Synthesis of β-ketophosphonates with electron rich β-aryl groups as useful organophosphorus reagents in lignans synthesis

Article abstract of DOI:10.1016/j.tet.2009.03.025

Investigation of the oxidation reaction of electron rich alkoxy substituted β-aryl β-hydroxyphosphonates to corresponding β-ketophosphonates, which may be utilized in syntheses of lignans with various oxidizing agents (PCC, PDC, SIBX, CAN, Oxone

Full text of DOI:10.1016/j.tet.2009.03.025

Tetrahedron 65 (2009) 4017–4024
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
b
-ketophosphonates with electron rich
b-aryl groups as useful
organophosphorus reagents in lignans synthesis
a
a
a
b
´
Marek Koprowski , Dorota Szymanska , Agnieszka Bodzioch , Bernard Marciniak ,
b
a,b,
*
_
´
Ewa Rozycka-Soko1owska , Piotr Ba1czewski
a
´ ´
Department of Heteroorganic Chemistry, Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Łodz, Sienkiewicza 112, Poland
b Institute of Chemistry and Environmental Protection, Jan Długosz University of Cze˛stochowa, 42-200 Cze˛stochowa, Armii Krajowej 13/15, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Investigation of the oxidation reaction of electron rich alkoxy substituted b-aryl b-hydroxyphosphonates
Received 21 November 2008
Received in revised form 18 February 2009
Accepted 6 March 2009
to corresponding b-ketophosphonates, which may be utilized in syntheses of lignans with various oxi-
dizing agents (PCC, PDC, SIBX, CAN, OxoneÒ, KMNO4/SiO2, KMnO4/MS 4 Å, KMnO4/CuSO4, KMnO4/CuSO4/
Al2O3, MnO2, CrO3/SiO2, H2O2/salen) is described. The effect of oxidants and reaction conditions on the
reaction efficiency and yield was also investigated.
Available online 19 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of 1-lithio alkylphosphonates with aldehydes, which usu-
ally are commercially available and cheap. In most cases this step is
b-Ketophosphonates are useful compounds in organic chemis-
very efficient and proceeds almost quantitatively.4 However, in
try, especially in the synthesis of biologically active and natural
contrast to
tion step of the corresponding b
b
-alkyl substituted
b
-hydroxyphosphonates, the oxida-
-aryl analogs creates synthetic
products as reagents introducing
ties and enabling modifications (e.g., by substitution in the
tion or nucleophilic substitution at the carbonyl group) of the
-ketoalkyl chain.1 Their attractiveness lies in the ease of anion
formation in the -position to the phosphoryl group, which enables
further applications in Horner–Wittig olefinations.
Syntheses of -aryl substituted -ketophosphonates by the
a,
b-unsaturated carbonyl moie-
a
posi-
problems and there are few reports known on oxidation of the
latter. The described methods are not general and concern
oxidations of single compounds.5 Among them, most constitute
b
a
a,
a
0-difluoro substituted
sponding
b-hydroxyphosphonates and the corre-
b
-ketophosphonates,5a which cannot be further utilized
b
b
in the Horner–Wittig olefination.
Electron rich alkoxy substituted
constitute a peculiar subclass of
investigations are utilized in syntheses of both natural and syn-
thetic lignans.6 However, the only known protocol of synthesis of
electron rich dimethyl 2-(1,4-dimethoxy-2-methyl-3-naphthyl)-2-
oxoethylphosphonate, using MnO2 as an oxidant, remains in-
complete, since the amount of the latter has not been given.5b
Therefore, searching for new methods of synthesis of such electron
existing methods usually are not very practical and suffer from
several drawbacks. The standard condensation of dialkyl 1-lithio-
methylphosphonates with carboxylic acid esters usually proceeds
in ca. 50% yield and half of the substrate is lost due to hydrogen
exchange between the lithiated substrate and the product. The
modified Arbuzov reaction of chloromethyl ketones, potassium
iodide, and trialkyl phosphites in acetone/acetonitrile affords the
desired phosphonates in good yields but in turn it is limited by
a troublesome synthesis of the starting carbonyl compounds2 as the
reaction of labile aryloyl chlorides with dialkyl 1-lithio-
methylphosphonates.3
b-aryl
b-ketophosphonates
b-ketophosphonates and in our
rich substituted
corresponding secondary
b-aryl
b-ketophosphonates via oxidation of the
b
-hydroxy derivatives is still open and it
became a fragment of our investigations on the total syntheses of
new classes of lignans, which are known from ancient times6b as
a very rich class of plant isolated and biologically active compounds
possessing polyalkoxy substituted aryls. Some representatives are
shown in Scheme 1.
Finally, a very convenient and general method constitutes the
two-step synthesis involving formation and oxidation of
b-
hydroxymethylphosphonates. The latter can be obtained from the
In this paper, we would like to report our results on synthesis of
the polyalkoxy substituted b-aryl b-ketophosphonates, which may
be utilized in various syntheses of lignans as organophosphorus
reagents transferring the aryloylmethyl functionality.
* Corresponding author. Tel.: þ48 42 6803202; fax: þ48 42 6847126.
E-mail address: pbalczew@bilbo.cbmm.lodz.pl (P. Ba1czewski).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.025

4018
M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
OH
O
O
O
O
P(O)(OR)2
OBn
O
O
O
O
O
COOH
OMe
[O]
O
3a, b
8a, b
MeO
OMe
MeO
a: R = Me
b: R = Et
MeO
Scheme 3.
OMe
OMe
OMe
OMe
Thuriferic acid
Podophyllotoxin
O
O
MeO
The unreacted substrate in these experiments (Table 1, entries 1-
3) was exposed to additional portions of PCC. At first, 3a was oxi-
dized with 1.2 equiv PCC for 2 h at 20 ꢀC (like in entry 3) and then
the resulting mixture was reoxidized with an additional amount of
PCC (0.3 equiv) for 18 h at the same temperature (Table 1, entry 4),
unexpectedly isolating only 41% of the product 8a (61% by NMR
after water workup). The same result (37% isolated yield) was
obtained in the oxidation of 3a with 1.5 equiv PCC in one portion for
20 h at room temperature (60% in crude mixture after water
workup). In the NMR spectra of crude mixtures (Table 1, entries 4
and 5), only traces of the unreacted substrate 3a were observed in
OH
MeO
O
MeO
MeO
O
MeO
OMe
OMe
O
O
Gomosin O
Eupomatiolone-6
Scheme 1.
both cases indicating
a hydrolysis of the labile dimethoxy-
phosphoryl moiety as the most probable side reaction.
2. Results
The oxidation of 3a in the presence of 2.0 equiv of PCC (Table 1,
entry 7) for 1 h at higher temperature of 40 ꢀC gave the crude 8a in
a similar 60% yield (after water workup). Replacement of methy-
lene chloride for DMF or THF and use of even larger excess of the
oxidating agent (3.0 equiv PCC) brought a further decrease in the
yield of the product 8a (only trace amounts).
We have synthesized
a series of 2-aryl-2-hydroxymethyl-
phosphonates 3a, 3b, 5a, 5b, 7 in the reaction of the corresponding
aryl aldehydes 1, 4a, 4b, 6 with dimethyl or diethyl 1-lithio-methyl-
phosphonates in good yields (Scheme 2). In the case of phosphonates
3a and 3b, a mixture of two diastereoisomers was formed (ca. 1:1).
These isomers were well visible in NMR spectra (1H, 31P, and 13C) but
were inseparable by column chromatography.
Another standard oxidizing reagent for benzyl alcohols is pyr-
idinium dichromate (PDC). This compound gave worse results than
PCC. For instance, the oxidation of 3a with 1.1 equiv of PDC in
CH2Cl2 at room temperature overnight gave the keto product 8a in
39% (conversion determined by NMR) and 36% isolated yield (Table
1, entry 10, compare with entry 2). A large excess of PDC (4.0 equiv),
like with PCC, brought a complex mixture containing only 20% of
the expected product 8a after 3 h at 20 ꢀC (Table 1, entry 11).
