Sulfinimine-mediated asymmetric synthesis of acyclic and cyclic α-aminophosphonates

Article abstract of DOI:10.1055/s-2008-1067247

Nucleophilic addition of dialkylphosphites to N-tert-butanesufinimines proceeds smoothly at room temperature in the presence of potassium carbonate or potassium fluoride, affording acyclic α-alkyl-α-aminophosphonates and a series of cyclic α-aminophosphonates in good chemical yields and modest to high diastereoselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067247

2986
PAPER
Sulfinimine-Mediated Asymmetric Synthesis of Acyclic and Cyclic
a-Aminophosphonates
S
ulfinimine-Media
i
ted Sy
a
a
n
-Aminophos
y
phonates i Chen, Jinfeng Li, Chengye Yuan*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
Fax +86(21)54925379; E-mail: yuancy@mail.sioc.ac.cn.
Received 14 May 2008; revised 9 June 2008
O
S
O
Abstract: Nucleophilic addition of dialkylphosphites to N-tert-bu-
tanesufinimines proceeds smoothly at room temperature in the pres-
ence of potassium carbonate or potassium fluoride, affording
acyclic a-alkyl-a-aminophosphonates and a series of cyclic a-ami-
nophosphonates in good chemical yields and modest to high diaste-
reoselectivities.
S
HN
Me
R1
O
N
OR2
OR2
K2CO3
OR2
OR2
+
HP
P
R1
Et2O, r.t.
O
(SS)-1
(SS,RC)-3
2
R1 = Ph, 4-NO2C6H4, 4-MeOC6H4, t-Bu; R2 = Me, Et, Pr, i-Pr
Key words: asymmetric synthesis, cyclic a-aminophosphonates,
w-chloro-a-aminophosphonate, w-phosphoryl-a-aminophospho-
nate
Scheme 1
Table 1 Synthesis of Chiral Acyclic Quaternary a-Aminophos-
phonates 3
a-Aminoalkylphosphonic acids are of considerable value
due to their potential biological activities.1 Since the bio-
activity of these compounds depends on the absolute con-
figuration of the molecules, studies on the asymmetric
synthesis of aminophosphonic acids has aroused great in-
terest from organic chemists.2–6 While many methods are
so far available for the preparation of acyclic a-amino-
alkylphosphonates, few routes leading to chiral cyclic
a-aminoalkylphosphonates and w-phosphoryl-a-amino-
phosphonates have been developed.7–9 The most remark-
able of the latter approaches was initiated by Shibasaki,
and was based on chiral heterobimetallic lanthanoid cata-
lytic enantioselective hydrophosphonylation, which led to
cyclic a-aminophosphonates.10
Entry
R1
R2
Time
(h)
Yield
(%)a
de
(%)b
3ac
3b
3c
3d
3e
3f
Ph
Me
Et
24
48
72
40
72
72
48
72
72
48
48
85
84
>95
>95
>95
85
>95
91
85
–
Ph
p-MeOC6H4
p-NO2C6H4
Ph
Et
82
Et
88
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
81
p-MeOC6H4
p-NO2C6H4
Ph
70
3g
3h
3i
85
<20
<10
74
Recently, we have reported a convenient N-tert-butyl-
sulfinimine-mediated asymmetric synthesis of chiral a-
aminophosphonates at room temperature using potassium
carbonate as a base,11 which gave reasonable chemical
and enantiomeric yields. Herein we wish to describe fur-
ther results obtained using N-tert-butylsulfinimines12 as
chiral auxiliaries under similar reaction conditions, but
leading to different chiral acyclic and cyclic quaternary a-
aminophosphonates. Our strategy involved, firstly, the
synthesis of chiral acyclic quaternary a-aminophospho-
nates using different dialkyl phosphites. Particularly im-
portantly, a one-pot synthesis of chiral cyclic a-
aminophosphonates or chiral functionalized a-amino-
phosphonates starting from w-chloro-substituted sulfin-
imine was then developed.
p-MeOC6H4
p-NO2C6H4
t-Bu
–
3j
18
–
3k
N.R.
a Isolated yield of two isomers.
b From the 31P NMR of the crude product.
c Detailed spectral data for 3a have been previously reported.11
electron-donating groups on the phenyl ring, to dialkyl
phosphite 2 (Scheme 1). The results are shown in Table 1.
