A new and efficient method for conjugate addition of trialkylphosphites to 3-acylsubstituted coumarins

Article abstract of DOI:10.1016/j.tet.2004.08.069

A new and efficient conjugate addition of trialkylphosphites to 3-ω-bromoacetylcoumarin 1 catalysed by p-toluenesulfonic acid (TsOH) has been studied. Under the same conditions, an enolphosphate gave the corresponding esters of 3-acetyl-4-phosphono-2-oxochromans in high yields. The use of TsOH in the reaction of 3-acetyl-, 3-benzoyl-, and 3-ethoxycarbonyl coumarins led mainly to 1,4-addition products - the corresponding 3-acyl-4-dialkylphosphono-2- oxochromans - in very good yields. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.069

Tetrahedron 60 (2004) 10335–10342
A new and efficient method for conjugate addition of
trialkylphosphites to 3-acylsubstituted coumarins
Rositca D. Nikolova,a Anka G. Bojilovaa and Nestor A. Rodiosb,
*
aDepartment of Organic Chemistry, University of Sofia, J. Bourchier Avenue 1, Sofia 1126, Bulgaria
bLaboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, GR-54006 Thessaloniki, Greece
Received 1 April 2004; revised 28 July 2004; accepted 19 August 2004
Available online 17 September 2004
Abstract—A new and efficient conjugate addition of trialkylphosphites to 3-u-bromoacetylcoumarin 1 catalysed by p-toluenesulfonic acid
(TsOH) has been studied. Under the same conditions, an enolphosphate gave the corresponding esters of 3-acetyl-4-phosphono-2-
oxochromans in high yields. The use of TsOH in the reaction of 3-acetyl-, 3-benzoyl-, and 3-ethoxycarbonyl coumarins led mainly to
1,4-addition products—the corresponding 3-acyl-4-dialkylphosphono-2-oxochromans—in very good yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
involves the SN2 displacement of the bromine by the
phosphite. It should be emphasized that this transform-
ation (1/3) goes only with the less reactive2,9,16
triphenylphosphite whereas with trialkylphosphites no
such products were isolated. This different behavior of
triphenyl- and trialkylphosphites in the reaction with the
bromoketone 1 could be explained via the formation of
the more stable triphenyl phosphonium salt7 and its
thermal decomposition to the phosphonate 3.
In a previous paper1 we described the reaction of 3-(u-
bromoacetyl)coumarin 1 with trialkylphosphites, from
which, depending on the reaction conditions and the
phosphite used, the corresponding enolphosphates 2, for
RZCH3 or C2H5, or the 2-oxophosphonate 3, for RZPh
were the only isolated products. On the other hand, the
interaction of the bromoderivative 1 with diethyl and
dibutylphosphite under phase transfer conditions gave the
corresponding epoxyphosphonates 4 as the main products.
2. It also seems clear that the formation of epoxyphos-
phonates 4 proceeds under the Michaelis-Becker reac-
tion conditions.10–12 The first step is the nucleophilic
addition of the deprotonated dialkylphosphite anion to
the C]O group of 1, followed by elimination of the
bromine and cyclization to the epoxyphosphonates 4.
In fact, the transformation of 1 into epoxy derivative 4
proceed as another variation of the classic Darzen’s
reaction17 and it looks normal that it proceeds with a
stronger nucleophile as is the dialkylphosphite anion
(Scheme 1).
3. The transformation of the bromoacetyl coumarin 1 into
the enolphosphates 2, realized under various conditions,
typical for the Arbuzov/Perkow reaction, took place only
with trialkyl phosphites. Surprisingly, when the reaction
was performed in acetic acid, it was completed within
5 min giving the enolphosphate 2 in 84% yield.
The preparation of dialkyl 2-oxophosphonates 3 (CH3 or
C2H5) were realized1 only when the carbonyl group in the
starting ketone 1 was protected by the ethoxycarbonyl-
hydrazono group, followed by Arbuzov reaction.
The experimental findings, concerning the mechanisms of
the above transformations, taking into account theoretical
considerations and the experimental data available for
Perkow, Arbuzov and Michaelis-Becker reactions,2–16
could be explained as follows:
1. The transformation of bromoderivative 1 to 2-oxophos-
phonates 3 proceeds as an Arbuzov reaction. According
to the proposed mechanism for this reaction4–9 the most
simple and more likely pathway for this transformation
It has been reported3,15,16 that the reaction of a-haloketones
with trialkylphosphites in the presence of acetic acid favors
the formation of enolphosphates and a similar action has
been observed14 when this reaction was performed in the
presence of phosphoric acid. The dramatic acceleration
observed1 in our case in the reaction of 1 with
Keywords: 2-Oxo-2H-1-benzopyranes; 3-Acylsubstituted coumarins;
Trialkylphosphites; 1,4-Addition/conjugated addition; Phosphonates;
p-Toluenesulfonic acid.
* Corresponding author. Tel.: C30-2310-99-78-03; fax: C30-2310-99-76-
79; e-mail: rodios@chem.auth.gr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.069

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R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
Scheme 1.
trialkylphosphites, prompted us to investigate what would
be the result of this reaction in the case of carrying it out in
the presence of a stronger acid such as p-toluenesulfonic
acid (TsOH).
