The preparation of dimethyl α-hydroxyphosphonates and the chemical shift non-equivalence of their diastereotopic methyl ester groups

Article abstract of DOI:10.1080/10426500701690905

Dimethyl α-hydroxyalkyl-, α-hydroxybenzyl-, α-hydroxyfurfuryl-, and α-hydroxy-α-thienylmethyl-phosphonates have been prepared in good yield by the alumina-catalyzed reaction of dimethyl phosphite with the corresponding alkanals, aryl aldehydes (or aryl methyl ketones), furfuraldehyde, and 2- or 3-thiophenecarboxaldehyde, respectively, thus confirming the general utility of this synthetic procedure. The 1H and 13C nmr spectra of the products exhibit characteristic chemical shift non-equivalence of the diastereotopic methyl ester groups, for which a tentative order of non-equivalence is reported and discussed. Copyright Taylor & Francis Group, LLC.

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The Preparation of Dimethyl
α -Hydroxyphosphonates
and the Chemical Shift
Non-Equivalence of Their
Diastereotopic Methyl Ester
Groups
Harry R. Hudson a , Ramon O. Yusuf a & Ray W.
Matthews a
a Department of Health and Human Sciences ,
London Metropolitan University , London, UK
Published online: 24 Jun 2008.
To cite this article: Harry R. Hudson , Ramon O. Yusuf & Ray W. Matthews
(2008) The Preparation of Dimethyl α -Hydroxyphosphonates and the
Chemical Shift Non-Equivalence of Their Diastereotopic Methyl Ester Groups,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:7, 1527-1540, DOI:
10.1080/10426500701690905
To link to this article: http://dx.doi.org/10.1080/10426500701690905
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Phosphorus, Sulfur, and Silicon, 183:1527–1540, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701690905
The Preparation of Dimethyl α-Hydroxyphosphonates
and the Chemical Shift Non-Equivalence of Their
Diastereotopic Methyl Ester Groups
Harry R. Hudson, Ramon O. Yusuf, and Ray W. Matthews
Department of Health and Human Sciences, London Metropolitan
University, London, UK
Dimethyl α-hydroxyalkyl-, α-hydroxybenzyl-, α-hydroxyfurfuryl-, and α-hydroxy-
α-thienylmethyl-phosphonates have been prepared in good yield by the alumina-
catalyzed reaction of dimethyl phosphite with the corresponding alkanals,
aryl aldehydes (or aryl methyl ketones), furfuraldehyde, and 2- or 3-
thiophenecarboxaldehyde, respectively, thus confirming the general utility of this
1
13
synthetic procedure. The H and C nmr spectra of the products exhibit charac-
teristic chemical shift non-equivalence of the diastereotopic methyl ester groups, for
which a tentative order of non-equivalence is reported and discussed.
Keywords α-Hydroxyphosphonate; benzyl; diastereotopic; furfuryl; NMR; thienyl
INTRODUCTION
α-Hydroxyphosphonates (3) are of importance as chemical
intermediates,1,2 complexing agents,3 and biologically active
molecules.4 Some examples have been shown to act as transition state
analogue inhibitors of renin.5 In addition, the α-hydroxyphosphonate
moiety is an important structural feature in nucleoside phosphonates
of relevance in various aspects of medicinal chemistry.6,7 Prepar-
ative methods for α-hydroxyphosphonates8 are generally based on
the Abramov reaction,9 i.e., the base-catalysed addition of dialkyl
phosphite (1) to a carbonyl compound (2) (Scheme 1).
A variety of catalysts has been employed, including an alkoxide or
tertiary amine,10 caesium fluoride,11 potassium fluoride,11,12 alumina,13
potassium fluoride supported on alumina,14 various solvent-free phos-
phate supports,15 lithium bis(trimethylsilyl)amide,16 quaternary am-
monium hydroxide resin,17 and anhydrous potassium carbonate.18 The
Received 8 August 2007; accepted 17 August 2007.
Address correspondence to Harry R. Hudson, Emeritus Professor of Chemistry, Lon-
don Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK. E-mail:
HarryRHudson@aol.com
1527

1528
H. R. Hudson et al.
R2
O
P
R2
C
O
P
R1O
R1O
R1O
R1O
base
+
H
C
OH
O
R3
R3
(1)
(2)
(3)
SCHEME 1
hydrogen chloride-catalyzed addition of trialkyl phosphites to carbonyl
compounds has also been reported.19 Although no reaction mechanism
was proposed for this latter synthesis, it can be envisaged that nucle-
ophilic attack of phosphite on the protonated carbonyl compound is in-
volved, followed by dealkylation of the intermediate quasiphosphonium
species (4) (Scheme 2).
O
_
+
+
H
Cl
OH
(RO)3P
(RO)2P
C
C
OH
(RO)3P
C
O
(4)
SCHEME 2
However, the known rapid mono-dealkylation of trialkyl phosphites
by hydrogen chloride20 suggests that the addition of dialkyl phosphite
to the carbonyl compound could also be involved.
Surprisingly, there are very few references to the use of alumina as
catalyst in the Abramov reaction beyond the original report,13 although
we have found basic alumina (chromatographic grade), in the absence
of solvent, to be convenient and efficient in a number of cases.21 We now
report the use of basic alumina in the preparation of a wider range of
α-hydroxyphosphonates, and we comment further on the chemical shift
non-equivalence of the methyl ester groups in these compounds.22
RESULTS AND DISCUSSION
Preparations
Basic alumina was used as a heterogeneous catalyst, in the absence
of solvent, for the reaction of dimethyl phosphite with a range of car-
bonyl compounds (Scheme 1; base = alumina). Products 3a–3y were

