N-Thiophosphoryl imines: convenient substrates in the aza-Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2009.08.025

In the presence of 1,1,3,3-tetramethylguanidine (TMG), N-diethoxythiophosphorylimines 1 and N-diphenylthiophosphinoylimines 2 exhibited good reactivity in the aza-Henry reaction. The corresponding products were obtained in excellent chemical yields under

Full text of DOI:10.1016/j.tetasy.2009.08.025

Tetrahedron: Asymmetry 20 (2009) 2178–2184
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N-Thiophosphoryl imines: convenient substrates in the aza-Henry reaction
*
*
Kuang Hu , Chungui Wang , Xinpeng Ma, Youming Wang , Zhenghong Zhou , Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2009
Accepted 18 August 2009
Available online 25 September 2009
In the presence of 1,1,3,3-tetramethylguanidine (TMG), N-diethoxythiophosphorylimines 1 and N-diph-
enylthiophosphinoylimines 2 exhibited good reactivity in the aza-Henry reaction. The corresponding
products were obtained in excellent chemical yields under mild conditions. Moreover, the asymmetric
version of the N-thiophosphoryl imine 1-based aza-Henry reaction was also realized with ee values up
to 87% by employing Takemoto’s thiourea as the catalyst.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselectivity of 76% ee by Takemoto who employed a chiral
bifunctional thiourea as the catalyst.5a Recently, we developed a
The nucleophilic addition of nitroalkanes to the C@N bond of
imines, known as the aza-Henry (or nitro-Mannich) reaction, is a
useful carbon–carbon bond-forming process in organic synthesis.1
The resulting b-nitroamine derivatives can be readily transformed
into valuable building blocks or biologically active compounds,
such as vicinal diamines via reduction of the nitro group2 and
convenient method for the preparation of N-thiophosphoryl imi-
nes,7 which have been successfully employed as novel electro-
philes in some organic transformations.8 Compared to N-
diphenylphosphinoyl imines, the thio analogue has the advantages
of ease of preparation and its stability to water, heat as well as sil-
ica gel. For this reason, we thought that it would be of interest to
employ N-thiophosphoryl protected imines in the aza-Henry reac-
tions. Herein, we report our results on N-thiophosphorylimine-
based aza-Henry reaction.
a
-amino acids by means of the Nef reaction.3 As a result, much
attention has been paid to the aza-Henry reaction, especially for
the catalytic asymmetric version of this reaction, over the past sev-
eral years.4,5 Most of the recent efforts on this reaction have been
directed toward the search for efficient chiral catalysts to promote
efficiency (yields) and selectivity (ee values), and have seldom
dealt with the scope of the reaction. In the reported aza-Henry
reactions, N-carbamate-activated imines, derived from aryl, het-
eroaryl, and aliphatic aldehydes, are the commonly used electro-
philes. However, a common drawback associated with the use of
this type of imines is certain precautions have to be taken in their
preparation, handling, and storage because of their substantial
hydrolytic liability. In contrast, N-phosphinoyl imine has rarely
been used due to its troublesome preparation, poor stability, and
relatively low reactivity, although phosphinoyl could be easily
deprotected via acidic hydrolysis from the aza-Henry adduct.
Shibasaki reported the first metal-catalyzed aza-Henry reaction
of N-phosphinoyl imines, in which up to 91% ee was obtained.4a,b
Ricci developed the TMG-catalyzed aza-Henry reaction of N-diphe-
nylphosphinoyl imine.2e An alternative organocatalyzed aza-Henry
reaction of N-diphenylphosphinoyl imine was later developed by
Terada by employing TMG or phosphazene as the catalyst.6 An
asymmetric version of the organocatalyzed aza-Henry reaction of
N-diphenylphosphinoyl imine was also realized with a highest
2. Results and discussion
According to the reported procedure, N-diethoxythiophospho-
ryl-protected imines 1 and N-diphenylthiophosphinoyl-blocked
imines 2 were synthesized in good to excellent yield through
thermal condensation of acetals and the corresponding thiophos-
phoramides.7
Firstly, different organic bases were screened as the catalyst
using the coupling of N-diethoxythiophosphorylimines 1a and
nitromethane as the model (Table 1, entries 1–6). Except for 4-
dimethylaminopyridine (DMAP), all the other bases evaluated
exhibited good catalytic activities in this transformation. Among
them, 1,1,3,3-tetramethylguanidine (TMG) was found to be partic-
ularly effective. The use of only 10 mol % of TMG afforded a clean
and fast reaction in 3 h (Table 1, entry 1). Total conversion of the
imine 1a was also observed in less than 24 h even when the cata-
lyst loading was reduced to 5 mol % (Table 1, entry 2).
On the basis of these results, N-thiophosphoryl imines 1- and N-
thiophosphoryl imines 2-based aza-Henry reactions were thor-
oughly investigated employing TMG as the catalyst. The results
are summarized in Tables 2 and 3, respectively.
As shown in Table 2, the aza-Henry reaction between N-thiophos-
phoryl imines 1 and nitromethane in the presence of 10 mol % of
* Corresponding authors. Tel.: +86 22 23504232; fax: +86 22 23508939 (Z.Z.).
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
These two authors equally contributed to this work.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.025

K. Hu et al. / Tetrahedron: Asymmetry 20 (2009) 2178–2184
2179
Table 1
Compared to imine 1, imine 2 exhibited much higher reactivity
(as shown in Table 3). In most cases, the reaction was completed in
less than 35 min with excellent chemical yields. A somewhat long-
er reaction time was required for 4-nitro-substituted substrate 2e,
but it still gave excellent results (Table 3, entry 5, 95%, 2.4 h). It is
worth noting that the inherently less reactive ketimine 2g was also
tolerated in this reaction, and the corresponding adduct 4g was ob-
tained in a fair yield after a prolonged reaction time (Table 3, entry
7, 57%, 48 h).
