Synthesis of cyclopentenones via intramolecular HWE and the palladium-catalyzed reactions of allylic hydroxy phosphonate derivatives

Article abstract of DOI:10.1021/jo8004028

(Chemical Equation Presented) Palladium-catalyzed decarboxylative rearrangement of nonracemic phosphono allylic acetoacetates, or the intermolecular allylic substitution of nonracemic phosphono allylic carbonates with tert-butyl acetoacetate followed by h

Full text of DOI:10.1021/jo8004028

Synthesis of Cyclopentenones via Intramolecular HWE and the
Palladium-Catalyzed Reactions of Allylic Hydroxy Phosphonate
Derivatives
Bingli Yan and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of Missouri-St. Louis, One UniVersity BouleVard,
St. Louis, Missouri 63121-4499
cspill@umsl.edu
ReceiVed February 18, 2008
Palladium-catalyzed decarboxylative rearrangement of nonracemic phosphono allylic acetoacetates, or
the intermolecular allylic substitution of nonracemic phosphono allylic carbonates with tert-butyl
acetoacetate followed by hydrolysis and decarboxylation, gave ω-ketovinyl phosphonates. A highly
regioselective Wacker oxidation gave the ω,ꢀ-diketophosphonates which underwent intramolecular HWE
reaction to give nonracemic cyclopentenones. An aldol condensation leading to phosphonocyclopentenones
was competitive with the HWE reaction. The stereochemistry of the cyclopentenone and the ratio of
HWE to aldol products were dependent upon the choice of base used in the reaction.
SCHEME 1. Formation of Cyclopentenones via the
Intramolecular HWE Reaction
Introduction
The cyclopentenone ring system is a structural feature found
in numerous natural products.1 Consequently, methods for the
synthesis of the cyclopentenone ring system, particularly with
control of absolute stereochemistry, are highly desirable.2 An
attractive method for generating cyclopentenones is the in-
tramolecular Horner-Wadsworth-Emmons (HWE) reaction
(Scheme 1),3 which has seen application in natural product
synthesis, for example Jasmone,3a Jatraphone,3b modhephene,3c
and carbacephalosporins.3d
The formation of cyclopentenones 3 via the intramolecular
HWE reaction requires access to the precursor diketophospho-
nates 2. Among the published methods for forming diketo
phosphonates 2, the Wacker oxidation of the vinyl phosphonates
1 caught our attention.4 In this remarkable reaction, a vinyl
phosphonate 1 is oxidized with high regioselectivity to give a
ꢀ-ketophosphonate 2.
(1) For examples of cyclopenentone-containing natural products see: (a)
Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem. Soc., Perkin Trans. 1
2002, 1735. (b) Howe, G. A. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 12317.
(2) For examples of cyclopentenone synthesis see: (a) Piancatelli, G.; D’Auria,
M.; D’Onofrio, F. Synthesis 1994, 867, and references cited therein. (b) Schore,
N. E. Org. React. 1991, 40, 1. (c) Pauson, P. L. Tetrahedron 1985, 41, 5855.
(d) Llebaria, A.; Moreto´, J. M. J. Organomet. Chem. 1993, 451, 1. (e) Piancatelli,
G. Heterocycles 1982, 19, 1735. (f) Ellison, R. A. Synthesis 1973, 397.
(3) (a) Clark, R. D.; Kozar, L. G.; Heathcock, C. H. Synth. Commun. 1975,
5, 1. (b) Han, Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692. (c) Kraus,
G. A.; Shi, J. J. Org. Chem. 1991, 56, 4147. (d) Stocksdale, M. G.; Ramurthy,
S.; Miller, M. J. J. Org. Chem. 1998, 63, 1221. (e) Aristoff, P. A. J. Org. Chem.
1981, 46, 1954. (f) Dauben, W. G.; Walker, D. M. Tetrahedron Lett. 1982, 23,
711. (g) Piers, E.; Abeysekera, B.; Scheffer, J. R. Tetrahedron Lett. 1979, 3279.
(h) Begley, M. J.; Cooper, K.; Pattenden, G. Tetrahedron Lett. 1981, 22, 257.
(i) Aristoff, P. A. Synth. Commun. 1983, 13, 145. (j) Poss, A. J.; Belter, R. K.
J. Org. Chem. 1987, 52, 4810. (k) Davidsen, S. K.; Heathcock, C. H. Synthesis
1986, 842. (l) Altenbach, H. J.; Rainer, K. Angew. Chem. 1982, 94, 388. (m)
Connolly, P. J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 4135.
As part of an ongoing program5 exploring the chemistry of
allylic hydroxy phosphonates 4 and following the original work
of Zhu and Lu,6 we had shown that substituted vinyl phospho-
(4) (a) Sturtz, G.; Pondaven-Raphalen, A. J. Chem. Res. (S) 1980, 175. (b)
Poss, A. J.; Smyth, M. S. Synth. Commun. 1987, 17, 1735.
(5) (a) De la Cruz, M. A.; Shabany, H.; Spilling, C. D. Phosphorus, Sulfur
Silicon 1999, 144-146, 181. (b) Shabany, H.; Spilling, C. D. Tetrahedron Lett.
1998, 39, 1465. (c) Thanavaro, A.; Spilling, C. D. Phosphorus, Sulfur Silicon
2002, 177, 1583. (d) Boehlow, T. R.; Spilling, C. D. Tetrahedron Lett. 1996,
37, 2717.
(6) (a) Zhu, J.; Lu, X. Chem. Commun. 1987, 1318. (b) Zhu, J.; Lu, X.
Tetrahedron Lett. 1987, 28, 1897.
10.1021/jo8004028 CCC: $40.75
Published on Web 06/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5385–5396 5385

Yan and Spilling
SCHEME 2. Palladium-Catalyzed Nucleophilic Substitution Reaction of Phosphono Allylic Carbonates
SCHEME 3. Proposed Methods for the Asymmetric Synthesis of Diketophosphonates
SCHEME 4. The Palladium-Catalyzed Carroll
Rearrangement
substrates for the intramolecuar HWE reaction and therefore
develop a route to nonracemic cyclopentenones (Scheme 3). In
particular, two pathways can be envisioned that would allow
the stereospecific introduction of a ketone via C-C bond
formation, for example, palladium-catalyzed intermolecular
nucleophilic substitution (path A) or palladium-catalyzed in-
tramolecular rearrangement of acetoacetoxy phosphonates (path
B). Clearly, other well-known reactions of allylic alcohols, such
as the variants of the Claisen rearrangement,12 could also prove
fruitful.
The Carroll rearrangement,13 which was first reported in the
1940s, is the thermal 3,3 sigmatropic rearrangement of allylic
acetoacetate esters to ꢀ-keto acids followed by decarboxylation
to afford γ,δ-unsaturated ketones. However, since the reaction
requires a high temperature (usually higher than 180 °C) and is
sensitive to the structure of the substrate, it has not been widely
used in organic synthesis.14 In 1980, Tsuji and co-workers
reported the palladium-catalyzed Carroll rearrangement (Scheme
4).15 The rearrangement of allylic esters 8 or 9 in the presence
of Pd(OAc)2 and phosphine ligands in refluxing THF proceeded
smoothly to give a regioisomeric mixture of γ,δ-unsaturated
methyl ketones 10 and 11. There have been several recent
reports of methods to control both the regio- and enantioselec-
SCHEME 5. Preparation of Allylic Hydroxy Phosphonates
(10) (a) Rowe, B. J.; Spilling, C. D. Tetrahedron: Asymmetry 2001, 12, 1701.
(b) Groaning, M. D.; Rowe, B. R.; Spilling, C. D. Tetrahedron Lett. 1998, 39,
5485. (c) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
1993, 4, 1779. (d) Rath, N. P.; Spilling, C. D. Tetrahedron Lett. 1994, 35, 227.
(e) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993,
4, 1783. (f) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. J. Chem. Soc., Perkin
Trans. 1 1997, 1527. (g) Sasai, H.; Bougauchi, M.; Arai, T.; Shibasaki, M.
Tetrahedron Lett. 1997, 38, 2717. (h) Arai, T.; Bougauchi, M.; Sasai, H.;
Shibasaki, M. J. Org. Chem. 1996, 61, 2926. (i) Duxbury, J. P.; Cawley, A.;
Thorton-Pett, M.; Wantz, L.; Warne, J. N. D.; Greatrex, R.; Brown, D.; Kee,
T. P. Tetrahedron Lett. 1999, 40, 4403. (j) Ward, C. V.; Jiang, M.; Kee, T. P.
Tetrahedron Lett. 2000, 41, 6181. (k) Saito, B.; Katsuki, T. Angew. Chem., Int.
Ed. 2005, 44, 4600. (l) Ito, K.; Tsutsumi, H.; Setoyama, M.; Saito, B.; Katsuki,
T. Synlett 2007, 1960.
nates 6 could be formed by the palladium-catalyzed nucleophilic
substitution reactions of the carbonate derivatives 5 of allylic
hydroxy phosphonates 4 (Scheme 2).7,8 Addition of the nucleo-
phile takes place exclusively at the 3-position to give the
γ-substituted vinyl phosphonates 6 in high yield and studies
with nonracemic allylic hydroxy phosphonate derivatives dem-
onstrate that the reaction proceeds with complete chirality
transfer.8 Furthermore, continued research has led to methods
for forming hydroxy phosphonates with high enantiopurity.9 In
particular, the metal-catalyzed asymmetric phosphonylation of
aldehydes10 and enzymatic kinetic resolution11 provides efficient
methodsforasymmetricsynthesisofallylichydroxyphosphonates.
It was hypothesized that using the exquisite control of regio-
and stereochemistry afforded by the phosphonate moiety, it
should be possible to construct nonracemic diketophosphonate
(11) (a) Li, Y.-F.; Hammerschmidt, F. Tetrahedron: Asymmetry 1993, 4, 109.
(b) Drescher, M.; Li, Y.-F.; Hammerschmidt, F. Tetrahedron 1995, 51, 4933.
(c) Drescher, M.; Hammerschmidt, F.; Ka¨hlig, H. Synthesis 1995, 1267. (d)
Eidenhammer, G.; Hammerschmidt, F. Synthesis 1996, 748. (e) Drescher, M.;
Hammerschmidt, F. Tetrahedron 1997, 53, 4627. (f) Zhang, Y.; Yuan, C.; Li,
Z. Tetrahedron 2002, 58, 2973. (g) Pa´mies, O.; Ba¨ckvall, J.-E. J. Org. Chem.
2003, 68, 4815.
(12) Cooper, D.; Trippett, S. J. Chem. Soc., Perkin Trans. 1 1981, 2127.
(13) (a) Carroll, M. F. J. Chem. Soc. 1940, 704. (b) Carroll, M. F. J. Chem.
Soc. 1940, 1266. (c) Carroll, M. F. J. Chem. Soc. 1941, 507. (d) Kimel, W.;
Cope, A. C. J. Am. Chem. Soc. 1943, 65, 1992.
(7) Rowe, B. J.; Spilling, C. D. J. Org. Chem. 2003, 68, 9502.
(8) (a) De la Cruz, A.; He, A.; Thanavaro, A.; Yan, B.; Spilling, C. D.; Rath,
N. P. J. Organomet. Chem. 2005, 690, 2577. (b) Yan, B.; Spilling, C. D. J. Org.
Chem. 2004, 69, 2859.
(14) Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722.
(9) For recent reviews see: (a) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry
2005, 16, 3295. (b) Wiemer, D. F. Tetrahedron 1997, 53, 16609. (c) Davies,
S. R.; Mitchell, M. C.; Cain, C. P.; Devitt, P. G.; Taylor, R. J.; Kee, T. P. J.
Organomet. Chem. 1998, 550, 29.
(15) (a) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu,
I. J. Org. Chem. 1987, 52, 2988. (b) Shimizu, I.; Yamada, T.; Tsuji, J.
Tetrahedron Lett. 1980, 21, 3199. (c) Tsuji, J. Pure Appl. Chem. 1982, 54, 197,
and references cited therein.
