Alpha alkylation of ketones by primary alcohols using iron catalysts

Abstract

The present invention relates to process of alkylating a ketone of the formula (I) with an alcohol of the formula (II) having at least one primary and optionally at least one secondary hydroxyl group in the presence of an iron catalyst of the formula (III).

Description

[0001] ALPHA ALKYLATION OF KETONES BY PRIMARY ALCOHOLS USING IRON CATALYSTS

[0002] Technical Field

[0003] The present invention relates to the field of synthesis of alphadisubstituted alkyl- or cycloalkyl ketones.

[0004] Background of the invention

[0005] Alpha-disubstituted alkyl- or cycloalkyl ketones are important products or intermediates in the field of fragrances and perfumes.

[0006] Recently, potentially cheap diaminocyclopentadienone iron tricarbonyl complexes have been suggested to be used for alkylations of specific organic compounds.

[0007] L. Bettoni et al., Org. Lett. 2019, 21, 8404-8408 disclose a beta-alkylation of some 2-arylethanol using diaminocyclopentadienone iron tricarbonyl complexes to yield alkylated alcohols.

[0008] L. Bettoni et al., Org. Lett. 2019, 3057-3061 discloses an iron-catalysed three-component alkylation in which a benzylic alcohol, an aromatic ketone and methanol are reacted in the presence of a diaminocyclopentadienone iron tricarbonyl complex to yield an alkylated aromatic ketone disubstituted in its beta position.

[0009] C. Seck et al., ChemCatChem 2017, 4410-4416 discloses an alkylation of aryl ketones with benzylic alcohol (2-phenyl ethanol) in the presence of phosphine-free iron complexes to yield an alkylated ketone having an aryl group in beta position to the keto group.

[0010] L. Bettoni et al., Org. Lett. 2020, 2064-2069 disclose an alpha alkylation of aromatic ketones with secondary alcohols in the presence of diaminocyclopentadienone iron tricarbonyl complexes.

[0011] However, these methods generally have substrate specificity, insufficient catalytic activity for practical use and conditions which are incompatible with most substrates of interest in perfumery. For example, in ChemCatChem 2017, 4410-4416 is clearly showed that in presence of 2 mol.% iron catalyst, alkylation of 4-methoxyacetophenone (1 eq.) with benzyl alcohol (1.3 eq.) and caesiumcarbonate as a base affords the expected product in 95% yield only when the reaction is run at 140°C while decreasing the reaction temperature to 90°C the product is obtained in only 45% yield after 24h. Moreover, the same publication reveals that the alkylation of 4-methylcyclohexanone (1equiv.) with benzyl alcohol 5 (1,3 equiv.) requires the previous displacement of a carbonyl ligand by photoactivation or a phosphorous ligand and affords the dialkylated product even at 90°C.

[0012] Under such circumstances, it is desired to develop a method for alkylating an aliphatic ketone using a non-benzylic alcohol that realizes higher catalytic io activity and higher selectivity, especially to synthesize alpha-disubstituted alkyl- or cycloalkyl ketones.

[0013] Summary of the invention

[0014] 15 Therefore, the problem to be solved by the present invention is to offer a method for the synthesis of alpha-substituted alkyl- or cycloalkyl ketones being devoid of aromatic groups in the beta-position of the keto groups and in a selective manner.

[0015] Surprisingly, it has been found that the process according to claim 1 offers 20 a solution to this problem.

[0016] It is particularly surprising that the iron catalyst of formula (III) can be used to alkylate alkyl- or cycloalkyl ketones in alpha position to the keto group.

[0017] Further aspects of the invention are subject of further independent claims.

[0018] 25 Particularly preferred embodiments are subject of dependent claims.

