WO2026027792A1

WO2026027792A1 - Process for producing fragrances and fragrance intermediates using metal catalysts

Info

Publication number: WO2026027792A1
Application number: PCT/EP2025/072305
Authority: WO
Inventors: Jorge Sanchez Quesada; Yigal Becker; Shay Eliyahu; Antonio LEVYA-PEREZ; Ana María COLLADO PÉREZ; Paloma MINGUEZA-VERDEJO
Original assignee: International Flavors and Fragrances Inc
Current assignee: International Flavors and Fragrances Inc
Priority date: 2024-08-02
Filing date: 2025-08-02
Publication date: 2026-02-05
Anticipated expiration: 2027-02-02

Abstract

An exemplary method for producing fragrance and fragrance intermediates produces an intermediate mixture of isomers of 3-(1,1-dimethyl-2,3-dihydro-1H-inden-ar-yl)prop-1-en-1-yl acetate, by using catalysts that are not iron compounds.

Description

Process for producing fragrances and fragrance intermediates using metal catalysts

Field of the Invention

[0001] The field relates to methods for producing fragrance intermediates and ingredients relating to 3-(1 ,1-dimethylindanyl)-propanal.

Background

[0002] Well-known fragrance ingredients which are a mixture of isomers and are collectively represented and are known in the art as 3-(2, 3-dihydro-1 , 1-dimethyl-1 H- inden-ar-yl)-propanal. For the foregoing chemical name, the indene moiety and the propanal are generically attached to an aromatic group of the indene moiety at an unspecified position. The term “ar” indicates that the substitution radical is in the “aromatic ring.” In one naming alternative, the mentioned 3-(2, 3-dihydro-1 , 1-dimethyl-1 H-inden-ar- yl)-propanal is also known in the art as “1 H-lndene-ar-propanal, 2, 3-dihydro-1 ,1 -dimethyl" or“2,3-dihydro-1 ,1-1 H-dimethyl-indene-ar-propanal." In yet another naming alternative, 3- (2,3-dihydro-1 ,1-dimethyl-1 H-inden-ar-yl)-propanal can be collectively referred to as 3- (1 ,1-dimethylindanyl)-propanal, which is a more simplified term.

[0003] The mentioned 3-(2,3-dihydro-1 ,1-dimethyl-1 H-inden-ar-yl)-propanal is prepared by deprotection of a fragrance intermediate mixture of isomers 3-(1 ,1-dimethyl- 2,3-dihydro-1 H-inden-ar-yl) prop-1 -en-1-yl acetate. This deprotection step known in the art and is accomplished by hydrolysis. However, the preparation of the mentioned fragrance intermediate mixture is variable and there are different methods to product the fragrance intermediate mixture including use of different catalysts. The “ar” in this context for both mentioned chemical compounds also means that the substitution radical is in the “aromatic ring.”

[0004] In one example, the mentioned fragrance intermediate mixture is prepared by Friedel-Crafts alkylation of 1 ,1-dimethyl-2,3-dihydro-1 H-indene with acrolein diacetyl acetal. These specific Friedel Crafts alkylation reactions involving the coupling of an aromatic substrate and acrolein diacyl acetal derivatives such as the foregoing reaction are known in the art as a “Scriabine reaction.” See Bull. Chim. Soc. Fr. 1961 , 1194-1198. [0005] An exemplary synthesis of a mixture of isomers of the mentioned final end fragrance ingredients of 3-(2,3-dihydro-1 ,1-dimethyl-1 H-inden-ar-yl)-propanal, useful as perfumery ingredients, are prepared by a series of reactions starting from 1 ,1—dimethyl—

2.3-dihydro-1 H-indene and acrolein diacetyl acetal by using an initial synthetic sequence consisting of the mentioned Scriabine reaction with stoichiometric amounts of catalysts such as TiCU, and further by diacetyl acetal acidic hydrolysis, with lower yields (EP685444, 1995).

[0006] An alternative protocol for the Scriabine reaction employing the same starting materials has also been described employing catalytic amounts of FeCl3'6H2O dissolved in acetic acid leading to higher yields, 70%. See US7524983B2, 2009, such as Example 5 of the mentioned patent. However, it is believed that the high quantities of large starting material of 1 ,1-dimethyl-2,3-dihydro-1 H-indene as a reactant as well the requirements to use both acetic acid and acetic anhydride lead to increased costs, such as the requirements disclosed in Example 5-C of US7524983B2.

[0007] There remains a need for an easier and more effective catalytic system to perform the synthesis of the fragrance intermediate mixture of isomers of 3-(1 ,1-dimethyl-

2.3-dihydro-1 H-inden-ar-yl)prop-1-en-1-yl acetate.

