Alcoholysis of phosphaisocoumarins and synthesis of 2-(2-oxoalkyl) phenylphosphonates

Article abstract of DOI:10.1002/ejoc.200800616

Phosphaisocoumarins do not undergo aminolysis, but instead they were found to be susceptible to alcoholysis in the presence of alcohols and primary amines. This paper examined this unexpected alcoholysis reaction and found that in the presence of Et₃N or K₂CO₃, 4-unsubstituted- and 4-chlorophosphaisocoumarins underwent the alcoholysis reaction smoothly to give a series of 2-(2-oxoalkyl)phenylphosphonates in good yields, whereas 4-iodo- and 4-bromophosphaisocoumarins underwent a dehalogenation-alcoholysis tandem reaction. The possible mechanism for the alcoholysis reaction was discussed. In addition, direct access to 2-(2-oxoalkyl)-phenylphosphonates was developed by the mercury(II)-catalyzed hydration of 2-(1-alkynly)phenylphosphonates with high regioselectivity. In a preliminary study, the obtained novel keto phosphonates showed medium inhibitory activity towards α-chymotrypsin. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800616

FULL PAPER
DOI: 10.1002/ejoc.200800616
Alcoholysis of Phosphaisocoumarins and Synthesis of
2-(2-Oxoalkyl)phenylphosphonates
Ai-Yun Peng,*[a] Yu-Juan Guo,[a] Zhi-Hai Ke,[a] and Shizheng Zhu[b]
Keywords: Alcoholysis / Phosphonates / Phosphorus heterocycles / Hydration / Alkynes
Phosphaisocoumarins do not undergo aminolysis, but instead
they were found to be susceptible to alcoholysis in the pres-
ence of alcohols and primary amines. This paper examined
this unexpected alcoholysis reaction and found that in the
reaction. The possible mechanism for the alcoholysis reaction
was discussed. In addition, direct access to 2-(2-oxoalkyl)-
phenylphosphonates was developed by the mercury(II)-cata-
lyzed hydration of 2-(1-alkynly)phenylphosphonates with
presence of Et3N or K2CO3, 4-unsubstituted- and 4-chloro- high regioselectivity. In a preliminary study, the obtained
phosphaisocoumarins underwent the alcoholysis reaction
smoothly to give a series of 2-(2-oxoalkyl)phenylphosphon-
ates in good yields, whereas 4-iodo- and 4-bromophosphaiso-
coumarins underwent a dehalogenation–alcoholysis tandem
novel keto phosphonates showed medium inhibitory activity
towards α-chymotrypsin.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Although phosphonates are not very abundant in nature,
their diverse bioactivities have attracted considerable syn-
thetic[1] and pharmacological[2] interest. They are usually
recognized as effective transition-state analogue inhibitors
for a variety of enzymes including proteases and ester-
ases.[2a–2c] They have also been developed to be used as in-
secticides, herbicides, fungicides, plant growth regulators,
and drugs to treat bone disorders.[2d]
In recent years, we have synthesized novel cyclic phos-
phonates, that is, phosphaisocoumarins,[3] some of which
preliminarily showed medium inhibitory activity towards
protein tyrosine phosphatase 1B (PTP1B), medium antitu-
mor activity, and good insecticidal activity.[4] However, the
chemical properties and reactivities of phosphaisocoumar-
ins are still not very clear.
Scheme 1.
aminolysis product, but instead afforded alcoholysis prod-
uct 2aa whether the reaction was carried out under thermal
conditions or at room temperature (Scheme 2).
Because isocoumarins could be converted into the corre-
sponding isoquinolones readily by treatment with primary
amines in solvent, such as alcohol and chloroform,[5] we
reasoned that phosphaisoquinolones might be synthesized
in a similar way (Scheme 1).
However, to our surprise, the reaction of 3-phenyl-7-
methoxyphosphaisocoumarin (1a) with an excess amount
of aqueous ethylamine in ethanol did not lead to any
Scheme 2. Reaction of 1a with aqueous ethylamine in ethanol. Rea-
gents and conditions for thermal reaction: 1a (0.25 mmol), EtOH
(2.5 mL), aq. EtNH2 (30 equiv.), 90 °C, 6 h, yield: 45%. Reagents
and conditions for room-temperature reaction: 1a (0.25 mmol),
EtOH (2.5 mL), aq. EtNH2 (8 equiv.), r.t., 48 h, yield: 73%.
