Synthesis of new (3-aminopyrrolidin-3-yl)phosphonic acid - A cucurbitine analogue - and (3-aminotetrahydrothiophen-3-yl)phosphonic acid via phosphite addition to heterocyclic hydrazones

Article abstract of DOI:10.1055/s-2008-1067130

Hydrazones were prepared by condensation of carbocyclic and heterocyclic ketones with benzoyl- and tosylhydrazines. These hydrazones underwent nucleophilic addition with phosphite to provide efficiently (3- hydrazinopyrrolidin-3-yl)-, (3-hydrazinotetrahydrothiophen-3-yl)-, (3-hydrazinotetrahydrofuran-3-yl)-, and (1-hydrazinocyclopentyl)phosphonates. Cleavage of the hydrazine N-N bonds followed by acidic hydrolysis of the phosphonate functions of the (3-aminoheterocyclopentyl)phosphonates gave the new (3-aminopyrrolidin-3-yl)- and (3-aminotetrahydrothiophen-3-yl)phosphonic acids. This synthesis was achieved in a four-step sequence from the appropriate ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067130

PAPER
2353
Synthesis of New (3-Aminopyrrolidin-3-yl)phosphonic Acid – A Cucurbitine
Analogue – and (3-Aminotetrahydrothiophen-3-yl)phosphonic Acid via
Phosphite Addition to Heterocyclic Hydrazones
S
ynthesis of Pyrro
i
lidinyl-
c
and Tetrah
o
ydrothiophe
l
nylphos
a
phonic
A
c
s
ids Rabasso, Antoine Fadel*
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420,
Univ Paris-Sud, 91405 Orsay, France
Fax +33(1)69156278; E-mail: antfadel@icmo.u-psud.fr
Received 11 January 2008; revised 11 April 2008
O
OH
O
OH
OH
COOH
NH2
Abstract: Hydrazones were prepared by condensation of carbo-
cyclic and heterocyclic ketones with benzoyl- and tosylhydrazines.
These hydrazones underwent nucleophilic addition with phosphite
to provide efficiently (3-hydrazinopyrrolidin-3-yl)-, (3-hydrazino-
tetrahydrothiophen-3-yl)-, (3-hydrazinotetrahydrofuran-3-yl)-, and
(1-hydrazinocyclopentyl)phosphonates. Cleavage of the hydrazine
N–N bonds followed by acidic hydrolysis of the phosphonate func-
tions of the (3-aminoheterocyclopentyl)phosphonates gave the new
(3-aminopyrrolidin-3-yl)- and (3-aminotetrahydrothiophen-3-
yl)phosphonic acids. This synthesis was achieved in a four-step se-
quence from the appropriate ketones.
P
P
OH
NH2
NH2
X
N
X
H
1a X = NH
1b X = O
1c X = S
2
3a X = NH
3b X = O
3c X = S
(–)-cucurbitine
Figure 1 Heterocyclic a-aminocarboxylic and phosphonic acids
rahydrofuranyl- and tetrahydrothiophenylphosphonic
acid analogues 3b and 3c are still unknown (Figure 1).
Key words: phosphonic acids, heterocycles, amines, cucurbitine
We previously reported a simple and convenient synthesis
of 1-aminocyclopropanephosphonic acids [aminocyclo-
propanecarboxylic acid (ACC) analogues], in three steps,
starting from cyclopropanone hemiacetals and proceeding
via aminophosphonates.8 Furthermore, we have very re-
cently reported, in racemic series, an efficient three-step
synthesis of new heterocyclic a-aminophosphonic acids
1a–c in good yields from readily available ketones 4 via
aminophosphonates 5 (Scheme 1).20 We also applied the
same sequence to obtain (3-aminopiperidin-3-yl)phos-
phonic acids from the corresponding cyclic ketones.20
analogue, nucleophilic additions
Several a-aminophosphonic acids show activity as en-
zyme inhibitors, antibacterials, herbicides, or plant
growth regulators.1 These acid derivatives, in which the
tetrahedral phosphorus moiety acts as a transition-state
analogue of peptide bond cleavage, selectively inhibit
peptidases and proteinases (e.g., HIV protease,2 serine
protease3). Thus, in recent years, many cyclic a-amino-
phosphonic acids have been prepared,4–11 and when from
cycloalkanones, mainly by Mannich-type reactions.12
O
OEt
OEt
O
OH
OH
Very few examples of heterocyclic a-aminophosphonic
acids 1 or the corresponding phosphonates have been re-
ported; only the 4-aminobutyric acid (GABA)13 analogue
1a,14 the tetrahydropyranylphosphonate derivative of
1b,15 and tetrahydrothiopyranylphosphonate derivative of
1c are described (Figure 1).16 In all these synthetic ap-
proaches, the Kabatschnick–Fields reaction15a was used
from heterocyclohexanones, to provide a-aminophospho-
nates in moderate to good yields.
O
P
P
RNH2
NHR
NH2
X
P(OEt)3
X
X
X = NMe, O, S
4
5
1a–c
Scheme 1
Herein, we report our efforts towards the synthesis of
phosphonocucurbitine 3a and related compounds 3b,c
(Figure 1). We decided to first apply our methodology in-
volving the addition of a phosphite to iminium intermedi-
ate 6 as a key step (Scheme 2). Unfortunately, we realized
that for the five-membered-ring heterocyclic ketones 7–9
(X = NCO2Et, O, or S), the failure of formation of imini-
ums 6 limited the formation of the corresponding amino-
phosphonates 10–12 (Scheme 2). Attempts to isolate and
characterize such imine intermediates (corresponding to
iminiums 6) also failed (Scheme 2).20
(–)-Cucurbitine (2; Figure 1), isolated from the seeds of
several species of Cucurbitaceae, has been used as an an-
tiallergenic agent for the preparation of cosmetics and
pharmaceuticals. Despite its interesting biological activi-
ty,17 only few syntheses have been described, in which the
Bucherer–Bergs reaction is used to introduce the a-amino
acid moiety.18,19 In contrast, (3-aminopyrrolidin-3-
yl)phosphonic acid (3a) (a cucurbitine analogue) and tet-
In addition, we tried different conditions for the phosphite
additions to 3-pyrrolidinone 7 [P(OEt)3, HP(OEt)2 under
acidic conditions, or LiP(O)(OEt)2 under basic condi-
tions] (Scheme 2).21 However, none of these conditions
SYNTHESIS 2008, No. 15, pp 2353–2362
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067130; Art ID: T00708SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2354
N. Rabasso, A. Fadel
PAPER
OEt
OEt
O
H+
romethanesulfonic acid, were carried out at 0 °C for one
hour, and then the mixtures were warmed slowly to room
temperature for four hours (method A); this gave the cor-
responding hydrazinophosphonates 18a,b in good yields
(60–96%) (Table 2, entries 1 and 3). Conducting the same
reaction with tetrahydrofuran-3-one hydrazone 15b or tet-
rahydrothiophen-3-one hydrazone 16b gave hydrazino-
phosphonates 19b or 20b, respectively, in lower yields
(Table 2, entries 5 and 7).
Nu
P
H2NCH(Me)Ph
O
Ph
N
N
X
P(OEt)3, 50 °C
X
X
H
H
Ph
7 X = NCO2Et
8 X = O
6
10 X = NCO2Et
11 X = O
9 X = S
12 X = S
Scheme 2
OEt
OEt
OH
OH
O
O
HN R1
On the other hand, the reactions of benzoylhydrazones
14b, 15b, and 16b with triethyl phosphite (1.1 equiv) in
the presence of 0.5 equivalents trifluoromethanesulfonic
acid in dichloromethane at room temperature for 18–24
hours (method B), furnished the expected hydrazinophos-
phonates 18b, 19b, and 20b, respectively, in slightly in-
creased yields (Table 2, entries 4, 6 and 8). Likewise,
cyclopentanone hydrazones 17a27a and 17b,27b by meth-
ods A and B, respectively, gave hydrazinophosphonates
21a and 21b, respectively, in the same yields obtained for
the pyrrolidine derivatives (Table 2, cf. entries 1 and 9;
and entries 4 and 10).
P
P
O
N
N
NH
R1
X
NH2
X
X
X
H
3a–d
18–21
X = NR, O, S, CH2
14–17
7–9, 13
Scheme 3
gave the corresponding aminophosphonate 10.
Microwave22 or solvent- and catalyst-free23 reactions also
failed.
Therefore, knowing that hydrazones are much more stable
than their corresponding imines, we decided to investigate
their reactivity. Such hydrazones are readily available
from heterocyclic and carbocyclic ketones 7–9 and 13
(Scheme 3). Addition of phosphite to hydrazones 14–17
should24 give the desired aminophosphonates 18–21, pre-
cursors of aminophosphonic acids 3a–d (Scheme 3).
HN R1
P(O)(OEt)2
H
Method A or B
N
N
H
N
X
X
R1
14–17
18–21
Scheme 5
Hydrazone formation was carried out under mild condi-
tions. Ketones 725 and 8,26 as well as commercially avail-
able ketones 9 and 13, reacted with tosylhydrazine 22a
and benzoylhydrazine 22b in ethanol at 50 °C, to give the
desired E/Z-configured hydrazones 14–17 in good yields
(72–89%) (Scheme 4, Table 1). The thus obtained hydra-
zones 14–17 were used in the next step without further pu-
rification.
