To provide α-substituted vinyltin useful for the search for function-developing substances such as pharmaceuticals/agrichemicals and functional materials and for the construction of a compound library.An α-substituted vinyltin compound represented by the formula (1), a tautomer or salt of the compound or a solvate thereof:R2CH═C(R3)Sn(R1)3  (1)wherein R1 is a C1-10 alkyl group, a C2-14 aryl group or the like, R2 is a C2-14 aryl group, a C2-9 heterocyclyl group, a C3-10 cycloalkyl group or the like, and R3 is a carbamoyl group, a thiocarbamoyl group, an isocyanate group, an isothiocyanate group, a formylamino group, a thioformylamino group, an isonitrile group, an urea group, a carbamate group or the like.

TECHNICAL FIELD

The present invention relates to α-substituted vinyltin compounds.

A vinyltin compound is a useful intermediate capable of introducing a wide range of substituents by means of coupling reaction to tin. In addition, an α-substituted vinyltin compound further having a functional group having reactivity different from that of a tin functional group at the α-position is a useful compound capable of preparing an α,α-disubstituted vinyl compound by further introduction of a substituent or conversion of a functional group.

BACKGROUND ART

A compound having a tin functional group has been known to be converted to various compounds e.g. by Stille reaction (e.g. Non-Patent Documents 1, 2, 3 and 4). Further, it has been known to undergo homocoupling in the presence of a palladium catalyst (e.g. Non-Patent Document 5).

Further, it has been known that in a compound having a vinyltin functional group, the tin functional group is further stereoselectively converted to a halide atom as the case requires (e.g. Non-Patent Documents 6, 7, 8, 20, 21 and 22) and that a vinyl halide compound reacts with various organometric reagents (e.g. Non-Patent Documents 4, 20, 21 and 22).

On the other hand, a compound having a carbamoyl group or a thiocarbamoyl group may undergo, for example, Curtius rearrangement using lead tetraacetate to prepare a compound having an isocyanate group or a isothiocyanate group (e.g. Non-Patent Document 9).

An isocyanate group and an isothiocyanate group can be converted to various substituents utilizing their reactivity. For example, they are useful for preparation of a urea compound or a thiourea compound by reaction with an amine (e.g. Non-Patent Document 10) or of a carbamate compound or a thiocarbamate compound by reaction with an alcohol (e.g. Non-Patent Document 11).

Further, in preparation of an isocyanate compound or a thioisocyanate compound, by subsequent reaction with an amine or an alcohol directly without isolation and purification, a urea compound or a carbamate compound can be prepared (e.g. Non-Patent Document 12).

Further, by reducing a compound having an isocyanate group or an isothiocyanate group, a compound having a formylamino group or a thioformylamino group can be obtained (e.g. Non-Patent Document 13). Such groups can be converted to an isonitrile group by the action of p-tosyl chloride (e.g. Non-Patent Document 14) or phosphorus oxychloride (e.g. Non-Patent Document 15).

Many compounds having an isonitrile group are present naturally and develop various physiological activities (e.g. Non-Patent Document 16). As one example, xanthocillin X analogs may be mentioned. Xanthocillin analogs have been known to have a wide range of antimicrobial action and have been reported to have antiviral action, VEGF and COX-2 inhibitory action (e.g. Patent Document 1), aromatase inhibitory action (e.g. Patent Document 2), antitumor action (e.g. Patent Documents 3 and 4), insecticidal action (e.g. Patent Document 5), etc. in addition. Further, as found by the applicants, they are useful compounds which have been known to have thrombopoietin receptor affinity and agonist activity (e.g. Patent Document 6).

Further, by utilizing an isonitrile group which is a reactive functional group, a group of compounds can be prepared by utilizing Ugi reaction and Passerini reaction (e.g. Non-Patent Documents 17, 18 and 19).

As α-substituted vinyltin compounds having a reactive functional group at the α-position in addition to a tin functional group, the following have been known, but one having a nitrogen functional group or one having a carbamoyl group as its starting material has not yet been known.

3) α-alkylaminocarbonyl-substituted vinyltin compounds which are vinyltin compounds having a nitrogen functional group at the α-position, for which patents have been applied by BASF (e.g. Patent Documents 7 and 8).

