Hydrazinophosphonates and hydrazinobisphosphonates: Novel mitsunobu and arbuzov-type multicomponent application of the Morrison-Brunn-Huisgen betaine

Article abstract of DOI:10.1055/S-0029-1218681

A novel protocol for hydrazinophosphonate and hydrazi-nobisphosphonate synthesis by acylation, sulfonylation, and phosphorylation of the Morrison-Brunn-Huisgen zwitterion has been found. Interestingly, the reaction leads to hydrazinophosphonates via an Arbuzov-type multicomponent pathway. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218681

PAPER
1543
Hydrazinophosphonates and Hydrazinobisphosphonates: Novel Mitsunobu
and Arbuzov-Type Multicomponent Application of the Morrison–Brunn–
Huisgen Betaine
N
ovel Synthesis of
b
H
ydrazinop
d
hosphonates
o
and
H
ydrazi
l
nobisph
a
osphonate
l
s
i Alizadeh,* Sadegh Rostamnia
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: aalizadeh@modares.ac.ir; E-mail: abdol_alizad@yahoo.com
Received 18 December 2009; revised 24 December 2009
apart from its pivotal role in the Mitsunobu reaction11 of-
Abstract: A novel protocol for hydrazinophosphonate and hydrazi-
nobisphosphonate synthesis by acylation, sulfonylation, and phos-
phorylation of the Morrison–Brunn–Huisgen zwitterion has been
found. Interestingly, the reaction leads to hydrazinophosphonates
via an Arbuzov-type multicomponent pathway.
fering the most reliable and universally accepted synthetic
protocol for the stereochemical inversion of a hydroxy
group, the chemistry of the Huisgen zwitterion 6 has re-
ceived only scant attention. According to recent studies
conducted by Lee and co-workers,12 Liu and co-work-
ers,13 Kolasa and Miller,14 and Nair and co-workers,15 re-
action of the Huisgen zwitterion 6 with various
compounds leads to unexpected molecular transforma-
tions based on two-component conditions and phosphine
oxide removal. The application of phosphite instead of
phosphine, however, has received only very limited atten-
tion for synthesis of the Morrison zwitterion.
Key words: trialkyl phosphites, diisopropyl azodicarboxylate, hy-
drazinobisphosphonates, hydrazinophosphonates, multicomponent
reactions
Multicomponent reactions (MCRs), by virtue of their con-
vergence, productivity, facile execution, and generally
high yields of products, have attracted much attention
from the viewpoint of combinatorial chemistry.1
Regarding our interest in the development of zwitterionic
MCRs,16 we tried to develop Johnson–Tebby reactions
wherein the zwitterionic species are generated in situ from
alkynes and trivalent phosphorus (Scheme 2).17
Phosphonates are important synthetic intermediates2 and
have been investigated as biologically active compounds.3
In medicinal chemistry, phosphonates and bisphospho-
nates often exhibit interesting biological properties.4 This
is the case, for instance, for nucleotide-5 or polyiso-
prenoid-derived6 vinylic phosphonates. The synthesis of
phosphonates has been widely examined and a variety of
noncatalytic and catalytic approaches have been described
in the literature.7 The preparation of alkylphosphonates
from phosphites via the Arbuzov reaction is among the
most common synthetic routes.8
CO2R2
+
O
P
O
X
O
X
R1O
R1O
Ar
(R1O) P
+
3
Ar
Cl
R2O2C
CO2R2
CO2R2
X = C, SO
X = C cis-isomer
SO trans-isomer
Scheme 2 Johnson–Tebby zwitterions in the diastereoselective syn-
thesis of vinylphosphonates
In 1958, Morrison described the reaction of trialkyl phos-
phites with azodicarboxylates for the first time
(Scheme 1).9
In this paper, the first examples of Arbuzov-type, three-
component Morrison reactions with formation of P–N and
N–C (N–S, N–P) bonds are reported (Scheme 3).
Brunn and Huisgen clearly demonstrated the intermediary
formation of a zwitterion in the Morrison reaction of
phosphorus(III) with azoesters.10 After this discovery,
The results for the aroylhydrazinophosphonates 3a–j are
summarized in Figure 1. The products were characterized
by spectroscopic analysis. The IR spectrum of 3a exhibit-
O
R1Cl
Arbuzov reaction
P
OMe
R1
OMe
(R1O)3P
1
(MeO)3P
+
O
P
E
N
Morrison reaction
E
O
P
E
N
N
E
N
MeO
MeO
toluene, reflux
8 h
E
N
N
E
Me
E
N
R1O
R1O
N
E
R2
E = CO2R2
+
O
O
Scheme 1 Phosphonate synthesis via the Arbuzov reaction versus
the Morrison reaction
3
Cl
E = CO2i-Pr
2
R2
SYNTHESIS 2010, No. 9, pp 1543–1549
x
x
.
x
x
.2
0
1
0
Advanced online publication: 24.02.2010
DOI: 10.1055/s-0029-1218681; Art ID: Z27509SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Three-component synthesis of aroylhydrazinophosphon-
ates 3

1544
A. Alizadeh, S. Rostamnia
PAPER
ed absorption bands at 1693, 1603, 1539 and 1424 corre- nates 5 were produced. The reaction trend was found to be
sponding to the carbonyl group of the esters, the ArC=O general with various substrates, and the functionalized hy-
group, and the aryl group, respectively. The absorption drazinophosphonates were obtained in good yield. The re-
bands of the phosphonate moiety were observed at 1275 sults are summarized in Figure 2.
(P=O), 1105 and 1010 (PO–Me), and 926 (P–O) cm–1.
Finally, the one-step, Arbuzov-type, three-component
Morrison phosphonate synthesis highlighted the potential
O
P
E
N
O
P
E
N
of the present protocol in the preparation of biologically
interesting hydrazinobisphosphonates18 4 (Scheme 4 and
Figure 2). The structures of 4 and 5 were established by
spectroscopic analysis.
