WO2024180230A1 - 5-methyl-1,3-dihydroisobenzofuran-4-ol prepared from 5-methylfurfuryl alcohol and propargyl alcohol - Google Patents

Abstract

The present invention relates to the formation of 5-methyl-1,3- dihydroisobenzofuran-4-ol. It can be produced in a one-pot procedure from 5- methylfurfuryl alcohol and propargyl alcohol in the presence of ether or aromatic hydrocarbon and a platinum catalyst.

Description

5-METHYL-1,3-DIHYDROISOBENZOFURAN-4-OL PREPARED FROM 5- METHYLFURFURYL ALCOHOL AND PROPARGYL ALCOHOL

Technical Field

The present invention relates to the manufacturing of 5-methyl-1 ,3- dihydroisobenzofuran-4-ol.

Background of the invention

5-Methyl-1 ,3-dihydroisobenzofuran-4-ol is a compound of great interest for the synthesis of a-tocopherols.

Hashmi et al., J. Am. Chem. Soc. 2000, 122, 11553-11554 discloses that it can be obtained from the ether of 5-methylfurfuryl alcohol and propargyl alcohol in the presence of a homogeneous gold catalyst in acetonitrile.

In the field of industrial homogeneous catalysis, however, gold catalysts are less frequently used than platinum catalysts. On the other hand, platinum catalysts are regularly used on industrial large scale, particularly in hydrogenation and oxidation reactions. Hence, the availability of suitable gold catalysts is significantly limited in volume and, hence, the use of cost of gold catalysts is significantly higher than for platinum catalysts.

Summary of the invention

Therefore, the problem to be solved by the present invention is to offer a process for manufacturing 5-methyl-1 ,3-dihydroisobenzofuran-4-ol from (5-methyl- furan-2-yl)methanol in an efficient way without the use of expensive gold catalysts.

Surprisingly, it has been found that this problem can be solved by a process according to claim 1 .

It has been found that 5-methyl-1 ,3-dihydroisobenzofuran-4-ol can be obtained in a one-pot procedure, especially a domino reaction procedure, from 5- methylfurfuryl alcohol and propargyl alcohol. As both starting materials are available from renewable sources, this process offers a very sustainable method for 5-methyl-1 ,3-dihydroisobenzofuran-4-ol. Additional to these benefits, in this synthetic pathway significantly lower amounts of, preferably no, dimers or any other side products of (5-methylfuran-2-yl)methanol, such as bis(5-methylfuran-2- yl)methane, have been observed.

Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.

Detailed description of the invention

In a first aspect, the present invention relates to a process for manufacturing in a one-pot procedure the compound of the formula (I)

comprising the step of reacting 5-methylfurfuryl alcohol of the formula (II) with

in the presence of a) a solid catalyst which is a polymer carrying sulfonic acid groups; b) an organic solvent which is either an aromatic hydrocarbon or an ether; and with c) at least one Pt catalyst, which is either in the form of

-supported Pt (0); or

-a Pt (II) salt; or

-a Pt (II) complex. For sake of clarity, some terms used in the present document are defined as follows:

In the present document, any dotted line in formulae represents the bond by which a substituent is bound to the rest of a molecule.

A “one-pot procedure” in this document is a reaction procedure in which an intermediate formed is not needed to be separated but either reacts with an ingredient which is either already present in the reaction mixture or is added after formation of the intermediate to said reaction mixture.

A “supported Pt (0)” in this document is a platinum (0) which is supported on a suitable carrier material.

5-Methylfuran-2-yl-methanol (= 5-methylfurfuryl alcohol, formula (II)) is reacted with propargyl alcohol (=prop-2-yn-1-ol, formula (III)).

Both substances can be produced from renewable raw materials.

The reaction of 5-methylfurfuryl alcohol (II) and propargyl alcohol (III) is performed in the presence of a solid catalyst which is a polymer carrying sulfonic acid groups (a):

C> ,0

V

''' ^OH .

An advantage of a solid catalyst is its easy separation from the reaction mixture, for example by filtration and re-use of the solid catalyst.

The solid catalyst is a solid polymer. Preferably, the solid catalyst carrying sulfonic groups is a polymer comprising sulfonic acid groups.

In a preferred embodiment, the solid catalyst carrying sulphonic acid groups is polymer-bound p-toluene sulfonic acid. Such catalysts are commercially broadly available. Preferably, they are macroporous and in the form of beads, particularly of a size of between 10-100 mesh, particularly of 25-65 mesh. The loading of p-toluene sulfonic acid is preferably 0.5-100 mmol/g polymer, preferably 1-10 mmol/g polymer. ln another preferred embodiment, the solid catalyst carrying sulfonic acid groups is a microporous copolymer, preferably a copolymer of styrene and divinyl benzene, carrying sulfonic acid groups. Such microporous copolymers carrying sulfonic acid groups are well known in the market. Particularly suitable solid catalysts are the products as commercialized as AMBERLYST™ 15, AMBERLYST™ 16 or AMBERLYST™ 31 , particularly, AMBERLYST™ 15.

The reaction of 5-methylfurfuryl alcohol of the formula (II) with propargyl alcohol of the formula (III) is performed in the presence of an organic solvent which is either an aromatic hydrocarbon or an ether (b).

Preferred aromatic hydrocarbons are aromatic hydrocarbons having a boiling point of less than 160°C, preferably less than 150°C, more preferably less than 140°C, at ambient pressure. The aromatic hydrocarbon is particularly selected from the group consisting of benzene, toluene, ethylbenzene, n-propyl benzene, isopropyl benzene, o-xylene, m-xylene, p-xylene and mesitylene as well as mixtures thereof. The most preferred aromatic hydrocarbon is toluene.

Preferred ethers are acyclic and cyclic ethers, particularly with a boiling point of less than 90°C and/or a molar mass of less than less than 90 g/mol.

Particularly preferred is the ether either are te/Y-butyl methyl ether (MTBE) or 2-methyl tetrahydrofuran (2-Me-THF).

It is preferred that the organic solvent is a solvent with is obtained from renewable resources. Therefore, particularly preferred as organic solvent is 2- methyl tetrahydrofuran.

It is preferred that the organic solvent is selected from the group consisting of toluene, 2-methyl tetrahydrofuran and te/Y-butyl methyl ether. The solvent is preferably toluene. It is preferred that the concentration of 5-methylfurfuryl alcohol of the formula (II) in the organic solvent is in the range of 10 - 500 mM, preferably 20 - 400 mM, more preferably 40 - 200 mM.

It is, furthermore, advantageous that the propargyl alcohol of the formula (II) is present in a stoichiometric excess relative to 5-methylfurfuryl alcohol of the formula (II).

It is particularly preferred that the molar ratio of amount of 5-methylfurfuryl alcohol of the formula (II) to propargyl alcohol of the formula (III) is between 1 :2 and 1 :20, preferably between 1 :4 and 1 :10.

It is preferred that the reaction of 5-methylfurfuryl alcohol of the formula (II) with propargyl alcohol of the formula (III) is performed at a temperature between 20°C and 120°C, preferably between 25°C and 100°C, more preferably between 35°C and 65°C.

To enable the reaction of 5-methylfurfuryl alcohol of the formula (II) and propargyl alcohol of the formula (III) (b) to occur, next to the solid catalyst carrying sulfonic acid groups (a), also a Pt catalyst (c) is required for the reaction.

The current process is a one-pot reaction procedure. This allows to have the two subsequent reactions (as shown in figure 1 ) a) reacting 5-methylfurfuryl alcohol of the formula (II) with propargyl alcohol of the formula (III) to form the compound of the formula (II’) in the presence of the said solid catalyst carrying sulfonic acid groups and the said organic solvent;

P) -rearrangement of the compound of the formula (II’) to yield the compound of the formula (I) in the presence of said Pt catalyst in the same reactor without the need of isolating or purifying the intermediate of the formula (II’). The possibility of designing the reaction as a one- pot reaction is surprising as this requires that the ingredients being present after the step a), particularly the solid catalyst carrying sulfonic acid groups, do not have a negative influence on the reaction of the subsequent reaction p). In a particularly preferred embodiment, the reaction is performed in a domino procedure reaction. In this embodiment, all ingredients are mixed at the start of step a). The fact that even this reaction design is possible, is due to the surprising effect that the platinum catalyst does not negatively interfere with the influence of the solid catalyst carrying sulfonic acid groups in the reaction of 5- methylfurfuryl alcohol with the propargyl alcohol.

The platinum catalyst is either in the form of a supported Pt(O) or in the form of a platinum (II) salt or a platinum (II) complex.

If the platinum catalyst is in the form of a supported Pt(O), it is preferred that the Pt catalyst is platinum on carbon (Pt/C). This kind of platinum catalyst is frequently used in hydrogenation and oxidation reactions.

The amount of platinum is preferably in the range of 0.5 - 20 weight-%, more preferably in the range of 1 - 10 weight-%, even more preferably in the range of 2 - 8 weight-%, most preferably in the range of approximately 5 weight-%, based on the total weight of the platinum catalyst.

If the platinum catalyst is in the form of a Pt(ll) salt or a Pt(ll) complex, it is preferred that the platinum catalyst is bis(benzonitrile)dichloroplatinum(ll) or bis(acetonitrile)dichloroplatinum(ll) or PtC , more preferably bis(benzonitrile)di- chloroplatinum(ll) or PtCh

It is important to mention that it has been found that neither platinum (IV) salts or its complexes lead to the formation of the desired product of formula (I).

It is preferred that the Pt catalyst is present in an amount of 0.5 - 10 mol- %, particularly 1 - 2.5 mol-%, in relation to the 5-methylfurfuryl alcohol of the formula (II). The platinum catalyst (c) can be added before, together with or after the solid catalyst carrying sulfonic groups (a). During the acid catalyzed reaction an intermediate of formula (II’) is formed.

Next to this intermediate (furfuryl propargyl ether (FPE)), the reaction of the compound of the formula (II) and of compound of the formula (III) in the presence of an acid catalyst, some undesired side-products of 5-methylfurfuryl alcohol, such as bis(5-methylfuran-2-yl)methane (II”), can be formed(see figure 1 ).

It has been observed, that particularly when using different solvents or different acids as required by the present invention, the formation of such sideproducts is very pronounced. Therefore, it has been observed that the process of the present invention is also advantageous in that the formation of any sideproducts, particularly of bis(5-methylfuran-2-yl)methane (II”), is strongly reduced or even can be avoided.

When adding the platinum catalyst (c) to the reaction mixture comprising the intermediate of the formula (II’) said intermediate is reacted to yield the compound of the formula(l).

In one of the embodiments, the platinum catalyst (c) is added to the mixture of 5-methylfurfuryl alcohol and propargyl alcohol and the organic solvent (b) only after a time of at least 4 hours, particularly 4-8 hours, of stirring at a temperature of between 25°C and 70°C. In a preferred embodiment, the platinum catalyst (c), is added directly with or within 30 minutes after the adding of the solid catalyst carrying sulphonic acid groups (a). In this embodiment, the platinum catalyst can be added together with or without the organic solvent.

In a most preferred embodiment, in a domino-procedure, the platinum catalyst (c) is present in a mixture with compound of the formula (II) and (III) the organic solvent (b) and the solid catalyst (a).

Instead of having two different catalysts (i.e. the solid catalyst carrying sulfonic acid groups (a) and a (separate) platinum catalyst (c)), a bifunctional catalyst (ac) (i.e. a catalyst where the platinum and the sulfonic acid groups are localized on the same solid carrier, particularly in the form of platinum on a sulfonated polymer)), is used. This represents a further embodiment of the present invention

It has been surprisingly found that the two catalysts, i.e. the solid catalyst carrying sulfonic groups (a) and the platinum catalyst (c) do not interact negatively with each other and that no isolation of any intermediates is required. The above reaction is a one-pot reaction, particularly a domino reaction, and is, hence, particularly advantageous, as it leads to the desired end product without any additional steps and/or isolation and/or purification during the reaction from 5- methylfurfuryl alcohol to the desired product, i.e. 5-methyl-1 ,3-dihydroisobenzo- furan-4-ol. The one-pot reaction is highly time and cost efficient. The reaction proceeds with high yield and high selectivity. It has been, furthermore, observed that dimerization products or any other side-products of 5-methylfurfuryl alcohol, such as bis(5-methylfuran-2-yl)methane (Formula (II”)), are formed in significantly lower amounts in the process of the present invention.

In specific cases, it has been observed that such dimers or side-products are not at all formed. The side-product of formula (II”) has been identified by NMR:

¹H-NMR (300 MHz, chloroform-d) 5 ppm: 2.25 (s, 6 H), 3.89 (s, 2 H), 5.87 (d, J=2.83 Hz, 2H), 5.94 (d, J=3.1 Hz, 2 H).

¹³C-NMR (75 MHz, chloroform-d) 5 ppm: 13.56; 27.55; 106.13; 106.94; 150.01 ; 150.95.

In a further aspect, the present invention relates to a composition comprising i) 5-methylfurfuryl alcohol of the formula (II); ii) propargyl alcohol of the formula (III); iii) a solid catalyst which is a polymer carrying sulfonic acid groups; iv) an organic solvent which is either an aromatic hydrocarbon or an ether; and v) at least one Pt catalyst, which is either in the form of a supported Pt(O), or of a Pt (II) salt, or of a Pt (II) complex;

the concentration of 5-methylfurfuryl alcohol of the formula (II) in the organic solvent is in the range of 10 - 500 mM; the molar ratio of amount of 5-methylfurfuryl alcohol of the formula (II) to propargyl alcohol of the formula (III) is between 1 :2 and 1 :20; the amount of the Pt catalyst is present in an amount of 0.5 - 10 mol-%, in relation to the 5-methylfurfuryl alcohol of the formula (II).

