New efficient synthesis of 1-hydroxymethylene-1,1-bisphosphonate monomethyl esters

Article abstract of DOI:10.1055/s-2004-837226

A new efficient procedure for the synthesis of 1-hydroxymethylene-1,1- bisphosphonate monomethyl esters in three steps from acid chlorides is reported here. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-837226

LETTER
425
New Efficient Synthesis of 1-Hydroxymethylene-1,1-Bisphosphonate
Monomethyl Esters
S
ynthesis of 1-H
v
ydroxymeth
e
ylene-1,1-B
l
isphos
y
phonate
M
o
n
nomethyl
E
st
e
er
s
Migianu, Erwann Guénin, Marc Lecouvey*
Laboratoire de Chimie Structurale Biomoléculaire (UMR 7033-CNRS), UFR S.M.B.H., Université Paris 13., 74, Rue Marcel Cachin,
93017 Bobigny Cedex, France
Fax +33(1)48387625; E-mail: m.lecouvey@smbh.univ-paris13.fr
Received 22 October 2004
derivatives are not stable at physiological pH as they rear-
range into phosphonophosphate pentaesters.15 For this
reason, synthesis of HMBP partial esters has been inves-
tigated. Turhanen et al. reported a synthetic method to
prepare such compounds, by using regioselective dealkyl-
ation of HMBP tetraesters by different metal halides or
trimethylsilyliodide.16 Recently, our laboratory described
a one-pot synthesis of HMBP di-and trimethylesters.17
HMBP P,P¢-diesters were synthesized from acid chlorides
and two equivalents of methyl bis(trimethylsilyl) phos-
phite whereas HMBP P,P-diesters and trimethylesters
were prepared by reaction of one equivalent of tris(tri-
methylsilyl) phosphite or methyl bis(trimethylsilyl) phos-
phite, respectively, with a-ketophosphonates. These last
intermediates were preferred to acid chlorides in order to
avoid a second attack of the phosphite on the carbonyl of
the acid chloride.
Abstract: A new efficient procedure for the synthesis of 1-hy-
droxymethylene-1,1-bisphosphonate monomethyl esters in three
steps from acid chlorides is reported here.
Key words: 1-hydroxymethylene-1,1-bisphosphonates,
phosphonates, bis(silylated) phosphite, Arbuzov reaction
a-keto-
Derivatives of 1-hydroxymethylene-1,1-bisphosphonates
(HMBPs) have gained considerable interest in recent
years because of their biological properties and medical
applications.1–3 They are an important class of products
used in the treatment of a variety of diseases showing an
abnormal calcium metabolism such as Paget’s disease, os-
teoporosis and metastatic bone diseases.4–6 More recently,
HMBPs have been found to have an effect on treatment of
metastatic cancer.7 It has been reported that they inhibit
bone metastases proliferation in prostate and breast can-
cers.8–10 These compounds, characterized by a P-C-P link-
age, are stable structural analogues of pyrophosphate and
are completely resistant to enzymatic hydrolysis. Howev-
er, the major drawback in the efficacy of these products is
their poor oral bio-availability (only 3–7% of the drug is
metabolized).11 This results from their low lipophilicity
due to their high ionization at physiological pH values.
Moreover, absorption of HMBPs is further reduced by
their strong complexation of calcium and other divalent
metal cations in the intestinal lumen.11 To circumvent
these problems, a prodrug strategy was considered that
would deliver bisphosphonates with an improved gas-
trointestinal absorption. Only few reports about the design
of bisphosphonate prodrugs have been published in the
literature.12,13 Among them, Ezra et al. have shown that
the introduction of a dipeptide as the side chain in bis-
phosphonate increased the specificity of the drug signifi-
cantly.14 Another interesting approach is the modification
of the phosphonic acid function itself, by introducing an
ester group. Thus, by masking the negative charges of
HMBPs with suitable bioreversible substituents, the lipo-
philicity of bisphosphonates could be enhanced and the
complexation with divalent cations decreased. Bisphos-
phonate prodrugs should then release bisphosphonic acids
via enzymatic and/or chemical hydrolysis. HMBP tet-
raesters could be the best prodrugs. Unfortunately, these
Concerning the synthesis of HMBP monomethyl esters, a
similar strategy was considered. Initial attempts employed
acid chlorides and one equivalent of tris(trimethylsilyl)
phosphite without solvent in order to obtain the bis(silyl-
ated) a-ketophosphonate (Scheme 1).18 Addition of one
equivalent of methyl bis(trimethylsilyl) phosphite and
methanolysis gave the expected HMBP monomethyl es-
ters with satisfactory crude yields (44% and 62%, respec-
tively, for R = CH3 and R = i-Pr). However, although the
reaction was carried out at –20 °C, the major HMBP
monomethyl ester was obtained as a mixture with the cor-
responding bisphosphonic acid and HMBP P,P¢-dimethyl
ester; these three compounds being difficult to separate.
