ETHYL 4-(TRIPHENYLPHOSPHORANYLIDENE)ACETOACETATE 1

Ethyl 4-(Triphenylphosphoranylidene)- TrO

O OH
TrO
O
CO2Et
(1)
acetoacetate acetonitrile
O (3)
O O reflux, 90 h O O
95%
O O
PPh3 β:α = 2:1
RO

The in situ transformation of the carbonyl group in (1) into its

(1; R = Et)
enolate counterpart using Sodium Hydride activated by the addi-
[13148-05-5] C24 H23 O3 P (MW 390.40) tion of a few drops of water results in dramatic enhancement of
InChI = 1S/C24H23O3P/c1-2-27-24(26)18-20(25)19-28(21-12- reactivity of the ylide and reversal of stereoselectivity in Wittig
6-3-7-13-21,22-14-8-4-9-15-22)23-16-10-5-11-17-23/ reactions.1 Under these conditions, a high degree of (Z) selec-
h3-17,19H,2,18H2,1H3 tivity can be achieved in reactions with aliphatic straight-chain
InChIKey = QYXSFVCJCUXGJH-UHFFFAOYSA-N aldehydes as well as with α-branched aldehydes (eq 4).1,9
(2; R = Me)
[98815-59-9] C23 H21 O3 P (MW 376.37) O
InChI = 1S/C23H21O3P/c1-26-23(25)17-19(24)18-27(20-11-5- CO2Et
OHC
2-6-12-20,21-13-7-3-8-14-21)22-15-9-4-10-16-22/h2- SMe
16,18H,17H2,1H3 NaH (2 equiv) SMe
H2O (2 drops), THF
InChIKey = ZXAIAXRMRNCCHC-UHFFFAOYSA-N 62% (Z):(E) = 9:1

(Wittig reagent for the stereoselective synthesis of (Z)-enones;1

(1) (4)
annulation reagent for the synthesis of cyclohexenones2 ) OHC O
Physical Data: R = Et, mp 105–106 ◦ C; R = Me, mp 126 ◦ C. O O
Solubility: insol cold ether and cold benzene; sol THF, CH2 Cl2 , OBn CO2Et
and chloroform. NaH (2 equiv)
O
Preparative Methods: the title compound (1) and its methyl H2O (2 drops), THF
75%
analog (2) are prepared in two steps from ethyl or methyl 4- O
chloroacetoacetates (see Ethyl 4-Chloroacetoacetate), respec-
OBn
tively, in 58–68% overall yield (eq 1).3,4
(Z):(E) = 9:1
O Ph3P
O
EtO2C Cl EtO2C PPh3 Cl–
benzene
reflux Annulation Reactions. In the presence of an added base, a
70%
variety of α,β-unsaturated aldehydes participate in a [3 + 3] annu-
O lation reaction with reagent (1) to give cyclohexenones in modest
NaHCO3, H2O
EtO2C PPh3 (1) yield (eq 5).2,10 An excess of sodium hydride activated by a few
83% drops of water is the most effective base for promoting this reac-
(1)
tion. Dienals produce a mixture of products resulting from initial
1,2- and 1,4-reactivity under these conditions. However, the use
of a catalytic amount of Potassium Hydride instead of water for
Original Commentary the activation of sodium hydride improves the selectivity of cy-
clohexenone formation (eq 6).11 Annulation reaction of a highly
Shridhar G. Hegde reactive trifluoromethyl enone with reagent 2 proceeds efficiently
Monsanto Company, St Louis, MO, USA without any added base (eq 7).12 The [3 + 3] annulation reactions
of (1) and (2) provide useful alternatives to the commonly used
Wittig Reactions. Under neutral conditions, reagent (1) ex- [4 + 2] counterpart, the Robinson annulation, for the synthesis of
hibits only moderate reactivity in Wittig reactions with aldehydes cyclohexenones.
and, like other stabilized Wittig reagents, generally produces (E)-
H
enones (eq 2).3,5 Although acid catalysis with p-Toluenesulfonic CHO (1)
O O
Acid or benzoic acid is known to effect rate acceleration, the reac- (5)
NaH (2 equiv)
tion conditions are too destructive in the case of simple aliphatic H2O (2 drops) O
H
aldehydes.1,6 Wittig reaction of (1) with protected ribose deriva- THF, rt CO2Et
tives provides C-glycosides (eq 3), which serve as precursors for 50%