We next tried to obtain the aminophosphonates starting
from other imine analogues (such as oximes or phosphin-
imides), which are known to be easily cleaved in the final
sequence affording free amines. Thus, imine 23, prepared
from cyclopentanone oxime and chlorodiphenylphos-
phine,28 reacted with triethyl phosphite to give the desired
aminophosphonate 24 in low yield and with a mixture of
unidentified products (Scheme 6). Similarly, the addition
of diethoxyphosphorylpotassium in the presence of three
equivalents of boron trifluoride–diethyl ether complex to
the easily prepared carbocyclic and heterocyclic oximes
25a and 25b29 yielded the expected aminophosphonates
26a and 26b, respectively, in only 30% and 24% yields,
respectively, with 30–55% recovered starting materials
(Scheme 6). Finally, optically active hydrazone 27, pre-
pared from (R)-(+)-1-amino-2-(methoxymethyl)pyrroli-
The standard reactions (Scheme 5) of pyrrolidin-3-one
hydrazones 14a,b with diethyl phosphite, used as solvent
and reagent, in the presence of 0.3 equivalents trifluo-
HN R1
H2N–NHR1 (22), EtOH
O
N
X
X
50 °C, 2 h
7–9, 13
14–17
Scheme 4
Table 1 Preparation of Hydrazones 14–17 from Ketones 7–9 and 13a
Entry
Ketone 7–9
X
Hydrazine 22
22a
R1
Ts
Bz
Bz
Bz
Ts
Bz
Hydrazone 14–17 Yield (%)
1
2
3
4
5
6
7
7
NCO2Et
NCO2Et
O
14a
14b
15b
16b
17a
17b
82
89
74
84
88
72
22b
8
22b
9
S
22b
13
CH2
CH2
22a
13
22b
a See Scheme 4. Reaction conditions: ketone 7, 8, 9, or 13, hydrazine 22a or 22b (1 equiv), EtOH, 50 °C, 2 h.
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolidinyl- and Tetrahydrothiophenylphosphonic Acids
2355
Table 2 Preparation of Hydrazinophosphonates 18–21 from Hydrazones 14–17a
Entry
X
R1
Ts
Ts
Bz
Hydrazone
14a
Conditionsa
Phosphonate 18–21
Yield (%)
PO(OEt)2
H
1
2
3
NCO2Et
NCO2Et
NCO2Et
A
18a
96
N
N
N
N
Ts
H
EtO2C
c
14a
Ab
A
18a
18b
–
PO(OEt)2
H
14b
60
N
N
Bz
H
EtO2C
4
5
NCO2Et
Bz
Bz
Bz
Bz
Bz
Ts
Bz
14b
15b
15b
16b
16b
17a
17b
B
A
B
A
B
A
B
18b
19b
19b
20b
20b
21a
21b
68
29
37
34
40
90
61
PO(OEt)2
H
O
N
N
O
Bz
H
6
O
PO(OEt)2
H
7
S
N
N
S
Bz
H
8
S
PO(OEt)2
H
R1 = Ts
1 = Bz
9
CH2
N
N
R
R1
H
10
CH2
a See Scheme 5. Reaction conditions: Method A: hydrazone, HP(O)(OEt)2 (excess), TfOH (0.3 equiv), 0 °C to r.t., 4 h; Method B: hydrazone,
P(OEt)3 (1.1 equiv), TfOH (0.5 equiv), CH2Cl2, 0 °C, 1 h, then r.t., 18–24 h.
b ZnBr2 in DMF was used instead of TfOH.
c No reaction took place.
dine (RAMP) and heterocyclic ketone 7, reacted with a We then subjected (benzoylhydrazino)phosphonates
phosphonate in the presence of titanium(IV) chloride to 18b–21b to cleavage of the hydrazine N–N bonds
provide an inseparable diastereomeric mixture of amino- (Scheme 8, Table 3). Reaction of hydrazinophosphonate
phosphonates 28 in moderate yield (Scheme 7). Because 18b under the mild conditions of 2.2 equivalents samari-
of these unsatisfactory results, aminophosphonates 24, um(II) iodide in tetrahydrofuran–methanol30 at 0 °C re-
26a, 26b, and 28 are not used for the next steps.
sulted in cleavage of the N–N bond, affording free
aminophosphonate 29 in low yield (Table 3, entry 1). Al-
though the reaction as monitored by TLC gave the desired
aminophosphonate 29 cleanly, the workup and purifica-
tion on silica gel seem to be the limiting step for this reac-
tion. Use of hexamethylphosphoramide as cosolvent,
known to increase the reduction power of the samari-
um(II) iodide solution towards functional groups,31 did
not improve the yield (20%). Attempt to cleave the N–N
bond of tosylhydrazine 18a under the same conditions
(SmI2, MeOH) failed. The best result was obtained when
the cleavage reaction of 18b was carried out with sodium/
ammonia in ethanol,32 giving the free amine 29 in 55%
yield (Table 3, entry 2). Unexpectedly, this reduction step
required 35 equivalents of sodium for complete N–N bond
cleavage. Furthermore, other reduction agents, such as
Raney nickel/hydrogen in ethanol,32 hydrogen/palladi-
um(II) hydroxide/carbon in acetic acid, hydrogen/plati-
num(IV) oxide in acetic acid,33a zinc/acetic acid/
trifluoroacetic acid,33b sodium borohydride/nickel(II)
O
Ph
Ph
P(O)(OEt)2
Ph
P
TfOH, P(OEt)3
N
N
P
Ph
CH2Cl2, 0 °C → r.t.
H
O
24
36%
23
KOP(OEt)2, (6 equiv)
P(O)(OEt)2
OBn
OBn
BF3⋅OEt2 (3 equiv)
N
N
X
H
X
toluene, 0 °C → r.t., 2 h
26a (30%)
26b (24%)
X = NCO2Et
X = CH2
25a
25b
Scheme 6
P(O)(OEt)2
(MeO)2P(O)TMS
TiCl4
N
N
N
N
X
H
X
CH2Cl2–Et2O, –78 °C → r.t.
OMe
X = NCO2Et
27
28
dr 65:35
54%
OMe
Scheme 7
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

2356
N. Rabasso, A. Fadel
PAPER
the new amino acid hydrochloride 3a·2HCl (a cucurbitine
analogue) quantitatively (Scheme 10). Hydrolysis of ami-
nophosphonates 31 and 32 with six molar hydrochloric
acid at reflux, followed by treatment with propylene
oxide, provided the new (3-aminotetrahydrothiophen-3-
yl)phosphonic acid (3c) and (1-aminocyclopentyl)phos-
phonic acid (3d),9b in quantitative yields (Scheme 10).
Additionally, hydrolysis of 32 was also achieved with tri-
methylsilyl iodide, followed by treatment with propylene
oxide.34
O
OEt
O
OEt
OEt
P
P
OEt
Method A: SmI2
N
NH
NH2
29–32
Method B: Na/NH3
X
X
H
Bz
18b–21b
Scheme 8
Table 3 Cleavage of the N–N Bonds of Hydrazines 18b–21ba
Entry Hydrazine X
Conditionsa
A: SmI2
Yield (%)Product
1
2
3
4
5
6
18b
18b
19b
20b
21b
21b
NCO2Et
NCO2Et
O
20
29
29
30
31
32
32
O
OH
OH
O
OEt
OEt
P
P
i. 6 M HCl, reflux, 60 h
B: Na/NH3
A: SmI2
55
O
NH2
NH2
ii. EtOH,
decb
50
X
X
29 X = NCO2Et
31 X = S
3a X = NH
3c X = S
quant.
S
A: SmI2
32 X = CH2
3d X = CH2
CH2
A: SmI2
32
Scheme 10
CH2
B: Na/NH3
15
a See Scheme 8. Reaction conditions: Method A: SmI2 (2.2 equiv),
THF, MeOH, 0 °C to r.t., 1 h; Method B: Na (35 equiv), liquid NH3,
THF–EtOH, –50 °C to r.t., 1 h.
In summary, we have developed an easy and efficient
four-step synthesis of new (3-amino-3-heterocyclopen-
tyl)phosphonic acids 3a and 3c and (aminocyclopen-
tyl)phosphonic acid 3d. Thus, starting from readily
available 3-heterocyclic ketones 7–9 and commercially
available cyclopentanone (13), we have demonstrated that
the hydrazones formed from these ketones undergo nu-
cleophilic addition of phosphites to give the heterocyclic
aminophosphonates 18–21 in good to acceptable yields.
Subsequent cleavage of the N–N bonds with sodium/liq-
uid ammonia or samarium(II) iodide was accomplished in
acceptable yields. Finally, acid hydrolysis of the phospho-
nate functions provided amino-substituted phosphonic
acids in quantitative yields. This new approach to the syn-
thesis of aminophosphonates from five-membered hetero-
cyclic ketones and hydrazines constitutes an interesting
and useful alternative to our previously reported method
on six-membered-ring heterocycles.20 This series of ex-
periments confirms that the reactivity of five-membered-
ring compounds is very often different from that of the
six-membered analogues.
b Decomposition.
chloride in ethanol,33c and sodium bis(2-methoxy-
ethoxy)aluminum hydride in toluene at reflux,33d did not
cleave hydrazinophosphonates 18.
Cleavage of (benzoylhydrazino)phosphonate 19b (a furan
derivative) under the same conditions afforded a mixture
of degradation products (Table 3, entry 3). In contrast, the
tetrahydrothiophene derivative 20b and cyclopentyl de-
rivative 21b reacted with samarium(II) iodide to furnish
the desired free aminophosphonates 31 and 32 in the ac-
ceptable yields of 50% and 32%, respectively (Table 3,
entries 4 and 5). In addition, 21b was reduced by sodium/
ammonia or tributylstannane to give 32 in 15% yield
(Table 3, entry 6) or to form degradation products, respec-
tively.