Organic bases in the aza-Henry reaction of N-thiophosphoryliminea
S
S
P(OEt)2
P(OEt)2
N
HN
Ph
Cat. (mol%)
+
CH3NO2
NO2
Solvent free, rt
Ph
H
1a
3a
Entry
Catalyst (mol %)
Time (h)
Conversion (%)
1
2
3
4
5
6
TMG (10)
TMG (5)
Et3N (10)
DMAP (10)
DABCO (10)
iPr2NEt (10)
3
24
12
120
48
48
>99
>99
>99
Trace
>99
>99
The asymmetric version of this reaction was also carried out
using chiral tertiary amines as the catalyst. A brief survey of differ-
ent amino alcohols 5,9 6,10 and chiral thioureas 7–1011,5a,k,12 (Fig. 1)
identified Takemoto’s thiourea 8 to be an effective catalyst for the
addition of nitromethane to N-diethoxythiophosphorylimine 1a.
The corresponding adduct was obtained in 89% yield with an
enantioselectivity of 85% ee (Table 4, entry 4). With respect to
imine 2a, only the N-thiophosphorylated thiourea 9 could promote
the reaction to afford the addition product 4a in moderate yield, al-
beit with quite low stereoselectivity (Table 4, entry 8).
In further experiments, other factors, such as solvent, catalyst
loading, and reaction temperature, which could influence the reac-
tion, were thoroughly investigated by employing 8 as the catalyst
and the reaction between N-diethoxythiophosphorylimine 1a and
nitromethane as the model. The results are listed in Table 5.
Solvent evaluation revealed that all of the solvents studied, ex-
cept for methanol, afforded the desired product in good yield and
ee values (Table 5, entries 1–6). Among the solvents tested, CHCl3
was proven to be the best one in terms of both chemical yield and
selectivity. The investigation of different catalyst loadings revealed
that there was no significant influence on the stereoselectivity of
the reaction. For example, the reaction proceeded in both high
yield and ee value in the presence of 20 mol % 8 (Table 5, entry
6). The enantioselectivity was maintained when the catalyst load-
ing was reduced to 15 mol % (Table 5, entry 7). Although almost the
same selectivity was obtained at 10 mol % catalyst loading, the
reaction became slightly sluggish, and only 80% conversion of the
imine was observed after stirring for 144 h (Table 5, entry 8). In
addition, performing the reaction at lower or higher temperature
resulted in a little loss of stereocontrol (Table 5, entries 9 and 10,
81% and 80% ee, respectively).
Under the optimal reaction conditions (15 mol % of 8 as the cat-
alyst, at 25 °C in CHCl3), we next examined a variety of N-diethoxy-
thiophosphorylimines with different structures in this asymmetric
aza-Henry reaction. The results are summarized in Table 6.
As shown in Table 6, the reaction was general, and a number of
diverse aryl-substituted aza-Henry adducts were obtained in good
yields with high enantioselectivities (77–87% ee). The introduction
of electron-donating or electron-withdrawing groups on the aro-
matic ring of imines did not affect the enantioselectivities (Table
6, entries 2–8). Moreover, the reaction also tolerated sterically hin-
dered ortho-substituted imines 1c, 1f, and 1g, giving the corre-
sponding o-methoxy, o-chloro, and o-trifluoromethyl-substituted
product with 84%, 82%, and 87% ee, respectively (Table 6, entries
3, 6, and 7). The electron-rich heteroaryl-substituted imine 2i also
appeared to be a good candidate, albeit with a slight decrease in
stereoselectivity (Table 6, entry 9, 77% ee).
In order to determine the absolute configuration of the newly
generated stereogenic center, the aza-Henry adduct 3a was trans-
formed into compound 11 via successively dephosphorylation and
N-Boc-protection (Scheme 1). By comparison of the sign of the spe-
cific rotation value, the absolute configuration of the major enan-
tiomer of compound 11 could be assigned as (R).5k Since none of
the bonds to the stereogenic carbon have been broken during the
sequence of reactions, the original configuration of adduct 3a is re-
tained. Therefore, the aza-Henry adduct 3a obtained by thiourea 8-
catalyzed aza-Henry reaction between N-thiophosphoryl imine 1a
a
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
TMG at room temperature led to promising results. The desired ad-
ducts were attained in excellent chemicalyield in all the cases exam-
ined. Compared to electron-donating group-substituted imines,
those imines bearing electron-withdrawinggenerally demonstrated
higher reactivity, and required less reaction time for completion (Ta-
ble 2, entries 6–8 vs entries 2–5).
Table 2
TMG-catalyzed aza-Henry reaction of imine 1a
S
S
P(OEt)2
P(OEt)2
N
HN
TMG (10 mol%)
Solvent free, rt
+
CH3NO2
NO2
Ar
H
Ar
1a–i
3a–i
Entry
Ar
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ph (a)
3
3
3.5
3
3
96
92
94
90
93
89
87
97
91
4-MeC6H4 (b)
2-MeOC6H4 (c)
3-MeOC6H4 (d)
4-MeOC6H4 (e)
2-ClC6H4 (f)
2-F3CC6H4 (g)
3-FC6H4 (h)
2-Furyl (i)
2
1.5
1.5
3
a
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
b
Isolated yield after column chromatography on silica gel.
Table 3
TMG-catalyzed aza-Henry reaction of imine 2a
S
S
PPh2
PPh2
N
HN
R
TMG (10 mol%)
Solvent free, rt
+
CH3NO2
NO2
Ar
Ar
R
2a−g
4a–g
Entry
Ar
Ph (a)
4-MeOC6H4 (b)
3-FC6H4 (c)
4-BrC6H4 (d)
4-NO2C6H4 (e)
3-F3CC6H4 (f)
Ph (g)
R
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
H
H
H
H
H
H
Me
10
10
10
10
2.4 h
35
48 h
98
98
92
90
95
98
57
a
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
b
Isolated yield after column chromatography on silica gel.

2180
K. Hu et al. / Tetrahedron: Asymmetry 20 (2009) 2178–2184
H
H
OH
Me
OH
N
N
CF3
N
Me
OH
NMe2
N
S
H
O2N
Me
CF3
Ph
6
7
5
CF3
OAc
S
S
P
NMe2
O
S
H
H
AcO
AcO
N
N
Ph
Ph
N
N
N
N
CF3
OAc
10
H
H
H
H
NMe2
S
NMe2
9
8
Figure 1. Screened catalysts for the addition of nitromethane to N-thiophosphorylimines 1a and 2a.
