Reaction of 1-amino bisphosphinic acids with acid chlorides: Synthesis of novel cyclic 1-Hydroxy-1-amino-1,1-bisphosphinic acids

Article abstract of DOI:10.1055/s-0030-1258115

Treatment of 1-amino bisphosphinic acids with HMDS followed by reaction with acid chlorides gives 1′-hydroxy-1′-amino-1,1-bisphosphinic acid in good yields. The reaction gave a mixture of the racemate and meso form of 1′-hydroxy-1′-amino-1,1-bisphosphinic acid. The stereochemistry of the readily separable diastereomer was confirmed after converting to the corresponding novel cyclic 1-hydroxy-1-amino-1,1-bisphosphinic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258115

LETTER
1837
Reaction of 1-Amino Bisphosphinic Acids with Acid Chlorides: Synthesis of
Novel Cyclic 1-Hydroxy-1¢-amino-1,1-bisphosphinic Acids
N
a
ovel Cyclic 1-
H
a
ydroxy-1
¢
-
b
amino-1,1-bi
a
sphosphini
k
c
A
cids Kaboudin,*a Fariba Saadati,a Tsutomu Yokomatsub
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
Fax +98(241)4249023; E-mail: kaboudin@iasbs.ac.ir
b
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horonouchi, Hachioji, Tokyo 192-0392, Japan
Received 23 April 2010
Since cyclic P–N–P phosphinates can be considered as an-
alogues of amino acids, we were interested in synthesiz-
ing novel cyclic P–N–P phosphinates from simple
building blocks. We recently described a new method for
Abstract: Treatment of 1-amino bisphosphinic acids with HMDS
followed by reaction with acid chlorides gives 1-hydroxy-1¢-amino-
1,1-bisphosphinic acid in good yields. The reaction gave a mixture
of the racemate and meso form of 1-hydroxy-1¢-amino-1,1-bisphos-
phinic acid. The stereochemistry of the readily separable diastereo- the synthesis of novel 1-amino bisphosphinic acids
(Scheme 1).12 One of the diastereomers of compound 2
mer was confirmed after converting to the corresponding novel
cyclic 1-hydroxy-1¢-amino-1,1-bisphosphinic acid.
was readily isolated by washing with polar solvents but
Key words: bisphosphinic acids, aminophosphinic acids, acid
chlorides, hydroxyphosphinic acids
we were unable to determine its stereochemistry.
O
P
H
O
H
P
N
HO
OH
OH
R
H
R
Bisphosphonic and phosphinic acids constitute an impor-
tant class of biologically active compounds, used, for ex-
ample, in the treatment of common disorders of bone
metabolism, including Paget’s disease, osteoporosis, and
bone-tumor metastases.1 The synthesis of a-substituted
bisphosphoryl derivatives (phosphonic and phosphinic
acids) has attracted significant attention due to their bio-
logical activities with broad applications as enzyme inhib-
itors, antimetabolites, and antibiotics.2 1-Hydroxy-1,1-
bisphosphonic acids have been used as powerful inhibi-
tors of bone resorption and are widely used in the treat-
ment of diseases characterized by abnormal calcium
metabolism.3 Cyclic geminal bisphosphonates, especially
those containing a nitrogen atom in the ring, are also very
potent in treatment of breast cancer.4 In contrast to the
widely studied 1-hydroxy-1,1-bisphosphonic acid deriva-
tives,5–7 relatively few papers and patents describe the
chemistry of 1-hydroxy 1,1-bisphosphinic acids.8 In addi-
tion to their biological importance, 1-hydroxy-1,1-bisphos-
phinic acids are also known as stabilizers for the epoxy
resins, increasing storage stability, in particular at higher
temperatures.9
R
1) NH4OH (aq)
2) H3PO2
(R*,R*)-2
N
N
RCHO
O
P
H
O
P
H
1
H
N
R
R
HO
R
R
(R*,S*)-2
Scheme 1 Synthesis of 1-aminobisphosphinic acid
Herein we report a phosphorus–carbon bond-formation
protocol for the synthesis of novel 1-hydroxy-1¢-amino-
1,1-bisphosphinic acids via intramolecular cyclization of
compound 2 by reaction with acid chlorides in the pres-
ence of HMDS (Scheme 2). Cyclic novel P–N–P phos-
phinates 5 have high rigidity and, as a result, the
stereochemistry of the separated diastereomer of com-
pound 2 could be determined by NMR analysis.
