Cinchonine catalyzed diastereo- and enantioselective Michael addition of α-lithiated phosphonates to nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2007.11.001

Conjugate addition of α-lithiated benzyl- and alkylphosphonates to a variety of aromatic and heteroaromatic nitroalkenes in the presence of 50 mol % of cinchonine-Li catalyst system proceeded in high yields, diastereo- and enantioselectivities in most cases.

Full text of DOI:10.1016/j.tetasy.2007.11.001

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2719–2726
Cinchonine catalyzed diastereo- and enantioselective Michael addition
of a-lithiated phosphonates to nitroalkenes
Vishal Rai,a Shaikh M. Mobinb and Irishi N. N. Namboothiria,*
aDepartment of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076, India
bNational Single Crystal X-ray Diffraction Facility, Indian Institute of Technology, Bombay, Mumbai 400 076, India
Received 17 October 2007; accepted 2 November 2007
Abstract—Conjugate addition of a-lithiated benzyl- and alkylphosphonates to a variety of aromatic and heteroaromatic nitroalkenes in
the presence of 50 mol % of cinchonine–Li catalyst system proceeded in high yields, diastereo- and enantioselectivities in most cases.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aminophosphonates are attractive synthetic targets
primarily because of their ability to mimic biological
processes, particularly, as transition state analogue inhibi-
tors.1 There are numerous methods, including asymmetric
versions, for the synthesis of a-aminophosphonates2 and
their b-analogues.3 However, only sporadic reports have
appeared in the literature for the synthesis of c-amino
phosphonates.4,5 We envisaged that c-nitrophosphonate,
the isosteric analogue of c-aminophosphonate, could serve
as a key intermediate for GABA (c-aminobutyric acid)
aminotransferase inactivation. We also felt that c-nitro-
phosphonates having diverse functionalities in the flexible
chain would substantially enhance the scope and potential
of small synthetic molecules as enzyme mimics in the bio-
logical domain.
Our preliminary experiments involving ‘interaction-based
catalyst optimization (IBCO)’, base, solvent and nitroalk-
ene screening for the Michael addition of benzylphospho-
nate 2a enabled us to optimize the chemical yield and
diastereoselectivity. Thus, the LDA (3 equiv) mediated
Michael addition of benzylphosphonate 2a to p-chloro-
nitrostyrene 1a in the presence of ( )-BINOL (0.5 equiv)
in THF provided the Michael adduct 3a in excellent yield
(97%) and diastereoselectivity (88:12). Subsequently, 1a
and 2a were chosen as model substrates for the enantio-
selective version of the reaction (Table 1). However, in
the presence of (S)-(À)-BINOL L1, the reaction proceeded
with only moderate enantioselectivity (38%, Table 1, entry
1). Compound (À)-DET L2, L-proline L3 and (R)-diphe-
nylprolinol L4 also provided moderate results (Table 1,
entries 2–4 and Fig. 1).8 In this scenario, the success of
bifunctional cinchona alkaloids in catalyzing various
organic reactions, including Michael addition, in recent
years prompted us to screen catalyst L5 for our reac-
tion.9,10 Interestingly, although cinchona alkaloids have
been used as organocatalysts in various asymmetric reac-
tions,9 including Michael addition to nitroalkenes,10 to
the best of our knowledge, a Li–alkaloid complex has not
been employed as a catalyst.11
Recent developments in the catalytic asymmetric conjugate
addition of various nucleophiles to nitroalkenes6 and our
own sustained interest in the chemistry of nitroalkenes7
encouraged us to employ nitroalkenes for the stereoselec-
tive synthesis of c-nitrophosphonates via the addition of
phosphonate stabilized carbanions in the presence of suit-
able chiral catalysts. To the best of our knowledge, there
are no reports in the literature on the asymmetric version,
catalytic or otherwise, of the conjugate addition of phos-
phonates to nitroalkenes.
It is interesting to note that 50 mol % of cinchonine L5 pro-
vided the desired product 3a in high yield, and diastereo-
and enantioselectivities (Table 1, entry 5). At higher catalyst
loadings (1–3 equiv), the yield and enantioselectivity
remain high, but the diastereoselectivity drops considerably
*
Corresponding author. Tel.: +91 22 2576 7196; fax: +91 22 2576 7152;
e-mail: irishi@iitb.ac.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.001

2720
V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
Table 1. Screening of chiral catalysts for the synthesis of nitrophosphonate 3a
EtO
EtO
O
Cl
P
O
OEt
OEt
LDA (3 equiv), THF
Catalyst (mol %)
Cl
P
+
NO2
-78 ºC (8 h) to rt (10 h)
NO2
1a
2a
3a
Entry
Catalyst
mol %
Yielda (%) of 3a
drb major/minor
% eec major
1
2
3
4
5
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
50
50
50
50
50
94
30
41
80
81
91
93
91
79
81
88:12
65:35
77:23
46:54
96:04
62:38
64:36
51:49
90:10
88:12
38 (R,R)
16 (S,S)
78 (S,S)
37 (R,R)
>99 (R,R)
>99 (R,R)
>99 (R,R)
>99 (R,R)
94 (R,R)
92 (R,R)
6
7
8
9
100
200
300
40
10
30
a Isolated yield after purification by silica gel column chromatography.
b Determined by 1H NMR.
c Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane), the absolute configuration of 3a was determined by X-ray crystallography (vide
infra).
H
EtO2C
EtO2C
OH
OH
Ph
Ph
OH
OH
OH
OH
COOH
N
N
N
H
H
H
N
(-)-DET, L2 L-Proline, L3 (R)-Diphenyl-
prolinol, L4
(S)-(-)-BINOL, L1
(+)-Cinchonine, L5
Figure 1. Catalysts screened.
(Table 1, entries 6–8). As the catalyst loading was gradually
decreased from 0.5 equiv to 0.4 and 0.3 equiv, the selectivi-
ties also decreased (Table 1, entries 9 and 10). Therefore,
50 mol % of the catalyst was used consistently in further
reactions (Table 1, entry 5).
the reaction of nitroalkene 1a with p-chlorobenzylphosph-
onate 2b provided the desired Michael adduct 3i in good
yield (69%) and excellent diastereo- and enantioselectivities
(Table 3, entry 2). Comparable yield and remarkably high
selectivities were maintained for the formation of Michael
adduct 3k from 1a and naphthylphosphonate 2d as well
(Table 3, entry 4). Although low yield and moderate ee
were encountered for the formation of Michael adduct 3j
from 1a and p-nitrobenzylphosphonate 2c, the diastereo-
selectivity remained high as in other cases (92:8, Table 3,
entry 3). Finally, we investigated the reactivity of selected
nitroalkenes with alkyl phosphonates 2e–f (Table 3, entries
5–8). It is interesting to note that nitroalkene 1a reacted
well with methyl phosphonate 2e and delivered the Michael
adduct 3l in a satisfactory yield and remarkable ee (>99%,
Table 3, entry 5). On the other hand, moderate results were
obtained when nitrostyrene 1b and its p-methoxy analogue
1c were reacted with phosphonate 2e (Table 3, entries 6 and
7). The yield and selectivities were moderate in the case of
alkylphosphonate 2f as well (Table 3, entry 8).
