Diastereo- and enantioselective nitro-Mannich reaction of α-substituted nitroacetates to N-phosphoryl imines catalyzed by cinchona alkaloid thiourea organocatalysts

Article abstract of DOI:10.1039/c3ob40335a

The asymmetric nitro-Mannich reaction of N-phosphoryl imines with α-substituted nitroacetates was performed by using cinchona alkaloid thioureas as organocatalysts in toluene at -20 °C. The present method was highly tolerable to functionalized N-phosphoryl imines and provided a reliable synthetic route to obtain the corresponding β-nitro ethylphosphoramidates with adjacent quaternary and tertiary chiral centers in high yield (up to 86%) and high enantiostereoselectivity (up to 99% ee) and diastereoselectivity (up to 99:1, anti-selectivity). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40335a

Organic &
Biomolecular Chemistry
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Diastereo- and enantioselective nitro-Mannich reaction
of α-substituted nitroacetates to N-phosphoryl imines
catalyzed by cinchona alkaloid thiourea
organocatalysts†
Cite this: Org. Biomol. Chem., 2013, 11,
3223
Weidong Fan, Shasha Kong, Yan Cai, Guiping Wu and Zhiwei Miao*
The asymmetric nitro-Mannich reaction of N-phosphoryl imines with α-substituted nitroacetates was per-
formed by using cinchona alkaloid thioureas as organocatalysts in toluene at −20 °C. The present
method was highly tolerable to functionalized N-phosphoryl imines and provided a reliable synthetic
route to obtain the corresponding β-nitro ethylphosphoramidates with adjacent quaternary and tertiary
chiral centers in high yield (up to 86%) and high enantiostereoselectivity (up to 99% ee) and diastereo-
selectivity (up to 99 : 1, anti-selectivity).
Received 15th February 2013,
Accepted 26th March 2013
DOI: 10.1039/c3ob40335a
www.rsc.org/obc
centers have been obtained with excellent diastereo- and
enantioselectivity.1d,7
Introduction
The catalytic asymmetric nucleophilic addition of nitroalkanes
Beyond these metal-catalyzed variants, enantioselective
to the CvN bond of imines, called the catalytic asymmetric organocatalytic nitro-Mannich reactions have also been develo-
nitro-Mannich reaction, is a useful carbon–carbon bond- ped. Takemoto and co-workers reported the enantioselective
forming process that can provide chiral β-nitroamines with addition of nitromethane to a variety of aromatic N-phosphi-
two contiguous nitrogen-bearing stereogenic centers.1 The noyl imines catalyzed by bifunctional thiourea catalysts.8 Fur-
development of C–C bond-forming reactions that create two thermore, Johnston developed a chiral bis-amidine triflate salt
new stereogenic centers with high diastereo- and enantioselec- that effects the diastereoselective addition of nitroethane to a
tivity in a single step can open new routes to valuable building range of electron-deficient N-Boc imines.9 However, despite
blocks or biologically active compounds.2 The concurrent syn- these important advances, the applications of α-substituted
thesis of adjacent quaternary and tertiary stereogenic centers nitroacetates in this field, in which adjacent quaternary and
is even more appealing since it allows the assembly of highly tertiary chiral centers must be constructed concurrently, are
functionalized molecules such as 1,2-diamines, α-amino car- rarely explored.10
bonyl compounds3 and biologically active compounds.4 As a
Phosphoramidate derivatives have attracted attention
result, considerable effort has been directed toward the because of their pharmaceutical applications and excellent
development of catalytic asymmetric versions of the nitro- inhibitory bioactivities, such as anticancer and antivirus activi-
Mannich reaction over the past several years. In their pioneer- ties.11 On the other hand, the 1,2-diamine structural motif is
ing work, Shibasaki and co-workers have described a chiral important in biologically active natural products,12 in medic-
ytterbium5 and aluminum6 catalyzed enantioselective addition inal chemistry,13 and more recently as a core unit in chiral
of nitroalkanes to N-phosphinoyl imines. Jørgensen also auxiliaries and chiral ligands for use in asymmetric catalysis.14
reported enantioselective addition of nitro compounds to Some general and asymmetric synthetic methods exist for the
imines catalyzed by chiral bisoxazoline–CuII complexes. The preparation of 1,2-diamine derivatives;12a however, phosphora-
optically active β-nitro-α-amino esters with two new stereogenic midites bearing 1,2-diamine derivatives have rarely been
described. Particularly, the presence of a quaternary stereocen-
ter in a highly substituted phosphoramidite unit, will interact
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
with certain proteases and resist proteolytic degradation. Con-
University, Tianjin 300071, China. E-mail: miaozhiwei@nankai.edu.cn;
tinuing with our interest in the chemistry of aminophosphorus
Fax: +86 2350 2351; Tel: +86 2350 4783
†Electronic supplementary information (ESI) available. CCDC reference number
derivatives,15 here we report the first example of β-nitro ethyl-
phosphoramidates with an adjacent synthesis of quaternary
and tertiary chiral centers promoted by cinchona alkaloid
CCDC 908739. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob40335a
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Table 1 Screening of catalystsa
thiourea organocatalysts. The reactions proceeded with good
yields and high diastereo- and enantioselectivities.
