Synthesis of α-amino tetrahydropyranyl-, tetrahydrothiopyranyl-, 4- and 3-piperidinyl-phosphonic acids via phosphite addition to iminium ions

Article abstract of DOI:10.1016/j.tet.2006.05.016

α-Amino cyclobutyl-, cyclopentyl-, cyclohexyl- and 4- and 3-heterocyclohexyl-phosphonates were efficiently prepared from carbocyclic and heterocyclic ketones, by nucleophilic addition of phosphite to the iminium ion formed by in situ condensation of these

Full text of DOI:10.1016/j.tet.2006.05.016

Tetrahedron 62 (2006) 7445–7454
Synthesis of a-amino tetrahydropyranyl-, tetrahydrothiopyranyl-,
4- and 3-piperidinyl-phosphonic acids via phosphite addition
to iminium ions*
*
Nicolas Rabasso, Nicolas Louaisil and Antoine Fadel
´
´
Laboratoire de Syntheꢀse Organique et Methodologie, UMR 8182, Institut de Chimie Moleculaire et des
´
^
´
Materiaux d’Orsay Bat. 420, Universite Paris-Sud, 91405 Orsay, France
Received 3 March 2006; revised 2 May 2006; accepted 10 May 2006
Available online 5 June 2006
Abstract—a-Amino cyclobutyl-, cyclopentyl-, cyclohexyl- and 4- and 3-heterocyclohexyl-phosphonates were efficiently prepared from
carbocyclic and heterocyclic ketones, by nucleophilic addition of phosphite to the iminium ion formed by in situ condensation of these ketones
with benzylic amines. Cleavage of the benzyl groups and acidic hydrolysis of the resulting a-amino heterocyclohexyl-phosphonates gave, in
a three-step sequence from ketones, new 4- and 3-heterocyclohexyl-phosphonic acids.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
by Mannich-type reactions,13 or from cycloalkylphospho-
nates by electrophilic azidation.10b
Due to their potential biological activity1 and their use as
building blocks for phosphorus-containing peptide mi-
metics, derivatives of phosphonic acid analogues of a-amino
acids are of considerable current interest. Several a-amino-
phosphonic acid derivatives show activity as enzyme inhib-
itors, antibacterials, herbicides, fungicides or plant growth
regulators.2 Other a-aminophosphonic acid derivatives, in
particular phosphorus-containing peptide mimetics, have
been prepared. These acid derivatives, in which the tetra-
hedral phosphorus moiety acts as a transition-state analogue
of peptide bond cleavage, selectively inhibit peptidases and
proteinases (e.g., HIV protease,3 serine protease4). Such an
impressive array of applications has recently stimulated
considerable effort towards the asymmetric synthesis of
a-aminophosphonic acids.5–7
However, very few examples of heterocyclic a-aminophos-
phonic acids 2 or the corresponding phosphonates have
been reported in the literature; only the 4-aminobutyric
acid (GABA)14 analogue 2a (X¼NH),15 the pyran phospho-
nate derivative of 2b (X¼O)16 and thiopyran phosphonate
derivative of 2c (X¼S) are described.17 Among these syn-
thetic approaches, only one describes a total synthesis and
isolation of free a-amino(4-pyrrolidine)phosphonic acid 2a
(X¼NH).15c In contrast, pyran acid 2b, thiopyran acid 2c
and especially 3-pyrrolidine acid analogue 3 are still un-
known. In all these synthetic approaches, the Kabachnick–
Fields reaction16a was used from heterocyclohexanones, to
provide a-aminophosphonates with moderate to good yields,
accompanied, in some cases, with a-hydroxyphosphonate
derivatives as byproducts (Scheme 1).
In addition, cyclic or heterocyclic rings introduced into the
molecular skeleton increase its rigidity and modify elec-
tronic effects. Thus in recent years, many cyclic a-amino-
phosphonic acids 1 (R¼H) or -phosphonates 1 (R¼alkyl)
have been prepared, such as derivatives of a-aminocyclopro-
pylphosphonic acid,8–10 as well as their cyclobutyl,10b cyclo-
pentyl11 and cyclohexyl analogues.12 These compounds
were prepared either from cycloalkanones or derivatives
O
O
O
P(OR)2
NHR'
P(OH)2
NH2
P(OH)2
NH2
X
( )n
HN
R = H, alkyl
R' = H, alkyl
n = 0, 1, 2, 3
2a: X= NH
b: X= O
c: X= S
3
1
Scheme 1.
*
Part of this study was previously reported at the Organic Chemistry
We have previously reported a simple and convenient syn-
thesis of 1-aminocyclopropanephosphonic acids 4 (ACC
analogues), in three steps, starting from cyclopropanone
Symposium at Marseille (GECO 46, September 2005), France.
* Corresponding author. Tel.: +33 1 69 15 72 52; fax: +33 1 69 15 62 78;
e-mail: antfadel@icmo.u-psud.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.016

7446
N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
hemi-acetals 5 and proceeding via aminophosphonates 6
(Scheme 2).9
19d, were selected for their efficient reaction to form the
iminium ions A, and in particular for their straightforward
cleavage by catalytic hydrogenolysis at the end of the syn-
thetic sequence. In addition, the phenylglycinol derivative
can be cleaved by an oxidative degradation with NaIO4,
whereas, the p-methoxybenzyl group can be cleaved by
a DDQ oxidation followed by basic hydrolysis.
O
O
OEt
OEt
OH
OH
P(OEt)3,
EtOH
OH
P
P
R
R
R
R*NH2,
AcOH
OEt
HN R*
NH2
5
6
4
Scheme 2.
The standard one-pot procedure of ketones 7–12 with amine
derivatives 19 was carried out in EtOH in the presence of
2 equiv of AcOH, 1 equiv of MgSO4 and 1.5 equiv of triethyl
phosphite at 50–60 ꢀC for 1 day. The commercially available
heterocyclic ketones 7–9 were reacted with benzylamine
derivatives 19a–d, to give the iminium ion intermediates A
before triethyl phosphite addition to furnish aminophospho-
nates 13–15 in good yields (46–92%) (Table 1, entries 1–7).
As part of our ongoing programme in this area, we decided to
study the addition of triethyl phosphite to the iminium ions A
of readily available heterocyclic ketones 7–12. This one-pot
reaction, involving the iminium species A as intermediate,
should occur in the presence of benzylamine derivatives to
give the desired aminophosphonates 13–18 (Scheme 3).
By comparison, conducting the same reaction with cyclic
ketones (cyclohexanone 10 and cyclobutanone 12), in
EtOH for 1–4 days, gave the corresponding aminophospho-
nates 16 and 18 in good yields (93% and 50%, respectively)
(Table 1, entries 8 and 10). However, lower yields were
obtainedforaminophosphonates16–18inDMSOasasolvent
in the presence of MgSO4 at 55 ꢀC for 2 days (Table 1, entries
8–10). These new aminophosphonates 16–18 are of particu-
lar interest, since the dibutyl phosphonate analogue of 16,
known as TrakephonÒ, is a highly efficient herbicide.12a,b
O
O
P(OEt)2
NHR
13-18
P(OH)2
NH2
X
( )n
X
( )n
2
n = 0,1
P(OEt)3
H
X
( )n
X
O
N
R
( )n
7-12
A
X = NCH3, S, O, CH2
Scheme 3.
On the other hand, the commercially available N-Boc-3-
piperidone 20a, in which the heteroatom is in the 3-position
to the carbonyl function, underwent a one-pot reaction with
amine 19a to give aminophosphonate 21a, for the first time,
in 54% yield as a mixture of two diastereoisomers. However,
with the benzylamine 19b aminophosphonate 21a0 was
2. Results and discussion
The reactions were carried out using a one-pot procedure.
Benzylamine derivatives, a-methylbenzylamine 19a, benzyl-
amine 19b, a-phenylglycinol 19c and p-methoxybenzylamine
Table 1. Preparation of aminophosphonates 13–18 from ketones 7–12a
O
OEt
i. RNH2 19, solvent, AcOH
ii. P(OEt)3, 60 °C, 1–2 days
P
OEt
NH-R
X
O
X
( )n
( )n
7-12
13-18
Entry
Ketone 7–12
RNH2 19a–db
Solvent
Time
(h)
Yield (%)
Phosphonates
13–18
EtOH (DMSO)c
n
X
P(O)(OEt)2
1
2
7
7
2
2
N-Me
N-Me
19a
19a
EtOH
18
18
71 (36)
30
13
13
Toluene/CH3CNd
N
H
N
Ph
P(O)(OEt)2
N
3
8
2
O
19a
EtOH
30
66
14a
O
H
Ph
P(O)(OEt)2
N
4
5
8
9
2
2
O
S
19b
19a
EtOH
EtOH
22
18
55
92
14b
15a
O
H
Ph
P(O)(OEt)2
N
S
H
Ph
(continued)

N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
7447
Table 1. (continued)
Entry
Ketone 7–12
RNH2 19a–db
Solvent
EtOH
Time
(h)
Yield (%)
Phosphonates
13–18
EtOH (DMSO)c
n
X
P(O)(OEt)2
OH
6
7
8
9
9
2
S
19c
39
24
46
15b
15c
16
N
H
S
S
Ph
P(O)(OEt)2
9
2
2
1
0
S
19d
19a
19a
19a
EtOH
EtOH
DMSO
EtOH
80
N PMB
H
P(O)(OEt)2
N
10
11
12
CH2
CH2
CH2
20
93 (43)
NRe (76)
50 (30)
H
Ph
P(O)(OEt)2
N
48
17
H
Ph
P(O)(OEt)2
10
100
18
HN
Ph
a
Reactions of ketones 7–12 with amines 19 were carried out in the presence of MgSO4.