KMnO4 a powerful oxidizing agent, which is widely used in
organic synthesis for certain oxidation processes and may be
activated by impregnation onto inorganic supports such as mo-
At the outset, 2-hydroxymethylphosphonate 3a was oxidized to
the b-ketophosphonate 8a (Scheme 3, Table 1) using pyridinium
chlorochromate (PCC).7 Initially, an excess of PCC (1.2–1.5 equiv) in
methylene chloride, as the standard solvent for this oxidant, was
applied. It turned out that tuning of this reaction was rather diffi-
cult. The first experiment was carried out at 0 ꢀC for 18 h in pres-
ence of 1.2 equiv of PCC (Table 1, entry 1). The 31P NMR spectrum of
the crude mixture indicated the formation of 53% of the keto
compound 8a and 30% of the unreacted substrate, however, the
product could be isolated in 25% yield only. The oxidation of 3a at
elevated temperature (20 ꢀC) in the presence of 1.2 equiv of PCC for
18 h (Table 1, entry 2) increased the yield up to 64% of the oxidized
product 8a and remaining 24% of the substrate (by 31P NMR).
Shortening of the reaction time to 2 h using the same reaction
conditions (20 ꢀC) gave 8a in the unexpected 71% yield (by 31P
NMR) and 61% after isolation (Table 1, entry 3).
lecular sieves and silica gel.8 However, oxidation of the
b-
hydroxyphosphonate 3a using KMnO4 under various conditions
brought the keto product 8a in low yields only (Table 1, entries
12–14).
Lee and Shaabani9 reported that secondary alcohols were
converted into the corresponding ketones by potassium per-
manganate mixed with copper sulfate pentahydrate (or a 20/80
mixture of copper sulfate and alumina) in good yields. For the
OH
CHO
OBn
O
O
O
P(O)(OR)2
O
O
(RO)2PCH2
a: R = Me
b: R = Et
2 =
1) 2a or 2b
OBn 3a (81%)
3b (78%)
2) H
MeO
OMe
MeO
OMe
OMe
OMe
1
O
OH
O
CHO
OMe
OH
X
1) 2a
MeO
MeO
P(OMe)2
CHO
X
O
P(OMe)2
O
O
1) 2a
2) H
2) H
O
MeO
OMe
7 (76%)
5a (84%)
5b (88%)
OMe
a: X = Br
b: X = H
4a, b
6
Scheme 2.

M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
4019
Table 1
Oxidation of 2-aryl-2-hydroxymethylphosphonates 3a, 3b, 5a, 5b, 7
Entry
Substrate
Oxidating agent (equiv)
Conditions
Ratioa product/substrate
Isolated yield (%)
25
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
7
PCC (1.2)
PCC (1.2)
PCC (1.2)
CH2Cl2, 18 h, 0 ꢀ
C
53:30
64:24
71:26
61:4
CH2Cl2, 18 h, 20 ꢀ
C
CH2Cl2, 2 h, 20 ꢀ
C
61
36
37
46
PCC (1.2þ0.3)
CH2Cl2, 2 hþ18 h, 20 ꢀ
C
C
PCC (1.5)
CH2Cl2, 20 h, 20 ꢀ
C
60:2
PCC (1.2þ0.5)
PCC (2.0)
PCC (3.0)
PCC (3.0)
PDC (1.1)
CH2Cl2, 18 hþ2 h, 20 ꢀ
78:22
60:40
0:44
CH2Cl2, 1 h, 40 ꢀ
C
DMF, 2.5 h, 20 ꢀC
THF, 1.5 h, 0 ꢀC
9
4:87
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
CH2Cl2, 18 h, 20 ꢀ
C
39:32
20:25
15:67
24:70
13:66
5:95
36
PDC (4.0)
CH2Cl2, 3 h, 20 ꢀ
C
KMnO4/MS 4 Å (10.0)
KMnO4/MS 4 Å (3.0)
KMnO4/SiO2 (3.0)
KMnO4/CuSO4$5H2O (10.0)
KMnO4/CuSO4/Al2O3 (10.0)
CrO3/SiO2 (10.0)
H2O2/salen (10.0)
Oxone (2.0)
Benzene, 8.5 h, 80 ꢀ
Benzene, 60 h, 80 ꢀ
Benzene, 8 h, 80 ꢀ
C
C
C
Neat, 2 h, 20 ꢀC, 10 min, 50 ꢀ
Neat, 2 h, 20 ꢀC, 10 min, 50 ꢀ
C
C
10:90
0:0
CH2Cl2, 18 h, 20 ꢀ
THF, 1 h, 20 ꢀ
C
C
0:100
0:100
15:58
33:40
56:32
68:8
53:18
86:14
65:25
76:22
64:0
56:34
75:25
78:22
100:0
63:47
68:32
5:90
EtOAc/H2O (1:1), 2 h, 20 ꢀ
C
CAN (3.0)
SIBX (1.2)
CH3CN/H2O (9:1), 18 h, 20 ꢀ
Toluene, 1.5 h, 80 ꢀC
C
SIBX (1.2þ1.2)
Toluene, 1.5 hþ1.5 h, 80 ꢀ
C
44
65b
44
27
SIBX (1.2)
THF, 0.5 h, 60 ꢀC
SIBX (3.0)
PCC (1.2)
SIBX (1.2)
SIBX (1.5)
SIBX (3.0)
PCC (1.1)
PCC (1.1)
PCC (1.5)
CH2Cl2, 3 d, 20 ꢀ
CH2Cl2, 2 h, 20 ꢀ
C
C
THF, 0.5 h, 60 ꢀC
61
Toluene, 2 h, 20 ꢀC, 3 h, 80 ꢀ
Toluene, 3 h, 80 ꢀ
C
69b
59
C
CH2Cl2, 3 h, 20 ꢀ
CH2Cl2, 1 h, 40 ꢀ
CH2Cl2, 2 h, 40 ꢀ
CH2Cl2, 2 h, 40 ꢀ
C
C
C
C
PCC (2.0)
52b
KMnO4/MS 4 Å (3.0)
KMnO4/MS 4 Å (3.0)
MnO2 (2.0)
MnO2 (10.0)
PCC (1.5þ1.5)
KMnO4/MS 4 Å (3.0)
PCC (1.5þ1.5)
PCC (1.5)
Benzene, 6 h, 80 ꢀ
C
Benzene, 10 h, 80 ꢀ
CHCl3, 4 h, 60 ꢀ
C
C
C
CHCl3, 10 h, 60 ꢀ
83:17
97:3
80:20
90:10
91:0
CH2Cl2, 1.5 hþ1.5 h, 20 ꢀ
C
C
61b
47
Benzene, 10 h, 80 ꢀ
C
CH2Cl2, 1.5 hþ1.5 h, 20 ꢀ
36
7
7
CH2Cl2, 1 h, 40 ꢀ
C
39
KMnO4/MS 4 Å (3.0)
Benzene, 13 h, 80 ꢀ
C
80:20
65b
By 31P NMR.
The best optimized yield.
a
b
hydroxyphosphonate 3a only 5% and 10% conversions (by 31P
NMR) were observed at conditions reported in literature (Table 1,
entries 15 and 16).
formation of 8a in 56% yield in the crude mixture and the isolated
yield was 44%. The reaction of 3a with SIBX performed in THF gave
much better results. By the use of 1.2 equiv of SIBX in this solvent
after only 0.5 h at 60 ꢀC, 3a was converted into 8a in 68% yield.
Isolated yield of 8a was 65% and only traces of the substrate (8%)
were observed in the crude mixture (Table 1, entry 23). Large excess
of SIBX (3.0 equiv) in methylene chloride oxidized 3a after 3 days at
room temperature in 53% yield (by NMR). The b-ketophosphonate
8a was isolated after a standard workup in 44% of yield (Table 1,
entry 24).
