Efficient approach to 4-Oxo-2-alkenylphosphonates via regiospecific friedel - Crafts acylation

Article abstract of DOI:10.1021/jo0003504

Treatment of allylic and vinylic phosphorates with excess LiHMDS, followed by addition of chlorotrimethylsilane, afforded α- and γ-silylated allylic phosphonate mixtures. Without separation, these mixtures underwent the Friedel - Crafts reaction and base-

Full text of DOI:10.1021/jo0003504

J . Org. Chem. 2000, 65, 4175-4178
4175
Efficien t Ap p r oa ch to 4-Oxo-2-a lk en ylp h osp h on a tes via
Regiosp ecific F r ied el-Cr a fts Acyla tion
Bum Sung Lee, Shi Yong Lee, and Dong Young Oh*
Department of Chemistry, Korea Advanced Institute of Science and Technology,
373-1, Kusong-dong, Yusong-gu, Taejon 305-701, Korea
Received March 13, 2000
Treatment of allylic and vinylic phosphonates with excess LiHMDS, followed by addition of
chlorotrimethylsilane, afforded R- and γ- silylated allylic phosphonate mixtures. Without separation,
these mixtures underwent the Friedel-Crafts reaction and base-promoted isomerization to give
4-oxo-2-alkenylphosphonates, which can serve as building blocks for the construction of polyethylenic
chains.
In tr od u ction
Resu lts a n d Discu ssion
Our attempts to prepare 4-oxo-2-alkenylphosphonates
from easily obtainable starting materials were concen-
trated on selective γ-acylation of allylphosphonates, and
the Friedel-Crafts reaction seemed to be the most
appropriate solution. As shown in Scheme 1, R- and
γ-silylated allylphosphonates afford respectively 4-oxo-
2-alkenylphosphonates (i) and 4-oxo-1-alkenylphospho-
nates (ii), which can be easily isomerized to i, through
electrophilic addition of allylsilanes or vinylsilanes, and
a subsequent desilylation process.9
In this concept, silylation was carried out by treatment
of phosphonates 1 and 2 with excess LiHMDS in THF at
-78 °C followed by addition of chlorotrimethylsilane. Not
only allylic phosphonates,10 but also vinylic phospho-
nates,11 which were equivalent to allylic phosphonates
in the presence of base, were silylated as shown in
Scheme 2. It is noteworthy that the employment of vinylic
phosphonates expands the range of starting allylic phos-
phonates. The results of silylation are summarized in
Table 1. As expected, silylated allylic phosphonates were
obtained as mixtures of R- and γ-silylated products in
good yields. The ratios of R-addition products 4 are
increased, according to the bulkiness of the γ-substitu-
ents. Fortunately, the double bonds of all γ-silylated
phosphonates were completely migrated to afford γ-sily-
lated allylic phosphonates 3. This migration is attributed
to different anion-stabilizing power between the phos-
phonate and silane group.
The construction of polyethylenic structures, exhibited
in natural compounds such as retinoids and cartenoids,
by carbon chain elongation of a carbonyl compound has
been of great interest over the years.1 γ-Phosphonocro-
tonates2 and protected phosphonoaldehydes3 appeared to
be very useful reagents under the Horner-Wadsworth-
Emmons olefination conditions, whereas the preparation
and the application of 4-oxo-2-alkenylphosphonates are
less known.4 Recently, we synthesized 4-oxo-2-alke-
nylphosphonate by γ-acylation of allylic phosphonates
utilizing isoxazoline as an intermediate.5 In the course
of our study, it was found that regiospecific acylation at
the terminus of an allylic phosphonate containing various
substituents remains to be solved, because the substit-
uents are inclined to lessen site selectivity in nucleophilic
reactions of allylic phosphonates.6
As a result of our efforts to seek a more efficient
method, we disclose here the absolute regiospecific
synthesis of 4-oxo-2-alkenylphosphonates from variously
substituted allylic and vinylic phosphonates, using double
bond migration7 of vinylic phosphonate into allylic phos-
phonate and the aliphatic Friedel-Crafts acylation of
silanes.8
* To whom correspondence should be addressed. Phone: 82-42-869-
2819. Fax: 82-42-869-2810. E-mail: dyoh@sorak.kaist.ac.kr.
(1) For reviews, see: (a) Liu, R. S. H.; Asato, A. E. Tetrahedron 1984,
40, 1931. (b) Sporn, M. B.; Roberts, A. B.; Goodman D. S. The
retinoids: Biology, Chemistry and Medicine, 2nd ed.; Raven Press:
New York, 1994; pp 319-387.