DISCLOSURE OF THE INVENTION

Object to be Accomplished by the Invention

α-substituted vinyltin compounds having a tin functional group and at the α-position, a carbamoyl group, a thiocarbamoyl group, an isocyanate group, an isothiocyanate group, a formylamino group, a thioformylamino group, an isonitrile group, an urea group, a carbamate group or the like, have functional groups differing in the reactivity and are thereby capable of being converted to various compounds sequentially by introduction of a substituent or conversion of a functional group depending on the reactivity and are very useful. Further, various analogs can be prepared from a common intermediate, and the present invention is particularly useful for the search for function-developing substances such as pharmaceuticals/agrichemicals and functional materials and for the construction of a compound library.

Means to Accomplish the Object

The present inventor has conducted extensive studies to find such useful α-substituted vinyltin compounds and as a result, found compounds of the present invention and accomplished the present invention.

Namely, the present invention provides the following.1. An α-substituted vinyltin compound represented by the formula (1), a tautomer or salt of the compound or a solvate thereof:
R2CH═C(R3)Sn(R1)3(1)
wherein R1is a C1-10alkyl group (the C1-10alkyl group may be substituted by a halogen atom) or a C2-14aryl group (the C2-14group may be substituted by a C1-6alkyl group (the C1-6alkyl group may be substituted by a halogen atom) or a halogen atom);

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the present invention will be described in detail.

First, the terms in the respective substituents R1to R18will be explained.

As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be mentioned.

A C1-3alkyl group may be linear, branched or a C3cycloalkyl group, and methyl, ethyl, n-propyl, i-propyl and c-propyl or the like may be mentioned.

A C2-10alkynyl group may be linear, branched or a C3-10cycloalkynyl group, and in addition to those mentioned above, 1-methyl-n-hexynyl, 1,2-dimethyl-n-hexynyl, 1-ethyl-n-hexynyl, 1-n-heptynyl, 2-n-heptynyl, 3-n-heptynyl, 4-n-heptynyl, 1-n-octynyl, 2-n-octynyl, 3-n-octynyl or the like may be mentioned.

As a C1-7acyl group, a formyl group may be mentioned in addition to the above C1-6alkylcarbonyl groups.

A C2-9heterocyclyl group may be a heteromonocyclic or fused heterobicyclic group consisting of at least one atom selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms and from 2 to 9 carbon atoms. Specifically, the following examples are mentioned:

A C2-14aryl group may be a C6-14aryl group containing no hetero atoms as ring constituting atoms or a C2-9aromatic heterocyclic group. A C2-9aromatic heterocyclic group may be a 5 to 7-membered C2-6heteromonocyclic group or 8 to 10-membered C5-9fused heterobicyclic group containing from 1 to 3 atoms selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms singly or in combination.

A C2-14aryloxy group may be a C6-14aryloxy group containing no hetero atoms as ring constituting atoms or a C2-9aromatic heterocyclyloxy group, and a C2-9aromatic heterocyclyloxy group may be a 5 to 7-membered C2-6monocyclic heterocyclyloxy group or 8 to 10-membered C5-9fused bicyclic heterocyclyloxy group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms singly or in combination.

