A versatile and highly stereoselective synthesis of diethyl (l-Aminoalkyl)thiophosphonates

Article abstract of DOI:10.1055/s-0029-1217054

A series of chiral diethyl (l-aminoalkyl)thiophosphonates was synthesized in high yield and excellent enantioselectivity by nucleophilic addition of diethyl thiophosphonate to N-(tert-butylsulfinyl)imines under mild conditions. There is no evidence indica

Full text of DOI:10.1055/s-0029-1217054

3930
PAPER
A Versatile and Highly Stereoselective Synthesis of Diethyl
(1-Aminoalkyl)thiophosphonates
Synthesis of
D
ie
h
thyl (1-Ami
i
noalky
l
l)thioph
o
osphonate
s
ng Chen, Jinfeng Li, Chengye Yuan*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-lin Rd, Shanghai, 200032, P. R. of China
Fax +86(21)54925379; E-mail: yuancy@mail.sioc.ac.cn
Received 8 June 2009; revised 21 July 2009
reaction took place with the slightly stronger base rubidi-
um carbonate, providing optically pure (1-aminoalkyl)-H-
phosphinates with two stereogenic atoms. These experi-
mental data support Hu’s report that the stability and nu-
Abstract: A series of chiral diethyl (1-aminoalkyl)thiophospho-
nates was synthesized in high yield and excellent enantioselectivity
by nucleophilic addition of diethyl thiophosphonate to N-(tert-bu-
tylsulfinyl)imines under mild conditions. There is no evidence indi-
cating that the reaction is influenced by electronic or steric effects cleophilicity of the nucleophiles are critical for the
reaction involving sulfinylimines.8
of the substrates.
Key words: nucleophilic additions, thiophosphonates, imines, sul-
finamides, sulfonamides
Replacement of the phosphoryl oxygen of the (1-amino-
alkyl)phosphonates by a sulfur atom would result in an-
other group of potent biologically active molecules,
namely dialkyl (1-aminoalkyl)thiophosphonates. Thomp-
son’s group9 described a method for the synthesis of di-
alkyl (1-aminoalkyl)thiophosphonates on the basis of a
diastereoselective addition of dimethyl thiophosphonates
to benzaldimines bearing chiral auxiliary groups. Unfor-
tunately, both the chemical yield and the diastereoselec-
tivity of that method are not high enough for the procedure
to be used synthetically. To the best of our knowledge,
this is the only paper that describes the asymmetric syn-
thesis of (1-aminoalkyl)thiophosphonates. Herein we re-
port a convenient and highly stereoselective synthetic
protocol for the preparation of chiral diethyl (1-amino-
alkyl)thiophosphonates by nucleophilic addition of dieth-
yl thiophosphonate to Ellman’s sulfinylimine. In
comparison with Thompson’s report, our method pro-
vides much better chemical yields and remarkably higher
stereoselectivity.
As phosphorus analogues of natural a-aminocarboxylic
acids, (1-aminoalkyl)phosphonates have demonstrated
significant biological activities.1 These bioactivities are,
however, closely related to the stereoconfiguration of the
chiral atom of the molecule. Consequently, the asymmet-
ric synthesis of such compounds is attracting much atten-
tion amongst organic chemists.2–4
As reported by our laboratory, induced asymmetric addi-
tion of dialkyl phosphonates to chiral aldimines is one of
the convenient methods for the synthesis of optically ac-
tive (1-aminoalkyl)phosphonates. It is important to note
that, initiated by Davis,5 and then modified and signifi-
cantly improved by Ellman, N-(tert-butylsulfinyl)imines6
have become extremely useful chiral auxiliaries for the
preparation of optically active amines and their deriva-
tives. As found by our group very recently,3a diethyl phos-
phonates smoothly undergo nucleophilic addition with
Ellman’s sulfinylimine, affording chiral (1-amino-
alkyl)phosphonates in excellent chemical yield and high
enantioselectivity.5 In this protocol, the reaction condi-
tions were remarkably simplified: potassium carbonate
could be used instead of lithium hexamethyldisilazide as
required in the standard procedure, and, consequently, the
reaction temperature could be changed from –78 °C to
ambient temperature. It should be emphasized that this is
the first time that the reaction involving nucleophilic ad-
dition to Ellman’s sulfinylimine could be carried out at
room temperature. This special report greatly aroused our
interest, and we presumed that the weak P–H bond may be
stable at room temperature and suited to a sulfinylimine.
On the basis of this postulation, Zhang7 used ethyl (di-
ethoxymethyl)methylphosphinate as another kind of nu-
cleophile containing a P–H bond. As expected, the
In the initial experiments, (S)-N-(tert-butylsulfinyl)-p-
chlorobenzylideneamine (1f) was chosen as the model
substrate to study the reaction (Scheme 1, Table 1). With
diethyl thiophosphonate as the nucleophile, potassium
carbonate as the base, and dichloromethane as the solvent,
the reaction proceeded smoothly, and was completed at
room temperature within 24 hours. To our delight, the re-
action afforded the desired product 2f in extremely high
chemical yield (99%) and excellent enantioselectivity
(92%) (entry 1). From Table 1 it can be seen that other
bases were ineffective in promoting the reaction (entries
2–4), usually requiring longer reaction times. In compari-
O
S
O
S
NH
N
S
S
base, solvent
r.t.
+
HP OEt
OEt
P
OEt
H
OEt
Cl
Cl
SYNTHESIS 2009, No. 23, pp 3930–3940
x
x.
x
x
.
2
0
0
9
1f
2f
Advanced online publication: 19.10.2009
DOI: 10.1055/s-0029-1217054; Art ID: F11709SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

PAPER
Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates
3931
son with our previous research involving dimethylphos-
phinates and/or ethyl diethoxymethylphosphinates,3a,7 it
seems that a weaker base should increase the enantiose-
lectivity of the reaction. However, this was not observed
when weaker bases were used. Other solvents, such as di-
ethyl ether (entry 5), toluene (entry 6), tetrahydrofuran
(entry 7), and n-hexane (entry 8), did promote the reac-
tion, but they afforded no better results than dichlo-
romethane. According to these optimization results, we
decided to select the reaction conditions of entry 1 as stan-
dard for studying the scope and applications with different
sulfinylimines.
Table 2 Addition of Diethyl Thiophosphonate to (S)-N-(tert-Butyl-
sulfinyl) Aldimines 1a
Entry Product R
Time Yieldb dec
31P NMR
(h)
24
36
24
48
24
24
24
36
24
36
24
12
12
24
(%)
99
80
99
88
98
99
99
99
99
99
99
87
98
84
(%)
(d)
1
2
2a
2b
2c
2d
2e
2f
Ph
94
92.1
92.2
91.9
91.8
91.6
91.2
91.0
92.2
92.6
90.5
89.8
96.5
96.4
91.7
4-MeC6H4
4-PhC6H4
2-naphthyl
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-Me2NC6H4
4-MeSC6H4
2-HSC6H4
Bn
>95
92
3
4
94
5
94
Table 1 Optimization of the Reaction Conditionsa
6
94
7
2g
2h
2i
92
Entry Base
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Time (h) Yieldb (%) dec (%)
8
94
1
2
3
4
5
6
7
8
K2CO3
24
120
120
120
12
99
99
92
71
9
>95
90
Na2CO3
Li2CO3
KF
10
11
12
13
14
2j
d
d
–
–
2k
2l
>95
>95
>95
>95
83
99
70
99
99
71
65
78
44
72
K2CO3
K2CO3
K2CO3
K2CO3
2m
i-Pr
toluene
THF
12
2n
E-CH=CHPh
12
a Reagents and conditions: imine (0.5 mmol), diethyl thiophosphonate
n-hexane
12
(2.0 equiv), K2CO3 (2.0 equiv).
b Isolated yield.
a Reagents and conditions: imine (0.5 mmol), diethyl thiophosphonate
c The de was determined by 31P NMR spectroscopy of the crude prod-
ucts.
(2.0 equiv), base (2.0 equiv), in air.
b Isolated yield.
c The de was determined by 31P NMR spectroscopy of the crude prod-
ucts.
On the basis of our previous work, we supposed that under
the same conditions, (S)-N-(tert-butylsulfinyl) methyl
ketimines might also react with diethyl thiophosphonate
(Scheme 3, Table 3). A similar study was carried out with
3a as our model substrate (Table 3, entry 1). To our de-
light, we found that the desired product 4a was obtained
in both good yield (99%) and excellent enantioselectivity
(>95%, by 31P NMR of the crude product). Further studies
on this reaction were carried out, with the results summa-
rized in Table 3. As expected, good yields and enantio-
selectivities were observed with either electron-donating
or electron-withdrawing groups of the aromatic system.
Other substrates also gave excellent results.
d No reaction was observed.
Further investigation into the reaction was carried out un-
der the standard conditions (Scheme 2, Table 2). A vari-
ety of structurally diverse (S)-N-(tert-butylsulfinyl)
aldimines 1 were tested, including aromatic and aliphatic
ones. All reactions gave (1-aminoalkyl)thiophosphonates
2 in high yields and excellent enantioselectivities. It is
noteworthy that there were few influences on the yield
and enantioselectivity concerning the electronic or steric
properties of the substrates. Slightly better enantioselec-
tivities could be observed in the electron-rich aromatic
systems compared to the electron-poor ones; alkyl sub-
strates gave better results (entries 12 and 13, >95% de).
Note that products 2l and 2m are the analogues of valine
and phenylalanine, respectively. In the case of an unsatur-
ated system (entry 14), only 1,2-addition products were
afforded.
O
O
S
NH
S
S
S
N
K2CO3, CH2Cl2
r.t.
+
HP OEt
OEt
R
P
OEt
R
OEt
4
3
O
Scheme 3
O
S
S
NH
S
S
N
K2CO3, CH2Cl2
r.t.
