JPH08269018A - Production of 5-substituted hydantoin compound - Google Patents

Abstract

PURPOSE: To readily obtain the subject compound which is a synthetic intermediate for amino acids, etc., useful for medicines, etc., from a readily available raw material according to a new method for using a hydantoin compound unsubstituted at 'the 5-position as a raw material. CONSTITUTION: A hydantoin compound unsubstituted at the 5-position [preferably a compound of the formula (R1 is H or a protecting group of N atom; R2 is H, a 1-8C alkyl, etc.)] is reacted with a halogenating agent (e.g. N- chlorosuccinimide), preferably at 30-100 deg.C reactional temperature for 0.5-8 hr reactional time and the resultant reactional product is then reacted with an electrophilic agent (e.g. phenyl isocyanate) or a nucleophilic agent except a phenol compound (e.g. butene), preferably at 0-110 deg.C) reactional temperature for 3-18hr reactional time. Acetic acid or dioxane without containing water is preferred as a reactional solvent. An acid such as hydrochloric acid or a radical reactional initiator such as di-t-butyl peroxide is preferably made to coexist in reacting the hydantoin compound with the halogenating agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a 5-substituted hydantoin compound. The 5-substituted hydantoin compound is a natural compound useful for medicines, agricultural chemicals, chelating agents, etc.
And important synthetic intermediates such as unnatural amino acids.

[0002]

BACKGROUND OF THE INVENTION It is known that 5-substituted hydantoin compounds are classically synthesized by the reaction of the corresponding aldehyde with ammonium carbonate and sodium cyanide by the Bucherer-Burger method (J. Prakt. Chem. .,
p291 140 [1934]). Many methods are known, such as a method of reacting hydantoin and an alkyl halide under basic conditions.

[0003]

The Bucherer-Burger method requires dangerous sodium cyanide, and the resulting crude hydantoin produces a large amount of by-products due to the side reaction of the oxidation of the unsaturated ring under alkaline conditions. Included and colored. In addition, in the reaction of hydantoin with an alkyl halide under basic conditions, side reactions such as ring opening and N-alkylation of hydantoin occur, making it difficult to isolate and purify the product and to reduce the yield. Resulting in.

[0004]

As a result of intensive studies to solve these problems, the present inventor has found a completely novel method for producing a 5-substituted hydantoin compound using a hydantoin compound as a raw material, which is easily available. The present invention has been completed. That is, the present invention relates to a 5-substituted hydantoin compound characterized by reacting an unsubstituted hydantoin compound at the 5-position with a halogenating agent and then reacting it with an electrophilic agent or a nucleophile other than a phenol compound. It relates to a manufacturing method.

The halogenating agent in this reaction is a general term for reagents capable of introducing a halogen atom into a hydantoin compound. The electrophilic agent in the present reaction is a general term for reagents which can electrophilically react with a hydantoin compound to introduce a carbon-carbon bond into the hydantoin compound.
In this reaction, nucleophiles except phenol compounds (hereinafter,
Simply called a nucleophile. ) Is a generic term for reagents capable of reacting a carbon atom nucleophilically with a hydantoin compound to introduce a carbon-carbon bond into the hydantoin compound. However, the phenol compound represented by the following formula (II) is excluded.

Embedded image (In the formula, R ₃ represents a hydrogen atom or a protective group for a phenolic hydroxyl group, and R _{4 to} R ₇ represent groups that do not substantially impair the para orientation of the R ₃ O group.) The 5-substituted hydantoin compound is a general term for hydantoin compounds in which a monovalent group selected from aliphatic compounds, aromatic compounds other than phenol compounds, and heterocyclic compounds is bonded to the 5-position of hydantoin.

The reaction relating to the method for producing a 5-substituted hydantoin is represented by the following formula.

Embedded image (In the formula, R and R'represent a substituent having a monovalent group of any of an aliphatic compound, an aromatic compound other than a phenol compound, and a heterocyclic compound.) In the above reaction, a nucleophile and The electrophilic agent is preferably added after the reaction between the hydantoin compound and the halogenating agent is completed. A nucleophile or an electrophile may be added in the presence of a halogenating agent, but a halide of the nucleophile or the electrophile may be produced as a by-product to lower the yield per nucleophile and electrophile. is there. The volatile halogenating agent can be removed by introducing a gas such as nitrogen, but the non-volatile halogenating agent may be decomposed and removed by using an appropriate reducing agent or the like.