the synthesis of C-nucleosides.7,8

O
O (1) CO2Et
CHO (6)
OHC O EtO2C O Bu
(1) NaH
(2) KH (catalytic) Bu
O toluene, rt THF, rt trans:cis = 85:15
O
63% 45%
2 ETHYL 4-(TRIPHENYLPHOSPHORANYLIDENE)ACETOACETATE

i-Pr
O O R2 R3
+
MeO2C Ph3P C6H6, reflux, 5 h
(2) R1 15–48%
toluene, rt
O O O
F3C O 76%
R2 R3 R2 R3
i-Pr i-Pr O O O OH
MeO2C CO2Me MeO2C CO2Me R1 O O R1 O O
+ (7) keto enol
F3C O F3C OH
or (9)
1:4
O
O O O O
3 O OH O
R
First Update R1
R3
R 2 R1
R2
George Nikonov
Gainesville, FL, USA keto enol

Wittig Reactions. The reagent (3-ethoxycarbonyl-2- R1 = OMe, OEt, O-iPr

oxopropylidene)triphenylphosphorane can be deprotonated at the R2 = H, Me, OEt
active C(3) methylene position by the action of a base. The result- R3 = H, Me
ing anionic ylide reacts with aldehydes at the phosphorus-bearing R4 = H, Me
C(1) atom in a Wittig reaction; the formation of the enolate at
the β-ketoester unit strongly reduces the ylide stabilization and O O
OH O
consequently induces a substantial Z selectivity. This reaction Ph3P
R1 R4
was successfully used in one of the stages of the total synthesis of NaH
the common diterpenoid tricyclic skeleton of surcodictyins and THF, reflux
eleutherobin.13,14 O O R3 OH
Functionalized furans were prepared by ‘Feist–Benary R2 R2
R1 O
cyclocondensation’ of (2,4-dioxobutylidene)phosphoranes with
chloroacetaldehyde and subsequent Wittig reactions (eq 8).15,16 R3 O 16–64%
4 (10)
PPh3 O O R
Cl O
n-BuLi, R1
DCM, reflux PPh3 R1 = OMe, OEt, i-OPr
O THF, 0 ºC
24 h
COOR R2 = H, Me, Et, i-Pr, Cl, Br, I, NO2
COOR
R3 = H, Me
R = Me, Et, i-Pr R4 = H, Me, Cl, Br
71–73%
O R1 The possible tandem reaction of stabilized phosphorus ylide
(8)
and cinnamaldehyde was initially investigated by the catalysis of
COOR a secondary amine R,R-diphenylprolinol O-TMS eq 11).20 This
method was developed later in Ref. 21.
R = i-Pr, R1 = Me, Et, Ph, 3-Py, 3-MeC6H4,
3-ClC6H4, 3,4-(Me)2C6H3, 4-MeOC6H4, cat (20 mol %)
O O O
4-(Me2N)C6H4, 3-O2NC6H4 additive (20 mol %)
30–74% Ph3P +
OR1 Ph CHCl3, rt, 48 h
65–98%
Synthesis of butenolides (eq 9) by the reaction of ylide 3- R = Et, t-Bu
(ethoxycarbonyl)-2-oxopropylidene triphenylphosphorane with O
maleic anhydride was described in Ref. 17. Thorough optimiza-
OR (11)
tion studies showed that the solvent, temperature, reaction time,
concentration, and stoichiometry play an important role. Ph
4-(2-Hydroxybenzoyl)salicylic esters and amides were
prepared by domino ‘Michael–Retro–Michael–Wittig’ reactions additive: BzOH, NaOAc, DBACO, DBACO+LiClO4
of (2,4-dioxobutylidene)triphenylphosphoranes with 3-formyl-
chromones (eq 10).18,19 The ylides 3-(methoxycarbonyl)-2-oxo- The reaction of phthalic dialdehyde with (2,4-dioxobutyl-
propylidene]triphenylphosphorane and 3-(iso-propoxy- idene)triphenylphosphorane, available in one step from ethyl 4-
carbonyl)-2-oxopropylidenetriphenylphosphorane were also chloroacetoacetate, afforded the 4,5-benzotropone in 75% yield
widely used. (eq 12).22
 ETHYL 4-(TRIPHENYLPHOSPHORANYLIDENE)ACETOACETATE 3

O O CHO N
N
Ph3P + THF, reflux
N3
R O O N
CHO COOEt
Ph3P +
OEt
R
O R
(12)
O N
R N
NaOH N
R = OEt (75%), OMe (45%), t-Bu (54%), Ph (54%) COOH (15)
H2O

One more example of Wittig reaction was given in Ref. 23.