Summary of the Invention

[0008] A method for producing fragrances and fragrance intermediates of formula (I):

[0009] wherein the wavy line indicates that the double bond can be in a configuration E or Z or a mixture thereof;

[0010] the two R¹, taken separately, can represent a hydrogen atom and the other a C1-C4 alkyl group; or the two R¹, when taken together, represent a C3-C5 alkanediyl or alkenediyl group optionally substituted;

[0011] R² or R³ represents, taken separately, a hydrogen atom or a C1-C4 alkyl group; and

[0012] R⁴ represents a C1-C4 acyl group; [0013] the method comprising the coupling of a compound of formula (II) with a compound of formula (III),

^R,O R,¹ (II)

[0014] wherein R¹ to R⁴ have the meaning indicated in formula (I) by using compounds of indium as a catalyst, the compounds being in anhydrous or hydrated form, and including salts thereof.

[0015] In some embodiments, the method comprises producing an intermediate mixture of isomers of 3-(1,1-dimethyl-2,3-dihydro-1H-inden-ar-yl)prop-1-en-1-yl acetate, comprising the steps of reacting 1,1-dimethyl-2,3-dihydro-1 H-indene with acrolein diacetyl acetal by using the compounds of the indium as the catalyst, wherein the fragrance and fragrance intermediates of formula (I) comprises the intermediate mixture of the isomers of 3-(1,1-dimethyl-2,3-dihydro-1H-inden-ar-yl)prop-1-en-1-yl acetate, the compound of formula (II) comprises the 1 ,1-dimethyl-2,3-dihydro-1 H-indene and the compound of formula (III) comprises the acrolein diacetyl acetal.

[0016] In some embodiments, the method comprises producing an intermediate mixture of isomers of 3-(1,1-dimethyl-2,3-dihydro-1H-inden-ar-yl)prop-1-en-1-yl acetate, comprising the steps of reacting 1,1-dimethyl-2,3-dihydro-1 H-indene with acrolein diacetyl acetal by using the compounds of the indium as the catalyst, wherein the fragrance and fragrance intermediates of formula (I) comprises the intermediate mixture of the isomers of 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)prop-1-en-1-yl acetate, the compound of formula (II) comprises the 1 ,1-dimethyl-2,3-dihydro-1 H-indene and the compound of formula (III) comprises the acrolein diacetyl acetal.

[0017] In some embodiments, the step of using the compounds of the indium provides a salt of indium including providing InCh in anhydrous form.

[0018] In some embodiments, the step of providing the InCh in anhydrous form includes providing 4 mol% of the InCh at reaction conditions of 75 °C & four hours.

[0019] In some embodiments, the method further comprises adding acetic anhydride. [0020] In some embodiments, the method further comprises providing acetic acid.

[0021] In some embodiments, the step of reacting is conducted in the absence of a solvent.

[0022] In some embodiments, the step of providing the InCh in anhydrous form includes providing 1 mol% of the InCh at reaction conditions of 100 °C & nine hours.

[0023] In some embodiments, the step of using the compounds of the indium provides a salt of indium includes providing InChin anhydrous form and includes providing a salt of aluminum.

[0024] In some embodiments, the step of using the compounds of the indium provides a salt of indium includes providing InChin anhydrous form and includes providing AlCh as the salt of aluminium, where the AICI3 is used in combination with the InCh.

[0025] In some embodiments, the step provides InCh on a 1 :1 basis with AICI3.

[0026] In some embodiments, the InCh is provided in an amount of 2 mol% and the AICI3 is provided in an amount of 2 mol% at reaction conditions of 75 °C & four hours.

[0027] In some embodiments, the InCh is provided in an amount of 1 mol% and the AICI3 is provided in an amount of 1 mol% at reaction conditions of 75 °C & four hours.

[0028] In some embodiments, the catalyst is supported on a silica substrate.

Brief Description of Figures

[0029] The above objects and other advantages of the invention will become more readily apparent upon reading the following description and drawings, in which:

[0030] Figure 1 is a general synthesis route of the end fragrance ingredients as 3- (1 ,1-dimethylindanyl)-propanal collectively represented by “4” with only the well-known last step from “3a” and “3b” proceeding to “4” shown with reagents. The preceding synthetic step leading to “3a” and “3b” is variable, as mentioned in the background of this specification.

[0031] Figure 2 shows an exemplary claimed intermediate synthesis route for producing the intermediate products, positional isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H- inden-ar-yl)prop-1-en-1-yl acetate which collectively is the name for a mixture of isomers. These intermediate products are mostly these isomers, 3-(1 ,1-dimethyl-2,3-dihydro-1 H- inden-5-yl)prop-1-en-1-yl acetate [represented by 3a] and 3-(1 ,1-dimethyl-2,3-dihydro-1 H- inden-6-yl)-prop-1-en-1-yl acetate,” represented by 3b] by reacting 1 , 1— dimethyl— 2,3— dihydro-1 H-indene represented by “1 ” with acrolein diacetyl acetal, represented by “2.” For purposes of simplicity, other reagents are omitted in the Scriabine reaction between 1,1— dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal.

[0032] Figure 3 shows the kinetic curve results for the Scriabine reaction between

1.1-dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal with 1 or 4 mol% of InCh as the catalyst at 75 °C.