This unexpected alcoholysis reaction attracted our inter-
ests. On the one hand, in this reaction, it was the weaker
nucleophile ethanol instead of ethylamine that attacked the
phosphorus atom; the examination of this reaction would
help us to further understand the differences between car-
boxylates and phosphonates. On the other hand, from the
viewpoint of retrosynthesis, 2-(2-oxoalkyl)phenylphos-
phonates 2 might be useful intermediates for the prepara-
tion of other phosphonates. For example, the reduction of
[a] School of Chemistry & Chemical Engineering, Sun Yat-sen
University,
135 Xingangxi Lu, Guangzhou 510275, China
Fax: +86-020-84112425
E-mail: cespay@mail.sysu.edu.cn
[b] Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences,
354 Fenglin Lu, Shanghai 200032, China
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A.-Y. Peng, Y.-J. Guo, Z.-H. Ke, S. Zhu
FULL PAPER
2 followed by thermal condensation would afford 3,4-dihy- Table 1. Alcoholysis of 1a under various conditions.[a]
drophosphaisocoumarins according to the synthesis of 3,4-
dihydroisocoumrins.[6] However, to the best of our knowl-
edge, there are no reports about the synthesis and applica-
tions of 2, except that we obtained two of these phosphon-
ates as minor products in the iodocyclization of 2-(1-
alkynyl)phenylphosphonates. Thus, in this paper, we de-
Entry
R
Catalyst
(equiv.)
Temp.
[°C]
Time
[h]
Isolated
yield [%]
cided to investigate the alcoholysis of phosphaisocoumarins
and tried to develop a general method to synthesize 2-(2-
oxoalkyl)phenylphosphonates 2.
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
iPr
tBu
No catalyst
nBuNH2 (4)
nBuNH2 (4)
Et3N (15)
Et3N (15)
pyridine (4)
NaOH (1.5)
85
r.t.
80
r.t.
60
60
85
36
48
24
24
36
36
24
24
18
36
24
24
24
24
24
no reaction
74 (2aa)
44 (2aa)
trace
78 (2aa)
Results and Discussion
65 (2aa)
[a]
–
NaHCO3 (1.5) 85
no reaction
80 (2aa)
Ͻ50 (2aa)
no reaction
no reaction
55 (2ab)
Starting materials 1 were prepared according to our pre-
vious procedure (Scheme 3).[3,7] We first examined the
alcoholysis of 1a under various conditions and the results
are summarized in Table 1. The catalyst was essential, as
without any catalyst 1a was recovered unchanged (Table 1,
entry 1). Similar to EtNH2 mentioned in Scheme 2,
nBuNH2 was more effective to catalyze this reaction at
room temperature than under thermal conditions (Table 1,
entries 2 and 3), whereas Et3N was more efficient at 60 °C,
leading to 2aa in 78% yield, in which an excess amount of
volatile Et3N was added so as to ensure completion of the
reaction (Table 1, entries 4 and 5). The use of inorganic
bases was also examined, and the results showed that
NaOH only led to the hydrolysis product,[8] NaHCO3 did
not afford 2aa at all, and K2CO3 (1.5 equiv.) at 85 °C gave
2aa in 80% yield (Table 1, entries 7–10). In addition, al-
though acid was used to catalyze the alcoholysis of the car-
boxylates,[9] it could not catalyze this reaction (Table 1, en-
tries 11 and 12). The methanolysis of 1a also proceeded
smoothly under Et3N-catalyzed conditions, but the isolated
yield of desired product 2ab was relatively low (Table 1, en-
try 13). It was found that 2ab decomposed slowly to an un-
identified compound with strong polarity upon chromatog-
raphy with silica gel, probably because it was easily hy-
drolyzed to the monoester under weakly acidic condi-
tions.[10] The reaction of 1a with secondary or tertiary
alcohols, such as iPrOH or tBuOH, did not proceed at all
under the same conditions (Table 1, entries 14 and 15).
9
K2CO3 (1.5)
K2CO3 (1.5)
H2SO4 (1)
p-TsOH (1)
Et3N (15)
Et3N (15)
Et3N (15)
85
r.t.
85
85
60
60
60
10
11
12
13
14
15
no reaction
no reaction
[a] The reaction led to the hydrolysis product of 1a (2, R = H).
yields by this ethanolysis reaction. Functionalities, for ex-
ample, R1 = methoxy, chlorine, hydrogen; R2 = aryl, alkyl,
cyclopropyl, were able to withstand the reaction conditions.
K2CO3 was efficient in most cases, but for substrates 1e
and 1g, most of the starting materials were recovered under
K2CO3-catalyzed conditions (Table 2, entries 4 and 7). The
use of Et3N instead of K2CO3 afforded desired products 2e
and a racemic mixture of (Ϯ)-2g in good yields for 1e and
1g, respectively (Table 2, entries 5 and 8).
