Synthesis of a new class of phosphinic acids: Synthesis of novel four-membered cyclic oxaphosphetanes by intramolecular mitsunobu reaction of bis(-hydroxyalkyl)phosphinic acids

Article abstract of DOI:10.1055/s-0030-1260170

A novel class of phosphinic acid derivatives, four-membered cyclic oxaphosphetanes, was synthesized by the reaction of bis(hydroxymethyl)phosphinic acids with a mixture of triphenylphosphine and diisopropyl azodicarboxylate in toluene-dichloromethane at r

Full text of DOI:10.1055/s-0030-1260170

PAPER
3185
Synthesis of a New Class of Phosphinic Acids: Synthesis of Novel
Four-Membered Cyclic Oxaphosphetanes by Intramolecular Mitsunobu
Reaction of Bis(a-hydroxyalkyl)phosphinic Acids
S
ynthesis of
a
No
a
vel Class
o
b
f
Cyclic Pho
a
sphinic
A
ci
k
ds Kaboudin,*a Hamideh Haghighat,a Tsutomu Yokomatsub
a
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan 45137-66731, Iran
Fax +98(241)4214949; E-mail: kaboudin@iasbs.ac.ir
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horonouchi, Hachioji, Tokyo 192-0392, Japan
b
Received 20 June 2011; revised 13 July 2011
hydroxy group into a potent leaving group that can be dis-
placed by a wide variety of nucleophiles. The Mitsunobu
reaction allows the conversion of primary and secondary
alcohols into esters, phenyl ethers, thioethers, and various
Abstract: A novel class of phosphinic acid derivatives, four-mem-
bered cyclic oxaphosphetanes, was synthesized by the reaction of
bis(hydroxymethyl)phosphinic acids with a mixture of triphe-
nylphosphine and diisopropyl azodicarboxylate in toluene–dichlo-
romethane at room temperature via an intramolecular Mitsunobu other compounds; it is a stereospecific reaction. The nu-
reaction.
cleophile employed should be acidic, since dialkyl azodi-
carboxylate must be protonated during the course of the
reaction to prevent side reactions. As a part of our effort
to explore the utility of novel reactions for the synthesis of
organophosphorus compounds,13 we recently described a
new method for the synthesis and separation of bis(a-hy-
droxyalkyl)phosphinic acids from the reaction of hypo-
phosphorus acid with aldehydes.14 Herein, we report the
synthesis of a new class of cyclic four-membered phos-
phinic acids via the reaction of bis(a-hydroxyalkyl)phos-
phinic acids with a mixture of triphenylphosphine and
diisopropyl azodicarboxylate via intramolecular Mitsuno-
bu reaction.
Key words: bis(a-hydroxyalkyl)phosphinic acids, oxaphosphet-
ane, cyclic phosphinic acids, Mitsunobu reaction
Organophosphorus compounds occupy an important
place among the various types of organoelemental com-
pounds in which chemists are now interested.1 Among the
organophosphorus compounds, phosphinic acids are an
important class of compounds that exhibit a variety of in-
teresting and useful properties. Phosphinic acids have
attracted growing attention because of their novel
applications in the areas of industrial, agricultural, medic-
inal, and synthetic intermediates.2–5 In addition, the struc-
ture of the phosphinic functional group mimics the
transition state of peptide hydrolysis and the symmetric
nature of the phosphinic acid derivatives are expected to
benefit in their binding to the homodimer of HIV-protease
having C2-axis symmetry.6 The presence of the phospho-
rus atom in the heterocycle could regulate important bio-
logical functions and also increase the biological activity
of this type of compound, in a similar way to that reported
for enzymatic inhibitors and for other pharmaceuticals.7
In contrast to extensive studies on the synthesis of hetero-
cyclic compounds8 and phosphinic derivatives,9,10 rela-
tively few papers have been reported on the synthesis of
heterocyclic phosphinic compounds.11 Since heterocycles
have shown a variety of biological activity, and since
phosphinic acids can be used in industry, agriculture, and
medicine, and in organic synthesis, we set out to expand
the range of compounds accessible from simple building
blocks.
We first carried out the reaction of benzaldehyde with hy-
pophosphorus acid (1a) as a model reaction. When the
reaction was carried out at 90 °C for one hour, a diastereo-
meric mixture of bis[hydroxy(phenyl)methyl]phosphinic
acid (2a) was obtained in 82% yield (in a 56:45 ratio of
diastereomers (Scheme 1). The 31P NMR spectrum of this
mixture exhibited two peaks at d = 38.55 and 36.38 due to
the diastereomers. When the reaction mixture was sub-
jected to washing with successively nonpolar and polar
solvents, only rac-2a was extracted with methanol, a
highly polar solvent. The stereochemistry of rac-2a was
confirmed by conversion into the corresponding methyl
ester using trimethyl orthoformate under microwave irra-
diation for 10 minutes. The syn-methyl ester was formed
as a mixture of two diastereomers due to the new stereo-
genic center at the phosphorus atom; the anti-isomer is a
dl pair and thus would have only one stereoisomer
(Scheme 2). We have also shown that enantiomerically
pure bis[hydroxy(phenyl)methyl]phosphinic acid can be
accessed by the fractional crystallization of salts formed
The Mitsunobu reaction, a dehydration–condensation re-
action between alcohols and various nucleophiles, has
gained wide application in organic synthesis due to its ef-
fectiveness and versatility.12 This mild reaction converts a
O
P
O
P
O
90 °C, 1 h
Ph
Ph
Ph
Ph
H
P
H
Ph CHO
+ 2
+
OH
OH
OH
1a
OH OH
OH OH
SYNTHESIS 2011, No. 19, pp 3185–3189
x
x.
x
x
.
2
0
1
1
rac-2a
meso-2a
Advanced online publication: 12.08.2011
DOI: 10.1055/s-0030-1260170; Art ID: Z62811SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

3186
B. Kaboudin et al.
PAPER
H
H
H
H
H
OH
HO
Ph
OH
Ph
HO
Ph
OH
Ph
HO
Ph
H
OH OH
P
HC(OMe)3
P
P
P
Ph
OMe
Ph
Ph
OMe
O
O
MeO
O
OH
O
2a (mixture of two
diastereoisomers)
syn
anti
Scheme 2
O
P
Ph
Ph
Ph
Ph
O
O–
+
NH3
OH OH
Ph
P
Ph
Ph
EtOH
HCl
+
(R,R)-2a
OH
O
OH OH
NH2
P
Ph Ph
rac-2a
O–
+
OH OH
NH3
Scheme 3
from racemic bis[hydroxy(phenyl)methyl]phosphinic yields (entries 2–10). Treatment of 2k with triphenylphos-
acid and enantiopure 1-phenylethylamine (Scheme 3).14
phine and diisopropyl azodicarboxylate under the same
conditions failed, after 24 hours, to form 3k (entry 11), the
reaction of bis[hydroxy(naphthyl)methyl]phosphinic ac-
ids rac-2l and 2m also failed to give 3l and 3m under the
same conditions after 24 hours (entries 12 and 13).
We were interested in studying the synthesis of a novel
class of cyclic phosphinic acid. The treatment of bis[hy-
droxy(phenyl)methyl]phosphinic acid (rac-2a) with a
mixture of triphenylphosphine and diisopropyl azodicar-
boxylate dry in toluene was studied, and the progress of
the reaction was monitored by TLC; the reaction failed to
form 3a after 24 hours. When the reaction was carried out
in a mixture of dry toluene and dichloromethane (5:1) at
room temperature for six hours, 2,4-diphenyl-1,3-oxa-
phosphetan-3-ol 3-oxide (3a) was formed in 86% isolated
yield (Scheme 4).
Table 1 Reaction of Bis(hydroxyalkyl)phosphinic Acids with a
Mixture of Triphenylphosphine and Diisopropyl Azodicarboxylate
O
OH
O
P
P
Ph3P, DIAD
H
R
H
R
R
R
toluene–CH2Cl2
r.t., 6–12 h
O
OH
OH OH
rac-2
3
O
OH
O
P
Entry
R
Time
(h)
Product Yielda 31P
P
Ph3P, DIAD
(%)
86
48
53
46
54
70
60
64
87
52
NMR d
Ph
Ph
H
Ph
H
Ph
toluene–CH2Cl2
r.t., 6 h
OH
O
OH OH
1
2
Ph
2a
6
12
12
12
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
–
26.81
27.22
23.27
25.90
25.11
26.03
27.20
25.73
26.53
27.17
–
rac-2a
3a
2-MeC6H4
2-BrC6H4
2-FC6H4
2b
2c
2d
2e
2f
Scheme 4
3
4
The structure of 3a was confirmed by NMR data and mass
analysis. In the 31P NMR spectrum, a single peak appeared
at d = 26.81. The 1H NMR spectrum had a doublet at d =
5.64 (JHP = 1.6 Hz) which corresponds with the hydrogens
P–CH(R)–O in the product 3a (due to small cyclic rigid
structure, small CH–P coupling constant was observed).
The 13C NMR spectrum exhibited a doublet at d = 97.9
(JCP = 72.3 Hz). The structure was supported by its
HRMS (ESI) (m/z [M + Na]+ calcd for C14H13O3PNa:
283.0500; found: 283.0497).
5
3-BrC6H4
3-FC6H4
6
8
7
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
2g
2h
2i
10
10
10
10
12
12
12
8
9
10
11
12
13
2j
b
Treatment of different bis[aryl(hydroxy)methyl]phos-
phinic acid derivatives rac-2a–m with a mixture of tri-
phenylphosphine and diisopropyl azodicarboxylate in
toluene–dichloromethane at room temperature was exam-
ined (Table 1); Different ortho-, meta-, and para-substi-
tuted aryl derivatives 2b–j afforded the corresponding
oxaphosphetane derivatives 3b–j in 46–87% isolated
n-Hex
2k
2l
–
b
1-naphthyl
2-naphthyl
–
–
–
b
2m
–
–
–
a Yields refer to the isolated pure products.
b The reaction failed to give the product.
Synthesis 2011, No. 19, 3185–3189 © Thieme Stuttgart · New York

PAPER
Synthesis of a Novel Class of Cyclic Phosphinic Acids
3187
3.07 mmol) in a mixture of anhyd toluene–CH2Cl2 (5:1, 18 mL) at
0 °C under argon and the soln was stirred at 0 °C for 30 min. Stirring
was continued at r.t. for 6 h and then MeOH (0.2 mL) was added.
After 30 min the solvent was removed in vacuo. The residue was
purified by chromatography (CHCl3–MeOH) to give cyclic oxa-
phosphetanes 3 in 46–87% yield. All products gave satisfactory
spectral data in accord with the assigned structures.
The proposed mechanism is an intramolecular Mitsunobu
reaction mechanism. Triphenylphosphine and diisopropyl
azodicarboxylate quickly form a betaine intermediate that
is able to deprotonate the phosphinic acid in the bis(hy-
droxyalkyl)phosphinic (Scheme 5). The generated phos-
phinate anion deprotonates the alcoholic moiety forming
an alkoxide which can then attack the betaine at phospho-
rus. The other alcoholic group participates in an intramo-
lecular condensation nucleophilic displacement of
triphenylphosphine oxide which proceeds with inversion.
2,4-Diphenyl-1,3-oxaphosphetan-3-ol 3-Oxide (3a)
White solid; mp ~320 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.64 (d, JHP = 1.6 Hz, 2 H),
7.21 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 8.0 Hz, 4 H), 7.41 (d, J = 7.6
Hz, 4 H).
13C NMR (100.6 MHz, DMSO-d6): d = 97.9 (d, JPC = 72.3 Hz),
126.6, 126.9 (d, JPC = 4.4 Hz), 128.07, 140.5 (d, JPC = 12.5 Hz).
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 26.81.
HRMS: m/z [M + Na]+ calcd for C14H13O3PNa: 283.0500; found:
O
PPh3
N
O
Ph3P
OiPr
N
OiPr
iPrO
iPrO
N
iPrO
R
N
O
O
O
O
P
R
O
H
283.0497.
N
OH
OH OH
OiPr
R
P
R
2
N
O
PPh3
O
OH OH
2,4-Bis(2-methylphenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3b)
White solid; mp 160–162 °C.
O
1H NMR (400 MHz, DMSO-d6): d = 2.29 (s, 6 H), 5.95 (d, J = 4.4
O
OH
R
P
R
P
Hz, 2 H), 7.04–7.91 (m, 8 H).
R
H
R
H
OH
O
OH
13C NMR (100 MHz, DMSO-d6–TMS): d = 19.3, 97.33 (d, JPC = 71
Hz), 125.1 (d, JPC = 4 Hz), 125.6 (d, JPC = 2 Hz), 125.7 (d, JPC = 2.0
Hz), 133.0 (d, JPC = 4.0 Hz), 134.4 (d, JPC = 11.0 Hz), 135.8 (d,
JPC = 3.0 Hz), 139.1 (d, JPC = 8 Hz).
O
3
Ph3P
Scheme 5
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 27.22.
HRMS: m/z [M + Na]+ calcd for C16H17O3PNa: 311.0813; found:
The reaction is a stereospecific reaction and due to the
rapid prototopic transfer of the acidic proton between
phosphoryl (P=O) and acidic (P–OH) sites, only one sig-
nal is observed in 31P NMR spectrum (Table 1).
311.0918.
2,4-Bis(2-bromophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3c)
White solid; mp ~300 °C (dec).
In summary, we have developed a simple and practical ap-
proach for the synthesis of a new class of organophospho-
rus compounds. Through an intramolecular Mitsunobu
cyclization of bis(hydroxyalkyl)phosphinic acids with a
mixture of triphenylphosphine and diisopropyl azodicar-
boxylate in toluene–dichloromethane at room tempera-
ture, novel four-membered cyclic oxaphosphetanes can be
synthesized cleanly and in good yield. The structure of the
novel four-membered cyclic oxaphosphetanes was deter-
mined by HRMS analysis and NMR data, which showed
the cyclic phosphinic acid. Some of the major advantages
of this protocol are: a simple procedure, easy workup, and
good yields.
1H NMR (400 MHz, DMSO-d6): d = 6.04 (d, J = 5.6 Hz, 2 H), 7.17–
7.73 (m, 8 H).
13C NMR (100 MHz, DMSO-d6–TMS): d = 97.52 (d, JPC = 74.0
Hz), 120.2 (d, JPC = 6 Hz), 127.6, 128.2, 128.8, 132.1, 139.6.
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 23.27.
HRMS: m/z [M + Na]+ calcd for C14H11Br2O3PNa: 438.8710;
found: 438.8881.
2,4-Bis(2-fluorophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3d)
White solid; mp ~300 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 6.04 (d, J = 5.6 Hz, 2 H), 7.17–
7.73 (m, 8 H).
13C NMR (100 MHz, DMSO-d6–TMS): d = 91.8 (d, JPC = 73.0 Hz),
114.7 (dd, JPC = 2.0 Hz, JFC = 10.0 Hz), 123.8 (d, JPC = 2.0 Hz),
124.4 (d, JPC = 2.0 Hz), 127.9 (dd, JPC = 3 Hz, JFC = 10 Hz), 131.9,
132.0, 132.5 (d, JPC = 2.0 Hz).
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 25.90.
