Addition of organometallic nucleophiles to β-keto phosphonates

Article abstract of DOI:10.1021/jo990388k

The reaction of some Grignard reagents with β-keto phosphonates results in nucleophilic addition to the carbonyl group to afford β-hydroxy phosphonates with extension of the carbon skeleton. Additions of allylmagnesium reagents have proven particularly efficient, especially in the presence of BF₃·OEt₂. Reactions of allylic zinc reagents with β-keto phosphonates also gave the desired β-hydroxy phosphonates, often in even better yields. With crotyl and prenyl organometallic reagents, the reactions proceed with allylic transposition. Because these allylation reactions expand the functionality of the original substrate, various transformations can be conducted on the initial products to provide convenient access to a variety of new phosphonates.

Full text of DOI:10.1021/jo990388k

J . Org. Chem. 1999, 64, 5205-5212
5205
Ad d ition of Or ga n om eta llic Nu cleop h iles to â-Keto P h osp h on a tes
LoriAnn M. Lentsch and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
Received March 4, 1999
The reaction of some Grignard reagents with â-keto phosphonates results in nucleophilic addition
to the carbonyl group to afford â-hydroxy phosphonates with extension of the carbon skeleton.
Additions of allylmagnesium reagents have proven particularly efficient, especially in the presence
of BF3‚OEt2. Reactions of allylic zinc reagents with â-keto phosphonates also gave the desired
â-hydroxy phosphonates, often in even better yields. With crotyl and prenyl organometallic reagents,
the reactions proceed with allylic transposition. Because these allylation reactions expand the
functionality of the original substrate, various transformations can be conducted on the initial
products to provide convenient access to a variety of new phosphonates.
Sch em e 1
Recent applications of phosphonates as enzyme inhibi-
tors and metabolic probes,1 in addition to continuing
attention to their more traditional roles as intermediates
in organic synthesis,2 have spurred interest in the
preparation of more complex examples.3 Many â-keto
phosphonates can be prepared by well-known methods
for formation of the carbon-phosphorus bond, such as
the Arbuzov reaction4 or by acylation of an alkyl phos-
phonate anion.5 Whereas both of these classical reactions
rely upon use of phosphorus nucleophiles, a number of
more contemporary methods for â-keto phosphonate
synthesis are based on free radical reactions6 or electro-
philic phosphorus reagents. These later approaches
include rearrangements of vinyl phosphates to â-keto
phosphonates7 and reaction of P(III) halides with enolates
followed by oxidation.8 The success of these later reac-
tions in providing access to varied phosphonates has
encouraged us to consider other reactions in which an
electrophilic phosphorus reagent is paired with a nucleo-
philic partner. One particularly attractive strategy would
involve addition of organometallic nucleophiles to the
carbonyl group of â-keto phosphonates (Scheme 1).
Because such additions would extend the carbon skeleton
and may introduce additional functionality, they could
significantly expand the range of accessible phospho-
nates.
A few cases of nucleophilic additions to â-keto phos-
phonates have been reported. For example, Berkowitz
and co-workers have shown that methylmagnesium
bromide can be added to the carbonyl group of an R,R-
difluoro-â-keto phosphonate (3), to give an (R,R-difluo-
roalkyl)phosphonate analogue of a secondary phosphate
(4), without attack at phosphorus.9 Earlier examples from
(1) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
1990, 31, 5587-5590. (b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.
Tetrahedron Lett. 1990, 31, 5591-5594. (c) Pompliano, D. L.; Rands,
E.; Schaber, M. D.; Mosser, S. D.; Anthony, N. J .; Gibbs, J . B.
Biochemistry 1992, 31, 3800-3807. (d) Stowasser, B.; Budt, K. H.; Li,
J . Q.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625-6628.
(e) Hohl, R. J .; Lewis, K.; Cermak, D. M.; Wiemer, D. F. Lipids 1998,
33, 39-46.
(2) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(3) Wiemer, D. F. Tetrahedron 1997, 53, 16609-16644.
(4) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307-335.
(5) (a) Corey, E. J .; Kwiatkowski, G. T. J . Am. Chem. Soc. 1966, 88,
5654-5656. (b) Mathey, F.; Savignac, P. Tetrahedron 1978, 34, 649-
654. (c) Aboujaoude, E. E., Collignon, N.; Savignac, P. J . Organomet.
Chem. 1984, 264, 9-17.
(6) (a) Peterson, A. C.; Levsen, S. M.; Cremer, S. E. Phosphorus,
Sulfur, Silicon Relat. Elem. 1996, 115, 241-254. (b) Barton, D. H. R.;
Gero, S. D.; Quiclet-Sire, B.; Samadi, M. Tetrahedron 1992, 48, 1627-
1636. (c) Wnuk, S.; Robins, M. J . J . Am. Chem. Soc. 1996, 118, 2519-
2520.
(7) (a) Baker, T.; Wiemer, D. F. J . Org. Chem. 1998, 63, 2613-2618.
(b) An, J .; Wilson, J .; An, Y. Z.; Wiemer, D. F. J . Org. Chem. 1996, 61,
4040-4045. (c) An, Y. Z.; An, J .; Wiemer, D. F. J . Org. Chem. 1994,
59, 8197-8202. (d) Calogeropoulou, T.; Hammond, G. B.; Wiemer, D.
F. J . Org. Chem. 1987, 52, 4185-4190. (e) Gloer, K. B.; Calogeropoulou,
T.; J ackson, J . A.; Wiemer, D. F. J . Org. Chem. 1990, 55, 2842-2846.
(8) (a) Lee, K.; Wiemer, D. F. J . Org. Chem. 1991, 56, 5556-5560.
(b) Boeckman, R. K., J r.; Kamenecka, T. M.; Nelson, S. G.; Pruitt, J .
R.; Barta, T. E. Tetrahedron Lett. 1991, 32, 2581-2584. (c) Lee, K.;
J ackson, J . A.; Wiemer, D. F. J . Org. Chem. 1993, 58, 5967-5971.
Burton’s group, for example, conversion of phosphonate
5 to olefin 6 by Grignard addition followed by phosphate
elimination, also made it appear unlikely that reaction
at phosphorus would be competitive with addition to the
carbonyl group.10 However, in these examples a fully
substituted R carbon ensured that proton transfer would
not be encountered. For more general utility, it would
be important to establish whether addition to the car-
bonyl group of a â-keto phosphonate could be successful
even in the presence of a relatively acidic R hydrogen. A
(9) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemaker, R. K. J . Org.
Chem. 1996, 61, 4666-4675.
(10) Tsai, H. J .; Thenappan, A.; Burton, D. J . J . Org. Chem. 1994,
59, 7085-7091.
10.1021/jo990388k CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/19/1999

5206 J . Org. Chem., Vol. 64, No. 14, 1999
Lentsch and Wiemer
Ta ble 1. Rea ction of Allylm a gn esiu m Ch lor id e w ith
It is well-known that addition of cerium chloride will
improve the reaction of Grignard reagents with readily
enolizable ketones,14 but when CeCl3 was added to these
reactions at a variety of temperatures the yields were
not significantly improved. However, in the presence of
boron trifluoride etherate the allylation of each of these
phosphonates was greatly improved. For example, allyl
addition to diethyl 2-oxopropylphosphonate (13) had
resulted in only a 22% yield of the desired hydroxy
phosphonate in the absence of BF3‚OEt2, but in the
presence of this Lewis acid the yield increased to 80%.
The more enolizable phosphonates still gave moderate
yields, but even these were improved relative to the
parallel reactions conducted in the absence of the Lewis
acid.