The other oxidant, for example, CrO3 supported on silica gel10
(Table 1, entry 17) was similarly unsuccessful. Most probably CrO3
oxidized other functional groups in the substrate. Oxidation of 3a
by H2O2 in the presence of salen as a catalyst11 or by OxoneÒ12 gave
no conversions (Table 1, entries 18 and 19). Another strong oxidant
CAN13 gave only 15% of the desired product 8a (Table 1, entry 19).
Our continuing interest in the oxidation chemistry of
b-
hydroxyphosphonates led us to examine the behavior of 3a in the
presence of SIBX (Stabilized IBXd2-iodoxybenzoic acid) a new
hypervalent iodine compound, which has been introduced by
Quideau et al.14 for mild oxidations of primary and secondary al-
cohols (mainly benzylic and allylic) to aldehydes and ketones,
respectively. Authors reported that the best solvents for SIBX were
toluene and THF. Initial attempt (Table 1, entry 21) to oxidize 3a
with 1.2 equiv of SIBX in toluene for 1.5 h at 80 ꢀC led to the for-
mation of 8a in only 33% (by NMR). The crude mixture contained
large quantities of the substrate (40%). Reoxidation of the remain-
ing substrate by additional portion of 2-iodoxybenzoic acid
(1.2 equiv) and heating for additional time (1.5 h) at the same
temperature (Table 1, entry 22) brought only a little progress in
formation of the expected product 8a. NMR spectra indicated the
Since the lability of the dimethoxyphosphoryl group was most
probably responsible for moderate yields of oxidation of 3a, we
synthesized the
b-hydroxyphosphonate 3b bearing a diethoxy-
phosphoryl group, which was known to be much more resistant to
hydrolytic conditions and oxidized it with PCC, one of the best
oxidant for 3a. During oxidation with 1.2 equiv of PCC in methylene
chloride at room temperature after 2 h, the conversion was better
(86% by NMR) but the isolated yield was still unexpectedly very low
(27%) (Table 1, entry 25) most probably due to oxidative debenzy-
lation on silica gel.15
In the next experiment, 3b (R¼Et) was mixed with SIBX
(1.5 equiv) in THF at 60 ꢀC and after 0.5 h, the corresponding ketone
8b was obtained in 65% yield (61% of isolated yield) (Table 1, entry
26). The oxidation of 3b performed in toluene with 1.5 equiv SIBX

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M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
for 2 h at 20 ꢀC and then for 3 h at 80 ꢀC gave 69% of the ketone 8b
and 22% of the substrate (Table 1, entry 27). To reoxidize it, 3b was
treated with a large excess of SIBX (3.0 equiv) in toluene for 3 h at
80 ꢀC (Table 1, entry 28). NMR spectra of the crude mixtures in-
dicated no substrate and the product present in 64% yield. Standard
isolation gave 59% of the desired ketone.
In a summary, the best oxidizing reagent for 3a and 3b was SIBX
at elevated temperature. The best solvent for the first one was THF
(2 h at 60 ꢀC, Table 1, entry 23) and for the second one toluene (2 h
at 20 ꢀC, 3 h at 80 ꢀC, Table 1, entry 27). Isolated yields for 3a and 3b
were 65% and 69%, respectively.
Figure 2. A part of the crystal structure of 9b, showing the formation of a chain built
from R22(16) and R22(20) rings. All H-atoms not involved in the intermolecular C–H/O
hydrogen bonds (dashed lines) and the minor disorder component of the dimethoxy-
phosphoryl group, have been omitted for clarity. Symmetry codes: (i) 1ꢁx, 2ꢁy, 1ꢁz;
(ii) 1ꢁx, 1ꢁy, 1ꢁz.
The results concerning oxidation of another electron rich alkoxy
substituted
b-aryl b-ketophosphonate, i.e., dimethyl 2-(benzo[d]
[1,3]dioxol-5-yl)-2-hydroxyethyl phosphonate 5b and its 6-bromo
analog 5a are summarized in Table 1 (Scheme 4).
room temperature in 61% of the isolated yield (97% by 31P NMR).
Typical oxidation of 5b by KMnO4 on molecular sieves (reflux,
O
P(O)(OMe)2
O
O
[O]
benzene, 10 h) provided the corresponding
b-ketophosphonate 9b
5a, b
in 47% isolated yield only (80% by 31P NMR).
X
X-ray crystal structure of the molecule 9b and its situation in the
elemental cell are shown in Figures 1 and 2 (see also Experimental
section).
a: X = Br
b: X = H
9a, b
Scheme 4.
Summarizing, optimum results for oxidations of 5a and 5b were
obtained using standard oxidizing agents such as PCC and KMnO4
on molecular sieves.
The standard oxidation of 5a by pyridinium chlorochromate
(1.1 equiv) in methylene chloride at room temperature for 3 h gave
the oxidized product in 56% yield. Elevation of the reaction tem-
perature (CH2Cl2 at reflux) increased the yield up to 75% (after only
1 h). The use of 1.5 equiv of PCC in CH2Cl2 for 2 h, at reflux gave only
a slight increase in yield (up to 78%) When 2.0 equiv of the same
oxidizing agent was used, the 100% conversion (observed by 31P
NMR) was observed but the isolated yield was only 52% in this case.
Potassium permanganate on molecular sieves (3.0 equiv) in
CH2Cl2 at reflux was able to convert 5a in 63% of yield after 6 h.
Prolongation of the reaction time to 10 h gave only a little increase
in the yield up to 68% (32% of the substrate still remained in the
crude mixture).
Our attempts to oxidize another electron rich alkoxy substituted
b-aryl b-ketophosphonate, i.e., dimethyl 2-hydroxy-2-(3,4,5-tri-
methoxyphenyl)ethylphosphonate (7) are presented in Scheme 5
and in Table 1.
O
MeO
MeO
P(O)(OMe)2
[O]
7
10
OMe
Scheme 5.
The use of active manganese dioxide16 in chloroform at reflux
for oxidation of 5a gave a good result (83% yield), however, it was
necessary to use a large excess of MnO2d10.0 equiv. Additionally
a long reaction time (10 h) was required. Using only 2 equiv of the
same oxidant for a shorter timed4 h (in chloroform at reflux, too)
gave only the 5% conversion (monitored by 31P NMR).
Dimethyl 2-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy ethylphosphonate
5b was transformed into the corresponding b-aryl b-ketophosphonate
9b with PCC (initially 1.5 equiv of the oxidant for 1.5 h and then
additional 1.5 equiv for the next 1.5 h) in methylene chloride at
Oxidation of 7 under standard conditions by PCC (CH2Cl2 at
room temperature for 3 h) and at elevated temperature (reflux in
CH2Cl2 for 1 h) gave similar results, i.e., 90% and 91% (conversion
indicated by NMR), respectively. The isolated yield in case of 10 was
only 36% and 39% for PCC. Oxidation of 7 by KMnO4 on 4 Å mo-
lecular sieves in boiling benzene (for 13 h) gave a lower conversion
than that for PCC (80%, indicated by 31P NMR spectra) but isolated
yield was higherd65%. The crude mixture still contained 20% of the
substrate.
In conclusion, in this work we presented general investigations
on the effective oxidation of
b-aryl-b-hydroxyphosphonates
substituted in the aryl moiety by electron rich alkoxy substituents,
for the first time touching this problem. The oxidation of this
synthetically useful and sensitive subgroup of
b-hydroxy-
phosphonates is usually troublesome unlike oxidation of their
b
-
alkyl substituted analogs and can be achieved in every particular
case by two steps: (1) a choice of appropriate oxidizing agent for
a selected substrate and (2) a careful tuning of reaction conditions.