2. Results and discussion
The results of the reaction of 1 with trimethyl and
triethylphosphites and in the presence of TsOH, performed
Table 1. Interaction of 3-bromoacetylcoumarin 1 with trialkylphosphites P(OR)3 in the presence of TsOHa
Method
Reaction condition
Time [min]
Yields, %
2b
5b
Ratio 1:P(OR)3:TsOH
a
b
a
b
A
A1
B
C
C1
1:2:1/D/toluene
1:5:1/D/toluene
1:5:0.1/CH2Cl2/)))c
1:5:1/CH2Cl2/)))
1:5:2/CH2Cl2/)))
150
90
20
20
54
30
33
86
17
10
55
8
76
82
94
5
3
Trace
90
93
20
a
TsOHZp-toluenesulfonic acid.
a: RZCH3, b: RZC2H5.
))): Reaction carried out under ultrasound irradiation.
b
c
Scheme 2.

R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
10337
in refluxing toluene (Methods A, A1) or in methylene
chloride under ultrasound irradiation (Methods B, C and C1)
and in different bromoketone 1:trialkylphosphite:toluene-
sulfonic acid ratios are presented in Table 1.
1:TsOH ratio to 1:2 did not substantially change the yields
of the reaction products (Table 1, Method C1).
The formation of the 1,4-adducts 5 from the reaction of
bromoacetylcoumarin 1 and trialkylphosphites in the
presence of TsOH could be explained by initial protonation
of the C]O group. The protonated ketone A acting as an
activated conjugate system reacts easily with trialkylpho-
sphites to form the intermediate 1,4-adduct B. The
transformation of the latter to the products 5 goes most
probably with the participation of the TsOH anion
(Scheme 3). The formation of the corresponding esters of
p-toluenesulfonic acid was proved by their isolation from
the reaction mixtures in yields of 70–75% and by comparing
their Rf-values and IR spectra with authentic samples.
The course of the reaction of 1 with P(OR)3 in the presence
of TsOH was completely different to that with acetic acid,1
giving, in addition to the expected enolphosphates 2a,b,
new 1,4-addition products 5a,b (Table 1, Scheme 2). Thus
in refluxing toluene (Methods A, A1), the reaction of 1 with
P(OR)3 gave the enolphosphates 2a and 2b in 33, 54% and
the 1,4-adducts 5a and 5b in 30, 55% yields, respectively.
The results, concerning yields and the 2:5 ratios were
significantly different when the reaction took place in
methylene chloride and under the action of ultrasound
irradiation (Methods B, C, C1). The reaction was completed
within 20 min and the yields of the isolated products 2 and 5
depended on the amount of TsOH used to perform the
reaction. When TsOH was used in catalytic amounts (Table
1, Method B) the enolphosphates 2a, 2b were the main
products, with yields of 86 and 94%, respectively. By
increasing the bromocoumarin 1:TsOH ratio to 1:1 (Table 1,
Method C) the 1,4-addition products 5a, 5b were the main
ones, with yields of 76 and 90%, respectively, whereas the
corresponding enolphosphates 2a, 2b were isolated in yields
of 17 and 5%, respectively. A further increase of the
In the reaction mixture containing P(OR)3 and TsOH,
however, the possibility of trialkylphosphite to have been
transformed into the corresponding dialkylphosphite19
should be taken into account. In order therefore to prove
the real reagent in the reaction of 1,4-addition of the
phosphites to compound 1, trialkylphosphite or dialkylphos-
phite, the reaction of 1 with dialkylphosphite under
ultrasound irradiation in methylene chloride, without and
in the presence of TsOH, was carried out. In both cases the
starting coumarin 1 was isolated in quantitative yield.
When the reaction of 1 with dialkylphosphites was,
however, carried out in refluxing toluene, a complicated
reaction mixture (TLC) was obtained from which 3-acetyl-
coumarin 7 (at 2–5%), the corresponding enolphosphates 2
(at w20%) and the products of 1,4-addition of dialkylphos-
phites to 3-acetylcoumarin (8a,b) were isolated (Table 2,
Scheme 4).
The behavior of the enolphosphate 2a in the reaction with
trialkylphosphites in refluxing toluene and in the presence of
TsOH was also studied. From this reaction (Methods A2 and
A3, Table 3, Schemes 2 and 5) the 1,4-adducts 8a and 8b
were isolated. When this reaction was performed in two
stages, i.e. first the solution of 2a and TsOH in toluene is
refluxed for 5 min and after that addition of P(OR)3 (Method
A3, Table 3), the transformation of 2a to 8a was almost
quantitative (the enolic forms of the 3-acetyl-4-dialkylphos-
phono-2-oxochromans 8a and 8b were isolated in 87 and
93%, respectively, with no unreacted starting compound).
These findings indicate that in the above reaction, the
enolphosphate 2 is first hydrolyzed to 3-acetylcoumarin 7 by
the strong acid TsOH2 (and this was proved in a separate
experiment, where hydrolysis of 2a to 7 was completed
within 15 min with 90% yield) and in a second step the 1,4
addition of trialkylphosphite is taking place (Scheme 5).
Scheme 3.
Table 2. Interactiona of 3-bromoacetylcoumarin 1 with dialkylphosphites
(RO)2PH
R
2
7
8
a
b
CH3
C2H5
20
6
2
5
7
17
a
In refluxing toluene, 4 h.
Scheme 4.

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R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
Table 3. Interaction of enolphosphates 2a with trialkylphosphites
Method
Reaction conditions
Time, h
Unreacted 2
Yields, %
Ratio 2a:P(OR)3:TsOH
8a
8b
A2
A3
1:5:2.5/D/toluene
1:2:2/D/toluene, 2-stage
4
0.5
15/26a
43
87
39
93
a
When the reaction was carried out in one stage.
Scheme 5.