[0033] Figure 4 shows the kinetic curve results for the Scriabine reaction between

1.1-dimethylindane and acrolein diacetyl acetal with different combined amounts of InCH and AlCh as catalysts.

Detailed Description of the Invention

[0034] The examples provided in the detailed description are merely examples and should not be used to limit the scope of the claims in any claim construction or interpretation.

[0035] The mentioned final mixture of isomers of 3-(2, 3-dihydro-1 ,1 -dimethyl-1 H- inden-ar-yl)-propanal, collectively represented by “4” includes the isomers of “3-

(2,3-dihydro-1 , 1 -dimethyl-1 H-inden-5-yl)-propanal and 3-(2,3-dihydro-1 , 1 -dimethyl-1 H- inden-6-yl)-propanal” as shown separately in Figure 1. The foregoing isomers of “4” are not separately identified in Figure 1 for purposes of simplicity because they are not subject of the claimed method.

[0036] As shown in Figure 2, which shows an example of the claimed method,

1.1-dimethyl-2,3-dihydro-1 H-indene (“1" in Figure 2) reacts with acrolein ketal (“2” in Figure 2) to yield this intermediate mixture of isomers of the mentioned 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl)prop-1-en-1-yl acetate,” mostly the isomers represented by 3a and 3b) in the presence of a compound of indium, InCH. Figure 2 omits an additional minor isomer, for purposes of simplicity. The claimed reactions as disclosed will produce “all intermediates,” including a minor isomer, as previously mentioned.

[0037] As known in the art, 1 ,1-dimethyl-2,3-dihydro-1 H-indene is also referred to as “1 ,1-dimethylindane” or referred to as “an indane” in this specification for simplicity.

[0038] In this specification, “intermediate mixture” and “intermediate products” are used interchangeably. [0039] In one example of a process, the Scriabine reaction of the indane 1 with the acrolein ketal 2 occurs to yield the intermediate mixture.

[0040] The intermediates products 3a and 3b are a mixture of positional isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl)prop-1-en-1-yl acetate, mostly the following intermediates, consisting of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)prop-1-en-1-yl acetate [represented by 3a] and 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-6-yl)-prop-1-en-1- yl acetate,” represented by 3b],

[0041] The end synthetic process starting from deprotection of fragrance intermediate mixture of isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl)prop-1-en- 1-yl acetate for producing the final end mixture of isomers which is shown as “4” in Figure 1 is known in the art. Figure 1 shows the final well-known last step of deprotection by hydrolysis.

[0042] However, the present specification discloses an improved process for forming an intermediate mixture of isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl) prop-1 - en-1-yl acetate using improved catalysts such as indium or a combination of indium and aluminum. InCh is a more soluble than FeCh in non-polar-organic solvents since the I n3⁺ cation has a lower positive charge I cationic radius than the Fe3⁺ cation. Many prior art processes to yield the intermediate mixture are burdened by high costs and the claimed process aims to reduce costs, by using the mentioned improved catalysts.

[0043] As shown in Figure 2, this claimed process focuses on the process to form intermediate products such as 3a and 3b by using salts of indium such as indium chloride as catalysts. The process of using these catalysts to form the mentioned intermediate products is believed to be not known in the art.

[0044] Moreover, it is believed that the claimed process uses lower amounts of 1 ,1 dimethyl indane as starting reactant material such as amounts of 100 mol%, 200 mol% or 400 mol%, for example, than what is believed to be known in the art by the inventors.

[0045] As known in the art, the abbreviations of “AcO” and “OAc”, used interchangeably in Figure 2, represent the acetoxy group while “AcOH” represents “acetic acid.” The term “Ac2O” in Figure 2 represents “acetic anhydride.”

[0046] Mol% being with reference to acrolein diacetyl acetal. The term “with mol% being with reference to acrolein diacetyl acetal,” as used in the specification means that 100 mol% of acrolein diacetyl acetal was used for a given experimental sample. For calculation of reagents, catalysts, solvents, etc., as well as yields, the reference is with respect to 100 mol% of acrolein diacetyl acetal as stated in the specification. [0047] The following describes the general experimental procedures followed in the examples in the specification.

Examples

Synthesis of intermediate products 3 (a)-(b)

[0048] The following describes an exemplary synthesis of all intermediate products including 3(a)-(b) in the presence of lnCl3'4H2O.

[0049] Acrolein diacetate (2.5 mmol), 1 ,1-dimethyl-2,3-dihydro-1 H-indene (400 mol%), and acetic anhydride (40 mol%) were mixed in a round-bottom flask and stirred at room temperature. lnCl3'4H2O (4 mol%) was dissolved in acetic acid and added to the mixture and allowed to react during the indicated reaction time at room temperature, 50 or 75 °C. The reaction was followed by GC and GC-MS.

Reactions with lower amounts of 1,1-dimethyl-2,3-dihydro-1 H-indene and without acetic anhydride

[0050] The foregoing procedure explained the process to obtain the intermediates including 3(a)-(b) for 3-(1 ,1-dimethylindanyl)-propanal, which was generally followed.