[0019] Detailed description of the invention

[0020] In a first aspect the present invention relates to a Process of alkylating a ketone of the formula (I) with an alcohol of the formula (II) having at least one primary and 30 optionally at least one secondary hydroxyl group in the presence of a catalyst of the formula (III)

[0021]

[0022] wherein R1

[0023] either represents a Ci -1 o-alkyl group or a Cs-w-cycloalkyl group or a C5-10-cycloalkenyl group;

[0024] or, together with R2, forms a Cs-20-alkylene group or a C3-2o-alkenylene group;

[0025] R2either represents H or a Ci -1 o-alkyl group or a Cs-w-cycloalkyl group;

[0026] or, together with R1, forms a Cs-20-alkylene group or a Cs-20-alkenylene group;

[0027] R3represents H or - R - Hor - R - OH;

[0028] wherein R represents Ci-w-alkylene group or a C2-w-alkenylene group or a C2-W-alkynylene group or a Cs-w-cycloalkylene group or a Cs-w-cycloalkenylene group, and wherein the hydroxyl group in - R - OH jsoptionally protected with an alcohol protecting group; with the proviso that the hydroxyl group in - R - OH is a primary or a secondary hydroxyl group;

[0029] RI, RII, RIIIand RIV, independently from each other, represents H, a C1-10-alkyl group, which optionally comprises at least one N and / or O atom, or a C6-10-aryl group, which is optionally substituted by at least one Ci-w-alkoxy group or at least one halogenated Ci-4-alkyl group;

[0030] to yield an alkylated ketone of the formula (A)

[0031]

[0032] and / or, in case of a R3being - R - OH, wherein the - R - OH group is not protected with an alcohol protecting group; an alkylated ketone of the formula (A-1 ) and / or (A-2),

[0033] R R

[0034] R

[0035]

[0036] wherein any single dotted line in any formulae represents the bond by which said substituent is bound to the rest of a molecule; and;

[0037] wherein the process is performed in the absence of any alcohols with aromatic substituents, particularly in the absence of benzylic alcohols.

[0038] In an embodiment the present invention relates to a Process of alkylating a ketone of the formula (I) with an alcohol of the formula (II) having at least one primary and optionally at least one secondary hydroxyl group in the presence of a catalyst of the formula (III)

[0039]

[0040] R3(II)

[0041]

[0042] either represents a C1-10-alkyl group or a C5-10-cycloalkyl group or a C5-10-cycloalkenyl group;

[0043] or, together with R2, forms a C3-20-alkylene group or a C3-20-alkenylene group;

[0044] R2

[0045] either represents H or a Ci-w-alkyl group or a Cs-w-cycloalkyl group; or, together with R1, forms a C3-2o-alkylene group or a C3-2o-alkenylene group;

[0046] R3represents H or - R - Hor - R - OH

[0047] wherein R represents Ci-w-alkylene group or a C2-w-alkenylene group or a C2-w-alkynylene group or a Cs-w-cycloalkylene group or a Cs-w- cycloalkenylene group; with the proviso that the hydroxy group in - R - OH is a primary or a secondary hydroxyl group;

[0048] RI, RII, RIIIand RIV, independently from each other, represents H, a C1-10-alkyl group, which optionally comprises at least one N and / or O atom, or a C6-10- aryl group, which is optionally substituted by at least one C1-10-alkoxy group or at least one halogenated C1-4-alkyl group;

[0049] to yield an alkylated ketone of the formula (A)

[0050] o

[0051] R1R3

[0052]

[0053] R2

[0054] and / or, in case of a R3being - R - OH; an alkylated ketone of the formula (A-1) and / or (A-2),o R2

[0055] (A-1)

[0056] (A-2)

[0057]

[0058] wherein any single dotted line in any formulae represents the bond by which said substituent is bound to the rest of a molecule; and;

[0059] wherein the process is performed in the absence of any alcohols with aromatic substituents, particularly in the absence of benzylic alcohols.

[0060] For sake of clarity, some terms used in the present document are defined as follows:

[0061] In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e., for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3 is considered as a C4-alkyl group.

[0062] A “Cx-y-alkylene” group is an alkylene group comprising x to y carbon atoms. An alkylene is a substituent which, formally, is obtained from an alkane by removal of 2 H atoms and forms a carbon-carbon bond with each of the two rests of the molecule the alkylene group is bound to. For example, a Ci-3-alkylene group is an alkylene group comprising 1 to 3 carbon atoms. The alkylene group can be linear or branched. For example,

[0063] -CH2-CH2-CH2- and -CH(CH3)-CH2- and -C(CH2-CH3)- and -C(CH3)2- are all considered as a Cs-alkylene group.