(2) (a) Van den Tempel, P. J .; Huisman, H. O. Tetrahedron 1966,
22, 293. (b) Gedye, R. N.; Westaway, K. C.; Arora, P.; Bisson, R.; Khalil,
A. H. Can. J . Chem. 1977, 55, 1218. (c) Liu, R. S. H.; Asato, A. E.
Methods Enzymol. 1982, 88, 506.
To diversify silylated allylic phosphonates, R-alkylation
of 3 was carried out as shown in Scheme 3. The lithiated
derivative of 3a underwent nucleophilic reaction toward
ethyl iodide to give R-alkylated phosphonate 3a ′ in a good
yield of 90%.
Without any effort to separate R- and γ-silylated
mixtures, the resultant phosphonates were acylated by
reaction with acyl chloride in the presence of aluminum
chloride, followed by treatment of triethylamine to pro
vide 4-oxo-2-alkenylphosphonates in excellent yields
(Table 2).
(3) Duhamel, L.; Guillemont, J .; Le Gallic, Y.; Ple, G.; Poirier, J .-
M.; Ramondenc, Y.; Chabardes, P. Tetrahedron Lett. 1990, 31, 3129.
(4) Font, J .; De March, P. Tetrahedron 1981, 37, 2391.
(5) Lee, S. Y.; Lee, B. S.; Oh, D. Y. J . Org. Chem. 2000, 65, 259.
(6) (a) Alan, R. K.; Michaela, P.; Hengyuan, L.; Ernst A. Chem. Rev.
1999, 99, 665-722. (b) Yuan, C.; Chaozhong, L. Heteroat. Chem. 1992,
3, 637. (c) Geber, K. P.; Modro, T. A.; Muller, E. L.; Phillips, A. M. M.
M. Phosphorus, Sulfur, Silicon Relat. Elem. 1993, 75, 19. (d) Al-Bardri,
H.; About-J audt, E.; Combret, J .-C.; Collignon, N. Synthesis 1995, 1401.
(e) Al-Bardri, H.; About-J audt, E.; Collignon, N. Tetrahedron Lett. 1995,
36, 393.
(7) Kiddle, J . J .; Babler, J . H. J . Org. Chem. 1993, 58, 3572.
(8) (a) Colvin, E. W. Chem. Soc. Rev. 1978, 7, 15. (b) Magnus, P.;
Sarkar, T.; Djuric, S. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press:
Oxford, 1982; Vol. 7, p 515. (c) Colvin, E. W. Silicon Reagents in
Organic Synthesis; Academic Press: London, 1988.
As depicted in Scheme 4, the initial products after
acylation were mixtures of 4-oxo-2-alkenylphosphonates
(9) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761. (b) Parnes, Z.;
Bolestova, G. I. Synthesis 1984, 991.
(10) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307.
(11) Waszkuc, W.; J anecki, T.; Bodalski, R. Synthesis 1984, 1025.
10.1021/jo0003504 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/02/2000

4176 J . Org. Chem., Vol. 65, No. 13, 2000
Lee et al.
Ta ble 2. F r ied el-Cr a fts Acyla tion of r- a n d γ-Silyla ted
Sch em e 1
P r od u cts a n d Isom er iza tion
Sch em e 2
Ta ble 1. Sila tion of Allylic a n d Vin ylic P h osp h on a tes
a
b
P ) P(O)(OEt)2. Yield of isolated product. c The purified
d
product was a mixture of E/Z isomers in a ratio of 1:1.5. The
purified product was a mixture of E/Z isomers in a ratio of 4.5:1.
Sch em e 4
a
b
P ) P(O)(OEt)2.
The ratio was determined by 1H NMR
analysis. c Yield of isolated product.