[0051] The following is an exemplary synthesis of the all intermediate products including 3(a)-(b) for 3-(1 ,1-dimethylindanyl)-propanal, in the presence of InCh.

[0052] Different amounts of 1 ,1-dimethyl-2,3-dihydro-1 H-indene were mixed with acrolein diacetate (2.5 mmol) in a round-bottom flask and stirred at different temperatures in the presence of different amounts of catalysts dissolved in acetic acid. The reaction was followed by GC and GC-MS.

Isolation of intermediates in gram-scale with InCh catalyst.

[0053] Following the above procedure for 400 mol% of 1 ,1-dimethyl-2,3-dihydro- 1 H-indene and 4 mol% of InCh at 75 °C, the reaction was stopped after 4 h, and the products were purified by flash column chromatography after aqueous work-up. The reference to “1” refers to “1” in Figure 2. The desired intermediates 3a and 3b were isolated with a 48% yield (896 mg).

[0054] In one example, the present process uses lnCh-4H2O as a catalyst.

[0055] The following Table 1 shows the results at room temperature for 72 hours reaction time, using 4 mol% of salt of indium metal as a catalyst and 5 mol% acetic anhydride and 1000 mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal (with mol% being with reference to acrolein diacetyl acetal). 5 mol% acetic acid was used for the experiments in Table 1. Thus, for 1000 mol% of 1 ,1-dimethyl-2,3-dihydro- 1 H-indene, 100 mol% of acrolein diacetyl acetal was used.

[0056] The corresponding anhydrous catalysts, after adding external water or not, were also examined.

Use of anhydrous InCh and increased temperature beneficial for catalytic results

[0057] The following Table 1 describes the results for the Scriabine reaction between 1 ,1-dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal with 4 mol% indium catalyst at 25 °C and 72 hours reaction time, with hydrated or anhydrous catalysts after addition of external water or no external water. However, the process for entry 4 was performed at 75 °C and 4 hours reaction time.

Table 1

[0058] The results show that using anhydrous InCh was optimal and increasing the temperature accompanied by reduced time was beneficial.

[0059] As the following will show, the use of anhydrous InCh is optimal, as the addition of water decreases the reaction. It can be seen that the conversion, selectivity and total yield results are significantly better with the anhydrous InCh as shown by entry 2 than with the hydrated complex catalyst (entry 1). For example, the yield percentage using anhydrous InCh is 15 times greater than the yield using lnCh 4H2O and water. [0060] It is also noted that the addition of external water to the reaction including anhydrous InCh as a catalyst decreases the conversion and yield (entry 3). Thus, it is preferrable to use anhydrous InCh for the synthesis reaction.

[0061] The following describes the conditions for entry 4 mentioned in Table 1 above.

Increased temperature followed by substantially decreased reaction time increased yield rates, conversion and selectivity rates

[0062] In order to further increase the reaction yield for the InCh catalyst and also decrease the reaction times, the temperature was increased from 25 °C to 75 °C, and the results at 4 hours reaction time (entry 4 of Table 1) show that a 4 mol% of InCh gives 98% conversion rate with approximately 69% selectivity rate for the desired products, maintaining the same isomer distribution of all intermediates.

[0063] Thus, the results in Table 1 show that the use of anhydrous conditions is preferred and that InCh is a very good catalyst for the reaction. In addition, substantially increased reaction temperature (three times greater, for example) accompanied by reduced reaction time are also factors influencing conversion rate, selectivity and yield rate.

HCI is not a catalyst for the reaction of 1,1-dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal in presence of InCh.

[0064] In order to disregard the effects and influence of catalytically active HCI produced by the potential decomposition of InCh during the reaction, the reaction was also performed with different amounts of HCI either combined with water or not including water.

[0065] The following Table 2 describes the reactions mentioned in Table 1 but using HCI and a temperature of 50 °C. The following reactions for Table 2 did not include InCh or lnCh'4H2O.

Table 2

[0066] The results in Table 2 show that HCI does not catalyze the reaction (entry 1), even when combined with H2O (entry 2). Thus, the results show that that the catalyst of the reaction is the anhydrous metal salt of indium.

[0067] The results in Tables 1 and 2 above employ 1000 mol% of 1 , 1— dimethyl— 2,3— dihydro-1 H-indene (acting both as reagent and solvent) and some acetic anhydride (~5 mol%).

[0068] The high excess of 1 , 1-dimethyl-2,3-dihydro-1 H-indene as a solvent can be explained by at least two main reasons: (1) for improvement of the activation of the inert C-H bond, and (2) to avoid the self-coupling of the more reactive acrolein derivative by dilution of the latter.

[0069] The following discusses kinetic studies using 1 mol % and 4 mol % of InCH. Kinetic studies were then performed with InCh as the catalyst (T=75 °C) to analyze the conversion at different times. Figure 3 shows that, indeed, at 120 minutes, the conversion was already >90%, when 4 mol% of InCh as catalyst were used. In view of this result, the amount of InCh was decreased to 1 mol%, and the corresponding kinetic curve shows that a 70% conversion is obtained after around 480 minutes increasing very slowly after that reaction time.

