Preparation of asymmetric α-ketophosphonates by [3,3]-sigmatropic shift of enolphosphonates

Article abstract of DOI:10.1021/jo049133j

α-Ketophosphonates are prepared by a [3,3]-sigmatropic shift of enolphosphonates.

Full text of DOI:10.1021/jo049133j

SCHEME 1 a
P r ep a r a tion of Asym m etr ic
r-Ketop h osp h on a tes by [3,3]-Sigm a tr op ic
Sh ift of En olp h osp h on a tes
Kamyar Afarinkia,* Andrew J . Twist, and Hiu-wan Yu
Department of Chemistry, King’s College,
Strand, London WC2R 2LS, United Kingdom
kamyar.afarinkia@kcl.ac.uk
Received May 24, 2004
a
Reagents and conditions: (a) SO2Cl2 (1.3 equiv), 7 h, dark, rt;
Abstr a ct: R-Ketophosphonates are prepared by a [3,3]-
sigmatropic shift of enolphosphonates.
(b) H2O2 (4 equiv), NaHCO3 (4 equiv), CH2Cl2.
SCHEME 2 a
R-Ketophosphonates are one of the most interesting
and versatile classes of organophosphorus compounds.
R-Ketophosphonates undergo a diverse range of reactions
and therefore, have found many useful synthetic applica-
tions toward both the preparation of other organophos-
phorus compounds and the synthesis of non-phosphorus-
containing molecules.1 For instance, the reduction of
R-ketophosphonates affords the corresponding R-hydroxy-
phosphonates;2 treatment of R-ketophosphonates with a
Wittig reagent affords the corresponding vinylphospho-
nates;3 the corresponding oximes4 and hydrazones5 can
be obtained from the reactions of R-ketophosphonates
with hydroxylamine and hydrazine; â,γ-unsaturated-R-
ketophosphonates can be epoxidized6 and also undergo
a very facile Diels-Alder cycloaddition both as diene7 and
hetero-dienophile.8 Finally, the C-P bond in R-ketophos-
phonates is susceptible to facile cleavage under nucleo-
philic attack, for instance during acidic and basic hy-
drolysis,9 and therefore, R-ketophosphonates can be
considered as synthetic equivalents to acid chlorides.
More recently, asymmetric R-ketophosphonates contain-
ing a chiral phosphorus atom are prepared which provide
exciting opportunities for introducing an asymmetric
dimension in one or all of these reactions.10
a
Reagents and conditions: (a) LHMDS, THF, -78 °C, then
benzaldehyde.
SCHEME 3
One of the reactions of R-ketophosphonates which has
as yet remained unexplored is their C-alkylation at the
adjacent position to the CdO. Indeed, there are very few
examples in the literature pertaining to derivatization
at the â-carbon of R-ketophosphonates. Two examples of
halogenation of R-ketophosphonates are reported with
use of either elemental bromine or chlorine,11 or sulfuryl
chloride (Scheme 1).12 No base is required for either
reaction and it is not certain if the reactions proceed
through enolization of R-ketophosphonates or whether
they are radical initiated. Evans reported isolation of an
aldol product from the reaction of R-ketophosphonates 1
(Scheme 2) although the reaction affords substantial
quantities of a byproduct and its mechanism is unclear.10
Here, we report on a methodology for the C-allylation
of R-ketophosphonates 2 via a [3,3]-sigmatropic shift of
the corresponding allylenolphosphonates, 3 (Scheme 3).
Furthermore, we will show that asymmetric R-ketophos-
phonates undergo this reaction with diastereoselectivity
and that the selectivity in these reactions is influenced
by chirality at the phosphorus.
(1) (a) Afarinkia, K.; Vinader, M. V. The Synthesis of Acyl Phos-
phorus, -Arsenic, -Antimony or -Bismuth Functions. In Comprehensive
Organic Functional Group Transformations; Moody, C. J ., Ed.; Per-
gamon: London, 1995; Vol. 5, p 393. (b) Savignac, P.; Igora, B.
Ketophosphonates. In Modern Phosphonate Chemistry; CRC Press:
New York, 2003; p 319. (c) Afarinkia, K. The Synthesis of Acyl
Phosphorus, -Arsenic, -Antimony or -Bismuth Functions. In Compre-
hensive Organic Functional Group Transformations II; J ones, R. C.
F., Ed.; Elsevier: London, 2004; Vol. 5, in press.