3. Experimental
3.1. General
Figure 1. A plot of the molecule 9b, showing the atom numbering scheme. Dis-
placement ellipsoids are drawn at the 20% probability level and H atoms are shown as
small spheres of arbitrary radii. The minor disorder component of the dimethoxy-
phosphoryl group has been omitted for clarity.
The 1H NMR (200.16 MHz), 31P NMR (81.03 MHz), and 13C NMR
(50.33 MHz) spectra were recorded using a Bruker AC-200 spec-
trometer in C6D6 or in CDCl3. Chemical shifts are given in parts per

M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
4021
million. The mass spectra of pure compounds were obtained using
a Finnigan Mat 95 spectrometer. IR spectra were recorded using an
ATI Mattson Infinity FTIR 60 spectrometer. Column chromatogra-
phy was done using Merck silica gel (F254 60, 70–230, and 270–400
mesh). Organic solvents were purified by standard procedures.
an appropriate aldehyde (1, 4a, 4b, 6) (1.2 equiv) in dry THF (20 mL)
was added. The reaction mixture was stirred for 30 min at the same
temperature and then was slowly warmed to ꢁ20 ꢀC. Then, the
mixture was cooled to ꢁ78 ꢀC and saturated aqueous solution of
NH4Cl (20 mL) was added. The solvent was evaporated and the
residue was partitioned between water (20 mL) and ethyl acetate
(40 mL). The organic phase was washed with saturated aqueous
NH4Cl (10 mL), water (10 mL), dried (MgSO4), filtered, and con-
centrated in vacuo to give the crude product, which was purified by
column chromatography on silica gel using ethyl acetate/petroleum
ether as the eluent.
3.1.1. Crystallographic data of 9b
C11H13O6P, M¼272.18, monoclinic, P21/c, a¼7.6521(5) Å,
b¼7.2978(4) Å, c¼22.5690(12) Å,
b
¼98.898(5)ꢀ, V¼1245.16(13) Å,
Z¼4 molecules per unit cell, Dc¼1.452 g/cm3, F(000)¼568, crystal size
0.28ꢂ0.15ꢂ0.06 mm. Diffraction data were collected at 290(2) K, us-
ing an Oxford Diffraction Xcalibur 3Ô diffractometer with graphite-
monochromated Mo K
a
radiation. The structure was solved by direct
3.2.1. Dimethyl 2-(6-(benzyloxy (3,4,5-trimethoxyphenyl) methyl)
benzo[d][1,3]dioxol-5-yl)-2-hydroxy ethylphosphonate (3a)
A colorless oil; yield: 81%; Rf¼0.50 (ethyl acetate); IR (thin film)
methods and refined by full-matrix least-squares on F2 with SHELXL-
97.18 During refinement, two methoxy groups in 9a were found to be
disordered over two sites with occupancies of 0.80(2) and 0.20(2). The
C and O atoms of main component were refined anisotropically, while
those belonging to the minor component were refined isotropically.
All aromatic and methyl H atoms were positioned geometrically and
constrained to ride on their parent atoms, with C–H distances of 0.93
n
/cmꢁ1: 3329 (br m, O–H), 2952 (m, O–CH2–O), 2849 (m, OCH3),
1591 (s), 1503 (s), 1482 (s), 1462 (s, C(O)–CH2), 1420 (m), 1331 (m),
1233 (s, P]O),1127 (s, CH–O–CH),1065 (s, C–OH),1036 (vs, P–O–C),
849 (m), 828 (m), 801 (w), 736 (m), 700 (m); 31P NMR (C6D6):
d
32.48, 32.40 ppm (two diastereoisomers); 1H NMR (C6D6):
d 2.05–
and 0.96 Å, respectively, and with Uiso(H) values of 1.2 Ueq(Caromatic
and 1.5 Ueq(Cmethyl). H atoms bonded to C1 and C9 atoms were located
)
2.17 (m, 2H, CH2P(O)), 3.22 (d, JPH¼10.9 Hz, 6H, P(O)(OCH3)2), 3.34
(d, JPH¼11.0 Hz, 3H, P(O)OCH3), 3.38 (d, JPH¼11.0 Hz, 3H, P(O)OCH3),
3.44 (s, 6H, Ar(OCH3)2), 3.51 (s, 6H, Ar(OCH3)2), 3.82 (s, 3H,
ArOCH3), 3.84 (s, 3H, ArOCH3), 4.54 (dAB, JHH¼11.6 Hz, 1H, OCH2Ph),
4.57 (s, 2H, OCH2Ph), 4.72 (dAB, JHH¼11.6 Hz, 1H, OCH2Ph), 4.87 (s,
OH), 5.06 (s, OH), 5.28–5.34 (m, 2H, OCH2O), 5.34–5.38 (m, 2H,
OCH2O), 5.72–5.88 (m, 1H, CHOH), 5.87 (s, 1H, CHOBn), 5.92 (s, 1H,
CHOBn), 6.86 (s, 2H, o-C6H2(OCH3)2), 6.89 (s, 2H, o-C6H2(OCH3)2),
7.04–7.18 (m, 3H, m-Ph, p-Ph), 7.09 (s, 1H, ArH), 7.15 (s, 1H, ArH),
7.34–7.39 (m, 2H, o-Ph), 7.40 (s, 1H, ArH), 7.46 (s, 1H, ArH); 1H NMR
in difference maps and refined with Uiso(H) set at 1.5 Ueq(C), giving C–
H distances in the range 0.87(4)–1.00(3) Å. R[F2>2
s
(F2)]¼0.0437,
wR(F2)¼0.1273, S¼1.026 for 2176 independent reflections [1383 re-
flections with I>2s(I)] and 197 parameters. Further details on the
crystal structure investigation have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
number CCDC 705171.
3.1.2. Crystallographic discussion on 9b
(CDCl3): d 1.27–1.43 (m, 1H, CH2P(O)), 1.53–1.66 (m, 1H, CH2P(O)),
Compound 9b crystallized in the monoclinic P21/c space group
with four molecules per unit cell. In the dimethoxyphosphoryl
group region of this molecule, a disorder on atoms O5, O6, C10, and
C11 was identified and refined over two positions with an occu-
pancy of 0.80(2) for the major component for which only the
geometric parameters will be presented. As can be seen from Fig-
ure 1, the benzene and dioxolane rings as a whole are essentially
planar with the largest deviations from the best least-squares plane
of 0.071(4) Å for atom C1, and the C8, C9, and O3 atoms are nearly
coplanar, with deviations from the plane of 0.120(3), 0.291(3), and
0.112(2) Å, respectively. The phosphorus and oxygen atoms be-
longing to the dimethoxyphosphoryl group, i.e., P1, O4, O5, and O6,
lie 1.244(1), 1.868(2), 2.104(6), and 0.670(9) Å below this plane,
respectively, and the angle between the C9–P1 bond and the plane
formed by benzene and dioxolane rings is 57.4(1)ꢀ. The crystal
packing of 9b is stabilized by two weak non-conventional in-
termolecular C–H/O hydrogen bonds. Atom C6 in benzene ring at
(x, y, z) acts as hydrogen bond donor to atom O4 at (1ꢁx, 1ꢁy, 1ꢁz),
linking the two molecules into a dimer unit, so generating a cen-
trosymmetric R22(16) ring17 centered at (1/2, 1/2, 1/2). Moreover, the
atom C1 in the dioxolane ring at (x, y, z) acts as a donor, via H1A,
towards atom O4 at (1ꢁz, 2ꢁy, 1ꢁz), generating a centrosymmetric
R22(20) ring centered at (1/2, 1, 1/2). The combined effect of these
two C–H/O hydrogen bonds is the formation of a chain running
parallel to the [010] direction and build from the fused R22(16) and
R22(20) rings (Fig. 2).
