Regioselectivity in the reaction of ethyl diethoxyphosphorylacetate with 1-aryl-2-haloalkan-1-ones: Effective synthesis of 4-aryl-2-diethoxyphosphoryl-4- oxobutanoates

Article abstract of DOI:10.1055/s-2007-966060

The regioselectivity of the reaction of ethyl diethoxyphosphorylacetate with 1-aryl-2-haloalkan-1-ones has been investigated. It has been found that, depending on the nature of the halogen atom in 1-aryl-2-haloalkan-1-ones and the reaction conditions, alk

Full text of DOI:10.1055/s-2007-966060

PAPER
1671
Regioselectivity in the Reaction of Ethyl Diethoxyphosphorylacetate with
1-Aryl-2-haloalkan-1-ones: Effective Synthesis of 4-Aryl-2-diethoxyphos-
phoryl-4-oxobutanoates
Effective
Synthesis
o
c
f
4-Aryl-2-d
e
iethoxypho
k
sphoryl-4-oxobuta
F
noates . Koszuk, Anna Albrecht, Tomasz Janecki*
Institute of Organic Chemistry, Technical University of Łódź, Żeromskiego 116, 90924 Łódź, Poland
Fax +48(42)6365530; E-mail: tjanecki@p.lodz.pl
Received 5 February 2007; revised 2 April 2007
rylacetate with chloro or bromoacetone and a-chloroace-
tophenone yielded the olefination products. Additionally,
a very recent study by Warren reports the successful alky-
lation of diphenyl(2-phenyl-2-oxoethyl)phosphine oxide
Abstract: The regioselectivity of the reaction of ethyl diethoxy-
phosphorylacetate with 1-aryl-2-haloalkan-1-ones has been investi-
gated. It has been found that, depending on the nature of the halogen
atom in 1-aryl-2-haloalkan-1-ones and the reaction conditions,
alkylation or olefination products can be obtained with excellent or with a-bromoacetophenone using sodium methoxide in
tetrahydrofuran (THF).6 Despite the lack of detail, this lat-
even full selectivity.
ter information implied that careful selection of the reac-
tants and the reaction conditions may enable control of
regioselectivity and consequently the effective alkylation
of 1 with a-halo ketones. Therefore, we have undertaken
more systematic studies focused on this problem.
Key words: alkylations, Horner–Wadsworth–Emmons olefination,
regioselectivity, ethyl diethoxyphosphorylacetate, a-haloketones
Alkylations of double-activated methylene compounds
with a-halo ketones and a-halo esters are frequently em-
ployed in order to obtain highly functionalized structures
containing carbonyl or alkoxycarbonyl groups. Accord-
ingly, phosphorylacetates 1 are effectively alkylated with
a-halo esters 2a, producing phosphorylated succinates 3,
which are valuable intermediates in organic synthesis.1
However, in the reactions of 1 with a-halo ketones 2b the
Horner–Wadsworth–Emmons olefination competes ef-
fectively with the alkylation and 4-halo-2-alkenoates 4 are
usually formed (Scheme 1).
In the initial experiments we performed the reaction of
ethyl 2-diethoxyphosphorylacetate (5) with chloro- and
bromoacetophenone 6 and 7a in THF using sodium ethox-
ide (EtONa) or sodium hydride (NaH) as base (Scheme 2,
Table 1). Combined yields and the alkylation to olefina-
tion product ratios were determined by analysis of the 31P
NMR spectra of the reaction mixtures. For this purpose,
integration of the signals of the alkylation product 8a and
the signal arising from diethyl hydrogen phosphate, which
is one of the products of the olefination reaction, were
compared with the integration of all the remaining signals
31
O
O
in P NMR spectrum and to each other. It was assumed
R2P
that the intensity of the diethyl hydrogen phosphate signal
was indicative of the amount of the olefination product 9
or 10. As can be seen from Table 1, the regiochemistry of
this reaction can be easily controlled simply by choosing
chloro- or bromoacetophenone as substrate, with the
former favoring olefination and the latter the alkylation
reaction. Furthermore, the use of NaH as a base gave ex-
cellent or even full selectivity of the alkylation or olefina-
tion reaction, respectively.
OR1
OR3
Y = OR3
R2
O
O
O
O
R2
3
base
+
Y
R2P
OR1
X
2a, Y = OR3
2b, Y = R4
R4
O
1
Y = R4
R2
OR1
X
4
O
Scheme 1
O
O
conditions
Ph
+
(EtO)2P
OEt
X
Thus, the olefination products were obtained in the reac-
tions of alkyl diethoxyphosphorylacetate with a-fluoro2 as
well as a-chloro3 and a-bromo4 ketones. However, Fuji-
wara described the alkylation of ethyl diethoxyphospho-
rylacetate with a-bromoacetophenone.5 Unfortunately, no
details for this reaction were given. In the same paper it
was reported that the reaction of ethyl diethoxyphospho-
6, X = Cl
7a, X = Br
5
O
O
Ph
O
(EtO)2P
OEt
OEt
+
Ph
X
O
SYNTHESIS 2007, No. 11, pp 1671–1676
Advanced online publication: 11.05.2007
x
x.
x
x
.