The possibility of the enolphosphate 2a being transformed
into 3-u-bromoacetylcoumarin 1 was also studied. This was
achieved in a one pot two-stage reaction by the action of
TsOH for the hydrolysis of 2a and then of NBS for the
bromination of the hydrolysis product of 3-acetylcoumarin
7. Compound 1 was obtained in almost quantitative yield.
By repeating the same reaction and, in a third stage, by
adding trimethylphosphite to the reaction mixture, com-
pounds 2a (33%) and 5a (46%) were isolated (Scheme 6).
Almost the same proportion (2a/5a) were obtained from
reaction of 1 with P(OCH3)3, (Table 1, Method A1).
substantially shortens the reaction time, we investigated
the same reactions of trialkylphosphites with 3-acetylcou-
marin 7 as well as with 3-benzoyl and 3-ethoxycarbonyl
coumarins 10 and 11 respectively, in the presence of TsOH
and under ultrasound irradiation. The results (Table 4) show
that the corresponding 4-dialkylphosphono-2-oxocromans
8/9, 12/13 and 14 (Scheme 7) were obtained in yields from
60 to 95% (Table 4, Method C).
The structures of the isolated compounds were assigned
mainly on the basis of their 1H and 13C NMR spectral data.
Thus, compounds 5/6a,b and 8/9a,b appeared exclusively in
the enol-tautomeric forms 5 and 8 respectively, and this is in
agreement with the reported21,23 structure of compound
8/9a,b. Compounds 12/13b and 14a,b on the other hand
appeared exclusively in the keto-tautomeric form 13 and 14
respectively, whereas compound 12/13a appeared as a
mixture of both tautomers 12a$13a, with a 12:13 ratio of
Over the last few years the reaction of 3-acetylcoumarin
7 with dialkyl- and trialkylphosphites, from which the
1,4-addition products 8 were obtained in 40–80% yields on
refluxing for 8–10 h, has been reported.20–23 Since we have
found that the use of TsOH favors the 1,4-addition of
trialkylphosphites to 3-bromoacetylcoumarin 1 and
Scheme 6.
Table 4. Reaction of trialkylphosphites with 3-acylsubstituted coumarins
Starting Compd.
Method
Reaction conditions
(Ratio coumarin:
P(OR)3:TsOH)
Time[min]
Reaction product
Yield %
a
b
7
7
7
A1
C
D
1:5:1/D/toluene
15
30
30
8/9
8/9
8/9
90
95
86
91
95
94
1:5:1/CH2Cl2/)))
1:5/CH2Cl2CROH/
))), without TsOH
1:5/CH3COOH/))),
without TsOH
7
E
15
8/9
87
93
10
11
C
C
1:5:1/CH2Cl2/)))
1:5:1/CH2Cl2/)))
30
30
12/13
14
94
58
69
88

R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
10339
Scheme 7.
9:1 (1H NMR), which, on standing the sample in the NMR-
tube (CDCl3) for one week, changed to w1:1.
been also reported.22 However, the NMR spectral data
provided to support this suggestion are not as complete as
they should be to support the proposed appearance of the
two tautomers.
The 1H NMR spectra of the enol-forms 5a,b, 8a,b and 12a
showed an OH peak at dw13 ppm, exchangeable with D2O.
The 4-H proton appeared as a doublet at dZ4.19–4.45 ppm
2
with a JHCPz22 Hz, and the enolic methyl group of
3. Conclusions
compounds 8a,b, ]C–CH3, showed a doublet with a
5JHPz3 Hz (homoallylic), whereas the corresponding two
methylenic protons of compounds 5a,b, ]C–CH2Br
From the experimental data given above together with
the results reported earlier,1 it is concluded that the
3-bromoacetyl coumarin shows a special behavior in the
reaction with phosphites:
appeared at w4 and 4.5 ppm as dd (2JHCHZ11.2 Hz,
5
5JHPz1 Hz) and ddd (2JHCHZ11.2 Hz, JHPz5JHH
z
1.5 Hz) respectively. Of interest is the observed coupling
between the hydroxyl proton and one of the two methylenic
4
1. It reacts with triphenylphosphite giving the 2-oxophos-
phonate 3 (RZPh).
2. With trialkylphosphites compound 1 may react in two
protons of the CHAHBr group, JH,OHZ1.5–1.7 Hz. This
indicates a fixed W disposition of these two protons, as a
result of a restricted rotation of the CH2Br group due to the
bulky bromine atom, and of the OH group due to hydrogen
bonding of the OH proton to the 2-oxochroman carbonyl
oxygen. This hydrogen bonding has been also observed23 in
the crystal structure of compounds 7/8. In their 13C NMR
spectra the enolic forms gave a peak for C-4 at w37.5 ppm
coupled with the phosphorus atom with 1JCPZ141–144 Hz
directions:
i. To the formation of the enolphosphates 2 (maybe by
the initial 1,2 addition of the trialkylphosphites to the
conjugated system of the 3-bromoacethylcoumarin)
and
ii. To the formation mainly (about 90%) of the
corresponding 3-(u-bromoacetyl)-4-dialkyphos-
phono-2-oxochromans 5/6 by the 1,4-addition of the
trialkylphosphites to the bromoacetylcoumarin 1.
This direction was realized only when the reaction
was carried out in the presence of TsOH.
2
and a peak for C-3 at w90 ppm, with a JCPZ8.9 Hz. The
enolic carbon ]C–OH appeared as doublet, (3JCPz6–
7 Hz) at dZ176–179 ppm and the carbonyl carbon (C-2)
gave a peak at dz169 ppm. The absence of the keto-form
peaks for the 3-H protons in the 1H NMR spectra and for the
saturated C-3 in the 13C NMR spectra is characteristic of
these tautomeric compounds.
