Quinidine thiourea-catalyzed enantioselective synthesis of β-nitrophosphonates: Beneficial effects of molecular sieves

Article abstract of DOI:10.1016/j.tet.2011.07.059

An efficient method for enantioselective synthesis of β- nitrophosphonates via the Michael addition of diphenyl phosphite to nitroalkenes using the readily available quinidine thiourea organocatalyst has been developed. The desired β-nitrophosphonates wer

Full text of DOI:10.1016/j.tet.2011.07.059

Tetrahedron 67 (2011) 7479e7484
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Quinidine thiourea-catalyzed enantioselective synthesis of b-nitrophosphonates:
beneficial effects of molecular sieves
*
Santhi Abbaraju, Mayur Bhanushali, Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 May 2011
Received in revised form 18 July 2011
Accepted 20 July 2011
Available online 26 July 2011
An efficient method for enantioselective synthesis of b-nitrophosphonates via the Michael addition of
diphenyl phosphite to nitroalkenes using the readily available quinidine thiourea organocatalyst has
been developed. The desired -nitrophosphonates were obtained in good ee values. Molecular sieves
were found to be crucial for achieving high reproducible yields in this reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
b
Keywords:
Nitrophosphonates
Organocatalyst
Thiourea
Molecular sieves
Enantioselective synthesis
1. Introduction
used as the catalyst, the Michael addition of DPP to trans-b-nitro-
styrene gave only 38% yield and 11% ee for the S-enantiomer of the
product.1c,8 We recently reinvestigated this reaction, and found the
reaction may be dramatically improved by using molecular sieves
as the additives. Furthermore, we obtained much higher ee values
in this reaction after the optimizations. Herein we wish to report
our findings.
In recent years
considerable interest1 because they are the direct precursors for the
synthesis of
-aminophosphonic acids.2 As non-proteinogenic an-
alogues of -amino acids, the latter compounds have been reported
to possess many biological activities.3,4 Interestingly,
-amino-
phosphonic acid was also found in the nature.5 Several enantiose-
b-nitrophosphonate derivatives have received
b
b
b
lective methods have been reported for the synthesis of
b-
P( )( Ph)
O O
nitrophosphonate derivatives.1aeh Among these methods, enan-
tioselective Michael addition of phosphites to nitroalkenes1aef ap-
parently is one of the most direct approaches.6
catalyst
2
N
O2
+
(Ph ) P( )H
( )
1
O
O
Ph
N
O2
2
Ph
a
2
a
3
1
Our group is interested in developing novel methods for the
enantioselective synthesis of phosphonate compounds.1g,7 In this
regard, we have reported a nitroaldol reaction of
nates for the highly enantioselective synthesis of
nitrophosphonates.1g During the course of this study, we became
interested in the organocatalyzed enantioselective synthesis of
a
-ketophospho-
a
-hydroxy-
b-
2. Results and discussion
b
-
nitrophosphonates using the Michael addition of diphenyl phos-
phite (DPP) to nitroalkenes (Eq. 1). It should be pointed out that
Wang’s group1c has reported a cinchona alkaloid-catalyzed Michael
addition of DPP to nitroalkenes, in which thioureas, such as quinine
thiourea, were briefly evaluated as the catalyst. Nevertheless, poor
results were obtained. For example, when quinine thiourea (4) was
Using quinidine thiourea (5), i.e., the pseudo-enantiomer of
catalyst 4, as the catalyst, the Michael addition reaction of DPP (1)
to trans-b-nitrostyrene (2a) was conducted initially (Eq. 1). Al-
though we also obtained a low yield of this product (42%), we did
obtain a much higher ee value for product (72% ee for the R-en-
antiomer, Table 1, entry 1). Because a good ee value was obtained,
we decided to carry out further study to improve the yield of this
reaction. The results of this study are summarized in Table 1. As
shown by the data in Table 1, although the ee value of the product
remained constant during the study, to our surprise, we found the
* Corresponding author. Tel.: þ1 210 458 5432; fax: þ1 210 458 7428; e-mail
address: cong.zhao@utsa.edu (C.-G. Zhao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.059

7480
S. Abbaraju et al. / Tetrahedron 67 (2011) 7479e7484
Table 1
Optimization of the reaction conditions for the Michael addition of DPP to trans-b
-nitrostyrenea
Entry
Conditions
Time (h)
Yieldb (%)
eec (%)
1d
2
3
DPP-1 (upon opening)
24
24
24
24
24
24
24
24
24
24
24
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
42
34
25
0
40
36
0
72
72
72
d
DPP-1 (3 days after opening)
DPP-1 (7 days after opening)
DPP-1 (10 days after opening)
DPP-2 (upon opening)
DPP-3 (upon opening)
Distilled DPP
4
5d
72
72
d
6e
7
8
9
Distilled DPPþ10% phenol
25
0
72
d
DPP (passed through Na2HPO4)
ꢀ
10
11f
12f
13g
14h
15f,i
16j
17k
18l
19f,l
DPP (passed through MS 4 A)
35
37
91
87
27
55
26
26
13
83
72
72
73
73
68
68
72
72
70
72
ꢀ
DPPþMS 4 A in the reaction
ꢀ
ꢀ
DPP (passed through MS 4 A)þMS 4 A in the reaction
ꢀ
ꢀ
DPP (passed through MS 4 A)þMS 3 A in the reaction
ꢀ
ꢀ
DPP (passed through MS 4 A)þMS 5 A in the reaction
ꢀ
ꢀ
DPP (passed through MS 4 A)þMS 4 AþH2O in the reaction
DPP (passed through Na2SO4)þNa2SO4 in the reaction
DPP (passed through MgSO4)þMgSO4 in the reaction
Ò
ꢀ
DPP (passed through MS 4 A)þDOWEX in the reaction
Ò
ꢀ
ꢀ
DPP (passed through MS 4 A)þDOWEX þMS 4 A in the reaction
a
Unless otherwise indicated, all reactions were carried out with DPP (1, 0.10 mmol), trans-b-nitrostyrene (2a, 0.20 mmol), and quidine thiourea (5) as the catalyst
(0.01 mmol, 10 mol %) in CH2Cl2 (0.5 mL) at rt.
b
Yield of the isolated product.
c
Determined by HPLC analysis on a ChiralPak AS column. The stereochemistry was assigned by comparison of the measured optical rotation with those reported data.
The DPP samples DPP-1 and DPP-2 were purchased from SigmaeAldrich.
d
e
f
The DPP sample DPP-3 was purchased from Wako Chemicals.