The protecting group in a protected hydroxyl group, a protected thiol group, a protected amino group, a protected tetrazole group, a protected phosphonic acid group and a protected sulfonic acid group may be a C1-4alkoxymethyl group (such as a MOM (methoxymethyl) group, a MEM (2-methoxyethoxymethyl) group, an ethoxymethyl group, a n-propoxymethyl group, an i-propoxymethyl group, a n-butoxymethyl group, an iBM (isobutyloxymethyl) group, a BUM (t-butoxymethyl) group, a POM (pivaloyloxymethyl) group, a SEM (trimethylsilylethoxymethyl) group and the like, preferably a MOM (methoxymethyl) group, a MEM (2-methoxyethoxymethyl) group, a POM (pivaloyloxymethyl) group or the like), an aryloxymethyl group (such as a BOM (benzyloxymethyl) group, a PMBM (p-methoxybenzyloxymethyl) group, a p-AOM (p-anisyloxymethyl) group and the like, preferably a benzyloxymethyl group), a C1-4alkylaminomethyl group (such as a dimethylaminomethyl group), a substituted acetamidomethyl group (such as an Acm (acetamidomethyl) group, a Tacm (trimethylacetamidomethyl) group and the like), a substituted thiomethyl group (such as a MTM (methylthiomethyl) group, a PTM (phenylthiomethyl) group, a Btm (benzylthiomethyl) group and the like), a carboxyl group, a C1-7acyl group (such as a formyl group, an acetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a propionyl group, a Pv (pivaloyl) group, a tigloyl group and the like), an arylcarbonyl group (such as a benzoyl group, a p-bromobenzoyl group, a p-nitrobenzoyl group, a 2,4-dinitrobenzoyl group, a benzoylformyl group, a benzoylpropionyl group, a 3-phenylpropionyl group and the like), a C1-4alkoxycarbonyl group (such as a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an i-propoxycarbonyl group, a n-butoxycarbonyl group, an i-butoxycarbonyl group, a BOC (t-butoxycarbonyl group), an AOC (t-amyloxycarbonyl) group, a VOC (vinyloxycarbonyl) group, an AOC (allyloxycarbonyl) group, a Teoc (2-(trimethylsilyl)ethoxycarbonyl) group, a Troc (2,2,2-trichloroethoxycarbonyl) group and the like, preferably a BOC group and the like), an aryloxycarbonyl group (such as a Z (benzyloxycarbonyl) group, a p-nitrobenzyloxycarbonyl group, a MOZ (p-methoxybenzyloxycarbonyl) group and the like), a C1-4alkylaminocarbonyl group (such as a methylcarbamoyl group, an Ec (ethylcarbamoyl) group, a n-propylcarbamoyl group and the like), an arylaminocarbonyl group (such as a phenylcarbamoyl group and the like), a trialkylsilyl group (such as a TMS (trimethylsilyl) group, a TES (triethylsilyl) group, a TIPS (triisopropylsilyl) group, a DEIPS (diethylisopropylsilyl) group, a DMIPS (dimethylisopropylsilyl) group, a DTBMS (di-t-butylmethylsilyl) group, an IPDMS (isopropyldimethylsilyl) group, a TBDMS (t-butyldimethylsilyl) group, a TDS (thexyldimethylsilyl) group and the like, preferably a TBDMS (t-butyldimethylsilyl) group and the like), a trialkylarylsilyl group (such as a DPMS (diphenylmethylsilyl) group, a TBDPS (t-butyldiphenylsilyl) group, a TBMPS (t-butyldimethoxyphenylsilyl) group, a TPS (triphenylsilyl) group and the like), an alkylsulfonyl group (such as a Ms (methanesulfonyl) group, an ethanesulfonyl group, a benzylsulfonyl group and the like) or an arylsulfonyl group (such as a benzenesulfonyl group, a Ts (p-toluenesulfonyl) group, a p-chlorobenzenesulfonyl group, a MBS (p-methoxybenzenesulfonyl) group, a m-nitrobenzenesulfonyl group, an iMds (2,6-dimethoxy-4-methylbenzenesulfonyl) group, a Mds (2,6-dimethyl-4-methoxybenzenesulfonyl) group, a Mtb (2,4,6-trimethoxybenzenesulfonyl) group, a Mte (2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl) group, a Mtr (2,3,6-trimethyl-4-methoxybenzenesulfonyl) group, a Mts (2,4,6-trimethylbenzenesulfonyl) group, a Pme (pentamethylbenzenesulfonyl) group and the like), and a triphenylmethyl group (a trityl group) and the like.

In addition, a 1-methyl-1-methoxyethyl group, a 1-ethoxyethylgroup, a 2,2,2-trichloroethyl group, a 2-trimethylsilylethoxy group, a t-butyl group, an allyl group, a benzyl group, a p-methoxybenzyl group, a 2,4-dinitrophenyl group, a p-chlorophenyl group, a p-methoxyphenyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group or the like may be mentioned.

