Darzens reaction of acyl phosphonates with α-bromo ketones: Selective synthesis of cis- and trans-epoxyphosphonates

Article abstract of DOI:10.1021/jo801818p

(Chemical Equation Presented) Acyl phosphonates with α-halo ketones in the presence of bases at room temperature afford cis- and trans-epoxyphosphonates in good chemical yields and high selectivities using different bases. The diastereoselectivity of this reaction is easily controlled by changing the base. Changing the base from Cs₂CO₃ to DBU changed the diastereomeric ratio (transieis) from 3/2 to 9/1. Moreover, the treatment of the trans isomer with DBU showed a complete conversion to the corresponding cis isomer.

Full text of DOI:10.1021/jo801818p

Darzens Reaction of Acyl Phosphonates with r-Bromo Ketones:
Selective Synthesis of cis- and trans-Epoxyphosphonates
Ayhan S. Demir,* Mustafa Emrullahoglu, Eser Pirkin, and Nazmiye Akca
Department of Chemistry, Middle East Technical UniVersity, 06531 Ankara, Turkey
asdemir@metu.edu.tr
ReceiVed August 14, 2008
Acyl phosphonates with R-halo ketones in the presence of bases at room temperature afford cis- and
trans-epoxyphosphonates in good chemical yields and high selectivities using different bases. The
diastereoselectivity of this reaction is easily controlled by changing the base. Changing the base from
Cs2CO3 to DBU changed the diastereomeric ratio (trans/cis) from 3/2 to 9/1. Moreover, the treatment of
the trans isomer with DBU showed a complete conversion to the corresponding cis isomer.
Introduction
the cyclization of halohydrins in the presence of a base,2,5 the
Darzens-type reaction of chloromethyl phosphonates with
carbonyl compounds,2,6 and a rather recently published work,
including a rhodium acetate-mediated reaction of diazoben-
zylphosphonates with carbonyl compounds.7 Although there are
many methods for the preparation of these important intermedi-
ates, many of these methods lack stereoselectivity, efficiency,
and ease of preparation of the starting materials, so there is still
a need for alternative synthetic approaches.
Epoxides rank among the most versatile synthetic intermedi-
ates, constituting convenient building blocks for the synthesis
of many products of biological interest. Among them, 1,2-
epoxyphosphonates have attracted considerable interest since
the first discovery of the antibiotic fosfomycin.1 (1R,2S)-(-)-
(1,2)-Epoxypropyl phosphonic acid is a clinically important drug
with wide-spectrum antibiotic activity. A vast number of
fosfomycin derivatives have been synthesized over the years
with biological activities, of which many have included the
synthesis of epoxyphosphonates as intermediates.2
A straightforward method for the preparation of epoxyphos-
phonates is the direct epoxidation of the corresponding alkenyl
phosphorus compound;3 however, several other methods also
are available.4-6 These methods include the reaction of R-halo
ketones and R-tosyl ketones with metal dialkyl phosphites,2-4
(3) (a) Glamkowski, E. J.; Gal, G.; Purick, R.; Davidson, A. J.; Sletzinger,
M. J. Org. Chem. 1970, 35, 3510–3512. (b) Slates, H. L.; Wendler, N. L. Chem.
Ind. (London, U.K.) 1978, 430–431. (c) Wang, X.-Y.; Shi, H.-C.; Sun, C.; Zhang,
Z.-G. Tetrahedron 2004, 60, 10993–10998. (d) Ono, Y.; Han, L.-B. Tetrahedron
Lett. 2006, 47, 421–424. (e) Begum, S.; Rahman, M. M.; Takagi, R.; Ohkata,
K. Heterocycles 2004, 62, 251–262. (f) Cristau, H.-J.; Mbianda, X. Y.; Geze,
A.; Beziat, Y.; Gasc, M.-B. J. Organomet. Chem. 1998, 571, 189–193. and the
references cited therein.
(4) (a) Haake, P.; Springs, B. J. Org. Chem. 1976, 41, 1165–1168. (b) Griffin,
C. E.; Kundu, S. K. J. Org. Chem. 1964, 34, 1532–1539.
(5) (a) Bandini, C.; Martinelli, F.; Spinta, G.; Panunzio, M. Tetrahedron:
Asymmetry 1995, 5, 2127–2130. (b) Wang, K.; Zhang, Y.; Yuan, C. Org. Biomol.
