Synthesis of 3-(phosphorylmethyl)cycloalkenones by forced conjugate addition of α-phosphonate carbanions to cyclic enones

Article abstract of DOI:10.1055/s-2007-965982

Cycloalkenones were found to react with α-lithiated diethyl (phenylselanyl)methylphosphonate preferentially or exclusively at the carbonyl group giving 1,2-adducts. When complexes of cycloalkenones with aluminum tris(2,6-diphenylphenoxide) were used for t

Full text of DOI:10.1055/s-2007-965982

PAPER
1225
Synthesis of 3-(Phosphorylmethyl)cycloalkenones by Forced Conjugate
Addition of a-Phosphonate Carbanions to Cyclic Enones
S
ynthesis of 3-(Phosph
a
orylmethyl
r
)cycloalk
i
e
none
a
s
n Mikolajczyk,* Wieslawa Perlikowska
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry,
Sienkiewicza 112, 90-363 Lodz, Poland
Fax +48(42)6847126; E-mail: marmikol@bilbo.cbmm.lodz.pl
Received 25 October 2006; revised 13 February 2007
O
Abstract: Cycloalkenones were found to react with a-lithiated di-
ethyl (phenylselanyl)methylphosphonate preferentially or exclu-
sively at the carbonyl group giving 1,2-adducts. When complexes of
cycloalkenones with aluminum tris(2,6-diphenylphenoxide) were
used for this reaction, regioselective 1,4-addition was observed.
Upon oxidation the thus-formed 1,4-adducts gave the correspond-
ing 3-(phosphorylmethyl)cycloalk-2-enones. An alternative ap-
proach to the latter compounds involved 1,4-addition of diethyl
lithiomethylphosphonate to 2-sulfinylcycloalk-2-enones followed
by sulfoxide elimination.
O
O
X
P(OMe)2
O
O
2a
Me Me
X =
O
P(OR)2
O
Me
1a R = Et
1a′ R = Me
O
O
X
P(OMe)2
Key words: conjugate addition, cycloalkenones, a-phosphonate
carbanions, 3-phosphorylcycloalk-2-enones
O
2b
Figure 1
Cycloalkenones are valuable intermediates in a variety of
synthetic transformations and useful building blocks in
the synthesis of biologically active compounds. Among
them, cyclopentenones are particularly interesting due to
the presence of this structural motif in a wide range of im-
portant natural products, such as jasmonoids, cyclopen-
tanoid antibiotics, and prostanoids. As part of our broad
program on the application of phosphorus and sulfur re-
agents in organic synthesis,1 we have also been engaged
in the invention and development of general methods for
the synthesis of functionalized cyclopentenones and cy-
clopentanones.2 These endeavors resulted in the elabora-
tion of new and efficient routes to racemic rosaprostol3
and enantiomeric prostaglandin B1 methyl esters4 starting
from 3-[(dimethoxyphosphoryl)methyl]cyclopent-2-enone
(1a¢) as a key intermediate and to both enantiomers of
isoterrein5 and neplanocin A6 from the diastereomeric
camphor protected 3-[(dimethoxyphosphoryl)methyl]-
4,5-dihydroxycyclopent-2-enones 2a and 2b.
a-phosphonate anions to cycloalkenones,8 while the sec-
ond was based on substitution of the b-methoxy group in
cyclic enones by a-lithiated alkylphosphonates.9
To gain further flexibility in the preparation of 3-(phos-
phorylmethyl)-substituted cycloalk-2-enones 1 and to
overcome some limitations in the existing methods, we
decided to devise a new strategy for the synthesis of these
systems. According to our simple retrosynthetic analysis
shown in Scheme 1, it should involve two steps: (a) con-
jugate addition of a phosphorylmethyl selenide to a cyclic
enone and (b) oxidative selenide elimination.