+
HP OEt
OEt
To confirm the absolute configuration of the products, a
single-crystal X-ray analysis of 4g was carried out.10 As
shown in Figure 1, the configuration of the chiral carbon
atom of the product is proved to be R.
R
P
OEt
H
R
OEt
1
2
Scheme 2
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

3932
Z. Chen et al.
PAPER
Table 3 Addition of Diethyl Thiophosphonate to (S)-N-(tert-Butyl-
sulfinyl) Ketimines 3a
O
S
O
O
S
NH
NH
O
Time Yieldb dec
31PNMR
S
Entry Product R
RuCl3⋅H2O, NaIO4
P
OEt
P
OEt
(h)
24
24
36
24
18
24
12
(%) (%)
(d)
CH2Cl2, MeCN, H2O
68%
OEt
OEt
MeO
MeO
1
2
4a
4b
4c
4d
4e
4f
Ph
99
80
95
88
99
90
99
99
99
99
99
98
94
87
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
95.7
95.9
95.5
95.7
95.2
94.9
94.7
96.0
93.7
94.0
93.8
(RC)-5h 94% ee
(SS,RC)-2h
4-MeC6H4
4-PhC6H4
2-naphthyl
4-FC6H4
4-ClC6H4
4-BrC6H4
Scheme 4 Conversion of a [1-(tert-butylsulfinylamino)alkyl]thio-
phosphonate into the corresponding [1-(tert-butylsulfonylamino)al-
kyl]phosphonate
3
4
5
eral and convenient route to optically pure [1-(sulfonyl-
amino)alkyl]phosphonates.
6
Compounds 2 and 4 can easily be converted into the cor-
responding (1-aminoalkyl)thiophosphonates (Scheme 5,
Table 4). Initially, the reaction was carried out under re-
flux with 6 N hydrochloric acid, but this failed to provide
the product, and we found that the reactant had decom-
posed. After careful examination and analysis, we con-
cluded that the conditions might have been too harsh. The
high acid concentration and reflux very probably led to
the decomposition of the reactant. Therefore, we de-
7
4g
4h
4i
8
4-morpholinophenyl 36
9
4-O2NC6H4
4-NCC6H4
2-HSC6H4
2-pyridyl
E-CH=CHPh
n-Bu
12
12
24
18
24
18
10
11
12
13
14
4j
4k
4l
>95 100.3
4m
>95
>95
95.1
94.2
O
S
NH2
R1
R2
4n
NH
4 N aq HCl
r.t., 3–6 h
S
R1
R2
S
P
OEt
a Reagents and conditions: imine (0.5 mmol), diethyl thiophosphonate
P
OEt
OEt
(1.0 mmol), K2CO3 (1.0 mmol).
OEt
2 or 4
6
b Isolated yield.
c The de was determined by 31P NMR spectroscopy of the crude prod-
ucts.
Scheme 5
Table 4 Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates 6
Entry Product R1
R2
Yielda (%) eeb (%)
1
2
3
4
6a
6b
6c
6d
H
Ph
95
97
97
98
94
>95
>95
>95
H
4-MeOC6H4
4-BrC6H4
4-NCC6H4
Me
Me
Figure 1 X-ray crystal structure and absolute configuration of
(SS,RC)-4g
a Isolated yield.
b The ee value depends on the ee value obtained in the formation of
compound 2 or 4.
To determine the accurate de values of the products, we
oxidized (SS,RC)-2h with ruthenium(III) chloride hydrate
and sodium periodate (Scheme 4).11 Surprisingly, in addi-
tion to the tert-butylsulfinyl group, the thiophosphoryl
(P=S) group was also oxidized to phosphoryl (P=O)! This
reaction is therefore a convenient approach to converting
(1-aminoalkyl)thiophosphonates into the corresponding
(1-aminoalkyl)phosphonates. Thompson reported their at-
tempts to oxidize thiophosphoryl (P=S) to phosphoryl
(P=O) with various oxidation agents: m-chloroperoxyben-
zoic acid, tert-butyl hydroperoxide, monoperoxyphthalic
acid, magnesium salt (MMPP), and hydrogen peroxide.
Unfortunately, 5h only formed in low yield (29%)
(Scheme 4), and the enantiomeric excess of the oxidation
product (RC)-5h was determined by chiral HPLC. The
high ee value indicates that this synthetic method is a gen-
FmocHN
R3
O
NH2
R1
R2
CH2Cl2
NHFmoc
COCl
HN
R1
R2
S
+
S
P
OEt
R3
K2CO3, reflux
P
OEt
OEt
OEt
Fmoc
NHFmoc
HN
O
HN
O
P(S)(OEt)2
P(S)(OEt)2
NC
MeO
7a 85%
7b 98%
Scheme 6 Synthesis of peptide or amide linkages with (1-aminoal-
kyl)thiophosphonates
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

PAPER
Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates
3933
O
S
S
SH
P
SM
P
base
N
E
+
HP OR
OR
RO
OR
RO
OR
R1
R2
2
M = metal cation
1 R = Et
R1 = H, Me
O
S
R2 = alkyl, aryl
O
S
S
S
N
M
NH
R
R1
PH
P
O
O
O
O
R
R2
O
R
R
R1 = H, Me, R2 = Ar
favored
S
M
N
OR
S
Rc
HP
R1
OR
R2
S
O
S
P
S
O
S
P
chelating control
in five-membered
transition state
N
M
HN
R
R2
O
O
O
O
R
R1
R
R
R
1 = H, Me, R2 = Ar
disfavored
Sc
Scheme 7 Postulated mechanism
HP 5989A apparatus. HRMS data were recorded on a MAT 8430
spectrometer. Elemental analysis was conducted on a Heraeus Rap-
id-CHNO apparatus. Optical rotation values were measured on a
Perkin-Elmer 241 M instrument. All reactions were monitored with
the aid of TLC. Diethyl thiophosphonate,9 (S)-N-(tert-butylsulfinyl)
aldimine 1,3 and (S)-N-(tert-butylsulfinyl) ketimine 37,12 were pre-
pared according to literature procedures, and the spectroscopic data
of 13 and 37,12 were identical to those provided in the literature.
creased the concentration of the hydrochloric acid, and the
reaction was carried out at room temperature, and, finally,
positive results were obtained.
Furthermore, peptide or amide linkage could be estab-
lished with (1-aminoalkyl)thiophosphonates in excellent
yields, as demonstrated in Scheme 6.
It was assumed that the mechanism of the reaction might
be associated with a chelating effect. The nucleophilic ad-
dition occurred in favor of the bigger function group R2
occupying the equatorial position and therefore resulted in
the RC products, as indicated in Scheme 7.
Stereoselective Synthesis of Diethyl (SS,RC)-(+)-1-(tert-Butyl-
sulfinylamino)alkylthiophosphonates (SS,RC)-2; General Proce-
dure
The appropriate imine 1 (0.5 mmol) was added to a 20-mL Schlenk
flask containing diethyl thiophosphonate (158 mg, 1 mmol) and
K2CO3 (138 mg, 1 mmol) in CH2Cl2 (2.5 mL) at r.t. The mixture
was then stirred for 24 h while carefully monitored by TLC. After
the reaction had gone to completion, H2O (5 mL) was added to
quench it. Then the organic layer was separated and the aqueous
layer was washed with Et2O (3 × 10 mL). The organic layer was
again washed with brine (3 × 10 mL) and dried overnight (Na2SO4).
The solvent was removed under reduced pressure and the residue
was purified by chromatography (silica gel); this afforded the cor-
responding pure (SS,RC)-2.
In summary, we have reported for the first time a facile
and convenient synthetic method for the preparation of
chiral (1-aminoalkyl)thiophosphonates in excellent yields
and high enantioselectivities on the basis of nucleophilic
addition of dialkyl thiophosphonates to Ellman’s imine.
All reactions were performed under a N2 or argon atmosphere, un-
less indicated otherwise. All reagents were purchased from com-
mercial sources and used as received. THF was freshly distilled
over Na. Column chromatography was performed over silica gel
(300–400 mesh). All yields given refer to isolated yields. IR spectra
were obtained on a Shimadzu IR-440 spectrometer. 1H NMR spec-
tra (300 MHz) were recorded on a Bruker AM-300 spectrometer
with CDCl3 as solvent and TMS as internal standard, unless indicat-
ed otherwise. 13C NMR spectra (100 MHz) were recorded on a
Bruker AM-400 spectrometer with CDCl3 as solvent, unless indi-
cated otherwise. 19F NMR spectra (282 MHz) were recorded on a
Bruker AM-300 spectrometer with CDCl3 as solvent and TFA as in-
ternal standard, downfield shifts being designated as negative, un-
less indicated otherwise. 31P NMR (100 MHz) spectra were
recorded on a Bruker AM-400 spectrometer with CDCl3 as solvent
and 85% H3PO4 as internal standard, unless indicated otherwise.
Mass spectra were recorded at 2010 eV on a Hewlett-Packard and
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(phenyl)meth-
yl]thiophosphonate (2a)
Colorless oil; yield: 182 mg (99%); [a]D25 +128.3 (c 0.99, CHCl3).
IR (KBr): 3231, 2981, 1494, 1475, 1455, 1052 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.41 (m, 5 H), 4.77 (dd,
J = 15.7, 3 Hz, 1 H), 4.16 (dd, J = 9.3, 3.0 Hz, 1 H), 4.10–4.19 (m,
2 H), 3.90–3.96 (m, 1 H), 3.80–3.85 (m, 1 H), 1.32 (t, J = 3.6 Hz, 3
H), 1.28 (s, 9 H), 1.13 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 134.0 (d, J = 4.5 Hz, 1 C), 129.2
(d, J = 6.0 Hz, 2 C), 128.3 (d, J = 3.7 Hz, 1 C), 128.0 d, J = 2.9 Hz,
2 C), 64.1 (d, J = 6.7 Hz, 1 C), 63.9 (d, J = 7.5 Hz, 1 C), 60.5 (d,
JPC = 118.3 Hz, 1 C), 56.1 (s, 1 C), 22.5 (s, 3 C), 16.1 (d, J = 6.7 Hz,
1 C), 15.8 (d, J = 6.7 Hz, 1 C).
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

3934
Z. Chen et al.
PAPER
31P NMR (100 MHz, CDCl3): d = 92.1 (s, 1 P).