â-Keto P h osp h on a tes
Although diastereomers might be formed in additions
to phosphonates 7, 9, and 11, in each case one major
product could be detected by 31P NMR analysis of the
reaction mixtures. Detailed analysis of the spectra of the
major diastereomer of phosphonate 10 suggested that
this product was the cis isomer as shown. The observed
couplings of the R hydrogen (δ 1.85, J HP ) 19.4 Hz; J HH
) 11.6, 4.1 Hz) indicated a conformation in which this
hydrogen was in an axial orientation with the phosphoryl
group equatorial. Observation of NOE between the R
hydrogen and an allylic hydrogen and between the R
hydrogen and the vinylic methine suggested that the allyl
group was an equatorial substituent on the adjacent
carbon. Whether this outcome is the result of a mecha-
nism involving complexation and delivery or whether the
product stereochemistry is governed by the steric bulk
of the phosphoryl group is not yet clear. Because phos-
phonates 7 and 11 gave only a single diastereomer as
the product, it would be reasonable to assume formation
of cis products 8 and 12 in these cases as well. This was
confirmed in the case of phosphonate 12 when catalytic
hydrogenation gave phosphonate 17, identical with ma-
terial prepared by hydrogenation of phosphonate 10.
a
Reactions were run at 0 °C in the presence of BF3OEt2 or were
allowed to warm to rt prior to quenching in the absence of
BF3‚OEt2. In this case, 1.5 equiv of the Grignard reagent was
employed, in all other cases, 5 equiv was used.
b
parallel process, allylation of â-keto amides and â-keto
esters,11 has been accomplished with magnesium and/or
zinc reagents even in cases where the R carbon was
unsubstituted and proton transfer from the activated
methylene position was possible. In part because of this
precedent and in part because the allyl group can be
easily converted to a variety of other functional groups,12
we began this survey by examining the reactions of
several representative â-keto phosphonates with allyl
Grignard reagents.13
In the first experiment, a slight excess of allylmagne-
sium chloride in THF was added to phosphonate 7 (Table
1) at 0 °C, and the reaction was allowed to warm to room
temperature over several hours. The desired hydroxy
phosphonate (8) was obtained, albeit in low yield (18%).
Reaction with excess Grignard reagent significantly
improved the yield (61%), and only a single product was
observed by 31P NMR. When the reaction was attempted
at reflux, none of the desired product was observed.
To gauge the scope of this reaction, a number of cyclic
and acyclic â-keto phosphonates were subjected to reac-
tion with allylmagnesium chloride under identical reac-
tion conditions. Unfortunately, the results varied dra-
matically depending upon the â-keto phosphonate utilized.
The six-membered ring phosphonates (9 and 11) gave
only moderate yields of adducts 10 and 12, and varied
results were obtained with acyclic examples 13 and 15.
Nucleophilic additions of other types of Grignard
reagents were not as successful under these reactions
conditions. For example, addition of phenylmagnesium
chloride to a solution of phosphonate 7 in THF did not
afford the desired â-hydroxy phosphonate. Use of Ph-
MgBr in ether gave the hydroxy phosphonate, but only
in low yield. At this time, parallel reactions attempted
with methylmagnesium halides and vinylmagnesium
halides have resulted in just minor amounts of the
desired products, even in the presence of Lewis acids.
Grignard reagents more closely related to allylmagne-
sium chloride showed better reactivity (Table 2). For
example, benzylmagnesium bromide undergoes addition
to phosphonate 7 under these reaction conditions to
afford â-hydroxy phosphonate 18 in modest yield. Other
representative â-keto phosphonates (9, 13, and 15)
subjected to the same reaction conditions also gave the
benzylated products in moderate yields, with acyclic
(11) Taniguchi, M.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. J pn.
1995, 68, 645-653.
(12) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-2293.
(13) Presented in part at the XIVth International Conference on
Phosphorus Chemistry, Cincinnati, OH, J uly, 1998.
(14) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392-4398.

Organometallic Additions to â-Keto Phosphonates
J . Org. Chem., Vol. 64, No. 14, 1999 5207
Ta ble 2. Rea ction of Ben zyl- a n d Cr otylm a gn esiu m
Ta ble 3. Rea ction of Or ga n ozin c Rea gen ts w ith â-Keto
Ha lid es w ith â-Keto P h osp h on a tes
P h osp h on a tes
phosphonate 13 affording the best yield of the desired
adduct (53%). However, addition of Lewis acids did not
significantly improve the yields of these reactions. For
example, reaction of phosphonate 7 with benzylmagne-
sium bromide in the presence of BF3‚OEt2 gave virtually
the same yield observed in the absence of this Lewis acid.
Addition of crotyl substituents was examined primarily
to explore the special reactivity of allyl Grignard reagents
with this class of compounds. Reaction of crotylmagne-
sium chloride with phosphonates 7 and 13 resulted in
addition with complete allylic transposition to afford
hydroxy phosphonates 22 and 23 in 33% and 59% yield,
respectively.
In cases where moderate yields of addition products
were observed, analysis of the reaction mixture by 31P
NMR immediately after workup generally indicated the
presence of only two phosphorus-containing materials,
the desired product and some of the starting â-keto
phosphonate. Because the presence of the starting â-keto
phosphonate may reflect proton transfer to the Grignard
reagent followed by protonation upon workup, we chose
to examine some organometallic reagents likely to be less
reactive.15 Zinc reagents, especially allylzinc reagents, are
readily accessible and are known to add to carbonyl
groups, often with high stereoselectivity.11,16 The reaction
of allylzinc bromide with phosphonate 7 provided hydroxy
phosphonate 8 in 83% yield as a single product by 31P
NMR (Table 3). The zinc reagent appeared to be advan-
tageous relative to the allylmagnesium chloride-BF3‚
OEt2 system. Addition of allylzinc bromide to our selec-
tion of keto phosphonates gave the corresponding
â-hydroxy phosphonates in yields that were generally
improved relative to those obtained using Grignard
reagents. Additions of crotyl and prenyl groups through
the corresponding zinc reagents proceeded with complete
allylic transposition and generally in attractive yields.
With prenyl bromide and phosphonate 13, the reaction
gave far better yield when conducted in the presence of
NH4Cl than in its absence (86% vs 28%). Therefore,
reactions with phosphonates 7 and 11 also were con-
ducted in the presence of NH4Cl, and comparable yields
were obtained (77% and 86%, respectively). These condi-
tions also gave an improved yield for reaction of phos-
phonate 9 with allylzinc bromide (73%) and crotylzinc
bromide (52%).
The â-hydroxy phosphonates produced as the initial
products of nucleophilic addition to â-keto phosphonates
offer a number of opportunities for further reactions,
some based on the functionality of the newly introduced
allyl group and others that are not. For example, treat-
ment of phosphonate 12 with J ones reagent resulted in
oxidation with allylic transposition17 and gave rise to the
“vinylogous â-keto phosphonate” 29. On the basis of the
(15) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2188.
(b) Knochel, P.; Almena Perea, J . J .; J ones, P. Tetrahedron, 1998, 54,
8275-8319.
(16) Ahonen, M.; Sjoholm, R. Chem. Lett. 1995, 341-342. (b)
Einhorn, C.; Luche, J .-L. J . Organomet. Chem. 1987, 177-183.
(17) O¨ hler, E.; Zbiral, E. Synthesis 1991, 357-361.

5208 J . Org. Chem., Vol. 64, No. 14, 1999
Lentsch and Wiemer
tography (80% ethyl acetate, 20% hexanes) gave hydroxy
phosphonate 8 (109 mg, 61%) as a clear oil.
Meth od B. Boron trifluoride etherate (0.3 mL, 2.3 mmol)
was added to a stirred solution of allylmagnesium chloride (1.1
mL, 2.0 M in THF) in THF (10 mL) at 0 °C. After 20 min, a
solution of phosphonate 7 (100 mg, 0.45 mmol) in THF (2 mL)
was added. After stirring for 2 h at 0 °C, the reaction was
quenched by addition of 3 M NaOH, and the mixture was
stirred for 1 h at room temperature. Brine was added to the
reaction mixture, and the layers were separated. The aqueous
layer was washed with ether, and the combined organic
extracts were dried over Na2SO4 and concentrated in vacuo.
Purification of the residue by flash column chromatography
gave hydroxy phosphonate 8 (93 mg, 78%).
Meth od C. Allyl bromide (0.24 mL, 2.8 mmol) was added
to a suspension of zinc dust (180 mg, 2.8 mmol) in THF (6
mL). The mixture was allowed to stir at room temperature
until a yellow-gray color was observed. After the resulting
allylzinc bromide was cooled to -78 °C, a solution of phospho-
nate 7 (197 mg, 0.89 mmol) in THF (4 mL) was added via
cannula, and the reaction was stirred at -78 °C for 1 h. The
reaction mixture was added to 1 M HCl (20 mL), the aqueous
layer was extracted with ether, and the combined organic
extracts were dried over Na2SO4 and concentrated in vacuo.
Purification of the residue by flash column chromatography
gave hydroxy phosphonate 8 (196 mg, 83%): 1H NMR δ 5.95-
5.84 (m, 1H), 5.15-5.10 (m, 2H), 4.22-4.08 (m, 4H), 3.78 (s,
1H, exchanges in D2O), 2.63 (dd, J ) 13.8, 7.0 Hz, 1H), 2.38
(dd, J ) 13.8, 7.7 Hz, 1H), 2.21-2.05 (m, 2H), 1.98-1.85 (m,
2H), 1.79-1.55 (m, 3H), 1.34 (dt, J HP ) 6.7 Hz, J ) 6.8 Hz,
6H); 31P NMR 32.3; 13C NMR δ 134.1, 118.1, 81.7 (d, J CP ) 3.7
Hz), 62.2 (d, J CP ) 6.6 Hz), 61.4 (d, J CP ) 6.5 Hz), 45.1, 44.1
(d, J CP ) 141.6 Hz), 38.7 (d, J CP ) 13.1 Hz), 26.2, 22.4 (d, J CP
) 14.5 Hz), 16.3 (d, J CP ) 6.6 Hz), 16.3 (d, J CP ) 5.8 Hz); HRMS
calcd for C12H23O4P 262.1333, found 262.1316.