Chem. 2003, 1, 3564–3569. (c) Kobayashi, Y.; William, A. D.; Tukoro, Y. J.
Org. Chem. 2001, 66, 7903–7906. (d) Wroblewski, A. E.; Bak-Sypien, I. I.
Tetrahedron: Asymmetry 2007, 18, 520–526.
(1) (a) Hendlin, D.; Stapley, E. O.; Jackson, M.; Wallick, H.; Miller, A. K.;
Wolf, F. J.; Miller, T.; Chaiet, W. L.; Kahan, F. M.; Foltz, E. L.; Woodruff,
H. B.; Mata, J. M.; Hernandez, S.; Mochales, S. Science 1969, 166, 122–123.
(b) Christensen, B. G.; Leanza, J. W.; Beattie, T. R.; Patchett, A. A.; Arison,
B. H.; Ormond, R. F.; Kuehl, F. A.; Albers-Shongerg, G.; Jardetzky, O. Science
1969, 166, 123–125.
(2) (a) Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC Press:
Boca Raton, FL, 2003; pp 139-181. Reviews: (b) Iorga, B.; Eymery, F.;
Savignac, P. Synthesis 1999, 207–224. (c) Fields, S. C. Tetrahedron 1999, 55,
12237–12273. (d) Redmore, D. Chem. ReV. 1971, 71, 315–326.
(6) (a) Sturtz, G. Bull. Soc. Chim. Fr. 1964, 2333–2340. (b) Ulman, A.;
Sprecher, M. J. Org. Chem. 1979, 44, 3703–3707.
(7) Li, Z.-C.; Zhang, Ji.; Hu, W.-H.; Chen, Z.-Y.; Yu, X.-Q. Synlett 2005,
1711–1715.
8992 J. Org. Chem. 2008, 73, 8992–8997
10.1021/jo801818p CCC: $40.75 2008 American Chemical Society
Published on Web 10/25/2008

Darzens Reaction of Acyl Phosphonates with Ketones
SCHEME 1. Darzens Reaction of Benzoylphosphonates with r-Bromoacetophenone
TABLE 1. Darzens Reaction of Benzoylphosphonate with
r-Bromoacetophenone under Different Reaction Conditions
The Darzens reaction is one of the most powerful methodolo-
gies for the synthesis of R,ꢀ-epoxy carbonyl and related
compounds and, therefore, has been recognized as one of the
most significant C-C, C-O bond-forming processes in syn-
thetic organic chemistry.8 It employs the base-induced conden-
sation of R-halo carbonyl compounds with aldehydes for the
construction of highly functionalized oxiranes.
In light of this reaction, and on the basis of our previous
studies carried out with acyl phosphonates,9ae we report an
approach for the diastereoselective synthesis of highly func-
tionalized epoxyphosphonates by applying a Darzens-type
reaction of R-halo ketones with acyl phosphonates.f
T
trans- cis-
4
5
6
7
entry
base
K2CO3 CH3CN
K2CO3 CH3CN 25
K2CO3 CH3CN 60
solvent (°C) 3a (%) 3a (%) (%) (%) (%) (%)
1
2
3
4
5
6
7
8
9
0
5
29
35
15
12
35
-
-
5
-
5
-
5
-
-
-
_
-
20
-
-
-
-
-
-
-
20
_
10 15
15 25
15 10
12 20
15 20
10
10
10
20
-
5
KOH
THF
25
25
tBuOK THF
Cs2CO3 CH3CN 25
DMAP CH3CN 25
-
10
15 20
80
-
5
DBU
DBU
CH3CN 25
THF 25
CH3CN 25
45
_
_
_
10 Et3N
_
_
_
-
_
Results and Discussion
At first, the reaction of benzoylphosphonate, 2a, with R-bro-
moacetophenone, 1a, is initially carried out at room temperature
in the presence of K2CO3, and the formation of the products is
monitored by TLC. At the end of the reaction (10 h), two
diastereomeric epoxyphosphonates, 3a (trans/cis) (34%), are
isolated as major products together with minor products, 4 (5%),
5 (10%), and 6 (15%), as shown in Scheme 1. The reaction is
carried out by using different bases and solvents at room
temperature. The use of bases such as KOH, NaOH, and tBuOK
is avoided in order to prevent the hydrolysis of the acyl
phosphonate, which would cause acyl phosphonates to easily
decompose. The desired product is formed in low yield together
with side products (Table 1, entries 4-5). The reaction time
decreases at higher temperatures (6 h, 45%), whereas the
conversion is very slow at low temperatures (Table 1, entry 1,
24 h, 5%).