Amines, 19a: H2N–CH(CH3)Ph; 19b: H2N–CH2Ph; 19c: H2N–CH(CH2OH)Ph; 19d: H2N–CH2C6H4–pOMe.
Reactions in DMSO were run at 55 ꢀC for 2 days.
The reaction was run with HP(O)(OEt)2 and catalyzed with 5 mol % of Me2AlCl (Ref. 18).
NR¼not run.
b
c
d
e
obtained in 76% yield. In contrast, the N-benzyl-
3-piperidone 20b did not lead to the expected phosphonate
21b, but to a mixture of degradation products (Scheme 4).
22a–c, but none among them gave the corresponding
aminophosphonates 23a–c under these conditions. We can
tentatively explain this by the fact that the iminium interme-
diate B is not favoured, and undergoes a double bond migra-
tion to the heterocyclic enamines C and D, thus preventing
the nucleophilic attack of the phosphite on imine B. Such
migration has already been reported,19 and could allow elec-
trophilic reaction of enamine C or D (Scheme 5).20
O
OEt
P
O
OEt
i. RNH2, AcOH
NHR
ii. P(OEt)3, EtOH, 60 °C
N
N
R'
R'
We then submitted the heterocyclic phosphonates 13–15 to
the deprotection sequence. The aminophosphonates 13 and
14a reacted under mild conditions (20% Pd(OH)2/C, and
1 atm H2) to cleave the benzyl group affording free amino-
phosphonates 24 and 25, in a good yield (Scheme 6).
R = CH(CH3)Ph, 21a (54%)
R = CH2Ph, 21a' (76%)
R = CH(CH3)Ph, 21b (0%)
20a : R'= Boc
20b : R'= Bn
Scheme 4.
Subsequent hydrolysis of aminophosphonate 24 was accom-
plished by 6 N HCl solution at reflux for 7 h, followed by
To better understand this behaviour, we attempted to react
a-methylbenzylamine 19a with 3-heterocyclopentanones
Nu
E
O
RNH2
19a
OEt
P
R
N
R
R
P(OEt)3
O
OEt
N
N
H+
X
X
X
X
NHR
H
X
H
D
22a : X = N-CO2Et
22b : X = O
22c : X = S
B
23a–c
C
E
R = CH(CH3)Ph
Scheme 5.
O
O
O
P(OEt)2
a) TMSI or HCl,
∆
P(OEt)2
H2, Pd(OH)2/C
AcOH, 18 h
P(OH)2
X
X
X
N
H
O
NH2
b) then ,
NH2
Ph
13 : X = NCH3
14a : X = O
24
25
73%
86%
2a
2b
98%
43%
Scheme 6.

7448
N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
treatment with propylene oxide to provide, the previously
unknown N-methyl-4-aminopiperidine-phosphonic acid 2a.
Surprisingly, hydrolysis of the phosphonate moiety of 24
with TMSI led only to the formation of byproducts with
a small amount of the desired acid 2a. On the other hand,
treatment of aminophosphonate 25 with the trimethylsilyl
iodide in dichloromethane followed by the addition of
propylene oxide in ethanol furnished, for the first time,
aminophosphonic acid 2b in 43% yield.
TMSBr followed by propylene oxide treatment gave a mix-
ture of acid 2c and degradation products. It is worthy of note
that the NMR spectra of 2a in D2O solution showed two
diastereomers, due to the pyramidalization of the nitrogen
atom in acidic medium, as previously described by
Kafarski.15c Deprotection of the ring nitrogen in neutral or
basic solution speeds up the nitrogen inversion and makes the
whole process faster. Thus, the coalescence of the two
singlets in 31P NMR was observed on addition of NaOD to
the solution, and forming 2a sodium salt (Scheme 9, see also
Section 4).
N-Benzyl cleavage of 15a (X¼S) was unsuccessful under
the same conditions (H2, Pd(OH)2/C, AcOH), or with other
known debenzylation procedures (H2, Pd/C, HCl; Na/NH3
liq. or Na/naphthalene). Knowing that the sulfur group could
poison the palladium catalyst, we oxidized 15a by mCPBA
(1 equiv) to afford a mixture of unseparable sulfoxides 27
(cis/trans: 37/63) in 91% yield. Subsequent hydrogenolysis
(H2, Pd(OH)2/C) of this cis/trans 27 mixture did not furnish
the expected free amine 28 (cis/trans), returning the starting
sulfoxides unreacted (Scheme 7). Similarly, an attempted
cleavage of the phenylglycinol group of 15b by a known
oxidative degradation with Pb(OAc)421 did not furnish 26.
O
O
NH3
P
O
O
O
P
O
NH3
N
H
N
H
cis
trans
H+
H+ NaOD
NH2
NaOD
O
ONa
ONa
P
ONa
ONa
P
N
inversion
NH2
N
O
O
P
2a sodium salt
O
P
OEt
OEt
OEt
OEt
H2
Scheme 9.
X
X
HN
Pd(OH)2/C
NH2
Ph
15a X = S
26 X = S
mCPBA
91%
On the other hand, in the 3-heterocyclic system, cleavage of
the benzyl group of compounds 21a or 21a0 under mild
conditions (20% Pd(OH)2/C and 1 atm H2) furnished the
corresponding free amine 30 in good yield 76% or 88%,
respectively. Phosphonate hydrolysis and Boc deprotection
of 30 were accomplished simultaneously in 6 N aq HCl solu-
tion at reflux, to give quantitatively the amino acid hydro-
chloride 3$2HCl. Treatment of this amino acid salt with
27 X = SO (cis/trans)
28 X = SO
Scheme 7.
Nevertheless, cleavage of 15c (Table 1, entry 6) by DDQ
(H2O/CH2Cl2: 1/9) at 20 ꢀC,22 provided, after purification
on silica gel, the corresponding free aminophosphonate 26,
accompanied by imine 29 (Scheme 8). However, treatment
O
P
O
P
O
OEt
OEt
OEt
OEt
P(OH)2
1) DDQ
2) KOH
PhCO-NHNH2
88%
12N HCl
90%
S
26
S
S
CH2Cl2/
H2O
NH2
N
HN
PMB
2c
15c
PMB = p-methoxybenzyl
29
O
Scheme 8.
ofthereaction mixturewith2 NKOH inthepresenceofbenz-
oyl hydrazine, to trap the highly reactive p-anisaldehyde,
furnished exclusively the desired aminophosphonate 26 in
88% yield.
propylene oxide provided for the first time the racemic
free aminophosphonic acid 3 in excellent yield. However,
the use of TMSI for hydrolysis of 30 was ineffective once
more (Scheme 10).
O
OEt
OEt
P
PO3H2
21a
H2, Pd(OH)2/C
AcOH, 18 h
58 – 88%
a) 6N HCl, reflux
or
NH2
NH2
O
b) then ,
98%
21a'
N
Boc
N
H
3
30
Scheme 10.
Hydrolysis of 26 with 12 N HCl solution at reflux, followed
by treatment with propylene oxide provided the new 4-tetra-
hydrothiopyranylphosphonic acid 2c, in quantitative yield.
We found that hydrolysis of phosphonate 26 with TMSI or
3. Conclusion
We have developed an easy and efficient three-step synthesis
of new heterocyclic a-aminophosphonic acids 2 and 3. Thus,

N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
7449
starting from readily available cyclic and heterocyclic ke-
tones 7–12 and 20, we have demonstrated that the iminium
ion formed from these ketones undergoes nucleophilic addi-
tion of phosphite to give the cyclic and heterocyclic amino-
phosphonates 13–18 and 21 in good yield. Subsequent
hydrogenolysis of the benzyl group (for tetrahydropyran
14 and piperidine derivatives 13 and 21) and hydrolysis of
phosphonate functions were accomplished with good yields.
However, deprotection of the N-PMB group (for the tetra-
hydrothiopyran derivative) required oxidation with DDQ.
The stable cyclic aminophosphonates 16–18, analogues of
the biologically active molecule TrakephonÒ, were not
transformed into their corresponding aminophosphonic
acids, but may be performed straightforwardly using a repor-
ted method.9c We are currently developing an asymmetric
version to prepare the homochiral 3-heterocyclic amino-
phosphonic acids.
4.2.1. Diethyl 4-(10-methylbenzyl)amino-1-methylpiperi-
din-4-yl-phosphonate (13). Following procedure A:
reaction of N-methylpiperidin-4-one 7 (545 mg, 5 mmol),
EtOH (10 mL), a-methylbenzylamine 19a (910 mg,
7.50 mmol), MgSO4 (420 mg), AcOH (600 mL, 10 mmol)
and P(OEt)3 (1.25 g, 7.5 mmol) for 18 h at 55 ꢀC gave, after
standard work-up and purification by FC (eluent, MeOH/
CH2Cl2/NH3: 2/98/1), 1.260 g (71%) of aminophosphonate
13 as a colourless oil. Rf¼0.65 (MeOH/CH2Cl2: 50/50+
2% NH3 aq). IR (neat) n: 3449, 3353, 2932, 1235 (P]O),
1050 and 1025 (P–O), 957 cmꢁ1 1H NMR (CDCl3,
.