(2) (a) Oshikawa, T.; Yamashita, M. Bull. Chem. Soc. J pn. 1990,
63, 2728. (b) Karaman, R.; Goldblum, A.; Breuer E.; Leader, H. J .
Chem. Soc., Perkin Trans. 1 1989, 765.
(3) Yamashita, M.; Kojima, M.; Yoshida, H.; Ogata T.; Inokawa, S.
Bull. Chem. Soc. J pn. 1980, 53, 1625.
(4) (a) Breuer, E.; Schlossman, A.; Safadi, M.; Gibson, D.; Chorev
M.; Leader, H. J . Chem. Soc., Perkin Trans. 1 1990, 3263. (b) Breuer,
E.; Zaher H.; Tashma, Z. Tetrahedron Lett. 1992, 2067.
(5) Scherer, H.; Hartmann, A.; Regitz, M.; Tunggal, B. D.; Gu¨nther,
H. Chem. Ber. 1972, 105, 3357.
(6) (a) O¨ hler, E.; Zbiral, E.; El-Badawi, M. Tetrahedron Lett. 1983,
24, 5599. (b) Hammerschmidt F.; Zbirol, E. Ann. Chem. 1979, 492.
(7) (a) Evans, D. A.; J ohnson, J . S.; Olhava, E. J . J . Am. Chem. Soc.
2000, 122, 1635. (b) Telan, L. A.; Poon, C.-D.; Evans, S. A., J r. J . Org.
Chem. 1996, 61, 7455.
(8) S. Hanessian, P.; Compain Tetrahedron 2002, 58, 6521.
(9) (a) Kume, A.; Fujii, M.; Sekine M.; Hata, T. J . Org. Chem. 1984,
49, 2139. (b) Sekine, M.; Satoh, M.; Yamagata, H.; Hata, T. J . Org.
Chem. 1980, 45, 4162. (c) Fujii, M.; Ozaki, K.; Sekine, M.; Hata, T.
Tetrahedron 1987, 43, 3395. (d) Breuer, E.; Karaman, R.; Goldblum,
A.; Leader, H. J . Chem. Soc., Perkin Trans. 2 1988, 2029. (e) Karaman,
R.; Goldblum, A.; Breuer, E.; Leader, H. J . Chem. Soc., Perkin Trans.
1 1989, 765.
We had previously demonstrated that the enol tau-
tomers of R-ketophosphonates are thermodynamically
(10) (a) Gordon, N. J .; Evans, S. A. J . Org. Chem. 1993, 58, 5293.
(b) Gordon, N. J .; Evans, S. A. Phosphorus Sulfur Silicon Relat. Elem.
1995, 75(1-4), 47.
(11) O¨ hler, E.; El-Badawi, M.; Zbiral, E. Chem. Ber. 1984, 117, 3034.
(12) Stevens, C.; De Buyck, L.; De Kimpe, N. Tetrahedron Lett. 1998,
39, 8739.
10.1021/jo049133j CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004
6500
J . Org. Chem. 2004, 69, 6500-6503

SCHEME 4
SCHEME 5 a
a
Reagents and conditions: (a) KHMDS, THF, -78 °C, 3 h; (b)
quite stable. Indeed, simple R-ketophosphonates undergo
very facile tautomerization to the extent that at room
temperature in polar solvents, significant quantities of
the enol tautomer can be spectroscopically observed
(Scheme 4).13 The enol tautomers can be “trapped” as
vinyl acetates,13 silylenol ethers,13 and sulfonates14 which
have in all cases been isolated as the E isomer. Although
a study of the relative stability of the enolate anions of
R-ketophosphonates has not been carried out, it can be
assumed that they are also thermodynamically quite
stable and that their formation is facile. Therefore, it was
doubtful from the outset if the enolates derived from
R-ketophosphonates would be reactive enough to undergo
C-alkylation. Indeed, enolate formation by treatment of
R-ketophosphonates 4a and 4b with organolithium bases
such as LDA and BuLi and attempted C-alkylation with
various electrophiles failed to give any desired product,
affording instead mainly unreacted R-ketophosphonates.