These results are probably explained by the formation of
the radical 33 in the presence of samarium(II) iodide or
sodium/ammonia, which by fragmentation gives radical
34 (Scheme 9). By hydrogen abstraction, free amines 29–
32 form (Scheme 9). Although we were not able to isolate
any byproducts, the possible ring-opening rearrangement
of heterocyclic radical 34 cannot be excluded.
All reactions were carried out under an argon atmosphere and under
magnetic stirring. rac-a-Methylbenzylamine, tosylhydrazine (22a),
benzoylhydrazine (22b), RAMP, AcOH, TfOH, cyclopentanone
(13), dihydrothiophen-3-one (9), TFA, BF3·OEt2, Pd(OH)2/C
(20%), P(OEt)3, HP(OEt)2, (MeO)2P(O)TMS, KHMDS, and propy-
lene oxide were purchased from Aldrich. Dihydropyrrolidin-3-one
Subsequent phosphonate hydrolysis and methoxycarbon-
yl group deprotection of 29 was accomplished simulta-
neously in six molar hydrochloric acid at reflux, to give
35
7,25 dihydrofuran-3-one (8),26 and SmI2 were prepared by litera-
ture procedures. P(OEt)3 and HP(OEt)2 were distilled under reduced
pressure and stored over 4-Å molecular sieves under argon. DMF,
toluene, DMSO, HMPA, and CH2Cl2 were freshly distilled over
CaH2 under argon before use. TLC (source of reported Rf) was car-
ried out on 0.25-mm silica gel plates (Merck F254). Flash chroma-
tography 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 points were de-
termined on a Büchi B-545 capillary melting point apparatus and
are uncorrected. 1H and 13C NMR spectra were measured on a Bruk-
er DRX250 (1H, 250 MHz; 13C, 62.9 MHz) or Bruker AC360 (1H,
M
[P]
O
[P]
NH
SmI2
or
Na/NH3
18–21
N
H
N
Ph
X
X
H
33
34
M = Na+, SmIII
[P] = P(O)(OEt)2
29–32
Scheme 9 Proposed mechanism of N–N bond reduction
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolidinyl- and Tetrahydrothiophenylphosphonic Acids
2357
360 MHz; 13C, 90.56 MHz) spectrometer. Chemical shifts d are re-
ported relative to the solvent resonance (1H: CDCl3, d = 7.27; D2O,
d = 4.8; 13C: CDCl3, d = 77.16). 31P NMR spectra were recorded on
a Bruker AM250 (101.25 MHz) spectrometer, and chemical shifts d
are reported relative to internal 85% H3PO4 (d = 0). HRMS was car-
ried out on a Finnigan MAT 95S spectrometer. All new compounds
were determined to be >95% pure by 1H NMR spectroscopy.
ESI-HRMS: m/z [M + Na]+ calcd for C14H17O3N3Na: 298.1162;
found: 298.1160.
Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C,
60.85; H, 6.13; N, 14.94.
N¢-[(E/Z)-Dihydrofuran-3(2H)-ylidene]benzohydrazide (15b)
Yield: 74%; mp 159 °C; Rf = 0.29 (MeOH–Et2O–NH3, 5:95:0.5).
IR (neat): 3195, 2955, 1635, 1600, 1576, 1530, 1300, 1137, 1044
cm–1.
1H NMR (360 MHz, CDCl3): d (E/Z) = 2.64 (t, 3JH,H = 6.7 Hz, 2 H,
4-H, E), 2.86 (m, 2 H, 4-H, Z), 4.07 (t, 3JH,H = 6.7 Hz, 2 H, 5-H, Z),
4.16 (t, 3JH,H = 6.7 Hz, 2 H, 5-H, E), 4.38 (br s, 2 H, 2-H, Z), 4.42
(br s, 2 H, 2-H, E), 7.30–7.63 (m, 3 H, Harom), 7.63–8.00 (m, 2 H,
Hydrazones 14–17; General Procedure
A procedure published by Shapiro was followed.27a Tosylhydrazine
(22a; 1.115 g, 6 mmol) or benzoylhydrazine (22b; 817 mg, 6 mmol)
was added to a soln of one of ketones 7–9 or 13 (6 mmol) in EtOH
(8 mL). The mixture was heated at 50 °C for 12–24 h. After cooling
to r.t., the mixture was concentrated in vacuo to dryness, and the sol-
id residue was filtered and washed with Et2O; this afforded hydra-
zones 14–17 as white solids; yields: 72–89%. Hydrazones 14a, 14b,
15b, 16b, 17a, and 17b thus obtained were used in the next step
without further purification.
Harom), 8.20 (s, 1 H, NH, Z), 8.59 (s, 1 H, NH, E).
13C NMR (62.9 MHz, CDCl3): d (E/Z) = 27.9 (C-4, E), 32.7 (C-4,
Z), 66.0 (C-2, Z), 67.9 (C-5, E/Z), 69.8 (C-2, E), [6 Carom: 127.3/
127.5 (CH, Z/E), 128.9 (2 CH, E/Z), 132.3 (2 CH, E/Z), 133.1 (C,
E/Z)], 150.1/153.9 (C-3, E/Z), 168.4/166.0 (CON, E/Z).
ESI-HRMS: m/z [M + Na]+ calcd for C11H12N2O2Na: 227.0791;
found: 227.0795.
Ethyl (Z/E)-3-(Tosylhydrazono)pyrrolidine-1-carboxylate
(14a)
Yield: 82%; mp 161 °C; Rf = 0.61 (EtOAc–PE, 70:30).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92, N, 13.72. Found: C,
64.33; H, 5.84; N, 13.82.
IR (neat): 3442, 3054, 2985, 1694, 1674, 1600, 1435, 1385, 1167,
1034, 1010 cm–1.
1H NMR (250 MHz, CDCl3): d (E/Z or Z/E, 60:40) = 1.24 (t,
3JH,H = 7.2 Hz, 3 H, CH3), 2.44 (s, 3 H, CH3 tolyl), 2.54 (t, 3JH,H = 7.2
Hz, 2 H, 4-H, E or Z), 2.71 (t, 3JH,H = 7.2 Hz, 2 H, 4-H, Z or E), 3.50–
3.76 (m, 2 H, 5-H), 3.90–4.07 (m, 2 H, 2-H), 4.12 (q, 3JH,H = 7.2 Hz,
2 H, CH2O), 7.33 (d, 3JH,H = 8.0 Hz, 2 H, Harom), 7.47 (br s, 1 H, NH,
Z or E), 7.68 (s, 1 H, NH, E or Z), 7.83 (d, 3JH,H = 8.0 Hz, 2 H, Harom).
1H NMR (250 MHz, DMSO-d6): d (E/Z) = 1.63 (t, 3JH,H = 7.0 Hz, 3
H, CH3), 2.30 (s, 3 H, CH3 tolyl), 2.43–2.72 (sharp m, 2 H, 4-H),
3.29–3.62 (m, 2 H, 5-H, Z/E), 3.85/4.04 (s, 2 H, 2-H, E/Z), 4.02 (q,
3JH,H = 7.0 Hz, 2 H, CH2O), 7.40 (d, 3JH,H = 8.0 Hz, 2 H), 7.74 (d,
3JH,H = 8.0 Hz, 2 H), 10.37/10.42 (s, 1 H, NH, Z/E).
13C NMR (62.9 MHz, CDCl3): d = 14.8 (CH3), 21.8 (CH3 tolyl), 30.8/
31.6 (C-4, E/Z), 43.9 (C-5, E), 44.3 (C-5, Z), 46.4 (C-2, Z), 49.6 (C-
2, E), 61.7 (CH2O, Z), 61.9 (CH2O, E), [6 Carom: 128.2 (2 CH), 129.9
(2 CH), 135.2 (C-SO2), 144.6 (C)], 153.3 (OCON), 159.6 (C=N).
13C NMR (62.9 MHz, DMSO-d6): d = 14.6 (CH3), 21.0 (CH3 tolyl),
27.6/30.1 (C-4, E/Z), 43.4/44.1 (C-5, Z/E), 46.9/49.1 (C-2, E/Z),
60.6/60.7 (CH2O, E/Z), [6 Carom: 127.4 (2 CH), 129.5 (2 CH), 136.2
(C–SO2), 143.3 (C)], 154.0/154.1 (OCON, E/Z), 160.2/160.4 (C=N,
E/Z).
N¢-[(E/Z)-Dihydrothiophen-3(2H)-ylidene]benzohydrazide
(16b)
Yield: 84%; white solid; mp 191.0 °C; Rf = 0.39 (MeOH–Et2O–aq
NH3, 5:95:0.5).
IR (film): 3210, 3048, 3003, 1650, 1640, 1600, 1578, 1530, 1286,
907 cm–1.
1H NMR (360 MHz, CDCl3): d (E/Z) = 2.74 (t, 3JH,H = 6.8 Hz, 2 H,
4-H, E), 2.90–3.04 (m, 4 H, 2 4-H, Z, and 2 5-H, E), 3.07 (t, 3JH,H
=
6.8 Hz, 2 H, 5-H, Z), 3.52 (app s, 2 H, 2-H, Z), 3.68 (br s, 2 H, 2-H,
E), 7.40–7.57 (m, 3 H, Harom), 7.75–7.81 (m, 2 H, Harom), 8.63 (s, 1
H, NH, Z), 8.74 (s, 1 H, NH, E).
13C NMR (62.9 MHz, CDCl3): d (E/Z) = 28.4 (C-5, E), 29.1 (C-4,
E), 29.6 (C-5, Z), 30.0 (C-2, Z), 36.4 (C-4, Z), 37.4 (C-2, E),
[6 Carom: 127.4 (CH), 128.8 (2 CH), 132.2 (2 CH), 133.2 (C)], 152.5/
155.7 (C-3, E/Z), 163.3/168.3 (CON, E/Z).
