Process for producing alpha-(benzylidene)acetonylphosphonates

A process for producing an .alpha.-(benzylidene)acetonylphosphonate of the formula: ##STR1## wherein Ar is phenyl substituted by at least one substituent selected from the group consisting of fluorine, chlorine, bromine, nitro, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, --CO.sub.2 R.sup.7 wherein R.sup.7 is C.sub.1 -C.sub.5 alkyl, --CONR.sup.7 R.sup.8 wherein R.sup.7 is as defined above and R.sup.8 is C.sub.1 -C.sub.5 alkyl, --C(O)R.sup.7 wherein R.sup.7 is as defined above, --OC(O)R.sup.7 wherein R.sup.7 is as defined above, --OSO.sub.3 R.sup.7 wherein R.sup.7 is as defined above, --OCF.sub.3, --S(.dbd.O).sub.2 R.sup.7 wherein R.sup.7 is as defined above, --CN and --SO.sub.3 R.sup.7 wherein R.sup.7 is as defined above, and each of R.sup.1 and R.sup.2 which may be the same or different is a saturated or unsaturated C.sub.1 -C.sub.12 aliphatic group, or R.sup.1 and R.sup.2 together form 1,2-ethylene, 1,3-propylene or 1,4-butylene, which is unsubstituted or substituted by from one to four C.sub.1 -C.sub.3 alkyl groups, which comprises: (a) reacting an aldehyde of the formula: EQU ArCHO (I) wherein Ar is as defined above, with an acetonylphosphonate of the formula: ##STR2## wherein R.sup.1 and R.sup.2 are as defined above, in the presence of a secondary amine of the formula: ##STR3## wherein each of R.sup.3 and R.sup.4 which may be the same or different is C.sub.1 -C.sub.4 alkyl, or R.sub.3 and R.sub.4 together form 1,4-butylene or 1,5-pentylene, which is unsubstituted or substituted by from one to four C.sub.1 -C.sub.2 alkyl groups, --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 NHCH.sub.2 CH.sub.2 --, and an .alpha.-halogeno fatty acid of the formula: ##STR4## wherein X is fluorine, chlorine, bromine or iodine, and each of R.sup.5 and R.sup.6 which may be the same or different is hydrogen, fluorine, chlorine, bromine, iodine or C.sub.1 -C.sub.4 alkyl; or (b) reacting a compound of the formula ##STR5## wherein Ar, R.sup.1 and R.sup.2 are as defined above, with an acetonylphosphonate of the formula II as defined above, in the presence of an .alpha.-halogeno fatty acid of the formula V as defined above.

The present invention relates to a process for producing 
.alpha.-(benzylidene)acetonylphosphonates. The 
.alpha.-(benzylidene)acetonylphosphonate derivatives prepared by the 
present invention are useful as intermediates for poly substituted 
phosphonate derivatives (F. BARBOT, E. AISO and Ph. MIGINIAC, 
Tetrahedron Lett., 25 (39), 4369-4370 (1984)), as intermediates for the 
preparation of conjugated dienes (J. M. McIntosh and R. A. Sieler, Can. J. 
Chem., 56, 226-231 (1977)) or as intermediates for medicines (Japanese 
Unexamined Patent Publications No. 161392/1984, No. 69089/1985, No. 
248693/1985, No. 258194/1985, No. 030591/1986, No. 63688/1986 and No. 
63689/1986). 
The reaction of an acetonylphosphonate with an aromatic aldehyde was first 
reported by Pudovik et al (A. N. Pudovik, G. E. Yastrebova and V. I. 
Nikitina, Zh. Obsh. Khim., 37 (2), 510-511 (1967)). They conducted the 
condensation reaction of benzaldehyde with diethyl acetonylphosphonate in 
the presence of a piperidine catalyst to obtain 
.alpha.-(benzylidene)acetonylphosphonate in a yield of 64.7%, as 
represented by the following scheme 1. 