Results and discussion
Yieldsb d.r.
Entry Catalyst Solvent Time [h] [%]
Bifunctional organocatalysts possessing thioureas and tertiary
amine groups have been utilized successfully in a number of
1,2 or 1,4-addition reactions.16 Recently our laboratory has
identified a family of chiral carbohydrate combined thiourea
organocatalysts that catalyze asymmetric aldol reactions15a and
the Biginelli reaction17 with high levels of enantioselectivity.
Based on previous achievements in organocatalysis, we began
our investigation by developing a catalytic asymmetric nitro-
Mannich reaction. Bifunctional thioureas (1–3) with diversely
structured scaffolds were chosen as the catalyst candidates
(Fig. 1).18
(anti/syn)c eec [%]
1
2
3
4
5
6
7
8
1a
1b
2
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2 32
MeOH
THF
17
17
17
17
17
—
60
65
80
77
68
40
64
60
70
82
—
51 : 49
89 : 11
>99 : 1
96 : 4
91 : 9
94 : 6
85 : 15
90 : 10
87 : 13
>99 : 1
—
56
97
98
−99
99
92
96
3a
3b
3a
3a
3a
3a
3a
3a
32
32
24
32
17
9
CHCl3
PhCH3
PhCH3
95
97
98
10d
11e
a Unless otherwise specified all reactions were carried out using
diethyl benzylidenephosphoramidate 4a (0.3 mmol, 1 equiv.) and
methyl 2-nitropropanoate 5a (0.45 mmol, 1.5 equiv.) in 3 mL solvent
with 10 mol% of catalyst at −20 °C. b Yield of isolated product of 6a
after column chromatography. c Determined by HPLC (Chiralcel
AD-H). d The reaction was performed at 0 °C. e 5 mol% of catalyst 3a
was used.
Initially, the reaction of benzaldehyde-derived N-phosphoryl
imine 4a19 with methyl 2-nitropropanoate 5a was conducted in
the presence of a catalytic amount of 1a (10 mol%) in toluene
at −20 °C. There was no product 6a detected with saccharide-
derived thiourea catalyst 1a (Table 1, entry 1). The use of N,N-
dimethyl-protected thiourea catalyst 1b gave β-nitro ethylphos-
phoramidate 6a in good yield with moderate enantioselectivity.
However, the diastereoselectivity of the major isomer was
low (51 : 49 d.r.; Table 1, entry 2). This result suggested that a
tertiary amine thiourea structure is essential to effect this reac-
tion. Next, we explored the 3,5-bis(trifluoromethyl)phe-
nylthiourea 2 and cinchona-based thioureas 3a and 3b as
catalysts, and found that the desired products were obtained
in yields of 60–80%, and with the highest diastereo- and
enantioselectivities (Table 1, entries 3–5).
With the best thiourea catalyst 3a being identified, we next
optimized the other reaction parameters, such as solvent,
temperature, and catalyst loading. Among the various solvents
tested, dichloromethane, methanol, tetrahydrofuran and tri-
chloromethane afforded moderate to good yields of the
expected product 6a with high diastereo- and enantioselectivi-
ties (Table 1, entries 6–9). The most suitable solvent was found
to be toluene. When the reaction was carried out at 0 °C using
3a as the catalyst, a lower enantiomeric excess value of 97%
was obtained (Table 1, entry 10). In addition, decreasing the
amount of the catalyst from 10 to 5 mol% did not affect
the stereoselectivity and resulted in a higher yield (Table 1,
entry 11). Under similar reaction conditions, the use of
quinine-derived catalyst 3b gave the product 6a with a high
level of stereoselectivity and with the opposite sense of asym-
metric induction (Table 1, entry 5). Thus, the optimal reaction
conditions for this transformation were determined to be
0.3 mmol of N-phosphoryl imine 4a, 1.5 equivalents of methyl
2-nitropropanoate 5a and 5 mol% of 3a in 2 mL toluene as the
solvent at −20 °C.