[0064] A “Cx-y-alkenylene” group is an alkylene group comprising x to y carbon atoms. An alkenylene is a substituent which, formally, is obtained from an alkene by removal of 2 H atoms and forms a carbon-carbon bond with each of the two rests of the molecule the alkylene group is bound to. For example, a C3-6-alkenylene group is an alkenylene group comprising 3 to 6 carbon atoms. The alkenylene group can be linear or branched.

[0065]

[0066] alkenylene group.

[0067] A “Cx-y-alkynylene” group is an alkylene group comprising x to y carbon atoms. An alkynylene is a substituent which, formally, is obtained from an alkyne by removal of 2 H atoms and forms a carbon-carbon bond with each of the two rests of the molecule the alkylene group is bound to. For example, a C3-6-alkynylene group is an alkynylene group comprising 3 to 6 carbon atoms. The alkynylene group can be linear or branched. For example, both

[0068]

[0069] and / are considered to be a C4-alkynylene group.

[0070] The term “olefinically unsaturated" means in this document that an olefinic unsaturation (C=C) is present. This is used to contrast to unsaturations which are present in alkynes (C-C triple bonds) or double bonds of carbon atoms to hetero atoms such as C=O, or C=N.

[0071] In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises said same label.

[0072] The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.

[0073] In the present document, any dotted single line in formulae represents the bond by which a substituent is bound to the rest of a molecule.Any wavy line in any formula of this document represents a carbon-carbon bond which is linked to an adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration. In other words, a formula having a wavy line represents a formula covering the E as well as the Z isomer.

[0074] Ketone of the formula (I)

[0075] In the process of the invention a ketone of the formula (I) is alkylated

[0076] o

[0077]

[0078] R2

[0079] In one of the embodiments, the ketone of the formula (I) is a linear ketone. In this case, R1represents a Ci -1 o-alkyl group or a Cs-w-cycloalkyl group or a C5-10- cycloalkenyl group and R2represents H or a C1-1 o-alkyl group or a Cs-w-cycloalkyl group.

[0080] Examples for ketones having a Cs-w-cycloalkyl group or a Cs-w- cycloalkenyl group are ketones of the formulas

[0081]

[0082] wherein and any double bond having dotted line ( - ) represents independently from each other either a single carbon-carbon bond or a carboncarbon double bond; with the proviso that said ketone does not comprise two cumulated carbon-carbon double bonds and that at least one of the double bond having dotted line ( - ) represents a carbon-carbon double bond.

[0083] R1particularly represents a Ci-s-alkyl group, preferably a Cs-5-alkyl group. R2particularly represents H or a Ci -s-alkyl group, preferably H. with the proviso that the compound of the formula (I) does not comprise two cumulated carbon-carbon double bonds and that at least one of the double bond having dotted line ( ) represents a carbon-carbon double bond.It is preferred that in this embodiment the compound of the formula (I) is selected from the group consisting of

[0084] o O

[0085] and

[0086]

[0087] In another embodiment, the ketone of the formula (I) is a cyclic ketone. In this case, R1forms together with R2a C3-2o-alkylene group or a C3-20- alkenylene group. This C3-2o-alkylene group or a C3-2o-alkenylene group may also comprise cyclic structures. Example of ketones of for such C3-20- alkylene group or a C3-2o-alkenylene group are

[0088]

[0089] R1forms together with R2preferably a C3-2o-alkylene group or a C3-20- alkenylene group.

[0090] It is particularly preferred that the cyclic ketone has a ring size of 4 to 20 atoms, particularly of 5 to 17 carbon atoms.It is preferred that in this embodiment the compound of the formula (I) is selected from the group consisting of the compound of the formula (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-C), (l-H), (l-J), (l-K) and (l-L)

[0091]

[0092] Alcohol of the formula (II)

[0093] In the process of the invention the ketone of the formula (I) is alkylated with an alcohol of the formula (II)

[0094] HO^^^R3( )-

[0095] The alcohol of the formula (II) is a primary alcohol, i.e. it carries at least one primary hydroxyl group.

[0096] In one embodiment, the alcohol of the formula (I) is a primary monohydric alcohol.