##STR6## 
However, it is reported that when the aromatic ring is substituted by an 
electron attracting group, a dephosphonation reaction called Horner-Emmons 
reaction proceeds preferentially, whereby the desired phosphonate 
derivative is hardly obtainable (S. Patai and A. Schwartz, J. Org. Chem., 
25, 1232-1234 (1960)). The present inventors have conducted the reaction 
under the same condition as in the scheme 1 and have confirmed that the 
Horner-Emmons reaction proceeds preferentially (see the scheme 2 and 
Comparative Example 2). 
##STR7## 
Patai et al discovered that good results could be obtained when 
piperidine-acetic acid was used as a catalyst for the condensation of an 
aromatic aldehyde with .alpha.-methylene phosphonate (S. Patai and A. 
Schwartz, J. Org. Chem., 25, 1232-1234 (1960)). Since then, this method 
has been widely employed (scheme 3). 
##STR8## 
Many .alpha.-(benzylidene)acetonylphosphonate derivatives have been 
synthesized by using this method (Japanese Unexamined Patent Publications 
No. 161392/1984 and No. 248693/1985). However, the yield is very low 
particularly when an aromatic aldehyde is substituted by a strong electron 
attractive group such as a NO.sub.2 group. According to the research by 
the present inventors, this is caused by the Horner-Emmons reaction which 
produces a methyl styryl ketone derivative of the formula: 
EQU Ar.sup.a --CH.dbd.CHCOCH.sub.3 (a) 
wherein Ar.sup.a is phenyl substituted by an electron attractive group, as 
a by-product as well as a compound of the formula: 
##STR9## 
wherein Ar.sup.a is as defined above, and each of R.sup.a and R.sup.b 
which may be the same or different is alkyl, or R.sup.a and R.sup.b 
together form alkylene and a compound of the formula: 
##STR10## 
wherein Ar.sup.a is as defined above, as by-products. 
Thus, even if an acetonylphosphonate of formula: 
##STR11## 
wherein R.sup.a and R.sup.b are as defined above is reacted with a 
substituted benzaldehyde of the formula: 
EQU Ar.sup.a CHO (e) 
wherein Ar.sup.a is as defined above, in accordance with the conventional 
methods, the yield of an .alpha.-(benzylidene)acetonylphosphonate 
derivative of the formula: 
##STR12## 
wherein Ar.sup.a, R.sup.a and R.sup.b are as defined above, is low. 
It is an object of the present invention to improve the yield for the 
preparation of an .alpha.-(benzylidene)acetonylphosphonate derivative of 
the formula (f) by reacting a substituted benzaldehyde of the formula (e) 
with an acetonylphosphonate of the formula (d). 
The present invention provides a process for producing an 
.alpha.-(benzylidene)acetonylphosphonate of the formula: 
##STR13## 
wherein Ar is phenyl substituted by at least one substituent selected from 
the group consisting of fluorine, chlorine, bromine, nitro, chloromethyl, 
dichloromethyl, trichloromethyl, trifluoromethyl, --CO.sub.2 R.sup.7 
wherein R.sup.7 is C.sub.1 -C.sub.5 alkyl, --CONR.sup.7 R.sup.8 wherein 
R.sup.7 is as defined above and R.sup.8 is C.sub.1 -C.sub.5 alkyl, 
--C(O)R.sup.7 wherein R.sup.7 is as defined above, --OC(O)R.sup.7 wherein 
R.sup.7 is as defined above, --OSO.sub.3 R.sup.7 wherein R.sup.7 is as 
defined above, --OCF.sub.3, --S(.dbd.O).sub.2 R.sup.7 wherein R.sup.7 is 
as defind above, --CN and --SO.sub.3 R.sup.7 wherein R.sup.7 is as defined 
above, and each of R.sup.1 and R.sup.2 which may be the same or different 
is a saturated or unsaturated C.sub.1 -C.sub.2 aliphatic group, or R.sup.1 
and R.sup.2 together form 1,2-ethylene, 1,3-propylene or 1,4-butylene, 
which is unsubstituted or substituted by from one to four C.sub.1 -C.sub.3 
alkyl groups, which comprises: 
(a) reacting an aldehyde of the formula: 
EQU ArCHO (I) 
wherein Ar is as defined above, with an acetonylphosphonate of the formula: 
##STR14## 
wherein R.sup.1 and R.sup.2 are as defined above, in the presence of a 
secondary amine of the formula: 
##STR15## 
wherein each of R.sup.3 and R.sup.4 which may be the same or different is 
C.sub.1 -C.sub.4 alkyl, or R.sub.3 and R.sub.4 together form 1,4-butylene 
or 1,5-pentylene, which is unsubstituted or substituted by one to four 
C.sub.1 -C.sub.2 alkyl groups, --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 -- 
or --CH.sub.2 CH.sub.2 NHCH.sub.2 CH.sub.2 --, and an .alpha.-halogeno 
fatty acid of the formula: 
##STR16## 
wherein X is fluorine, chlorine, bromine or iodine, and each of R.sup.5 
and R.sup.6 which may be the same or different is hydrogen, fluorine, 
chlorine, bromine, iodine, C.sub.1 -C.sub.4 alkyl; or 
(b) reacting a compound of the formula: 
##STR17## 
wherein Ar, R.sup.1 and R.sup.2 are as defined above, with an 
acetonylphosphonate of the formula II as defined above, in the presence of 
an .alpha.-halogeno fatty acid of the formula V as defined above. 