Having optimized the reaction conditions, the reaction
scope for N-phosphoryl imines 419 and α-substituted nitro-
acetates 5 was investigated. The results were summarized in
Table 2. In general the major chiral isomers 6 could be directly
isolated in pure form in good to high yields. A variety of aro-
matic N-phosphoryl imines 4 bearing diverse electron-with-
drawing or electron-donating substitutions were found to be
suitable coupling partners with methyl 2-nitropropanoate 5a.
Good results were obtained with excellent diastereo- and
enantioselectivities (Table 2, entries 1–11). The ortho-, meta-
and para-positions of the substituents on the phenyl ring have
almost no influence on the stereoselectivity. When heteroaryl
imine 4l and cinnamylidene N-phosphoryl imine 4m were
employed as substrates, the reactions gave the corresponding
products with excellent stereoselectivities and moderate yields
(Table 2, entries 12–13). Other α-substituted nitroacetates were
also studied; the α-ethyl derivative 5b gave lower diastereo-
selectivities in the reaction with ortho- and meta-chloro substi-
tuent N-phosphoryl imines with longer reaction time (Table 2,
entries 14–15). To date, results using imines from aliphatic
aldehydes such as acrolein are less satisfactory (Table 2, entry
16).20 In addition, the X-ray crystal structure of 6a revealed the
configuration, and the relative anti-selectivity and its
Fig. 1 The catalysts’ structures.
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Table 2 Scope of the reactiona
Entry
R1
R2
Product
Time [h]
Yieldb [%]
d.r.c
eec [%]
1
2
3
4
5
6
7
8
Ph (4a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Et (5b)
Et (5b)
Me (5a)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
17
17
17
17
17
17
17
17
17
17
17
17
17
42
42
36
82
86
81
72
82
70
75
85
80
70
74
75
65
68
71
—
>99 : 1
94 : 6
87 : 13
92 : 8
91 : 9
96 : 4
91 : 9
91 : 9
89 : 11
90 : 10
>99 : 1
>99 : 1
>99 : 1
55 : 45
72 : 28
—
98
99
97
96
98
95
99
99
98
98
>99
>99
96
90
93
—
o-FC6H4 (4b)
o-BrC6H4 (4c)
m-FC6H4 (4d)
m-ClC6H4 (4e)
m-BrC6H4 (4f)
p-FC6H4 (4g)
p-ClC6H4 (4h)
p-BrC6H4 (4i)
p-MeC6H4 (4j)
m-CH3C6H4 (4k)
Furyl (4l)
9
10
11
12d
13
14
15
16
trans-PhCHvCH (4m)
o-ClC6H4 (4n)
m-ClC6H4 (4e)
CH2vCH (4o)
a Reaction conditions: phosphoramidate 4 (0.3 mmol), 2-nitropropanoate 5 (0.45 mmol), in 3 mL of toluene at −20 °C in the presence of 5 mol%
of catalyst 3a. b Isolated yield after silica gel chromatography. c Determined by chiral HPLC analysis. d Determined after one recrystallization.
Fig. 2 X-ray crystal structure of 6a.
stereochemistry at the quaternary stereogenic center was suc-
cessfully determined to be the S configuration (Fig. 2).21
In Scheme 1 a proposal for the catalytic cycle of the new
Scheme 1 Plausible reaction mechanism.
nitro-Mannich reaction is suggested to account for the catalytic
activity, and for the diastereo- and enantioselectivity. Accord-
ing to our observations, a double hydrogen bonding inter-
action may be formed between the two N–H groups of the
thiourea and the PvO group of the N-phosphoryl imine as
complex A to increase its electrophilicity. When methyl 2-nitro-
propanoate 5a was added to the mixture, another double
hydrogen bonding interaction would occur between the proto-
nated tertiary amine group and the carbonyl and nitro groups
of the α-substituted nitroacetate (intermediate B). Sub-
sequently, the Si-face attack of the electrophilic imine through
the Si-face of the enolate is restricted by the cinchona alkaloid
scaffold of the catalyst and affords the desired Mannich
adduct 6 with (S,S) configuration (intermediate C). The mech-
anism indicates that the thiourea and cinchona alkaloid
scaffold of the bifunctional catalyst play a significant role in
controlling the enantioselectivity of the addition reaction.