Dimethyl α-Hydroxyphosphonates
1529
R2
C
O
P
R1O
R1O
OH
R3
R1 = Me, R2 = H, R3 = Prn (3a), Bun (3b), 4-MeC6H4 (3c), 4-MeOC6H4 (3d), 4-
Me2CHC6H4 (3e), 2,4,6-Me3C6H2 (3f), 2-HOC6H4 (3g), 4-ClC6H4 (3h), 4-FC6H4
(3i), 3-FC6H4 (3j), 4-Br-2-HOC6H4 (3k), 3,4-(MeO)2C6H3 (3l), 3,4-CH2O2C6H3
(3m), 2-O2NC6H4 (3n), 4-O2NC6H4 (3o), 1-C10H7 (3p), 2-C10H7 (3q), 2-C4H3O
(furyl) (3r), 2-C4H3S (thienyl) (3s), 3-C4H3S (thienyl) (3t)
R1 = R2 = Me, R3 = Ph (3u), 4-MeC6H4 (3v), 4-BrC6H4 (3w), 4-FC6H4 (3x),
2-O2NC6H4 (3y)
obtained in good yield by extraction of the crude reaction product with
dichloromethane, followed by recrystallization from cyclohexane. The
mechanism by which alumina acts catalytically in the Abramov reac-
tion has not been studied in detail but it is reasonable to suppose that
it functions, together with adsorbed water, as a phase transfer cata-
lyst, providing surface hydroxyl groups for interaction with the dialkyl
phosphite (Scheme 3).
O
(RO)2P
_
OH
_
O
H2O
C
OH
(RO)2P(O)H
(RO)2P
C
O
SCHEME 3
Structural and NMR studies
Our earlier studies on dimethyl 1-chloromethyl-1-hydroxybenzyl-
phosphonate (3, R1 = Me, R2 = CH2Cl, R3 = Ph) showed that this
compound exists as hydrogen-bonded dimers in the solid state, with
H-bonding between the phosphoryl oxygen atom of each molecule of
the dimer and the hydroxyl hydrogen atom of the other.22 In each
dimeric unit, one molecule of (S)-configuration is associated with
one of (R)-configuration.22 In other more sterically constrained ex-
amples, e.g., diethyl α-hydroxy-p-isopropylbenzylphosphonate (3, R1 =
Et, R2 = H, R3 = 4-Me2CHC6H4), intermolecular hydrogen-bonding

1530
H. R. Hudson et al.
TABLE I 1H and 13C nmr Chemical Shifts (ppm) for the
Diastereotopic Methoxy Groups in Dimethyl
α-Hydroxyalkanephosphonates (3, R1 = Me, R2 = H)
R3
δH (MeO)
ꢀδH (MeO)
δC (MeO)
ꢀδC (MeO)
3a
Prn
3.81 3.81
3.81 3.81
0
0
53.24
53.29
53.24
53.23
0
0.06
3b Bun
can give rise to the formation of hydrogen-bonded chains rather than
dimers.23 The extent to which such hydrogen-bonding persists in so-
lution and might contribute to some restriction of rotation about
the P-Cα bond in α-hydroxyphosphonates is uncertain but the mag-
netic non-equivalence of the alkyl ester groups is attributed primar-
ily to the presence of the chiral α-carbon atom.22 Thus, similar non-
equivalence is shown by the ester groups of the corresponding dimethyl
α-methoxybenzylphosphonates, (MeO)2P(O)CHArOMe, in which nei-
ther intra- nor inter-molecular hydrogen-bonding can occur.22
1H and 13C nmr chemical shifts for the diastereotopic methyl ester
groups in the α-hydroxyphosphonates reported in this paper are shown
in Tables I–IV. The differences in chemical shift (ꢀδH or ꢀδC) for the two
methyl groups are scarcely detectable in the aliphatic series, typified by
dimethyl α-hydroxybutyl- and α-hydroxypentylphosphonates (Table I)
and ꢀδH values are also quite small in the α-aryl or α-heteroaryl se-
ries (Tables II and III), being 0.01–0.05 ppm in all cases except those
in which R2 = H, R3 = mesityl (3f), and R2 = H, R3 = 2-furyl (3r), for
which differences of ca. 0.20–0.21 ppm are observed. However, the 13
C
chemical shifts of the diastereotopic methyl groups in the α-aryl or α-
heteroaryl derivatives exhibit slightly greater differences of up to 0.9
ppm, and we have listed the data for these compounds (Tables II and
III) in order of decreasing ꢀδC in an attempt to reveal any structurally
related trends that might be discernable. 1H and 13C NMR data for six of
the α-hydroxybenzylphosphonates (3c, 3d, 3n, 3o, 3p, 3q) have been re-
ported previously in the course of a study on the asymmetric hydrophos-
phonylation of aldehydes16,24 and we have noted that the chemical shift
differences recorded for the methyl ester group carbon atoms16 agree
well with those which we have determined for the same compounds
(See Table II); and also follow the same order, giving us confidence that
the trends reported here, although small, are essentially correct.
The overall pattern is seen more clearly in Figure 1, from which it is
evident that the chemical shift for each of the methoxy groups shows a
slight but definite trend to higher field as the benzyl substituent groups

