WO1993010071A1

WO1993010071A1 - Process for the production of carbonyls

Info

Publication number: WO1993010071A1
Application number: PCT/US1992/010097
Authority: WO
Inventors: Roy A. Periana
Original assignee: Catalytica Inc
Current assignee: Catalytica Inc
Priority date: 1991-11-22
Filing date: 1992-11-23
Publication date: 1993-05-27
Anticipated expiration: 1994-05-22

Abstract

This invention is a noncatalyzed process for the production of carbonyls, particularly β-hydroxy aldehydes, by the aldol condensation of, for example, acetophenone and formaldehyde. In this process, neither base nor acid is added to the reaction mixture. Operation of a specific variation of the process results in a high yield of 3-hydroxy-1-phenyl-1-propanone and, because of the absence of added catalysts and of the choice of reaction conditions, does not produce significant amounts of dehydration products such as 1-phenyl-2-propene-1-one or of overcondensation products.

Description

PROCESS FOR THE PRODUCTION OF CARBONYLS

Field of the Invention

This invention is a noncatalyzed process for the production of carbonyls, particularly /S-hydroxy aldehydes or ketones, by the aldol condensation of, for example, acetophenone and formaldehyde. In this process, neither base nor acid is present nor added to the reaction mixture. Operation of a specific variation of the process results in a high yield of 3-hydroxy-l- phenyl-1-propanone and, because of the absence of added catalysts and of the choice of reaction conditions, does not produce significant amounts of dehydration products such as l-phenyl-2-propene-l-one (in the case of a desired 3-hydroxy-l-phenyl-l-propene product) or of overcondensation products.

Background of the Invention

Aldol condensations are among the most well known and important carbon-carbon forming reactions available to the chemist. In aldol reactions, two molecules of a carbonyl combine to form a /3-hydroxyaldehyde or a S-hydroxyketone. The product results from addition of one molecule of aldehyde or ketone to another aldehyde or ketone molecule such that the α-carbon of the second becomes attached to the carbonyl carbon of the first. These reactions typically require the use of acid or base catalysts.

Aldol reactions using two different carbonyl compounds -- so-called "crossed-aldol condensation" reactions -- are not always desirable reaction schemes in that four different reaction products may be directly produced. If the products are separable, perhaps the crossed aldol process may be made into an acceptable procedure, but this is not necessarily true. Under certain conditions, a good yield of a single product may be obtained from a crossed-aldol condensation if one reactant contains no α-hydrogens and therefore is not capable of condensing with itself (e.g., aromatic aldehydes or formaldehydes) . However, even in this case it is usually difficult to stop the reaction at the aldol product, 3-hydroxy-ketone, since this product is typically more reactive than the starting materials. Thus, the aldol product (3-hydroxy-ketone) can readily react to produce 1,2-unsatura ed carbonyl compounds by dehydration reactions or 3,4-dihydroxy-ketones by further reaction of the aldol product with more aldehyde. Since dehydration and overcondensation reactions are predominant reaction pathways in aldol reaction media, many workers have developed techniques to avoid these reactions and allow isolation of the intermediate S-hydroxy-carbonyl products. These techniques all require the use of added regents used in stoichiometric amounts (e.g., lithium diisopropyl amide, trimethyl silyl fluoride, ZnCl₂, or TiCl₄) . See, for instance, J. March, Advanced Organic Chemistry. Second ed., McGraw-Hill, 1977. The use of these reagents greatly adds to the cost of preparing 0-hydroxy-ketone products via the aldol reaction of ketones and aldehydes. Elimination of the need for these reactants would represent a significant improvement in the procedure of forming jS-hydroxy-ketones from ketones and aldehydes. This "overreac ion" problem in the classic aldol reaction as the reaction is used in the production of β-hydroxy-carbonyls is clearly illustrated by the attempted synthesis of 3-hydroxy-l-phenyl-l-propanone from acetophenone and formaldehyde.