H
H
R
N
R
R
R
N
heat
HMDS
2
P(OSiMe3)2
Ar
workup
ArCOCl
O
P
P
O
OH
O
P
HO
Me3SiO
OH
Ar
O
The structure of the phosphinic functional group mimics
the transition state of peptide hydrolysis. On the other
hand, the symmetrical nature of the phosphinic acid deriv-
atives might be expected to benefit their binding to the ho-
modimer of HIV-protease having C2-axis symmetry.10
Indeed, the conjunction of two functionalities in the same
molecule, as for example in 1-amino-1¢-hydroxyphos-
phinic acids, affords powerful inhibitors of HIV-1 pro-
tease.11
4
5
Scheme 2 A phosphorus–carbon bond formation
Aminobisphosphinic acid 2a was prepared as a mixture of
diastereomers by the reaction of the diimine prepared
from p-methylbenzaldehyde and ammonia, with hypo-
phosphorus acid under reflux for 11 hours (Scheme 3).12
The resulting diastereomeric mixture of 2a was activated
by silylation with HMDS,13 and subsequently reacted with
benzoyl chloride for 12 hours at room temperature. The
reaction gave a 56% yield of a white solid that was deter-
mined to have the molecular formula C23H25NO5P2 by
SYNLETT 2010, No. 12, pp 1837–1840
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258115; Art ID: D10510ST
© Georg Thieme Verlag Stuttgart · New York

1838
B. Kaboudin et al.
LETTER
ESI-HRMS (m/z found: 458.1291 [MH]+) and elemental
analysis. This molecular formula is consistent with cyclic
Table 1 Reaction of 1-Amino Bisphosphinic Acids dl-2 with Acyl
Chlorides
H
1-hydroxy-1¢-amino-1,1-bisphosphinic
Scheme 3).
acid
(5a,
H
R1
N
R1
R1
O
N
R1
O
3) HMDS, 110 °C
1) NH4OH (aq)
2) H3PO2
R1 CHO
4) R2COCl (3)
O
HO
P
P
O
OH
PH HP
OH OH
dl-2
1
R2
Me
Me
HO
H
dl-5
1) NH4OH (aq)
N
Me
CHO
Entry 2 R1 =
3 R2 =
Time (h) Yield of dl-5
2) H3PO2
O
PH HP O
(%)a
OH OH
1a
2a
1
2
2a 4-MeC6H4 3a Ph
12
10
12
12
12
12
56
78
68
65
67
68
50
62
35
80
85
62
3) HMDS, 110 °C
4) PhCOCl
2b Ph
2c Ph
2d Ph
2e Ph
2f Ph
2g Ph
3b Ph
3
3c 2-ClC6H4
3d 3-ClC6H4
3e 2-FC6H4
3f 4-FC6H4
Me
Me
Me
Me
4
H
H
N
N
5
HO(O)P
HO
P(O)OH
Ph
HO(O)P
P(O)OH
Ph
6
HO
7
3g C6H4CH=CH2 10
dl-5a
meso-5a
8
2h 4-ClC6H4 3h Ph
10
12
12
10
12
12
Scheme 3 Synthesis of novel 1-hydroxy-1¢-amino 1,1-bisphosphin-
ic acid (5a)
9
2i 4-ClC6H4
2j 4-ClC6H4
2k 4-FC6H4
2l 4-FC6H4
2m Ph
3i 2-ClC6H4
10
11
12
13
3j 2-FC6H4
3k Ph
This cyclic compound can exist in three diastereomeric
forms (meso-trans-5a, meso-cis-5a, and dl-5a). Careful
analyses of the crude materials by H NMR, 13C NMR,
1
3l 2-FC6H4
3m Me
and 31P NMR spectroscopy revealed that two of the three
diastereomers were preferentially formed in this reaction.
b
–
The 31P NMR spectrum of the product exhibited two
peaks due to the two diastereomers of 5a. A singlet peak
at d = 21.47 ppm (meso-5a) and two sets of doublets (dl-
5a) appeared at d = 21.62 (J = 9.1 Hz) and 22.35 (J = 9.1
Hz) ppm due to the coupling of two different phosphorus
a Yields refer to the isolated pure products.
b Unknown mixture.