Diet h yl [2-H yd r oxy-2-(2-p r op en yl)cycloh exyl]p h os-
p h on a te (10). According to general procedure A, diethyl (2-
oxocyclohexyl)phosphonate7d (9, 110 mg, 0.47 mmol) was added
to allylmagnesium chloride (1.2 mL, 2.0 M in THF) at 0 °C.
The reaction was stirred for 30 min at 0 °C and then allowed
to warm to room temperature. Standard workup and purifica-
tion by flash column chromatography (60% hexanes, 40% ethyl
acetate) yielded hydroxy phosphonate 10 (47 mg, 36%) as a
2.5:1 mixture of diastereomers.
According to general procedure B, BF3‚OEt2 (0.27 mL, 2.1
mmol) was added to allylmagnesium chloride (1.1 mL, 2.0 M
in THF) in THF (10 mL) at 0 °C and allowed to stir for 25
min. Phosphonate 9 (70 mg, 0.3 mmol in 2 mL THF) was
added, and the reaction was stirred for 2 h. Standard workup
and purification by flash column chromatography afforded
hydroxy phosphonate 10 (42 mg, 51%) as a 17.5:1 mixture of
diastereomers.
known reactivity of γ-phosphono crotonates,18 it would
be reasonable to expect compounds such as 29 to undergo
Horner-Wadsworth-Emmons condensations under stan-
dard conditions. Treatment of phosphonate 8 with O2 in
19
the presence of PdCl2 and Cu(OAc)2 resulted in oxida-
tion of the allyl group to the corresponding ketone 30,
providing a product with multiple sites for further
reactivity.
In conclusion, despite the acidity of â-keto phospho-
nates, allyl organometallic reagents add efficiently to the
carbonyl group. Addition of allyl Grignard reagents is
facilitated by BF3, but in several cases the corresponding
allylzinc reagents give the carbonyl addition products in
higher yield even in the absence of added Lewis acids.
The products of allyl addition reactions have been shown
to undergo several additional transformations, further
expanding the range of phosphonates accessible through
this strategy. Future work will focus on extension of these
carbonyl addition reactions to other â-keto phosphonates
and organometallic reagents, as well as other transfor-
mations of the resultant â-hydroxy phosphonates.
Exp er im en ta l Section
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium/benzophenone immediately prior to use. All nonaque-
ous reactions were conducted in oven-dried glassware, under
an atomosphere of argon, and with magnetic stirring. Zinc dust
was activated by washing several times with 1 M HCl followed
by successive washings with water, methanol, and ether. After
vacuum-drying, the zinc was stored under argon until used.
Flash chromatography was carried out on silica gel with 40
µm average particle diameter. NMR spectra were recorded at
360 MHz for 1H with CDCl3 as solvent and (CH3)4Si (1H) or
CDCl3 (13C, 77.0 ppm) as internal standards unless otherwise
noted. 31P NMR chemical shifts are reported in ppm relative
to 85% H3PO4 (external standard). High resolution and FAB
mass spectra were obtained at the University of Iowa Mass
Spectrometry Facility. Elemental analyses were performed by
Atlantic Microlab, Inc. (Norcross, GA).
Dieth yl [2-Hyd r oxy-2-(2-p r op en yl)cyclop en tyl]p h os-
p h on a t e (8). Met h od A. A solution of diethyl (2-oxocyclo-
pentyl)phosphonate7d (7, 151 mg, 0.69 mmol) in THF (2 mL)
was added dropwise via cannula to a stirred solution of
allylmagnesium chloride (1.8 mL, 2.0 M in THF) in THF (1.5
mL) at 0 °C. After the reaction mixture was stirred at 0 °C for
1.5 h, it was allowed to warm to room temperature and
quenched by slow addition of saturated aqueous NH4Cl. The
aqueous layer was extracted with ether, and the combined
organic extracts were dried over Na2SO4 and then concentrated
in vacuo. Purification of the residue by flash column chroma-
According to general procedure C, phosphonate 9 (51 mg,
0.22 mmol in 2 mL THF) was added to allylzinc bromide (1.0
mmol in 3 mL THF) via cannula at -78 °C. The reaction was
quenched after 30 min by addition to 1 M HCl (20 mL).
Standard workup and purification by flash column chroma-
tography gave hydroxy phosphonate 10 (35 mg, 58%) as a 12:1
mixture of diastereomers. HRMS calcd for C13H25O4P 276.1490,
found 276.1488. Anal. Calcd for C13H25O4P: C, 56.51; H, 9.12.
Found: C, 56.54; H, 9.07.
For the major diastereomer: 1H NMR (600 MHz) ((CD3)2-
SO) δ 5.87-5.80 (m, 1H), 5.06-5.02 (m, 2H), 4.31 (s, 1H),
4.03-3.93 (m, 4H), 2.59 (dd, J ) 13.5, 7.4 Hz, 1H), 2.36 (dd, J
) 13.6, 8.0 Hz, 1H), 1.85 (ddd, J HP ) 19.4 Hz, J ) 11.6, 4.1
Hz, 1H), 1.71-1.60 (m, 3H), 1.57-1.48 (m, 2H), 1.38-1.35 (m,
1H), 1.26 (tm, J ) 13.0 Hz, 1H), 1.21 (dt, J HP ) 1.5 Hz, J )
7.0 Hz, 6H), 1.14-1.08 (m, 1H); 31P NMR 33.4; 13C NMR δ
135.0, 117.5, 70.6 (d, J CP ) 5.1 Hz), 61.3 (d, J CP ) 6.5 Hz),
60.2 (d, J CP ) 6.5 Hz), 46.6, 41.7 (d, J CP ) 133.7 Hz), 36.4 (d,
J CP ) 12.4 Hz), 24.8 (d, J CP ) 13.8 Hz), 22.9, 20.7, 16.2 (d, J CP
) 5.8 Hz), 16.2 (d, J CP ) 5.8 Hz).
(18) Evans, D. A.; Fitch, D. M. J . Org. Chem. 1997, 62, 454-455.
(b) Marko, I. E.; Southern, J . M.; Adams, H. Tetrahedron Lett. 1992,
33, 4657-4660.
(19) Smith, A. B., III; Young, S.-C.; Friestad, G. K. Tetrahedron Lett.
1998, 39, 8765-8768.
For the minor diastereomer: 1H NMR (600 MHz) ((CD3)2-
SO) δ 5.89-5.82 (m, 1H), 5.06-5.02 (m, 2H), 4.43 (s, 1H),
4.04-3.95 (m, 4H), 2.43 (dd, J ) 14.4, 9.1 Hz, 1H), 2.37 (dd, J

Organometallic Additions to â-Keto Phosphonates
J . Org. Chem., Vol. 64, No. 14, 1999 5209
) 14.5, 4.8 Hz, 1H), 1.94 (ddd, J HP ) 19.6 Hz, J ) 10.9, 3.8
Hz, 1H), 1.83-1.77 (m, 1H), 1.74-1.70 (m, 1H), 1.63-1.60 (m,
According to general procedure C, phosphonate 15 (92 mg,
0.33 mmol in 2 mL THF) was added to allylzinc bromide (1.1
mmol in 3 mL THF) via cannula at -78 °C. The reaction was
quenched after 1 h by addition to 1 M HCl (20 mL). Standard
workup and purification by flash column chromatography (30%
ethyl acetate, 70% hexanes) gave hydroxy phosphonate 16 (78
mg, 74%): 1H NMR (600 MHz) δ 5.89-5.77 (m, 1H), 5.13-
5.08 (m, 2H), 4.17-4.06 (m, 4H), 3.84 (s, 1H), 2.42 (dd, J )
7.4, 1.2 Hz, 2H), 2.01 (dd, J HP ) 23.7 Hz, J ) 15.8 Hz, 1H),
1.98 (dd, J HP ) 23.8 Hz, J ) 15.8 Hz, 1H), 1.88 (br d, J ) 12.7
Hz, 1H), 1.74 (br d, J ) 12.9 Hz, 1H), 1.68-1.60 (m, 3H), 1.56-
1.49 (m, 2H), 1.45-1.41 (m, 1H), 1.34 (dt, J HP ) 1.4 Hz, J )
7.0 Hz, 6H), 1.29-1.20 (m, 2H), 1.17-1.10 (m, 1H), 1.02-0.95
(m, 2H); 31P NMR 31.1; 13C NMR δ 134.0, 118.5, 72.9 (d, J CP
) 5.1 Hz), 61.6 (d, J CP ) 6.5 Hz), 61.6 (d, J CP ) 6.5 Hz), 47.5
(d, J CP ) 9.4 Hz), 45.2 (d, J CP ) 9.5 Hz), 35.7 (d, J CP ) 135.8
Hz), 35.1, 34.9, 33.3, 26.4, 26.3, 26.2, 16.3 (d, J CP ) 6.5 Hz,
2C). Anal. Calcd for C16H31O4P: C, 60.36; H, 9.81. Found: C,
60.28; H, 9.76.