360 MHz) d: 1.30 (t, J¼7.2 Hz, 3H, CH3–CH2O), 1.33 (t,
0
J¼7.2 Hz, CH3–CH2O), 1.33 (d, J¼6.8 Hz, 3H, CH3–C1 ),
1.42–1.90 (m, 5H, 4Hcycle and NH), 1.90–2.20 (m, 2Hcycle),
2.10 (s, 3H, CH3N), 2.30–2.60 (m, 2H, 1H–C2 and 1H–C6),
2
4.10 (qd, J¼7.2 Hz, JPC¼7.2 Hz, 2H, CH2OP), 4.13 (qd,
2
J¼7.2 Hz, JPC¼7.2 Hz, 2H, CH2OP), 4.44 (qd, J¼6.8 Hz,
4
JPH¼2.5 Hz, 1H–C1 ), 7.08–7.48 (m, 5H). 13C NMR
0
(CDCl3, 62.9 MHz) d: 16.6 (CH3–CH2O), 16.7 (CH3–
0
2
4. Experimental
4.1. General
CH2O), 27.0 (CH3–C1 ), 27.9 (d, JPC¼4.1 Hz, C3 or C5),
3
32.6 (s, C5 or C3), 46.2 (CH3N), 49.4 (d, JPC¼12.1 Hz,
3
0
C2 or C6), 49.55 (d, JPC¼9.8 Hz, C6 or C2), 52.5 (C1 ),
1
2
54.8 (d, JPC¼143.1 Hz, C4), 61.7 (d, JPC¼8.0 Hz,
2
Except where otherwise indicated, all reactions were carried
out under argon with magnetic stirring. Di- and triethylphos-
phite were distilled at reduced pressure and stored under
argon (see Table 1). Rf values refer to TLC on 0.25 mm silica
gel plates (Merck F254). Flash chromatography (FC) was
performed on silica gel 60 (0.040–0.063 mm). Yields refer
to chromatographically and spectroscopically pure com-
pounds, except where noted. IR spectra were recorded on
a Perkin–Elmer (spectrum one) spectrophotometer. Melting
CH2OP), 61.9 (d, JPC¼8.0 Hz, CH2OP), [6 arom C: 126.3
(1C), 126.8 (2C), 128.0 (2C), 148.4 (s)]. 31P NMR
(CDCl3, 101.25 MHz) d: 29.51. ES+ MS, m/z: 377.2
[M+Na]+. HRMS data were not obtained.23
4.2.2. Diethyl 4-(10-methylbenzyl)amino-tetrahydro-2H-
pyran-4-yl-phosphonate (14a). Following procedure A:
reaction of tetrahydropyran-4-one 8 (172 mg, 1.72 mmol),
EtOH (4.5 mL), a-methylbenzylamine 19a (330 mL,
2.68 mmol), MgSO4 (155 mg), AcOH (200 mL, 3.43 mmol)
and P(OEt)3 (442 mL, 2.58 mmol) for 30 h at 55 ꢀC furnished,
after standard work-up and purification by FC (eluent,
MeOH/CH2Cl2/NH3: 2/98/0.5), 387 mg (66%) of tetra-
hydropyranphosphonate 14a as a colourless oil. Rf¼0.35
(MeOH/CH2Cl2: 5/95). IR (neat) n: 3468, 3333, 1233
(P]O), 1047 and 1026 (P–O), 950. 1H NMR (CDCl3,
250 MHz) d: 1.37 (t, J¼7.0 Hz, 3H, CH3–CH2O), 1.40 (t,
J¼7.0 Hz, CH3–CH2O), 1.41 (d, J¼6.8 Hz, 3H, CH3),
1.30–1.70 (m, 3H, 2Hcycle and NH), 1.70–1.90 (m, 1Hcycle),
1.90–2.28 (m, 1Hcycle), 3.06–3.35 (m, 2Hcycle, CH2O),
points were determined on a Buchi B-545 capillary melting
¨
point apparatus and are uncorrected. 1H NMR spectra were
measured on a Bruker AM250 (250 MHz) or Bruker AC360
(360 MHz) spectrometer. Chemical shifts were recorded in
parts per million from the solvent resonance (CDCl3 at
7.27 ppm and D2O at 4.8 ppm). 13C NMR spectra were mea-
sured on a Bruker AM250 (62.9 MHz), or Bruker AC360
(90.56 MHz) spectrometer. Chemical shifts were recorded
in parts per million from the solvent resonance (CDCl3 at
77.16 ppm). 31P NMR spectra were recorded on a Bruker
AM250 (101.25 MHz), and chemical shifts were quoted
relative to internal 85% H3PO4 (d¼0 ppm). Mass spectra
were recorded on a Finnigan DSQ-Thermo. High-resolution
mass spectra were recorded on a Finnigan MAT 95S. All new
compounds were determined to be >95% pure by 1H NMR
spectroscopy.
3.61–3.77 (m, 1Hcycle, CH2O), 3.98 (tt, J¼10.7 Hz, J¼
3
1.9 Hz, 1Hcycle, CH2O), 4.16 (qd, J¼7.3 Hz, JPH
¼
3
7.0 Hz, 2H, CH2OP), 4.22 (qd, J¼7.3 Hz, JPH¼7.0 Hz,
4
0
2H, CH2OP), 4.49 (qd, J¼6.8 Hz, JPH¼2.8 Hz, 1H–C1 ),
7.10–7.25 (m, 1H), 7.25–7.36 (m, 2H), 7.36–7.50 (m, 2H).
13C NMR (CDCl3, 62.9 MHz) d: 16.5 (q, CH3–CH2O),
2
0
4.2. General procedure A
16.6 (q, CH3–CH2O), 26.8 (CH3-C1 ), 27.8 (d, JPC¼2.2 Hz,
1
0
C3 or C5), 32.8 (C5 or C3), 52.8 (C1 ), 55.0 (d, JPC
¼
2
To a solution of heterocyclic ketones 7–12 or 20 (5 mmol) in
EtOH (10 mL), was added benzylamine 19 (7.50 mmol),
AcOH (600 mL, 10 mmol) and MgSO4 (420 mg, 3.50
mmol). After stirring and heating at 55 ꢀC for 4–5 h, P(OEt)3
(1.25 g, 1.31 mL, 7.50 mmol) was added. The mixture
was heated at 55 ꢀC for 1–3 days. It was then concentrated
in vacuo, concd aq ammonia (2 mL) was added and the
resulting mixture was filtered through a 3 cm pad of silica
gel eluting with ethyl acetate (50 mL). The filtrate was
concentrated in vacuo to give the crude phosphonate. Purifi-
cation by flash chromatography (FC) on silica gel (MeOH/
CH2Cl2: 1/9) gave pure aminophosphonates 13–18 or 21.
144.3 Hz, C4), 61.7 (d, JPC¼7.3 Hz, CH2OP), 61.8 (C2 or
2
C6), 61.9 (C6 or C2), 62.0 (d, JPC¼7.6 Hz, CH2OP), [6
arom C: 126.4 (d), 126.6 (d, 2C), 128.1 (d, 2C), 148.0 (s)].
31P NMR (CDCl3, 101.25 MHz) d: 28.35. HRMS (ESI,
m/z): calcd mass for C17H28O4NPNa, [M+Na]+: 364.1648.
Found: 364.1653.
4.2.3. Diethyl 4-(benzylamino)-tetrahydro-2H-pyran-4-
yl-phosphonate (14b). Following procedure A: reaction
of tetrahydropyran-4-one 8 (200 mg, 2.0 mmol), EtOH
(5.0 mL), benzylamine 19b (325 mL, 2.98 mmol), MgSO4
(180 mg), AcOH (230 mL, 3.96 mmol) and P(OEt)3

7450
N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
(493 mL, 2.97 mmol) for 22 h at 50 ꢀC provided, after
standard work-up and purification by FC (eluent, MeOH/
CH2Cl2/NH3: 2/98/0.5), 354 mg (55%) of tetrahydropyran-
phosphonate 14b as a colourless oil. Rf¼0.42 (MeOH/
CH2Cl2: 10/90). IR (neat) n: 3468, 3312, 1240 (P]O),
1047 and 1027 (P–O), 958. 1H NMR (CDCl3, 250 MHz) d:
1.37 (t, J¼7.0 Hz, 6H, CH3), 1.50–1.70 (m, 2H, 1H–C3
and 1H–C5), 1.94–2.17 (m, 3H, 1H–C3, 1H–C5 and 1NH),
3.54–3.71 (m, 2H, 1H–C2 and 1H–C6), 3.77–3.95 (m, 4H,
2Hbenzyl, 1H–C2 and 1H–C6), 3.95–4.24 (m, 4H, 2CH2OP),
7.10–7.43 (m, 5H). 13C NMR (CDCl3, 62.9 MHz) d: 16.5
(q, CH3), 16.6 (q, CH3), 29.8 (C3 and C5), 47.1 (CH2–N),
53.4 (d, JPC¼146.7 Hz, C4), 61.6 (d, JPC¼2.7 Hz,
2CH2OP), 61.8 (C2 and C6), [6 arom C: 126.8 (d), 128.0
(2C), 128.2 (2C), 140.8 (s)]. 31P NMR (CDCl3,
101.25 MHz) d: 27.60. HRMS (ESI, m/z): calcd mass for
C16H26NO4PNa, [M+Na]+: 350.1492. Found: 350.1496.