Table 4
Table 6
Catalyst screening for the asymmetric aza-Henry reaction of N-thiophosphorylimine a
Chiral thiourea 8-catalyzed asymmetric aza-Henry reaction of imine 1a
S
S
S
S
PR2
PR2
P(OEt)2
P(OEt)2
N
HN
Ph
N
8 (15 mol %)
HN
Cat. (mol-%)
CH2Cl2, rt
+
+
CH3NO2
CH3NO2
NO2
NO2
CHCl3, 25 °C
Ar
H
Ar
Ph
H
3a–i
1a–i
R = EtO, 3a
R = Ph, 4a
R = EtO, 1a
R = Ph, 2a
Entry
Ar
Ph (a)
4-MeC6H4 (b)
2-MeOC6H4 (c)
3-MeOC6H4 (d)
4-MeOC6H4 (e)
2-ClC6H4 (f)
Time (d)
Yieldb (%)
eec (%)
Entry
Imine
Catalyst (mol %)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
5
6
6
6
6.5
5
5
5
8
94
84
87
83
78
89
93
88
80
85
86
84
87
87
82
87
83
77
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
5 (20)
6 (20)
7 (20)
8 (20)
9 (20)
10 (15)
7 (20)
8 (20)
9 (20)
10 (15)
10 d
10 d
48
120
24
48
48
72
24
80
72
95
89
NR
NR
21
16
17
85
2-CF3C6H4 (g)
3-FC6H4 (h)
2-Furyl (i)
Trace
Trace
52
10
a
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
10
48
Trace
b
a
Isolated yield after column chromatography on silica gel.
Determined by chiral HPLC analysis.
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
c
b
Isolated yield after column chromatography on silica gel.
Determined by chiral HPLC analysis.
c
noting that the aza-Henry reaction with N-benzylidenedi-
phenylphosphinamide afforded the corresponding antipode adduct
with much lower enantioselectivity under the same conditions
(85% vs 67% ee).5a These results indicate that the protecting group
on the nitrogen atom of imine has a determinant effect on the
absolute configuration of the addition product and the enantio-
meric excess.
The high degree of selectivity observed in the current reaction
indicates a catalyst-associated complex with a high degree of coor-
dination.13 To account for the observed enantioselectivity of the
reaction, a ternary complex of catalyst 8, imine 1, and nitronate
is proposed as a plausible transition state (Fig. 2). In the transition
state, imine 1 and the nitronate anion coordinate to the thiourea
moiety and tertiary amino group of catalyst 8 by hydrogen-bond-
ing interaction, respectively.5b Then the si-facial attack of the nitr-
onate anion leads to the formation of the (R)-enantiomer as the
major product (except for 3i in which the priority of the four
groups is changed).
Table 5
Optimization of the reaction conditionsa
S
S
P(OEt)2
N
P(OEt)2
HN
Ph
8 (x mol-%)
+
CH3NO2
NO2
Solvent, T °C
Ph
H
3a
1a
Entry
8 (mol %)
Solvent
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
15
10
15
15
MeOH
CH3CN
EA
PhCH3
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
25
25
25
25
25
25
25
25
0
120
120
120
120
120
120
123
144
120
120
66 (75)d
84
87
85
89
39
70
79
81
85
85
85
84
81
80
94
94
70 (80)d
84
10
40
88
a
All the reactions were carried out on a 0.5 mmol scale using 10 equiv of
nitromethane.
3. Conclusion
b
Isolated yield after column chromatography on silica gel.
Determined by chiral HPLC analysis.
c
We have developed a readily available and stable N-thiophos-
phoryl imine-based aza-Henry reaction. The corresponding ad-
ducts were obtained in excellent yields in the presence of
10 mol % of TMG. Moreover, an asymmetric version of aza-Henry
reaction of N-diethoxythiophosphorylimine was realized employ-
ing Takemoto’s thiourea as the catalyst. Compared with reaction
d
Data in the parentheses are the conversion of the imine 1a.
and nitromethane was assigned as (R), and those of the other
adducts 3b–i were deduced on the basis of these results. It is worth

K. Hu et al. / Tetrahedron: Asymmetry 20 (2009) 2178–2184
2181
S
Boc
.
P(OEt)2
NH2 HCl
HN
Ph
Boc2O/NaHCO3
THF/H2O
85%
6M HCl/dioxane
reflux
HN
Ph
NO2
NO2
NO2
Ph
51%
3a (84.9% ee)
[α]D20 = -18.0 (c 1.0, CHCl3)
11 (84.5% ee)
20 = -19.0 (c 1.0, CHCl3)
[α]D
Scheme 1. Transformation of b-nitroamine 3a into 11.
(s, 2H), 5.09 (s, 1H), 7.29–7.41 (m, 11Harom), 7.90 (s, 4Harom).
13C NMR (CDCl3, 75.0 MHz): 53.27, 79.78, 126.28, 128.06, 128.13,
128.22, 128.38, 128.64, 130.83, 130.98, 131.36, 131.51, 131.61,
131.76, 132.33, 132.91, 133.69, 134.27, 137.49, 137.55. Anal. Calcd
for C20H19N2O2PS: C, 62.81; H, 5.01; N, 7.33. Found: C, 62.65; H,
4.95; N, 7.31.
S
Ar
S
N
H
N
H
O
N
P(OEt)2
HN
H
O
H
H
P
NMe2
NO2
Ar
Ar
N
S
OEt
OEt
H
4.2.2. N-(1-(4-Methoxyphenyl)-2-nitroethyl)-N,N-diphenylphos-
phino-thioamide 4b
White solid, 98% yield, mp 106–107 °C. 31P NMR (CDCl3, 121.3
MHz): d = 60.76. 1H NMR (CDCl3, 400 MHz): d = 3.59 (s, 1H), 3.78
(s, 3H), 4.94 (s, 2H), 4.97 (s, 1H), 6.85 (d, J = 8.0 Hz, 2Harom),
7.19 (d, J = 8.0 Hz, 2Harom), 7.37–7.51 (m, 6Harom), 7.86 (dd,
J = 7.6 and 13.6 Hz, 2Harom), 7.92 (dd, J = 7.6 and 13.6 Hz, 2Har-
om). 13C NMR (CDCl3, 100.6 MHz): 53.04, 55.23, 80.21, 80.23,
114.31, 127.69, 128.40, 128.53, 128.66, 129.68, 129.74, 131.14,
131.25, 131.71, 131.82, 131.93, 132.07, 132.68, 133.29, 133.70,
134.30, 159.49. Anal. Calcd for C21H21N2O3PS: C, 61.15; H, 5.13;
N, 6.79. Found: C, 60.91; H, 5.28; N, 6.74.