The use of TsOH in the reaction of 3-acyl-coumarines with
trialkylphosphites leads mainly to 1,4-addition products,
giving, in good yields and shorter reaction times, the
corresponding 3-acyl-4-dialkylphosphono-2-oxochromans.
The keto-forms on the other hand, 13a,b and 14a,b, showed a
doublet for the 4-H proton at dZ3.8–3.9 ppm, coupled with
the phosphorus atom with 2JHCPZ23–24 Hz and a peak for
3-H proton at dZ4.5–5.2 ppm coupled with the phosphorus
4. Experimental
3
atom with JHPZ10.4–14.5 Hz and with 4-H with a very
3
3
small JZ0.8–1 Hz. The very small J value between 4-H
and 3-H suggests a dihedral angle of H–C4–C3–H of about
908, which, as also revealed by inspection of stereomodels,
Melting points were determined on a Kofler hot-stage
apparatus and are uncorrected. IR spectra were recorded
with a Specord IR 71 or IR 75 spectrophotometers. 1H NMR
and 13C NMR spectra, reported in d units, were obtained
with a Bruker WM 250 (at 250 and 62.9 MHz, respectively)
or a Bruker AM 300 (at 300 and 75.4 MHz, respectively)
instruments. All NMR spectra were obtained by using TMS
as internal standard in CDCl3. E.I. mass spectra were
obtained at 70 eV a VG TS-250 spectrometer. Elemental
analyses of C, H, P and N were carried out in the Laboratory
of Elemental Analysis at the Department of Organic
Chemistry, University of Sofia.
indicates a trans disposition of the two protons. In their 13
C
NMR spectra the most characteristic peaks are those of C-3 at
dZ47–49 ppm and of C-4 at dw39 ppm, coupled with the
phosphorus atom with 2JCP of 2.3–3.5 Hz and 1JCPz144 Hz,
respectively. The carbonyl carbon of the 3-benzoyl group in
13a,b appeared at dZ192 ppm and that of the ethoxy-
carbonyl group in 14a,b at dz166 ppm. In both cases these
carbons were strongly coupled with phosphorous atom with a
3JCP value of w17–22 Hz.
It is noted that a mixture of the two tautomers from the
reaction of 7 with dialkylphosphites 8/9a,b, i.e. 8$9, has
Column chromatography was carried out on silica gel
(Merck or Fluka 0.063–0.2 mm) using as eluent

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R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
n-hexane/EtOAc mixtures with increasing polarity. Sonica-
tions were effected with Bransonic 321 (390 W, 50 kHz).
3JCPZ6.8 Hz; ]COH), 168.8 (d, 3JCPZ1.7 Hz; C-2), 150.9
3 3
(d, JCPZ5.6 Hz; C-8a), 129.6 (d, JCPZ2.9 Hz; C-5),
129.6 (d, 5JCPZ1.8 Hz; C-7), 125.1 (d, 4JCPZ3.4 Hz; C-6),
4
2
117.2 (d, JCPZ3.6 Hz; C-8), 116.5 (d, JCPZ8.5 Hz;
4.1. Preparation of the starting materials
2
2
C-4a), 91.0 (d, JCPZ9.9 Hz; C-3), 54.1 (d, JCOP
Z
2
7.7 Hz; POCH3) 54.0 (d, JCOPZ7.3 Hz; POCH3), 37.3 (d,
The starting 3-substituted 2-oxo-2H-1-benzopyrans were
prepared according to the literature procedures1,18,24–26 and
their spectroscopic characteristics (IR, H NMR and MS)
1JCPZ142.7 Hz; C-4), 25.5 (CH2Br).
1
were in agreement with their structures. Trialkyl phosphites
and dialkyl phosphites are commercially available (Fluka).
4.2.2. Diethyl 3-(2-bromo-1-hydroxyaethylidene)-2-oxo-
chroman-4-ylphosphonate (5b). From 1 and triethyl
phosphite. Method B: 0.38 g, 94%, white crystals, mpZ
147–149 8C (ethyl acetate); [Found: C, 44.61; H, 4.40.
C15H18O6PBr requires C, 44.47; H, 4.48%]; IR (nujol): nZ
1730, 1635, 1500, 1190, 1090, 1050, 1020 cmK1. 1H NMR
(300 MHz): dZ13.17 (s; OH, 1H), 7.32–7.40 (m; 5-, 7-H,
2H), 7.21 (m as t, JZ7.5 Hz; 6-H, 1H), 7.12 (d, JZ8.0 Hz;
8-H, 1H), 4.55 (ddd as dt, 2JHHZ11.1 Hz, 4JH,OHZ1.7 Hz,
5JHPZ1.2 Hz; CHAHBr, 1H), 4.28 (d, 2JHPZ21.8 Hz; 4-H,
1H), 3.93–4.12 (m; CHHBBr, POCH2, 5H), 1.26 (t, JZ
7.0 Hz; CH3), 1.24 (t, JZ7.0 Hz; CH3). 13C NMR
4.2. Interaction of 3-bromoacetylcoumarin 1 with
trialkylphosphites. General procedure
Depending of the reaction conditions (ratio of the reagents,
temperature, etc.) the following methods are distinguished:
Method A. A solution of 3-bromoacetylcoumarin 1 (0.27 g,
1 mmol), the corresponding phosphite (2 mmol) and
p-toluenesulfonic acid (0.19 g, 1 mmol) was refluxed in
dry toluene (3 mL) until the starting coumarin was
consumed (TLC-monitoring). The solvent was removed
under reduced pressure. To the residue methylene chloride
(20 mL) was added, washed with water (40 mL), with 10%
solution of potassium carbonate (20 mL), again with water
(30 mL) and dried (Na2SO4). The precipitate obtained after
the removal of the solvent was filtered and washed with
ethyl acetate (10 mL).
