NO178190B - 3,3-bis- (optionally substituted) -phenyl-2- (1-methyl-1H-tetrazol-5-yl) -1-propenal - Google Patents

Description

The present invention relates to a 3,3-bis-(optionally substituted)-phenyl-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal.

The natural fermentation products cmpacin (R=H) described by A. Endo et al., in Journal of Antibiotics, Vol 29, 1976, p. 1346-1348, and mevinolin (R=CH 3 ) described by A.W. Alberts et al., in J. Proe. Nati. Acad. Sei., U.S.A., Vol 77, 1980, p. 3957, are highly active antihypercholesterolemic agents, which limit cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme and natural point of cholesterologenesis regulation in mammals, including humans . Compactin (R=H) and mevinolin (R=CH3, also known as lovastatin) have the following structure

A number of structurally related synthetic compounds useful in the treatment of hypercholesterolemia have also been described in various patents and other publications. The previously known, closely related synthetically produced compounds are the following: In US Patent 4,198,425 hitherto unknown meva-lonolactone derivatives are described, which are useful in the treatment of hyperlipidemia and which have the following general formula

where A is a direct bond, a methylene, ethylene, trimethylene or vinyl group, and

R , R and R are different substituents.

In EP patent application 24,348, hitherto unknown hypocholesterolemic and hypoipemic compounds with the formula are described

where A is H or methyl,

E is a direct bond -CH2~, -(CH2)9-, -(CH2)3- or

-CE=CH-,

in 2 3

R<*>, R and R are each different substituents,

as well as the corresponding dihydroxy acids which originate from the hydrolytic opening of the lactone ring.

US patent 4,375,475 largely describes similar structures and agrees with the above-mentioned EP patent application 24,348.

In EP patent application 68.03 8, the split trans-enantiomer is described, a method for its preparation, as well as pharma-

and the corresponding dihydroxy acid, or a pharmaceutically acceptable salt thereof. PCT application V70 84/02131 describes analogues of mevalonolactone with the structure n where either R or R<w> is

while the other is primary or secondary C-, _ g.- alk. vl, C, ^-cycloalkyl or phenyl -(CH2) -,

X is -(CK_) - or -CH=CH-,

a n

n is 0, 1, 2 or 3,

R4, R<5>, R<5a> and R^ are different substituents.

PCT application WO 84/02903 describes mevalonolacetone analogues with the structures

where X is -( CE.)- or

2 n

n is 0, 1, 2 or 3, and

both q are 0, or one is 0 and the other is 1, and

In EP patent application 14 2.14 6, oxo analogues of mevinolin-like antihypercholesterolemic agents are described with the structure where the dashed lines represent possible double bonds, as there can be 0, 1 or 2 double bonds.

G. E. Stokker et al. describes in J. Med. Chem., Vol 28, 1985, p. 347-358 preparation and testing of a number of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives.

W. F. Hoffman et al. describes in J. Med. Chem, Vol 29, 1986, p. 159-169 preparation and testing of a variety of 7-(substituted aryl)-3,5-dihydroxy-6-heptene-(heptane) acids and their lactone derivatives. One of the preferred compounds among those described above has the structure

G. E. Stokker et al. describes in J. Med. Chem., Vol 29, 1986, p. 170-181 synthesis of a variety of 7-[3,5-disubstituted-(1,1'-diphenyl)-2-yl]-3,5-dihydroxy-6-heptenoic acids and their lactones. Two of the preferred compounds described in the above-mentioned article have the structures US patent 4,613,601 describes pyrazole analogues of mevalonolactone and derivatives thereof, which are useful in the treatment of hyperlipoproteinemia and atherosclerosis. These pyrazole analogues have the general formula

where X is -(CHJ -CH=CH-, -CH=CH-CH_- or -CH_-CH=CH-,

2 n 2 2

n is 0, 1, 2 or 3, and

R<1>, R<2>, R3, R4, R<5>, R6, R<7> and Z are different substituents.

The compounds according to the present invention are not described or suggested in any of the above-mentioned patent documents or articles. The unique structural feature, which consists in the incorporation of a tetrazole part into the compounds, deviates to a significant extent from the state of the art.

The propenal according to the invention is characterized by having the formula (III)

where

R<1> and R<4> are each independently hydrogen, halogen, C 1-4 -alkyl, C 1-4 -alkyl or trifluoromethyl, and

R^, r<3>, r<5> and R^ are each independently hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy.

The compound with the formula (III) can be used for the preparation of antihypercholesterolemic agents with the formulas

where R<*> and R<4> are each independently hydrogen, halogen, C1__4-alkylf<C>1_4~ alkoxy or trifluoromethyl,

R^, r<3>, r<5> and R^ each independently of one another are hydrogen, halogen, C 1-4 -alkyl or C 1-4 -alkyl,

n is 0, 1 or 2, and

R<7> is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic, pharmaceutically acceptable salt.

The terms "C 1-4 alkyl" and "C 1-4 alkoxy" denote, unless otherwise stated, unbranched or branched alkyl or alkoxy groups, such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl or tert-butyl. These groups preferably contain 1 or 2 carbonates. Unless otherwise stated, the term "halogen" includes chlorine, fluorine, bromine or iodine.

The antihypercholesterolemic compounds of the formulas (Ila) and (Ilb) can be prepared by various methods, preferably by using intermediate products of the formula (III).

The compounds of the formula III can be prepared by

(a) that a compound with the formula

where R1, R<2>, R3, R<4>, r<5>, r<6> and B have the above meaning, is reacted with an anion of a compound of the formula to produce a compound of the formula (VII ), where R<8 >is hydrogen, C1_g- alkoxycarbonyl or methyl, (b) that the product from step (a) is dehydrated to produce a compound of the formula (IV), and (c) either that the anion of the compounds of the formula ( IV), where R<8> is hydrogen, which is prepared in situ in an inert organic solvent, treated with a strong base, or

(c') that the compounds of the formula (V), where R<8> is methyl, are treated with an N-halide succinimide in the presence of a catalyst, and that the product is then reacted with 2-nitropropane to produce a compound of the formula (III ).

The compounds of formula (IV) can be prepared from optionally substituted benzophenones of formula (V) by alkylation with a suitable 5-substituted 1-methyltetrazole of formula (VII), followed by dehydrogenation of the resulting tertiary alcohol of formula (VII), as as shown in reaction core 1.

In the reaction core 1, R 1 , R <2> R <3> R^, R <5> , R <6> and R <8> have the meaning stated above. The optionally substituted benzophenones of formula (V) can be prepared by means of the general and well-known Friedel-Crafts reaction using a substituted phenyl catalyzed by a Lewis acid, e.g. aluminum chloride in carbon tetrachloride at approx. 0°C. A large number of substituted benzophenones are known and their preparation has been previously described, while many others are commercially available. Many have the starting materials with the formula (V) e.g. described by G. Olah in "Friedel Crafts and Related Reactions", Volume 3, Parts 1 and 2, Interscience Publishers, New York, 1964, and in references cited therein. The Friedel-Crafts reaction can produce a mixture of benzophenones, in which case the mixture can be separated in a conventional manner.

The starting materials of the formula (VI), where R Q is hydrogen, are commercially available, while the starting materials where R is C 1-6 -alkoxycarbonyl or methyl can be prepared by reacting 1,5-dimethyltetrazole with a strong base, such as butyllithium, at a temperature of from -70°C to 0°C, and the resulting anion thereof is added to or treated preferably with ethyl chloroformate or methyl iodide, respectively, as described herein.

The appropriate 5-substituted 1-methyltetrazole of formula (VI) can be treated with a strong base, such as n-butyllithium, at a low temperature of from -20°C to -78°C, preferably at from -40°C to -78° C, in an inert organic solvent, e.g. tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or the like. The resulting anion of formula (VI) can then be treated with the desired benzophenone of formula (V) to produce the corresponding tertiary alcohols of formula (VII).

The compounds of formula (IV) can be prepared from the compounds of formula (VII) using conventional dehydrogenation methods. The dehydrogenation can be carried out by heating the alcohol of the formula (VII) in a suitable inert organic solvent, e.g. toluene, benzene or xylene, with a small amount of an organic acid or a mineral acid, such as p-toluenesulfonic acid or sulfuric acid, in the presence of a drying agent, e.g. Na2S0^, MgSO^, molecular sieves or the like, and the water that forms is preferably removed azeotropically with a Dean-Stark trap or a similar device. Alternatively, the alcohol of formula (VII) can simply be heated with potassium hydrogen sulphate at a temperature of approx. 190°C.