2
0
0
7
9, X = Cl
10, X = Br
8a
DOI: 10.1055/s-2007-966060; Art ID: T02207SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1672
J. F. Koszuk et al.
PAPER
Table 1 Initial Reactions of Ethyl 2-Diethoxyphosphorylacetate (5) with Chloro- and Bromoacetophenones
Entry
Basea
Chloroacetophenone (6)
Bromoacetophenone (7a)
Yield (%)b
Selectivity
Yield (%)b
Selectivity
(alkylation/olefination)b
(alkylation/olefination)b
1
2
EtONa
NaH
83
77
5:95
60
88
60:40
95:5
0:100
a Reaction conditions: THF, 0 °C→r.t., 20 h.
b Determined by the analysis of the 31P NMR spectra of the reaction mixture.
We then turned our attention to the reaction of 5 with 1- With these results in hand, we decided to examine the ef-
aryl-2-halopropan-1-ones. Reaction with chloropro- fectiveness of the THF/NaH system in the reaction of eth-
piophenone (11), using the THF/NaH system described yl 2-diethoxyphosphorylacetate (5) with various 1-aryl-2-
above, gave exclusively the olefination product 14 with bromoethanones 7a–d (Scheme 4). All reactions proceed-
excellent yield (Scheme 3, Table 2, entry 1). Disappoint- ed well and, after standard work-up, crude products were
ingly, bromopropiophenone (12a), under the same condi- purified by column chromatography to give 4-aryl-2-di-
tions, yielded a mixture of alkylation and olefination ethoxyphosphoryl-4-oxobutanoates 8a–d in good to ex-
products 13a and 15, respectively, in a 50:50 ratio and in cellent yields (Table 3).
moderate yield (54%). Addition of 10 mol% tetrabutylam-
monium iodide (TBAI) improved the yield significantly
but did not change the selectivity, whereas performing
this reaction in a mixture of THF and DMSO (1:1 ratio)
led to improvements in both the yield and selectivity (en-
tries 3 and 4, respectively). Finally, a combination of these
improvements gave an excellent 93% yield and satisfacto-
ry 90:10 selectivity (entry 4).
Applying optimized conditions to the reaction of 5 with 1-
aryl-2-bromopropan-1-ones 12a–d gave, after standard
work up and column chromatography, pure 4-aryl-2-di-
ethoxyphosphoryl-3-methyl-4-oxobutanoates 13a–c in
excellent yields (Table 3). Disappointingly, the alkylation
of phosphonoacetate 5 with 2-bromo-1-(naphthalen-1-
yl)propan-1-one 12d gave a complex mixture of products
which were difficult to isolate. Pleasingly, the same reac-
tion performed in THF alone provided, after standard
work-up procedure and column chromatography, the ex-
pected butanoate 13d in moderate yield.
O
O
O
conditions
Ph
+
(EtO)2P
OEt
X
Butanoates 13a–d were formed as mixtures of diastereo-
mers in the ratios shown in Table 3. Diastereomers of bu-
tanoate 13b were successfully separated using column
11, X = Cl
12a, X = Br
5
O
O
Ph
O
O
O
(EtO)2P
OEt
Ph
O
(EtO)2P
+
NaH
OEt
OEt
Ar
R1
O
O
solvent, additives
Ar
X
+
(EtO)2P
R1
0 °C to r.t.
OEt
O
Br
7a–d, 12a–d
O
13a
14, X = Cl
15, X = Br
8a–d, 13a–d
5
Scheme 3
Scheme 4
Table 2 Reactions of Ethyl 2-Diethoxyphosphorylacetate (5) with Chloro- and Bromopropiophenone
Entry
Conditionsa
Chloropropiophenone (11)
Bromopropiophenone (12a)
Yield (%)b
Selectivity
Yield (%)b
Selectivity
(alkylation/olefination)b
(alkylation/olefination)b
1
2
3
4
THF, NaH
95
–
0:100
54
80
63
93
50:50
50:50
75:25
90:10
THF, NaH, TBAI (10 mol%)
THF–DMSO 1:1, NaH
–
–
–
–
THF–DMSO 1:1, NaH, TBAI (10 mol%)
–
a Reaction conditions: THF, 0 °C→r.t., 20 h.
b Determined by the analysis of the 31P NMR spectra of the reaction mixture.
Synthesis 2007, No. 11, 1671–1676 © Thieme Stuttgart · New York

PAPER
Effective Synthesis of 4-Aryl-2-diethoxyphosphoryl-4-oxobutanoates
1673
Table 3 Synthesis of 2-Diethoxyphosphoryl-4-oxo-4-arylbutanoates 8a–d and 13a–d
Compound
8a
R1
H
Ar
Solvent/additives
syn/anti
Yield (%)a
Ph
THF
75
70
80
85
79
71
84
40
8b
H
p-BrC6H4
p-MeOC6H4
1-naphthyl
Ph
THF
8c
H
THF
8d
H
THF
13a
13b
13c
Me
Me
Me
Me
THF–DMSO 1:1, TBAI (10 mol%)
THF–DMSO 1:1, TBAI (10 mol%)
THF–DMSO 1:1, TBAI (10 mol%)
THF, TBAI (10 mol%)
65:35
60:40
65:35
65:35
p-BrC6H4
p-MeOC6H4
1-naphthyl
13d
a Yield of isolated product after column chromatography.