ꢀ
MS 4 A (60.0 mg) was added to the reaction mixture.
g
h
i
ꢀ
MS 3 A (60.0 mg) was used to the reaction mixture.
ꢀ
MS 5 A (60.0 mg) was used to the reaction mixture.
Water (0.10 mmol) was added to the reaction mixture.
Na2SO4 (60.0 mg) was added to the reaction mixture.
j
k
l
MgSO4 (60.0 mg) was added to the reaction mixture.
DOWEXÒ 50WX8, hydrogen form (100e200 mesh, 10 wt % of DPP) was added to the reaction mixture.
product yield could not be improved. Actually, the reaction has very
Nonetheless, no product was obtained after such a treatment (en-
ꢀ
poor reproducibility in terms of the product yield. For example,
with the DPP sample we purchased from SigmaeAldrich (DPP-1),
a 42% yield of the desired product was obtained upon the opening
of this sample for the first time (entry 1). Nonetheless, with the
gradual aging of this sample, dwindling yields were obtained (en-
tries 2e4), and no product could be isolated from the reaction
mixture after the sample was only 10 days old after the opening
(entry 4). To make sure this was not due to sample quality varia-
tions, we ordered another sample from SigmaeAldrich (DPP-2),
and a similar 40% yield of the desired product was obtained upon
the first use (entry 5). Once again, this yield was not reproducible
when this new sample was aged (data not shown). We then noticed
that, in several reports where DPP was used, the samples were
purchased from Wako Chemicals.1a,b Thus, we also ordered a sam-
ple from Wako Chemicals (DPP-3). However, as the results in Table
1 show, there was no improvement at all (entry 6). According to the
product specification, the DPP sample from SigmaeAldrich con-
tains up to 15% phenol (according to the 1H NMR of the sample, it
contains about 15e16% phenol), we speculated whether phenol
was the culprit that limited the conversion of the substrates. Thus,
we distilled the DPP under nitrogen protection, and the freshly
distilled DPP was then applied in this reaction (after repeated dis-
tillation the phenol concentration was negligible according to its 1H
NMR). Surprisingly, no formation of the desired product was ob-
served (entry 7). Nevertheless, upon intentionally adding 10% of
phenol to this distilled sample, the desired product was again
obtained in 25% yield (entry 8). These results show that phenol
does not do any harm to the reaction. On the contrary, it may have
helped the reaction in some ways.
try 9). Molecular sieves 4 A was also used as an acid scavenger for
DPP.1b However, passing DPP through a pad of activated MS 4 A and
ꢀ
Celite immediately before use did not improve the conversion
(entry 10), either, although 31P NMR indicates that the sample has
much less phosphorus-containing impurities as compared to the
ꢀ
untreated sample. Similarly, adding freshly activated MS 4 A
(60 mg) directly to the reaction mixture containing untreated DPP
was not helpful (entry 11). In contrast, when freshly activated MS
ꢀ
4 A (60 mg) was added to the reaction mixture that contained the
MS-treated DPP, a dramatic improvement was observed: The
product yield was improved to 91% and the reaction time was
shortened from 24 h to 0.5 h (entry 12). Also the ee value of the
ꢀ
product was slightly improved to 73% (entry 12). Using MS 3 A
ꢀ
instead of MS 4 A lead to a similar yield of the product with the
same ee value (entry 13). However, the use of MS 5 A showed no
ꢀ
improvement as compared to those results without such an addi-
tive (entry 14). Since MS with smaller pore sizes work better, it
seems reasonable to believe that the species that inhibits the re-
ꢀ
ꢀ
action is pretty small. Since MS 3 A and 4 A are known to be a very
ꢀ
good absorbent for water and MS 5 A is not, we speculated that
water might have played some role in inhibiting this reaction. In-
deed, when 1 equiv of water was intentionally added to the
aforementioned best reaction system, a much lower yield (55%) and
a slightly lower ee value of the product was obtained (entry 15).
Nonetheless, using neutral drying agents, such as Na2SO4 and
ꢀ
MgSO4, instead of MS 4 A failed to improve the product yield (en-
tries 16 and 17). These results clearly evince that water itself is only
partially responsible for the low yield of this reaction.
ꢀ
Previously Terada and co-workers found MS 4 A can improve the
It is known that DPP is sensitive toward moisture,9 and some
acidic species generated during the hydrolysis may inhibit the ca-
talysis. Pretreatment of DPP with a base1a,8 to remove such acidic
species is known. Thus, we passed the DPP sample through a pad of
sodium hydrogen phosphate immediately before the reaction.1a
product yields in a chiral guanidine-catalyzed Michael addition,
and its role was described as an acid scavenger, although no direct
evidence was provided.1b In our hand, this is partially verified by
comparing the 31P NMR of the purchased DPP sample and that of
ꢀ
the sample pretreated with MS 4 A: The latter shows much less

S. Abbaraju et al. / Tetrahedron 67 (2011) 7479e7484
7481
unidentified peaks (both the number of peaks and their intensities
reduced) around the main peak for DPP (0.9 ppm), which indicates
ꢀ
that MS 4 A helps remove some of the impurities in the commercial
DPP sample. These impurities most likely are resulted from the
decomposition of DPP and from the reaction of DPP with moisture.
Conceivably, some acidic species formed in these reactions are able
ꢀ
to neutralize the catalyst so that the reaction is inhibited. MS 4 A
added to the reaction mixture removes the acidic species and
eliminates water simultaneously and thus prevents the hydrolysis
ꢀ
of DPP from happening. To further clarify the role of MS 4 A as an
acid scavenger, we conducted the reaction with the MS-treated DPP
in the presence of an acidic resin DOWEXÒ with and without MS
ꢀ
ꢀ
4 A. As the data in Table 1 show, without MS 4 A in the reaction
mixture, DOWEXÒ almost totally inhibited the reaction (entry 18).