3.15 (br s, 1H, OH), 3.54–3.75 (m, 6H, P(O)(OCH3)2), 3.80 (s, 3H, p-
C6H2(OCH3)3), 3.81 (s, 3H, 2ꢂm-C6H2(OCH3)3), 3.84 (s, 3H, 2ꢂm-
C6H2(OCH3)3), 4.45–4.66 (m, 2H, OCH2Ph), 4.67 (s, 2H, OCH2Ph),
5.28–5.55 (m, 1H, CHOH), 6.61 (s, 1H, CHOBn), 5.92–5.96 (m, 2H,
OCH2O), 6.53 (s, 2H, o-C6H2(OCH3)2), 6.60 (s, 2H, o-C6H2(OCH3)2),
6.67 (s, 1H, Ar–H), 7.12 (s, 1H, Ar–H), 7.34–7.40 (m, 5H, Ph); 13C NMR
(C6D6):
d
33.72 (d, JPC¼135.0 Hz, CH2P(O)), 34.34 (d, JPC¼135.4 Hz,
CH2P(O)), 52.04 (d, JPC¼6.5 Hz, P(O)(OCH3)), 52.54 (d, JPC¼6.5 Hz,
P(O)(OCH3)), 55.93 (s, Ar(OCH3)2), 60.66 (s, ArOCH3), 64.01 (d,
JPC¼8.9 Hz, CHOH), 64.09 (d, JPC¼8.9 Hz, CHOH), 70.59 (s, OCH2Ph),
70.78 (s, OCH2Ph), 78.98 (s, CHOBn), 79.22 (s, CHOBn), 101.08 (s,
OCH2O), 104.07 (s, 2ꢂo-C6H2(OMe)3), 104.68 (s, Ar–H), 106.18 (s,
Ar–H),127.52 (s, m-Ph),127.77 (s, p-Ph),128.26 (s, o-Ph),131.19 (s, p-
C6H2(OMe)3), 136.20 (s, C–CHO–),136.42 (s, ipso-Ph), 137.30 (s, ipso-
C6H2(OMe)3), 137.85 (d, JPC¼7.1 Hz, C–CHOH), 146.82 (s, C–OCH2O),
147.50 (s, C–OCH2O), 153.21 (s, m-C6H2(OMe)2); MS (CI) (m/z): 561
(1.5%, MþþH), 560 (2, M), 543 (8, MþþH(ꢁH2O)), 453 (100,
MþþH(ꢁBnOH)), 451 (52, MþþH(ꢁP(O)(OMe)2)), 435 (25,
MþþH(ꢁH2O, ꢁBnOH)). Anal. C28H33O10P requires: C, 60.00%; H,
5.93%. Found: C, 59.70%; H, 5.88%.
3.2.2. Diethyl 2-(6-(benzyloxy (3,4,5-trimethoxyphenyl) methyl)
benzo[d][1,3]dioxol-5-yl)-2-hydroxy ethylphosphonate (3b)
A colorless oil; yield: 78%; Rf¼0.53 (ethyl acetate); IR (thin film)
n
/cmꢁ1: 3327 (br m, O–H), 2950 (m, O–CH2–O), 2847 (m, O–CH3),
1591 (s), 1510 (m), 1477 (m), 1460 (s), 1236 (s, P]O), 1126 (s, CH–O–
CH), 1061 (s, C–OH), 1036 (vs, P–O–C), 960 (m), 789 (m), 801 (w),
3.2. Synthesis of 2-aryl-2-hydroxymethylphosphonates 3a,
3b, 5a, 5b, 7
736 (m), 700 (m); 31P NMR (C6D6):
d
29.60, 29.91 ppm (1:1)
(two diastereoisomers); 1H NMR (C6D6):
d
0.88–1.09 (m, 6H,
P(O)(OCH2CH3)2), 1.90–2.26 (m, 2H, CH2P(O)), 3.43 (s, 6H, 1 isomer
2ꢂo-C6H2(OCH3)3), 3.50 (s, 6H, 2 isomer-2ꢂo-C6H2(OCH3)3), 3.74–
3.92 (m, 4H, P(O)(OCH2CH3)2), 3.82 (s, 3H,1 isomer p-C6H2(OCH3)3),
3.84 (s, 3H, 2 isomer-p-C6H2(OCH3)3), 4.52 (dAB, JHH¼11.8 Hz, 1H, 2
isomer OCH2Ph), 4.55 (dAB, JHH¼9.8 Hz, 1H, 1 isomer OCH2Ph), 4.58
(dAB, JHH¼11.8 Hz, 1H, 2 isomer OCH2Ph), 4.69 (dAB, JHH¼9.8 Hz, 1H,
To a stirred solution of dialkyl methylphosphonate (2a or 2b)
(0.03 mmol) in anhydrous THF (50 mL), a solution of n-BuLi (1.2 M,
27.5 mL, 0.033 mmol, 1.1 equiv) was added at ꢁ78 ꢀC. After 30 min,
the temperature was raised to ꢁ30 ꢀC and stirring was continued
for 15 min. Then, the temperature was lowered again to ꢁ78 ꢀC and

4022
M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
1 isomer OCH2Ph), 4.47 (s, 1H, OH), 5.27–5.33 (m, 2H, 1 isomer
OCH2O), 5.33–5.36 (m, 2H, 2 isomer OCH2O), 5.68–5.51 (m, 1H,
HP(O)(OCH3)2); HRMS (EI) (m/z): calcd for C11H15PO6: 274.060627,
found: 274.06098.
CHOH), 5.52 (s, 1H, CHOBn), 6.87 (s, 2H,
2
isomer 2ꢂo-
C6H2(OCH3)3), 6.89 (s, 2H, 1 isomer 2ꢂo-C6H2(OCH3)3), 7.05–7.17
(m, 3H, 2ꢂm-, p-Ph), 7.37–7.43 (m, 2H, 2ꢂo-Ph), 7.37 (s, 1H, 2 iso-
mer Ar), 7.41 (s, 1H, 1 isomer Ar), 7.49 (s, 1H, 1 isomer Ar), 7.53 (s,
3.2.5. Dimethyl 2-hydroxy-2-(3,4,5-trimethoxyphenyl)
ethylphosphonate (7)
A colorless oil; yield: 76%; Rf¼0.05 (hexane/ethyl acetate 1:1 v/
1H,
2
isomer Ar); 13C NMR (C6D6):
d
17.08 (d, J¼5.8 Hz,
v), 0.16 (hexane/ethyl acetate 1:4 v/v); IR (KBr) n
/cmꢁ1: 3393 (br m),
2ꢂP(O)(OCH2CH3)2), 35.54 (d, J¼32.1 Hz, 1 isomer CH2P(O)), 38.21
(d, J¼32.4 Hz, 2 isomer CH2P(O)), 56.56 (s, 2ꢂm-C6H2(OCH3)3),
61.13 (s, p-C6H2(OCH3)3), 62.11 (d, J¼6.9 Hz, P(O)(OCH2CH3)2), 62.69
(d, J¼5.9 Hz, P(O)(OCH2CH3)2), 65.43 (d, J¼20.3 Hz, CHOH), 71.66 (s,
OCH2Ph), 80.43 (s, CHOBn), 101.87 (s, 2ꢂo-C6H2(OMe)3), 105.95 (s, 1
isomer OCH2O), 106.55 (s, 2 isomer OCH2O), 107.68 (s, 1 isomer Ar–
H), 107.79 (s, 2 isomer Ar–H), 109.07 (s, Ar–H), 127.48 (s, m-Ph),
127.70 (s, p-Ph), 129.00 (s, o-Ph), 133.03 (s, 1 isomer p-C6H2(OMe)3),
133.19 (s, 2 isomer p-C6H2(OMe)3), 137.80 (s, 1 isomer C–CHO–),
138.15 (s, 2 isomer C–CHO–), 138.59 (s, ipso-Ph), 139.33 (s, ipso-
C6H2(OMe)3), 139.50 (s, 1 isomer C–CHOH), 139.81 (s, 2 isomer
C–CHOH), 148.05 (s, 1 isomer C–OCH2O), 148.37 (s, 2 isomer C–
OCH2O), 148.57 (s, 1 isomer C–OCH2O), 148.71 (s, 2 isomer
C–OCH2O), 154.92 (s, 1 isomer m-C6H2(OMe)2), 154.98 (s, 2 isomer
m-C6H2(OMe)2); MS (CI) (m/z): 571 (11%, MþþH(ꢁH2O)), 463 (100,
MþþH(ꢁH2O, ꢁBnOH)). Anal. C30H37O10P requires: C, 61.22%; H,
6.34%. Found: C, 61.37%; H, 6.47%.