MS (EI): m/z = 364.1 [M + H]+, 386.2 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 91.8 (s, 1 P).
ESI-MS: m/z = 414.1 [M + H]+, 436.1 [M + Na]+.
Anal. Calcd for C15H26NO3PS: C, 49.57; H, 7.21; N, 3.85. Found:
C, 49.77; H, 7.21; N, 3.69.
Anal. Calcd for C19H28NO3PS2: C, 55.18; H, 6.64; N, 3.39. Found:
C, 55.28; H, 6.74; N, 3.38.
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(4-tolyl)meth-
yl]thiophosphonate (2b)
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(4-fluorophe-
nyl)methyl]thiophosphonate (2e)
Colorless oil; yield: 151 mg (80%); [a]D25 +113.5 (c 1.00, CHCl3).
Colorless oil; yield: 212 mg (98%); [a]D25 +118.8 (c 1.05, CHCl3).
IR (KBr): 3228, 2980, 1514, 1022, 832 cm–1.
IR (KBr): 3228, 2981, 1604, 1510, 1389, 1021, 964, 846, 785 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28 (d, J = 7.5 Hz, 2 H), 7.25 (d,
J = 7.5 Hz, 2 H), 4.74 (dd, J = 15.3, 3.0 Hz, 1 H), 4.42 (dd, J = 8.1,
3.0 Hz, 1 H), 4.09–4.19 (m, 2 H), 3.92–4.01 (m, 1 H), 3.79–3.88 (m,
1 H), 2.35 (s, 3 H), 1.27–1.32 (m, 3 H), 1.22 (s, 9 H), 1.15 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.2 (s, 1 C), 130.0 (d, J = 5.2
Hz, 1 C), 129.2 (d, J = 5.2 Hz, 2 C), 128.8 (d, J = 2.2 Hz, 2 C), 64.1
(d, J = 7.4 Hz, 1 C), 63.9 (d, J = 7.4 Hz, 1 C), 60.5 (d, JPC = 119.9
Hz, 1 C), 56.0 (s, 1 C), 22.6 (s, 3 C), 22.1 (s, 1 C), 16.1 (d, J = 6.7
Hz, 1 C), 16.0 (d, J = 6.7 Hz, 1 C).
1H NMR (300 MHz, CDCl3): d = 7.35–7.41 (m, 2 H), 7.04 (d,
J = 8.1 Hz, 2 H), 4.775 (dd, J = 15.3, 3.0 Hz, 1 H), 4.43 (dd, J = 9.0
Hz, 3.0 Hz, 1 H), 4.10–4.20 (m, 2 H), 3.86–3.99 (m, 2 H), 1.32 (t,
J = 3.6 Hz, 3 H), 1.25 (s, 9 H), 1.15 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.7 (s, 0.5 C), 161.2 (s, 0.5 C),
131.0 (m, 2 C), 129.7 (m, 1 C), 115.2 (m 2 C), 64.2 (d, J = 7.5 Hz,
1 C), 64.0 (d, J = 7.5 Hz, 1 C), 59.8 (d, JPC = 119.8 Hz, 1 C), 56.1
(s, 1 C), 22.5 (s, 3 C), 16.1 (d, J = 6.7 Hz, 1 C), 16.0 (d, J = 6.7 Hz,
1 C).
31P NMR (100 MHz, CDCl3): d = 91.6 (d, J = 14.4 Hz, 1 P).
19F NMR (282 MHz, CDCl3): d = 114.1 (s, 1 F).
ESI-MS: m/z = 382.0 [M + H]+, 404.0 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 92.2 (s, 1 P).
ESI-MS: m/z = 378.1 [M + H]+, 400.1 [M + Na]+.
Anal. Calcd for C16H28NO3PS2: C, 50.91; H, 7.48; N, 3.71. Found:
C, 50.66; H, 7.49; N, 3.58.
Anal. Calcd for C15H25FNO3PS2: C, 47.23; H, 6.61; N, 3.67. Found:
C, 47.28; H, 6.83; N, 3.55.
Diethyl (SS,RC)-(+)-[(Biphenyl-4-yl)(tert-butylsulfinylami-
no)methyl]thiophosphonate (2c)
Colorless solid; yield: 215 mg (99%); mp 115–117 °C; [a]D
+102.2 (c 1.00, CHCl3).
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(4-chlorophe-
nyl)methyl]thiophosphonate (2f)
25
Colorless oil; yield: 201 mg (99%); [a]D25 –1.85 (c 0.98, CHCl3).
IR (KBr): 3231, 2981, 1492, 1389, 1017, 963, 792 cm–1.
IR (KBr): 3230, 2987, 1488, 1390, 1071, 1013, 972, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38 (m, 4 H), 4.76 (dd, J = 16.5,
3.0 Hz, 1 H), 4.44 (dd, J = 9.6, 3.0 Hz, 1 H), 4.11–4.21 (m, 2 H),
3.89–4.02 (m, 2 H), 1.32 (t, J = 2.1 Hz, 3 H), 1.28 (s, 9 H), 1.18 (t,
J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 134.4 (s, 1 C), 132.7 (d, J = 5.2
Hz, 1 C), 1130.6 (d, J = 5.2 Hz, 2 C), 128.3 (d, J = 2.9 Hz, 2 C), 64.2
(d, J = 6.7 Hz, 1 C), 64.1 (d, J = 7.4 Hz, 1 C), 59.9 (d, JPC = 119.0
Hz, 1 C), 56.2 (s, 1 C), 22.5 (s, 3 C), 16.1 (d, J = 6.7 Hz, 1 C), 15.9
(d, J = 6.0 Hz, 1 C).
1H NMR (300 MHz, CDCl3): d = 7.57–7.62 (m, 4 H), 7.41–7.48 (m,
4 H), 4.82 (dd, J = 15.7, 3 Hz, 1 H), 4.49 (dd, J = 9.0, 3.0 Hz, 1 H),
4.12–4.22 (m, 2 H), 3.86–4.01 (m, 1 H), 3.80–3.85 (m, 1 H), 1.32 (t,
J = 3.0 Hz, 3 H), 1.30 (s, 9 H), 1.16 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 141.2 (d, J = 3.7 Hz, 1 C), 140.5
(s, 1 C), 133.0 (d, J = 5.2 Hz, 1 C), 129.7 (d, J = 5.9 Hz, 2 C), 127.8
(s, 2 C), 127.4 (s, 2 C), 127.0 (s, 2 C), 126.8 (d, J = 2.2 Hz, 2 C),
64.3 (d, J = 7.4 Hz, 1 C), 64.0 (d, J = 7.5 Hz, 1 C), 60.53 (d,
JPC = 119.1 Hz, 1 C), 56.1 (s, 1 C), 22.5 (s, 3 C), 16.2 (d, J = 6.7 Hz,
1 C), 16.0 (d, J = 6.7 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 91.2 (s, 1 P).
MS (EI): m/z = 398.1 [M + H]+, 420.1 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 91.9 (s, 1 P).
ESI-MS: m/z = 462.3 [M + Na]+.
Anal. Calcd for C15H25ClNO3PS2: C, 45.28; H, 6.33; N, 3.52.
Found: C, 45.03; H, 6.39; N, 3.38.
Anal. Calcd for C21H30NO3PS2: C, 57.38; H, 6.88; N, 3.19. Found:
C, 57.58; H, 6.99; N, 3.04.
Diethyl (SS,RC)-(+)-[(4-Bromophenyl)(tert-butylsulfinylami-
no)methyl]thiophosphonate (2g)
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(2-naph-
thyl)methyl]thiophosphonate (2d)
Colorless oil; yield: 216 mg (99%); [a]D25 +117.3 (c 0.99, CHCl3).
Colorless solid; yield: 184 mg (88%); mp 109–114 °C; [a]D25 +80.3
(c 1.04, CHCl3).
IR (KBr): 3228, 2980, 1448, 1405, 1389, 1074, 1050, 1020, 964,
840, 792 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (d, J = 5.4 Hz, 2 H), 7.27 (dd,
J = 5.4, 2.4 Hz, 2 H), 4.73 (dd, J = 15.9, 3.0 Hz, 1 H), 4.43 (dd,
J = 9.0, 3.0 Hz, 1 H), 4.10–4.20 (m, 2 H), 3.87–4.00 (m, 2 H), 1.30
(t, J = 7.2 Hz, 3 H), 1.25 (s, 9 H), 1.16 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 133.2 (d, J = 5.2 Hz, 1 C), 131.3
(d, J = 3.0 Hz, 2 C), 130.9 (d, J = 5.2 Hz, 2 C), 122.5 (s, 1 C), 64.2
(d, J = 7.4 Hz, 1 C), 64.1 (d, J = 8.2 Hz, 1 C), 60.0 (d, JPC = 119.1
Hz, 1 C), 56.2 (s, 1 C), 22.5 (s, 3 C), 16.1 (d, J = 6.7 Hz, 1 C), 16.0
(d, J = 6.7 Hz, 1 C).