In order to further investigate the mechanism, the for-
mation of 6a was followed by 31P NMR spectroscopy as shown
in Fig. 3.22 The starting material diethyl benzylidenephosphor-
amidate 4a in toluene showed 31P NMR at 7.68 ppm. After cata-
lyst 3a (0.0085 g, 5 mol%) and methyl 2-nitropropanoate 5a
were added to the solution of 4a, the single peak changed
from 7.68 to 8.26 ppm, which can be assigned to complex A,
and a new single peak at 5.67 ppm appeared. The new single
peak was assigned to the intermediate C. The expected nucleo-
philic addition product was formed (single peak at 5.67 ppm)
in 1.5 hours (complex C). As time passed, the 31P NMR signals
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General procedure for the synthesis of β-nitro ethylphos-
phoramidates 6. To a solution of N-phosphoryl imines 4
(0.3 mmol) and chiral catalyst 3a (0.015 mmol, 5 mol%) in
toluene (3.0 mL) was added 2-nitropropanoate 5 (0.45 mmol,
1.5 equiv.) at −20 °C under a nitrogen atmosphere. The
mixture was stirred for the corresponding time at −20 °C
(monitored by TLC). Then saturated NH4Cl aq. (3 mL) was
added, and the mixture was extracted with ethyl acetate (3 ×
5 mL). The organic layers were washed with brine (2 mL),
dried over MgSO4, filtered and concentrated in vacuo to yield
the crude products 6, which were purified by flash column
chromatography on silica gel [petroleum ether (60–90 °C)–
ethyl acetate, 1 : 1 (v/v)] to provide pure products 6.
Fig. 3 Time elapsed 31P NMR spectra for the synthesis of 6a (ppm).
Methyl 3-((diethylphosphoryl)amino)-2-methyl-2-nitro-3-phenyl-
propanoate (6a). White solid; mp 114–117 °C; [α]2D0 = 48.8°
(c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ 7.30–7.38 (m,
5H), 4.92 (dd, J = 11.5, 9.7 Hz, 1H), 4.83 (t, J = 11.5 Hz, 1H),
3.73–3.95 (m, 6H), 3.50–3.65 (m, 1H), 1.70 (s, 3H), 1.20 (t, J =
7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H); 13C-NMR (101 MHz,
CDCl3): δ 165.96, 136.74, 128.74, 128.61, 128.50, 94.89 (d, J =
8.1 Hz), 62.49 (d, J = 5.0 Hz), 62.37 (d, J = 5.0 Hz), 62.00, 53.60,
22.56, 16.00 (d, J = 7.5 Hz), 15.77 (d, J = 7.5 Hz); 31P-NMR
(162 MHz, CDCl3): δ 5.86, 5.67; HRMS (MALDI) calculated for
[C15H23N2O7P + H]+: 375.1321, found 375.1315.
of the starting material disappeared gradually, and the signals
of 6a (single peaks at 5.67 ppm) increased. The reaction was
almost completed after 17 h according to the 31P NMR spectra
(Fig. 3).
Conclusions
In conclusion, we have presented the highly stereoselective
nitro-Mannich reaction of α-substituted nitroacetate and
N-phosphoryl aldimines by employing bifunctional thiourea–
tertiary amine catalysts. This methodology provides facile
access to substituted β-nitro ethylphosphoramidate derivatives
with adjacent quaternary and tertiary chiral centers with good
to excellent diastereo- and enantioselectivities. Further appli-
cation of these catalysts to other asymmetric reactions and
expansion of the new bifunctional organocatalysts are cur-
rently underway in our laboratory.