By screening the bases, K2CO3 is replaced with the more
active base, Cs2CO3. The reaction is carried out at room
temperature in CH3CN. In this way, not only is the reaction
time decreased (6 h), but the reaction yield is increased, and 3a
was obtained in a 55% yield together with side products 5 and
6 (Table 1, entry 6). The diastereomeric ratio was found to be
35/20 (trans/cis), which was determined by using NMR
spectroscopy. The diastereomers are easily separated by flash
column chromatography.
To the best of our knowledge, a Darzens-type reaction
including the use of acyl phosphonates has not been reported
so far. Moreover, there are a vast number of methods for the
synthesis of epoxyphosphonates,1-7 in which there are no
examples affording this type of highly functionalized epoxy-
phosphonates that could be useful intermediates in several
reactions.
In the present study, we examined the reactions of a broad
range of acyl phosphonates, containing electron-withdrawing
and electron-donating substituents with R-halo ketones under
various conditions. Although the classical Darzens condensation
is still performed in the presence of strong bases such as RONa,
ROK, and NaNH2 and is carried out under anhydrous conditions
and at low temperatures,8 the sensitivity of acyl phosphonates
to such bases prompted us to use comparably milder bases such
as carbonates or organic bases to prevent the hydrolysis of acyl
phosphonates.
(8) (a) Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–440. (b)
Ballester, M. Chem. ReV. 1955, 55, 283–300. (c) Arai, S.; Suzuki, T.; Tokumaru,
K.; Shioiri, T. Tetrahedron Lett. 2002, 43, 833–836. (d) Arai, S.; Shioiri, T.
Tetrahedron 2002, 58, 1407–1413. (e) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri,
T. Chem. Commun. (Cambridge, U.K.) 1999, 49–50. (f) Xu, L. W.; Xia, C. G.;
Li, J. W.; Zhou, S. L.; Hu, X. X. Synlett 2003, 2337. (g) Zhang, G. L.; Li, Z.;
Wang, X. C. Synth. Commun. 2002, 32, 3107–3112. (h) Aggarwal, V. K.; Hynd,
G.; Picoul, W.; Vasse, J.-L. J. Am. Chem. Soc. 2002, 124, 9964–9965. (i) Palomo,
C.; Oiarbide, M.; Sharma, A. K.; Gonzalez-Rego, M. C.; Linden, A.; Garcia,
J. M.; Gonzalez, A. J. Org. Chem. 2000, 65, 9007–9012.
To illustrate the generality of this reaction, a range of acyl
phosphonates, 2a-h, are treated with variously substituted
R-bromo ketones, 1a-c, under optimized reaction conditions
(Cs2CO3, CH3CN, rt; or DBU, CH3CN, rt). The results are
shown in Table 2. The use of electron-donating and electron-
withdrawing groups furnished a comparable yield.
¨
˙
(9) (a) Demir, A. S.; Reis, O.; Ig˘dir, C¸ .; Esiringu¨, I.; Eymur, S. J. Org. Chem.
2005, 70, 10584–10587. (b) Demir, A. S.; Eymur, S. J. Org. Chem. 2007, 72,
¨
8527–8530. (c) Demir, A. S.; Reis, B.; Reis, O.; Eymu¨r, S.; Go¨llu¨, M.; Tural,
¨
S.; Saglam, G. J. Org. Chem. 2007, 72, 7439–7442. (d) Demir, A. S.; Reis, O.;
Kayalar, M.; Eymur, S.; Reis, B. Synlett 2006, 3329–3333. (e) Demir, A. S.;
¨
Reis, O.; Esiringu¨, I.; Reis, B.; Baris, S. Tetrahedron 2006, 63, 160–165. (f)
Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. Darzens Condensation
with Acyl Phosphonates. Abstracts of Papers, 235th National Meeting of the
American Chemical Society, New Orleans, LA, April 6-10, 2008; American
Chemical Society, Washington, DC, 2008; ORGN 027.
For the epoxidation reactions, organic bases also were
screened. Among the bases DMAP, DABCO, DBU, and
triethylamine, the use of DBU in CH3CN gives 3a in a 50%
J. Org. Chem. Vol. 73, No. 22, 2008 8993

Demir et al.