Figure 2. Proposed transition state of the thiourea-catalyzed aza-Henry reaction.
of N-diphenylphosphinoylimine, which gave moderate to good
enantioselectivities (63–76% ee),5a this reaction provided better re-
sults (77–87% ee), which indicates that the protecting groups play
an important role on the enantioselectivity of the reaction.
4. Experimental
4.1. Preparation of chiral N-thiophosphinoyl thiourea 9
4.2.3. N-(1-(3-Fluorophenyl)-2-nitroethyl)-N,N-diphenylphos-
phino-thioamide 4c
To a solution of diphenylphosphinothioic acid isothiocyanate14
(530 mg, 1.9 mmol) in dry THF (2 mL) was added dropwise a solu-
tion of (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (270 mg,
1.9 mmol) in anhydrous THF (4 mL) under a nitrogen atmosphere.
The resulting mixture was stirred at room temperature for 5 h.
After removal of the solvent, the residue was purified through col-
umn chromatography on silica gel (200–300 mesh, eluted with
ethyl acetate/petroleum ether: 1/1) to give the thiourea catalyst
White solid, 92% yield, mp 99–100 °C. 31P NMR (CDCl3,
121.3 MHz): d = 61.29. 1H NMR (CDCl3, 300 MHz): d = 3.68–3.73
(m, 1H), 4.81–5.04 (m, 3H), 6.90–7.00 (m, 3Harom), 7.19–7.48
(m, 7Harom), 7.79 (dd, J = 7.2 and 13.5 Hz, 2Harom), 7.86 (dd,
J = 7.2 and 13.5 Hz, 2Harom). 13C NMR (CDCl3, 75.0 MHz): 52.97,
79.86, 79.90, 113.58, 113.88, 115.25, 115.33, 122.11, 122.15,
128.38, 128.56, 128.73, 130.52, 130.63, 131.08, 131.23, 131.61,
131.76, 131.99, 132.03, 132.12, 132.16, 132.35, 132.96, 133.12,
132.16, 132.35, 132.96, 133.72, 134.32, 140.20, 140.28, 140.37,
161.18, 164.46. Anal. Calcd for C20H18FN2O2PS: C, 59.99; H, 4.53;
N, 7.00. Found: C, 60.09; H, 4.57; N, 7.06.
as a white solid. 190 mg, 38% yield, mp 116–118 °C, ½a D20
¼ ꢁ44:9
ꢀ
(c 1.0, CHCl3). 31P NMR (CDCl3, 161.7 MHz): d = 51.50. 1H NMR
(CDCl3, 400 MHz): d = 1.10–1.22 (m, 4H), 1.58–1.74 (m, 4H), 1.99
(s, 6H), 2.24–2.26 (m, 1H), 2.49–2.52 (m, 1H), 3.81 (br s, 1H),
7.48–7.57 (m, 6Harom), 7.83–7.94 (m, 4Harom), 8.72 (br s, 1H).
13C NMR (CDCl3, 100.6 MHz): 22.01, 24.35, 24.82, 39.75, 56.91,
57.93, 66.05, 128.71, 128.78, 128.85, 128.92, 131.15, 131.27,
4.2.4. N-(1-(4-Bromophenyl)-2-nitroethyl)-N,N-diphenylphos-
phino-thioamide 4d
131.48, 131.60, 132.56, 140.56, 189.81. Anal. Calcd for C21H28
N3PS2: C, 60.40; H, 6.76; N, 10.06. Found: C, 60.20; H, 6.96; N,
10.07.
-
White solid, 90% yield, mp 120–1121 °C. 31P NMR (CDCl3, 121.3
MHz): d = 61.24. 1H NMR (CDCl3, 300 MHz): d = 3.74 (dd, J = 5.7,
13.2 Hz, 1H) 4.85–5.05 (m, 3H), 7.14 (d, J = 8.4 Hz, 2Harom), 7.37–
7.52 (m, 8Harom), 7.83 (dd, J = 7.2 and 13.5 Hz, 2Harom), 7.91 (dd,
J = 7.2 and 13.5 Hz, 2Harom). 13C NMR (CDCl3, 75.0 MHz): 52.92,
79.83, 79.87, 122.44, 128.23, 128.39, 128.55, 128.71, 131.07,
131.22, 131.57, 131.72, 131.97, 132.02, 132.11, 132.15, 132.35,
132.92, 133.72, 134.27, 136.73, 136.81. Anal. Calcd for C20H18Br-
N2O2PS: C, 52.07; H, 3.93; N, 6.07. Found: C, 51.75; H, 4.35; N, 5.57.
4.2. General procedure for TMG-catalyzed aza-Hentry reaction
of nitromethane with N-thiophosphoryl imines 1 and 2
A mixture of TMG (11.5 mg, 0.1 mmol), N-thiophosphoryl imine
(1 mmol), and nitromethane (1 mL) was stirred at room tempera-
ture until the imine substrate had disappeared. After removal of
the excess nitromethane under reduced pressure, the crude prod-
uct was purified via column chromatography on silica gel (200–
300 mesh, gradient eluted with petroleum ether and ethyl acetate)
to provide the desired adduct.