In the specific example where R g is ethoxycarbonyl, the reaction of ethyl 1-methyl-5-tetrazolyl acetate with a benzophenone of the formula (V) can be carried out in the presence of titanium tetrachloride and carbon tetrachloride to directly produce, in one step, the corresponding olefin of the formula (IV).

The preferred aldehydes of the formula (III) can be prepared by different methods from the compounds of the formula (IV), depending on the R 8 -substituent used in the process. It is thus obvious to a person skilled in the art that the compounds of formula (IV), where R is ethoxycarbonyl (Ia), hydrogen (Ic) or methyl (Id), can be converted to aldehydes of formula (III) as shown in reaction core 2.

In the reaction core 2, R 1 , R <2> R <3> , R <5> and R <6> have the meaning stated above. The alcohols of formula (Ib) can preferably be prepared in one step by reducing the tetrazole ester of formula (Ia) with reducing agents, such as diisobutylaluminum hydride, in a non-reducible inert solvent, such as methylene chloride or tetrahydrofuran, at low temperatures and preferably at approx. -78°C. The resulting allyl alcohols of the formula (Ib) can then be easily oxidized at ambient temperature using conventional oxidizing agents, such as pyridine chlorochromate, in a non-reactive solvent, preferably methylene chloride, to produce the desired aldehyde of the formula (III).

The compounds with the formula (Ic) can be converted directly to the aldehydes with the formula (III) by treating the anion with the formula (Ic), which is produced in situ in an inert organic solvent, e.g. tetrahydrofuran or 1,2-dimethoxyethane, in a strong base, such as n-butyllithium, with ethyl formate.

The compounds of formula (III) can also be prepared from the compounds of formula (Id) by first treating the compounds of formula (Id) with N-bromosuccinimide in the presence of a catalyst, such as azobis-isobutyronitrile or benzoyl peroxide, in carbon tetrachloride, and then treating the resulting allyl bromide of the formula (Ie) with 2-nitropropane by the general method described here and in Org. Sight. Coll., volume IV, p. 932. Alternatively, the allyl bromide of the formula (le) can be prepared from the alcohol of the formula (Ib) by treatment with carbon tetrabromide and triphenylphosphine.

The preferred compounds of the formula (III) can be converted into the preferred compounds of the formula (Ila) and (Ilb) by general methods which are described here and in American patent application 18,542 as well as in Danish patent application 972/88. The use of the aldehydes with the formula (III) is shown in reaction core 3.

1 2 3 5 6

In the reaction core 3 ha9 r R , R , R , R4. , R and R the meaning given above, and R is a hydrolyzable ester group. The aldehydes with the formula (III) can generally be converted to dienaldehydes with the formula (VIII), where n is 1, by reaction with approx. 1 equivalent of triphenylphosphoranylidene acetaldehyde in an inert organic solvent, such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyoxyethane or the like. It is appropriate to carry out the conversion at reflux temperature. If desired, the dienealdehyde with the formula (VIII), where n is 1, can be reacted with a further equivalent of triphenylphosphoranylidene acetaldehyde to produce the trienaldehyde with the formula (VIII), where n is 2.

The penultimate intermediate, with the formula (IX), where R q is a hydrolyzable ester group, can be prepared from the corresponding aldehyde with the formula (VIII) by reaction with the acetoacetate ester dianion described above, prepared in situ. The reaction can be carried out in an inert organic solvent, such as tetrahydrofuran, at low temperatures of from -78°C to 0°C, preferably from -78°C to -40°C, until the reaction is practically complete.

The ketone ester of the formula (IX) can be reduced to the dihydroxy ester of the formula (Ila) with reducing agents known in the art, e.g. sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamyl borane, diborane, ammonia borane, tert-butylamine borane, pyridine borane, lithium tri-s-butyl borohydride or other similar reducing agents, which neither reduce nor hydrolyze the carboxyl ester group. The reduction is preferably carried out in a stereospecific manner by a two-step stereospecific reduction in order to achieve maximum formation of the preferred erythro-isomer of the compound of formula (Ila). The stereospecific reduction of a compound of the formula (IX) is carried out with trisubstituted alkylboranes, preferably triethylborane, or alkoxydialkylboranes, preferably methoxydiethylborane or ethoxydiethylborane (Tetrahedron Letters, Vol 28, 1987, p. 155) at a temperature of from -70°C to ambient temperature. The complex formed is then reduced with sodium borohydride at a temperature of from -50°C to at least -78°C in an inert organic solvent, such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is terminated by the addition of methanol. The resulting compound of formula (X) can then be converted into the compounds of general formulas (Ila) and (IIb) in a conventional manner known to those skilled in the art.

In an alternative method for producing the compounds with the formulas (Ila) and (Ilb), intermediate products with the formulas (If) and (Ig) which are shown in reaction core 4 are also produced.

In the reaction nucleus 4, R"*", R2, R^, R^, R<5> and R<6> have the meaning indicated above. The allyl bromide of formula (le) can be reacted in a conventional manner with phosphines, such as triphenylphosphine, in an inert organic solvent, such as cyclohexane, to produce the phosphonium salt of formula (If), where R^""<*>" is phenyl, which is unsubstituted or substituted with one or two substituents selected from C 1-4 alkyl and chlorine, and X is bromine, chlorine or iodo. The allyl bromide of formula (Ie) can alternatively be reacted in a conventional manner with phosphites, such as trimethylphosphite and triethylphosphite , without solvent or in an inert organic solvent, preferably without solvent for the preparation of a phosphonate of the formula (Ig), where R^ is C^_^-alkyl.

The intermediate products with the formulas (If) or (Ig) can then be converted into the antihypercholesterolemic compounds with the formulas (Ila) and (Ilb) by a series of reactions as shown in reaction diagram 5.

12 3 4 5 6 In reaction scheme 5, R , R , R , R", R and R have the above-9 12 for indicated meanings. R is a hydrolyzable ester group, R is tert-butyldiphenylsilyl, and Z is

where R"1"0 is C^_^-alkyl, R1"1" is phenyl which is unsubstituted or substituted with 1 or 2 C^_^-alkyl or chlorine substituents, and X is bromine, chlorine or iodine. The phosphonium salt of the formula (If) or the phosphonate of the formula (Ig) can be reacted with a silyl-protected aldehyde of the formula (IX), which itself is prepared by methods described in Tetrahedron Letters, Vol 25, 1984, p. 2435 and in US Patent 4,571,428 for the preparation of the silyl-protected compound of formula (XII). The reaction can be carried out in an inert organic solvent, such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a strong base, e.g. lithium diisopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature of from -78°C to 0°C. The compound of formula (XII) can then be desilylated in a well-known manner, such as with 48 percent hydrofluoric acid or preferably with tetrabutylammonium fluoride in an inert organic solvent, such as tetrahydrofuran or acetonitrile, in the presence of a small amount of organic acid, to produce the erythro compounds of the formula (X). The resulting compound of formula (X) can then be converted into the compounds of general formulas (Ila) and (IIb) in a conventional manner well known to those skilled in the art.

In a preferred embodiment of the present invention, the compounds of formula (I) have the structure

12 3 5 6

where R , R , R , R 4 , R and R are each independently hydrogen, fluorine, methyl or methoxy, and B is hydrogen or C 1-6 -alkoxycarbonyl.

The compounds with the formulas (Ila) and (Ilb) are competitive inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme (A)

(HMG-CoA)-reductase, which is the rate-limiting enzyme in cholesterol biosynthesis, and are therefore selective suppressors of cholesterol biosynthesis in mammals, including humans. They are therefore useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The biological activity of the compounds with the formulas (Ila) and (Ilb) can be shown by inhibition of cholesterol biosynthesis in rats.