Dimethyl α-Hydroxyphosphonates
1531
TABLE II 1H and 13C nmr Chemical Shifts (ppm) for the
Diastereotopic Methoxy Groups in Dimethyl
α-Hydroxybenzylphosphonates (3, R1 = Me, R2 = H)
R3
δH (MeO)
ꢀδH (MeO)
δC (MeO)
ꢀδC (MeO)
3g
3n
2-HOC6H4
2-O2NC6H4
3.73
3.68
3.71
3.72
3.77
3.76
3.74
3.73
3.74
3.67
3.51
3.52
3.66
3.65
3.64
3.67
3.53
3.70
3.66
3.64
3.68
3.72
0.05
0.02
0.02
0.02
0.02
0.02
0.02
0
0.01
0.09
0.12
0.02
0.05
0.03
0.04
0.20
0.03
0.05
0.05
0.03
0.06
54.34
53.41
53.70
53.58
53.67
53.71
54.03
53.64
53.71
53.66
53.57
53.55
53.59
53.52
53.67
53.68
53.33
53.58
53.56
53.60
53.43
53.68
0.93
0.90
3.73
(3.74
3.79
(3.78
3.76
3.75
3.74
3.68
3.60
(3.64
3.68
(3.70
3.67
(3.71
3.73
3.73
(3.71
3.69
3.71
3.66
54.60
54.48
54.51
54.42
54.67
54.10
54.15
54.09
53.90
53.86
53.91
53.82
53.98
53.94
53.61
53.84
53.79
53.82
53.64
53.81
0.90)a
0.84
3o
4-O2NC6H4
0.71)a
0.64
0.46
0.44
0.43
3k
3i
3j
3h
3p
2-HO-4-BrC6H3
4-FC6H4
3-FC6H4
4-ClC6H4
1-C10H7
0.33
0.31)a
0.32
3c
3q
4-MeC6H4
2-C10H7
0.30)a
0.31
0.26)a
0.28
3f
3d
2,4,6-Me3C6H2
4-MeOC6H4
0.26
0.23)a
0.22
3e
3m
3l
4-Me2CHC6H4
3,4-CH2O2C6H3
3,4-(MeO)2C6H3
0.21
0.13
aData from Ref. 16 shown for comparison.
vary throughout the series in the order shown in Table II. The trend
is greater for the downfield methoxy carbon atom, with a consequent
change in chemical shift non-equivalence (ꢀδC) throughout the series.
The largest 13C chemical shift differences (0.8–0.9 ppm) were ob-
served for the 2-hydroxybenzyl derivative (3g), and for compounds 3n
TABLE III 1H and 13C nmr Chemical Shifts (ppm) for the
Diastereotopic Methoxy Groups in Dimethyl
α-Hydroxy-α-heteroarylmethanephosphonates (3, R1 = Me,
R2 = H)
R3
δH (MeO)
ꢀδH (MeO)
δC (MeO)
ꢀδC (MeO)
3r 2-furyl
3.76 3.97
3.73 3.71
3.69 3.65
0.21
0.02
0.04
53.93 53.29
54.11 53.83
53.83 53.66
0.64
0.28
0.17
3s
3t
2-thienyl
3-thienyl

1532
H. R. Hudson et al.
FIGURE 1 Variation in 13C chemical shift of the two diastereotopic methyl
ester groups in dimethyl α-hydroxybenzylphosphonates (3, R1 = Me, R2 = H,
R3 = Ar) in the order listed in Table II: 3g (1), 3n (2), 3o (3), 3k (4), 3i (5), 3j
(6), 3h (7), 3p (8), 3c (9), 3q (10), 3f (11), 3d (12), 3e (13), 3m (14), 3l (15).
high field signal; ꢁ = low field signal; dotted lines show overall trends.
=
ꢀ
and 3o in which a nitro group is present in the 2- or 4-position of the
benzyl ring. The 13C chemical shift difference in the 2-hydroxy-4-bromo-
(3k) derivative is next in order, at 0.64 ppm, followed by the 4-chloro-
, and 3- or 4-fluoro-substituted compounds (3h, 3i, 3j), for which the
13C chemical shift differences observed were 0.43–0.46 ppm. Similar
differences in 13C chemical shift (0.43 – 0.46 ppm) were recorded for
the methyl ester carbon atoms of the 2-, 3-, and 4-bromo-derivatives.25
All these compounds, it should be noted, contain one or more
TABLE IV 1H and 13C nmr Chemical Shifts (ppm) for the
Diastereotopic Methoxy Groups in Dimethyl
α-Hydroxy-α-methylbenzylphosphonates (3, R1 = Me, R2 = Me)
R3
δH (MeO)
ꢀδH (MeO)
δ
C
(MeO)
ꢀδ (MeO)
C
3w 4-BrC6H4
3.77 3.68
3.73 3.78
3.73 3.63
3.75 3.65
3.72 3.62
0.09
0.05
0.10
0.10
0.10
54.03 54.58
54.18 54.71
53.82 53.42
54.25 53.87
53.84 54.15
0.55
0.53
0.40
0.38
0.31
3y
3v
3x
3u
2-O2NC6H4
4-MeC6H4
4-FC6H4
Ph