Under the above optimized conditions, that is, 3 equiv of
LDA and 50 mol % of cinchonine L5 in THF at À78 ꢁC,
we reacted a variety of aromatic and heteroaromatic nitroal-
kenes 1b–h with benzylphosphonate 2a (Table 2). The reac-
tion of benzylphosphonate 2a with nitrostyrene 1b provided
the Michael adducts 3b in high yield (95%), low diastereo-
selectivity (68:32) and high enantioselectivity (>99%, Table 2,
entry 2). The yield was quantitative and the diastereo- and
enantioselectivities were moderate for p-methoxynitrosty-
rene 1c (Table 2, entry 3). Although the yield and selectivities
were excellent in the case of aromatic nitroalkene 1d (Table
2, entry 4), all these factors were moderate for aromatic
nitroalkenes possessing strongly electron-donating (NMe2)
or strongly electron-withdrawing (NO2) groups (entries 5
and 6). As for the reactivity of heteroaromatic nitroalkenes,
while 1g was excellent in terms of yield and selectivities, 1h
reacted with benzyl phosphonate 2a to afford the Michael
adduct 3h in moderate yield and diastereoselectivity, but
with high enantioselectivity (Table 2, entries 7 and 8).
The structure and stereochemistry of 3a were determined
by detailed NMR, including 2D-NOE, analysis. In princi-
ple, four stereoisomers, including two diastereomers and
their enantiomers as well as their conformational isomers,
can be visualized. The coupling between the two vicinal
methine protons was in the range of J = 9.3–11.3 Hz
in compounds 3a–3k and 3o, which suggested that their
The scope of the reaction was subsequently extended to
other benzyl- and alkylphosphonates 2b–f (Table 3). Thus,

V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
Table 2. Michael addition of benzylphosphonate 2a to various nitroalkenes 1a–ha
2721
EtO
EtO
O
LDA (3 equiv), THF
O
OEt
OEt
P
L5 (50 mol %)
P
+
Ar
Ar
NO2
Ph
Ph
-78 ºC (8 h) to rt (10 h)
1
2a
3
NO2
Entry
1, Ar
3, yieldb (%)
drc
eec (%) major
1
2
3
4
5
6
7
8
1a, 4-ClPh
1b, Ph
1c, 4-MeOPh
1d, Ard
1e, 4-NMe2Ph
1f, 4-NO2Ph
1g, 2-Furyl
1h, 3-Furyl
3a, 81
3b, 95
3c, 99
3d, 95
3e, 63
3f, 65
3g, 90
3h, 60
96:04
68:32
88:12
100:0
52:48
68:32
96:04
62:38
>99 (R,R)
>99 (R,R)
82 (R,R)
94 (R,R)
86 (R,R)
78 (R,R)
>99 (R,R)
98 (R,R)
a The absolute configuration of 3a was determined by X-ray crystallography (vide infra) and of 3b–h based on comparison of 1H NMR chemical shifts for
the CH2NO2 group.
b Isolated yield after purification by silica gel column chromatography.
c Determined by HPLC (Chiralcel OD-H column, 5–20% IPA in n-hexane).
d 3,4-OCH2OPh.
Table 3. Michael addition of phosphonates 2a–f to various nitroalkenes 1a–ca
EtO
EtO
O
LDA (3 equiv), THF
L5 (50 mol%)
P
O
OEt
OEt
Ar
P
Ar
R
NO2
+ R
-78 ºC (8 h) to rt (10 h)
1
2
3
NO2
Entry
1, Ar
2, R
2a, Ph
2b, 4-ClPh
2c, 4-NO2Ph
2d, 2-Naph
2e, H
2e, H
2e, H
2f, n-Pr
3, yieldb (%)
drc
96:04
100:0
92:08
100:0
—
—
—
72:28
eec (%) major
1
2
3
4
5
6
7
8
1a, 4-ClPh
1a, 4-Cl–Ph
1a, 4-Cl–Ph
1a, 4-Cl–Ph
1a, 4-Cl–Ph
1b, Ph
3a, 81
3i, 69
3j, 45
3k, 74
3l, 61
3m, 41
3n, 43
3o, 47
>99 (R,R)
>99 (R,R)
80 (R,R)
>99d
>99e
68e
1c, 4-MeOPh
1a, 4-Cl–Ph
82e
86 (R,R)
a The absolute configuration of 3a was determined by X-ray crystallography and of 3i, 3j and 3o based on comparison of 1H NMR chemical shifts for the
CH2NO2 group.
b Isolated yield after purification by silica gel column chromatography.
c Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane).
d (R,S) or (S,R).
e Absolute configuration was not determined for 3l–3n (entries 5–7).
relative stereochemistry was anti. Additionally, 1H–1H 2D-
NOE experiments on 3a showed strong NOE between the
nitromethyl protons and the CH2 group of diethylphospho
nate moiety, thus suggesting that the nitromethyl and phos-
phonate groups are syn to each other. Furthermore, NOE
between the nitromethyl protons and the proton a to the
phosphonate moiety together with lack of any appreciable
NOE between the two vicinal benzylic protons indicated
that the stereochemistry is either (1R,2R)-syn or (1S,2S)-
syn. This was further unambiguously established by single
crystal X-ray analysis (Fig. 2, see also Section 4). Thus, X-
ray confirmed the syn relationship between the two aryl
groups (dihedral angle 45.2ꢁ) as well as between the nitro-
methyl group and the phosphonate moiety (dihedral angle
70ꢁ) and the absolute stereochemistry (R,R). The configu-
ration of 3b–k and 3o were assigned by correlating the
1H NMR chemical shifts of the nitromethyl group in these
compounds with that of 3a.
The proposed mechanism envisages that the alkaloid moi-
ety possessing a hydroxyl group (Brønsted acid) and a
bridgehead nitrogen (Lewis base) acts as a bidentate ligand
and chelates with a lithium coordinated with the carbanion
(Scheme 1). The p-interaction between the quinoline moi-
ety and the aromatic ring, if any, in the substrate provides
a third point of interaction.12
3. Conclusions
A catalytic asymmetric version of the conjugate addition of
phosphonate stabilized carbanions to nitroalkenes has been
developed for the first time. Under the influence of a cin-
chonine–Li complex, various benzyl- and alkylphospho-
nates reacted with a variety of aromatic and hetero
aromatic nitroalkenes to afford the adducts in high yields,
and diastereo- and enantioselectivities.

2722
V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
adducts were purified by column chromatography on silica
gel (60–120 mesh) using a mixture of ethyl acetate and
petroleum ether as eluent. Nitroalkenes13 and phospho-
nates14 were prepared following the literature protocols.
4.2. General procedure for the Michael addition of
phosphonate 2 to nitroalkene 1 in the presence of
an Li–cinchonine L5 complex
A solution of LDA (3 mmol) in THF (3 ml) was prepared
by the dropwise addition of n-BuLi (3 mmol, 1.6 M solu-
tion in hexanes) to diisopropylamine (3 mmol) in THF
(3 ml) at 0 ꢁC followed by stirring for 30 min at the same
temperature. To this freshly prepared LDA, cooled to
À78 ꢁC, was added phosphonate 2 (1 mmol) dropwise.
After stirring the reaction mixture for 1 h, cinchonine L5
in THF (2 ml) was added and the reaction mixture was stir-
red for an additional 30 min. Subsequently, nitroalkene 1
(1.5 mmol) in THF (1 ml) was added to the reaction mix-
ture and the temperature was maintained at À78 ꢁC for
an additional 8 h. The reaction mixture was warmed to
ambient temperature and stirring continued for 10 h. The
reaction mixture was quenched with saturated aqueous
NH4Cl (2 ml), further saturated with NaCl and extracted
with ethyl acetate (3 · 10 ml). The combined organic layers
were washed with brine (5 ml), dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (ethyl acetate/pet
ether, 0–50%, gradient elution). The compound was further
purified by recrystallization (CH2Cl2/pet ether ꢀ10:1).
Figure 2. Single crystal X-ray structure of Michael adduct 3a.