chromatography. The assignment of the relative configu- gauche alignment of the phosphoryl and carbonyl groups.
ration for the major syn-13b and minor anti-13b diaste- These data allowed for the assignment of the relative con-
reomers was possible by careful analysis of the 1H and 13C figuration for the major diastereomer as syn-13b and for
NMR spectra (Figure 1 and Table 4).
the minor diastereomer as anti-13b. We believe that sim-
ilar spectroscopic characteristics present in the NMR
spectra of diastereomeric 13a, 13c and 13d permit the as-
signment of the syn configuration for all major diaste-
reomers and the anti configuration for all minor
diastereomers.
H-3
H-3
P(O)(OEt)2
EtOOC
Me
COOEt
(EtO)2(O)P
Me
C(O)p-BrC6H4
C(O)p-BrC6H4
H-2
H-2
syn-13b
anti-13b
In conclusion, excellent control of regioselectivity was
achieved in the reaction of ethyl diethoxyphosphorylace-
tate with 1-aryl-2-haloalkan-1-ones. Appropriate choice
of halogen, solvent, base and additives enable substantial
suppression of the olefination reaction and effective syn-
thesis of 2-diethoxyphosphoryl-4-oxo-4-arylbutanoates 8
and 13. It is worth stressing that, according to the litera-
ture data, the availability of butanoates of this structure
have been so far limited to ethyl 2-diethoxyphosphoryl-4-
oxo-4-phenylbutanoate (8a), prepared in 67% yield by the
reaction of diethyl hydrogen phosphite with ethyl 4-oxo-
4-phenyl-2-butenoate.7 We believe that the highly func-
tionalized butanoates 8 and 13 will prove valuable inter-
mediates in organic synthesis and will find various
synthetic applications. For example, they can be trans-
formed into biologically important a-alkylidene-g-lac-
tones and lactams such as 3-alkylidenedihydrofuran-
2(3H)-ones or 4-alkylpyridazin-3(2H)-ones, using meth-
odology which has been recently developed in our labora-
tory.8 Further studies in this area are currently under
investigation.
Figure 1
Table 4 Selected 1H and 13C NMR Data for the Major and Minor
Diastereomers of 13ba
NMR Assignment Major diastereomer
Minor diastereomer
anti-13b
syn-13b
1H
H-2
3.49 (dd, J = 21.7,
10.9 Hz)
3.66 (dd, J = 21.2,
10.2 Hz)
13C
Me
16.3 (s)
16.5 (d, J = 14.1 Hz)
C-4
200.5 (d, J = 16.9 Hz) 199.5 (d, J = 3.2 Hz)
a Data taken from the spectra of the separated isomers.
1
The H NMR spectra of both isomers showed well-
resolved signals arising from the H-2 protons with
JH-2/H-3 = 0.9 and 10.2 Hz for the major and minor diaste-
reomer, respectively. According to the Carplus equation,
these values indicate an antiperiplanar alignment of the H-
2 and H-3 protons in both syn-13b and anti-13b. On the
other hand, the 13C NMR spectra of syn-13b and anti-13b
showed characteristic signals for the methyl group and
C-4. Large JP/C-4 coupling and the absence of significant
JP/Me coupling in the spectrum of syn-13b suggest an anti-
periplanar alignment of the phosphoryl and carbonyl
groups and a gauche alignment of the phosphoryl and
methyl groups, respectively. In the spectrum of anti-13b,
a large JP/Me and a small JP/C-4 indicated an antiperiplanar
positioning of the phosphoryl and methyl groups and a
Organic solvents and reagents were purified by the appropriate stan-
dard procedures. Column chromatography was performed using
Fluka silica gel 60 (230–400 mesh). IR spectra were recorded on
Specord M-80 spectrometer. 1H NMR (250 MHz), 13C NMR (62.9
MHz), and 31P NMR (101 MHz) spectra were recorded on a Bruker
1
DPX-250 spectrometer with TMS as an internal standard for H
NMR and 13C NMR, and 85% H3PO4 as an external standard for 31
P
NMR. 31P NMR spectra were recorded using broad-band proton de-
coupling. In the optimization experiments, in which the yield was
determined by 31P NMR spectroscopy, two methods of 31P decou-
Synthesis 2007, No. 11, 1671–1676 © Thieme Stuttgart · New York

1674
J. F. Koszuk et al.
PAPER
pling were examined: (i) the inverse-gated decoupling with 90°
pulse and 5T1 repetition time, as well as the regular broad-band pro-
ton decoupling. Both methods gave the same integrations ratio,
within an accuracy of 1%. Therefore, further NMR measurements
were performed using less time-consuming, routine broad-band
proton decoupling. Elemental analyses were performed on a
Perkin–Elmer PE-2400 analyzer.
3.93 (m, 2 H, H-3), 4.13–4.28 [m, 6 H, P(O)(OCH2CH3)2,
C(O)OCH2CH3], 7.08–7.28 (m, 5 H, Ar-H).