3292 (s, O–H), 3004 (m), 2941 (m, O–CH2–O), 2842 (m, O–CH2),
1592 (s), 1507 (m), 1463 (s), 1417 (s), 1339 (m), 1235 (s, P]O), 1217
(s), 1124 (vs, CH–O–CH), 1054 (s), 1026 (vs, P–O–C), 857 (m), 803
(m); 31P NMR (C6D6):
d d 2.05–2.18 (m, 2H,
32.13; 1H NMR (C6D6):
CH2P(O)), 3.28 (d, J¼11.1 Hz, 3H, P(O)OCH3), 3.32 (d, J¼10.9 Hz, 3H,
P(O)OCH3), 3.41 (s, 6H, 2ꢂm-C6H2(OCH3)3), 3.85 (s, 3H, p-
C6H2(OCH3)3), 4.68 (br s, 1H, OH), 5.21–5.33 (m, 1H, CH(OH)), 6.67
(s, 2H, 2ꢂo-C6H2(OCH3)3); 1H NMR (CDCl3):
d 2.14–2.28 (m, 2H,
CH2P(O)), 3.77 (d, J¼11.0 Hz, 3H, P(O)OCH3), 3.80 (d, J¼11.0 Hz, 3H,
P(O)OCH3), 3.83 (s, 3H, p-C6H2(OCH3)3), 3.87 (s, 6H, 2ꢂm-
C6H2(OCH3)3), 5.00–5.12 (m, 1H, CH(OH)), 5.30 (s, 1H, OH), 6.62 (s,
2H, 2ꢂo-C6H2(OCH3)3); 13C NMR (C6D6):
d
37.15 (d, J¼135.9 Hz,
CH2P(O)), 52.32 (d, J¼6.6 Hz, P(O)OCH3), 53.15 (d, J¼6.0 Hz,
P(O)OCH3), 56.54 (s, 2ꢂm-C6H2(OCH3)3), 61.14 (s, p-C6H2(OCH3)3),
69.76 (d, J¼4.2 Hz, CH(OH)), 104.08 (s, 2ꢂo-C6H2(OCH3)3), 139.21 (s,
p-C6H2(OCH3)3), 141.71 (d, J¼16.5 Hz, ipso-C6H2(OCH3)3), 154.87 (s,
2ꢂm-C6H2(OCH3)3); MS (CI) (m/z): 320 (3%, Mþ), 303 (100,
Mþ(ꢁOH)); MS (EI) (m/z): 320 (33%, Mþ), 302 (13, Mþ(ꢁH2O)), 287
(7, Mþ(ꢁH2O, ꢁCH3)), 210 (100, Mþ(ꢁHP(O)(OMe)2)); HRMS (EI)
(m/z): calcd for C13H21PO7: 320.10249, found: 320.10228.
3.2.3. Dimethyl 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-2-hydroxy
ethylphosphonate (5a)
A light-yellow oil; yield: 84%; Rf¼0.52 (petroleum ether/acetone
1:1 v/v); IR (KBr) n
/cmꢁ1: 3312 (br s, O–H), 2957 (w), 2918 (w, O–
CH2–O), 2851 (w, O–CH3), 1495 (m), 1478 (s), 1255 (m, P]O), 1224
(s), 1088 (m), 1033 (vs, P–O–C, C–OH), 930 (w), 869 (w), 829 (m);
3.3. Oxidations of 2-aryl-2-hydroxymethylphosphonates 3a,
3b, 5a, 5b, 7
31P NMR (CDCl3):
d
31.56; 1H NMR (CDCl3):
d
2.00 (dddAB
,
3JHH¼10.5 Hz, JPH¼14.8 Hz, JHH¼15.3 Hz, 1H, CH2P(O)), 2.30
(dddAB, 3JHH¼2.0 Hz, 2JHH¼15.3 Hz, 2JPH¼18.4 Hz, 1H, CH2P(O)), 3.75
(d, J¼11.2 Hz, 3H, P(O)OCH3), 3.82 (d, J¼11.2 Hz, 3H, P(O)OCH3), 4.21
To a solution of 3a (0.2 mmol) in CH3CH/H2O (9:1 v/v) (5 mL),
CAN (0.6 mmol, 3.0 equiv) was added in one portion at room
temperature. The reaction mixture was stirred at 20 ꢀC for 18 h. The
reaction mixture was diluted with CH2Cl2 (10 mL). The organic
layer was washed with water (3ꢂ10 mL), dried (MgSO4), and then
the solvent was removed in vacuo. The crude product was purified
by column chromatography (petroleum ether/EtOAc).
2
2
3
3
3
(br s, 1H, OH), 5.30 (ddd, JHH¼2.0 Hz, JPH¼10.4 Hz, JHH¼10.5 Hz,
1H, CH(OH)), 5.96 (s, 2H, OCH2O), 6.94 (s, 1H, 5-Ar–H), 7.17 (s, 1H, 2-
Ar–H); 13C NMR (CDCl3):
d
33.24 (d, J¼135.0 Hz, CH2P(O)), 52.63 (s,
P(O)(OCH3)2), 67.57 (d, J¼4.3 Hz, CH(OH)), 101.69 (s, OCH2O), 107.06
(s, 2-Ar–H), 111.06 (s, C–Br), 112.28 (s, 5-Ar–H), 136.19 (d, J¼17.9 Hz,
1-Ar), 147.56 (s, C–OCH2O), 147.77 (s, C–OCH2O); MS (CI) (m/z): 355
To a solution of 3a (0.2 mmol) in ethyl acetate (1 mL), OxoneÒ
(0.4 mmol, 2.0 equiv) dissolved in H2O (1 mL) was added dropwise at
20 ꢀC. The reaction mixture was stirred at the same temperature for
2 h. The reaction mixture was diluted with ethyl acetate (5 mL). The
organic layer was washed with water (3ꢂ10 mL), dried (MgSO4), and
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography (petroleum ether/EtOAc).
The oxidations of 3a, 3b, 5a, 5b, 7 by PCC or PDC were performed
according to the literature procedure7 under conditions indicated
in Table 1 in a 1 mmol scale.
The oxidations of 2-aryl-2-hydroxymethylphosphonates per-
formed by KMnO4 on silica gel8 or KMnO4/CuSO4$5H2O or KMnO4/
CuSO4/Al2O3 were performed according to Shaabani and Lee pro-
cedures9 under conditions shown in Table 1.
The oxidations of 2-aryl-2-hydroxymethylphosphonates with
CrO3 supported on SiO2 and H2O2 in the presence of salen as
a catalyst were performed according to Kiasat et al.10 and Mardani
and Golchoubian11 procedures, respectively.
(6%, MþþH
(
80Br)), 353 (5, MþþH
(
79Br)), 337 (91, MþþH
(
80Br)(ꢁH2O)), 337 (89, MþþH (79Br)(ꢁH2O)), 273 (100, Mþ(ꢁBr)),
273 (27, Mþ(ꢁBr, ꢁH2O)); HRMS (CI) (m/z): calcd for C11H14PBrO6:
351.971150, 353.969303, found: 353.97062.