ESI-HRMS: m/z [M + Na]+ calcd for C11H12N2OSNa: 243.0563;
found: 243.0570.
Anal. Calcd for C11H12N2OS: C, 59.97; H, 5.49; N, 12.72. Found:
C, 59.61; H, 5.47; N, 12.56.
ESI-HRMS: m/z [M + Na]+ calcd for C14H19O4N3NaS: 348.0988;
N¢-Cyclopentylidene-4-toluenesulfonohydrazide (17a)
found: 348.0994.
Compound 17a was prepared according to the procedure in ref. 27a.
Ethyl (Z/E)-3-(2-Benzoylhydrazono)pyrrolidine-1-carboxylate
(14b)
Yield: 89%; white solid; mp 118.2 °C; Rf = 0.30 (MeOH–Et2O–aq
NH3, 10:90:0.5).
Yield: 88%; white solid.
1H NMR (360 MHz, CDCl3): d (E/Z) = 1.64–1.77 (m, 2 H, 4-H),
1.77–1.90 (m, 2 H, 3-H), 2.14 (t, 3JH,H = 7.2 Hz, 2 H, 5-H), 2.37 (t,
3JH,H = 7.2 Hz, 2 H, 2-H), 2.44 (s, 3 H, CH3), 7.04 (s, 1 H, NH), 7.32
(d, 3JH,H = 8.3 Hz, 2 H, Harom), 7.86 (d, 3JH,H = 8.3 Hz, 2 H, Harom).
IR (KBr): 3680, 3195, 3007, 1708, 1640, 1602, 1578, 1544, 1430,
1112 cm–1.
Analytical data were in accord with the literature values.27a
1H NMR (250 MHz, CDCl3): d (E/Z, 6:4) = 1.29/1.28 (t, 3JH,H = 7.0
Hz, 3 H, CH3), 2.74 (t, 3JH,H = 7.2 Hz, 2 H, 4-H, E), 2.95 (m, 2 H, 4-
H, Z), 3.65–3.76 (m, 2 H, 5-H, Z), 3.79 (t, 3JH,H = 7.2 Hz, 2 H, 5-H,
E), 3.80–3.40 (m, 2 H, 2-H), 4.19 (q, 3JH,H = 7.0 Hz, 2 H, CH2O),
7.33–7.54 (m, 3 H, Harom), 7.76 (d, 3JH,H = 7.6 Hz, 2 H, Harom), 9.27/
9.41 (br s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): d (Z/E or E/Z, 70:30) = 14.7 (CH3),
31.0/31.6 (C-4, E/Z), 43.6/44.3 (C-5, E/Z), 46.4/49.6 (C-2, Z/E),
61.5/61.6 (CH2O, E/Z), [6 Carom: 127.6 (2 CH), 128.5 (2 CH), 132.0
(CH), 133.0 (C)], 154.9 (COON), 159.5 (C=N), 164.4 (NCOPh).
N¢-Cyclopentylidenebenzohydrazide (17b)
Yield: 72%; mp 150.1 °C; Rf = 0.45 (MeOH–Et2O–aq NH3,
10:90:0.5).
1H NMR spectral data were in accord with the literature values,27b
but 13C NMR data were not previously reported.
1H NMR (250 MHz, CDCl3): d = 1.70–1.88 (m, 2 H, 4-H), 1.88–
2.05 (m, 2 H, 3-H), 2.29–2.40 (m, 2 H, 5-H), 2.45–2.75 (m, 2 H, 2-
H), 7.35–7.62 (m, 3 H, Harom), 7.63–7.96 (m, 2 H, Harom), 8.51 (br s,
1 H, NH).
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

2358
N. Rabasso, A. Fadel
PAPER
3
13C NMR (90.56 MHz, CDCl3): d = 24.8 (C-4), 24.9 (C-3), 27.5 (C-
5), 33.7 (C-2), [6 Carom: 127.3 (CH), 128.8 (2 CH), 131.9 (2 CH),
133.8 (C)], 155.5 (C-1), 167.7 (CON).
H, NH), 7.30–7.60 (m, 3 H, Harom), 7.80 (d, JH,H = 8.0 Hz, 2 H,
arom), 8.80 (d, 3JH,H = 6.5 Hz, 1 H, NH).
H
1H NMR (360 MHz, DMSO-d6, 300 K): d = 1.14 (t, 3JH,H = 7.2 Hz,
3 H, CH3), 1.25 (t, 3JH,H = 7.2 Hz, 3 H, CH3), 1.26 (t, 3JH,H = 7.2 Hz,
Hydrazinophosphonates 18–21 by Method A; General Proce-
dure
3 H, CH3), 2.10–2.30 (m, 2 H), 3.37–3.70 (m, 4 H), 3.99 (q, 3JH,H
7.2 Hz, 2 H, CH2O), 4.03–4.17 (m, 4 H, 2 CH2OP), 5.58 (dd, 3JH,H
=
=
TfOH (55 mL, 0.6 mmol, 0.3 equiv) was added to a soln of a hydra-
zone 14–17 (2 mmol) in HP(O)(OEt)2 (2.06 mL, 16 mmol, 8 equiv)
at 0 °C. The mixture was warmed to r.t. over 4 h, and then concen-
trated to dryness in vacuo. The residue was mixed with sat. aq
NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 30 mL). The or-
ganic layers were dried (MgSO4), filtered, and then concentrated in
vacuo to give the crude phosphonate. Purification by flash chroma-
tography (silica gel, MeOH–Et2O, 5:95) gave pure hydrazinophos-
phonates 18–21; yields: 29–96%.
6.1 Hz, 3JP,H = 7.0 Hz, 1 H, NH), 7.43–7.58 (m, 3 H, Harom), 7.79 (d,
3JH,H = 7.2 Hz, 2 H, Harom), 9.78 (d, 3JH,H = 6.1 Hz, 1 H, NH).
13C NMR (90.56 MHz, CDCl3): d (rotamers a/b) = 14.5
(CH3 carbamate), 16.3 (2 CH3CH2OP), 29.2/29.4 (C-4, a/b), 44.1/44.2
(d, J = 8.5 Hz, C-5, a/b), 50.5/51.2 (d, J = 6.7 Hz, C-2, a/b), 61.0
(CH2OCO, a), 61.3 (d, J = 5.6 Hz, CH2OCO, b), 62.8/63.0 (d, 2JP,C
=
6.6 Hz, CH2OP, a/b), 63.3/63.6 (d, 2JP,C = 5.8 Hz, CH2OP, a/b), 64.9
(d, JP,C = 171.6 Hz, C-3, a), 65.7 (d, 1JP,C = 172.9 Hz, C-3, b),
1
[6 Carom: 126.8 (2 CH), 128.4 (2 CH), 132.7 (CH), 132.1/132.6 (C,
a/b)], 154.6/154.9 (C, a/b), 165.9 (CON).
31P NMR (101.25 MHz, CDCl3): d [two rotamers (a/b, 70:30)] =
Hydrazinophosphonates 18–21 by Method B; General Proce-
dure
P(OEt)3 (380 mL, 2.2 mmol) and TfOH (76 mL, 0.5 equiv) were add-
ed successively to a soln of a hydrazone 14–17 (2 mmol) in CH2Cl2
(15 mL) at 0 °C. The mixture was then stirred at r.t. for 12–24 h. Af-
ter addition of sat. aq NaHCO3 (5 mL), the reaction mixture was ex-
tracted with CH2Cl2 (2 × 30 mL). The organic layer was dried,
filtered, and concentrated under vacuum. The resulting residue was
purified by flash chromatography (silica gel); this gave pure hy-
drazinophosphonates 18–21; yields: 37–68%.
23.64/23.95.
ESI-HRMS: m/z [M + Na]+ calcd for C18H28N3NaO6P: 436.1608;
found: 436.1615.
Anal. Calcd for C18H28N3O6P: C, 52.30; H, 6.83; N, 10.16. Found:
C, 51.83; H, 6.91; N, 9.86.
Diethyl [3-(Benzoylhydrazino)]tetrahydrofuran-3-yl]phospho-
nate (19b)
Prepared by Method B.
Diethyl [1-(Ethoxycarbonyl)-3-(2-tosylhydrazino)pyrrolidin-3-
yl]phosphonate (18a)
Prepared by Method A.
Yield: 37%; colorless oil; Rf = 0.35 (MeOH–Et2O–aq NH3,
5:95:0.5).
Yield: 96%; colorless viscous oil; Rf = 0.33 (MeOH–Et2O–aq NH3,
5:95:0.5).
IR (neat): 3479, 3298, 3057, 2983, 1682, 1602, 1581, 1521, 1277,
1216, 1048, 1020, 968 cm–1.
IR (neat): 3437, 3560, 3121, 2982, 1693, 1682, 1428, 1330, 1230,
1160, 1050 cm–1.
3
1H NMR (250 MHz, CDCl3): d = 1.34 (t, JH,H = 7.0 Hz, 6 H, 2
CH3CH2O), 2.03–2.35 (m, 2 H, 4-H), 3.79–4.00 (m, 3 H, 2 5-H and
2-H), 4.00–4.38 (m, 5 H, 2 CH2OP and 2-H), 5.48 (dd, 3JP,H = 28.5
Hz, 3JH,H = 8.2 Hz, 1 H, NH), 7.32–7.65 (m, 3 H, Harom), 7.75–7.95
(m, 2 H, Harom), 8.85 (d, 3JH,H = 8.2 Hz, 1 H, HNCO).