However, if MS 4 A was added, the reactivity was almost totally
ꢀ
ꢀ
recovered (entry 19). These findings clearly indicate that MS 4 A is
functioning as an acid scavenger.10
On the other hand, the facts that DPP freshly treated with
Na2HPO4 (Table 1, entry 9) and freshly distilled DPP (Table 1, entry
ꢀ
7) do not participate in the reaction and that MS 4 A must be added
to the reaction mixture to achieve the optimal results suggests
molecular sieves have additional role in promoting the reaction
than just a scavenger for water and acid. A tentative explanation is
that, as a heterogeneous Lewis acid, MS is able to facilitate the
equilibrium between the phosphonate and the phosphite forms of
the DPP and favors the formation of the latter (Eq. 2). The phosphite
form maybe is more reactive than the phosphonate form in the
Michael addition. 31P NMR spectra provide some evidence for this
explanation. DPP sample from SigmaeAldrich shows a major peak
at 0.9 ppm and a minor peak appear at 128.5 ppm. The former
corresponds to the phosphonate form of DPP, and the latter is most
likely the phosphite form according to its chemical shift.11 31P NMR
of the untreated sample from SigmaeAldrich shows the phosphite
form is about 1.0% of the phosphonate form. After filtration through
ꢀ
the MS 4 A pad, this ratio increases to 1.1%. If the sample is filtered
ꢀ
and treated with MS 4 A for 30 min, then the ratio further increases
to 1.4%. Although the phosphite form still remains as a minute
component even after the treatment, the increase of its concen-
tration is considerable (about 40% increases).
O
P
H
H
O
P
M
S
4
Å
Ph
Ph
O
O
Ph
Ph
O
O
With the optimized conditions at hand, we screened other
cinchona alkaloid thioureas as the catalyst (Fig. 1) in the reaction of
DPP and trans-
rized in Table 2.
b-nitrostyrene (Eq. 1), and the results are summa-
Fig. 1. Catalyst screened in the Michael addition reaction of DPP to trans-
styrene (Ar¼3,5-(CF3)2C6H3e).
b-nitro-
As is evident from Table 2, besides quinidine thiourea (5, entry
1), other cinchona thiourea catalysts also lead to good results under
the optimized conditions. For example, with cinchonine thiourea
(6), the product 3a was obtained in 71% ee (entry 2). Similarly, the
S-enantiomer was obtained in 84% yield and 70% ee within 6 h of
reaction when quinine thiourea (4) was used (entry 3). These re-
sults are much better than those reported (24 h, 38% yield, and 11%
ee).1c Cinchonidine thiourea (7) gave the expected S-enantiomer in
84% and 73% ee (entry 4). Modification of the aryl group attached to
the thiourea moiety shows almost no effects on the reactivity as
well as the enantioselectivity of this reaction, since quinidine de-
rived thiourea catalysts 8 and 9 (entries 5 and 6) give similar results
as those of catalyst 5. Similarly, the increase of the steric hindrance
at 60-position by replacing the methyl with an isopropyl group
(catalysts 10 and 11) shows almost no effect (entries 7 and 8), ei-
ther. Since catalyst 5 leads to the highest reactivity and stereo-
selectivity in this reaction, it was chosen for further optimization.
As shown in Table 2, good ee values may be obtained in polar
chlorinated solvents, such as CH2Cl2 (entry 1), CHCl3 (entry 9), and
ClCH2CH2Cl (entry 10). Lower ee values were obtained in nonpolar
solvents, such as CCl4 (entry 11) and toluene (entry 12), in ethereal
solvents, such as Et2O (entry 13) and THF (entry 14), and in CH3CN
(entry 15). We found that, by lowering the reaction temperature to
5 ꢀC, the ee value was increased to 79% (entry 16). However, further
dropping the temperature to ꢁ15 ꢀC showed no effects (entry 17).
Furthermore, temperature has not much effect on the reactivity of
this reaction (entries 16 and 17).
Next the scope of this reaction was evaluated with different
nitroalkenes and the results are summarized in Table 3. As the re-
sults in Table 3 show, the reaction works very well with aryl-
substituted nitroalkenes (entries 1e13). The reaction generally is
not sensitive toward the electronic nature of the substituents on
the phenyl ring: Nitroalkenes with both an electron-donating and
an electron-withdrawing group on the phenyl ring give almost the
same yields and ee values (ca. 80%, entries 1e6). Similarly, the

7482
S. Abbaraju et al. / Tetrahedron 67 (2011) 7479e7484
Table 2
3. Conclusion
Catalyst screening and further optimizationsa
Yieldb (%)
eec (%)
In summary, we reinvestigated the Michael addition reaction of
diphenyl phosphite and nitroalkenes catalyzed by cinchona alka-
loid thioureas, and discovered that a dramatic improvement of the
efficiency of this reaction may be achieved by simply filtering the
Entry
Catalyst
Solvent
Time (h)
1
2
5
6
4
7
8
9
10
11
5
5
5
5
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CCl4
Toluene
Et2O
THF
CH3CN
CH2Cl2
CH2Cl2
0.5
2.0
6.0
2.5
3.0
3.5
3.0
2.0
2.0
2.0
2.0
1.0
1.0
3.0
4.0
0.5
0.5
91
58
84
84
80
84
90
82
85
70
65
94
90
48
40
91
90
73
71
70
73
72
67
73
73
71
73
57
60
60
55
60
79
79
3d
4d
5
ꢀ
ꢀ
diphenyl phosphite sample through MS 4 A and by adding MS (4 A
ꢀ
or 3 A) to the reaction mixture. The MS was found to act as
6
7
8
9
10
11
12
13
14
15
16e
17f
a scavenger of water and acid to remove the impurities in DPP
samples and may facilitate the equilibrium between the phospho-
nate and phosphite forms of the DPP. The synergistic effects of
these functions promote the reaction dramatically. After such
a modification of the reaction procedure, high and reproducible
yields of the desired b-nitrophosphonates may be obtained in very
good ee values (up to 84% ee).
4. Experimental section
a
Unless otherwise indicated, all reactions were carried out with DPP (1,
ꢀ
0.10 mmol, pretreated with MS 4 A immediately before reaction), trans-b-nitro-
styrene (0.20 mmol), the catalyst (0.01 mmol, 10 mol %), and MS 4 A (60.0 mg) in the
ꢀ
4.1. General information
specified solvent (0.5 mL) at rt.
b
Yield of the isolated product.
Determined by HPLC analysis on a ChiralPak AS column.