3
(75.4 MHz): dZ173.6 (d, JCPZ7.1 Hz; ]COH), 168.9
3
3
(d, JCPw1.0 Hz; C-2), 150.2 (d, JCPZ5.4 Hz; C-8a),
129.7 (d, 3JCPZ4.4 Hz; C-5), 129.5 (d, 5JCPZ3.7 Hz; C-7),
125.0 (d, 4JCPZ3.5 Hz; C-6), 117.1 (d, 4JCPZ3.6 Hz; C-8),
116.8 (d, 2JCPZ8.7 Hz; C-4a), 91.2 (d, 2JCPZ9.9 Hz; C-3),
3
3
63.6 (d, JCPZ7.0 Hz; POCH2), 63.5 (d, JCPZ7.4 Hz;
POCH2), 37.7 (d, 1JCPZ142.6 Hz; C-4), 25.6 (CH2Br), 16.4
3
3
(d, JCPZ4.8 Hz; CH3), 16.3 (d, JCPZ4.8 Hz; CH3). MS
m/z (%): 406/404 (MC) (4), 325 (61), 283 (60), 268/266
(72), 188 (73), 173 (84), 146 (33), 118 (69), 77 (38), 29
(100).
Method A1. The same as in Method A but the amount of the
corresponding phosphite was 5 mmol.
Method B. A solution of 3-bromoacetylcoumarin 1 (0.27 g,
1 mmol), the corresponding phosphite (5 mmol) and
p-toluenesulfonic acid (catalytic amount) in methylene
chloride (3 mL) was irradiated with ultrasound at room
temperature until the starting coumarin was consumed
(TLC-monitoring). The reaction mixture was poured out
into ice water (40 mL) and extracted with methylene
chloride (3!30 mL). The organic layer was washed with
water (30 mL) and dried (Na2SO4). After evaporation of
the solvent the obtained crystals were isolated from ethyl
acetate (5 mL). The filtrate was chromatographed on a silica
gel column with n-hexane–ethyl acetate (with increasing
polarity) as eluent.
4.3. Interaction of enolphosphate 2a and 3-acetyl-
coumarin 7 with trialkyl phosphites. General procedure
Depending of the reaction conditions the following methods
are distinguished:
Method A2. The ratio of the reagents 2a:phosphites:TsOH
1:2:2.5 in refluxing toluene (3 mL). The reaction carried out
and worked up as mentioned above for Method A.
Method A3. To the refluxing solution of the starting
coumarin (0.27 g, 1 mmol) in dry toluene (3 mL) was
added 4-toluenesulphonic acid (0.38 g, 2 mmol). After
5 min to the reaction mixture the corresponding trialkyl
phosphite (2 mmol) was added and refluxed until the
starting coumarin was consumed (TLC-monitoring) for
about 15 min. The solvent was removed under reduced
pressure and the residue was chromatographed on a silica
gel column with n-hexane–ethyl acetate (with increasing
polarity) as an eluent.
Methods C and C1. The same as in Method B, but the
amount of the p-toluenesulfonic acid was 1 and 2 mmol,
respectively.
4.2.1. Dimethyl 3-(2-bromo-1-hydroxyaethylidene)-2-
oxochroman-4-ylphosphonate (5a). From 1 and trimethyl
phosphite. Method B: 0.32 g, 86%, white crystals, mpZ
151–153 8C (ethyl acetate); [Found: C, 41.21; H, 3.43.
C13H14O6PBr requires C, 41.40; H, 3.74%]; IR (nujol): nZ
Method D. A solution of the starting coumarin (0.27 g,
1 mmol) and the corresponding phosphite (5 mmol) in
alcohol (methanol, resp. ethanol (2 mL)) and methylene
chloride (1 mL) was irradiated with ultrasound at room
temperature until the starting coumarin was consumed
(TLC-monitoring). The solvent was distilled under reduced
pressure. To the residue was added a small quantity of
corresponding alcohol (1 mL) and water (drop wise) for
crystallization at low temperature. The obtained crystals
were filtrated.
1720, 1630, 1590, 1190, 1080, 1055 cmK1 1H NMR
.
(300 MHz): dZ13.15 (s; OH, 1H), 7.31–7.38 (m; 5-, 7-H,
2H), 7.21 (m as t, JZ7.5 Hz; 6-H, 1H), 7.11 (d, JZ8.3 Hz;
8-H, 1H), 4.50 (ddd as dt, 2JHHZ11.2 Hz, 4JH,OHw1.5 Hz,
5JHPw1.3 Hz; CHAHBr, 1H), 4.30 (d, JZ21.9 Hz; 4-H,
2
5
1H), 3.99 (dd, JHHZ11.2 Hz, JHPZ1.0 Hz; CHHBBr,
3
3
1H), 3.68 (d, JHPZ10.4 Hz; POCH3, 3H), 3.66 (d, JHP
Z
10.2 Hz; POCH3, 3H). 13C NMR (75.4 MHz): dZ173.8 (d,

R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
10341
Method E. A solution of the coumarin (0.27 g, 1 mmol) and
the corresponding phosphite (5 mmol) in glacial acetic acid
(2 mL) was irradiated with ultrasound at low temperature
(ice-water-bath) until the starting coumarin was consumed
(TLC-monitoring). The reaction mixture was decomposed
on ice-water (50 mL). The obtained crystals were filtrated
and washed with water to neutral pH.