Sch em e 3
bearing a methyl group at the 2-position was obtained
as a mixture of E and Z isomers in a ratio of 1:1.5. The
bulky isopropyl group at the 3-position of 6g led to
formation of (Z)-olefin as a minority in a ratio of 4.5:1,
whereas, for 6f with a less bulky ethyl group at the same
position, the Z isomer was not observed at all.
(6) and 4-oxo-1-alkenylphosphonates (5), and 5 under-
went double bond migration by promotion of triethyl-
amine to give 6, which is identical to the product from 3.
Only when benzoyl chloride was used as an electrophile
(6b), the yield of acylation was somewhat low, which
seems to be due to the fact that the phenyl group
competes with an allyl- or vinylsilane in the Friedel-
Crafts reaction. Most products were typically in only the
E configuration except 6c and 6g.12 The product 6c
Con clu sion
In conclusion, 4-oxo-2-alkenylphosphonates could be
obtained from allylic and vinylic phosphonates, which are
easily accessible starting materials, using Friedel-Crafts
acylation of silanes in good yields. This synthetic route
to 4-oxo-2-alkenylphosphonates is so short that the
overall yields are high. Also, this result might enlarge
the range of regiospecific acylation reactions of various
other allyl moieties.
(12) The configurations and the ratios of (E)- and (Z)-olefins were
determined by NOE experiments and 1H NMR analyses. These are
described precisely in the Supporting Information.

Efficient Approach to 4-Oxo-2-alkenylphosphonates
J . Org. Chem., Vol. 65, No. 13, 2000 4177
(dd, J ) 16.0, 4.7 Hz, 1H), 6.57-6.70 (m, 1H). 13C NMR (75
MHz, CDCl3): δ ) 16.2 (d, J ) 5.9 Hz), 26.8, 30.7 (d, J ) 137.6
Hz), 62.2 (d, J ) 6.7 Hz), 134.9 (d, J ) 13.1 Hz), 136.4 (d, J )
11.1 Hz), 197.4 (d, J ) 2.9 Hz). HRMS: m/z (M+) calcd for
C9H17O4P 220.0864, found 220.0873.
Dieth yl (E)-4-Oxo-4-ph en yl-2-bu ten ylph osph on ate (6b).
1H NMR (300 MHz, CDCl3): δ ) 1.25-1.32 (m, 6H), 2.84 (dd,
J ) 6.8, 22.9 Hz, 2H), 4.03-4.14 (m, 4H), 6.84-7.04 (m, 2H),
7.35-7.56 (m, 5H). 13C NMR (75 MHz, CDCl3): δ ) 16.4 (d, J
) 5.9 Hz), 31.0 (d, J ) 137.2 Hz), 62.3 (d, J ) 6.8 Hz), 128.5,
129.9, 130.1, 132.9, 137.5, 189.8. HRMS: m/z (M+) calcd for
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were conducted under
an atmosphere of N2 in oven-dried glassware with magnetic
stirring. THF was dried over and distilled from sodium metal
with benzophenone as the indicator. 1H NMR and 13C NMR
spectra were recorded in CDCl3 using TMS, residual CHCl3,
or solvent as an internal standard. The starting materials were
synthesized as described in the literature with minor modifica-
tion.
Gen er a l P r oced u r e for Silyla tion of Allylic a n d Vi-
n ylic P h osp h on a tes. To a stirred solution of allylic or vinylic
phosphonate (2.0 mmol) in dry THF (10 mL) under N2 at -78
°C was added the proper base (LiHMDS, 4.0 mL of a 1.0 M
solution in THF for allylic phosphonates, 4.0 mmol; LDA, 2.0
mL of a 2.0 M solution in heptane/THF/ethylbenzene for vinylic
phosphonates, 4.0 mmol) dropwise. Stirring the mixture for
about 1 h was followed by addition of chlorotrimethylsilane
(0.244 g, 2.2 mmol). The cooling bath was removed, and the
mixture was stirred at rt for 1 h. An aqueous NH4Cl solution
(2 mL) was added, and the resulting solution was extracted
with diethyl ether. The combined organic extracts were washed
with water, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography (ethyl acetate/hexane, 3:2) to give the sily-
lated allylic phosphonate 3 and/or 4 as a colorless oil.