O
O
O
P
O
P
n
n
SeR
O
The starting cyclopentenones 1 and 2 (Figure 1) have
been obtained by general methods for the synthesis of 3-
(phosphorylmethyl)cycloalk-2-enones developed in our
laboratory involving the reaction of dicarboxylic acid es-
ters with a-phosphonate carbanions and subsequent in-
tramolecular Horner reaction of bis(b-oxophosphonates),
which were formed in the initial step.7 This method com-
plemented two other approaches to 3-(phosphorylmeth-
yl)cycloalk-2-enones. The first employed oxidation of
cyclic allylic alcohols obtained in the carbonyl addition of
O
+
CH2
SeR
P
n
Scheme 1
To realize our goal, the first reaction in the above scheme
is crucial. However, addition of a-phosphonate carb-
anions to enones is a complex reaction that can follow
different mechanistic pathways i.e. 1,2-addition, 1,4-addi-
tion, or addition–elimination, and the reaction outcome
depends on the nature of a-phosphonate carbanion as well
as on the substitution pattern of the enone.9,10 Therefore,
we initially examined the regioselectivity of the reaction
SYNTHESIS 2007, No. 8, pp 1225–1229
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965982; Art ID: T16106SS
© Georg Thieme Verlag Stuttgart · New York

1226
M. Mikolajczyk, W. Perlikowska
PAPER
between cyclic enones and the lithium derivative of dieth- of 1a and 1b were consistent with those reported in the
yl (phenylselanyl)methylphosphonate (3)11 as a nucleo- literature7,9 (Scheme 3). There is no doubt that the sele-
philic reaction partner. The addition of Li-3 to cyclopent- noxides formed upon oxidation of 5a and 5b undergo
2-enone afforded two adducts 4a and 5a in a 93:7 ratio; spontaneous elimination of benzeneselenenic acid13 and
each of them is a mixture of two diastereomers. The major the 3-exocyclic C=C bond in the elimination products is
adduct 4a, isolated in 68% yield, resulted from the addi- transformed into the thermodynamically more stable en-
tion of Li-3 to the carbonyl group (1,2-addition) whereas docyclic a,b-unsaturated system of 1.
5a was formed according to the 1,4-addition pattern.
When the reaction was carried out in a mixture of tetrahy-
ATPH
O
O
ATPH
CH2Cl2
drofuran and hexamethylphosphoramide, a solvent pre-
ferring 1,4-addition, the 4a to 5a ratio was 69:31. With
cyclohex-2-enone, the Li-3 reacted exclusively in a 1,2-
fashion affording the product 4b (mixture of two diaste-
reomers) in 80% yield (Scheme 2).
n
n
1. Li-3, THF
–78 °C, 1.5–3 h
2. H3O+, –78 °C
O
O
H2O2,
CH2Cl2
0 °C
+
LiCHP(OEt)2
O
O
n
SePh
O
O
Li-3
P(OEt)2
P(OEt)2
n
n
1. THF, –78 °C, 1.5 h
2. NH4Cl(aq), –78 °C
SePh
1a, n = 1, 91%
P = 23.2
1b, n = 2, 97%
P = 24.2
δ
5a, n = 1, 40%
P = 25.6, 25.5 (1:2.4)
5b, n = 2, 57%
P = 25.1, 25.0 (1:2)
δ
PhSe
O
δ
O
HO
P(OEt)2
δ
Ph
Ph
O
P(OEt)2
+
n
n
O
Al
SePh
5a, n = 1
δ
P = 25.6, 25.5 (1:1.7)
3
4a, n = 1, 68%
P = 26.7, 26.3 (2.3:1)
93:7
ATPH
δ
4b, n = 2, 80%
Scheme 3
δ
P = 26.7, 25.8 (1.9:1)
Scheme 2
It should be emphasized that, in addition to a simple ac-
cess to 1, another advantage of the present strategy is that
both synthetic steps, i.e. conjugate addition and oxidation,
may be performed as a one-pot reaction leading to higher
yields of the final products 1a and 1b (55% and 78%, re-
spectively).