3.2.4. Dimethyl 2-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy
ethylphosphonate (5b)
A colorless oil; yield: 88%; Rf¼0.15 (hexane/ethyl acetate 1:1 v/v),
0.33 (hexane/ethyl acetate 1:4 v/v); IR (KBr)
n
/cmꢁ1: 3320 (s, O–H),
3009 (w), 2960 (w, O–CH2–O), 2914 (w, O–CH3), 2855 (w, O–CH3),
1505 (m),1488 (m),1440 (m),1246 (m, P]O),1229 (m),1081 (m),1034
(vs, P–O–C, C–OH), 838 (m), 811 (m); 31P NMR (C6D6): 32.03; 1H NMR
d
2
2
(C6D6):
CH2P(O)), 2.03 (dddAB
d
1.94 (dddAB
,
,
3JHH¼3.2 Hz, JPH¼11.8 Hz, JHH¼18.0 Hz, 1H,
2
2
3JHH¼9.9 Hz, JPH¼15.3 Hz, JHH¼18.0 Hz, 1H,
CH2P(O)), 3.28 (d, J¼10.9 Hz, 3H, P(O)OCH3), 3.33 (d, J¼10.8 Hz, 3H,
3
3
P(O)OCH3), 5.00 (bs, 1H, OH), 5.15 (ddd, JHH¼3.2 Hz, JPH¼10.1 Hz,
3JHH¼9.9 Hz, 1H, CH(OH)), 5.30 (s, 1H, OCH2O), 5.31 (s, 1H, OCH2O),
6.63 (d, J¼7.9 Hz, 1H, 6-Ar–H), 6.73 (d, J¼7.9 Hz, 1H, 5-Ar–H), 7.01 (s,
Reactions with SIBX were performed according to the Ozanne
et al. procedure.14
1H, 2-Ar–H); 13C NMR (C6D6):
d
36.69 (d, J¼135.1 Hz, CH2P(O)), 52.31
(d, J¼6.9 Hz, P(O)OCH3), 52.93 (d, J¼6.6 Hz, P(O)OCH3), 69.31 (d,
J¼4.3 Hz, CHOH), 101.60 (s, OCH2O), 107.39 (s, 2-Ar), 108.88 (s, 5-Ar),
119.82 (s, 6-Ar), 140.34 (d, J¼16.5 Hz, 1-Ar), 147.93 (s, COCH2O),148.94
(s, COCH2O); MS (CI) (m/z): 274 (18%, Mþ), 257 (15, MþþH(ꢁH2O)); MS
(EI) (m/z): 274 (21%, Mþ), 256 (15, Mþ(ꢁH2O)), 164 (100,
Mþ(ꢁHP(O)(OCH3)2)), 146 (24, Mþ(ꢁHP(O)(OCH3)2, ꢁH2O)), 124 (37,
3.3.1. Dimethyl 2-(6-(benzyloxy (3,4,5-trimethoxyphenyl) methyl)
benzo[d][1,3]dioxol-5-yl)-2-oxoethylphosphonate (8a)
A light-yellow oil; Rf¼0.55 (ethyl acetate); IR (thin film)
n :
/cmꢁ1
2994 (m, O–CH2–O), 2953 (m, O–CH2), 2851 (m, O–CH3), 1677 (s,
C]O), 1591 (s), 1505 (s), 1487 (s), 1456 (s, C(O)–CH2), 1419 (m), 1330
(m), 1242 (vs, P]O), 1127 (s, CH–O–CH), 1036 (vs, P–O–C), 808 (m),

M. Koprowski et al. / Tetrahedron 65 (2009) 4017–4024
4023
737 (w), 701 (w); 31P NMR (CDCl3):
d
23.04; 31P NMR (C6D6):
3.3.4. Dimethyl 2-(benzo[d][1,3]dioxol-5-yl)-2-
oxoethylphosphonate (9b)
d
22.59; 1H NMR (CDCl3):
d
3.383.43 (m, 1H, CH2P(O)), 3.49–3.54
(m,1H, CH2P(O)), 3.75 (d, JPH¼11.2 Hz, 6H, P(O)(OCH3)2), 3.81 (s, 3H,
p-C6H2(OCH3)3), 3.82 (s, 6H, 2ꢂm-C6H2(OCH3)3), 4.48 (s, 2H,
OCH2Ph), 6.01–6.04 (m, 2H, OCH2O), 6.15 (s, 1H, CHOBn), 6.71 (s,
2H, 2ꢂo-C6H2(OCH3)3), 7.10 (s, 1H, Ar–H), 7.28 (s, 1H, Ar–H), 7.28–
A white solid; mp¼78–80 ꢀC (from petroleum ether/ethyl ace-
tate 3:1 v/v); Rf¼0.20 (hexane/ethyl acetate 1:1 v/v), 0.40 (hexane/
ethyl acetate 1:4 v/v); IR (KBr) n
/cmꢁ1: 3434 (br w), 3068 (w), 3031
(w), 2956 (w, O–CH2–O), 2913 (w, O–CH3), 2853 (w, O–CH3), 1668
(s, C]O), 1600 (m), 1496 (m), 1447 (s, C(O)–CH2), 1271 (vs, P]O),
1245 (s), 1061 (s), 1030 (vs, P–O–C), 1005 (s), 927 (m), 901 (m), 872
7.38 (m, 6H, Ar–H, Ph); 1H NMR (C6D6)
d
3.21 (d, JPH¼22.3 Hz, 2H,
CH2P(O)), 3.34 (d, JPH¼11.2 Hz, 3H, P(O)OCH3), 3.37 (d, JPH¼11.3 Hz,
3H, P(O)OCH3), 3.47 (s, 6H, 2ꢂm-C6H2(OCH3)3), 3.83 (s, 3H, p-
C6H2(OCH3)3), 4.61 (s, 2H, OCH2Ph), 5.13–5.22 (m, 2H, OCH2O), 6.57
(s, 1H, CHOBn), 7.08 (s, 2H, 2ꢂo-C6H2(OCH3)3), 7.09–7.21 (m, 3H,
(m), 832 (m), 813 (m); 31P NMR (C6D6):
d
22.81; 1H NMR (C6D6):
d
3.23 (d, J¼22.7 Hz, 2H, CH2P(O)), 3.38 (d, J¼11.0 Hz, 6H,
P(O)(OCH3)2), 5.13 (s, 2H, OCH2O), 6.46 (d, J¼7.4 Hz, 1H, 6-Ar–H),
Ph), 7.25 (s, 1H, Ar), 7.46 (s, 1H, Ar); 13C NMR (C6D6):
d 41.59 (d,
7.47 (d, J¼7.4 Hz, 1H, 5-Ar–H), 7.60 (s, 1H, 2-Ar–H); 13C NMR (C6D6):
JPC¼128.2 Hz, CH2P(O)), 52.94 (d, JPC¼6.4 Hz, P(O)OCH3), 53.16 (d,
JPC¼6.2 Hz, P(O)OCH3), 56.55 (s, 2ꢂm-C6H2(OCH3)3), 60.99 (s, p-
C6H2(OCH3)3), 71.97 (s, OCH2Ph), 78.94 (s, CHOBn), 102.47 (s,
OCH2O), 105.76 (s, 2ꢂo-C6H2(OCH3)3), 109.44 (s, Ar–H), 109.87
(s, Ar–H), 127.50 (s, m-Ph), 127.80 (s, p-Ph), 128.20 (s, o-Ph), 132.44
(s, p-C6H2(OCH3)3), 138.55 (s, C–C(O)), 139.25 (s, ipso-Ph), 139.68 (s,
C–CHOBn), 140.78 (s, ipso-C6H2(OCH3)3), 147.53 (s, C–OCH2O),
151.67 (s, C–OCH2O), 154.77 (s, 2ꢂm-C6H2(OCH3)3), 194.41 (d,
JPC¼6.0 Hz, C]O); MS (CI) (m/z): 558 (0.2%, Mþ), 541 (2,
MþþH(ꢁH2O)), 451 (100, MþþH(ꢁBnOH)). Anal. C28H31O10P re-
quires: C, 60.21%; H, 5.59%. Found: C, 59.92%; H, 5.50%.
d
38.72 (d, J¼128.8 Hz, CH2P(O)), 53.31 (d, J¼6.0 Hz, 2ꢂP(O)-
(OCH3)2), 102.57 (s, OCH2O), 108.61 (s, 2-Ar–H), 109.56 (s, 5-Ar–H),
126.92 (s, 6-Ar–H), 132.70 (s, C–(C]O)), 149.22 (s, COCH2O), 153.05
(s, COCH2O), 190.11 (d, J¼6.1 Hz, C]O); MS (CI) (m/z): 273 (100%,
MþþH), 257 (4, MþþH(ꢁO)); HRMS (CI) (m/z): calcd For C11H13PO6:
272.04497, found: 272.04442.
