Synthesis of 4-Oxo-2-alkenylphosphonates via Nitrile Oxide Cycloaddition: γ-Acylation of Allylic Phosphonates

Full text of DOI:10.1021/jo991261y

256
J . Org. Chem. 2000, 65, 256-257
Sch em e 1
Syn th esis of 4-Oxo-2-a lk en ylp h osp h on a tes
via Nitr ile Oxid e Cycloa d d ition :
γ-Acyla tion of Allylic P h osp h on a tes
Shi Yong Lee, Bum Sung Lee, Chi-Wan 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 August 9, 1999
A long polyethylenic chain is frequently exhibited in
the structure of natural compounds such as retinoids and
carotenoids.1 Accordingly, considerable interest has been
devoted to the construction of long conjugated chains, and
many of the attempted methods have employed function-
alized phosphonates under Wadsworth-Emmons olefi-
nation conditions. γ-Phosphonocrotonates2 and protected
phosphonoaldehydes3 have been mainly used as building
blocks, whereas the preparations and the applications of
4-oxo-2-alkenylphosphonates are less known.4 A few
literature references for 4-oxo-2-alkenylphosphonates
furnish synthetic approaches to them that involve Wittig
reaction of 2-oxoalkylphosphonium ylides with R-phospho-
noaldehydes5 and the oxidation of the corresponding
alcohols within the limits of aromatic derivatives.6 We
herein present the synthesis of 4-oxo-2-alkenylphospho-
nates from allylic phosphonates using 2-isoxazolines as
intermediates. Nitrile oxide cycloaddition chemistry has
been well developed as a tool for the introduction of
various functionalities,7 but no one has used it yet to
prepare 4-oxo-2-alkenylphosphonates.
Ta ble 1. Cycloa d d ition of Nitr ile Oxid es to Allylic
P h osp h on a tes a n d Elim in a tive Rin g Op en in g of
P h osp h on oa lk yl-2-isoxa zolin es
Nitrile oxides, generated via a Mukaiyama procedure,8
were cycloadded to allylic phosphonates (1) that were
available from an Arbuzov reaction9 and R-alkylation10
of the resultant allylphosphonate (Scheme 1). A cycload-
dition reaction under the condition of anhydrous THF,
room temperature, and 15 h afforded the phosphonate-
containing 2-isoxazolines (2) in good yields (Table 1). As
expected for the terminal olefins as dipolarophiles,7,11 the
substituents bearing the phosphonate moiety occupied
* 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.
(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) (a) Ohler, E.; Kang, H.-S.; Zbiral, E. Chem. Ber. 1988, 121, 299.
(b) Ohler, E.; Kang, H.-S.; Zbiral, E. Synthesis 1988, 623.
(6) Muller, E. L.; Modro, A. M.; Modro, T. A. Org. Prep. Proced. Int.
1999, 31, 216.
(7) For reviews, see: Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH: New York, 1988.
(8) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339.
(9) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307.
the 5-position of the 2-isoxazoline rings uniformly, and
no regio-inverted products were observed. When internal
olefins such as crotyl- and 2-cyclohexenylphosphonate
were employed, regio-confused mixtures whose two com-
ponents are not separable from each other were obtained
in poor yields.
The phosphonoalkyl-2-isoxazolines 2 underwent elimi-
native ring fission on treatment with LDA in anyhdrous
THF at -78 °C followed by addition of AcOH to give
γ-phosphono-R,â-unsaturated oximes (3) (Scheme 1).12
After general workup without additional purification, the
oximes 3 were treated with an aqueous HCl solution of
titanium(III) chloride in DMF, and the mixture was
stirred for about 7 h at room temperature to afford the
hydrolyzed 4-oxo-2-alkenylphosphonates (4).
(10) (a) Yuan, C.; Zhang, R.; Yao, J . Chem. Abstr. 1987, 107, 39948t.
(b) Phillips, A. M. M. M.; Modro, T. A. Phosphorus, Sulfur Silicon Relat.
Elem. 1991, 55, 41.
(11) Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 291-
392.
(12) J ager, V.; Grund, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
50.