5386 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of Cyclopentenones Via Intramolecular HWE
SCHEME 6. Preparation of the Acetoacetate and Methylcarbonate Derivatives of Hydroxy Allylic Phosphonates
TABLE 1. The Palladium-Catalyzed Decarboxylative
Rearrangement of Phosphono Allylic Acetoacetates
tivity of the Carroll rearrangement through the choice of metal
complex employed as the catalyst.16
Results
By using previously published reaction procedures, the
racemic hydroxy phosphonates 4a-d were prepared (Scheme
5) by the Et3N-catalyzed addition of dimethyl phosphite to the
corresponding aldehyde 12.17 The nonracemic (R) phosphonates
4a-d (∼70% ee) were prepared by catalytic asymmetric
phosphonylation, using (L)-dimethyl tartrate and titanium iso-
propoxide as catalysts.10a Alternatively, the hydroxy phospho-
nates could be prepared by the cross-metathesis reaction of
phosphonates 4a or 4b with a terminal alkene.18 In particular,
the phosphonates with high enantiomeric excess (4c-f) were
prepared from the cross-metathesis between the cinnamyl
hydroxy phosphonate 4b and the corresponding alkenes. The
hydroxy phosphonate 4b can be crystallized to high enantiomeric
purity (90-95% ee).
The phosphono allylic carbonates 5 were prepared either from
corresponding hydroxy phosphonate 4 by reaction with methyl
chloroformate and pyridine in CH2Cl2 (Scheme 6) or by cross-
metathesis between the acrolein phosphono carbonate 5a and a
terminal alkene (Scheme 6) as previously described.18 Alter-
natively, reaction of hydroxy phosphonates 4 with diketene in
the presence of a catalytic amount of DMAP yielded the
phosphono acetoacetates 7 in 81-91% yields (Scheme 6). The
phosphono acetoacetates 7 were not stable and decomposed to
starting material if stored for prolonged periods of time. The
phosphono acetoacetates 7 could also be prepared by cross-
metathesis.18 Reaction of 7a with 4-methyl-1-pentene and
Grubbs second generation catalyst in CH2Cl2 gave phosphono
acetoacetate 7e.
% yield 1
entry compd
R
% ee (4)
(% ee)a
% yield 13b
1
2
3
4
b
c
d
e
Ph
71
65
70
(()
56 (71)
61 (65)
71 (70)
35 (()
n-C5H11
27
2
31
CH3
CH2CH(CH3)2
a Isolated yield; Conversion measured by 31P NMR spectroscopy
b
Palladium-catalyzed intramolecular decarboxylative rear-
rangement [Pd2(dba)3, dppe] of the phosphono acetoacetates 7
gave the vinyl phosphonates 3 (Table 1). However, with the
exception of 7b, which does not possess a δH, the competitive
formation of diene 13 as a mixture of geometric isomers was
observed. In each of the examples studied, the enantiomeric
ratio of the vinyl phosphonate product 1 reflected the enantio-
meric ratio of the starting hydroxy phosphonate 4, demonstrating
the stereospecific nature of the reaction. Attempts to improve
the yield of vinyl phosphonate 3 relative to the diene 13 by
changes in solvent, ligand, or adding base were not successful.
Attempted thermal rearrangement resulted in a multitude of
products.
Treatment of phosphono allylic carbonates 5 with tert-butyl
acetoacetate, Pd2(dba)3, and dppe in refluxing THF provided
the vinyl phosphonates 14 as intermediates, which were taken
directly into the next reaction without purification. After
removing THF in vacuo, the reaction mixture was dissolved in
toluene and TFA and heated at 80 °C for 1 h to afford the vinyl
phosphonates 1 in good to high chemical yields (Table 2). The
enantiomeric ratio of the vinyl phosphonates 1b-f, determined
(16) (a) Tunge, J. A.; Burger, E. C. Eur. J. Chem. 2005, 1715. (b) Burger,
E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. (c) Burger, E. C.; Tunge, J. A.
Chem. Commun. 2005, 2835. (d) He, H.; Zheng, X.-J.; Dai, L.-X.; You, S.-L.
Org. Lett. 2007, 9, 4339.
(17) (a) Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini, G. P.; Simoni, D.
Synthesis 1982, 653. (b) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165.
(18) He, A.; Yan, B.; Thanavaro, A.; Spilling, C. D.; Rath, N. P. J. Org.
Chem. 2004, 69, 8643.
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Yan and Spilling
TABLE 2. Palladium-Catalyzed Intermolecular Nucleophilic Substitution
a Determined by 31P NMR spectroscopy.
SCHEME 7. Addition of Ethyl 2-Cyclohexanone
Carboxylate
SCHEME 8. Wacker Oxidation of Vinyl Phosphonates
2-cyclohexanone carboxylate in the presence of Pd2(dba)3, dppe
and NaH in THF solution afforded vinyl phosphonate 15 in 53%
isolated yield as a 6:1 mixture of diastereoisomers. However,
in this case, formation of the diene 13c (17%) accompanied
the substitution reaction.
Treatment of vinyl phosphonates 1 with PdCl2, CuCl in DMF,
and H2O under 1 atm of oxygen yielded corresponding ω,ꢀ-
diketophosphonates 2 (Scheme 8). It was found that pretreating
the solution of PdCl2 and CuCl in DMF and H2O with O2 for
half an hour before the addition of the vinyl phosphonate 1 gave
better results.
by HPLC, reflected the enantiomeric ratio of the starting
phophono carbonate 5, again demonstrating that the reaction is
stereospecific. Unfortunately, the diastereomers 1g could not
be separated by HPLC. However, each diastereomer showed a
unique signal in the 31P NMR spectrum and therefore the ratio
could be determined by integration.
In general, the intermolecular allylic substitution gave much
better yields than the intramolecular decarboxylative rearrange-
ment. For example, when R ) Ph and CH2CH(Me)2, the
intermolecular substitution gave the vinyl phosphonate 1 in 97%
and 79% yield, respectively (Table 2, entries 1 and 3), whereas
the intramolecular decarboxylative rearrangement gave the vinyl
phosphonates 1 in 56% and 35% yield, respectively (Table 1,
entries 1 and 4). However, in the formation of vinyl phosphonate
1c, the intermolecular substitution and intermolecular rearrange-
ment gave a similar result (56% and 61% yield, respectively).
To further examine the nucleophilic substitution, a more
sterically hindered nucleophile was examined (Scheme 7).
Reaction of the phosphono allylic carbonate 5c with ethyl
The Wacker oxidation is slow and usually takes 3 days at
room temperature to go to completion. However, the reaction
is clean with high regioselectivity and no other products are
observed. The yields are generally very good (2b-f, 80-86%).
Oxidation of the vinyl phosphonate 1g was unique and gave
the diketophosphonate 2g in a lower 65% yield. This may be
due to the small electron-withdrawing effect of the benzyloxy
propyl group, which reduces the reactivity of alkene. Unfortu-
nately, the diketophosphonates 2 would not separate on any of
the several chiral stationary phases examined. However, it is
probable that the Wacker oxidation would not result in any
detectable levels of racemization. This fact was supported by
analysis of the NMR spectra (1H, 13C, 31P) of 2g, which showed
the same diastereomer ratios as the starting vinyl phosphonate
1g.
5388 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of Cyclopentenones Via Intramolecular HWE
SCHEME 9. The Intramolecular Aldol Reaction of
Diketophosphonates
crown-6 in THF at 40 °C provided cyclopentenones 3 in yields
ranging from 77% to 91% (Table 3, entries 1, 2, and 4).
Cyclization of the diketophosphonate 2d gave the cyclopen-
tenone 3d in a somewhat lower yield (63%), probably because
the product was volatile.
Unfortunately, when nonracemic diketophosphonates 2 were
used in the HWE reaction, the cyclopentenones were obtained
with variable levels of racemization. When phosphonates 2c
and 2e with 92% and 88% ee, respectively, (Table 3 entries 2
and 6), were subjected to the HWE reaction, the cyclopentenones
3c and 3e were isolated with 75% and 69% ee, respectively.
Reaction of the phosphonate 2b (Table 3, entry 1) always gave
the corresponding cyclopentenone as a racemic mixture. The
enolate is conjugated to the aromatic ring (Scheme 11) and is
therefore more stable and forms easily.
SCHEME 10. Wacker Oxidation and Aldol Condensation
Roush and Masamune reported that the combination of K2CO3
and 18-C-6 is capable of racemizing chiral centers next to a
ketone in the HWE.21 They also observed that a silyloxy group
(OSiMe2t-Bu) at the δ-position was eliminated when using
K2CO3 as the base. Whereas, DBU/LiCl avoided the problem
of elimination, these conditions failed to cyclize the diketo-
phosphonates 2.
The biphase system reported by Heathcock for intramolecular
HWE reactions was also investigated.3j,k Treatment of the
ketophosphonates 2c (65% ee) and 2e (83% ee) with 0.85 equiv
of 40 wt % of Bu4N+ -OH in H2O solution in toluene provided
products 3c and 3e in 60% and 42% isolated yield and with a
reduced 44% and 67% ee, respectively (Table 3, entries 4 and
7). Aldol products 16 were isolated and showed considerable
racemization of chiral center. Lithium hydroxide (Table 3 entry
10) gave similar results.
Paterson reported that Ba(OH)2 can be used as a base for
sensitive substrates in the intermolecular HWE reaction.22
Aldehydes and ketophosphonates bearing chiral centers R to
the carbonyl group, or with silyloxy groups (OSiMe2t-Bu) which
were prone to elimination, underwent HWE reaction smoothly
to yield the desired products without racemization, epimeriza-
tion, or elimination.
Treatment of diketophosphonate 2 with 0.8-0.95 equiv of
Ba(OH)2 in THF at room temperature gave the desired cyclo-
pentenones 3 with competitive formation of R-phosphonato-
R,ꢀ-unsaturated cyclopentenones 16 (Table 3, entries 2, 8, 11,
The diketophosphonates 2 are sensitive to silica gel and during
prolonged column chromatography an aldol reaction takes place
to give the R-phosphonato-R,ꢀ-unsaturated cyclopentenones 16
(Scheme 9). The rate of formation of aldol product varies greatly
depending on the substituents. No aldol products were observed
after the chromatographic purification of diketophosphonates
2b and 2d (R ) Ph and Me). However, chromatographic
purification of diketophosphonates 2c, 2e, 2f, and 2g always
resulted in some formation of the aldol product 16.
The role of SiO2 in formation of aldol products 16 was
verified by stirring diketophosphonates 2 in EtOAc over silica
gel and monitoring the reaction progress by 31P NMR spec-
troscopy. R-Phosphonato-R,ꢀ-unsaturated cyclopentenones 16
are very attractive synthetic intermediates and similar structures
were reported earlier by Oh and co-workers.19 However, it
appears that the R-phosphonato-R,ꢀ-unsaturated cyclopenten-
ones 16 racemize under the mildly acidic conditions in which
they form. The SiO2-catalyzed aldol reaction of the diketophos-
phonates 2c (>90% ee) gave the corresponding cyclopentenone
16c with <60% ee (Scheme 9). Indeed, the stereochemistry of
a sample stored in chloroform continued to erode.
The Wacker oxidation of the more hindered vinyl phospho-
nate 15 proceeded smoothly to afford diketophosphonate 17.
Again, a mixture of expected keto product 17 (31P ) 23 ppm)
and the aldol product R-phosphonato-R,ꢀ-unsaturated cyclo-
pentenone 18 (31P ) 14 ppm) with a 1:1.5 ratio was observed
after column chromatography (Scheme 10).