We were able to obtain crystals for dl-5h suitable for X-
ray analysis and the crystal structure of dl-5h is illustrated
in Figure 1. It is noteworthy that the cycle exists in a boat-
like conformation with the phenyl groups in quasi-equato-
rial positions as expected and likewise the acidic site
(POH) of the phosphinate function.15
1
atoms in the racemate. The H NMR spectrum had two
sets of doublet peaks at d = 5.02 (JHP = 10.5 Hz) and 5.27
(JHP = 10.5 Hz) ppm for dl-5a, along with a broad triplet
peak at d = 4.90 ppm for meso-5a. The 13C NMR spectrum
exhibited two doublet peaks at d = 55.9 and 59.4 ppm cor-
responding to the HCP in the dl form and one doublet peak
at d = 59.9 ppm in the meso form.
To obtain the cyclic phosphinate 5a in a diastereomerical-
ly pure state, the previously separated pure diastereomer
of 2a was activated by silylation with HMDS and then
reacted with benzoyl chloride to give a single diastereo-
mer 5a in 56% yield. We tentatively assigned the single
diastereomer to be dl-5a on the basis of the NMR spec-
trum. With these results the stereochemistry of the separa-
ble diastereomer of 2 was determined as racemic S*,S*
and R*,R*-2 (Scheme 1).
This process was successfully applied to other amino bis-
phosphinic acids (dl-2) as summarized in Table 1, where-
in the reaction of the activated racemic amino
bisphosphinic acids (dl-2) with acyl chlorides 3 afforded
dl-5a–l in good yield.
Figure 1 ORTEP depiction of dl-5h
In summary, we have developed a simple and practical ap-
proach for the synthesis of a new class of organophospho-
Synlett 2010, No. 12, 1837–1840 © Thieme Stuttgart · New York

LETTER
Novel Cyclic 1-Hydroxy-1¢-amino-1,1-bisphosphinic Acids
1839
M. D.; Culp, J. S.; Debouck, C.; Tomaszek, T. A. Jr.; Meek,
T. D. Biochemistry 1993, 32, 7972. (b) Cristau, H.-J.;
Herve, A.; Virieux, D. Tetrahedron 2004, 60, 877.
(c) Kaboudin, B.; Haruki, T.; Yamaghishi, T.; Yokomatsu,
T. Tetrahedron 2007, 63, 8199. (d) Kaboudin, B.; Haruki,
T.; Yamagishi, T.; Yokomatsu, T. Synthesis 2007, 3226.
(12) Kaboudin, B.; Saadati, F. Tetrahedron Lett. 2009, 50, 1450.
(13) Matziari, M.; Georgiadis, D.; Dive, V.; Yiotakis, A. Org.
Lett. 2001, 3, 659.
rus compounds. Through an intramolecular cyclization of
1-amino bisphosphinic acids with acid halides, 1-hy-
droxy-1¢-amino-1,1-bisphosphinic acids can be synthe-
sized cleanly and in good yield. The structure and
stereochemistry of novel 1-hydroxy-1¢-amino-1,1-bispho-
sphinic acids was unambiguously determined by X-ray
crystallographic analysis and NMR data which showed
the cyclic bisphosphinic acid, the stereochemistry of the
separable diastereomer of 2 to be the racemate (S*,S*- and
R*,R*-2). Further investigations on the complexation
ability of the products are now in progress.14
(14) The aldehyde (3 mmol) was added to ammonium hydroxide
(30%, 15 mL), and the solution was stirred for 5 h at reflux.