1H), 1.57-1.49 (m, 2H), 1.24-1.10 (m, 3H), 1.21 (dt, J HP
1.5 Hz, J ) 7.0 Hz, 6H); 31P NMR 32.0; 13C NMR δ 134.5, 117.0,
71.2 (d, J CP ) 2.2 Hz), 61.2 (d, J CP ) 6.6 Hz), 60.8 (d, J CP
)
)
7.3 Hz), 45.7 (d, J CP ) 133.7 Hz), 39.0, 35.7 (d, J CP ) 11.7 Hz),
24.4 (d, J CP ) 12.3 Hz), 23.8, 21.7, 16.2 (d, J CP ) 5.8 Hz), 16.2
(d, J CP ) 5.8 Hz).
Dieth yl [2-Hydr oxy-2-(2-pr open yl)cyloh ex-3-en yl]ph os-
p h on a te (12). According to general procedure C, phosphonate
117e (94 mg, 0.41 mmol in 2 mL THF) was added to allylzinc
bromide (1.4 mmol in 3 mL THF) via cannula at -78 °C. The
reaction was quenched after 35 min by addition to 1 M HCl
(20 mL). Standard workup and purification by flash column
chromatography (3:1 CHCl3/EtOAc) gave hydroxy phosphonate
12 (80 mg, 72%): 1H NMR δ 5.90-5.85 (m, 1H), 5.82-5.68
(m, 1H), 5.65-5.60 (m, 1H), 5.17-5.09 (m, 2H), 4.20-4.10 (m,
4H), 3.69 (s, 1H), 2.73 (dd, J ) 13.7, 8.4 Hz, 1H), 2.56 (dd, J
) 13.7, 6.1 Hz, 1H), 2.22-2.10 (m, 2H), 1.98-1.89 (m, 3H),
1.34 (dt, J HP ) 3.6 Hz, J ) 7.1 Hz, 6H); 31P NMR 32.1; 13C
NMR δ 133.8, 132.0 (d, J CP ) 10.9 Hz), 129.2, 118.4, 69.8 (d,
J CP ) 4.3 Hz), 62.2 (d, J CP ) 6.5 Hz), 61.2 (d, J CP ) 6.5 Hz),
Hyd r ogen a tion of P h osp h on a te 12. A solution of hydroxy
phosphonate 12 (32 mg, 0.12 mmol) in MeOH (3 mL) was
hydrogenated at 50 psi in the presence of 10% Pd on activated
carbon (∼20 mg) at room temperature for 8 h. The catalyst
was removed by filtration, and the solvent was removed in
vacuo. Purification of the residue by flash column chromatog-
raphy (60% hexanes, 40% ethyl acetate) gave compound 17
(30 mg, 92%) as a clear oil: 1H NMR δ 4.21-4.01 (m, 4H),
3.80 (d, J ) 2.2 Hz, 1H), 1.95-1.66 (m, 8H), 1.50-1.44 (m,
1H), 1.42-1.31 (m, 2H), 1.34 (dt, J HP ) 4.1 Hz, J ) 7.0 Hz,
6H), 1.27-1.13 (m, 2H), 0.92 (t, J ) 7.3 Hz, 3H); 31P NMR
33.7; 13C NMR δ 71.4 (J CP ) 5.1 Hz), 62.5 (d, J CP ) 6.5 Hz),
60.9 (d, J CP ) 8.0 Hz), 45.8 (J CP ) 2.2 Hz), 42.2 (J CP ) 132.9
Hz), 35.9 (J CP ) 13.8 Hz), 25.8 (J CP ) 15.2 Hz), 22.6, 20.9,
17.1, 16.5 (J CP ) 5.8 Hz), 16.3 (J CP ) 6.6 Hz), 14.6; HRMS
calcd for C13H27O4P 278.1647, found 278.1631.
46.1 (d, J CP ) 1.5 Hz), 40.7 (d, J CP ) 138.8 Hz), 24.6 (d, J CP
)
13.1 Hz), 20.0 (d, J CP ) 3.6 Hz), 16.3 (d, J CP ) 6.6 Hz), 16.3 (d,
J CP ) 6.5 Hz); HRFABMS calcd for C13H23O4P (M + Na)+
297.1232, found 297.1228.
Dieth yl (2-Hyd r oxy-2-m eth yl-4-p en ten yl)p h osp h on a te
(14). According to general procedure C, phosphonate 13 (96
mg, 0.49 mmol in 2 mL THF) was added to allylzinc bromide
(1.6 mmol in 3 mL THF) via cannula at -78 °C. The reaction
was quenched after 30 min by addition to 1 M HCl. Standard
workup and purification by flash column chromatography (50%
ethyl acetate, 50% hexanes) gave hydroxy phosphonate 14 (116
mg, 99%): 1H NMR δ 5.94-5.80 (m, 1H), 5.15-5.08 (m, 2H),
4.19-4.06 (m, 4H), 3.75 (s, 1H), 2.35 (d, J ) 7.3 Hz, 2H), 2.11-
1.90 (m, 2H), 1.34 (t, J ) 7.2 Hz, 6H), 1.34 (s, 3H); 31P NMR
31.1; 13C NMR δ 133.8, 118.5, 70.2 (d, J CP ) 4.6 Hz), 61.6 (d,
J CP ) 4.5 Hz), 61.5 (d, J CP ) 4.5 Hz), 47.9 (d, J CP ) 11.9 Hz),
Hydrogenation of a sample of phosphonate 10, a 2.5:1
mixture of diastereomers, gave a mixture of the two saturated
diastereomers. The major diastereomer was identical to the
product obtained by hydrogenation of compound 12 (by 13C and
31P NMR). For the minor diastereomer: 31P NMR 32.2; 13C
36.7 (d, J CP ) 135.8 Hz), 28.0 (d, J CP ) 8.5 Hz), 16.3 (d, J CP
)
6.1 Hz, 2C); HRFABMS calcd for C10H21O4P (M + Na)+
NMR δ 72.2 (J CP ) 4.3 Hz), 61.7 (J CP ) 6.5 Hz), 61.3 (J CP
)
259.1075, found 259.1095.
7.9 Hz), 47.7 (J CP ) 134.5 Hz), 36.5 (J CP ) 2.2 Hz), 35.7 (J CP
) 16.0 Hz), 25.8 (J CP ) 14.5 Hz), 24.5 (J CP ) 5.8 Hz), 22.7,
16.4 (J CP ) 5.1 Hz), 16.3 (J CP ) 5.8 Hz), 15.7, 14.6.
Dieth yl (3-Cycloh exyl-2-oxop r op yl)p h osp h on a te (15).
n-Butyllithium (2.42 M in hexanes, 2.75 mL, 6.7 mmol) was
added dropwise to a solution of diethyl methylphosphonate
(1.01 g, 6.6 mmol) in THF (7 mL) at -78 °C.20 The resulting
solution was stirred for 30 min at -78 °C followed by slow
addition of ethyl cyclohexylacetate (0.70 g, 4.1 mmol in 1.5 mL
THF). The reaction was allowed to warm to room temperature
and then quenched by addition of saturated aqueous NH4Cl.