To suppress the undesired 1,2-addition of the a-phospho-
nate carbanion derived from 3 to cycloalkenones, we took
advantage of the fact that the reactivity of the carbonyl
group in a,b-unsaturated carbonyl compounds can effec-
tively be diminished by complexation with bulky alumi-
num reagents and that these complexes react with
nucleophiles with 1,4-selectivity.12
In our further quest to develop a convenient approach to
the synthesis of the title compounds, we were attracted by
a series of papers by Posner et al.,14 who demonstrated us-
ing many examples that 2-sulfinyl-substituted cycloalk-2-
enones add organometallic reagents in a 1,4-fashion. In
this case, the conjugate addition to cycloalkenone sulfox-
ides is forced by the presence of a sulfinyl substituent in
position 2. On the other hand, it is well known that alkyl
sulfoxides bearing a hydrogen at the b-carbon atom un-
dergo thermal decomposition to form unsaturated com-
pounds.15 Having this in mind, we decided to investigate
the reaction between easily available 2-(phenylsulfi-
nyl)cyclopent-2-enone16 with diethyl lithiomethylphos-
phonate as a key step in the synthesis of the title
compounds. In fact, treatment of the above cyclopenten-
one sulfoxide with Li-3 at –78 °C in tetrahydrofuran gave
the expected 1,4-adduct 6a, which was obtained in 40%
yield after purification by column chromatography. The
lower yield of 6a is due to slow elimination of benzene-
Among many of such bulky Lewis acids designed by
Yamamoto for selective organic synthesis,12 aluminum
tris(2,6-diphenylphenoxide) (ATPH) was selected for our
study. It was gratifying to find that the addition reaction of
Li-3 to the freshly prepared complex of cyclopentenone
and aluminum tris(2,6-diphenylphenoxide) resulted in ex-
clusive formation of the 1,4-adduct 5a (two diastereo-
mers) in 60% yield as determined by 31P NMR. Puri-
fication by column chromatography gave pure 5a in 40%
yield. A similar procedure with cyclohex-2-enone was
more efficient; the 1,4-adduct 5b was formed as the sole
product in 80% yield (31P NMR assay) and obtained in a
pure state by column chromatography in 57% yield. Oxi-
dation of compounds 5a and 5b with hydrogen peroxide
afforded almost quantitatively the expected 3-(phospho-
rylmethyl)cycloalkenones 1a and 1b; spectroscopic data
Synthesis 2007, No. 8, 1225–1229 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(Phosphorylmethyl)cycloalkenones
1227
sulfenic acid that takes place at room temperature. This oxidative elimination of selenide or sulfoxide. Facile ac-
elimination was preparatively carried out by heating 6a in cessibility of the starting alkenones as well as one-pot pro-
a benzene solution at 40 °C for two hours and the desired cedures make this method very attractive for the design
cyclopentenone 1a was obtained in 80% yield and synthesis of functionalized biologically active cy-
(Scheme 4).
cloalkenones.
A similar reaction of lithiomethylphosphonate with 2-
(phenylsulfinyl)cyclohex-2-enone17 requires some addi-
tional comments (Scheme 4). As expected, it afforded the
1,4-adduct 6b as a mixture of two diastereomers in a
2.5:1. However, the crude product was already contami-
nated with 3-(phosphorylmethyl)cyclohexenone 1b (6b/
1b 7:1). Attempts to purify 6b by column chromatogra-
phy led to a mixture of both compounds in a 2:1 ratio.
Melting and boiling points were uncorrected. THF was distilled
over K/benzophenone, and benzene was distilled over Na wire, both
immediately before use. CH2Cl2 was distilled over P2O5 and stored
over anhyd Na2CO3. Reactions with organolithium reagents were
carried out under dry argon. Column chromatography was per-
formed using Merck 60F254 silica gel (70–230 mesh), and flash
chromatography used Merck 60F254 silica gel (320–400 mesh). Re-
action mixtures were analyzed by TLC using Merck 60F254 TLC
Therefore, the conjugate addition and benzenesulfenic plates. NMR spectra were recorded with Bruker AC 200 instrument
at 200 MHz for 1H, 80 MHz for 31P, and 50 MHz for 13C with CDCl3
acid elimination were performed as a one-pot reaction,
which gave 1b in 87% yield.
1
as solvent, unless noted otherwise. H and 13C chemical shifts are
reported relative to TMS as an external standard. 31P NMR down-
In an extension to the present work, 2-alkyl-substituted
cyclopentenones 7 and 8 were also synthesized starting
from the key intermediate 6a. In this case, alkylation of
the oxo sulfoxide anion generated from 6a with potassium
tert-butoxide in 1,3-dimethyl-2,3,4,5-tetrahydropyrimi-
din-2(1H)-one (DMPU) and elimination of benzene-
sulfenic acid under the conditions described above were
performed in a one-pot procedure giving disubstituted cy-
clopentenones 7 and 8 in 60% and 48% yield, respective-
ly. In this way we could overcome the problems
connected with the poor C2-alkylation of the anion de-
rived from 3-(phosphorylmethyl)cyclopent-2-enone 1a,
especially when reactive and long-chain aliphatic alkyl
halides and sulfonates were used.
field chemical shifts are expressed with a positive sign relative to an
external standard of 85% H3PO4. HRMS were recorded on a Finni-
gan MAT 95 apparatus.
