢁC otherwise noted.
P
b
46% yield
3% ee (R)
60% yield
7% ee (S)
Reaction was performed at ꢀ78 ꢁC for 1 h after addition of SiCl4.
78% yield
0% ee
c
(S)-PHANEPHOS dioxide (10 mol %) was used instead of (S)-BINAPO.
d
Reaction was performed at ꢀ78 ꢁC for 10 h after addition of SiCl4.
e
Figure 2. Screening of Lewis base catalyst; conditions: 1a (0.5 mmol), P(OEt)3
Reaction was performed at ꢀ78 ꢁC for 12 h after addition of SiCl4.
i
f
(1.5 equiv), Pr2NEt (1.5 equiv), and SiCl4 (1.5 equiv slowly added over 2 h) at ꢀ78 ꢁC.
The ee was determined by 31P NMR analysis using quinine.15

K. Nakanishi et al. / Tetrahedron 64 (2008) 6415–6419
6417
3. Conclusion
We have demonstrated that chiral Lewis bases catalyze asym-
metric phosphonylation of aldehydes with trialkyl phosphites. Al-
though the selectivity is not yet satisfactory, this is the first catalytic
enantioselective Abramov-type phosphonylation of aldehydes.
Further improvement of the selectivity by developing new Lewis
base catalysts is currently under investigation.
4. Experimental
4.1. General
Melting points were uncorrected. 1H, 13C{1H}, and 31P{1H} NMR
spectra were measured in CDCl3 with JEOL JNM-ECX400 spectrom-
eter otherwise noted. Tetramethylsilane (TMS) (
d
¼0 ppm), CDCl3
(d
¼77.0 ppm), and aq phosphoric acid sealed in a glass capillary
(d
¼0 ppm) were used for internal standards for 1H, 13C, and 31P NMR
analyses, respectively. Infrared spectra were recorded on JIR-6500W.
Mass spectra were measured with JEOL JMS-DX303HF mass spec-
trometer. Optical rotations were recorded on JASCO P-1010 polar-
imeter. High pressure liquid chromatography (HPLC) was performed
with JASCO P-980 and UV-1575. Thin-layer chromatography (TLC)
analysiswascarriedoutusingMerk silicagelplates. Visualizationwas
accomplished with UV light and/or phosphomolybdic acid. Column
chromatography was performed using Kanto Chemical Silica Gel 60N
(spherical, neutral, 63–210 mm). All reactions were performed under
argon atmosphere using oven- and heating gun-dried glassware
equipped with a rubber septum and a magnetic stirring bar.
Dichloromethane (dehydrated) was purchased from Kanto
Chemical and stored over 4 Å MS prior to use. All other solvents
were purified based on standard procedures. Silicon tetrachloride
was purchased from Tokyo Kasei Kogyo (TCI) and used without
further purification. (S)-BINAP dioxide was prepared by oxidation
of (S)-BINAP with hydrogen peroxide in acetone.11f Triethyl phos-
phite was distilled from sodium. Diisopropylethylamine was dis-
tilled from calcium hydride. All other chemicals were purified
based on standard procedures.
4.2. General procedure for phosphonylation of aldehydes
catalyzed by BINAPO
A phosphite (0.75 mmol) was added to a solution of an aldehyde
(0.5 mmol), iPr2NEt (0.75 mmol), and (S)-BINAPO (10 mol %) in
dichloromethane (2 mL) at ꢀ78 ꢁC and then silicon tetrachloride
(0.75 M dichloromethane solution, 1.0 mL) was introduced over 2 h
using a syringe pump. After checking completion of the reaction by
TLC analysis, deionized water (2 mL), satd aq NaHCO3 (5 mL), and
ethyl acetate (5 mL) were added in turn to the reaction mixture.
After being stirred for 1 h, the mixture was filtered via a Celite pad
and extracted with ethyl acetate (3ꢂ5 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated under reduced pressure. The residue was
purified with silica gel column chromatography (silica gel 15 g,
hexane/acetone 2/1 then 1/1) to give the corresponding
Chart 1. 31P{1H} NMR analysis of phosphonylation of benzaldehyde with triethyl
phosphite in CD2Cl2 at ꢀ78 ꢁC. (a) P(OEt)3 and BINAPO; (b) (a)þSiCl4; (c) (b)þPhCHO;
(d) quenched with ethanol.