1170, 1055, 1030 cmK1. 1H NMR (300 MHz): dZ7.98 (m;
20, 60-H, 2H), 7.64 (dddd as tt, J0Z7.4, 1.3 Hz; 40-H, 1H),
7.50 (dddd as tt, JZ7.4, 1.5 Hz; 3 , 50-H, 2H), 7.32 (dddd as
tt, JZ7.7, 2.0 Hz; 7-H, 1H), 7.21 (ddd as dt, JZ8.0, 2.0 Hz;
5-H, 1H), 7.08–7.14 (m, 6-, 8-H, 2H), 5.20 (dd, JZ14.0,
0.9 Hz; 3-H, 1H), 4.11–4.23 (m; POCH2), 3.88 (dq, JZ8.2,
7.1 Hz; POCH2), 3.73 (bd, 2JHCPZ23.3 Hz; 4-H, 1H), 1.36
(t, JZ7.1 Hz; CH3, 3H), 1.24 (t, JZ7.0 Hz; CH3, 3H). 13
C
NMR (75.4 MHz): dZ192.0 (d, 3JCPZ17.1 Hz; CO), 163.3
4.3.1. Dimethyl 3-(1-hydroxyaethylidene)-2-oxochro-
man-4-ylphosphonate (8a). From 2a or 7 and trimethyl
phosphite. Method C: 0.28 g, 95%, white crystals, mpZ
127–129 8C (ethyl acetate), (lit.21,22 129–130 8C).
3
3
(d, JCPZ2.2 Hz; C-2), 151.3 (d, JCPZ5.7 Hz; C-8a),
3
134.4 (C-40), 133.2 (C-10), 130.0 (d, JCPZ4.4 Hz; C-5),
129.7 (d, 5JCPZ4.2 Hz; C-7), 129.2 (C-20,-60), 129.1 (C-30,
4
4
-50), 124.8 (d, JC2PZ3.2 Hz; C-6), 117.2 (d, JCPZ3.2 Hz;
2
C-8), 114.7 (d, JCPZ7.7 Hz; C-4a), 63.8 (d, JCOP
Z
4.3.2. Diethyl 3-(1-hydroxyaethylidene)-2-oxochroman-
4-ylphosphonate (8b). From 2a or 7 and triethyl phosphite.
Method C: 0.31 g, 95%, white crystals, mpZ145–148 8C
(ethyl acetate), (lit.21,22 147–148 8C).
7.5 Hz; POCH2), 63.4 (d, 2JCOPZ7.2 Hz; POCH2), 49.2 (d,
2JCPZ3.5 Hz; C-3), 38.9 (d, 1JCPZ143.5 Hz; C-4), 16.3 (d,
3JCPZ6.2 Hz; CH3), 16.2 (d, JCPZ5.5 Hz; CH3). MS m/z
3
(5): 389 (MHC) (57), 388 (MC) (21), 282 (74), 250 (58),
228 (92), 173 (41), 146 (52), 118 (43) 105 (100), 78 (92), 77
(79).
4.3.3. Dimethyl 3-benzoyl-2-oxochroman-4-ylphospho-
nate (12/13a). From 3-benzoylcoumarin 10 and trimethyl
phosphite. Method D: 0.34 g, 94%, white crystals, mpZ
120–134 8C (methanol), (mixture of the two tautomers
12a$13a, with a 9:1 ratio (1H NMR), which on staying the
sample in the NMR tube for about 1 week (CDCl3) changed
to w1:1); [Found: C, 60.07; H, 4.90. C18H17O6P requires C,
60.00; H, 4.76%]; IR (CH3Cl): nZ1780, 1700, 1625, 1060,
4.3.5. Ethyl 4-(dimethoxyphosphoryl)-2-oxo-3-chroma-
necarboxylate (14a). From ethyl 2-oxo-2H-1-benzopyran-
3-carboxylate 11 and trimethyl phosphite. Method C:
0.19 g, 58%, colorless needles, mpZ94–95 8C (methanol);
[Found: C, 50.84; H, 5.00. C14H17O7P requires C, 51.23; H,
5.22%]; IR (CH3Cl): nZ1795, 1755, 1620, 1160, 1030,
1030 cmK1 1H NMR (300 MHz), enol-form (12a): dZ
.
1045 cmK1 1H NMR (300 MHz): dZ7.30–7.37 (m; 5-,
.