Bisphosphonic acid was formed due to the addition of
tris(trimethylsilyl) phosphite on silylated a-ketophospho-
nate whereas HMBP dimethyl ester resulted from the
reaction between methyl bis(trimethylsilyl) phosphite and
the unreacted acid chloride. Consequently, a new proce-
dure reported herein was investigated using bis(silylated)
a-ketophosphonates (prepared in two steps from acid
chlorides) and methyl bis(trimethylsilyl) phosphite.
O
C
O
C
1 equiv P(OSiMe3)3
OSiMe3
OSiMe3
R
Cl
R
P
O
OH
C
1 equiv P(OMe)(OSiMe3)2
then MeOH
MeO
HO
OH
OH
P
P
SYNLETT 2005, No. 3, pp 0425–0428
1
6.
0
2.
2
0
0
5
Advanced online publication: 22.12.2004
O
R
O
DOI: 10.1055/s-2004-837226; Art ID: D31704ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

426
E. Migianu et al.
LETTER
The first step of the synthesis consisted of an Arbuzov re- crude compounds 4 were purified as indicated in Table 2.
action between the acid chloride 1 and trimethylphosphite Oils 4a and 4b were purified by washes with diethyl ether
in order to furnish the corresponding a-ketophosphonate (entries 11 and 12) or by precipitation in diethyl ether for
2 (Scheme 2). The reaction, realized without solvent products 4c and 4f (entries 13 and 16) or methanol for
under argon, was exothermic and carried out at –10 °C products 4d and 4e (entries 14 and 15). HMBP mono-
during the addition of acid chloride. After being warmed methyl esters 4 were synthesized very efficiently both in
to room temperature, the reaction mixture was stirred for aliphatic or aromatic series with good yields.
two hours. The end of the reaction was easily monitored
by 31P {1H} NMR (appearance of a peak with a chemical
shift about 0 ppm, different from the starting product at
d = 141.0 ppm) or by IR spectroscopy (disappearance of
the acid chloride signal about 1800 cm–1).
O
O
2.5 equiv Me3SiBr
THF or CH2Cl2
OMe
OMe
OSiMe3
OSiMe3
R
C
P
R
C
P
O
O
2
3
OSiMe3
OSiMe3
MeO
P
1.
O
C
O
C
OH
1 equiv P(OMe)3
OMe
OMe
MeO
HO
OH
OH
R
P
R
Cl
P
C
R
P
O
2. MeOH
O
O
2
1
4
Scheme 2
Scheme 3 Synthesis of monomethyl esters 4, Method A
Table 1 shows the different alkyl or aryl a-ketophospho-
nate dimethyl esters 2a–f obtained in excellent yields
from 74% to 90% (entries 1–6). We indicate here the pu-
rification method used for each a-ketophosphonate 2a–f
Because of the presence of two stereogenic centers, four
stereoisomers were expected. However, the two dia-
stereoisomers were not distinguished by NMR spectros-
copy. Indeed, the 31P {1H} NMR spectra of HMBP
monomethyl esters 4 showed the presence of only two dif-
31
and its characteristic chemical shift in P {1H} NMR in
CDCl3 solution. We note that these compounds, kept cold
under argon, are stable for several months.