Dimethyl α-Hydroxyphosphonates
1533
electronegative substituents bearing lone electron pairs which might
be expected to exert a differential screening effect on the diastereotopic
methyl ester groups. Nitro groups, with two polarized oxygen atoms,
and hydroxyl groups in the 2-position appear to be the most influential.
Compounds in which smaller chemical shift differences (ꢀδC
0.13–0.35 ppm) are observed are the usubstituted dimethyl α-
hydroxybenzylphosphonate (ꢀδC 0.35 ppm)25 and those in which ring
substituents bearing lone electron pairs are absent, viz. 3c, 3e, and
3f (which contain electron-donating alkyl groups) or in which oxygen
atoms, if present, are in the 3- and/or 4-positions and have alkyl groups
attached (3l, 3m).
The effect of sulfur in the thiophene ring (3s, 3t) is less than that
of the more electronegative oxygen in furan (3r), but with the effect
decreasing in the order 2-furyl > 2-thienyl > 3-thienyl, indicating again
the significance of substitution in position 2 with an electronegative
atom bearing lone pair electrons (Table III).
Within the di-α-substituted series (R2 = Me, Table IV), the great-
est non-equivalence (0.55 and 0.53 ppm) was shown by the 4-bromo-
(3w) and 2-nitro- (3y) derivatives, respectively, and the least by the
unsubstituted benzyl compound 3u (R2 = Me, R3 = Ph), for which
ꢀδC = 0.31. The overall order here does not accord in every detail
with that given above for the mono-α-substituted series but it is possi-
ble that it is influenced by the steric effect of the additional α-methyl
substituent.
CONCLUSIONS
Basic alumina has been confirmed as a useful catalyst in the synthesis
of α-hydroxyphosphonates by the Abramov reaction.
A preliminary attempt to correlate chemical shift non-equivalence
of the methyl ester groups with the structure of dimethyl α-
hydroxyphosphonates indicates that the overall effects are complex and
no doubt subject to a variety of contributory factors. Nevertheless, it
seems in general that strongly electronegative atoms bearing lone elec-
tron pairs, especially in the 2-position are the most influential in gener-
ating a differential screening effect on the two methyl ester groups. It is
also possible that the influence of aromatic ring currents and the extent
to which these are modified by ring substituents, together with stereo-
chemical factors controlling the populations of significant rotamers, are
all involved in determining differential through-space screening.
Molecular modelling studies may be helpful in obtaining a clearer
insight into the factors involved.

1534
H. R. Hudson et al.
EXPERIMENTAL
Starting materials, solvents, and chromatographic grade basic alumina
were obtained commercially. Dichloromethane and cyclohexane were
dried and stored over molecular sieves. Other materials were used as
1
1
supplied. H, 13C, and 31P{ H} NMR spectra were recorded for solu-
tions in CDCl3 on a Bruker AM250 instrument, operating at 250.133
MHz, 62.896 MHz, or 101.256 MHz, respectively. Chemical shifts are
reported relative to TMS (internal reference) for H and 13C spectra,
1
and 85% phosphoric acid (external reference) for 31P spectra. Micro-
analysis (for C and H) was carried out on a Carlo Erba 1106 Elemental
Analyser.
Preparation of α-Hydroxyphosphonates
Aluminium oxide (basic, chromatographic grade) (40 g) was added grad-
ually to a stirred mixture of dimethyl phosphite (11.0 g, 0.100 mol) and
the appropriate carbonyl compound (0.100 mol) at room temperature.
The reactants were completely adsorbed on the alumina. After 72 h,
the product was extracted with dichloromethane (2 × 200 ml) and the
extract was evaporated under reduced pressure to give the crude phos-
phonic ester, which was either distilled (3a, 3b) or purified by recrys-
tallization from cyclohexane to give the following products.
Dimethyl α-Hydroxybutylphosphonate (3a)
Colorless viscous liquid, b.p. 121–122◦C at 0.05 mmHg (yield 86%)
(Found: C, 39.49; H, 8.57. Calc. for C6H15O4P: C, 39.56; H, 8.24%);
δP(CDCl3) 27.75; δH(CDCl3) 0.95 (CH3, 3H, t, JHCCH 7.13 Hz), 1.48–1.75
(CH2CH2, 4H, m), 3.81 (CH3O, 3H, d, JPOCH 10.40 Hz), 3.81 (CH3O, 3H,
d, JPOCH 10.39 Hz), 3.87–3.97 (α-CH, 1H, m), 4.96 (OH, 1H, s); δC(CDCl3)
13.72 (CH3, s), 18.91 (CH2CH3, d, J
13.71 Hz), 33.45 (CHCH2, d,
PCCC
J
PCC
1.13 Hz), 53.24 (CH3O x 2, d, J
6.89 Hz), 67.11 (α-C, d, J
POC
PC
161.65 Hz).
Dimethyl α-Hydroxypentylphosphonate (3b)
Colorless viscous liquid, b.p. 124–126◦C at 0.05 mmHg (yield 78%)
(Found: C, 42.50; H, 8.67. Calc. for C7H17O4P: C, 42.85; H, 8.67%);
δP(CDCl3) 27.72; δH(CDCl3) 0.92 (CH3, 3H, t, JHCCH 6.99 Hz), 1.21–1.76
[(CH2)3, 6H, m], 3.81 (CH3O, 3H, d, JPOCH 10.27 Hz), 3.81 (CH3O, 3H, d,
J
POCH
10.35 Hz), 3.77–3.94 (α-CH, 1H, m), 5.04 (OH, 1H, s); δC(CDCl3)
13.95 (CH3, s), 22.41 (CH2CH3, s), 27.86 (CH2CH2CH3, d, J
13.52
PCCC
Hz), 31.12 (CHCH2, s), 53.29 (CH3O, d, J
7.09 Hz), 53.23 (CH3O, d,
POC
J
POC
7.00 Hz), 64.44 (α-C, d, J 167.31 Hz).
PC