13.290 (s; OH,01H), 7.58–7.65 (m; 20-, 60-H, 2H), 7.46–7.54
(m; 3 -, 50-, 4 -H, 3H), 7.26–7.37 (m; 5-H, 7-H, 2H), 7.12–
7-H, 2H), 7.17 (ddd as dt, JZ7.5, 1.0 Hz; 6-H, 1H), 7.10 (d,
3
3
2
JZ8.5 Hz; 8-H, 1H), 4.15 (dd, JHHZ1.3 Hz, JHP
Z
7.19 (m; 6-H, 8-H, 2H), 4.45 (d, JHPZ23.9 Hz; 4-H, 1H),
11.1 Hz; 3-H, 1H), 4.12 (dq, 3JZ7.1 Hz, JHPZ2.6 Hz;
6
3
3
3.49 (d, JHPZ10.6 Hz; OCH3, 3H), 3.41 (d, JHP
Z
2
10.6 Hz; OCH3, 3H). Keto-form (13a): 7.96–7.99 (m, 20-,
60-H, 2H),07.65 (dddd as tt, JZ7.4, 1.4 Hz; 40-H, 1H), 7.48–
7.55 (m; 3 -H, 50-H, 2H), 7.34 (dddd as tt, JZ7.7, w2.0 Hz;
7-H, 1H), 7.22 (ddd as dt, JZ8.2, w2.1 Hz; 5-H, 1H), 7.11–
7.17 (m; 6-, 8-H, 2H), 5.19 (dd, JHPZ13.7 Hz, JHH
0.8 Hz; 3-H, 1H), 3.80 (bd, JHPZ23.4 Hz; 4-H, 1H), 3.81
OCH2, 2H), 3.95 (bd, JHPZ22.6 Hz; 4-H, 1H), 3.75 (d,
3JHPZ10.8 Hz; POCH3, 3H), 3.75 (d, JHPZ10.8 Hz;
3
POCH3, 3H), 1.11 (t, JZ7.1 Hz; CH3, 3H). 13C NMR
(75.4 MHz): dZ166.0 (d, 3JCPZ22.7 Hz; C]O), 162.2 (d,
3JCPZ2.2 Hz; C-2), 151.2 (d, JCPZ5.3 Hz; C-8a), 130.1
3
3
3
Z
(d, 3JCPZ5.2 Hz; C-5), 129.9 (d, 5JCPZ3.4 Hz; C-7), 125.1
(d, 4JCPZ3.2 Hz; C-6), 117.3 (d, 4JCPZ3.2 Hz; C-8), 115.4
2
3
3
(d, JHPZ10.8 Hz; OCH3, 3H), 3.68 (d, JHPZ10.8 Hz;
2
2
OCH3, 3H). 13C NMR (75.4 MHz), enol-form (12a): dZ
(d, JCCPZ7.5 Hz; C-4a), 63.0 (OCH2), 53.9 (d, JCCOP
Z
7.4 Hz; POCH3), 53.7 (d, 2JCOPZ7.4 Hz; POCH3), 46.9 (d,
3
3
175.5 (d, JCPZ6.7 Hz; ]COH), 169.1 (d, JCPw1 Hz;
2JCPZ2.3 Hz; C-3), 38.7 (d, JCPZ144.5 Hz; C-4), 13.8
1
3
4
C-2), 150.9 (d, JCPZ5.5 Hz; C-8a), 133.6 (d, JCP
Z
(CH3). MS m/z (%): 328 (MC) (22), 282 (7), 255 (100), 219
(24), 173 (87), 146 (11), 118 (13), 79 (6).
3
2.2 Hz; C-10), 130.9 (C-40), 129.9 (d, JCPZ4.5 Hz; C-5),
5
129.3 (d, JCP!5 Hz; C-7), 128.8 (C-30,-50), 128.2 (C-20,
4
2
-60), 125.0 (d, JCPZ3.3 Hz; C-6), 117.7 (d, JCPZ7.5 Hz;
C-4a), 117.1 (d, 4JCPZ3.9 Hz; C-8), 89.7 (d, 2JCPZ9.9 Hz;
4.3.6. Ethyl 4-(diethoxyphosphoryl)-2-oxo-3-chromane-
carboxylate (14b). From ethyl 2-oxo-2H-1-benzopyran-3-
carboxylate 11 and triethyl phosphite. Method C: 0.32 g,
88%, light-yellow oil; [Found: C, 53.59; H, 5.96.
C16H21O7P requires C, 53.93; H, 5.94%]; IR (CH3Cl): nZ
2
2
C-3), 53.6 (d, JCOPZ7.6 Hz; POCH3), 53.3 (d, JCOP
Z
7.4 Hz; POCH3), 37.6 (d, 1JCPZ140.8 Hz; C-4). Keto-form
3
3
(13a): 191.7 (d, JCPZ17.5 Hz; CO), 163.2 (d, JCP-
3
w0.5 Hz; C-2), 151.2 (d, JCPZ6.5 Hz; C-8a), 134.5
3
1790, 1750, 1625, 1600, 1170, 1060sh, 1030 cmK1 1H
.
(C-40), 133.2 (C-10), 129.4 (d, JCPZ2.9 Hz, C-5), 129.2
5
(C-20,-60), 129.2 (d, JCP!5.2 Hz; C-7), 129.2 (C-30,-50),
NMR (250 MHz) dZ7.29–7.36 (m; 5-, 7-H, 2H), 7.16 (dd
as t, JZ7.2 Hz; 6-H, 1H), 7.09 (d, JZ8.2 Hz; 8-H, 1H), 4.15
(d, JZ14.4 Hz; 3-H, 1H), 3.92–4.61 (m; CH2O, 6H), 3.90
(d, 2JHPZ24.2 Hz; 4-H, 1H), 1.32 (t, JZ7.0 Hz; CH3, 3H),
1.21 (t, JZ7.0 Hz; CH3, 3H), 1.11 (t, JZ7.1 Hz; CH3, 3H).
125.0 (d, 4JCPZ3.3 Hz; C-6), 117.3 (d, 4JCPZ3.6 Hz; C-8),
2
2
114.5 (d, JCPZ7.8 Hz; C4a), 54.1 (d, JCOPZ6.7 Hz;
POCH3), 53.8 (d, 2JCOPZ7.6 Hz; POCH3), 49.1 (d, 2JCCP
Z
1
3.4 Hz; C-3), 38.5 (d, JCPZ143.9 Hz; C-4). MS m/z (%):
361 (MHC) (51), 360 (MC) (20), 328 (18), 254 (48), 174
(81), 146 (52), 118 (49), 111 (79), 105 (50), 76 (100).