3-hydroxy-l-phenyl-l-propanone is a material used in the manufacture of pharmaceutical intermediates and as a precursor to perfume intermediates. It is typically made using the selective reduction of methyl-3- phenyl-3-keto-l-propionate (Chem. Pharm. Bull., 34(7) 3029, 1986) or by the selective oxidation of 1,3- dihydroxy-1-phenyl-propane (Tet. Lett. 30(19), 2559, 1989).

The aldol reaction of acetophenone and formaldehyde has been studied by several researchers. As is typical of aldol reactions, these materials are reacted in the presence of base or acid catalysts. Under typical aldol conditions, the condensation reaction leads to low yields of 3-hydroxy-l-phenyl-l-propanone. The major products result from overcondensation reactions of 3-hydroxy-l-phenyl-l-propanone. See, Heeringa et al., RECUIEL, "On the Reaction of Acetophenone with Formaldehyde", 76, pp. 213-220 (1957); Fuson et al., J. Am. Chem. Soc, 60, 2935 (1938).

In contrast to these teachings, a report by Russian workers (Mek tiev et al., Dokl. Akad. Nauk Azerb. SSR, 27(5), 38-40 (1971)) describes the acid-catalyzed reaction of acetophenone with formaldehyde. The reaction product is said to include 3-hydroxy-l-phenyl-l-propanone in high yield (64%) . This product is unexpected in that the reaction was carried out under "standard" aldol conditions using I^PO^ as the catalyst. None of these documents show an uncatalyzed aldol process for the production of organic carbonyls from aldehydes and ketones. S-_ππιarγ of the Invention

I have surprisingly found that by carefully eliminating the acidic and basic catalytic materials taught as necessary for classic aldol reactions and by controlling the temperature of the reaction (so as not to thermally decompose the β-hydroxy-carbonyl product) , the yield of β-hydroxy-ketones is quite high. The mechanisms of acid- and base-catalyzed aldol reactions have been extensively investigated and are well known (see J. March, Advanced Organic Chemistry, Second Ed., McGraw- Hill, 1977) . In the case of acid catalysis, the mechanism is proposed to occur via attack of the protonated aldehyde on the enol form of the ketone. Thus, the presence of protonated aldehydes and the extent of enolization of the ketone are important factors in determining the relative reactivity of ketones in acid- catalyzed reactions. Since /S-hydroxy-ketones readily produce the enol form, these materials are very susceptible to overcondensation by reaction with protonated aldehydes. This typically leads to low yields of jff-hydroxy-ketones in acid-catalyzed aldol reactions.

In the case of base-catalyzed aldol reactions, reaction is typically initiated by the formation of enolate species by reaction of the base with the acidic alpha-hydrogens of the ketone. These species then attack the aldehyde in a condensation reaction to produce the hydroxy-ketone. Thus, the acidity of the alpha-hydrogens in the ketone is an important factor in determining the relative reactivity of ketones in the reaction. Since β- hydroxy-ketones are relatively acidic and readily produce reactive enolates, these materials are also susceptible to overcondensation with aldehydes in base-catalyzed aldol reactions. This typically leads to low yields of ?-hydroxy-ketones in base-catalyzed aldol reactions. Additionally, since the dehydration of β- hydroxy-ketones can be either acid- or base-catalyzed, aldol reactions catalyzed by these species typically result in dehydration and formation of α,j8-unsaturated carbonyl compounds as the main product.

I have found novel conditions permitting the aldol condensation to produce high yields of the ø-hydroxy-ketones. In contrast to the classical aldol conditions, my process involves the careful exclusion of all general bases (species that could allow the generation of enolates) and general acids (species that could coordinate to carbonyl oxygen and generate electrophilic carbonyl species) and the use of high temperature to allow thermal reaction of the carbonyl compounds.

Since bases and acids are substantially excluded from the reaction system, the concentrations of species such as protonated aldehydes (produced by protonation) or enolates (produced by base attack) are low. Product decomposition by these intermediates or by acid/base-catalyzed dehydration is minimized.

In addition to the generic usage of this process, it is especially suitable for the production of 3-hydroxy-l-phenyl-l-propanone from acetophenone and formaldehyde in high yield.

The condensation reaction is between an "acceptor compound" which is capable of forming an anion at the carbon o. to the carbonyl and a "donor compound" which provides the electron poor carbonyl carbon.

Description of the Invention

This invention is a process for the condensation of aldehydes or ketones or mixtures of ketones and aldehydes to produce jS-hydroxyketones. The process does not use either an acid or a base catalyst nor any other identifiable catalytic material.

This process may employ acceptor aldehydes or ketones of the formula:

wherein each of R¹ and R² is independently H, a branched or linear alkyl or alkylene group having one to 12 carbon atoms, an alkylaryl group having seven to 20 carbon atoms, or an aryl group having six to 20 carbon atoms; wherein any of said aryl group is unsubstituted or substituted by 1-5 substituents such as alkyl(1-6C), nitro, halo, alkoxy(l-6C) and the like, with the proviso that at least one of R¹ and R² must contain an αH.

The carbonyl donor is of the similar formula,

(2),

wherein R³ and R⁴ are defined as for R¹ and R², except that the proviso is not required. Preferably, one of R³ and R⁴ is H. The process may use single ketones, mixtures of ketones, single aldehydes, mixtures of aldehydes, and mixtures of ketones and aldehydes.

Preferred embodiments of the acceptor compound include those wherein one of R¹ or R² is alkyl(1-6C) and the other is aryl. Especially preferred aryl substituents include phenyl, optionally substituted with

1-3 alkyl(1-6C), halo, or nitro, or combinations thereof.

An especially preferred alkyl substituent in the compound of formula (1) is methyl. Preferred embodiments of the donor compound include those wherein one of R³ and R⁴ is H, especially wherein both of R³ and R⁴ are H. Preferably, the process couples a ketone to an aldehyde. The reaction, as noted elsewhere, is carried out in the substantial absence of all general bases (species tending to form the generation of enolates) and all general acids (species tending to coordinate to carbonyl oxygen and generate carbonyl species) . No acidic or basic material is added to the reaction mixture, and the feedstocks are treated to remove, in a substantial fashion, any acids or bases which may be found in those feeds.

The temperature of reaction is somewhat higher than that used in classical aldol reactions, typically 100°C or greater. Preferred is 100°C to the boiling point of the feeds at the pressure of operation. More preferred is 100°C to 225°C.

Pressure of operations is not important except to the extent required to maintain the reaction mixture in the liquid phase and at the chosen temperature.

Reaction solvents may be used, if so desired. Polar solvents are particularly suitable.

I have applied these novel reaction conditions to the condensation of acetophenone and formaldehyde in order to produce 3-hydroxy-l-phenyl-l-propanone. As discussed above, this material is useful as a perfume intermediate and pharmaceutical intermediate, and an inexpensive synthesis is desirable. The present commercial syntheses involving reduction of methyl 3- phenyl-keto-1-propionate or the oxidation of 1,3- dihydroxy-1-phenyl-propane are more expensive than a direct route from acetophenone and formaldehyde. However, as discussed above, no method based on the application of acid- or base-catalyzed aldol reactions allows this material to be generated in isolatable quantities. However, by the application of our conditions, acetophenone and formaldehyde can be reacted to produce 3-hydroxy-propiophenone in ~47% isolated yield.

As with the generic process, the rigorous exclusion of acid or basic species is required. The reaction with acetophenone and formaldehyde should be run about 100°C. Decomposition can occur at higher temperatures and the reaction is best run between 100°C and 225°C. The yield of product is also dependent upon reaction time and upon the reaction temperature. In general, shorter reaction times are required with higher temperatures, and at 175°C a desirable reaction time is 1 hr. At longer reaction times, product decomposition occurs, leading to lower yields. The ratio of reactants (acetophenone:formaldehyde) is not critical. However, to maximize selectivity, the reaction is best run with an excess of the acetophenone over the formaldehyde. As the excess of acetophenone is increased, the selectivity is increased. To ensure this excess of acetophenone over formaldehyde during reaction while maximizing selectivity, the reaction can be carried out with the slow addition of formaldehyde to the acetophenone. Under these conditions, the ratio of acetophenone to formaldehyde will be the highest resulting in high yields. Reaction solvents may be used, so long as the solvent is stable to the reaction conditions. The reaction may also be run without a solvent. In the case of acetophenone and formalin (a 37°C aqueous solution of formaldehyde) , agitation of the reaction mixture is desirable. However, if the reactants are miscible, stirring is not required. At reaction temperatures above the^' boiling points of the reactants, pressurizing the reactor so to maintain the reactants in the liquid phase is desirable.

I have found that the reaction works best if the reactants are carefully purified to remove all basic or acidic species. In the case of acetophenone, this is easily done by distillation, although other methods such as the use of ion-exchange columns are suitable. In the case of formalin, since this material cannot be distilled, it should be purified by the use of ion- exchange resins. Although purification of commercially available laboratory feedstocks is not absolutely necessary, it is a desirable step. Good yields can be obtained with commercial grade formalin. However, since formalin typically contains formic acid that can catalyze undesirable side reactions, the highest yields are obtained if such materials are removed. Importantly, I have found that simple neutralization of these solutions with an acid or base leads to poor yields since the products of the neutralization, e.g., sodium formate generated from the neutralization of formic acid with sodium hydroxide, are themselves catalysts which promote side reactions. In general, I have found most salts will catalyze undesirable side reactions. Thus, in addition to the reactants, all equipment should be free of salts, acids, and bases.

The reaction is stopped by cooling the mixture, preferably to less than 50°C. Product isolation can be carried out simply by flash distillation to remove excess reagents or solvents, followed by a second flash distillation to isolate the product. Any reaction vessel capable of containing the reaction without excessive corrosion would be suitable.

In the reaction between acetophenone and formaldehyde, various forms of formaldehyde may be used. Reaction with formalin (a commercial solution of 37% formaldehyde in water) , dimethoxy methane (the dimethyl acetal of formaldehyde) , trioxane (the trimer of formaldehyde) or gaseous formaldehyde will result in formation of 3-hydroxy-propiophenone. However, because of its commercial availability, formalin is the most preferred form.

I have shown the invention above by direct description. The examples below are intended to further the description of the invention. They are, however, only examples and are not to limit the claimed scope of the invention in any way.

Examples

Example 1

A 5-gallon reactor (carefully cleaned to remove any impurities that may act as catalysts) was charged with 13.41 of acetophenone and 1.7 1 of 37 wt% formaldehyde in water (5:1 molar ratio of acetophenone to formaldehyde) . The reactor was sealed, purged with N₂, and heated to 175°C with stirring. After 70 minutes, the reaction was stopped by cooling the reactor to room temperature. The solution was allowed to separate into aqueous and organic layers. The organic layer was removed. The organic layer was flash-distilled to remove the excess acetophenone (100^βC under 10 mmHg) and the crude 3-hydroxy-1-phenyl-propanone was obtained by distillation of the crude material, discarding the first and last cuts. The yield of 3-hydroxy-1-phenyl-l- propanone was 1.6 kg (47% based on added formaldehyde).

Example 2

To show that para-formaldehyde was suitable as a feedstock in the process, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 0.68 g of finely ground solid para-formaldehyde. The yield of 3- hydroxy-l-phenyl-l-propanone was 0.2 g (6% based on added formaldehyde) .

Example 3

To show that trioxane was suitable as a feedstock in the process, the procedure of Example 1 was repeated with 13.4 ml of acetophenone, 0.68 g of trioxane (a tri er of formaldehyde) and 1 g of water. The yield of 3-hydroxy-l-phenyl-l-propanone was 0.1 g (3% based on added formaldehyde) .

Example 4

To show that dimethoxymethane was suitable as a feedstock in the process, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 1.74 g of dimethoxy methane (an acetal of formaldehyde) and 1 g of water. The yield of 3-hydroxy-l-phenyl-l-propanone was 0.6 g (18% based on added formaldehyde) .