In the following examples, melting point was recorded in a Thomas-Hoover capillary melting point apparatus, and boiling point was measured at specific pressure (mm Hg), and both temperature readings are uncorrected. Proton magnetic resonance (NMR) spectra were recorded with a Bruker "AM 300", Bruker "WM 360" or Varian "T-60 CW" spectrometer. All spectra were determined in CDCl3, DMSO-dg or D2O, unless otherwise stated, and chemical shifts noted in 5 units are recorded for the internal standard tetramethylsilane (TMS), and internal proton coupling constants are recorded in Hertz (Hz) . Cleavage patterns are named as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multi-spot, br. = broad peak and dd = doublet of doublet. Carbon-13 nuclear magnetic resonance (NMR) spectra were recorded in a Bruker "AM 3 00" or Bruker "WM 3 60" spectrometer and were broadband proton decoupled. All spectra were determined in CDCl3, DMSO-dg, or D2O unless otherwise noted, with internal deuterium lock, and chemical shifts were recorded in 5 units downstream from tetramethylsilane. IR spectra were determined with a Nicolet "MX-1 FT" spectrometer from 4000 cm<-1> to 400 cm<-1>, calibrated to 1601 cm<-1 >absorption using a polystyrene film and recorded in reciprocal centimeters ( cm "*"). Relative intensities indicated as follows: s (strong), m (medium) and w (weak).

Gas chromatographic mass spectra (GC-MS) were determined in a Finnigan "4500" gas chromatographic quadruple mass spectrometer at an ionization potential of 70 eV. Mass spectra were then recorded with a Kratos "Ms-50" instrument using a fast atom bombardment (FAB) technique. Mass data are expressed in the format: parent ion (M<+>) or protonated ion (M+H)<+>.

Analytical thin-layer chromatography was performed on pre-coated silica gel plates (60F-254), which were made visible using UV light, iodine vapors and/or staining with one of the following reagents: (a) methanolic phosphormolidic acid (2%) and heating , (b) reagent (a) followed by 2% cobalt sulfate in 5 M H2S<0>4 and heating. Column chromatography, also called flash column chromatography, was carried out in a glass column using finely divided silica gel (32-63 µm on silica gel-H) and pressure slightly above atmospheric pressure with the listed solvents. All solvent evaporations were carried out under reduced pressure. By the term "hexanes" is meant here a mixture of isomeric C 1 -hydrocarbons as specified by the American Chemical Society, and the term "inert" atmosphere means an argon or nitrogen atmosphere unless otherwise indicated.

Example 1

3, 3- bis-(4-fluorophenyl)-2-(1-methylH-tetrazol-5-yl)-2- propenal

a) Ethyl-2-cyano-3,3-bis(4-fluorophenyl)-2-propenoate

A mixture of 20.0 g (92 mmol) of 4,4<1->difluorobenzophenone and

11.0 g (97 mmol) of ethyl cyanoacetate in a solvent mixture consisting of 100 ml of dry benzene and 20 ml of glacial acetic acid containing a catalytic amount of γ-alanine (0.9 g) was refluxed while separating water using a Dean -Strong water trap. The water separation took place rapidly in the first 2 hours (0.4 ml aqueous layer was collected), but then slowly. Azeotropic distillation continued for 14 days. Analytical thin-layer chromatography showed elution with 10 volume! EtOAc in hexanes (Merck plate, 0.25 mm silica gel-F) two spots at Rf = 0.2 (desired product) and Rf = 0.45 (4,4<1->difluorobenzophenone starting material). The crude reaction mixture was washed with water (2 x 40 mL) and the combined organic washings were extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure, whereby the product crystallized as light cubic crystals. The crude product was collected, washed with 1:1 EtOAc in hexanes (v/v) and then crystallized

from 8:1 hexanes:ethyl acetate (v/v), whereby 16.2 g (56.3%) of an analytically pure compound was obtained, m.p. 114-116°C.

IR (KBr) v , : 3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513

may j\ s -.

(s), 1250 (s), 844 (s) cm<-1>.

<1>H NMR (CDCl 3 ) δ: 1.19 (3H, t, J=7.1 Hz), 4.18 (2H, q, J=7.1 Hz), 7.08-7.15 ( 6H, m), 7.40-7.42 (2H, m).

<13>C NMR (CDClg) δ: 13.75, 62.27, 104.05, 116.69, 115.53 (d, <2>JC_F=22.7 Hz), 115.88 (d, < 2>JC_F=22.7 Hz), 131.64 (d, 3JC_F=9.1 Hz), 132.66 (d, <3>J^ „=9.1 Hz), 134.25, 134.31 , 134.36, 164.01 (d, 1 C_F 1

<J>C_F=252.9 Hz), 164.52 (d, Jc__=254.0 Hz), 166.5 ppm.

Analysis for Clg<H>13N02F2:

Calculated: C: 69.01%; H: 4.15%; N: 4.47%.

Found: C: 68.91%; H: 4.15%; N: 4.62%.

b) Ethyl-3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate

A dry 50 mL round bottom flask was charged with 5.0 g (16.0 mmol) of ethyl 2-cyano-3,3-bis-(4-fluorophenyl)-2-propenoate, followed by 8.0 g (24.1 mmol ) azidotributylstannane (prepared as described in Rev. Trav. Chim., Vol 81, 1962, p. 202-205) and 2.0 ml of reagent grade toluene. The heterogeneous mixture was stirred and heated to reflux temperature (110°C) in an oil bath behind a safety screen. The solid starting material was dissolved gradually using a pale yellow thick syrup, and the homogeneous mixture was stirred and refluxed for 20 hours. By analytical thin-layer chromatography, elution with 20 vol% MeOH in CHCl 3 showed the product at Rf = 0.26 (stripe). The crude reaction mixture was diluted with an equal volume of diethyl ether and poured into a vigorously stirred, saturated aqueous solution of KF (200 mL containing 2 mL of 48 percent HBF^). A voluminous precipitate (Bu3SnF) was observed soon after mixing, and the hydrolysis continued for 16 hours. The suspension was filtered and the filtrate extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure. The title compound was crystallized from the concentrate, yielding 4.54 g (77%) of a white, analytically pure material, m.p. 159-161°C.

IR (KBr) vmax: 3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s), 841 (s) cm<-1>.

<1>H NMR (CDCl 2 ) 6 : 0.92 (3H, t, J=7.6 Hz), 3.98 (2H, q, J=7.6 Hz), 7.3-6.7 ( 8H, m), 10 (1H, v.br.).

<13>C NMR (CDC13) 6 : 166.52, 163.54 (d, <1>JC_F<=2>50.7 Hz), 163.46 (d, <1>JC_F=262.7 Hz) , 157.14, 136.40, 134.74, 131.71 (d, <2>Jc_p=62.7 Hz), 131.59 (d, 2JC_F=66.4 Hz), 115.75 (d, 3JC_F=18.9 Hz), 115.45 (d, 3JC_F=18.1 Hz), 62.11, 13.47 ppm.

Analysis for ci8H14<F>2<N>4°2<:>

Calculated: C: 60.27%; H: 4.06%; N: 15.50%.

Found: C: 60.67%; H: 3.96%; N: 15.72%.

c) Ethyl-3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate

To a solution of 0.5 g (1.40 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate from step b) in 100 ml of dry benzene, 100 mg (60% in mineral oil, 2.5 mmol) of sodium hydride was added in one portion at 45°C under argon. The greyish suspension was stirred at 45°C for 30 minutes, and then 1 ml (16.1 mmol) of methyl iodide was added, after which the flask was closed with a rubber stopper. The alkylation mixture was allowed to stand at 40-45°C for a total of 4 days. By analytical thin layer chromatography, elution 2 times with 20% EtOAc in hexanes showed only two isomeric products at R^ = 0.16 (major isomer) and R^ = 0.22 (biisomer). The crude reaction mixture was washed with an equal volume of water, and the aqueous phase was extracted once with 50 ml of diethyl ether. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give a crude product.

The crude product mixture (5.0 g), which was prepared as described above, was taken up in 20 ml of hot ethyl acetate, to which was added 40 ml of hot hexane mixture. The clear solution was slowly cooled to room temperature to give 2.16 g (52%) of the title compound as colorless large needles, m.p. 144-145°C.

IR (KBr) vmax: 1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s), 838 (s) cm-1.

<13>C NMR (CDCl3 ) δ: 165.44, 163.6 (d, <1>JC_F<=2>50.7 Hz), 163.4 (d, <1>J-w=252.9 Hz) , 156.85, 152.37, 135.88, 131.32 (d, 3Jn ^ =8, 3

C-t C-F

Hz), 115.94 (d, <*>JC_F=21.9 Hz), 115.64 (d, JC_F=22.7 Hz), 61.84, 33.76 13.59 ppm.

Analysis for ci9Hi6F2<N>4°2<:>

Calculated: C: 61.62; H: 4.35%; N: 15.13%.