IR (KBr): 3302, 2977, 1600, 1508, 1473, 1398, 1365, 1075, 962,
747 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.81–7.86 (m, 4 H), 7.47–7.56 (m,
4 H), 4.95 (dd, J = 15.7, 3 Hz, 1 H), 4.54 (dd, J = 9.0, 3.0 Hz, 1 H),
4.11–4.121 (m, 1 H), 3.90–3.96 (m, 1 H), 3.91–3.97 (m, 1 H), 3.81–
3.87 (m, 1 H), 1.22–1.33 (m, 12 H), 1.11 (t, 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 133.3 (s, 1 C), 132.9 (d, J = 2.9,
1 C), 131.5 (d, J = 6.0 Hz, 1 C), 129.0 (d, J = 7.4 Hz, 1 C), 128.0 (s,
1 C), 127.7 (d, J = 1.4 Hz, 2 C), 126.5 (d, J = 3.7 Hz, 1 C), 126.3 (s,
1 C), 126.2 (s, 1 C), 64.3 (d, J = 7.4 Hz, 1 C), 64.0 (d, J = 7.5 Hz, 1
C), 60.8 (JPC = 119.1 Hz, 1 C), 56.1 (s, 1 C), 22.6 (s, 3 C), 16.2 (d,
J = 6.9 Hz, 1 C), 15.9 (d, J = 6.9 Hz, 1 C).
31P NMR (100 MHz, CDCl3, H3PO4), d = 91.0 (s, 1 P).
ESI-MS: m/z = 444.0 [M + H]+, 466.0 [M + Na]+.
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

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Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates
3935
Anal. Calcd for C15H25BrNO3PS2: C, 40.73; H, 5.90; N, 3.17.
Found: C, 41.04; H, 5.95; N, 3.03.
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(2-sulfanylphe-
nyl)methyl]thiophosphonate (2k)
Pale yellow oil; yield: 181 mg (99%); [a]D25 +57.0 (c 1.00, CHCl3).
Diethyl (SS,RC)-(+)-[(tert-Butylsulfinylamino)(4-methoxyphe-
nyl)methyl]thiophosphonate (2h)
IR (KBr): 3231, 2981, 1494, 1475, 1455, 1052 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.35 (m, 1 H), 7.14 (t, J = 3.6
Hz, 1 H), 7.01 (t, J = 3.6 Hz, 1 H), 5.08 (dd, J = 15.0, 3.0 Hz, 1 H),
4.51 (dd, J = 8.1, 3.6 Hz, 1 H), 3.98–4.22 (m, 1 H), 1.31–1.35 (m,
15 H).
13C NMR (100 MHz, CDCl3): d = 137.2 (d, J = 6.0 Hz, 1 C), 128.4
(d, J = 16.4 Hz, 1 C), 126.8 (d, J = 2.8 Hz, 1 C), 126.7 (d, J = 3.6
Hz, 1 C), 64.7 (d, J = 7.6 Hz, 1 C), 64.4 (d, J = 7.6 Hz, 1 C), 57.4
(d, JPC = 124.4 Hz, 1 C), 56.5 (s, 1 C), 22.8 (s, 3 C), 16.4 (d, J = 6.8
Hz, 1 C), 16.3 (d, J = 6.0 Hz, 1 C).
Colorless oil; yield: 197 mg (99%); [a]D25 +116.3 (c 1.00, CHCl3).
IR (KBr): 3231, 2980, 1612, 1513, 1467, 1251, 1023, 962, 840, 744
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34 (d, J = 9.0 Hz, 2 H), 6.89 (d,
J = 9.0 Hz, 2 H), 4.74 (dd, J = 14.7, 3.0 Hz, 1 H), 4.41 (dd, J = 8.1,
3.0 Hz, 1 H), 4.10–4.20 (m, 2 H), 3.84–4.00 (m, 2 H), 1.32 (t, J = 7.2
Hz, 3 H), 1.28 (s, 9 H), 1.17 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.0 (s, 1 C), 130.7 (d, J = 6.0
Hz, 2 C), 125.8 (s, 1 C), 113.8 (d, J = 5.2 Hz, 2 C), 64.4 (d, J = 7.4
Hz, 1 C), 64.1 (d, J = 7.5 Hz, 1 C), 60.2 (d, JPC = 121.3 Hz, 1 C),
56.2 (s, 1 C), 55.4 (s, 1 C), 22.8 (s, 3 C), 16.4 (d, J = 6.7 Hz, 1 C),
16.2 (d, J = 6.7 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 92.2 (s, 1 P).
ESI-MS: m/z = 394.1 [M + H]+, 416.1 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 89.8 (s, 1 P).
ESI-MS: m/z = 370.0 [M + H]+, 392.0 [M + Na]+.
Anal. Calcd for C13H24NO3PS3: C, 42.26; H, 6.65; N, 3.79. Found:
C, 42.52; H, 6.62; N, 3.66.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-2-phenyleth-
yl]thiophosphonate (2l)
ESI-HRMS: m/z [M + 23] calcd for C16H28NO4PS2Na+: 416.10934;
found: 416.10896.
Colorless oil; yield: 164 mg (87%); [a]D25 –8.5 (c 1.00, CHCl3).
IR (KBr): 3030, 2980, 2929, 1604, 1474, 1456, 1389, 1365, 1083,
1050, 1026, 962, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.41 (m, 5 H), 4.77 (dd,
J = 15.7, 3 Hz, 1 H), 4.16 (dd, J = 9.3, 3.0 Hz, 1 H), 4.10–4.19 (m,
2 H), 3.90–3.96 (m, 1 H), 3.80–3.85 (m, 1 H), 1.32 (t, J = 3.6 Hz, 3
H), 1.28 (s, 9 H), 1.13 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 137.2 (d, J = 14.0 Hz, 1 C), 129.6
(s, 2 C), 128.4 (s, 2 C), 126.2 (s, 1 C), 64.7 (d, J = 7.6 Hz, 1 C), 63.0
(d, J = 7.6 Hz, 1 C), 59.6 (d, JPC = 117.6 Hz, 1 C), 56.4 (s, 1 C), 37.5
(d, J = 7.6 Hz, 1 C), 22.5 (s, 3 C), 16.2 (d, J = 6.8 Hz, 1 C), 16.1 (d,
J = 4.4 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 96.5 (s, 1 P).
ESI-MS: m/z = 378.1 [M + H]+, 400.1 [M + Na]+.
Diethyl (SS,RC)-(+)-{(tert-Butylsulfinylamino)[4-(dimethylami-
no)phenyl]methyl}thiophosphonate (2i)
Colorless oil; yield: 209 mg (99%); [a]D25 +156.0 (c 1.05, CHCl3).
IR (KBr): 3305, 2979, 2896, 1615, 1525, 1450, 1361, 1074, 1044,
1018, 950, 824, 759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24 (dd, J = 9.0, 3.6 Hz, 2 H),
6.68 (d, J = 9.0 Hz, 2 H), 4.68 (dd, J = 13.8, 3.0 Hz, 1 H), 4.36 (dd,
J = 7.5, 3.0 Hz, 1 H), 4.07–4.17 (m, 2 H), 3.96–3.98 (m, 1 H), 3.83–
3.86 (m, 1 H), 2.96 (s, 6 H), 1.29 (td, J = 6.6, 3.9 Hz, 3 H), 1.24 (s,
9 H), 1.17 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 150.4 (s, 1 C), 130.2 (d, J = 6.0
Hz, 2 C), 120.3 (s, 1 C), 111.8 (2 C, s), 64.1 (d, J = 7.4 Hz, 1 C),
63.7 (d, J = 7.4 Hz, 1 C), 60.2 (d, JPC = 121.4 Hz, 1 C), 55.8 (s, 1 C),
40.3 (s, 2 C), 22.6 (s, 3 C), 16.2 (d, J = 6.4 Hz, 1 C), 16.0 (d, J = 5.9
Hz, 1 C).
HRMS (ESI): m/z [M + 23] calcd for C16H28NO3PS2Na+: 400.1144;
found: 400.1140.
31P NMR (100 MHz, CDCl3): 92.6 (s, 1 P).
ESI-MS: m/z = 398.0 [M + H]+, 420.0 [M + Na]+.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-2-methylpro-
pyl]thiophosphonate (2m)
Anal. Calcd for C17H31N2O3PS2: C, 50.22; H, 7.69; N, 6.89. Found:
C, 50.44; H, 7.78; N, 6.68.
Colorless oil; yield: 157 mg (98%); [a]D25 +89.3 (c 1.00, CHCl3).
IR (KBr): 3246, 2978, 2933, 1474, 1388, 1203, 1087, 793 cm–1.
1H NMR (300 MHz, CDCl3): 4.16–4.25 (m, 5 H), 3.48 (dd, J = 18.6,
8.4 Hz, 1 H), 2.31–2.37 (m, 1 H), 1.24–1.38 (m, 15 H), 0.96–1.00
(m, 6 H).
13C NMR (100 MHz, CDCl3): d = 64.1 (d, J = 8.2 Hz, 1 C), 63.0 (d,
J = 8.2 Hz, 1 C), 62.0 (d, JPC = 112.4 Hz, 1 C), 57.1 (s, 1 C), 29.8
(d, J = 5.9 Hz, 1 C), 23.0 (s, 3 C), 21.2 (d, J = 12.4 Hz, 2 C), 16.3
(d, J = 32.0 Hz, 1 C), 16.1 (d, J = 6.7 Hz, 1 C).
Diethyl (SS,RC)-(+)-{(tert-Butylsulfinylamino)[4-(methylsulfa-
nyl)phenyl]methyl}thiophosphonate (2j)
Colorless oil; yield: 203 mg (99%); [a]D25 +112.8 (c 0.99, CHCl3).
IR (KBr): 3228, 2980, 1598, 1494, 1389, 1080, 1019, 964, 835, 792
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.31 (d, J = 6.0 Hz, 2 H), 7.21 (d,
J = 6.0 Hz, 2 H), 4.73 (dd, J = 12.0, 3.0 Hz, 1 H), 4.41 (dd, J = 6.0,
3.0 Hz, 1 H), 4.10–4.19 (m, 2 H), 3.85–4.00 (m, 2 H), 2.94 (s, 3 H),
1.32 (t, J = 2.1 Hz, 3 H), 1.27 (s, 9 H), 1.16 (t, J = 7.5 Hz, 3 H).
31P NMR (100 MHz, CDCl3): d = 96.4 (s, 1 P).
ESI-MS: m/z = 330.1 [M + H]+, 352.1 [M + Na]+.