2
ferent doublets with equal JP-P coupling constants. The
2
31P {1H} NMR chemical shifts and JP-P coupling con-
The same reaction conditions (no solvent, temperature
about –10 °C, then r.t. for 2 h) were applied to phenyl-
acetyl chloride 1g. As reported previously,19 a mixture of
the desired a-ketophosphonate 2g as the minor product
along with its corresponding enolic form as the major
product was obtained. We modified the solvent and tem-
perature conditions as shown in Table 1 (entries 8–10) in
order to try to push the reaction towards formation of the
a-ketophosphonate. Attempts were carried out in distilled
THF or dichloromethane at low temperature (–70 °C) and
gave the same results as previously. By using trimethyl
phosphite, the corresponding enolic form of 2g was al-
ways obtained as the major compound whatever the tem-
perature. No more purification was attempted and another
method for the synthesis of the HMBP monomethyl ester
2g was subsequently investigated.
stants were sensitive to the substituent R on the central
carbon. They were, respectively, about 20–22 ppm and
36–43 Hz for aliphatic compounds 4a–c (entries 11–13)
and about 16–18 ppm and 26–31 Hz for aromatic com-
pounds 4d–f (entries 14–16). The chemical shift differ-
ences between these two doublets were very low (about
only 1–2 ppm) because of the presence of only one methyl
ester group. Use of coupled 31P NMR spectroscopy al-
lowed us to assign the two different signals of phosphorus
atoms of HMBP monomethyl esters 4. The chemical shift
of phosphonic acid fragment was always higher. More-
13
over, the C {1H} NMR spectra showed a characteristic
1
signal about d = 70–80 ppm (dd) with JC-P coupling
constants about 140–145 Hz for the central carbon.
In order to synthesize HMBP monomethyl ester 4g
(R = PhCH2) and to avoid the formation of the enol as de-
scribed previously, we used tris(trimethylsilyl) phosphite
instead of trimethyl phosphite. In the first procedure, as
indicated in Scheme 1, P(OMe)3 was applied to phenyl-
acetyl chloride 1g. Nevertheless, the reaction carried out
at very low temperature to avoid a second attack of the
tris(trimethylsilyl) phosphite on the carbonyl of acid chlo-
ride. Thus, one equivalent of tris(trimethylsilyl) phosphite
was added dropwise at –70 °C to phenylacetyl chloride 1g
in dichloromethane (Method B, Scheme 4). After 30 min-
utes at this temperature, 31P {1H} NMR spectroscopy in-
dicated the disappearance of tris(trimethylsilyl) phosphite
(d = 114.0 ppm) and the formation of the intermediate
bis(silylated) a-ketophosphonate 3g about –20 ppm. Un-
der these conditions, the formation of the enolic form was
not observed. Compound 3g was not isolated but directly
Next, a-ketophosphonates 2a–f were silylated via an Ar-
buzov reaction. Thus, addition of 2.5 equivalents of fresh-
ly distilled trimethylsilyl bromide to a cooled solution of
the appropriate a-ketophosphonate 2 in distilled THF or
dichloromethane under argon was carried out (Method A,
Scheme 3). The reaction was exothermic and the temper-
ature had to be maintained below 10 °C. The bis(silylated)
a-ketophosphonate 3 was obtained, usually after five
hours at room temperature; the end of the reaction being
monitored by 31P {1H} NMR. After evaporation of vola-
tile fractions and solvent under reduced pressure, the
bis(silylated) intermediate 3 was treated with one equiva-
lent of methyl bis(trimethylsilyl) phosphite20 at 0 °C un-
der argon. The reaction mixture was stirred overnight,
furnishing HMBP monomethyl esters 4 after methanoly-
sis. After vacuum evaporation of volatile fractions, the
Synlett 2005, No. 3, 425–428 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Hydroxymethylene-1,1-Bisphosphonate Monomethyl Esters
427
Table 1 Synthesis of a-Ketophosphonate Dimethyl Esters 223
Entry
Compound
R
Solvent
Temp
Purification method Yield (%)
31P {1H} NMR
[(CDCl3, d (ppm)]
1
2
2a
2b
2c
2d
2e
2f
Me
–
–10 °C then r.t.
–10 °C then r.t.
–10 °C then r.t.
–10 °C then r.t.
–10 °C then r.t.
–10 °C then r.t.
–10 °C then r.t.
–70 °C then r.t.
–70 °C
Distillation
86
–0.6
–0.3
–0.4
–0.9
1.8
i-Pr
–
Distillation
86
3
C15H31
Ph
–
No purification
89
4
–
Distillation
74
5
p-MeOPh
p-BrPh
PhCH2
PhCH2
PhCH2
PhCH2
–
Distillation
89
6
–
Extraction in Et2O
90
0.4
7
2g
2g
2g
2g
–
–
–
–
–
Nda
Nda
Nda
Nda
–0.7
–0.7
–0.7
–0.7
8
THF
THF
CH2Cl2
9
10
–70 °C
a Nd = not determined.