4. Experimental
4.1. General
The melting points were recorded on Thermonik melting
point apparatus and are uncorrected. IR spectra were
recorded on an Impact 400/Nicolet or Perkin Elmer Spec-
trum One FT spectrometer. NMR spectra (1H, 13C and
31P) were recorded on an AMX-400 (Varian Mercury Plus
OXFORD, broad band, auto switchable and inverse
probe) or VXR-300S spectrometer. TMS was the internal
standard for 1H and 13C and phosphoric acid was the exter-
nal standard for 31P. The coupling constants (J values) are
given in Hertz. Mass spectra (LR and HR) were recorded
at 60–70 eV on a Micromass Q-TOF mass spectrometer
under ESI mode. Enantioselectivities were determined with
JASCO (PU-2080PLUS pump with UV-2075PLUS detec-
tor) HPLC using Chiralcel OD-H column. The Michael
4.2.1. Diethyl 2-(4-chlorophenyl)-3-nitro-1-phenylpropyl-
phosphonate 3a. Colourless solid; Yield 81% (mixture of
diastereomers, crude 96:04, after recrystallization 100:0).
Major diastereomer: Rf 0.30 (EtOAc/pet ether 1:1); mp
122–123 ꢁC; IR (film, cmÀ1) 3055 (m), 2985 (m), 1556 (s),
1
1494 (m), 1379 (m), 1266 (s), 967 (m), 740 (s); H NMR
(CDCl3) d 1.08 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.1 Hz,
3H), 3.34 (dd, J = 21.0, 10.8 Hz, 1H), 3.61 (m, 1H), 3.84–
3.98 (m, 1H), 4.00–4.16 (m, 2H), 4.18–4.27 (m, 1H), 4.79
(dd, J = 13.2, 10.6 Hz, 1H), 5.32 (dd, J = 13.2, 4.8 Hz,
1H), 6.93 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H),
7.12–7.22 (m, 5H); 13C NMR (CDCl3) d 15.9 (d,
J = 6.1 Hz), 16.1 (d, J = 6.1 Hz), 44.9, 47.7 (d,
J = 135.8 Hz), 62.0 (d, J = 7.7 Hz), 63.2 (d, J = 7.7 Hz),
79.0, 127.4, 128.3, 128.4, 129.5, 129.6 (d, J = 7.7 Hz),
133.1, 133.7 (d, J = 6.1 Hz), 135.7 (d, J = 3.8 Hz).
Multiplicities and J values indicated are only for C–P
coupling; 31P NMR (CDCl3) d 23.36; MS (TOF ES+) m/e
(rel intensity) 434 (MNa+, 40), 413 ([M+2]+, 80), 397
(10), 365 (4), 295 (3), 227 (15), 205 (10), 149 (100);
HRMS: (MNa+) calcd for C19H23NO5NaPCl, 434.
0900; found, 434.0912. Selected X-ray crystallographic data
for 3a: C19H23ClNO5P, M = 411.80, orthorhombic,
O
OEt
OEt
P
R
2
LDA
OEt
OEt
OEt
Ar
O
R
P
N
O
OH
P
OEt
NO2
N
R
3
L5
Li
I
EtO
OEt
P
R
N
O
O
Li
N
O
O
O
N
OEt
Ar
Li
N
P
OEt
O
II
˚
˚
space group Pc21b, a = 9.4400(7) A, b = 11.585(2) A,
III
3
N
R
˚
˚
c = 18.6550(9) A, a = b = c = 90ꢁ; U = 2040.2(4) A , Dc =
3
˚
1.341 Mg/m , Z = 4, F(000) = 864, k = 0.71073 A, l =
0.295 mmÀ1, total/unique reflections = 1893/1893 [Rint
=
Ar
NO2
0.0000], T = 293(2) K, h range = 2.16–24.98ꢁ, Final R indi-
ces [I > 2r(I)] R1 = 0.0416, wR2 = 0.0864, R indices (all
1
data) R1 = 0.1012, wR2 = 0.1005, Flack
ter = 0.0557 (0.1302). Crystallographic data (excluding
x parame-
Scheme 1. Proposed mechanism of the Michael addition of phosphonate 2
to nitroalkene 1 catalyzed by an Li–cinchonine complex.

V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
2723
structure factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Cen-
tre as Supplementary Publication Number CCDC 654262.
Copies of the data can be obtained free of charge on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk].
1H), 6.63 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H),
7.09–7.19 (m, 5H); 13C NMR (CDCl3) d 16.1 (d,
J = 6.1 Hz), 16.3 (d, J = 6.1 Hz), 44.9, 48.1 (d,
J = 135.8 Hz), 55.0, 62.0 (d, J = 7.6 Hz), 63.2 (d, J =
6.9 Hz), 79.6 (d, J = 1.5 Hz), 113.7, 127.3 (d, J = 2.3 Hz),
128.3 (d, J = 2.3 Hz), 128.9 (d, J = 14.5 Hz), 129.2, 129.8
(d, J = 6.9 Hz), 134.2 (d, J = 6.9 Hz), 158.6. Multiplicities
and J values indicated are only for C–P coupling; 31P
NMR (CDCl3) d 23.88; MS (TOF ES+) m/e (relative inten-
sity) 430 (MNa+, 55), 408 (MH+, 100), 361 (30), 158 (11),
141 (20); HRMS: (MH+) calcd for C20H27NO6P, 408.1576;
found, 408.1584.
4.2.2. Diethyl 3-nitro-1,2-diphenylpropylphosphonate 3b.
Colourless solid; Yield 95% (inseparable mixture of diaste-
reomers crude 68:32, after attempted separation by silica
gel column chromatography and fractional crystallization
ꢀ50:50); Rf 0.30 (EtOAc/pet ether 1:1); mp 117–118 ꢁC;
IR (film, cmÀ1) 3064 (w), 3033 (w), 2983 (w), 2909 (w),
1603 (w), 1554 (s), 1496 (m), 1455 (m), 1380 (m), 1242
(m), 1054 (s), 1026 (s), 968 (s) 701 (s).
4.2.4. Diethyl 2-(benzo[d][1,3]dioxol-6-yl)-3-nitro-1-phenyl-
propylphosphonate 3d. Colourless solid; Yield 95% (single
diastereomer); Rf 0.30 (EtOAc/pet ether 1:1); mp 145–
146 ꢁC; IR (film, cmÀ1) 2985 (w), 2906 (w), 1554 (s), 1504
(m), 1491 (m), 1445 (m), 1381 (m), 1249 (s), 1040 (s), 967
1
Diastereomer 1: H NMR (CDCl3) d 1.09 (t, J = 7.1 Hz,
1
3H), 1.29 (t, J = 7.3 Hz, 3H), 3.39 (dd, J = 21.0, 10.8 Hz,
1H), 3.62 (m, 1H), 3.95 (m, 1H), 4.10 (m, 2H), 4.23 (dABq,
J = 14.8, 10.8 Hz, 1H), 4.84 (dd, J = 12.8, 10.8 Hz, 1H),
5.34 (dd, J = 14.8, 12.8 Hz, 1H), 7.09–7.30 (m, 10H). Mul-
tiplicities and J values indicated are both for H–H and P–H
coupling; 13C NMR (CDCl3) d 15.9 (d, J = 3.0 Hz), 16.0
(d, J = 3.0 Hz), 45.0, 48.5 (d, J = 140.3 Hz), 61.3 (d,
J = 7.7 Hz), 62.9 (d, J = 6.9 Hz), 78.7 (d, J = 14.6 Hz),
127.9, 128.2, 128.4, 128.5, 129.0, 129.6 (d, J = 6.9 Hz),
133.6 (d, J = 6.1 Hz), 137.5 (d, J = 4.0 Hz). Multiplicities
and J values indicated are only for C–P coupling; 31P
NMR (CDCl3) d 23.29.
