Patent Application
20050261513
The present invention relates to the field of organic synthesis. More particularly it provides a process for making an indenol ester or ether from an α-substituted cinnamic aldehyde derivative such as an acetal or an acylal. This reaction is promoted by the use of strong mineral acids, sulphonic acids, acidic zeolites or Lewis acids.
The organic compounds of formula (I), as defined below, can be useful as perfuming ingredients or as starting material for the synthesis of compounds having a more complex skeleton. The methods of preparation of such compounds as reported in the prior art are in general quite long and/or expensive. Thus, there is a need for improved processes for preparing such compounds.
It would be highly desirable to access such compounds by means of a simple and efficient isomerization process wherein the starting material is an easily accessible material. To the best of our knowledge, there is no report in the prior art of an isomerization process giving a direct access to compounds of formula (I) from the compound of formula (II).
In order to solve the problems aforementioned, a first embodiment of the present invention provides a process for making a compound of formula
wherein m is 0, 1 or 2;
For the invention purpose, it is important that R2 is not a hydrogen atom, indeed if R2 is H then the reaction does not take place.
According to an embodiment of the present invention, m is preferably 0 or 1, or even more preferably 0.
Furthermore, according to one of the above-described embodiments, R1 may also represent a group of formula —(CO)n—R-T, in which n is 0 or 1, R is a C6H4 group or a C1-C(5-n) alkanediyl or alkenediyl group and T is OH, COOH or a hydrogen atom. Alternatively R1 may also represent a group of formula —(CO)n—R-T, in which n is 0 or 1, R is a C1-C(3-n) alkanediyl group and T is OH, COOH or a hydrogen atom.
According to these embodiments R2 may represent a C1-6 alkyl group.
Moreover, in such embodiments, at least two R3 may represent a hydrogen atom and the other R3 may represent each a hydrogen atom or a C1-5 alkyl or alkoxy group.
Furthermore, R4 may represent a hydrogen atom or a C1-6 alkyl group, and preferably is a hydrogen atom.
The invention also relates to certain compounds that are made by these processes.
According to a particular embodiment of the invention the compounds of formula (1) are of formula
and are obtained by cyclization of the corresponding compounds of formula
wherein R1, R2, R3 and R5 have the same meaning as indicated above.
The compounds of formula (I′) wherein one R3 is a hydrogen atom and the other R3 is a C1-5 alkyl group are new compounds and can be used as starting compounds for the synthesis of indenols. Amongst these compounds can be cited the 2-methyl, the 2,5-dimethyl or the 2,6-dimethyl derivatives of formula (I′).
The catalyst, which can be used in the invention's process, is a strong mineral protic acid, a suphonic acid, an acidic zeolite or a Lewis acid. By “mineral” we mean here an acid having an anion which does not contain a carbon atom. By “strong” we mean here a protic acid having a pKAB<3, preferably below 2.
The catalyst can be in the anhydrous form or also in the hydrate form, except for those acids which are unstable in the presence of water.
According to another particular embodiment of the invention, the catalyst is selected from the group consisting of H2SO4, p-toluenesulphonic acid, NaHSO4, KHSO4, H3PO4, HCl, HNO3, BF3 and its adducts with C2-6 ethers or with C2-6 carboxylic acids, poly(styrene sulphonic acid) based resins, K-10 Clay, SnX4, FeX3 and ZnX2, X representing a halogen atom, such as Cl or Br, or a C1-6 carboxylate, such as acetate or trifluoroacetate, or a C1-7 sulphonate, such as a triflate or tosylate.
Preferably, the catalyst is H3PO4, FeX3 or ZnX2.
The catalyst can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite catalyst concentrations ranging from 0.001 to 0.30 molar equivalents, relative to the molar amount of the starting compound (II). Preferably, the catalyst concentrations will be comprised between 0.005 and 0.15 molar equivalents. It goes without saying that the optimum concentration of catalyst will depend on the nature of the catalyst and on the desired reaction time.