Table 2. Base-catalyzed ethanolysis of 1.[a]
Entry
1
Base
Time
[h]
Isolated
R1
R2
X
(equiv.)
yield [%]
1
2
3
4
5
6
7
8
OMe
H
H
Cl
Cl
Cl
H
cPr
nBu
Ph
cPr
cPr
Ph
H (1b)
H (1c)
H (1d)
H (1e)
H (1e)
H (1f)
Cl(1g)
Cl (1g)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
Et3N (15)
K2CO3 (1.5)
K2CO3 (1.5)
Et3N (15)
18
24
24
36
36
36
24
18
74 (2b)
79 (2c)
75 (2d)
1e+2e[b]
71 (2e)
65 (2f)
Ph
Ph
1g + (Ϯ)-2g[b]
82 [(Ϯ)-2g]
H
Scheme 3. Synthesis of all kinds of phosphaisocoumarins 1.
[a] Reactions were carried out with 1, K2CO3 at 85 °C or Et3N at
60 °C in EtOH. [b] The reaction mixture was not isolated but de-
tected by TLC.
To further explore the scope of this reaction, the etha-
nolysis of other phosphaisocoumarins 1 with various sub-
stituents was investigated in the presence of K2CO3 or
However, when 4-iodophosphaisocoumrin 1h was treated
Et3N. As shown in Table 2, for those cases where X is hy- with ethanol and Et3N at 60 °C for 60 h, precursor 1h dis-
drogen and chlorine, the corresponding 2-(2-oxoalkyl)phen- appeared completely and iodide-free phosphaisocoumarin
ylphosphonates 2 could be obtained in good-to-excellent 1a was obtained in 69% yield (Table 3, entry 1). A similar
5278
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Alcoholysis of Phosphaisocoumarins
result was obtained when K2CO3 was used as the catalyst
(Table 3, entry 2). With the addition of an excess amount
of Et3N, iodide-free ethanolysis product 2a was detected by
TLC (Table 3, entry 3). In this reaction, the base was essen-
tial (Table 3, entry 4). Under similar conditions, 4-iodo- and
4-bromophosphacoumarins 1i–k only gave the dehalogena-
tion–ethanolysis products (Table 3, entries 5–7).
Table 3. Ethanolysis of 4-iodo- or 4-bromophosphaisocoumarins.[a]
Scheme 4. Possible mechanisms for the alcoholysis and dehalogena-
tion reactions.
Entry
1
R2
Base
Time
[h]
Isolated
HgSO4/H2SO4 only yielded 2a–f and regioisomers 4 were
not detected (Table 4). These results are not surprising, be-
cause internal alkynes bearing a π-accepting substituent
(e.g., amides, esters, phosphonates) are usually hydrated by
conjugate addition to give β-keto compounds.[13] However,
in most cases, the yield of the desired ketone was not very
satisfactory, although the starting material has totally dis-
appeared in each case (Table 4, entries 2–6). Some unidenti-
fied phosphonate-hydrolyzed byproducts were observed in
the crude reaction mixture under these conditions, which
might be the reason for the relatively low yields of the
ketones.
R1
X
(equiv.)
yield [%]
1
2
3
4
5
6
7
OMe Ph
OMe Ph
OMe Ph
OMe Ph
OMe Ph
I (1h)
I (1h)
I (1h)
I (1h)
Br (1i) Et3N (35)
I (1j) Et3N (20)
Br (1k) Et3N (20)
Et3N (15)
K2CO3 (1.0)
Et3N (35)
No base
60
4
69 (1a)
1i +1a[b]
1a+2a[b]
no reaction
50 (2a)
36
36
36
36
36
H
H
Ph
Ph
59 (2d)
60 (2d)
[a] Reactions were carried out with 1, K2CO3 at 85 °C or Et3N at
60 °C in EtOH. [b] The reaction mixture was not isolated but de-
tected by TLC.
On the basis of the above results, plausible mechanisms
are proposed in Scheme 4. Alcohol (ROH) is a weak nu-
cleophile, and it alone cannot promote the alcoholysis and
dehalogenation reactions (Table 1, entry 1; Table 3, entry 4).
However, the base can enhance the nucleophilicity of ROH
by the formation of an R–O–H···base hydrogen bond. The
attack of the activated ROH on the phosphorus atom of 1
(X = H, Cl) followed by proton transfer would lead to de-
sired products 2. In contrast, activated ROH might also at-
tack the positively polarized iodide or bromine atom of 1
(X = I, Br), resulting in the formation of intermediate C
and ROI or ROBr. In 2006, Gazizov and coworkers[11] re-
ported a similar debromoalkoxylation reaction with the for-
mation of unstable EtOBr. Intermediate C would transform
into phosphaisocoumarin 1 (X = H) by proton transfer,
which could undergo the subsequent alcoholysis reaction.
Among these, amidation of phosphaisocoumarins was not
detected when a primary amine was used as the catalyst,
probably because the formed P–O bond is stronger than the
P–N bond, which means that the alcoholysis product is
more stable than the aminolysis product.