Unless otherwise mentioned all the trans-
were purchased from SigmaeAldrich. 4-CN-trans-
b
b
-nitrostyrenes
-nitrostyrene
(2f) was purchased from TCI America. These compounds were
c
d
The S-enantiomer was obtained as the major product.
e
Carried out at 5 ꢀC.
f
Carried out at ꢁ15 ꢀC.
used as received. trans-b-Nitrostyrenes (2k, 2l, 2m, 2n) were
prepared according to the literature procedures.12,13 Celite was
purchased from Fluka. Diphenyl phosphite was purchased from
SigmaeAldrich (contains 15e16% of phenol according to its 1H
NMR) and Wako (contains 5e6% of phenol according to its 1H
NMR). Unless otherwise noted, this compound was passed
Table 3
Scope of the quinidine thiourea-catalyzed Michael addition reactiona
O
ꢀ
through a pad of Celite (lower layer) and molecular sieves (4 A,
5
NO2
PhO
P
OPh
NO2
top layer) right before the reaction. Molecular sieves were pur-
chased from SigmaeAldrich and were activated and powdered
before use (MS was activated at an oven temperature of 110 ꢀC
overnight). All the solvents used for purification were purchased
from Fischer Scientific. Dichloromethane (GC grade) that was
used in the reaction as the solvent was purchased Fischer
Scientific. All the thiourea catalysts were prepared according to
the literature procedure.14
(PhO) P(O)H
+
2
R
4
MS
CH Cl , 5 C
Å
R
°
2
2
1
2
3
Entry
R
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph (3a)
0.5
0.5
0.5
0.5
0.5
1.0
0.5
0.5
1.0
1.0
0.5
1.0
2.0
2.0
91
92
89
90
90
75
88
92
91
90
90
70
79
60
79
80
80
80
80
70
80
80
80
77
84
77
68
64
4-MeC6H4 (3b)
4-MeOC6H4 (3c)
4-ClC6H4 (3d)
4-BrC6H4 (3e)
4-CNC6H4 (3f)
2-MeOC6H4 (3g)
2-BrC6H4 (3h)
2-NO2C6H4 (3i)
3-BrC6H4 (3j)
4.2. General procedure for the enantioselective synthesis of
Michael addition of diphenyl phosphite to nitroalkenes
9
A mixture of trans-b-nitrostyrene (29.8 mg, 0.20 mmol), catalyst
10
11
12
13
14
ꢀ
5 (5.9 mg, 0.010 mmol, 10 mol %), and freshly activated MS 4 A
(60.0 mg) in dichloromethane (0.5 mL) was cooled to 5 ꢀC and
stirred for 20 min at this temperature. Right before addition,
diphenyl phosphite was passed through a bed of powdered acti-
1-Naphthyl (3k)
Thiophen-2-yl (3l)
c-C6H11 (3m)
Me2CH (3n)
a
ꢀ
Unless otherwise indicated, all reactions were carried out with DPP (1,
vated MS 4 A and Celite. A portion of the filtered diphenyl phos-
ꢀ
0.10 mmol, pretreated with MS 4 A immediately before reaction), nitroalkenes
phite (23.5 mg, 0.10 mmol) was added to the reaction mixture
immediately. The reaction mixture was further stirred for 30 min
(monitored by TLC). After the reaction was completed, the mixture
was directly transferred to a silica gel column. The product was
purified by flash column chromatography (hexane/AcOEt¼9.6/0.4
to 8/2) to give (R)-diphenyl 2-nitro-1-phenylethylphosphonate (1a,
35.0 mg, 91% yield).
ꢀ
(0.20 mmol), catalyst 5 (0.01 mmol, 10 mol %), and MS 4 A (60.0 mg) in CH2Cl2
(0.5 mL) at 5 ꢀC.
b
Yield of the isolated product.
Determined by HPLC analysis on a ChiralPak AS column.
c
position of the substituent on the phenyl has almost no influence
on the enantioselectivity and reactivity, either (entries 7e10). Good
results were also obtained for 1-naphthyl-substituted nitroalkene
(entry 11) and a nitroalkene with a thiophene substituent (entry
12). Besides nitroalkenes with an aryl substituent, the reaction also
works with nitroalkenes with an aliphatic substituent: nitroalkenes
with a cyclohexyl and an isopropyl substituent give the desired
product in slight lower ee values in 68% and 64%, respectively
(entries 13e14). The product yields are also lower as compared to
their aromatic counterparts.
4.2.1. (R)-Diphenyl 2-nitro-1-phenylethylphosphonate
(3a)1aec. White solid, yield 91%, 79% ee, 1H NMR (300 MHz,
CDCl3)
5.26e5.07 (m, 2H; CH2), 4.44 (ddd, JHP¼24.5 Hz, J1¼11.5, J2¼5.1 Hz,
1H; CH); 13C NMR (75 MHz, CDCl3)
d
7.46e7.09 (m, 13H; Ar), 6.74 (d, J¼8.0 Hz, 2H; Ar),
d
150.0 (d, JCP¼9.3 Hz), 149.9 (d,
JCP¼9.8 Hz), 130.7 (d, JCP¼7.6 Hz), 130.1, 129.8, 129.4, 129.1, 125.9,
125.6, 120.5 (d, JCP¼4.4 Hz), 120.3 (d, JCP¼4.3 Hz), 75.2 (d,
JCP¼4.8 Hz), 43.7 (d, JCP¼140.3 Hz). HPLC conditions: Chiralpak AS

S. Abbaraju et al. / Tetrahedron 67 (2011) 7479e7484
7483
column, i-PrOH/hexane 20:80, flow rate 0.5 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼14.8 min, tR (minor)¼22.5 min.
126.0, 125.6, 120.6 (d, JCP¼4.6 Hz), 120.4 (d, JCP¼4.5 Hz), 120.1 (d,
JCP¼4.4 Hz), 118.2, 113.2, 74.6 (d, JCP¼4.1 Hz), 43.8 (d, JCP¼140.0 Hz),
30.1; nmax (neat, cmꢁ1): 3070, 3021, 2922, 2226, 1589, 1563, 1374,
1269, 1214; HRMS calcd for C21H18N2O5P (MþH)þ 409.0953; found
409.0921. HPLC conditions: Chiralpak AS column, i-PrOH/hexane
10:90, flow rate 1.0 mL/min at 25 ꢀC, UV detection at 226 nm, tR
(major)¼24.2 min, tR (minor)¼33.1 min.