4.2.5. N-(2-Nitro-1-(4-nitrophenyl)ethyl)-N,N-diphenylphos-
phinothioamide 4f
Pale yellow solid, 95% yield, mp 164–165 °C. 31P NMR (CDCl3,
121.3 MHz): d = 60.21. 1H NMR (CDCl3, 300 MHz): d = 3.94 (s, 1H),
4.94 (dd, J = 4.8 and 12.9 Hz, 1H), 5.07 (dd, J = 4.8 and 12.9 Hz, 1H),
5.17 (s, 1H), 7.38–7.50 (m, 8Harom), 7.83 (dd, J = 7.5 and 13.5 Hz,
2Harom), 7.92 (dd, J = 7.5 and 13.5 Hz, 2Harom), 8.16 (d, J = 8.1 Hz,
2Harom). 13C NMR (CDCl3, 75.0 MHz): 53.01, 79.74, 79.77, 123.44,
123.47, 123.51, 123.55, 125.25, 125.28, 125.32, 125.36, 128.44,
4.2.1. N-(2-Nitro-1-phenylethyl)-N,N-diphenylphosphino-
thioamide 4a
White solid, 98% yield, mp 110–112 °C. 31P NMR (CDCl3, 121.3
MHz): d = 60.97. 1H NMR (CDCl3, 300 MHz): d = 3.81 (s, 1H), 4.93

2182
K. Hu et al. / Tetrahedron: Asymmetry 20 (2009) 2178–2184
128.57, 128.65, 128.78, 129.51, 130.00, 131.10, 131.21, 132.08,
132.11, 132.23, 132.26, 132.34, 133.00, 133.37, 134.02, 138.77,
138.82. Anal. Calcd for C20H18N3O4PS: C, 56.20; H, 4.24; N, 9.83.
Found: C, 55.91; H, 4.25; N, 10.03.
3.78 (m, 1H), 3.91–4.07 (m, 4H), 4.61 (dd, J = 5.6, 12.4 Hz, 1H), 4.69
(dd, J = 7.6, 12.4 Hz, 1H), 4.99–5.08 (m, 1H), 7.15 (d, J = 8.0 Hz, 2Har-
om), 7.20 (d, J = 8.0 Hz, 2Harom). 13C NMR (CDCl3, 75.0 MHz): 15.33
(d, J = 8.3 Hz), 15.54 (d, J = 8.2 Hz), 20.79, 53.96, 62.94 (d, J = 4.5 Hz),
63.14 (d, J = 4.7 Hz), 80.18 (d, J = 6.8 Hz), 126.03, 129.43, 134.84 (d,
J = 3.8 Hz), 138.12. Anal. Calcd for C13H21N2O4PS: C, 46.98; H, 6.37;
N, 8.43. Found: C, 46.77; H, 6.14; N, 8.28. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol = 98:2, flow rate = 1.0 mL/min,
wavelength = 254 nm): tR = 25.58 (minor), 29.55 min (major).
4.2.6. N-(2-Nitro-1-(3-(trifluoromethyl)phenyl)ethyl)-N,N-
diphenyl-phosphinothioamide 4e
White solid, 98% yield, mp 84–85 °C. 31P NMR (CDCl3,
161.7 MHz): d = 60.21. 1H NMR (CDCl3, 400 MHz): d = 3.80 (dd,
J = 6.0 and 10.4 Hz, 1H), 4.94 (dd, J = 4.5 and 13.2 Hz, 1H), 5.01
(dd, J = 5.6 and 13.2 Hz, 1H), 5.12–5.21 (m, 1H), 7.34–7.39 (m,
2Harom), 7.43–7.56 (m, 8Harom), 7.82 (ddd, J = 1.2, 8.4 and
13.6 Hz, 2Harom), 7.90 (ddd, J = 1.2, 8.4 and 13.6 Hz, 2Harom).
13C NMR (CDCl3, 100.6 MHz): 53.01, 79.74, 79.77, 123.44, 123.47,
123.51, 123.55, 125.25, 125.28, 125.32, 125.36, 128.44, 128.57,
128.65, 128.78, 129.51, 130.00, 131.10, 131.21, 132.08, 132.11,
132.23, 132.26, 132.34, 133.00, 133.37, 134.02, 138.77, 138.82.
Anal. Calcd for C21H18F3N2O2PS: C, 56.00; H, 4.03; N, 6.22. Found:
C, 55.85; H, 4.27; N, 6.26.
4.3.3. Diethyl-(R)-O,O-1-(2-methoxyphenyl)-2-nitroethylphos-
phorothioamidate 3c
White solid, mp 56–57 °C, ½a D20
ꢀ
¼ ꢁ23:0 (c 1.0, CHCl3), 84% ee. 31
P
NMR (CDCl3, 161.7 MHz): d = 69.71. 1H NMR (CDCl3, 400 MHz):
d = 1.13 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz), 3.66–3.72 (m, 1H),
3.90 (s, 3H), 3.92–4.05 (m, 3H), 4.38 (dd, J = 12.0, 14.4 Hz, 1H), 4.67
(ddd, J = 1.2, 6.0, 12.0 Hz, 1H), 4.81 (dd, J = 8.0, 12.0 Hz, 1H), 5.04–
5.13 (m, 1H), 6.90–6.96 (m, 2Harom), 7.23 (dd, J = 1.6, 7.6 Hz, 1Har-
om), 7.31 (dt, J = 1.6, 8.0 Hz, 1Harom). 13C NMR (CDCl3, 100.6 MHz):
15.37 (d, J = 8.6 Hz), 15.58 (d, J = 8.5 Hz), 53.25, 55.30, 62.76 (d,
J = 4.7 Hz), 63.02 (d, J = 4.8 Hz), 78.80 (d, J = 6.9 Hz), 110.91,
120.83, 125.10 (d, J = 2.9 Hz), 129.04, 129.80, 156.56. Anal. Calcd
for C13H21N2O5PS: C, 44.82; H, 6.08; N, 8.04. Found: C, 44.68; H,
5.95; N, 7.96. HPLC analysis (Chiralpak AS-H column, hexane/2-pro-
panol = 98:2, flow rate = 1.2 mL/min, wavelength = 254 nm): tR =
91.21 (major), 109.38 min (minor).