The layers were separated, and the aqueous portion was
extracted with ether. The organic extracts were combined,
dried over Na2SO4, and concentrated in vacuo. Purification of
the residue by flash column chromatography (3:1 ethyl acetate/
hexanes) gave â-keto phosphonate 15 as a clear oil (0.59 g,
52%): 1H NMR δ 4.19-4.10 (m, 4H), 3.06 (d, J HP ) 22.8 Hz,
2H), 2.50 (d, J ) 6.7 Hz, 2H), 1.91-1.78 (m, 1H), 1.73-1.62
(m, 5H), 1.34 (t, J ) 7.1 Hz, 6H), 1.30-1.06 (m, 3H), 1.00-
0.88 (m, 2H); 31P NMR 20.7; 13C NMR δ 201.7 (d, J CP ) 5.8
Hz), 62.4 (d, J CP ) 6.5 Hz, 2C), 51.6, 42.7 (d, J CP ) 126.4 Hz),
33.3, 32.9 (2C), 26.1, 25.9 (2C), 16.2 (d, J CP ) 5.9 Hz, 2C);
HRFABMS calcd for C13H25O4P (M + H)+ 277.1569, found
277.1569.
Dieth yl (2-Hyd r oxy-2-p h en ylm eth ylcyclop en tyl)p h os-
p h on a te (18). A three-neck flask equipped with an addition
funnel, condenser, and magnesium turnings (60 mg, 2.5 mmol)
was flame-dried and purged with argon. After the apparatus
had cooled, ether (1 mL) and one-third of the benzyl bromide
(0.08 mL, 0.67 mmol) were added to the vigorously stirred
magnesium. Once the reaction began to reflux, a solution of
the remaining benzyl bromide (0.20 mL, 1.7 mmol) in ether (5
mL) was added slowly to maintain reflux. After the benzyl
bromide addition was complete, the reaction was heated at
reflux for an additional hour and then allowed to cool to room
temperature. A solution of phosphonate 7 (105 mg, 0.48 mmol)
in ether (2 mL) was added dropwise to the Grignard reagent.
The reaction was allowed to stir at room temperature for 5 h
and then quenched by addition of 2 N HCl. The layers were
separated, and the aqueous layer was washed with ether. The
combined organic extracts were dried over Na2SO4 and con-
centrated in vacuo. Purification by flash column chromatog-
raphy (80% hexanes, 20% ethyl acetate) gave hydroxy phos-
phonate 18 (49 mg, 33%): 1H NMR δ 7.32-7.20 (m, 5H), 4.28-
4.10 (m, 4H), 3.88 (br s, 1H), 3.18 (d, J ) 13.5 Hz, 1H), 2.94
(d, J ) 13.5 Hz, 1H), 2.23-2.09 (m, 2H), 1.94-1.79 (m, 2H),
1.66-1.50 (m, 3H), 1.36 (dt, J HP ) 16.2 Hz, J ) 7.1 Hz, 6H);
31P NMR 32.5; 13C NMR δ 138.0, 130.4 (2C), 128.0 (2C), 126.3,
Diet h yl (2-Cycloh exylm et h yl-2-h yd r oxy-4-p en t en yl)-
p h osp h on a te (16). According to general procedure B, BF3‚
OEt2 (0.22 mL, 1.7 mmol) was added to allylmagnesium
chloride (0.86 mL, 2.0 M in THF) in THF (10 mL) at 0 °C, and
the mixture was allowed to stir for 20 min. Phosphonate 15
(96 mg, 0.35 mmol in 2 mL THF) was added, and the reaction
was stirred for 2 h. Standard workup and purification by flash
column chromatography (50% ethyl acetate, 50% hexanes)
yielded hydroxy phosphonate 16 (86 mg, 78%) as a clear oil.
82.5 (d, J CP ) 3.7 Hz), 62.2 (d, J CP ) 6.5 Hz), 61.4 (d, J CP
)
7.3 Hz), 46.4, 43.9 (d, J CP ) 141.0 Hz), 38.6 (d, J CP ) 14.5 Hz),
25.9, 22.0 (d, J CP ) 13.8 Hz), 16.5 (d, J CP ) 3.6 Hz), 16.4 (d,
J CP ) 3.7 Hz); HRFABMS calcd for C16H25O4P (M + H)+
313.1569, found 313.1576. Anal. Calcd for C16H25O4P: C, 61.53;
H, 8.07. Found: C, 61.65; H, 8.20.
(20) Wilson, J . M. PhD Thesis, University of Iowa, December, 1998.

5210 J . Org. Chem., Vol. 64, No. 14, 1999
Lentsch and Wiemer
Dieth yl (2-Hyd r oxy-2-p h en ylm eth ylcycloh exyl)p h os-
p h on a te (19). According to the procedure used for preparation
of compound 18, phosphonate 9 (92 mg, 0.39 mmol in 2 mL
ether) was treated with benzylmagnesium bromide prepared
in situ from benzyl bromide (0.23 mL, 1.9 mmol) and magne-
sium (50 mg, 2.1 mmol) in ether (3 mL). After 3 h at room
temperature, the reaction was quenched by addition of 2 N
HCl. Standard workup and purification by flash column
chromatography (50% hexanes, 50% ethyl acetate) gave hy-
droxy phosphonate 19 (37 mg, 29%): 1H NMR δ 7.31-7.19
(m, 5H), 4.25-4.09 (m, 4H), 4.00 (d, J ) 2.0 Hz, 1H, exchanges
in D2O), 3.28 (d, J ) 13.6 Hz, 1H), 2.81 (d, J ) 13.7 Hz, 1H),
2.04-1.72 (m, 4H), 1.64-1.48 (m, 2H), 1.42-1.34 (m, 1H), 1.36
(t, J ) 7.0 Hz, 6H), 1.23-1.04 (m, 2H); 31P NMR 33.5; 13C NMR
δ 137.5, 130.7 (2C), 127.8 (2C), 126.1, 71.5 (d, J CP ) 4.4 Hz),
62.7 (d, J CP ) 7.3 Hz), 61.2 (d, J CP ) 7.3 Hz), 48.7, 43.7 (d, J CP
) 133.7 Hz), 36.1 (d, J CP ) 13.1 Hz), 25.5 (d, J CP ) 15.2 Hz),
22.9, 20.8, 16.5 (d, J CP ) 5.0 Hz), 16.3 (d, J CP ) 6.5 Hz);
HRFABMS calcd for C17H27O4P (M + Na)+ 349.1545, found
349.1540.
Diet h yl (2-H yd r oxy-2-m et h yl-3-p h en ylp r op yl)p h os-
p h on a te (20). According to the procedure for preparation of
compound 18, phosphonate 13 (100 mg, 0.51 mmol in 2 mL
ether) was treated with benzylmagnesium bromide prepared
in situ from benzyl bromide (0.31 mL, 2.6 mmol) and magne-
sium (62 mg, 2.6 mmol) in ether (30 mL). After 5 h at room
temperature, the reaction was quenched by addition of 2 N
HCl. Standard workup and purification by flash column
chromatography (80% hexanes, 20% ethyl acetate) gave hy-
droxy phosphonate 20 (78 mg, 53%): 1H NMR δ 7.33-7.22
(m, 5H), 4.18-4.05 (m, 4H), 3.90 (br s, 1H), 2.94-2.84 (m, 2H),
2.10-1.90 (m, 2H), 1.33 (s, 3H), 1.33 (t, J ) 7.1 Hz, 6H); 31P
NMR 30.7; 13C NMR δ 137.2, 130.6 (2C), 128.0 (2C), 126.5,
centrated in vacuo. Purification by flash column chromatog-
raphy (50% ethyl acetate, 50% hexanes) gave hydroxy phos-
phonate 22 (40 mg, 33%) as a 2:1 mixture of diastereomers.
Meth od C. Crotyl bromide (0.24 mL, 2.3 mmol) was added
to a suspension of zinc dust (150 mg, 2.3 mmol) in THF (3
mL). The mixture was allowed to stir at room temperature
until a yellow-gray color was observed. After the crotylzinc
bromide was cooled to -78 °C, a solution of phosphonate 7
(93 mg, 0.42 mmol) in THF (2 mL) was added slowly via
cannula. After stirring for 1 h at -78 °C, the reaction was
quenched by addition to 1 M HCl (20 mL). The aqueous layer
was extracted with ether, and the combined organic extracts
were dried over Na2SO4 and concentrated in vacuo. Purifica-
tion by flash column chromatography yielded hydroxy phos-
phonate 22 (91 mg, 78%) as a 1:5.8 mixture of diastereomers:
HRFABMS calcd for C13H25O4P (M + Na)+ 299.1388, found
299.1388.