J¼7.0 Hz, 2H, CH2O), 4.15 (dq, J¼7.2 Hz, J¼7.0 Hz, 2H,
13C NMR (CDCl3, 62.9 MHz) d: 16.5 (CH3), 16.55 (CH3),
0
CH2O), 4.30–4.46 (m, 1H–C1 ), 7.08–7.50 (m, 5H arom).
2
2
21.5 (d, JPC¼14.1 Hz, C2 or C6), 21.7 (d, JPC¼10.8 Hz,
3
C6 or C2), 29.1 (d, JPC¼4.0 Hz, C3 or C5), 33.6 (C5 or
1
0
C3), 56.7 (d, JPC¼141.0 Hz, C4), 58.9 (C1 ), 61.9 (d,
2JPC¼8.2 Hz, CH2O), 62.4 (d, JPC¼8.2 Hz, CH2O), 68.1
2
(CH2OH), [6 arom C: 127.0 (1C), 127.2 (2C), 128.2 (2C),
143.4 (s)]. 31P NMR (CDCl3, 101.25 MHz) d: 29.58.
HRMS (ESI, m/z): calcd mass for C17H28NO4PSNa,
[M+Na]+: 396.1369. Found: 396.1363.
1
2
4.2.6. Diethyl 4-(4-methoxybenzyl)amino-tetrahy-
dro-2H-thiopyran-4-yl-phosphonate (15c). Following
procedure A: condensation reaction of tetrahydrothio-
pyran-4-one 9 (618 mg, 5.39 mmol), EtOH (14 mL),
p-methoxybenzylamine 19d (1.04 mL, 8.0 mmol),
MgSO4 (480 mg) and AcOH (590 mL, 10.66 mmol) was
stirred and heated for 17 h). Then addition of P(OEt)3
(1.37 mL, 8.0 mmol), (24 h at 50 ꢀC) gave, after standard
work-up and purification by FC (eluent, MeOH/CH2Cl2/
NH3: 2/98/0.5), 1.60 g (80%) of PMB aminophosphonate
15c as a colourless oil. Rf¼0.74 (MeOH/CH2Cl2: 10/90).
IR (neat) n: 3463, 3318, 2977, 1510, 1243 (P]O), 1044,
4.2.4. Diethyl 4-(10-methylbenzyl)amino-tetrahydro-2H-
thiopyran-4-yl-phosphonate (15a). Following procedure
A: reaction of tetrahydrothiopyran-4-one 9 (430 mg,
4.75 mmol), EtOH (12 mL), a-methylbenzylamine 19a
(910 mL, 7.13 mmol), MgSO4 (420 mg, 3.5 mmol), AcOH
(520 mL, 9.50 mmol) and P(OEt)3 (1.22 g, 7.13 mmol) for
20 h at 50 ꢀC gave, after standard work-up and purification
by FC (eluent, MeOH/CH2Cl2/NH3: 1/99/0.5), 1.560 g
(92%) of thiopyran phosphonate 15a as a colourless oil.
Rf¼0.57 (MeOH/CH2Cl2: 5/95). IR (neat) n: 3457, 3333,
1
954. H NMR (CDCl3, 250 MHz) d: 1.35 (t, J¼7.0 Hz,
3H, CH3), 1.80 (br s, NH), 2.00–2.24 (m, 4H, 2H–C3
and 2H–C5), 2.29 (d, J¼12.7 Hz, 2H, 1H–C2 and 1H–
C6), 3.26 (ddd, J¼2.5 Hz, J¼12.2 Hz, J¼12.7 Hz, 2H,
1
4
2982, 1210 (P]O), 1055 and 1026 (P–O), 954. H NMR
1H–C2 and 1H–C6), 3.83 (s, 3H, OMe), 3.87 (d, JPH
3.0 Hz, 2H, CH2–N), 4.14 (dq, JPH¼7.2 Hz, J¼7.0 Hz,
¼
3
(CDCl3, 250 MHz) d: 1.38 (t, J¼7.0 Hz, 3H, CH3–CH2O),
3
0
1.39 (t, J¼6.8 Hz, 3H, CH3–C1 ), 1.40 (t, J¼7.0 Hz, 3H,
2H, CH2O), 4.17 (dq, JPH¼7.2 Hz, J¼7.0 Hz, 2H,
CH3–CH2O), 1.67 (br s, 1H, NH), 1.78–2.24 (m, 5Hcycle),
2.24–2.50 (m, 2Hcycle), 3.28 (tt, J¼12.7 Hz, J¼2.0 Hz,
CH2O), 6.87 (like d, J¼8.5 Hz, 2Haryl), 7.32 (like
d, J¼8.5 Hz, 2Haryl). 13C NMR (CDCl3, 62.9 MHz)
d: 16.45 (CH3), 16.5 (CH3), 21.2 (C2 or C6), 21.4 (C6
or C2), 30.5 (C3 and C5), 46.0 (CH2–N), 54.8 (d,
1JPC¼141.6 Hz, C4), 55.0 (CH3O), 61.7 (CH2O), 61.8
(CH2O), [6 arom C: 113.6 (2C), 129.1 (2C), 132.7 (s),
158.5 (s)]. 31P NMR (CDCl3, 101.25 MHz) d: 28.22.
HRMS (ESI, m/z): calcd mass for C17H28NO4PSNa,
[M+Na]+: 396.1369. Found: 396.1365.
2
1H–C2 or 1H–C6), 4.16 (qd, J¼7.0 Hz, JPH¼7.0 Hz, 2H,
2
CH2OP), 4.22 (qd, J¼7.0 Hz, JPH¼6.5 Hz, 2H, CH2OP),
4
0
4.46 (qd, J¼6.8 Hz, JPH¼2.5 Hz, 1H–C1 ), 7.14–7.24 (m,
1H), 7.24–7.35 (m, 2H), 7.35–7.50 (m, 2H). 13C NMR
(CDCl3, 62.9 MHz) d: 16.5 (CH3–C–O), 16.6 (CH3–C–O),
2
2
21.5 (d, JPC¼13.7 Hz, C2 or C6), 21.7 (d, JPC¼10.6 Hz,
0
C6 or C2), 26.8 (CH3–C1 ), 29.0 (C3 or C5), 33.7 (C5 or
1
0
C3), 52.4 (C1 ), 56.6 (d, JPC¼141.0 Hz, C4), 61.7 (d,
2JPC¼7.5 Hz, CH2OP), 61.9 (d, JPC¼7.7 Hz, CH2OP), [6
4.2.7. Diethyl 1-[(10-methylbenzyl)amino]cyclohexane-
phosphonate (16). Following procedure A: reaction of
cyclohexanone 10 (294 mg, 3 mmol), EtOH (6 mL),
a-methylbenzylamine 19a (410 mg, 4.5 mmol), MgSO4
(250 mg), AcOH (360 mL, 6 mmol) and P(OEt)3 (750 mg,
4.5 mmol), for 20 h at 55 ꢀC furnished, after standard
work-up and purification by FC (eluent, ether), 930 mg
(93%) of pure aminophosphonate 16 as a colourless oil.
Rf¼0.40 (MeOH/CH2Cl2: 5/95). IR (neat) n: 3463, 3061,
2
arom C: 126.5 (d, 2C), 128.2 (d, 3C), 148.1 (s)]. 31P NMR
(CDCl3, 101.25 MHz) d: 28.87. HRMS (ESI, m/z): calcd
mass for C17H28NO3PSNa, [M+Na]+: 380.1420. Found:
380.1424.
4.2.5. Diethyl 4-[(10-hydroxymethyl)benzylamino]tetra-
hydro-2H-thiopyran-4-yl-phosphonate (15b). Following
procedure A: reaction of tetrahydrothiopyran-4-one 9
(210 mg, 1.8 mmol), EtOH (4.5 mL), a-hydroxymethylbenz-
ylamine 19c (370 mg, 2.7 mmol), MgSO4 (162 mg), AcOH
(200 mL, 3.62 mmol) and P(OEt)3 (465 mL, 2.70 mmol), for
40 h at 50 ꢀC furnished, after standard work-up and purifica-
tion by FC (eluent, MeOH/CH2Cl2/NH3: 1/99/0.5), 311 mg
(46%) of aminophosphonate 15b as a colourless oil.