MeO
MeO
EtO
EtO
N
E
N
E
O
O
3a
94%
3b
90%
Cl
Br
Cl
O
O
P
E
N
O
P
E
N
O
P
E
N
P
PhO
PhO
OPh
OPh
Cl
EtO
EtO
MeO
MeO
N
E
N
E
RO
RO
N
E
4
P
toluene, reflux
O
O
O
(RO)3P
+
3d
88%
3c
89%
O
E
Br
N
N
E
O
P
E
N
O
P
E
N
E
toluene, reflux
P
N
Ar
RO
RO
N
S
EtO
EtO
MeO
MeO
N
E
O O
N
E
E = CO2i-Pr
O
O
E
5
S
O
O
Ar
Cl
3e
91%
3f
88%
Scheme 4 Application of the MBH zwitterion for sulfonylhydrazi-
nophosphonate 5 and hydrazinobisphosphonate 4 synthesis
NO2
O
P
E
N
O
E
N
O
O
P
S
MeO
MeO
MeO
N
E
N
N
Ph
MeO
H
O
P
E
N
O
P
E
N
O
E
O
OPh
OPh
OPh
OPh
MeO
MeO
EtO
EtO
3g
93%
3h
88%
N
E
N
E
P
P
O
O
4b
87%
4a
O
P
E
N
O
E
N
88%
O
O
P
MeO
MeO
EtO
EtO
N
E
N
N
N
O
P
E
N
O
P
E
N
O
E
O
O
O
EtO
EtO
MeO
MeO
N
E
N
E
S
S
3i
86%
3j
85%
O
O
O O
5b
94%
5a
95%
Figure 1 Structures of the synthesized aroylhydrazinophosphonates
3a–j
O
P
E
N
O
P
E
N
MeO
MeO
EtO
EtO
N
E
S
N
E
S
The 1H NMR spectrum of 3a exhibited two sharp doublets
O
O
O O
readily recognized as arising from the methoxy groups
5c
92%
5d
91%
3
[d = 3.95 and 4.01, JP–H = 12.2 and 12.2 Hz, P(OMe)2],
and two doublets at 0.97 (3JH–H = 6.2 Hz) and 1.06 (3JH–H
=
Et
O
P
E
N
6.0 Hz), a heptet at 4.87 (3JH–H = 6.2 Hz) and a multiplet
at 5.10, all due to the isopropoxy groups. The aryl moiety
exhibited characteristic signals in the aromatic region of
the spectrum. The 1H-decoupled 13C NMR spectrum of 3a
showed 13 resonances, in agreement with the diisopropyl
1-benzoyl-2-(dimethoxyphosphoryl)-1,2-hydrazinedicar-
EtO
EtO
N
E
S
O
O
5e
88%
Figure 2 Structures of the synthesized hydrazinobisphosphonates
4a,b and sulfonylhydrazinophosphonates 5a–e
1
boxylate structure. The H- and 13C-decoupled 31P NMR
spectrum of 3a exhibited one sharp singlet at d = 1.49,
readily recognized as arising from the phosphonate moi-
ety.
The following mechanism may be postulated to rational-
ize the reaction.10d–g,11–15 Thus, in the synthesis of aroylhy-
drazinophosphonates, Huisgen zwitterion 6, produced
from trialkyl phosphite and azoester, attacks the aroyl
chloride to form an ion pair 7 which presumably gives the
hydrazinophosphonate 3 by elimination of alkyl chloride
via a process resembling the Arbuzov-type reaction
(Scheme 5).
Taking into account the interesting results obtained in the
reaction of the Morrison–Brunn–Huisgen (MBH) betaine
with aroyl chlorides, we extended our studies to sulfonyl
chlorides (Scheme 4). Analogous to the above-described
reaction, when the acyl chloride was replaced by a sulfo-
nyl chloride, functionalized sulfonylhydrazinophospho-
Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Hydrazinophosphonates and Hydrazinobisphosphonates
1545
MS: m/z (%) = 417 (54) [M+ + 1], 313 (16), 127 (46), 105 (100), 77
(21), 43 (33).
Cl
O
N
R
N
(RO)3P
E
E
(RO)2P
E
E
(RO)3P
Anal. Calcd for C17H25N2O8P: C, 49.04; H, 6.05; N, 6.73. Found: C,
49.10; H, 6.10; N, 6.80.
N
N
3
– RCl
O
E
N
Cl
Ar
N
E
Ar
6
7
Diisopropyl 1-Benzoyl-2-(diethoxyphosphoryl)-1,2-hydra-
zinedicarboxylate (3b)
E = CO2i-Pr
O
Yield: 0.4 g (90%); yellow viscous liquid.
Scheme 5 Proposed Arbuzov-type mechanism for hydrazinophos-
phonate synthesis
IR (KBr): 1749 and 1705 (C=O), 1574 and 1435 (Ar), 1273 (P=O),
1337 and 1161 (C–O), 1100 and 1024 (PO–CH2), 874 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 0.91 [d, JH–H = 6.2 Hz, 3 H,
3
In conclusion, a novel synthesis of hydrazinophospho-
nates via a Morrison–Brunn–Huisgen zwitterion reaction
with aroyl, sulfonyl, and phosphoryl chlorides has been
uncovered. This will be a useful strategy for the conver-
OCH(CH3)], 1.00 [m, 3 H, OCH(CH3)], 1.28 [m, 6 H, OCH(CH3)2],
1.33 (t, 3JH–H = 7.1 Hz, 3 H, POCH2CH3), 1.37 (t, 3JH–H = 7.1 Hz, 3
H, POCH2CH3), 4.28 (m, 2 H, POCH2CH3), 4.35 (m, 2 H,
POCH2CH3), 4.80 [heptet, 3JH–H = 6.2 Hz, 1 H, OCH(CH3)2], 5.05
sion of phosphites and azoesters into hydrazinophospho- [m, 1 H, OCH(CH3)2], 7.37 (t, 3JH–H = 7.5 Hz, 2 H, 2 × CH of Ph),
7.46 (t, 3JH–H = 7.2 Hz, 1 H, CH of Ph), 7.55 (d, 3JH–H = 7.7 Hz, 2 H,
nate
and
hydrazinobisphosphonate
derivatives.
2 × CH of Ph).
Furthermore, this new implementation of phosphites, in-
stead of phosphines, produces a novel research area for
the application of MCRs in the synthesis of hydrazino-
phosphonic acid derivatives under Mitsunobu conditions.
13C NMR (125.75 MHz, CDCl3): d = 15.98 (d, JP–C = 7.6 Hz,
3
3
POCH2CH3), 16.08 (d, JP–C = 7.5 Hz, POCH2CH3), 20.99, 21.22,
and 21.70 [2 × OCH(CH3)2], 64.74 [P(OCH2CH3)2], 72.05 and
72.51 [2 × OCH(CH3)2], 128.04 (4 × CH of Ph), 131.61 (CH of Ph),
135.66 (Cipso of COPh), 152.36 and 152.49 (2 × CO2i-Pr), 170.15
(COPh).
31P NMR (202.45 MHz, CDCl3): d = –1.73.
MS: m/z (%) = 445 (16) [M+ + 1], 341 (82), 155 (100), 105 (77), 77
All reactions were carried out in oven-dried glassware. The
progress of reactions was monitored by thin-layer chromatography,
while purification was effected by column chromatography using
silica gel (Merck 230–240 mesh). Diisopropyl azodicarboxylate
(DIAD), acid chlorides, and phosphites were obtained from Merck
(Germany) and Fluka (Switzerland), and were used without further
purification. Elemental analyses for C, H, and N were performed us-
ing a Heraeus CHN–O–Rapid analyzer. Mass spectra were recorded
on a Finnigan MAT 8430 mass spectrometer operating at an ioniza-
(32), 43 (84).