In order to gain mechanistic insights, the reaction of benzalde-
hyde with triethyl phosphite in deuterated dichloromethane
at ꢀ78 ꢁC was monitored by 31P{1H} NMR analysis (Chart 1). First,
the signals of BINAPO (10 mol %) and P(OEt)3 appeared at 27.9 and
136.5 ppm, respectively (spectrum a). Upon the addition of SiCl4,
the BINAPO signal shifted to 36.5 ppm, whereas that of P(OEt)3 did
not shift (spectrum b). These observations support the formation of
a SiCl4/BINAPO complex and deny the possibility that a new
phosphonylating agent is generated from P(OEt)3 and SiCl4. Next,
when benzaldehyde was added to the mixture, the P(OEt)3 signal
disappeared completely, but signals near 16 ppm emerged (spec-
trum c). This observation supports that trivalent P(OEt)3 is trans-
formed into pentavalent phosphonate products, which is consistent
with the assumed mechanism shown in Figure 1. Finally,
a-hydroxyphosphonate. After separation of the product, BINAPO
could be recovered quantitatively by eluting with dichloro-
methane/ethanol (10/1) without loss of the optical activity.
4.3. Physical data of products
a
-hydroxyphosphonate 2a was liberated at 21.9 ppm after
4.3.1. (R)-Diethyl 1-hydroxy-1-phenylmethylphosphonate (2a)16
quenching with ethanol (spectrum d). According to this mecha-
nism, the enantio-determining step is the attack of phosphites to
the aldehyde/SiCl4/BINAPO complex. However, a detailed pro-
jection of the transition state for this step remains unclear.
TLC: Rf 0.41 (hexane/acetone¼1/1, stained blue with phospho-
27
molybdic acid/EtOH); [
a
]
þ14.8 (c 1.01, CHCl3) for 41% ee (R). [lit.3a
D
20
[a
]
þ19.1 (c 1.0, CHCl3) for 53% ee (R)]; 1H NMR (CDCl3):
d 1.22 (t,
D
3H, J¼7.3 Hz), 1.27 (t, 3H, J¼7.3 Hz), 3.20 (br s, 1H), 3.22–4.09 (m,

6418
K. Nakanishi et al. / Tetrahedron 64 (2008) 6415–6419
4H), 5.03 (dd, 1H, J¼5.0, 10.5 Hz), 7.28–7.40 (m, 3H), 7.48–7.50 (m,
3259, 2979, 1578, 1486, 1230, 733 cmꢀ1; mp: 69.0–71.0 ꢁC; 1H NMR
(CDCl3):
1.25 (t, 3H, J¼6.9 Hz), 1.28 (t, 3H, J¼6.9 Hz), 1.71 (br s, 1H),
4.00–4.11 (m, 4H), 4.99 (d, 1H, J¼11.0 Hz), 7.35–7.38 (m, 2H), 7.49–
7.51 (m, 2H); 13C NMR (CDCl3):
16.32, 16.37, 63.1 (Jcp¼7.6 Hz), 63.5
2H); 31P NMR (CDCl3):
d
21.4; HPLC (Daicel Chiralpak AS, flow rate:
d
1.0 mL/min, hexane/iPrOH¼19/1, UV detection at 254 nm):
tR¼17.2 min (R, major), 22.5 min (S, minor).
d
(Jcp¼6.7 Hz), 70.1 (Jcp¼159.2 Hz), 121.9 (Jcp¼3.81 Hz), 128.7
4.3.2. (R)-Dimethyl 1-hydroxy-1-phenylmethylphosphonate3e
(Jcp¼4.77 Hz), 131.3, 135.8; 31P NMR (CDCl3):
d 20.6; MS (FAB): m/z
TLC: Rf 0.23 (hexane/acetone¼1/1, stained blue with phospho-
121, 185, 305, 307, 323, 325 [MþH]þ; HRMS: calcd for C11H17O4BrP
323.0048 (100), 325.0029(99), found 323.0043; HPLC (Daicel
Chiralpak AS, flow rate: 1.0 mL/min, hexane/iPrOH¼9/1, UV
detection at 254 nm): tR¼11.0 min (major), 14.8 min (minor).
20
molybdic acid/EtOH); [
a
]
þ21.5 (c 0.80, CHCl3) for 28% ee (R).