13C NMR (CDCl3): d = 13.9 [s, C(O)OCH2CH3], 16.2 [d, J = 2.5
Hz, P(O)(OCH2CH3)2], 35.9 (d, J = 1.9 Hz, C-3), 40.1 (d, J = 131.6
Hz, C-2), 61.5 [s, C(O)OCH2CH3], 62.8 [d, J = 6.9 Hz,
P(O)(OCH2CH3)2], 128.0 (s, 2 × Ar-C), 128.5 (s, Ar-C), 133.4 (s,
2 × Ar-C), 135.9 (s, Ar-C), 168.3 (d, J = 4.5 Hz, C-1), 196.4 (d,
J = 18.9 Hz, C-4).
1-Aryl-2-bromoethanones 7b,d and 1-aryl-2-bromopropan-1-ones
12b,d were prepared by bromination of the corresponding methyl or
ethyl aryl ketones applying a previously described literature proce-
dure.9 1-(Naphthalen-1-yl)propan-1-one was prepared as described
in the literature.10 Other methyl or ethyl aryl ketones and ethyl 2-di-
ethoxyphosphorylacetate were purchased from Fluka and used
without further purification.
31P NMR (CDCl3): d = 23.07.
Anal. Calcd for C16H23O6P: C, 56.14; H, 6.77. Found: C, 56.25; H,
6.80.
Ethyl 4-(4-Bromophenyl)-2-(diethoxyphosphoryl)-4-oxo-
butanoate (8b)
Yield: 5.25 g (70%); yellow oil; Rf = 0.20 (CHCl3–acetone, 99:1).
IR (film): 1732, 1688, 1256 cm–1.
Reaction of Ethyl 2-Diethoxyphosphorylacetate (5) with
Chloro- and Bromoacetophenone 6 and 7a; General Procedure
To a mixture of EtONa (76 mg, 1.1 mmol) or NaH (26 mg, 1.1
mmol) in THF (2 mL) a solution of ethyl 2-diethoxyphosphoryl-
acetate (5; 225 mg, 1.0 mmol) in THF (0.5 mL) was added. The
mixture was stirred at r.t. for 30 min then cooled to 0 °C and a solu-
tion of chloro- or bromoacetophenone 6 or 7a (1.0 mmol) in THF
(1.0 mL) was added dropwise. Stirring was continued at r.t. for an
additional 20 h. After this time, a sample from the reaction mixture
(300 mL) was placed in an NMR tube, AcOH (30 mL) was added and
a 31P NMR spectrum was recorded. Integrations of the signals of 8a
(d = 23.07 ppm), diethyl hydrogen phosphate (d = 1.03 ppm) and
other signals present in the spectrum were compared in order to de-
termine yield.
1H NMR (CDCl3): d = 1.23–1.40 [m, 9 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 3.34 (ddd, J = 2.5, 9.0, 18.2 Hz, 1 H, H-2), 3.59–
3.85 (m, 2 H, H-3), 4.12–4.27 [m, 6 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 7.59–7.86 (m, 4 H, Ar-H).
13C NMR (CDCl3): d = 13.7 [s, C(O)OCH2CH3], 16.0 [d, J = 2.5
Hz, P(O)(OCH2CH3)2], 35.6 (s, C-3), 39.9 (d, J = 131.6 Hz, C-2),
61.4 [s, C(O)OCH2CH3], 62.7 [d, J = 5.6 Hz, P(O)(OCH2CH3)2],
128.4 (s, Ar-C), 129.3 (s, 2 × Ar-C), 131.6 (s, 2 × Ar-C), 134.4 (s,
Ar-C), 168.0 (d, J = 5.6 Hz, C-1), 195.2 (d, J = 15.2 Hz, C-4).
31P NMR (CDCl3): d = 23.15.
Anal. Calcd for C16H22BrO6P: C, 45.62; H, 5.26. Found: C, 45.67;
H, 5.34.
Reaction of Ethyl 2-Diethoxyphosphorylacetate (5) with
Chloro- and Bromopropiophenone 11 and 12a; General Proce-
dure
Ethyl 2-(Diethoxyphosphoryl)-4-(4-methoxyphenyl)-4-oxo-
butanoate (8c)
Yield: 5.3 g (80%); yellow oil; Rf = 0.25 (CHCl3–acetone, 99:1).
IR (film): 1736, 1680, 1260 cm–1.
1H NMR (CDCl3): d = 1.26–1.40 [m, 9 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 3.30–3.47 (m, 1 H, H-2), 3.55–3.80 (m, 2 H, H-3),
3.87 (s, 3 H, OCH3), 4.16–4.25 [m, 6 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 6.89–7.99 (m, 4 H, Ar-H).
13C NMR (CDCl3): d = 13.7 [s, C(O)OCH2CH3], 15.9 [d, J = 3.1
Hz, P(O)(OCH2CH3)2], 35.2 (s, C-3), 39.9 (d, J = 131.6 Hz, C-2),
55.1 (s, OCH3), 61.2 [s, C(O)OCH2CH3], 62.5 (d, J = 5.6 Hz,
P(O)(OCH2CH3)2], 62.5 [d, J = 6.1 Hz, P(O)OCH2CH3], 114.4 (s,
2 × Ar-C), 128.7 (s, Ar-C), 130.0 (s, 2 × Ar-C), 163.4 (s, Ar-C),
168.1 (d, J = 5.3 Hz, C-1), 194.4 (d, J = 15.7 Hz, C-4).