With respect to 1 mol equivalent of the hydantoin compound,
Since the halogenating agent is preferably 1 mol equivalent, it is preferably used in the vicinity thereof. The reaction temperature is about 0 to 120 ° C, preferably 30 to 100 ° C. The reaction time is preferably 0.5 to 8 hours.

The amount of the electrophilic agent or nucleophile added to 1 mol equivalent of the hydantoin compound charged varies depending on the reaction conditions, but it can be used in the vicinity of 1 mol equivalent. In order to improve the yield of the reaction product with respect to the charged hydantoin compound and to shorten the reaction time in the reaction at low temperature, 2-3 mol equivalent of an electrophilic agent or a nucleophile is preferably used. . It is desirable to raise the reaction temperature to about -10 to 180 ° C, preferably 0 to 110 ° C.
If the reaction temperature is lower than this temperature condition, the time required for completion of the reaction becomes extremely long, and if the reaction temperature is high, the reaction substrate decomposes and the yield of the 5-substituted hydantoin compound decreases.
The reaction time is preferably 3 to 18 hours. The reaction time depends on the addition amount of the nucleophile and electrophilic agent and the reaction temperature, and depending on the types of the hydantoin compound, the nucleophile, and the electrophilic agent, the nucleophilic amount is 2 to 3 times that of the hydantoin compound charged. If an agent or an electrophilic agent is added and the reaction temperature is set to 0 to 100 ° C, the reaction is almost completed in 2 to 12 hours. Of course, the reaction temperature and the reaction time are appropriately selected depending on the combination of the reaction raw material, a hydantoin compound, a halogenating agent, and a nucleophile or an electrophilic agent.

As the halogenating agent in this production method, chlorine,
Halogen molecules such as bromine and iodine, bromine chloride (BrC
l), mixed halogen molecules such as iodine bromide (IBr),
N-chlorosuccinimide, N-bromosuccinimide, haloimides such as N-bromoacetamide, haloamides, calcium hypochlorite (Ca (ClO))
₂ ), perhalogen acid salts such as t-butyl hypochlorite, perhalogen acid esters, chlorides and bromides such as sulfuryl chloride and sulfuryl bromide are used, and the halogenating agent applicable to the present invention is the halogenating agent described above. The halogenating agent that is generally used in organic synthesis can be used without being limited to the agent.

Examples of the nucleophile used in the present production method include monoenes such as butene and hexene, conjugated dienes such as butadiene and isoprene, enol ethers such as ethyl vinyl ether and butyl vinyl ether, N-vinylmorpholine and N-vinylpiperidine. Other compounds such as enamines such as, vinyl sulfides such as ethyl vinyl sulfide and phenyl vinyl sulfide, ketene acetals such as 1,1-dimethoxyethene and 1-methoxy-1-t-butyldimethylsilyloxy-ethene, and the like In addition, enols generated from carbonyl compounds such as acetone and dimethyl malonate, acetaldehyde dimethyl acetal,
Precursors of enol ethers such as acetone diethyl acetal, orthoacetates such as trimethylorthoacetate and triethylorthoacetate, and the like that exhibit nucleophilicity by decomposition during the reaction are also included. The nucleophile applicable to the present invention is not limited to the above-mentioned nucleophiles, and a nucleophile in which a carbon atom generally used in organic synthesis causes a nucleophilic attack can be used.

As the electrophilic agent in the present production method, ketene such as phenylketene and dichloroketene, and isocyanates such as phenyl isocyanate and chlorosulfonyl isocyanate are shown. Since ketene is generally unstable, a compound capable of forming ketene in the reaction system may be used as a raw material so that dichloroketene is generated from trichloroacetic acid chloride and zinc. The electrophilic agent applicable to the present invention is not limited to the above-mentioned electrophilic agent, and an electrophilic agent in which a carbon atom generally used in organic synthesis undergoes electrophilic addition can be used.