[0097] In this embodiment, R3represents H or R-H; R being either a C1-10-alkyl group or a C2-10-alkenylene group or a C2-10-alkynylene group or a C5-10-cycloalkyl group.

[0098] Non-limiting examples for such primary monohydric alcohols having a C5-10-cycloalkyl group are

[0099]

[0100] or with R' being a C1-4 alkyl group.

[0101] Non-limiting examples for such primary monohydric alcohols having a C2-10-alkenylene group are

[0102] OH

[0103]

[0104] with R" being a C1-8 alkyl group.

[0105] It is particularly preferred that the monohydric alcohol is selected from the group consisting of methanol, ethanol, propanol, propargyl alcohol and 5-hexen-1- ol.

[0106] In another embodiment, the alcohol of the formula (II) is a primary dihydric alcohol. It is either diol having two primary hydroxyl groups or it is a diol having a next to the primary hydroxy group also a secondary hydroxyl group.

[0107] In this embodiment, R3represents a substituent of the formula - R - OH,R being either a C2-10-alkylene group or a C2-10-alkenylene group or a C2-10-alkynylene group or a C5-10-cycloalkylene group, wherein the hydroxyl group in - R - OH is optionally protected with an alcohol protecting group.

[0108] The alcohol protecting group may be any alcohol protecting group.

[0109] Suitable alcohol protecting groups include, for example ether, silyl ether, enolether phenyl and acetal groups. Non-limiting examples of suitable alcohol protecting groups include acetate (Ac), benzyl (Bn), paramethoxybenzyl (PMB), triphenylmethyl (Tr), allyl (All), methyl (Me), trimethylsilyl (TMS), t-butyldimethylsiyl (TBDMS), triisopropylsilyl (TIPS), methoxymethyl (MOM), tetrahydropyranyl (THP), tetrahydrofuranyl, [3-D-galactopyranosyl, [3-D-galactopyranosyl, a-D-mannopyranosyl including O-methyl or O-acetyl derivatives thereof, 2-methoxyethoxym ethyl (MEM) and 2-(Trimethylsilyl)ethoxymethyl (SEM), 1-Cyclohexenyl, 1 -cyclopentenyl, 1 -cyclooctenyl, 1 -Dodecenyl, 3-(Bicyclo[2.2.1]hept-2-en-2-yl, Phenyl, Pentamethylphenyl, 3,4-Diaminophenyl, 2-naphtalenyl, 3-(1H-Benz[f]inden-4-yl.

[0110] It is particularly preferred that the dihydric alcohol has 2 primary hydroxyl groups.

[0111] It is particularly preferred that the dihydric alcohol is selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, and pentylene glycol.

[0112] It is preferred that the alcohol of the formula (II) is selected from the group consisting of methanol, ethanol, propanol, propargyl alcohol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol and 5-hexen-1-ol.

[0113] Catalyst of the formula (III)

[0114] In the process of the invention the ketone of the formula (I) is alkylated with an alcohol of the formula (II) in the presence of a catalyst of the formula (III)

[0115]

[0116] The substituents RI, RII, RIIIand RIV, independently from each other, represents H, a C1-10-alkyl group, which optionally comprises at least one N and / or O atom, or a C6-10-aryl group, which is optionally substituted by at least one C1-10-alkoxy group or at least one halogenated C1-4-alkyl group.

[0117] It is preferred that the two substituents RIare identical, and preferably represent both a phenyl group.

[0118] It is further preferred that the two substituents RIIare identical, and preferably represent both a methyl group.

[0119] It is further preferred that RIII= RIV, and preferably represent both H.

[0120] It is particularly preferred that RI= phenyl and RII= methyl and RIII= RIV, particularly RIII= RIV= H.

[0121] The catalyst compound of the formula (III) is particularly selected from the group consisting of compounds of the formula (III-A), (III-B), (III-C), (III-D), (III-E) and (III-F), particularly of (III-A)

[0122]

[0123] (III-A) (III-B)

[0124]

[0125] (lll-D) (lll-E) wherein Ph represents a phenyl group.

[0126] In a very preferred embodiment, the catalyst of the formula (III) is the catalyst of the formula (III-A)

[0127]

[0128] wherein Ph represents a phenyl group.