Dimethyl α-Hydroxyphosphonates
1535
Dimethyl α-Hydroxy-4-methylbenzylphosphonate (3c)
White crystalline solid, m.p 98◦C (yield 68%); δP(CDCl3) 23.88;
δH(CDCl3) 2.34 (4-CH3, 3H, d, 7J 1.79 Hz), 3.68 (CH3O, 3H, d, J
PH
POCH
10.45 Hz), 3.66 (CH3O, 3H, d, JPOCH 10.28 Hz), 4.88 (OH, 1H, dd, J
HCOH
5.59 Hz, JPCOH 5.86 Hz), 4.98 (α-CH, 1H, dd, JPCH 10.88 Hz, JHOCH 5.59
6
Hz), 7.16–7.39 (4H, arom); δC(CDCl3) 21.19 (4-CH3, d, J 1.07 Hz),
PC
53.59 (CH3O, d, J
7.29 Hz), 53.91 (CH3O, d, J
7.04 Hz), 70.37
POC
POC
(α-C, d, J 160.71 Hz), 124.22–144.02 (arom).
PC
Dimethyl α-Hydroxy-4-methoxybenzylphosphonate (3d)
White crystalline solid, m.p. 72◦C (yield 72%) (Found: C, 48.80;
H, 6.21. Calc. for C10H15O5P: C, 48.78; H, 6.09%); δP(CDCl3) 23.98;
δH(CDCl3) 3.73 (CH3OP, 3H, d, J
10.38 Hz), 3.70 (CH3OP, 3H,
POCH
d, J
10.22 Hz), 3.85(-C6H4OCH3-4, 3H, s), 5.04 (α-CH, 1H, d,
POCH
J
PCH
10.69 Hz), 5.31 (OH, 1H, br), 6.91–7.48 (4H, arom); δC(CDCl3)
53.58 (CH3OP, d, J
7.36 Hz), 53.84 (CH3OP, d, J
6.98 Hz), 55.20
POC
POC
(-C6H4OCH3-4, s), 69.95 (α-C, d, JPC 162.91 Hz), 113.73–128.87 (arom).
Dimethyl α-Hydroxy-4-isopropylbenzylphosphonate (3e)
White crystalline solid, m.p. 69◦C (yield 75%) (Found: C, 56.29;
H, 6.85. Calc. for C12H19O4P: C, 55.81; H, 7.36%); δP(CDCl3) 23.87;
δH(CDCl3) 1.23(Me2CH, 6H, d, JHCCH 6.95 Hz), 2.89 (Me2CH, 1H, septet,
J
d, J
6.90 Hz), 3.69 (CH3O, 3H, d, J
POCH
10.39 Hz), 3.64 (CH3O, 3H,
10.34 Hz), 5.00 (α-CH, 1H, d, J 10.94 Hz), 7.18–7.41 (4H,
PCH
HCCH
POCH
arom); δC(CDCl3) 23.94 (Me2CH, s), 33.84 (Me2CH, s), 53.82 (CH3O, d,
6.79 Hz), 53.60 (CH3O, d, J 6.98 Hz), 70.44 (α-C, d, J 161.09
J
POC
POC
PC
Hz), 126.44–148.90 (arom).
Dimethyl α-Hydroxy-2,4,6-trimethylbenzylphosphonate (3f)
White crystalline solid, m.p. 115◦C (yield 78%); δP(CDCl3) 26.10;
δH(CDCl3) 2.24 (4-CH3, 3H, s), 2.45 (2,6-Me2, 6H, s), 3.73 (CH3O, 3H,
d, J
10.62 Hz), 3.53 (CH3O, 3H, d, J
10.37 Hz), 4.80 (OH, 1H,
POCH
POCH
s), 5.48 (α-CH, 1H, d, J
15.55 Hz), 6.82–7.27 (2H, arom); δC(CDCl3)
PCH
20.96 (4-CH3, s), 21.01 (2,6-Me2, s), 53.33 (CH3O, d, J
6.90 Hz),
POC
53.61(CH3O, d, J
6.9 Hz), 68.26 (α-C, d, J 162.16 Hz), 129.61–
POC
PC
137.49 (arom).
Dimethyl α-Hydroxy-2-hydroxybenzylphosphonate (3g)
Very light green crystalline solid, m.p. 90◦C (yield 80%) (Found: C,
46.29; H, 4.85. Calc. for C9H13O5P: C, 46.55; H, 5.60%); δP(CDCl3) 24.34;
δH(CDCl3) 3.73 (CH3O, 3H, d, J
10.45 Hz), 3.68 (CH3O, 3H, d,
POCH
J
POCH
10.89 Hz), 5.01 (OH, 1H, br), 5.12 (α-CH, 1H, d, J
12.24 Hz),
PCH