As shown in Table 1, the R2 group of dialkyl phosphite 2
has a crucial influence on both the reaction rate and the
diastereoselectivity; these also depend to a lesser extent
on the electronic effect of the substituents on phenyl ring.
Electron-withdrawing groups accelerate the reaction, but
have a deleterious effect on the diastereoselectivity.
Optically active acyclic quaternary a-aminophosphonates
were obtained through the nucleophilic addition of keto-
sulfinimine 1, containing either electron-withdrawing or
Optically active cyclic quaternary a-aminophosphonates
and chiral functionalized a-aminophosphonates were ob-
tained through the reaction of w-chloro-substituted keto-
sulfinimine 4 with dimethyl phosphite under similar
reaction conditions.
SYNTHESIS 2008, No. 18, pp 2986–2990
x
x.
x
x
.
2
0
0
8
Advanced online publication: 04.09.2008
DOI: 10.1055/s-2008-1067247; Art ID: F10808SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sulfinimine-Mediated Synthesis of a-Aminophosphonates
2987
O
S
presence of Cs2CO3, gave only 2-phenyl-2-dimethylphos-
phorylpyrrolidine 6c (Scheme 5).
O
S
N
HPO(OMe)2
N
R
As indicated in Table 2, chiral cyclic three-, four- and
five-membered a-aminophosphonates, chiral w-chloro-a-
aminophosphonates or chiral w-phosphoryl-a-amino-
phosphonates were prepared in good yields and medium
to high diastereoselectivities. It is interesting that all the
compounds can be prepared selectively simply by chang-
OMe
OMe
Cl
n
base, solvent
r.t.
P
R
n
O
4
6
O
S
O
S
O
P
HN
HN
MeO
MeO
HPO(OMe)2
OMe
OMe
Cl
OMe
OMe
P
P
n R
O
O
O
O
7
OMe
5
n = 1, 2, 3
S
P
N
OMe
HPO(OMe)2
Ph
Scheme 2
K2CO3, CH2Cl2
r.t.
O
S
6b 78% de
O
S
N
w-Chloro-substituted sulfinimines were prepared by con-
densing commercially available (S)-tert-butylsulfinimine
with chloro-substituted aldehydes and ketones in the pres-
ence of Ti(OEt)4 (2–3 equiv).13 With the w-chloro-substi-
tuted sulfinimines in hand, treatment of these compounds
with two equivalents of dimethyl phosphonate in the pres-
ence of potassium fluoride, potassium carbonate or cesi-
um carbonate, afforded the corresponding quaternary a-
aminophosphonates in good to excellent yields and dia-
stereoselectivities (Scheme 2). The product obtained de-
pended on the sulfinimine and base used. When n = 1 and
R = Me, aziridinyl 2-phosphonate 6a was obtained using
K2CO3 as a base at room temperature. The diastereoselec-
tivity improved dramatically through the use of KF in-
stead of K2CO3 (Scheme 3, Table 2). When n = 1 and
R = H, 2-phosphoryl-1-aminophosphonate 7a was ob-
tained in high diastereoselectivity and good yield in the
presence of K2CO3 (Scheme 3).
Cl
Ph
n
HN
HPO(OMe)2
MeO
MeO
OMe
(n = 2)
P
P
Cs2CO3, CH2Cl2
r.t.
Ph
OMe
O
O
7b 22% de
Scheme 4
O
HPO(OMe)2
K2CO3, CH2Cl2
r.t., 24 h
S
HN
Cl
OMe
OMe
P
R = Me
Me
O
S
O
5 87% de
N
O
Cl
OMe
P
OMe
R
n
(n = 3)
N
Ph
HPO(OMe)2
O
S
Cs2CO3, CH2Cl2
r.t., 48 h
R = Ph
O
S
6c 42% de
KF, CH2Cl2
r.t.