Anal. Calcd for C19H29N2O8P: C, 51.35; H, 6.58; N, 6.30. Found: C,
51.50; H, 6.70; N, 6.40.
Diisopropyl 1-(4-Chlorobenzoyl)-2-(dimethoxyphosphoryl)-
1,2-hydrazinedicarboxylate (3c)
1
tion potential of 70 eV. H and 13C NMR spectra were measured
(CDCl3 solution) with a Bruker DRX-500 Avance spectrometer at
500.13 and 125.75 MHz, respectively. IR spectra were recorded on
a Shimadzu IR-460 spectrometer; absorbencies are reported in
cm–1.
Yield: 0.40 g (89%); yellow viscous liquid.
IR (KBr): 1741 and 1711 (C=O), 1595 and 1451 (Ar), 1277 (P=O),
1349 and 1181 (C–O), 1143 and 1037 (PO–Me), 910 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 0.98 [d, JH–H = 6.1 Hz, 3 H,
3
3
OCH(CH3)], 1.07 [d, JH–H = 5.0 Hz, 3 H, OCH(CH3)], 1.29 [m, 6
Diisopropyl 1-Benzoyl-2-(dimethoxyphosphoryl)-1,2-hydra-
zinedicarboxylate (3a); Typical Procedure
H, OCH(CH3)2], 3.88 (d, 3JP–H = 12.1 Hz, 3 H, POCH3), 3.95 (d,
3JP–H = 11.9 Hz, 3 H, POCH3), 4.85 [heptet, JH–H = 6.2 Hz, 1 H,
3
To a magnetically stirred soln of DIAD (0.20 g, 1 mmol) and BzCl
(0.14 g, 1 mmol) in anhyd toluene (2 mL) was added dropwise a
soln of (MeO)3P (0.12 g, 1 mmol) in anhyd toluene (3 mL) at r.t.
over 10 min. The reaction mixture was then stirred for 8 h under re-
flux. The solvent was removed under reduced pressure, and the res-
idue was separated by silica gel column chromatography (hexane–
EtOAc); yield: 0.39 g (94%); yellow viscous liquid.
OCH(CH3)2], 5.05 [m, 1 H, OCH(CH3)2], 7.38 (d, 3JH–H = 7.2 Hz, 2
H, 2 × CH of Ar), 7.65 (d, 3JH–H = 7.2 Hz, 2 H, 2 × CH of Ar).
13C NMR (125.75 MHz, CDCl3): d = 21.04, 21.24, and 21.59
[2 × OCH(CH3)2], 54.92 (d, 2JP–C = 4.6 Hz, POMe), 55.09 (POMe),
72.29 and 72.86 [2 × OCH(CH3)2], 128.36 (2 × CH of Ar), 129.52
(2 × CH of Ar), 133.87 (Cipso of COAr), 137.94 (Cipso of Cl), 152.04
(CO2i-Pr), 152.22 (d, 3JP–C = 14.2 Hz, CO2i-Pr), 168.98 (COAr).
31P NMR (202.45 MHz, CDCl3): d = 1.27.
MS: m/z (%) = 452 (16) [M+ + 1], 276 (16), 139 (100), 111 (21), 43
IR (KBr): 1693 (C=O), 1603 (NCO), 1539 and 1424 (Ar), 1275
(P=O), 1306 and 1192 (C–O), 1105 and 1010 (PO–Me), 926 cm–1
(P–O).
3
1H NMR (500.13 MHz, CDCl3): d = 0.97 [d, JH–H = 6.2 Hz, 3 H,
(97).
3
OCH(CH3)], 1.06 [d, JH–H = 6.0 Hz, 3 H, OCH(CH3)], 1.35 [m, 6
H, OCH(CH3)2], 3.95 (d, 3JP–H = 12.2 Hz, 3 H, POCH3), 4.01 (d, 3JP–
Anal. Calcd for C17H24ClN2O8P: C, 45.29; H, 5.37; N, 6.21. Found:
C, 45.40; H, 5.50; N, 6.40.
3
H = 12.2 Hz, 3 H, POCH3), 4.87 [heptet, JH–H = 6.2 Hz, 1 H,
OCH(CH3)2], 5.10 [m, 1 H, OCH(CH3)2], 7.44 (t, 3JH–H = 7.4 Hz, 2
H, 2 × CH of Ph), 7.53 (t, 3JH–H = 7.4 Hz, 1 H, CH of Ph), 7.74 (d,
3JH–H = 7.3 Hz, 2 H, 2 × CH of Ph).
Diisopropyl 1-(4-Chlorobenzoyl)-2-(diethoxyphosphoryl)-1,2-
hydrazinedicarboxylate (3d)
Yield: 0.42 g (88%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 21.00, 21.21, 21.66, and 21.68
[2 × OCH(CH3)2], 55.01 [P(OMe)2], 72.26 and 72.65
[2 × OCH(CH3)2], 128.05 (2 × CH of Ph), 128.08 (2 × CH of Ph),
131.68 (CH of Ph), 135.55 (Cipso of COPh), 152.32 and 152.45
(2 × CO2i-Pr), 170.01 (COPh).
IR (KBr): 1686 (C=O), 1593 and 1418 (Ar), 1285 (P=O), 1347 and
1175 (C–O), 1120 and 1006 (PO–CH2), 924 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 0.93 [d, 3JH–H = 6.2 Hz, 3 H,
3
OCH(CH3)], 1.02 [d, JH–H = 4.5 Hz, 3 H, OCH(CH3)], 1.25 [m, 6
H, OCH(CH3)2], 1.29 (t, 3JH–H = 7.1 Hz, 3 H, POCH2CH3), 1.32 (t,
3JH–H = 7.0 Hz, 3 H, POCH2CH3), 4.21 (m, 2 H, POCH2CH3), 4.30
31P NMR (202.45 MHz, CDCl3): d = 1.49.
3
(m, 2 H, POCH2CH3), 4.80 [heptet, JH–H = 6.2 Hz, 1 H,
Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York

1546
A. Alizadeh, S. Rostamnia
PAPER
OCH(CH3)2], 5.01 [m, 1 H, OCH(CH3)2], 7.33 (d, 3JH–H = 8.3 Hz, 2
H, 2 × CH of Ar), 7.61 (d, 3JH–H = 8.3 Hz, 2 H, 2 × CH of Ar).
IR (KBr): 1737 (C=O), 1601 and 1483 (Ar), 1525 and 1346 (NO2),
1262 (P=O), 1308 and 1181 (C–O), 1104 and 1037 (PO–Me), 935
cm–1 (P–O).