4.2.2. (R)-Diphenyl 1-(4-methylphenyl)-2-nitroethylphosphonate
(3b)1b,c. White solid, yield 92%, 80% ee, 1H NMR (500 MHz, CDCl3)
d
7.33e7.29 (m, 4H; Ar), 7.19e7.16 (m, 5H; Ar), 7.12e7.08 (m, 3H; Ar),
6.78 (d, J¼8.0 Hz, 2H; Ar), 5.18 (ddd, JHP¼13.5 Hz, J1¼8.0, J2¼5 Hz,1H;
CH2), 5.09 (ddd, JHP¼17.0 Hz, J1¼11.5, J2¼7.5 Hz, 1H), 4.39 (ddd,
JHP¼24.6 Hz, J1¼11.0, J2¼4.5 Hz, 1H; CH), 2.33 (s, 3H; CH3); 13C NMR
4.2.7. (R)-Diphenyl 1-(2-methoxyphenyl)-2-nitroethylphosphonate
(125 MHz, CDCl3)
d
150.0 (d, JCP¼9.6 Hz),149.9 (d, JCP¼10.1 Hz),138.7,
(3g)1aec. White solid, yield 88%, 80% ee, 1H NMR (300 MHz,
129.9,129.6,129.0,129.02 (d, JCP¼6.7 Hz),127.4 (d, JCP¼7.7 Hz),125.6,
125.4,120.3 (d, JCP¼3.8 Hz),120.1 (d, JCP¼3.8 Hz), 75.0 (d, JCP¼5.5 Hz),
43.0 (d, JCP¼140.6 Hz), 21.0. HPLC conditions: Chiralpak AS column,
i-PrOH/hexane 10:90, flow rate 0.5 mL/min at 25 ꢀC, UV detection at
254 nm, tR (major)¼14.1 min, tR (minor)¼21.6 min.
CDCl3)
d
7.49e7.48 (td, J1¼7.6, J2¼1.8 Hz, 1H; Ar), 7.34e7.31 (m, 3H;
Ar), 7.23e7.17 (m, 3H; Ar), 7.14e7.09 (m, 3H; Ar), 7.01e6.98 (m, 1H;
Ar), 6.90 (d, J¼8.5 Hz, 1H; Ar), 6.85 (d, J¼8 Hz, 2H; Ar), 5.26e5.07
(m, 3H; CH, CH2), 3.78 (s, 3H; OCH3); 13C NMR (75 MHz, CDCl3)
d
157.6 (d, JCP¼6.7 Hz), 150.3 (d, JCP¼9.5 Hz), 150.2 (d, JCP¼9.4 Hz),
130.2 (d, JCP¼3.2 Hz), 130.0, 129.8, 129.4 (d, JCP¼5.5 Hz), 125.5 (d,
JCP¼14.4 Hz), 120.5 (d, JCP¼4.5 Hz), 120.3 (d, JCP¼4.5 Hz), 119.4 (d,
JCP¼7.6 Hz), 111.6, 74.9 (d, JCP¼4.7 Hz), 56.1, 36.5 (d, JCP¼142.8 Hz).
HPLC conditions: Chiralpak AS column, i-PrOH/hexane 10:90, flow
rate 0.5 mL/min at 25 ꢀC, UV detection at 254 nm, tR (major)¼
21.5 min, tR (minor)¼28.8 min.
4.2.3. (R)-Diphenyl 1-(4-methoxyphenyl)-2-nitroethylphosphonate
(3c)1aec. White solid, yield 89%, 80% ee, 1H NMR (300 MHz,
CDCl3) d 7.37e7.29 (m, 5H; Ar), 7.21e7.17 (m, 3H; Ar), 7.12e7.09 (m,
2H; Ar), 6.89 (d, J¼8.5 Hz, 2H; Ar), 6.78 (d, J¼7.6 Hz, 2H; Ar), 5.18
(ddd, JHP¼13.5 Hz, J1¼6.9, J2¼4.7 Hz, 1H; CH2), 5.07 (ddd,
JHP¼18.2 Hz, J1¼10.8, J2¼7.5 Hz, 1H; CH2), 4.39 (ddd, JHP¼24.5 Hz,
J1¼10.8, J2¼4.6 Hz, 1H; CH), 3.8 (s, 3H; OCH3); 13C NMR (75 MHz,
4.2.8. (R)-Diphenyl 1-(2-bromophenyl)-2-nitroethylphosphonate
CDCl3)
d
157.6 (d, JCP¼6.7 Hz), 150.4 (d, JCP¼9.6 Hz), 150.3 (d,
(3h)1a,b. White solid, yield 92%, 80% ee, 1H NMR (300 MHz, CDCl3)
JCP¼9.7 Hz), 130.2 (d, JCP¼3.2 Hz), 130.0, 129.8, 129.4 (d, JCP¼5.5 Hz),
125.6, 125.4, 121.3 (d, JCP¼2.9 Hz), 120.5 (d, JCP¼4.5 Hz), 120.2 (d,
JCP¼4.4 Hz), 119.4 (d, JCP¼7.6 Hz), 111.6, 74.8 (d, JCP¼4.6 Hz), 56.1,
36.5 (d, JCP¼142.8 Hz). HPLC conditions: Chiralpak AS column, i-
PrOH/hexane 20:80, flow rate 1.0 mL/min at 25 ꢀC, UV detection at
254 nm, tR (major)¼10.5 min, tR (minor)¼16.0 min.
d 7.63 (d, 2H; Ar), 7.35e7.30 (m, 3H; Ar), 7.19e7.07 (m, 7H; Ar), 6.78
(d, J¼8.1 Hz, 2H; Ar), 5.29e5.08 (m, 3H; CH, CH2); 13C NMR (75 MHz,
CDCl3)
d
150.1 (d, JCP¼9.5 Hz), 149.9 (d, JCP¼10 Hz), 134.0 (d,
JCP¼2.4 Hz), 130.9 (d, JCP¼7 Hz), 130.4 (d, JCP¼3.2 Hz), 130.1, 129.9,
129.3 (d, JCP¼4.5 Hz), 128.4 (d, JCP¼3.1 Hz), 126.6 (d, JCP¼9.3 Hz),
125.9, 125.6, 120.6 (d, JCP¼4.4 Hz), 120.1 (d, JCP¼4.5 Hz), 74.9 (d,
JCP¼4.9 Hz), 43.0 (d, JCP¼142.0 Hz). HPLC conditions: Chiralpak AS
column, i-PrOH/hexane 10:90, flow rate 0.5 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼20.1 min, tR (minor)¼34.9 min.