(m); H NMR (CDCl3) d 1.09 (t, J = 7.2 Hz, 3H), 1.29 (t,
J = 7.1 Hz, 3H), 3.32 (dd, J = 20.8, 11.0 Hz, 1H), 3.58–
3.64 (m, 1H), 3.83–4.97 (m, 1H), 4.04–4.20 (m, 3H), 4.75
(dd, J = 12.9, 11.0 Hz, 1H), 5.30 (dd, J = 12.9, 4.6 Hz,
1H), 5.83 (dd, J = 2.2, 1.5 Hz, 2H), 6.44 (dd, J = 7.9,
1.7 Hz, 2H), 6.50 (d, J = 1.7 Hz, 1H), 7.10–7.25 (m, 5H);
13C NMR (CDCl3) d 16.0 (d, J = 6.1 Hz), 16.1 (d,
J = 6.1 Hz), 45.3, 47.9 (d, J = 135.0 Hz), 61.9 (d,
J = 7.7 Hz), 63.1 (d, J = 6.1 Hz), 79.4, 100.9, 107.9,
121.8, 127.2, 128.2 (·2), 129.6 (d, J = 7.7 Hz), 130.8 (d,
J = 15.3 Hz), 134.0 (d, J = 6.1 Hz), 146.6, 147.4. Multiplic-
ities and J values indicated are only for C–P coupling; 31P
NMR (CDCl3) 23.72; MS (TOF ES+) m/e (rel intensity)
444 (MNa+, 75), 422 (MH+, 100), 375 (12), 159 (5);
HRMS: (MH+) calcd for C20H25NO7P, 422.1369; found,
422.1367.
1
Diastereomer 2: H NMR (CDCl3) d 0.87 (t, J = 6.9 Hz,
3H), 1.00 (t, J = 7.1 Hz, 3H), 3.38 (dd, J = 22.1, 9.4 Hz,
1H), 3.79 (m, 1H), 3.95 (m, 1H), 4.10 (m, 2H), 4.32 (ABqd,
J = 9.4, 4.1 Hz, 1H), 4.51 (dd, J = 12.6, 9.4 Hz, 1H), 4.64
(dd, J = 12.6, 4.1 Hz, 1H), 7.20–7.40 (m, 10H). Multiplici-
ties and J values indicated are both for H–H and P–H cou-
pling; 13C NMR (CDCl3) d 16.2 (d, J = 8.1 Hz), 16.3 (d,
J = 8.1 Hz), 45.6, 47.9 (d, J = 135.7 Hz), 62.0 (d, J =
6.9 Hz), 63.3 (d, J = 7.7 Hz), 79.3, 127.4 (d, J = 3.8 Hz),
127.5, 128.3, 128.4, 128.6, 129.7 (d, J = 6.9 Hz), 134.0 (d,
J = 6.8 Hz), 137.2 (d, J = 14.4 Hz). Multiplicities and J
values indicated are only for C–P coupling; 31P NMR
(CDCl3) d 23.79.
4.2.5. Diethyl 2-(4-(dimethylamino)phenyl)-3-nitro-1-phen-
ylpropylphosphonate 3e. Colourless solid; Yield 63%
(mixture of diastereomers in 52:48 ratio, the major isomer
was isolated in diastereomerically pure form by repeated
recrystallization from CH2Cl2/pet ether 10:1). Major dia-
stereomer: Rf 0.30 (EtOAc/pet ether 1:1); mp 140–142 ꢁC;
IR (film, cmÀ1) 2920 (w), 1617 (m), 1548 (s), 1525 (m),
1380 (m), 1354 (m), 1234 (m), 1164 (w), 1046 (m), 1017
(m), 947 (m); 1H NMR (CDCl3) d 1.09 (t, J = 7.0 Hz,
3H), 1.30 (t, J = 6.9 Hz, 3H), 2.82 (s, 6H), 3.37 (dd,
J = 21.1, 10.5 Hz, 1H), 3.54–3.69 (m, 1H), 3.84–3.96 (m,
1H), 3.98–4.18 (m, 3H), 4.77 (dd, J = 12.7, 10.5 Hz, 1H),
5.26 (dd, J = 12.7, 5.0 Hz, 1H), 6.45 (d, J = 8.8 Hz, 2H),
6.83 (d, J = 8.8 Hz, 2H), 7.10–7.18 (m, 5H); 13C NMR
(CDCl3) d 16.2 (d, J = 5.3 Hz), 16.3 (d, J = 6.1 Hz), 40.3,
44.8 (d, J = 1.6 Hz), 48.2 (d, J = 134.3 Hz), 61.9 (d,
J = 7.6 Hz), 63.2 (d, J = 7.6 Hz), 79.7 (d, J = 2.3 Hz),
112.2, 124.3 (d, J = 14.5 Hz), 127.2 (d, J = 3.1 Hz), 128.3
(d, J = 2.3 Hz), 128.8, 129.9 (d, J = 6.1 Hz), 134.4 (d,
J = 6.1 Hz), 149.6. Multiplicities and J values indicated
are only for C–P coupling; 31P NMR (CDCl3) d 24.23;
MS (TOF ES+) m/e (rel intensity) 421 (MH+, 100), 374
(11), 360 (7), 236 (16), 149 (20), 134 (30); HRMS: (MH+)
calcd for C21H30N2O5P, 421.1892; found, 421.1900.
The peaks for the two diastereomers could be distinguished
from NMR of the crude product (ratio 68:32).
MS (TOF ES+) m/e (rel intensity) 400 ([M+Na]+, 45), 378
([MH+, 100), 331 (5), 204 (5); HRMS: (MH+) calcd for
C19H25NO5P, 378.1470; found, 378.1470.
4.2.3. Diethyl 2-(4-methoxyphenyl)-3-nitro-1-phenylpropyl-
phosphonate 3c. Colourless solid; Yield 99% (mixture of
diastereomers, crude 88:12, after recrystallization 100:0).
Major diastereomer: Rf 0.30 (EtOAc/pet ether 1:1); mp
123–124 ꢁC; IR (film, cmÀ1) 3055 (w), 2986 (w), 1556 (s),
1
1514 (m), 1380 (m), 1266 (s), 966 (m), 741 (s); H NMR
(CDCl3) d 1.09 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 6.9 Hz,
3H), 3.35 (dd, J = 21.0, 10.8 Hz, 1H), 3.57–3.70 (m, 1H),
3.67 (s, 3H), 3.84–3.98 (m, 1H), 4.00–4.24 (m, 3H), 4.78
(dd, J = 12.8, 10.6 Hz, 1H), 5.29 (dd, J = 12.8, 4.8 Hz,
4.2.6. Diethyl 3-nitro-2-(4-nitrophenyl)-1-phenylpropyl-
phosphonate 3f. Colourless solid; Yield 65% (mixture of

2724
V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
diastereomers in 68:32 ratio, separated by repeated recrys-
tallization from CH2Cl2/hexane 10:1).
Minor diastereomer: 1H NMR (CDCl3) d 0.93 (t,
J = 6.9 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 3.43 (m, 1H),
3.57 (dd, J = 22.0, 8.8 Hz, 1H), 3.66 (m, 1H), 3.75 (m,
2H), 4.45 (ABqd, J = 8.8, 3.6 Hz, 1H), 4.50 (dd, J = 11.7,
8.8 Hz, 1H), 4.58 (dd, J = 11.7, 3.6 Hz, 1H), 6.23 (d,
J = 3.3 Hz, 1H), 6.29 (dd, J = 3.3, 1.6 Hz, 1H), 7.40 (d,
J = 1.6 Hz, 1H), 7.20–7.40 (m, 5H). Multiplicities and J
values indicated are both for H–H and P–H coupling; 31P
NMR (CDCl3) d 22.97.