10.1021/jo991261y CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/15/1999

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 257
internal standard. The starting materials were synthesized as
described in the literature with minor modification.
Sch em e 2
Gen er a l P r oced u r e for th e Cycloa d d ition of Nitr ile
Oxid es to Allylic P h osp h on a tes. To a stirred solution of allylic
phosphonate 1 (2.0 mmol), nitroalkane (2.4 mmol), and 4-chlo-
rophenyl isocyanate (0.627 g, 4.0 mmol) in anhydrous THF (6
mL) under N2 at room temperature was added 10 drops of
triethylamine. After being stirred for 15 h, the mixture was
diluted with diethyl ether, washed with water, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (EtOAc/acetone, 80/
20) to give phosphonoalkyl-2-isoxazoline 2 as a colorless oil.
5-Dieth ylp h osp h on om eth yl-3-m eth yl-2-isoxa zolin e (2a ):
1H NMR (300 MHz, CDCl3) δ 1.26 (t, J ) 5.0 Hz, 6H), 1.91-
2.05 (m, 1H), 1.94 (s, 3H), 2.17-2.30 (m, 1H), 2.79-2.87 (m, 1H),
2.99-3.09 (m, 1H), 4.00-4.11 (m, 4H), 4.72-4.82 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 13.1, 16.3 (d, J ) 6.1 Hz), 31.7 (d, J )
136.7 Hz), 44.3 (d, J ) 4.1 Hz), 61.8 (d, J ) 6.5 Hz), 75.0, 155.6;
MS m/z (relative intensity) 236 (M+ + H+, 0.84), 235 (M+, 0.46),
125 (100).
Gen er a l P r oced u r e for t h e Syn t h esis of 4-Oxo-2-a l-
k en ylp h osp h on a tes (4) fr om P h osp h on oa lk yl-2-isoxa zo-
lin es (2). To a stirred solution of phosphonoalkyl-2-isoxazoline
2 (1.0 mmol) in anhydrous THF (6 mL) under N2 at -78 °C was
added LDA (0.50 mL of a 2.0 M solution in heptane/THF/
ethylbenzene, 1.0 mmol) dropwise by syringe, and the mixture
was stirred for 1 h. The cooling bath was removed, and the
mixture was allowed to reach room temperature. After 30 min,
glacial acetic acid (0.12 mL, 2.0 mmol) and brine solution (2 mL)
were added in turn, and then the mixture was extracted with
dichloromethane. The combined organic extracts were washed
once with water and filtered through a short column packed with
MgSO4. Removal of the solvent left a crude oil, which then was
dissolved in DMF (4 mL), treated with titanium(III) chloride (6.2
mL of an 8.6% solution in 28% hydrochloric acid), and stirred
for ca. 7 h at room temperature. After addition of water (10 mL)
the reaction mixture was extracted with diethyl ether. The
combined extracts were washed with water and saturated
NaHCO3 solution, dried over MgSO4, and concentrated in vacuo.
The residue was subjected to silica gel chromatography (EtOAc/
EtOH, 95/5) to give 4 as a colorless oil.
The results are summarized in Table 1. The products
bearing no substituent at the 2-position (4a -c) were
typically in only E configuration, whereas for 4d and 4e
the (Z)-olefins were obtained as the major products along
with the (E)-olefins in the ratio of 1.7:1.13 These results
are attributed to a steric interaction of the 2-methyl
group, which is from the starting allylic phosphonate 1c.
Comparing starting materials with products, the over-
all procedure represents the regioselective acylation of
allylic phosphonates at the γ-position. In general, lithi-
ated derivatives of allylic phosphonates show both R- and
γ-orientation or exclusive R-orientation in their nucleo-
philic reactions toward acyl chlorides, esters, or other
appropriate carbonyl electrophiles.14 For the exclusive
γ-carbonylation of allylic phosphonates, Collignon and co-
workers recently tried the transient introduction of a
bulky trimethylsilyl group at the R-position for blocking.15
For the purpose of practical application of our products
4 as building blocks for synthesis of polyethylene-
structured natural compounds such as retinoids, their
olefinating ability under Wadsworth-Emmons conditions
must be examined. Actually, our attempt to olefinate an
aldehyde directly with 4 proved to be successful. As
shown in Scheme 2, the reaction of benzaldehyde with
the sodium anion of diethyl 4-oxo-2-hexenylphosphonate
(4b) gave the corresponding dienone 5 with the E
configuration in a good yield of 86%. There is a literature
example that 4-oxo-2-alkenylphosphonate was applied to
the synthesis of retinoids as an important building block.