Specific preferred examples of the substituent R1are a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a s-butyl group, a t-butyl group, a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group, a phenyl group, a thienyl group (a 2-thienyl group, a 3-thienyl group), a furyl group (a 2-furyl group, a 3-furyl group) and a pyridyl group (a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group) (each of the phenyl group, thienyl group, furyl group and pyridyl group may be substituted by a C1-6alkyl group.

Particularly preferred specific examples are a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a c-hexyl group, a phenyl group and a p-methylphenyl group.

The following examples are mentioned as the heterocyclyl group:

Preferred examples of R3are a carbamoyl group, an isonitrile group, an isocyanate group, a formylamino group, and NHCO2t-Bu.

Favorable compounds as the α-substituted vinyltin compound of the present invention are as follows.1) E-form compounds represented by the formula (1) wherein R1is n-butyl, R3is carbamoyl and R2has the following structure, tautomers or salts of the compounds or solvates thereof:

2) E-form compounds represented by the formula (1) wherein R1is n-butyl, R3is carbamoyl and R2has the following structure, tautomers or salts of the compounds or solvates thereof:

3) Z-form compounds represented by the formula (1) wherein R1is n-butyl, R3is carbamoyl and R has the following structure, tautomers or salts of the compounds or solvates thereof:

4) Z-form compounds represented by the formula (1) wherein R1is n-butyl, R3is carbamoyl and R2has the following structure, tautomers or salts of the compounds or solvates thereof:

5) The compounds according to 1) to 4), wherein R1is converted to methyl, tautomers or salts of the compounds or solvates thereof.6) The compounds according to 1) to 4), wherein R1is converted to phenyl, tautomers or salts of the compounds or solvates thereof.7) The compounds according to 1) to 4), wherein R1is converted to p-methylphenyl, tautomers or salts of the compounds or solvates thereof.8) The compounds according to 1) to 4), wherein R1is converted to cyclohexyl, tautomers or salts of the compounds or solvates thereof.9) The compounds according to 1) to 8), wherein R3is converted to thiocarbamoyl, tautomers or salts of the compounds or solvates thereof.10) The compounds according to 1) to 8), wherein R3is converted to isonitrile, tautomers or salts of the compounds or solvates thereof.11) The compounds according to 1) to 8), wherein R3is converted to isocyanate, tautomers or salts of the compounds or solvates thereof.12) The compounds according to 1) to 8), wherein R3is converted to isothiocyanate, tautomers or salts of the compounds or solvates thereof.13) The compounds according to 1) to 8), wherein R3is converted to formylamino, tautomers or salts of the compounds or solvates thereof.14) The compounds according to 1) to 8), wherein R3is converted to thioformylamino, tautomers or salts of the compounds or solvates thereof.15) The compounds according to 1) to 8), wherein R3is converted to the following structure, tautomers or salts of the compounds or solvates thereof:

16) The compounds according to 1) to 8), wherein R3is converted to the following structure, tautomers or salts of the compounds or solvates thereof:

17) The compounds according to 1) to 8), wherein R3is converted to the following structure, tautomers or salts of the compounds or solvates thereof:

18) The compounds according to 1) to 8), wherein R3is converted to the following structure, tautomers or salts of the compounds or solvates thereof:

The compounds of the present invention represented by the formula (1) or acceptable salts thereof may be in the form of arbitrary crystals or arbitrary hydrates, depending on the production conditions. The present invention covers these crystals, hydrates and mixtures thereof. They may be in the form of solvates with organic solvents such as acetone, ethanol and tetrahydrofuran, and the present invention covers any of these forms.

The compounds of the present invention represented by the formula (1) may be converted to acceptable salts or may be liberated from the resulting salts, if necessary. The acceptable salts of the present invention may be, for example, salts with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. They may be salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid) and organic acids (such as acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid and p-toluenesulfonic acid).

EXAMPLES

Now, the present invention will be described in further detail with reference to Reference Synthetic Examples and Synthetic Examples. However, it should be understood that the present invention is by no means restricted by these specific Examples.