Major diastereomer: Rf 0.39 (EtOAc/pet ether 1:1); mp
139–140 ꢁC; IR (film, cmÀ1) 2991 (m), 2919 (w), 1604
(w), 1552 (s), 1520 (s), 1382 (m), 1345 (s), 1227 (s), 1042
1
(s), 1015 (s), 965 (s), 944 (m), 754 (m); H NMR (CDCl3)
d 1.08 (t, J = 7.0 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 3.39
(dd, J = 20.4, 11.1 Hz, 1H), 3.56–3.66 (m, 1H), 3.88–3.99
(m, 1H), 4.08–4.17 (m, 2H), 4.33–4.41 (m, 1H), 4.86 (dd,
J = 13.4, 10.9 Hz, 1H), 5.39 (dd, J = 13.4, 4.7 Hz, 1H),
7.10–7.27 (m, 7H), 7.99 (d, J = 9.0 Hz, 2H); 13C NMR
(CDCl3) d 16.2 (d, J = 6.1 Hz), 16.4 (d, J = 6.1 Hz), 45.4,
47.7 (d, J = 137.3 Hz), 62.4 (d, J = 7.7 Hz), 63.7 (d,
J = 6.9 Hz), 78.7, 123.7, 128.0 (d, J = 2.3 Hz), 128.8 (d,
J = 1.5 Hz), 129.4, 129.7 (d, J = 6.9 Hz), 133.4 (d, J =
6.1 Hz), 145.1 (d, J = 14.6 Hz), 147.2. Multiplicities and J
values indicated are only for C–P coupling; 31P NMR
(CDCl3) d 22.71. MS (TOF ES+) m/e (relative intensity)
423 (MH+, 85), 159 (15), 99 (100); HRMS: (MH+) calcd
for C19H24N2O7P, 423.1321; found, 423.1333.
13C NMR (CDCl3, mixture of diastereomers) d 15.9 (d,
J = 6.1 Hz), 16.0 (2 · d, J = 5.3 Hz), 16.2 (d, J = 5.4 Hz),
38.8, 39.7, 45.3 (d, J = 16.8 Hz), 46.7 (d, J = 19.8 Hz),
61.6 (d, J = 7.6 Hz), 62.1 (d, J = 7.6 Hz), 63.1 (d,
J = 7.6 Hz), 63.2 (d, J = 7.6 Hz), 76.5 (d, J = 13.7 Hz),
76.8, 109.0, 109.1, 110.0, 110.4, 127.5, 128.2, 128.3, 129.0,
129.3, 129.4, 133.1 (d, J = 5.3 Hz), 133.8 (d, J = 6.8 Hz),
142.0, 142.3, 149.6 (d, J = 15.2 Hz), 149.9 (d, J = 6.1 Hz).
Multiplicities and J values indicated are only for C–P cou-
pling. MS (TOF ES+) m/e (relative intensity) 390 (MNa+,
5), 368 (MH+, 100), 321 (28); HRMS: (MH+) calcd for
C17H23NO6P, 368.1263; found, 368.1258.
Minor diastereomer: Rf 0.40 (EtOAc/pet ether 1:1); mp
134–136 ꢁC; IR (film, cmÀ1) 2990 (m), 2921 (m), 2953
(w), 1604 (w), 1552 (s), 1520 (s), 1382 (m), 1346 (s), 1227
(s), 1213 (m), 1042 (s), 1014 (s), 965 (s), 944 (s), 854 (m),
4.2.8. Diethyl 2-(furan-3-yl)-3-nitro-1-phenylpropylphospho-
nate 3h. Colourless solid; Yield 60% (inseparable mixture
of diastereomers in 62:38 ratio); Rf 0.30 (EtOAc/pet ether
1:1); mp 92–93 ꢁC; IR (film, cmÀ1) 2982 (s), 2020 (s),
1547 (s), 1446 (m), 1383 (m), 1231 (s), 1040 (s), 963
(s), 795 (m), 557 (m); 1H NMR (CDCl3) d 0.92
(t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H), 1.18 (t,
J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H), 3.32 (dd,
J = 21.1, 10.3 Hz, 1H), 3.34 (dd, J = 22.0, 8.4 Hz, 1H),
3.40–3.50 (m, 1H), 3.58–3.69 (m, 1H), 3.76–4.29 (m, 8H),
4.33 (ABq, J = 10.3 Hz, 1H), 4.68 (dd, J = 12.7, 5.0 Hz,
1H), 4.71 (ABq, J = 10.3 Hz, 1H), 5.15 (dd, J = 13.0,
5.0 Hz, 1H), 6.12 (t, J = 0.9 Hz, 1H), 6.25 (t, J = 0.9 Hz,
1H), 7.00–7.02 (unresolved m, 1H), 7.16–7.26 (m, 6H),
7.32–7.40 (m, 7H). Multiplicities and J values indicated
are both for H–H and P–H coupling; 13C NMR (CDCl3)
d 15.8 (d, J = 8.1 Hz), 15.9 (d, J = 8.1 Hz), 16.0 (d,
J = 8.1 Hz), 16.1 (d, J = 8.1 Hz), 36.0, 36.5, 46.5 (d,
J = 55.4 Hz), 48.3 (d, J = 59.2 Hz), 61.3 (d, J = 7.6 Hz),
61.9 (d, J = 6.8 Hz), 62.9 (d, J = 7.6 Hz), 63.1 (d,
J = 6.8 Hz), 78.2 (d, J = 12.9 Hz), 78.6 (d, J = 3.0 Hz),
108.7, 109.2, 121.1 (d, J = 15.2 Hz), 121.5 (d, J = 6.8 Hz),
127.5 (d, J = 2.3 Hz), 128.0, 128.3, 128.9, 129.4, 129.6 (d,
J = 2.3 Hz), 129.7, 133.4 (d, J = 5.3 Hz), 134.0 (d,
J = 6.9 Hz), 140.8, 142.9, 143.0, Multiplicities and J values
indicated are only for C–P coupling; 31P NMR (CDCl3) d
23.43 (minor) 23.46 (major). MS (TOF ES+) m/e (relative
intensity) 390 (MNa+, 5), 368 ([MH+, 18), 321 (4), 158 (22),
156 (35), 141 (45); HRMS: (MH+) calcd for C17H23NO6P,
368.1263; found, 368.1274.
697 (m), 566 (m); 1H NMR (CDCl3)
d 0.87 (t,
J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H), 3.25–3.40 (m,
1H), 3.32 (dd, J = 21.8, 9.5 Hz, 1H), 3.61–3.86 (m, 3H),
4.30 (ABqd, J = 9.5, 3.9 Hz, 1H), 4.48 (dd, J = 12.8,
9.5 Hz, 1H), 4.63 (dd, J = 12.8, 3.9 Hz, 1H), 7.19 (d,
J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.37 (m, 5H);
13C NMR (CDCl3) d 16.1 (2 · d, J = 5.4 Hz), 44.6, 48.7
(d, J = 139.5 Hz), 61.6 (d, J = 7.7 Hz), 63.4 (d,
J = 7.7 Hz), 78.6 (d, J = 14.6 Hz), 128.5 (d, J = 2.3 Hz),
128.9, 129.4 (d, J = 1.5 Hz), 129.7 (d, J = 6.9 Hz), 129.9,
133.3 (d, J = 6.1 Hz), 134.0, 136.2 (d, J = 5.4 Hz). Multi-
plicities and J values indicated are only for C–P coupling;
31P NMR (CDCl3) d 22.92. MS (TOF ES+) m/e (relative
intensity) 423 (MH+, 100), 159 (75), 99 (58); HRMS:
(MH+) calcd for C19H24N2O7P, 423.1321; found, 423.1337.