Another parameter of the invention's process is the temperature. In order to allow the cyclization to occur, it is useful to carry out the invention's process at a temperature of at least 10° C. Below this temperature the speed of the reaction decreases quite rapidly. The upper limit of temperature range is fixed by the reflux temperature of the reaction mixture that, as skilled persons know, depends on the exact nature of the starting and final product and optionally, as explained below, of the solvent. However, as non-limiting example, one can cite a preferred temperature ranging between 60° C. and 180° C. Of course, a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as of the solvent.
The process of the invention can be carried out in the presence or in the absence of solvent. As a person skilled in the art can anticipate, the presence of a solvent is mandatory only in the case in which the starting compound is a solid compound under the reaction conditions.
According to a preferred embodiment of the invention, and independently of the physical state of the starting compound, the process is advantageously carried out in the presence of a solvent. Preferably, the solvent is anhydrous or does not contain more than 5% w/w water.
Non-limiting examples of such a solvent are C4-C8 ethers, C3-C6 esters, C3-C6 amides, C6-C9 aromatic solvents, C5-C7 linear or branched or cyclic hydrocarbons, C1-C2 chlorinated solvents and mixtures thereof.
Furthermore, the reaction can also be carried out in the presence of a solvent belonging to the family of carboxylic anhydride of formula R2C(O)O(O)CR2, R2 being defined as above, optionally containing the corresponding carboxylic acid R2COOH.
The compound of formula (II) can be made and isolated according to any prior art method. Alternatively, compound (II) can be also generated in situ, i.e. in the reaction medium just before its use, according to any know prior art method. In particular, preferably the compound of formula (II) is made or generated by a method using the corresponding enal as starting material. Indeed, the enal can be easily obtained by an aldolic condensation, as a person skilled in the art knows well.
Therefore, another object of the present invention is an invention's process, as defined above, further comprising the step of generating in situ the compound of formula (II) starting from the corresponding enal of formula
wherein R2, R3, R4 and R5 have the same meaning indicated above.
A process comprising the in situ generation of the compound of formula (II) is particularly useful when the compound (II) is an acetal or an acylal, the latter being a geminal dicarboxylate.
Now, when the compound of formula (II) is an acylal, we have also noticed that the catalysts that are able to promote the cyclization of the acylal are also useful to promote the conversion of the enal into the corresponding acylal.
Therefore, another object of the present invention, and in fact a particular embodiment of the above-mentioned process, is a process for making an ester of formula (I), as defined above, comprising the step of reacting, in the presence of a catalyst as defined for the cyclization step, an enal of formula (III), as defined above, with a carboxylic anhydride of formula R7C(O)O(O)CR7, wherein R7, taken separately, represents a R2 group as defined above or the R7, taken together, represent a R group as defined above.
The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (° C.). The NMR spectral data were recorded in CDCl3 at 400 MHz or 100 MHz for 1H or 13C, respectively, the chemical displacements 8 are indicated in ppm with respect to TMS as standard, and the coupling constants J are expressed in Hz. All the abbreviations have the usual meaning in the art.
4.13 ml of a 0.25 M solution of FeCl3, 6H2O in Ac2O (1.03 mmol) where diluted into Ac2O (30.2 g) and the resulting solution was added dropwise during 1 hour to a stirred solution of 2-pentylcinnamaldehyde (20 g, 99 mmol) in AcOH (18.5 g) at reflux. After a further 2 hours at reflux the cooled mixture was poured into a mixture of H2O and Et2O. Then, solid Na2CO3 (44.7 g) was added portionwise to the stirred mixture. After one hour stirring the aqueous phase was saturated with NaCl and extracted with Et2O. The organic layers were dried over anhydrous Na2SO4, and the solvent evaporated to afford a crude product, which was further purified by distillation in vacuum to give the desired compound (yield=87%).