Table 4. Hydration of 2-(1-alkynyl)phenylphosphonates 3 to syn-
thesize 2.[a]
Entry
R1
R2
Time [h]
Isolated yield [%]
1
2
3
4
5
6
OMe
OMe
H
H
Cl
Ph (3a)
cPr (3b)
nBu (3c)
Ph (3d)
cPr (3e)
Ph (3f)
3
2
2
3
2
2
87 (2a)
40 (2b)
35 (2c)
64 (2d)
47 (2e)
45 (2f)
Cl
[a] Reactions were carried out with
(0.02 mmol), concentrated H2SO4 (2 drops), MeOH (10.0 mL), and
3
(0.2 mmol), HgSO4
H2O (0.4 mL) at reflux for 2–3 h.
However, the above alcoholysis reaction is not a very
All 2-(2-oxoalkyl)phenylphosphonates 2, except 2f,[3b] are
convenient method to prepare 2-(2-oxoalkyl)phenylphos- new compounds, and their structures were confirmed by
phonates 2. Because the catalytic hydration of alkynes can spectroscopic methods (see Experimental Section). For ex-
provide direct access to carbonyl compounds,[12] we specu- ample, the structure of 2a was confirmed by the existence
1
lated that compounds 2 might be synthesized directly and of two benzyl protons (δ =4.65 ppm) in the H NMR spec-
conveniently by hydration of 2-(1-alkynyl)phenylphos- trum, the carbonyl carbon atom (δ =197.30 ppm) in the 13
C
phonates 3. Although hydration reactions of internal al- NMR spectrum, and the appearance of a band at 1690 cm–1
kynes often gives a mixture of regioisomeric ketones, the in the IR spectrum. It is interesting to note that there was
1
hydration of alkynes 3a–f with a catalytic amount of no benzyl proton in the H NMR spectrum for the racemic
Eur. J. Org. Chem. 2008, 5277–5282
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A.-Y. Peng, Y.-J. Guo, Z.-H. Ke, S. Zhu
FULL PAPER
cyclopropyl acetylene (0.45 mL, 5.31 mmol) at room temperature.
After stirring at 60 °C for 5 h under an atmosphere of nitrogen, the
reaction mixture was diluted with EtOAc and washed with aqueous
NH4Cl until neutral. The mixture was then washed with brine and
dried (Na2SO4), and the solvents were evaporated in vacuo. The
residue was chromatographed on silica gel [petroleum ether (b.p.
60–90 °C)/EtOAc, 5:1–2:1] to give corresponding product 3b
mixture of (Ϯ)-2g; their structures were confirmed by the
existence of a positive DEPT signal at δ = 57.20 ppm in the
13C NMR spectrum and the appearance of the molecular
cation at m/z = 366 [M]+.
In addition, we tested the obtained 2-(2-oxoalkyl)phenyl-
phosphonates 2 preliminarily as inhibitors of α-chymotryp-
sin. Some of them showed medium inhibitory activity
towards α-chymotrypsin. For example, the IC50 values of
2ab and 2f were 53.9 and 30.1 µ, respectively. Further bio-
chemical evaluation of these compounds is underway.
1
(361 mg, 67%) as a yellow oil. H NMR (300 MHz, CDCl3): δ =
7.37–7.51 (m, 2 H), 6.94–6.98 (m, 1 H), 4.06–4.25 (m, 4 H), 3.84
(s, 3 H), 1.43–1.52 (m, 1 H), 1.37 (t, J = 6.9 Hz, 6 H), 0.85–0.90
(m, 4 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 158.20 (d, JC,P
= 18.1 Hz), 134.91 (d, JC,P = 15.1 Hz), 131.05 (d, JC,P = 185.1 Hz),
118.86 (d, JC,P = 11.1 Hz), 118.65 (d, JC,P = 7.0 Hz), 118.28 (d,
JC,P = 3.0 Hz), 97.12, 73.73 (d, JC,P = 6.0 Hz), 62.17 (d, JC,P
5.0 Hz), 55.49, 16.27 (d, JC,P = 7.0 Hz), 8.38, 0.38 ppm. IR (KBr):
ν = 2980, 1723, 1481, 1397, 1238, 1152, 1027, 966 cm–1. MS (ESI):
=
Conclusions
In summary, the alcoholysis of phosphaisocoumarins
˜
into 2-(2-oxoalkyl)phenylphosphonates was examined for m/z (%) = 309 (14) [M + H]+, 372 (100), 331 (8). C16H21O4P
(308.31): calcd. C 62.33, H 6.87; found C 62.35, H 6.85.
the first time. For this alcoholysis reaction, a basic catalyst
was essential, and acid could not catalyze the reaction at
all. 4-Iodo- and 4-bromophosphaisocoumarins were found
to undergo a dehalogenation–alcoholysis tandem reaction
under the reaction conditions. In addition, alternative and
direct access to 2-(2-oxoalkyl)phenylphosphonates was de-
veloped by the mercury(II)-catalyzed hydration of 2-(1-
alkynly)phenylphosphonates with high regioselectivity. The
obtained novel keto phosphonates showed medium inhibi-
tory activity towards α-chymotrypsin in a preliminary study
and these compounds might also serve as important syn-
thetic intermediates.