2-(Phenylsulfinyl)cyclohex-2-enone
Prepared by a literature procedure.16
White solid; yield: 9.5 g (87%); mp 56–57 °C (Et2O).
1H NMR (200 MHz, CDCl3): d = 1.82–2.13 (m, 2 H), 2.18–2.69 (m,
4 H), 7.31–7.47 (m, 3 H), 7.67–7.75 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 22.02, 26.13, 38.29, 124.53,
125.18, 128.91, 131.09, 143.95 (d, J = 21.2 Hz), 149.18, 194.59.
HRMS: m/z [M]+ calcd for C12H12SO2: 220.05540; found:
220.05580.
Anal. Calcd for C12H12O2S: C, 65.43; H, 5.49. Found: C, 65.19; H,
5.75.
In conclusion, two simple synthetic routes were devel-
oped to access 3-(phosphorylmethyl)cycloalkenones. The
key step in both procedures was the forced, conjugate ad-
dition of the appropriate a-phosphonate carbanion to a cy-
cloalkenone or 2-sulfinylcycloalk-2-enone followed by
Addition of Diethyl (Phenylselanyl)methylphosphonate (3) to
Cycloalkenones; General Procedure
A soln of 2.4 M BuLi in hexane (1.3 mol equiv) in THF (3 mL per
mmol of 3) was cooled to –78 °C. To this soln was added dropwise
with stirring a soln of diethyl (phenylselanyl)methylphosphonate11
O
1. DMPU, 0 °C,
t-BuOK
2. I(CH2)6CO2Me
3. benzene, 40 °C, 2 h
(CH2)6CO2Me
O
P(OEt)2
O
O
8 δP = 24.1, 48%
SPh
n
O
O
O
1. THF, –78 °C, 1.5 h
2. NH4Cl(aq), –40 °C
n = 1,2
SPh
O
benzene, 40 °C, 2 h
O
+
P(OEt)2
P(OEt)2
n
n
(EtO)2PCH2Li
O
6a, n = 2, 40%
P = 28.6, 28.5 (2:1)
6b, n = 2
P = 28.7, 28.4 (2.5:1)
1a, n = 1, 80%
P = 23.2
δ
δ
1b, n = 2, 87%
P = 24.2
δ
δ
1. DMPU, 0 °C,
t-BuOK
2. MeI
O
3. benzene, 40 °C, 2 h
Me
O
P(OEt)2
7 δP = 24.2, 60%
Scheme 4
Synthesis 2007, No. 8, 1225–1229 © Thieme Stuttgart · New York

1228
M. Mikolajczyk, W. Perlikowska
PAPER
3-[(Diethoxyphosphoryl)(phenylselanyl)methyl]cyclopen-
tanone (5a)
Colorless oil; yield: 0.16 g (40%).
1H NMR (200 MHz, CDCl3): d = 1.28 (m, 6 H), 1.57–2.52 (m, 6 H),
2.64–2.86 (m, 1 H), 3.12 (dd, J = 17 Hz, J = 5.1 Hz, 1 H, minor iso-
mer), 3.16 (dd, J = 17 Hz, J = 4.4 Hz, 1 H, major isomer), 4.04–4.26
(m, 4 H), 7.24 (m, 3 H), 7.58 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 16.5 (d, J = 5.7 Hz), 28.1, 28.3,
37.6, 38.4, 43.4 (d, J = 9.2 Hz), 45.0 (d, J = 149.6 Hz), 62.8 (d,
J = 7.2 Hz), 63.1 (d, J = 7.2 Hz), 128.1, 129.0, 133.9, 208.2.
(3, 1 mol equiv, typically 3 mmol) in THF (1 mL per 1 mmol of 3)
and the resulting soln was stirred at –78 °C for 0.5 h. Then, a soln
of enone (1.3 mol equiv) in THF (1 mL per 1 mmol of enone) was
added, and the mixture was stirred for 1.5 h. Sat. aq NH4Cl soln (10
mL) was added at –78 °C and the mixture was allowed to warm to
r.t. The mixture was extracted with Et2O (3 × 15 mL) and the com-
bined organic layers were dried (MgSO4) and evaporated in vacuo.