During this time, a white precipitate formed. The precipitate
was removed by filtration and dried. The solid was dissolved
in 5 mL of EtOH, H3PO2 (5 mmol, anhyd) was added to this
mixture, and the resulting solution was stirred for 2–12 h at
reflux. The solvent was evaporated and the mixture resolved
in acetone by heating. Dropwise addition of H2O gave the
crude product as a white solid. The crude product was
washed with EtOH and dried in air at r.t. to give product 2 in
40–71% yield.12 The solid product was washed with EtOH–
H2O (50 mL, 9:1) and dried in air at r.t. to give a single
diastereomer. A mixture of phosphinic acid 2 (one
diastereomer, 1 mmol) and 1,1,1,3,3,3-hexamethyl-
disilazane (5 mmol, 1 mL) was heated at 110 °C for 2 h
under Ar. The mixture was then cooled to r.t. Acid chloride
(1 mmol) was added dropwise, and the resulting mixture was
stirred at r.t. for 12 h. The mixture was cooled in an ice bath,
absolute EtOH (10 mL) was added, and the reaction mixture
was stirred for 2 h at r.t. The removal of the solvent gave a
residue, out of which a white solid precipitated after adding
absolute EtOH (10 mL). The solid was washed with EtOAC
(50 mL) and EtOH (50 mL), and gave pure novel cyclic
amino bisphosphinic acid dl-5 as a white solid. All products
gave satisfactory spectroscopic data in accordance with the
assigned structures.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2009IASBS120. The authors thank to Mr. Haruhiko
Fukaya, Tokyo University of Pharmacy and Life Sciences for his
help in carrying out the X-ray crystallographic analysis. We would
also like to thank Mr. Bahman Farnudi, The English Language Sec-
tion, IASBS, for editing the manuscript.
References and Notes
(1) (a) Ghosh, S. G.; Chan, J. M. W.; Lea, C. R.; Meints, G. A.;
Lewis, J. C.; Tovian, Z. S.; Flessner, R. M.; Loftus, T. C.;
Bruchhaus, I.; Kendrick, H.; Croft, S. L.; Kemp, R. G.;
Kobayashi, S.; Nozaki, T.; Oldfield, E. J. Med. Chem. 2004,
47, 175. (b) Martin, B. M.; Grimley, J. S.; Lewis, J. C.;
Heath, L. H.; Bailey, B. N.; Kendrick, H.; Yardley, V.;
Caldera, A.; Lira, R.; Urbina, J. A.; Moreno, S. N. J.;
Docampo, R.; Croft, S. L.; Oldfield, E. J. Med. Chem. 2001,
44, 909. (c) Takeuchi, M.; Sakamoto, S.; Yoshida, M.; Abe,
T.; Isomura, Y. Chem. Pharm. Bull. 1993, 41, 688.
(d) Gittens, S. A.; Bansal, G.; Zernicke, R. F.; Uludag, H.
Adv. Drug Deliv. Rev. 2005, 57, 1011. (e) Kavanagh, K. L.;
Guo, K.; Dunford, J. E.; Wu, X.; Knapp, S.; Ebetino, F. H.;
Rogers, M. J.; Russel, R. G. G.; Opermann, U. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 7829. (f) Sanders, J. M.;
Gómez, A. O.; Mao, J.; Meints, G. A.; Van Brussel, E. M.;
Burzynska, A.; Kafarski, P.; Gonzáles-Pacanowska, D.;
Oldfield, E. J. Med. Chem. 2003, 46, 5171.
Analytical and Spectral Data for Compounds dl-5
Compound 5a: mp 234–236 °C. 1H NMR (250 MHz, D2O):
d = 2.21 (6 H, s), 5.02 (1 H, d, J = 10.3 Hz), 5.27 (1 H, d,
J = 10.5 Hz), 7.10–7.85 (13 H, m). 31P NMR (101.2 MHz,
D2O–NaOD–H3PO4): d = 21.58 (d, Jpp = 9.1 Hz), 22.29 (d,
Jpp = 9.1 Hz). 13C NMR (62.9 MHz, D2O): d = 20.1, 56.2 (d,
JPC = 89.3 Hz), 59.3 (d, JPC = 86.7 Hz), 78.5 (dd, JPC = 87.4,
71.4 Hz), 126.5–130.2 (m, Ar), 132.6, 133.7, 135.7, 137.5,
132.7. HRMS: m/z calcd for C23H25NO5P2 [MH+]: 458.1286;
found: 458.1291.
(2) Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629;
Compound 5b: mp 238–240 °C. 1H NMR (250 MHz, D2O):
d = 4.61 (1 H, d, J = 11.5 Hz), 4.73 (1 H, d, J = 11.5 Hz),
7.10–7.38 (13 H, m), 7.64 (2 H, d, J = 7.5 Hz). 31P NMR
(101.2 MHz, D2O–H3PO4): d = 21.03 (d, Jpp = 9.1 Hz), 22.08
(d, Jpp = 9.1 Hz). 13C NMR (62.9 MHz, D2O): d = 56.8 (d,
JPC = 87.2 Hz), 59.2 (d, JPC = 86.2 Hz), 78.5 (dd, JPC = 86.4,
69.3 Hz,), 126.5–127.8 (m, Ar), 128.3, 135.9, 136.5, 137.8.
HRMS: m/z calcd for C21H21NO5P2 [MH+]: 430.0973;
found: 430.0966.
and references cited therein.