[0070] Acetic anhydride can be used to quench the water in reaction, and then improve the dryness of the reaction system and the catalytic activity.

[0071] Further use of catalytic InCh results in lower amounts of indane and absence of acetic anhydride

Reactions using 4 mol% of indium catalyst

[0072] The following Table 3 shows the results for the coupling reaction between different mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene or “indane” (“1” in Figure 2) and acrolein diacetyl acetal (“2” in Figure 2) (with mol% being with reference to acrolein diacetyl acetal) using 4 mol% catalyst (either in InCh or lnCl3.4H2O as a catalyst at 75° C and four hours reaction time with or without acetic anhydride. 5 mol% acetic acid was used for the experiments in Table 3.

Table 3

Complete conversion of acrolein diacetyl acetal was observed in all cases.

[0073] It can be seen that decreasing the amount of 1 , 1-dimethyl-2,3-dihydro-1 H- indene as a solvent from 1000 mol% (as performed in all entries in Tables 1 and 2) to 400 mol% such as entry 1 in Table 3 leads to a slight loss of yield (/.e., entry 1 in Table 3 with 66% yield vs entry 4 in Table 1 with 67.5%) despite all acrolein derivative being consumed.

[0074] By-products of acrolein diacetyl acetal were not detected by gas chromatography, which infers that these by-products are hydrolysis (acrolein) or oligomer by-products. Thus, the dilution of acrolein diacetyl acetal in the indane is mainly focused on diminishing these by-reactions.

[0075] Gratifyingly, reproduction of the reaction at 3 grams-scale could be performed, /.e., following the reaction conditions in entry 1 for Table 3, to isolate nearly 1 gram of intermediate products after column chromatography (48% yield).

[0076] A further decrease in the equivalents of 1 , 1-dimethyl-2,3-dihydro-1 H-indene from 400 mol% to 100 mol% (entries 3-5 and 8) produces a progressive decrease in the final yield, from 47% to 28%, still with complete conversion of acrolein diacetyl acetal in all cases.

Use of acetic anhydride

[0077] Regarding the use of hydrated metal salt and the absence of acetic anhydride, it can be seen (entries 2 and 5-7) that a similar and significant decrease in yield occurs in both cases (-9%), which in any case provides support that acetic anhydride helps to further dry the reaction mixture, without being bound by theory. Thus, the use of acetic anhydride may be beneficial.

[0078] When acetic anhydride is used, 5 mol% of acetic anhydride are used in Tables 1 and 3.

Use of acetic acid

[0079] A very small amount of acetic acid (~0.5 mol%) is still added to better dissolve the catalytic metal salt, and that other potential roles of the acetates (stabilizing the catalyst or reactant acrolein diacetyl acetal and better interaction between reactants) cannot be discarded. In other words, acetic acid could still be necessary but in very low amounts.

[0080] Without being bound by theory, the hydrolysis of acrolein diacetyl acetal to acrolein is a plausible theory, and that a throughout dryness of the reaction mixture may be needed.

Inclusion of AlChwith lnCI₃

[0081] The following describes the reaction of 120 mol% 1 ,1-dimethyl-2,3-dihydro- 1 H-indene with respect to acrolein diacetyl acetal in presence of InCh and AlCh .

[0082] The optimization of catalyst amount, reaction time and temperature were then evaluated using 120 mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene.

[0083] AlCh was also used, in combination with InCh. The results are shown in Table 4. Complete conversion of acrolein diacetyl acetal was observed in all cases.

[0084] The following T able 4 shows the results for the coupling reaction between 1,1— dimethyl-2,3-dihydro-1 H-indene (“1” in Figure 2) (120 mol%) and acrolein diacetyl acetal (“2” in Fig. 2) (with mol% being with reference to acrolein diacetyl acetal) using [0085] different amounts of catalyst (with reference to acrolein diacetyl acetal), with or without acetic anhydride. Complete conversion of acrolein diacetyl acetal was observed in all cases. 0.1 mg of InCh corresponds to 4 mol%.

Table 4

[0086] 5 mol% of acetic anhydride was used in the examples with acetic anhydride.

[0087] Acetic acid was not used in Table 4.

[0088] Optimal results are achieved using (1) a mixture of InCh and AICI3 (entry 3) at 75 °C, and (2) decreasing the amount of InCh (without AICI3) and increasing temperature and reaction time as shown in entry 7 at 100 °C.

Acetic anhydride needed in certain cases

[0089] As shown in entry 12 (without acetic anhydride), the presence of acetic anhydride is needed for many optimal conditions tested, because the yield for entry 12 decreases considerably when compared with entry 7 with acetic anhydride and 1 mol% of lnCI₃.

Acetic anhydride not needed in other cases

[0090] Nevertheless, under other reaction conditions for a combination of 1 mol% InCh and 1 mol% AlCh, the presence of acetic anhydride may not be needed in some particular cases, when comparing entry 4 (with acetic anhydride) and entry 11 without the presence of acetic anhydride.

[0091] Similarly, the results in entry 5 (with acetic anhydride), entry 10 (without acetic anhydride) and 11 (without acetic anhydride) are also good, using a mixture of lnCI₃ and AlCh.

[0092] For example, acetic anhydride and acetic acid assist the same catalytic system in order for the reaction to proceed to their maximum yields, but when they are used, they can contribute to a slight increase in yield, e.g., ⁺5-10% yield; however, their use must be considered in terms of cost considerations for any particular reaction conditions.

Use of N2 is beneficial unlike molecular sieves

[0093] As the following shows, the use of N2 atmosphere improves the reaction process slightly with use of molecular sieves being detrimental.

[0094] The use of a N2 atmosphere and molecular sieves, in order to avoid any water in the reaction medium, was tested, thus obtaining the results shown in Table 5.

[0095] Table 5 shows the results for the Scriabine reaction between 1 ,1—dimethyl— 2,3-dihydro-1 H-indene and acrolein diacetyl acetal with 4 mol% of lnCI₃ 4H2O at 50 °C, under N2 atmosphere and with or without molecular sieves.

Table 5

[0096] The presence of molecular sieves severely hampers the reaction yield, thereby leading to <10 % of the product, while the N2 atmosphere is somewhat beneficial to the reaction, although acrolein diacetate continues yielding by-products. The slightly better yield of the reaction under N2 atmosphere can be associated with the better residence of the volatile acetal in the liquid phase, due to the pressure, thus having a better contact with the other reagents.

[0097] In order to discard the formation of the more volatile acrolein from the acetal, (under typical reaction conditions having no N2 pressure), the reaction is performed in a sealed vial, where a sample of the gas phase is taken and analyzed on the GC-MS. However, peaks with a molecular weight of 56 g/mol (acrolein) were not observed.

[0098] Solvent-free conditions are better than using decaline as a solvent and higher temperature of 50 °C is optimal rather than lower temperature of 30 °C

[0099] As the following shows, the choice of a solvent and a decrease in reaction temperature were tested as factors influencing the rate of the reaction.

[00100] Then, the use of a solvent and decreasing the reaction temperature were tested in order to diminish the decomposition of acrolein diacetate.

[00101] Table 6 shows the results and the reaction ran slower under these conditions, and by-products are still forming.

[00102] Table 6 shows the results for the Scriabine reaction between 120 mol% 1 ,1— dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal (with mol% being with reference to acrolein diacetyl acetal) with 4 mol% of lnCl3'4H2O at 50 °C, using decaline as a solvent or decreasing the reaction temperature to 30 °C.

Table 6 Faster rates with InCh in early stages of reaction but replacement by AICI3 later on in reaction does not affect final outcome

[00103] Now different combinations of AICI3 and InCh were tested, in order to replace InCh by cheaper AlCh. Kinetic results are shown in Figure 4, where it can be seen that, after 24 h reaction time, up to 60% of InCh catalyst can be replaced by AlCh without a substantial erosion in the final yield, such as sample 0.06 mmol AlCh and 0.04 mmol of InCh. Although it is true that the initial rate is faster when more InCh is present in the reaction, final conversions are similar.

[00104] Figure 4 shows the kinetic results for the Scriabine reaction between 1,1— dimethyl-2,3-dihydro-1 H-indene and acrolein diacetyl acetal with 4 mol% of InCh + AlCh at 50 °C, in different proportions.

[00105] Different combinations of catalytic InCh and AlCh are symbiotic for the reaction, thus giving higher catalytic activity than if the salts were used separately. See Figure 4.

Use of acetic acid is optional

[00106] Then, the possible removal of acetic acid from the reaction medium was studied by adding InCh directly without dissolving. The yield of the intermediate products achieved was 32.0%, only 3.0% less than obtained with acetic acid. Thus, the results indicate that acetic acid can be removed, allowing to increase the throughput of the reaction.

[00107] In summary so far, InCh in combination or not with AlCh can be employed as a catalyst for the reaction, and a reduced level of <0.5 mol% of InCh allows one to achieve >60% or >40% yield (with 400 or 120 mol% of indane, respectively).

[00108] The use of AlCh as a co-catalyst is recommendable from an economic point of view as it is cheaper than InCh.

Solubility of InCh and AlCh in acetic anhydride

[00109] As the following shows, the addition of acetic anhydride from the reaction was studied. [00110] In the reaction conditions, 80 microliters (1 mmol, 40 mol%) of acetic anhydride per 29 mg (0.1 mmol, 4 mol% of lnCl3'4H2O or AICI3) . The foregoing amount of acetic anhydride is not enough to dissolve the catalysts.

[00111] Thus, sequentially added increasing amounts of acetic anhydride were made until dissolution of the salts, which occurred for InCh when 1 ml (12 mmol, 500 mol%) of acetic anhydride was added.

[00112] In contrast, AICI3 remained insoluble. Without being bound by theory, the results indicate that the role of acetic anhydride is not to dissolve the catalytic salts.