Rf ¼0.45 (MeOH/CH2Cl2: 5/95). 1H NMR (CDCl3,
250 MHz) d: 1.31 (t, J¼7.0 Hz, 3H, CH3–CH2O), 1.32 (t,
J¼7.0 Hz, CH3–CH2O), 1.70–2.18 (m, 5H, 2H–C3, 2H–C5
and 1H–C2 or 1H–C6), 2.18–2.46 (m, 2H, 1H–C2 and 1H–
C6), 3.20 (br t, J¼12.5 Hz, 1H–C6 or 1H–C2), 3.42 (dd,
1
2932, 1232 (P]O), 1062 and 1025 (P–O), 955. H NMR
(CDCl3, 360 MHz) d: 0.92–1.21 (m, 3Hcycle), 1.30 (t,
0
J¼7.0 Hz, 3H, CH3), 1.31 (d, J¼6.9 Hz, CH3–C1 ), 1.325
(t, J¼7.0 Hz, 3H, CH3), 1.38–1.90 (m, 7Hcycle and 1NH),
3
4.10 (qd, J¼7.0 Hz, JPH¼7.0 Hz, 2H, CH2O), 4.12 (qd,
3
J¼7.0 Hz, JPH¼7.0 Hz, 2H, CH2O), 4.37 (qd, J¼6.9 Hz,
4
JPH¼2.2 Hz, 1H–C1 ), 7.00–7.40 (m, 5H). 13C NMR
0
(CDCl3, 62.9 MHz) d: 16.35 (CH3–CH2O), 16.4 (CH3–
CH2O), 19.55 (d, JPC¼12.2 Hz, C2), 19.85 (d, JPC
2
2
¼
9.8 Hz, C6), 25.3 (C4), 26.8 (CH3–C1), 27.9 (d, 3JPC¼4.1 Hz,
1
0
C5), 32.4 (C3), 52.2 (C1 ), 57.1 (d, JPC¼137.6 Hz, C1),
2
2
0
J¼9.0 Hz, J¼11.0 Hz, 1H, CH2–C1 ), 3.63 (dd, J¼4.2 Hz,
61.25 (d, JPC¼7.8 Hz, CH2O), 61.5 (d, JPC¼7.9 Hz,
3
0
J¼11.0 Hz, 1H, CH2–C1 ), 4.12 (dq, JPH¼7.2 Hz,
CH2O), [6 arom C: 125.8, 126.3 (2C), 127.7 (2C), 148.5

N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
7451
(s)]. 31P NMR (CDCl3, 101.25 MHz) d: 31.21. ES+ MS, m/z:
IR (neat) n: 3468, 3979, 2929, 1694 (CON), 1427, 1276,
1245, 1054, 1024, 964. H NMR (CDCl3, 250 MHz) d:
1
362.2 [M+Na]+. HRMS data were not obtained.23
two diastereomers a/b (63/37): 1.14 (t, J¼7.0 Hz, 3H, b),
4.2.8. Diethyl 1-[(10-methylbenzyl)amino]cyclopentane-
phosphonate (17). Following procedure A, with DMSO as
solvent: reaction of cyclopentanone 11 (252 mg, 3 mmol),
DMSO (6 mL), a-methylbenzylamine 19a (545 mg,
4.5 mmol), MgSO4 (250 mg), AcOH (360 mL, 6 mmol) and
P(OEt)3 (750 mg, 4.5 mmol), for 48 h at 55 ꢀC furnished,
after standard work-up and purification by FC (eluent,
EtOAc/hexane: 20/80), 740 mg (76%) of pure aminophos-
phonate 17 as a colourless oil. Rf¼0.47 (EtOAc/CH2Cl2:
0
1.20–1.45 (m, 9H, 6H a/b CH3–C1 and CH3–CH2–, 1NH
a/b, and 3H a), 1.50 (s, 9H t-Bu, a/b), 1.45–2.10 (m, 3.4H,
2H–C5 a/b, 1H–C4 a/b, and 1H–C4, b), 2.60 (ddd,
J¼3.2 Hz, J¼12.7 Hz, 0.6H–C4 a), 2.80–3.65 (m, 2H–C6,
a/b), 2.65–3.97 (m, 2H–C2 a/b), 3.97–4.22 (m, 4H, CH2O,
0
a/b), 4.22–4.42 (m, 1H–C1 , a/b), 7.03–7.20 (m, 5H
arom, a/b). 13C NMR (CDCl3, 62.9 MHz) d: two diastereo-
mers a/b (63/37): 16.4–16.6 (d, 3JPC¼5.5 Hz, 2CH3–CH2O,
3
b/a), 19.4 (d, JPC¼10.4 Hz, C5, a), 20.0 (d, J¼8.2 Hz, C5,
1
0
b), 26.5 (C4, a/b), 27.1 (CH3–C1 , a/b), 28.3/28.5
15/85). H NMR (CDCl3, 360 MHz) d: 1.31 (d, J¼6.8 Hz,
0
CH3–C1 ), 1.33 (t, J¼7.0 Hz, CH3–CH2O), 1.36 (t,
(C(CH3)3, b/a), 43.5/44.6 (C6, b/a), 49.0/50.2 (d, J¼
0
0
J¼7.0 Hz, CH3–CH2O), 1.20–1.50 (m, 2Hcycle), 1.50–1.70
9.2 Hz, C2, a/b), 52.3 (C1 , a), 52.6 (C1 , b), 56.5 (d,
J¼145.4 Hz, C3, b), 57.5 (d, J¼141.5 Hz, C3, a), 61.7
(OCH2, a), 62.1 (d, J¼7.7 Hz, CH2O, b), 79.3 (C(CH3)3,
a/b), [6 arom C: 126.3, 126.4 (2C), 128.1 (2C), 148.1/
148.7 (s, a/b)], 155.1/155.6 (COO, a/b). 31P NMR (CDCl3,
101.25 MHz) d: two diastereoisomers a/b (63/37): 27.48/
27.78 (b/a). HRMS (ESI, m/z): calcd mass for
C22H37N2O5PNa, [M+Na]+: 463.2332. Found: 463.2348.
(m, 4Hcycle), 1.70–2.10 (m, 3H, 2Hcycle and NH), 4.06–
4.24 (m, J¼7.0 Hz, 4H, CH2O), 4.32 (qd, J¼6.8 Hz,
4
JPH¼2.3 Hz, 1H–C1 ), 7.10–7.45 (m, 5H). 13C NMR
0
3
(CDCl3, 62.9 MHz) d: 16.7 (d, JPC¼4.2 Hz, CH3–CH2O),
3
2
16.75 (d, JPC¼4.2 Hz, CH3–CH2O), 24.1 (dd, JPC
¼
3
0
11.1 Hz, d, JPC¼4.2 Hz, C3), 27.1 (CH3–C1 ), 29.7 (C4),
3
3
31.9 (d, JPC¼9.1 Hz, C2), 37.4 (d, JPC¼7.4 Hz, C5), 53.4
2
2
0
(C1 ), 61.6 (d, JPC¼7.7 Hz, CH2O), 62.0 (d, JPC¼7.5 Hz,
1
CH2O), 64.5 (d, JPC¼144.0 Hz, C1), [6 arom C: 126.2
4.2.11. Diethyl 3-benzylamino-1-(tert-butyloxycarbonyl)-
piperidin-3-yl-phosphonate (21a0). Following procedure
A: condensation reaction of 255 mg (1.62 mmol) of ketone
20a, benzylamine 19b (174 mg, 1.62 mmol), AcOH
(200 mL) and MgSO4 (164 mg) was heated and stirred at
50 ꢀC for 4 h. Then heating with P(OEt)3 (410 mL,
2.43 mmol) at 50 ꢀC overnight, gave after usual work-up
and purification by FC (eluent, MeOH/CH2Cl2/NH3: 3/97/
0.5), 530 mg (76%) of pure aminophosphonate 21a0 as a
colourless oil. Rf ¼0.65 (MeOH/CH2Cl2/NH3: 5/95/0.5). IR
(neat) n: 3560, 2980, 1693 (CON), 1428, 1276 and 1246
(3C), 128.1 (2C), 149.1 (s)]. 31P NMR (CDCl3,
101.25 MHz) d: 31.90. ES+ MS, m/z: 348.2 [M+Na]+.
HRMS data were not obtained.23
4.2.9. Diethyl 1-[(10-methylbenzyl)amino]cyclobutane-
phosphonate (18). Following procedure A, with DMSO as
solvent: reaction of cyclobutanone 12 (210 mg, 3 mmol),
DMSO (6 mL), a-methylbenzylamine 19a (545 mg,
4.50 mmol), MgSO4 (250 mg), AcOH (360 mL, 6 mmol)
and P(OEt)3 (750 mg, 4.5 mmol), for 3 days at 55 ꢀC gave,
after standard work-up and purification by FC (eluent,
EtOAc/petroleum ether, 40/60/60/40), 470 mg (51%) of
aminophosphonate 18. Mp 93.6 ꢀC. Rf¼0.30 (EtOAc/
CH2Cl2: 3/7). IR (neat) n: 3420, 3320 (NH), 1250 and
1
(P]O), 1161, 1028. H NMR (CDCl3, 250 MHz) d: 1.36
(t, J¼7.2 Hz, 6H, CH3ester), 1.44 (s, 9H, t-Bu), 1.20–2.10
(m, 5H, 4Hcycle and NH), 2.40–3.70 (m, 2Hcycle), 3.87 (d,
J¼12.2 Hz, 1Hbenzyl), 4.08 (d, J¼12.2 Hz, 1Hbenzyl), 4.40–
4.90 (m, 5H, 2CH2O and 1Hcycle), 7.10–7.50 (5H arom).