(3) Widler, L.; Jaeggi, K. A.; Glatt, M.; Muller, K.; Bachmann,
R.; Bisping, M.; Born, A. R.; Cortesti, R.; Guiglia, G.; Jeker,
H.; Klein, R.; Ramseier, U.; Schmid, J.; Schreiber, G.;
Seltenmeyer, Y.; Green, J. R. J. Med. Chem. 2002, 89, 3721.
(4) Fleisch, H. Breast Cancer Res. 2002, 4, 30.
(5) Kotsikorou, E.; Song, Y.; Chan, J. M. W.; Faelens, S.;
Tovian, Z.; Broderick, E.; Bakarala, N.; Docampo, R.;
Oldfield, E. J. Med. Chem. 2005, 48, 6128.
Compound 5c: mp 220–222 °C. 1H NMR (250 MHz, D2O):
d = 4.75 (1 H, d, J = 15.0 Hz), 5.02 (1 H, d, J = 8.5 Hz),
7.05–7.40 (13 H, m), 8.20–8.32 (1 H, br). 31P NMR (101.2
MHz, D2O–H3PO4): d = 19.60 (d, Jpp = 10.1 Hz), 22.93 (d,
Jpp = 10.1 Hz). 13C NMR (62.9 MHz, D2O): d = 56.9 (d,
JPC = 90.6 Hz), 58.8 (dd, JPC = 87.4, 5.0 Hz), 80.0 (dd,
JPC = 87.4, 64.2 Hz), 126.0, 127.2, 127.5, 127.9 (d, JPC = 5.0
Hz), 128.3, 128.4, 128.5, 130.5, 132.0, 133.1, 134.2 (d,
JPC = 3.8 Hz), 136.2 (d, JPC = 3.8 Hz), 137.5. HRMS: m/z
calcd for C21H20ClNO5P2 [MH+]: 464.0584; found:
464.0587.
(6) Du, Y.; Jung, K. Y.; Wiemer, D. F. Tetrahedron Lett. 2002,
43, 8665.
(7) Abdou, W. M.; Shaddy, A. A. ARKIVOC 2009, (ix), 143.
(8) Luckman, S. P.; Coxon, F. P.; Ebetino, F. H.; Russell, G. G.;
Rogers, M. J. J. Bone Miner. Res. 1998, 13, 1668.
(9) Kleiner, H.-J.; Regnat, D. US 5,624,979, 1997.
(10) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625.
(11) (a) Dreyer, G. B.; Abdel-Meguid, S. S.; Zhao, B.; Murthy,
K.; Winborne, E.; Choi, J. W.; DesJarlais, R. L.; Minnich,
Compound 5d: mp 241–243 °C. 1H NMR (250 MHz, D2O):
d = 4.74 (1 H, d, J = 14.0 Hz), 4.91 (1 H, d, J = 10.8 Hz),
Synlett 2010, No. 12, 1837–1840 © Thieme Stuttgart · New York

1840
B. Kaboudin et al.
LETTER
JPC = 3.8 Hz), 130.4, 131.9, 132.5, 132.8, 133.1, 133.2,
134.0 (d, JPC = 3.8 Hz), 134.5 (d, JPC = 3.8 Hz), 135.9.
HRMS: m/z calcd for C21H18Cl3NO5P2 [MH+]: 531.9804;
found: 531.9803.