3-Cyclopropyl-1-ethoxy-7-methoxy-2,1-benzoxaphosphorin 1-Oxide
(1b): Compound 3b (308.3 mg, 1.0 mmol) and aqueous sodium hy-
droxide (1 , 6.0 mL, 6.0 mmol) were combined in ethanol
(5.0 mL) and heated at reflux for 2 h. The reaction mixture was
evaporated in vacuo to remove the ethanol, then diluted with water
(20 mL), cooled in an ice bath, neutralized with concentrated hy-
drochloric acid, and extracted with EtOAc. The extracts were evap-
orated in vacuo to give the corresponding monoester (252 mg,
90%) as a yellow oil, which was used without further purification.
A mixture of the above monoester (160.1 mg, 0.50 mmol) and CuI
(9.5 mg, 0.05 mmol) was dissolved in DMF (5.0 mL). After stirring
at room temperature for 24 h, the reaction mixture was then diluted
with EtOAc and washed with saturated NH4Cl and brine, and then
dried (Na2SO4); the solvents were evaporated in vacuo. The residue
was chromatographed on silica gel [petroleum ether (b.p. 60–90 °C)/
EtOAc, 5:1–2:1] to give product 1b (104 mg, 65%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.33 (m, 1 H), 7.11–7.16
(m, 2 H), 5.94 (d, J = 0.9 Hz, 1 H), 4.09–4.20 (m, 2 H), 3.86 (s, 3
H), 1.34 (t, J = 6.9 Hz, 3 H), 1.01–1.07 (m, 1 H), 0.81–0.91 (m, 4
Experimental Section
General Remarks: NMR spectra were recorded with a Varian Mer-
cury-Plus 300 instrument in CDCl3 by using the residual solvent
signal at δ = 7.27 (1H) or 77.0 (13C) ppm as the internal standard.
31P NMR spectra used the 85% H3PO4 as the external reference.
Elemental analyses were determined with a Vario EL Elemental
Analyzer. EI mass spectra were recorded with a Thermo DSQ EI-
mass spectrometer. ESI mass spectra were recorded with a LCMS-
2010A Liquid Chromatograph mass spectrometer. HRMS were de-
termined by using a Thermo MAT95XP High-Resolution mass
spectrometer. IR spectra were recorded as potassium bromide pel-
lets with a Bruker Equinox 55 FTIR spectrometer. Anhydrous eth-
anol and methanol were purified by distillation from magnesium.
Et3N was purified by distillation from calcium hydride. All other
commercially available reagents were used as received. Column
chromatography was performed on 200–300 mesh silica gel. Thin-
layer chromatography was conducted on Kieselgel 60 F254
(Merck). Spots were observed under UV irradiation (254 nm). An-
hydrous Na2SO4 were used to dry organic solutions during workup,
and evaporation of the solvents was performed under vacuum with
a rotary evaporator.
H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 158.24 (d, JC,P
19.1 Hz), 152.73 (d, JC,P = 10.0 Hz), 131.27 (d, JC,P = 7.0 Hz),
127.36 (d, JC,P = 140.8 Hz), 120.83 (d, JC,P = 3.0 Hz), 120.37 (d,
=
JC,P = 180.1 Hz), 112.33 (d, JC,P = 10.0 Hz), 102.92 (d, JC,P
=
12.1 Hz), 62.66 (d, JC,P = 6.1 Hz), 55.6, 16.33 (d, JC,P = 7.1 Hz),
14.39 (d, JC,P = 6.1 Hz), 5.87, 5.12 ppm. MS (ESI): m/z (%) = 281
(5) [M + H]+, 344 (100), 385 (33). IR (KBr): ν = 2928, 1487, 1270,
˜
1176, 1027, 962 cm–1. C14H17O4P (280.26): calcd. C 60.00, H 6.11;
found C 60.25, H 6.14.
General Procedure for the Synthesis of 2 by the Alcoholysis of 1: To
a solution of 1 (0.2 mmol) in anhydrous alcohol (2.0 mL) was
added K2CO3 (41 mg, 0.3 mmol) or Et3N (0.42 mL, 3.0 mmol). Af-
ter stirring at 85 °C or 60 °C until material 1 was completely or
mostly disappeared by TLC monitoring, the reaction mixture was
concentrated. The residue was chromatographed on silica gel [pe-
troleum ether (b.p. 60–90 °C)/EtOAc, 6:1–3:1] to give correspond-
ing product 2.