Found: C: 61.63; H: 4.45%; N: 15.21%.

d) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoic acid

To a solution of 4.0 g (10.8 mmol) ethyl 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate from step c) in a mixture containing 20 ml of methanol and 20 ml of tetrahydrofuran, a 3 molar solution of lithium hydroxide in water (9 ml) was added at 0°C (ice-water bath). The saponification reaction was carried out overnight (approx. 16 hours) whereby a clear, homogeneous solution was formed. By analytical thin-layer chromatography, elution 2 times with 30 vol% in hexanes showed the desired compound at the starting point. The crude reaction mixture was acidified by the addition of 10 ml of a 3 molar HCl solution, and the organic material was extracted twice with 2 x 20 ml of ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give the product as a pale yellow solid. Recrystallization from an EtOAc-hexane mixture (1:9, v/v) gave 3.8 g (100%) of the title compound, m.p. 205-206°C.

IR (KBr) v . : 3438 (br), 2900 (br), 1725 (s), 1713 (s), 1600 (s), 1501 (s), 1231 (vs), 1156 (s), 850 (s) cm".

1 H NMR (CDCl 3 ): 7.9-6.4 (8H, m), 3.68 (3H, s).

<13>C NMR (CDCl3) δ: 166.57, 163.3 (d, <1>JC_F=249.9 Hz), 163.03 (d, <1>J-^=250Hz), 155.68 , 152.61, 135.58, 134.74, 131.75 (d, 3 JC_F=8.3 Hz), 131.28 (d, 3JJC_F=9.1 Hz), 117, 115.7 (d, <2>Jc_p=22.6 Hz), 115.4 (d, <2>JC_F=22.6 Hz), 33.6 ppm.

Analysis for ci7Hi2F2N4°2:

Calculated: C: 59.05%; H: 3.53%; N: 16.37%.

Found: C: 59.54%; H: 3.58%; N: 16.27%.

e) 3,3-bis-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenyl chloride

To a solution of 3.8 g (11.0 mmol) dry (0.1 mm Hg at SO^C) of the 3,3-bis(4-fluorophenyl)-2-(1-methyl) prepared in step b) -1H-tetrazol-5-yl)-2-propenoic acid in 20 ml of dry methylene chloride, 4 ml (46.0 mmol) of purified oxalyl chloride (redistilled over CaH2) was added in one portion. The reaction mixture was gradually heated to reflux temperature for 2 hours. The mixture was evaporated under reduced pressure to remove volatile solvent. Then, excess oxalyl chloride was removed under vacuum (20 mm Hg) at ambient temperature for 2 hours and under high vacuum (0.1 mm Hg) at 50°C for 16 hours to obtain the title compound.

f) 3,3-bis-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenol

The acyl chloride prepared in step C was dissolved in 150 ml of tetrahydrofuran and cooled to -78°C under argon. To this light brownish solution, 8.0 ml of lithium aluminum hydride in tetrahydrofuran solution (1.0 molar) was added at -78°C. Analytical thin layer chromatography showed after 15 minutes only one mobile spot with R 2 = 0.23 (50 vol% EtOAc in hexanes). The crude reaction mixture was diluted with 2 M H 2 SO 4 > The aqueous layer was extracted with 2 x 40 mL ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The crude allyl alcohol compound was immediately used in the next step without further purification.

MS (Cl): m/e = 328 for (M+H)<+>.

IR (KB<r>) <v>max: 3388 (v.br.), 1600 (s), 1501 (s), 1225 (s), 1156 (s), 838 (s), 750 (s) cm "<1>.

■"•R NMR (CDCl 3 ) & : 7.5-6.9 (8H, m), 4.52 (2H, br), 3.42 (3H, s), 3.75 (1H, br, D ^ O switchable).

<1>H NMR (DMS0-d6) s : 7.5-6.9 (8H, m), 5.23 (1H, t, J=5.5 Hz), 4.27 (2H, d, J =5.5 Hz), 3.54 (3H, s) ppm.

g) 3,3-bis-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To 3.64 g of a vigorously stirred solution of the crude allyl alcohol compound prepared in step f in 40 ml of methylene chloride, 2.6 g (12.0 mmol) of pyridine chlorochromate 1 was added in one portion at room temperature. Analytical thin layer chromatography immediately afterwards showed R^ = 0.34 for about 50% of the product together with R^ = 0.14 for the starting material (elution with 50 vol% EtOAc in hexanes). The oxidation took place at room temperature for a total of 16 hours. During this time, all starting material was consumed and only the compound was detected by thin layer chromatography. The crude reaction suspension was filtered through a layer of silica gel, washed with 1 1 10 vol% ethyl acetate in hexanes and 1 1 20 vol% ethyl acetate in hexanes. The desired compound was crystallized by concentration under reduced pressure, whereby 2.7 g (74%) of the title compound was obtained, m.p. 141-142°C.

MS (Cl): m/e = 326 for (M+H)<+>.

IR (KBr) vmax: 3075 (m), 2875 (m), 1675 (s), 1600 (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 (s) cm"1.

<1>H NMR (CDCl3 ) δ : 9.63 (1H, s), 9.5-6.9 (8H, m), 3.74 (3H, s).

<13>C NMR (CDCl3) δ : 188.92, 165.44, 164.68 (d, <1>JC_F=254.4 Hz), 164.10 (d, 1Jn =255.9 Hz), 151 .34, 134.31, 133.77 (d, 3J^ „=8.3 Hz), 132.69, 132.33 (d, ^Jn =7.5 Hz), 123.70, 116.26 ( d, 2 JL _ —r =21.9 Hz), 116.18 (d, C2J„ v_—r=22.7 Hz), 34.10 ppm.

Analysis for ci7Hi2<F>2<N4:>

Calculated: C: 62.58%; H: 3.71%; N: 17.17%.

Found: C: 62.41%; H: 3.85%; N: 16.98%.

Example 2

3, 3-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

a) 4,4'-difluoro-3,3'-dimethylbenzophenone

8 ml (73 mmol) of 2-fluorotoluene was added to a vigorously stirred mixture of 61.43 g (460 mmol) of aluminum chloride and 135 ml

carbon tetrachloride at 0°C. After 10 minutes, 92 ml (837 mmol) of 2-fluorotoluene in 75 ml of carbon tetrachloride was added dropwise over 4 hours, and the mixture was stirred for 2 hours at 0°C. It should be noted as a warning that a spontaneous, vigorous reaction occurred after the addition of 2-fluorotoluene. The mixture was cooled to -20°C and the reaction was quenched with 250 mL of 2N HCl. The organic layer was separated, washed with brine and dried with MgSOA. The solvent was removed by evaporation, and the residue was dissolved in 200 ml of benzene and treated with 200 ml of water and 50 ml of acetic acid. After stirring for 15 hours, the organic layer was separated, dried with MgSO 4 and evaporated. Crystallization from ethanol gave 50 g (49%) of the title compound, m.p. 128-130°C.

IR (KBr) <v>max: 1650om"1.

<1>H NMR (CDCl 3 ) s: 7.66 (d, J=7.3 Hz, 2H), 7.58 (m, 2H), 7.09 (t, J=8.8 Hz, 2H) , 2.32 (p, 6H).

Analysis for ci5Hi2<F>2<0:>

Calculated: C: 73.16%; H: 4.91%.

Found: C: 72.96%; H: 4.80%.

b) 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-ethanol

A solution of 2.55 g (26 mmol) of 1,5-dimethyltetrazole in 15 ml of dry tetrahydrofuran was treated at -78°C with 12.5 ml of a 2.5 M solution of n-butyllithium in hexane (31.2 mmol), and the mixture was stirred for 15 minutes. 5 g (20.3 mmol) of 4,4'-difluoro-3,3<1->dimethylbenzophenone from step a) in 20 ml of dry tetrahydrofuran was added, the mixture was stirred for 1 hour, and the reaction was then quenched with 250 ml (2 N HCl). The aqueous phase was extracted with 3 x 50 mL ethyl acetate, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by silica gel column chromatography using 20 vol% EtOAc-hexane as eluent to give 3.7 g (52%) of the compound. Recrystallization from EtOAc-hexanes gave the title compound, m.p. 41-42°C.

IR (KBr) vmax: 3400 (br) cm<-1>.

<1>H NMR (CDCl 3 ) δ: 7.20 (d, J=7.1 Hz, 2M), 7.10 (m, 2H), 6.88 (t, J=8.6 Hz, 2H) , 4.84 (s, 1H), 3.77 (s, 3H), 3.71 (s, 2H), 2.20 (s, 6H) .

Analysis for ci<gH1>8<F>2<N>40:

Calculated: C: 62.79%; H: 5.27%; N: 16.27%.