The Intramolecular Horner-Wadsworth-Emmons (HWE)
Reaction. The intramolecular HWE results in the formation of
carbocycles (and heterocycles) and has been applied to the
preparation of rings of various sizes. There have been several
sets of reaction conditions reported for both the intra- and the
intermolecular HWE reaction.3,20 The choice of base for the
intramolecular HWE reaction of diketophosphonates 2 proved
to be critical. Commonly used reaction conditions for intermo-
lecular HWE reactions (e.g., DBU/LiCl) failed to give the
desired products. Some of the stronger bases (e.g., NaH in DME)
gave cyclopentenone in low isolated yield (<10%). Fortunately,
treatment of the diketophosphonates 2 with K2CO3 and 18-
(20) (a) Ru¨bsam, F.; Evers, A. M.; Michel, C.; Giannis, A. Tetrahedron 1997,
53, 1707. (b) Heathcock, C. H.; Hadley, C. R.; Rosen, T.; Theisen, P. D.; Hecker,
S. J. J. Med. Chem. 1987, 30, 1858. (c) Heathcock, C. H.; Rosen, T. J. Am.
Chem. Soc. 1985, 107, 3731. (d) Astles, P. C.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 845. (e) Roush, W. R.; Warmus, J. S.; Works, A. B.
Tetrahedron Lett. 1993, 34, 4427. (f) Marshall, J. A.; DuBay, W. J. J. Org.
Chem. 1994, 59, 1703. (g) Mulzer, J.; Berger, M. Tetrahedron Lett. 1998, 39,
803. (h) Bonadies, F.; Cardilli, A.; Lattanzi, A.; Orelli, L. R.; Scettri, A.
Tetrahedron Lett. 1994, 35, 3383. (i) Blackwell, C. M.; Davidson, A. H.;
Launchbury, S. B.; Lewis, C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.;
Tipping, A. S.; Todd, R. S. J. Org. Chem. 1992, 57, 1935. (j) Rathke, M. W.;
Nowak, M. J. Org. Chem. 1985, 50, 2624. (k) Yamanoi, T.; Akiyama, T.; Ishida,
E.; Abe, K.; Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335. (l) Kann, N.; Rein,
T. J. Org. Chem. 1993, 58, 3802. (m) Kiefel, M. J.; Maddock, J.; Pattenden, G.
Tetrahedron Lett. 1992, 33, 3227.
(21) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(22) (a) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774. (b)
Paterson, I.; Yeung, K.-S.; Watson, C.; Ward, R. A.; Wallace, P. A. Tetrahedron
1998, 54, 11935. (c) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35,
9477. (d) Ibarra, C. A.; Arias, S.; Ferna´ndez, M. J.; Sinisterra, J. V. J. Chem.
Soc., Perkin Trans. II 1989, 503. (e) Lafontaine, J. A.; Porvencal, D. P.; Gardelli,
C.; Leahy, J. W. J. Org. Chem. 2003, 68, 4215. (f) Ghosh, A. K.; Gong, G.
J. Am. Chem. Soc. 2004, 126, 3704. (g) Bach, J.; Berenguer, R.; Garcia, J.;
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J. Org. Chem. Vol. 73, No. 14, 2008 5389

Yan and Spilling
TABLE 3. The Intramolecular Horner-Wadsworth-Emmons (HWE) Reaction
SCHEME 11. Facile Racemization of Cyclopentenone 3b
SCHEME 12. Stereochemistry of the Palladium-Catalyzed
Intermolecular Nucleophilic Substitution
and 12). It appears that when using Ba(OH)2 as base, the
cyclopentenones were formed with no erosion in the stereo-
chemistry. For example, diketophosphonate 2e [R
)
CH2CH(Me)2] in 88% ee gave the cyclopentenone 3e with
>85% ee (Table 3, entry 8). Similarly, diketophosphonate 2f
(95% ee) and 2g (90% de) gave cyclopentenones 3f and 3g
without loss of stereochemistry (95% ee and 90% de, respec-
tively, Table 3 entries 11 and 12). However, cyclization of
diketophosphonate 2b again gave racemic cyclopentenone 3b
(Table 3, entry 2). Unfortunately, in all cases the yields of the
cyclopentenone are quite low, ranging from 21% to 36%, mainly
due to competitive formation of the aldol products 16. Using a
larger excess of Ba(OH)2 did not help improve the yields of
the cyclopentenone and resulted in more racemization (Table
3, entries 9 and 13).
Discussion
The palladium-catalyzed intermolecular substitution reaction
of soft nucleophiles with allylic acetates and carbonates has been
extensively studied.23 It is generally accepted that the allylic
system 20 reacts with palladium(0) to form the π-allylpalladium
complex 21 with inversion of configuration (Scheme 12).
Nucleophilic attack on the π-allylpalladium complex also
(23) (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921, and
references cited therein. (b) Wills, M. Chem. Soc. ReV. 1995, 177, and references
cited therein. (c) Prat, M.; Ribas, J.; Moreno-Mao`as, M. Tetrahedron 1992, 48,
1695. (d) Bystro¨m, S. E.; Aslanian, R.; Ba¨ckvall, J.-E. Tetrahedron Lett. 1985,
26, 1749. (e) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51,
723. (f) Tsuji, Y.; Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.; Tanaka, S.;
Ebihara, M. l.; Kawamura, T. Organometallics 1998, 17, 4835.
5390 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of Cyclopentenones Via Intramolecular HWE
SCHEME 13. The Fiaud Study
SCHEME 14. A Comparison of the Stereochemical
Outcome in the Inter- and Intramolecular reactions
proceeds with inversion of configuration to give the products
22 with overall retention (Scheme 12). The regiochemistry is
generally driven by the steric and electronic biases in the
π-allylpalladium complex. The addition of nucleophiles to
phosphonate-substituted π-allylpalladium complexes, unlike all-
carbon substituted π-allylpalladium complexes, is highly
regioselective.
The decarboxylative rearrangement of allylic acetoacetates
(Carroll rearrangement) can be somewhat more complex. Fiaud
and co-workers investigated the stereochemical outcome of the
palladium-catalyzed Carroll rearrangement24 using the now
standard substituted cyclohexenol substrates (Scheme 13). When
the substituent is a phenyl group 23a with a cis/trans ratio of
95/5, a product 24a with a cis/trans ratio of 80/20 is recovered.
This result is mirrored with the isopropyl substituent 23b with
a cis/trans ratio of 91/9, which gives the product 24b with a
cis/trans ratio of 86/14. However, when the substituent is a
phenyl group and predominant in the trans isomer (cis/trans ratio
24/76), the product is formed with a cis/trans ratio of 66/34. It
was concluded that when the substituent and acetoacetate are
cis to each other (diequatorial), the major reaction pathway is
stereospecific and goes with retention of configuration. However,
when the substituent and the acetoacetate are trans to each other
(axial-equatorial), other factors come into play and the major
reaction pathway results in a loss of stereochemistry. The loss
of the selectivity was attributed to the palladium-assisted
epimerization of the starting acetoacetates 23a,b.
Although the cyclohexyl derivatives have been used to probe
the stereochemistry of π-allylpalladium-mediated reactions, the
presence of the additional stereocenter can have undue influence
on the stereochemical outcome of the reaction. It is better to
observe the reaction on a nonracemic compound in the absence
of additional chiral centers. A comparison of the HPLC data of
the vinyl phosphonates 1b derived from the inter- and intramo-
lecular reactions (Scheme 14) and originating from the same
hydroxy phosphonate 4b sample showed that products were
identical in absolute configuration and ee. Since it is generally
assumed that the intermolecular nucleophilic substitution takes
place with retention of configuration, it can be concluded that
the intramolecular rearrangement also proceeds with retention
of configuration
SCHEME 15. Proposed Mechanism for the Rearrangement
the enolate disassociates from the palladium and attacks the back
face of the π-allylpalladium complex 27 affording the vinyl
phosphonate 2 with overall retention.
The competitive formation of cyclopentenones 3 and R-phos-
phonato-R,ꢀ-unsaturated cyclopentenones 16 under basic condi-
tions appears to be a function of the base used in the reaction.
Under mildly acidic conditions (SiO2), the aldol reaction is
dominant. Under basic conditions, the diketophosphonates 2 will
be deprotonated to form anionic intermediate 28 (Scheme 16).
Nucleophilic attack of anion to the carbonyl group will give
the cyclopentanone intermediates 29, which can react in two
different ways. The desired HWE reaction appears to be favored
with the more nucleophilic potassium alkoxide (K2CO3, 18-
crown-6). However, these reaction conditions also promote
racemization. Alternatively, under milder, nonracemizing condi-
tions [Ba(OH)2], the elimination of H2O to form R-phosphonato-
R,ꢀ-unsaturated cyclopentenones 16 becomes competitive.
In summary, we have demonstrated that palladium-catalyzed
reactions of phosphono carbonates and acetoacetates proceed
with complete transfer of chirality. The two-step intermolecular
nucleophilic substitution/decarboxylation protocol gave the vinyl
phosphonates in higher overall yield. The Wacker oxidation of
vinyl phosphonates provided diketophosphonates in good
chemical yields with high regioselectivity. ꢀ-Ketophosphonates
were prone to aldol reaction to form R-phosphonato-R,ꢀ-
unsaturated cyclopentenones. ꢀ,ω-Diketophosphonates readily
underwent the intramolecular HWE reaction with K2CO3 and
18-C-6 as base affording cyclopentenones with high chemical
A reasonable mechanistic rationale for the stereochemistry
observed in decarboxylative rearrangement of allylic acetoac-
etates is provided in Scheme 15.24 Oxidative addition of
palladium to the allylic phosphonate 7 proceeds with inversion
of configuration to form the π-allylpalladium complex 25.
Decarboxylation of π-allylpalladium 25 yields the intermediate
26, which can potentially react in two different ways. Direct
reductive elimination would yield the vinyl phosphonate with
overall inversion of configuration. However, it is proposed that
(24) (a) Fiaud, J. C.; Aribi-Zouioueche, L. Tetrahedron Lett. 1982, 23, 5279.
(b) Ba¨ckvall, J.-E.; Nordberg, R. E.; Vågberg, J. Tetrahedron Lett. 1983, 24,
411.
J. Org. Chem. Vol. 73, No. 14, 2008 5391

Yan and Spilling
SCHEME 16. Formation of Cyclopentenones and
r-Phosphonato-r,ꢀ-unsaturated Cyclopentenones
s), 3.81 (3H, d, JHP ) 10.6 Hz), 3.80 (3H, d, JHP ) 10.7 Hz), 2.02
(1H, m), 1.64-1.75 (4H, m), 1.04-1.33 (6H, m); 13C NMR
3
3
(CDCl3) δ 154.9 (d, JCP ) 9.4 Hz), 144.3 (d, JCP ) 12.2 Hz),
118.1 (d, 2JCP ) 3.6 Hz), 73.4 (d, 1JCP ) 169.7 Hz), 55.5, 54.1 (d,
2
5
2JCP ) 6.9 Hz), 53.9 (d, JCP ) 6.5 Hz), 40.6, 32.5 (d, JCP ) 2.1
Hz), 32.3 (d, 5JCP ) 2.0 Hz), 26.2, 26.0; 31P{1H} NMR (CDCl3) δ
20.3; HRMS (EI, M+) calcd for C13H23O6P 306.1232, found
306.1235.
Dimethyl [1-(Methoxycarbonyloxy)-5-benzyloxy-2-hexenyl]-
phosphonate, 5g. Phosphono carbonate 5a (1.0 g, 4.6 mmol),
2-benzyloxy-4-pentene (1.83 g, 9.16 mmol), and Grubbs second
generation catalyst (0.194 g, 0.229 mmol) in CH2Cl2 (10 mL) were
heated for 24 h at 40 °C. Evaporation of the solvent and column
chromatography (SiO2, hexane:EtOAc, 3:1) gave the 5g (mixture
of diastereomers) as a pale yellow oil (1.5 g, 90%). IR (neat, NaCl)
1755 cm-1; 1H NMR (CDCl3) δ 7.29 (5H, m), 6.00 (1H, m), 5.65
(1H, m), 5.47 (1H, dd, JHH ) 7.7 Hz, JHP ) 12.9 Hz), 4.52 (2H,
m), 3.81 (9H, m), 3.61 (1H, m), 2.43 (1H, m), 2.32 (1H, m), 1.20
(1.5 H, d, JHH ) 6.2 Hz), 1.19 (1.5H, d, JHH ) 6.2 Hz); 13C NMR
3
(CDCl3) δ 155.0, 154.9, 138.9, 134.9 (d, JCP ) 12.5 Hz), 134.8
3
2
(d, JCP ) 12.5 Hz), 128.6, 127.8, 127.7, 127.6, 122.9 (d, JCP
)
3.2 Hz), 122.8 (d, 2JCP ) 3.6 Hz), 74.3, 74.2, 73.1 (d, 1JCP ) 170.6
Hz), 73.0 (d, 1JCP ) 169.9 Hz), 70.7, 55.6, 54.0 (d, 2JCP ) 7.6 Hz),
53.5 (d, JCP ) 7.1 Hz), 39.7, 39.6, 19.7; 31P{1H} NMR (CDCl3)
2
δ 20.2 and 20.3; HRMS (FAB, MH+) calcd for C17H26O7P
373.1416, found 373.1419.
yields, but with significant erosion of the stereochemistry. The
application Ba(OH)2 as base gave cyclopentenones without
racemization, but in generally low (21-36%) yields due to
competitive formation of R-phosphonato-R,ꢀ-unsaturated cy-
clopentenones.