Reference Synthetic Example 1

Synthesis of 1-(2,2-dibromovinyl)-4-methoxybenzene

Triphenylphosphine (57.8 g, 220 mmol) was dissolved in dichromomethane (200 ml) in nitrogen atmosphere, and carbon tetrabromide (36.5 g, 110 mmol) was added little by little under cooling with ice, followed by stirring for 30 minutes. Then, p-anisic aldehyde (10.0 g, 73.4 mmol) was dropwise added under cooling with ice, followed by stirring for 10 minutes. The reaction solution was subjected to filtration, silica gel (50 g) was added to the filtrate, and the filtrate was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired compound 1-(2,2-dibromovinyl)-4-methoxybenzene (21.4 g, quant.) as pale yellow solid.

Reference Synthetic Example 2

Synthesis of (4-methoxyphenyl)propionic acid

1-(2,2-dibromovinyl)-4-methoxybenzene (17.38 g, 59.5 mmol) prepared in Reference Synthetic Example 1 was dissolved in tetrahydrofuran (230 ml) in nitrogen atmosphere, and a 2.59 mol/l n-butyllithium/hexane solution was dropwise added at −78° C. After the dropwise addition, the solution was returned to 0° C. and stirred for 90 minutes, and then cooled to −78° C. again, and crushed dry ice was added. After stirring for 30 minutes, water was added to the solution and the solution was concentrated under reduced pressure. The residue was diluted with diethyl ether, and extracted with a 1 mol/l sodium hydroxide aqueous solution twice. The obtained aqueous layer was acidified (pH=1) with hydrochloric acid and extracted with ethyl acetate twice. The obtained organic layer was washed with water and a saturated salt solution, dried over anhydrous sodium sulfate, subjected to filtration and concentrated under reduced pressure to give the desired compound (4-methxoyphenyl)propionic acid (9.73 g, 93%) as crude crystals.

Reference Synthetic Example 3

Synthesis of (3-(4-methoxyphenyl)propionic acid amide

(4-methoxyphenyl)propionic acid (20.0 mg, 0.11 mmol) prepared in Reference Synthetic Example 2 was dissolved in tetrahydrofuran (500 μl) in nitrogen atmosphere, and triethylamine (17 μl, 0.12 mmol) and ethyl chloroformate (11 μl, 0.12 mmol) were dropwise added under cooling with ice, followed by stirring for 15 minutes. A 28% ammonia aqueous solution was dropwise added, followed by stirring for 5 minutes, and the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2 to 1:2) to give the desired compound 3-(4-methoxyphenyl)propionic acid amide (18.9 mg, 95%) as colorless needle crystals.

Synthetic Example 1

Synthesis of (E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide

3-(4-methoxyphenyl)propionic acid amide (10.3 mg, 0.059 mmol) prepared in Reference Synthetic Example 3 was dissolved in tetrahydrofuran (500 μl) in nitrogen atmosphere, tetrakistriphenylphosphine palladium (1.4 mg, 0.0012 mmol) was added under cooling with ice, and a tetrahydrofuran solution of tri-n-butyltin hydride (20 μl, 0.074 mmol) was dropwise added. After stirring for 10 minutes, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired compound (E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (18.6 mg, 68%) as a colorless oily substance.

Synthetic Example 2

Synthesis of [(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)]vinyl isocyanate

(E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (130.2 mg, 0.28 mmol) prepared in the same manner as in Synthetic Example 1 was dissolved in tetrahydrofuran (2.8 ml) in nitrogen atmosphere, and lead tetraacetate (136.2 mg, 0.31 mmol) was added at room temperature. After stirring for 30 minutes, the reaction solution was subjected to filtration with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired compound [(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)]vinyl isocyanate (114.1 mg, 88%) as a pale yellow oily substance. IR (film): 2,206 cm−1(—NCO).

Synthetic Example 3

Synthesis of N-[(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide

[(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyhenyl)]vinyl isocyanate (17.5 mg, 0.038 mmol) prepared in Synthetic Example 2 was dissolved in tetrahydrofuran (800 μl) in nitrogen atmosphere, and a 1.0 mol/l lithium triethylborohydride/tetrahydrofuran solution (40 μl, 0.040 mmol) was dropwise added at −78° C. After stirring for 2 hours, 20 μl (0.020 mmol) of the solution was further added dropwise, followed by stirring for one hour. The reaction was terminated by a saturated ammonium chloride aqueous solution, silica gel was added, and the reaction solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the aimed compound N-[(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide (12.3 mg, 70%) as a pale yellow oily substance.