Dieth yl (E)-3-Tr im eth ylsilyl-2-p r op en ylp h osp h on a te
C
14H19O4P 282.1021, found 282.1026.
Dieth yl 2-Meth yl-4-oxo-2-p en ten ylp h osp h on a te (6c). A
mixture of E and Z stereoisomers was obtained in a ratio of
1:1.5 determined by NOE experiment and 1H NMR analysis.
1H NMR (300 MHz, CDCl3): δ ) 1.23-1.31 (several peaks,
6H), 2.00 (dd, J ) 3.8, 1.4 Hz, 3 × 17/27H), 2.14 (s, 3 × 17/
27H), 2.15 (s, 3 × 10/27H), 2.22 (dd, J ) 3.5, 1.4 Hz, 3 × 10/
27H), 2.62 (d, J ) 23.6 Hz, 2 × 10/27H), 3.43 (d, J ) 25.2 Hz,
2 × 17/27H), 4.01-4.11 (m, 4H), 6.16 (br d, J ) 4.8 Hz, 1H).
NOE: 6.16 (2.00, 3.0%; 2.22, 0.1%; 2.62, 2.2%; 3.43, 0.9%). 13
C
NMR (50 MHz, CDCl3): δ ) 16.2 (d, J ) 6.3 Hz), 16.3 (d, J )
6.0 Hz), 20.4 (d, J ) 2.8 Hz), 26.2 (d, J ) 2.1 Hz), 26.3, 31.1
(d, J ) 131.5 Hz), 31.7, 31.8, 38.6 (d, J ) 133.9 Hz), 61.9 (d, J
) 6.5 Hz), 62.1 (d, J ) 6.7 Hz), 125.9 (d, J ) 11.3 Hz), 127.3
(d, J ) 11.5 Hz), 147.8 (d, J ) 11.2 Hz), 197.9, 198.0. HRMS:
m/z (M+) calcd for C10H19O4P 234.1021, found 234.1030.
Dieth yl (E)-3-Meth yl-4-oxo-2-pen ten ylph osph on ate (6d).
1H NMR (300 MHz, CDCl3): δ ) 1.24 (t, J ) 7.1 Hz, 6H), 1.73
(d, J ) 5.0 Hz, 3H), 2.24 (s, 3H), 2.72 (dd, J ) 7.9, 23.0 Hz,
2H), 3.99-4.09 (m, 4H), 6.54 (q, J ) 8.2 Hz, 1H). NOE: 1.73
(2.72, 5.5%; 6.54, 1.8%). 13C NMR (75 MHz, CDCl3): δ ) 11.2
(d, J ) 2.3 Hz), 16.3 (d, J ) 5.9 Hz), 25.5, 27.8 (d, J ) 137.9
Hz), 62.2 (d, J ) 6.8 Hz), 131.3 (d, J ) 11.3 Hz), 140.9 (d, J )
13.3 Hz), 198.9 (d, J ) 2.9 Hz). HRMS: m/z (M+) calcd for
1
(3a ). H NMR (300 MHz, CDCl3): δ ) 0.00 (s, 9H), 1.24 (t, J
) 7.1 Hz, 6H), 2.62 (dd, J ) 6.2, 21.9 Hz, 2H), 3.95-4.08 (m,
4H), 5.77-5.94 (m, 2H). 13C NMR (75 MHz, CDCl3): δ ) -1.5,
16.3 (d, J ) 6.0 Hz), 34.7 (d, J ) 135.5 Hz), 61.8 (d, J ) 6.7
Hz), 134.4 (d, J ) 11.0 Hz), 136.8 (d, J ) 12.2 Hz).
Alk yla tion of γ-Silyla ted Allylp h osp h on a te. To a stirred
solution of diethyl 3-trimethylsilyl-2-propenylphosphonate (3a ;
0.225 g, 0.90 mmol) in anhydrous THF (4 mL) under N2 at
-78 °C was added LiHMDS (0.90 mL of a 1.0 M solution in
THF, 0.90 mmol) dropwise. Stirring the mixture for about 1 h
was followed by addition of iodoethane (0.12 mL, 1.5 mmol).