13C NMR (125.75 MHz, CDCl3): d = 15.88 (d, JP–C = 7.5 Hz,
3
3
3
POCH2CH3), 15.99 (d, JP–C = 7.5 Hz, POCH2CH3), 21.00, 21.21,
1H NMR (500.13 MHz, CDCl3): d = 1.01 [d, JH–H = 6.2 Hz, 3 H,
and 21.58 [2 × OCH(CH3)2], 64.62 [P(OCH2CH3)2], 72.08 and
72.66 [2 × OCH(CH3)2], 128.29 (2 × CH of Ar), 129.49 (2 × CH of
Ar), 133.97 (Cipso of COAr), 137.80 (Cipso of Cl), 152.05 (CO2i-Pr),
152.33 (d, 3JP–C = 12.7 Hz, CO2i-Pr), 169.10 (COAr).
31P NMR (202.45 MHz, CDCl3): d = –1.97.
MS: m/z (%) = 479 (7) [M+], 155 (92), 139 (100), 111 (19), 43 (72).
OCH(CH3)], 1.10 [m, 3 H, OCH(CH3)], 1.28–1.33 [m, 6 H,
OCH(CH3)2], 3.92 (d, 3JP–H = 12.2 Hz, 3 H, POCH3), 3.99 (d, 3JP–H
12.0 Hz, 3 H, POCH3), 4.88 [heptet, JH–H = 6.2 Hz, 1 H,
OCH(CH3)2], 5.10 [m, 1 H, OCH(CH3)2], 7.86 (d, 3JH–H = 8.4 Hz, 2
H, 2 × CH of Ar), 8.28 (d, 3JH–H = 8.4 Hz, 2 H, 2 × CH of Ar).
=
3
13C NMR (125.75 MHz, CDCl3): d = 21.01, 21.20, and 21.55
[2 × OCH(CH3)2], 55.03 [P(OMe)2], 72.59 and 73.34
[2 × OCH(CH3)2], 123.26 (2 × CH of Ar), 128.55 (2 × CH of Ar),
130.79 (Cipso of COAr), 149.24 (CO2i-Pr), 151.48 (Cipso of NO2),
151.48 (d, 3JP–C = 12.6 Hz, CO2i-Pr), 168.20 (COAr).
Anal. Calcd for C19H28ClN2O8P: C, 47.66; H, 5.89; N, 5.85. Found:
C, 47.80; H, 5.90; N, 6.10.
Diisopropyl 1-(4-Bromobenzoyl)-2-(dimethoxyphosphoryl)-
1,2-hydrazinedicarboxylate (3e)
31P NMR (202.45 MHz, CDCl3): d = 1.48.
Yield: 0.45 g (91%); yellow viscous liquid.
MS: m/z (%) = 431 (3), 313 (4), 167 (43), 140 (77), 127 (56), 43
(100).
IR (KBr): 1751 and 1704 (C=O), 1584 and 1455 (Ar), 1277 (P=O),
1369 and 1229 (C–O), 1098 and 1040 (PO–Me), 903 cm–1 (P–O).
Anal. Calcd for C17H24N3O10P: C, 44.26; H, 5.24; N, 9.11. Found:
C, 44.40; H, 5.30; N, 9.20.
3
1H NMR (500.13 MHz, CDCl3): d = 1.02 [d, JH–H = 6.2 Hz, 3 H,
3
OCH(CH3)], 1.10 [d, JH–H = 5.1 Hz, 3 H, OCH(CH3)], 1.32 [m, 6
Diisopropyl 1-(Dimethoxyphosphoryl)-2-{(2S)-2-[(phenylsulfo-
nyl)amino]propanoyl}-1,2-hydrazinedicarboxylate (3h)
Yield: 0.46 g (88%); yellow viscous liquid.
H, OCH(CH3)2], 3.89 (d, 3JP–H = 12.0 Hz, 3 H, POCH3), 3.93 (d,
3JP–H = 9.0 Hz, 3 H, POCH3), 4.88 [m, 1 H, OCH(CH3)2], 5.08 [m,
1 H, OCH(CH3)2], 7.57 (d, 3JH–H = 8.5 Hz, 2 H, 2 × CH of Ar), 7.60
(d, 3JH–H = 8.5 Hz, 2 H, 2 × CH of Ar).
IR (KBr): 1744 (C=O), 1582 and 1463 (Ar), 1372 and 1180 (SO2),
1257 (P=O), 1287 and 1145 (C–O), 1101 and 1044 (PO–Me), 899
cm–1 (P–O).
13C NMR (125.75 MHz, CDCl3): d = 21.13, 21.33, and 21.69
[2 × OCH(CH3)2], 55.02 and 55.15 [P(OMe)2], 72.39 and 72.99
[2 × OCH(CH3)2], 126.46 (Cipso of Br), 129.66 (2 × CH of Ar),
131.41 (2 × CH of Ar), 134.35 (Cipso of COAr), 152.10 (CO2i-Pr),
152.30 (d, 3JP–C = 14.1 Hz, CO2i-Pr), 169.22 (COAr).
1H NMR (500.13 MHz, CDCl3): d = 1.07 [m, 3 H, OCH(CH3)],
1.18–1.30 [m, 9 H, OCH(CH3)2 and CH3], 1.34 [d, 3JH–H = 6.2 Hz,
3 H, OCH(CH3)], 3.85 [m, 1 H, NCH(CH3)], 3.90 (d, 3JP–H = 12.0
Hz, 3 H, POCH3), 4.01 (d, 3JP–H = 12.0 Hz, 3 H, POCH3), 4.89 [hep-
tet, 3JH–H = 6.3 Hz, 1 H, OCH(CH3)2], 5.07 [m, 1 H, OCH(CH3)2],
6.95 (br, 1 H, NH), 7.52 (t, 3JH–H = 7.7 Hz, 2 H, 2 × CH of Ph), 7.62
31P NMR (202.45 MHz, CDCl3): d = 0.59.
MS: m/z (%) = 495 (2) [M+], 311 (11), 185 (87), 127 (78), 43 (100).
3
3
(t, JH–H = 7.2 Hz, 1 H, CH of Ph), 8.22 (d, JH–H = 7.8 Hz, 2 H,
2 × CH of Ph).
Anal. Calcd for C17H24BrN2O8P: C, 41.23; H, 4.88; N, 5.66. Found:
C, 41.30; H, 5.10; N, 5.80.
13C NMR (125.75 MHz, CDCl3): d = 21.41, 21.47, and 21.54
2
Diisopropyl 1-(4-Bromobenzoyl)-2-(diethoxyphosphoryl)-1,2-
hydrazinedicarboxylate (3f)
Yield: 0.46 g (88%); yellow viscous liquid.