1H NMR (250 MHz, CDCl3): d (two rotamers a/b) = 1.15–1.40 (m,
9 H, CH3 carbamate + 2 CH3CH2OP), 1.90–2.40 (m, 2 H, 4-H), 2.43 (s,
3 H, CH3 tolyl), 3.20–3.61 (m, 4 H, 2 2-H and 2 5-H), 3.91/3.96 (s, 1
H, NH), 4.00–4.25 (m, 6 H, CH2OCO and 2 CH2OP), 6.87/6.91 (s,
13C NMR (62.9 MHz, CDCl3): d = 16.6 (2 CH3CH2O), 31.5 (d,
1 H, NHTs), 7.30 (d, 3JH,H = 8.0 Hz, 2 H, Harom), 7.75/7.76 (d, 3JH,H
=
2JP,C = 4.6 Hz, C-4), 63.0 (d, 2JP,C = 7.2 Hz, CH2OP), 63.8 (d, 2JP,C
=
8.0 Hz, 2 H, Harom).
6.9 Hz, CH2OP), 67.5 (d, 1JP,C = 174.0 Hz, C-3), 67.9 (d, JP,C = 9.9
Hz, C-2 or C-5), 72.8 (d, JP,C = 7.2 Hz, C-5 or C-2), [6 Carom: 126.9
(2 CH), 128.7 (2 CH), 131.9 (CH), 132.3 (C)], 165.6 (CON).
13C NMR (62.9 MHz, CDCl3): d = 14.8 (CH3 carbamate), 16.5 (2
CH3CH2OP), 21.6 (CH3 tolyl), 30.5 (d, 2JP,C = 2.0 Hz, C-4), 44.3 (C-
2
5), 50.2/51.7 (d, JP,C = 6.5 Hz, C-2), 61.1 (CH2OCO), 63.1 (2
31P NMR (101.25 MHz, CDCl3): d = 24.57.
1
CH2OP), 65.1/64.6 (d, JP,C = 164.9 Hz, C-3), [6 Carom: 128.3 (2
ESI-HRMS: m/z [M + Na]+ calcd for C15H23N2O5PNa: 365.1237;
CH), 129.4 (2 CH), 134.6 (C-SO2), 143.9 (C)], 154.9 (COON).
31P NMR (101.25 MHz, CDCl3): d = 25.11; (101.25 MHz, DMSO-
d6): d (two rotamers) = 24.97/25.11.
found: 365.1244.
Diethyl [3-(Benzoylhydrazino)tetrahydrothiophen-3-yl]phos-
phonate (20b)
ESI-HRMS: m/z [M + Na]+ calcd for C18H30N3NaO7PS: 486.1434;
Prepared by Method B.
found: 486.1433.
Yield: 40%; colorless oil; Rf = 0.79 (MeOH–Et2O–aq NH3,
10:90:0.5).
Anal. Calcd for C18H30N3O7PS: C, 46.64; H, 6.52; N, 9.07. Found:
C, 46.64; H, 6.56; N, 8.73.
IR (neat): 3445, 3261, 3062, 2928, 1659, 1603, 1580, 1447, 1278,
1049, 1025, 972 cm–1.
Diethyl [3-(2-Benzoylhydrazino)-1-(ethoxycarbonyl)pyrroli-
din-3-yl]phosphonate (18b)
Prepared by Method B.
1H NMR (250 MHz, CDCl3): d = 1.23–1.48 (m, 6 H, 2 CH3), 1.88–
2.18 (m, 1 H, 4-H), 2.46–2.68 (m, 1 H, 4-H), 2.88–3.02 (m, 2 H, 2-
H), 3.15–3.35 (m, 2 H, 5-H), 4.10–4.40 (m, 4 H, 2 CH2O), 5.83 (dd,
3JP,H = 32.5 Hz, 3JH,H = 8.8 Hz, 1 H, NH), 7.35–7.70 (m, 3 H, Harom),
7.75–7.95 (m, 2 H, Harom), 8.84 (d, 3JH,H = 8.8 Hz, 1 H, NH).
Yield: 68%; colorless viscous oil; Rf = 0.42 (MeOH–Et2O–aq NH3,
10:90:0.5).
IR (neat): 3445, 3268, 3061, 2925, 1694, 1682, 1603, 1580, 1428,
1232, 1051, 1024, 970 cm–1.
1H NMR (250 MHz, CDCl3, 300 K): d (two rotamers a/b) = 1.13–
1.31 (m, 3 H, CH3), 1.31–1.50 (m, 6 H, 2 CH3), 2.07–2.32 (m, 2 H,
4-H), 3.45–3.75 (m, 4 H, 2 5-H and 2 2-H), 4.00–4.37 (m, 6 H, 2
CH2OP and CH2O), 5.23/5.33 (dd, 3JH,H = 6.5 Hz, 3JP,H = 6.6 Hz, 1
13C NMR (62.9 MHz, CDCl3): d = 16.6 (CH3), 16.7 (CH3), 29.9 (C-
2
4), 33.4 (d, JP,C = 8.6 Hz, C-2), 36.8 (C-5), 62.9 (CH2O), 64.3
1
(CH2O), 69.6 (d, JP,C = 170.1 Hz, C-3), [6 Carom: 126.9 (2 CH),
128.8 (2 CH), 131.9 (CH), 134.0 (C)], 166.4 (CON).
31P NMR (101.25 MHz, CDCl3): d = 24.45.
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolidinyl- and Tetrahydrothiophenylphosphonic Acids
2359
ESI-HRMS: m/z [M + Na]+ calcd for C15H23N2NaO4PS: 381.1008;
found: 381.1009.
1H NMR (300 MHz, CDCl3): d = 1.70 (m, 4 H, 2 H-C-3 and 2 H-4),
2.54–2.60 (m, 4 H, 2 H-2 and 2 H-5), 7.29–7.38 (m, 6 H, Harom).
Anal. Calcd for C15H23N2O4PS: C, 50.27; H, 6.47; N, 7.82. Found:
C, 50.32; H, 6.51; N, 8.14.
13C NMR (90.56 MHz, CDCl3): d = 24.3 (C-3 and C-4), 38.5 (C-2
or C-5), 38.7 (C-5 or C-2), [12 Carom: 128.0 (2 CH), 128.2 (2 CH),
131.1 (CH), 131.2 (CH), 131.3 (2 CH),131.4 (2 CH), 133.3 (C)
135.0 (C)], 202.8 (d, 2JP,C = 10.2 Hz, C-1).
Diethyl [1-(2-Tosylhydrazino)cyclopentyl]phosphonate (21a)
Prepared by Method A.
31P NMR (121.49 MHz, CDCl3): d = 19.39.
Yield: 90%; white solid; mp 121.5 °C; Rf = 0.27 (MeOH–CH2Cl2–
aq NH3, 5:95:0.5).
Diethyl {1-[(Diphenylphosphoryl)amino]cyclopentyl}phospho-
nate (24)
IR (film): 3425, 3300, 3150, 2958, 1596, 1439, 1330, 1220, 1162,
1041, 1022, 966 cm–1.
Prepared by Method B (as for preparation of phosphonates 18–21)
from amide 23.
3
1H NMR (360 MHz, CDCl3): d = 1.34 (t, JH,H = 7.2 Hz, 6 H, 2
Yield: 36% (triple purification on silica gel from a mixture of uni-
dentified products); colorless oil; Rf = 0.40 (MeOH–Et2O–aq NH3,
5:95).
1H NMR (300 MHz, CDCl3): d = 1.33 (t, J = 7.0 Hz, 6 H, CH3),
1.46–1.70 (m, 2 H), 1.70–1.88 (m, 2 H), 1.88–2.18 (m, 4 H), 3.35
(dd, 2JP,H = 8.4 Hz, 3JP,H = 3.0 Hz, 1 H, NH), 4.17 (q, J = 7.0 Hz, 2
H), 4.20 (q, J = 7.0 Hz, 2 H), 7.12–7.58 (m, 6 H), 7.59–8.08 (m, 4
H).
CH3CH2O), 1.40–1.90 (m, 8 Hcycle), 2.44 (s, 3 H, CH3 tolyl), 3.71 (s,
1 H, NH), 4.00–4.20 (m, 4 H, 2 CH2OP), 6.49 (s, 1 H, HNSO2), 7.31
(d, 3JH,H = 8.0 Hz, 2 H, Harom), 7.79 (d, 3JH,H = 8.0 Hz, 2 H, Harom).
13C NMR (90.56 MHz, CDCl3): d = 16.3 (CH3CH2O), 16.4
(CH3CH2O), 21.3 (CH3 tolyl), 24.1 (C-4), 24.2 (C-3), 32.37 (C-5),
32.43 (C-2), 62.2 (d, 2JP,C = 6.8 Hz, 2 CH2OP), 66.0 (d, 1JP,C = 148.3
Hz, C-1), [6 Carom: 128.1 (2 CH), 129.1 (2 CH), 135.0 (C-CH3),
143.4 (C-SO2)].
31P NMR (161.9 MHz, CDCl3): d = 21.28 (d, JP,P = 25.3 Hz,
3
31P NMR (101.25 MHz, CDCl3): d = 30.15.
POPh2), 30.12 [d, 3JP,P = 25.3 Hz, PO(OEt)2].
Anal. Calcd for C16H27N2O5PS: C, 49.22; H, 6.97; N, 7.17. Found:
C, 49.26; H, 7.12; N, 7.17.
1-(Ethoxycarbonyl)pyrrolidin-3-one O-Benzyloxime (25a)
O-Benzyloxime 25a was prepared by a general procedure from pyr-
rolidinone 7 (353 mg, 2.25 mmol), H2NOBn·HCl (358 mg, 2.25
mmol), and K2CO3 (310 mg, 2.25 mmol) in EtOH (10 mL). Purifi-
cation by chromatography (silica gel, Et2O–PE, 90:10) gave an E/Z
mixture of oxime 25a.