General Procedure for the Preparation of Acetoacetates 7
from Hydroxy Phosphonates 4. Diketene (0.30 mL, 4.15 mmol)
was added to a solution of hydroxy phosphonate 4 (3.19 mmol) in
THF (5 mL) and CH2Cl2 (5 mL) at -20 °C, followed by addition
of DMAP (0.009 g, 0.0013 mmol). The reaction mixture was stirred
at -20 °C for 30 min. The mixture was allowed to warm to room
temperature, and then it was stirred overnight. The reaction mixture
was washed with 0.1% NaOH (twice) and the aqueous layer was
re-extracted with CH2Cl2. The combined organic layers were dried
over anhydrous MgSO4 and the solvent was evaporated in vacuo.
The crude product was purified by chromatography (SiO2, hexane:
EtOAc, 1:1) to give the acetoacetate 7 as pale yellow oil (usually
∼86% keto and ∼14% enol) and the dienes 13.
Experimental Section
(R)-Dimethyl [1-Hydroxy-2-octenyl]phosphonate, 4c10a. Hy-
droxy phosphonate 4b (0.50 g, 2.1 mmol), 1-heptene (1.7 mL, 12
mmol), and Grubbs second generation catalyst (0.088 g, 0.10 mmol)
in CH2Cl2 (6 mL) were heated for 24 h at 40 °C. Evaporation of
the solvent and column chromatography (SiO2, hexane:EtOAc, 3:1)
gave the pure product 4c as a colorless oil (0.32 g, 66%). 1H NMR
(CDCl3) δ 5.88 (1H, m), 5.59 (1H, m), 4.45 (1H, dd, JHH ) 7.1
Hz, JHP ) 10.4 Hz), 3.80 (3H, d, JHP ) 10.4 Hz), 3.79 (3H, d, JHP
) 10.4 Hz), 2.08 (2H, m), 1.31 (6H, m), 0.87 (3H, t, JHH ) 6.6
Hz); 13C NMR (CDCl3) δ 135.8 (d, 3JCP ) 13.2 Hz), 124.2 (d, 2JCP
Dimethyl [1-(2-Ketobutanoyloxy)-3-phenyl-2-propenyl]phos-
phonate, 7b. Diketene (0.85 mL, 11 mmol) was added to hydroxy
phosphonate 4b (2.34 g, 9.68 mmol) in THF (15 mL) and CH2Cl2
(15 mL) at -20 °C, followed by addition of DMAP (0.005 g, 0.04
mmol). The product 7b was obtained as pale yellow oil (2.57 g,
81%). IR (neat, NaCl) 1752, 1750 cm-1; 1H NMR (CDCl3) δ 7.16
(5H, m), 6.65 (1H, dd, JHP ) 3.9 Hz, JHH ) 15.9 Hz,), 6.09 (1H,
m), 5.75 (1H, ddd, JHH ) 7.5, 0.8 Hz, JHP ) 13.7 Hz), 3.67 (3H,
d, JHP ) 10.7 Hz), 3.65 (3H, d, JHP ) 10.7 Hz), 3.43 (2H, s), 2.13
(3H, s); 13C NMR (CDCl3) δ 199.7, 165.6 (d, 3JCP ) 7.9 Hz), 135.9
(d, 3JCP ) 12.6 Hz), 135.5 (d, 4JCP ) 2.2 Hz), 128.7, 128.6, 126.9
(d, 5JCP ) 1.4 Hz), 119.2 (d, 2JCP ) 4.7 Hz), 69.9 (d, 1JCP ) 170.4
1
2
) 3.7 Hz), 69.4 (d, JCP ) 160.8 Hz), 53.8 (d, JCP ) 5.1 Hz),
53.7 (d, 2JCP ) 5.3 Hz), 32.5 (d, 4JCP ) 1.3 Hz), 31.5, 28.8 (d, 5JCP
) 2.7 Hz), 22.7, 14.2; 31P{1H} NMR (CDCl3) δ 25.1.
(R)-Dimethyl [1-Hydroxy-3-cyclohexyl-2-propenyl]phospho-
nate, 4f. Hydroxy phosphonate 4b (0.50 g, 2.1 mmol), vinyl
cyclohexane (2.0 mL, 14 mmol), and Grubbs second generation
catalyst (0.088 g, 0.10 mmol) in CH2Cl2 (6 mL) were heated for
24 h at 40 °C. Evaporation of the solvent and column chromatog-
raphy (SiO2, hexane:EtOAc, 3:1) gave the pure product 4f as a
2
2
1
colorless oil (0.34 g, 66%). IR (neat, NaCl) 3300 cm-1; H NMR
Hz), 53.9 (d, JCP ) 7.0 Hz), 53.8 (d, JCP ) 6.5 Hz), 49.9, 30.2;
31P{1H} NMR (CDCl3) δ 21.2 (enol), 20.7 (keto); HRMS (CI,
MH+) calcd for C15H20O6P 327.0998, found 327.0992.
(CDCl3) δ 5.78 (1H, m), 5.49 (1H, m), 4.38 (1H, dd, JHH ) 10.3
Hz, JHP ) 7.1 Hz), 3.74 (3H, d, JHP ) 10.4 Hz), 3.73 (3H, d, JHP
) 10.4 Hz), 2.79 (1H, broad), 1.96 (1H, m), 1.65 (4H, m),
Dimethyl [1-(2-Ketobutanoyloxy)-2-octenyl]phosphonate, 7c.
Diketene (0.85 mL, 11 mmol) was added to a solution of hydroxy
phosphonate 4c (1.99 g, 8.45 mmol) in THF (12 mL) and CH2Cl2
(12 mL) at -20 °C, followed by addition of DMAP (0.004 g, 0.034
mmol). The product 7c was obtained as a pale yellow oil (2.4 g,
91%). IR (neat, NaCl) 1753, 1721 cm-1; 1H NMR (CDCl3) δ 5.94
(1H, m), 5.70 (1H, ddd, JHH ) 7.8, 0.7 Hz, JHP ) 12.4 Hz), 5.56
(1H, m), 3.81 (3H, d, JHP ) 10.9 Hz), 3.79 (3H, d, JHP ) 10.7 Hz),
3.53 (2H, s), 2.29 (3H, s), 2.09 (2H, m), 1.33 (6H, m), 0.89 (3H,
t, JHH ) 6.6 Hz); 13C NMR (CDCl3) δ 199.8, 165.7 (d, 3JCP ) 7.8
Hz), 139.5 (d, 3JCP ) 12.5 Hz), 120.2 (d, 2JCP ) 4.0 Hz), 70.1 (d,
3
0.76-1.26 (6H, m); 13C NMR (CDCl3) δ 141.5 (d, JCP ) 12.9
Hz), 121.7 (d, 2JCP ) 3.8 Hz), 69.6 (d, 1JCP ) 160.3 Hz), 53.9 (d,
2
4
2JCP ) 6.1 Hz), 53.8 (d, JCP ) 6.8 Hz), 40.9 (d, JCP ) 1.4 Hz),
32.8 (d, 5JCP ) 2.5 Hz), 32.7 (d, 5JCP ) 2.3 Hz), 26.3, 26.1; 31P{1H}
NMR (CDCl3) δ 25.0; HRMS (EI, M+) calcd for C11H21O4P
248.1177, found 248.1173.
Dimethyl [1-(Methoxycarbonyloxy)-3-cyclohexanyl-2-prope-
nyl]phosphonate, 5f. Phosphono carbonate 5a (0.676 g, 3.02
mmol), vinyl cyclohexane (2.50 mL, 18.2 mmol), and Grubbs
second generation catalyst (0.128 g, 0.151 mmol) in CH2Cl2 (10
mL) were heated for 24 h at 40 °C. Evaporation of the solvent and
column chromatography (SiO2, hexane:EtOAc, 3:1) gave the pure
product 5f as a pale yellow oil (0.82 g, 74%). IR (neat, NaCl) 1755
2
2
1JCP ) 170 Hz), 53.9 (d, JCP ) 5.4 Hz), 53.8 (d, JCP ) 4.7 Hz),
4
5
50.1, 32.6 (d, JCP ) 1.0 Hz), 31.5, 30.3, 28.5 (d, JCP ) 2.6 Hz),
22.6, 14.2; 31P{1H} NMR (CDCl3) δ 21.4 (enol), 20.9 (keto);
HRMS (EI, M+) calcd for C14H25O6P 320.1389, found 320.1381.
1
cm-1; H NMR (CDCl3) δ 5.93 (1H, m), 5.52 (2H, m), 3.82 (3H,
5392 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of Cyclopentenones Via Intramolecular HWE
Dimethyl [1-(2-Ketobutanoyloxy)-2-butenyl]phosphonate, 7d.
Diketene (1.1 mL, 14 mmol) was added to a solution of hydroxy
phosphonate 4d (1.92 g, 10.7 mmol) in THF (14 mL) and CH2Cl2
(14 mL) at -20 °C, followed by addition of DMAP (0.005 g, 0.043
mmol). The product 7d was obtained as a pale yellow oil (2.53 g,
90%). IR (neat, NaCl) 1751, 1719 cm-1; 1H NMR (CDCl3) δ 5.95
(1H, m), 5.65 (1H, m), 5.54 (1H, m), 3.78 (3H, d, JHP ) 10.7 Hz),
3.76 (3H, d, JHP ) 10.7 Hz), 3.51 (2H, s), 2.25 (3H, s), 1.74 (3H,
m); 13C NMR (CDCl3) δ 199.9, 165.7 (d, 3JCP ) 7.9 Hz), 134.2 (d,
Dimethyl [3-(2-Ketopropyl)-1-octenyl]phosphonate, 1c. In-
tramolecular Rearrangement. To a solution of Pd2(dba)3 (0.016
g, 0.018 mmol) and dppe (0.021 g, 0.053 mmol) in anhydrous THF
(5 mL) was added phosphono acetotoacetate 7c (0.112 g, 0.350
mmol) in THF (2 mL) to give the product 1c as pale yellow oil
(0.059 g, 61% yield). IR (neat, NaCl) 1716 cm-1; 1H NMR (CDCl3)
δ 6.58 (1H, ddd, JHH ) 17.2, 8.4 Hz, JHP ) 25.6 Hz), 5.59 (1H,
ddd, JHH ) 17.2, 1.0 Hz, JHP ) 20.5 Hz), 3.68 (3H, d, JHP ) 11.1
Hz), 3.67 (3H, d, JHP ) 11.1 Hz), 2.75 (1H, m), 2.49 (2H, m),
1.98 (3H, s), 1.32 (6H, m), 0.84 (3H, t, JHH ) 6.5 Hz); 13C NMR
2
1
3JCP ) 12.8 Hz), 121.5 (d, JCP ) 4.1 Hz), 69.8 (d, JCP ) 171
2
1
2
2
(CDCl3) δ 206.7, 157.0 (d, JCP ) 4.3 Hz), 115.9 (d, JCP ) 186
Hz), 53.9 (d, JCP ) 6.7 Hz), 53.8 (d, JCP ) 6.1 Hz), 49.9, 30.2,
18.2 (d, 4JCP ) 1.1 Hz); 31P{1H} NMR (CDCl3) δ 21.4 (enol), 20.9
(keto); HRMS (EI, M+) calcd for C10H17O6P 264.0763, found
264.0757.