1
1200 (P]O), 1050 (P–O). H NMR (CDCl3, 250 MHz) d:
3
0
1.35 (d, J¼6.8 Hz, 3H–C1 ), 1.36 (t, J¼7.1 Hz, CH3–
13C NMR (CDCl3, 62.9 MHz) d: 16.6 (d, JPC¼5.2 Hz,
3
CH2O), 1.37 (t, J¼7.1 Hz, CH3–CH2O), 1.70 (br s, NH),
1.70–2.10 (m, 4Hcycle), 2.10–2.50 (m, 2Hcycle), 4.00–4.40
(m, J¼7.1 Hz, 4H, CH2O), 7.10–7.55 (m, 5H). 13C NMR
CH3ester), 19.5 (d, JPC¼10.0 Hz, C5), 27.6 (C4), 28.3
(CH3)3C), 43.5 (C6), 47.2 (CH2benzyl), 47.8 (C2), 56.0 (d,
1JPC¼146.6 Hz, C3), 61.9 (d, 2JPC¼7.7 Hz, CH2O), 62.2 (d,
2JPC¼7.4 Hz, CH2O), 79.6 (C(CH3)3), [6 arom C: 126.7
(1C), 128.0 (2C), 128.1 (2C), 141.0 (s)], 155.2 (CON). 31P
NMR (CDCl3, 101.25 MHz) d: 26.78. HRMS (ESI, m/z):
calcd mass for C21H35N2O5PNa, [M+Na]+: 449.2176.
Found: 449.2182.
2
(CDCl3, 62.9 MHz) d: 15.4 (d, JPC¼7.1 Hz, C4), 16.6 (d,
3
3JPC¼2.4 Hz, CH3–C–O), 16.65 (d, JPC¼2.4 Hz, CH3–C–
3
O), 26.0 (CH3), 28.0 (C3), 30.6 (C2), 53.5(d, JPC¼5.2 Hz,
1
2
0
C1 ), 57.9 (d, JPC¼147.2 Hz, C1), 61.9 (d, JPC¼7.6 Hz,
2
CH2–O), 62.2 (d, JPC¼7.6 Hz, CH2–O), [6 arom C: 126.4
(2C), 126.5, 128.2 (2C), 148.1 (s)]. 31P NMR (CDCl3,
101.25 MHz) d: 28.70. MS (m/z): 311 (M+, 0.4), 111 (12),
105 (100), 104 (11), 70 (20). HRMS (EI, m/z): calcd mass
for C16H26NO3P: 311.1650. Found: 311.1653.
4.3. Diethyl [1-oxido-4-(10-methylbenzyl)amino-tetra-
hydro-2H-thiopyran-4-yl-phosphonate (27)
To
a solution of aminophosphonate 15a (159 mg,
4.2.10. Diethyl 1-(tert-butyloxycarbonyl)-3-(1-methyl-
benzyl)amino-piperidin-3-yl-phosphonate (21a). Follow-
ing procedure A: reaction of N-Boc-piperidone 20a
(600 mg, 3 mmol), EtOH (6 mL), a-methylbenzylamine
19a (410 mg, 4.5 mmol), MgSO4 (250 mg), AcOH
(360 mL, 6 mmol) and P(OEt)3 (750 mg, 4.5 mmol), for
14 h at 55 ꢀC furnished, after standard work-up and purifica-
tion by FC (eluent, MeOH/CH2Cl2: 5/95), 680 mg (54%) of
piperidinephosphonate 21a as a mixture of two diastereoiso-
mers in 63/37 ratio. Rf¼0.29 (EtOH/petroleum ether: 50/50).
0.415 mmol) in 2 mL of CH2Cl2, was added at 0 ꢀC mCPBA
(77%, 146 mg, 0.415 mmol). The mixture was stirred at 0 ꢀC
for 20 min then 5 mL of saturated solution of Na2S2O3/
NaHCO3 (1/1) was added, vigorously stirred for 1 h, then
extracted with CH2Cl2 (3ꢂ50 mL). The organic layer was
dried over MgSO4, filtered and concentrated under vacuum
to furnish 168 mg (100%) of clean sulfoxide 27 as a colour-
less oil mixture of two isomers (40/60, cis/trans or trans/cis).
Rf ¼0.44 (MeOH/CH2Cl2: 10/90). IR (neat) n: 3447, 3354,
2925, 1266 and 1233 (P]O), 1199, 1163 (S]O), 1029

7452
N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
1
(P–O), 962. 1H NMR (CDCl3, 250 MHz) d: (two isomers a/
b: 40/60): 1.25–1.40 (m, 9H, CH3, a/b), 1.50–1.67 (m, 0.6H–
C3, b), 1.67–2.20 (m, 4.4H, 3Hcycle a/b and NH and 1H a),
2.25–2.85 (m, 2.6H, 2H a/b and 0.6H b), 2.90–3.10 (m,
1H, a/b), 3.10–3.26 (m, 0.4H, a), 4.02–4.24 (m, 4H,
3380, 2951, 1235 (P]O), 1049 and 1026 (P–O), 959. H
NMR (CDCl3, 250 MHz) d: 1.28 (t, J¼7.0 Hz, 6H, CH3),
1.30–1.45 (m, 2H, 1H–C3 and 1H–C5), 1.74 (br s, 2HN),
1.90–2.10 (m, 2H, 1H–C3 and 1H–C5), 3.62–3.72 (m,
2Hcycle, CH2O), 3.76–3.88 (m, 2Hcycle, CH2O), 4.08 (q,
J¼7.0 Hz, 2H, CH2OP), 4.11 (q, J¼7.0 Hz, 2H, CH2OP).
3
CH2OP, a/b), 4.39 (qd, J¼6.8 Hz, JPH¼2.3 Hz, 0.4H, H–
3
3
0
0
C1 , a), 4.46 (qd, J¼6.8 Hz, JPH¼2.5 Hz, 0.6H, H–C1 , b),
7.08–7.40 (m, 5H, a/b). 13C NMR (CDCl3, 62.9 MHz) d:
(two isomers, a/b: 40/60): 16.6 (CH3–CH2O, a/b), 16.7
13C NMR (CDCl3, 62.9 MHz) d: 16.5 (d, JPC¼5.2 Hz,
1
2CH3–CH2O), 31.4 (C3 and C5), 49.2 (d, JPC¼155.0 Hz,
2
C4), 61.7 (C2), 61.77 (d, JPC¼7.7 Hz, CH2OP), 61.85
2
(CH3–CH2O, a/b), 17.1 (d, JPC¼6.5 Hz, C3 or C5, b),
(C6), 62.4 (d, J¼7.7 Hz, CH2OP). 31P NMR (CDCl3,
101.25 MHz) d: 28.61. HRMS (ESI, m/z): calcd mass for
C9H20NO4PNa, [M+Na]+: 260.1022. Found: 260.1030.
2
2
21.8 (d, JPC¼3.2 Hz, C5 or C3, b), 24.5 (d, JPC¼7.6, C3
0
0
or C5, a), 26.7 (CH3–C1 , b), 26.8 (CH3–C1 , a), 28.5 (d,
2JPC¼2.8 Hz, C5 or C3, a), 39.2 (d, JPC¼10.4 Hz, C2 or
3
3
C6, b), 39.5 (d, JPC¼13.8 Hz, C6 or C2, b), 44.3 (C2 or
4.4.3. Diethyl 3-amino-1-(tert-butyloxycarbonyl)-piperi-
din-3-yl-phosphonate (30). Following procedure B: reac-
tion of N-Boc phosphonate 21a0 (350 mg, 0.82 mmol),
AcOH (6 mL) and 20% Pd(OH)2/C (140 mg) under H2
(1 atm) for 18 h followed by FC (eluent: MeOH/CH2Cl2/
NH3: 5/93/2), gave 285 mg (88%) of aminophosphonate 30
as a colourless oil. Rf¼0.63 (ether). 1H NMR (CDCl3,
250 MHz) d: 1.34 (t, J¼7.0 Hz, 6H, CH3–CH2O), 1.46 (s,
9H, t-Bu), 1.40–2.00 (m, 6H, 2H–C4, 2H–C5, and NH2),
2.67–2.90 (m, 1H, 1H–C6), 3.04–3.32 (m, 1H–C6), 3.80–4.10
(m, 2H–C2), 4.05–4.37 (m, 4H, CH2OP). 13C NMR (CDCl3,
62.9 MHz) d: 16.7 (2CH3–CH2O), 19.5 (C5), 28.5 ((CH3)3–
C), 30.5 (d, JPC¼2.4 Hz, C4), 51.6 (d, JPC¼155.8 Hz,
C3), 62.8 (C6), 76.6 (C2), 77.2 (CH2OP), 77.6 (CH2OP),
79.9 (s, C(CH3)3), 155.7 (COO). 31P NMR (CDCl3,
101.25 MHz) d: 27.84. HRMS (ESI, m/z): calcd mass for
C14H29N2O5PNa, [M+Na]+: 359.1706. Found: 359.1723.