Found: C: 62.73%; N: 5.32%; N: 16.16%.

c) 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 3.58 g (10.9 mmol) of 1,1-bis(4-fluoro-3-methyl-phenyl)2-(1-methyl-1K-tetrazol-5-yl)ethanol from step b) and 530 mg

potassium hydrogen sulfate was heated at 195°C for 1.5 hours. The mixture was then cooled to 70°C and 50 ml of chloroform was added. Insoluble material was removed by filtration, and the filtrate was evaporated. The residue was crystallized from EtOAc-hexane to give 3.38 g (100%) of the title compound, m.p. 138-139°C.

<1>H NMR (CDCl3 ) δ: 7.20-6.80 (m, 6H), 6.65 (s, 1H), 3.56 (s, 3H), 2.28 (s, 3H), 2.18 (p, 3H),

Analysis for ci8H18<F>2N40:

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.15%; H: 5.05%; N: 17.24%.

d) 3,3-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

A solution of 3.78 g (11.0 mmol) of 1,1-bis(4-fluoro-3-methyl-phenyl)-2-(1-methyltetrazol-5-yl)ethene from step c) in 20 ml of dry tetrahydrofuran at -78°C was treated with 5.3 ml of a 2.5 M solution of n-butyllithium in hexane (13.25 mmol) and the mixture was stirred at -78°C for one hour. 1.33 mL (1.22 g, 16.5 mmol) of ethyl formate was added and the mixture was warmed to 23°C over 1 h, after which the reaction was quenched with 250 mL of 2 N HCl. The aqueous phase was extracted with 3 x 50 mL ethyl acetate, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 20% EtOAc-hexane as eluent to give 2.2 g (57%) of the title compound as a foam.

MS (Cl): m/e = 355 for (M+H)<+>.

IR (KBr) v mak, s: 2660 cm"<1,>

<1>H NMR (CDCl3 ) 6 : 9.62 (s, 1H), 7.25-7.05 (m, 3H), 6.85-6.65 (m, 3H), 3.73 (s , 3H), 2.34 (s, 3H), 2.13 (s, 3H).

Analysis for <c>i9<H>]_<gF>2<N>4<0:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.60%; H: 4.70%; N: 15.62%.

Example 3

3, 3- bis( 2, 4- dimethylphenyl)- 2-( 1- methyl- 1H- tetraol- 5- yl)- 2- propenal

a) 1,1-bis-(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl) ethanol

A solution of 8.9 g (91.0 mmol) of 1,5-dimethyltetrazole in 100

ml of dry tetrahydrofuran was treated at -60°C with 48 ml of a 1.89 M solution of n-butyllithium (91 mmol). After stirring for 20 minutes, 18 g (76 mmol) of 2,2',4,4'-tetramethyl-benzophenone (prepared by the method described in J. Am. Chem. Soc., Vol 81, 1959, p . 4858) in 50 mL of dry tetrahydrofuran, and the solution was stirred for 1 hour while warming to -20°C. The reaction was quenched with 1 N HCl, and then

the solution extracted with chloroform. The combined organic extracts were dried with MgSO 4 and evaporated to give 22 g of the title compound, m.p. 175-177°C.

IR (KBr) v • 3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s)

2^ ulaA S

cm

<1>H NMR (CDCl3 ) « : 7.26 (2H, d), 6.95-6.83 (4H, m), 4.00 (1H, s), 3.82 (2H, s), 3.41 (3H, s), 2.23 (6H, s), 1.83 (6H, s) ppm.

<13>C NMR (CDCl3 ) « : 152.34, 139.28, 137.32, 135.79, 133.24, 126.26, 125.92, 77.47, 35.04, 32.99, 21.28, 20.76 ppm.

Analysis for C^H^^O:

Calculated: C: 71.41%; H: 7.20%, N: 16.67%.

Found: C: 70.82%; H: 7.26%; N: 16.45%.

b) 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 1.8 g (5.4 mmol) of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol from step a) and 100 mg of potassium hydrogen sulfate was placed in an oil bath preheated to 190°C. After 15 minutes the melt was cooled and methylene chloride was added to the residue. The insoluble materials were removed and the solution was evaporated. The residue was crystallized from isopropyl ether, whereby 1.2 g of the title compound was obtained, m.p. 143-143.5°C.

IR (KBr) vmax: 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820 (s), 740 (s) cm-1.

<1>H NMR (CDCl 3 ) 6 : 7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36 (3H, s), 2.30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm.

<13>C NMR (CDC13) « : 154.18, 152.21, 138.54, 138.38, 138.06, 135.67, 135.40, 135.18, 131.78, 131.72, 129.90, 129.66, 126.77, 126.55, 111.99, 33.65, 21.02, 20.69, 19.95 ppm.

Analysis for C2<qH2>2<N>4<:>

Calculated: C: 75.45%; H: 6.97%; N: 17.60%.

Found: C: 75.04%; H: 7.03%; N: 17.63%.

c) 3,3-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

A solution of 1.0 g (3.1 mmol) of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene from step b) in 10 ml of dry tetrahydrofuran was treated with 1.64 mL of a 1.89 M solution (3.1 mmol) of n-butyllithium at -78°C. After stirring with cooling for 30 minutes, 0.3 g (4.0 mmol) of ethyl formate was added, and the mixture was stirred with cooling for 2 hours. The reaction was quenched with 1 N HCl, and the solution was extracted with chloroform. The combined organic extracts were dried with MgSO 4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 10 vol% ethyl acetate in hexane, whereby 0.9 g of product was obtained as an oil. Treatment of the oil with isopropyl ether gave the title compound as a solid, m.p. 117-120°C.

MS (Cl): m/e = 347 for (M+H)<+>.

<1>E NMR (CDCl 3 ) S: 9.58 (1H, s), 7.25-6.78 (7H, m), 3.70 (3H, s), 2.40 (3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.90 (3H, s) ppm.

<13>C NMR (CDC13)5 : 189.49, 168.80, 151.05, 140.87, 140.26, 137.06, 135.86, 134.87, 133.28, 132.04, 129.60, 126.62, 125.28, 34.17, 21.21, 21.06, 20.37, 20.07 ppm.

Analysis for C22<H>22<N>4<0:>

Calculated: C: 72.81%; H: 6.41%; N: 16.18%.

Found: C: 72.99%; H: 6.43%; N: 16.09%.

Example 4

3, 3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

a) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol

To a solution of 0.98 g (10.0 mmol) 1,5-dimethyltetrazole i

4.7 ml of a 2.14 M solution (10.0 mmol) of n-butyllithium was added to 20 ml of tetrahydrofuran at -30°C. After stirring for 1/4 hour, the solution was cooled to -50°C, and 1.74 g (8.0 mmol) of 4,4'-difluorobenzophenone was added. After stirring for 1 hour at -50°C and 1 hour at -10°C, the reaction was stopped with 1 N HCl. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 40 vol% ethyl acetate in hexane, whereby 2.0 g of the title compound was obtained, m.p. 116-118°C.

Analysis for C]_6<Hi>4F2<N>4°<:>

Calculated: C: 60.75%; H: 4.47%; N: 17.72%.

Found: C: 60.62%; H: 4.52%; H: 17.63%.

b) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 4.2 g (12.7 mmol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (prepared in step a) and potassium hydrogen sulfate was heated at 195°C for h hour. After cooling, the mixture was dissolved in chloroform and washed with water. The organic layer was dried and evaporated in vacuo. The residue was treated with diethyl ether, whereby 3.9 g of the title compound was obtained, m.p. 169-171°C.

Analysis for ci7<H>]_2<F>2<N>4°<:>

Calculated: C: 62.58%; H: 3.71%; N: 17.18%.

Found: C: 62.15%; H: 3.82%; N: 16.75%.

c) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

To a finely divided suspension of 1.0 g (3.3 mmol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (prepared in step

b) in 10 ml of tetrahydrofuran was added at -80°C 1.54 ml of a 2.14 M solution (3.3 mmol) of n-butyllithium, which resulted in

formation of a dark purple color. After stirring for 40 minutes at -80°C, 0.32 g (4.3 mmol) of ethyl formate was added, and the mixture was stirred for 2.5 hours at -80°C. The mixture was hydrolyzed with 1N HCl and extracted with methylene chloride. The extracts were dried with MgSO 4 and evaporated in vacuo. The residue was treated with diethyl ether, whereby 0.77 g of a yellow solid, m.p. 128-131°C. The solid was crystallized from isopropyl acetate:hexane to give 0.55 g of the title compound, m.p. 130-132°C.