The crude adducts were purified by column chromatography (hex-
ane–acetone, 2:1). The major adducts 4a (68% yield) and 4b (80%
yield) were obtained in an analytically pure state as mixtures of two
stereoisomers and characterized.
31P NMR (80 MHz, CDCl3): d = 25.6, 25.5 (1:2.4).
MS (EI, 70 eV): m/z (%) = 390 (100) [M + H]+, 308 (28), 233 (22),
Diethyl (1-Hydroxycyclopent-2-enyl)(phenylselanyl)methyl-
phosphonate (4a)
Colorless oil; yield: 0.79 g (68%).
157 (19).
Anal. Calcd for C16H23O4PSe: C, 49.37; H, 5.96. Found: C, 49.25;
H, 5.72.
1H NMR (200 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 6 H), 2.10 (m,
2 H), 2.42 (m, 2 H), 3.35 (d, J = 14.8 Hz, 1 H), 4.02–4.25 (m, 4 H),
4.51 (br s, 1 H), 5.62 (m, 1 H, minor isomer), 5.94 (m, 1 H, major
isomer), 7.25 (m, 3 H), 7.55 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 16.4 (d, J = 5.8 Hz), 31.1, 31.3,
39.8 (d, J = 10.1 Hz), 48.5 (d, J = 138.2 Hz), 49.78 (d, J = 139.5
Hz), 61.8 (d, J = 6.3 Hz), 61.8 (d, J = 6.3 Hz), 83.3 (d, J = 5.2 Hz),
126.9, 127.5, 128.8, 129.3, 130.2, 133.5, 136.2 (d, J = 9.7 Hz),
152.1.
3-[(Diethoxyphosphoryl)(phenylselanyl)methyl]cyclohexanone
(5b)
Colorless oil; yield: 0.23 g (57%).
1H NMR (200 MHz, CDCl3): d = 1.30 (t, J = 7.0 Hz, 3 H), 1.32 (t,
J = 7.0 Hz, 3 H), 1.65 (m, 2 H), 1.86–2.20 (m, 2 H), 2.25–2.85 (m,
5 H), 3.0 (dd, J = 2.5 Hz, J = 18.2 Hz, 1 H, minor isomer), 3.17 (dd,
J = 2.1 Hz, J = 18.2 Hz, 1 H, major isomer), 4.07–4.27 (m, 4 H),
7.26 (m, 3 H), 7.60 (m, 2 H).
31P NMR (80 MHz, CDCl3): d = 26.7, 26.3 (2.3:1).
13C NMR (50 MHz, CDCl3): d = 16.25 (d, J = 5.8 Hz), 24.4, 29.6,
39.5, 40.7 (d, J = 6.5 Hz), 46.7 (d, J = 143.5 Hz), 48.7, 63.2, 127.9,
129.2, 130.1, 133.6, 210.3.
31P NMR (80 MHz, CDCl3): d = 25.09, 24.97 (1:2).
Anal. Calcd for C16H23O4PSe: C, 49.37; H, 5.96; P, 7.96. Found: C,
49.20; H, 5.68; P, 7.72.
Diethyl (1-Hydroxycyclohex-2-enyl)(phenylselanyl)methyl-
phosphonate (4b)
Colorless oil; yield: 0.96 g (80%).
MS (EI, 70 eV): m/z (%) = 404 (32) [M + H]+, 403 (100) [M]+, 308
(66), 247 (38), 157 (35).
1H NMR (200 MHz, CDCl3): d = 1.33 (m, 6 H), 1.55–2.1 (m, 6 H),
3.21 (d, J = 15.5 Hz, 1 H), 4.05–4.28 (m, 4 H), 4.45 (br s, 1 H), 5.45
(m, 1 H, minor isomer) and 5.90 (m, 1 H, major isomer), 7.25 (m, 3
H), 7.57 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 15.7 (d, J = 4.7 Hz), 17.9 (d,
J = 9.4 Hz), 23.4, 24.3 (d, J = 10.6 Hz), 32.9, 34.5 (d, J = 5.9 Hz),
49.1 (d, J = 138.1 Hz), 50.9 (d, J = 139.9 Hz), 62.5 (2q, J = 7.1 Hz,
J = 19.2 Hz), 70.3, 71.6, 127.0, 127.5, 128.5, 129.1, 129.3, 130.4 (d,
J = 5.4 Hz), 130.7, 131.0, 132.2, 133.6.