Starting Material 1: All precursors 1 were prepared according to
our previous procedures.[3,7] Among them, 1b and 3b (Scheme 3)
are new compounds. Procedures for their preparation and their
characterization data are noted below.
Diethyl
[5-Methoxy-2-(2-oxo-2-phenylethyl)phenyl]phosphonate
(2aa): According to the general procedure, the reaction of 1a
(70 mg, 0.22 mmol) with K2CO3 (46 mg, 0.33 mmol) in anhydrous
EtOH (3.0 mL) at 85 °C afforded 2aa (64 mg, 80%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 3.6 Hz, 2 H), 7.45–
Diethyl (2-Cyclopropylethynyl-5-methoxyphenyl)phosphonate (3b):
To
a mixture of the corresponding perfluoroalkanesulfonate
(944.3 mg, 1.75 mmol), PdCl2(PPh3)2 (36.8 mg, 0.0525 mmol), CuI 7.60 (m, 4 H), 7.05–7.19 (m, 2 H), 4.65 (s, 2 H), 3.94–4.14 (m, 4
(33.8 mg, 0.175 mmol), anhydrous LiCl (223 mg, 5.25 mmol), Et3N
(1.0 mL, 7.10 mmol), and DMF (5.0 mL) was added dropwise the
H), 3.86 (s, 3 H), 1.25 (dt, J1 = 22.8 Hz, J2 = 7.2 Hz, 6 H) ppm.
13C NMR (75.4 MHz, CDCl3): δ = 197.30, 157.80 (d, JC,P
=
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Alcoholysis of Phosphaisocoumarins
18.5 Hz), 136.70, 133.47, 133.24, 132.82, 130.03 (d, JC,P = 9.1 Hz),
128.16 (d, JC,P = 180.7 Hz), 128.25 (d, JC,P = 24.3 Hz), 118.77 (d,
4.73 (s, 2 H), 3.95–4.10 (m, 4 H), 1.22 (t, J = 5.7 Hz, 6 H) ppm.
13C NMR (75.4 MHz, CDCl3): δ = 196.89, 138.43 (d, J = 5.2 Hz),
JC,P = 10.6 Hz), 118.25 (d, JC,P = 4.4 Hz), 62.10 (d, JC,P = 8.4 Hz), 136.70, 133.70 (d, J = 4.7 Hz), 132.85, 132.23 (d, JC,P = 1.6 Hz),
55.42, 43.13 (d, JC,P = 5.1 Hz), 16.17 (d, JC,P = 7.2 Hz) ppm. 31P
132.02, 128.42, 128.10, 127.28 (d, JC,P = 182.5 Hz), 126.49 (d, JC,P
NMR (121.4 MHz, CDCl ): δ = 19.36 ppm. IR (film): ν = 2924, = 7.2 Hz), 62.05 (d, JC,P = 2.8 Hz), 44.05 (d, JC,P = 1.5 Hz), 16.16
˜
3
1690, 1445, 1331, 1248, 1218, 1140, 1081, 1022, 964 cm–1. MS (EI):
(d, JC,P = 3.4 Hz) ppm. 31P NMR (121.4 MHz, CDCl3): δ =
m/z (%) = 362 (25) [M]+, 257 (28), 105 (100), 77 (28). HRMS (EI): 19.32 ppm. IR (film): ν = 2983, 1691, 1478, 1247, 1217, 1140, 1081,
˜
calcd. for C19H23O5P 362.1278; found 362.1279.
1020, 966 cm–1. MS (EI): m/z (%) = 332 (10) [M]+, 227 (5), 105
(100), 77 (15). HRMS (EI): calcd. for C18H21O4P 332.1172; found
332.1171.