Diethyl [1-(Benzoylhydrazino)cyclopentyl]phosphonate (21b)
Prepared by Method B.
Yield: 61%; colorless oil; Rf = 0.70 (MeOH–Et2O–aq NH3,
10:90:0.5).
Yield: 380 mg (64%); colorless oil.
IR (neat): 3480, 3274, 3061, 2977, 1652, 1603, 1580, 1455, 1225,
1049, 1026, 968 cm–1.
1H NMR (250 MHz, CDCl3): d (E/Z, 70:30) = 1.27 (t, J = 7.0 Hz, 3
H, E/Z), 2.72/2.80 (t, J = 7.5 Hz, 2 H, E/Z), 3.55/3.70 (m, 2 H, E/Z),
4.01/4.26 (m, 2 H, E/Z), 4.16 (t, J = 7.0 Hz, 2 H, CH2CH3, E/Z),
5.10/5.11 (s, 2 H, HBn, E/Z), 7.36 (br s, 5 H, E/Z).
3
1H NMR (360 MHz, CDCl3): d = 1.32 (t, JH,H = 7.0 Hz, 6 H, 2
CH3CH2O), 1.66 (sharp m, 2 H, Hcycle), 1.68–2.10 (m, 6 H, Hcycle),
4.07–4.24 (m, 4 H, 2 CH2OP), 5.01 (dd, 3JH,H = 7.0 Hz, 3JP,H = 27.0
Hz, 1 H, NH), 7.30–7.50 (m, 3 H, Harom), 7.70–7.90 (m, 2 H, Harom),
8.90 (d, 3JH,H = 7.0 Hz, 1 H, NH).
Diethyl {3-[(Benzyloxy)amino]-1-(ethoxycarbonyl)pyrrolidin-
3-yl}phosphonate (26a)
13C NMR (90.56 MHz, CDCl3): d = 16.6 (2 CH3CH2O), 24.6 (C-3),
24.7 (C-4), 32.4 (C-2 and C-5), 63.0 (d, 2JP,C = 7.3 Hz, 2 CH2OP),
67.1 (d, 1JP,C = 167.0 Hz, C-1), [6 Carom: 126.9 (2 CH), 128.7 (2 CH),
131.7 (CH), 132.7 (C)], 165.5 (CON).
31P NMR (101.25 MHz, CDCl3): d = 28.81.
HRMS data could not be obtained.36
BF3·OEt2 (300mL, 3 eq, 2.463 mmol) was added to a soln of oxime
25a (215 mg, 0.821 mmol) in toluene at 0 °C. After the mixture had
stirred for 10 min, a soln of KP(O)(OEt)2 [prepared from
HP(O)(OEt)2 (640 mL, 4.92 mmol) and a soln of KHMDS (9.84 mL,
4.92 mmol) in toluene (1 mL)] was added. The mixture was stirred
at r.t. for 24 h. Sat. aq NaHCO3 (5 mL) was added to the mixture,
which was then extracted with EtOAc (3 × 70 mL). The organic lay-
er was concentrated and purified by chromatography (silica gel,
MeOH–Et2O–NH3, 2:98:0.5); this gave starting oxime 25a (120
mg, 55%) and phosphonate 26a.
N-Cyclopentylidene-P,P-diphenylphosphinic Amide (23)
Cyclopentanone oxime was prepared by a general procedure from
cyclopentanone (13; 555 mg, 6.6 mmol), H2NOH·HCl (459 mg, 6.6
mmol), and K2CO3 (912 mg, 6.6 mmol) in EtOH (10 mL). This gave
crude cyclopentanone oxime, which was used without further puri-
fication; yield: 643 mg (98%).
Yield: 100 mg (30%); colorless oil; Rf = 0.66 (MeOH–Et2O–aq
NH3, 10:90:0.5).
1H NMR (250 MHz, CDCl3): d = 1.02/1.36 (m, 9 H, 3 CH3), 1.84–
2.02 (m, 1 H, H-4), 2.02–2.38 (m, 1 H, H-4), 3.30–3.77 (m, 4 H, 2
H-2 and 2 H-5), 3.93–4.26 (m, 6 H, 2 CH2OP and CH2OOC), 4.68
(br s, 2 H, CH2ON), 5.94 (d, 3JP,H = 10.5 Hz, 1 H, HNO), 7.32 (br s,
5 H).
13C NMR (62.9 MHz, CDCl3): d (two rotamers) = 14.9
(CH3CH2OCO), 16.4 (CH3CH2OP), 16.5 (CH3CH2OP), 29.8/30.1
(C-4), 44.6/44.9 (d, 3JP,C = 8.4 Hz, C-5), 50.1/50.5 (d, 2JP,C = 11.0
Phosphinic amide 23 was prepared according to a literature proce-
dure.28 A soln of crude cyclopentanone oxime (640 mg, 6.46 mmol)
in CH2Cl2 (10 mL) was cooled to –78 °C and then successively
treated with Et3N (1.012 mL, 7.26 mmol) and Ph2PCl (1.60 g, 7.26
mmol). The mixture was stirred at –78 °C to r.t. for 3 h. Sat. aq
NH4Cl (10 mL) was added to the reaction mixture, which was then
extracted with CH2Cl2 (3 × 70 mL). The organic layer was dried
(MgSO4), filtered, and concentrated. Purification (silica gel,
CH2Cl2–PE, 20:80) afforded amide 23.
2
Hz, C-2), 61.2 (CH3CH2OCO), 62.4/62.6 (d, JP,C = 5.6 Hz,
1
CH2OP), 65.7/64,9 (d, JP,C = 152.0 Hz, C-3), 77.7 (CH2Ph), [6
Yield: 1.39 g (76%); viscous oil; Rf = 0.24 (Et2O–PE, 80:20).
IR (neat): 3230, 3057, 1699, 1635, 1591, 1438, 1184, 1125 cm–1.
Carom: 128.1 (CH), 128.4 (2 CH), 128.8 (2 CH), 137.0 (C)], 155.6
(COO).
31P NMR (101.25 MHz, CDCl3): d = 26.0.
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

2360
N. Rabasso, A. Fadel
PAPER
Diethyl {1-[(Benzyloxy)amino]cyclopentyl}phosphonate (26b)
Phosphonate 26b was prepared from benzyloxime 25b29 by the pro-
cedure described above for the preparation of 26a.
Free Aminophosphonate 29 by Cleavage of the Hydrazine N–N
Bond with Sodium/Ammonia32 (Method B)
Liquid NH3 (4 mL) was condensed into a soln of hydrazinophos-
phonate 18b (0.6 mmol) in THF (1 mL) and absolute EtOH (1 mL)
cooled to –78 °C. Then Na (485 mg, 35 equiv) was added in small
portions. The mixture was warmed to –50 °C and stirred at this tem-
perature for 1 h. Then the reaction mixture was degassed at r.t. with
argon to remove the excess liquid NH3. The resulting residue was
quenched with solid NH4Cl (1 g) and extracted with EtOAc (3 × 10
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, MeOH–Et2O–aq NH3,
10:90:0.5); this provided free aminophosphonate 29.
Yield: 24%; colorless oil; Rf = 0.74 (MeOH–Et2O–aq NH3,
5:95:0.5).
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.0 Hz, 6 H, CH3),
1.62/1.84 (m, 6 H, HBn), 1.91–2.08 (m, 2 H, 1 H-2 and 1 H-5), 4.04–
4.24 (m, 4 H, CH2OP), 4.74 (s, 2 H, CH2ON), 5.81–5.90 (br s, 1 H,
NH), 7.31–7.39 (m, 5 H).
3
13C NMR (62.9 MHz, CDCl3): d = 16.4 (d, JP,C = 5.8 Hz, 2
CH3CH2OP), 25.1 (C-3), 25.2 (C-4), 32.4 (d, 2JP,C = 4.5 Hz, C-2 and
C-5), 61.8 (d, 2JP,C = 6.8 Hz, 2 CH2OP), 67.8 (d, 1JP,C = 148.4 Hz,
C-1), 77.3 (CH2ON), [6 Carom: 127.7 (2 CH), 128.2 (2 CH), 128.5
(CH), 137.5 (C)].
Yield: 97 mg (55%).
31P NMR (101.25 MHz, CDCl3): d = 31.07.
Free Aminophosphonates 29–32 by Cleavage of the Hydrazine
N–N Bond with Samarium(II) Iodide30 (Method A); General
Procedure
(R)-N-[1-(Ethoxycarbonyl)pyrrolidin-3-ylidene]-2-(methoxy-
methyl)pyrrolidin-1-amine (27)
Pyrrolidin-1-amine 27 was prepared by a general procedure from
pyrrolidinone 7 (277 mg, 1.76 mmol) and RAMP (235 mL, 1.76
mmol) in EtOH (4 mL) at 50 °C for 2 h. After purification by chro-
matography (silica gel, MeOH–Et2O, 2:98) an E/Z mixture of hy-
drazone 27 was obtained.
A 1.2 M soln of SmI2 in THF (3.6 mmol) was added to a soln of one
of the hydrazinophosphonates 18b–21b (0.43 mmol) in MeOH (3
mL) at 0 °C. The mixture was stirred for 20 min at the same temper-
ature and then concentrated under reduced pressure to remove the
solvents. The residue was extracted with 1 M HCl (2 × 5 mL) and
the aqueous layers were washed with Et2O (8 mL), made alkaline
with 1 M aq NaOH, and extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with H2O (2 × 1 mL) and
brine (2 × 2 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy (silica gel, MeOH–Et2O–aq NH3, 10:90:0.5); this afforded free
aminophosphonates 29, 31, and 32; yields: 20–50%.