Namely, by the reaction (a) or (b), the 
.alpha.-(benzylidene)acetonylphosphonate derivative of the formula III can 
be obtained in high yield. 
Further, the present inventors have found that the 
.alpha.-(benzylidene)acetonylphosphonate can be obtained in high yield 
also by forming an aminal of the formula VI from a secondary amine of the 
formula IV and a substituted benzaldehyde of the formula I and reacting 
the reaction solution containing the aminal with an acetonylphosphonate of 
the formula II in the presence of an .alpha.-halogeno fatty acid of the 
formula V in the same reaction solution. 
The aminal of the formula VI is a known compound, which can be prepared by 
a known method (e.g. M. Sekiya and H. Sakai, Chem. Pharm. Bull., 17 (1), 
32-35 (1969)). The temperature for the reaction for the preparation of an 
.alpha.-(benzylidene)acetonylphosphonate of the formula III is within a 
range of from cooling with ice to the reflux temperature of the solvent, 
preferably within a range of from cooling with ice to 100.degree. C. 
The molar ratios of the respective compounds used for the synthesis 
according to the present invention are as follows. 
Namely, the molar ratios of the compounds of the formulas I, II, IV and V 
are I:II:IV:V=0.8-1.2:0.8-1.2:0.01-2.4:0.01-2.4, preferably 
I:II:IV:V=0.95-1.05:0.95-1.05:0.1-2.0:0.1-2.0. 
Further, the molar ratios of the compounds of the formulas II, V and VI are 
II:V:VI=0.8-1.2:1.6-2.4:0.8-1.2, preferably 
II:V:VI=0.95-1.05:1.9-2.1:0.95-1.05. 
As the reaction solvent, an ether solvent such as THF (tetrahydrofuran), an 
amide solvent such as DMF (dimethylformamide), DMA (dimethylacetamide) or 
N-methylpyrrolidone, a halogenoalkane solvent such as dichloromethane or 
chloroform, a sulfoxide solvent such as DMSO (dimethylsulfoxide) a nitrile 
solvent such as acetonitrile, an aromatic hydrocarbon solvent such as 
benzene, toluene or xylene, or an ester solvent such as ethyl acetate, can 
be used. Among these solvents, preferred solvents include toluene, 
benzene, tetrahydrofuran, acetonitrile and chloroform. Particularly 
preferred solvents are toluene and benzene. 
Now, the present invention will be described in further detail with 
reference to Reference Examples, Comparative Examples and Working 
Examples. However, it should be understood that the present invention is 
by no means restricted by these specific Examples. 
REFERENCE EXAMPLE 1 
5.31 g (50.0 mmol) of benzaldehyde was dissolved in 30 ml of benzene, and 
5.80 g of boric anhydride powder was suspended therein. Then, 10.5 g (121 
mmol) of morpholine was added thereto under stirring. After the heat 
generation ceased, the mixture was heated again and reacted at 50.degree. 