B.p. 86-93°/0.05 mbar
1H-NMR: 0.90 (br.t, J=7, 3H); 1.35 (4H); 1.58 (m, 2H); 2.17 (s, 3H); 2.29 (m, 2H); 6.21 (s, 1H); 6.43 (s, 1H); 7.09 (dd, J=7, J=7, 1H); 7.13 (d, J=7, 1H); 7.23 (m, 1H); 7.37 (d, J=7, 1H)
13C-NMR: 171.4(s); 149.2(s); 143.7(s); 142.0(s); 128.9(d); 128.2(d); 125.1(d); 124.2(d); 120.4(d); 77.5(d); 31.6(t); 28.2(t); 27.7(t); 22.5(t); 21.1(q); 14.0(q)
Using the same experimental procedure as under a), 2-hexylcinnamaldehyde (20 g, 92.6 mmol), FeCl3, 6H2O (3.85 ml of a 0.25 M solution in Ac2O, 0.96 mmol), Ac2O (28.3 g, 0.28 mol) in AcOH (17.4 g) were reacted together. After a further 3 hours at reflux the cooled mixture was treated to the same workup as before to provide the title compound (yield=83%)
B.p. 89-101°/0.035 mbar
1H-NMR: 0.89 (t, J=7, 3H); 1.25-1.40 (6H); 1.58(m, 2H); 2.17 (s, 3H); 2.29 (m, 2H); 6.21 (s, 1H); 6.43 (s, 1H); 7.09 (dd, J=7, J=7, 1H); 7.13 (d, J=7, 1H); 7.22 (m, 1H); 7.36 (d, J=7, 1H)
13C-NMR: 171.4(s); 149.3(s); 143.7(s); 142.0(s); 128.9(d); 128.2(d); 125.1(d); 124.2(d); 120.4(d); 77.5(d); 31.7(t); 29.1(t); 28.3(t); 28.0(t); 22.6(t); 21.1(q); 14.1(q)
Using the same experimental procedure as under a), 2-methylcinnamaldehyde (21 g, 0.14 mol) in AcOH (27 g), FeCl3-6H2O (6 ml of a 0.25 M solution in Ac2O, 1.5 mmol) in Ac2O (53 g) were reacted together. After a further 2 hours at reflux the cooled mixture was treated to the same workup and purification as before to provide the title compound (yield=70%)
B.p. 70-95°/0.04 mbar.
1H-NMR: 1.98 (s, 3H); 2.18 (s, 3H); 6.15 (s, 1H); 6.41 (s, 1H); 7.09 (dd, J=7, 7, 1H); 7.12 (d, J=7, 1H); 7.23 (m, 1H); 7.37 (d, J=7, 1H)
13C-NMR: 171.5(s); 144.4(s); 143.7(s); 142.1(s); 129.3(d); 128.9(d); 125.1(d); 124.2(d); 120.3(d); 78.4(d); 21.1 (q); 14.0(q)
A solution of FeCl3 anhydrous (42 mg, 0.25 mmol) in BuOAc (4 ml) was added dropwise during 10 minutes to a stirred solution of the 3,3-dimethoxy-2-methyl-1-phenyl-1-propene (5 g, 24.7 mmol) in BuOAc (13 ml) at 123° C. After 3 hours the cooled mixture was diluted with Et2O (50 ml) and washed with saturated aqueous NaHCO3 and brine. Extraction, drying over anhydrous Na2SO4, concentration and fractional distillation in vacuum gave a crude product that was further purified by chromatography (SiO2, cyclohexane/AcOEt 95:5 then AcOEt/Et2O 1:1). There was thus obtained the title compound with a yield of 33%.
B.p. 32-43° 0.07 mbar
1H-NMR: 2.03 (s, 3H); 3.03 (s, 2H); 4.85 (s, 1H); 6.44 (s, 1H); 7.09 (dd, J=7, J=7, 1H); 7.11 (d, J=7, 1H); 7.22 (m, 1H) 7.41 (d, J=7, 1H)
13C-NMR: 145.9(s); 143.9(s); 141.8(s); 128.7(d); 128.4(d); 124.6(d); 123.7(d); 120.1(d); 84.9(d); 51.8(q); 14.1(q)
A solution of FeCl3 anhydrous (21 mg, 0.125 mmol) in BuOAc (2 ml) was added dropwise during 5 minutes to a stirred solution of the 2-methyl-3-phenyl-2-propenylidene diacetate (3.1 g, 12.5 mmol) in BuOAc (8 ml) at 123°. After 2 h at 123° the reaction was stopped and worked-up as above. Chromatography (SiO2, cyclohex/AcOEt 9:1) of the crude product allowed the isolation of the title acetate (62% yield). Identical spectra as previously described.