A feature of this reaction is that both a nucleophile and an electrophile can react with the 5-position of an unsubstituted hydantoin compound at the 5-position, facilitating the carbon-carbon bond important for organic synthesis. It can be built. That is, according to the present production method, as shown in the following formula, an aliphatic compound (formula (a), (b),
(C), (d), (e), (f)), which has a monovalent group of any one of aromatic compounds (formula (g)) and heterocyclic compounds (formula (h)) excluding phenol compounds 5 The -substituted hydantoin compound can be conveniently synthesized in one step from a hydantoin compound whose starting material at the 5-position is unsubstituted.

[Chemical 4] In this reaction, a cyclization reaction is carried out with a nucleophile or an electrophile which is used in combination with an unsubstituted hydantoin compound at the 1-position to obtain a bicyclic hydantoin compound as a cyclic amino acid raw material. For example, using butadiene as the nucleophile gives the bicyclic dehydropyridine derivative (VI).

Embedded image When ketene is used as the electrophilic agent, the bicyclic β-
This gives the lactam derivative (VII).

[Chemical 6] As described above, according to this production method, the cyclic amino acid precursor can be easily synthesized.

In the present invention, the 5-position unsubstituted hydantoin compound is a generic name for hydantoin compounds in which a nitrogen atom at the 1-position of hydantoin may be substituted with a protecting group and an organic group may be substituted at the 3-position nitrogen atom. Is. The nitrogen atom-protecting group at the 1-position is a substituent capable of regenerating the nitrogen-hydrogen bond under appropriate deprotection conditions. The requirements of the protecting group here are in accordance with the concept of the protecting group generally accepted in synthetic organic chemistry and satisfy the following requirements. 1) No change during the reaction, 2) Does not hinder the intended reaction, 3) After the reaction, the protecting group can be deprotected without damaging the part other than the protecting group. For reference, see Theodora W. Greene, Peter GM Wuts, the de facto standard for protecting groups.
`` Protective Groups in Organic Synthesis Second E
dition ”, JOHN WILEY & SONS, INC.
As the nitrogen atom-protecting group (R ₁ ), a methyl group, C 3
C10 alkenyl group (eg allyl group), C3 to C10
Alkynyl group (propargyl group, etc.), C2-C10
An acyl group (acetyl group, propionyl group, benzoyl group, etc.), an aralkyl group which may have a substituent on the benzene ring (benzyl group, p-methoxybenzyl group, etc.), and an amino group which may have a hydrogen atom substituted. Carbonyl group (N-methylaminocarbonyl group etc.), C3 to C8
An alkoxycarbonyl group (such as a methoxycarbonyl group or an ethoxycarbonyl group), an aryloxycarbonyl group that may have a substituent on the benzene ring (such as a phenyloxycarbonyl group), or an aralkyloxycarbonyl group that may have a substituent on the benzene ring ( Benzyloxycarbonyl group, etc.) is applicable. These protecting groups have to be compatible with halogenation and subsequent reaction with nucleophiles or electrophiles and may be deprotected during the isolation procedure after the reaction. Three
The organic group (R ₂ ) on the nitrogen atom at the position is a C1-C8 alkyl group (methyl group, ethyl group, octyl group, etc.), C
3 to C10 alkenyl group (eg allyl group), C3 to C
10 alkynyl groups (propargyl group, etc.), C2-C
C6 to C1 which may have 10 acyl groups (acetyl group, propionyl group, benzoyl group, etc.) or a substituent.
0 aryl group (phenyl group, toluyl group, etc.), C7
To C16 aralkyl groups (benzyl group, p-methoxybenzyl group, etc.), C1 to C10 aminocarbonyl groups (N-
Methylaminocarbonyl group, etc.), C2-C8 alkoxycarbonyl group (methoxycarbonyl group, etoxycarbonyl group, etc.), C7-C10 aryloxycarbonyl group (phenyloxycarbonyl group, etc.), C8-C
17 aralkyloxycarbonyl groups (benzyloxycarbonyl group, etc.), nitrogen substituents (azo group, etc.), C1
To C8 sulphenyl group, C1 to C8 sulphonyl group and the like. As the hydantoin compound, hydantoin, 3-methylhydantoin, 1-benzylhydantoin, 1-acetylhydantoin, 1-1-benzyl-3-methylhydantoin and the like are preferably used, but the hydantoin compound applicable to the present invention is the hydantoin compound described above. It is not limited to compounds.