Ethyl Methyl [5-Methoxy-2-(2-oxo-2-phenylethyl)phenyl]phos-
phonate (2ab): According to the general procedure, the reaction of
1a (63 mg, 0.20 mmol) with Et3N (0.42 mL, 3.0 mmol) in anhy-
drous MeOH (3.0 mL) at 60 °C afforded 2ab (38 mg, 55%) as a
Diethyl [5-Chloro-2-(2-cyclopropyl-2-oxoethyl)phenyl]phosphonate
(2e): According to the general procedure, the reaction of 1e (80 mg,
0.28 mmol) with Et3N (0.59 mL, 4.2 mmol) in anhydrous EtOH
(3.0 mL) at 60 °C afforded 2e (66 mg, 71%) as a yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.86–7.91 (m, 1 H), 7.45–7.49 (m, 1
H), 7.15–7.20 (m, 1 H), 4.27 (s, 2 H), 4.01–4.20 (m, 4 H), 2.01–2.09
(m, 1 H), 1.32 (dt, J = 9.0 Hz, J = 6.0 Hz, 6 H), 1.07–1.12 (m, 2
H), 0.90–0.97 (m, 2 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ =
207.17, 150.03 (d, JC,P = 4.8 Hz), 134.49, 133.81 (d, JC,P = 7.3 Hz),
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 8.06 (d, J = 3.7 Hz,
2 H), 7.47–7.62 (m, 4 H), 7.07–7.24 (m, 2 H), 4.64 (s, 2 H), 3.98–
4.14 (m, 2 H), 3.87 (s, 3 H), 3.63 (d, J = 11.1 Hz, 3 H), 1.28 (dt, J
= 14.4 Hz, J = 7.2 Hz, 3 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ
= 197.42, 157.91 (d, JC,P = 19.0 Hz), 136.77, 133.68, 133.41, 132.97,
130.25 (d, JC,P = 9.0 Hz), 128.35 (d, JC,P = 30.0 Hz), 127.44 (d,
JC,P = 173.3 Hz), 118.95 (d, JC,P = 9.4 Hz), 118.55 (d, JC,P
=
4.4 Hz), 62.38 (d, JC,P = 3.2 Hz), 55.50, 52.58 (d, JC,P = 4.7 Hz),
133.63, 132.54, 129.79 (d, JC,P = 183.1 Hz), 62.77 (d, JC,P
=
43.25 (d, JC,P = 4.3 Hz), 16.28 (d, JC,P = 6.9 Hz) ppm. 31P NMR
6.1 Hz), 48.19, 20.84, 16.64 (d, JC,P = 7.2 Hz), 11.49 ppm. 31P
(121.4 MHz, CDCl ): δ = 20.88 ppm. IR (film): ν = 2963, 1686,
˜
3
NMR (121.4 MHz, CDCl ): δ = 17.36 ppm. IR (film): ν = 2924,
˜
3
1408, 1261, 1021, 873 cm–1. MS (EI): m/z (%) = 348 (30) [M]+, 243
(24), 105 (100), 77 (19). HRMS (EI): calcd. for C18H21O5P
348.1121; found 348.1105.
1657, 1407, 1269, 1118, 1022, 874 cm–1. MS (EI): m/z (%) = 330
(30) [M]+, 262 (73), 206 (39), 69 (100). HRMS (EI): calcd. for
C15H20ClO4P 330.0782; found 330.0782.
Diethyl [2-(2-Cyclopropyl-2-oxoethyl)-5-methoxyphenyl]phosphonate
(2b): According to the general procedure, the reaction of 1b (84 mg,
0.30 mmol) with K2CO3 (62 mg, 0.45 mmol) in anhydrous EtOH
(3.0 mL) at 85 °C afforded 2b (73 mg, 74%) as a yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.41–7.48 (m, 1 H), 7.01–7.16 (m, 2
H), 4.18 (s, 2 H), 4.00–4.15 (m, 4 H), 3.83 (s, 3 H), 1.97–2.06 (m,
1 H), 1.31 (dt, J = 6.9 Hz, J = 0.6 Hz, 6 H), 1.03–1.08 (m, 2 H),
0.85–0.91 (m, 2 H) ppm. 13C NMR (75.4 MHz): δ = 207.83, 157.78
Diethyl
[5-Chloro-2-(2-oxo-2-phenylethyl)phenyl]phosphonate
(2f):[3b] According to the general procedure, the reaction of 1f
(40 mg, 0.125 mmol) with K2CO3 (26 mg, 0.188 mmol) in anhy-
drous EtOH (2.0 mL) at 85 °C afforded 2f (30 mg, 65%) as a yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.90–8.10 (m, 3 H),7.46–7.62
(m, 4 H), 7.20–7.26 (m, 1 H), 4.70 (s, 2 H), 3.95–4.13 (m, 4 H),
1.25 (t, J = 7.2 Hz, 6 H) ppm. MS (EI): m/z (%) = 366 (6) [M]+,
228 (2), 105 (100), 77 (17). HRMS (EI): calcd. for C18H20ClO4P
366.0782; found 366.0785.
(d, JC,P = 16.4 Hz), 133.17 (d, JC,P = 18.7 Hz), 129.90 (d, JC,P
9.2 Hz), 128.15 (d, JC,P = 181.0 Hz), 118.68, 118.46 (d, JC,P
=
=
19.5 Hz), 62.16 (d, JC,P = 3.8 Hz), 55.42, 50.63, 47.66, 20.25, 16.31
Diethyl [2-(1-Chloro-2-oxo-2-phenylethyl)phenyl]phosphonate (؎)-
2g: According to the general procedure, the reaction of 1g (60 mg,
0.187 mmol) with Et3N (0.40 mL, 288 mg, 2.846 mmol) in anhy-
drous EtOH (2.0 mL) at 60 °C afforded (Ϯ)-2g (56 mg, 82%) as a
(d, JC,P = 6.4 Hz), 11.04 ppm. 31P NMR (121.4 MHz, CDCl3): δ =
19.43 ppm. IR (film): ν = 2925, 1700, 1492, 1384, 1284, 1251, 1146,
˜
1070, 1021, 963 cm–1. MS (EI): m/z (%) = 326 (48) [M]+, 258 (100),
257 (35), 69 (35). HRMS (EI): calcd. for C16H23O5P 326.1278;
found 326.1280.