C. for two hours. The reaction mixture was cooled to room temperature and 
subjected to filtration under suction to remove solid substance. The 
solvent was distilled off from the filtrate. The residue thus obtained 
(oily under heating) was dissolved in 40 ml of isopropyl ether, and the 
solution was gradually cooled and then left to stand overnight in a 
refrigerator, whereby 11.02 g (yield: 84%) of desired aminal was obtained 
as colorless crystals having a melting point of from 102.degree. to 
103.degree. C. 
REFERENCE EXAMPLES 2 TO 5 
In the same manner as in Reference Example 1, the following aminals were 
prepared. The reaction scheme is represented as follows: 
##STR18## 
______________________________________ 
Reference Yield Melting point 
Solvent for 
Example No. 
X (%) (.degree.C.) 
precipitation 
______________________________________ 
2 p-Cl 90 133-137 Isopropyl 
ether 
3 p-NO.sub.2 
64 Decomposed at 
Benzene 
180-182 
4 m-NO.sub.2 
73 134-135 Isopropyl 
ether 
5 o-NO.sub.2 
92 125-129 Isopropyl 
ether 
______________________________________

EXAMPLE 1 
2.62 g (10.0 mmol) of 1,1'-benzylidene dimorpholine was dissolved in 20.0 g 
of toluene, and 2.28 g (20.0 mmol) of trifluoroacetic acid was dropwise 
added thereto under stirring. After the completion of the dropwise 
addition, the mixture was heated to 60.degree. C., and 15 minutes later, 
2.06 g (10.0 mmol) of 2,2-dimethylpropylene acetonylphosphonate was added 
and dissolved therein. After confirming the dissolution, the warm bath was 
taken off. While the mixture was left to cool, the reaction was continued 
for 30 minutes to complete the reaction. The reaction mixture was cooled 
with ice, and 20.0 g of cold water was added thereto to dissolve a 
trifluoroacetate of morpholine. Then, the mixture was subjected to liquid 
separation, and toluene layer was taken and dried over anhydrous sodium 
sulfate. Then, the solvent was distilled off. 2.49 g of a slightly yellow 
residue thus obtained was purified by column chromatography (silica gel: 
200 g, ethyl acetate/benzene=1/1) to obtain 2.04 g (yield: 69%) of desired 
2,2-dimethylpropylene .alpha.-(benzylidene)acetonylphosphonate as a 
slightly yellow oily substance. (This oily substance was crystallized when 
left to stand at room temperature for three days.) From the NMR analysis, 
this substance was found to be a mixture of E-isomer/Z-isomer=80/20. 
NMR(CDCl.sub.3).delta.(ppm): 0.73(s), 1.06(s), 1.11(s), 1.21(s), total 6H; 
2.24(s), 2.5(s), total 3H; 3.4-4.5(m), 4H; 6.7-7.7(m), 5H; 7.80(s), 
8.29(s), total 1H. 
EXAMPLE 2 
In the same manner as in Example 1, 2,2-dimethylpropylene 
.alpha.-(benzylidene)acetonylphosphonate (a compound of the formula III 
wherein R.sup.1 and R.sup.2 together form --CH.sub.2 C(CH.sub.3).sub.2 
CH.sub.2 -- and Ar is p-chlorophenyl) was prepared by using 
1,1'-(p-chlorobenzylidene)dimorpholine instead of 1,1'-benzylidene 
dimorpholine. 
Yield: 85% 
NMR integral ratio: E/Z=80/20 
NMR(CDCl.sub.3).delta.(ppm): 0.77(s), 1.07(s), 1.13(s), 1.24(s), total 6H; 
2.28(s), 2.56(s) total 3H; 3.3-4.5(m), 4H; 6.6-8.5(m), 5H. 
EXAMPLE 3 
3.07 g (10.0 mmol) of 1,1'-(p-nitrobenzylidene)dimorpholine was suspended 
in 20.0 g of toluene, and 2.28 g (20.0 mmol) of trifluoroacetic acid was 
dropwise added thereto under stirring. After the completion of the 
dropwise addition, the mixture was heated to 60.degree. C., and 15 minutes 
later, 2.06 g (10.0 mmol) of 2,2-dimethylpropylene acetonylphosphonate was 
added and dissolved therein. After confirming the dissolution, the warm 
bath was removed, and while the mixture was left to cool, the reaction was 
continued for 30 minutes to complete the reaction. This reaction mixture 
was cooled with water, and 20.0 g of cold water was added thereto for 
precipitation to obtain 2.82 g (yield: 83%) of desired 
2,2-dimethylpropylene .alpha.-(p-nitrobenzylidene)acetonylphosphonate 
(Compound of the formula III, wherein R.sup.1 and R.sup.2 together form 
--CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 -- and Ar is p-nitrophenyl) as 
substantially colorless crystals. From the NMR analysis, this substance 
was found to be a mixture of E-isomer/Z-isomer=95/5. 