2
2
Hz), 52.4 (d, JCP ) 5.6 Hz), 52.3 (d, JCP ) 5.6 Hz), 47.9, 39.6
(d, JCP ) 21.2 Hz), 33.9, 31.8, 30.7, 26.8, 22.6, 14.1; 31P{1H}
3
NMR (CDCl3) δ 21.5; HRMS (EI, MH+) calcd for C13H26O4P
277.1569, found 277.1580. Anal. Calcd for C13H25O4P·1/4H2O: C,
55.61; H, 9.09; O, 24.24. Found: C, 56.40; H, 9.25; O, 24.49.
Dimethyl [(1E),(3E)-Octadienyl]phosphonate, 13ca. 1H NMR
(CDCl3) δ 6.94 (2H, m), 6.03 (1H, m), 5.37 (1H, m), 3.73 (3H, d,
JHP ) 11.2 Hz), 2.20 (2H, q, JHH ) 6.7 Hz), 1.39 (4H, m), 0.90
General Procedure for the Intramolecular Rearrangement
of Phosphono Acetoacetates 7. Pd(OAc)2 (0.134 g, 0.598 mmol)
and PPh3 (0.627 g, 2.39 mmol) were stirred together in anhydrous
THF (15 mL) for 5 min at room tempertaure. A solution of
phosphono acetoacetate 7 (11.9 mmol) in THF (5 mL) was added.
The reaction flask was placed in a preheated oil bath and heated at
70 °C for 1 h. The reaction mixture was allowed to cool, and then
it was partitioned between brine and Et2O. After separation, the
aqueous layer was re-extracted with Et2O and the combined organic
layers were dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give the crude product, which was purified
by chromatography (SiO2, EtOAc:hexanes, 3:1) to give the
product 1.
General Procedure for the Intermolecular Allylic Substitu-
tion of Phosphono Allylic Carbonates 5 with tert-Butyl Ac-
etoacetate. Pd2(dba)3 (0.044 g, 0.048 mmol) and dppe (0.058 g,
0.14 mmol) were stirred together in anhydrous THF (7 mL) for 5
min. at room temperature. tert-Butyl acetoacetate (0.32 mL, 1.9
mmol) was added, followed by a solution of phosphono carbonate
5 (0.968 mmol) in anhydrous THF (2 mL). The reaction flask was
placed in a preheated oil bath and heated at 75 °C for 1 h. The
reaction mixture was allowed to cool, and then the solvent was
evaporated in vacuo to give the crude product. The crude product
was redissolved in anhydrous toluene (4 mL) and then trifluoroacetic
acid (1.5 mL) was added. The reaction flask was placed in a
preheated oil bath and heated at 80 °C for 1 h. The reaction mixture
was allowed to cool and then it was diluted with CH2Cl2 and washed
with saturated aqueous Na2CO3. After separation, the aqueous layer
was re-extracted with CH2Cl2 and the combined organic layers were
dried over anhydrous MgSO4. The solvent was evaporated in vacuo
to give the crude product, which was purified by chromatography
(SiO2, EtOAc:hexanes, 3:1) to provide the vinyl phosphonate 1.
(3H, t, JHH ) 7.1 Hz) ppm; 13C NMR (CDCl3) δ 150.2 (d, 2JCP
)
3.7 Hz), 145.7 (d, 4JCP ) 2.2 Hz), 127.5 (d, 3JCP ) 9.5 Hz), 111.0
(d, 1JCP ) 183 Hz), 52.3 (d, 2JCP ) 5.5 Hz), 32.8, 31.1, 22.5, 14.1;
31P{1H} NMR (CDCl3) δ 21.0.
Dimethyl [(1E),(3Z)-Octadienyl]phosphonate, 13cb. 1H NMR
(CDCl3) δ 7.09 (1H, ddd, JHH ) 16.9, 9.7 Hz, JHP ) 26.6 Hz),
6.13 (2H, m), 5.53 (1H, dd, JHH ) 16.9 Hz, JHP ) 19.7 Hz), 3.72
(6H, d, JHP ) 11.1 Hz), 2.16 (2H, q, JHH ) 6.0 Hz), 1.38 (4H, m),
0.91 (3H, t, JHH ) 7.0 Hz); 13C NMR (CDCl3) δ 150.6 (d, 2JCP
)
3
1
6.1 Hz), 144.9, 129.6 (d, JCP ) 26.5 Hz), 113.1 (d, JCP ) 191
Hz), 52.7 (d, 2JCP ) 5.5 Hz), 32.9, 31.2, 22.6, 14.2; 31P{1H} NMR
(CDCl3) δ 23.2.
Intermolecular Allylic Substitution. To a solution of Pd2(dba)3
(0.050 g, 0.055 mmol) and dppe (0.066 g, 0.16 mmol) in THF were
added tert-butyl acetoacetate (0.36 mL, 2.2 mmol) and phosphono
carbonate 5c (0.32 g, 1.1 mmol) to give, after treatment with toluene
and TFA, the product 1c as a pale yellow oil (0.17 g, 56%).
Dimethyl [3-(2-Ketopropyl)-1-butenyl]phosphonate, 1d. In-
tramolecular Rearrangement. A solution of Pd(PPh3)4 (0.361 g,
0.313 mmol) and phosphono acetoactetae 7d (2.17 g, 8.21 mmol)
in anhydrous THF (35 mL) gave the product 1d as a pale yellow
1
oil (1.27 g, 71%). IR (neat, NaCl) 1710 cm-1; H NMR (CDCl3)
δ 6.71 (1H, ddd, JHH ) 17.3, 6.7 Hz, JHP ) 23.9 Hz), 5.59 (1H,
ddd, JHH ) 17.3, 1.4 Hz, JHP ) 20.1 Hz), 3.69 (3H, d, JHP ) 11.1
Hz), 3.68 (3H, d, JHP ) 11.1 Hz), 2.88 (1H, m), 2.49 (2H, m),
2.11 (3H, s), 1.05 (2H, d, JHH ) 6.8 Hz); 13C NMR (CDCl3) δ
206.6, 157.9 (d, 2JCP ) 4.4 Hz), 114.4 (d, 1JCP ) 187 Hz), 52.5 (d,
2JCP ) 5.6 Hz), 49.1 (d, 5JCP ) 1.0 Hz), 33.5 (d, 3JCP ) 21.5 Hz),
30.6, 18.9 (d, 4JCP ) 0.8 Hz); 31P{1H} NMR (CDCl3) δ 21.7; HRMS
(EI, MH+) calcd for C9H18O4P 221.0943, found 221.0934.
Dimethyl [3-(2-Ketopropyl)-3-phenyl-1-propenyl]phospho-
nate, 1b. Intramolecular Rearrangement. To a solution of
Pd(OAc)2 (0.134 g, 0.598 mmol) and PPh3 (0.627 g, 2.39 mmol)
in anhydrous THF (15 mL) was added a solution of phosphono
acetoacetate 7b (3.90 g, 11.9 mmol) in THF (5 mL) to give the
1
Dimethyl [(1E),(3E)-Butadienyl]phosphonate, 13d. H NMR
(CDCl3) δ 7.08 (1H, m), 6.43 (1H, m), 5.64 (3H, m), 3.74 (3H, d,
JHP ) 11.1 Hz), 3.72 (3H, JHP ) 11.1 Hz); 13C NMR (CDCl3) δ
150.1 (d, 2JCP ) 5.9 Hz), 136.0 (d, 3JCP ) 26.8 Hz), 116.9 (d, 1JCP
) 190 Hz), 52.8 (d, 2JCP ) 5.6 Hz); 31P{1H} NMR (CDCl3) δ 22.2;
HRMS (EI, M+) calcd for C6H11O3P 162.0446, found 162.0443.
product 1b as pale yellow oil (1.87 g, 56%). IR (neat, NaCl) 1714
1
cm-1; H NMR (CDCl3) δ 6.96 (5H, m), 6.64 (1H, ddd, JHH
)
17.2, 6.5 Hz, JHP ) 23.6 Hz), 5.28 (1H, ddd, JHH ) 17.3, 1.3 Hz,
JHP ) 19.3 Hz), 3.81 (1H, m), 3.41 (3H, d, JHP ) 11.1 Hz), 3.39
(3H, d, JHP ) 11.1 Hz), 2.67 (2H, dd, JHH ) 7.3 Hz, JHP ) 1.4
Hz), 1.82 (3H, s); 13C NMR (CDCl3) δ 206.0, 155.3 (d, 2JCP ) 5.1
Dimethyl [3-(2-Ketopropyl)-5-methyl-1-hexenyl]phosphonate,
1e. Intramolecular Rearrangement. To a solution of Pd2(dba)3
(0.106 g, 0.116 mmol) and dppe (0.139 g, 0.349 mmol) in
anhydrous THF (40 mL) was added a solution of phosphono
actoacetate 7e (0.711 g, 2.32 mmol) in THF (5 mL) to give the
product 1e as a pale yellow oil (0.324 g, 35%). IR (neat, NaCl)
Hz), 140.4 (d, 4JCP ) 0.8 Hz), 128.8, 127.7, 127.1, 116.1 (d 1JCP
186 Hz), 52.2 (d, JCP ) 5.5 Hz), 48.3, 44.4 (d, JCP ) 21.6 Hz),
29.9; 31P{1H} NMR (CDCl3) δ 22.3; HRMS (CI, MH+) calcd for
C14H20O4P 283.1099, found 283.1097.
)
2
3
1
1715 cm-1; H NMR (CDCl3) δ 6.58 (1H, ddd, JHH ) 17.2, 8.7
Intermolecular Allylic Substitution. To a solution of Pd2(dba)3
(0.044 g, 0.048 mmol) and dppe (0.058 g, 0.145 mmol) in
anhydrous THF (7 mL) was added tert-butyl acetoacetate (0.32 mL,
1.9 mmol) and phosphono carbonate 5b (0.29 g, 0.97 mmol) in
anhydrous THF (2 mL) to give, after treatment with toluene and
TFA, the product 1b as a pale yellow oil (0.26 g, 97%) spectro-
scopically identical with the products described above.
Hz, JHP ) 25.8 Hz), 5.62 (1H, dd, JHH ) 17.2 Hz, JHP ) 20.6 Hz),
3.70 (3H, d, JHP ) 11.1 Hz), 3.69 (3H, d, JHP ) 11.1 Hz), 2.87
(1H, m), 2.49 (2H, d, JHH ) 6.7 Hz), 2.11 (3H, s), 1.53 (1H, m),
1.24 (2H, m), 0.88 (3H, d, JHH ) 6.5 Hz), 0.87 (3H, d, JHH ) 6.6
2
Hz); 13C NMR (CDCl3) δ 206.6, 157.1 (d, JCP ) 2.8 Hz), 116.0
1
2
2
(d, JCP ) 186 Hz), 52.5 (d, JCP ) 5.6 Hz), 52.4 (d, JCP ) 5.6
3
Hz), 48.4, 43.3, 37.7 (d, JCP ) 21.2 Hz), 30.8, 25.7, 23.4, 21.8;
J. Org. Chem. Vol. 73, No. 14, 2008 5393

Yan and Spilling
31P{1H} NMR (CDCl3) δ 21.3; HRMS (EI, M+) calcd for
C12H23O4P 262.1334, found 262.1336. Anal. Calcd for C12H23O4P·1/
4H2O: C, 54.03; H, 8.82; O, 25.52. Found: C, 53.76; H, 8.77; O,
25.77.
in anhydrous THF (5 mL) was added. The reaction flask was placed
in a preheated oil bath and heated at 75 °C for 1 h. The reaction
mixture was allowed to cool and then it was washed with 5% HCl
until the solution was neutral. After separation, the aqueous layer
was re-extracted with CH2Cl2 and the combined organic layers were
dried over anhydrous MgSO4. The solvent was evaporated in vacuo
to give the crude product, which was purified by chromatography
(SiO2, EtOAc:hexanes, 1:5) to give 15 as a pale yellow oil (0.083
Dimethyl [(1E)(3E)-5-Methylhexadienyl]phosphonate, 13ea.