4.2.7. N-(1-Nitro-2-phenylpropan-2-yl)-N,N-diphenylphosphino-
thioamide 4g
White solid, 57% yield, mp 143–144 °C. 31P NMR (CDCl3,
161.7 MHz): d = 53.61. 1H NMR (CDCl3, 400 MHz): d = 1.62 (s, 3H),
4.25 (s, 1H), 5.01 (d, J = 13.6 Hz, 1H), 6.20 (d, J = 13.6 Hz, 1H), 7.30
(t, J = 7.6 Hz, 1Harom), 7.39 (t, J = 7.6 Hz, 2Harom), 7.46–7.54 (m,
8Harom), 7.98 (dd, J = 7.2 and 13.2 Hz, 2Harom), 8.26 (dd, J = 7.2
and 14.0 Hz, 2Harom). 13C NMR (CDCl3, 100.6 MHz): 26.53, 26.57,
60.67, 60.69, 82.09, 124.35, 127.77, 128.38, 128.51, 128.65, 128.77,
128.88, 130.41, 130.53, 131.73, 131.76, 131.86, 131.89, 132.17,
132.28, 134.30, 135.08, 135.35, 136.10, 143.44, 143.52. Anal. Calcd
for C21H21N2O2PS: C, 63.62; H, 5.34; N, 7.07. Found: C, 63.65; H,
5.12; N, 7.03.
4.3.4. Diethyl-(R)-O,O–1-(3-methoxyphenyl)-2-nitroethylphos-
phorothioamidate 3d
White solid, mp 55–56 °C, ½a D20
¼ ꢁ10:0 (c 1.0, CHCl3), 87% ee.
ꢀ
31P NMR (CDCl3, 161.7 MHz): d = 69.51. 1H NMR (CDCl3,
400 MHz): d = 1.14 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz), 3.73–
3.78 (m, 1H), 3.79 (s, 3H), 3.89–4.09 (m, 4H), 4.63 (ddd, J = 1.2,
5.6, 12.4 Hz, 1H), 4.70 (dd, J = 8.0, 12.4 Hz, 1H), 5.01–5.10 (m,
1H), 6.83–6.84 (m, 3Harom), 7.26–7.30 (m, 1Harom). 13C NMR
(CDCl3, 100.6 MHz): 15.52 (d, J = 8.5 Hz), 15.71 (d, J = 8.3 Hz),
54.22, 55.24, 63.19 (d, J = 4.3 Hz), 63.39 (d, J = 4.6 Hz), 80.21 (d,
J = 6.6 Hz), 112.22, 113.76, 118.27, 130.11, 139.41 (d, J = 3.7 Hz),
159.96. Anal. Calcd for C13H21N2O5PS: C, 44.82; H, 6.08; N, 8.04.
Found: C, 44.79; H, 5.93; N, 7.94. HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol = 98:2, flow rate = 1.0 mL/min, wave-
length = 254 nm): tR = 45.57 (minor), 48.53 min (major).
4.3. General procedure for the enantioselective aza-Henry
reaction of nitromethane with N-thiophosphoryl imine 1
Nitromethane (10 equiv, 305 mg) was added to a stirred solu-
tion of imine 1 (0.5 mmol) and thiourea 8 (0.15 equiv, 31 mg) in
chloroform, and the resulting mixture was stirred at room temper-
ature for the total consumption of the imine 1 (monitored by TLC).
Then the reaction mixture was concentrated in vacuo, and the ob-
tained residue was purified by column chromatography on silica
gel (200–300 mesh, gradient eluted with petroleum ether and
ethyl acetate) to afford the desired adduct 3.
4.3.5. Diethyl-(R)-O,O-1-(4-methoxyphenyl)-2-nitroethylphos-
phorothioamidate 3e
White solid, mp 59–60 °C, ½a D20
ꢀ
¼ ꢁ4:7 (c 1.0, CHCl3), 87% ee. 31
P
4.3.1. Diethyl-(R)-O,O-2-nitro-1-phenylethylphosphorothio-
NMR (CDCl3, 161.7 MHz): d = 69.28. 1H NMR (CDCl3, 400 MHz):
d = 1.12 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz), 3.68–3.75 (m, 1H),
3.77 (s, 3H), 3.90–4.06 (m, 4H), 4.59 (ddd, J = 1.2, 5.6, 12.4 Hz, 1H),
4.69 (dd, J = 7.6, 12.4 Hz, 1H), 4.98–5.06 (m, 1H), 6.86 (d, J = 8.4 Hz,
2Harom), 7.22 (d, J = 8.4 Hz, 2Harom). 13C NMR (CDCl3,
100.6 MHz): 15.50 (d, J = 8.6 Hz), 15.68 (d, J = 8.5 Hz), 53.70, 55.19,
63.08 (d, J = 4.7 Hz), 63.30 (d, J = 4.9 Hz), 80.29 (d, J = 6.5 Hz),
114.26, 127, 44, 129.85 (d, J = 5.7 Hz), 159.53. Anal. Calcd for
C13H21N2O5PS: C, 44.82; H, 6.08; N, 8.04. Found: C, 44.73; H, 6.01;
N, 7.96. HPLC analysis (Chiralpak AD-H column, hexane/2-propa-
nol = 98:2, flow rate = 1.0 mL/min, wavelength = 254 nm): tR =
43.67 (minor), 50.95 min (major).
amidate 3a
Pale yellow liquid, n1D0 1.5207, ½a D20
¼ ꢁ18:0 (c 1.0, CHCl3), 85% ee.
ꢀ
31P NMR (CDCl3, 161.7 MHz): d = 69.12. 1H NMR (CDCl3, 400 MHz):
d = 1.08 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 3.65–3.75 (m,
1H), 3.90–4.10 (m, 4H), 4.62 (ddd, J = 1.2, 5.2, 12.4 Hz, 1H), 4.71
(dd, J = 8.0, 12.4 Hz, 1H), 5.03–5.12 (m, 1H), 7.28–7.37 (m, 5Harom).
13C NMR (CDCl3, 100.6 MHz): 15.42 (d, J = 8.7 Hz), 15.66 (d,
J = 8.6 Hz), 54.22, 63.08 (d, J = 4.7 Hz), 63.31 (d, J = 5.0 Hz), 80.18
(d, J = 6.7 Hz), 126.19, 128.49, 128.93, 137.77 (d, J = 3.3 Hz). Anal.
Calcd for C12H19N2O4PS: C, 45.28; H, 6.02; N, 8.80. Found: C, 45.02;
H, 5.95; N, 8.63. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 98:2, flow rate = 1.0 mL/min, wavelength = 254 nm):
tR = 28.17 (minor), 31.83 min (major).