1
0
C6, a), 44.45 (C6 or C2, a), 52.7 (C1 , a/b), 55.1 (d, JPC
1
142.4 Hz, C4, a), 55.3 (d, JPC¼143.1 Hz, C4, b), 62.2 (d,
2JPC¼7.8 Hz, CH2OP, b), 62.5 (d, JPC¼7.7 Hz, CH2OP,
2
a), [6 arom C: 126.4/126.5 (2C, b/a), 126.8/126.9 (1C,
b/a), 128.5 (2C, a/b), 147.3/147.9 (s, a/b)]. 31P NMR
(CDCl3, 101.25 MHz) d: (a/b: 40/60): 28.44/27.54. HRMS
(EI, m/z): calcd mass for C17H28NO4PSNa, [M+Na]+:
396.1369. Found: 396.1361.
4.4. Hydrogenolysis: general procedure B
2
1
To a solution of aminophosphonates 13–18 or 21 (1 mmol)
in 5 mL of AcOH, was added 20% Pd(OH)2/C (Pearlman’s
catalyst, 150 mg (40% w/w)). The flask was connected
to a hydrogenation apparatus equipped with a graduated
burette containing water that allowed the uptake of hydrogen
to be monitored. TLC control showed that under 1 atm for
18 h, the reaction was complete. Then degassed under
a stream of argon, filtered through paper and the collected
solid was washed with EtOH (2ꢂ10 mL). The combined
filtrate and washings were concentrated and purified by FC
on silica gel (20 g), eluent (MeOH/CH2Cl2/NH3: 10/90/
0.5) to give free amines 24–26 or 30.
4.5. Diethyl 4-amino-tetrahydro-2H-thiopyran-4-yl-
phosphonate (26)
To a solution of N-PMB aminophosphonate 15c (240 mg,
0.64 mmol) in 2.5 mL of a mixture of CH2Cl2/H2O (9/1),
was added DDQ (16.2 mg, 0.70 mmol). The mixture was
stirred at rt for 3 h. Then 350 mL of 2 N KOH solution was
added and stirred for 1 h. The reaction mixture was filtered
over CeliteÒ and concentrated, and the residue was purified
by FC (eluent: MeOH/CH2Cl2/NH3 aq: 1/99/0.5) to afford
65 mg (40%) of the free aminophosphonate 26 as a yellow
viscous oil accompanied with 120 mg (50%) of imine inter-
mediate 29. Or treatment of the crude mixture (26 and 29)
with KOH (2 N) in the presence of benzoyl hydrazine
(1 equiv) gave after FC the desired free amine 26 (143 mg,
88%).
4.4.1. Diethyl 4-amino-1-methylpiperidin-4-yl-phospho-
nate (24). Following procedure B: reaction of phosphonate
13 (274 mg, 0.773 mmol), AcOH (4 mL) and 20% Pd(OH)2/
C (132 mg) under H2 (1 atm) for 18 h followed by FC
(CH2Cl2/MeOH/NH3: 90/10/0.5/80/20) gave 140 mg
(73%) of aminophosphonate 24 as a colourless oil. Rf¼0.20
1
(MeOH/CH2Cl2: 10/90). H NMR (CDCl3, 250 MHz) d:
1.25 (t, J¼7.0 Hz, 6H, CH3–CH2O), 1.46–1.61 (m, 2H,
1H–C3 and 1H–C5), 1.94–2.12 (m, 2H, 1H–C3 and 1H–C5),
2.27 (s, 3H, CH3N), 2.47 (br t, J¼11.3 Hz, 1H–C2 and
1H–C6), 2.66 (br d, J¼11.3 Hz, 2H, 1H–C2 and 1H–C6),
4.5.1. Data for free amine (26). Rf¼0.42 (MeOH/
CH2Cl2+NH3: 10/90). IR (neat) n: 3468, 2980, 1605, 1248,
1026, 965. 1H NMR (CDCl3, 250 MHz) d: 1.34 (t,
J¼7.0 Hz, 6H, CH3), 1.40–1.90 (br s, 2H–N), 1.83–2.01
(m, 2H, 1H–C3 and 1H–C5), 2.01–2.22 (m, 2H, 1H–C3
and 1H–C5), 2.37 (br d, J¼12.7 Hz, 2H, 1H–C2 and 1H–
C6), 3.13 (dddd, J¼2.2 Hz, J¼2.2 Hz, J¼12.7 Hz, J¼
12.2 Hz, 2H, 1H–C2 and 1H–C6), 4.13 (q, J¼7.0 Hz,
2H, CH2O), 4.16 (q, J¼7.0 Hz, 2H, CH2O). 13C NMR
3
3.12 (br s, 2HN), 4.07 (qd, J¼7.0 Hz, JPH¼7.0 Hz, 4H,
3
CH2OP). 13C NMR (CDCl3, 62.9 MHz) d: 16.5 (d, JPC
¼
5.3 Hz, 2CH3–CH2O), 30.6 (C3 and C5), 45.4 (CH3-N), 48.7
1
2
(d, JPC¼154.9 Hz, C4), 48.8 (d, JPC¼11.6 Hz, 2CH2OP),
62.4 (C2 or C6), 62.5 (C6 or C2). 31P NMR (CDCl3,
101.25 MHz) d: 29.50. HRMS (ESI, m/z): calcd mass for
C10H23N2O3PNa, [M+Na]+: 273.1339. Found: 273.1349.
3
4.4.2. Diethyl 4-amino-tetrahydro-2H-pyran-4-yl-phos-
phonate (25). Following procedure B: reaction of phospho-
nate 14a (140 mg, 0.410 mmol), AcOH (2.40 mL) and 10%
Pd(OH)2/C (70 mg) under H2 (1 atm) for 18 h followed by
FC gave 83 mg (86%) of aminophosphonate 25 as a colour-
less oil. Rf¼0.23 (MeOH/CH2Cl2: 10/90). IR (neat) n: 3457,
(CDCl3, 62.9 MHz) d: 16.7 (d, JPC¼5.2 Hz, 2CH3), 21.7
(C2 or C6), 21.9 (C6 or C2), 32.3 (C3 and C5), 50.7 (d,
J¼151.2 Hz, C4), 62.6 (d, J¼7.7 Hz, 2CH2O). 31P NMR
(CDCl3, 101.25 MHz) d: 29.36. HRMS (ESI, m/z): calcd
mass for C9H20NO3PSNa, [M+Na]+: 276.0794. Found:
276.0800.

N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
7453
1
4.5.2. (E)-Diethyl 3-(40-methoxybenzylideneamino)tetra-
hydro-2H-thiopyran-4-yl-phosphonate (29). Rf ¼0.83
(MeOH/CH2Cl2+NH3: 5/95+0.5). IR (neat) n: 3044, 2982,
1630 (C]N), 1605, 1575, 1512, 1245, 1029, 967. 1H
NMR (CDCl3, 250 MHz) d: 1.30 (t, J¼7.0 Hz, 6H, 2CH3),
2.20–2.50 (m, 4H, 1H–C3, 1H–C5 and 1H–C2, 1H–C6),
2.50–2.78 (m, 2H, 1H–C3 and 1H–C5), 2.78–3.10 (m, like
t, 2H, 1H–C2 and 1H–C6), 3.86 (s, 3H, OCH3), 4.06 (q,
J¼7.0 Hz, 2H, CH2O), 4.09 (q, J¼7.0 Hz, 2H, CH2O),
6.95 (d, J¼8.7 Hz, 2Haryl), 7.77 (d, J¼8.7 Hz, 2Haryl), 8.52
solid. Mp 237 ꢀC decomp. H NMR (D2O, 250 MHz) d:
1.60–1.77 (m, 2H, 1H–C3 and 1H–C5), 2.01–2.23 (m, 2H,
1H–C3 and 1H–C5), 3.60 (ddd, J¼2.8 Hz, J¼10.3 Hz,
J¼12.3 Hz, 2H, 1H–C2 and 1H–C6), 3.87 (ddd, J¼4.7 Hz,
J¼4.7 Hz, J¼12.3 Hz, 2H, 1H–C2 and 1H–C6). 13C NMR
1
(D2O, 62.9 MHz) d: 30.0 (C3 and C5), 52.9 (d, JPC
¼
138.5 Hz, C4), 62.4 (C2 or C6), 62.5 (C6 or C2). 31P NMR
(D2O, 101.25 MHz) d: 13.31. ES+ MS, m/z: 204.1
[M+Na]+. HRMS data were not obtained.23
4
(d, JPH¼4.7 Hz, 1Himine). 13C NMR (CDCl3, 62.9 MHz)
4.6.3. 4-Amino-tetrahydro-2H-thiopyran-4-yl-phos-
phonic acid (2c). Following procedure C: reaction of di-
ethylphosphonate 26 (127 mg, 0.50 mmol), 12 N HCl (2 mL)
at reflux for 5 h, then EtOH (2.5 mL) and propylene oxide
(2 mL) for 17 h at rt gave, after usual work-up, 92 mg
(90%) of aminophosphonic acid 2c. Mp 242 ꢀC decomp.