D
20
[lit.17
[
a
]
D
ꢀ45 (c 0.80, CHCl3) for 90% ee (S)]; mp: 91.0–92.5 ꢁC; 1H
NMR (CDCl3):
d
3.22–3.27 (m, 1H), 3.67 (d, 3H, J¼10.1 Hz), 3.72 (d,
3H, J¼10.5 Hz), 5.06 (dd,1H, J¼5.0,11.0 Hz), 7.31–7.40 (m, 3H), 7.49–
7.50 (m, 2H); 31P NMR (CDCl3):
d
23.5; HPLC (Daicel Chiralpak AS,
4.3.8. Diethyl 1-hydroxy-1-(1-naphthyl)methylphosphonate (2d)20
flow rate: 1.0 mL/min, hexane/iPrOH¼9/1, UV detection at 254 nm):
tR¼15.7 min (R, major), 19.9 min (S, minor).
TLC: Rf 0.13 (hexane/acetone¼2/1, stained blue with phospho-
19
molybdic acid/EtOH); [
a
]
D
þ11.5 (c 1.01, CHCl3) for 9% ee. [lit.20
20
[a
]
þ19.4 (c 1.19, CHCl3) for 35% ee]; mp: 114.0–115.5 ꢁC; 1H NMR
D
4.3.3. (R)-Diisopropyl 1-hydroxy-1-phenylmethylphosphonate17
(CDCl3):
d
1.05 (t, 3H, J¼6.9 Hz), 1.25 (t, 3H, J¼6.9 Hz), 3.32 (dd, 1H,
TLC: Rf 0.57 (hexane/acetone¼1/1, stained blue with phospho-
J¼5.5, 11.5 Hz), 3.72–3.82 (m, 1H), 3.92–4.12 (m, 3H), 5.86 (dd,
1H, J¼5.5, 11.5 Hz), 7.48–7.56 (m, 3H), 7.82–7.88 (m, 3H), 8.10 (d, 1H,
19
molybdic acid/EtOH); [
a]
þ12.2 (c 1.01, CHCl3) for 40% ee (R). [lit.18
D
20
[a
]
D
ꢀ17.3 (c 1.0, CHCl3) for 65% ee (S)]; mp: 85.0–86.5 ꢁC; 1H NMR
J¼8.2 Hz); 31P NMR (CDCl3):
d 21.7; HPLC (Daicel Chiralpak AS, flow
(CDCl3):
d
1.13 (d, 3H, J¼6.0 Hz), 1.24 (d, 3H, J¼6.0 Hz), 1.276 (d, 3H,
rate: 1.0 mL/min, hexane/iPrOH¼9/1, UV detection at 254 nm):
tR¼12.4 min (major), 42.3 min (minor).
J¼6.4 Hz), 1.281 (d, 3H, J¼6.0 Hz), 3.19 (br s, 1H), 4.57–4.67 (m, 2H),
4.96(d,1H, J¼11.0 Hz), 7.28–7.38(m, 3H), 7.48–7.50(m, 2H); 31PNMR
(CDCl3):
d
19.9; HPLC (Daicel Chiralpak AS, flow rate: 1.0 mL/min,
4.3.9. Diethyl 1-hydroxy-(2-naphthyl)methylphosphonate (2e)
hexane/iPrOH¼39/1): tR¼12.1 min (R, major), 14.5 min (S, minor).
TLC: Rf 0.21 (hexane/acetone¼2/1, stained blue with phospho-
22
molybdic acid/EtOH); [
a
]
þ11.9 (c 1.0, CHCl3) for 33% ee (R); IR
D
4.3.4. Di-n-butyl 1-hydroxy-1-phenylmethylphosphonate
(KBr): 3273, 2981, 1630, 1600, 1234, 1016, 762 cmꢀ1; mp: 88.0–
TLC: Rf 0.35 (hexane/acetone¼2/1, stained blue with phospho-
89.0 ꢁC; 1H NMR (CDCl3):
d
1.21 (t, 3H, J¼6.9 Hz), 1.26 (t, 3H,
20
molybdic acid/EtOH); [
a
]
þ8.8 (c 1.05, CHCl3) for 33% ee; IR
J¼6.9 Hz), 3.89–4.18 (m, 5H), 5.20 (dd, 1H, J¼4.1, 11.0 Hz), 7.46–7.50
D
(neat): 3282, 2960, 1454, 1236, 1058, 734 cmꢀ1 1H NMR (CDCl3):
;
(m, 2H), 7.60 (d, 1H, J¼8.7 Hz), 7.82–7.85 (m, 3H), 7.96 (s, 1H); 13C
d
0.87 (t, 3H, J¼7.3 Hz), 0.90 (t, 3H, J¼7.3 Hz), 1.24–1.39 (m, 4H),
NMR (CDCl3):
d
16.31, 16.35, 63.1 (Jcp¼6.7 Hz), 63.4 (Jcp¼7.6 Hz),
1.50–1.63 (m, 4H), 3.34 (dd, 1H, J¼5.0, 10.3 Hz), 3.88–4.11 (m, 4H),
5.02 (dd, 1H, J¼5.0, 11.0 Hz), 7.27–7.38 (m, 3H), 7.47–7.49 (m, 2H);
70.9 (Jcp¼158.3 Hz), 124.9 (Jcp¼3.8 Hz), 126.05, 126.11, 127.6, 127.8,
128.0, 133.0, 134.16, 134.20; 31P NMR (CDCl3):
d 21.4; MS (FAB): m/z
13C NMR (CDCl3):
d
13.8, 18.8 (Jcp¼4.8 Hz), 32.7 (Jcp¼4.8 Hz), 66.8
157, 277, 295 [MþH]þ; HRMS: calcd for C15H20O4P 295.1099, found
295.1100; HPLC (Daicel Chiralpak AS, flow rate: 1.0 mL/min,
hexane/iPrOH¼4/1, UV detection at 254 nm): tR¼8.3 min (major),
9.9 min (minor).