The cooling bath was removed, and the mixture was allowed
to reach rt. After 1 h an aqueous NH4Cl solution (1 mL) was
added, and the resulting solution was extracted with diethyl
ether. The combined organic extracts were washed with water,
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by chromatography on a silica gel
column using a mixture of ethyl acetate and hexane (1:1) as
eluent to give the alkylated product 3a ′ (0.226 g, 90%) as a
colorless oil.
C
10H19O4P 234.1021, found 234.1014.
Dieth yl (E)-3-Meth yl-4-oxo-2-h exen ylph osph on ate (6e).
1H NMR (300 MHz, CDCl3): δ ) 1.02 (t, J ) 7.2 Hz, 3H), 1.25
(t, J ) 7.0 Hz, 6H), 1.76 (d, J ) 3.9 Hz, 3H), 2.63 (q, J ) 7.2
Hz, 2H), 2.73 (dd, J ) 7.9, 23.1 Hz, 2H), 4.00-4.10 (m, 4H),
6.54 (q, J ) 8.0 Hz, 1H). NOE: 1.76 (2.73, 4.0%; 6.54, 1.4%).
13C NMR (75 MHz, CDCl3): δ ) 8.5, 11.5 (d, J ) 2.2 Hz), 16.3
(d, J ) 5.9 Hz), 27.7 (d, J ) 138.2 Hz), 30.5, 62.2 (d, J ) 6.8
Hz), 129.6 (d, J ) 11.2 Hz), 140.3 (d, J ) 13.3 Hz), 201.6 (d, J
) 2.9 Hz). HRMS: m/z (M+) calcd for C11H21O4P 248.1177,
found 248.1166.
Diet h yl (E)-3-E t h yl-5-m et h yl-4-oxo-2-h ep t en ylp h os-
p h on a te (6f). 1H NMR (300 MHz, CDCl3): δ ) 0.81 (t, J )
7.4 Hz, 3H), 0.91 (t, J ) 7.5 Hz, 3H), 1.02 (d, J ) 6.8 Hz, 3H),
1.29 (t, J ) 7.0 Hz, 6H), 1.26-1.40 (m, 1H), 1.58-1.72 (m, 1H),
2.31 (q, J ) 7.5 Hz, 2H), 2.77 (dd, J ) 8.0, 23.2 Hz, 2H), 3.08
(sextet, J ) 6.7 Hz, 1H), 4.04-4.14 (m, 4H), 6.49 (q, J ) 7.5
Hz, 1H). NOE: 2.31 (2.77, 6.3%; 6.49, 1.7%). 13C NMR (75
MHz, CDCl3): δ ) 11.7, 13.4, 16.4 (d, J ) 5.9 Hz), 17.1, 19.3,
27.5 (d, J ) 137.8 Hz), 40.9, 62.2 (d, J ) 6.7 Hz), 128.8 (d, J
) 10.7 Hz), 146.3 (d, J ) 13.2 Hz), 205.2. HRMS: m/z (M+)
calcd for C14H27O4P 290.1647, found 290.1635.
Dieth yl 3-Isopr opyl-4-oxo-2-pen ten ylph osph on ate (6g).
A mixture of E and Z stereoisomers was obtained in a ratio of
4.5:1 determined by NOE experiment and 1H NMR analysis.
1H NMR (300 MHz, CDCl3): δ ) 1.05 (d, J ) 6.8 Hz, 2/11 ×
3H), 1.15 (d, J ) 7.0 Hz, 9/11 × 3H), 1.31 (t, J ) 7.1 Hz, 6H),
2.27 (s, 3H), 2.68-2.88 (m, 1H), 2.80 (dd, J ) 8.1, 23.3 Hz,
2H), 4.01-4.16 (m, 4H), 6.40 (q, J ) 7.6 Hz, 1H). NOE: 1.15
(2.80, 19.2%; 6.40, 3.3%). 13C NMR (75 MHz, CDCl3): δ ) 16.4
(d, J ) 5.9 Hz), 20.7 (d, J ) 1.9 Hz), 27.2 (d, J ) 138.5 Hz),
27.6 (d, J ) 15.5 Hz), 62.2 (d, J ) 6.8 Hz), 129.8, 150.2, 199.9.