4.3.6. Diethyl-(R)-O,O-1-(2-chlorophenyl)-2-nitroethylphosphoro-
thioamidate 3f
4.3.2. Diethyl-(R)-O,O-1-(4-methylphenyl)-2-nitroethylphos-
White solid, mp 90–91 °C, ½a D20
ꢀ
¼ ꢁ5:0 (c 1.0, CHCl3), 82% ee. 31
P
phorothioamidate 3b
NMR (CDCl3, 161.7 MHz): d = 69.02. 1H NMR (CDCl3, 400 MHz):
d = 1.09 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz), 3.69–3.79 (m, 1H),
3.91–4.12 (m, 3H), 4.26 (t, J = 11.6 Hz), 4.73 (d, J = 6.4 Hz, 2H),
5.41–5.49 (m, 1H), 7.28–7.31 (m, 2Harom), 7.38–7.42 (m, 2Harom).
Pale yellow liquid, n1D0 1.5379, ½a D20
¼ ꢁ5:6 (c 1.0, CHCl3), 86% ee.
ꢀ
31P NMR (CDCl3, 161.7 MHz): d = 69.28. 1H NMR (CDCl3, 400 MHz):
d = 1.12 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.68–

K. Hu et al. / Tetrahedron: Asymmetry 20 (2009) 2178–2184
2183
13C NMR (CDCl3, 75.0 MHz): 15.48 (d, J = 8.3 Hz), 15.73 (d,
J = 8.1 Hz), 52.26, 63.27 (d, J = 4.6 Hz), 63.50 (d, J = 4.7 Hz), 78.76
(d, J = 6.2 Hz), 127.46, 128.65, 129.84, 130.19, 132.18, 135.11. Anal.
Calcd for C12H18ClN2O4PS: C, 40.86; H, 5.14; N, 7.94. Found: C,
40.67; H, 5.01; N, 7.74. HPLC analysis (Chiralpak AS-H column,
hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
254 nm): tR = 43.25 (minor), 56.02 min (major).
suction and dried in vacuo to provide the corresponding 2-nitro-
1-phenylethylamine hydrochloride as a white solid (31.0 mg, 51%
yield).
To a stirred mixture of the aforementioned b-nitroamine hydro-
chloride (30.0 mg, 0.15 mmol), sodium hydrogencarbonate (39 mg,
0.45 mmol), water (1 mL), and THF (1 mL) was added a solution of
Boc2O (39 mg, 0.18 mmol) in THF (1 mL) at 0 °C. After stirring at
the same temperature for 30 min, the reaction mixture was warmed
to room temperature for an additional 5 h. The solvent was removed
under reduced pressure, and the residue was purified through col-
umn chromatography on silica gel (200–300 mesh, gradient eluted
with petroleum ether and ethyl acetate) to afford compound 11 as
4.3.7. Diethyl-(R)-O,O-2-nitro-1-(2-(trifluoromethyl)phenyl)-
ethyl-phosphorothioamidate 3g
White solid, mp 106–108 °C, ½a D20
¼ ꢁ10:4 (c 1.0, CHCl3), 87% ee.
ꢀ
31P NMR (CDCl3, 161.7 MHz): d = 67.84. 1H NMR (CDCl3, 400 MHz):
d = 0.96 (t, J = 6.8 Hz, 3H), 1.30 (t, J = 6.8 Hz), 3.59–3.69 (m, 1H),
3.86–4.11 (m, 3H), 4.22–4.30 (m, 1H), 4.55 (dd, J = 8.4, 12.4 Hz,
1H), 4.63 (ddd, J = 2.0, 4.0, 12.4 Hz, 1H), 5.49 (dq, J = 4.0, 9.2 Hz,
1H), 7.46 (t, J = 7.2 Hz, 1Harom), 7.57 (d, J = 6.8 Hz, 1Harom), 7.61
(t, J = 7.2 Hz, 1Harom), 7.70 (d, J = 8.0 Hz, 1Harom). 13C NMR
(CDCl3, 100.6 MHz): 15.10 (d, J = 8.8 Hz), 15.56 (d, J = 8.5 Hz),
50.33, 63.03 (d, J = 4.7 Hz), 63.47 (d, J = 4.7 Hz), 80.10 (d, J =
7.6 Hz), 122.58, 125.30, 126.16 (d, J = 5.4 Hz), 127.6 (q, J =
30.2 Hz), 128.04, 128.58, 132.63, 137.03. Anal. Calcd for C13H18F3-
N2O4PS: C, 40.42; H, 4.70; N, 7.25. Found: C, 40.17; H, 4.52; N,
7.01. HPLC analysis (Chiralpak AS-H column, hexane/2-propanol =
90:10, flow rate = 1.0 mL/min, wavelength = 254 nm): tR = 11.72
(minor), 17.99 min (major).
a white solid (33.5 mg, 85%). ½a D20
¼ ꢁ19:0 (c 0.3, CHCl3), 84.5% ee.
ꢀ
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20772058) for generous financial support for our
programs.
References
1. For recent advances on this reaction, see: (a) Westermann, B. Angew. Chem., Int.
Ed. 2003, 42, 151; (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797; (c)
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2401.
2. (a) Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986, 51, 4294; (b) Barrett, A. G. M.;
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3. For recent review on the Nef reaction, see: (a) Ballini, R.; Petrini, M. Tetrahedron
2004, 60, 1017; (b) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol.
Chem. 2003, 1, 4275; (c) Matt, C.; Wagner, A.; Moiskowski, C. J. Org. Chem. 1997,
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1999, 38, 3504; (b) Yamada, K.-i.; Moll, G.; Shibasaki, M. Synlett 2001, 980; (c)
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Ed. 2001, 40, 2992; (d) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843; (e) Knudsen, K. R.; Jørgensen,
K. A. Org. Biomol. Chem. 2005, 3, 1362; (f) Anderson, J. C.; Blake, A. J.; Howell, G.
P.; Wilson, C. J. J. Org. Chem. 2005, 70, 549; (g) Anderson, J. C.; Howell, G. P.;
Lawrence, R. M.; Wilson, C. J. J. Org. Chem. 2005, 70, 5665; (h) Palomo, C.;
Oiarbide, M.; Halder, R.; Laso, A.; López, R. Angew. Chem., Int. Ed. 2006, 45, 117;
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Y.; Deng, M.; Qian, C. Chirality 2006, 18, 741; (k) Lee, A.; Kim, W.; Lee, J.; Hyeon,
T.; Kim, B. M. Tetrahedron: Asymmetry 2004, 15, 2595; (l) Tan, C.; Liu, X.-H.;
Wang, L.-W.; Wang, J.; Feng, X.-M. Org. Lett. 2008, 10, 5305.