1H NMR (CDCl3) δ 6.89 (2H, m), 5.96 (1H, m), 5.35 (1H, dd, JHH
) 11.7 Hz, JHP ) 17.2 Hz), 3.71 (6H, d, JHP ) 11.2 Hz), 2.45
(1H, m), 1.03 (6H, d, JHH ) 6.8 Hz); 13C NMR (CDCl3) δ 152.2
g, 53%) (mixture of diastereomers). IR (neat, NaCl) 1713 cm-1
;
4
2
3
(d, JCP ) 2.3 Hz), 150.4 (d, JCP ) 5.7 Hz), 124.7 (d, JCP ) 9.5
Hz), 111.2 (d, 1JCP ) 184 Hz), 52.2 (d, 2JCP ) 5.4 Hz), 31.7, 22.1;
31P{1H} NMR (CDCl3) δ 20.9.
1H NMR (CDCl3) δ 6.53 (1H, JHH ) 17.1, 10.3 Hz, JHP ) 27.3
Hz), 5.58 (1H, dd, JHH ) 17.1 Hz, JHP ) 21.3 Hz), 4.17 (2H, q,
JHH ) 7.1 Hz), 3.71 (3H, d, JHP ) 11.0 Hz), 3.70 (3H, d, JHP
)
Dimethyl [(1E)(3Z)-5-Methylhexadienyl]phosphonate, 13ed.
1H NMR (CDCl3) δ 7.09 (1H, m), 6.08 (2H, m), 5.55 (1H, dd, JHH
) 16.9 Hz, JHP ) 19.7 Hz), 3.71 (6H, d, JHP ) 11.1 Hz), 2.40
(1H, m), 1.03 (6H, d, JHH ) 6.8 Hz); 13C NMR (CDCl3) δ 151.1,
150.6 (d, 2JCP ) 6.0 Hz), 126.6 (d, 3JCP ) 26.7 Hz), 113.2 (d, 1JCP
11.0 Hz), 2.79 (1H, m), 2.40 (3H, m), 1.97 (1H, m), 1.67 (4H, m),
1.29 (11H, m), 0.88 (3H, t, JHH ) 7.4 Hz); 13C NMR (CDCl3) δ
205.9, 170.7, 153.2 (d, 2JCP ) 4.6 Hz), 119.0 (d, 1JCP ) 184.4 Hz),
2
2
64.7, 61.7, 52.5 (d, JCP ) 5.1 Hz), 52.4 (d, JCP ) 5.5 Hz), 49.1
3
2
) 191 Hz), 52.5 (d, JCP ) 5.5 Hz), 31.5, 21.9; 31P{1H} NMR
(d, JCP ) 21.6 Hz), 41.8, 31.8, 31.7, 29.7, 27.9, 26.9, 22.7, 22.6,
14.3, 14.2; 31P{1H} NMR (CDCl3) δ 20.7; HRMS (EI, MH+) calcd
for C19H33O6P 389.2093, found 389.2091.
(CDCl3) δ 23.3.
Intermolecular Allylic Substitution. To a solution of Pd2(dba)3
(0.153 g, 0.167 mmol) and dppe (0.199 g, 0.499 mmol) in
anhydrous THF (22 mL) was added tert-butyl acetoacetate (1.1 mL,
6.7 mmol) and phosphono carbonate 5e (0.977 g, 3.49 mmol) in
anhydrous THF (5 mL) to give, after treatment with toluene and
TFA, the product 1e as a pale yellow oil (0.69 g, 79%).
Dimethyl [3-(2-Ketopropyl)-3-cyclohexyl-1-propenyl]phos-
phonate, 1f. Intermolecular Allylic Substitution. To a solution
of Pd2(dba)3 (0.019 g, 0.021 mmol) and dppe (0.025 g, 0.062 mmol)
in THF were added tert-butyl acetoacetate (0.20 mL, 1.2 mmol)
and the phosphono carbonate 5f (0.180 g, 0.589 mmol) in THF (8
mL) to give, after treatment with toluene and TFA, the product 1f
as a pale yellow oil (0.12 g, 70%). IR (neat, NaCl) 1715 cm-1; 1H
NMR (CDCl3) δ 6.62 (1H, ddd, JHH ) 8.7 Hz, JHH ) 17.2 Hz, JHP
General Procedure for the Wacker Oxidation. PdCl2 (0.052
g, 0.29 mmol) and CuCl (0.145 g, 1.46 mmol) were dissolved in
H2O (1 mL) and DMF (1.4 mL). The reaction mixture was stirred
under O2 (1 atm) for 0.5 h at room temperature, then a solution of
vinyl phosphonate 1 (1.46 mmol) in DMF (1 mL) was added. The
reaction was stirred for 3 days at room temperature, then the reaction
was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl
(2×). After separation, the aqueous layer was re-extracted with
CH2Cl2 and the combined organic layers were dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give the crude
product, which was purified by chromatography (SiO2, EtOAc:
hexanes 3:1) to give the product 2. Prolonged residence on the
column also gave the phsophono cyclopentenones 16.
Dimethyl [3-(2-Ketopropyl)-2-keto-3-phenylpropyl]phospho-
nate, 2b. PdCl2 (0.052 g, 0.29 mmol), CuCl (0.145 g, 1.46 mmol),
and vinyl phosphonate 1b (0.412 g, 1.46 mmol) were stirred in
H2O (1 mL) and DMF (2.4 mL) under O2 (1 atm) to give 2b as a
) 25.9 Hz), 5.58 (1H, ddd, JHH ) 0.8 Hz, JHH ) 17.2 Hz, JHP
)
20.9 Hz), 3.70 (3H, d, JHP ) 11.1 Hz), 3.69 (3H, d, JHP ) 11.1
Hz), 2.59 (2H, m), 2.12 (3H, s), 1.69 (6H, m), 0.88-1.40 (6H, m);
2
13C NMR (CDCl3) δ 207.1, 155.9, (d, JCP ) 4.4 Hz), 116.9 (d,
1
pale yellow oil (0.352 g, 81%). IR (neat, NaCl) 1706 cm-1; H
2
2
1JCP ) 185 Hz), 52.5 (d, JCP ) 5.6 Hz), 52.4 (d, JCP ) 5.6 Hz),
3
NMR (CDCl3) δ 7.36 (5H, m), 4.49 (1H, dd, JHH ) 9.6, 4.3 Hz),
45.3 (d, JCP ) 20.9 Hz), 45.2, 41.3, 30.9, 30.8, 30.1, 26.6, 26.5;
31P{1H} NMR (CDCl3) δ 21.7; HRMS (EI, M+) calcd for
C14H25O4P 288.1490, found 288.1491. Anal. Calcd for C14H25-
O4P·1/2 H2O: C, 56.57; H, 8.75. Found: C, 56.62; H, 8.57.
Dimethyl [3-(2-Ketopropyl)-5-(R)-benzyloxyl-1-propenyl]phos-
phonate, 1g. Intermolecular Allylic Substitution. To a solution
of Pd2(dba)3 (0.139 g, 0.152 mmol) and ddpe (0.182 g, 0.456 mmol)
in THF were added tert-butyl acetoacetate (1.26 mL, 7.60 mmol)
and phosphonate carbonate 5g (1.41 g, 3.80 mmol) in anhydrous
THF (27 mL total) to give, after treatment with toluene and TFA,
the product (1:1 mixture of diastereoisomers) 1g as a pale yellow
3.84 (3H, d, JHP ) 11.2 Hz), 3.75 (3H, d, JHP ) 11.3 Hz), 3.46
(1H, dd, JHH ) 17.9, 9.6 Hz), 3.24 (1H, JHH ) 14.8 Hz, JHP
)
22.3 Hz), 3.03 (1H, JHH ) 14.8 Hz, JHP ) 21.3 Hz), 2.69 (1H, JHH
) 17.9, 4.3 Hz), 2.23 (3H, s); 13C NMR (CDCl3) δ 206.2, 200.7
(d, 2JCP ) 6.1 Hz), 137.1, 129.5, 128.7, 128.1, 54.5 (d, 3JCP ) 3.2
2
2
Hz), 53.2 (d, JCP ) 6.5 Hz), 53.1 (d, JCP ) 6.3 Hz), 46.5, 39.7
(d, JCP ) 133 Hz), 30.1; 31P{1H} NMR (CDCl3) δ 23.6; HRMS
1
(CI, MH+) calcd for C14H20O5P 299.1040, found 299.1048.
Dimethyl [3-(2-Ketopropyl)-2-ketooctyl]phosphonate, 2c.
PdCl2 (0.03 g, 0.169 mmol), CuCl (0.084 g, 0.844 mmol), and vinyl
phosphonate 1c (0.233 g, 0.844 mmol) were stirred in H2O (1 mL)
and DMF (1.4 mL) under O2 atmosphere to give 2c as a pale yellow
oil (0.197 g, 80%). IR (neat, NaCl) 1711 cm-1; 1H NMR (CDCl3)
δ 3.78 (3H, d, JHP ) 11.2 Hz), 3.77 (3H, d, JHP ) 11.2 Hz), 3.24
(2H, d, JHP ) 21.9 Hz), 3.08 (1H, m), 2.92 (1H, ddd, JHH ) 17.9,
1
oil (0.94 g, 70%). IR (neat, NaCl) 1715 cm-1; H NMR (CDCl3)
δ 7.34 (5H, m), 6.61 (1H, m), 5.56 (1H, m), 4.58 (1H, dd, JHH
)
11.5, 9.5 Hz), 4.35 (1H, dd, JHH ) 19.4, 11.5 Hz), 3.66 (6H, m),
3.48 (1H, m), 3.01 (1H, m), 2.49 (2H, m), 2.06 (3H, d, JHH ) 8.2
Hz), 1.69 (1H, m), 1.47 (1H, m), 1.21 (1.5H, d, JHH ) 6.2 Hz),
1.19 (1.5H, d, JHH ) 6.5 Hz); 13C NMR (CDCl3) δ 206.5, 206.4,
9.5 Hz, JHP ) 1.7 Hz), 2.49 (1H, ddd, JHH ) 17.9, 3.9 Hz, JHP
)
2
2
1.4 Hz), 2.13 (3H, d, JHP ) 1.9 Hz), 1.66 (1H, m), 1.38 (1H, m),
156.8 (d, JCP ) 4.4 Hz), 156.6 (d, JCP ) 4.2 Hz), 138.8, 138.7,
128.6, 128.5, 128.0, 127.9, 127.8, 116.7 (d, 1JCP ) 185 Hz), 115.7
(d, 1JCP ) 186 Hz), 72.5, 72.1, 70.5, 70.3, 52.5 (d, 2JCP ) 5.3 Hz),
1.24 (6H, m), 0.86 (3H, t, JHH ) 6.4 Hz); 13C NMR (CDCl3) δ
2
2
207.2, 204.8 (d, JCP ) 6.5 Hz), 53.2 (d, JCP ) 6.5 Hz), 53.0 (d,
2JCP ) 6.4 Hz), 47.7 (d, 3JCP ) 3.6 Hz), 44.8, 40.5 (d, 1JCP ) 132
Hz), 31.9, 30.7, 29.9, 26.8, 22.6, 14.1; 31P{1H} NMR (CDCl3) δ
23.7; HRMS (EI, MH+) calcd for C13H26O5P 293.1518, found
293.1514.
52.5 (d, 2JCP ) 5.3 Hz), 52.44 (d, 2JCP ) 5.5 Hz), 52.40 (d, 2JCP
)
3
5.4 Hz), 48.6, 47.3, 41.7, 40.8, 36.8 (d, JCP ) 21.7 Hz), 36.2 (d,
3JCP ) 21.5 Hz), 30.6, 30.5, 19.9, 19.6; 31P{1H} NMR (CDCl3) δ
21.7 and 21.6; HRMS (EI, MH+) calcd for C18H28O5P 355.1674,
found 355.1679. Anal. Calcd for C18H27O5P·1/2H2O: C, 59.50; H,
7.71; O, 24.24. Found: C, 59.78; H, 7.67; O, 24.03.