1536
H. R. Hudson et al.
7.00–7.53 (4H, arom); δC(CDCl3) 53.41 (CH3O, d, J
6.86 Hz), 54.34
POC
(CH3O, d, J
7.29 Hz), 69.86 (α-C, d, J 162.91 Hz); 117.87–129.85
POC
PC
(arom).
Dimethyl α-Hydroxy-4-chlorobenzylphosphonate (3h)
White crystalline solid, m.p. 68◦C (yield 75%) (Found: C, 43.41;
H, 4.80. Calc.for C9H12ClO4P: C, 43.11; H, 4.80%); δP(CDCl3) 23.08;
δH(CDCl3) 3.68 (CH3O, 3H, d, J
10.58 Hz), 3.67 (CH3O, 3H, d,
POCH
J
POCH
10.33 Hz), 5.16 (α-CH, 1H, d, J
11.43 Hz), 7.27–7.42 (4H,
PCH
arom); δC(CDCl3) 53.66 (CH3O, d, J
7.61 Hz), 54.09 (CH3O, d, J
POC
POC
6.91 Hz), 69.82 (α-C, d, J 161.53 Hz), 128.38–136.32 (arom).
PC
Dimethyl α-Hydroxy-4-fluorobenzylphosphonate (3i)
White crystalline solid, m.p. 98◦C (yield 82%) (Found: C, 46.33; H,
5.16. Calc. for C9H12FO4P: C, 46.15; H, 5.12%); δP(CDCl3) 23.19 (d, 6 J
FP
6.71 Hz); δH(CDCl3) 3.75 (CH3O, 3H, d, J
10.59 Hz), 3.73 (CH3O,
POCH
3H, d, JPOCH 13.38 Hz), 5.45 (α-CH, 1H, d, JPCH 10.50 Hz), 5.47 (OH, 1H,
s), 7.01–7.74 (4H, arom); δC(CDCl3) 53.64 (CH3O, d, JPOC 7.23 Hz), 54.10
(CH3O, d, J
7.11 Hz), 63.41 (α-C, d, J 161.27 Hz), 114.82–162.00
POC
PC
(arom).
Dimethyl α-Hydroxy-3-fluorobenzylphosphonate (3j)
White crystalline solid, m.p. 97◦C (yield 82%) (Found: C, 46.05; H,
5.06. Calc. for C9H12FO4P: 46.15; H. 5.12%); δP(CDCl3) 28.48 (d, 5 J
FP
4.97 Hz); δH(CDCl3) 3.74 (CH3O x 2, 6H, d, JPOCH 10.07 Hz), 5.06 (α-CH,
1H, d, JPCH 11.96 Hz), 5.52 (OH, 1H, s), 6.93–7.34 (4H, arom); δC(CDCl3)
53.71 (CH3O, d, JPOC 7.49 Hz), 54.15 (CH3O, d, JPOC 1.89 Hz), 64.87 (α-C,
dd, J 164.92 Hz, 4 J 1.89 Hz), 113.85–164.76 (arom).
PC
FC
Dimethyl α-Hydroxy-2-hydroxy-4-bromobenzylphosphonate
(3k)
Very light green crystalline solid, m.p. 95◦C (yield 78%) (Found: C,
34.79; H, 3.63. Calc. for C9H12BrO5P: C, 34.83; H, 3.87%); δP(CDCl3)
23.4; δH(CDCl3) 3.76 (CH3O, 3H, d, JPOCH 10.48 Hz), 3.74 (CH3O, 3H, d,
J
POCH
10.53 Hz), 4.72 (OH, 1H, br); 5.15 (α-CH, 1H, d, J
12.57 Hz),
PCH
6.89–7.68 (3H, arom); δP(CDCl3) 54.03 (CH3O, d, J
7.42 Hz), 54.67
POC
(CH3O, d, J
7.17 Hz), 68.98 (α-C, d, J 163.09 Hz), 111.37–160.53
POC
PC
(arom).
Dimethyl α-Hydroxy-3,4-dimethoxybenzylphosphonate (3l)
Off-white crystalline solid, m.p. 124◦C (yield 92%); δP(CDCl3) 23.77;
δH(CDCl3) 3.72 (CH3OP, 3H, d, J
10.45 Hz), 3.66 (CH3OP, 3H, d,
POCH
JPOCH 10.33 Hz), 3.89 (3-CH3O, 3H, s), 3.88 (4-CH3O, 3H, s), 4.99 (α-CH,