For the major diastereomer from the zinc reaction: 1H NMR
δ 5.99 (ddd, J ) 17.5, 9.9, 7.7 Hz, 1H), 5.17-5.05 (m, 2H),
4.19-4.06 (m, 4H), 3.68 (s, 1H), 2.58 (dq, J ) 7.0, 6.9 Hz, 1H),
2.39-2.26 (m, 1H), 2.20-2.04 (m, 1H), 1.95-1.81 (m, 2H),
1.75-1.51 (m, 3H), 1.34 (dt, J HP ) 7.0 Hz, J ) 3.6 Hz, 6H),
1.06 (d, J ) 6.9 Hz, 3H); 31P NMR 32.4; 13C NMR δ 140.5,
115.1, 84.3 (d, J CP ) 3.6 Hz), 62.1 (d, J CP ) 4.4 Hz), 61.2 (d,
J CP ) 7.2 Hz), 46.1, 42.6 (d, J CP ) 141.0 Hz), 35.7 (d, J CP
)
12.3 Hz), 26.7, 22.6 (d, J CP ) 13.8 Hz), 16.4 (d, J CP ) 5.9 Hz),
16.3 (d, J CP ) 5.8 Hz), 15.0.
For the minor diastereomer from the zinc reaction: 1H NMR
δ 5.76 (ddd, J ) 17.3, 10.3, 8.5 Hz, 1H), 5.17-5.05 (m, 2H),
4.19-4.06 (m, 4H), 3.81 (s, 1H), 2.65 (dq, J ) 7.5, 7.3 Hz, 1H),
2.39-2.26 (m, 1H), 2.20-2.04 (m, 1H), 1.95-1.81 (m, 2H),
1.75-1.51 (m, 3H), 1.34 (dt, J HP ) 7.0 Hz, J ) 3.6 Hz, 6H),
1.13 (d, J ) 6.8 Hz, 3H); 31P NMR 32.8; 13C NMR δ 140.4,
116.2, 84.5 (d, J CP ) 2.9 Hz), 62.1 (d, J CP ) 6.5 Hz), 61.2 (d,
J CP ) 7.3 Hz), 46.2, 42.8 (d, J CP ) 140.2 Hz), 34.4 (d, J CP )
13.8 Hz), 26.4, 22.5 (d, J CP ) 14.5 Hz), 16.4 (d, J CP ) 5.9 Hz),
16.3 (d, J CP ) 5.8 Hz), 15.2.
70.8 (d, J CP ) 4.3 Hz), 61.7 (d, J CP ) 6.7 Hz), 61.6 (d, J CP
)
6.8 Hz), 49.5 (d, J CP ) 12.9 Hz), 37.0 (d, J CP ) 136.1 Hz), 28.1
(d, J CP ) 6.7 Hz), 16.3 (d, J CP ) 6.1 Hz, 2C). Anal. Calcd for
C
14H23O4P: C, 58.73; H, 8.10. Found: C, 58.48; H, 8.20.
Dieth yl (2-Cycloh exylm eth yl-2-h yd r oxy-3-p h en ylp r o-
Dieth yl (2-Hyd r oxy-2,3-d im eth yl-4-p en ten yl)p h osp h o-
n a te (23). According to general procedure C, phosphonate 13
(108 mg, 0.55 mmol in 2 mL THF) was added to crotylzinc
bromide (2.5 mmol in 3 mL THF) via cannula at -78 °C. The
reaction was quenched after 1 h by addition to 1 M HCl.
Standard workup and purification by flash column chroma-
tography (50% hexanes, 50% ethyl acetate) afforded hydroxy
phosphonate 23 (136 mg, 98%) as a 1.3:1 mixture of diaster-
eomers. HRFABMS calcd for C11H23O4P (M + Na)+ 273.1232,
found 273.1247.
p yl)p h osp h on a te (21). According to the usual procedure,
phosphonate 15 (106 mg, 0.38 mmol) was treated with ben-
zylmagnesium bromide prepared in situ from benzyl bromide
(0.22 mL, 1.9 mmol) and magnesium (50 mg, 2.1 mmol) in 3
mL ether. After 4 h at room temperature, the reaction was
quenched by addition of 2 N HCl. Standard workup and
purification by flash column chromatography (50% hexanes,
50% ethyl acetate) gave hydroxy phosphonate 21 (40 mg,
28%): 1H NMR δ 7.31-7.21 (m, 5H), 4.17-4.03 (m, 4H), 3.70
(s, 1H), 2.97 (dd, J ) 13.6, 2.2 Hz, 1H), 2.92 (d, J ) 13.6 Hz,
1H), 1.96 (d, J HP ) 18.4 Hz, 2H), 1.88 (dm, J ) 12.7 Hz, 1H),
1.79 (dm, J ) 13.0 Hz, 1H), 1.70-1.52 (m, 5H), 1.43 (ddd, J )
14.3, 4.8, 1.7 Hz, 1H), 1.36-1.23 (m, 2H), 1.32 (dt, J HP ) 11.5
Hz, J ) 7.1 Hz, 6H), 1.20-1.11 (m, 1H), 1.03-0.93 (m, 2H);
31P NMR 31.0; 13C NMR δ 137.4, 130.8 (2C), 128.0 (2C), 126.3,
For the major diastereomer: 1H NMR δ 5.79 (ddd, J ) 17.2,
10.4, 8.2 Hz, 1H), 5.12-5.06 (m, 2H), 4.21-4.12 (m, 4H), 3.83
(s, 1H), 2.44-2.31 (m, 1H), 2.22-1.91 (m, 2H), 1.35 (t, J ) 7.1
Hz, 6H), 1.30 (s, 3H), 1.06 (d, J ) 6.9 Hz, 3H); 31P NMR 31.6;
13C NMR δ 139.9, 116.2, 72.1, 62.3 (d, J CP ) 6.5 Hz, 2C), 49.0
(d, J CP ) 13.1 Hz), 35.9 (d, J CP ) 138.1 Hz), 24.1 (d, J CP ) 6.5
Hz), 16.3 (d, J CP ) 5.8 Hz, 2C), 14.0.
73.5 (d, J CP ) 4.4 Hz), 61.6 (d, J CP ) 6.6 Hz), 61.6 (d, J CP
)
6.6 Hz), 47.6 (d, J CP ) 8.0 Hz), 46.9 (d, J CP ) 10.2 Hz), 35.6 (d,
J CP ) 135.9 Hz), 35.1, 35.1, 33.5, 26.5, 26.4, 26.3, 16.3 (d, J CP
) 5.9 Hz), 16.3 (d, J CP ) 5.8 Hz). Anal. Calcd for C20H33O4P:
C, 65.20; H, 9.03. Found: C, 65.04; H, 9.05.
For the minor diastereomer: 1H NMR δ 5.89 (ddd, J ) 16.6,
11.0, 7.8 Hz, 1H), 5.12-5.06 (m, 2H), 4.21-4.12 (m, 4H), 3.72
(s, 1H), 2.44-2.31 (m, 1H), 2.22-1.91 (m, 2H), 1.35 (t, J ) 7.1
Hz, 6H), 1.30 (s, 3H), 1.05 (d, J ) 6.9 Hz, 3H); 31P NMR 31.6;
13C NMR δ 139.6, 116.1, 72.1, 62.3 (d, J CP ) 7.3 Hz, 2C), 48.7
(d, J CP ) 13.8 Hz), 35.1 (d, J CP ) 138.8 Hz), 25.4 (d, J CP ) 5.8
Hz), 16.3 (d, J CP ) 5.8 Hz, 2C), 14.3.
Dieth yl [2-Hyd r oxy-2-(1-m eth yl-2-p r op en yl)cyclop en -
tyl]p h osp h on a te (22). Meth od A. A two-neck flask equipped
with an addition funnel, condenser, and magnesium turnings
(60 mg, 2.5 mmol) was flame-dried and purged with argon.
After the apparatus had cooled, ether (1 mL) and one-third of
the crotyl chloride (0.07 mL, 0.72 mmol) were added to the
vigorously stirred magnesium. Once the reaction began to
reflux, a solution of the remaining crotyl chloride (0.15 mL,
1.5 mmol) in ether (2 mL) was added slowly to maintain reflux.
After the crotyl chloride was added, the reaction was heated
at reflux for an additional hour and then cooled to room
temperature. A solution of phosphonate 7 (96 mg, 0.43 mmol)
in ether (2 mL) was added dropwise to the Grignard reagent.
The reaction was allowed to stir at room temperature for 4 h
and then quenched by addition of 2 N HCl. The layers were
separated, and the aqueous layer was washed with ether. The
combined organic extracts were dried over Na2SO4 and con-
Dieth yl [2-Hyd r oxy-2-(1-m eth yl-2-p r op en yl)cycloh ex-
yl]p h osp h on a te (24). According to procedure C, phosphonate
9 (55 mg, 0.24 mmol in 2 mL THF) was added to crotylzinc
bromide (1.1 mmol in 2 mL THF) via cannula at -78 °C. The
reaction was quenched after 1 h by addition to 1 M HCl (20
mL). Standard workup and purification by flash column
chromatography (60% hexanes, 40% ethyl acetate) gave hy-
droxy phosphonate 24 (27 mg, 40%) as a 1.1:1.0 mixture of
diastereomers. HRFABMS calcd for C14H27O4P (M + Na)+
313.1545, found 313.1548.