Main Component

Accessory Component

Synthetic Example 4

Synthesis of (Z)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide

3-(4-methoxyhenyl)propionic acid amide (1.92 g, 11.0 mmol) prepared in the same manner as in Reference Synthetic Example 3 was dissolved in tetrahydrofuran (110 ml) in nitrogen atmosphere, and tri(n-butyl)tin hydride (3.8 ml, 14.1 mmol) and 2,2′-azobisisobutyronitrile (36.1 mg, 0.22 mol) were added under cooling with ice, followed by stirring for 20 hours. Carbon tetrachloride and potassium fluoride were added, followed by stirring further for one hour, the reaction solution was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:2) to give the desired compound (Z)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (2.37 g, 46%) as colorless needle crystals. In addition, compound (E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (0.33 g, 6%) as a colorless oily substance and the starting material 3-(4-methoxyphenyl)propionic acid amide (0.48 g, 25%) were recovered.

Synthetic Example 5

Synthesis of [(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)]vinyl isocyanate

(Z)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (1.09 g, 2.34 mmol) prepared in Synthetic Example 4 was dissolved in tetrahydrofuran (23 ml) in nitrogen atmosphere, and lead tetraacetate (1.15 g, 2.59 mmol) was added at room temperature. After stirring for 15 minutes, the reaction solution was subjected to filtration with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired compound [(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)]vinyl isocyanate (0.98 g, 90%) as a pale yellow oily substance. IR (film): 2,267 cm−1(—NCO).

Synthetic Example 6

Synthesis of N-[(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide

[(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)]vinyl isocyanate (905.2 mg, 1.94 mmol) prepared in Synthetic Example 5 was dissolved in tetrahydrofuran (15 ml) in nitrogen atmosphere, and a 1.0 mol/l lithium triethylborohydride/tetrahydrofuran solution (3.0 ml, 3.0 mmol) was dropwise added at −78° C. After stirring for 2 hours, 1.0 ml (1.0 mmol) of the solution was further added dropwise, followed by stirring for 30 minutes. The reaction was terminated by ethyl acetate, and the reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate twice. The organic layer put together was washed with water and a saturated salt solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired compound N-[(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide (715.2 mg, 79%) as a pale yellow oily substance.

Main Component

Accessory Component

Reference Synthetic Example 4

Synthesis of 1,1′-[(1Z,3Z)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene]

N-[(E)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide (142.5 mg, 0.31 mmol) prepared in the same manner as in Synthetic Example 3 was dissolved in tetrahydrofuran (3.1 ml) in nitrogen atmosphere, and palladium acetate (6.9 mg, 0.031 mmol) and copper(II) chloride (41.7 mg, 0.31 mmol) were added under cooling with ice, followed by stirring for 30 minutes. Triethylamine (86 μl, 0.62 mmol) and silica gel were added, and the reaction solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (toluene:acetone=4:1 to 3:2, containing 1% v/v triethylamine) to give the desired compound 1,1′-[(1Z,3Z)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (33.0 mg, 61%) as colorless solid.

Reference Synthetic Example 5

Reference Synthetic Example 6

Synthesis of 1,1′-[(1E,3E)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene]

N-[(Z)-1-{tri(n-butyl)stannyl}-2-(4-methoxyphenyl)vinyl]formamide (34.0 mg, 0.073 mmol) prepared in Synthetic Example 6 was dissolved in tetrahydrofuran (730 μl) in nitrogen atmosphere, and palladium acetate (1.6 mg, 0.007 mmol) and copper(II) chloride (9.8 mg, 0.073 mmol) were added under cooling with ice, followed by stirring for 20 minutes. Triethylamine (20 μl, 0.14 mmol) and silica gel were added, and the solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (toluene:acetone=4:1 to 3:2, containing 1% v/v triethylamine) to give the desired compound 1,1′-[(1E,3E)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (33.0 mg, 61%) as pale yellow solid.