The solvent used in this production method may be any solvent as long as the hydantoin compound as the raw material, the halogenating agent, the nucleophile added later, and the electrophilic agent can be dissolved even in traces. In this reaction, the effect of the solvent is remarkable, and acetic acid and dioxane are preferably used. The solvent used in this reaction may be a single solvent or a mixed solvent, and is appropriately selected from the reagents used in the reaction, the reaction temperature, and the ease of isolation of the product. Further, the solvent used in the halogenation reaction of the hydantoin compound in the first stage of the reaction and the reaction with the nucleophile and the electrophilic agent in the second stage may be the same, may be different, or may be a mixed solvent. Alternatively, the solvent may be distilled off and replaced with another solvent. As the reaction solvent, the following solvent systems containing substantially no water are preferably used, but the present invention is not limited to these solvents. Ether system: Dioxane, tetrahydrofuran, dimethoxyethane, diglyme, triglyme etc. Alcohol system: ethanol, methanol, isopropanol, butanol, etc. Carboxylic acid system: Acetic acid, propionic acid, etc. Nitrile system: Acetonitrile, propionitrile, butyronitrile, adiponitrile, etc. Halogen system : Chloroform, dichloroethane, etc. Aprotic polar solvent: Dimethylformamide, dimethylsulfoxide, etc.

In the reaction between the hydantoin compound and the halogenating agent, the reaction is effectively promoted by the presence of acid. The following acids are preferably used as the acid, but the present invention is not limited to these acids. Inorganic acid: hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid Organic acid: acetic acid, propionic acid, oxalic acid, succinic acid, adipic acid, trifluoroacetic acid, paratoluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid , Trifluoromethanesulfonic acid Lewis acid: titanium tetrachloride, zirconium tetrachloride, vanadium oxychloride, iron trichloride, iron tribromide, aluminum chloride,
Aluminum bromide, boron trifluoride, ether complex, boron trichloride, boron tribromide, tellurium tetrachloride, antimony trichloride, antimony pentachloride, silicon tetrachloride, bismuth trichloride, bismuth tribromide, zinc chloride, odor Zinc oxide, zinc trifluoromethanesulfonate, stannous chloride, stannic chloride,
Tin primary trifluoromethanesulfonate Solid acids: silica gel, acidic alumina, acidic clay, zeolite In this reaction, hydrogen halide derived from halogen is liberated as the reaction progresses and accelerates the reaction. But it's okay. When an organic acid or an inorganic acid is used, it is 1/1000 to 1/5 with respect to the hydantoin compound charged.
00 mol equivalent is preferably used, and when a Lewis acid or a solid acid is used, 1/500 to 1/100 mol equivalent is preferably used, but it is not limited to this range and can be used.

In the reaction between the hydantoin compound and the halogenating agent, the reaction is effectively promoted by the presence of the radical reaction initiator. The following radical reaction initiators are preferably used as the radical reaction initiator, but the present invention is not limited to these radical reaction initiators. Dialkyl peroxides: di-t-butyl peroxide Diacyl peroxides: dibenzoyl peroxide Peresters: di-t-butyl peroxalate Azo compounds: azobisisobutyrylonitrile, phenylazotriphenylmethane This reaction is a reaction As the halogen halide derived from halogen is liberated and the reaction is promoted as it progresses, a very small amount of radical reaction initiator may be added initially. The radical reaction initiator is 1/1000 to 1/5 with respect to the charged hydantoin.
00 mol equivalents are preferably used.

The structures of the hydantoin compound and the compound formed by the halogenating agent are very unstable, so that isolation and production are difficult, but the structure is presumed to be a 5-halohydantoin compound from the following experimental facts. For example, a compound obtained by the reaction of 1 mol of hydantoin and 1 mol of bromine in a dioxane solvent is reacted with 1) water to give 5-hydroxyhydantoin, 2) urea to react with allantoin, and 3) to react with phenol. Then, all of 5- (p-hydroxyphenyl) hydantoin can be obtained in high yield. Although different from the reaction substrate of this reaction, 5-phenylhydantoin is known to undergo a bromination reaction with bromine in an acetic acid solvent to introduce bromine at the 5-position of the hydantoin ring (Chem. Rev., p403 (1949)). From these facts, the experimental facts can be well explained by assuming that 5-bromohydantoin (generally, 5-halohydantoin compound) is produced by the reaction of hydantoin and bromine.

