Synthesis of New Arylhydroxymethylphosphinic Acids and Derivatives

Article abstract of DOI:10.1055/s-2003-41045

The synthesis of a new series of arylhydroxymethylphosphinic acid derivatives is described. The protected compounds were prepared by a palladium(0) catalysed arylation of ethyl benzyloxymethylphosphinate with aryl halides. Subsequent hydrogenolysis of the

Full text of DOI:10.1055/s-2003-41045

2216
PAPER
Synthesis of New Arylhydroxymethylphosphinic Acids and Derivatives
Synthesis of
N
ew A
.
r
ylhy
-
droxym
J
ethylphosp
.
hinic
AcidsCand Derivatives ristau,* A. Hervé, F. Loiseau, D. Virieux*
Laboratoire de Chimie Organique, UMR 5076, Ecole Nationale Supérieure de Chimie de Montpellier, 8, Rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France
Fax +33(4)67144319; E-mail: cristau@cit.enscm.fr; E-mail: virieux@cit.enscm.fr
Received 28 May 2003
hydroxymethyl group is converted into a benzyloxymeth-
Abstract: The synthesis of a new series of arylhydroxymethylphos-
yl group.
phinic acid derivatives is described. The protected compounds were
prepared by a palladium(0) catalysed arylation of ethyl benzyl-
oxymethylphosphinate with aryl halides. Subsequent hydrogenoly-
sis of the benzyl protecting group followed by acidic hydrolysis of
the ester function readily afforded the target compounds. Selective
removal of the ester group was achieved by basic hydrolysis where-
as acidic hydrolysis directly gave the totally deprotected com-
pounds.
Compound 3 was synthesized (63% overall yield) in two
steps: first by the pseudo-Arbuzov reaction of the in situ
generated bis(trimethylsilyl)phosphonite (BTSP) (1)24–26
with benzyl chloromethyl ether to give benzyloxymeth-
ylphosphinic acid 2, and then by esterification of the phos-
phinic acid group with tetraethoxysilane (Scheme 1).27
Key words: phosphorus, phosphinates, palladium, arylations, pro-
tecting groups
During the last decade, phosphonic acids aroused a grow-
ing interest due to their potential application in biomolec-
ular chemistry.1–4 More particularly, the synthesis of
arylphosphonic acids has been extensively studied as they
are valuable intermediates for the preparation of medici-
nal molecules.5–11 In this context, we developed the syn-
thesis of new arylphosphinic acids containing
a
Scheme 1 Reagents and conditions: i) HMDS (4 equiv), 100 °C,
N2, 2 h; ii) ClCH2OCH2Ph (1 equiv), 0 to 20 °C, N2, 12 h; iii) HCl–
H2O, 15 min; iv) Si(OEt)4 (1 equiv), PhMe, reflux, N2, 12 h.
hydroxymethyl group. The change of a hydroxy group of
the phosphonic function by the hydroxymethyl group
could improve, by the change of lipophilicity, the bio-
availability and the trans-membranar transport of the mol-
ecule.12 Indeed, some phosphonic acids derivatives are
known to have a very low bio-availability due to their high
ionic character in body fluids.13
Ethyl arylbenzyloxymethylphosphinates 4a–g were then
prepared by the palladium catalysed arylation of 3 with
the corresponding aryl halides in the presence of triethyl-
amine (Scheme 2).
But, although a number of arylphosphonic acids have
been prepared, to date much less work has been devoted
to arylphosphinic acids.14–18 Moreover, to the best of our
knowledge, there are very few papers in the literature
dealing with the arylation of functionalized hydrogeno-
phosphinic acids.19–21 Our synthetic methodology relies
on a palladium(0) catalysed arylation of a nucleophilic
precursor, derived from hydroxymethylhydrogenophos-
phinic acid with different aryl halides.
Scheme 2
This reaction displays broad scope for a single set of con-
ditions as listed in Table 1. Indeed, aromatic iodide (entry
1) and bromides (entries 2 to 5) as well as heteroaromatic
bromides (entries 6 and 7) afford moderate to excellent
yields (53–84%). Products 4a–g were isolated by column
chromatography in 27–70% yields. They were fully char-
To perform this reaction, the acidic function of the phos-
phinic acid precursor needed to be protected. The hy-
droxymethyl group has also to be protected in order to
avoid a retroformylation reaction in basic conditions22,23
and also a possible competitive arylation of the oxygen at-
om. Thus, as the precursor of the target compounds, we
selected ethyl benzyloxymethylphosphinate 3 in which
the acidic function is protected as an ethyl ester and the
acterized by 31P, H, 13C NMR, mass and IR spectrome-
tries (Tables 2 and 3).
1
Finally, selective debenzylation28,29 of compounds 4b–d
by hydrogenolysis on Pd/C readily afforded ethyl arylhy-
droxymethylphosphinates 7b–d, respectively, in 100%,
88% and 93% yields (Scheme 3). Hydroxymethylphosph-
inates 7b and 7d were hydrolysed with concentrated hy-
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,14,2216,2220,ftx,en;P04203SS.pdf.
DOI: 10.1055/s-2003-41045
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of New Arylhydroxymethylphosphinic Acids and Derivatives
2217
drochloric acid at 80 °C for 3 hours to give the
corresponding complete deprotection products, leading to
arylhydroxymethylphosphinic acids 8b and 8d in 91 and
100% yields.30,31 These two steps can be combined in a
one step procedure by the direct acidic hydrolysis of phos-
phinate 4a which gave, after 5 hours of stirring at 80 °C,
the corresponding free hydroxymethylphosphinic acid 8a
which was isolated in 96% yield. Finally, selective depro-
tection of the phosphinic acid function of compound 4e
was achieved by basic hydrolysis in the presence of a
threefold excess of sodium hydroxide at room tempera-
ture for 5 hours.32,33 The corresponding sodium salt 9e was
isolated in a quantitative yield.
In conclusion, several aryl- or heteroarylhydroxymeth-
ylphosphinic acid derivatives were prepared by palladi-
um(0) catalysed arylation of ethyl benzyl-
oxymethylphosphinate (3), with aromatic or heteroaro-
matic bromides or iodides. Finally, total or selective
deprotections have been performed to confirm the com-
Scheme 3 Reagents and conditions: i) H2, Pd/C, EtOH, Patm, r.t.; ii)
aq HCl (35%; 11 equiv), 80 °C, 3 h; iii) aq HCl (35%; 11 equiv),
80 °C, 5 h; iv) NaOH (3 equiv), EtOH, r.t., 5 h.
Table 1 Preparation of Ethyl Arylbenzyloxymethylphosphinates 4a–g (Scheme 2)
Entry
ArX
Reaction
time (h)
Product
Compd
Yield (%)a
84
Isolated Yield
(%)
1
2.5
4a
70
2
3
4
2.5
5
4b
4c
4d
80
73
70
66
55
54
7
5
2
4e
69
50
6
7
12
12
4f
84
53
56
27
4g
a Yields were determined by 31P NMR with 16 s as delay for relaxation time using invgate sequence.
Synthesis 2003, No. 14, 2216–2220 © Thieme Stuttgart · New York

2218
H.-J. Cristau et al.
PAPER
Table 2 NMR Data of Compounds 4a–g (CDCl3)
Product
31P NMR
1H NMR
13C NMR
δ
δ, J (Hz)
δ, J (Hz)
4a
34.33
36.06
34.33
37.32
1.26 (t, 3 H, 3JHH = 7.1, CH3), 3.75–3.93 (2 dd,
16.24 (d, 3JPC = 6.1, CH3), 60.12 (d, 2JPC = 6.4, CH2), 65.80
(d, 1JPC = 168.3, CH2), 74.54 (d, 3JPC = 11.7, CH2), 127.51
(s, 2 C, CH), 127.57 (s, CH), 128.06 (s, 2 C, CH), 128.20
ABX system,
= 3.80,
= 3.90, 2JHAHB
=
HA
HB
–13.6, 2JPHA = 5.8, 2JPHB = 8.5, CH2), 3.92–4.12
(m, 2 H, CH2), 4.52 (s, 2 H, CH2), 7.13–7.24 (m, 5 (d, 2JPC = 12.8, CH), 129.19 (d, 1JPC = 127.5, C), 131.74 (d,
H, CH), 7.42–7.47 (m, 3 H, CH), 7.79–7.83 (m, 2 2JPC = 9.7, CH), 132.34 (d, 4JPC = 2.1, CH), 136.72 (s, C).
H, CH).
4b
4c
4d
1.31–1.37 (m, 3 H, CH3), 3.80–4.17 (m, 4 H, 2
16.23 (d, 3JPC = 6.0, CH3), 61.42 (d, 2JPC = 6.2, CH2), 65.76
CH2), 4.55 (s, 2 H, CH2), 7.16–7.18 (m, 2 H, CH), (d, 1JPC = 120.9, CH2), 74.79 (d, 3JPC = 12.0, CH2), 123.58
7.25–7.28 (m, 3 H, CH), 7.71–7.73 (m, 2 H, CH), (q, 1JCF = 272.8, CF3), 125.28 (qd, 3JCF = 3.7, 3JPC = 12.6,
7.79–7.83 (m, 2 H, CH).
CH), 127.92 (s, CH), 128.08 (s, CH), 128.42 (s, CH),
131.96 (d, 2JPC = 10.1, CH), 133.40 (d, 1JPC = 125.6, C),
134.21 (qd, 2JCF = 32.8, 4JPC = 3.0, C), 136.57 (s, C).
1.24 (t, 3JHH = 7.0, 3 H, CH3), 3.74–4.11 (m, 4 H, 16.49 (d, 3JPC = 6.3, CH3), 55.22 (s, CH3), 60.83 (d,
2 CH2), 3.99 (s, 3 H, CH3), 6.93–6.97 (m, 2 H,
2JPC = 6.3, CH2), 66.77 (d, 1JPC = 120.6, CH2), 74.89 (d,
CH), 7.18–7.27 (m, 5 H, CH), 7.73–7.80 (m, 2 H, 3JPC = 11.4, CH2), 114.01 (d, 3JPC = 13.8, CH), 120.37 (d,
CH).
1JPC = 134.4, C), 127.79 (s, CH), 127.82 (s, CH), 128.31 (s,
CH), 134.00 (d, 2JPC = 11.2, CH), 137.00 (s, C), 163.03 (d,
4JPC = 3.0, C).
1.25–1.35 (m, 3 H, CH3), 3.79 (s, 3 H, CH3), 3.81– 16.53 (d, 3JPC = 6.3, CH3), 55.36 (s, CH3), 61.21 (d,
4.15 (m, 4 H, 2 CH2), 4.56 (s, 2 H, CH2), 7.07–7.40 JPC = 6.7, CH2), 66.66 (d, 1JPC = 120.2, CH2), 75.02 (d,
2
(m, 9 H, CH).
3JPC = 11.5, CH2), 116.49 (d, 2JPC = 11.2, CH), 119.17 (d,
4JPC = 2.6, CH), 124.17 (d, 2JPC = 9.3, CH), 127.88 (CH),
127.92 (CH), 128.37 (CH), 129.75 (d, 3JPC = 14.9, CH),
130.59 (d, 1JPC = 126.4, C), 136.94 (C), 159.61 (d,
3JPC = 15.6, C).
4e
38.10
1.35–1.39 (m, 3 H, CH3), 4.02–4.24 (m, 4 H, 2
16.55 (d, 3JPC = 6.3, CH3), 31.35 (d, 2JPC = 6.3, CH2), 67.38
CH2), 4.53 (s, 2 H, CH2), 7.08–7.09 (m, 2 H, CH), (d, 1JPC = 118.7, CH2), 74.89 (d, 3JPC = 11.2, CH2), 124.73
7.10–7.20 (m, 3 H, CH), 7.52–7.59 (m, 2 H, CH), (d, 3JPC = 13.4, CH), 126.25 (d, 3JPC = 11.2, CH), 125.90
7.56 (ddd, 1 H, JHH = 8.2, 3JHH = 7.1, 4JPH = 2.6,
(d, 1JPC = 122.1, C), 127.79 (s, CH), 127.81 (s, CH), 128.24
(s, CH), 133.11 (d, 2JPC = 11.2, C), 133.61 (d, 3JPC = 10.8,
CH), 7.89–7,94 (m, 1 H, CH), 8.07 (ddd, 1 H,
3JHH = 8.2, 4JHH = 1.2, 5JPH = 1.2, CH), 8.25 (ddd, C), 136.84 (s, C),126.14 (CH), 126.21 (CH), 126.35 (CH),
1 H, 3JHH = 7.1, 4JHH = 1.2, 3JPH = 14.4, CH).
126.97 (CH), 127.50 (CH), 128.97 (CH), 129.00 (CH),
133.82 (CH), 133.88 (CH), 134.83 (CH), 135.00 (CH).
4f
33.62
31.96
1.33–1.36 (m, 3 H, CH3), 3.97–4.18 (2 dd, ABX
16.38 (d, 3JPC = 6.0, CH3), 60.97 (d, 2JPC = 6.7, CH2), 64.69
(d, 1JPC = 121.7, CH2), 74.93 (d, 3JPC = 10.8, CH2), 126.33
system, HA = 4.02, HB = 4.13, 2JHAHB = –13.6,
2JPHA = 8.2, 2JPHB = 5.7), 4.01–4.24 (m, 2 H, CH2), (d, 4JPC = 3.4, CH), 127.86 (s, CH), 127.90 (s, CH), 128.31
4.52–4.63 (2 d, 2 H, AB system, HA = 4.55,
(s, CH), 128.84 (d, 3JPC = 21.7, CH), 136.28 (d, 2JPC = 6.7,
HB = 4.59, 2JHAHB = –12.4, CH2), 7.19–7.29 (m, 5 CH), 136.82 (C), 150.40 (d, 3JPC = 20.5, CH), 152.30 (d,
H, CH), 7.41 (m, 1 H, CH), 7.80–7.83 (m, 1 H,
CH), 8.04–8.09 (m, 1 H, CH), 8.74 (m, 1 H, CH).
1JPC = 158.6, C).
4g
1.21–1.36 (m, 3 H, CH3), 3.80–4.18 (m, 4 H, 2
16.38 (d, 3JPC = 6.2, CH3), 61.40 (d, 2JPC = 6.7, CH2), 67.00
CH2), 4.60 (s, 2 H, CH2), 7.19–7.32 (m, 6 H, CH), (d, 1JPC = 128.8, CH2), 75.06 (d, 3JPC = 11.9, CH2), 127.87
7.69–7.73 (m, 2 H, CH).
(d, JPC = 15.0, CH), 127.93 (s, CH), 128.11 (s, CH), 128.42
(s, CH), 128.92 (d, 1JPC = 139.9, C), 134.37 (d, JPC = 5.6,
CH), 136.30 (s, C), 137.20 (d, 2JPC = 10.8, CH).
(Merck, SIL, G/UV254) or 31P NMR. Merck silica gel (70–200 m)
was used for column chromatography. 1H, 13C and 31P NMR spectra
were recorded on Bruker AC 200 (1H at 200.13 MHz, 13C at 50.32
MHz and 31P at 81.01 MHz) and on Bruker AC 250 spectrometers
(1H at 250.13 MHz, 13C at 62.89 MHz and 31P at 101.25 MHz).
Chemical shifts are expressed in ppm and coupling constants in Hz.
IR spectra were obtained with Perkin–Elmer 377 and Nicolet FT-IR
210 spectrometers. Mass spectra were measured with a Jeol JMS
DX-300 spectrometer (positive FAB ionisation and high resolution,
glycerol-thioglycerol or p-nitrobenzyl alcohol).
patibility and the complementarity of the protecting
groups on the phosphorus atom and on the hydroxymethyl
group. The synthetic sequence affords a reliable and gen-
eral access to this class of phosphinic acids.
All reactions involving air or moisture sensitive reagents or inter-
mediates were carried out under dry nitrogen in flame-dried glass-
ware. Reagents and solvents were purified before use and stored
under a nitrogen atmosphere. All reactions were monitored by TLC
Synthesis 2003, No. 14, 2216–2220 © Thieme Stuttgart · New York

PAPER
Synthesis of New Arylhydroxymethylphosphinic Acids and Derivatives
2219
Preparation of Phosphinates 4a–g; General Procedure
Pos FAB MS (NBA): m/z = 269 (100, [M + H]+).
In a typical procedure, a mixture of ethyl benzyloxymethylphosph-
inate (1 equiv) and aryl halide (1 equiv) in dry toluene was placed
in a two-necked flask under a nitrogen atmosphere. Tetrakis[triphe-
nylphosphine]palladium (0.1 equiv) and Et3N (3 equiv) were added
and the reaction mixture was heated in an oil bath at 100–110 °C for
2–12 h. After the mixture had been cooled, EtOAc was added and
the solid filtered off. The oily residue was purified by column chro-
matography [silica gel; petroleum ether (bp 60–90 °C)–EtOAc].
HRMS: m/z calcd for C10H13F3O3P: 269.0554; found: 269.0551.
Ethyl Hydroxymethyl-(4-methoxyphenyl)phosphinate (7c)
Yield: 88%. Yellow oil.
IR (NaCl): 3370 (OH), 1260 (P=O), 1070 [(P)O–C] cm–1.
1H NMR (CDCl3): = 1.06 (t, 3JHH = 7.2, 3 H, CH3), 3.77 (s, 3 H,
CH3), 3.83–4.18 (m, 4 H, 2 CH2), 5.04 (br s, OH), 6.97 (dd,
4JPH = 2.27, 3JHH = 8.6, 2 H, CH), 7.73 (dd, 3JPH = 10.7, 3JHH = 8.6,
2 H, CH).
Table 3 IR and Mass Data of Compounds 4a–g
3
13C NMR (CDCl3): = 16.49 (d, JPC = 6.0, CH3), 55.31 (s, CH3),
Prod- IR (cm–1)
uct
Pos FAB MS
(NBA) m/z (%)
60.19 (d, 1JPC = 116.5, CH2), 61.18 (d, 2JPC = 6.7, CH3), 114.24 (d,
2JPC = 13.4, CH), 118.85 (d, 1JPC = 130.2, C), 133.95 (d, 3JPC = 11.2,
CH), 163.08 (s, C).
4a
4b
4c
1400 (C=C), 1250 (P=O), 1225
(P=O), 1175 [(O)–O–C], 1130
[(O)-O-C].
291 (42, [M + H]+),
91 (100, C7H7 ).
+
31P NMR (CDCl3): = 40.87.
Pos FAB MS (NBA): m/z = 231 (100, [M + H]+), 203 (30, [M + H
1410 (C=C), 1340 (C-F), 1260
(P=O), 1240 (P=O), 1180 [(C)O–
C], 1145 [(C)O–C].
359 (10, [M + H]+),
– Et]+), 77 (38, Ph+).
+
91 (100, C7H7 ),
HRMS: m/z calcd for C10H16O4P: 231.0786; found: 231.0788.
77 (18, Ph+).
Ethyl Hydroxymethyl-(3-methoxyphenyl)phosphinate (7d)
1410 (C=C), 1380 (C=C), 1330
321 (39, [M + H]+),
+
Yield: 93%; yellow oil.
[(Ph)O–C], 1315 [(Ph)O–C], 1260 91 (100, C7H7 ).
(P=O), 1230 (P=O), 1140 [(C)O–
C], 1130 [(C)O–C], 1050 [(P)O–C].
IR (NaCl): 3390 (OH), 1250 (P=O), 1190 [(P)O–C], 1050 [(P)O–C]
cm–1.
1H NMR (CDCl3): = 1.24 (t, 3JHH = 7.0, 3 H, CH3), 3.88 (s, 3 H,
CH3), 3.89–4.13 (m, 4 H, 2 CH2), 5.02 (br s, OH), 7.00–7.05 (m, 1
H, CH), 7.25–7.35 (m, 3 H, CH).