For the major diastereomer: 1H NMR δ 5.91 (ddd, J ) 17.5,
10.4, 6.9 Hz, 1H), 5.18-5.02 (m, 2H), 4.22-4.04 (m, 4H), 3.96
(d, J ) 2.4 Hz, 1H, exchanges in D2O), 2.90-2.77 (m, 1H), 2.14
(ddd, J HP ) 19.7 Hz, J ) 12.3, 4.4 Hz, 1H), 1.94-1.57 (m, 5H),

Organometallic Additions to â-Keto Phosphonates
J . Org. Chem., Vol. 64, No. 14, 1999 5211
1.53-1.44 (m, 1H), 1.34 (dt, J HP ) 3.4 Hz, J ) 7.1 Hz, 6H),
1.21-1.10 (m, 2H), 1.10 (d, J ) 6.9 Hz, 3H); 31P NMR 34.0;
2.2 mmol) and zinc dust (140 mg, 2.2 mmol) were added to a
stirred solution of phosphonate 11 (99 mg, 0.43 mmol) in THF
(2 mL) and NH4Cl (3 mL). After 1 h, the reaction mixture was
diluted with ether. Standard workup and purification by flash
column chromatography (50% ethyl acetate, 50% hexanes)
afforded hydroxy phosphonate 27 (111 mg, 86%): 1H NMR δ
6.08 (dd, J ) 17.6, 10.9 Hz, 1H), 5.98 (dm, J ) 10.2 Hz, 1H),
5.69 (d, J ) 10.5 Hz, 1H), 5.06 (dd, J ) 10.7, 1.3 Hz, 1H), 5.03
(dd, J ) 17.5, 1.4 Hz, 1H), 4.17-4.07 (m, 4H), 3.77 (s, 1H),
2.71 (dm, J HP ) 23.5 Hz, 1H), 2.31-2.22 (m, 1H), 2.09-1.98
(m, 1H), 1.95-1.84 (m, 2H), 1.31 (dt, J HP ) 4.9 Hz, J ) 7.1
Hz, 6H), 1.12 (s, 3H), 1.07 (s, 3H); 31P NMR 31.9; 13C NMR δ
145.1, 130.2, 129.4, 112.7, 73.2 (d, J CP ) 5.0 Hz), 62.0 (d, J CP
) 7.2 Hz, 2C), 46.0 (d, J CP ) 8.0 Hz), 39.1 (d, J CP ) 138.8 Hz),
23.3 (d, J CP ) 5.0 Hz), 23.1, 21.8 (d, J CP ) 4.3 Hz), 21.4, 16.3
(d, J CP ) 6.6 Hz, 2C); HRFABMS calcd for C15H27O4P (M +
Na)+ 325.1545, found 325.1538.
13C NMR δ 140.3, 115.5, 73.5 (d, J CP ) 4.3 Hz), 62.7 (d, J CP
)
7.3 Hz), 61.0 (d, J CP ) 7.3 Hz), 45.7 (d, J CP ) 3.0 Hz), 41.2 (d,
J CP ) 132.2 Hz), 29.9 (d, J CP ) 13.0 Hz), 25.8 (d, J CP ) 15.3
Hz), 23.2 (d, J CP ) 2.9 Hz), 20.5, 16.5 (d, J CP ) 5.1 Hz), 16.2
(d, J CP ) 6.6 Hz), 12.9.
For the minor diastereomer: 1H NMR δ 6.12 (ddd, J ) 17.2,
10.6, 6.6 Hz, 1H), 5.18-5.02 (m, 2H), 4.22-4.04 (m, 4H), 3.76
(d, J ) 2.1 Hz, 1H, exchanges in D2O), 2.90-2.77 (m, 1H), 2.14
(ddd, J HP ) 19.7 Hz, J ) 12.3, 4.4 Hz, 1H), 1.94-1.57 (m, 5H),
1.53-1.44 (m, 1H), 1.34 (dt, J HP ) 3.4 Hz, J ) 7.1 Hz, 6H),
1.21-1.10 (m, 2H), 1.04 (d, J ) 6.9 Hz, 3H); 31P NMR 33.3;
13C NMR δ 140.1, 114.9, 73.8, 62.5 (d, J CP ) 7.3 Hz), 60.9 (d,
J CP ) 5.1 Hz), 45.9 (d, J CP ) 2.9 Hz), 40.8 (d, J CP ) 133.7 Hz),
30.6 (d, J CP ) 13.1 Hz), 25.6 (d, J CP ) 14.5 Hz), 22.9 (d, J CP
)
2.9 Hz), 20.6, 16.5 (d, J CP ) 5.1 Hz), 16.2 (d, J CP ) 6.6 Hz),
14.2.
Dieth yl (2-Hyd r oxy-2,3,3-tr im eth yl-4-p en ten yl)p h os-
p h on a te (28). According to the general procedure shown for
compound 26, 4-bromo-2-methyl-2-butene (0.3 mL, 2.6 mmol)
and zinc dust (170 mg, 2.6 mmol) were added to a stirred
solution of phosphonate 13 (100 mg, 0.5 mmol) in THF (2 mL)
and NH4Cl (3 mL). After 1 h, the reaction mixture was diluted
with ether. Standard workup and purification by flash column
chromatography (60% hexanes, 40% ethyl acetate) gave hy-
droxy phosphonate 28 (117 mg, 86%): 1H NMR δ 6.09 (dd, J
) 17.6, 10.9 Hz, 1H), 5.06 (dd, J ) 10.8, 1.4 Hz, 1H), 5.02 (dd,
Dieth yl [2-Hyd r oxy-2-(1-m eth yl-2-p r op en yl)cycloh ex-
3-en yl]p h osp h on a te (25). According to procedure C, phos-
phonate 11 (99 mg, 0.43 mmol in 2 mL THF) was added to
crotylzinc bromide (2.2 mmol in 3 mL THF) via cannula at
-78 °C. The reaction was quenched after 1 h by addition to 1
M HCl (20 mL). Standard workup and purification by flash
column chromatography (3:1 chloroform/ethyl acetate) afforded
hydroxy phosphonate 25 (92 mg, 75%) as a 2:1 mixture of
diastereomers. HRFABMS calcd for C13H25O4P (M + Na)+
311.1388, found 311.1390.