Reference Synthetic Example 7

Synthesis of 1,1′-[(1E,3E)-2,3-diisocyano-1,3-butadiene-1,4-diyl]bis[methoxybenzene]

Reference Synthetic Example 8

Synthesis of 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amido

4-hydroxybenzaldehyde (8.21 g, 67.2 mmol) was dissolved in acetonitrile (164 ml) in nitrogen atmosphere, and imidazole (6.87 g, 100.8 mmol) was added at room temperature. Tert-butyldimethylsilyl chloride was added under cooling with ice, followed by stirring for 30 minutes. Methanol was added to terminate the reaction, the reaction solution was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-(tert-butyldimethylsilyloxy)benzaldehyde (15.23 g, 96%) as a pale yellow oily substance.

Triphenylphosphine (3.44 g, 13.1 mmol) was dissolved in dichloromethane (25 ml) in nitrogen atmosphere, carbon tetrabromide (2.18 g, 6.56 mmol) was added little by little under cooling with ice, and triethylamine (4.4 ml, 26.2 mmol) was dropwise added, followed by stirring for 10 minutes. Then, under cooling with ice, a dichloromethane solution (20 ml) of 4-(tert-butyldimethylsilyloxy)benzaldehyde (10.0 g, 73.4 mmol) prepared in 1) was dropwise added, followed by stirring for 1 hour. Silica gel (50 g) was added to the reaction solution, the reaction solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1, containing 0.1% v/v triethylamine) to give 1,1-dibromo-2-(tert-butyldimethylsilyloxyphenyl)ethylene (2.77 g, 81%) as a pale yellow oily substance.

1,1-dibromo-2-(tert-butyldimethylsilyloxyphenyl)ethylene (190.9 mg, 0.487 mmol) prepared in 2) was dissolved in tetrahydrofuran (2.9 ml) in nitrogen atmosphere, and a 1.58 mol/l n-butyllithium/hexane solution (832 μl, 1.31 mmol) was dropwise added at −78° C. After stirring for one hour, crushed dry ice was added to return the solution to 0° C. After stirring for 10 minutes, water was added, and the solution was concentrated under reduced pressure. The residue was diluted with diethyl ether and extracted with water. The obtained aqueous layer was acidified (pH=4) with a saturated potassium hydrogen sulfate aqueous solution and extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, dried over anhydrous sodium sulfate, subjected to filtration and concentrated under reduced pressure to give 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (134.6 mg, quant.) as crude crystals.

3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (2.13 g, 7.71 mmol) prepared in 3) was dissolved in tetrahydrofuran (32 ml) in nitrogen atmosphere, and triethylamine (1.16 ml, 8.41 mmol) and ethyl chloroformate (0.726 ml, 8.41 ml) were dropwise added under cooling with ice, followed by stirring for 30 minutes. Then, a 28% ammonia aqueous solution was dropwise added, followed by stirring for 5 minutes. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate twice. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.60 g, 76%) as colorless solid.

Synthetic Example 7

Synthesis of (E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide

3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.13 g, 4.12 mmol) prepared in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (23 ml) in nitrogen atmosphere, and tetrakistriphenylphosphine palladium(0) (95.2 mg, 0.082 mmol) was added under cooling with ice, and then a tetrahydrofuran solution (17 ml) of tri-n-butyltin hydride (5.2 ml, 19.3 mmol) was dropwise added. After stirring for 30 minutes, carbon tetrachloride was added to terminate the reaction, and potassium fluoride was added, followed by stirring for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give (E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide (1.51 g, 65%) as a pale yellow oily substance.

Synthetic Example 8

Synthesis of {(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)}vinyl isocyanate

(E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide (1.50 g, 2.65 mmol) prepared in Synthetic Example 7 was dissolved in tetrahydrofuran (27 ml) in nitrogen atmosphere, and lead tetraacetate (1.30 g, 2.91 mmol) was added at room temperature. After stirring for 20 minutes, hexane (27 ml) was added, the solution was subjected to filtration with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give {(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)}vinyl isocyanate (1.32 g, 88%) as a colorless oily substance.