Font et al. prepared the ethylene ketal of dimethyl 4-oxo-
2-pentenylphosphonate by Arbuzov reaction of trimethyl
phosphite with the ethylene ketal of 5-bromo-3-penten-
2-one, which was rather difficult to obtain.16 Condensa-
tion of this phosphonate with â-ionone using NaH as a
base yielded â-C18-tetraenone, which is an important
precursor to retinol derivatives,1 after acidic hydrolysis.
In conclusion, we have provided a novel synthetic route
to 4-oxo-2-alkenylphosphonates, which can serve as use-
ful building blocks for synthesis of natural products
containing a polyethylenic chain by four-carbon chain
elongation. The synthetic procedure to 4-oxo-2-alke-
nylphosphonates from allylic phosphonates via 2-isox-
azolines, generated through cycloaddition of nitrile ox-
ides, presents a new method for regioselective γ-acylation
of allylic phosphonates.
Dieth yl (E)-4-oxo-2-p en ten ylp h osp h on a te (4a ): 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 (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.
7-P h en yl-4,6-h ep ta d ien -3-on e (5). To a suspension of so-
dium hydride (0.020 g, 60%, 0.50 mmol) in anhydrous THF (2
mL) at room temperature was added diethyl 4-oxo-2-hex-
enylphosphonate (4b; 0.110 g, 0.47 mmol) in anhydrous THF (3
mL) slowly. The mixture was stirred until hydrogen evolution
had ceased and the solution was homogeneous (ca. 1 h), and then
benzaldehyde (0.057 mL, 0.56 mmol) was added. After the
mixture stirred for ca. 1 h, the reaction was quenched with an
aqueous NH4Cl solution, and the resulting solution was ex-
tracted with dichloromethane. The organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to give the crude
product. Purification by flash silica gel chromatography (EtOAc/
hexane, 10/90) furnished the dienone 5 as a colorless oil (0.075
g, 86%): 1H NMR (300 MHz, CDCl3) δ 1.12 (t, J ) 7.4 Hz, 3H),
2.61 (q, J ) 7.4 Hz, 2H), 6.27 (d, J ) 15.4 Hz, 1H), 6.81-6.94
(several peaks, 2H), 7.27-7.37 (several peaks m, 4H), 7.44-7.47
(several peaks, 2H); 13C NMR (75 MHz, CDCl3) δ 8.3, 33.9, 126.7,
127.2, 128.8, 129.1, 129.4, 136.1, 141.0, 142.2, 201.0.
Exp er im en ta l Section
Gen er a l. All reactions were conducted under an atmosphere
of nitrogen in oven-dried glassware with magnetic stirring. THF
was dried over and distilled from sodium metal with benzophe-
none as the indicator. 1H and 13C NMR spectra were recorded
in CDCl3 using either TMS, residual CHCl3, or solvent as an
Ack n ow led gm en t. This research was supported by
a grant from the Korea Advanced Institute of Science
and Technology.
(13) The configurations and the ratios of (E)- and (Z)-olefins were
determined by NOE experiment and 1H NMR analysis.
(14) (a) Yuan, C.; Chaozhong, L. Heteroat. Chem. 1992, 3, 637. (b)
Gerber, K. P.; Modro, T. A.; Muller, E. L.; Phillips, A. M. M. M.
Phosphorus, Sulfur Silicon Relat. Elem. 1993, 75, 19. (c) Al-Badri, H.;
About-J audet, E.; Combret, J .-C.; Collignon, N. Synthesis 1995, 1401.
(15) Al-Badri, H.; About-J audet, E.; Collignon, N. Tetrahedron Lett.
1995, 36, 393.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 2, 4, and 5. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) Camps, J .; Font, J .; De March, P. Tetrahedron 1981, 37, 2493.
J O991261Y