Treatment of 3,5-dimethoxybenzaldehyde with the anion of the
ylide afforded a mixture of the E- and Z-γ,δ-unsaturated δ-(3,5-
dimethoxyphenyl)-β-keto esters in 90% yield (eq 13). The reac-
tion was carried out under the exposure to laboratory or ultraviolet
light. Under minimal light the expected E-product dominated in
a ratio of 9:1 as measured by 1 H NMR spectroscopy. It was pos-
tulated that the favored E products from aromatic aldehydes, in
contrast to Z products from aliphatic aldehydes, are inherent to
the reaction itself and not the result of subsequent light- or acid-
catalyzed isomerization.
R
R = H, Me, Cl, NO2 reaction conditions and yields see Ref. 25
In searching for derivatives of pyrazofurin that could display
antiviral properties, 3-oxo-4-[5 -deoxy-2 ,3 -(di-(O-benzyl)-α-
and β-d-ribofuranosyl]butanoate was synthesized as a precursors
by treatment of 5-deoxy-2,3-(di-O-benzyl)-d-ribofuranose with
the ylide 3-(ethoxycarbonyl-2-oxopropylidene)triphenylphos-
phorane (eq 16).26

O O OH
O O
O O OMe
NaH Ph3P +
Ph3P + MeCN, reflux
OEt
OEt THF, rt BnO OBn 48 h
78%
OMe
O O
O O O OEt (16)
OMe
OMe
EtO
+ (13)
O BnO OBn
OMe
OMe EtO O 72%

Annulation Reactions. The reaction of R-perillaldehyde Related Reagents. Ethyl acetoacetate; ethyl 4-chloroaceto-
with the ylide Ph3 P=CHC(O)CH2 CO2 Et provided an annulated acetate; methyl dilithioacetoacetate; methyl vinyl ketone; triph-
cyclohexenone (eq 14).24 enylphosphine; azides, 4,5-benzotropone; 3,5-dimethoxybenzal-
dehyde; butenolides; cinnamaldehyde; chloroacetaldehyde;
PPh3 NaH (2 equiv) eleutherobin; 4-(2-hydroxybenzoyl)salicylic esters; 3-formyl-
O
H2O (traces)
+ chromones; furan; maleic anhydrides; phthalic dialdehyde;
O THF, 35 ºC pyrazofurin; surcodictyin; triazolylacetates.
35 h
COOEt

(14) 1. Pietrusiewicz, K. M.; Monkiewicz, J., Tetrahedron Lett. 1986, 27, 739.
O 2. Pietrusiewicz, K. M.; Monkiewicz, J.; Bodalski, R., J. Org. Chem. 1983,
H
EtOOC 48, 788.
3. Muxfeldt, H.; Grethe, G.; Uhlig, K.; Zeugner, H., Chem. Ber. 1963, 96,
31% (ratio 5:1) 2943.
4. Lopez Herrera, F. J.; Uraga Baelo, C., Chem. Abstr. 1985, 103, 196 355g.
5. Leonard, J.; Mohialdin, S.; Swain, P. A., Synth. Commun. 1989, 19, 3529.
Miscellaneous. The reaction of azides with ylide in various 6. Serratosa, F.; Sole, E., Chem. Abstr. 1967, 66, 2623.
solvents and bases including benzene, Et3 N in benzene, NaH in 7. Katagiri, N.; Takashima, K.; Kato, T., J. Chem. Soc., Chem. Commun.
benzene, NaOMe in methanol, and KOH in DMSO was studied 1982, 664.
(eq 15).25 It was found that carrying out the reaction in benzene 8. Katagiri, N.; Takashima, K.; Haneda, T.; Kato, T., J. Chem. Soc., Perkin
gave the best yield of triazolylacetates that underwent hydrolysis Trans. 1 1984, 553.
to acids without their separation. 9. Corey, E. J.; Kamiyama, K., Tetrahedron Lett. 1990, 31, 3995.
4 ETHYL 4-(TRIPHENYLPHOSPHORANYLIDENE)ACETOACETATE

10. Moorhoff, C. M.; Schneider, D. F., Tetrahedron Lett. 1987, 28, 4721. 21. Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C., Org. Lett. 2010, 12,
11. Pietrusiewicz, K. M.; Salamończyk, I., J. Org. Chem. 1988, 53, 2837. 2766.
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13. Ceccarelli, S.; Piarulli, U.; Gennari, C., Tetrahedron Lett. 1999, 40, 153. 23. Jamie, J. F.; Rickards, R. W., J. Chem. Soc., Perkin Trans. 1 1997, 24,
3613.
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