NMR of E-isomer (CDCl.sub.3).delta.(ppm) 1.07(s, 3H), 1.17(s, 3H), 2.31(s, 
3H), 3.2-4.6(m, 4H), 7.1-8.6(m, 5H) 
EXAMPLES 4 AND 5 
By using 1,1'-(m-nitrobenzylidene(dimorpholine or 
1,1'-(o-nitrobenzylidene)dimorpholine instead of 
1,1'-(p-nitrobenzylidene)dimorpholine, the corresponding 
.alpha.-substituted (benzylidene)acetonylphosphonate derivative was 
prepared in the same manner as in Example 3. However, as is different from 
Example 3, recovery of the recovery was conducted also from the mother 
liquor for precipitation by means of column chromatography (silica gel, 
ethyl acetate). 
The test results are shown in the following Table. 
______________________________________ 
E/Z 
(NMR 
Example 
Substit- 
Yield integral 
NMR(CDCl.sub.3) 
No. uent (%) ratio) .delta.-value 
______________________________________ 
4 m-NO.sub.2 
90 95:5 E-isomer 
1.07(s, 3H), 1.19(s, 3H) 
2.33(s, 3H), 3.2-4.6(m, 4H), 
7.0-8.6(m, 5H) 
5 o-NO.sub.2 
57 30:70 0.82(s), 1.02(s), 1.17(s), 
1.30(s), total 6H; 
2.28(s), 2.58(s), total 3H; 
3.3-4.4(m, 4H), 
6.8-8.9(m, 5H) 
______________________________________ 
EXAMPLE 6 
15.1 g of m-nitrobenzaldehyde and 17.0 g of piperidine were dissolved in 
200 g of benzene, and the mixture was refluxed for 3 hours. Water formed 
as the reaction proceeded, was removed azeotropically. The reaction 
solution was cooled with ice, and 22.8 g of trifluoroacetic acid was 
dropwise added thereto. The mixture was stirred for 30 minutes under 
cooling with ice. Then, 20.6 g of 2,2-dimethylpropylene 
acetonylphosphonate was added, and the reaction solution was heated to 
50.degree. C. and maintained at that temperature for 30 minutes, and then 
cooled again with ice. The formed crystals were collected by filtration 
and dried to obtain 22.0 g of desired 2,2-dimethylpropylene 
.alpha.-(m-nitrobenzylidene)acetonylphosphonate. The filtrate was washed 
twice with 75 g of water and cooled with ice, whereby 6.0 g (dry weight) 
of crystals of the desired product was further obtained. 
Yield: 83%, mp: 148.degree.-149.degree. C. 
EXAMPLE 7 
10.3 g of 2,2-dimethylpropylene acetonylphosphonate and 7.55 g of 
m-nitrobenzaldehyde were dissolved in 100 ml of toluene. Then, 5.7 g of 
trifluoroacetic acid and 4.25 g of piperidine were added thereto, and the 
mixture was subjected to azeotropic water removal for two hours. The 
reaction solution was cooled with ice for 2 hours, and precipitated 
crystals were removed by filtration. The filtrate was washed with 50 ml of 
water. The toluene solution was left to stand at 0.degree. C. for 10 hours 
to obtain 9.2 g (yield: 54%) of desired 2,2-dimethylpropylene 
.alpha.-(m-nitrobenzylidene)acetonylphosphonate as crystals. 