(Jcp¼7.6 Hz), 67.7 (Jcp¼7.6 Hz), 71.0 (Jcp¼158.3 Hz), 127.4 (Jcp
¼
5.7 Hz), 128.1 (Jcp¼3.0 Hz), 128.3, 137.1; 31P NMR (CDCl3):
d 21.3; MS
(FAB): m/z 107, 173, 227, 301 [MþH]þ; HRMS: calcd for C15H26O4P
301.1569, found 301.1588; HPLC (Daicel Chiralpak AS, flow rate:
1.0 mL/min, hexane/iPrOH¼39/1, UV detection at 254 nm):
tR¼12.0 min (major), 16.9 min (minor).
4.3.10. (1R,2E)-Diethyl 1-hydroxy-3-phenylprop-2-enyl-
phosphonate (2f)21
TLC: Rf 0.34 (hexane/acetone¼1/1, stained blue with phospho-
18
4.3.5. (R)-Dibenzyl 1-hydroxy-1-phenylmethylphosphonate19
molybdic acid/EtOH); [
a
]
D
þ7.7 (c 0.92, CHCl3) for 49% ee (R). [lit.20
20
TLC: Rf 0.27 (hexane/acetone¼2/1, stained blue with phospho-
[a
]
þ4.7 (c 0.59, CHCl3) for 41% ee (R)]; mp: 99.0–99.5 ꢁC; 1H NMR
D
18
molybdic acid/EtOH); [
a
]
D
þ0.4 (c 1.01, MeOH) for 8% ee (R). [lit.19
(CDCl3):
d
1.34 (t, 6H, J¼7.1 Hz), 2.66 (dd, 1H, J¼3.6, 5.5 Hz), 4.16–
19
[
a]
ꢀ16.3 (c 1.0, MeOH) for 99% ee (S)]; mp: 103.0–104.0 ꢁC; 1H
4.24 (m, 4H), 4.64–4.70 (m, 1H), 6.32 (ddd, 1H, J¼5.5, 5.7, 16.0 Hz),
NMR (CDCl3):
d
3.33 (dd, 1H, J¼5.0, 9.8 Hz), 4.84–4.97 (m, 4H), 5.07
6.78 (dd, 1H, J¼4.6, 16.0 Hz), 7.25–7.42 (m, 5H); 31P NMR (CDCl3):
(dd, 1H, J¼4.1, 10.3 Hz), 7.19–7.22 (m, 2H), 7.26–7.36 (m, 11H), 7.44–
d 21.9; HPLC (Daicel Chiralpak AS, flow rate: 1.0 mL/min,
7.46 (m, 1H); 31P NMR (CDCl3):
d
22.1; HPLC (Daicel Chiralpak AS,
hexane/iPrOH¼9/1, UV detection at 254 nm): tR¼14.0 min (R,
major), 23.0 min (S, minor).
flow rate: 1.0 mL/min, hexane/iPrOH¼4/1, UV detection at 254 nm):
tR¼9.2 min (R, major), 15.5 min (S, minor).