Anal. Calcd for C17H25O4PSe: C, 50.63; H, 6.25. Found: C, 50.56;
H, 6.51.
3-[(Diethoxyphosphoryl)methyl]cyclopent-2-enone (1a);7,9
Typical Procedure
To a soln of selenide 5a (0.389 g, 1 mmol) in CH2Cl2 (5 mL) was
added 30% aq H2O2 (0.125 mL, 1.1 mmol) at 0 °C and the mixture
was stirred vigorously for 2 h. Then, H2O (5 mL) was added and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL), dried
(MgSO4), and evaporated. The crude product was purified by col-
umn chromatography (silica gel, hexane–acetone, 2:1) to give 1a as
a colorless oil; yield: 0.21 g (91%).
31P NMR (80 MHz, CDCl3): d = 26.7, 25.8 (1.9:1).
Anal. Calcd for C17H25O4PSe: C, 50.63; H, 6.25; P, 7.68. Found: C,
50.38; H, 6.42; P, 7.55.
1H NMR (200 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 6 H), 2.40–
2.45 (m, 2 H), 2.70–2.76 (m, 2 H), 3.0 (d, J = 23.5 Hz, 2 H), 4.1 (dq,
J = 7.1 Hz, J = 11.0 Hz, 4 H), 6.1 (m, 1 H).
31P NMR (80 MHz, CDCl3): d = 23.2.
Addition of Diethyl (Phenylselanyl)methylphosphonate (3) to
Cycloalkenone–Aluminum Tris(2,6-diphenylphenoxide) Com-
plexes; General Procedure
A soln of 2 M Me3Al in hexane (0.75 mL, 1.5 mmol) was added
dropwise to magnetically stirred soln of 2.6-diphenylphenol (1.1 g,
4.5 mmol) in CH2Cl2 (10 mL) at r.t. and the soln was stirred for 0.5
h to furnish aluminum tris(2,6-diphenylphenoxide). In the next step,
this soln was cooled to –78 °C and cycloalkenone (1 mmol) was
added at this temperature. To a soln of the complex obtained was
added a soln of Li-3 (2 mmol) [prepared by treatment of diethyl
(phenylselanyl)methylphosphonate (3, 0.643 g, 2.1 mmol) dis-
solved in THF (10 mL) with 2 M BuLi in hexane (1 mL, 2 mmol) at
–78 °C]. The whole mixture was stirred at –78 °C for 2 h and al-
lowed to warm to r.t. Then, the mixture was quenched with 10% aq
HCl (15 mL). The aqueous phase was extracted with Et2O (5 × 10
mL) and the combined organic phases were dried (MgSO4) and
evaporated under reduced pressure. The crude products 5a and 5b
formed as mixtures of two diastereomers were purified by column
chromatography (silica gel, hexane–acetone, 2:1) and character-
ized.
3-[(Diethoxyphosphoryl)methyl]cyclohex-2-enone (1b)7,9
Oxidation of selenide 5b (0.40 g, 1 mmol) according to the proce-
dure described above gave 1b as a colorless oil; yield: 0.24 g (97%).
1H NMR (200 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 6 H), 1.98 (q,
J = 6.1 Hz, 2 H), 2.34–2.48 (m, 4 H), 2.80 (d, J = 23.5 Hz, 2 H), 4.1
(dq, J = 7.1 Hz, J = 11.2 Hz, 4 H), 5.93 (br d, J = 5.6 Hz, 1 H).
31P NMR (80 MHz, CDCl3): d = 24.2.
3-[(Diethoxyphosphoryl)methyl]-2-(phenylsulfinyl)cyclopen-
tanone (6a)
A 2.5 M soln of BuLi in hexane (1.58 mL, 3.96 mmol) was diluted
with THF (10 mL). To this soln, cooled to –78 °C, was added drop-
wise a soln of diethyl methylphosphonate (0.548 g, 3.6 mmol) in
THF (4 mL) and stirring was continued for 0.5 h. A soln of 2-(phe-
nylsulfinyl)cyclopentenone16 (0.816 g, 3.96 mmol) in THF (4 mL)
Synthesis 2007, No. 8, 1225–1229 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(Phosphorylmethyl)cycloalkenones
1229
was then added and the resulting mixture was stirred at –78 °C for
1.5 h. It was then warmed to –40 °C and sat. aq NH4Cl (10 mL) was
added. The aqueous phase was extracted with Et2O (3 × 15 mL) and
the combined organic layers were dried (MgSO4) and evaporated.