7.12–7.80 (14 H, m). 31P NMR (101.2 MHz, D2O–H3PO4):
d = 18.78 (d, Jpp = 8.5 Hz), 19.98 (d, Jpp = 8.5 Hz). 13C NMR
(62.9 MHz, D2O): d = 56.7 (d, JPC = 88.1 Hz), 59.3 (dd,
JPC = 90.6, 4.0 Hz), 78.2 (dd, JPC = 87.2, 65.1 Hz), 125.3,
126.7, 126.8, 127.5, 127.7, 128.4, 128.5, 128.6, 128.9,
132.8, 135.2, 136.3, 138.0. HRMS: m/z calcd for
Compound 5j: mp 246–248 °C. 1H NMR (250 MHz, D2O):
d = 4.60–4.80 (1 H, br), 4.93 (1 H, d, J = 8.2 Hz), 6.90–7.50
(11 H, m), 7.75–7.95 (1 H, br). 31P NMR (101.2 MHz, D2O–
H3PO4): d = 20.26 (d, Jpp = 19.9 Hz), 21.16 (d, Jpp = 19.8
Hz). 13C NMR (62.9 MHz, D2O): d = 56.2 (d, JPC = 87.4 Hz),
57.8 (d, JPC = 92.5 Hz), 75.5–79.5 (m), 116.1 (d, JFC = 25.2
Hz), 123.7, 124.3, 128.4, 129.0, 129.8, 130.0, 132.5, 132.7,
135.0, 135.9, 160.5 (d, JFC = 242.2 Hz). HRMS: m/z calcd
for C21H18Cl2FNO5P2 [MH+]: 516.0100; found: 516.0097.
Compound 5k: mp 245–247 °C. 1H NMR (250 MHz, D2O):
d = 5.07 (1 H, d, J = 10.0 Hz), 5.34 (1 H, d, J = 10.5 Hz),
6.90–7.35 (10 H, m), 7.42 (1 H, t, J = 7.8 Hz), 7.58 (1 H, t,
J = 7.8 Hz), 7.70 (1 H, d, J = 7.2 Hz). 31P NMR (101.2 MHz,
D2O–H3PO4): d = 12.10, 13.50. 13C NMR (62.9 MHz, D2O):
d = 55.4 (d, JPC = 89.5 Hz), 59.4 (d, JPC = 85.7 Hz), 78.1 (dd,
JPC = 87.4, 75.5 Hz), 115.5–117.0 (m, Ar), 126.0–132.0 (m,
Ar), 134.2, 163.1 (d, JFC = 246.7 Hz). HRMS: m/z calcd for
C21H19F2NO5P2 [MH+]: 466.0785; found: 466.0805.
Compound 5l: mp 242–244 °C. 1H NMR (250 MHz, D2O):
d = 4.69 (1 H, d, J = 7.5 Hz), 5.15 (1 H, d, J = 7.5 Hz), 6.90–
7.50 (11 H, m), 7.81 (1 H, t, J = 7.5 Hz). 31P NMR (101.2
MHz, D2O–H3PO4): d = 19.83 (d, Jpp = 23.3 Hz), 20.63 (d,
Jpp = 23.3 Hz). 13C NMR (62.9 MHz, D2O): d = 56.0 (d,
JPC = 86.9 Hz), 57.5 (d, JPC = 86.4 Hz), 78.1 (dd, JPC = 83.0,
66.7 Hz), 115.1 (d, JFC = 21.5 Hz), 116.1 (d, JFC = 23.6 Hz),
123.7, 124.3, 124.4, 128.8–130.4 (m, Ar), 132.2, 133.0
160.5 (d, JFC = 244.5 Hz), 161.9 (d, JFC = 243.0 Hz), 162.1
(d, JFC = 243.2 Hz). HRMS: m/z calcd for C21H18F3NO5P2
[MH+]: 484.0691; found: 484.0723.
C21H20ClNO5P2 [MH+]: 464.0584; found: 464.0593.
Compound 5e: mp 239–241 °C. 1H NMR (250 MHz, D2O):
d = 4.84 (1 H, d, J = 8.0 Hz), 5.18–5.32 (1 H, br), 6.80–7.60
(13 H, m), 7.70–7.90 (1 H, br). 31P NMR (101.2 MHz, D2O–
H3PO4): d = 17.27, 18.05. 13C NMR (62.9 MHz, D2O): d =
56.7 (d, JPC = 86.7 Hz), 58.1 (d, JPC = 93.7 Hz), 78.3 (dd,
JPC = 84.9, 74.7 Hz), 115.8, 116.2, 123.9, 128.2 (d, JPC = 7.5
Hz), 128.5–130.5 (m, Ar), 134.2, 134.9, 160.2 (d,
JFC = 245.4 Hz). HRMS: m/z calcd for C21H20FNO5P2
[MH+]: 448.0879; found: 448.0883.