Dimethyl [3-(2-Ketopropyl)-2-ketobutyl]phosphonate, 2d.
PdCl2 (0.135 g, 0.763 mmol), CuCl (0.382 g, 3.82 mmol), and vinyl
phosphonate 1d (0.840 g, 3.82 mmol) were stirred in H2O (4 mL)
and DMF (6 mL) under O2 atmosphere to give 2d as a pale yellow
oil (0.717 g, 80%). IR (neat, NaCl) 1709 cm-1; 1H NMR (CDCl3)
δ 4.05 (3H, d, JHP ) 11.2 Hz), 4.01 (3H, d, JHP ) 11.2 Hz), 3.47
Dimethyl [3-(1-Ethoxycarbonyl-2-ketocyclohexyl)-1-octe-
nyl]phosphonate, 15. A solution of Pd2(dba)3 (0.019 g, 0.020
mmol) and dppe (0.024 g, 0.060 mmol) in anhydrous THF (3 mL)
was stirred at room temperature for 5 min, then a solution of NaH
(0.021 g, 0.052 mmol), ethyl 2-cyclohexanone carboxylate (0.10
mL 0.60 mmol), and phosphono carbonate 5c (0.119 g, 0.403 mmol)
(2H, m), 3.20 (1H, dd, JHH ) 18.1, 8.8 Hz), 2.72 (1H, dd, JHH
)
18.1, 4.5 Hz), 2.37 (3H, s), 1.39 (3H, dd, JHH ) 7.2 Hz, JHP ) 0.9
5394 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of Cyclopentenones Via Intramolecular HWE
Hz); 13C NMR (CDCl3) δ 207.0, 205.1 (d, 2JCP ) 6.3 Hz), 53.2 (d,
Hz); 13C NMR (CDCl3) δ 208.2 (d, 2JCP ) 11.3 Hz), 190.3 (d, 2JCP
1 2
2
3
2JCP ) 6.6 Hz), 53.1 (d, JCP ) 6.5 Hz), 47.1, 42.4 (d, JCP ) 2.9
) 13.8 Hz), 128.7 (d, JCP ) 189 Hz), 52.9 (d, JCP ) 5.8 Hz),
3 3
1
Hz), 40.1 (d, JCP ) 131 Hz), 29.9, 16.4; 31P{1H} NMR (CDCl3)
44.9 (d, JCP ) 10.4 Hz), 42.6 (d, JCP ) 18.2 Hz), 40.7, 26.8,
23.5, 21.9, 20.0 (d, 3JCP ) 2.6 Hz); 31P{1H} NMR (CDCl3) δ 14.5;
HRMS (EI, MH+) calcd for C12H22O4P 261.1256, found 261.1254.
Anal. Calcd for C12H21O4P·1/4H2O: C, 54.44; H, 8.26. Found: C,
54.21; H, 8.26.
δ 23.5; HRMS (EI, MH+) calcd for C9H18O5P 237.0892, found
237.0899.
Dimethyl [3-(2-Ketopropyl)-2-keto-5-methylhexyl]phospho-
nate, 2e. PdCl2 (0.113 g, 0.638 mmol), CuCl (0.316 g, 3.19 mmol),
and vinyl phosphonate 1e (0.811 g, 3.10 mmol) were stirred in
H2O (3.5 mL) and DMF (7.5 mL) under O2 (1 atm) to give 2e as
(2-Dimethylphosphonato-3-methyl-5-cyclohexyl)-2-cyclopen-
tenone, 16f. IR (neat, NaCl) 1703 cm-1; 1H NMR (CDCl3) δ 3.79
(3H, d, JHP ) 11.4 Hz), 3.77 (3H, d, JHP ) 11.4 Hz), 2.74 (1H, m),
2.55 (1H, m), 2.48 (3H, m), 2.42 (1H, m), 1.89 (1H, m), 1.69 (4H,
m), 0.93-1.42 (6H, m); 13C NMR (CDCl3) δ 207.9 (d, 2JCP ) 11.2
Hz), 191.3 (d, 2JCP ) 13.9 Hz), 129.7 (d, 1JCP ) 188 Hz), 52.9 (d,
2JCP ) 5.9 Hz), 52.8 (d, 2JCP ) 5.7 Hz), 51.8 (d, 3JCP ) 10.0 Hz),
1
a pale yellow oil (1.29 g, 86%). IR (neat, NaCl) 1709 cm-1; H
NMR (CDCl3) δ 3.73 (6H, d, JHP ) 11.2 Hz), 3.19 (2H, dd, JHH
)
1.3 Hz, JHP ) 21.1 Hz), 3.08 (1H, m), 2.84 (1H, dd, JHH ) 18.1,
9.6 Hz), 2.46 (1H, dd, JHH ) 18.1, 3.8 Hz), 2.08 (3H, s), 1.47 (2H,
m), 1.14 (1H, m), 0.87 (3H, d, JHH ) 6.3 Hz), 0.83 (3H, d, JHH
)
2
3
6.0 Hz); 13C NMR (CDCl3) δ 207.3, 205.1 (d, JCP ) 6.5 Hz),
39.3, 38.6 (d, JCP ) 18.2 Hz), 31.2, 27.8, 26.6, 26.4, 26.2, 20.0
2
2
3
2
53.2 (d, JCP ) 6.4 Hz), 52.9 (d, JCP ) 6.4 Hz), 45.9 (d, JCP
)
(d, JCP ) 2.5 Hz); 31P{1H} NMR (CDCl3) δ 14.4; HRMS (EI,
3.9 Hz), 45.2, 40.4 (d, 1JCP ) 133 Hz), 39.7, 29.9, 25.9, 23.2, 21.9;
31P{1H} NMR (CDCl3) δ 23.9; HRMS (EI, MH+) calcd for
C12H24O5P 279.1361, found 279.1358.
M+) calcd for C14H23O4P 286.1334, found 286.1330.
[2-Dimethylphosphonato-3-methyl-5-(2R-benzoxylpropyl)]-2-
cyclopentenone, 16g. 1:1 mixture of diastereoisomers: IR (neat,
1
NaCl) 1708 cm-1; H NMR (CDCl3) δ 7.25 (5H, m), 4.55 (0.5H,
Dimethyl [3-(2-Ketopropyl)-2-keto-3-cyclohexylpropyl]phos-
phonate, 2f. PdCl2 (0.025 g, 0.14 mmol), CuCl (0.068 g, 0.69
mmol), and vinyl phosphonate 1f (0.199 g, 0.690 mmol) were stirred
in H2O (1.5 mL) and DMF (3 mL) under O2 atmosphere to give 2f
d, JHH ) 11.8 Hz), 4.51 (0.5H, d, JHH ) 11.8 Hz), 4.38 (0.5H, d,
JHH ) 11.8 Hz), 4.27 (0.5H, d, JHH ) 11.8 Hz), 3.72 (6H, m), 3.57
(1H, m), 2.83 (1H, m), 2.61 (1H, m), 2.41 (1H, m), 2.38 (1.5H,
m), 2.33 (1.5H, m), 1.91 (1H, m), 1.37 (1H, m), 1.15 (1.5H, d, JHH
) 6.0 Hz), 1.15 (1.5H, d, JHH ) 6.0 Hz); 13C NMR (CDCl3) δ
as a pale yellow oil (0.173 g, 83%). IR (neat, NaCl) 1709 cm-1
;
1H NMR (CDCl3) δ 3.79 (6H, d, JHP ) 11.2 Hz), 3.31 (1H, dd,
JHH ) 15.6 Hz, JHP ) 21.9 Hz), 3.24 (1H, dd, JHH ) 15.6 Hz, JHP
) 21.9 Hz), 3.00 (2H, m), 2.46 (1H, d, JHH ) 16.3 Hz), 2.15 (3H,
s), 1.48-1.79 (5H, m), 0.83-1.32 (6H, m); 13C NMR (CDCl3) δ
2
2
207.9 (d, JCP ) 11.6 Hz), 190.9 (d, JCP ) 13.8 Hz), 190.7 (d,
2JCP ) 13.7 Hz), 138.9, 138.8, 128.7 (d, JCP ) 184 Hz), 128.5,
1
1
128.4 (d, JCP ) 190 Hz), 128.0, 127.9, 127.8, 74.2, 72.6, 70.8,
2
3
2
3
207.6, 204.6 (d, JCP ) 6.9 Hz), 53.6 (d, JCP ) 4.8 Hz), 53.3 (d,
2JCP ) 6.4 Hz), 52.9 (d, 2JCP ) 6.3 Hz), 41.5, 40.9 (d, 1JCP ) 135
Hz), 38.8, 31.9, 30.1, 29.2, 26.8, 26.6, 26.3; 31P{1H} NMR (CDCl3)
δ 21.7; HRMS (EI, M+) calcd for C14H25O5P 304.1439, found
304.1433.
70.4, 52.9 (d, JCP ) 5.7 Hz), 44.1 (d, JCP ) 10.6 Hz), 43.5 (d,
3JCP ) 8.4 Hz), 43.3, 42.4, 42.2, 38.8, 37.9, 20.1, 19.8; 31P{1H}
NMR (CDCl3) δ 14.6 and 14.5; HRMS (EI, M+) calcd for
C18H25O5P 352.1439, found 352.1441.
Genera Procedure for the Horner-Wadsworth-Emmons
Cyclization with K2CO3 as the Base. Diketophosphonate 2 (0.144
mmol) was dissolved in anhydrous THF (3 mL), then K2CO3 (0.040
g, 0.29 mmol) and 18-crown-6 (0.011 g, 0.043 mmol) were added.
The reaction flask was placed in a preheated oil bath and heated at
40 °C for 24 h. The reaction mixture was allowed to cool and then
it was washed with 5% HCl until the solution was neutral. After
separation, the aqueous layer was re-extracted with CH2Cl2 and
the combined organic layers were dried over anhydrous MgSO4.
The solvent was evaporated in vacuo to give the crude product,
which was purified by chromatography (SiO2, EtOAc:hexanes, 1:5)
to give the cyclopentenone 3.
(3-Methyl-5-phenyl)-2-cyclopentenone, 3b. Diketophosphonate
2b (0.043 g, 0.14 mmol) gave 3b as a white solid (0.019 g, 77%).
(3-Methyl-5-pentyl)-2-cyclopentenone, 3c. Diketophosphonate
2c (0.162 g, 0.555 mmol) gave 3c as a colorless liquid (0.084 g,
91%).
(3,5-Dimethyl)-2-cyclopentenone, 3d. Diketophosphonate 2d
(0.627 g, 2.66 mmol) gave 3d as a colorless liquid (0.183 g, 63%).
[3-Methyl-5-(2-methylpropyl)]-2-cyclopentenone, 3e. Diketo-
phosphonate 2e (1.462 g, 5.257 mmol) gave 3e as a pale yellow
oil (0.705 g, 88%).
[3-Methyl-5-(2-benzoxylpropyl)]-2-cyclopentenone, 3g. Dike-
tophosphonate 2g (0.101 g, 0.272 mmol) gave 3g as a colorless
liquid (0.044 g, 67%).
General Procedure for the Horner-Wadsworth-Emmons
Cyclization with Bu4N+OH- as the Base. Diketophosphonate 2
(0.247 mmol) was dissolved in toluene (3 mL) and H2O (3 mL).
Then a 40 wt % Bu4N+OH- solution (0.14 mL, 0.222 mmol) was
added. The reaction mixture was stirred vigorously for 1 h at room
temperature. The layers were separated and the aqueous layer was
re-extracted with Et2O and the combined organic layers were dried
over anhydrous MgSO4. The solvent was evaporated in vacuo to
give the crude product, which was purified by chromatography
(SiO2, EtOAc:hexanes, 1:5) to give the products 3 and 16.
(3-Methyl-5-pentyl)-2-cyclopentenone, 3c. Diketophosphonate
2c (0.072 g, 0.25 mmol) gave 3c (0.024 g, 60%).