N
Me
OMe
OMe
Scheme 5
P
HPO(OMe)2
R = Me
O
S
O
6a 84% de
Table 2 Distribution of Reaction Products from Nucleophilic Addi-
tion of Dimethyl Phosphonate to Sulfinimine in Dichloromethane
N
O
S
Cl
R
HPO(OMe)2
n
Entry n
R
Base
Time Yield (%)a
de
O
P
HN
K2CO3, CH2Cl2
r.t.
(n = 1)
MeO
MeO
(h)
10
24
30
10
48
24
24
72
5
6
7
(%)b
OMe
P
R = H
OMe
1
2
3
4
5
6
7
8
1
1
1
1
2
2
3
3
Me
Me
Me
H
K2CO3
CsF
84
80
75
0
0
0
0
0
0
0
0
0
59
67
O
>95% de
7a
Scheme 3
KF
84
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
86
0
>95
78
When n = 2 and R = Ph, azetidinyl 2-phosphonate 6b was
obtained in good yield and medium diastereoselectivity in
the presence of K2CO3. However, 1,3-bis(O,O-dimeth-
ylphosphoryl)-1-butylsulfinylamino-1-phenylpropane (7b)
was obtained in a poor diastereoselective excess when us-
ing Cs2CO3 as a base (Scheme 4).
Ph
Ph
Me
Ph
82
0
87
0
0
22
0
85
0
87
83
0
42
When n = 3 and R = Me, 4-chloro-1-methyl-1-amino-
phosphonate 5 was obtained in good yield and diastereo-
selectivity using K2CO3 as a base; the reaction in the
a Isolated yield.
b Determined by 31P NMR of the crude product.
Synthesis 2008, No. 18, 2986–2990 © Thieme Stuttgart · New York

2988
Q. Chen et al.
PAPER
Dialkyl (R)-1-[(S)-tert-Butylsulfinylamino]ethylphosphonates
(3); General Procedure
ing the base used in the reaction. Unfortunately, the dia-
stereoisomers 5, 6 and 7 are inseparable by ordinary
chromatography. The absolute configuration of the prod-
ucts are predicted on the basis of our earlier report.10
To a 15 mL round-bottom flask fitted with a magnetic stir bar, was
placed a solution of dialkyl phosphite 2 (4 mmol) in Et2O (10 mL)
and K2CO3 (0.690 g, 5 mmol). The reaction mixture was stirred for
15 min at r.t., then sulfinimine (S)-(+)-1 (1.0 mmol) was added. Af-
ter stirring for 24–72 h at this temperature, the reaction mixture was
quenched with sat. aq NH4Cl (5 mL), then extracted into CH2Cl2
(2 × 5 mL). The organic layer was successively washed with H2O (5
mL) and brine (5 mL), then dried (Na2SO4). The solvent was re-
moved and the residue was subjected to column chromatography on
silica gel (acetone–EtOAc, 1:2).
Addition of dimethylphosphonate 2 to cyclic sulfinimine
8 also proceeds smoothly under these reaction conditions,
providing the corresponding b-chloro-substituted cyclic
product 9 in medium chemical yield and diastereoselec-
tivity (Scheme 6).
O
S
O
S
Data for compound 3a have been previously reported.11
O
N
NH OMe
P
OMe
Diethyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-phenylethylphos-
phonate (3b)
Yield: 84%; colorless oil; de >95%.
K2CO3, CH2Cl2
r.t., 48h
Cl
Cl
HPO(OMe)2
+
78%
1H NMR (300 MHz, CDCl3): d = 1.26 (s, 9 H), 1.25 (m, 6 H), 2.12
(d, J = 15.9 Hz, 3 H), 4.04 (m, 4 H), 4.10 (m, 1 H), 7.48 (m, 3 H),
7.81 (m, 2 H).