Synthetic Example 9

Synthesis of N-{(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)vinyl}formamide

{(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)}vinyl isocyanate (26.5 mg, 0.047 mmol) prepared in Synthetic Example 8 was dissolved in tetrahydrofuran (470 ml) in nitrogen atmosphere, and a 1.0 mol/l lithium triethylborohydride/tetrahydrofuran solution (49 ml, 0.049 mmol) was dropwise added at −78° C. After stirring for 30 minutes, a saturated ammonium chloride aqueous solution was added to terminate the reaction, then silica gel was added, the solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give N-{(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)vinyl}formamide (26.1 mg, 98%) as a pale yellow oily substance.

Synthetic Example 10

Synthesis of (E)-2-(tributylstannyl)-3-(3,4-dichlorophenyl)acrylamide

3-(3,4-dichlorophenyl)propionic acid amide (21 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=3:1) to give (E)-2-(tributylstannyl)-3-(3,4-dichlorophenyl)acrylamide (12.3 mg, 24%) as a pale yellow oily substance.

Synthetic Example 11

Synthesis of (E)-2-(tributylstannyl)-3-(3,4-dimethoxyphenyl)acrylamide

3-(3,4-dimethoxyphenyl)propionic acid amide (20.5 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=1:1) to give (E)-2-(tributylstannyl)-3-(3,4-dimethoxyphenyl)acrylamide (14.8 mg, 30%) as a pale yellow oily substance.

Reference Synthetic Example 9

Synthesis of (1Z,3Z)-2,3-diformamino-bis(4-tert-butyldimethylsilyloxyphenyl)buta-1,3-diene

N-{(E)-1-tributylstannyl-2-(4-tert-butyldimethylsilyloxyphenyl)vinyl}formamide (236.6 mg, 0.32 mmol) prepared in Synthetic Example 9 was dissolved in tetrahydrofuran (4.2 ml) in oxygen atmosphere, and copper(I) chloride (92.4 mg, 0.84 mmol) was added under cooling with ice, followed by vigorous stirring for 4 hours. After filtration, silica gel was added to the filtrate, and the filtrate was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (toluene:acetone=6:1) to give (1Z,3Z)-2,3-diformamino-bis(4-tert-butyldimethylsilyloxyphenyl)buta-1,3-diene (57.8 mg, 50%) as a colorless powder.

Reference Synthetic Example 10

Reference Synthetic Example 11

(1Z,3Z)-2,3-diisocyano-1,4-bis(4-tert-butyldimethylsilyloxyphenyl)buta-1,3-diene (74.0 mg, 0.14 mmol) prepared in Reference Synthetic Example 10 was dissolved in tetrahydrofuran in nitrogen atmosphere, and acetic acid (21 ml, 0.36 mmol) was added under cooing with ice. Then, a 1.0 mol/l tetra-n-butylammonium fluoride/tetrahydrofuran solution (280 ml, 0.28 mmol) was slowly added dropwise. The reaction solution was returned to room temperature, followed by stirring for 3 hours, and the reaction solution was purified as it was by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (1Z, 3Z)-2,3-diisocyano-1,4-bis(4-hydroxyphenyl)buta-1,3-diene (48.2 mg, 85%) as a yellow powder.

The structural formulae of the compounds obtained in Examples are given below.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a tin functional group and at the α-position, functional groups, such as a carbamoyl group, a thiocarbamoyl group, an isocyanate group, an isothiocyanate group, a formylamino group, a thioformylamino group, an isonitrile group, an urea group and a carbamate group, differing in the reactivity, and are thereby capable of being converted to various compounds sequentially by introduction of a substituent and conversion of a functional group depending upon the reactivity and are thereby very useful. Various analogs can be prepared from a common intermediate, and the present invention is particularly useful for creation of function-developing substances such as pharmaceuticals/agrichemicals and functional materials.

The entire disclosures of Japanese Patent Application No. 2005-117593 filed on Apr. 14, 2005 and Japanese Patent Application No. 2005-365795 filed on Dec. 20, 2005 including specifications, claims and summaries are incorporated herein by reference in their entireties.