Methyl 3-((diethylphosphoryl)amino)-3-(2-fluorophenyl)-2-
methyl-2-nitropropanoate (6b). White solid; mp 68–71 °C;
1
[α]2D0 = 56.4° (c = 0.005, CH2Cl2); H-NMR (300 MHz, CDCl3): δ
7.28–7.39 (m, 2H), 7.12–7.21 (m, 1H), 7.01–7.12 (m, 1H), 5.37
(dd, J = 11.4, 10.4 Hz, 1H), 4.75 (t, J = 11.4 Hz, 1H), 3.79–4.01
(m, 6H), 3.57–3.71 (m, 1H), 1.74 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H),
1.04 (t, J = 7.0 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 165.81,
160.20 (d, J = 247.2 Hz), 130.46, 129.46, 124.68, 124.36, 115.50
(d, J = 22.9 Hz), 94.81 (d, J = 7.9 Hz), 62.64 (d, J = 5.3 Hz), 62.39
(d, J = 5.4 Hz), 54.33 (s), 53.64 (s), 21.36 (d, J = 2.6 Hz), 15.98
(d, J = 7.4 Hz), 15.67 (d, J = 7.5 Hz); 31P-NMR (162 MHz,
CDCl3):
δ
5.65, 5.39; HRMS (MALDI) calculated for
[C15H22FN2O7P + H]+: 415.1046, found 415.1044.
Experimental
General remarks
Methyl 3-((diethylphosphoryl)amino)-3-(2-bromophenyl)-2-
methyl-2-nitropropanoate (6c). White solid; mp 80–83 °C; [α]D20
All reactions were carried out under an inert atmosphere and = 9.8° (c = 0.01, CH2Cl2); 1H-NMR (300 MHz, CDCl3): δ
in heat-dried glassware. Solvents were dried and distilled prior 7.49–7.65 (m, 1H), 7.25–7.38 (m, 2H), 7.11–7.24 (m, 1H), 5.66
to use according to the standard methods. Flash column (t, J = 10.3 Hz, 1H), 4.91 (t, J = 11.6 Hz, 1H), 3.76–4.07 (m, 6H),
chromatography was performed on silica gel (particle size 3.44–3.61 (m, 1H), 1.75 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.00 (t,
10–40 μm, Ocean Chemical Factory of Qingdao, China). 1H J = 7.0 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 166.72, 136.60,
and 13C NMR spectra were recorded on a Bruker-400 spectro- 133.05, 130.22, 128.57, 128.41, 125.33, 96.43 (d, J = 8.8 Hz),
meter (400 MHz for 1H, 100 MHz for 13C, 121 MHz for 31P). 62.79 (d, J = 5.6 Hz), 62.41 (d, J = 5.5 Hz), 57.85, 54.00, 20.60,
Chemical shifts were reported in ppm downfield from internal 16.12 (d, J = 7.7 Hz), 15.74 (d, J = 7.7 Hz); 31P-NMR (162 MHz,
Si(CH3)4. HPLC analyses were recorded on a chiral column CDCl3):
Daicel Chiralcel AD-H column or a AS-H column, at 220 nm. [C15H22BrN2O7P + Na]+: 475.0246, found 475.0242.
The crystal structure was determined on a Bruker SMART 1000 Methyl 3-((diethylphosphoryl)amino)-3-(3-fluorophenyl)-2-
δ
5.27, 5.14; HRMS (MALDI) calculated for
CCD diffractometer. Mass spectra were recorded on a LCQ methyl-2-nitropropanoate (6d). White solid; mp 90–93 °C;
1
advantage spectrometer with ESI resource. HR-MS were [α]2D0 = 51.2° (c = 0.005, CH2Cl2); H-NMR (300 MHz, CDCl3): δ
recorded on APEXII and ZAB-HS spectrometer. Optical 7.27–7.38 (m, 1H), 6.97–7.20 (m, 3H), 4.92 (dd, J = 11.5, 9.4 Hz,
rotations were recorded on a Perkin Elmer 241 Polarimeter. 1H), 4.79 (t, J = 11.5 Hz, 1H), 3.75–3.99 (m, 6H), 3.51–3.75 (m,
Melting points were determined on a T-4 melting point appar- 1H), 1.71 (s, 3H),1.21 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H);
atus (uncorrected).