Analysis for ci7<H>i2<F>2<N>4<0:>

Calculated: C: 62.58%; H: 3.71%; N: 17.18%.

Found: C: 62.15%; H: 3.82%; N: 16.75%.

Example 5

3, 3- bis-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

a) 5-ethyl-1-methyl-1H-tetrazole

To a slurry of 4.9 g (0.05 mol) 1,5-dimethyltetrazole

in 50 ml of dry tetrahydrofuran, it remained in the course of 15 minutes

-78°C under an inert atmosphere added 20 ml of 2.5 M n-butyllithium (0.05 mmol) in hexanes. The mixture was stirred for 30 minutes, during which time a yellowish precipitate formed. 3.7 mL (0.06 mmol) of methyl iodide was then added over 15 minutes. After stirring for a further 30 minutes, the clear reaction mixture was diluted with water and extracted with 3 x 50 ml of ethyl acetate. The aqueous layer was washed with 2 x 25 mL chloroform, and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil was purified by distillation to give 5.2 g (92%) of the title compound, bp: 89-90°C at 0.05 mm Hg. <1>H NMR (CDCl3 ) δ: 4.05 (s, 3H), 2.86 (q, 2H), 1.41 (t, 3H). <13>C NMR (CDCl3 ) S : 156.0, 33.24, 16.75, 11.20. b) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol To a solution of 5.6 g (0.05 mmol) 5-ethyl-1-methyl -1H-tetrazole (prepared in step a) in 60 ml of dry tetrahydrofuran, 20 ml of 2.5 M n-butyllithium (0.05 mmol) was added during 5 minutes at -78°C (bath temperature) under an inert atmosphere in hexane. The mixture was stirred for 30 minutes, and a solution of 10.8 g (0.5 mol) of 4,4'-difluorobenzophenone in 25 ml of dry tetrahydrofuran was added over 5 minutes. The mixture was stirred for a further 2 hours, while the bath temperature slowly rose to -20°C. The reaction was quenched with 1 N HCl and extracted with 3 x 50 mL ethyl acetate and 3 x 50 mL chloroform. The combined organic layers were dried over sodium sulfate and concentrated under reflux

pressure to give a white solid. The solid was purified by crystallization from ethanol-hexane, whereby 10.8 g (65%) of the title compound was obtained, m.p. 160-161°C.

IR (KBr) * maK, s: 3400 cm"<1>.

<1>H NMR (CDCl3 ) δ: 7.8-7.02 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H), 1.29 (d, 2H).

<13>C NMR (CDCl3) s : 162.57, 162.37, 159.14, 156.71, 142.48, 140.54, 128.25, 128.13, 127.52, 127.42, 114.67, 114.41, 144.38, 78.56, 36.99, 33.43, 14.52.

Analysis for C]_7<H>]_6<F>2<N>4<0:>

Calculated: C: 61.81%; H: 4.88%; N: 16.96%.

Found: C: 61.79%; H: 4.90%; N: 17.09%.

c) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propene

A slurry of 8.25 g (0.025 mmol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol (prepared in step b) and 100 mg of p-toluenesulfonic acid monohydrate in 60 ml of xylene was refluxed for 12 hours using a Dean-Stark overhead collector. The reaction mixture was washed with 10 mL of 1 N NaOH while hot and with 100 mL of water. Concentration of the organic layer gave off-white crystals of the product. This was purified by recrystallization from ethanol-hexane, whereby 7.1 g (91%) of the title compound was obtained as white crystals, m.p. 146-147°C.

IR (KBr) vmakg: 1575, 1500 cm"<1.>

<X>H NMR (CDCl 3 ) 6 : 7.42-6.85 (m, 8H 9 , 3.53 (s, 3H), 2.14 (s, 3H).

<13>C NMR (CDC13)6 : 163.37, 163.08, 160.13, 155.61, 144.60, 145.34, 136.47, 136.42, 136.24, 136.19, 131.65, 131.54, 131.11, 131.01, 119.53, 115.51, 115.27, 115.22, 33.50, 21.20.

Analysis for ci7<Hi4F>2<N4:>

Calculated: C: 65.37%; H: 4.51%; N: 17.94%.

Found: C: 65.64%; H: 4.61%; N: 18.09%.

d) 3,3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene

A slurry of 61.46 g (0.198 mol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (prepared in step c), 35, 06 g (0.197 mol) of N-bromosuccinimide and a catalytic amount of azobis-isobutyronitrile or benzoyl peroxide in 1.2 liters of carbon tetrachloride were refluxed in an inert atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature, and the solid from the reaction mixture was filtered off. The filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals, m.p. 159-160°C.

IR (KBr) v mak, s: 1600 cm"<1>,

<1>H NMR (CDCl3 ) δ : 7.5-7.1 (m, 8H), 4.44 (s, 2H), 3.53 (s, 3H).

<13>C NMR (CDCl3) S : 163.94, 163.74, 160.60, 160.45, 143.42, 149.68, 135.20, 135.15, 134.69, 131.43, 131.31, 130.90, 130.80, 119.57, 115.94, 115.77, 115.65, 115.50.

Analysis for C^7H13<F>2BrN4:

Calculated: C: 52.19%; H: 3.34%; N: 14.32%.

Found: C: 52.58%; H: 3.47%; N: 14.49%.

e) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of sodium ethoxide (3.93 g sodium metal,

0.17 mol) in 500 ml of absolute ethanol, 16.66 g (0.187 mol) of 2-nitropropane were added slowly over 5 minutes. The bromine compound prepared in step d above (67.1 g, 0.17 mol) was added portionwise over 10 minutes. The reaction mixture was stirred for 2 hours and the ethanol was removed in vacuo. The residue was dissolved in 500 ml of CE₂C₂, washed with 250 ml of water and dried over sodium sulfate. The organic layer was concentrated below

reduced pressure, whereby an oil was obtained. The oil was dissolved in 350 ml of hot toluene,' and treatment with 350 ml of hexane gave 50.6 g (91%) of the title compound as white crystals, m.p. 135-137°C.

Example 6

3, 3-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

a) 4,4'-difluoro-2,2'-dimethylbenzophenone

To a thoroughly stirred mixture of 6.1 g (46.0 mmol) of aluminum chloride in 14 ml of carbon tetrachloride was added at 0°C 3-fluorotoluene (1 g of a total of 10 g, 90.0 mmol), the remaining amount of 3- fluorotoluene in 9 ml of carbon tetrachloride was added and the mixture was stirred at 0°C for 4 hours. The mixture was cooled to -20°C and hydrolyzed by the addition of 25 ml of 1 N HCl. The organic layer was separated and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of 20 ml of benzene, 20 ml of water and 5 ml of acetic acid. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were dried with MgSO 4 and concentrated in vacuo. Analytical thin layer chromatography of the residue showed 3 spots, Rf = 0.67, 0.59 and 0.56 (5 vol% ethyl acetate in hexane on silica gel). Column chromatography on silica gel with 0.5 vol% ethyl acetate in hexane and collection of the fractions containing material with R 2 = 0.67 (5 vol% ethyl acetate in hexane) gave 1.3 g of the title compound, m.p. 50-52°C.

MS (Cl): m/e = 247 for (M+H)<+>.

<1>H NMR (CDCl3 ) δ : 7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s).

Analysis for cj5<H>]_2<F>2<0:>

Calculated: C: 73.17%; H: 4.92%.

Found: C: 73.34%; H: 5.02%.

b) 1,1-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-ethanol

To a suspension of 3.8 g (39.0 mmol) of 1,5-dimethyltetrazole in 40 ml of tetrahydrofuran, 17.7 ml of a 2.2 M solution (39.0 mmol) of butyllithium was added at -40°C. After stirring for 10 minutes, 8 g (32.5 mmol) of 4,4<1->difluoro-2,2<1->dimethylbenzophenone from step a) were added and the solution was stirred for 3 hours. The reaction was quenched with 1 N HCl. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phases were dried with MgSO 4 and concentrated in vacuo to give 7.5 g of the title compound, m.p. 186-188°C.

Analysis for ci8H18F2N40:

Calculated: C: 62.99%; H: 5.27%; N: 16.27%.