[0129] The complexes of the formula (III) can be obtained by heating of the respective ligand of the formula (IV) with a respective iron carbonyl complex, such as Fe2(CO)g in a hydrocarbon, such as toluene, at elevated temperature of between 80 and 110 °C, particularly as described in C. Seck et al., ChemCatChem 2017, 4410-4416 in the experimental section on page 4414 for [Fe1 ].

[0130]

[0131] It is preferred that the alkylation is performed in the presence of a base, particularly an alkali metal hydroxide, preferably in molar ratio of said base to the ketone of the formula (I) of between 0.01:1 to 0.75: 1, particularly between 0.1:1 to 0.5:1, more particularly between 0.1: 1 and 0.25:1.The preferred base is NaOH.

[0132] It is furthermore preferred that the molar ratio of the catalyst of the formula (III) to the alcohol of formula (II) is in the range of between 0.01: 1 and 0.0005: 1, preferably between 0.01: 1 and 0.001: 1, more preferably between 0.005: 1 and 0.002:1.

[0133] It is surprising that even with low concentrations, resp. such low molar ratio of the catalyst of the formula (III) to the alcohol of formula (II), the alkylation can be performed to give very high conversions, yield and selectivities.

[0134] The alkylation of the ketone of the formula (I) is preferably performed at a temperature of between 50 and 110°C, preferably between 80 and 100 °C.

[0135] The alkylation of the ketone of the formula (I) is preferably performed in the presence of an organic solvent, particularly of an aromatic hydrocarbon, preferably toluene, an ether, preferably 1,4-dioxane, tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2-Me-THF) or tert. -butanol, preferably at a temperature of between 50 and 110°C, preferably between 80 and 100 °C.

[0136] It is important to stress, however, that any alcohols with aromatic substituents, such as benzylic alcohols, are not suited as solvents.

[0137] Alkylated ketone

[0138] The above process yields in high conversion, yield and selectivity the alkylated ketone of the formula (A) and / or, in case of a R3being - R - OH; the alkylated ketone of the formula (A-1 ) and / or (A-2).

[0139] R'

[0140]

[0141] O R2

[0142] R2O

[0143]

[0144] In the case where the alcohol of the formula is a monohydric alcohol, i.e. R3= H or - R - H, the alkylated ketone is of formula (A) is obtained in high selectivity, and alkylated compounds of the formula (A-1 ) and / or (A-2) are not observed.

[0145] In this case, it is preferred that the molar ratio of the alcohol of the formula (II) to the ketone of the formula (I) is in the range of between 10:1 and 0.5:1, preferably between 5:1 and 0.5:1, more preferably between 3:1 and 1:1, to allow good conversion and high yield and selectivity in the alkylated ketone of the formula (A).

[0146] In case, where the alcohol of the formula is a dihydric alcohol, i.e.

[0147] R3= - R - OH, an alkylated ketone is of formula (A) and / or formula (A-1) and I or (A-2) is obtained.

[0148] In this case the alkylated formula (A) is of formula (A-0)

[0149] o

[0150] OH

[0151] (A-0)

[0152] R1

[0153]

[0154] R2

[0155] The alkylated ketone of the formula (A-0) is a monoalkylated ketone, which has a hydroxyl group, and is, therefore also an alcohol, which can alkylate, intermolecularly, in a subsequent step, another molecule of a ketone of the formula (I), forming an alkylated ketone of the formula (A-1 ).

[0156] In the case, where R2, the compound of the formula (A-0) can form, by intramolecular alkylation, by which a ring is formed, the ketone of the formula (A-2).Depending on the conditions chosen, the ratio of compounds of the formula (A) (i.e. (A-0) and (A-1) and (A-2) can be varied as desired.

[0157] A major factor for said ratio in the products formed is the ratio of alcohol of the formula (II) to the ketone of the formula (I) to chosen ion the alkylation. If said ratio is higher than 1, the major product is ketone of the formula (A-0) and / or (A-2). If said ratio is smaller than 0.5 the major product is the ketone of the formula (A-1 ). The ratio between ketone of the formula (A-0) and (A-2) can be influenced particularly by temperature and reaction time.