4.2.4. (R)-Diphenyl 1-(4-chlorophenyl)-2-nitroethylphosphonate
(3d)1c. White solid, yield 90%, 80% ee, 1H NMR (500 MHz, CDCl3)
d
7.42e7.32 (m, 6H; Ar), 7.27e7.20 (m, 3H; Ar), 7.16e7.10 (m, 3H;
Ar), 6.81 (d, J¼9.8 Hz, 2H; Ar), 5.20 (ddd, JHP¼13.9 Hz, J1¼6.9,
J2¼4.3 Hz, 1H; CH2), 5.09 (ddd, JHP¼18.2 Hz, J1¼11.2, J2¼7.0 Hz, 1H;
CH2), 4.42 (ddd, JHP¼24.7 Hz, J1¼11.2, J2¼4.2 Hz, 1H; CH); 13C NMR
4.2.9. (R)-Diphenyl 1-(2-nitrophenyl)-2-nitroethylphosphonate
(3i)1a,b. White solid, yield 91%, 80% ee, 1H NMR (300 MHz, CDCl3)
d
7.98 (d, J¼8 Hz, 1H; Ar), 7.81 (d, J¼9.9 Hz, 1H; Ar), 7.63 (t, J¼7.4 Hz,
(125 MHz, CDCl3)
d
150.1 (d, JCP¼9.6 Hz),150.0 (d, JCP¼9.7 Hz),135.3,
1H; Ar), 7.49 (t, J¼9.3 Hz,1H; Ar), 7.33 (t, J¼7.5 Hz, 2H; Ar), 7.22e7.05
(m, 6H; Ar), 6.83 (d, J¼8.2 Hz, 2H; Ar), 5.74 (ddd, JHP¼26 Hz, J1¼10.4,
J2¼4.8 Hz, 1H; CH2), 5.26 (ddd, JHP¼14.5 Hz, J1¼6.9, J2¼4.9 Hz, 1H;
CH2), 5.17 (ddd, JHP¼17.5 Hz, J1¼10.4, J2¼7.2 Hz, 1H; CH2). 13C NMR
130.7 (d, JCP¼6.6 Hz), 130.1 (d, JCP¼27.7 Hz), 129.7, 129.5 (d,
JCP¼7.6 Hz), 125.9 (d, JCP¼25.7 Hz), 120.5 (d, JCP¼3.8 Hz), 120.3 (d,
JCP¼4.8 Hz), 75.0, 43.1 (d, JCP¼140.8 Hz). HPLC conditions: Chiralpak
AS column, i-PrOH/hexane 10:90, flow rate 0.5 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼21.4 min, tR (minor)¼28.0 min.
(75 MHz, CDCl3)
d
150.1, 150.0 (d, JCP¼9.5 Hz), 149.9 (d, JCP¼9.9 Hz),
133.7, 130.2, 129.9, 129.8, 129.7, 126.6 (d, JCP¼6.7 Hz), 126.4, 125.8,
120.5 (d, JCP¼4.4 Hz),120.04 (d, JCP¼4.5 Hz) 74.7 (d, JCP¼4.4 Hz), 37.2
(d, JCP¼140.9 Hz). HPLC conditions: Chiralpak AS column, i-PrOH/
hexane 20:80, flow rate 0.5 mL/min at 25 ꢀC, UV detection at 254 nm,
tR (major)¼12.3 min, tR (minor)¼19.1 min.
4.2.5. (R)-Diphenyl 1-(4-bromophenyl)-2-nitroethylphosphonate
(3e)1aec. White solid, yield 90%, 80% ee, 1H NMR (300 MHz, CDCl3)
d
7.50 (d, J¼8.2 Hz, 2H; Ar), 7.35e7.30 (m, 4H; Ar), 7.22e7.20 (m, 3H;
Ar), 7.11e7.08 (m, 3H; Ar), 6.81 (d, J¼8.2 Hz, 2H; Ar), 5.20 (ddd,
JHP¼13.9 Hz, J1¼6.9, J2¼4.5 Hz, 1H; CH2), 5.08 (ddd, JHP¼18.0 Hz,
J1¼11.0, J2¼7.0 Hz, 1H; CH2), 4.41 (ddd, JHP¼24.6 Hz, J1¼10.8,
4.2.10. (R)-Diphenyl 1-(3-bromophenyl)-2-nitroethylphosphonate
(3j)1a. White solid, yield 90%, 77% ee, 1H NMR (300 MHz, CDCl3)
J2¼4.4 Hz,1H; CH); 13C NMR (75 MHz, CDCl3)
d
150.1 (d, JCP¼7.2 Hz),
d
7.58 (d, J¼1.7 Hz, 1H; Ar), 7.48 (d, J¼7.7 Hz, 1H; Ar), 7.39 (d,
149.9 (d, JCP¼9.7 Hz), 132.6, 131.0 (d, JCP¼6.5 Hz), 130.2, 130.0, 126.0,
125.8, 123.4, 120.5 (d, JCP¼4.4 Hz), 120.2 (d, JCP¼4.4 Hz), 74.5 (d,
JCP¼4.9 Hz), 43.2 (d, JCP¼141.1 Hz). HPLC conditions: Chiralpak AS
column, i-PrOH/hexane 10:90, flow rate 0.5 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼23.5 min, tR (minor)¼31.1 min.
J¼7.6 Hz, 1H; Ar), 7.33 (t, J¼7.6 Hz, 2H; Ar), 7.26e7.09 (m, 7H; Ar),
6.8 (d, J¼7.9 Hz, 2H; Ar), 5.19 (ddd, JHP¼13.9 Hz, J1¼7.1, J2¼4.5 Hz,
1H; CH2), 5.08 (ddd, JHP¼18 Hz, J1¼10.8, J2¼7.1 Hz, 1H; CH2), 4.4
(ddd, JHP¼24.5 Hz, J1¼10.7, J2¼4.4 Hz, 1H; CH); 13C NMR (75 MHz,
CDCl3)
d
150.1 (d, JCP¼9.5 Hz), 149.9 (d, JCP¼9.9 Hz), 134.0 (d,
JCP¼2.3 Hz), 130.9 (d, JCP¼6.9 Hz), 130.4 (d, JCP¼3.1 Hz), 130.2, 129.9,
129.3 (d, JCP¼4.5 Hz), 128.4 (d, JCP¼3.1 Hz), 126.6 (d, JCP¼9.3 Hz),
125.9, 125.6, 120.6 (d, JCP¼4.4 Hz), 120.1 (d, JCP¼4.5 Hz), 74.9 (d,
JCP¼4.8 Hz), 42.0 (d, JCP¼142.0 Hz). HPLC conditions: Chiralpak AS
column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼8.3 min, tR (minor)¼16.7 min.