4.2.7. Diethyl 2-(furan-2-yl)-3-nitro-1-phenylpropylphospho-
nate 3g. Brown liquid; Yield 90% (inseparable mixture of
diastereomers in 96:04 ratio, part of the major diastereo-
mer was removed during attempted purification, that is,
removal of unreacted benzyl phosphonate and probably
an unexpected change at the configurationally labile C–P
carbon changed the original ratio of 96:04 to 60:40, see
1H NMR); Rf 0.30 (EtOAc/pet ether 1:1); IR (film, cmÀ1
)
2984 (m), 2910 (w), 1556 (s), 1497 (w), 1455 (w), 1378
(m), 1244 (m), 1053 (s), 1024 (s), 970 (s).
Major diastereomer: 1H NMR (CDCl3)
d 1.09 (t,
J = 7.2 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 3.51 (dd,
J = 20.5, 10.2 Hz, 1H), 3.90 (m, 2H), 4.07 (m, 2H), 4.33
(ABqd, J = 10.2, 4.8 Hz, 1H), 4.86 (dd, J = 13.2, 10.2 Hz,
1H), 5.20 (dd, J = 13.2, 4.8 Hz, 1H), 5.89 (d, J = 3.3 Hz,
1H), 6.06 (dd, J = 3.3, 1.6 Hz, 1H), 7.19 (d, J = 1.6 Hz,
1H), 7.15–7.40 (m, 5H). Multiplicities and J values indi-
cated are both for H–H and P–H coupling; 31P NMR
(CDCl3) d 23.23.
4.2.9. Diethyl 1,2-bis(4-chlorophenyl)-3-nitropropylphospho-
nate 3i. Colourless solid; Yield 69% (single diastereomer);
Rf 0.32 (EtOAc/pet ether 1:1); mp 175–176 ꢁC; IR (film,
cmÀ1) 2985 (m), 2922 (m), 1550 (s), 1492 (m), 1379 (m),
1235 (s), 1164 (m), 1092 (m), 1044 (s), 1014 (s), 937 (s),
745 (m), 569 (s); H NMR (CDCl3) d 1.14 (t, J = 7.0 Hz,
3H), 1.30 (t, J = 7.0 Hz, 3H), 3.34 (dd, J = 21.1, 10.7 Hz,
1H), 3.64–3.75 (m, 1H), 3.90–4.00 (m, 1H), 4.02–4.21 (m,
1

V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
2725
3H), 4.77 (dd, J = 12.8, 10.5 Hz, 1H), 5.31 (dd, J = 12.8,
4.9 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 7.05 (dd, J = 8.6,
1.8 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz,
2H); 13C NMR (CDCl3) d 16.1 (d, J = 5.3 Hz), 16.2 (d,
J = 6.1 Hz), 44.8, 47.1 (d, J = 35.7 Hz), 62.2 (d, J =
7.6 Hz), 63.4 (d, J = 6.9 Hz), 78.9, 128.6 (d, J = 1.6 Hz),
128.7, 129.4, 130.8 (d, J = 6.1 Hz), 132.4 (d, J = 6.8 Hz),
133.4 (d, J = 3.0 Hz), 133.5, 135.4 (d, J = 15.2 Hz). Multi-
plicities indicated are only for C–P coupling; 31P NMR
(CDCl3) d 22.72; MS (TOF ES+) m/e (relative intensity)
446 (MH+, 5), 158 (7), 141 (40), 124 (100); HRMS:
(MH+) calcd for C19H23NO5PCl2, 446.0690; found,
446.0691.
4.20 (m, 5H), 4.60 (dd, J = 12.8, 9.0 Hz, 1H), 4.89 (dd,
J = 12.8, 6.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.32 (d,
J = 8.4 Hz, 2H); 13C NMR (CDCl3) d 16.3, d 16.4, 30.2
(d, J = 141.7 Hz), 38.3 (d, J = 2.6 Hz), 62.0 (d,
J = 6.9 Hz), 62.1 (d, J = 6.9 Hz), 79.8 (d, J = 10.4 Hz),
128.8, 129.2, 134.0, 137.5 (d, J = 10.1 Hz). Multiplicities
and J values indicated are only for C–P coupling; 31P
NMR (CDCl3) d 24.93; MS (TOF ES+) m/e (relative inten-
sity) 358 (MNa+, 50), 336 ([MH+, 100), 125 (5), 97 (10);
HRMS: (MH+) calcd for C13H20NO5PCl, 336.0768; found,
336.0759.
4.2.13.
Diethyl
3-nitro-2-phenylpropylphosphonate
3m. Light red liquid; Yield 41%; Rf 0.28 (EtOAc/pet ether
4.2.10. Diethyl 2-(4-chlorophenyl)-3-nitro-1-(4-nitrophenyl)
propylphosphonate 3j. Colourless solid; Yield 45% (mixture
of diastereomers in 92:08 ratio, the major isomer was
isolated in pure form by repeated recrystallization from
CH2Cl2/pet ether 10:1); Rf 0.38 (EtOAc/pet ether 1:1);
mp 162–163 ꢁC; IR (film, cmÀ1) 2985 (m), 1600 (m), 1521
(s), 1348 (vs), 1247 (s), 1026 (vs), 969 (s), 861 (m); 1H
NMR (CDCl3) d 1.19 (t, J = 7.1 Hz, 3H), 1.31 (t,
J = 7.1 Hz, 3H), 3.55 (dd, J = 21.0, 11.3 Hz, 1H), 3.79–
3.85 (m, 1H), 3.99–4.23 (m, 4H), 4.81 (dd, J = 13.2,
10.4 Hz, 1H), 5.37 (dd, J = 13.2, 4.5 Hz, 1H), 6.94 (d,
J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.30 (d,
J = 8.6 Hz, 2H), 8.38 (d, J = 8.6 Hz, 2H); 13C NMR
1:1); IR (film, cmÀ1) 2984 (m), 2930 (m), 1555 (s), 1380 (m),
1236 (s), 1028 (s), 965 (m), 788 (m), 763 (m), 701 (m); H
1
NMR (CDCl3) d 1.22 (td, J = 7.0, 1.7 Hz, 6H), 2.19 (dd,
J = 7.6, 3.5 Hz, 1H), 2.23 (dd, J = 7.3, 3.1 Hz, 1H), 3.80–
4.10 (m, 5H), 4.63 (dd, J = 12.7, 8.9 Hz, 1H), 4.87 (dd,
J = 12.7, 6.1 Hz, 1H), 7.20–7.30 (m, 5H); 13C NMR
(CDCl3) 16.0 (d, J = 3.1 Hz), 16.1 (d, J = 3.1 Hz), 29.3
(d, J = 11.5 Hz), 38.6 (d, J = 2.3 Hz), 61.8 (d, J = 6.1 Hz),
62.0 (d, J = 6.9 Hz), 79.9 (d, J = 3.1 Hz), 127.2, 127.9,
128.8, 138.8 (d, J = 9.2 Hz), Multiplicities and J values
indicated are only for C–P coupling; 31P NMR (CDCl3)
d 25.47; MS (TOF ES+) m/e (relative intensity) 302
([MH+, 100), 256 (5), 228 (5), 153 (5), 125 (18); HRMS:
(MH+) calcd for C13H21NO5P, 302.1157; found, 302.1155.