8
9 73% de
Scheme 6
31P NMR (120 MHz, CDCl3): d = 23.40.
IR (KBr): 3500, 2983, 1448, 1240, 1047, 968, 803, 570 cm–1.
MS (ESI): m/z = 384.2 [M + Na]+.
In the presence of methanolic hydrochloric acid (4N), the
N-sulfinyl group of the w-chloro-substituted a-amino-
phosphonate compounds can easily be eliminated to give
the corresponding cyclic product in excellent yield.
(Scheme 7).
HRMS: m/z [M+Na]+ calcd for C16H28NO4PSNa: 384.1379; found:
384.1369.
Anal. Calcd for C16H28NO4PS: C, 53.17; H, 7.81; N, 3.88. Found:
C, 53.06; H, 8.32; N, 3.31.
O
Diethyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-(4-methoxyphe-
nyl)ethylphosphonate (3c)
Yield: 82%; colorless oil; de >95%.
S
O
HN
OMe
1) 4 N HCl, MeOH
P
Cl
OMe
OMe
OMe
P
2) Et3N, Et2O
83%
N
H
Me
Me
1H NMR (300 MHz, CDCl3): d = 1.27 (s, 9 H), 1.26 (m, 6 H), 2.13
(d, J = 15.9 Hz, 3 H), 3.77 (s, 3 H), 4.02 (m, 4 H), 4.08 (m, 1 H),
7.68 (m, 2 H), 7.88 (m, 2 H).
O
10
5
Scheme 7
31P NMR (120 MHz, CDCl3): d = 23.58.
IR (KBr): 3486, 2983, 1611, 1513, 1255, 1048, 838, 567 cm–1.
MS (ESI): m/z = 414.2 [M + Na]+.
Mild reaction conditions (weak base) were essential for
the transformation described here, since the substituted
product resulted when stronger bases (NaOR, LiHMDS)
were applied.
Anal. Calcd for C17H30NO5PS: C, 52.16; H, 7.72; N, 3.58. Found:
C, 51.94; H, 7.94; N, 3.82.
Diethyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-(4-nitrophe-
nyl)ethylphosphonate (3d)
Yield: 88%; colorless oil; de 85%.
In conclusion, a simple and efficient methodology involv-
ing nucleophilic addition of dialkylphosphites to N-tert-
butanesulfinimines leading to chiral acyclic a-amino-
phosphonates and chiral cyclic a-aminophosphonates has
been developed in good chemical yields and modest to
high diastereoselectivities under mild conditions using
K2CO3 or KF as base at room temperature.
1H NMR (300 MHz, CDCl3): d = 1.27 (s, 9 H), 1.25 (m, 6 H), 2.15
(d, J = 15.9 Hz, 3 H), 4.03 (m, 4 H), 4.15 (m, 1 H), 7.80 (m, 2 H),
8.23 (m, 2 H).
31P NMR (120 MHz, CDCl3): d = 21.86.
IR (KBr): 3483, 2984, 1737, 1523, 1349, 1018, 856, 562 cm–1.
MS (ESI): m/z = 429.2 [M + Na]+.
All chemicals were obtained from commercial suppliers and used
without further purification unless otherwise noted. All solvents
were dried by standard procedures. Petroleum ether (PE), where
used, had a boiling range of 60–90 °C. 1H NMR and 13C NMR spec-
tra were recorded at 300 MHz with CDCl3 as solvent (unless other-
wise indicated) on a Bruker Avance 300 or a Varian Mercury 300
spectrometer, and 31P NMR spectra were taken at 120 MHz with
CDCl3 as solvent on a Varian EM 390 or a Bruker AM 300 spec-
trometer (external 85% H3PO4). IR spectra were taken on a
Shimadzu IR 440 spectrometer, EI-MS measurements were per-
formed on an HP 5989A apparatus. HRMS data were recorded on a
Finnigan MAT 8430 spectrometer. Elemental analyses were con-
ducted on a Heraeus Rapid CHNO apparatus.