[0158] The formation of ketone of the formula (A-1 ) and / or (A-2) can also be influenced by the alcohol of the formula (II). If the alcohol is a dihydric alcohol has secondary OH group, the reaction will rather yield to the formation of ketone of formula (A-0) rather than in formation of the ketone of the ketone of the formula (A-1) and / or (A-2). Therefore, in case of an secondary OH group, the alkylation can be directed so to yield only the ketone of the formula (A-0).

[0159] This is exemplified by alkylation of tert. butyl methyl ketone (I1) (R2=H) with pentane-1,5-diol (II1) (R = butylene) in the presence of catalyst of the formula (III).

[0160] (A-01)

[0161]

[0162] This alkylation can lead to the formation of an alkylated ketone of the formula (A), i.e. of the formula (A-01) as well as to a compound of the formula (A-1 ), i.e. of the formula (A-1 ') (intermolecular alkylation of (A-01)) as well as to a compound of the formula (A-2), i.e. of the formula (A-21) (Intramolecular alkylation of (A-0')).Furthermore, it is also surprising that in the alkylation process of the present invention, any ketones of the formula (I) having a methylene group in alpha' position to the carbonyl group (coming from R1) do not form significant amounts of a, a'- dialkylated ketones (DA).

[0163] This is exemplified by alkylation of cyclopentanone (I") with an alcohol of the formula (II), such as butanol or hexanol in the presence of catalyst of the formula (III) yield in high yield and selectivity the corresponding alkylated ketone of the formula (A) and a not the a, a'- dialkylated ketone of the corresponding formula (DA1).

[0164]

[0165] The present invention offers a surprisingly efficient process of producing alkylated ketones of the formula (A) and / or (A-1 ) and / or (A-2) from ketones of the formula (I). Particularly surprising is that said process yields in high conversion, yield and selectivity. Particularly said process does not involve the use of benzylic alcohols.

[0166] Examples

[0167] The following examples are provided to further illustrate the process and effects of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

[0168] General procedure of alkylation of ketones

[0169] Into a dry Schlenk tube, equipped with magnetic stirrer and a nitrogen inlet, were introduced solid NaOH, and a degassed solution of the iron catalyst of formula (lll-A) in the alcohol of the formula (II) as given in table 1 (1 eq.) and theketone of the formula (I) as given in table 1 in amounts as given in table 1. The reaction mixture was heated to 80°C under stirring for 6h. Details and results of these experiments have been indicated in table 1.Ketone of Amount of Amount Alcohol

[0170] Solvent Conv.1Sei.2Example the NaOH of Fe cat of the formula (II) Product

[0171] [mol / l]* [%] formula (I) [%

[0172] [eg] [eg] amount [eg] ] 0 0

[0173] |i

[0174] \ IL MeOH

[0175] 1 0.25 0.035 - 95 92

[0176] 2

[0177] 0

[0178] MeOH

[0179] 2 ^5 0.25 0.035 98 90

[0180] 2.5

[0181] o

[0182] Ethanol \ I

[0183] 3 0.25 0.035 - 99 87

[0184] 1

[0185] 0 0

[0186] II

[0187] x 1

[0188] 4 \ A 0.25 0.035 - 87 76

[0189] 1

[0190] 0 0

[0191] \ 1

[0192] 5 0.035 \ Z\

[0193] 0.25 - 97 91

[0194] 1

[0195]

[0196] o 0

[0197] \Jl^ \ J]

[0198] 6 0.25 0.035 - 96 90

[0199] I^J 1

[0200] MeOH

[0201] 7 0.25 0.035 - 88 78

[0202] 5

[0203] EtOH Toluene

[0204] 8 0.25 0.035 56 77

[0205] 1 5

[0206] Toluene

[0207] j /

[0208] 9 c^S 0.1 0.035 _ 87 54

[0209] 1 0.5

[0210] Toluene - /

[0211] 10 0.1 0.035 72 60

[0212] 1

[0213] ^^7 0.5 _

[0214] Toluene —

[0215] H 0

[0216] 11 0.05 0.035 h II, _ J / 71 68

[0217] 0.9“

[0218] 1 _ J

[0219]

[0220]

[0221] "part of toluene was added to the ketone (4mol / L) was added during 4 hours at 75°C the rest of toluene was added to alcohol at beginning.