To a mixture of NaH (26 mg, 1.1 mmol) in THF (2 mL) or a mixture
of DMSO (2.0 mL) and THF (0.5 mL) a solution of ethyl 2-dieth-
oxyphosphorylacetate (5; 225 mg, 1.0 mmol) in THF (0.5 mL) was
added. The mixture was stirred at r.t. for 30 min, cooled to 0 °C,
then a solution of chloro- or bromopropiophenone 11 or 12a (1.0
mmol), either with or without TBAI (Table 2; 37 mg, 0.1 mmol), in
THF (1.0 mL) was added dropwise. Stirring was continued at r.t. for
an additional 20 h. After this time a sample from the reaction mix-
ture (300 mL) was placed in an NMR tube, AcOH (30 mL) was added
and a 31P NMR spectrum was recorded. Integrations of the signals
of syn- and anti-13a (d = 22.58 and 21.71 ppm), diethyl hydrogen
phosphate (d = 1.03 ppm) and other signals present in the spectrum
were compared in order to determine yield.
31P NMR (CDCl3): d = 23.33.
Ethyl 4-Aryl-2-diethoxyphosphoryl-4-oxobutanoates 8a–d;
General Procedure
Anal. Calcd for C17H25O7P: C, 54.84; H, 6.77. Found: C, 54.97; H,
6.84.
To a suspension of NaH (0.45 g, 18.7 mmol) in THF (40 mL), a so-
lution of ethyl 2-diethoxyphosphorylacetate (5; 4.0 g, 17.8 mmol) in
THF (5 mL) was added. The mixture was stirred at r.t. for 30 min,
cooled to 0 °C, then a solution of the appropriate 1-aryl-2-bromo-
ethanone 7a–d (17.8 mmol) in THF (5 mL) was added dropwise.
Stirring was continued at r.t. for an additional 20 h then the reaction
was quenched with H2O (20 mL) and the solvent was evaporated.
The residue was extracted with CH2Cl2 (3 × 20 mL) and the com-
bined organic layers were dried (MgSO4) and evaporated to afford
the crude products which were purified by column chromatography
(silica gel; CHCl3–acetone, 99:1).
Ethyl 2-(Diethoxyphosphoryl)-4-(naphthalen-1-yl)-4-oxo-
butanoate (8d)
Yield: 5.95 g (85%); yellow oil; Rf = 0.15 (CHCl3–acetone, 99:1).
IR (film): 1732, 1684, 1256 cm–1.
1H NMR (CDCl3): d = 1.23–1.46 [m, 9 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 3.51 (ddd, J = 2.5, 7.7, 17.7 Hz, 1 H, H-2), 3.60–
3.93 (m, 2 H, H-3), 4.16–4.29 [m, 6 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 7.48–8.60 (m, 7 H, Ar-H).
13C NMR (CDCl3): d = 13.8 [s, C(O)OCH2CH3], 16.1 [d, J = 2.5
Hz, P(O)(OCH2CH3)2], 38.7 (s, C-3), 40.4 (d, J = 131.7 Hz, C-2),
61.5 [s, C(O)OCH2CH3], 62.7 [d, J = 5.6 Hz, P(O)(OCH2CH3)2],
124.1 (s, Ar-C), 125.4 (s, Ar-C), 126.3 (s, Ar-C), 127.8 (s, 2 × Ar-
C), 128.2 (s, Ar-C), 129.8 (s, Ar-C), 132.9 (s, Ar-C), 133.6 (s, Ar-
Ethyl 2-(Diethoxyphosphoryl)-4-oxo-4-phenylbutanoate (8a)
Yield: 4.6 g (75%); yellow oil; Rf = 0.20 (CHCl3–acetone, 99:1).
IR (film): 1736, 1688, 1256 cm–1.
1H NMR (CDCl3): d = 1.25–1.37 [m, 9 H, P(O)(OCH2CH3)2 and
C(O)OCH2CH3], 3.46 (ddd, J = 2.5, 7.7, 17.7 Hz, 1 H, H-2), 3.55–
Synthesis 2007, No. 11, 1671–1676 © Thieme Stuttgart · New York

PAPER
Effective Synthesis of 4-Aryl-2-diethoxyphosphoryl-4-oxobutanoates
1675
C), 134.4 (s, Ar-C), 168.3 (d, J = 5.6 Hz, C-1), 200.1 (d, J = 15.7
Hz, C-4).
31P NMR (CDCl3): d = 23.02.
13C NMR (CDCl3): d = 13.4 [s, C(O)OCH2CH3], 15.8 [d, J = 5.8
Hz, P(O)(OCH2CH3)2], 16.3 (s, CH3C-3), 39.9 (s, C-3), 47.8 (d,
J = 130.7 Hz, C-2), 60.9 [s, C(O)OCH2CH3], 62.3 [d, J = 7.1 Hz,
P(O)(OCH2CH3)2], 62.4 [d, J = 8.1 Hz, P(O)(OCH2CH3)2], 127.8
(s, Ar-C), 129.5 (s, 2 × Ar-C), 131.5 (s, 2 × Ar-C), 133.6 (s, Ar-C),
168.1 (d, J = 5.2 Hz,C-1), 200.5 (d, J = 16.9 Hz, C-4).