Found: C: 63.01%; H: 5.34%; N: 16.18%.

c) 1,1-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 0.5 g (1.5 mmol) of 1,1-bis(4-fluoro-2-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol from step b) and 0.2 g of p-toluenesulfonic acid was refluxed in 30 ml of toluene for 16 hours. The mixture was cooled, diluted with 50 ml of diethyl ether and extracted with a saturated sodium bicarbonate solution and water. The organic layer was dried with MgSO 4 and concentrated in vacuo. The residue was treated with diethyl ether, whereby 0.3 g of the title compound was obtained, m.p. 120-125°C.

Analysis for C]_<g>Hi6F2N4:

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.55%; H: 4.92%; N: 16.84%.

d) 3,3-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of 1.6 g (5.0 mmol) of 1,1-bis(4-fluoro-2-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene from step c ) in tetrahydrofuran, 2.3 ml of a 2.2 M solution (5.0 mmol) of butyllithium was added at -70°C. After stirring for 0.25 hours, 0.44 g (6.0 mmol) of ethyl formate was added and the mixture was stirred for 2 hours. The reaction was quenched with 1N HCl and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 1.0 g of the title compound, m.p. 135-136°C.

Analysis for ci9<Hi>6F2<N>4°<:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.22%; H: 4.59%; N: 15.50%.

Example 7

3, 3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

a) 2,2'-difluoro-4,4'-dimethylbenzophenone

Concentration of the fractions with the material with R f = 0.56

from silica gel column chromatography example 6a) and treatment of the residue with hexane gave 1.2 g of the title compound, m.p. 84-85.5°C.

"""H NMR (CDCl 3 ) 6 : 7.57 (2H, t, JH_H=8 Hz, JFH=8 Hz), 7.02 (2H, d, JR_H=8 Hz), 6.89 (2H, d , JFH=8 Hz), 2.39 (6H, s).

Analysis for ci5<Hi>2<F>2<0:>

Calculated: C: 73.17%; H: 4.92%.

Found: C: 73.19%; H: 4.88%.

b) 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-ethanol

To a solution of 4.6 g (4.7 mmol) of 1,5-dimethyltetrazole in 40 ml of tetrahydrofuran, 21.4 ml of a 2.2 M solution (4.7 mmol) of butyllithium was added at -50°C. After stirring for 10 minutes, a solution of 2,2<1->difluoro-4,4'-dimethylbenzophenone from step a) in tetrahydrofuran (15 ml) was added. The solution was stirred for 2.5 hours while warming to -10°C. The reaction was stopped by the addition of 1 N HCl. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried with MgSO 4 and evaporated. The residue was treated with diethyl ether and crystallized from isopropyl acetate, whereby 8.0 g of the title compound was obtained, m.p. 150-151°C.

MS: M+ = 344.

Analysis for ci8<H>18<F>2<N>4<0:>

Calculated: C: 62.79%; H: 5.27%; N: 16.27%.

Found: C: 62.84%; H: 5.23%; N: 16.28%.

c) 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-ethene

A suspension of 7.3 g (21.0 mmol) of 1,1-bis(2-fluoro-4-methylphenyl)-2(1-methyl-1H-tetrazol-5-yl)ethanol from step b) in 200 ml toluene was mixed with 3 g of p-toluenesulfonic acid, and the mixture was refluxed for 14 hours. After cooling, the mixture was diluted with diethyl ether and extracted with a saturated sodium bicarbonate solution and water. The organic layer was dried with MgSO 4 and evaporated. The residue was treated with isopropyl ether to give the title compound, m.p. 58-60°C.

Analysis for cig<H>16<F>2<N>4<:>

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.27%; H: 4.945; N: 16.93%.

d) 3,3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of 1.6 g (5.0 mmol) of 1,1-bis(2-fluoro-4-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene from step c ) in 20 ml of tetrahydrofuran, 2.3 ml of a 2.2 M solution (5 mmol) of butyllithium was added at -78°C. After stirring for 15 minutes, 0.44 g (6.0 mmol) of ethyl formate was added, and the solution was stirred with cooling for 2 hours. The reaction was quenched with 1 N hydrochloric acid, and the mixture was extracted with diethyl ether. The extracts were dried with MgSO 4 and evaporated. The residue was crystallized from isopropyl acetate, whereby 0.66 g of the title compound was obtained, m.p. 154-155°C.

Analysis for <c>i9<H>i6<F>2<N>4<0:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.44%; H: 4.63%; N: 15.58%.

Example 8

( E )- 3-( 4- fluorophenyl)- 2-( 1- methyl- 1H- tetrazol- 5- yl)- 3- phenylpropenal and ( Z )- 3-( 4- fluorophenyl)- 2-( 1- methyl - 1H-tetrazol-5-yl)-3-phenylpropenal

a) 1-(4-fluorophenyl-2-(1-methyl-1H-tetrazol-5-yl)-1-phenylethanol

A solution of 29.25 g (0.298 mmol) of 1,5-dimethyltetrazole in

400 ml of tetrahydrofuran was cooled to -78°C and treated for 30 minutes with 133 ml of a 2.5 M solution in hexane (0.3325 mol) of n-butyllithium. The mixture was stirred at -78°C for 30 minutes and treated with 50 g (0.25 mol) of 4-fluorobenzophenone. The mixture was stirred at -78°C for 30 minutes and warmed to 23°C for 2 hours. The reaction was quenched with 100 ml of 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 2 x 100 mL CHCl 2 , and the combined organic layers were dried with Na 2 SO 4 and evaporated to give a brown oil.

Purification by chromatography eluting with 20% EtOAc in hexane gave 46.3 g (62%) of the title compound as a white solid, m.p. 113-114°C (crystallized from StOAc-hexane).

MS (Cl): m/e = 299 for (M+H)<+>.

IR (KBr) vmax: 3300 (br), 1605, 1510 cm<-1>.

<1>H NMR s: 7.34-7.15 (m, 7H), 6.93 (m, 2H), 4.93 (s, 1H), 3.73 (s, 2H), 3.6 7 (s, 3H) ppm.

<13>C NMR s- 163.57, 160.29, 152.28, 144.94, 141.12, 141.08,

128.043, 127.87, 127.75, 127.67, 125.76, 115.25, 114.96, 77.03, 35.38, 33.45 ppm.

Analysis for C16H15FN40:

Calculated: C: 64.42%; H: 5.07%; N: 18.79%.

Found: C: 64.32%; H: 5.05%; N: 18.84%.

b) (E)-1-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-phenylethene and (Z)-1-(4-fluorophenyl)-2-(1 - methyl-1H-tetrazol-5-yl)-1-phenylethene

A mixture of 3.2 g (10.74 mmol) of tetrazolyl ethanol (prepared in step a) and 800 mg of potassium hydrogen sulfate was heated at 195°C for 30 minutes. After cooling to 100°C, 30 ml of chloroform was added and the mixture was treated until almost all of the solid had dissolved. The insoluble and inorganic material was removed by filtration and the solvent was evaporated to give 2.8 g (93%) of a mixture of the title compounds as a light brown solid. The product was crystallized from EtOAc-hexane.

MS (Cl): m/e = 281 for (M+H)<+>.

IR (KBr) vmax: 1640, 1600, 1510, 1445, 1220 cm"<1>.

<1>H NMR S : 7.50-6.90 (m, 9H), 6.75 (s, 1H), 3.60 (s, 1.7H), 3.43

(p, 1,3H).

<13>C NMR 6 : 165.19, 164.58, 161.26, 153.14, 152.97, 152.22,

152.13, 140.53, 137.81, 136.71, 133.99, 133.94, 131.74, 131.62, 130.38, 129.67, 127.29, 128.85, 128, 65, 128.38, 115.97, 115.74, 115.66, 155.45, 108.29, 108.15, 33.70 ppm.

Analysis for C]_6H]_3FN4 :

Calculated C: 68.56%; H: 4.68%; N: 19.99%.

Found: C: 68.63%; H: 4.77%; N: 20.37%.

c) ( E )- 3-( 4- fluorophenyl)- 2-( 1- methyl- 1H- tetrazol- 5- yl)- 3- phenylpropenal and ( Z )- 3-( 4- fluorophenyl)- 2-( 1 - methyl-1H-tetrazol-5-yl)-3-phenylpropenal

A suspension of 20 g (71.43 mmol) of the olefin produced in step b) in 200 ml of tetrahydrofuran was cooled to -78°C and treated with 31.5 ml of a 2.5 M solution in hexane (78.75 mmol) of butyllithium, and the resulting mixture was stirred at -78°C for 30 minutes. 6.9 g (93 mmol) of ethyl formate was added and the mixture was stirred at -78°C for 2 hours and warmed to 23°C for 1 hour. The reaction was quenched with 100 mL of 2 N HCl, the organic solvent was removed by evaporation, and the residue was extracted with 3 x 75 mL of EtOAc. The combined organic layers were dried with MgSO 4 and evaporated, and the residue was purified by chromatography using 35% EtOAc in hexane as eluent to afford 7.75 g (35%) of the title compound as a mixture of aldehydes.