4d
1400 (C=C), 1380 (C=C), 1340
[(C)O–C], 1300 [(C)O–C], 1260
(P=O), 1230 (P=O), 1140 [(P)O–
C], 1120 [(P)O–C], 1100 [(P)O–C].
321 (47, [M + H]+),
+
91 (100, C7H7 ),
77 (12, Ph+).
3
13C NMR (CDCl3): = 16.46 (d, JPC = 5.9, CH3), 55.34 (s, CH3),
59.89 (d, 1JPC = 116.1, CH2), 61.44 (d, 2JPC = 7.1, CH2), 116.61 (d,
4e
4f
1400 (C=C), 1230 (P=O), 1220
(P=O), 1160 [(P)O–C], 1120
[(P)O–C], 1050 [(C)O–C].
341 (98, [M + H]+),
2
2JPC = 10.8, CH), 118.88 (4JPC = 2.6, CH), 123.98 (d, JPC = 9.6,
+
91 (100, C7H7 ).
3
1
CH), 129.86 (d, JPC = 14.5, CH), 130.08 (d, JPC = 122.1, C),
159.54 (3JPC = 15.2, C).
1400 (C=C), 1250 (P=O), 1230
(P=O), 1180 [(P)O–C], 1050
[(C)O–C].
292 (65, [M + H]+),
31P NMR (CDCl3): = 40.80.
+
91 (100, C7H7 ).
+
Pos FAB MS (NBA): m/z = 231 (100, [M + H]+), 91 (9, C7H7 ).
HRMS: m/z calcd for C10H16O4P: 231.0786; found: 231.0782.
4g
1260 (P=O), 1230 (P=O), 1130
[(P)O–C].
297 (98, [M + H]+),
91 (100, C7H7 ).
+
Preparation of Phosphinic Acids 8b and 8d; General Procedure
In a typical procedure, phosphinates 7b and 7d (ca. 1 mmol) were
stirred with aq HCl (35%; 11 equiv) at 80 °C for 3 h. Evaporation
of the solvent and drying (P4O10) afforded the corresponding acids
8b and 8d as oils.
Preparation of Phosphinates 7b–d; General Procedure
In a typical procedure, Pd/C (10%; 0.2 equiv) was added to a solu-
tion of phosphinates 4b–d (ca. 1 mmol) in absolute EtOH (10 mL).
The mixture was placed under hydrogen at atmospheric pressure
and r.t. After consumption of the required volume of hydrogen, the
mixture was filtered on Celite, and the filtrate was concentrated un-
der reduced pressure to afford the corresponding phosphinates 7b–
d as oils.
Hydroxymethyl-(4-trifluoromethylphenyl)phosphinic Acid
(8b)
Yield: 91%; yellow oil.
IR (NaCl): 3300 (OH), 1330 (CF), 1270 (P=O) cm–1.
2
1H NMR (CD3OD): = 3.99 (d, JPH = 5.6, 2 H, CH2), 5.78 (br s,
OH), 7.80–7.83 (m, 2 H, CH), 8.00–8.09 (m, 2 H, CH).
Ethyl Hydroxymethyl-(4-trifluoromethylphenyl)phosphinate
(7b)
Yield: 100%; yellow oil.
1
13C NMR (CD3OD): = 60.78 (d, JPC = 119.5, CH2), 125.23 (q,
3
3
1JCF = 272.0 Hz, CF3), 126.39 (qd, JPC = 8.2, JCF = 3.7, CH),
2
2
IR (NaCl): 1320 (CF), 1220 (P=O), 1170 [(P)O–C], 1130 [(P)O–C],
1100 [(P)O–C], 1060 [(P)O–C] cm–1.
1H NMR (CDCl3): = 1.24 (t, 3JHH = 6.9, 3 H, CH3), 3.87–4.09 (m,
4 H, 2 CH2), 5.09 (br s, OH), 7.64–7.67 (m, 2 H, CH), 7.85–7.94 (m,
2 H, CH).
134.30 (d, JPC = 10.0, CH), 135.05 (q, JCF = 32.0, C), 136.63 (d,
1JPC = 125.8, C).