4.2.6. (R)-Diphenyl 1-(4-cyanophenyl)-2-nitroethylphosphonate
(3f). White solid, yield 75%, 70% ee, ½a D25
ꢂ
ꢁ6.7 (c 1.5 in CH2Cl2),
mp: 90e92 ꢀC 1H NMR (300 MHz, CDCl3):
d 7.69e7.57 (m, 4H; Ar),
7.35e7.06 (m, 9H; Ar), 6.79 (d, J¼8.4 Hz, 1H; Ar), 5.23 (ddd,
JHP¼14.1 Hz, J1¼6.9, J2¼4.4 Hz, 1H; CH2), 5.12 (ddd, JHP¼17.5 Hz,
J1¼11.0, J2¼6.5 Hz, 1H; CH2), 4.49 (ddd, JHP¼24.8 Hz, J1¼11.0,
J2¼4.4 Hz, 1H; CH); 13C NMR (75 MHz, CDCl3)
d
150.1, 149.9 (d,
4.2.11. (R)-Diphenyl 1-(1-naphthyl)-2-nitroethylphosphonate
JCP¼10.7 Hz), 149.7 (d, JCP¼9.6 Hz), 136.5, 133.0, 132.6, 130.3 (d,
JCP¼2.8 Hz), 130.2, 130.0 (d, JCP¼4.2 Hz), 128.6 (d, JCP¼5.8 Hz), 126.2,
(3k)1a,b. White solid, yield 90% 84% ee, 1H NMR (300 MHz, CDCl3)
d
8.25 (d, J¼8.5 Hz, 1H; Ar), 7.90e7.82 (m, 3H; Ar), 7.62e7.43 (m, 3H;

7484
S. Abbaraju et al. / Tetrahedron 67 (2011) 7479e7484
Ar), 7.33e6.98 (m, 8H; Ar), 6.59 (d, J¼7.9 Hz, 2H; Ar), 5.50e5.28 (m,
3H; CH2); 13C NMR (75 MHz, CDCl3)
150.2 (d, JCP¼9.6 Hz), 150.1 (d,
Supplementary data
d
JCP¼10.0 Hz), 134.4, 132.1 (d, JCP¼6.6 Hz), 130.2, 129.7, 129.3, 127.4,
127.2 (d, JCP¼7.5 Hz), 126.5, 125.9, 125.5, 122.9, 120.6 (d, JCP¼4.4 Hz),
120.1 (d, JCP¼4.4 Hz), 75.7 (d, JCP¼4.2 Hz), 37.4 (d, JCP¼140.0 Hz).
HPLC conditions: Chiralpak AS column, i-PrOH/hexane 20:80, flow
rate 1.0 mL/min at 25 ꢀC, UV detection at 254 nm, tR (major)¼
8.5 min, tR (minor)¼14.7 min.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.059.
References and notes
1. For examples, see: (a) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed.
2010, 49, 153e156; (b) Terada, M.; Ikehara, T.; Ube, H. J. Am. Chem. Soc. 2007,
129, 14112e14113; (c) Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.;
Wang, W. Adv. Synth. Catal. 2007, 349, 1052e1056; (d) Rai, V.; Namboothiri, I. N.
N. Tetrahedron: Asymmetry 2008, 19, 2335e2338; (e) Enders, D.; Tedeschi, L.;
Foerster, D. Synthesis 2006, 1447e1460; (f) Enders, D.; Tedeschi, L.; Bats, J. W.
Angew. Chem., Int. Ed. 2000, 39, 4605e4607; (g) Mandal, T.; Samanta, S.; Zhao,
C.-G. Org. Lett. 2007, 9, 943e945; (h) Chen, X.; Wang, J.; Zhu, Y.; Shang, D.; Gao,
B.; Liu, X.; Feng, X.; Su, Z.; Hu, C. Chem.dEur. J. 2008, 14, 10896e10899; (i) Jiang,
Z.; Zhang, Y.; Ye, W.; Tan, C.-H. Tetrahedron Lett. 2007, 48, 51e54; (j) Samanta, S.;
Zhao, C.-G. ARKIVOC 2007, 13, 218e226; (k) Sobhani, S.; Rezazadeh, S. Synlett
2010, 1485e1488.
4.2.12. (R)-Diphenyl 1-(thiophen-2-yl)-2-nitroethylphosphonate
(3l)1aec 1H NMR (300 MHz, CDCl3)
. d 7.31e7.23 (m, 3H; Ar),
7.25e7.14 (m, 5H; Ar), 7.11e7.07 (m, 2H; Ar), 7.00e6.97 (m, 1H; Ar),
6.87 (d, J¼8.5 Hz, 2H; Ar), 5.24e5.14 (m,1H; CH2), 5.07e4.96 (m,1H;
CH2), 4.73 (ddd, JHP¼24.4 Hz, J1¼10.7, J2¼4.2 Hz, 1H; CH); 13C NMR
(75 MHz, CDCl3)
d
150.1 (d, JCP¼9.7 Hz),149.9 (d, JCP¼9.7 Hz),131.9 (d,
JCP¼8.9 Hz), 130.1, 129.9, 128.8 (d, JCP¼8.0 Hz), 127.6, 126.9, 125.9 (d,
JCP¼12.9 Hz), 120.5 (d, JCP¼4.3 Hz), 120.3 (d, JCP¼4.4 Hz), 76.1 (d,
JCP¼5.5 Hz), 39.2 (d, JCP¼146.0 Hz). HPLC conditions: Chiralpak AS
column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min at 25 ꢀC, UV
detection at 254 nm, tR (major)¼8.2 min, tR (minor)¼16.7 min.
2. (a) Kadyrov, R.; Holz, J.; Schaeffner, B.; Zayas, O.; Almena, J.; Boerner, A. Tet-
rahedron: Asymmetry 2008, 19, 1189e1192; (b) Doherty, S.; Knight, J. G.; Bell, A.
L.; El-Menabawey, S.; Vogels, C. M.; Decken, A.; Westcott, S. A. Tetrahedron:
Asymmetry 2009, 20, 1437e1444; (c) Ref. 1g. For examples of catalytic asym-
metric synthesis of
b-aminophosphonates and related compounds, see: (d)
4.2.13. (R)-Diphenyl 1-cyclohexyl-2-nitroethylphosphonate
Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti, M. Tetrahe-
dron: Asymmetry 1998, 9, 745e748; (e) Thomas, A. A.; Sharpless, K. B. J. Org.
Chem. 1999, 64, 8379e8385; (f) Wilt, J. C.; Pink, M.; Johnston, J. N. Chem.