Dimethyl α-Hydroxyphosphonates
1537
1H, d, J
10.48 Hz), 6.83–7.48 (3H, arom); δC(CDCl3) 53.68 (CH3OP,
PCH
d, J
7.55 Hz), 53.81(CH3OP, d, J
6.98 Hz), 55.87 (3-CH3O, s),
POC
POC
55.92 (4-CH3O, s), 70.23 (α-C, d, JPC 161.78 Hz), 108.97–148.94 (arom).
Dimethyl α-Hydroxypiperonylphosphonate (3m)
White crystalline solid, m.p. 104.5◦C (yield 84%); δP(CDCl3) 23.4;
δH(CDCl3) 3.71 (CH3O, 3H, d, JPOCH 10.58 Hz), 3.68 (CH3O, 3H, d, J
POCH
10.32 Hz), 4.95 (α-CH, 1H, d, J
10.87 Hz), 5.24 (OH, 1H, s), 5.94 (O-
PCH
CH2-O, 2H, s), 6.74–7.42 (3H, arom); δC(CDCl3) 53.64 (CH3O, d, J
POC
7.36 Hz), 53.43 (CH3O, d, J
7.17 Hz), 70.23 (α-C, d, J 162.85 Hz),
POC
PC
101.13 (O-CH2-O), 129.61–137.47 (arom).
Dimethyl α-Hydroxy-2-nitrobenzylphosphonate (3n)
Light green crystalline solid, m.p. 166.5◦C (yield 87%) (Found: C,
41.84; H, 4.17; N, 5.23. Calc. for C9H12NO6P: C, 41.3; H, 4.59; N. 5.36%);
δP(CDCl3) 22.18; δH(CDCl3) 3.73 (CH3O, 3H, d, J
10.53 Hz), 3.71
POCH
(CH3O, 3H, d, J
10.63 Hz); 5.57 (OH, 1H, br), 6.29 (α-CH, 1H, d,
POCH
J
PCH
14.19 Hz), 7.29–8.03 (4H, arom); δC(CDCl3) 53.70 (CH3O, d, J
POC
6.92 Hz), 54.60 (CH3O, d, J
7.49 Hz), 65.45 (α-C, d, J 162.03 Hz),
PC
POC
124.66–147.52 (arom).
Dimethyl α-Hydroxy-4-nitrobenzylphosphonate (3o)
Off-white crystalline solid, m.p. 101◦C (yield 88%) (Found: C, 40.96;
H, 4.88; N, 5.83. Calc. for C9H12NO6P: C, 41.37; H, 4.59; N, 5.36%);
δP(CDCl3) 21.88; δH(CDCl3) 3.79 (CH3O, 3H, d, J
10.44 Hz), 3.77
POCH
(CH3O, 3H, d, JPOCH 10.76 Hz); 5.24 (α-CH, 1H, d, JPCH 12.56 Hz); 7.28–
8.43 (4H, arom); δC(CDCl3) 53.67 (CH3O, d, JPOC 4.97 Hz), 54.51 (CH3O,
d, J
7.29 Hz), 69.91(α-C, d, J 159.19 Hz), 123.44–147.63 (arom).
POC
PC
Dimethyl α-Hydroxy-α-(1-naphthyl)methanephosphonate (3p)
White crystalline solid, m.p. 139◦C (yield 84%) (Found: C, 59.01;
H, 5.36. Calc. for C13H15O4P: C, 58.64; H, 5.63%); δP (CDCl3) 23.68;
δH(CDCl3) 3.60 (CH3O, 3H, d, JPOCH 10.46 Hz), 3.51 (CH3O, 3H, d, J
POCH
10.31 Hz), 4.99 (OH, 1H, dd, JPCOH 9.89 Hz, JHCOH 5.98 Hz), 5.36 (α-CH,
1H, dd, JPCH 11.74 Hz, JHOCH 5,32 Hz), 7.42–8.07 (7H, arom); δC(CDCl3)
53.57 (CH3O, d, JPOC 7.61 Hz), 53.90 (CH3O, d, JPOC 7.04 Hz), 67.03 (α-C,
d, J 162.28 Hz), 123.40–136.68 (arom).
PC
Dimethyl α-Hydroxy-α-(2-naphthyl)methanephosphonate (3q)
White crystalline solid, m.p. 129◦C (yield 82%) (Found: C, 59.31;
H. 5.29. Calc. for C13H15O4P: C, 58.64; H, 5.63%); δP(CDCl3) 23.59;
δH(CDCl3) 3.67 (CH3O, 3H, d, JPOCH 10.45 Hz), 3.64 (CH3O, 3H, d, J
POCH
10.33 Hz), 5.05 (OH, 1H, s), 5.22 (α-CH, 1H, d, JPCH 11.42 Hz), 7.24–7.93

1538
H. R. Hudson et al.
(7H, arom); δC(CDCl3) 53.67 (CH3O, d, J
7.36 Hz), 53.98 (CH3O, d,
POC
J
POC
7.11 Hz), 70.72 (α-C, d, J 160.39 Hz), 124.84–135.14 (arom).
PC
Dimethyl α-Hydroxyfurfurylphosphonate (3r)
Brown crystalline solid, m.p. 45◦C (yield 78%); δP(CDCl3) 21.67;
δH(CDCl3) 3.76 (CH3O, 3H, d, JPOCH 10.61 Hz), 3.97 (CH3O, 3H, d, J
POCH
10.46 Hz), 5.06 (α-CH, 1H, dd, JPCH 13.73 Hz, JHOCH 7.19 Hz), 5.56 (OH,
1H, dd, JPCOH 7.50 Hz, JHCOH 7.50 Hz), 6.35–7.42 (3H, arom); δC(CDCl3)
53.29 (CH3O, d, J
6.79 Hz), 53.93 (CH3O, d, J
7.40 Hz), 64.21 (α-
POC
POC
C, d, J 168.57 Hz), 140.17 (C-2, s), 142.81 (C-5, d, J
2.07 Hz),
PC
PCCOC
110.75 (C-3, d, J
1.64 Hz), 109.35 (C-4, d, J
6.60 Hz).
PCCC
PCCCC
Dimethyl α-Hydroxy-α-(2-thienyl)methanephosphonate (3s)
Yellow crystalline solid, m.p. 82◦C (yield 86%) (Found: C, 37.36;
H, 4.72. Calc. for C7H11O4PS: C, 37.83; H, 4.95%); δP(CDCl3) 21.94;
δH(CDCl3) 3.73 (CH3O, 3H, d, JPOCH 10.41 Hz), 3.71 (CH3O, 3H, d, J
POCH
10.39 Hz), 5.27 (α-CH, 1H, d, JPCH 12.14 Hz), 5.52 (OH, 1H, s), 6.97–7.30
(3H, arom); δC(CDCl3) 53.83 (CH3O, d, J
7.29 Hz), 54.11 (CH3O, d,
POC
J
POC
7.39 Hz), 66.55 (α-C, d, J 168.57 Hz), 125.76–139.62 (arom).
PC
Dimethyl α-Hydroxy-α-(3-thienyl)methanephosphonate (3t)
Light yellow crystalline solid, m.p. 72◦C (yield 98%) (Found: C, 37.36;
H, 4.72. Calc. for C7H11O4PS: C, 37.83; H, 4.95%); δP(CDCl3) 23.19;
δH(CDCl3) 3.69 (CH3O, 3H, d, JPOCH 9.62 Hz), 3.65 (CH3O, 3H, d, J
POCH
9.56 Hz), 5.12 (α-CH, 1H, d, J
11.20 Hz, J
6.49 Hz), 5.35 (OH,
PCH
HOCH
1H, dd, JPCOH 8.23 Hz, JHCOH 6.52 Hz), 7.16–7.41 (3H, arom); δC(CDCl3)
53.66 (CH3O, d, JPOC 6.98 Hz), 53.83 (CH3O, d, JPOC 7.63 Hz), 66.98 (α-C,
d, J 162.90 Hz), 122.97–137.63 (arom).
PC
Dimethyl α-Hydroxy-α-methylbenzylphosphonate (3u)
White crystalline solid, m.p. 130◦C (yield 52%) (Found: C, 52.37;
H, 6.52. Calc. for C10H15O4P: C, 52.17; H, 6.52%); δP(CDCl3) 26.02;
δH(CDCl3) 1.83 (α-CH3, 3H, d, J
15.63 Hz), 3.72 (CH3O, 3H, d,
PCCH
J
POCH
10.18 Hz), 3.62 (CH3O, 3H, d, J
10.26 Hz), 7.23–7.64 (5H,
POCH
arom); δC(CDCl3) 25.81 (α-CH3, d, J
3.89 Hz), 53.84 (CH3O, d, J
PCC
POC
7.67 Hz), 54.15 (CH3O, d, J
7.36 Hz), 73.73 (α-C, d, J 159.57 Hz),
POC
PC
125.84–141.12 (arom).
Dimethyl α-Hydroxy-α-methyl-4-methylbenzylphosphonate
(3v)
White crystalline solid, m.p. 150◦C (yield 52%) (Found: C, 54.06;
H, 6.15. Calc. for C11H17O4P: C, 54.09; H, 6.96%); δP(CDCl3) 26.25;
δH(CDCl3) 1.81 (α-CH3, 3H, d, J
15.70 Hz), 2.34 (4-CH3, 3H, d,
PCCH