4.3.11. (R)-Diethyl 1-hydroxy-3-phenylpropylphosphonate (2g)20
4.3.6. (R)-Diethyl 1-hydroxy-1-(4-methoxyphenyl)-
TLC: Rf 0.39 (hexane/acetone¼1/1, stained blue with phospho-
20
methylphosphonate (2b)20
molybdic acid/EtOH); [
a
]
ꢀ3.7 (c 1.0, CHCl3) for 17% ee; 1H NMR
D
TLC: Rf 0.34 (hexane/acetone¼1/1, stained blue with phospho-
(CDCl3): d 1.30–1.35 (m, 6H), 1.95–2.14 (m, 2H), 2.67–2.78 (m, 2H),
18
molybdic acid/EtOH); [
a
]
D
þ14.1 (c 1.01, CHCl3) for 40% ee (R). [lit.20
2.92–2.99 (m, 1H), 3.82–3.89 (m, 1H), 4.12–4.19 (m, 4H), 7.18–7.31
20
[
a]
þ29.8 (c 1.49, CHCl3) for 74% ee (R)]; mp: 119.0–120.0 ꢁC; 1H
(m, 5H); 13C NMR (CDCl3):
d
16.4 (d, Jcp¼4.8 Hz),16.5 (d, Jcp¼4.8 Hz),
D
NMR (CDCl3):
d
1.23 (t, 3H, J¼6.9 Hz), 1.29 (t, 3H, J¼6.9 Hz), 2.68–
31.6 (d, Jcp¼14.3 Hz), 32.9, 62.5 (d, Jcp¼7.7 Hz), 62.8 (d, Jcp¼7.7 Hz),
2.74 (m, 1H), 3.82 (s, 3H), 3.92–4.11 (m, 4H), 4.95 (dd, 1H, J¼5.0,
66.8 (d, Jcp¼160.2 Hz), 125.9, 128.4, 128.6, 141.3; 31P NMR (CDCl3):
10.1 Hz), 6.91 (d, 2H, J¼8.2 Hz), 7.26–7.43 (m, 2H); 31P NMR (CDCl3):
d
25.3. The enantiomeric excess was determined by 31P NMR
d
21.8; HPLC (Daicel Chiralpak AS, flow rate: 1.0 mL/min,
analysis of a solution of the phosphonate (5 mg) and quinine
(40 mg) in CDCl3 (0.6 mL).15
hexane/iPrOH¼4/1, UV detection at 254 nm): tR¼11.0 min (R, ma-
jor), 14.7 min (S, minor).
4.3.12. Diethyl 1-hydroxy-1-cyclohexylmethylphosphonate (2h)22
4.3.7. Diethyl 1-hydroxy-1-(4-bromophenyl)methyl-
phosphonate (2c)
TLC: Rf 0.35 (hexane/acetone¼2/1, stained blue with phospho-
21
molybdic acid/EtOH); [
a
]
ꢀ1.5 (c 1.16, CHCl3) for 23% ee; 1H NMR
D
TLC: Rf 0.48 (hexane/acetone¼1/1, stained blue with phospho-
(CDCl3):
d
1.35 (t, 3H, J¼6.9 Hz), 1.35 (t, 3H, J¼6.9 Hz), 1.09–1.35 (m,
22
molybdic acid/EtOH); [
a
]
þ7.2 (c 0.99, CHCl3) for 22% ee; IR (KBr):
5H), 1.66 (br d, 1H, J¼11.4 Hz), 1.72–1.82 (m, 4H), 2.00 (br d, 1H,
D

K. Nakanishi et al. / Tetrahedron 64 (2008) 6415–6419
6419
6. (a) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. J. Org. Chem.
1998, 63, 2428–2429; (b) Denmark, S. E.; Barsanti, P. A.; Beutner, G. L.;
Wilson, T. W. Adv. Synth. Catal. 2007, 349, 567–582. See also Refs. 11b and
11d.
J¼12.8 Hz), 2.17 (t, 1H, J¼6.9 Hz), 3.64–3.69 (m, 1H), 4.13–4.21
(m, 4H); 31P NMR (CDCl3):
d 25.9. The enantiomeric excess was
determined as 2g.
7. Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199–6200.
8. (a) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405–
13407; (b) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800–7801;
(c) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. E. J. Am. Chem. Soc.
2005, 127, 3774–3789; (d) Denmark, S. E.; Heemstra, J. R., Jr. J. Am. Chem. Soc.
2006, 128, 1038–1039; (e) Denmark, S. E.; Heemstra, J. R., Jr. J. Org. Chem. 2007,
72, 5668–5688.
Acknowledgements
This work is partially supported by a Grant-in-Aid of Scientific
Research from the Ministry of Education, Science, Sports, and
Culture of Japan.