31P NMR (CD3OD): = 35.72.
Pos FAB MS (NBA): m/z = 241 (100, [M + H]+).
HRMS: m/z calcd for C8H9F3O3P: 241.0241; found: 241.0238.
3
13C NMR (CDCl3):
= 16.32 (d, JPC = 6.0, CH3), 59.50 (d,
1JPC = 116.7, CH2), 61.93 (d, JPC = 7.1, CH2), 125.34 (qd,
3JCF = 3.7, 3JPC = 7.4, CH), 131.73 (d, 2JPC = 10.1, CH), 133.08 (d,
1JPC = 120.9, C), 134.30 (qd, 4JPC = 3.0, 2JCF = 32.9, C), 136.60 (q,
1JCF = 272.8, CF3).
2
Hydroxymethyl-(3-methoxyphenyl)phosphinic Acid (8d)
Yield: 100%; yellow oil.
IR (NaCl): 3300 (OH), 1220 (P=O) cm–1.
31P NMR (CDCl3): = 39.16.
Synthesis 2003, No. 14, 2216–2220 © Thieme Stuttgart · New York

2220
H.-J. Cristau et al.
PAPER
(3) Kukhar, V. P.; Hudson, H. R. In Aminophosphonic and
1H NMR (CD3OD): = 3.82 (s, 3 H, CH3), 3.96 (d, 2JPH = 5.2, 2 H,
CH2), 5.69 (br s, OH), 7.13–7.46 (m, 4 H, CH).
Aminophosphinic Acids: Chemistry and Biological Activity;
John Wiley & Sons Ltd: Chichester, UK, 2000.
(4) Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.;
Sanchez, F.; Pirat, J.-L. J. Organomet. Chem. 2002, 643-
645, 381.
(5) Schuman, M.; Lopez, X.; Karplus, M.; Gouverneur, V.
Tetrahedron 2001, 57, 10299.
(6) Lei, H.; Stoakes, M. S.; Schwabacher, A. W. Synthesis 1992,
1255.
(7) Johansson, T.; Stowinski, J. Chem. Commun. 2001, 2564.
(8) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J.;
Schwabacher, A. W. J. Org. Chem. 1994, 59, 4206.
(9) Petrakis, K. S.; Nagabhushan, T. L. J. Am. Chem. Soc. 1987,
109, 2831.
(10) Ma, D.; Tian, H. J. Chem. Soc, Perkin Trans. 1 1997, 3493.
(11) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66, 348.
(12) Cristau, H.-J.; Brahic, C.; Pirat, J.-L. Tetrahedron 2001, 57,
9149.
(13) Sietsema, W. K.; Ebetino, F. H. Exp. Opin. Invest. Drugs
1994, 3, 1255.
(14) Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1983,
377.
(15) Xu, J.; Zhang, J. Synthesis 1984, 778.
(16) Xu, Y.; Zhang, J. J. Chem. Soc., Chem. Commun. 1986,
1606.
(17) Zhang, J.; Xu, Y.; Huang, G.; Guo, H. Tetrahedron Lett.
1988, 1955.
(18) Montchamp, J.-L.; Dumond, Y. R. J. Am. Chem. Soc. 2001,
123, 510.
(19) Bennett, S. N. L.; Hall, R. G. J. Chem. Soc., Perkin Trans. 1
1995, 1145.
(20) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J.;
Schwabacher, A. W. J. Org. Chem. 1994, 4206.
(21) Luke, G. P.; Shakespeare, W. C. Synth. Commun. 2002,
2951.
(22) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9389.
(23) Cristau, H.-J.; Virieux, D. Tetrahedron Lett. 1999, 40, 703.
(24) Boyd, E. A.; Regan, A. C.; James, K. Tetrahedron Lett.
1992, 33, 813.
(25) Boyd, E. A.; Regan, A. C.; James, K. Tetrahedron Lett.
1994, 35, 4223.
(26) Chen, S.; Cowards, J. K. J. Org. Chem. 1998, 63, 502.
(27) Dumond, R.; Backer, L. R.; Montchamp, J. L. Org. Lett.