During the subsequent extensive studies with various
additives and reaction conditions, we failed to obtain any
C-alkylation products. Careful examination of some reac-
tion mixtures, however, revealed the presence of small
quantities of O-alkylation products. After further explo-
ration, it became possible to isolate phosphoenols 5a -
7a and 5b-7b by treatment of R-ketophosphonates 4a
and 4b with organopotassium bases such as t-BuOK and
KHMDS, followed by an excess of electrophiles such as
allyl bromide, crotyl chloride, and cinnamyl bromide
(Scheme 5). The enol configuration in all compounds was
found to be exclusively trans as determined by large 3J PH
couplings of 10-12 Hz, indicative of a cis arrangement
between the phosphorus atom and the olefinic hydrogen.
This is consistent with the previous observations on the
O-acylation, O-silylation, and O-sulfonation of enolphos-
phonates.13,14
allyl bromide, 25 °C, 15 h; (c) crotyl chloride, 25 °C, 15 h; (d)
cinnamyl bromide, 25 °C, 15 h.
SCHEME 6 a
a
Reagents and conditions: (a) toluene, reflux, 4 h.
SCHEME 7
room temperature for a period of days suggesting the
rearrangement is a facile reaction.
When heated at reflux in toluene, phosphoenols 5a -
7a and 5b-7b underwent a clean and facile [3,3]-sigma-
tropic rearrangement to the corresponding R-ketophos-
phonates 8a -10a and 8b-10b (Scheme 6). Interestingly,
all six phosphoenols showed trace amounts of the corre-
sponding rearranged R-ketophosphonates when stored at
Compounds 9a -10a and 9b-10b were obtained as a
single diastereomer as determined by 31P NMR spectro-
scopy. The relative configuration of the rearranged
products was deduced from a proposed chair transition
state for the sigmatropic shift (Scheme 7).
(13) Afarinkia, K.; Echenique J .; Nyburg, S. C. Tetrahedron Lett.
1997, 38, 1663.
(14) Okauchi, T.; Yano, T.; Fukomachi, T.; Ichikawa, J .; Minami,
T. Tetrahedron Lett. 1999, 40, 5337.
Having shown that the [3,3]-sigmatropic shift is a
viable method for the synthesis of Câ-alkylated nonasym-
metric R-ketophosphonates, we next prepared asym-
J . Org. Chem, Vol. 69, No. 19, 2004 6501

SCHEME 8 a
SCHEME 10 a
a
Reagents and conditions: (a) BuLi, THF, -72 °Ca; (b) allyl
bromide (excess), warm to rt.
SCHEME 9 a
a
Reagents and conditions: (a) toluene, reflux, 5 h.
all six phosphoenols undergo an exceptionally facile
rearrangement even at room temperature.
All six R-ketophosphonates 18a -20a and 18b -20b
were obtained as diastereomeric mixtures as determined
by integration of the corresponding signals in 31P NMR
spectra. Compounds 18a (R1 ) Me) and 18b (R1 ) i-Pr)
were obtained as 78:22 and 72:28 ratio of diastereomers,
respectively. Best selectivities were observed for com-
pounds 20a (R1 ) Me) and 20b (R1 ) i-Pr) with ratio of
diastereomers being 87:13 and 82:18, respectively. The
relative configuration of the major diastereomer in 20b
was confirmed by X-ray crystallography to be the (RP,S,S)/
(SP,R,R) enantiomeric pair.
a
Reagents and conditions: (a) KHMDS, THF, -78 °C, 3 h; (b)
allyl bromide, 25 °C, 15 h; (c) crotyl chloride, 25 °C, 15 h; (d)
cinnamyl bromide, 25 °C, 15 h.
metric R-ketophosphonates 11a and 11b.15 It is expected
that the chiral phosphorus atom will induce asymmetry
in the C-C bond formation resulting in the formation of
asymmetric R-ketophosphonates.
Treatment of R-ketophosphonates 11a and 11b with
organolithium bases such as LDA and BuLi followed by
addition of allyl bromide failed to afford the expected
product. However, allylphosphonamidate 1316 was ob-
tained in moderate yield, presumably through the forma-
tion of phosphite anion 14 (Scheme 8). This result was
entirely consistent with the observations by Evans during
the attempted aldol reactions of 1 (Scheme 1).