Anal. Calcd for C16H27N2O6PS: C, 47.28; H, 6.70; N, 6.89. Found:
C, 47.01; H, 6.84; N, 6.92.
Dipropyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-phenylethyl-
phosphonate (3e)
Yield: 81%; colorless oil; de >95%.
1H NMR (300 MHz, CDCl3): d = 0.91 (m, 6 H), 1.27 (s, 9 H), 1.63
(m, 4 H), 2.13 (d, J = 15.9 Hz, 3 H), 3.91 (m, 4 H), 4.15 (s, 1 H),
7.35 (m, 3 H), 7.73 (m, 2 H).
31P NMR (120 MHz, CDCl3): d = 23.14.
IR (KBr): 3493, 2970, 1464, 1239, 1065, 792, 571 cm–1.
Synthesis 2008, No. 18, 2986–2990 © Thieme Stuttgart · New York

PAPER
Sulfinimine-Mediated Synthesis of a-Aminophosphonates
2989
MS (ESI): m/z = 412.2 [M + Na]+.
31P NMR (120 MHz, CDCl3): d = 23.04.
IR (KBr): 3480, 2961, 1655, 1458, 1253, 1031, 840 cm–1.
MS (ESI): m/z = 270.2 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C18H32NO4PSNa: 412.1695; found:
412.1682.
HRMS: m/z [M+] calcd for C9H20NO4PS: 269.0851; found:
269.0862.
Dipropyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-(4-methoxyphe-
nyl)ethylphosphonate (3f)
Yield: 70%; colorless oil; de 91%.
Dimethyl (R)-1-[(S)-tert-Butylsulfinyl]-2-phenylazetidin-2-
ylphosphonate (6b)
Yield: 82%; colorless oil; de 78%.
1H NMR (300 MHz, CDCl3): d = 0.90 (m, 6 H), 1.26 (s, 9 H), 1.63
(m, 4 H), 2.12 (d, J = 15.6 Hz, 3 H), 3.75 (s, 3 H), 3.90 (m, 4 H),
4.13 (s, 1 H), 7.55 (m, 2 H), 7.93 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 9 H), 1.95–2.24 (m, 2 H),
3.40 (m, 2 H), 3.69 (d, J = 3.0 Hz, 3 H), 3.73 (d, J = 3.0 Hz, 3 H),
7.30 (d, J = 8.4 Hz, 2 H), 7.39 (m, 3 H).
31P NMR (120 MHz, CDCl3): d = 23.31.
IR (KBr): 3472, 2970, 1611, 1513, 1255, 1002, 838, 567 cm–1.
MS (ESI): m/z = 442.3 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 136.2, 133.4, 128.7, 128.1, 55.4,
52.5, 31.6, 31.5, 22.1, 19.6.
Anal. Calcd for C19H34NO5PS: C, 54.40; H, 8.17; N, 3.34. Found:
C, 54.47; H, 8.35; N, 3.69.
31P NMR (120 MHz, CDCl3): d = 31.74.
IR (KBr): 3467, 2958, 1688, 1597, 1245, 1031, 693 cm–1.
MS (ESI): m/z = 346.2 [M + H]+.
Dipropyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-(4-nitrophe-
nyl)ethylphosphonate (3g)
Yield: 85%; colorless oil; de 85%.
HRMS: m/z [M + H]+ calcd for C15H25NO4PS: 346.1225; found:
346.1236.
1H NMR (300 MHz, CDCl3): d = 0.90 (m, 6 H), 1.27 (s, 9 H), 1.64
(m, 4 H), 2.15 (d, J = 15.6 Hz, 3 H), 3.93 (m, 4 H), 4.15 (s, 1 H),
7.79 (m, 2 H), 8.24 (m, 2 H).
Dimethyl (R)-1-[(S)-tert-Butylsulfinyl]-2-phenylpyrrolidin-2-
ylphosphonate (6c)
Yield: 83%; colorless oil; de 42%.