A solution of (2E)-2-methyl-3-(4-methylphenyl)-2-propenal (100.0 g, 0.62 mol) in cyclohexane (300.0 g) was added dropwise in 2 hours to a stirred solution of zinc chloride (3.1 g, 22 mmol) in acetic anhydride (188.4 g, 1.85 mol) at 80° C. The reaction mixture was stirred further at 80° C. for 18 hours and then cooled to 25° C. The mixture was washed twice with water (100.0 g) and a 5% aqueous solution of sodium carbonate (100.0 g) and concentrated under reduced pressure. The crude product was flash-distilled (B.p.: 75-90° C./0.1 mbar) affording 88.5 g of the desired acetate (69%) as a yellow liquid (purity: 97.1% GC).
1H-NMR: 7.19 (s, H); 7.03 (d, J=7.9, H); 6.99 (d, J=7.9, H); 6.37 (s, H); 6.11 (s, H); 2.31 (s, 3H); 2.17 (s, 3H); 1.95 (s, 3H).
13C-NMR: 171.5 (s); 143.3 (s); 142.3 (s); 141.0 (s); 134.8 (s); 143.3 (s); 129.2 (d); 125.2 (d); 120.0 (d); 78.4 (d); 21.3 (q); 21.1 (q); 14.0 (q).
General Procedure
A solution of (2E)-2-methyl-3-(4-methylphenyl)-2-propenal (100.0 g, 0.62 mol) in acetic anhydride (100.0 g) was added dropwise in 2 hours to a stirred solution of the catalyst in acetic anhydride (88.4 g, 1.85 mol in total) at 80° C. The reaction mixture was stirred further at 80° C. until the complete conversion of the starting material and then cooled to 25° C. The mixture was diluted with methyl tert-butyl ether (300.0 g), washed successively with water (twice 100.0 g) and a 5% aqueous solution of sodium carbonate-(100.0 g) and concentrated under reduced pressure. The crude product was flash-distilled (B.p.: 75-90° C./0.1 mbar) affording the desired acetate as a yellow liquid.
The results obtained are listed in the following table:
eq. = molar equivalents in respect to the starting material
h = hours
A mixture of 2-butylcinnamic aldehyde (5 g, 26.7 mmol.), triethyl orthoformate (5.9 g, 40 mmol.), absolute ethanol (10 g, 217 mmol.) and Amberlyst® 15 (0.52 g) was heated at reflux (85° C. oil bath). After three days, the mixture was filtered and concentrated under vacuum. The residue % as subjected to silica gel flash chromatography (hexane/ethyl acetate 98:2), yielding 3.8 g (17.6 mmol., 66% yield) of the indenyl ethyl ether.
1H-NMR: 0.95 (t, J=7.4, 3H), 1.15 (t, J=6.9, 3H), 1.46-1.36 (m, 2H), 1.70-1.50 (m, 2H), 2.45-2.30 (m, 2H), 3.27-3.15 (m, 2H), 4.95 (s, 1H), 6.41 (s, 1H), 7.1 (t, J=7.2, 1H), 7.13 (d, J=7.2, 1H), 7.21 (t, J=7.2, 1H), 7.42 (d, J=7.2, 1H).
13C-NMR: 14.0 (q), 15.7 (q), 22.7 (t), 28.1 (t), 30.5 (t), 60.0 (t), 83.4 (d), 120.2 (d), 123.7(d), 124.6 (d), 126.9 (d), 128.3 (d), 142.5 (s), 143.6 (s), 151.3 (s).