[2 × OCH(CH3)], 21.62 (CH3), 55.22 (d, JP–C = 5.7 Hz, POMe),
2
55.50 (d, JP–C = 5.6 Hz, POMe), 72.00 (NCH), 72.88 and 73.29
[2 × OCH(CH3)2], 128.47 (2 × CH of Ph), 129.72 (2 × CH of Ph),
133.94 (CH of Ph), 138.72 (Cipso of SO2Ar), 150.58 (CO2i-Pr),
152.68 (d, 3JP–C = 16.0 Hz, CO2i-Pr), 155.76 (CON).
IR (KBr): 1738 (C=O), 1508 and 1452 (Ar), 1273 (P=O), 1372 and
1179 (C–O), 1100 and 1046 (PO–CH2), 900 cm–1 (P–O).
31P NMR (202.45 MHz, CDCl3): d = 0.60.
3
1H NMR (500.13 MHz, CDCl3): d = 0.92 [d, JH–H = 6.2 Hz, 3 H,
3
OCH(CH3)], 1.01 [d, JH–H = 4.3 Hz, 3 H, OCH(CH3)], 1.23 [m, 6
MS: m/z (%) = 421 (3), 313 (69), 140 (100), 127 (81), 43 (54).
H, OCH(CH3)2], 1.27 (t, 3JH–H = 7.1 Hz, 3 H, POCH2CH3), 1.31 (t,
Anal. Calcd for C19H30N3O10PS: C, 43.59; H, 5.78; N, 8.03. Found:
C, 43.80; H, 5.90; N, 8.20.
3JH–H = 7.0 Hz, 3 H, POCH2CH3), 4.20 (m, 2 H, POCH2CH3), 4.28
3
(m, 2 H, POCH2CH3), 4.78 [heptet, JH–H = 6.2 Hz, 1 H,
OCH(CH3)2], 4.99 [m, 1 H, OCH(CH3)2], 7.48 (d, 3JH–H = 8.3 Hz, 2
H, 2 × CH of Ar), 7.53 (d, 3JH–H = 8.3 Hz, 2 H, 2 × CH of Ar).
Diisopropyl 1-(Dimethoxyphosphoryl)-2-[2-(1,3-dioxo-1,3-di-
hydro-2H-isoindol-2-yl)acetyl]-1,2-hydrazinedicarboxylate (3i)
Yield: 0.43 g (86%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 15.89 (d, JP–C = 7.5 Hz,
POCH2CH3), 16.00 (d, JP–C = 7.4 Hz, POCH2CH3), 21.00, 21.21,
and 21.59 [2 × OCH(CH3)2], 64.61 [P(OCH2CH3)2], 72.05 and
72.65 [2 × OCH(CH3)2], 126.16 (Cipso of Br), 129.59 (2 × CH of
Ar), 131.26 (2 × CH of Ar), 134.45 (Cipso of COAr), 152.01 (CO2i-
Pr), 152.29 (d, 3JP–C = 12.8 Hz, CO2i-Pr), 169.15 (COAr).
3
3
IR (KBr): 1772 and 1722 (C=O), 1607 and 1481 (Ar), 1247 (P=O),
1313 and 1191 (C–O), 1115 and 1083 (PO–Me), 953 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 1.28–1.32 [m,
6 H,
3
OCH(CH3)2], 1.38 [d, JH–H = 6.2 Hz, 3 H, OCH(CH3)], 1.41 [d,
3JH–H = 6.2 Hz, 3 H, OCH(CH3)], 3.85 (d, JP–H = 12.0 Hz, 3 H,
3
31P NMR (202.45 MHz, CDCl3): d = –2.01.
POCH3), 3.92 (d, 3JP–H = 11.7 Hz, 3 H, POCH3), 5.02–5.12 [m, 3 H,
OCH(CH3)2 and NCH2], 5.14–5.19 [m, 1 H, OCH(CH3)2], 7.73–
7.75 (m, 2 H, 2 × CH of Ar), 7.87–7.89 (m, 2 H, 2 × CH of Ar).
MS: m/z (%) = 523 (3) [M+], 185 (63), 155 (97), 43 (100).
Anal. Calcd for C19H28BrN2O8P: C, 43.61; H, 5.39; N, 5.35. Found:
C, 43.80; H, 5.50; N, 5.50.
13C NMR (125.75 MHz, CDCl3): d = 21.47, 21.61, 21.64, and 21.70
[2 × OCH(CH3)2], 42.70 (NCH2), 55.32 and 55.36 [P(OMe)2],
72.34 and 73.43 [2 × OCH(CH3)2], 123.53 (2 × CH of Ar), 132.23
(2 × C fused), 134.04 (2 × CH of Ar), 151.70 (d, JP–C = 14.1 Hz,
CO2i-Pr), 151.91 (CO2i-Pr), 167.13 (CONN), 167.35 [N(CO)2].
31P NMR (202.45 MHz, CDCl3): d = –0.91.
Diisopropyl 1-(Dimethoxyphosphoryl)-2-(4-nitrobenzoyl)-1,2-
hydrazinedicarboxylate (3g)
3
Yield: 0.43 g (93%); yellow viscous liquid.
Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Hydrazinophosphonates and Hydrazinobisphosphonates
1547
3
MS: m/z (%) = 279 (2), 211 (12), 140 (100), 127 (67), 43 (45).
13C NMR (125.75 MHz, CDCl3): d = 15.97 (d, JP–C = 7.5 Hz,
3
POCH2CH3), 16.11 (d, JP–C = 7.4 Hz, POCH2CH3), 21.51, 21.57,
Anal. Calcd for C20H26N3O10P: C, 48.10; H, 5.25; N, 8.41. Found:
C, 48.20; H, 5.30; N, 8.50.
and 21.76 [2 × OCH(CH3)2], 64.68 and 64.86 [P(OCH2CH3)2],
71.96 and 72.79 [2 × OCH(CH3)2], 120.63 (2 × CH of Ph), 120.95
(d, 4JP–C = 3.5 Hz, 2 × CH of Ph), 125.45 and 125.49 (4 × CH of Ph),
Diisopropyl 1-(Diethoxyphosphoryl)-2-[2-(1,3-dioxo-1,3-dihy-
dro-2H-isoindol-2-yl)acetyl]-1,2-hydrazinedicarboxylate (3j)
Yield: 0.45 g (85%); yellow viscous liquid.
3
129.39 and 129.64 (2 × CH of Ph), 150.51 (d, JP–C = 13.3 Hz,
CO2i-Pr), 150.57 (d, 3JP–C = 13.3 Hz, CO2i-Pr), 152.84 (Cipso of OP),
152.95 (Cipso of OP).
IR (KBr): 1725 and 1721 (C=O), 1613 and 1465 (Ar), 1249 (P=O),
1308 and 1179 (C–O), 1104 and 1027 (PO–CH2), 956 cm–1 (P–O).
31P NMR (202.45 MHz, CDCl3): d = –9.38, –1.43.