Table 2 Synthesis of 1-Hydroxymethylene-1,1-bisphosphonate Monomethyl Esters 424
Entry
Compound
R
Method
Purification method
Yield (%) 31P {1H} NMR [D2O or CDCl3, d
(ppm)]a
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
4f
Me
A
A
A
A
A
A
B
Washes with Et2O
75
73
48
88
80
84
20.6, d; 21.8, d, 2JP-P = 36.2 Hz
20.6, d; 21.3, d, 2JP-P = 37.7 Hz
20.0, d; 21.6, d, 2JP-P = 43.2 Hz
17.0, d; 17.9, d, 2JP-P = 26.6 Hz
17.2, d; 18.1, d, 2JP-P = 30.8 Hz
16.3, d; 16.9, d, 2JP-P = 26.8 Hz
18.8, d; 20.3, d, 2JP-P = 29.4 Hz
i-Pr
Washes with Et2O
C15H31
Ph
Precipitation in Et2O
Precipitation in MeOH
Precipitation in MeOH
Precipitation in Et2O
p-MeOPh
p-BrPh
PhCH2
4g
Reverse phase chromatography 47
a 31P {1H} NMR spectra were realized in D2O for products 4a,b and 4d–g and in CDCl3 for product 4c.
used without further purification. One equivalent of meth- synthesis of nucleoside-5¢-(1-hydroxymethylene-1,1-bis-
yl bis(trimethylsilyl) phosphite20 was then added drop- phosphonates).22
wise at –70 °C. The reaction mixture was stirred at this
temperature for 45 minutes before methanolysis. After
vacuum evaporation of volatile fractions, HMBP mono-
methyl ester 4g was obtained in 47% yield and purified by
reverse phase column chromatography using C-18 resin
(Polygoprep 60-130, Macherey-Nagel; see Table 2, entry
17).
O
OSiMe3
P
Cl
1 equiv P(OSiMe3)3
CH2Cl2, –70 °C
C
O
OSiMe3
C
O
1g
3g
OSiMe3
OSiMe3
1. MeO
OH
P
, –70 °C
To conclude, we have developed a new and efficient syn-
thesis of HMBP monomethyl esters from different ali-
phatic or aromatic acid chlorides via corresponding a-
ketophosphonates. Nevertheless, an alternative method
using tris(trimethylsilyl) phosphite had to be considered
in case of phenylacetyl chloride to avoid enol formation.
These procedures will be applied to other related systems
and should have applications in biology21 including the
OH
C
MeO
HO
P
P
OH
2. MeOH
O
CH2 O
4g
Scheme 4 Synthesis of monomethyl ester 4g, Method B
Synlett 2005, No. 3, 425–428 © Thieme Stuttgart · New York

428
E. Migianu et al.
LETTER
{1H} (80.9 MHz, CDCl3): d = –0.9 (s). 13C NMR {1H} (50.3
MHz, CDCl3): d = 53.0 (OCH3), 127.8 (p-C6H5), 128.3 (o-
C6H5), 129.0 (m-C6H5), 133.7 (C6H5-C=O), 202.1 (C=O). IR
(H2O): 1040, 1067 (P-O), 1270 (P=O), 1667 (C=O) cm–1.
Anal. Calcd for C9H11O4P: C, 50.48; H, 5.18; P, 14.46.
Found: C, 50.39; H, 5.20; P, 14.51.
References
(1) Page, P. C. B.; McKenzie, M. J.; Gallagher, J. A. J. Org.
Chem. 2001, 66, 3704.
(2) Page, P. C. B.; McKenzie, M. J.; Gallagher, J. A. Synth.
Commun. 2002, 32, 211.
(3) Vovk, A. I.; Kalchenko, V. I.; Cherenok, S. A.; Kukhar, V.
P.; Muzychka, O. V.; Lozynsky, M. O. Org. Biomol. Chem.
2004, 2, 3162.
(24) Typical Procedure for the Synthesis of 1-Hydroxy-
methylene-1,1-bisphosphonate Monomethyl Esters 4.
Method A: To a-ketophosphonate dimethyl ester 2 (5
mmol) in 4 mL of distilled THF or CH2Cl2 at 0 °C under
argon was added dropwise trimethylsilyl bromide (1.65 mL,
12.5 mmol). The reaction was exothermic and the
(4) Fleisch, H. Endocr. Rev. 1998, 19, 80.