Nevertheless, using an organopotassium base, we were
able to obtain reasonable yields of 15a -17a and 15b-
17b (Scheme 9). As before, phosphoenols 15a -17a and
15b-17b underwent a clean and facile [3,3]-sigmatropic
(Claisen) rearrangement when heated at reflux in toluene
to the corresponding R-ketophosphonates 18a -20a and
18b-20b (Scheme 10). Again there was evidence that
Although the difference between distereoselectivities
is fairly modest, two trends are discernible. First, the
distereoselectivity in the rearrangements of 15a , 16a ,
and 17a , where R1 is Me, is better than the corresponding
distereoselectivity in 15b, 16b, and 17b, where R1 is i-Pr.
This means that steric bulk in the R1 group disfavors the
formation of the major diastereomer. On the other hand,
distereoselectivity increases from 15a to 16a to 17a , and
(15) Afarinkia, K.; Angell, R.; J ones, C. L.; Lowman, J . Tetrahedron
Lett. 2001, 42, 743.
(16) (a) Denmark, S. E.; Chen, C.-T. J . Am. Chem. Soc. 1995, 117,
11879. (b) Denmark, S. E.; Chen, C.-T. J . Org. Chem. 1994, 59, 2922.
(c) Denmark, S. E.; Darrow, R. L. J . Org. Chem. 1990, 55, 5926.
6502 J . Org. Chem., Vol. 69, No. 19, 2004

SCHEME 11
Exp er im en ta l Section
Gen er a l P r oced u r e for P r ep a r a tion of P h osp h oen ols.
The corresponding alkyl halide (10 mmol) was added to a stirred
solution of R-ketophosphonate or R-ketophosphonamidate (0.5
mmol) in THF (25 mL) maintained under an argon atmosphere
at -78 °C. A 0.5 M solution of KHMDS in toluene (1.0 mL, 0.5
mmol) was added and the resulting solution was stirred at -78
°C for 3 h. The reaction mixture was allowed to warm to room
temperature and was stirred overnight. The reaction was
quenched by addition of 10% aqueous ammonium acetate (10
mL) and the organic products were extracted with diethyl ether
(3 × 20 mL). The combined organic extracts were washed with
brine (20 mL) and water (20 mL) and were dried over MgSO4.
The solvent was removed in vacuo to give the crude product.
The product was purified by column chromatography, using 50%
ethyl acetate in petroleum ether as eluent.
N-Tr it yl[3-m et h yl(3-p h en yl-2-p r op en yloxy)b u t -1-en e]-
1,3,2-oxa za p h op h or in a n e-2-on e, 17b: δH (CDCl3, 400 MHz)
0.55 and 1.33 (2H, m, CH2CH2CH2), 0.96 and 1.03 [2 × 3H, d,
J H ) 7 Hz, CH(CH3)2], 2.89 (1H, m, CHMe2), 3.06 and 3.54 (2H,
m, NCH2), 3.92 (2H, m, OCH2), 4.50 and 4.64 (2H, m, OCH2-
CHd), 5.72 (1H, m, CHdCHPh), 6.40 (1H, m, PCdCHCH3), 6.72
(1H, m, CHdCHPh), 7.08-7.51 (15H, m, ArH); δC {H} (CDCl3,
100 MHz) 21.0 and 22.7 [CH(CH3)2], 25.9 (d, J P ) 12 Hz,
CHMe2), 26.1 (d, J P ) 6 Hz, CH2CH2CH2), 46.5 (d, J P ) 25 Hz,
NCH2), 63.1 (d, J P ) 8 Hz, OCH2), 73.8 (CH2CHdCHPh), 77.8
(d, J P ) 3 Hz, CPh3), 125.3 (CH2CHdCHPh), 127.0 (aromatic
CH), 127.8 (aromatic CH), 130.8 (aromatic CH), 133.6 (CH2CHd
CHPh), 134.7 141.4 (d, J P ) 31 Hz, PCdCH), 143.4 (d, J P ) 215
Hz, PCdCH), 144.2 (aromatic C); δP {H} (CDCl3, 162 MHz) 16.7;
IR (liquid) 3060, 2968, 2912 (C-H str), 1638 (CdC str), 1255
(PdO str), 1050, 1024 (P-O str), 996 (P-O bnd), 918 (P-N bnd)
cm-1; m/z 563 (M+, 3), 363 (52), 243 (100, Ph3C+), 165 (22), 117
(18); found [M + Na]+ 586.2193, calcd for C36H38NO3PNa
586.2481.
also from 15b to 16b to 17b, where R2 (Scheme 11)
changes from hydrogen atom to methyl and then phenyl
groups.