J
) 17.6, 1.5 Hz, 1H), 4.19-4.05 (m, 4H), 3.80 (s, 1H,
For the major diastereomer: 1H NMR (600 MHz) δ 5.94
(ddd, J ) 10.2, 5.9, 1.8 Hz, 1H), 5.74 (ddd, J ) 10.2, 6.1, 2.4
Hz, 1H), 5.57 (ddd, J ) 17.2, 10.3, 9.2 Hz, 1H), 5.17-5.09 (m,
1H), 5.00 (d, J ) 10.3 Hz, 1H), 4.19-4.06 (m, 4H), 3.59 (s,
1H), 3.03 (dq, J ) 9.2, 6.9 Hz, 1H), 2.39 (dm, J HP ) 23.3 Hz,
1H), 2.21-2.10 (m, 1H), 2.04-1.86 (m, 3H), 1.36-1.31 (m, 6H),
1.15 (d, J ) 6.9 Hz, 3H); 31P NMR 32.4; 13C NMR δ 140.9,
130.4, 128.0 (d, J CP ) 10.9 Hz), 116.0, 71.5 (d, J CP ) 5.1 Hz),
exchanges in D2O), 2.15 (ddd, J HP ) 18.2 Hz, J ) 15.3, 1.0 Hz,
1H), 1.92 (dd, J HP ) 20.1 Hz, J ) 15.3 Hz, 1H), 1.38 (s, 3H),
1.33 (dt, J HP ) 2.9 Hz, J ) 7.1 Hz, 6H), 1.07 (s, 3H), 1.04 (s,
3H); 31P NMR 32.6; 13C NMR δ 144.8, 112.8, 73.6 (d, J CP ) 5.8
Hz), 61.8 (d, J CP ) 6.5 Hz), 61.4 (d, J CP ) 7.2 Hz), 44.6 (d, J CP
) 16.0 Hz), 33.2 (d, J CP ) 137.3 Hz), 23.6, 21.6 (2C), 16.3 (d,
J CP ) 5.8 Hz, 2C). Anal. Calcd for C12H25O4P: C, 54.53; H,
9.53. Found: C, 54.49; H, 9.63.
P h osp h on a te 29. A solution of hydroxy phosphonate 12
(60 mg, 0.22 mmol) in acetone (2.5 mL) was added dropwise
via cannula to a stirred solution of chromium(VI) oxide (46
mg, 0.46 mmol) in acetic acid (1 mL) at 15 °C. The reaction
mixture was stirred at 15 °C for 2 h and then concentrated in
vacuo. The residue was diluted with CH2Cl2 and poured into
aqueous saturated NaHCO3. The aqueous layer was extracted
with CH2Cl2, and the combined organic extracts were dried
over Na2SO4 and then concentrated in vacuo. Purification of
the residue by flash column chromatography (3:1 chloroform/
ethyl acetate) yielded phosphonate 29 (50 mg, 83%): 1H NMR
δ 6.01 (d, J ) 4.9 Hz, 1H), 5.79 (dddd, J ) 16.8, 10.2, 7.5, 6.1
Hz, 1H), 5.21-5.14 (m, 2H), 4.20-4.08 (m, 4H), 3.28-3.14 (m,
62.2 (d, J CP ) 6.5 Hz), 61.1 (d, J CP ) 6.6 Hz), 46.9 (d, J CP
)
1.5 Hz), 40.8 (d, J CP ) 137.3 Hz), 24.9 (d, J CP ) 13.8 Hz), 20.5
(d, J CP ) 3.6 Hz), 16.4 (d, J CP ) 5.8 Hz), 16.3 (d, J CP ) 7.2
Hz), 14.4.
For the minor diastereomer: 1H NMR (600 MHz) δ 6.09
(ddd, J ) 17.3, 10.4, 7.6 Hz, 1H), 5.87 (dm, J ) 10.2 Hz, 1H),
5.63 (dm, J ) 10.3 Hz, 1H), 5.17-5.09 (m, 1H), 5.00 (d, J )
10.3 Hz, 1H), 4.19-4.06 (m, 4H), 3.66 (s, 1H), 2.92 (dq, J )
6.9, 6.9 Hz, 1H), 2.39 (dm, J HP ) 23.3 Hz, 1H), 2.21-2.10 (m,
1H), 2.04-1.86 (m, 3H), 1.36-1.31 (m, 6H), 0.99 (d, J ) 6.8
Hz, 3H); 31P NMR 32.1; 13C NMR δ 139.7,129.8 (d, J CP ) 8.8
Hz),129.6, 116.1, 71.9 (d, J CP ) 5.1 Hz), 62.3 (d, J CP ) 7.3 Hz),
61.0 (d, J CP ) 7.2 Hz), 45.7 (d, J CP ) 3.6 Hz), 40.0 (d, J CP
)
139.2 Hz), 24.3 (d, J CP ) 12.3 Hz), 20.3 (d, J CP ) 4.4 Hz), 16.4
(d, J CP ) 5.8 Hz), 16.3 (d, J CP ) 7.2 Hz), 14.7.
2H), 2.92-2.74 (m, 2H), 2.51-2.41 (m, 1H), 2.36 (ddm, J HP
17.9 Hz, J ) 5.0 Hz, 1H), 2.29-2.09 (m, 1H), 1.33 (dt, J HP
)
)
Dieth yl [2-Hyd r oxy-2-(1,1-d im eth yl-2-p r op en yl)cyclo-
p en tyl]p h osp h on a te (26). 4-Bromo-2-methyl-2-butene (0.26
mL, 2.3 mmol) and zinc dust (150 mg, 2.3 mmol) were added
all at once to a stirred solution of phosphonate 7 (102 mg, 0.46
mmol) in THF (2 mL) and saturated aqueous NH4Cl (3 mL).
The reaction mixture was stirred for 1 h at room temperature
and then diluted with ether. The aqueous layer was extracted
with ether, and the combined organic layers were dried over
Na2SO4 and then concentrated in vacuo. Purification of the
residue by flash column chromatography (60% hexanes, 40%
ethyl acetate) gave hydroxy phosphonate 26 (104 mg, 77%):
1H NMR δ 6.02 (dd, J ) 18.0, 10.2 Hz, 1H), 5.10-5.05 (m,
2H), 4.18-4.05 (m, 4H), 3.83 (s, 1H), 2.50 (ddd, J HP ) 20.7
Hz, J ) 9.5, 4.5 Hz, 1H), 2.18-2.07 (m, 1H), 1.89-1.78 (m,
2H), 1.76-1.57 (m, 3H), 1.32 (t, J ) 7.0 Hz, 6H), 1.12 (s, 3H),
1.08 (s, 3H); 31P NMR 32.8; 13C NMR δ 144.7, 113.4, 86.7 (d,
J CP ) 5.0 Hz), 62.2 (d, J CP ) 6.5 Hz), 61.1 (d, J CP ) 6.5 Hz),
44.6, 42.4 (d, J CP ) 139.5 Hz), 37.8 (d, J CP ) 5.1 Hz), 29.8 (d,
11.3 Hz, J ) 7.1 Hz, 6H); 31P NMR 26.1; 13C NMR δ 198.3 (d,
J CP ) 4.3 Hz), 158.3 (d, J CP ) 8.7 Hz), 133.1, 128.5 (d, J CP
)
10.2 Hz), 118.8, 63.0 (d, J CP ) 7.2 Hz), 62.1 (d, J CP ) 7.3 Hz),
41.2, 37.9 (d, J CP ) 134.4 Hz), 33.8, 24.2 (d, J CP ) 4.3 Hz),
16.4 (d, J CP ) 6.6 Hz), 16.3 (d, J CP ) 5.8 Hz); HRMS calcd for
C
13H21O4P 272.1177, found 272.1180.
Keton e 30. A suspension of hydroxy phosphonate 8 (30 mg,
0.11 mmol), PdCl2 (2 mg, 0.01 mmol), and Cu(OAc)‚H2O (5 mg,
0.02 mmol) in N,N-dimethylacetamide (4 mL) and water (0.5
mL) was placed under an atmosphere of oxygen and stirred
for 3 days. The mixture was diluted with ether and filtered
through Celite. The ether filtrate was added to water and
extracted with ether. The organic extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Purifica-
tion by flash column chromatography (50% hexanes, 50% ethyl
acetate) afforded ketone 30 (19 mg, 59%): 1H NMR δ 4.18-
4.00 (m, 5H), 3.33 (d, J ) 16.7 Hz, 1H), 2.71 (d, J ) 16.8 Hz,
1H), 2.26-2.14 (m, 1H), 2.20 (s, 3H), 2.13-2.06 (m, 1H), 1.98-
1.87 (m, 3H), 1.76-1.65 (m, 2H), 1.32 (dt, J HP ) 2.1 Hz, J )
7.1 Hz, 6H); 31P NMR 31.6; 13C NMR δ 209.1, 80.2 (J CP ) 3.6
Hz), 62.3 (d, J CP ) 6.5 Hz), 61.0 (d, J CP ) 6.5 Hz), 52.1, 45.1
(d, J CP ) 142.4 Hz), 39.6 (J CP ) 14.6 Hz), 31.5, 25.6, 22.2 (d,
J CP ) 14.6 Hz), 16.5 (d, J CP ) 5.8 Hz), 16.4 (d, J CP ) 6.5 Hz);
HRMS calcd for C12H23O5P 278.1283, found 278.1269.
J CP ) 4.4 Hz), 24.6 (d, J CP ) 5.8 Hz), 22.7, 22.0, 16.4 (d, J CP
)
6.6 Hz), 16.2 (d, J CP ) 6.5 Hz); HRFABMS calcd for C14H27O4P
(M + Na)+ 313.1545, found 313.1543.
Dieth yl [2-Hyd r oxy-2-(1,1-d im eth yl-2-p r op en yl)cyclo-
h ex-3-en yl]p h osp h on a te (27). According to the procedure
shown for compound 26, 4-bromo-2-methyl-2-butene (0.25 mL,

5212 J . Org. Chem., Vol. 64, No. 14, 1999
Lentsch and Wiemer
Su p p or tin g In for m a tion Ava ila ble: 1H and/or 13C NMR
spectra for compounds 8, 12, 14, 15, 17, 19, 22-27, 29, and
30. This material is available free of charge from the Internet
at http://pubs.acs.org.
Ack n ow led gm en t. We thank Mr. Chad Schwitters
for his experimental assistance with preparation and
reactions of phosphonate 15. We thank Dr. J oseph and
Mrs. Ursil Callen, and the University of Iowa Center
for Biocatalysis and Bioprocessing, for fellowships
awarded to LML and the University of Iowa Graduate
College for partial support of this research.
J O990388K