[0018]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Hydantoin (4.0 g), dioxane (10 ml) and bromine (2.0 ml) were mixed at room temperature and stirred vigorously at 120 ° C. for 15 minutes. After cooling to 0 ° C., butyl vinyl ether 6.
0 g was added and reacted at 0 ° C. for 12 hours. The precipitate formed was collected by filtration and washed with 20 ml of dry acetone × 3,
After washing with water and drying under reduced pressure, 5.8 g of 5- (β-butoxyvinyl) hydantoin was obtained with a yield of 72%.

Example 2 Synthesis of DL-homoserine 4.0 g of 5- (β-butoxyvinyl) hydantoin obtained in the same manner as in Example 1 was added to 0.1N aqueous hydrochloric acid solution 50
The reaction was carried out in 0 ml at 0 ° C. for 1 hour. After the temperature was raised to room temperature, 4 g of sodium borohydride was added and reacted at 40 ° C. for 4 hours. After cooling to room temperature, 1N hydrochloric acid was added under ice cooling until hydrogen was not generated. The mixture was heated under reflux in 50 ml of 20% (w / w) aqueous sodium hydroxide solution for 24 hours. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with concentrated hydrochloric acid. The reaction solution was evaporated under reduced pressure. The crude product was recrystallized from water-ethanol (9: 1) to obtain 2.8 g of DL-homoserine in a yield of 58%.

Example 3 Hydantoin 4.0 g, acetic acid 30 ml, and bromine 2.
0 ml was mixed at room temperature and stirred vigorously at 60 ° C. for 2 hours. After cooling to room temperature, add 8 g of dimethyl malonate and add 14
The reaction was carried out at 0 ° C for 10 hours. The formed precipitate was collected by filtration, washed with water and dried to obtain hydantoin-5-dimethyl malonate 4.
4 g was obtained with a yield of 47%.

Example 4 Synthesis of DL-aspartic acid 9.6 g of dimethyl hydantoin-5-malonate obtained in the same manner as in Example 3 was reacted in a 2N aqueous sodium hydroxide solution at 100 ° C. for 24 hours. After cooling to room temperature, the pH is adjusted to 9 with concentrated hydrochloric acid, and the mixture is reacted at 50 ° C. for 2 hours. The reaction solution was evaporated under reduced pressure. The crude product is water-ethanol (1: 9)
Recrystallized from DL-aspartic acid 3.8 g yield 7
Obtained at 2%.

Example 5 4.0 g of hydantoin was dissolved in 40 ml of acetic acid at 100 ° C., and chlorine was introduced through a gas introduction tube for 8 hours. After cooling to room temperature, 8 g of dimethyl malonate was added and reacted at 140 ° C. for 10 hours. The precipitate formed was collected by filtration, washed with water and dried to give 3.6 g of dimethyl hydantoin-5-malonate in a yield of 38.
Earned in%.

Example 6 Hydantoin (4.0 g), dioxane (50 ml), sulfuryl chloride (5.4 g) and azobisisobutyronitrile (0.01 g) were mixed and stirred at 90 ° C. for 5 hours. After cooling to room temperature, 7.2 g of trimethyl orthoacetate was added to obtain 8
The reaction was carried out at 0 ° C for 5 hours. The formed precipitate was collected by filtration and recrystallized from water to obtain 0.33 g of 5- (β-carboxyethyl) hydantoin in a yield of 5.3%.

Example 7 Hydantoin (4.0 g), dioxane (50 ml), zinc bromide (0.1 g) and bromine (2.0 ml) were mixed at room temperature, and the mixture was heated to 60 ° C.
Vigorously stirred for 30 minutes. After cooling to room temperature, 9.1 g of allyltrimethylsilane was added and the reaction was carried out at 80 ° C. for 4 hours. The formed precipitate was collected by filtration, washed with water and dried to obtain 3.4 g of 5-allyl-hydantoin in a yield of 61%.