Anal. Calcd for C20H25O6P: C, 61.22; H, 6.42. Found: C, 61.39; H,
6.28.
31P NMR (CDCl3): d = 22.27.
Ethyl 4-Aryl-2-diethoxyphosphoryl-3-methyl-4-oxobutanoates
13a–c; General Procedure
Ethyl anti-4-(4-Bromophenyl)-2-(diethoxyphosphoryl)-3-meth-
yl-4-oxobutanoate (anti-13b)
To a suspension of NaH (0.45 g, 18.7 mmol) in DMSO (30 mL) and
THF (5 mL), a solution of ethyl 2-diethoxyphosphorylacetate (5;
4.0 g, 17.8 mmol) in THF (5 mL) was added. The mixture was
stirred r.t. for 0.5 h, cooled to 0 °C and a solution of the appropriate
1-aryl-2-bromopropan-1-one 12a–c (17.8 mmol) and TBAI (0.69 g,
10 mol%) in THF (20 mL) was added dropwise. After stirring for
20 h at this temperature, the reaction mixture was diluted with H2O
(50 mL) and extracted with CH2Cl2 (3 × 25 mL). The combined or-
ganic layers were washed with H2O (20 mL) and dried (MgSO4).
The solvent was evaporated and the crude product was purified by
column chromatography (silica gel, EtOAc–hexane, 4:1).
1H NMR (CDCl3): d = 1.18–1.28 [m, 9 H, P(O)(OCH2CH3)2, CH3],
1.33 [t, J = 7.1 Hz, 3 H, C(O)OCH2CH3], 3.66 (dd, J = 21.2, 10.2
Hz, 1 H, H-2), 3.96–4.21 [m, 5 H, P(O)(OCH2CH3)2, H-3], 4.27 [q,
J = 7.1 Hz, 2 H, C(O)OCH2CH3], 7.59–7.89 (m, 4 H, Ar-H).
13C NMR (CDCl3): d = 13.7 [s, C(O)OCH2CH3], 15.7 [d, J = 5.9
Hz, P(O)(OCH2CH3)2], 15.8 [d, J = 5.7 Hz, P(O)(OCH2CH3)2],
16.5 (d, J = 14.1 Hz, CH3C-3), 38.9 (d, J = 3.6 Hz, C-3), 47.6 (d,
J = 129.5 Hz, C-2), 61.1 [s, C(O)OCH2CH3], 62.3 [d, J = 7.2 Hz,
P(O)(OCH2CH3)2], 62.5 [d, J = 7.4 Hz, P(O)(OCH2CH3)2], 127.9
(s, Ar-C), 129.7 (s, 2 × Ar-C), 131.6 (s, 2 × Ar-C), 134.2 (s, Ar-C),
167.5 (d, J = 4.8 Hz, C-1), 199.5 (d, J = 3.2 Hz, C-4).
Ethyl 2-(Diethoxyphosphoryl)-3-methyl-4-oxo-4-phenyl-
butanoate (13a)
Yield: 5.0 g (79%); yellow oil; mixture of diastereoisomers in a
65:35 ratio; Rf = 0.36, 0.38 (EtOAc–hexane, 4:1).
31P NMR (CDCl3): d = 21.55.
Ethyl 2-(Diethoxyphosphoryl)-4-(4-methoxyphenyl)-4-methyl-
4-oxobutanoate (13c)
IR (film): 1732, 1684, 1252 cm–1.
Yield: 5.8 g (84%); yellow oil; mixture of diastereoisomers in a
65:35 ratio; Rf = 0.38, 0.42 (EtOAc–hexane, 4:1).
IR (film): 1732, 1676, 1256 cm–1.
1H NMR (CDCl3): d [major diastereomer (syn)]11 = 1.15–1.42 [m,
12 H, P(O)(OCH2CH3)2, C(O)OCH2CH3, CH3], 3.51 (dd, J = 21.4,
11.0 Hz, 1 H, H-2), 3.80 (s, 3 H, OCH3), 3.96–4.33 [m, 7 H,
P(O)(OCH2CH3)2, C(O)OCH2CH3, H-3], 6.94–8.04 (m, 4 H, Ar-
H).
1H NMR (CDCl3): d [major diastereomer (syn)]11 = 1.15–1.41 [m,
12 H, P(O)(OCH2CH3)2, C(O)OCH2CH3, CH3], 3.50 (dd, J = 21.6,
11.0 Hz, 1 H, H-2), 4.00–4.30 [m, 7 H, P(O)(OCH2CH3)2,
C(O)OCH2CH3, H-3], 7.40–7.60 (m, 5 H, Ar-H).
1H NMR (CDCl3): d [minor diastereomer (anti)]11 = 1.15–1.41 [m,
12 H, P(O)(OCH2CH3)2, C(O)OCH2CH3, CH3], 3.69 (dd, J = 21.2,
10.0 Hz, 1 H, H-2), 4.00–4.30 [m, 7 H, P(O)(OCH2CH3)2,
C(O)OCH2CH3, H-3], 7.40–7.60 (m, 5 H, Ar-H).