MS: m/z (%) = 525 (15), 479 (59), 395 (24), 127 (5), 94 (13), 77
(25), 43 (100).
1H NMR (500.13 MHz, CDCl3): d = 1.30–1.32 [m,
9 H,
OCH(CH3)2 and POCH2CH3], 1.34–1.39 (m, 3 H, POCH2CH3),
1.38 [d, 3JH–H = 6.4 Hz, 3 H, OCH(CH3)], 1.41 [d, 3JH–H = 6.3 Hz, 3
H, OCH(CH3)], 4.20–4.31 [m, 4 H, P(OCH2CH3)2], 5.02–5.17 [m,
4 H, 2 × OCH(CH3)2 and NCH2], 7.74–7.75 (m, 2 H, 2 × CH of Ar),
7.89–7.90 (m, 2 H, 2 × CH of Ar).
Anal. Calcd for C24H34N2O10P2: C, 50.35; H, 5.99; N, 4.89. Found:
C, 50.50; H, 6.00; N, 5.00.
Diisopropyl 1-(Dimethoxyphosphoryl)-2-(phenylsulfonyl)-1,2-
hydrazinedicarboxylate (5a)
Yield: 0.43 g (95%); yellow viscous liquid.
3
13C NMR (125.75 MHz, CDCl3): d = 15.99 (d, JP–C = 7.6 Hz,
3
POCH2CH3), 16.10 (d, JP–C = 7.6 Hz, POCH2CH3), 21.51, 21.60,
21.66, and 21.70 [2 × OCH(CH3)2], 42.70 (NCH2), 64.81 and 65.07
[P(OCH2CH3)2], 72.29 and 73.37 [2 × OCH(CH3)2], 123.53
(2 × CH of Ar), 132.22 (2 × C fused), 133.87 (2 × CH of Ar),
IR (KBr): 1747 (C=O), 1590 and 1460 (Ar), 1369 and 1172 (SO2),
1257 (P=O), 1222 and 1145 (C–O), 1099 and 1044 (PO–Me), 948
cm–1 (P–O).
3
151.76 (d, JP–C = 14.5 Hz, CO2i-Pr), 152.04 (CO2i-Pr), 168.79
1H NMR (500.13 MHz, CDCl3): d = 1.03 [m, 3 H, OCH(CH3)],
1.16 [d, 3JH–H = 5.7 Hz, 3 H, OCH(CH3)], 1.26 [d, 3JH–H = 5.6 Hz, 3
H, OCH(CH3)], 1.30 [d, 3JH–H = 6.2 Hz, 3 H, OCH(CH3)], 3.86 (d,
(CONN), 168.86 [N(CO)2].
31P NMR (202.45 MHz, CDCl3): d = –4.15.
3
3JP–H = 12.0 Hz, 3 H, POCH3), 3.99 (d, JP–H = 12.0 Hz, 3 H,
MS: m/z (%) = 480 (3), 453 (4), 168 (61), 155 (83), 43 (100).
POCH3), 4.86 [heptet, 3JH–H = 6.3 Hz, 1 H, OCH(CH3)2], 5.03 [hep-
tet, 3JH–H = 6.3 Hz, 1 H, OCH(CH3)2], 7.48 (t, 3JH–H = 8.1 Hz, 2 H,
Anal. Calcd for C22H30N3O10P: C, 50.10; H, 5.73; N, 7.97. Found:
C, 50.30; H, 5.90; N, 8.10.
3
2 × CH of Ph), 7.58 (t, JH–H = 7.5 Hz, 1 H, CH of Ph), 8.18 (d,
3JH–H = 8.4 Hz, 2 H, 2 × CH of Ph).
Diisopropyl 1-(Dimethoxyphosphoryl)-2-(diphenoxyphosphor-
yl)-1,2-hydrazinedicarboxylate (4a)
Yield: 0.48 g (88%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 21.41, 21.47, 21.54, and 21.63
[2 × OCH(CH3)2], 55.23 (d, 2JP–C = 5.9 Hz, POMe), 55.53 (POMe),
72.89 and 73.33 [2 × OCH(CH3)2], 128.48 (2 × CH of Ph), 129.72
(2 × CH of Ph), 133.95 (CH of Ph), 138.62 (Cipso of SO2Ar), 150.57
(CO2i-Pr), 152.68 (d, 3JP–C = 16.0 Hz, CO2i-Pr).
IR (KBr): 1760 and 1757 (C=O), 1591 and 1488 (Ar), 1265 (P=O),
1200 and 1159 (C–O), 1106 and 1034 (PO–Me), 947 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 1.20 [m, 6 H, OCH(CH3)2],
31P NMR (202.45 MHz, CDCl3): d = 1.84.
1.34 [d, 3JH–H = 6.2 Hz, 3 H, OCH(CH3)], 1.36 [d, 3JH–H = 6.2 Hz, 3
MS: m/z (%) = 139 (22), 77 (12), 58 (9), 43 (100).
3
H, OCH(CH3)], 3.79 (d, JP–H = 12.1 Hz, 3 H, POCH3), 3.90 (d,
3
3JP–H = 12.0 Hz, 3 H, POCH3), 4.99 [heptet, JH–H = 6.2 Hz, 1 H,
Anal. Calcd for C16H25N2O9PS: C, 42.48; H, 5.57; N, 6.19. Found:
C, 42.60; H, 5.90; N, 6.30.
OCH(CH3)2], 5.13 [heptet, 3JH–H = 6.2 Hz, 1 H, OCH(CH3)2], 7.12–
7.34 [m, 10 H, 10 × CH of P(OPh)2].
Diisopropyl 1-(Diethoxyphosphoryl)-2-(phenylsulfonyl)-1,2-hy-
drazinedicarboxylate (5b)
Yield: 0.45 g (94%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 21.48, 21.55, and 21.78
[2 × OCH(CH3)2], 55.04 (d, 2JP–C = 6.0 Hz, POMe), 55.22 (POMe),
72.19 and 72.87 [2 × OCH(CH3)2], 120.60 (2 × CH of Ph), 120.91
(d, 4JP–C = 4.3 Hz, 2 × CH of Ph), 125.51 (2 × CH of Ph), 129.43 and
129.67 (4 × CH of Ph), 150.47 (d, 3JP–C = 17.2 Hz, CO2i-Pr), 150.60
(d, 3JP–C = 17.1 Hz, CO2i-Pr), 152.76 (Cipso of OP), 152.88 (Cipso of
OP).
IR (KBr): 1770 and 1760 (C=O), 1580 and 1464 (Ar), 1369 and
1185 (SO2), 1270 (P=O), 1220 and 1146 (C–O), 1099 and 1031
(PO–CH2), 957 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 1.04 [m, 3 H, OCH(CH3)],
1.16 [m, 3 H, OCH(CH3)], 1.28–1.29 [m, 3 H, OCH(CH3)], 1.32 (td,
31P NMR (202.45 MHz, CDCl3): d = –9.01, 2.39.