(5) Fleisch, H. Prog. Mol. Subcell. Biol. 1999, 23, 197.
(6) Fleisch, H. Eur. Spine J. 2003, 12 Suppl. 2, S142.
(7) Green, J. R. Cancer 2003, 97, 840.
(8) Mercadante, S. Curr. Urol. Rep. 2002, 3, 244.
(9) Clezardin, P.; Fournier, P.; Boissier, S.; Peyruchaud, O.
Curr. Med. Chem. 2003, 10, 173.
temperature had to be maintained below 10 °C during the
addition. The reaction mixture was stirred at r.t. for 5–6 h
(the end of the reaction was controlled by 31P {1H} NMR)
and evaporation of volatile fractions (0.01 Torr) at 50 °C
gave bis(silylated) a-ketophosphonate 3. Methyl
bis(trimethylsilyl) phosphite (1.2 g, 5 mmol) was then added
dropwise to 3 at 0 °C under argon. The reaction mixture was
stirred overnight at r.t. and methanolysis for 2 h led to 1-
hydroxymethylene-1,1-bisphosphonate monomethyl esters
4. After reduced pressure evaporation of volatile fractions,
the crude compound 4 was purified as indicated in Table 2.
Method B [(preparation of 1-hydroxymethylene-1,1-
bisphosphonate monomethyl ester (4g)]: To phenyl acetyl
chloride 1g (0.66 mL, 5 mmol) in 25 mL of distilled CH2Cl2
at –70 °C under argon was added dropwise
tris(trimethylsilyl) phosphite (1.76 mL, 5 mmol). The
reaction mixture was stirred at –70 °C for 30 min and methyl
bis(trimethylsilyl) phosphite (1.2 g, 5 mmol) was then added
dropwise at the same temperature. After stirring at –70 °C
for 45 min, methanolysis for 2 h led to 1-hydroxymethylene-
1,1-bisphosphonate monomethyl ester (4g). After vacuum
evaporation of volatile fractions, the crude compound 4g
was purified by reverse phase column chromatography using
C-18 resin (Polygoprep 60-130, Macherey-Nagel) and
obtained with 47% yield.
(10) Fleisch, H. Breast Cancer Res. 2002, 4, 30.
(11) Lin, J. H. Bone 1996, 18, 75.
(12) Niemi, R.; Turhanen, P.; Vepsalainen, J.; Taipale, H.;
Jarvinen, T. Eur. J. Pharm. Sci. 2000, 11, 173.
(13) Vepsalainen, J. J. Curr. Med. Chem. 2002, 9, 1201.
(14) Ezra, A.; Hoffman, A.; Breuer, E.; Alferiev, I. S.;
Monkkonen, J.; El Hanany-Rozen, N.; Weiss, G.;
Stepensky, D.; Gati, I.; Cohen, H.; Tormalehto, S.; Amidon,
G. L.; Golomb, G. J. Med. Chem. 2000, 43, 3641.
(15) Fitch, S. J.; Moedritzer, K. J. Am. Chem. Soc. 1962, 84,
1876.
(16) Turhanen, P. A.; Ahlgren, M. J.; Jaervinen, T.;
Vepsaelaeinen, J. J. Synthesis 2001, 633.
(17) Migianu, E.; Mallard, I.; Bouchemal, N.; Lecouvey, M.
Tetrahedron Lett. 2004, 45, 4511.
(18) Mallard, I. Ph.D. Thesis; Université: Paris 13, 2002.
(19) El Manouni, D.; Leroux, Y.; Burgada, R. Phosphorus, Sulfur
Silicon Relat. Elem. 1989, 42, 73.
(20) Sekine, M.; Futatsugi, T.; Yamada, K.; Hata, T. J. Chem.
Soc., Perkin Trans. 1 1982, 11, 2509.
(21) Lecouvey, M.; Leroux, Y.; Kraemer, M.; Crepin, M.; El
Manouni, D.; Louriki, M. PCT Int. Appl. WO 03008425,
2003; Chem. Abstr. 2003, 138, 122736.
(22) Migianu, E.; Monteil, M.; Even, P.; Lecouvey, M.
Nucleosides, Nucleotides Nucleic Acids 2004, accepted.