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 7.41–8.14 (m, 9 H),
4.05–4.30 (m, 4 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.19 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 191.43, 139.00 (d,
Diethyl [2-(2-Oxohexyl)phenyl]phosphonate (2c): According to the
general procedure, the reaction of 1c (80 mg, 0.30 mmol) with
K2CO3 (62 mg, 0.45 mmol) in anhydrous EtOH (3.0 mL) at 85 °C
afforded 2c (74 mg, 79%) as a yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 7.32–7.93 (m, 3 H), 7.19–7.23 (m, 1 H), 4.11 (s, 2 H),
3.98–4.15 (m, 4 H), 2.55 (t, J = 7.2 Hz, 2 H), 1.55–1.65 (m, 2 H),
1.27–1.38 (m, 8 H), 0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 207.65, 138.37 (d, JC,P = 10.6 Hz), 133.78
JC,P = 9.3 Hz), 134.26, 133.59, 133.53, 132.90, 130.85 (d, JC,P
=
13.1 Hz), 129.17, 128.70 (d, JC,P = 168.2 Hz), 128.59, 128.51,
128.10 (d, JC,P = 29.2 Hz), 125.18, 62.66 (m, 2 P-OCH2), 57.20 (+,
in DEPT135 spectrum), 16.31 (d, JC,P = 7.4 Hz, P-OCH2CH3),
16.12 (d, JC,P = 7.4 Hz, P-OCH2CH3) ppm. 31P NMR (121.4 MHz,
CDCl ): δ = 18.34 ppm. IR (film): ν = 2927, 1699, 1408, 1261,
˜
3
1117, 1020, 873 cm–1. MS (EI): m/z (%) = 366 (7) [M]+, 105 (100),
77 (20). HRMS (EI): calcd. for C18H20O4ClP 366.0782; found
366.0783.
(d, JC,P = 9.2 Hz), 132.32 (d, JC,P = 5.3 Hz), 132.08 (d, JC,P
14.9 Hz), 126.58 (d, JC,P = 15.0 Hz), 125.93, 62.14 (d, JC,P
=
=
8.1 Hz), 48.20, 42.39, 25.84, 22.40, 16.33 (d, JC,P = 7.8 Hz),
General Procedure for the Synthesis of 2 by the Hydration of 3: A
solution of compound 3 (0.2 mmol) in MeOH (3 mL) was added
to a mixture of HgSO4 (6 mg, 0.02 mmol), MeOH (7 mL), H2O
(0.4 mL), and concentrated H2SO4 (2 drops), and the mixture was
heated at reflux for 2–3 h. H2O (10 mL) was added, MeOH was
removed under reduced pressure, and the remaining mixture was
extracted with EtOAc (3ϫ20 mL). The combined extracts were
washed with saturated aqueous NaHCO3 (2ϫ15 mL) and dried
with Na2SO4, and the solvents were evaporated in vacuo. The resi-
due was chromatographed on silica gel [petroleum ether (b.p. 60–
13.97 ppm. 31P NMR (121.4 MHz, CDCl3): δ = 19.82 ppm. IR
(film): ν = 2958, 1719, 1440, 1399, 1250, 1138, 1094, 1023, 963
˜
cm–1. MS (EI): m/z (%) = 312 (1) [M]+, 255 (3), 228 (100), 227 (20),
85 (2), 57 (5). HRMS (EI): calcd. for C16H25O4P 312.1485; found
312.1486.
Diethyl [2-(2-Oxo-2-phenylethyl)phenyl]phosphonate (2d): Accord-
ing to the general procedure, the reaction of 1d (57 mg, 0.20 mmol)
with K2CO3 (41 mg, 0.30 mmol) in anhydrous EtOH (3.0 mL) at
85 °C afforded 2d (50 mg, 75%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 7.91–8.06 (m, 3 H), 7.37–7.56 (m, 6 H), 90 °C)/EtOAc, 5:1–2:1] to give product 2. Their structures were
Eur. J. Org. Chem. 2008, 5277–5282
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5281

A.-Y. Peng, Y.-J. Guo, Z.-H. Ke, S. Zhu
FULL PAPER
confirmed by comparison of their H NMR spectra with those of
the corresponding alcoholysis products.
1
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Grant No. 20602043) and the Guangdong Natural Science
Foundation (Grant No. 5300530) for financial support.
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Received: June 23, 2008
Published Online: September 25, 2008
5282
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5277–5282