3
3JH–H = 7.3 Hz, 3JH–P = 1.0 Hz, 3 H, POCH2CH3), 1.37 (td, JH–H
=
MS: m/z (%) = 451 (4), 367 (4), 140 (61), 127 (36), 93 (3), 43 (100).
7.1 Hz, 3JH–P = 0.9 Hz, 3 H, POCH2CH3), 4.26 (dq, 3JP–H = 14.3 Hz,
3JH–H = 7.2 Hz, 2 H, POCH2CH3), 4.39 (dq, 3JP–H = 14.6 Hz, 3JH–H
=
Anal. Calcd for C22H30N2O10P2: C, 48.54; H, 5.55; N, 5.15. Found:
C, 48.30; H, 5.80; N, 5.20.
3
7.3 Hz, 2 H, POCH2CH3), 4.87 [heptet, JH–H = 6.3 Hz, 1 H,
OCH(CH3)2], 5.05 [m, 1 H, OCH(CH3)2], 7.49 (t, 3JH–H = 8.1 Hz, 2
H, 2 × CH of Ph), 7.58 (t, 3JH–H = 7.4 Hz, 1 H, CH of Ph), 8.21 (d,
3JH–H = 7.5 Hz, 2 H, 2 × CH of Ph).
Diisopropyl 1-(Diethoxyphosphoryl)-2-(diphenoxyphosphoryl)-
1,2-hydrazinedicarboxylate (4b)
Yield: 0.50 g (87%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 16.05 and 16.10
[P(OCH2CH3)2], 21.44, 21.48, 21.59, and 21.66 [2 × OCH(CH3)2],
IR (KBr): 1747 (C=O), 1589 and 1486 (Ar), 1260 (P=O), 1292 and
1161 (C–O), 1102 and 1024 (PO–CH2), 959 cm–1 (P–O).
2
2
64.96 (d, JP–C = 5.6 Hz, POCH2CH3), 65.25 (d, JP–C = 5.8 Hz,
POCH2CH3), 72.67 and 73.13 [2 × OCH(CH3)2], 128.44 (2 × CH of
Ph), 129.90 (2 × CH of Ph), 133.83 (CH of Ph), 138.84 (Cipso of
SO2Ar), 150.66 (CO2i-Pr), 152.80 (d, 3JP–C = 15.3 Hz, CO2i-Pr).
3
1H NMR (500.13 MHz, CDCl3): d = 1.19 [t, JH–H = 7.0 Hz, 6 H,
3
P(OCH2CH3)2], 1.30 [d, JH–H = 6.8 Hz, 12 H, 2 × OCH(CH3)2],
4.12–4.19 (m, 2 H, POCH2CH3), 4.26 (m, 2 H, POCH2CH3), 4.95
[m, 1 H, OCH(CH3)2], 5.08 [m, 1 H, OCH(CH3)2], 7.09–7.28 [m, 10
H, 10 × CH of P(OPh)2].
31P NMR (202.45 MHz, CDCl3): d = –1.83.
MS: m/z (%) = 416 (2), 167 (54), 77 (18), 43 (100).
Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York

1548
A. Alizadeh, S. Rostamnia
PAPER
3
Anal. Calcd for C18H29N2O9PS: C, 45.00; H, 6.08; N, 5.83. Found:
C, 45.10; H, 6.20; N, 6.00.
ArCH2CH3), 1.42 (t, JH–H = 7.1 Hz, 3 H, POCH2CH3), 2.73 (q,
3JH–H = 7.5 Hz,
H, ArCH2CH3), 4.29–4.47 [m, H,
2
4
3
P(OCH2CH3)2], 4.94 [heptet, JH–H = 6.1 Hz, 1 H, OCH(CH3)2],
5.10 [m, 1 H, OCH(CH3)2], 7.36 (d, 3JH–H = 8.2 Hz, 2 H, 2 × CH of
Ar), 8.15 (d, 3JH–H = 8.2 Hz, 2 H, 2 × CH of Ar).
Diisopropyl 1-(Dimethoxyphosphoryl)-2-[(4-methylphenyl)sul-
fonyl]-1,2-hydrazinedicarboxylate (5c)
Yield: 0.43 g (92%); yellow viscous liquid.
13C NMR (125.75 MHz, CDCl3): d = 15.00 (ArCH2CH3), 16.04 (d,
3JP–C = 6.7 Hz, POCH2CH3), 16.10 (d, 3JP–C = 7.3 Hz, POCH2CH3),
21.50, 21.53, 21.61, and 21.69 [2 × OCH(CH3)2], 28.93
IR (KBr): 1751 (C=O), 1595 and 1453 (Ar), 1369 and 1178 (SO2),
1262 (P=O), 1222 and 1145 (C–O), 1094 and 1036 (PO–Me), 953
cm–1 (P–O).
2
(ArCH2CH3), 64.92 (d, JP–H = 5.7 Hz, POCH2CH3), 65.23 (d,
2JP–H = 5.3 Hz, POCH2CH3), 72.61 and 73.03 [2 × OCH(CH3)2],
1H NMR (500.13 MHz, CDCl3): d = 1.15 [m, 3 H, OCH(CH3)],
1.25 [d, 3JH–H = 6.2 Hz, 3 H, OCH(CH3)], 1.34 [d, 3JH–H = 6.0 Hz, 3
H, OCH(CH3)], 1.38 [d, 3JH–H = 6.2 Hz, 3 H, OCH(CH3)], 2.45 (s, 3
127.91 (2 × CH of Ar), 129.97 (2 × CH of Ar), 130.75 (Cipso of
3
SO2Ar), 150.76 (CO2i-Pr), 151.04 (Cipso of Et), 152.85 (d, JP–C
15.8 Hz, CO2i-Pr).
=
3
3
H, ArCH3), 3.93 (d, JP–H = 12.0 Hz, 3 H, POCH3), 4.05 (d, JP–
3
H = 12.0 Hz, 3 H, POCH3), 4.95 [heptet, JH–H = 6.3 Hz, 1 H,
31P NMR (202.45 MHz, CDCl3): d = –0.91.
MS: m/z (%) = 509 (3) [M+ + 1], 508 (2), 167 (42), 105 (11), 43
OCH(CH3)2], 5.11 [heptet, 3JH–H = 6.2 Hz, 1 H, OCH(CH3)2], 7.35
(d, 3JH–H = 8.4 Hz, 2 H, 2 × CH of Ar), 8.12 (d, 3JH–H = 8.4 Hz, 2 H,
2 × CH of Ar).
(100).
Anal. Calcd for C20H33N2O9PS: C, 47.24; H, 6.54; N, 5.51. Found:
C, 47.30; H, 7.00; N, 6.10.