(CDCl3)
d 16.4 (2 · d, J = 6.1 Hz), 44.9, 47.9 (d,
J = 136.5 Hz), 62.9, 63.8, 79.1, 123.8, 129.2, 129.5, 130.6,
130.7, 134.1, 135.1, 147.2 (Multiplicities and J values indi-
cated are only for C–P coupling); 31P NMR (CDCl3) d
21.53; MS (TOF ES+) m/e (relative intensity) 457
([MH+, 100), 439 (10), 411 (5), 339 (5); HRMS: (M+) calcd
for C19H23N2O7PCl, 457.0931; found, 457.0933.
4.2.14. Diethyl 2-(4-methoxyphenyl)-3-nitropropylphospho-
nate 3n. Light red liquid; Yield 43%; Rf 0.15 (EtOAc/pet
ether 1:1); IR (film, cmÀ1) 3055 (m), 2986 (m), 1612 (m),
1555 (s), 1515 (s), 1442 (w), 1379 (m), 1266 (s), 1030 (s),
1
966 (m), 896 (m), 832 (m), 742 (s); H NMR (CDCl3) d
1.23 (t, J = 7.1 Hz, 6H), 2.12 (dd, J = 7.3, 4.4 Hz, 1H),
2.17 (dd, J = 7.3, 3.8 Hz, 1H), 3.76 (s, 3H), 3.90–4.10 (m,
5H), 4.56 (dd, J = 12.5, 8.9 Hz, 1H), 4.83 (dd, J = 12.5,
6.1 Hz, 1H), d 6.84 (d, J = 8.7 Hz, 2H), d 7.13 (d, J =
8.7 Hz, 2H); 13C NMR (CDCl3) d 16.1 (d, J = 3.1 Hz),
16.2 (d, J = 3.1 Hz), 29.6 (d, J = 140.3 Hz), 38.0 (d,
J = 2.3 Hz), 55.1, 61.7 (d, J = 6.9 Hz), 61.8 (d, J =
6.8 Hz); 80.2 (d, J = 10.7 Hz), 114.2, 128.3, 130.8 (d,
J = 10.0 Hz), 159.1. Multiplicities and J values indicated
are only for C–P coupling; 31P NMR (CDCl3) d 25.55;
MS (TOF ES+) m/e (relative intensity) 332 (MH+, 100),
285 (80), 271 (10), 158 (4), 99 (7), 73 (43); HRMS:
(MH+) calcd for C14H23NO6P, 332.1263; found, 332.1257.
4.2.11. Diethyl 2-(4-chlorophenyl)-1-(naphthalen-2-yl)-3-
nitropropylphosphonate 3k. Colourless solid; Yield 74%
(single diastereomer); Rf 0.39 (EtOAc/pet ether 1:1); mp
179–180 ꢁC; IR (film, cmÀ1) 2928 (m), 2853 (w), 1556 (s),
1494 (w), 1379 (w), 1247 (m), 1095 (m), 1027 (s), 971 (w),
1
913 (m), 742 (s); H NMR (CDCl3) d 0.81 (t, J = 7.2 Hz,
3H), 1.05 (t, J = 6.8 Hz, 3H), 3.30 (m, 1H), 3.50 (dd,
J = 22.0, 9.3 Hz, 1H), 3.70 (m, 2H), 3.86 (m, 1H), 4.40
(ABqd, J = 9.3, 3.7 Hz, 1H), 4.51 (dd, J = 12.0, 9.3 Hz,
1H), 4.64 (dd, J = 12.0, 3.7 Hz, 1H), 7.26–7.31 (m, 5H),
7.48–7.50 (m, 1H), 7.52–7.55 (m, 2H), 7.82 (m, 3H). Multi-
plicities and J values indicated are both for H–H and P–H
coupling; 13C NMR (CDCl3) d 16.0 (2 · d, J = 5.3 Hz),
44.5, 48.7 (d, J = 139.5 Hz), 61.5 (d, J = 6.9 Hz), 63.3 (d,
J = 6.8 Hz), 78.5 (d, J = 13.7 Hz), 126.6, 126.8, 127.7,
127.9, 128.8, 129.1, 129.8, 130.6, 130.7, 132.9, 133.3,
133.9, 135.98, 136.03; 31P NMR (CDCl3) d 22.82. MS
(TOF ES+) m/e (relative intensity) 464 (MH+, 100), 297
(9), 214 (4), 158 (6), 99 (10), 85 (12); HRMS: calcd for
C23H26NO5PCl, 462.1237; found, 462.1247.
4.2.15. Diethyl 2-(4-chlorophenyl)-1-nitrohexan-3-ylphospho
nate 3o. Light red liquid; Yield 47% (mixture of diaste-
reomers in 72:28 ratio, the major isomer was isolated in
pure form via silica gel column chromatography); Rf 0.30
(EtOAc/pet ether 1:1); IR (film, cmÀ1) 2963 (m), 2932
(m), 2974 (w), 1555 (s), 1494 (m), 1379 (m), 1236 (s),
1
1053 (s), 1026 (s), 963 (s); H NMR (CDCl3) d 0.86 (t,
J = 6.8 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.2,
3H), 1.38–1.50 (m, 2H), 1.52–1.64 (m, 1H), 2.10 (dddd,
J = 21.7, 9.9, 5.9, 3.8 Hz, 1H), 3.92–4.04 (m, 4H), 4.06–
4.16 (m, 2H), 4.96 (dd, J = 13.3, 9.7 Hz, 1H), 5.17 (dd,
J = 13.3, 5.9 Hz, 1H), d 7.29 (m, 4H). Multiplicities and
J values indicated are both for H–H and P–H coupling;
13C NMR (CDCl3) d 13.9, 16.3 (d, J = 6.1 Hz), 16.6 (d,
4.2.12. Diethyl 2-(4-chlorophenyl)-3-nitropropylphosphonate
3l. Light red liquid; Yield 61%; Rf 0.25 (EtOAc/pet ether
1:1); IR (film, cmÀ1) 2984 (m), 2929 (m), 1555 (s), 1294 (m),
1379 (m), 1235 (s), 1028 (s), 966 (s), 830 (m); H NMR
(CDCl3) d 1.26 (td, J = 7.1, 1.0 Hz, 6H), 2.13 (dd,
J = 7.2, 6.0 Hz, 1H), 2.17 (dd, J = 7.3, 5.3 Hz, 1H), 3.80–
1

2726
V. Rai et al. / Tetrahedron: Asymmetry 18 (2007) 2719–2726
Chem. 2003, 1, 3564; (k) Ordonez, M.; De la Cruz-Cordero,
´
˜
J = 5.4 Hz), 21.2 (d, J = 7.7 Hz), 28.2 (d, J = 3.8 Hz), 40.5
(d, J = 138.8 Hz), 42.1, 61.8 (d, J = 6.9 Hz), 62.3 (d,
J = 6.1 Hz), 76.9, 128.9 (d, J = 13.0 Hz), 129.9, 133.8,
135.8 (d, J = 8.4 Hz). Multiplicities and J values indicated
are only for C–P coupling; 31P NMR (CDCl3) d 27.82. MS
(TOF ES+) m/e (relative intensity) 400 (MNa+, 55), 378
(M+, 100), 331 (35), 275 (60), 179 (95), 151 (55); HRMS:
calcd for C16H25NO5PClNa, 400.1057; found, 400.1068.
´
´
R.; Quinones, C.; Gonzalez-Morales, A. Chem. Commun.
˜
2004, 672; For c-nitrophosphonates: (l) Blaszczyk, E.; Kra-
wczyk, H.; Janecki, T. Synlett 2004, 2685.