Claims

Claims1. Process of alkylating a ketone of the formula (I) with an alcohol of the formula (II) having at least one primary and optionally at least one secondary hydroxyl group in the presence of a catalyst of the formula (III)o(I)R2(II)(HI)either represents a C1-10-alkyl group or a C5-10-cycloalkyl group or a C5-10-cycloalkenyl group;or, together with R2, forms a C3-20-alkylene group or a C3-20-alkenylene group;R2either represents H or a C1-10-alkyl group or a C5-10-cycloalkyl group; or, together with R1, forms a C3-20-alkylene group or a C3-20-alkenylene group;R3represents H or - R - Hor - R - OHwherein R represents C1-10-alkylene group or a C2-10-alkenylene group or a C2-10-alkynylene group or a C5-10-cycloalkylene group or a C5-10-cycloalkenylene group, and wherein the hydroxyl group in - R - OH is optionally protected with an alcohol protecting group; with the proviso that the hydroxyl group in - R - OH is a primary or a secondary hydroxyl group;RI, RII, RIIIand RIV, independently from each other, represents H, a C1-10-alkyl group, which optionally comprises at least one N and / or O atom, or a C6-10-aryl group, which is optionally substituted by at least one C1-10-alkoxy group or at least one halogenated C1-4-alkyl group;to yield an alkylated ketone of the formula (A)o(A)R2and / or, in case of a R3being - R - OH wherein the - R - OH group is not protected with an alcohol protecting group; an alkylated ketone of the formula (A-1) and / or (A-2),o R2(A-1)(A-2)wherein any single dotted line in any formulae represents the bond by which said substituent is bound to the rest of a molecule; and;wherein the process is performed in the absence of any alcohols with aromatic substituents, particularly in the absence of benzylic alcohols.

2. The process according to claim 1, characterized in thatR1= phenyl and R" = methyl and R111= RIV, particularly R111= RIV= H.

3. The process according to any of the preceding claims characterized in that R3= H or - R - Hwherein R represents C1-10-alkylene group or a C2-10-alkenylene group or a C2-10-alkynylene group or a C5-10-cycloalkylene group or a C5-10-cycloalken-ylene group.

4. The process according to any of the preceding claims characterized in that the alcohol of the formula (II) is selected from the group consisting ofmethanol, ethanol, propanol, propargyl alcohol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol and 5-hexen-1-ol.

5. The process according to any of the preceding claims characterized in that the alcohol of the formula (II) has 2 primary hydroxyl groups.

6. The process according to any of the preceding claims characterized in that R1together with R2forms a C3-20-alkylene group or a C3-20-alkenylene group.

7. The process according to claim 4 characterized in that the compound of the formula (I) is selected from the group consisting of8. The process according to claim 1 to 6 characterized in that the compound of the formula (I) is selected from the group consisting of9. Process according to any of the preceding claims characterized in that the alkylation is performed in the presence of a base, particularly an alkali metal hydroxide, preferably in molar ratio of base to compound of the formula (I) of between 0.01:1 to 0.75: 1, particularly between 0.1:1 to 0.5: 1, more particularly between 0.1: 1 and 0.25:1.

10. Process according to any of the preceding claims characterized in that the molar ratio of the alcohol of the formula (II) to the ketone of the formula (I) is in the range of between 10:1 and 0.5:1, preferably between 5:1 and 0.5:1, more preferably between 3:1 and 1:1.

11. Process according to any of the preceding claims characterized in that the molar ratio of the catalyst of the formula (III) to the alcohol of formula (II) is in the range of between 0.01: 1 and 0.0005: 1, preferably between 0.01: 1 and 0.001: 1, more preferably between 0.005: 1 and 0.002: 1.

12. Process according to any of the preceding claims characterized in that the alkylation is performed at a temperature of between 50 and 110°C, preferably between 80 and 100 °C.

13. Process according to any of the preceding claims characterized in that the alkylation is performed in the presence of an organic solvent, particularly in the presence of an aromatic hydrocarbon, preferably toluene, or an ether, preferably 1,4-dioxane, tetrahydrofuran (=THF), 2-methyltetrahydrofuran (=2- Me-THF) or tert. -butanol.

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