13C NMR (125.75 MHz, CDCl3): d = 21.50 [ArCH3 and
OCH(CH3)], 21.54, 21.61, and 21.63 [3 × OCH(CH3)], 55.17 (d,
2JP–C = 5.8 Hz, POMe), 55.46 (d, 2JP–C = 5.8 Hz, POMe), 72.80 and
73.14 [2 × OCH(CH3)2], 129.05 (2 × CH of Ar), 129.87 (2 × CH of
Ar), 135.59 (Cipso of SO2Ar), 145.08 (Cipso of Me), 150.65 (CO2i-
Pr), 152.72 (d, 3JP–C = 16.1 Hz, CO2i-Pr).
References
(1) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A.; Ugi, I. Angew. Chem. 1993, 105,
634. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115 . For
excellent reviews on multicomponent applications, see:
(d) Dömling, A. Chem. Rev. 2006, 106, 17. (e) Zhu, J.;
Bienayme, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005.
31P NMR (202.45 MHz, CDCl3): d = 1.30.
MS: m/z (%) = 301 (53), 267 (100), 182 (84), 139 (22), 43 (31).
Anal. Calcd for C17H27N2O9PS: C, 43.78; H, 5.83; N, 6.01. Found:
C, 43.90; H, 6.10; N, 6.10.
(2) (a) Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64,
8379. (b) Shen, Y.; Jiang, G. F. Synthesis 2000, 99.
(3) Wester, R. T.; Chambers, R. J.; Green, M. D.; Murphy, W.
R. Bioorg. Med. Chem. Lett. 1994, 4, 2005.
(4) (a) Dolakova, P.; Dracinsky, M.; Masojidkova, M.;
Solinova, V.; Kasicka, V.; Holy, A. Eur. J. Med. Chem.
2009, 44, 2408. (b) Makras, P.; Hamdy, N. A. T.;
Zwinderman, A. H.; Ballieux, B. E. P. B.; Papapoulos, S. E.
Bone (N. Y.) 2009, 44, 766. (c) Chang, J. W.-C.; Hsieh, J.-J.;
Shen, Y.-C.; Yeh, K.-Y.; Wang, C.-H.; Li, Y.-Y.; Hsu, T.
Cancer Lett. 2009, 278, 17.
(5) (a) Harnden, M. R.; Parkin, A.; Parratt, M. J.; Perkins, R. M.
J. Med. Chem. 1993, 36, 1343. (b) Lazrek, H. B.; Rochdi,
A.; Khaider, H.; Barascut, J.-L.; Imbach, J.-L.; Balzarini, J.;
Witvrouw, M.; Pannecouque, C.; De Clercq, E. Tetrahedron
1998, 54, 3807.
Diisopropyl 1-(Diethoxyphosphoryl)-2-[(4-methylphenyl)sulfo-
nyl]-1,2-hydrazinedicarboxylate (5d)
Yield: 0.45 g (91%); yellow viscous liquid.
IR (KBr): 1772 and 1761 (C=O), 1594 and 1465 (Ar), 1367 and
1178 (SO2), 1274 (P=O), 1220 and 1147 (C–O), 1102 and 1024
(PO–CH2), 958 cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 1.13–1.37 [m, 15 H,
3
2 × OCH(CH3)2 and POCH2CH3], 1.42 (t, JH–H = 7.0 Hz, 3 H,
POCH2CH3), 2.44 (s,
3 H, ArCH3), 4.29–4.32 (m, 2 H,
3
3
POCH2CH3), 4.44 (dq, JP–H = 14.4 Hz, JH–H = 7.2 Hz, 2 H,
POCH2CH3), 4.94 [heptet, 3JH–H = 6.2 Hz, 1 H, OCH(CH3)2], 5.01
[m, 1 H, OCH(CH3)2], 7.33 (d, 3JH–H = 8.1 Hz, 2 H, 2 × CH of Ar),
8.12 (d, 3JH–H = 8.1 Hz, 2 H, 2 × CH of Ar).
13C NMR (125.75 MHz, CDCl3): d = 16.04 (d, JP–C = 5.8 Hz,
3
3
POCH2CH3), 16.09 (d, JP–C = 7.2 Hz, POCH2CH3), 21.54, 21.61,
(6) Holstein, S. A.; Cermak, D. M.; Wiemer, D. F.; Lewis, K.;
21.64, and 21.69 [2 × OCH(CH3)2], 21.92 (ArCH3), 64.92 (d, 2JP–H
=
Hohl, R. J. Bioorg. Med. Chem. 1998, 6, 687.
5.5 Hz, POCH2CH3), 65.22 (d, 2JP–H = 5.5 Hz, POCH2CH3), 72.61
and 73.03 [2 × OCH(CH3)2], 129.04 (2 × CH of Ar), 129.89
(2 × CH of Ar), 135.62 (Cipso of SO2Ar), 144.94 (Cipso of Me),
150.75 (CO2i-Pr), 152.85 (d, 3JP–C = 15.5 Hz, CO2i-Pr).
(7) (a) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
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(e) Cox, R. J.; Mayo-Martín, M. B.; Hadfield, A. T. Chem.
Commun. 2001, 1710.
31P NMR (202.45 MHz, CDCl3): d = –0.44.
MS: m/z (%) = 495 (2) [M+ + 1], 309 (11), 155 (43), 91 (18), 43
(100).
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Dreams; Seeman, J. I., Ed.; American Chemical Society:
Washington D.C., 1994, 62. (b) Huisgen, R.; Blaschke, H.;
Brunn, E. Tetrahedron Lett. 1966, 405. (c) Brunn, E.;
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 513. For
excellent reviews on MBH and other zwitterions, see:
(d) Kumar, N. S.; Kumar, K. P.; Kumar, K. V. P. P.;
Kommana, P.; Vittal, J. J.; Swamy, K. C. K. J. Org. Chem.
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Anal. Calcd for C19H31N2O9PS: C, 46.15; H, 6.32; N, 5.67. Found:
C, 46.30; H, 6.50; N, 6.00.
Diisopropyl 1-(Diethoxyphosphoryl)-2-[(4-ethylphenyl)sulfo-
nyl]-1,2-hydrazinedicarboxylate (5e)
Yield: 0.45 g (88%); yellow viscous liquid.
IR (KBr): 1748 (C=O), 1595 and 1464 (Ar), 1369 and 1172 (SO2),
1258 (P=O), 1222 and 1100 (C–O), 1170 and 1026 (PO–CH2), 958
cm–1 (P–O).
1H NMR (500.13 MHz, CDCl3): d = 1.12–1.38 [m, 15 H,
3
2 × OCH(CH3)2 and POCH2CH3], 1.26 (t, JH–H = 7.5 Hz, 3 H,
Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York

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Synthesis 2010, No. 9, 1543–1549 © Thieme Stuttgart · New York