The crude product was purified by column chromatography (hex-
ane–acetone, 2:1) to give the pure 6a (mixture of two diastere-
omers) as a colorless liquid; yield: 0.51 g (40%).
1H NMR (200 MHz, CDCl3): d = 1.34 (m, 6 H), 1.54–2.52 (m, 6 H),
3.34 (br d, J = 8.3 Hz, 1 H, minor isomer), 3.67 (br d, J = 8.3 Hz, 1
H, major isomer), 3.86–4.02 (m, 1 H), 4.1–4.18 (m, 4 H), 7.48–7.64
(m, 5 H).
Methyl 7-{2-[(Diethoxyphosphoryl)methyl]-5-oxocyclopent-1-
enyl}heptanoate (8)3
Colorless oil; yield: 0.08 g (48%).
1H NMR (200 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 6 H), 1.20–
1.50 (m, 6 H), 1.50–1.75 (m, 4 H), 2.16 (m, 2 H), 2.29 (t, J = 27.3
Hz, 2 H), 2.60 (m, 2 H), 2.96 (d, J = 24.0 Hz, 2 H), 3.65 (s, 3 H),
4.12 (q, J = 7.1 Hz, 4 H).
31P NMR (80 MHz, CDCl3): d = 24.1.
Acknowledgment
31P NMR (80 MHz, CDCl3): d = 28.6, 28.5 (2:1).
FAB-MS: m/z (%) = 359 (100) [M + H]+.
Financial support from the Ministry of Science and Higher Educa-
tion (Grant No. 4 T09A 047 25) is gratefully acknowledged.
3-[(Diethoxyphosphoryl)methyl]cyclopent-2-enone (1a)7,9
Cyclopentanone sulfoxide 6a (0.25 g, 0.7 mmol) was dissolved in
anhyd benzene (5 mL) and the soln was stirred at 40 °C for 2 h.
Then, benzene was evaporated and the residue was chromato-
graphed (hexane–acetone, 2:1) to give 1a as a colorless liquid;
yield: 0.13 g (80%).
References
(1) Mikolajczyk, M. Rev. Heteroat. Chem. 1993, 2, 19.
(2) Mikolajczyk, M.; Mikina, M.; Zurawinski, R. Pure Appl.
Chem. 1999, 71, 473.
(3) Mikolajczyk, M.; Mikina, M.; Jankowiak, A.; Mphahlele,
M. J. Synthesis 2000, 1075.
(4) Mikolajczyk, M.; Mikina, M.; Jankowiak, A. J. Org. Chem.
2000, 65, 5127.
(5) Mikolajczyk, M.; Mikina, M.; Wieczorek, M. W.;
Blaszczyk, J. Angew. Chem., Int. Ed. Engl. 1996, 35, 1560.
(6) Mikolajczyk, M.; Mikina, M.; Jankowiak, A. PL 366,531,
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(7) Mikolajczyk, M.; Mikina, M. J. Org. Chem. 1994, 59, 6760.
(8) Ohler, E.; Zbiral, E. Synthesis 1991, 3597.
(9) Mphahlele, M. J.; Modro, T. A. J. Org. Chem. 1995, 60,
8236.
(10) For a recent representative paper on this topic, see: Modro,
A. M.; Modro, T. A.; Mphahlele, M. J.; Perlikowska, W.;
Pienaar, A.; Sales, M.; van Rooyen, P. H. Can. J. Chem.
1998, 76, 1344; and references therein.
3-[(Diethoxyphosphoryl)methyl]cyclohex-2-enone (1b)7,9
A 2.4 M soln of BuLi in hexane (2.1 mL, 4.95 mmol) in THF (10
mL) was cooled to – 78 °C and diethyl methylphosphonate (0.82 g,
5.4 mmol) in THF (5 mL) was added dropwise. The mixture was
stirred at this temperature for 0.5 h and then a soln of 2-(phenylsulfi-
nyl)cyclohex-2-enone (1.1 g, 4.95 mmol) in THF (8 mL) was added
and the resulting mixture was stirred for 1.5 h. The reaction soln was
warmed to –40 °C and treated with sat. aq NH4Cl (15 mL). The
aqueous phase was extracted with Et2O (3 × 15 mL) and the com-
bined organic layers were dried (MgSO4) and evaporated. The
crude product was purified by column chromatography (hexane–ac-
etone, 2:1) to give a colorless liquid consisting of the adduct 6b
{MS (CI): m/z = 373.3 [M + H]+} and 1b {MS (CI): m/z = 247.2 [M
+ H]+}, in a 3:1 ratio.