13C NMR (100 MHz, CDCl3): d = 139.0 (s, 1 C), 130.4 (s, 1 C),
129.7 (d, J = 6.0 Hz, 2 C), 125.8 (d, J = 2.8 Hz, 2 C), 64.2 (d, J = 7.6
Hz, 1 C), 64.0 (d, J = 7.6 Hz, 1 C), 60.2 (d, JPC = 120.0 Hz, 1 C),
56.1 (s, 1 C), 22.6 (s, 3 C), 16.1 (d, J = 7.6 Hz, 1 C), 16.0 (d, J = 7.6
Hz, 1 C), 15.4 (s, 1 C).
31P NMR (100 MHz, CDCl3): d = 90.5 (1 P, s).
ESI-MS: m/z = 410.0 [M + H]+, 432.0 [M + Na]+.
Anal. Calcd for C12H28NO3PS2: C, 43.75; H, 8.57; N, 4.25. Found:
C, 43.81; H, 8.90; N, 4.04.
Diethyl (R,E)-1-[(S)-1,1-dimethylethylsufinamido]-3-phenyl-
allylphosphonate (2n)
Colorless oil; yield: 164 mg (84%); [a]D25 +129.4 (c 1.01, CHCl3).
IR (KBr): 3228, 2981, 1475, 1449, 1389, 1077, 1022, 794, 742
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43 (d, J = 7.8 Hz, 2 H), 7.30–
7.38 (m, 3 H), 6.75 (dd, J = 15.9, 5.4 Hz, 1 H), 6.00–6.10 (m, 1 H),
Anal. Calcd for C16H28NO3PS3: C, 46.92; H, 6.89; N, 3.42. Found:
C, 46.65; H, 6.96; N, 3.28.
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3936
Z. Chen et al.
PAPER
4.34–4.39 (m, 1 H), 4.10–4.26 (m, 5 H), 1.34 (t, J = 8.4 Hz, 3 H),
1.25–1.30 (m, 12 H).
Anal. Calcd for C17H30NO3PS2: C, 52.15; H, 7.72; N, 3.58. Found:
C, 52.01; H, 8.21; N, 3.42.
13C NMR (100 MHz, CDCl3): d = 136.1 (d, J = 3.4 Hz, 1 C), 128.6
(s, 2 C), 128.3 (d, J = 0.9 Hz, 1 C), 128.2 (s, 1 C), 126.8 (s, 2 C),
126.8 (s, 1 C), 121.7 (d, J = 2.2 Hz, 1 C), 64.0 (d, J = 1.7 Hz, 1 C),
63.8 (d, J = 0.4 Hz, 1 C), 60.0 (d, J = 7.6 Hz, 1 C), 56.0 (s, 1 C), 22.6
(s, 3 C), 16.2 (d, J = 0.2 Hz, 2 C).
31P NMR (100 MHz, CDCl3): d = 91.7 (s, 1 P).
MS (EI): m/z = 390.1 [M + H]+, 412.1 [M + Na]+.
Diethyl (SS,RC)-(+)-[1-(Biphenyl-4-yl)-1-(tert-butylsulfinylami-
no)ethyl]thiophosphonate (4c)
Colorless oil; yield: 203 mg (95%); [a]D25 +84.9 (c 0.99, CHCl3).
IR (KBr): 3248, 3050, 2981, 1599, 1474, 1376, 1077, 1020, 960,
790 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.99–8.01 (m, 1 H), 7.80–7.87 (m,
3 H), 7.69–7.73 (m, 1 H), 7.50–7.53 (m, 2 H), 4.57 (d, J = 6.3 Hz, 1
H), 4.00–4.10 (m, 4 H), 2.25 (d, J = 18.0 Hz, 3 H), 1.33 (s, 9 H),
1.21–1.28 (m, 6 H).
Anal. Calcd for C17H28NO3PS2: C, 52.42; H, 7.25; N, 3.60. Found:
C, 52.47; H, 7.45; N, 3.44.
13C NMR (100 MHz, CDCl3): d = 134.6 (s, 1 C), 132.7 (s, 1 C),
129.0 (s, 1 C), 128.3 (s, 1 C), 127.4 (s, 1 C), 126.9 (s, 1 C), 126.7 (s,
1 C), 126.1 (s, 1 C), 64.4 (d, J = 8.1 Hz, 1 C), 64.2 (d, J = 8.2 Hz, 1
C), 64.3 (d, JPC = 119.1 Hz, 1 C), 57.0 (s, 1 C), 24.5 (s, 1 C), 22.9
(s, 3 C), 16.1 (d, J = 6.0 Hz, 1 C), 16.0 (d, J = 5.2 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 95.5 (s, 1 P).
ESI-MS: m/z = 274.1, 428.2 [M + H]+, 450.2 [M + Na]+.
Stereoselective Synthesis of Diethyl (SS,RC)-(+)-1-(tert-Butyl-
sulfinylamino)alkylthiophosphonates (SS,RC)-4; General Proce-
dure
The appropriate imine 3 (0.5 mmol) was added to a 20-mL Schlenk
flask containing diethyl thiophosphonate (158 mg, 1 mmol) and
K2CO3 (138 mg, 1 mmol) in CH2Cl2 (2.5 mL) at r.t. The mixture
was then stirred for 24 h while carefully monitored by TLC. After
the reaction had gone to completion, H2O (5 mL) was added to
quench it. Then the organic layer was separated and the aqueous
layer was washed with Et2O (3 × 10 mL). The organic layer was
again washed with brine (3 × 10 mL) and dried overnight (Na2SO4).
The solvent was removed under reduced pressure and the residue
was purified by chromatography (silica gel); this afforded the cor-
responding pure (SS,RC)-4.
Anal. Calcd for C20H30NO3PS2: C, 56.18; H, 7.07; N, 3.28. Found:
C, 56.01; H, 7.40; N, 3.16.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(2-naph-
thyl)ethyl]thiophosphonate (4d)
Colorless oil; yield: 127 mg (88%); [a]D25 +85.0 (c 0.96, CHCl3).
IR (KBr): 3242, 2982, 1601, 1488, 1388, 1077, 1019, 961, 845, 786
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61–7.66 (m, 6 H), 7.37–7.49 (m,
3 H), 4.53 (d, J = 6.6 Hz, 1 H), 4.02–4.13 (m, 4 H), 2.16 (d, J = 18.0
Hz, 3 H), 1.33 (s, 9 H), 1.23–1.30 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 140.8 (s, 1 C), 140.6 (s, 1 C),
136.3 (s, 2 C), 129.9 (s, 2 C), 127.7 (s, 2 C), 126.4 (s, 1 C), 64.7 (d,
J = 8.2 Hz, 1 C), 64.6 (d, J = 8.2 Hz, 1 C), 64.2 (d, JPC = 110.9 Hz,
1 C), 57.3 (s, 1 C), 24.5 (s, 1 C), 23.1 (s, 3 C), 16.4 (d, J = 5.2 Hz, 1
C), 16.3 (d, J = 5.9 Hz, 1 C).
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(phenyl)eth-
yl]thiophosphonate (4a)
Colorless oil; yield: 189 mg (99%); [a]D25 +94.3 (c 0.99, CHCl3).
IR (KBr): 2982, 1495, 1474, 1448, 1386, 1079, 1020, 962, 794
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.57 (m, 2 H), 7.33–7.36 (m,
3 H), 4.50 (d, J = 6.6 Hz, 1 H), 3.97–4.15 (m, 4 H), 2.13 (d, J = 18.0
Hz, 3 H), 1.31 (s, 9 H), 1.25 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 137.0 (d, J = 5.2 Hz, 1 C), 129.2
(d, J = 4.4 Hz, 2 C), 127.9 (d, J = 3.7 Hz, 1 C), 127.5 (d, J = 3.0 Hz,
2 C), 64.4 (d, J = 7.4 Hz, 1 C), 64.2 (d, J = 8.2 Hz, 1 C), 64.0 (d,
JPC = 118.3 Hz, 1 C), 57.0 (s, 1 C), 24.1 (s, 1 C), 22.8 (s, 3 C), 16.1
(d, J = 4.5 Hz, 1 C), 16.0 (d, J = 5.9 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 95.7 (s, 1 P).
MS (EI): m/z = 300.1, 454.1 [M + H]+, 476.2 [M + Na]+.
ESI-HRMS: m/z calcd for C22H32NO3PS2Na+: 476.1464; found:
476.1453.
31P NMR (100 MHz, CDCl3): d = 95.7 (s, 1 P).
ESI-MS: m/z = 378.1 [M + H]+, 400.2 [M + Na]+.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-fluorophe-
nyl)ethyl]thiophosphonate (4e)
Anal. Calcd for C16H28NO3PS2: C, 50.91; H, 7.48; N, 3.71. Found:
C, 50.52; H, 7.73; N, 3.56.
Colorless oil; yield: 197 mg (99%); [a]D25 +97.9 (c 1.04, CHCl3).
IR (KBr): 3247, 2982, 1603, 1501, 1475, 1387, 1230, 1165, 1079,
1020, 961, 842, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49–7.54 (m, 2 H), 7.04 (t, J = 8.4
Hz, 2 H), 4.46 (d, J = 6.3 Hz, 1 H), 4.00–4.10 (m, 4 H), 2.11 (d,
J = 18.0 Hz, 3 H), 1.31 (s, 9 H), 1.25 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 163.7 (d, J = 243.9 Hz, 0.5 C),
161.2 (d, J = 243.9 Hz, 0.5 C), 132.7 (s, 1 C), 131.0 (m, 2 C), 114.5
(m, 2 C), 64.4 (d, J = 8.2 Hz, 1 C), 64.2 (d, J = 8.28 Hz, 1 C), 63.6
(d, JPC = 112.4 Hz, 1 C), 57.0 (s, 1 C), 24.2 (s, 1 C), 22.5 (s, 3 C),
16.1 (d, J = 5.2 Hz, 1 C), 16.0 (d, J = 6.0 Hz, 1 C).