HRMS: m/z [M + Na]+ calcd for C14H11F2O3PNa: 319.0312; found:
All chemicals were commercial products and distilled or recrystal-
lized before use. NMR spectra were taken with a 400 MHz Bruker
Avance instrument. Silica gel column chromatography was carried
out with Silica gel 100 (Merck No. 10184). Merck Silica Gel 60
F254 plates (No. 5744) were used for the preparative TLC. Mass
spectra were measured on a LCMASS micromass LCT and Micro-
mass Autospec. Melting points are uncorrected
319.0314.
2,4-Bis(3-bromophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3e)
White solid; mp ~320 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.72 (d, J = 3.2 Hz, 2 H), 7.22–
7.83 (m, 8 H).
Bis(a-hydroxyalkyl)phosphinic Acids rac-2; General Procedure
These compounds were obtained according to the method of our
previously published article.14b
13C NMR (100 MHz, DMSO-d6–TMS): d = 97.20 (d, JPC = 71 Hz),
121.8 (d, JPC = 2 Hz), 125.5 (d, JPC = 5 Hz), 129.4 (d, JPC = 4 Hz),
129.5 (d, JPC = 2 Hz), 130.4, 134.6, 134.8.
Oxaphosphetanes 3; General Procedure
The bis(hydroxyalkyl)phosphinic acid rac-2 (2 mmol) was added to
a stirred mixture of Ph3P (0.805 g, 3.07 mmol) and DIAD (0.6 mL,
Synthesis 2011, No. 19, 3185–3189 © Thieme Stuttgart · New York

3188
B. Kaboudin et al.
PAPER
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 25.11.
HRMS: m/z [M + Na]+ calcd for C14H11Br2O3PNa: 438.8710;
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2010IASBS120.
found: 438.8793.
2,4-Bis(3-fluorophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3f)
White solid; mp ~310 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.58 (s, 2.8 H), 7.10–7.60 (m,
8 H).
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White solid; mp 190–192 °C.
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Hz), 127.2 (d, JPC = 4 Hz), 128.6 (d, JPC = 2 Hz), 135.6 (d, JPC = 2
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2,4-Bis(4-chlorophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3h)
White solid; mp ~310 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.64 (d, J = 2.8 Hz, 2 H), 7.12–
7.66 (m, 8 H).
13C NMR (100 MHz, DMSO-d6–TMS): d = 97.3 (d, JPC = 70 Hz),
128.1 (d, JPC = 2 Hz), 128.6 (d, JPC = 5.0 Hz), 131.1 (d, JPC = 3.0
Hz), 139.2 (d, JPC = 8.0 Hz).
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 25.73.
HRMS: m/z [M + Na]+ calcd for C14H11Cl2O3PNa: 350.9721; found:
350.9719.
2,4-Bis(4-bromophenyl)-1,3-oxaphosphetan-3-ol 3-Oxide (3i)
White solid; mp ~300 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.72 (d, J = 2.4 Hz, 2 H), 7.32–
7.52 (m, 8 H).
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119.7, 129.0, 131.0, 139.5 (d, JPC = 8.0 Hz).
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 26.53.
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White solid; mp ~300 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 5.65 (d, J = 0.8 Hz, 2 H), 7.14–
7.48 (m, 8 H).
13C NMR (100 MHz, DMSO-d6–TMS): d = 96.8 (d, JPC = 72.0 Hz),
114.9 (dd, JPC = 1 Hz, JFC = 21.5 Hz), 129.1 (dd, JPC = 5 Hz,
JFC = 8.0 Hz), 137.7 (dd, JPC = 3 Hz, JFC = 8.0 Hz), 161.5 (dd,
JPC = 3 Hz, JFC = 240.5 Hz).
31P NMR (162 MHz, DMSO-d6–H3PO4): d = 27.17.
HRMS: m/z [M + Na]+ calcd for C14H11F2O3PNa: 319.0312; found:
(11) (a) Boyd, A. E.; Boyd, M. E. K.; Kerrigan, F. Tetrahedron
Lett. 1996, 37, 5425. (b) Regan, A. C.; Sciammetta, N.;
319.0316.
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