Yield: 300 mg (63%); Rf = 0.66 and 0.53 (Z/E), (MeOH–Et2O–aq
NH3, 10:90:0.5).
IR (neat): 2974, 2926, 2875, 1705, 1625, 1424, 1113 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.18 (t, J = 7.0 Hz, 3 H, Z), 1.28
(t, J = 7.0 Hz, 3 H, E), 1.38–1.64 (m, 1 H), 1.64–1.97 (m, 3 H), 2.14–
2.64 (m, 2 H), 3.01–3.47 (m, 5 H), 3.18/3.19 (s, 3 H, OCH3, Z/E),
3.47–3.80 (m, 2 H), 3.80–3.95 (m, 2 H), 4.00 (q, J = 7.0 Hz, 2 H,
CH2O, Z), 4.01 (q, J = 7.0 Hz, 2 H, CH2O, E).
13C NMR (62.9 MHz, CDCl3): d = 14.6 (CH3), 22.4 (C-4 RAMP),
26.3/26.6 (C-3 RAMP, E/Z), 28.5/29.1 (C-4, Z), 31.0/31.8 (C-4, E),
43.1/44.4 (C-5, E/Z), 47.0/47.3 (C-2, Z), 49.7 (C-2, E), 54.0/54.5
(C-5 RAMP, E/Z), 59.0 (C-2 RAMP), 61.0 (CH2OCO), 66.3 (CH3O),
75.1/75.6 (CH2OCH3, E/Z), 154.9 (COO), 159.9 (C=N).
Diethyl [3-Amino-1-(ethoxycarbonyl)pyrrolidin-3-yl]phospho-
nate (29)
The cleavage of the hydrazine N–N bond was achieved by Method
B (Na/NH3 method).
Yield: 55%; colorless oil; Rf = 0.15 (MeOH–Et2O–aq NH3,
10:90:0.5).
IR (neat): 3460, 3382, 3051, 2982, 1695, 1428, 1232, 1048, 1023,
966 cm–1.
Dimethyl ((R/S)-1-(Ethoxycarbonyl)-3-{[(R)-2-(methoxymeth-
yl)pyrrolidin-1-yl]amino}pyrrolidin-3-yl)phosphonate (28)
A soln of hydrazone 27 (122 mg, 0.453 mmol) in CH2Cl2 (2.3 mL)
was added to a 1 M soln of TiCl4 in CH2Cl2 (906 mL) at –78 °C. Af-
ter the mixture had stirred for 15 min at –78 °C, Et2O (200 mL) was
added, and 15 min later, (MeO)2P(O)TMS (130 mL, 0.680 mmol)
was added. The stirred reaction mixture was warmed slowly from
–78 °C to r.t. over 3 h. After hydrolysis with a sat. aq soln of KF/
NH4Cl, the mixture was extracted with CH2Cl2 (3 × 50 mL). Con-
centration of the organic layer and purification (silica gel, MeOH–
Et2O, 10:90) gave an inseparable diastereomeric mixture of hy-
drazinophosphonates 28.
1H NMR (250 MHz, CDCl3): d (two conformers a/b) = 1.24 (t,
3
3JH,H = 7.0 Hz, 3 H, CH3CH2OCO), 1.35 (t, JH,H = 7.0 Hz, 3 H,
CH3CH2OP), 1.36 (t, 3JH,H = 7.0 Hz, 3 H, CH3CH2OP), 1.51 (br s, 2
H, NH2), 1.70–1.84 (m, 1 H, 4-H), 2.17–2.37 (m, 1 H, 4-H), 3.29
(ABX, J = 2.5 Hz, JAB = 11.2 Hz, 1 H, 2-H, a), 3.38 (ABX, J = 1.5
Hz, JA,B = 11.2 Hz, 1 H, 2-H, b), 3.52–3.67 (m, 2 H, 5-H), 3.70
(ABX, JA,B = 11.2 Hz, J = 8.3 Hz, 1 H, 2-H, a), 3.75 (dd, JA,B = 11.2
Hz, 7.9 Hz, 1 H, 2-H, b), 4.04–4.24 (m, 6 H, 3 CH2O).
13C NMR (62.9 MHz, CDCl3): d (two conformers a/b) = 14.9
(CH3 carbamate), 16.7 (CH3CH2OP), 16.8 (CH3CH2OP), 34.0/34.7 (C-
4, a/b), 44.3/44.6 (d, 3JP,C = 9.3 Hz, C-5, a/b), 54.8/55.2 (d, 2JP,C
13.4 Hz, C-2, a/b), 57.2/58.3 (d, JP,C = 161.2 Hz, C-3, a/b), 61.3
(CH2OCO), 62.8 (CH2OP), 62.9 (CH2OP), 155.1/155.3 (COO, a/b).
=
1
Yield: 100 mg (54%); colorless oil; Rf = 0.33 (MeOH–Et2O–aq
NH3, 10:90:0.5).
31P NMR (101.25 MHz, CDCl3): d = 27.03.
ESI-HRMS: m/z [M + Na]+ calcd for C11H23N2NaO5P: 317.1237;
1H NMR (360 MHz, CDCl3, 320 K): d (diastereomers a/b, 65:35) =
1.27/1.28 (t, J = 7.2 Hz, 6 H, CH3, a/b), 1.48–1.65 (m, 1 H, HRAMP),
1.65–1.83 (m, 1 H, HRAMP), 1.83–2.00 (m, 1 H, HRAMP), 2.17–2.37
(m, 2 H, H-4), 2.37–2.64 (m, 1 H), 2.64–2.88 (m, 1 H), 3.00 (s, 1 H,
NH), 3.25–3.40 (m, 1 H), 3.32/3.35 (s, OCH3, b/a), 3.40–3.68 (m, 5
H), 3.68–3.95 (m, 1 H), 3.78 (s, 3 H, CH3OP, b), 3.80 (s, 3 H,
CH3OP, a), 3.81 (s, 3 H, CH3OP, b), 3.83 (s, 3 H, CH3OP, a), 4.15/
4.16 (q, J = 7.2 Hz, 2 H, CH2OCO, a/b).
found: 317.1239.
Diethyl (3-Aminotetrahydrothiophen-3-yl)phosphonate (31)
The cleavage of the hydrazine N–N bond was achieved by Method
A (SmI2 method).
Yield: 50%; pale yellow oil; Rf = 0.26 (MeOH–Et2O–aq NH3,
31P NMR (121.49 MHz, CDCl3): d (297 K) = 29.49/29.40 (b/a);
d (320 K) = 29.31 (a and b).
5:95:0.5).
IR (neat): 3420, 3290, 3049, 2925, 1445, 1395, 1238, 1163, 1021,
970 cm–1.
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolidinyl- and Tetrahydrothiophenylphosphonic Acids
2361
1H NMR (250 MHz, CDCl3): d = 1.38 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
1.60 (br s, 2 H, NH2), 2.03–2.33 (m, 2 H, 4-H), 2.72 (ddd, J = 11.0,
1.5, 1.5 Hz, 1 H, 2-H), 3.02 (ddd, J = 2.5, 7.2, 9.8, Hz, 1 H, 5-H),
3.14 (ddd, J = 7.2, 9.8, 10.7 Hz, 1 H, 5-H), 3.32 (dd, 3JH,H = 11.0 Hz,
3JP,H = 7.5 Hz, 1 H, 2-H), 4.21 (dq, 3JP,H = 1.8 Hz, 3JH,H = 7.0 Hz, 2
(1-Aminocyclopentyl)phosphonic Acid (3d)
Hydrolysis of aminophosphonate with TMSI according to our pre-
viously reported method:8b TMSI (150 mg, 107 mL, 0.75 mmol) was
added dropwise to a stirred soln of diethyl phosphonate 32 (55 mg,
0.25 mmol) in CH2Cl2 (3 mL) and stirring was continued at r.t. for
6 h. The volatiles were then removed in vacuo and a mixture of
EtOH (2 mL) and an excess of propylene oxide (1 mL) were added,
followed by stirring for 18 h. Once precipitation of pure aminophos-
phonic acid was complete, it was collected by filtration and dried
under high vacuum.
3
H, CH2O), 4.24 (dq, 3JP,H = 1.8 Hz, JH,H = 7.0 Hz, 2 H, CH2O).
13C NMR (62.9 MHz, CDCl3): d = 16.6 (d, 3JP,C = 5.5 Hz, 2 CH3),
29.3 (d, 2JP,C = 16.2 Hz, C-4), 39.5 (d, 3JP,C = 7.5 Hz, C-5), 40.3 (d,
2
2JP,C = 10.3 Hz, C-2), 62.8 (d, JP,C = 7.2 Hz, 2 CH2O), 71.6 (d,
1JP,C = 177.1 Hz, C-3).
Yield: 40 mg (100%); white solid; mp 243.5 °C (crystallized from
H2O–EtOH); Rf = 0.45 (aq NH3–MeOH, 20:80).
1H NMR (360 MHz, D2O): d = 1.70–1.90 (m, 6 H, Hcycle), 2.10–2.38
(m, 2 H, Hcycle).
31P NMR (101.25 MHz, CDCl3): d = 27.41.
HRMS data could not be obtained.36
Diethyl (1-Aminocyclopentyl)phosphonate (32)
The cleavage of the hydrazine N–N bond was achieved by Method
A (SmI2 method).
Analytical data were in accord with the literature values.9b
Yield: 32%; pale yellow oil; Rf = 0.29 (MeOH–Et2O–aq NH3,
10:90:0.5).