31P NMR (120 MHz, CDCl3): d = 21.60.
IR (KBr): 3500, 2971, 1523, 1349, 1002, 856, 561 cm–1.
MS (ESI): m/z = 457.2 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H), 2.02 (m, 2 H), 2.10
(m, 2 H), 2.45 (m, 1 H), 2.72 (m, 1 H), 3.75 (m, 6 H), 7.35 (m, 3 H),
7.58 (m, 2 H).
Anal. Calcd for C18H31N2O6PS: C, 49.76; H, 7.19; N, 6.45. Found:
C, 49.58; H, 7.36; N, 6.42.
13C NMR (75 MHz, CDCl3): d = 136.4, 133.5, 128.6, 128.1, 55.5,
52.7, 32.5, 30.8, 22.5, 20.1, 16.8.
Diisopropyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-(4-nitrophe-
nyl)ethylphosphonate (3j)
Yield: 74%; colorless oil; de 18%.
31P NMR (120 MHz, CDCl3): d = 24.71.
IR (KBr): 3420, 2975, 1702, 1223, 1060, 700 cm–1.
MS (ESI): m/z = 382.2 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 6.3 Hz, 3 H), 1.27 (m,
18 H), 2.13 (d, J = 15.9 Hz, 3 H), 4.10 (d, J = 5.7 Hz, 1 H), 4.58 (m,
2 H), 7.81 (m, 2 H), 8.23 (m, 2 H).
HRMS: m/z [M + H]+ calcd for C16H27NO4PS: 360.1385; found:
360.1393.
31P NMR (120 MHz, CDCl3): d = 19.81.
Tetramethyl (R)-1-[(S)-tert-Butylsulfinylamino]ethane-1,2-
diyldiphosphonate (7a)
Yield: 86%; colorless oil; de >95%.
IR (KBr): 3484, 2983, 1523, 1349, 1237, 987, 855, 564 cm–1.
MS (ESI): m/z = 457.2 [M + Na]+.
Anal. Calcd for C18H31N2O6PS: C, 49.76; H, 7.19; N, 6.45. Found:
C, 49.50; H, 7.35; N, 6.35.
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 9 H), 1.81 (m, 2 H), 3.88
(m, 12 H), 3.94 (m, 1 H), 5.32 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 57.0, 55.1, 54.8, 54.4, 31.1, 22.5,
16.5.
Synthesis of 5, 6, 7 and 9; General Procedure
In a N2-flushed 15 mL round-bottom flask fitted with a magnetic stir
bar was placed a solution of dimethyl phosphite (4 mmol) in Et2O
(10 mL) and base (5 mmol) was added. The reaction mixture was
stirred for 15 min at r.t., then the corresponding sulfinimine (1.0
mmol) was added. After stirring for 10–72 h at this temperature, the
reaction mixture was quenched with H2O (5 mL), and extracted
with CH2Cl2 (2 × 5 mL). The organic layer was successively
washed with H2O (5 mL) and brine (5 mL), then dried (Na2SO4).
The solvent was removed and the residue was subjected to column
chromatography on silica gel (PE–EtOAc, 1:2).
31P NMR (120 MHz, CDCl3): d = 22.25.
IR (KBr): 3484, 2962, 1672, 1495, 1250, 1038, 845 cm–1.
MS (ESI): m/z = 366.2 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C10H25NO7P2SNa: 388.07107;
found: 388.07192.
Anal. Calcd for C10H25NO7P2S: C, 32.88; H, 6.90; N, 3.83. Found:
C, 32.62; H, 7.11; N, 3.48.
Tetramethyl (R)-1-[(S)-tert-Butylsulfinylamino]-1-phenylpro-
pane-1,3-diyldiphosphonate (7b)
Yield: 87%; colorless oil; de 22%.