3.3.5. Dimethyl 2-oxo-2-(3,4,5-trimethoxyphenyl)
ethylphosphonate (10)
A light-yellow oil; Rf¼0.11 (hexane/ethyl acetate 1:1 v/v), 0.29
(hexane/ethyl acetate 1:4 v/v); IR (film) n
/cmꢁ1: 2953 (m), 2844 (m,
O–CH3),1675 (s, C]O),1585 (s),1506 (m, C]C),1459 (m, C]C),1417
(m),1336(vs, C(O)–CH2),1257(s, P]O),1228(vs, P–O–C),1032(vs, P–
3.3.2. Diethyl 2-(6-(benzyloxy (3,4,5-trimethoxyphenyl) methyl)
benzo[d][1,3]dioxol-5-yl)-2-oxoethylphosphonate (8b)
O–C), 808 (m); 31P NMR (CDCl3): 22.00; 1H NMR (CDCl3):
d d 3.61 (d,
A light-yellow oil; Rf¼0.58 (ethyl acetate); IR (thin film)
n
/cmꢁ1
:
J¼22.3 Hz, 2H, CH2P(O)), 3.79 (d, J¼11.1 Hz, 6H, P(O)(OCH3)2), 3.92 (s,
2982 (m), 2936 (m, O–CH2–O), 2838 (w, O–CH3), 1677 (m, C]O),
1591 (m), 1506 (s), 1487 (s), 1456 (m, C(O)–CH2), 1419 (m), 1330 (m),
1242 (vs, P]O),1127 (vs, CH–O–CH),1036 (vs, P–O–C), 968 (m), 791
9H, C6H2(OCH3)3), 7.30 (s, 2H, 2ꢂo-C6H2(OCH3)3); 13C NMR (CDCl3):
d
37.80 (d, J¼131.1 Hz, CH2P(O)), 53.22 (d, J¼6.5 Hz, 2ꢂP(O)(OCH3)2),
56.31 (s, 2ꢂo-C6H2(OCH3)3), 60.93 (s, p-C6H2(OCH3)3), 106.62 (s,
2ꢂo-C6H2(OCH3)3), 131.45 (s, ipso-C6H2(OCH3)3), 143.22 (s, p-
C6H2(OCH3)3),153.01(s, 2ꢂm-C6H2(OCH3)3),190.35(s, C]O); MS (CI)
(m/z): 319 (100%, MþþH). HRMS (CI) (m/z): calcd for C13H19PO7:
318.086842, found: 318.08656.
(w), 738 (w), 701 (w); 31P NMR (C6D6):
d
20.05; 1H NMR (C6D6):
d
0.99 (t, J¼7.1 Hz, 3H, P(O)OCH2CH3), 1.01 (t, J¼7.0 Hz, 3H,
P(O)OCH2CH3), 3.23 (d, J¼2.3 Hz, 1H, CH2P(O)), 3.35 (d, J¼1.3 Hz,
1H, CH2P(O)), 3.49 (s, 6H, 2ꢂm-C6H2(OCH3)3), 3.83 (s, 3H, p-
C6H2(OCH3)3), 3.83–3.97 (m, 4H, P(O)(OCH2CH3)), 4.62 (s, 2H,
OCH2Ph), 5.17 (s, 1H, OCH2O), 5.22 (s, 1H, OCH2O), 6.59 (s, 1H,
CHOBn), 7.06–7.19 (m, 3H, m-, p-Ph), 7.09 (s, 2H, 2ꢂo-C6H2(OCH3)3),
7.35 (s, 1H, Ar), 7.34–7.39 (m, 2H, o-Ph), 7.47 (s, 1H, Ar); 13C NMR
Acknowledgements
Financial support by the Ministry of Science and Higher Edu-
cation in 2007–2010 (Grant N204 022 32/0620) is gratefully
acknowledged.
(C6D6):
d
16.99 (d, J¼5.7 Hz, CH3, P(O)(OCH2CH3)2), 56.59 (s, CH3,
2ꢂm-C6H2(OCH3)3), 61.12 (s, CH3, p-C6H2(OCH3)3), 63.13 (d,
J¼8.8 Hz, CH2, P(O)(OCH2CH3)2), 72.13 (s, OCH2Ph), 79.13 (s,
CHOBn), 102.54 (s, CH, OCH2O), 106.05 (s, CH, 2ꢂo-C6H2(OCH3)3),
109.57 (s, Ar–H), 110.16 (s, Ar–H), 127.49 (s, m-Ph), 127.81 (s, p-Ph),
128.18 (s, o-Ph), 132.71 (s, p-C6H2(OCH3)3), 138.71 (s, C–C(O)),
139.49 (s, ipso-Ph), 139.85 (s, C–CHOBn), 140.91 (s, ipso-
C6H2(OCH3)3), 147.64 (s, C–OCH2O), 151.74 (s, C–OCH2O), 154.92 (s,
2ꢂm-C6H2(OCH3)3), 194.57 (d, J¼6.4 Hz, C]O); MS (CI) (m/z): 586
(0.4%, Mþ), 569 (5, MþþH(ꢁH2O)), 479 (100, MþþH(ꢁBnOH)). Anal.
C30H35O10P requires: C, 61.43%; H, 6.01%. Found: C, 61.49%; H, 6.10%.
References and notes
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3.3.3. Dimethyl 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-2-
oxoethylphosphonate (9a)
A light-yellow oil; Rf¼0.33 (petroleum ether/acetone 1:1 v/v);
IR (KBr) n
/cmꢁ1: 3433 (br w), 2961 (w), 2902 (w, O–CH2–O), 2855
(w, O–CH3), 1691 (s, C]O), 1612 (m, C]C), 1510 (m, C]C), 1496
(m, C]C), 1484 (m), 1343 (m), 1263 (s, P]O), 1238 (P–O–C), 1034
(vs, P–O–C), 1022 (vs), 806 (m); 31P NMR (CDCl3):
d
22.34; 1H
NMR (CDCl3):
J¼11.2 Hz, 6H, P(O)(OCH3)2), 6.03 (s, 2H, OCH2O), 7.02 (s, 1H, Ar–
H), 7.07 (s, 1H, Ar–H); 13C NMR (CDCl3):
d
3.66 (d, J¼22.3 Hz, 2H, CH2P(O)), 3.76 (d,
d
40.73 (d, J¼129.5 Hz,
CH2P(O)), 53.10 (d, J¼6.5 Hz, P(O)(OCH3)2), 102.54 (s, OCH2O),
109.83 (s, 2-Ar–H), 111.99 (s, C-Br), 113.76 (s, 5-Ar–H), 133.55 (s,
C–(C]O)), 147.44 (s, C–OCH2O), 150.72 (s, C–OCH2O), 193.25 (d,
J¼6.6 Hz, C]O); MS (CI) (m/z): 352 (98%, Mþ
(
81Br)), 350 (100,
Mþ
(
79Br)), 271 (24, Mþ(ꢁBr)); HRMS (CI) (m/z): calcd for
C11H12PBrO6: 349.9555, found: 349.95506.

4024
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