EXAMPLE 8 
A mixture comprising 302 g (2.00 mol) of m-nitrobenzaldehyde, 348 g (4.00 
mol) of morpholine and 200 g of benzene was refluxed for 4.5 hours while 
removing water azeotropically. The solution thereby obtained was cooled to 
30.degree. C. with water, and then 378 g (4.00 mol) of monochloroacetic 
acid was added thereto. The mixture was stirred for 30 minutes under 
cooling with water. Then, the mixture was heated again to an internal 
temperature of 60.degree. C., and 412 g (2.00 mol) of 
2,2-dimethylpropylene acetonylphosphonate was added thereto. The mixture 
was reacted for 1 hour. After the completion of the reaction, the reaction 
mixture was extracted with 1,400 g of warm water of 60.degree. C. while 
the mixture was still hot, to remove the monochloroacetate of morpholine. 
The benzene layer was collected, and 800 g of benzene was distilled off. 
Then, precipitation was conducted under cooling with ice to obtain 428 g 
(yield: 63%) of desired .alpha. -(m-nitrobenzylidene)acetonylphosphonate. 
EXAMPLE 9 
1.78 g of propylene acetonylphosphonate was suspended in 12 g of toluene, 
and 1.84 g of monochloroacetic acid was added and dissolved therein under 
stirring. After confirming the dissolution, 2.83 g of 
1,1'-(o-nitrobenzylidene)dimorpholine was added thereto, and the mixture 
was stirred at about 20.degree. C. for 2 hours. The reaction mixture was 
cooled with ice and 10 g of cold water was added thereto for precipitation 
to obtain 2.0 g (yield: 64.2%) of desired propylene 
.alpha.-(o-nitrobenzylidene)acetonylphosphonate as white crystals. From 
the NMR analysis, this product was found to be a mixture of 
E-isomer/Z-isomer=26/7. 
COMATIVE EXAMPLE 1 
(Conventional method: in the coexistence of piperidine and acetic acid) 
1.9 g of 2,2-dimethylpropylene acetonylphosphonate and 1.5 g of 
m-nitrobenzaldehyde were dissolved in 2 ml of benzene, and 0.5 ml of 
piperidine and two drops of acetic acid were added. The mixture was 
refluxed for 3 hours to remove water azeotropically. After cooling, the 
reaction solution was subjected to silica gel chromatography (eluate: 
ethyl acetate/methanol=9/1 (v/v), Rf: 0.7) to obtain 0.99 g (yield: 31%) 
of desired 2,2-dimethylpropylene 
.alpha.-(m-nitrobenzylidene)acetonylphosphonate. 
COMATIVE EXAMPLE 2 
(In the presence of piperidine) 
1.9 g of 2,2-dimethylpropylene acetonylphosphonate and 1.5 g of 
m-nitrobenzaldehyde were dissolved in 2 ml of benzene, and 0.5 ml of 
piperidine was added thereto. The mixture was refluxed for 1.5 hours to 
remove water azeotropically. After cooling, the reaction solution was 
subjected to a silica gel chromatography (eluate: ethyl 
acetate/methanol=9/1 (v/v), Rf: 0.7) to obtain 1.15 g (yield: 36% of 
desired 2,2-dimethylpropylene 
.alpha.-(m-nitrobenzylidene)-acetonylphosphonate. 
COMATIVE EXAMPLE 3 
(In the presence of piperidine) 
1 g of 2,2-dimethylpropylene acetonylphosphonate and 0.75 g of 
m-nitrobenzaldehyde or dissolved in 10 ml of benzene, and 1 g of 
piperidine was added thereto. The mixture was stirred at room temperature 
for 24 hours. This reaction solution was analyzed by high performance 
liquid chromatography (ODS reverse column, eluate: methanol/water=3/2 
(v/v), UV (254 nm) detection), whereby methyl(m-nitrostyryl)ketone was 
detected excusively as a product of the Horner-Emmons reaction. 
COMATIVE EXAMPLE 4 
(In the absence of a secondary amine) 0.515 g of 2,2-dimethylpropylene 
acetonylphosphonate and 0.38 g of m-nitrobenzaldehyde were dissolved in 5 
ml of benzene, and 0.1 ml of trifluoroacetic acid was added thereto. The 
mixture was refluxed for one hour, but the reaction did not proceed at 
all. 
The results of this experiment show that the addition of a secondary amine 
of the formula IV is essential for the reaction to proceed properly.