13C NMR (CDCl3): d [major diastereomer (syn)]11 = 13.3 [s,
C(O)OCH2CH3)], 15.5 (d, J = 5.2 Hz, P(O)(OCH2CH3)2], 16.2 (d,
J = 6.5 Hz, CH3C-3), 39.7 (s, C-3), 47.2 (d, J = 129.4 Hz, C-2), 60.6
[s, C(O)OCH2CH3], 61.9 [d, J = 15.5 Hz, P(O)(OCH2CH3)2], 127.5
(s, 2 × Ar-C), 127.8 (s, 2 × Ar-C), 132.4 (s, Ar-C), 134.4 (s, Ar-C),
167.3 (s, C-1), 199.9 (s, C-4).
13C NMR (CDCl3): d [minor diastereomer (anti)]11 = 13.1 [s,
C(O)OCH2CH3], 15.3 (d, J = 3.4 Hz, P(O)(OCH2CH3)2], 16.1 (d,
J = 5.3 Hz, CH3C-3), 38.5 (s, C-3), 47.7 (d, J = 130.6 Hz, C-2), 60.5
[s, C(O)OCH2CH3], 61.8 [d, J = 9.3 Hz, P(O)(OCH2CH3)2], 127.5
(s, 2 × Ar-C), 127.8 (s, 2 × Ar-C), 132.4 (s, Ar-C), 134.8 (s, Ar-C),
168.0 (s, C-1), 201.5 (d, J = 16.5 Hz, C-4).
1H NMR (CDCl3): d [minor diastereomer (anti)]11 = 1.15–1.42 [m,
12 H, P(O)(OCH2CH3)2, C(O)OCH2CH3, CH3], 3.69 (dd, J = 21.0,
10.1 Hz, 1 H, H-2), 3.91 (s, 3 H, OCH3), 3.96–4.33 [m, 7 H,
P(O)(OCH2CH3)2, C(O)OCH2CH3, H-3], 6.94–8.04 (m, 4 H, Ar-
H).
13C NMR (CDCl3): d [major diastereomer (syn)]11 = 13.2 [s,
C(O)OCH2CH3], 15.6 [d, J = 5.9 Hz, P(O)(OCH2CH3)2], 16.5 (s,
CH3C-3), 39.4 (s, C-3), 47.8 (d, J = 130.3 Hz, C-2), 54.8 (s, CH3O),
60.6 [s, C(O)OCH2CH3], 62.1 [d, J = 7.8 Hz, P(O)(OCH2CH3)2],
62.2 [d, J = 7.7 Hz, P(O)(OCH2CH3)2], 113.2 (s, 2 × Ar-C), 127.4
(s, Ar-C), 130.1 (s, 2 × Ar-C), 163.1 (s, Ar-C), 168.1 (d, J = 5.3 Hz,
C-1), 199.7 (d, J = 16.9 Hz, C-4).
31P NMR (CDCl3): d = 22.58 (major); 21.71 (minor).11
13C NMR (CDCl3): d [minor diastereomer (anti)]11 = 13.4 [s,
C(O)OCH2CH3], 15.5 [d, J = 5.6 Hz, P(O)(OCH2CH3)2], 15.4 [d,
J = 5.6 Hz, P(O)(OCH2CH3)2], 16.4 (s, CH3C-3), 38.1 (d, J = 3.5
Hz, C-3), 47.3 (d, J = 129.7 Hz, C-2), 54.8 (s, CH3O), 60.7 [s,
C(O)OCH2CH3], 61.9 [d, J = 8.8 Hz, P(O)(OCH2CH3)2], 62.1 [d,
J = 7.9 Hz, P(O)(OCH2CH3)2], 113.2 (s, 2 × Ar-C), 127.9 (s, Ar-C),
130.1 (s, 2 × Ar-C), 163.1 (s, Ar-C), 167.5 (d, J = 4.6 Hz, C-1),
198.4 (d, J = 3.2 Hz, C-4).
Anal. Calcd for C17H25O6P: C, 57.30; H, 7.07. Found: C, 57.41; H,
7.21.
Ethyl 4-(4-Bromophenyl)-2-(diethoxyphosphoryl)-3-methyl-4-
oxobutanoate (13b)
Yield: 5.5 g (71%); yellow oil; mixture of diastereoisomers in a
60:40 ratio; Rf = 0.42, 0.53 (EtOAc–hexane, 4:1).
31P NMR (CDCl3): d = 22.81 (major), 21.78 (minor).11
IR (film): 1732, 1688, 1256 cm–1.
Anal. Calcd for C18H27O7P: C, 55.95; H, 7.04. Found: C, 56.15; H,
7.21.
Anal. Calcd for C17H24BrO6P: C, 46.91; H, 5.56. Found: C, 46.85;
H, 5.69.