MS (Cl): m/e = 309 for (M+H)<+>.

<1>H NMR fi: 9.67 (s, 0.66H), 9.64 (s, 0.33H), 7.70-6.90 (m, 9H), 3.74 (s, 1H) , 3.68 (s, 2H) ppm.

Example 9

3, 3-diphenyl-2-(1-methyl-1H-tetrazol-5-yl)propenal

a) 2-(1-methyltetrazol-5-yl)-1,1-diphenylethanol

A solution of 20 g (0.204 mol) of 1,5-dimethyltetrazole in 200 ml

dry tetrahydrofuran was cooled to -78°C and treated with 91 ml of a 2.5 M solution in hexane (0.227 mol) of n-butyllithium, and the mixture was stirred at -78°C for 30 minutes. 31.1 g (0.171 mol)

benzophenone was added and the mixture was stirred at -78°C for 30 minutes and warmed to 23°C and stirred for 15 hours. The reaction was quenched with 100 mL of 2 N HCl, and the mixture was extracted with 3 x 150 mL of EtOAc. The combined layers were dried with MgSO 4 and evaporated. The residue was crystallized from EtOAc-hexane to give just over 5 g (22%) of the title compound as a white solid, m.p. 175-176°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 281 for (M+H)<+>.

IR (KBr) vmax: 3300 (br), 1530, 1500 cm<-1>.

1t H NMR δ : 7.50-7.20 (m, 10H), 5.45 (s, 1H), 3.82 (s, 2H), 3.80 (s, 3H) ppm.

<13>C NMR δ: 152.36, 145.63, 128.16, 127.28, 126.05, 125.94, 77.70, 35.90, 33.76 ppm.

Analysis for ci6<Hi>6<N>4<0:>

Calculated: C: 68.56%; H: 5.76%; N: 20.00%.

Found: C: 68.62%; H: 5.81%; N: 20.10%.

b) 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 2.15 g (7.68 mmol) of 2-(1-methyltetrazol-5-yl)-1,1-diphenylethanol and 300 mg of KHSO 4 was heated at 200°C for 20 minutes- After cooling to 50°C the mixture was treated with 50 ml of CHCl 2 , and the organic solvent was decanted from the inorganic residue. Evaporation gave 1.7 g (85%) of the title compound as a cream solid, m.p. 147-148°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 263 for (M+H)<+>.

IR (KBr) vmax: 1640, 1500, 1445 cm"<1.>

<1>H NMR 6 : 7.50-7.00 (m, 10H), 6.78 (s, 1H), 3.43 (s, 3H) ppm.

<13>C NMR S : 153.94, 152.18, 140.40, 137.83, 129.54, 129.37, 128.94, 128.59, 128.38, 128.28, 108.22 , 33.56 ppm.

Analysis for C^g<H>^4<N>4<:>

Calculated: C: 73.27%; H: 5.38%; N: 21.36%.

Found: C: 73.25%; H: 5.43%; N: 21.43%.

c) 3,3-diphenyl-2-(1-methyl-1H-tetrazol-5-yl)propenal

A solution of 3.75 g (14.29 mmol) of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene in 40 ml of dry tetrahydrofuran was cooled to -78°C and treated with 6.3 ml of a 2.5 M solution in hexane (15.75 mmol) of n-butyllithium, and the resulting mixture was stirred at -78°C for 30 minutes. 1.5 mL (18.58 mmol) of ethyl formate was added and the mixture was stirred at -78°C for 2 hours. The reaction was quenched with 2N HCl and the solvent was removed by evaporation. The residue was extracted with 3 x 30 mL EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 25-35% EtOAz-hexane as eluent to give 1.35 g (36%) of the starting material and 1.65 g (39%) of the desired title compound, m.p. 185-186°C (crystallized from EtOAc-hexane).

MS (EI): m/e = 290 for M<+>.

IR (KBr) v max: 1675, 1600, 1445 cm"<1>,

<1>H NMR « : 9.66 (s, 1H), 7.70-6.90 (m, 10H), 3.66 (s, 3H) ppm.

<13>C NMR 6: 189.45, 167.79, 151.44, 138.35, 136.65, 131.54, 131.34, 130.96, 129.63, 128.71, 123.55 , 33.91 ppm.

Analysis for ci7Hi4<N>4<0:>

Calculated: C: 70.34%; H: 4.87%; N: 19.30%.

Found: C: 70.63%; H: 4.99%; N: 19.33%.

Example 10

3, 3-bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

a) 2,2-bis(4-methoxyphenyl)-1-(1-methyl-1H-tetrazol-5-yl)ethene

A solution of 20 g (0.204 mol) of 1,5-dimethyltetrazole in 200 ml

dry tetrahydrofuran was cooled to -78°C and treated with 91 mL of a 2.5 M solution in hexane (0.227 mol) of n-butyllithium, and the mixture was stirred at -78°C for 30 minutes. 41.3 g (0.171 mol) of 4,4'-dimethoxybenzophenone was added and the mixture was stirred at -78°C for 30 minutes and then warmed to 23°C over 2 hours.

The mixture was acidified with 100 ml of 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 3 x 300 mL EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was crystallized from EtOAc-hexane to give 48 g of a light brown solid, which turned out to be a mixture of the desired compound and the starting aldol adduct (1,1-bis(4-methoxyphenyl)-2-(l -methyl-1H-tetrazol-5-yDethanol). The mixture was dissolved in 180 ml of xylene and refluxed for 1 hour with p-toluenesulfonic acid in a Dean-Stark apparatus. The cooled mixture was diluted with 100 ml of ether, and the resulting solid was removed by filtration to give 40 g of the title compound as a cream solid, mp 146-147°C (recrystallized from EtOAc-hexane).

MS (CI): m/e = 323 for (M+H).

IR (KBr) vmax= 1605, 1520, 1250 cm<-1.>

<1>H NMR «: 7.31 (d, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3, 42 (s, 3H) ppm.

<13>C NMR «: 160.79, 160.16, 153.29, 133.33, 131.25, 130.32, 129.95, 127.36, 114.14, 113.69, 105.57 , 55.40, 55.28, 33.71 ppm.

Analysis for C]_gHigN4°2:

Calculated: C: 67.07%; H: 5.63%; N: 17.38%.

Found: C: 66.93%; H: 5.63%; N: 17.05%.

b) 3,3-bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

A solution of 4.6 g (14.29 mmol) of the olefin produced in step a) in 50 ml of dry tetrahydrofuran was cooled to -78°C and treated with 6.3 ml of a 2 M solution in hexane (15, 75 mmol) of n-butyllithium, and the resulting solution was stirred at -78°C for 30 minutes. 1.5 ml of ethyl formate was added and the mixture was stirred at -78°C for 2 hours. The reaction was quenched with 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 3 x 30 mL EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by column chromatography using 25-35% EtOAc-hexane as eluent to give 0.84 g (18%) of the starting material. Further elution gave 1.78 g (36%) of the desired title compound, m.p. 130-131°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 351 for (M+H)<+>.

IR (KBr) vm k : 1675, 1605, 1515, 1260 cm"<1>.

■""H NMR 6 : 9.59 (s, 1H), 7.30 (d, J=8.6Hz, 1H), 7.00 (d, J=8.7Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) ppm.

<13>C NMR 6: 189.51, 167.47, 162.59, 161.98, 152.30, 133.91, 132.29, 130.79, 129.35, 121.05, 114.20 , 114.15, 55.80, 55.40, 33.94 ppm.

Analysis for C]_gHi9N403:

Calculated: C: 65.14%; H: 5.18%; N: 15.99%.

Found: C: 64.96%; H: 5.22%; N: 15.75%.

Claims (1)

3,3-bis-(optionally substituted)-phenyl-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal, characterized in that it has the formula (III) where R<1> and R<4> are each independently hydrogen, halogen, C1-4-alkyl, C1-4-alkoxy or trifluoromethyl, and R^, r<3>, r<5> and R^ are each independently independently of one another is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy.