JP3413386B2 - Method for producing allyl phosphonate compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing allylphosphonates. Specifically, the present invention relates to a method for producing an allylphosphonic acid ester by reacting a secondary cyclic phosphonic acid ester with a conjugated diene compound in the presence of a palladium catalyst.

It is known that the basic skeleton of allylphosphonates is naturally found, and that the allylphosphonates themselves show physiological activity by acting with enzymes and the like. Further, using the same compound as a starting material, for example, by an addition reaction to a carbonyl compound, Horner-Emmons can be efficiently used.
Since the reaction is achieved, it is widely used as a synthetic method for polyenes that are abundant in natural products. Therefore, allylphosphonates are a group of compounds that are useful as agents for forming carbon-carbon bonds and are particularly useful as synthetic intermediates for physiologically active substances such as pharmaceuticals and agricultural chemicals.

[0003]

2. Description of the Related Art As a method for synthesizing an allylphosphonate with formation of a carbon-phosphorus bond, generally,
It is known to replace the corresponding allyl halides with trialkyl phosphites. However, this method has a drawback that not only another type of halide compound is generated by the reaction but also a newly formed halide compound reacts with a trialkylphosphite, so that a large amount of a by-product is generated. Therefore, the conventional method cannot be said to be industrially advantageous.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned circumstances, and there is almost no side reaction or by-product, and the desired yield of allylphosphonates is high in a simple operation. An object of the present invention is to provide an industrially advantageous method for producing allylphosphonic acid esters obtained in 1.

[0005]

In order to avoid the above-mentioned problems of the conventional method, the present invention has conducted various studies as a result of earnest research on the reaction of readily available secondary cyclic phosphonates with dienes. It was found that allylphosphonates can be obtained in a high yield and a high selectivity by advancing the addition reaction in the presence of the palladium catalyst, and based on these facts, the present invention has been completed.

That is, the present invention provides a compound of the general formula (I) R ¹ R ² C = CR ³ -CR ⁴ = CR ⁵ R ⁶ (I) in the presence of a palladium catalyst, wherein R ^{1 to} R ⁶ are each And each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, and R ¹ and R ⁶ may be combined to form an alkylene group or a cycloalkylene group.). the diene compound represented by the general formula (II) HP (O) X (II) ( wherein X is ^{-OC (R 7 R 8) -C} (R 9 R 10) O-
And R ^{7 to} R ¹⁰ are each independently a hydrogen atom, an alkyl group, a cycloalkyl group,
Alternatively, it represents an aryl group. A secondary cyclic phosphonate represented by the formula (III) R ¹ R ² CH—CR ³ ═CR ⁴ —CR ⁵ R ⁶ [P (O) X] (III) ) (In formula, R < ¹ > -R < ⁶ >, R < ⁷ > -R < ¹⁰ > and X are the same as the above.) It is invention of the manufacturing method of the allyl phosphonic acid ester. Further, the present invention has the general formula ^{(III) R 1 R 2 CH} -CR 3 = CR 4 -CR 5 R 6 [P (O) X] (III) ( ^{wherein, R 1 ~R 6, R 7} ~ R ¹⁰ and X are the same as defined above, but allylphosphonic acid esters (provided that
R ⁴ is a hydrogen atom).

In the diene compound represented by the general formula (I) used in the present invention, the alkyl group represented by R ^{1 to} R ⁶ has 1 to 18 carbon atoms, preferably 1 to 1 carbon atoms.
Examples of the alkyl group include 0, and these may be linear or branched, and specific examples thereof include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group,
Hexyl group, heptyl group, octyl group, nonyl group, decyl group and the like are exemplified. Examples of the cycloalkyl group include cycloalkyl groups having 5 to 18 carbon atoms, preferably 5 to 12 carbon atoms, and specific examples thereof include cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group. , Cyclododecyl group and the like. The aryl group has 6 to 14 carbon atoms,
Preferable examples thereof include 6 to 12 aryl groups, and specific examples thereof include a phenyl group, a tolyl group, a xylyl group, a naphthyl group, a methylnaphthyl group, a benzylphenyl group, a biphenyl group and the like. Examples of the aralkyl group include an aralkyl group having a carbon number of 7 to 13, preferably 7 to 11, and specific examples thereof include, for example, a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a phenylbenzyl group, and a naphthyl group. A methyl group and the like are exemplified. The alkyl group, cycloalkyl group, aryl group and aralkyl group represented by R ^{1 to} R ⁶ are further functional groups inert to the reaction, for example, alkyl groups such as methyl group and ethyl group, for example, methoxy group and ethoxy group. Substituted with an alkoxy group such as, for example, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a cyano group, for example, an N, N-disubstituted amino group such as a dimethylamino group, a diethylamino group, a fluoro group, etc. Good. Examples of the diene compound preferably used in the present invention include 1,3-butadiene, isoprene, 1,3-pentadiene, and 2,3-dimethyl-1,3.
-Butadiene and the like are included, but the present invention is not limited thereto.

In the general formula (I), when R ¹ and R ⁶ are combined to form an alkylene group or a cycloalkylene group, the alkylene group has 1 to 2 carbon atoms.
0, preferably 1-10 alkylene groups are mentioned, and specific examples thereof include, for example, a methylene group, an ethylene group,
Examples thereof include a trimethylene group and a tetramethylene group. The cycloalkylene group includes a cycloalkylene group having 5 to 18 carbon atoms, preferably 5 to 10 carbon atoms, and specific examples thereof include, for example, a cyclopentylene group, a cyclohexylene group, a cycloheptylene group, and a cyclooctylene group. Group, cyclononylene group, cyclodecylene group and the like. In the general formula (I), when R ¹ and R ⁶ are combined to form an alkylene group or a cycloalkylene group, the diene compound becomes a cyclic diene compound, which is preferably used in the present invention. Specific examples of the diene compound include 1,3-cyclopentadiene,
Examples thereof include 1,3-cyclohexadiene, but are not limited thereto.

The above general formula (I
Secondary cyclic phosphonate ester, ^-OC represented by ^{X (R 7 R 8) -C} (R 9 R 10) O- comprising divalent ^R 7 ^{to R 10} alkyl groups represented in the group represented by I) Include an alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, which may be linear or molecular, and specific examples thereof include a methyl group, an ethyl group and a propyl group. , Butyl group, pentyl group, hexyl group and the like. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 12 carbon atoms, preferably 5 to 8 carbon atoms, and specific examples thereof include cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. To be done. Aryl group has 6 carbon atoms
~ 14, preferably 6 to 12 aryl groups,
Specific examples thereof include, for example, a phenyl group, a tolyl group,
Examples thereof include a xylyl group, a naphthyl group, a methylnaphthyl group, a benzylphenyl group and a biphenyl group.

In order to efficiently cause the reaction of the present invention,
The use of a palladium catalyst is mandatory and in the absence of catalyst the reaction either does not proceed or is very slow. As the catalyst, those having various structures can be used, but a suitable one is a so-called low-valent one, and a zero-valent complex having a tertiary phosphine or a tertiary phosphite as a ligand is particularly preferable. It is also a preferred embodiment to use an appropriate precursor complex that can be easily converted into a low valence complex in the reaction system. Furthermore, a complex not containing a tertiary phosphine or a tertiary phosphite as a ligand is used in combination with a tertiary phosphine or a tertiary phosphite, and the tertiary phosphine or the tertiary phosphite is used as a ligand in the reaction system. A method of forming a low valence complex is also a preferred embodiment. Although various tertiary phosphines and tertiary phosphites are mentioned as ligands that exhibit advantageous performance in any of these methods, those having an extremely strong electron donating property are not necessarily advantageous in terms of reaction rate. is not. Examples of ligands that can be preferably used include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,4
-Bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino) propane, 1,2-bis (diphenylphosphino) ethane, 1,1'-bis (diphenylphosphino) ferrocene, trimethylphosphite, Examples include triphenyl phosphite. Examples of the complex that does not contain a tertiary phosphine or a tertiary phosphite as a coordination used in combination therewith include a bis (dibenzylideneacetone) palladium complex and a palladium acetate complex, but are not limited thereto. Absent. Examples of the phosphine complex or phosphite complex that is preferably used include dimethylbis (triphenylphosphine) palladium complex, dimethylbis (diphenylmethylphosphine) palladium complex, tetrakis (triphenylphosphine) palladium complex, and the like. The palladium complex catalyst according to (1) is used by appropriately selecting one or more suitable ones depending on the reaction.

The amount of these complex catalysts used may be a so-called catalytic amount, and generally 20 mol% or less based on the diene compound is sufficient. Generally, the molar ratio of the diene compound to the secondary cyclic phosphonic acid ester is preferably 1: 1. However, if the molar ratio is larger or smaller than this, the occurrence of the reaction is not hindered. The reaction does not need to use a solvent, but can be carried out in a solvent if necessary.
Examples of the solvent include hydrocarbon solvents such as benzene, toluene, xylene, n-hexane and cyclohexane, and ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, 1,4-dioxane and tetrahydrofuran. Commonly used. If the reaction temperature is too low, the reaction does not proceed at an advantageous rate, and if the temperature is too high, the catalyst decomposes. Therefore, the reaction temperature is generally selected from the range of room temperature to 300 ° C, preferably in the range of 50 to 150 ° C. Be implemented. The intermediate of this reaction is sensitive to oxygen, and it is preferable to carry out the reaction in an atmosphere of an inert gas such as nitrogen, argon or methane. Isolation and purification of the product from the reaction mixture can be easily achieved by known isolation and purification methods commonly used in this field such as chromatography, distillation or recrystallization.

[0012]

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 To 3 ml of 1,4-dioxane, HP (O)
(OCMe_TwoCMe_TwoO) 2 mmol, 2,3-dimethyl
Ru-1,3-butadiene 2 mmol, Pd as catalyst
Me_Two[Ph_TwoP (CH_Two)_FourPPh_Two] (5 mol%)
And react at 100 ° C. for 12 hours in a nitrogen atmosphere.
It was The reaction mixture is concentrated and then purified by liquid chromatography.
When separated and purified, 2- (2,3-dimethyl-2-butenyl
) -4,4,5,5-Tetramethyl-1,3,2-di
Oxaphosphorane 2-oxide [Me _TwoC = CMeCH
_TwoP (O) {OCMe_TwoCMe_TwoO}] is 100%
Obtained at a rate. This compound is a new substance not listed in the literature.
The spectrum data is as follows.¹ H NMR (500 MHz, CDCl_Three) δ 2.64 (d, 2H, J_HP = 2
1.7 Hz), 1.56-1.67 (m, 12H), 1.37 (s, 6H), 1.21 (s,
 6H).^Thirteen C NMR (125.4 MHz, CDCl_Three) δ 129, 117.8, 87.6,
 33.5 (J_CP = 128.0Hz), 24.8, 23.9, 21.0, 20.7, 2
0.0.³¹ P NMR (201.9 MHz, CDCl_Three) δ 40.4. IR (liquid film) 2988, 2922, 1450, 1398, 1379, 1265, 113
9, 963, 932, 872 cm^{− 1}. C₁₂H₂₃O_ThreeHRMS as P, calculated: 246.1385, found
Value: 246.1398.

Example 2 Instead of 2,3-dimethyl-1,3-butadiene,
Using 1,3-butadiene, PdMe ₂ (bina
p) (binap = 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl) catalyst in the presence of Example 1
The compounds shown in Table 1 were reacted in the same manner as
(Trans form / cis form = 83/17). This compound is a novel substance not listed in the literature, and its spectral data are as follows. Trans-compound ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.57-5.62 (m, 1H),
5.39-5.45 (m, 1H), 2.62 (dd, 2H, J = 7.3, J _HP =
21.3 Hz), 1.64-1.68 (m, 3H), 1.45 (s, 6H), 1.30
(s, 6H). ¹³ C NMR (125.4 MHz, CDCl ₃ ) δ 130.9 (J _CP = 1
_{4.51 Hz), 119.5 (J C} P = 12.4 Hz), 88.0, 32.0 (J
_CP = 131.4 Hz), 24.7, 24.4, 18.0. ³¹ P NMR (201.9 MHz, CDCl ₃ ) δ 39.5. Cis compound ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.65-5.72 (m, 1H),
5.40-5.50 (m, 1H), 2.70 (dd, 2H, J = 7.9, J _HP =
21.9 Hz), 1.61-1.64 (m, 3H), 1.45 (s, 6H), 1.32
(s, 6H). ¹³ C NMR (125.4 MHz, CDCl ₃ ) δ 129.0 (J _CP = 1
4.5 Hz), 118.5 (J _CP = 11.4 Hz), 88.0, 27.0 (J _CP
= 132.4 Hz), 24.7, 23.8, 12.9. ³¹ P NMR (201.9 MHz, CDCl ₃ ) δ 39.6.

Example 3 Isoprene was used in place of 2,3-dimethyl-1,3-butadiene and reacted in the same manner as in Example 1 to give compounds shown in Table 1 in a total yield of 100% (product ratio). = 83/17)
Obtained in. This compound is a novel substance not listed in the literature, and its spectral data are as follows. ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.18-5.23 (m, 1H),
2.68 (dd, 2H, J = 7.6Hz, J _HP = 21.3 Hz), 1.74
(d, 3H, J _HP = 5.8 Hz), 1.65 (d, 3H, J _HP = 4.0 H
z), 1.48 (s, 6H), 1.34 (s, 6H). ¹³ C NMR (125.4 MHz, CDCl ₃ ) δ 137.0, 112.6, 87.
8, 28.0 (J _CP = 131.2 Hz), 25.7, 24.2, 18.0. ³¹ P NMR (201.9 MHz, CDCl ₃ ) δ 40.3.

Example 4 Instead of 2,3-dimethyl-1,3-butadiene, trans-1,3-pentadiene was used, and PdMe was used.
₂ (dppf) (dppf = 1,1′-bis (diphenylphosphino) ferrocene) In the presence of a catalyst, the reaction was carried out in the same manner as in Example 1, and the compounds shown in Table 1 were produced in a total yield of 93% (trans form / cis form). = 92/8). This compound is a novel substance not listed in the literature, and the spectral data of its trans form is as follows. ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.25−5.36 (m, 1H),
5.08−5.12 (m, 1H), 2.33 (dd, 2H, J = 7.4 Hz, J
_HP = 21.1 Hz), 1.70-1.78 (m, 2H), 1.17 (s, 6H),
1.03 (s, 6H), 0.66 (t, 3H, J = 7.6 Hz). ¹³ C NMR (125.4 MHz, CDCl ₃ ) δ 137.7, 117.5, 88.
0, 32.0 (J _CP = 132.3 Hz), 25.6, 24.9, 24.2, 13.
3. ³¹ P NMR (201.9 MHz, CDCl ₃ ) δ 39.0. IR (thin film) 2988, 1462, 1398, 1379, 1267, 1139, 101
1, 963, 932, 874 cm ^{- 1} .

Example 5 Instead of 2,3-dimethyl-1,3-butadiene, cyclo-1,3-hexadiene was used, and PdMe ₂ [P
h ₂ P (CH ₂ ) ₄ PPh ₂ ] catalyst was allowed to react in the same manner as in Example 1 to obtain the compounds shown in Table 1 in a yield of 100%. This compound is a new substance not listed in the literature,
The spectral data and elemental analysis values are as follows. ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.83−5.90 (m, 1H),
5.63−5.72 (m, 1H), 2.59−2.64 (m, 1H), 1.94−2.00
(m, 6H), 1.48 (s, 3H), 1.46 (s, 3H), 1.32 (s, 6
H). ¹³ C NMR (125.4 MHz, CDCl ₃ ) δ 131.3, 121.1, 87.
8, 36.5 (J _CP = 132.2 Hz), 25.1, 24.9, 24.5, 24.
4, 22.8, 20.5. ³¹ P NMR (201.9 MHz, CDCl ₃ ) δ 42.6. IR (KBr) 2989, 2869, 1454, 1392, 1376, 1263, 1145,
1132, 958, 923, 867 cm ^-1 . HRMS as C ₁₂ H ₂₁ O ₃ P, calculated: 244.1228, Found: 244.1252. Elemental analysis, calculated C, 59.00; H, 8.67. Found: C, 59.1
2; H, 8.00.

The structural formulas and yields of the products obtained in Examples 1 to 5 above are shown together with the structural formulas of the respective starting materials in Table 1 below.

[0019]

[Table 1]

[0020]

According to the method of the present invention, novel allylphosphonates useful for the synthesis of medicines, agricultural chemicals, etc.
It can be synthesized easily, safely and efficiently, and its isolation and purification are easy. Therefore, the present invention brings great effects industrially.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Han Tachibyo 1-1 East East Tsukuba City, Ibaraki Prefecture Institute of Industrial Science and Technology Institute of Industrial Science and Technology (72) Inventor Farzad Mirzai 2-37 4-502 Kasuga, Tsukuba, Ibaraki Prefecture (72) Masato Tanaka, Masato Tanaka 1-1, Higashi 1-1, Tsukuba City, Ibaraki Institute of Industrial Science and Technology (56) References JP 2001-247586 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07F 9/6574 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. In the presence of a palladium catalyst, R ¹ R ² C═CR ³ —CR ⁴ ═CR ⁵ R ⁶ (I) (wherein R ^{1 to} R ⁶ are independently hydrogen) in the presence of a palladium catalyst. A diene represented by an atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, and R ¹ and R ⁶ may combine with each other to form an alkylene group or a cycloalkylene group. the compounds of general formula (II) HP (O) X (II) ( wherein X is ^{-OC (R 7 R 8) -C} (R 9 R 10) O-
And R ^{7 to} R ¹⁰ are each independently a hydrogen atom, an alkyl group, a cycloalkyl group,
Alternatively, it represents an aryl group. A secondary cyclic phosphonate represented by the formula (III) R ¹ R ² CH—CR ³ ═CR ⁴ —CR ⁵ R ⁶ [P (O) X] (III) ) (In formula, R < ¹ > -R < ⁶ >, R < ⁷ > -R < ¹⁰ > and X are the same as the above.) The manufacturing method of the allyl phosphonic acid ester represented by these. 2. The production method according to claim 1, wherein the palladium catalyst is a low valence complex catalyst. 3. The production method according to claim 1, wherein the palladium catalyst is a zero-valent complex having a tertiary phosphine or a tertiary phosphite as a ligand. 4. The production method according to claim 1, wherein the palladium catalyst is a precursor complex which can be easily converted into a low-valence complex in the reaction system. 5. A palladium catalyst is formed in a reaction system by using a palladium complex containing no tertiary phosphine or tertiary phosphite as a ligand in combination with a tertiary phosphine and / or a tertiary phosphite. The production method according to claim 1, which is a low-valence complex having a tertiary phosphine or / and a tertiary phosphite as a ligand. 6. General formula (III) R ¹ R ² CH—CR ³ ═CR ⁴ —CR ⁵ R ⁶ [P (O) X] (III) (wherein R ^{1 to} R ⁶ and R ^{7 to} R) ¹⁰ and X are the same as those described above.
Except when R ⁴ is a hydrogen atom).