Example 8 Synthesis of DL-norvaline 5.6 g of 5-allyl-hydantoin obtained in the same manner as in Example 7 was heated under reflux in 50 ml of 20% (w / w) sodium hydroxide aqueous solution for 24 hours. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with concentrated hydrochloric acid. The product was separated by filtration and washed with 10 ml of water and 10 ml of acetone × 3. The obtained crude product was dissolved in 30 ml of acetic acid in a medium-pressure reducing apparatus, put, and 0.5 g of 5% Pd-C was added.
The reaction was carried out at 60 ° C. with vigorous shaking. Pd-C
Is filtered, the solvent is distilled off under reduced pressure, and DL-norvaline 3.9 is added.
g was obtained with a yield of 83%.

Example 9 A magnetic stirrer was placed in a 100 ml autoclave, 4.56 g of 3-methyl-hydantoin, 30 ml of acetic acid and 2.0 ml of bromine were mixed at room temperature, and the mixture was vigorously stirred at 80 ° C. for 2 hours. After cooling to 0 ° C, 6.5 g of butadiene was added to 1
The reaction was carried out at 80 ° C for 8 hours. The precipitate formed was collected by filtration, washed with water and dried to obtain 2 g of the hydantoin compound (VI) in a yield of 31.
Earned in%.

Example 10 Synthesis of DL-pipecolic acid A hydantoin compound (V obtained in the same manner as in Example 9)
I) 3.2 g was dissolved in 30 ml of acetic acid in a medium-pressure reducing apparatus, added with 0.5 g of 5% Pd-C, introduced with 3 atm of hydrogen, and reacted at 60 ° C. with vigorous shaking. Pd
-C was filtered and the solvent was distilled off under reduced pressure. The resulting crude product was mixed with 20 ml (w / w) aqueous sodium hydroxide solution (50 ml).
Heated at reflux for 24 hours. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with concentrated hydrochloric acid. The product was filtered off and washed with cold methanol 10 ml × 3. The crystals were recrystallized from water to obtain 1.7 g of DL-pipecolic acid in a yield of 66%.

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, a hydantoin compound having an unsubstituted 5-position is reacted with a halogenating agent and then reacted with a nucleophile or an electrophilic agent excluding a phenol compound, whereby the purity can be easily increased. Highly substituted 5-substituted hydantoins can be obtained. That is, the present invention provides a method for producing important synthetic intermediate raw materials such as natural and unnatural amino acids, which are useful for medicines, agricultural chemicals, chelating agents and the like.

Claims (7)

[Claims] 1. A 5-substituted hydantoin compound characterized by reacting an unsubstituted hydantoin compound at the 5-position with a halogenating agent and then reacting it with an electrophilic agent or a nucleophile other than a phenol compound. Production method. 2. A method for producing a 5-substituted hydantoin compound, which comprises reacting an unsubstituted hydantoin compound at the 5-position with a halogenating agent and then reacting it with an electrophilic agent. 3. A method for producing a 5-substituted hydantoin compound, which comprises reacting a hydantoin compound having an unsubstituted 5-position with a halogenating agent, and then reacting it with a nucleophile other than a phenol compound. 4. A hydantoin compound in which the 5-position is unsubstituted,
The following general formula (I): (In the formula, R ₁ represents a hydrogen atom or a nitrogen atom-protecting group, R ₂ represents a hydrogen atom, a C1 to C8 alkyl group, or a C3 to
A C10 alkenyl group, a C3-C10 alkynyl group,
C2-C10 acyl group, aryl group which may have a substituent, aralkyl group which may have a substituent on the benzene ring, aminocarbonyl group which may substitute a hydrogen atom of an amino group, C2-C8 alkoxy Carbonyl group, C7
To C10 aryloxycarbonyl groups, C8 to C17
The aralkyloxycarbonyl group, the C1-C8 sulfenyl group, and the C1-C8 sulfonyl group are shown. The production method according to claim 1, which is a compound represented by the formula (1). 5. The production method according to claim 1, wherein the reaction is carried out in the presence of an acid. 6. The production method according to claim 1, wherein the reaction is carried out in the presence of a radical initiator. 7. The method according to claim 1, wherein the reaction is carried out in a solvent containing substantially no water.