IR (KBr) n cmꢁ1: 3338, 3230, 3140, 2920, 1617, 1545,
1203, 1070, 1038, 912. 1H NMR (D2O, 250 MHz) d: 1.90–
2.14 (m, 2H, 1H–C3 and 1H–C5), 2.14–2.35 (m, 2H, 1H–
C3 and 1H–C5), 2.60–2.85 (m, 4H, 2H–C2 and 2H–C6). 1H
NMR (D2O+NaOD, 360 MHz) d: 1.00–1.32 (m, 4H, 2H–
C3 and 2H–C5), 1.60–1.80 (m, 2H, 1H–C2 and 1H–C6),
2.13–2.34 (m, 2H, 1H–C2 and 1H–C6). 13C NMR
(D2O+NaOD, 90.6 MHz) d: 21.3 (C2), 21.5 (C6), 32.0 (C3
3
d: 16.6 (d, JPC¼5.5 Hz, 2CH3ester), 22.3 (C2), 22.5 (C6),
1
32.5 (C3 and C5), 55.5 (OCH3), 61.3 (d, JPC¼146.7 Hz,
2
C4), 62.9 (d, JPC¼7.2 Hz, 2CH2O), [6 arom C: 144.1
(2C), 129.6 (s), 130.0 (2C), 161.1 (C–OCH3)], 163.4 (d,
3JPC¼10.4 Hz, N]C), 31P NMR (CDCl3, 101.25 MHz) d:
25.26. HRMS data were not obtained.23
4.6. Hydrolysis of aminophosphonates
4.6.1. 4-Amino-1-methylpiperidin-4-yl-phosphonic acid
(2a). General procedure C—Hydrolysis of aminophospho-
nates with HCl: A solution of diethylphosphonate 24
(119 mg, 0.38 mmol) in aq 6 N HCl (3 mL) was heated at
reflux for 7 h. The solvent was evaporated under reduced
pressure to dryness. The residue was dissolved in 4 mL of
CH2Cl2, then concentrated to dryness to give the crude
aminophosphonic acid$xHCl, hydrochloride. The crude
hydrochloride aminophosphonic acid$xHCl was dissolved
in minimum amount of EtOH (3 mL), then to which was
added dropwise an excess of propylene oxide (5 mL) and
stirring at rt for 18 h. The volatile compounds were removed
by evaporation under vacuum, to give 74 mg of phosphonic
and C5), 49.0 (d, JPC¼142.6 Hz, C4). 31P NMR (D2O,
1
101.25 MHz) d: 16.25; in (D2O+NaOD) d: 23.13.
Purification of a sample by FC (eluent, EtOH/H2O/concd
1
NH4OH: 30/3/10): H NMR (D2O, 360 MHz) d: 2.06–2.22
(m, 2H), 2.22–2.37 (m, 2H), 2.72–2.91 (m, 4H). 31P NMR
(D2O, 101.25 MHz) d: 13.78. HRMS data were not ob-
tained.23
acid 2a quantitatively. Mp>250 decomp. IR (KBr) n cmꢁ1
:
4.6.4. 3-Amino-piperidin-3-yl-phosphonic acid hydro-
chloride (3$2HCl). Following procedure C: reaction of
N-Boc phosphonate 30 (122 mg, 0.36 mmol), 6 N HCl
(4 mL) at reflux for 12 h, gave after usual work-up 99 mg
(100%) of crude aminophosphonic acid hydrochloride
3$2HCl. IR (KBr) n cmꢁ1: 3390, 2926, 1613, 1204, 1153,
1073, 982. 1H NMR (D2O, 250 MHz) d: 1.70–2.27 (m,
3H, 2H–C5 and 1H–C4), 2.27–2.57 (m, 1H, C4), 2.92–3.57
1
3413, 2925, 1617, 1206, 1080, 1057, 923. H NMR (D2O,
360 MHz) d: two diastereomers a/b (in 55/45 ratio): 1.87–
2.10 (m, 2H, 1H–C3 and 1H–C5, a), 2.10–2.25 (m, 2H,
1H–C3 and 1H–C5, b), 2.25–2.38 (m, 2H, 1H–C3 and 1H–
C5, b), 2.38–2.54 (m, 2H, 1H–C3 and 1H–C5, a), 2.81/2.83
(s, CH3, a/b), 3.02–3.20 (m, 2H, 1H–C2 and 1H–C6, b),
3.33–3.65 (m, 6H, 4H a and 2H b); in (NaOD/D2O,
250 MHz) d: 1.28–1.47 (m, 2H, 1H–C3 and 1H–C5), 1.67–
1.94 (m, 2H, 1H–C3 and 1H–C5), 2.06 (s, CH3), 2.08–2.30
(m, 2H, 1H–C2 and 1H–C6), 2.37–2.60 (m, 2H, 1H–C2 and
1H–C6). 13C NMR (D2O, 62.9 MHz) d: two diastereomers,
a/b (55/45): 26.4 (C3 and C5, b), 28.6 (C3 and C5, a), 43.0
(CH3, a/b), 48.2 (C2 and C6, a), 48.4 (C2 and C6, b), 50.2
1
(m, 3H, 2H–C6+1H–C2), 3.57–3.88 (m, 1H–C2). H NMR
(D2O+NaOD, 250 MHz) d: 1.20–1.41 (m, 1H–C5), 1.41–
1.64 (m, 2H), 1.64–1.85 (m, 1H–C4), 2.20–2.44 (m, 1H–
C6), 2.44–2.88 (m, 3H, 2H–C2 and 1H–C6). 13C NMR
(D2O, 62.9 MHz) d: 18.4 (C5), 27.7 (C4), 43.5 (C6), 46.0
(C2), 50.7 (d, 1JPC¼138.5 Hz, C3).
1
(d, 1JPC¼147.2 Hz, C4, a), 50.4 (d, JPC¼141.6 Hz, C4, b),
50.8 (C2 and C6, a); in (D2O+NaOD): 31.3 (C3 and C5),
44.8 (CH3), 48.44 (d, 1JPC¼144.1 Hz, C4), 49.1 (C2 or C6),
49.2 (C6 or C2). 31P NMR (D2O, 101.25 MHz) d: two diaste-
reomers, a/b (55/45): 12.09/12.85 (a/b); in (DMSO-d6):
14.91/15.72 (b/a); in (D2O+NaOD): 23.33 only one.
HRMS (ESI, m/z): calcd mass for C6H16N2O3P, [M+H]+:
195.0893. Found: 195.0899.
4.6.5. 3-Amino-piperidin-3-yl-phosphonic acid (3). Fol-
lowing procedure C: The crude aminophosphonic acid
hydrochloride 3$2HCl (80 mg) and propylene oxide (5 mL)
gave after concentration 74 mg (100%) of free aminophos-
phonic acid 3 as colourless solid. Mp >250 ꢀC decomp.
1H NMR (D2O, 250 MHz) d: 1.60–2.17 (m, 3H, 2H–C5
and 1H–C4), 2.17–2.37 (m, 1H–C4), 2.96 (m, 1H–C6),
3.13–3.04 (d, J¼12.7 Hz, 1H–C2), 3.32 (m, 1H–C6), 3.57–
3.54 (dd, J¼1.5 Hz, J¼12.7 Hz, 1H–C2); in (D2O+NaOD)
d: 1.22–1.30 (m, 1H–C5), 1.36–1.58 (m, 2H, 1H–C5 and
1H–C4), 1.58–1.80 (m, 1H–C4), 2.20–2.34 (m, 1H–C6),
2.42–2.58 (m, 1H–C2), 2.58–2.78 (m, 2H, 1H–C6 and
1H–C6). 13C NMR (D2O+NaOD, 62.9 MHz) d: 20.6
4.6.2. 4-Amino-tetrahydro-2H-pyran-4-yl-phosphonic
acid (2b). Hydrolysis of aminophosphonates with TMSI
according to our reported method:9b Reaction of diethyl-
phosphonate 25 (62 mg, 0.26 mmol), CH2Cl2 (3 mL),
TMSI (78 mg, 0.55 mmol), 6 h then EtOH (1.3 mL) and pro-
pylene oxide (1 mL), for 18 h at rt gave, after usual work-up,
20 mg (43%) of pure aminophosphonic acid 2b as a white
3
(d, JPC¼8.0 Hz, C5), 30.3 (C4), 44.7 (C6), 50.15 (d,
1JPC¼140.1 Hz, C3), 50.9 (d, JPC¼5.3 Hz, C2). 31P NMR
2

7454
N. Rabasso et al. / Tetrahedron 62 (2006) 7445–7454
11. (a) Ranu, B. C.; Hajra, A. Green Chem. 2002, 4, 551–554; (b)
Wieczorek, J. C.; Gancarz, R.; Bielecki, K.; Grzys, E.;
Sarapuk, J. Phosphorus, Sulfur Silicon Relat. Elem. 2001,
174, 119–128; (c) Stoikov, I. I.; Repejkov, S. A.; Antipin,
I. S.; Konovalov, A. I. Heteroat. Chem. 2000, 11, 518–527.
(D2O, 101.25 MHz) d: 11.81; in (D2O+NaOD) d: 21.97.
ES+ MS, m/z: 203.1 [M+Na]+. HRMS data were not
obtained.23
12. (a) Gunter, E.; Lohge, W. German Patent 1991; 2,022,228;
¨
¨
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a
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23. Unfortunately, HRMS were not obtained, even by using various
kind of measure: electro spray, electronic impact or chemical
ionisation.