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-tolyl)eth-
yl]thiophosphonate (4b)
Colorless oil; yield: 175 mg (90%); [a]D25 +100.2 (c 1.01, CHCl3).
IR (KBr): 3247, 2981, 2960, 1513, 1446, 1386, 1079, 1020, 961,
786 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43 (dd, J = 6.3, 2.4 Hz, 2 H),
7.17 (d, J = 8.4 Hz, 2 H), 4.45 (d, J = 6.0 Hz, 1 H), 3.98–4.13 (m, 4
H), 2.37 (d, J = 2.1 Hz, 3 H), 2.10 (d, J = 17.7 Hz, 3 H), 1.30 (s, 9
H), 1.22–1.28 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 140.0 (d, J = 3.7 Hz, 1 C), 134.1
(d, J = 4.4 Hz, 1 C), 129.3 (d, J = 4.5 Hz, 2 C), 128.6 (d, J = 3.0 Hz,
2 C), 64.6 (d, J = 7.5 Hz, 1 C), 64.4 (d, J = 8.2 Hz, 1 C), 64.2 (d,
JPC = 122.1 Hz, 1 C), 57.2 (s, 1 C), 24.4 (s, 1 C), 23.1 (s, 3 C), 21.3
(s, 1 C), 16.3 (d, J = 4.5 Hz, 1 C), 16.2 (d, J = 6.7 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 95.2 (d, J = 3.7 Hz, 1 P).
19F NMR (282 MHz, CDCl3): d = 114.8 (s, 1 F).
ESI-MS: m/z = 242.1, 396.1 [M + H]+, 418.1 [M + Na]+.
Anal. Calcd for C16H27FNO3PS2: C, 48.59; H, 6.88; N, 3.54. Found:
C, 48.29; H, 7.06; N, 3.40.
31P NMR (100 MHz, CDCl3): d = 95.9 (s, 1 P).
ESI-MS: m/z = 238.1, 392.2 [M + H]+, 414.1 [M + Na]+.
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

PAPER
Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates
3937
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-chloro-
phenyl)ethyl]thiophosphonate (4f)
IR (KBr): 3297, 2879, 1512, 1344, 1082, 1018, 967, 854, 792 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 6.3 Hz, 2 H), 7.72 (d,
J = 6.3 Hz, 2 H), 4.55 (d, J = 7.5 Hz, 1 H), 4.02–4.14 (m, 4 H), 2.16
(d, J = 18.0 Hz, 3 H), 1.31 (s, 9 H), 1.22–1.29 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 147.3 (s, 1 C), 145.1 (d, J = 5.2
Hz, 1 C), 130.1 (d, J = 4.5 Hz, 2 C), 122.5 (d, J = 2.2 Hz, 2 C), 64.7
(d, J = 8.2 Hz, 1 C), 64.5 (d, J = 8.2 Hz, 1 C), 64.2 (1 C, d,
JPC = 118.6 Hz), 57.3 (s, 1 C), 24.2 (s, 1 C), 22.8 (s, 3 C), 16.1 (d,
J = 6.0 Hz, 1 C), 16.0 (d, J = 7.4 Hz, 1 C).
Colorless oil; yield: 184 mg (90%); [a]D25 +94.7 (c 0.98, CHCl3).
IR (KBr): 2982, 1495, 1474, 1448, 1386, 1079, 1020, 962, 794
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (dd, J = 9.0, 3.0 Hz, 2 H),
7.33 (d, J = 9.0 Hz, 2 H), 4.47 (d, J = 6.3 Hz, 1 H), 4.00–4.11 (m, 4
H), 2.10 (d, J = 17.7 Hz, 3 H), 1.30 (s, 9 H), 1.22–1.28 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 136.0 (d, J = 6.0 Hz, 1 C), 134.3
(s, 1 C), 130.8 (d, J = 4.5 Hz, 2 C), 128.0 (d, J = 3.0 Hz, 2 C), 64.7
(d, J = 7.5 Hz, 1 C), 64.5 (d, J = 8.1 Hz, 1 C), 63.9 (d, JPC = 111.7
Hz, 1 C), 57.3 (s, 1 C), 24.4 (s, 1 C), 23.0 (s, 3 C), 16.3 (d, J = 6.0
Hz, 1 C), 16.2 (d, J = 6.0 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 94.9 (s, 1 P).
ESI-MS: m/z = 412.1 [M + H]+, 434.1 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 93.7 (s, 1 P).
ESI-MS: m/z = 393.8, 445.1 [M + Na]+.
Anal. Calcd for C16H27N2O5PS2: C, 45.48; H, 6.44; N, 6.63. Found:
C, 45.70; H, 6.47; N, 6.45.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-cyanophe-
nyl)ethyl]thiophosphonate (4j)
Anal. Calcd for C16H27ClNO3PS2: C, 46.65; H, 6.61; N, 3.40.
Found: C, 46.43; H, 6.62; N, 3.26.
Colorless solid; yield: 202 mg (99%); mp 81–83 °C; [a]D25 +94.3 (c
0.99, CHCl3).
Diethyl (SS,RC)-(+)-[1-(4-Bromophenyl)-1-(tert-butylsulfinyl-
amino)ethyl]thiophosphonate (4g)
IR (KBr): 3308, 2980, 2223, 1608, 1505, 1475, 1456, 1388, 1077,
1023, 972, 851, 798 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (s, 5 H), 4.31 (d, J = 7.5 Hz,
1 H), 4.02–4.12 (m, 4 H), 2.13 (d, J = 18.3 Hz, 3 H), 1.30 (s, 9 H),
1.23 (t, J = 6.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 143.0 (d, J = 5.2 Hz, 1 C), 131.2
(d, J = 4.5 Hz, 2 C), 129.9 (d, J = 4.4 Hz, 2 C), 118.6 (s, 1 C), 111.7
(d, J = 14.8 Hz, 1 C), 64.6 (d, J = 7.5 Hz, 1 C), 64.5 (d, J = 8.2 Hz,
1 C), 64.0 (d, JPC = 114.1 Hz, 1 C), 57.2 (s, 1 C), 24.0 (s, 1 C), 22.7
(s, 3 C), 16.1 (d, J = 5.9 Hz, 1 C), 16.0 (d, J = 6.7 Hz, 1 C).
Colorless solid; yield: 233 mg (99%); mp 102–104 °C; [a]D25 +75.4
(c 0.99, CHCl3).
IR (KBr): 3080, 2982, 1598, 1487, 1455, 1389, 1068, 1020, 968,
857, 792 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (d, J = 7.2 Hz, 2 H), 7.42 (d,
J = 7.2 Hz, 2 H), 4.46 (d, J = 6.6 Hz, 1 H), 4.00–4.11 (m, 4 H), 2.09
(d, J = 18.0 Hz, 3 H), 1.29 (s, 9 H), 1.22–1.28 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 136.3 (d, J = 5.2 Hz, 1 C), 130.9
(d, J = 4.5 Hz, 2 C), 130.7 (d, J = 2.2 Hz, 2 C), 122.3 (s, 1 C), 64.5
(d, J = 7.5 Hz, 1 C), 64.3 (d, J = 8.2 Hz, 1 C), 63.8 (d, JPC = 114.5
Hz, 1 C), 57.0 (s, 1 C), 24.1 (s, 1 C), 22.8 (s, 3 C), 16.1 (d, J = 6.1
Hz, 1 C), 16.0 (d, J = 6.0 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 94.7 (s, 1 P).
MS (EI): m/z = 378.0, 480.2 [M + Na]+.
31P NMR (100 MHz, CDCl3): d = 94.0 (s, 1 P).
MS (ESI): 270.9, 425.1 [M + Na]+, 537.0.
Anal. Calcd for C17H27N2O3PS2: C, 50.73; H, 6.76; N, 6.96. Found:
C, 50.97; H, 6.68; N, 6.81.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(2-sulfanyl-
phenyl)ethyl]thiophosphonate (4k)
Anal. Calcd for C16H27BrNO3PS2: C, 42.11; H, 5.96; N, 3.07.
Found: C, 42.38; H, 5.92; N, 2.89.
Pale yellow oil; yield: 192 mg (99%); [a]D25 +80.3 (c 1.03, CHCl3).
IR (KBr): 3238, 3075, 2982, 2904, 1474, 1386, 1079, 1024, 964,
790 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.35 (m, 1 H), 7.03–7.15 (m,
1 H), 7.00–7.03 (m, 1 H), 4.57 (d, J = 6.3 Hz, 1 H), 4.06–4.15 (m, 4
H), 2.13 (d, J = 17.7 Hz, 3 H), 1.25–1.31 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 142.0 (s, 1 C), 128.0 (d, J = 6.7
Hz, 1 C), 126.5 (d, J = 3.7 Hz, 1 C), 126.4 (d, J = 3.7 Hz, 1 C), 64.7
(d, J = 8.2 Hz, 1 C), 64.4 (d, J = 8.2 Hz, 1 C), 63.1 (d, JPC = 125.1
Hz, 1 C), 57.0 (s, 1 C), 25.0 (s, 1 C), 22.8 (s, 3 C), 16.1 (d, J = 6.7
Hz, 1 C), 16.0 (d, J = 6.7 Hz, 1 C).
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-morpholi-
nophenyl)ethyl]thiophosphonate (4h)
Colorless oil; yield: 231 mg (99%); [a]D25 +79.6 (c 1.03, CHCl3).