Compound 5f: mp 254–256 °C. 1H NMR (250 MHz, D2O):
d = 4.67 (1 H, d, J = 14.7 Hz), 4.79 (1 H, d, J = 11.2 Hz),
7.00 (2 H, t, J = 8.7 Hz), 7.10–7.35 (8 H, m), 7.41 (2 H, d,
J = 7.0 Hz), 7.65–7.80 (2 H, br). 31P NMR (101.2 MHz,
D2O–H3PO4): d = 20.82 (d, Jpp = 9.5 Hz), 21.84 (d, Jpp = 9.9
Hz). 13C NMR (62.9 MHz, D2O): d = 56.7 (d, JPC = 88.1 Hz),
59.5 (d, JPC = 85.5 Hz), 78.1 (dd, JPC = 87.4, 71.7 Hz), 114.3
(d, JFC = 25.2 Hz), 127.4, 127.7, 128.0–129.0 (m, Ar), 131.3,
135.3, 136.4, 161.8 (d, JFC = 240.3 Hz). HRMS: m/z calcd
for C21H20FNO5P2 [MH+]: 448.0879; found: 448.0868.
Compound 5g: mp 254–256 °C. 1H NMR (250 MHz, D2O):
d = 4.00–5.00 (2 H, br), 6.50–7.85 (17 H, m). 31P NMR
(101.2 MHz, D2O–H3PO4): d = 19.70. 13C NMR (62.9 MHz,
D2O): d = 56.1 (d, JPC = 84.9 Hz), 59.5 (d, JPC = 86.2 Hz),
79.6 (dd, JPC = 84.3, 78.0 Hz), 124.3, 126.5, 127.5, 127.7,
128.0–129.7 (m, Ar), 135.3, 136.0, 137.0. HRMS: m/z calcd
for C23H23NO5P2 [MH+]: 456.1130; found: 456.1125.
Compound 5h: mp 241–243 °C. 1H NMR (250 MHz, D2O):
d = 4.20–4.80 (2 H, br), 6.90–7.50 (11 H, m), 7.55–7.80 (2H,
br). 31P NMR (101.2 MHz, D2O–H3PO4): d = 20.56 (d,
Jpp = 8.8 Hz), 21.42 (d, Jpp = 8.9 Hz). 13C NMR (62.9 MHz,
D2O): d = 56.2 (d, JPC = 86.8 Hz), 58.7 (d, JPC = 89.3 Hz),
78.5 (dd, JPC = 83.0, 70.5 Hz), 126.8, 126.9, 128.2, 129.0 (d,
JPC = 3.8 Hz), 129.5, 129.8 (d, JPC = 3.8 Hz), 132.1, 132.5,
134.7, 135.1, 135.7, 136.4. HRMS: m/z calcd for
(15) The structure was solved by a direct method using SHELXS-
97 (Scheldrik,1997) and refined with a full-matrix least-
squares method. Molecular formula = C21H27Cl2NO9P2,
MW = 570.28, triclinic, space group = P-1, a = 8.9246 (17)
Å, b = 11.069 (2) Å, c = 13.181 (3) Å, V = 1280.1 (4) Å3,
T = 296 K, Z = 2, Dx = 1.479 Mg/m3, (Mo-Ka) = 0.71073 Å,
R = 0.0367 over independent reflections(5886).
Crystallographic data (excluding structure factors) for the X-
ray crystal structure analysis reported in this paper have been
deposited with the Cambridge Crystallographic Data Center
(CCDC) as supplementary publication No. CCDC 750864,
copies of these data can be obtained, free of charge, upon
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033 or e-mail:
C21H19Cl2NO5P2 [MH+]: 498.0194; found: 498.0204.
Compound 5i: mp 231–232 °C. 1H NMR (250 MHz, D2O):
d = 4.60–4.80 (1 H, br), 4.90–5.10 (1 H, br), 7.10–7.50 (11
H, m), 7.55–7.80 (1 H, br). 31P NMR (101.2 MHz, D2O–
H3PO4): d = 19.80 (d, Jpp = 5.8 Hz), 22.93 (d, Jpp = 5.8 Hz).
13C NMR (62.9 MHz, D2O): d = 56.2 (d, JPC = 91.2 Hz),
58.17 (d, JPC = 91.8 Hz), 79.9 (dd, JPC = 88.7, 66.0 Hz),
126.1, 128.3, 128.5, 129.5 (d, JPC = 3.8 Hz), 129.9 (d,
deposit@ccdc.cam.ac.uk].
Synlett 2010, No. 12, 1837–1840 © Thieme Stuttgart · New York

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