As discussed above in detail, said composition is suitable to be used for the synthesis of 5-methyl-1 ,3-dihydroisobenzofuran-4-ol. The amounts, ratio of i), ii), iii), iv) and v) as well as the preferred embodiments have been discussed already above for the process for manufacturing the compound of the formula (I) and are applicable also for said composition. Examples

The present invention is further illustrated by the following experiments.

Reaction of 5-methylfurfuryl alcohol with propargyl alcohol: step a)

In a 100 ml flask, one equivalent 5-methylfurfuryl alcohol (MFA) was mixed with 10 equivalents of propargyl alcohol (PA) and 16 mg of AMBERLYST™ 15 (dry) per mmol of 5-methylfurfuryl alcohol and the respective solvent of table 1 to obtain a concentration of MFA (CMFA) as indicated in table 1 . The reaction mixture was stirred for 6 hours at the temperature (T) given in table 1 and analysed by gas chromatography (GC). The amounts of the desired furfuryl propargyl ether (FPE) (formula (II’)) as well as the undesired side-product bis(5-methylfuran-2- yl)methane (formula (II”)) (SidePro) as measured by GC are given in table 1.

Table 1 . Reaction of MFA with PA in the presence of AMBERLYST™ (dry) as solid catalyst carrying sulfonic acid groups and different solvents.

¹ Concentration given in GC-area %

² MeCN: acetonitrile

³ MTBE: fe/Y-butyl methyl ether 42-Me-THF: 2-methyl tetrahydrofuran In Table 2, results of respective experiments using polymer-bound p-toluene- sulfonic acid (Aldrich, product number: 532312) as solid catalyst carrying sulfonic acid groups are compiled.

Table 2. Reaction of MFA with PA in the presence of polymer- bound p-toluenesulfonic acid as solid catalyst carrying sulfonic acid groups and different solvents.

¹ Concentration given in GC-area %

² MeCN: acetonitrile

³ MTBE: fe/Y-butyl methyl ether

The results of the respective experiments using various acids, instead of the solid catalyst carrying sulfonic acid groups, are compiled in table 3.

Table 3 Reaction of MFA with PA in the presence of different acids (5mol%) reaction time: 1 hour at 23°C.

¹ Concentration given in GC-area

²p-TsOH: p-toluenesulfonic acid

³TfOH: trifluoromethanesulfonic acid

⁴TFA: trifluoroacetic acid

⁵AcOH: acetic acid

⁶ Due to the complete decomposition no FPE was found

⁷ Due to the complete decomposition no SidePro was found Reaction of 5-methylfurfuryl alcohol with propargyl alcohol: step a) and B): “one-pot procedure

In a 100 ml flask, one equivalent 5-methylfurfuryl alcohol (MFA) was mixed with 10 equivalents of propargyl alcohol (PA) and 30 mg of AMBERLYST™ 15 (dry), respectively 70 mg of polymer-bound p-toluenesulfonic acid (Aldrich, product number: 532312), per mmol of 5-methylfurfuryl alcohol and the toluene, in the amount given in table 4, and stirred at 60°C until GC analysis showed complete conversion of MFA. At this point, PtC (Aldrich, product number 20609) was added to the reaction mixture in an amount as given in table 4 without any purification or isolation of the intermediate furfuryl propargyl ether (FPE). The reaction mixture was then stirred for another 2 hours at 60°C.

Any solids were removed from the reaction mixture by filtration. The solvent was evaporated under reduced pressure (40°C, 20 mbar) to yield a red-brown residue. The yield of the reaction was determined by quantitative ¹H NMR and indicated in table 4

Table 4 One-pot reaction of MFA with PA in toluene in the presence of different solid catalysts carrying sulfonic acid groups followed by addition of Pt.