13C-NMR (101 MHz, CDCl3): δ 165.87, 162.64 (d, J = 247.3 Hz),
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1
139.38, 130.11, 124.47, 115.75, 115.43, 94.72 (d, J = 7.9 Hz), [α]2D0 = 26.2° (c = 0.01, CH2Cl2); H-NMR (300 MHz, CDCl3): δ
62.59 (d, J = 5.3 Hz), 62.48 (d, J = 5.2 Hz), 61.48, 53.72, 22.27, 7.36–7.57 (m, 2H), 7.08–7.21 (m, 2H), 4.89 (dd, J = 11.4, 10.0
15.99 (d, J = 7.4 Hz), 15.79 (d, J = 7.4 Hz); 31P-NMR (162 MHz, Hz, 1H), 4.66 (t, J = 11.4 Hz, 1H), 3.78–4.00 (m, 6H), 3.64–3.78
CDCl3):
δ
5.88, 5.66; HRMS (MALDI) calculated for (m, 1H), 1.74 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz,
3H); 13C-NMR (101 MHz, CDCl3): δ 166.53, 135.54, 131.68,
[C15H22FN2O7P + Na]+: 415.1046, found 415.1043.
Methyl 3-((diethoxyphosphoryl)amino)-3-(3-chlorophenyl)-2- 130.07, 122.92, 95.88 (d, J = 8.5 Hz), 62.70, 62.62 (d, J = 5.8 Hz),
methyl-2-nitropropanoate (6e). White solid; mp 89–92 °C; [α]2D0 60.15, 53.84, 20.63, 16.03 (d, J = 7.2 Hz), 15.87 (d, J = 7.2 Hz);
50.8° (c = 0.005, CH2Cl2); 1H-NMR (300 MHz, CDCl3): δ 31P-NMR (162 MHz, CDCl3): δ 5.98, 5.77; HRMS (MALDI) calcu-
7.35–7.43 (m, 1H), 7.28–7.35 (m, 3H), 4.66–4.99 (m, 2H), lated for [C15H22BrN2O7P + Na]+: 475.0246, found 475.0244.
3.75–3.99 (m, 6H), 3.58–3.74 (m, 1H), 1.72 (s, 3H), 1.21 (t, J =
Methyl 3-((diethylphosphoryl)amino)-2-methyl-2-nitro-3-(p-
7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H); 13C-NMR (101 MHz, tolyl)propanoate (6j). White solid; mp 100–103 °C; [α]2D0
=
CDCl3): δ 165.84, 138.90, 134.52, 129.83, 128.90, 128.74, 44.0° (c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ
126.83, 94.70 (d, J = 8.1 Hz), 62.63 (d, J = 5.3 Hz), 62.50 (d, J = 7.23–7.27 (m, 2H), 7.14–7.19 (m, 2H), 4.87–4.95 (m, 1H), 4.81
5.2 Hz), 61.44, 53.73, 22.28, 16.00 (d, J = 7.4 Hz), 15.79 (d, J = (t, J = 11.4 Hz, 1H), 3.77–3.99 (m, 6H), 3.57–3.66 (m, 1H), 2.36
7.4 Hz); 31P-NMR (162 MHz, CDCl3): δ 5.87 (s), 5.65 (s); HRMS (s, 3H), 1.71 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz,
(MALDI) calculated for [C15H22ClN2O7P + Na]+: 431.0751, 3H); 13C-NMR (101 MHz, CDCl3): δ 166.00, 138.59, 133.69,
found 431.0748.
129.26, 128.35, 94.97 (d, J = 8.1 Hz), 62.47 (d, J = 5.1 Hz), 62.37
Methyl 3-((diethoxyphosphoryl)amino)-3-(3-bromophenyl)-2- (d, J = 4.9 Hz), 61.74, 53.57, 22.60, 21.09, 16.03 (d, J = 7.4 Hz),
methyl-2-nitropropanoate (6f). White solid; mp 73–75 °C; [α]2D0 15.80 (d, J = 7.4 Hz); 31P-NMR (162 MHz, CDCl3): δ 6.07, 5.87;
= 50.8° (c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ HRMS (MALDI) calculated for [C16H25N2O7P + Na]+: 411.1297,
7.50–7.56 (m, 1H), 7.43–7.50 (m, 1H), 7.28–7.34 (m, 1H), found 411.1293.