(23) Typical Procedure for the Synthesis of a-
Ketophosphonate Dimethyl Esters 2.
Compound 4a: 1H NMR (200 MHz, D2O): d = 1.44 (dd, 3 H,
3JP-H = 16.0 Hz and 3JP-H = 16.0 Hz, CH3C-OH), 3.58 (d, 3
H, 3JP-H = 9.8 Hz, OCH3). 31P NMR {1H} (80.9 MHz, D2O):
d = 20.6 [d, 1 P, 2JP-P = 36.2 Hz, P(O)(OH)(OMe)], 21.8 [d,
1 P, 2JP-P = 36.2 Hz, P(O)(OH)2]. 13C NMR {1H} (50.3
MHz, D2O): d = 21.5 (CH3C-OH), 55.8 (OCH3), 72.6 (dd,
1JC-P = 152.4 Hz and 1JC-P = 152.4 Hz, COH). IR (H2O):
1008, 1053, 1125 (P-O), 945, 1049 (P-O-CH3), 1190 (P=O)
cm–1. Anal. Calcd for C3H10O7P2: C, 16.37; H, 4.58; P,
28.15. Found: C, 16.47; H, 4.53; P, 28.19.
The adequate acid chloride 1 (50 mmol) was added dropwise
at –10 °C under argon to trimethylphosphite (5.9 mL, 50
mmol). The reaction mixture was then stirred at r.t. for 2 h
(the end of the reaction was ascertained by 31P {1H} NMR or
IR spectroscopy). The crude product was purified as
indicated in Table 1 to furnish the corresponding a-keto-
phosphonate dimethyl ester 2.
Compound 4d: 1H NMR (200 MHz, D2O): d = 3.53 (d, 3 H,
3JP-H = 4.0 Hz, OCH3), 7.33 (d, 1 H, 3JH-H = 7.6 Hz, H p-
C6H5), 7.38 (dd, 2 H, 3JH-H = 7.6 Hz and 3JH-H = 7.6 Hz, H
m-C6H5), 7.71 (d, 2 H, 3JH-H = 7.6 Hz, H o-C6H5). 31P NMR
{1H} (80.9 MHz, D2O): d = 17.0 [d, 1 P, 2JP-P = 26.6 Hz,
P(O)(OH)(OMe)], 17.9 [d, 1 P, 2JP-P = 26.6 Hz, P(O)(OH)2].
13C NMR {1H} (50.3 MHz, D2O): d = 56.8 (OCH3), 79.6 (dd,
1JC-P = 144.6 Hz and 1JC-P = 144.6 Hz, COH), 129.2 (o-
C6H5), 131.0 (p-C6H5), 131.4 (m-C6H5), 139.3 (C6H5-C=O).
IR (H2O): 1035, 1077, 1094 (P-O), 960, 1054 (P-O-CH3),
1200 (P=O) cm–1. Anal. Calcd for C8H12O7P2: C, 34.06; H,
4.29; P, 21.96. Found: C, 34.21; H, 4.32; P, 21.91.
Compound 2a: 1H NMR (200 MHz, CDCl3): d = 2.45 (d, 3
H, 3JP-H = 5.0 Hz, CH3C=O), 3.83 (d, 6 H, 3JP-H = 10.6 Hz,
OCH3). 31P NMR {1H} (80.9 MHz, CDCl3): d = –0.6 (s). 13
C
NMR {1H} (50.3 MHz, CDCl3): d = 29.9 (CH3C=O), 52.6
(OCH3), 202.1 (C=O). IR (H2O): 1040, 1060 (P-O), 1270
(P=O), 1703 (C=O) cm–1. Anal. Calcd for C4H9O4P: C,
31.59; H, 5.96; P, 20.37. Found: C, 31.70; H, 5.92; P, 20.33.
Compound 2d: 1H NMR (200 MHz, CDCl3): d = 3.58 (d, 6
H, 3JP-H = 10.8 Hz, OCH3), 7.17 (dd, 2 H, 3JH-H = 7.4 Hz and
3JH-H = 7.4 Hz, H m-C6H5), 7.33 (d, 1 H, 3JH-H = 7.4 Hz, H
p-C6H5), 7.92 (d, 2 H, 3JH-H = 7.4 Hz, H o-C6H5). 31P NMR
Synlett 2005, No. 3, 425–428 © Thieme Stuttgart · New York