On the basis of these observations, we can rationalize
the diastereoselectivity in the [3,3]-sigmatropic shifts
(Claisen rearrangements) by proposing two competing
transition states: TS-1 (which leads to the major dias-
tereomer) and TS-2 (which leads to the minor diastere-
omer) for the migration (Scheme 11). The axial placement
of the P-C bond is consistent with the previous observa-
tions of the preference for this conformation in 1,3,2-
oxazaphosphorinane-2-ones.15 Furthermore, we propose
that a near periplanar arrangement between ring P-X
(where X is a nitrogen or oxygen atom) and the C-O bond
is preferred. The previous successful models for alkyla-
tions of 2-alkyl-1,3,2-oxazaphosphorinanes16 and nucleo-
philic addition to 2-alkenyl-1,3,2-oxazaphosphorinanes17
are based on similar conformational preferences. Accord-
ing to this model, TS-1 is the preferred transition state
because the steric repulsion arising from the nitrogen
substituent can be accommodated at the expense of the
steric repulsion arising from the ring oxygen lone pair.
Gen er a l P r oced u r e for th e Th er m a l [3,3]-Sigm a tr op ic
Rea r r a n gem en t of P h osp h oen ols. A toluene (5 mL) solution
of phosphoenols (2 mmol) was refluxed for 5 h under an
atmosphere of argon. The solvent was removed in vacuo to give
the products.
N-Tr ityl-2-[1-oxo-4-(2-p r op yl)-3-p h en ylp en t-4-en yl]-1,3,2-
oxa za p h op h or in a n e-2-on e, 20b: δH (CDCl3, 400 MHz) 0.47
and 1.00 (2H, m, CH2CH2CH2), 0.95 and 1.02 [2 × 3H, d, J H
)
7 Hz, CH(CH3)2], 2.16 (1H, m, CHMe2), 2.71 and 3.44 (2H, m,
NCH2), 2.53 (1H, m, CHPh), 2.91 [2H, m, C(O)CH], 3.75 (2H,
m, OCH2), 5.05 (2H, m, CHdCH2), 5.94 (1H, m, CHdCH2), 7.01-
7.46 (20H, m, aromatic H); δC {H} (CDCl3, 100 MHz) 19.2 and
20.7 [CH(CH3)2], 25.6 (CH2CH2CH2), 28.9 (CHMe2), 46.4 (NCH2),
49.9 (CHPh), 60.9 [d, J P ) 48 Hz, C(O)CH], 66.5 (d, J P ) 9 Hz,
OCH2), 78.0 (d, J P ) 3 Hz, CPh3), 116.1 (CHdCH2), 126.7-144.4
(aromatic C and CH), 140.0 (CHdCH2), 217.6 [d, J P ) 156 Hz,
PC(O)]; δP {H} (CDCl3, 162 MHz) 2.7 (major), -0.3 (minor); IR
(CCl4) 3060, 2964, 2932 (C-H str), 1681 (CdO str), 1636 (CdC
str), 1263 (PdO str), 1046, 1028 (P-O str), 998 (P-O bnd), 912
(P-N bnd) cm-1; m/z 563 (M+, 6), 363 (100), 243 (100, Ph3C+),
165 (26), 117 (27); found [(2M + Na)]+ 1149.4901, calcd for
C72H76N2O6P2Na 1149.5071. Anal. Calcd for C36H38NO3P: C,
76.71; H, 6.80; N, 2.48. Found: C, 76.68; H, 6.85; N, 2.37.
In summary, we have shown that R-ketophosphonates
can be alkylated at the position adjacent to the CdO
function through a two-step process of O-allylation fol-
lowed by a [3,3]-sigmatropic shift. The reaction is ster-
eospecific affording exclusively the anti (threo) product.
Alkylation of asymmetric R-ketophosphonates is stereo-
selective affording the unlike18 enantiomeric pair (RP,S,S)/
(SP,R,R) as the major diastereomer.
Ack n ow led gm en t. We would like to thank EPSRC
and SmithKline Beecham for financial support to A.J .T.
and the Garlick Foundation for financial support to H.Y.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic characterization of all new com-
pounds and crystal data for compound 20b. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Afarinkia, K.; Binch, H. M.; De Pascale, M. E. Synlett 2000,
1769.
(18) For the use of the like and unlike nomenclature see ref 16b
and: Prelog, V.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1982, 21,
654.
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J . Org. Chem, Vol. 69, No. 19, 2004 6503