9. (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825–7827; (b) Denmark,
S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667–9676.
10. Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R., Jr. J. Am. Chem. Soc.
2007, 129, 14864–14865.
References and notes
11. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120,
6419–6420; (b) Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S. Tetrahedron
Lett. 2002, 43, 8827–8829; (c) Nakajima, M.; Kotani, S.; Ishizuka, T.; Hashimoto,
S. Tetrahedron Lett. 2005, 46, 157–159; (d) Tokuoka, E.; Kotani, S.; Matsunaga, H.;
Ishizuka, T.; Hashimoto, S.; Nakajima, M. Tetrahedron: Asymmetry 2005, 16,
2391–2392; (e) Kotani, S.; Hashimoto, S.; Nakajima, M. Synlett 2006, 1116–1118;
(f) Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122–3132.
12. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430.
13. The effectiveness of iPr2NEt has been observed in our group for Lewis base-
catalyzed reactions of chlorosilane reagents, see Ref. 11.
14. For discussion on formation of chlorohydrines, see Ref. 8c.
15. (a) Duxbury, J. P.; Cawley, A.; Thornton-Pett, M.; Wantz, L.; Warne, J. N. D.;
Greatrex, R.; Brown, D.; Kee, T. P. Tetrahedron Lett. 1999, 40, 4403–4406; (b)
Zymatlczyk-Duda, E.; Skwarczytlski, M.; Lejczak, B.; Kafarski, P. Tetrahedron:
Asymmetry 1996, 7, 1277–1280.
1. For example, see: (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
1990, 31, 5587–5590; (b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron
Lett. 1990, 31, 5591–5594; (c) Stowasser, B.; Budt, K.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625–6628.
2. (a) Pudovik, A. N. Dokl. Akad. Nauk SSSR 1950, 73, 499–502; Chem. Abstr. 1951, 45,
2856d;(b)Pudovik, A. N.;Kitaev, Yu. O. Zh. Obshch. Khim.1952, 22, 467–473;Chem.
Abstr.1952, 47, 2687a; (c) Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45, 2465–
2524; For a review: (d) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81–96.
3. For asymmetric metal catalysts, see: (a) Yokomatsu, T.; Yamagishi, T.; Shibuya,
S. Tetrahedron: Asymmetry 1993, 4, 1779–1782; (b) Yokomatsu, T.; Ymamagishi,
T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1783–1784; (c) Yokomatsu, T.;
Yamagishi, T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1997, 1527–1533; (d) Rath,
N. P.; Spilling, C. D. Tetrahedron Lett. 1994, 35, 227–230; (e) Arai, T.; Bougauchi,
M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1996, 61, 2926–2927; (f) Sasai, H.;
Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 2717–2720; (g)
Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2005, 44, 4600–4602; (h) Saito, B.;
Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 1978–1986; (i) Zhou, X.; Liu, X.;
Yang, X.; Shang, D.; Xin, J.; Feng, X. Angew. Chem., Int. Ed. 2008, 47, 392–394.
4. Wynberg et al. reported first asymmetric Pudovik-type phosphonylation using
quinine as an organocatalyst: (a) Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett.
1983, 24, 5899–5900; (b) Smaardijk, A. A.; Noorda, S.; Wynberg, H. Tetrahedron
Lett. 1985, 26, 493–496.
16. Skropeta, D.; Schmidt, R. R. Tetrahedron: Asymmetry 2003, 14, 265–274.
17. As the racemate: Li, Y. F.; Hammerschmidt, F. Tetrahedron: Asymmetry 1993, 4,
109–120.
18. Meier, C.; Laux, W. H. G. Tetrahedron: Asymmetry 1995, 6, 1089–1092.
19. Pawar, V. D.; Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc.
2006, 128, 6308–6309.
20. Qian, C.; Huang, T.; Zhu, C.; Sun, J. J. Chem. Soc., Perkin Trans. 1 1998, 13, 2097–
2103.
5. (a) Abramov, V. S. Dokl. Akad. Nauk SSSR 1950, 73, 487–489; Chem. Abstr. 1951,
45, 2855h; (b) Abramov, V. S. Dokl. Akad. Nauk SSSR 1954, 95, 991–992; Chem.
Abstr. 1955, 49, 6084d.
21. Yokomatsu, T.; Yamagishi, T.; Sada, T.; Suemune, K.; Shibuya, S. Tetrahedron
1998, 54, 781–790.
22. Guillemin, J. C.; Janati, T.; Denis, J. M. J. Org. Chem. 2001, 66, 7864–7868.