Effect of removal of acetic anhydride

[00113] The reaction was tested by removing acetic anhydride from the reaction mixture, and the results are shown in Table 7.

[00114] Table 7 shows the results for the Scriabine reaction between 120 mol% 1 ,1— dimethyl-2,3-dihydro-1 H-indene (“1 ” in Figure 2) and acrolein diacetyl acetal (“2” in Figure 2) (with mol% being with reference to acrolein diacetyl acetal) with 2-4 mol% of lnCl3'4H2O plus AICI3 at 75 °C, under the following conditions: (1) N2 atmosphere with acetic anhydride and acetic acid or (2) N2 atmosphere without neither acetic anhydride nor acetic acid. 5 mol% of acetic acid and 5 mol% of acetic anhydride were employed when noted.

Table 7

[00115] The results show that acetic anhydride can be removed from the reaction mixture without excessive decrease in the yield of products after 3 hours; contrast entry 2 vs. entry 3. Without being bound by theory, it is suggested that prolonging the reaction time in the absence of acetic anhydride will provide higher acceptable yields. Solvent effect on product yield

[00116] Finally, some solvents to increase the InCh and AICI3 solubility in the reaction of 120 mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene 1 and acrolein diacetyl acetal 2 (with mol% being with reference to acrolein diacetyl acetal) were tested. The amount of solvent added (280 mol%) is calculated to replace the amount of 1 , 1— dimethyl— 2,3— dihydro-1 H-indene when used in high excess (400 mol%). For example, 400 mol% of indane were replaced by 280 mol% of solvent accompanied by 120 mol% of indane.

[00117] The results are shown in Table 8.

[00118] Table 8 shows the yields obtained for the reaction with a mixture of soluble InCh (2 mol%) and AICI3 (2 mol%) in different organic solvents.

Table 8

[00119] Ratios of 1 ,1-dimethyl-2,3-dihydro-1 H-indene are described in the foregoing table with reference to acrolein diacetyl acetal used.

[00120] It can be seen that dichloromethane (DCM) and 1 ,2-dichlorobenzene (entries 1 and 6) provide similar yields as the solvent free reaction (entry 7), but are below the results with a similar reaction volume of 1 ,1-dimethyl-2,3-dihydro-1 H-indene (entry 8).

[00121] Thus, the results with using solvents in addition to 1 ,1-dimethyl-2,3-dihydro- 1 H-indene did not show improved results. Optimal results remained with using 400 mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene alone instead of 120 mol% of 1 , 1— dimethyl— 2,3— dihydro-1 H-indene in combination with solvents. Supported catalysts on solids

[00122] Since reactions can be conducted without acetic acid and acetic anhydride with similar reaction yields, two new solid catalysts with either InCh and AICI3 supported on high surface area silica were prepared.

[00123] Acetic acid and acetic anhydride are very polar molecules which easily promote the leaching of metal species from solids, but once these organic compounds are not present any longer in the reaction mixture, the reaction may be catalyzed by the supported salts without any leaching, since the reactants 1 ,1-dimethyl-2,3-dihydro-1 H- indene and acrolein diacetyl acetal are relatively non-polar compounds. Under the conditions of nonpolar compounds and the salts, the solid catalyst may be recycled and reused, enabling a cleaner, cheaper and more environmentally benign process, and also conceptually new from a catalytic point of view.

[00124] The synthetic procedure of the solid catalysts consists in a simple impregnation of the dissolved salts (1 wt%) in the silica until saturation, followed by dryness. This “incipient wetness” procedure is the more common procedure in industrial processes, since it is simple and affordable. Incipient wetness procedure is defined as the impregnation of the solid with a solution of the metal salt until the solid becomes a slurry.

[00125] With the solid catalysts in hand, reactions were tested under identical conditions but however, using salts. The results are shown in Table 9.

General procedure for the preparation of impregnated solid catalyst

[00126] The solid support was dried at 70 °C under vacuum for 4 h (70°C for silica, 150 °C for the zeolite). Then, the metal salt was dissolved in an organic solvent (InCh in acetonitrile) and added dropwise to the solid support (final metal content: 20 wt%). The mixture was stirred at room temperature for 3 hours and the solvent was evaporated by rotary evaporation. Finally, the catalyst was dried under vacuum, overnight.

Use of silica substrate

[00127] Table 9 shows the results for the Scriabine reaction between 120 mol% of 1 ,1-dimethyl-2,3-dihydro-1 H-indene (with mol% being with reference to acrolein diacetyl acetal )and acrolein diacetyl acetal catalyzed by 4 mol% (0.1 mmol) of InCh- silica or AlCh- sil ica, or both, at 75 °C, under N2 atmosphere, and without any acetic acid and any acetic anhydride.

Table 9

[00128] The yields obtained are only slightly lower than those obtained with the salts alone in solution.

[00129] As the above data shows, using AICI3 alone with a silica substrate did not yield results. However, reducing InCh concentration by a half and replacing the amount with AICI3 surprisingly led to a similar yield as the silica-supported InCh.