HRMS: m/z (M+) calcd for C12H23O4P 262.1334, found 262.1331.
Dieth yl (E)-1-Eth yl-4-oxo-2-p en ten ylp h osp h on a te (6h ).
1H NMR (300 MHz, CDCl3): δ ) 0.89 (t, J ) 7.4 Hz, 3H), 1.25
(dt, J ) 2.8, 7.0 Hz, 6H), 1.58-1.70 (m, 1H), 1.87-1.98 (m,
1H), 2.22 (s, 3H), 2.42-2.59 (m, 1H), 3.96-4.09 (m, 4H), 6.11
(dd, J ) 16.0, 4.5 Hz, 1H), 6.51-6.61 (m, 1H). 13C NMR (75
MHz, CDCl3): δ ) 12.4 (d, J ) 15.2 Hz), 16.4 (d, J ) 5.3 Hz),
21.4 (d, J ) 5.4 Hz), 27.0, 43.8 (d, J ) 136.4 Hz), 62.2 (dd, J
(E)-1-E t h yl-3-t r im et h ylsilyl-2-p r op en ylp h osp h on a t e
(3a ′). H NMR (300 MHz, CDCl3): δ ) 0.03 (s, 9H), 0.88 (t, J
1
) 7.4 Hz, 3H), 1.22-1.28 (m, 6H), 1.51-1.64 (m, 1H), 1.76-
1.89 (m, 1H), 2.31-2.43 (m, 1H), 3.98-4.09 (m, 4H), 5.78-
5.80 (m, 2H). 13C NMR (75 MHz, CDCl3): δ ) -1.3, 12.3 (d, J
) 15.6 Hz), 16.4 (dd, J ) 3.4, 6.0 Hz), 21.3 (d, J ) 4.9 Hz),
47.6 (d, J ) 134.5 Hz), 61.8 (dd, J ) 7.0, 42.5 Hz), 135.8 (d, J
) 11.7 Hz), 140.2 (d, J ) 9.5 Hz).
Gen er a l P r oced u r e for F r ied el-Cr a fts Acyla tion of
Silyla ted Allylic P h osp h on a tes. To a stirred suspension of
aluminum chloride (0.202 g, 1.5 mmol) in anhydrous dichlo-
romethane (5 mL) under N2 at 0 °C was added the proper acyl
chloride (1.5 mmol). The solution was stirred until it was clear,
after which 3 and/or 4 (1.0 mmol) in anhydrous dichlo-
romethane (3 mL) was added, and the mixture was stirred for
1 h at the same temperature. An aqueous NH4Cl solution (2
mL) was added, and the resulting solution was extracted with
diethyl ether. The combined organic extracts were washed with
water, dried over MgSO4, and concentrated in vacuo. The
residue was dissolved in dichloromethane (3 mL) and treated
with triethylamine (0.14 mL, 1.0 mmol), and the solution was
stirred for about 30 min at rt. After removal of triethylamine
and solvent under vacuum, the crude product was purified by
chromatography on a silica gel column (ethyl acetate/ethanol,
10:1) to give a colorless oil (6).
Dieth yl (E)-4-Oxo-2-pen ten ylph osph on ate (6a). 1H NMR
(300 MHz, CDCl3): δ ) 1.24 (t, J ) 7.1 Hz, 6H), 2.18 (s, 3H),
2.68 (ddd, J ) 23.1, 7.9, 1.0 Hz, 2H), 3.98-4.09 (m, 4H), 6.10

4178 J . Org. Chem., Vol. 65, No. 13, 2000
Lee et al.
) 12.9, 6.9 Hz), 134.2 (d, J ) 12.5 Hz), 142.2 (d, J ) 9.2 Hz),
197.6. HRMS: m/z (M+) calcd for C11H21O4P 248.1177, found
248.1166.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR and HRMS spectra of all compounds 6 and NOE spectra
of 6d , 6e, 6f, and 6g are described in the Experimental Section.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This research was supported by
a grant from the Korea Advanced Institute of Science
& Technology and Department of Chemistry & School
of Molecular Science (BK21).
J O0003504