6. For a recent review: (a) Berner, O. M.; Tedeschi, L.; Enders,
D. Eur. J. Org. Chem. 2002, 1877; see also: (b) Ballini, R.;
Barboni, L.; Bosica, G.; Fiorini, D.; Palmieri, A. Pure Appl.
Chem. 2006, 78, 1857.
7. For selected recent articles: (a) Muruganantham, R.; Mobin,
S. M.; Namboothiri, I. N. N. Org. Lett. 2007, 9, 1125; (b)
Dadwal, M.; Mohan, R.; Panda, D.; Mobin, S. M.;
Namboothiri, I. N. N. Chem. Commun. 2006, 338; (c) Rai,
V.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2006, 4693; (d)
Deb, I.; Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N.
Org. Lett. 2006, 8, 1201; (e) Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Biomol. Chem. 2006, 4, 2525; (f)
Namboothiri, I. N. N.; Ganesh, M.; Mobin, S. M.; Cojocaru,
M. J. Org. Chem. 2005, 70, 2235.
Acknowledgements
The authors thank DST, India, for financial assistance.
V.R. thanks CSIR, India for a research fellowship.
References
8. For ligand–metal complex catalyzed enantioselective Michael
addition, BINOL: (a) Majima, K.; Tosaki, S.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2005, 46, 5377; (b) Kumara-
swamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.;
Markondaiah, B. Adv. Synth. Catal. 2005, 347, 867; Tartrate
(c) Rueffer, M. E.; Fort, L. K.; MacFarland, D. K.
Tetrahedron: Asymmetry 2004, 15, 3297; Proline: (d) Yama-
guchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama,
M. Tetrahedron 1997, 53, 11223; Diphenylprolinol ether: (e)
Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253; (f) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
2005, 44, 4212.
1. (a) Kukhar, V. P.; Hudson, H. R. In Aminophosphonic and
Aminophosphinic Acids; John Wiley: Chichester, 2000; (b)
Kafarski, P.; Lejczak, B. Current Medicinal Chemistry: Anti-
Cancer Agents 2001, 1, 301; For a recent report on the
organocatalytic activity of a-aminophosphonate: (c) Diner,
P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4, 2091.
2. For selected recent reviews: (a) Lewkowski, J. Focus Orga-
nomet. Chem. Res. 2005, 167; (b) Syamala, M. Org. Prep.
Proc. Int. 2005, 37, 103; For an article on a-nitrophospho-
nates: (c) Franklin, A. S. Synlett 2000, 1154.
9. Cinchona alkaloids as catalysts, reviews: (a) Yoon, T. P.;
Jacobsen, E. N. Science 2003, 299, 1691; (b) Takashi, O.;
Maruoka, K. Acc. Chem. Res. 2004, 37, 526; (c) Bolm, C.;
Gladysz, J. A. Chem. Rev. 2003, 103, 2761; (d) Kacprzak, K.;
Gawronski, J. Synthesis 2001, 961; (e) Baiker, A. J. Mol.
Catal. A 1997, 115, 473.
10. For selected recent articles on cinchona catalyzed Michael
additions to nitroalkenes: (a) Poulsen, T. B.; Bell, M.;
Jorgensen, K. A. Org. Biomol. Chem. 2006, 4, 63; (b) Bartoli,
G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A.;
Sambri, L.; Melchiorre, P. Chem. Commun. 2007, 722; (c)
Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391;
(d) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906; (e) Xue, D.; Chen, Y.-C.; Wang, Q.-W.; Cun,
L.-F.; Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293; (f) Li, H.;
Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906; (g) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367; (h) Ye, J.; Dixon, D. J.; Hynes, P. S.
Chem. Commun. 2005, 35, 4481.
3. For a recent review: (a) Palacios, F.; Alonso, C.; De los
Santos, J. M. Chem. Rev. 2005, 105, 899; For selected recent
articles: (b) Park, H.; Cho, C.-W.; Krische, M. J. J. Org.
Chem. 2006, 71, 7892; (c) Van Meenen, E.; Moonen, K.;
Verwee, A.; Stevens, C. V. J. Org. Chem. 2006, 71, 7903; For
b-nitrophosphonates: (d) Mandal, T.; Samanta, S.; Zhao,
C.-G. Org. Lett. 2007, 9, 943; (e) Enders, D.; Tedeschi, L.;
Foerster, D. Synthesis 2006, 1447.
4. Via addition of diethyl difluoromethanephosphonate to
nitroalkenes: (a) Howson, W.; Hills, J. M.; Blackburn, G.
M.; Broekman, M. Bioorg. Med. Chem. Lett. 1991, 1, 501; c-
Nitrophosphonate synthesis via addition of alk-3-en-1-
ylphosphonate to nitroalkenes: (b) Yuan, C.; Li, C. Tetrahe-
dron Lett. 1993, 37, 5959.
5. For selected recent articles: (a) Foss, F. W.; Snyder, A. H.;
Davis, M. D.; Rouse, M.; Okusa, M. D.; Lynch, K. R.;
Macdonald, T. L. Bioorg. Med. Chem. 2007, 15, 663; (b) de la
Cruz, A.; He, A.; Thanavaro, A.; Yan, B.; Spilling, C. D.;
Rath, N. P. J. Organomet. Chem. 2005, 690, 2577; (c)
Castelot-Deliencourt, G.; Roger, E.; Pannecoucke, X.; Qui-
rion, J. C. Eur. J. Org. Chem. 2001, 3031; For enantiopure
synthesis: (d) Ordonez, M.; de la Cruz, R.; Fernandez-
Zertuche, M.; Munoz-Hernandez, M.-A. Tetrahedron: Asym-
metry 2002, 13, 559; (e) Wroblewski, A. E.; Halajewska-
Wosik, A. Tetrahedron: Asymmetry 2003, 14, 3359; Synthesis
via stereoselective reduction: (f) Yuan, C.; Wang, K.; Li, J.;
Li, Z. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 2391;
(g) Yuan, C.; Wang, K.; Li, J. Heteroatom Chem. 2002, 13,
11. For the only example, to our knowledge, for the application
of cinchona–Li complex in asymmetric reactions, see enan-
tioselective alkylation: Kuo, S.-C.; Chen, F.; Hou, D.; Kim-
Meade, A.; Bernard, C.; Liu, J.; Levy, S.; Wu, G. G. J. Org.
Chem. 2003, 68, 4984.
12. (a) Ref. 11; see also: (b) Wu, G.; Huang, M. Chem. Rev. 2006,
106, 2596.
13. Vogel’s Text Book of Practical Organic Chemistry, 5th ed.;
Addison Wesley Longman Ltd: Essex, England, 1989, p 1035.
14. (a) Vugts, D. J.; Koningstein, M. M.; Schmitz, R. F.; de
Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A. Chem. Eur. J.
2006, 12, 7178; (b) Heynekamp, J. J.; Weber, W. M.;
Hunsaker, L. A.; Gonzales, A. M.; Orlando, R. A.; Deck,
L. M.; Vander Jagt, D. L. J. Med. Chem. 2006, 49, 7182.
´
´
153; (h) Ordonez, M.; Gonzalez-Morales, A.; Salazar-Fern-
˜
´
andez, H. Tetrahedron: Asymmetry 2004, 15, 2719; (i) De la
´
´
´
Cruz-Cordero, R.; Hernandez-Nunez, E.; Fernandez-Zertu-
˜
´
´
˜
che, M.; Munoz-Hernandez, M. A.; Ordonez, M. ARKIVOC
˜
2005, 277; (j) Wang, K.; Zhang, Y.; Yuan, C. Org. Biomol.