7.19–7.25 (m, 1H), 4.88 (dd, J = 11.5, 9.2 Hz, 1H), 4.79 (t, J =
Methyl
3-((diethoxyphosphoryl)amino)-2-methyl-2-nitro-3-
11.5 Hz, 1H), 3.76–3.97 (m, 6H), 3.62–3.72 (m, 1H), 1.72 (s, (m-tolyl)propanoate (6k). White solid; mp 102–105 °C; [α]D20
=
3H), 1.22 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H); 13C-NMR 50.9° (c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ
(101 MHz, CDCl3): δ 165.83, 139.15, 131.85, 131.66, 130.11, 7.24–7.29 (m, 2H), 7.12–7.17 (m, 2H), 4.84–4.92 (m, 1H),
127.25, 122.61, 94.69 (d, J = 7.8 Hz), 62.64 (d, J = 5.2 Hz), 62.52 4.75–4.83 (m, 1H), 3.74–3.96 (m, 6H), 3.54–3.63 (m, 1H), 2.34
(d, J = 5.2 Hz), 61.45, 53.74, 22.38, 16.02 (d, J = 7.5 Hz), 15.81 (s, 3H), 1.69 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.0 Hz,
(d, J = 7.5 Hz); 31P-NMR (162 MHz, CDCl3): δ 5.87, 5.64; HRMS 3H); 13C-NMR (101 MHz, CDCl3): δ 164.96, 137.24, 135.64,
(MALDI) calculated for [C15H22BrN2O7P + Na]+: 475.0246, 128.41, 128.23, 127.47, 124.38, 93.86 (d, J = 8.0 Hz), 61.43 (d,
found 475.0243.
J = 5.0 Hz), 61.30 (d, J = 5.1 Hz), 60.96, 52.52, 21.63, 20.41,
Methyl 3-((diethylphosphoryl)amino)-3-(4-fluorophenyl)-2- 14.98 (d, J = 7.6 Hz), 14.74 (d, J = 7.6 Hz); 31P-NMR (162 MHz,
methyl-2-nitropropanoate (6g). White solid; mp 99–102 °C; CDCl3): δ 5.71; HRMS (MALDI) calculated for [C16H25N2O7P +
[α]2D0 = 28.0° (c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): Na]+: 411.1297, found 411.1295.
δ 7.34–7.42 (m, 2H), 7.01–7.11 (m, 2H), 4.93 (dd, J = 11.5,
Methyl 3-((diethylphosphoryl)amino)-3-(furan-2-yl)-2-methyl-
9.2 Hz, 1H), 4.80 (t, J = 11.5 Hz, 1H), 3.77–3.98 (m, 6H), 2-nitropropanoate (6l). White solid; mp 84–87 °C; [α]2D0 = 74.0°
3.62–3.73 (m, 1H), 1.72 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.09 (t, (c = 0.005, CH2Cl2); 1H-NMR (300 MHz, CDCl3): δ 7.34–7.37 (m,
J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 165.94, 162.73 1H), 6.28–6.46 (m, 2H), 5.11 (dd, J = 11.8, 9.9 Hz, 1H), 4.34 (t,
(d, J = 248.6 Hz), 132.70, 130.35, 115.55, 94.84 (d, J = 8.1 Hz), J = 11.8 Hz, 1H), 3.70–4.02 (m, 7H), 1.76 (s, 3H), 1.11–1.29 (m,
62.58 (d, J = 5.3 Hz), 62.49 (d, J = 5.3 Hz), 61.38, 53.67, 22.48, 6H); 13C-NMR (101 MHz, CDCl3): δ 165.71, 150.11, 142.65,
16.02 (d, J = 7.4 Hz), 15.84 (d, J = 7.4 Hz); 31P-NMR (162 MHz, 110.79, 109.77, 94.05 (d, J = 7.8 Hz), 62.66, 62.62, 55.51, 53.70,
CDCl3):
[C15H22FN2O7P + Na]+: 415.1046, found 415.1044.
Methyl 3-((diethylphosphoryl)amino)-3-(4-chlorophenyl)-2- 387.0933, found 387.0935.