The crude product was dissolved in anhyd benzene (15 mL) and the
soln was stirred at 40 °C for 2 h. After evaporation of benzene the
residue was purified by column chromatography (hexane–acetone,
2:1) to give 1b as a colorless liquid; yield: 1.05 g (87%).
(11) Balczewski, P.; Pietrzykowski, W. M.; Mikolajczyk, M.
Tetrahedron 1995, 51, 7727.
(12) For a review, see: Saito, S.; Yamamoto, H. Chem. Commun.
1997, 1585.
(13) For synthetic applications of selenoxide elimination, see:
Paulmier, C. Selenium Reagents and Intermediates in
Organic Synthesis; Pergamon: Oxford, 1986, 132–143.
(14) (a) Posner, G. H.; Mallamo, J. P.; Hulce, M.; Frye, L. L. J.
Am. Chem. Soc. 1982, 104, 4180. (b) Posner, G. H.; Kogan,
T. P.; Hulce, M. Tetrahedron Lett. 1984, 25, 383.
(c) Posner, G. H.; Kogan, T. P.; Haines, S. R.; Frye, L. L.
Tetrahedron Lett. 1984, 25, 2627. (d) Posner, G. H.; Frye,
L. L.; Hulce, M. Tetrahedron 1984, 40, 1041. (e)Posner, G.
H.; Asirvatham, E. J. Org. Chem. 1985, 50, 2589.
(f) Posner, G. H.; Switzer, C. J. Am. Chem. Soc. 1986, 108,
1239. (g) Posner, G. H.; Weitzberg, M.; Haill, T. G.;
Asirvatham, E.; Cun-Heng, H.; Clardy, J. Tetrahedron 1986,
42, 2919. (h) Posner, G. H. Acc. Chem. Res. 1987, 20, 72.
(15) Durst, T. In Comprehensive Organic Chemistry, Vol. 3;
Barton, D. R. H.; Ollis, W. D., Eds.; Pergamon: Oxford,
1979, 140–144.
2-Alkyl-Substituted 3-(Phosphorylmethyl)cyclopent-2-enones 7
and 8; General Procedure
To a stirred soln of t-BuOK (1.2 equiv) in freshly distilled DMPU
(2 mL per mmol) cooled to –10 °C was added a soln of 6a (1 mol
equiv) in DMPU (1 mL per mmol) and the resulting soln was stirred
at –10 °C for 1 h. Then, alkyl iodide (1.8 equiv) was added and the
mixture was stirred at 0 °C for 48 h. The mixture was quenched with
10% aq HCl (10 mL) and extracted with CHCl3 (3 × 15 mL). The
combined organic phases were dried (MgSO4) and evaporated un-
der reduced pressure. The residue was dissolved in benzene (5 mL)
and the resulting soln was stirred at 40 °C for 2 h. After evaporation
of benzene, the crude product was purified by column chromatog-
raphy (hexane–acetone, 2:1).
3-[(Diethoxyphosphoryl)methyl]-2-methylcyclopent-2-enone
(7)9
Colorless oil; yield: 0.066 g (60%).
(16) Yechezkel, T.; Ghera, E.; Ostercamp, D.; Hassner, A. J. Org.
1H NMR (200 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 6 H), 1.73 (t,
J = 2.1 Hz, 3 H), 2.16 (m, 2 H), 2.55 (m, 2 H), 2.96 (d, J = 23.9 Hz,
2 H), 4.10 (d, J = 7.1 Hz, J = 11.1 Hz, 4 H).
31P NMR (80 MHz, CDCl3): d = 24.2.
Chem. 1995, 60, 5135.
(17) The starting cyclohexenyl sulfoxide was prepared by
oxidation of the corresponding sulfide according to ref. 16.
However, our product was crystalline and not an oil as
reported. For full spectroscopic and analytical data, see the
experimental part.
Synthesis 2007, No. 8, 1225–1229 © Thieme Stuttgart · New York