[00130] These results lead to a new line of applicability covering recyclability of the solid catalysts, with an increase in the metal loading on the solid (more efficient), coincorporation of both metals on the same solid (symbiotic) and allowing for in-flow reactions, i.e. reactions in continuous mode, such in fixed-bed tubular reactors.

[00131] The following observations from the results in the specification are now discussed.

[00132] The synthesis of the intermediates for 3-(1 ,1-dimethylindanyl)-propanal is efficiently catalyzed by InCh, with or without AICI3 as a co-catalyst.

[00133] The catalytic salt may also be supported on solids, which further differentiates the disclosed process.

[00134] A decrease in the high excess of indane is allowed and this can lead to just 120 mol% of indane, which is believed to be lower than previously known procedures by the inventors.

[00135] The reaction may also be run in the absence of a solvent, with a good throughput. A preliminary economic analysis shows that the disclosed catalytic system is economically feasible and can be used to produce 3-(1,1-dimethylindanyl)-propanal in lower prices and can be profitably sold. Alternative catalysts

[00136] The specification discloses chloride salts of indium as exemplary catalysts. Salts of other halides such as fluoride, bromide and iodide may be used. For example, other indium (III) halides (fluoride, bromide, iodide) may be considered. In addition, Indium salts of carboxylic acids such as indium acetate may be used as additional alternatives.

For example, indium (III) salts of carboxylic acids, like indium (III) acetate, may be considered.

[00137] In addition, other salts of Group 13 elements may be used as alternative catalysts for the claimed method. [00138] The range of recited numerical values disclosed in the specification includes values, e.g., +/— 5-10% of the recited value, that a person of ordinary skill in the art would consider equivalent to the recited value, e.g., having the same function or result.

[00139] The claims are not limited by the preferred embodiments and examples but will cover many modifications and equivalents consistent with the written description as a whole.

Claims

What is claimed is:

1 . A method for producing fragrances and fragrance intermediates of formula (I): wherein the wavy line indicates that the double bond can be in a configuration E or Z or a mixture thereof; the two R¹, taken separately, can represent a hydrogen atom and the other a C1-C4 alkyl group; or the two R¹, when taken together, represent a C3-C5 alkanediyl or alkenediyl group optionally substituted;

R² or R³ represents, taken separately, a hydrogen atom or a C1-C4 alkyl group; and

R⁴ represents a C1-C4 acyl group; the method comprising the coupling of a compound of formula (II) with a compound of formula (III), wherein R¹ to R⁴ have the meaning indicated in formula (I) by using compounds of indium as a catalyst, the compounds being in anhydrous or hydrated form, and including salts thereof.

2. The method of Claim 1 , wherein the method for producing the fragrances and fragrance intermediates of formula (I) comprises producing an intermediate mixture of isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl)prop-1-en-1-yl acetate, the method comprising the steps of reacting 1 ,1-dimethyl-2,3-dihydro-1 H-indene with acrolein diacetyl acetal by using the compounds of the indium as the catalyst, the fragrance and fragrance intermediates of formula (I) comprises the intermediate mixture of the isomers of 3-(1 ,1-dimethyl-2,3-dihydro-1 H-inden-ar-yl)prop-1-en-1-yl acetate, the compound of formula (II) comprises the 1 ,1-dimethyl-2,3-dihydro-1 H-indene and the compound of formula (III) comprises the acrolein diacetyl acetal.

3. The method of Claim 2, wherein the step of using the compounds of the indium provides a salt of indium including providing InCh in anhydrous form.

4. The method of claim 3, wherein the step of providing the InCh in anhydrous form includes providing 4 mol% of the InCh at reaction conditions of 75 °C & four hours.

5. The method of Claim 3, further comprising adding acetic anhydride.

6. The method of Claim 3, further comprising providing acetic acid.

7. The method of Claim 2, wherein the step of reacting is conducted in the absence of a solvent.

8. The method of Claim 3, wherein the step of providing the InCh in anhydrous form includes providing 1 mol% of the InCh at reaction conditions of 100 °C & nine hours.

9. The method of Claim 3, wherein the step of using the compounds of the indium provides a salt of indium includes providing InChin anhydrous form and includes providing a salt of aluminum.

10. The method of Claim 3, wherein the step of using the compounds of the indium provides a salt of indium includes providing InCh in anhydrous form and includes providing AlCh as the salt of aluminium, where the AlCh is used in combination with the InCh.

11. The method of Claim 10, wherein the step provides InCh on a 1 :1 basis with AlCh.

12. The method of Claim 10, wherein the InCh is provided in an amount of 2 mol% and the AlCh is provided in an amount of 2 mol% at reaction conditions of 75 °C & four hours.

13. The method of Claim 10, wherein the InCh is provided in an amount of 1 mol% and the AlCh is provided in an amount of 1 mol% at reaction conditions of 75 °C & four hours.

14. The method of Claim 1 , wherein the catalyst is supported on a silica substrate.