δ
6.05, 5.84; HRMS (MALDI) calculated for 21.40, 16.07, 15.96 (d, J = 7.5 Hz); 31P-NMR (162 MHz, CDCl3):
δ 5.98; HRMS (MALDI) calculated for [C13H21N2O8P + Na]+:
methyl-2-nitropropanoate (6h). White solid; mp 103–105 °C;
Methyl 3-((diethylphosphoryl)amino)-2-methyl-2-nitro-5-phenyl-
1
[α]2D0 = 48.0° (c = 0.005, CH2Cl2); H-NMR (300 MHz, CDCl3): δ pent-4-enoate (6m). White solid; mp 57–60 °C; [α]D20 = 6.4° (c =
7.28–7.38 (m, 4H), 4.90 (dd, J = 11.5, 9.3 Hz, 1H), 4.79 (t, J = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ 7.30–7.47 (m,
11.5 Hz, 1H), 3.75–3.98 (m, 6H), 3.61–3.73 (m, 1H), 1.70 (s, 5H), 6.71 (d, J = 15.8 Hz, 1H), 6.17 (dd, J = 15.8, 8.5 Hz, 1H),
3H), 1.21 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13C-NMR 4.44 (dd, J = 20.4, 9.0 Hz, 1H), 3.81–4.11 (m, 8H), 1.89 (s, 3H),
(101 MHz, CDCl3): δ 165.87, 135.33, 134.74, 129.96, 128.76, 1.22–1.33 (m, 6H); 13C-NMR (101 MHz, CDCl3): δ 166.28,
94.73 (d, J = 7.9 Hz), 62.64 (d, J = 5.3 Hz), 62.54 (d, J = 5.3 Hz), 135.71, 135.57, 128.73, 128.50, 126.70, 124.43, 95.05 (d, J =
61.40 (d, J = 2.2 Hz), 53.71, 22.38, 16.02 (d, J = 7.4 Hz), 15.85 7.3 Hz), 62.76, 62.69 (d, J = 4.7 Hz), 60.82, 53.61, 21.66, 16.17,
(d, J = 7.4 Hz); 31P-NMR (162 MHz, CDCl3): δ 5.85, 5.63; HRMS 16.07 (d, J = 7.3 Hz); 31P-NMR (162 MHz, CDCl3): δ 6.73; HRMS
(MALDI) calculated for [C15H22ClN2O7P + Na]+: 431.0751, (MALDI) calculated for [C17H25N2O7P + Na]+: 423.1297, found
found 431.0747.
423.1295.
Methyl 3-((diethylphosphoryl)amino)-3-(4-bromophenyl)-2-
Methyl 2-((2-chlorophenyl)((diethylphosphoryl)amino) methyl)-
methyl-2-nitropropanoate (6i). White solid; mp 104–107 °C; 2-nitrobutanoate (6n). White solid; mp 59–62 °C; [α]2D0 = 7.0°
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(c = 0.01, CH2Cl2); H-NMR (400 MHz, CDCl3): δ 7.36–7.41 (m,
1H), 7.23–7.31 (m, 2H), 7.12–7.18 (m, 1H), 5.57–5.75 (m, 1H),
4.65–4.85 (m, 1H), 3.77–4.03 (m, 6H), 3.43–3.62 (m, 1H),
2.16–2.30 (m, 1H), 1.82–1.99 (m, 1H), 1.25 (t, J = 7.0 Hz, 3H),
1.01 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H); 13C-NMR
(101 MHz, CDCl3): δ 165.62, 135.10, 134.06, 129.92, 129.65,
127.94, 127.63, 100.74 (d, J = 8.4 Hz), 62.70 (d, J = 5.5 Hz),
62.40 (d, J = 5.5 Hz), 55.59, 53.57, 27.09, 16.09 (d, J = 7.5 Hz),
15.75 (d, J = 7.5 Hz), 9.12; 31P-NMR (162 MHz, CDCl3): δ 5.34,
5.19; HRMS (MALDI) calculated for [C16H24ClN2O7P + Na]+:
445.0907, found 445.0905.
5 K. Yamada, S. J. Harwood, H. Gröger and M. Shibasaki,
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Methyl
2-((3-chlorophenyl)((diethylphosphoryl)amino)-
methyl)-2-nitrobutanoate (6o). White solid; mp 58–60 °C; [α]2D0 10 Selected examples: (a) K. R. Knudsen and K. A. Jørgensen,
= 27.6° (c = 0.005, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ
7.22–7.35 (m, 3H), 7.13–7.20 (m, 1H), 4.93–5.03 (m, 1H),
4.67–4.78 (m, 1H), 3.79–3.97 (m, 6H), 3.63–3.74 (m, 1H),
1.95–2.09 (m, 2H), 1.22 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.3 Hz,
3H), 0.96 (t, J = 7.3 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ
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62.60 (d, J = 5.3 Hz), 62.50 (d, J = 5.1 Hz), 60.98, 53.49, 29.59,
15.99 (d, J = 7.5 Hz), 15.81 (d, J = 7.5 Hz), 9.02; 31P-NMR
(162 MHz, CDCl3): δ 5.75, 5.60; HRMS (MALDI) calculated for
[C16H24ClN2O7P + H]+: 423.1088, found 423.1086.
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