TABLE 2. Reaction of Acyl Phosphonates, 2a-h, with r-Halo Ketones, 1a-c, in the Presence of Bases in Acetonitrile
8994 J. Org. Chem. Vol. 73, No. 22, 2008

Darzens Reaction of Acyl Phosphonates with Ketones
SCHEME 2. Reaction of DBU with Acyl Phosphonate
SCHEME 3. Formation of a cis Isomer from a trans Isomer
SCHEME 4. Darzens Reaction of Acyl Phosphonate, 2i,
with r-Bromoacetophenone
yield (Table 1, entry 8). No product formation was observed
with DBU by using THF as a solvent (Table 1, entry 9). Other
bases such as DMAP and DABCO showed no product forma-
tion. The use of triethylamine as a base (Table 1, entry 10) in
the reaction proceeded to give compound 6, which is the main
characteristic behavior of acyl phosphonates in the presence of
amines.10 Dry conditions are crucial in order to prevent the
formation of halohydrin, 4, which is formed by proton abstrac-
tion of the corresponding intermediate.
experiments performed in the presence of Cs2CO3 gave a
product distribution of approximately 3/2 (trans/cis), whereas
the use of DBU significantly increased the selectivity to 9/1
(trans/cis).
The promising results prompted us to carry out the experi-
ments with DBU. The reaction of acyl phosphonates with
R-bromo ketones in the presence of DBU in CH3CN at room
temperature was carried out for maximum conversion with
monitoring by TLC. After the workup, the desired products were
obtained in 30-68% yields. The isomeric ratios of the products
are determined by NMR to be 5/1-9/1 trans/cis. Both isomers
were easily separated by flash column chromatography.
Close inspection of the reaction with DBU afforded interest-
ing results. With the careful monitoring of the reaction by TLC,
the distribution for both diastereomers in the presence of DBU
is easily controlled. Initially the trans isomer is formed in
relative excess to cis isomer (9/1). However, at a prolonged
reaction time, the trans isomer isomerizes to afford the cis
isomer. To support this observation, both of the isolated
diastereomeric epoxides are treated under the same reaction
conditions (1 equiv of DBU, CH3CN, rt). As a result of this
experiment, the trans epoxide isomerizes to afford the cis
epoxide, whereas the reverse is not the case.
1
The diasteromeric epoxides are easily characterized by H
NMR spectra. In the 1H NMR spectra, the single-bridge proton
appears as a doublet at 4.68 ppm for the cis epoxide and at
3.91 ppm for the trans isomer.11 In addition to these products,
three side products also were isolated. Two of them are
characterized as 5 and 6, and the last one is identified as a seven-
membered ring amide, 7. For the formation of 7, DBU reacted
with phosphonates, in which further hydrolysis afforded the
corresponding seven-membered ring amide. Similar reactions
of DBU with alkyl halides have been reported in the literature
(Scheme 2).12
With the Darzens condensation, the formation of the epoxide
is the favored course of the reaction. The carbanion of R-halo
ketones can attack the carbonyl carbon of phosphonate to form
the intermediate halohydrins, 8a and 8b. The positioning of the
halide trans to the oxygen, which is involved in the nucleophilic
attack, forms the epoxide. According to published works,8b,13
the Darzens intermediate (Scheme 3) is commonly formed in
the rate-determining step, in which the exclusive formation
of the trans product may be attributed to the steric inhibition in
the formation of the cis isomer.
As seen from the results, changing the base surprisingly
changed the stereoselectivity of this reaction. In general, the
(10) Sekine, M.; Satoh, M.; Yamagata, H.; Hata, T. J. Org. Chem. 1980, 45,
4162–416.
(11) Rahman, M. M.; Matano, Y.; Suzuki, H. J. Chem. Soc., Perkin Trans.
1 1999, 1533–1541.
J. Org. Chem. Vol. 73, No. 22, 2008 8995

Demir et al.
SCHEME 5
Clearly, a cis halohydrin anion, 8b, is not the intermediate
in the formation of the cis product in the Darzens reaction;14
rather, the only possible way in which cis can be obtained in
the Darzens reaction is through the formation of the trans
product, followed by base-catalyzed isomerization (Scheme 3).
The existence of a very large effect, in both the rates and
equilibrium of the ring-forming reactions, opposing the forma-
tion of cis substituents on small rings, constitutes a further basis
for assigning greater thermodynamic stability to a trans versus
a cis oxide.