Dimethyl α-Hydroxyphosphonates
1539
7J 1.54 Hz), 3.73 (CH3O, 3H, d, J
10.18 Hz), 3.63 (CH3O, 3H,
10.23 Hz), 4.27 (OH, 1H, d, J 5.01 Hz), 7.15–7.51 (4H,
PCOH
PH
POCH
d, J
POCH
arom); δC(CDCl3) 21.04 (4-CH3, s,), 25.80 (α-CH3, d, JPCC 4.40 Hz), 53.82
(CH3O, d, J 7.61 Hz), 53.42 (CH3O, d, J 7.61 Hz), 73.64 (α-C, d,
POC
POC
J
PC
159.33 Hz), 125.71–128.01 (arom).
Dimethyl α-Hydroxy-α-methyl-4-bromobenzylphosphonate
(3w)
White crystalline solid, m.p. 60◦C (yield 66%); δP(CDCl3) 25.28;
δH(CDCl3) 1.81 (α-CH3, 3H, d, J
15.88 Hz), 3.77 (CH3O, 3H, d,
10.27 Hz), 3.68 (CH3O, 3H, d, J 10.39 Hz), 6.45 (OH, 1H, s),
POCH
PCCH
J
POCH
7.29–7.83 (4H, arom); δC(CDCl3) 25.63 (α-CH3, s), 54.03 (CH3O, d, J
POC
7.80 Hz), 54.58 (CH3O, d, JPOC 7.61 Hz), 73.41 (α-C, d, J 159.83 Hz),
PC
121.74–140.03 (arom).
Dimethyl α-Hydroxy-α-methyl-4-fluorobenzylphosphonate
(3x)
White crystalline solid, m.p. 181.5◦C (yield 85%) (Found: C, 48.35;
H, 5.59. Calc. for C10H14FO4P: C, 48.38; H, 5.64%); δP(CDCl3) 25.78
(d, 6JFP 4.51 Hz); δH(CDCl3) 1.82 (α-CH3, 3H, d, J
15.60 Hz), 3.75
PCCH
(CH3O, 3H, d, J
10.10 Hz), 3.65 (CH3O, 3H, d, J
10.22 Hz),
POCH
POCH
4.28 (OH, 1H, d, 7J 4.23 Hz), 7.04–7.58 (4H, arom); δC(CDCl3), 25.91
HF
(α-CH3, d, J
4.21 Hz), 53.87 (CH3O, d, J
7.74 Hz), 54.25 (CH3O,
PCC
POC
d, J
7.80 Hz), 73.40 (α-C, d, J 160.40 Hz), 114.72–136.82 (arom).
POC
PC
Dimethyl α-Hydroxy-α-methyl-2-nitrobenzylphosphonate (3y)
White crystalline solid, m.p. 110◦C (yield 62%); δP(CDCl3) 23.98;
δH(CDCl3) 1.91 (α-CH3, 3H, d, J
15.57 Hz), 3.73 (CH3O, 3H, d,
10.22 Hz), 3.78 (CH3O, 3H, d, J 10.39 Hz), 5.25 (OH, 1H, s),
POCH
PCCH
J
POCH
7.27–8.12 (4H, arom); δC(CDCl3) 27.11 (α-CH3, s), 54.18 (CH3O, d, J
POC
7.67 Hz), 54.71 (CH3O, d, J
7.42 Hz), 74.92 (α-C, d, J 162.47 Hz),
POC
PC
123.98–138.04 (arom).
ACKNOWLEDGMENTS
We thank Mr John Crowder for assistance with the recording of NMR
spectra and Mr Stephen Boyer for microanalysis.
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