References
(1) (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193. (b) Maier, L. Phosphorus Sulfur
Relat. Elem. 1983, 14, 295. (c) Baylis, E. K.; Campbell, C.
D.; Dingwall, J.-G. J. Chem. Soc., Perkin Trans. 1 1984,
2845. (d) Maier, L. Phosphorus, Sulfur Silicon Relat. Elem.
1990, 53, 43. (e) Hudson, H. R.; Pianka, M. Phosphorus,
Sulfur Silicon Relat. Elem. 1996, 109-110, 345.
1H NMR (250 MHz, CDCl3): d = 1.35 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
1.40–1.65 (m, 4 H, 2 Hcycle and NH2), 1.65–1.80 (m, 2 Hcycle), 1.80–
2.00 (m, 2 Hcycle), 2.00–2.20 (m, 2 Hcycle), 4.17 (dq, 3JP,H = 7.2 Hz,
3JH,H = 7.0 Hz, 4 H, CH2O).
Analytical data were in accord with the literature values.9b
(3-Aminopyrrolidin-3-yl)phosphonic Acid Dihydrochloride
(3a·2HCl)
A soln of diethyl phosphonate 29 (59 mg, 0.2 mmol) in 6 M aq HCl
(3 mL) was heated at reflux for 12 h. The solvent was evaporated
under reduced pressure. The residue was dissolved in MeOH (2
mL), and then the soln was concentrated again, to afford the crude
aminophosphonic acid hydrochloride salt 3a·2HCl.
(2) Peyman, A.; Budt, K. H.; Spanig, J.; Ruppert, D. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1720.
(3) Cheng, L.; Goodwin, C. A.; Scully, M. F.; Kakkar, V. V.;
Claeson, G. Tetrahedron Lett. 1991, 32, 7333.
(4) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids; Wiley: New York, 2000.
(5) For recent enantioselective synthesis of a-aminophosphonic
acids, see: (a) Bennani, Y. L.; Hanessian, S. Chem. Rev.
1997, 97, 3161. (b) Kolodiazhnyi, O. I. Tetrahedron:
Asymmetry 1998, 9, 1279; and references cited therein.
(6) (a) Vercruysse, K.; Dejugnat, C.; Munoz, A.; Etemad-
Moghadam, G. Eur. J. Org. Chem. 2000, 281; and references
cited therein. (b) Joly, G. D.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 4102; and references cited therein.
(7) For recent synthesis of cyclopropyl aminophosphonic acids,
see: Yamazaki, S.; Takada, T.; Imanishi, T.; Moriguchi, Y.;
Yamabe, S. J. Org. Chem. 1998, 63, 5919; and references
cited therein.
(8) For synthesis of chiral nonracemic cyclopropyl amino-
phosphonic acids, see: (a) Fadel, A. J. Org. Chem. 1999, 64,
4953. (b) Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000,
2153. (c) Fadel, A.; Tesson, N. Tetrahedron: Asymmetry
2000, 11, 2023. (d) Tesson, N.; Dorigneux, B.; Fadel, A.
Tetrahedron: Asymmetry 2002, 13, 2267.
(9) (a) Hercouet, A.; Le Corre, M.; Carboni, B. Tetrahedron
Lett. 2000, 41, 197. (b) For cyclobutyl and cyclopentyl
derivatives, see: Guéguen, C.; About-Jaudet, E.; Collignon,
N.; Savignac, P. Synth. Commun. 1996, 26, 4131.
(10) For cyclopentyl derivatives, see: (a) Ranu, B. C.; Hajra, A.
Green Chem. 2002, 4, 551. (b) Wieczorek, J. C.; Gancarz,
R.; Bielecki, K.; Grzys, E.; Sarapuk, J. Phosphorus, Sulfur
Silicon Relat. Elem. 2001, 174, 119. (c) Stoikov, I. I.;
Repejkov, S. A.; Antipin, I. S.; Konovalov, A. I. Heteroat.
Chem. 2000, 11, 518.
Yield: 100%; mp 280 °C (dec); Rf = 0.66 (MeOH–1.4 M aq NH4OH,
1:1).
IR (KBr): 3431, 2963, 1526, 1446, 1403, 1215, 1080, 915 cm–1.
1H NMR (250 MHz, D2O): d = 2.30–2.55 (m, 1 H, 4-H), 2.59–2.85
(m, 1 H, 4-H), 3.54–3.82 (m, 3 H, 2-H and 2 5-H), 3.89 (dd, 3JP,H
12.5, 3JH,H = 13.2 Hz, 1 H, 2-H).
=
13C NMR (62.9 MHz, D2O): d = 32.1 (C-4), 45.5 (d, 3JP,C = 5.2 Hz,
C-5), 50.9 (d, 2JP,C = 3.7 Hz, C-2), 58.4 (d, 1JP,C = 148.0 Hz, C-3).
31P NMR (101.25 MHz, D2O): d = 11.71.
HRMS data could not be obtained.36
(3-Aminotetrahydrothiophen-3-yl)phosphonic Acid (3c)
Aminophosphonic acid·hydrochloride 3c·HCl, obtained by the pro-
cedure described above to prepare 3a·2HCl, was dissolved in a min-
imum amount of EtOH (1.5 mL); an excess of propylene oxide (5
mL) was added dropwise to this soln, which was stirred at r.t. for 1
h. The volatile compounds were removed by evaporation in vacuo.
Yield: 100%; mp 186 °C; Rf = 0.28 (aq NH3/EtOH/H2O, 20:30:3).
IR (KBr): 3385, 2941, 1538, 1448, 1408, 1175, 1078, 1001, 935
cm–1.
1H NMR (250 MHz, D2O): d = 2.24–2.38 (m, 2 H, 4-H), 2.82–2.98
(m, 2 H, 5-H and 2-H), 2.98–3.13 (ddd, JH,H = 6.0, 5.5 Hz, JA,B
=
11.5 Hz, 1 H, 5-H), 3.29 (dd, 3JP,H = 6.5 Hz, 3JH,H = 13.0 Hz, 1 H, 2-
H).
(11) (a) Wieczorek, J. S.; Gancarz, R.; Bielecki, L.; Grzys, E.;
Sarapuk, J. Phosphorus, Sulfur Silicon Relat. Elem. 2000,
166, 111. (b) Matveera, E. D.; Podrugina, T. A.;
13C NMR (62.9 MHz, D2O): d = 28.7 (d, 2JP,C = 11.7 Hz, C-4), 37.1
(C-5), 38.3 (d, 2JP,C = 2.0 Hz, C-2), 65.9 (d, 1JP,C = 136.1 Hz, C-3).
31P NMR (101.25 MHz, D2O): d = 11.25.
31P NMR (101.25 MHz, CDCl3): d = 12.43.
HRMS data could not be obtained.36
Tishkovskaya, E. V.; Tomilova, L. G.; Zefirov, N. S. Synlett
2003, 2321. (c) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.
Synthesis 2004, 2692.
Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York

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N. Rabasso, A. Fadel
PAPER
(21) For a review, see: Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003; and references cited therein.
(22) Kaboudin, B.; Rahmani, A. Synthesis 2003, 2705.
(23) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S.; Saritha,
B.; Prakash, S. J. Synlett 2003, 505.
(24) Additions of phosphites to hydrazones have been reported
rarely, see: (a) Inokawa, S.; Nakatsukasa, Y.; Horisaki, M.;
Yamashita, M.; Yosida, H.; Ogata, T. Synthesis 1977, 179.
(b) Yamashita, M.; Takeuchi, J.; Nakatani, K.; Oshikawa,
T.; Inokawa, S. Bull. Chem. Soc. Jpn. 1985, 58, 377.
(c) Yamamoto, H.; Hanaya, T.; Kawamoto, H.; Inokawa, S.
Chem. Lett. 1989, 121.
(25) (a) Wu, Y.-H.; Gould, W. A.; Lobeck, W. G. Jr.; Roth, H. R.;
Feldkamp, R. F. J. Med. Chem. 1962, 5, 752. (b) Yadav, J.
S.; Sarkar, S.; Chandrasekhar, S. Tetrahedron 1999, 55,
5449.
(12) For microwave assistance, see: Kabachnick, M. M.;
Zobnina, E. V.; Belatskaya, I. P. Synlett 2005, 1393; and
references cited therein.
(13) GABA-related drugs have shown promising properties as
antiepileptic, antispastic, and antidepressive agents:
Fonnum, F. In Psychopharmacology, Vol. 18; Meltzer, H.,
Ed.; Raven: New York NY, 1987, 173–182.
(14) (a) Tukanova, S. K.; Dzhiembaev, B. Z.; Butin, B. M.
Zh. Obshch. Khim. 1991, 61, 1118; Chem. Abstr. 1992, 116,
6637. (b) Gancarz, R.; Latajka, R.; Halama, A.; Kafarski, P.
Magn. Reson. Chem. 2000, 38, 867. (c) For aminophos-
phonic acid derivatives of substituted piperidines and
tetrathiophenes, see: Bosyakov, Y. G.; Maishinova, G. T.;
Logunov, A. P.; Revenko, G. P. Izv. Nats. Akad. Nauk. Resp.
Kaz., Ser. Khim. 1993, 6, 72; Chem. Abstr. 1995, 123,
112161.
(15) For aminophosphonates of substituted tetrahydropyrans,
see: (a) Kabatschnick, M. I. Izv. Akad. Nauk SSSR, Ser.
Khim. 1967, 1362. (b) Kabatschnick, M. I. Bull. Acad. Sci.
USSR, Div. Chem. Sci. (Engl. Transl.) 1967, 1379. (c) For
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Synthesis 2008, No. 15, 2353–2362 © Thieme Stuttgart · New York