3
13C NMR (62.59 MHz) dZ166.1 (d, JCPZ21.5 Hz; CO),
3
3
162.3 (d, JCPZ2.0 Hz; C-2), 151.2 (d, JCPZ4.7 Hz;
3
5
C-8a), 130.0 (d; JCPZ4.8 Hz; C-5), 129.7 (d, JCP
Z
Z
4.3.4. Diethyl 3-benzoyl-2-oxochroman-4-ylphosphonate
(13b). From 3-benzoylcoumarin 10 and triethyl phosphite.
Method D: 0.27 g, 69%, white solid, mpZ106–108 8C
(ethanol); [Found: C, 61.77; H, 5.65. C20H21O6P requires C,
61.86; H, 5.45%]; IR (CH3Cl): nZ1780, 1700, 1620, 1500,
3.7 Hz; C-7), 124.9 (d, 4JCPZ3.2 Hz; C-6), 117.1 (d, 4JCP
2
3.2 Hz; C-8), 115.6 (d, JCPZ7.2 Hz; C-4a), 63.5 (d,
2JCOPZ7.1 Hz; POCH2), 63.2 (d, JCOPZ7.1 Hz;
2
2
POCH2), 62.8 (COOCH2), 46.9 (d, JCPZ2.7 Hz; C-3),
39.5 (d, JCPZ144.2 Hz; C-4), 16.2 (d, JCPZ5.7 Hz;
1
3

10342
R. D. Nikolova et al. / Tetrahedron 60 (2004) 10335–10342
3
CH3CH2OP), 16.0 (d, JCPZ5.6 Hz; CH3CH2OP), 13.7
(CH3). MS m/z (%): 356 (MC 1(1), 284 (11), 218 (6), 211
(8), 183 (18), 173 (18), 146 (25), 118 (16), 77 (9), 28 (100).
National Program ‘Nanotechnology and new materials’ of
Bulgarian National Research Council.
4.4. Interaction of 3-bromoacetylcoumarin 1 with dialkyl
phosphites
References and notes
1. Nikolova, R.; Bojilova, A.; Rodios, N. A. Tetrahedron 1998,
52, 14407.
A solution of 3-bromoacetylcoumarin 1 (0.27 g, 1 mmol)
and the corresponding dialkyl phosphite (5 mmol) was
refluxed in dry toluene (3 mL) for 4 h. The complicated
reaction mixtures were worked up as usually (Method A)
and after the column chromatography were isolated the
compounds 2, 7 and 8—for the yields see Table 2.
2. Lichtenthaler, F. W. Chem. Rev. 1961, 61, 607.
3. Borowitz, I. J.; Anschel, M.; Firstenberg, S. J. Org. Chem.
1967, 32, 1723.
4. Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307.
5. Henning, F. G.; Hilgetag, G. Zeitschr. Chem. 1967, 7, 169.
6. Marguarding, D.; Ramirez, F.; Ugi, I.; Gillespie, P. Angew.
Chem. 1973, 85, 99.
Transformation of the enolphosphate 2a into 7. A solution
of enolphosphate 2a (0.29 g, 1 mmol) and 4-toluenesulfonic
acid (0.95 g, 5 mmol) in dry toluene (3 mL) was refluxed
until the starting compound was consumed (TLC-monitor-
ing). The reaction mixture was worked up as above and the
3-acetyl coumarin 7 (0.17 g, 90%) was isolated from
ethanol.
7. Arbuzov, B. A. Zeitschr. Chem. 1974, 14, 41.
8. Pudovik, A. N.; Gazizov, T. H. Izv. Akad. Nauk SSSR 1977,
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10. Kem, K. M.; Nguyen, N. V.; Cross, D. J. J. Org. Chem. 1981,
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Transformation of the enolphosphate 2a into 1. To the
refluxing solution of the starting coumarin 2a (0.29 g,
1 mmol) in dry toluene (3 mL) 4-toluenesulfonic acid
(0.19 g, 1 mmol) was added. After 5 min to the reaction
mixture N-bromosuccinimide (0.18 g, 1 mmol) was added
and refluxed until the starting coumarin was consumed
(TLC-monitoring) for about 30 min. The solvent was
removed under reduced pressure and the reaction mixture
was worked up as pointed above and from ethyl acetate were
isolated bromoacetylcoumarin 1 in quantitative yield.
11. Makosza, M.; Wojciechowski, K. Bull. Pol. Acad. Sci. 1984,
32, 175.
12. Ye, W.; Liao, X. Synthesis 1985, 986.
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17. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC:
Boca Raton, FL, 2003; p 139.
Transformation of the enolphosphate 2a into 5a. To the
refluxing solution of the starting coumarin 2a (0.29 g,
1 mmol) in dry toluene (3 mL) 4-toluenesulfonic acid
(0.19 g, 1 mmol) was added. After 5 min to the reaction
mixture was added N-bromosuccinimide (0.18 g, 1 mmol)
and after further 45 min the trimethylphosphite (0.25 g,
2 mmol) was added. The reaction mixture was refluxed until
the starting coumarin was consumed (TLC-monitoring) for
about 2 h. Standard workup and purification by column
chromatography gave enolphosphate 2a (0.09 g, 33%) and
the product of 1,4-addition 5a (0.17 g, 46%).
18. Koelsch, C. F. J. Am. Chem. Soc. 1950, 72, 2294.
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20. Fahmy, A. A.; Hafez, T. S.; El-Farargy, F. A.; Hamad,
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Phosph. Sulf. Sil. 1998, 133, 151.
22. Abdou, W. M.; Sediek, A. A. Tetrahedron 1999, 55, 14777.
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Acknowledgements
This work was financially supported by the University Fund
for Scientific Research of the University of Sofia and