IR (KBr): 3245, 3051, 2980, 1611, 1517, 1451, 1382, 1123, 1020,
960, 933, 829, 784 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42 (dd, J = 9.0, 2.7 Hz, 2 H),
6.89 (d, J = 9.0 Hz, 2 H), 4.41 (d, J = 6.3 Hz, 1 H), 4.00–4.10 (m, 4
H), 3.87 (t, J = 4.8 Hz, 4 H), 3.22 (t, J = 4.8 Hz, 4 H), 2.10 (d,
J = 17.4 Hz, 3 H), 1.29 (s, 9 H), 1.22–1.28 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 150.7 (s, 1 C), 130.4 (d, J = 5.2
Hz, 2 C), 127.4 (d, J = 5.9 Hz, 1 C), 114.2 (s, 2 C), 67.1 (s, 2 C),
64.5 (d, J = 7.4 Hz, 1 C), 64.3 (d, J = 8.2 Hz, 1 C), 64.0 (d,
JPC = 123.5 Hz, 1 C), 57.1 (s, 1 C), 48.8 (s, 2 C), 24.5 (s, 1 C), 23.1
(3 C, s), 16.4 (d, J = 6.7 Hz, 1 C), 16.3 (d, J = 6.0 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 93.8 (s, 1 P).
ESI-MS: m/z = 262.9, 384.1 [M + H]+, 406.1 [M + Na]+.
ESI-HRMS: m/z calcd for C14H26NO3PS3Na+: 406.0706; found:
406.0704.
31P NMR (100 MHz, CDCl3): d = 96.0 (1 P, s).
ESI-MS: m/z = 342.1, 485.2 [M + Na]+.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(2-py-
ridyl)ethyl]thiophosphonate (4l)
Colorless oil; yield: 185 mg (98%); [a]D25 +89.8 (c 1.00, CHCl3).
Anal. Calcd for C20H35N2O4PS2: C, 51.93; H, 7.63; N, 6.06. Found:
C, 51.93; H, 8.05; N, 5.82.
IR (KBr): 3464, 3245, 2982, 1575, 1476, 1419, 1380, 1076, 1021,
964, 788 cm–1.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-(4-nitrophe-
nyl)ethyl]thiophosphonate (4i)
1H NMR (300 MHz, CDCl3): d = 8.77–8.78 (m, 1 H), 8.54–8.56 (m,
1 H), 7.81–7.85 (m, 1 H), 7.30–7.32 (m, 1 H), 4.50 (d, J = 6.6 Hz, 1
H), 4.01–4.15 (m, 4 H), 2.13 (d, J = 17.7 Hz, 3 H), 1.30 (s, 9 H),
1.22–1.27 (m, 6 H).
Colorless solid; yield: 211 mg (99%); mp 65–67 °C; [a]D25 +90.1 (c
0.99, CHCl3).
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

3938
Z. Chen et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 150.4 (d, J = 4.5 Hz, 1 C), 148.6
(d, J = 3.7 Hz, 1 C), 136.6 (d, J = 4.5 Hz, 1 C), 133.1 (s, 1 C), 122.4
(d, J = 2.9 Hz, 1 C), 64.6 (d, J = 8.2 Hz, 1 C), 64.3 (d, J = 8.2 Hz, 1
C), 62.8 (d, JPC = 124.8 Hz, 1 C), 57.1 (s, 1 C), 23.8 (s, 1 C), 22.7
(s, 3 C), 16.1 (d, J = 7.5 Hz, 1 C), 15.9 (d, J = 7.4 Hz, 1 C).
31P NMR (100 MHz, CDCl3): d = 100.3 (s, 1 P).
ESI-MS: m/z = 379.1 [M + H]+, 400.1 [M + Na]+.
IR (KBr): 3215, 2985, 1742, 1613, 1469, 1313, 1233, 1132, 1022,
900, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.39 (m 2 H), 6.90–6.92 (m,
2 H), 5.87 (m, 1 H), 4.80 (dd, J = 24.0, 9.9 Hz, 1 H), 4.23–4.29 (m,
2 H), 3.91–3.95 (m, 1 H), 3.83 (s, 3 H), 3.69–3.72 (m, 1 H), 1.36–
1.42 (m, 3 H), 1.28 (s, 9 H), 1.11–1.16 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.7 (s, 1 C), 129.5 (d, J = 1.5
Hz, 2 C), 128.0 (s, 1 C), 114.3 (d, J = 0.6 Hz, 2 C), 63.8 (d, J = 1.9
Hz, 1 C), 60.3 (d, J = 0.4 Hz, 1 C), 55.5 (d, J = 1.7 Hz, 1 C), 54.0 (s,
1 C), 24.3 (s, 3 C), 16.6 (d, J = 1.5 Hz, 1 C), 16.2 (d, J = 1.5 Hz, 1
C).
31P NMR (100 MHz, CDCl3): d = 21.9 (s, 1 P).
ESI-MS: m/z = 394.1 [M + H]+, 416.1 [M + Na]+.
ESI-HRMS: m/z calcd for C15H27N2O3PS2Na+: 401.1080; found:
400.1093.
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-methyl-3-
phenylallyl]thiophosphonate (4m)
Colorless oil; yield: 191 mg (94%); [a]D25 +46.9 (c 0.99, CHCl3).
IR (KBr): 2981, 2958, 1470, 1388, 1079, 1051, 960, 785 cm–1.
ESI-HRMS: m/z [M + 23] calcd for C16H28NO6PSNa+: 416.1265;
found: 416.11267.
1H NMR (300 MHz, CDCl3): d = 4.11–4.25 (m, 4 H), 3.97–4.15 (m,
4 H), 3.92 (d, J = 4.8 Hz, 1 H), 1.82–1.86 (m, 2 H), 1.54 (d, J = 22.4
Hz, 3 H), 1.32–1.45 (m, 10 H), 1.30 (s, 9 H), 0.93 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 136.5 (d, J = 3.7 Hz, 1 C), 133.6
(d, J = 11.9 Hz, 1 C), 128.6 (s, 2 C), 128.1 (s, 1 C), 126.8 (s, 2 C),
126.7 (s, 1 C), 64.4 (d, J = 7.4 Hz, 1 C), 63.8 (d, J = 8.2 Hz, 1 C),
62.7 (d, JPC = 124.3 Hz, 1 C), 56.5 (s, 1 C), 22.6 (s, 1 C), 22.3 (s, 3
C), 16.3 (d, J = 6.7 Hz, 1 C), 16.2 (d, J = 6.0 Hz, 1 C).
HPLC (CHIRALPAK AD-H, 4.6 cm × 250 cm, n-hexane–i-PrOH,
80:20, 0.7 mL/min): tR = 16.5 min (major), 23.2 min (minor), 94%
ee.
Diethyl (1-Aminoalkyl)thiophosphonates 6; General Procedure
The appropriate 2 or 4 (ca. 0.3 mmol) was placed in a round-bot-
tomed glass bottle, and then 4 N aq HCl (3 mL) was added. The soln
was stirred for about 3–6 h, until 2 or 4 had disappeared (by TLC).
After completion of the reaction, the solvent was first removed, and
then excess Et3N was added; again the solvent was removed, and the
residue was subjected to flash chromatography (silica gel, EtOAc–
PE, 1:3 to 1:5); this afforded the corresponding pure 6.
31P NMR (100 MHz, CDCl3): d = 94.2 (s, 1 P).
ESI-MS: m/z = 358.1 [M + H]+, 380.1 [M + Na]+.
+
ESI-HRMS: m/z calcd for C14H33NO3PS2 : 358.1636; found:
358.1634.
Diethyl (R)-[(Amino)(phenyl)methyl]thiophosphonate (6a)
Colorless oil; yield: 75 mg (from 0.30 mmol 2a, 95%); [a]D25 +15.9
(c 1.00, CHCl3).
Diethyl (SS,RC)-(+)-[1-(tert-Butylsulfinylamino)-1-methylpen-
tyl]thiophosphonate (4n)
Colorless oil; yield: 155 mg (87%); [a]D25 +46.9 (c 0.99, CDCl3).
IR (KBr): 3375, 2982, 1602, 1493, 1389, 1160, 1050, 1025, 958,
812 cm–1.
IR (KBr): 2981, 2958, 1470, 1388, 1079, 1051, 960, 785 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.42 (m, 5 H), 4.30 (d,
J = 14.4 Hz, 1 H), 4.02–4.17 (m, 2 H), 3.90–3.93 (m, 1 H), 3.72–
3.74 (m, 1 H), 2.01 (s, 2 H), 1.17–1.32 (m, 3 H), 1.30 (t, J = 8.1 Hz,
3 H), 0.93 (t, J = 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 4.11–4.25 (m, 4 H), 3.97–4.15 (m,
4 H), 3.92 (d, J = 4.8 Hz, 1 H), 1.82–1.86 (m, 2 H), 1.54 (d, J = 22.4
Hz, 3 H), 1.32–1.45 (m, 10 H), 1.30 (s, 9 H), 0.93 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 136.8 (s, 1 C), 127.9 (s, 4 C),
127.4 (s, 1 C), 63.7 (d, J = 7.8 Hz, 1 C), 62.9 (d, J = 7.5 Hz, 1 C),
59.1 (d, JPC = 112.6 Hz, 1 C), 16.1 (d, J = 6.5 Hz, 1 C), 15.8 (d,
J = 6.4 Hz, 1 C).
13C NMR (100 MHz, CDCl3): d = 64.3 (d, J = 2.0 Hz, 1 C), 63.1 (d,
J = 2.0 Hz, 1 C), 60.4 (d, J = 30.1 Hz, 1 C), 56.5 (s, 1 C), 36.3 (d,
J = 1.1 Hz, 1 C), 25.1 (d, J = 2.0 Hz, 1 C), 23.0 (s, 1 C), 22.8 (s, 3
C), 19.8 (s, 1 C), 16.1 (d, J = 1.5 Hz, 2 C), 14.0 (d, J = 1.5 Hz, 1 C).
31P NMR (100 MHz, CDCl3, TMS), d = 97.7 (s, 1 P).
ESI-MS: m/z = 259.9 [M + H]+, 105.9 [MH – HPS(OEt)2]+.
31P NMR (100 MHz, CDCl3): d = 94.2 (s, 1 P).