Dimethyl (R)-1-[(S)-tert-Butylsulfinyl]-2-methylaziridin-2-
ylphosphonate (6a)
Yield: 75%; colorless oil; de 84%.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H), 2.18 (m, 2 H), 2.70
(m, 2 H), 3.47–3.80 (m, 12 H), 5.61 (s, 1 H), 7.28 (m, 3 H), 7.93 (m,
2 H).
1H NMR (300 MHz, CDCl3): d = 1.30 (s, 9 H), 1.71 (d, J = 12.3 Hz,
3 H), 2.21 (d, J = 7.5 Hz, 1 H), 2.67 (d, J = 8.7 Hz, 1 H), 3.81 (d,
J = 8.7 Hz, 3 H), 3.86 (d, J = 10.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.4, 133.5, 130.1, 128.4, 57.6,
55.7, 55.3, 54.8, 52.7, 22.3, 18.9, 15.5.
13C NMR (75 MHz, CDCl3): d = 57.7, 54.1, 53.3, 39.9, 34.7, 22.5,
22.2.
Synthesis 2008, No. 18, 2986–2990 © Thieme Stuttgart · New York

2990
Q. Chen et al.
PAPER
IR (KBr): 3403, 2955, 1636, 1456, 1218, 1058, 766, 570 cm–1.
31P NMR (120 MHz, CDCl3): d = 24.54 (dd, JP–P = 15.6 Hz,
JP–H = 129.6 Hz), 34.22 (dd, JP–P = 9.2 Hz, JP–H = 75.1 Hz).
MS (ESI): m/z = 194.1 [M + H]+.
IR (KBr): 3424, 2960, 1640, 1459, 1227, 1034, 836 cm–1.
HRMS: m/z [M + Na]+ calcd for C7H16NO3PNa: 216.0753; found:
216.0760.
MS (ESI): m/z = 456.2 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C17H31NO7PSNa: 478.1178; found:
478.1188.
Acknowledgment
Dimethyl (R)-5-Chloro-2-[(S)-tert-Butylsulfinylamino]pentan-
2-ylphosphonate (5)
Yield: 85%; colorless oil.
The project was supported by the National Natural Science Found-
ation of China (No 20372076 and 20672132).
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 9 H), 1.51 (d, J = 12.3 Hz,
3 H), 1.96 (m, 4 H), 3.54 (m, 2 H), 3.67 (d, J = 5.4 Hz, 1 H), 3.82
(m, 6 H).
References
(1) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids Chemistry and BiologicalActivities;
John Wiley: New York, 2000.
(2) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138.
(3) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4102.
(4) Bernardi, L.; Zhuang, W.; Jørgensen, A. K. J. Am. Chem.
Soc. 2005, 127, 5772.
13C NMR (75 MHz, CDCl3): d = 57.6, 54.4, 53.5, 45.1, 44.7, 31.1,
25.2, 22.6, 19.5.
31P NMR (120 MHz, CDCl3): d = 29.15.
IR (KBr): 3420, 2961, 1650, 1459, 1229, 1059, 830 cm–1.
MS (ESI): m/z = 356.2 [M + Na]+.
Anal. Calcd for C11H25ClNO4PS: C, 39.58; H, 7.55; N, 4.20. Found:
C, 39.50; H, 7.31; N, 4.15.
(5) Pettersen, D.; Marcolini, M.; Bernardi, L.; Francesco, F.;
Herrera, R. P. J. Org. Chem. 2006, 71, 6269.
Dimethyl (1R)-2-Chloro-1-[(S)-tert-butylsulfinylamino]cyclo-
hexylphosphonate (9)
Yield: 78%; colorless oil; de 73%.
(6) Bunnai, S.; Hiromichi, E.; Tsutomu, K. J. Am. Chem. Soc.
2007, 129, 1978.
(7) (a) Davis, F. A.; Lee, S. H.; Xu, H. J. Org. Chem. 2004, 69,
3774. (b) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.;
Prasad, K. R. J. Org. Chem. 2003, 68, 2410.