In the case of DBU-mediated trans-cis conversion, it is rather
possible that the carbanion-enolate intermediate of the epoxide
is responsible for the formation of the cis isomer, were the
formation of trans isomers from cis not possible. As shown in
Scheme 3, the carbanion-enolate structure, which gives the cis
isomer, should be more stable.14b This conclusion is only
tentative and is currently undergoing further investigation in
our laboratory.
Substituted benzoylphosphonates proceed efficiently to give
epoxides; however, the treatment of alkyl phosphonate, 2i,
under the same reaction conditions is not very efficient and
never yields the corresponding epoxides. This result revealed
that the alkyl phosphonates are comparably much more
reactive to the bases than benzoylphosphonates, and they
hydrolyze more easily. A great amount of work has been
conducted in order to find the conditions, but unfortunately,
in all cases, the product that is isolated is only compound
915 and 10 (Scheme 4).
Two representative reactions are carried out with cis-3a. The
methylation of cis-3a with Me3Al yielded the corresponding
epoxy alcohol, 11, with high selectivity (Scheme 5). The same
selectivity is obtained by the reduction of cis-3a with LiBH4 or
NaBH4 (2 equiv of NaBH4, THF, rt; or 2 equiv of LiBH4, THF,
rt), which furnished a mixture of diastereomeric epoxy alcohol,
12 (4/1). In both of the reactions, the epoxide ring is preserved.
These types of reactions open an entry for the selective synthesis
of new fosfomycin analogs.1
different bases. The diastereoselectivity of this reaction is
easily controlled by changing the base. Accordingly, changing
the base from Cs2CO3 to DBU changed the diastereomeric
ratio (trans/cis) from 3/2 to 9/1. Moreover, the treatment of
the trans isomer with DBU showed a complete conversion
to the corresponding cis isomer. These products with mul-
tifunctionality can be further converted to various interesting
compounds. As a representative example, selective reduction
of the carbonyl group and the methylation reaction is carried
out by keeping the epoxide ring. We are currently investigat-
ing the precise origin of the diasterocontrol, in which further
applications of these epoxides are currently under way.
Experimental Section
General Procedure for the Preparation of Epoxyphospho-
nates, 3a-l. (i) Method 1. DBU (2 mmol) is added slowly
(addition completed over 1-2 h, controlled by TLC) to a stirred
solution of 2a-i (1 mmol) and the R-bromo ketone, 1a-c, (2
mmol) in anhydrous acetonitrile at room temperature under an
argon atmosphere. The reaction mixture is stirred for several
hours (2-12 h). The reaction is monitored by TLC. Water is
added, and the mixture is extracted with ethyl acetate; the
combined organic layers are dried over MgSO4. After the
evaporation of the solvent under reduced pressure, the crude
product is purified on silica gel to afford 3a-l (ether/petroleum
ether, 5/1).
(ii) Method 2. Benzoylphosphonate, 2a-i (1 mmol), is added
to a mixture of R-bromo ketone, 1a-c (1.2 mmol), and Cs2CO3
(1.5 mmol) in anhydrous acetonitrile at room temperature under
an argon atmosphere. The reaction mixture is stirred for several
hours (2-12 h). The reaction is monitored by TLC. Water is added,
and the mixture is extracted with ethyl acetate; the combined organic
layers are dried over MgSO4. After the evaporation of the solvent
under reduced pressure, the crude product is purified on silica gel
to afford 3a-l (ether/petroleum ether, 5/1).
(iii) Dimethyl 3-Benzoyl-2-phenyloxiran-2-ylphosphonate (trans-
3a). Yield: 100 mg (30%), white solid (mp ) 125 °C). IR (KBr):
3007, 2352, 1650, 1220, 1059 cm-1. 1H NMR (400 MHz, CDCl3):
δ 3.51 (3H, s), 3.53 (3H, s), 3.91 (1H, d, J ) 4.16 Hz), 7.28-8.05
(10H, m). 13C NMR (100 MHz, CDCl3): δ 53.6 (d, JC-P ) 7.4
Hz), 54.3 (d, JC-P ) 6.9 Hz), 61.8 (d, JC-P ) 202 Hz), 66.0, 126.7
(d, JC-P ) 2.7 Hz), 128.6, 128.7, 129.0, 134.0 (d, JC-P ) 14.5
Hz), 134.4, 134.9, 190.6. 31P NMR: δ 16.121. Anal. Calcd for
C17H17O5P: C, 61.45; H, 5.16. Found: C, 61.32; H, 5.17.