4.3.8. Diethyl-(R)-O,O-1-(3-fluorophenyl)-2-nitroethylphosphoro-
thioamidate 3h
Pale yellow liquid, n1D0 1.5293, ½a D20
¼ ꢁ5:6 (c 1.0, CHCl3), 83% ee.
ꢀ
31P NMR (CDCl3, 161.7 MHz): d = 69.33. 1H NMR (CDCl3, 400 MHz):
d = 1.14 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz), 3.75–3.85 (m, 1H),
3.93–4.09 (m, 4H), 4.65 (ddd, J = 1.2, 5.2, 12.8 Hz, 1H), 4.72 (dd,
J = 7.2, 12.8 Hz, 1H), 5.05–5.14 (m, 1H), 6.99–7.12 (m, 3Harom),
7.31–7.37 (m, 1Harom). 13C NMR (CDCl3, 100.6 MHz): 15.50 (d,
J = 8.5 Hz), 15.68 (d, J = 8.3 Hz), 53.74, 63.30 (d, J = 4.9 Hz), 63.51
(d, J = 5.0 Hz), 79.93 (d, J = 6.6 Hz), 113.54 (d, J = 22.7 Hz), 115.49
(d, J = 21.0 Hz), 121.87 (d, J = 3.0 Hz), 130.66 (d, J = 8.1 Hz), 140.39
(dd, J = 3.3, 6.7 Hz), 162.79 (d, J = 247.8 Hz). Anal. Calcd for
C12H18FN2O4PS: C, 42.85; H, 5.39; N, 8.33. Found: C, 42.69; H,
5.06; N, 8.12. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 98:2, flow rate = 1.0 mL/min, wavelength = 254 nm):
tR = 23.73 (minor), 27.72 min (major).
5. (a) Okino, T.; Nakamura, A.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625;
(b) Xu, X. N.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem. Eur. J.
2006, 12, 466; (c) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
466; (d) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron
2006, 62, 375; (e) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62,
11499; (f) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
3418; (g) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007,
129, 3466; (h) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 15110; (i) Palomo, C.; Oiarbide, M.; Laso, A.; López, R. J. Am. Chem. Soc.
2005, 127, 17622; (j) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernadi,
L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975; (k) Wang, C. G.; Zhou, Z. H.;
Tang, C. C. Org. Lett. 2008, 10, 1707; (l) Rueping, M.; Antonchick, A. P. Org. Lett.
2008, 10, 1731; (m) Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-F.; Deng, J.-G.;
Chen, Y.-C. Chem. Eur. J. 2008, 14, 8094; (n) Rampalakos, C.; Wulff, W. D. Adv.
Synth. Catal. 2008, 350, 1785; (o) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-
Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606; (p) Gomez-Bengoa, E.; Linden,
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2008, 130, 7955.
4.3.9. Diethyl-(S)-O,O-1-(furan-2-yl)-2-nitroethylphosphoro-
thioamidate 3i
Brown liquid, n1D0 1.5130, ½a D20
ꢀ
¼ ꢁ18:6 (c 1.0, CHCl3), 77% ee. 31
P
NMR (CDCl3, 161.7 MHz): d = 69.70. 1H NMR (CDCl3, 400 MHz):
d = 1.26 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz), 3.77 (t, J = 11.2 Hz,
1H), 3.92–4.09 (m, 4H), 4.70 (dd, J = 6.0, 12.8 Hz, 1H), 4.78 (dd,
J = 6.8, 12.8 Hz, 1H), 5.13–5.22 (m, 1H), 6.32–6.35 (m, 2Harom),
7.37 (s, 1Harom). 13C NMR (CDCl3, 100.6 MHz): 15.74 (d, J = 8.3
Hz), 15.82 (d, J = 8.3 Hz), 48.53, 63.42 (d, J = 5.0 Hz), 63.57 (d,
J = 5.1 Hz), 78.01 (d, J = 5.3 Hz), 107.77, 110.67, 142.87, 450.38 (d,
J = 5.6 Hz). Anal. Calcd for C10H17N2O5PS: C, 38.96; H, 5.56; N,
9.09. Found: C, 38.78; H, 5.23; N, 8.85. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol = 94:6, flow rate = 1.0 mL/min,
wavelength = 254 nm): tR = 11.02 (minor), 13.11 min (major).
6. Pahadi, N. K.; Ube, H.; Terada, M. Tetrahedron Lett. 2007, 48, 8700.
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4.4. Procedure for the transformation of b-nitroamine 3a into
8. (a) Ma, X. P.; Wang, C. G.; Xu, X. Y.; Zhao, G. F.; Zhou, Z. H.; Tang, C. C. Lett. Org.
Chem. 2007, 4, 51; (b) Ma, X. P.; Xu, X. Y.; Wang, C. G.; Zhao, G. F.; Zhou, Z. H.;
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Z. H.; Tang, X. F.; He, Z. J.; Tang, C. C. Eur. J. Org. Chem. 2007, 4487; (d) Lu, A. D.;
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11
A mixture of aza-Henry adduct 3a (95.5 mg, 0.3 mmol, 84.9% ee)
in 5 mL of 6.0 M HCl/1,4-dioxane (v/v 1:1) was refluxed until the
total consumption of the starting material. After removal of solvent
under reduced pressure, 2 mL of ether was added and the resulting
mixture was stirred for 5 min. The precipitate was collected by
9. Tang, H. Y.; Zhao, G. F.; Zhou, Z. H.; Zhou, Q. L.; Tang, C. C. Tetrahedron Lett.
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