Ethyl 2-(Diethoxyphosphoryl)-3-methyl-4-(naphthalen-1-yl)-4-
oxobutanoate (13d)
To a suspension of NaH (0.45 g, 18.7 mmol) in THF (30 mL), a so-
lution of ethyl 2-diethoxyphosphorylacetate (5; 4.0 g, 17.8 mmol) in
THF (5 mL) was added. The mixture was stirred at r.t. for 30 min,
cooled to 0 °C and a solution of 2-bromo-1-(naphthalen-1-yl)pro-
Ethyl syn-4-(4-Bromophenyl)-2-(diethoxyphosphoryl)-3-meth-
yl-4-oxobutanoate (syn-13b)
1H NMR (CDCl3): d = 1.18 [t, J = 7.1 Hz, 3 H, C(O)OCH2CH3],
1.33–1.41 [m, 9 H, P(O)(OCH2CH3)2, CH3], 3.49 (dd, J = 21.7, 10.9
Hz, 1 H, H-2), 4.10 [q, J = 7.1 Hz, 2 H, C(O)OCH2CH3], 4.13–4.29
[m, 5 H, P(O)(OCH2CH3)2, H-3], 7.60–7.90 (m, 4 H, Ar-H).
Synthesis 2007, No. 11, 1671–1676 © Thieme Stuttgart · New York

1676
J. F. Koszuk et al.
PAPER
pan-1-one (12d; 4.7 g, 17.8 mmol) and TBAI (0.69 g, 10 mol%) in
THF (15mL) was added dropwise. Stirring was continued at r.t. for
an additional 20 h then the reaction was quenched with H2O (20
mL). The THF was evaporated and the residue was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(MgSO4) and evaporated to afford the crude products, which were
purified by column chromatography (silica gel; CHCl3–acetone,
99:1).
Acknowledgment
This work was financed by the Ministry of Education and Science
(Project No. 3 T09A 075 28).
References
(1) (a) Taylor, E. C.; Davies, H. M. L. J. Org. Chem. 1986, 51,
1537. (b) Dowd, P.; Wilk, B. K. Synth. Commun. 1993, 23,
2307. (c) Gallager, P. T.; Hicks, T. A.; Lightfoot, A. P.;
Owton, W. M. Tetrahedron Lett. 1994, 35, 289.
Yield: 2.9 g (40%); yellow oil; mixture of diastereoisomers in a
65:35 ratio; Rf = 0.40, 0.42 (EtOAc–hexane, 4:1).
IR (film): 1728, 1688, 1256 cm–1.
1H NMR (CDCl3): d (major and minor diastereomers)11 = 1.20–1.42
[m, 12 H, P(O)(OCH2CH3)2, C(O)OCH2CH3, CH3], 3.50 (dd,
J = 21.5, 11.1 Hz, 1 H, H-2 major), 3.60 (dd, J = 20.5, 10.1 Hz, 1 H,
H-2 minor), 4.06–4.32 [m, 7 H, P(O)(OCH2CH3)2, C(O)OCH2CH3,
H-3], 7.45–8.42 (m, 7 H, Ar-H).
13C NMR (CDCl3): d [major diastereomer (syn)]11 = 14.0 [s,
C(O)OCH2CH3], 15.7 [d, J = 5.2 Hz, P(O)(OCH2CH3)2], 16.05 (d,
J = 5.1 Hz, CH3C-3), 36.8 (s, C-3), 48.0 (d, J = 130.1 Hz, C-2), 60.4
[s, C(O)OCH2CH3], 62.6 [d, J = 6.0 Hz, P(O)(OCH2CH3)2], 124.2
(s, Ar-C), 125.2 (s, Ar-C), 126.2 (s, Ar-C), 127.5 (s, Ar-C), 127.8 (s,
Ar-C), 130.4 (s, Ar-C), 132.2 (s, Ar-C), 133.2 (s, Ar-C), 135.0 (s,
Ar-C), 139.6 (s, Ar-C), 167.8 (s, C-1), 205.4 (d, J = 17.0 Hz, C-4).
13C NMR (CDCl3): d [minor diastereomer (anti)]11 = 13.8 [s,
C(O)OCH2CH3], 15.5 [d, J = 3.2 Hz, P(O)(OCH2CH3)2], 15.5 (d,
J = 4.9 Hz, CH3C-3), 36.7 (s, C-3), 47.2 (d, J = 131.1 Hz, C-2), 60.4
[s, C(O)OCH2CH3], 62.6 [d, J = 6.0 Hz, P(O)(OCH2CH3)2], 124.2
(s, Ar-C), 125.2 (s, Ar-C), 126.2 (s, Ar-C), 127.5 (s, Ar-C), 127.8 (s,
Ar-C), 130.3 (s, Ar-C), 132.2 (s, Ar-C), 133.2 (s, Ar-C), 134.9 (s,
Ar-C), 139.8 (s, Ar-C), 167.9 (s, C-1), 203.6 (d, J = 6.0 Hz, C-4).
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(11) Values for specific isomer were taken from the spectrum of
the mixture of isomers.
31P NMR (CDCl3): d = 22.44 (major), 21.17 (minor).11
Anal. Calcd for C21H27O6P: C, 62.06; H, 6.70. Found: C, 62.21; H,
6.83.
Synthesis 2007, No. 11, 1671–1676 © Thieme Stuttgart · New York