(iv) Dimethyl 3-Benzoyl-2-phenyloxiran-2-ylphosphonate (cis-
3a). Yield: 64 mg (19%), white solid (mp ) 120-122 °C). IR
In summary, we described for the first time a synthesis of
epoxyphosphonates applying a Darzens-type reaction to acyl
phosphonates with R-bromo ketones in the presence of
(12) (a) Juneja, T. R.; Garg, D. K. Tetrahedron 1982, 38, 551–556. (b) Alder,
R. W.; Sessions, R. B. Tetrahedron Lett. 1982, 23, 1121–1124. (c) Alder, R. W.;
Heilbronner, E.; Honegger, E.; McEwen, A. B.; Moss, R. B.; Olefirowicz, E.;
Petillo, P. O.; Sessions, R. B.; Weisman, G. R.; White, J. M.; Yang, Z. J. Am.
Chem. Soc. 1993, 115, 6580–6591. (d) Kraft, A. J. Chem. Soc., Perkin Trans. 1
1999, 705–714. (e) Heidelberger, C.; Guggisberg, A.; Stephanou, E.; Hesse, M.
HelV. Chim. Acta 1981, 64, 399–406. (f) Lammers, H.; Cohen-Fernandes, P.;
Habraken, C. L. Tetrahedron 1994, 50, 865–870. (g) Wasserman, H. H.;
Robinson, R. P.; Matsuyama, H. Tetrahedron Lett. 1980, 21, 3493–3497. (h)
Chakrabarty, M.; Batabyal, A.; Patra, A. J. Chem. Res. 1996, 190–191. (i) Shi,
M.; Shen, Y.-M. HelV. Chim. Acta 2002, 85, 1355–1363.
(13) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd,
G.; Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.; Vasse, J.-L.; Winn, C. L.
J. Am. Chem. Soc. 2006, 128, 2105–2114.
(14) (a) Berson, J. A. J. Am. Chem. Soc. 1952, 74, 5175–5177. (b) Kwart,
H.; Kirk, L. G. J. Org. Chem. 1957, 22, 116–120. (c) Bachelor, F. W.; Bansal,
R. K. J. Org. Chem. 1957, 22, 116–120.
1
(KBr): 2968, 2360, 1688, 1258, 1059 cm-1. H NMR (400 MHz,
CDCl3): δ 3.71 (3H, d, J ) 10.7 Hz), 3.81 (3H, d, J ) 10.5 Hz),
4.68 (1H, d, J ) 5.6 Hz), 7.13-7.81 (10H, m). 13C NMR (100
MHz, CDCl3): δ 54.4 (d, JC-P ) 7.2 Hz), 54.5 (d, JC-P ) 6.5 Hz),
61.2 (d, JC-P ) 198 Hz), 61.7, 127.6 (d, JC-P ) 2.7 Hz), 128.1,
128.2, 128.8, 128.9, 129.6, 129.7, 133.9, 135.0, 189.7. 31P NMR:
δ 16.638. Anal. Calcd for C17H17O5P: C, 61.45; H, 5.16. Found:
C, 61.42; H, 5.20.
Isomerization of trans-3a to cis-3a. DBU (1 mmol) is added
to a solution of trans-3a (1 mmol) in anhydrous acetonitrile at room
temperature. The reaction mixture is stirred for 3 h. The reaction
is monitored by TLC. Water is added, and the mixture is extracted
(15) Russell, G. A.; Kulkarni, S. V.; Khanna, R. K. J. Org. Chem. 1990, 55,
1080–1086.
8996 J. Org. Chem. Vol. 73, No. 22, 2008

Darzens Reaction of Acyl Phosphonates with Ketones
with ethyl acetate; the combined organic layers are dried over
MgSO4. After the evaporation of the solvent under reduced pres-
sure, the crude product is purified on silica gel to afford cis-3a
(ether).
Planning Organization, and the Middle East Technical Univer-
sity (METU) is gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Scientific and
¨
Technological Research Council of Turkey (TUBITAK), the
¨
Turkish Academy of Sciences (TUBA), the Turkish State
JO801818P
J. Org. Chem. Vol. 73, No. 22, 2008 8997