Dimethyl [3-(2-Ketopropyl)-2-keto-5(R)-benzoxylhexyl]phos-
phonate, 2g. PdCl2 (0.0530 g, 0.296 mmol), CuCl (0.147 g, 1.48
mmol), and vinyl phosphonate 1g (0.524 g, 1.48 mmol) were stirred
in H2O (3.5 mL) and DMF (4.5 mL) under O2 atmosphere to give
2g (1:1 mixture of diastereomers) as a pale yellow oil (0.357 g,
1
65%). IR (neat, NaCl) 1709 cm-1; H NMR (CDCl3) δ 7.32 (5H,
m), 4.62 (0.5H, d, JHH ) 11.7 Hz), 4.51 (0.5H, d, JHH ) 11.7 Hz),
4.35 (0.5H, d, JHH ) 11.7 Hz), 4.29 (0.5H, d, JHH ) 11.7 Hz),
3.75 (6H, m), 3.52 (1H, m), 2.93-3.42 (3.5H, m), 2.83 (0.5H, m),
2.48 (0.5H, dd, JHH ) 17.9, 4.8 Hz), 2.35 (0.5H, dd, JHH ) 18.2,
4.8 Hz), 2.12 (1.5H, s), 2.08 (1.5H, s), 1.92 (0.5H, m), 1.81 (1H,
m), 1.42 (0.5H, m), 1.22 (1.5H, d, JHH ) 6.0 Hz), 2.11 (1.5H, d,
JHH ) 6.0 Hz); 13C NMR (CDCl3) δ 207.02, 207.0, 204.8 (d, 2JCP
2
) 6.5 Hz), 204.4 (d, JCP ) 6.1 Hz), 138.6, 138.4, 128.6, 128.5,
2
128.2, 127.9, 72.6, 71.9, 70.6, 70.3, 53.2 (d, JCP ) 6.2 Hz), 53.1
2
2
2
(d, JCP ) 6.5 Hz), 53.0 (d, JCP ) 6.2 Hz), 52.9 (d, JCP ) 6.4
3
3
Hz), 45.1, 44.9 (d, JCP ) 3.9 Hz), 44.8 (d, JCP ) 3.4 Hz), 44.7,
40.4 (d, 1JCP ) 132 Hz), 40.2 (d, 1JCP ) 132 Hz), 38.9, 37.8, 30.1,
29.9, 19.8, 19.7; 31P{1H} NMR (CDCl3) δ 24.3 and 24.1; HRMS
(FAB, MH+) calcd for C18H28O6P 371.1623, found 371.1626.
(2-Dimethylphosphonato-3-methyl-5-pentyl)-2-cyclopenten-
one, 16c. IR (neat, NaCl) 1707 cm-1; H NMR (CDCl3) δ 3.79
1
(3H, d, JHP ) 11.3 Hz), 3.78 (3H, d, JHP ) 11.4 Hz), 2.89 (1H, m),
2.49 (3H, m), 2.41 (2H, m), 1.80 (1H, m), 1.32 (7H, m), 0.88 (3H,
t, JHH ) 6.5 Hz); 13C NMR (CDCl3) δ 208.0 (d, JCP ) 11.2 Hz),
2
190.7 (d, 2JCP ) 13.8 Hz), 128.8 (d, 1JCP ) 189 Hz), 52.9 (d, 2JCP
) 5.9 Hz), 52.8 (d, 2JCP ) 5.9 Hz), 46.5 (d, 3JCP ) 10.3 Hz), 42.0
(d, 3JCP ) 18.1 Hz), 31.9, 31.5, 27.1, 22.7, 20.1 (d, 3JCP ) 2.6 Hz),
14.2; 31P{1H} NMR (CDCl3) δ 14.5; HRMS (EI, MH+) calcd for
C13H24O4P 275.1412, found 275.1414. Anal. Calcd for C13H23O4P:
C, 56.93; H, 8.39; O, 23.36. Found: C, 56.54; H, 8.38; O, 23.78.
[2-Dimethylphosphonato-3-methyl-5-(2-methylpropyl)]-2-cy-
clopentenone, 16e. IR (neat, NaCl) 1708 cm-1; 1H NMR (CDCl3)
δ 3.72 (3H, d, JHP ) 11.4 Hz), 3.71 (3H, d, JHP ) 11.4 Hz), 2.85
(1H, m), 2.42 (3H, m), 2.34 (m), 1.81 (1H, broad), 1.63 (2H, m),
1.13 (1H, m), 0.87 (3H, d, JHH ) 6.4 Hz), 0.85 (3H, d, JHH ) 6.4
J. Org. Chem. Vol. 73, No. 14, 2008 5395

Yan and Spilling
[3-Methyl-5-(2-methylpropyl)]-2-cyclopentenone, 3e. Diketo-
phosphonate 2e (0.064 g, 0.23 mmol) gave 3e (0.015 g, 42%) along
with the aldol product 16e (0.023 g, 38%).
[3-Methyl-5-(2-methylpropyl)]-2-cyclopentenone, 3e. Pale yel-
low oil; IR (neat, NaCl) 1698 cm-1; 1H NMR (CDCl3) δ 5.90 (1H,
br s), 2.75 (1H, m), 2.42 (1H, m), 2.23 (1H, m), 2.11 (3H, br s),
1.70 (2H, m), 1.18 (1H, m), 0.93 (3H, d, JHH ) 6 Hz), 0.92 (3H,
d, JHH ) 6 Hz); 13C NMR (CDCl3) δ 212.8, 177.2, 129.9, 45.4,
40.9, 40.6, 26.9, 23.6, 21.9, 19.6.
Genera Procedure for the Horner-Wadsworth-Emmons
Cyclization with Ba(OH)2 as the Base. Diketophosphonate 2
(0.091 mmol) was dissolved in anhydrous THF (1.2 mL), then
Ba(OH)2 ·8H2O (dried at 115 °C for 16 h before use, 0.015 g, 0.087
mmol) was added. The reaction mixture was stirred at room
temperature until the reaction was complete (TLC). The reaction
mixture was partitioned between brine and Et2O. After separation,
the aqueous layer was re-extracted with Et2O and the combined
organic layers were dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give the crude product, which was purified
by chromatography (SiO2, EtOAc:hexanes, 1:5) to give the products
3 and 16.
(3-Methyl-5-phenyl)-2-cyclopentenone. Diketophosphonate 2b
(0.105 g, 0.352 mmol) gave 3b as a white solid (0.013 g, 21%).
[3-Methyl-5-(2-methylpropyl)]-2-cyclopentenone, 3e. Diketo-
phosphonate 2e (0.018 g, 0.065 mmol) gave 3e (0.002 g, 23%).
(3-Methyl-5-cyclohexyl)-2-cyclopentenone, 3f. Diketophospho-
nate 2f (0.028 g, 0.091 mmol) gave 3f as a pale yellow oil (0.005
g, 31% yield).
(3-Methyl-5-cyclohexyl)-2-cyclopentenone, 3f. Pale yellow oil;
1
IR (neat, NaCl) 1698 cm-1; H NMR (CDCl3) δ 5.89 (1H, br s),
2.56 (1H, m), 2.38 (2H, m), 2.12 (3H, br s), 1.89 (1H, m), 1.70
(4H, m), 0.96-1.43 (6H, m); 13C NMR (CDCl3) δ 212.3, 178.0,
131.1, 52.4, 39.1, 36.3, 31.4, 27.5, 26.7, 26.5, 26.3, 19.6; HRMS
(EI, M+) calcd for C12H18O 178.1358, found 178.1359.
[3-Methyl-5-(2-benzoxylpropyl)]-2-cyclopentenone, 3g. Pale
yellow oil (1:1 mixture diastereomers); IR (neat, NaCl) 1696 cm-1
;
1H NMR (CDCl3) δ 7.32 (5H, m), 5.82 (1H, br s), 4.61 (0.5H, d,
JHH ) 11.8 Hz), 4.60 (0.5H, d, JHH ) 11.8 Hz), 4.78 (0.5H, d, JHH
) 11.8 Hz), 4.39 (0.5H, d, JHH ) 11.8 Hz), 3.73 (0.5H, m), 3.59
(0.5H, m), 2.71 (0.5H, m), 2.46 (1.5H, m), 2.26 (1H, m), 2.04 (0.5H,
m), 2.03 (1.5H, s), 1.99 (1.5H, s), 1.91 (0.5H, m), 1.47 (0.5H, m),
1.34 (0.5H, m), 1.17 (1.5H, d, JHH ) 6.0 Hz), 1.16 (1.5H, d, JHH
) 6.0 Hz); 13C NMR (CDCl3) δ 212.3, 212.2, 177.6, 177.5, 139.1,
130.1, 129.8, 128.5, 128.0, 127.9, 127.7, 74.6, 73.0, 70.8, 70.4,
44.6, 43.8, 41.5, 40.4, 39.1, 38.3, 20.1, 19.9, 19.6; HRMS (FAB,
MH+) calcd for C16H21O2 245.1541, found 245.1537.
[3-Methyl-5-(2-benzoxylpropyl)]-2-cyclopentenone, 3g. Dike-
tophosphonate 2g (0.085 g, 0.23 mmol) gave 3g as a pale yellow
oil (0.02 g, 36%).
(3-Methyl-5-phenyl)-2-cyclopentenone, 3b. White solid; 1H
NMR (CDCl3) δ 7.18 (5H, m), 5.95 (1H, br s), 3.55 (1H, dd, JHH
) 7.2, 2.8 Hz), 3.05 (1H, m), 2.61 (1H, m), 2.14 (3H, s); 13C NMR
(CDCl3) δ 209.4, 178.3, 140.2, 130.2, 129.2, 127.9, 127.3, 53.1,
43.2, 19.9; HRMS (EI, M+) calcd for C12H12O 172.0882, found
172.0887.
Acknowledgment. We are grateful to the National Science
Foundation for funding this work (CHE-0313736), we also thank
the National Science Foundation for grants to purchase the NMR
spectrometer (CHE-9974801) and the mass spectrometer (CHE-
9708640) used in this work. We thank the UMSL Graduate
School for a Fellowship for B.Y., and Mr. Joe Kramer and Prof.
REK Winter for mass spectra.
(3-Methyl-5-pentyl)-2-cyclopentenone, 3c. Colorless liquid; IR
(neat, NaCl) 1698 cm-1; 1H NMR (CDCl3) δ 5.87 (1H, br s), 2.71
(1H, m), 2.35 (1H, m), 2.23 (1H, m), 2.10 (3H, br s), 1.77 (1H,
m), 1.27 (7H, m), 0.86 (3H, t, JHH ) 6.7 Hz); 13C NMR (CDCl3)
δ 212.4, 177.4, 130.1, 46.9, 39.9, 31.9, 31.5, 27.1, 22.7, 19.5, 14.2;
HRMS (EI, MH+) calcd for C11H19O 167.1436, found 167.1437.
(3,5-Dimethyl)-2-cyclopentenone, 3d. Colorless liquid; IR (neat,
Supporting Information Available: General experimental
details, 1H and 13C NMR spectra for compounds 4c, 4f, 5b, 5f,
5g, 7b, 7c, 7d, 1b-g, 13c, 13e, 15, 2b-g, 3b-g, 16c, 16e,
16f, and 16 g and HPLC data for compounds 4b, 4c, 5b, 5f,
1c, 1e, 1f, 3c, 3e, 3f, 3g, and 16f. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
NaCl) 1697 cm-1; H NMR (CDCl3) δ 5.87 (1H, br s), 2.79 (1H,
m), 2.39 (1H, m), 2.15 (1H, m), 2.09 (3H, br s), 1.14 (3H, dd, JHH
) 7.5, 1.4 Hz); 13C NMR (CDCl3) δ 212.9, 177.2, 129.6, 42.0,
41.3, 19.5, 16.6; HRMS (EI, MH+) calcd for C7H10O 110.0732,
found 110.0731.
JO8004028
5396 J. Org. Chem. Vol. 73, No. 14, 2008