Example 5

To show that removal of acidic and basic impurities is a useful process step, the procedure of Example 1 was repeated with 13.4 ml of freshly distilled acetophenone and 1.7 ml of 37 wt% formalin which was neutralized by passing over basic alumina. The yield of 3-hydroxy-l-phenyl-l-propanone was 2 g (59% based on added formaldehyde) .

Example 6

To show the effect of reaction time on yield, the procedure of Example 1 was repeated with 13.4 of acetophenone and 1.7 ml of 37 wt% formalin. In contrast to the reaction time of Example 1 (70 minutes) , the reaction time was extended to 2 hours. The yield of 3- hydroxy-l-phenyl-l-propanone was 0.1 g (3% based on added formaldehyde) .

Example 7 In order to show the effect of temperature on the reaction, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 1.7 ml of 37 wt% formalin with a reaction temperature of 250°C. 3-hydroxy-l-phenyl-l-propanone could not be detected in or isolated from the reaction stream.

Example 8

To show the positive effect of stirring upon the reaction, the procedure of Example 1 (in which vigorous stirring was utilized) was again repeated using 13.4 ml of acetophenone and 1.7 ml of 37 wt% formalin but without stirring. In sharp contrast to the high yield of Example 1, the yield of 3-hydroxy-l-phenyl-l-propanone in this example was 0.7 g (21% based on added formaldehyde) .

Comparative Example

As comparative examples showing the effect of acids and bases upon the reaction, the procedure of Example 1 was repeated in a series of runs, both at 80°C and at 25°C variously in the presence of 5 mol% (based on formaldehyde) of: i) H₂S0₄, ii) H₃P0₅, iii) NaOH, and iv) KOH.

In each of these cases, the yield of 3-hydrox - propiophenone based on GC analysis was <2% and the desired product could not be isolated from the reaction mixture by distillation. The invention has been shown both by description and by examples. It is evident that those having ordinary skill in this art will envision other processes which are equivalent to those found in the claims which follow. It is my intent that those equivalents which are within the spirit of my invention should also be included in the protection of this patent.

Claims

What is claimed is:

1. A process for the condensation of an acceptor compound of the formula:

(1)

R¹ C R²

wherein each of R¹ and R² is independently H, a branched or linear alkyl group having one to 12 carbon atoms, an alkylaryl group having seven to 20 carbon atoms, wherein said aryl is substituted or unsubstituted, or a substituted or unsubstituted aryl group having six to 20 carbon atoms, with the proviso that at least one of R¹ and R² contains an αH, with a donor compound of the formula,

wherein each of R³ and R⁴ is independently H, a branched or linear alkyl group having one to 12 carbon atoms, an alkyaryl group having seven to 20 carbon atoms, wherein said aryl is substituted or unsubstituted, or an unsubstituted or substituted aryl group having six to 20 carbon atoms, comprising the step of contacting a compound of formula (1) or with a compound of formula (2) at a temperature above 100°C in the liquid phase in the substantial absence of general bases and general acids.

2. The process of claim 1 where the major condensation product is a j8-hydroxyketone.

3. The process of claim 1 where the temperature is between 100°C and 225°C.

4. The process of claim 1 where the compounds of formulas (1) and (2) are purified to substantially remove any general acids and general bases.

5. The process of claim 1 wherein in the acceptor compound of formula (1) at least one of R¹ and R² is CH₃.

6. The process of claim 1 wherein the donor compound is an aldehyde.

7. The process of claim 1 wherein the acceptor compound is acetophenone and the donor compound is formaldehyde.

8. A process for the production of 3-hydroxy- l-phenyl-l-propanone, or 3-hydroxypropiophenone, by the aldol condensation of acetophenone and formaldehyde in the substantial absence of base and acid in the reaction mixture.

9. The process of claim 1 in which the acetophenone and formaldehyde are treated to remove acids and bases.