¹ Yield determined by ¹H q-NMR

² polymer-bound p-toluenesulfonic acid (Aldrich product number: 532312)

Domino procedure

In a 100 ml flask, one equivalent 5-methylfurfuryl alcohol (MFA) was mixed with 10 equivalents of propargyl alcohol (PA) and 0.05 equivalent of AMBERLYST™ 15 (dry) and the respective solvent (if any) as indicated in table 5 to obtain a concentration of MFA of 1 .7 M and the catalyst in a concentration as indicated in table 5. The reaction mixture was then stirred for the time (f) at a temperature (T) as given in table 5 and then analysed by gas chromatography (GC). The amounts of the desired 5-methyl-1 ,3-dihydroisobenzofuran-4-ol (MIBF) (formula (I’)) as well as the remaining intermediate furfuryl propargyl ether (FPE) (formula (II’)) and the undesired side-product bis(5-methylfuran-2-yl)methane (formula (II”)) (SidePro) as measured by GC are given in table 5.

Table 5 All-in-one-one-pot reaction of MFA with PA in toluene in the presence of different solvents and Pt catalysts and AMBERLYST™ (dry) as solid catalyst carrying sulfonic acid groups.

¹ Yield determined by ¹H q-NMR

² Polymer-bound p-toluenesulfonic acid (Aldrich product number: 532312)

³ Aldrich, product number 20609 4 Bis(benzonitrile)dichloroplatinum(ll)

Claims

Claims

1 . A process for manufacturing in a one-pot procedure the compound of the formula (I)

comprising the step of reacting 5-methylfurfuryl alcohol of the formula (II) with propargyl alcohol of the formula (III)

in the presence of a) a solid catalyst which is a polymer carrying sulfonic acid groups; b) an organic solvent which is either an aromatic hydrocarbon or an ether; and with c) at least one Pt catalyst, which is either in the form of

- a supported Pt(O); or

-a Pt (II) salt; or

-a Pt (II) complex.

2. The process according to claim 1 , characterized in that the Pt catalyst is bis(benzonitrile)dichloroplatinum(ll) or bis(acetonitrile)dichloroplatinum(ll) or PtCI₂.

3. The process according to claim 1 , characterized in that the Pt catalyst is Pt on carbon.

4. The process according to any of the preceding claims, characterized in that that the solvent is selected from the group consisting of toluene, 2-methyl tetrahydrofuran and te/Y-butyl methyl ether, preferably is toluene.

5. The process according to any of the preceding claims, characterized in that the concentration of 5-methylfurfuryl alcohol of the formula (II) in the organic solvent is in the range of 10 - 500 mM, preferably 20 - 400 mM, more preferably 40 - 200 mM.

6. The process according to any of the preceding claims, characterized in that the solid catalyst carrying sulfonic groups is a polymer comprising sulfonic acid groups.

6. The process according to any of the preceding claims, characterized in that the solid catalyst carrying sulfonic acid groups is polymer-bound p-toluene sulfonic acid.

7. The process according to any of the preceding claims, characterized in that the solid catalyst carrying sulfonic acid groups is polymer-bound p-toluene sulfonic acid.

8. The process according to any of the preceding claims 1 to 6, characterized in that the solid catalyst carrying sulfonic acid groups is a microporous copolymer, preferably a copolymer of styrene and divinyl benzene, carrying sulfonic acid groups.

9. The process according to any of the preceding claims, characterized in that the molar ratio of amount of 5-methylfurfuryl alcohol of the formula (II) to propargyl alcohol of the formula (III) is between 1 :2 and 1 :20, preferably between 1 :4 and 1 :10.

10. The process according to any of the preceding claims, characterized in that the amount of the Pt catalyst is present in an amount of 0.5 - 10 mol-%, particularly 1 - 2.5 mol-%, in relation to the 5-methylfurfuryl alcohol of the formula (II).

11 . The process according to any of the preceding claims, characterized in that the reaction of 5-methylfurfuryl alcohol of the formula (II) with propargyl alcohol of the formula (III) is performed at a temperature between 20°C and 120°C, preferably between 25°C and 100°C, more preferably between 35°C and 65°C.

12. A composition comprising i) 5-methylfurfuryl alcohol of the formula (II); ii) propargyl alcohol of the formula (III); iii) a solid catalyst which is a polymer carrying sulfonic acid groups; iv) an organic solvent which is either an aromatic hydrocarbon or an ether; and v) at least one Pt catalyst, which is either in the form of a supported Pt(O), or of a Pt (II) salt, or of a Pt (II) complex;

the concentration of 5-methylfurfuryl alcohol of the formula (II) in the organic solvent is in the range of 10 - 500 mM; the molar ratio of amount of 5-methylfurfuryl alcohol of the formula (II) to propargyl alcohol of the formula (III) is between 1 :2 and 1 :20; the amount of the Pt catalyst is present in an amount of 0.5 - 10 mol-%, in relation to the 5-methylfurfuryl alcohol of the formula (II).