ESI-MS: m/z = 358.1 [M + H]+, 380.1 [M + Na]+.
ESI-HRMS: m/z calcd for C11H19NO2PS+: 260.0874; found:
260.0869.
+
ESI-HRMS: m/z calcd for C14H33NO3PS2 : 358.1636; found:
358.1634.
Diethyl (R)-[(Amino)(4-methoxyphenyl)methyl]thiophospho-
nate (6b)
Colorless oil; yield: 111 mg (from 0.40 mmol 2h, 97%); [a]D
+13.1 (c 1.01, CHCl3).
Diethyl (RC)-(+)-[(tert-Butylsulfonylamino)(4-methoxyphe-
nyl)methyl]phosphonate (5h)
25
RuCl3·H2O (3 mg, 1.0 mmol%) and NaIO4 (3.65 g, 15 equiv) were
added to a CH2Cl2–MeCN–H2O mixture (1.0:0.04:0.7, 38 mL), and
the resulting mixture was stirred for 1 h. A soln of (SS,RC)-2h (0.45
g, 1 mmol) in CH2Cl2 (2 mL) was added rapidly to the mixture. The
final concentration of (SS,RC)-2h was 0.03 M. When the reaction
was completed, as indicated by TLC (approximately 3.5 h), excess
anhyd MgSO4 was added to remove the H2O, and the mixture was
filtered through a plug of Celite and the solid was washed with
CH2Cl2 before the filtrate was again treated overnight with anhyd
MgSO4. The solvent was removed under reduced pressure and the
residue was subjected to flash chromatography (silica gel, EtOAc–
PE, 1:1); this afforded pure (RC)-5h.
IR (KBr): 3374, 2982, 2837, 1612, 1513, 1465, 1389, 1304, 1251,
1180, 1027, 956, 836 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25 (d, J = 5.6 Hz, 2 H), 6.89 (d,
J = 9.0 Hz, 2 H), 4.17 (d, J = 13.5 Hz, 1 H), 3.99–4.09 (m, 1 H),
3.74–3.81 (m, 1 H), 3.83 (s, 3 H), 3.61–3.72 (m, 1 H), 1.23 (t,
J = 7.2 Hz, 3 H), 1.05 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.1 (s, 1 C), 130.7 (s, 2 C),
129.8 (s, 1 C), 114.3 (s, 2 C), 64.7 (d, J = 7.9 Hz, 1 C), 63.8 (d,
J = 7.8 Hz, 1 C), 57.4 (d, JPC = 113.5 Hz, 1 C), 56.0 (s, 1 C), 17.0
(d, J = 6.3 Hz, 1 C), 16.9 (d, J = 6.4 Hz, 1 C).
Colorless solid; yield: 142 mg (68%); mp 90–95 °C; [a]D25 +24.2 (c
1.02, CDCl3).
31P NMR (100 MHz, CDCl3, H3PO4): d = 97.9 (s, 1 P).
Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York

PAPER
Synthesis of Diethyl (1-Aminoalkyl)thiophosphonates
3939
ESI-MS: m/z = 273.0 [M – CH2]+, 311.9 [M + Na]+.
ESI-HRMS: m/z calcd for C12H20NO3PSNa+: 312.0800; found:
2 C), 127.7 (s, 2 C), 127. 1 (s, 2 C), 126.5 (s, 2 C), 125.1 (s, 1 C),
125.0 (s, 2 C), 119.9 (s, 2 C), 113.7 (s, 2 C), 67.2 (s, 1 C), 64.0 (d,
JPC = 110.0 Hz, 1 C), 60.4 (s, 1 C), 55.0 (s, 1 C), 53.8 (s, 1 C), 50.5
(s, 1 C), 47.0 (s, 1 C), 18.6 (s, 1 C), 16.2 (d, J = 6.5 Hz, 1 C), 15.9
(d, J = 6.9 Hz, 1 C), 14.2 (s, 1 C).
312.0794.
Diethyl (R)-[1-Amino-1-(4-bromophenyl)ethyl]thiophospho-
nate (6c)
Colorless oil; yield: 126 mg (from 0.37 mmol 4g, 97%); [a]D
+37.4 (c 1.00, CHCl3).
IR (KBr): 2982, 1718, 1457, 1367, 1253, 1023, 956, 777 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45 (s, 4 H), 3.99–4.06 (m, 4 H),
1.99 (s, 2 H), 1.71 (d, J = 17.1 Hz, 3 H), 1.21–1.26 (m, 6 H).
31P NMR (100 MHz, CDCl3): d = 92.5 (s, 1 P).
25
ESI-MS: m/z = 429.1 [MH – C15H11NO2(Fmoc)+], 583.1 [M + H]+,
605.0 [M + Na]+.
Anal. Calcd for C30H35NO6PS: C, 61.84; H, 6.05; N, 4.81. Found:
C, 61.77; H, 6.38; N, 4.54.
Compound 7b
13C NMR (100 MHz, CDCl3): d = 140.5 (s, 1 C), 131.6 (s, 2 C),
129.7 (s, 2 C), 122.3 (s, 1 C), 64.8 (d, J = 6.0 Hz, 1 C), 64.7 (d,
J = 5.9 Hz, 1 C), 60.1 (d, JPC = 108.7 Hz, 1 C), 25.9 (d, J = 3.8 Hz,
1 C), 17.0 (s, 1 C), 16.9 (s, 1 C).
31P NMR (100 MHz, CDCl3, H3PO4): d = 100.0 (s, 1 P).
ESI-MS: m/z = 373.9 [M + Na]+, 304.1 [M – EtOH]+.
White solid; yield: 175 mg (from 0.30 mmol 6d, 98%); mp 74–76
°C; [a]D25 –27.5 (c 1.00, CHCl3).
IR (KBr): 3327, 2983, 2229, 1700, 1506, 1451, 1242, 1042, 1020,
963, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 7.8 Hz, 2 H) 7.59 (d,
J = 7.5 Hz, 2 H), 7.47–7.54 (m, 4 H), 7.24–7.37 (m, 5 H), 5.55 (d,
J = 7.2 Hz, 1 H), 4.41 (d, J = 3.9 Hz, 2 H), 4.21–4.32 (m, 2 H),
3.80–4.03 (m, 4 H), 2.06 (d, J = 16.8 Hz, 3 H), 1.39 (d, J = 7.2 Hz,
3 H), 1.09–1.26 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 171.6 (s, 1 C), 171.5 (s, 1 C),
156.2 (s, 2 C), 143.7 (s, 2 C,), 141.3 (s, 2 C), 131.4 (s, 2 C), 128.2
(s, 2 C), 127.5 (s, 2 C), 125.0 (s, 2 C), 120.1 (s, 2 C), 118.8 (s, 1 C),
111.1 (s, 1 C), 64.7 (s, 1 C), 64.7 (d, J = 7.7 Hz, 1 C), 64.5 (d, J = 7.7
Hz, 1 C), 61.9 (d, JPC = 115.6 Hz, 1 C), 51.0 (s, 1 C), 47.0 (s, 1 C),
22.5 (s, 1 C), 16.0 (s, 1 C), 16.0 (s, 1 C).
Anal. Calcd for C12H19BrNO2PS: C, 40.97; H, 5.44; N, 3.98. Found:
C, 41.23; H, 5.43; N, 3.75.
Diethyl (R)-[1-Amino-1-(4-cyanophenyl)ethyl]thiophospho-
nate (6d)
Colorless oil; yield: 203 mg (from 0.69 mmol 4j, 98%); [a]D25 +49.6
(c 1.03, CHCl3).
IR (KBr): 2983, 2229, 1608, 1506, 1388, 1159, 1097, 1045, 1021,
957, 842, 778 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 12.0 Hz, 2 H), 7.63 (d,
J = 11.7 Hz, 2 H), 4.02–4.07 (m, 4 H), 2.07 (s, 2 H), 1.74 (d,
J = 16.8 Hz, 2 H), 1.21–1.27 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 146.5 (s, 1 C), 131.6 (s, 2 C),
128.1 (s, 2 C), 119.1 (s, 1 C), 111.2 (s, 1 C), 64.3 (s, 1 C), 64.2 (s, 1
C), 60.0 (d, J = 108.7 Hz, 1 C), 25.2 (d, J = 2.2 Hz, 1 C), 16.4 (s, 1
C), 16.3 (s, 1 C).
31P NMR (100 MHz, CDCl3, TMS): d = 99.1 (s, 1 P).
ESI-MS: m/z = 145.0 [MH+ – HPS(OEt)2], 321.0 [M + Na]+.
ESI-HRMS: m/z calcd for C13H20N2O2PS+: 299.0974; found:
31P NMR (100 MHz, CDCl3): d = 94.5 (s, 1 P).
ESI-MS: m/z = 392.1 [M + H]+, 614.1 [M + Na]+.
ESI-HRMS: m/z calcd for C31H34N3O5PSNa+: 614.1832; found:
614.1849.
Acknowledgement
The project was supported by the National Nature Science Founda-
tion of China (grant nos. 20672132 and 20872165).
299.0978.
References
Dipeptide-Containing Thiophosphonates 7a and 7b
(1) (a) Williams, R. M. Synthesis of Optically Active a-Amino
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reaction, the soln was filtered to remove the K2CO3, and then the
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White solid; yield: 108 mg (from 0.22 mmol 6b, 85%); mp 69–71
°C; [a]D25 –0.1 (c 1.00, CHCl3).
(b) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9,
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IR (KBr): 3310, 2981, 1667, 1612, 1513, 1251, 1023, 960, 740
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 4.5 Hz, 2 H), 7.53–
7.57 (m, 2 H), 7.24–7.39 (m, 7 H), 6.76 (d, J = 8.7 Hz, 2 H), 5.67
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3.85–3.90 (m, 1 H), 3.69 (s, 3 H), 3.60–3.62 (m, 1 H), 1.43 (d,
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Synthesis 2009, No. 23, 3930–3940 © Thieme Stuttgart · New York