1H NMR (300 MHz, CDCl3): d = 1.32 (s, 9 H), 1.71–2.20 (m, 8 H),
2.67 (m, 1 H), 3.83 (m, 6 H), 4.22 (s, 1 H).
(8) Dolence, E. K.; Roylance, J. B. Tetrahedron: Asymmetry
2004, 15, 3307.
(9) Katritzky, A. R.; Cui, X.; Yang, B.; Steel, P. J. J. Org. Chem.
1999, 64, 1979.
13C NMR (75 MHz, CDCl3): d = 63.9, 57.6, 54.3, 53.5, 31.7, 29.0,
25.6, 23.1, 21.9, 18.7.
31P NMR (120 MHz, CDCl3): d = 26.10.
IR (KBr): 3487, 2954, 1458, 1248, 1029, 831, 592 cm–1.
MS (ESI): m/z = 368.0 [M + Na]+.
(10) Groeger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens,
J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 3089.
(11) Chen, Q.; Yuan, C. Synthesis 2007, 3779.
(12) (a) For reviews related to Ellman’s N-(tert-
butanesulfinyl)imines, see: Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (b) Davis, F. A.;
Chen, B. C. Chem. Soc. Rev. 1998, 27, 13. (c) Davis, F. A.;
Chen, B. C. Chem. Soc. Rev. 1998, 27, 13. (d) Davis, F. A.;
Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117, 3651.
(e) Mikoajczyk, M.; Łyꢀwa, P.; Drabowicz, J.; Wieczorek,
M. W.; Baszczyk, J. Chem. Commun. 1996, 1503. (f) Liu,
G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913. (g) Mikoajczyk, M.; Łyꢀwa, P.; Drabowicz, J.
Tetrahedron: Asymmetry 1997, 8, 3991. (h) Lefebvre, I. M.;
Evans, S. A. J. Org. Chem. 1997, 62, 7532. (i) Davis, F. A.;
Fanelli, D. L. J. Org. Chem. 1998, 63, 1981. (j) Davis, F.
A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951.
(k) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40,
249. (l) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett.
2001, 3, 1757. (m) Mikoajczyk, M.; Łyꢀwa, P.; Drabowicz,
J. Tetrahedron: Asymmetry 2002, 13, 2571. (n) Davis, F.
A.; Prasad, K. R. J. Org. Chem. 2003, 68, 7249. (o) Zhou,
P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(p) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han,
Z.; Gallou, I. Aldrichimica Acta 2005, 38, 93. (q) Mortona,
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
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2000, 65, 8704.
HRMS: m/z [M + Na]+ calcd for C12H25ClNO4PSNa: 368.0816;
found: 368.0823.
(R)-Dimethyl 2-Methylpyrrolidin-2-ylphosphonate (10)
In a 20 mL, single-neck, round-bottom flask equipped with a mag-
netic stirring bar, was placed 5 (0.36 g, 1.0 mmol) in MeOH (5 mL),
then 4 N HCl (5 mL) was added into the solution. The reaction mix-
ture was stirred at r.t. for 6 h then concentrated under vacuum for 30
min. CH2Cl2 (10 mL) was added and the solution was cooled to 0 °C
in an ice bath. Et3N was added until pH >7 then the aqueous phase
was extracted successively with Et2O (5 mL) and EtOAc (2 × 5
mL). The combined organic layers were washed with brine (20 mL)
and dried (Na2SO4). The solvent was removed and the residue was
subjected to column chromatography on silica gel (PE–EtOAc,
1:1).
Yield: 83%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.37 (d, J = 15.9 Hz, 3 H), 1.55–
1.95 (m, 4 H), 2.23 (m, 1 H), 3.05 (m, 2 H), 3.79 (d, J = 2.7 Hz,
3 H), 3.82 (d, J = 2.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 55.0, 52.6, 36.8, 36.0, 22.8, 20.3,
17.2.
31P NMR (120 MHz, CDCl3): d = 33.04.
Synthesis 2008, No. 18, 2986–2990 © Thieme Stuttgart · New York