Commun. 2008, 4177e4179.
3. For reviews on b-aminophosphonic acids and their derivatives, see: (a) Pala-
cios, F.; Alonso, C.; de Los Santos, J. M. Chem. Rev. 2005, 105, 899e931; (b)
Palacios, F.; Alonso, C.; de Los Santos, J. M. In Enantioselective Synthesis of
(3m)1a,b. White solid, yield 79%, 68% ee, 1H NMR (300 MHz,
CDCl3)
d 7.34e7.25 (m, 4H; Ar), 7.20e7.08 (m, 6H; Ar), 4.93 (td,
JHP¼14.0 Hz, J¼5.3 Hz, 1H; CH2), 4.75 (td, JHP¼14.0 Hz, J¼7.3 Hz, 1H;
CH2), 3.14 (dddd, JHP¼23.3 Hz, J1¼7.4, J2¼5.3, J3¼3.5 Hz, 1H; CH),
2.15e1.63 (m, 6H; C6H11),1.43e1.14 (m, 5H; CH2); 13C NMR (75 MHz,
b
-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: Hoboken,
New Jersey, 2005; pp 277e318.
4. For the biological activities of
CDCl3)
d
150.1 (d, JCP¼9.0 Hz), 149.9 (d, JCP¼10.2 Hz), 130.0, 125.7,
120.6, 72.8 (d, JCP¼3.9 Hz), 41.9 (d, JCP¼139.5 Hz), 37.5 (d,
JCP¼2.8 Hz), 31.6 (d, JCP¼11.0 Hz), 30.2 (d, JCP¼3.1 Hz), 26.9, 26.7,
26.1. HPLC conditions: Chiralpak AS column, i-PrOH/hexane 5:95,
flow rate 0.5 mL/min at 25 ꢀC, UV detection at 254 nm, tR (major)¼
18.8 min, tR (minor)¼22.4 min.
b
-aminophosphonic acids, see:Aminophosphonic
and Aminophosphinic Acids: Chemistry and Biological Activity; Kukhar, V. P.,
Hudson, H. R., Eds.; Wiley: New York, NY, 2000.
5. Korn, E. D.; Dearborn, E. D. J. Biol. Chem. 1974, 249, 3335e3341.
6. For reviews on the phospha-Michael reaction, see: (a) Pudovik, A. N.; Kono-
valova, I. V. Synthesis 1979, 81e96; (b) Enders, D.; Saint-Dizier, A.; Lannou, M. I.;
Lenzen, A. Eur. J. Org. Chem. 2006, 29e49.
7. (a) Perera, S.; Naganaboina, V. K.; Wang, L.; Zhang, B.; Guo, Q.; Rout, L.; Zhao,
C.-G. Adv. Synth. Catal. 2011, 353, 1729e1734; (b) Samanta, S.; Perera, S.; Zhao,
C.-G. J. Org. Chem. 2010, 75, 1101e1106; (c) Samanta, S.; Krause, J.; Mandal, T.;
Zhao, C.-G. Org. Lett. 2007, 9, 2745e2748; (d) Dodda, R.; Zhao, C.-G. Tetrahe-
dron Lett. 2007, 48, 4339e4342; (e) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8,
4911e4914; (f) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128,
7442e7443.
4.2.14. (R)-Diphenyl 3-methyl-1-nitrobutan-2-ylphosphonate
(3n)1a. White solid, yield 60%, 64% ee, 1H NMR (500 MHz, CDCl3)
d
7.36e7.27 (m, 4H; Ar), 7.19e7.06 (m, 6H; Ar), 4.93 (td, JHP¼14.0 Hz,
J¼5.6 Hz, 1H; CH2), 4.72 (td, JHP¼14.1 Hz, J¼7.3 Hz, 1H; CH2), 3.19
(dddd, J1¼3.5, J2¼5.3, J3¼7.1, J4¼23.3 Hz, 1H; CH), 2.45 (d septet d,
JHP¼20.5 Hz, J1¼7.2, J2¼3.8 Hz, 1H; CH), 1.16 (d, J¼6.7 Hz, 3H; CH3),
8. During the preparation of this manuscript, Herrera and co-workers published
their studies on this reaction catalyzed by some chiral thioureas in the presence
1.15 (d, J¼6.8 Hz, 3H; CH3); 13C NMR (125 MHz, CDCl3)
d 150.1 (d,
€
of Hunig’s base, including catalyst 4, but again poor ee value (9%) was obtained,
JCP¼9.0 Hz), 149.9 (d, JCP¼10.0 Hz), 130.0, 125.7, 125.6, 120.6 (d,
JCP¼4.5 Hz), 120.5 (d, JCP¼4.7 Hz), 72.5, 42.0 (d, JCP¼140.5 Hz), 27.6
(d, JCP¼2.8 Hz), 21.2 (d, JCP¼12.0 Hz), 19.5 (d, JCP¼3.3 Hz). HPLC
conditions: Chiralpak AS column, i-PrOH/hexane 10:90, flow rate
0.5 mL/min at 25 ꢀC, UV detection at 254 nm, tR (major)¼13.2 min,
tR (minor)¼16.1 min.
ꢁ
ꢁ
see: Alcaine, A.; Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Org.
Biomol. Chem. 2011, 9, 2777e2783.
9. (a) Arbuzov, A. E.; Imaev, M. G. Izv. Akad. Nauk SSSR, Ser. Khim. 1959, 171; (b)
Walsh, E. N. J. Am. Chem. Soc. 1959, 81, 3023e3026.
10. Since DOWEXÒ resin cannot be absorbed by MS 4 A, apparently the latter
ꢀ
absorbs the acidic species generated from the resin under the reaction
conditions.
11.
A closely related compound, methyldiphenylphosphite [(PhO)2P(OMe)]
shows a 31P absorption at 128.7 ppm, see: Oba, M.; Okada, Y.; Nishiyama, K.;
Ando, W. Org. Lett. 2009, 11, 1879e1881; The phosphonate form was reported
to have a chemical shift of 0 ppm, see Moedritzer, K. J. Inorg. Nucl. Chem. 1961,
22, 19e21.
Acknowledgements
The authors thank the NIH-SCORE program (Grant No. SC1-
082718) and the Welch Foundation (Grant No. AX-1593; AX-0026)
for the generous financial support of this research.
12. Trost, B.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438e2439.
13. Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559e2561.
14. Vakulya, B.; Varga, S.; Csampai, A.; Tibor, S. Org. Lett. 2005, 7, 1967e1969.