2000, 2, 3341.
13C NMR (CD3OD): = 54.06 (s, CH3), 58.91 (d, JPC = 118.7,
1
2
4
CH2), 115.81 (d, JPC = 11.2, CH), 117.63 (d, JPC = 2.6, CH),
122.88 (d, 2JPC = 10.0, CH), 129.08 (d, 3JPC = 14.5, CH), 130.09 (d,
1JPC = 122.4, C), 159.03 (d, 3JPC = 16.0, C).
31P NMR (CD3OD): = 37.83.
Pos FAB MS (NBA): m/z = 203 (100, [M + H]+).
HRMS: m/z calcd for C8H12O4P: 203.0473; found: 203.0466.
Hydroxymethyl(phenyl)phosphinic acid (8a)
Phosphinate 4a (140 mg, 0.48 mmol, 1 equiv) was stirred with aq
HCl (35%; 0.5 mL, 15 equiv) at 80 °C for 5 h. Evaporation of the
solvent and drying (P4O10) afforded the corresponding acid 8a.
Yield: 79 mg, 0.46 mmol (96%); yellow oil.
IR (NaCl): 3310 (OH), 1275 (P=O) cm–1.
2
1H NMR (CD3OD): = 3.93 (d, JPH = 5.5, 2 H, CH2), 5.05 (br s,
OH), 7.52–7.91 (m, 5 H, CH).
1
13C NMR (CD3OD): = 59.30 (d, JPC = 117.2, CH2), 121.9 (d,
2JPC = 11.5, CH), 122.98 (d, 3JPC = 15.1, CH), 122.13 (d, 4JPC = 2.5,
CH), 129.26 (d, 1JPC = 128.9, C).
31P NMR (CD3OD): = 37.00.
Pos FAB MS (NBA): m/z = 173 (100, [M + H]+).
HRMS: m/z calcd for C7H10O3P: 173.2322; found: 173. 2563.
Sodium Benzyloxymethyl(phenyl)phosphinate (9e)
Phosphinate 4e (200 mg, 0.59 mmol, 1 equiv) in EtOH (5 mL) was
stirred with 3 equiv of aq NaOH (1 M) at r.t. for 5 h. The reaction
mixture was concentrated under reduced pressure to yield com-
pound 9e.
Yield: quantitative; white solid.
IR (NaCl): 1225 (P=O), 1105 [(P)O–C] cm–1.
1H NMR (CD3OD): = 3.99 (d, 2JPH = 5.7, 2 H, CH2), 4.45 (s, 2 H,
CH2), 7.08–7.10 (m, 2 H, CH), 7.12–7.21 (m, 3 H, CH), 7.55–8,26
(m, CH).
1
13C NMR (CD3OD): = 69.37 (d, JPC = 115.2, CH2), 74.19 (d,
3JPC = 10.5, CH2), 127.83 (s, CH), 127.92 (s, CH), 128.30 (s, CH),
137.61 (s, C), 133.16 (d, 2JPC = 8.6, C), 133.62 (d, 3JPC = 10.5, CH),
125.17, 125.36, 126.20, 128.99, 131.12, 132.40, 132.44, 133.35,
133.44, 133.56.
(28) Hartung, W. H.; Simonoff, R.; Rorer, W. R. Org. React.,
Vol. VII; Wiley: London, 1953, 263–326.
(29) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93,
1746.
31P NMR (CD3OD): = 39.06.
(30) Kudzin, Z. H.; Stec, W. J. Synthesis 1978, 469.
(31) Yuan, C.; Chen, D. Synthesis 1992, 531.
(32) Boduszek, B. Tetrahedron 1996, 52, 12483.
(33) Bartlett, P. A.; Hanson, J. E.; Giannousis, P. P. J. Org. Chem.
1990, 55, 6228.
References
(1) Fields, S. C. Tetrahedron 1999, 55, 12237.
(2) Kafarski, P.; Lejczak, B. Phosphorous Sulfur Silicon 1991,
63, 193.
Synthesis 2003, No. 14, 2216–2220 © Thieme Stuttgart · New York