Selective aldol condensation or cyclotrimerization reactions catalyzed by FeCl3

Tetrahedron Letters xxx (2015) xxx–xxx

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Selective aldol condensation or cyclotrimerization reactions catalyzed by FeCl3 Renzo Arias-Ugarte, Francis S. Wekesa, Michael Findlater ⇑ Texas Tech University, Department of Chemistry and Biochemistry, Lubbock, TX 79409, USA

a r t i c l e

i n f o

Article history: Received 31 January 2015 Revised 4 March 2015 Accepted 10 March 2015 Available online xxxx Keywords: Aldehydes Aldol reactions Cyclotrimerization Lewis acid Catalysis

a b s t r a c t The inexpensive and commercially available FeCl3 catalyzes the selective homo-aldol condensation of aldehydes into the corresponding a–b unsaturated aldehydes, presumably through an unobserved aldol intermediate. Surprisingly the reaction course can be diverted to produce 1,3,5-trioxanes via aldehyde cyclotrimerization. Selectivity for trioxanes is achieved at lower temperatures and is enhanced by the presence of water, contrary to prior reports. A broad range of aliphatic and aromatic aldehydes are capable of undergoing these transformations; short reaction times, high yields, scalability, and easy purification processes are also described. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Aldol condensation reactions are one of the main synthetic tools for the construction of C–C bonds, both in nature and in synthetic chemistry.1 The resulting b hydroxy aldehydes are found in many important synthetic targets, including natural products.2a The dehydrated a–b unsaturated aldehyde derivatives are present in important biologically active compounds2b and find important applications in the fields of pharmaceutical, fragrance, plasticizer, detergent, and cosmetic chemistry.3 For example, 2-ethylhexenal is prepared from homo-aldol condensation of butanal. Both 2-ethylhexenal and the product of its hydrogenation (2-ethylhexanol) are valuable commodity chemicals and are used in the synthesis of detergents, plasticizers, coatings, and adhesives. Lastly, the homo-aldol product of pentanal is commercially important and used in the synthesis of plasticizers and detergent alcohols.4 However, the generation of homo-aldol condensation products is not a trivial nor straightforward matter as the reactions tend to be non-selective and generally these products are reported as side products from the more useful crossed-aldol reaction.5 Thus, a great deal of synthetic effort has been focused in this area. One of the major contributions achieved by the Mukaiyama aldol reaction has been the introduction of the use of enolizable aldehydes.6a This has been the basis for many developments in C–C bond ⇑ Corresponding author. Tel.: +1 806 834 8976. E-mail address: michael.fi[email protected] (M. Findlater).

formation chemistry.6b Nevertheless, the majority of the methods disclosed thus far have reported a reduction in the efficiency of the reaction when enolizable aldehydes are used.7 Classically, homo-aldol condensation reactions of aldehydes have been carried out in the presence of aqueous sodium hydroxide8 or boric acid in refluxing xylene,9 however these conditions are not environmentally friendly since higher concentrations of corrosive residues are produced. In that sense greener alternatives have been described in the literature to catalyze the homo-aldol condensation of aldehydes, for example, the use of pyrrolidine to catalyze the homo-aldol condensation of aliphatic aldehydes; in the presence of benzoic acid or (p-dimethylamino)benzoate as cocatalyst.10,11 Analogously, diphenylboron perchlorate (Ph2BClO4), has been successfully used for self and cross condensation reactions of aliphatic and aromatic aldehydes.12 Enhanced catalytic activity has been observed employing a heterogeneous catalyst system, 3-N-methylaminopropylated mesoporous silica was shown to possess catalytic activity higher than the homogenous amine.13 Moreover, the catalyst could be easily recovered by filtration.13 Other heterogeneous reactions have been reported using heteropolyacids,14 chlorinated silica gel,15 and a solid base catalyst containing aminopropyltrimethoxysilane functionalized chitosan.16 Further synthetic methodologies for the self condensation of aldehydes have been designed to be used under solvent free conditions; typically microwave irradiation is employed in the presence of catalytic amounts of lysine,17 and Et3N–LiClO4.18 In general, these synthetic methodologies are applicable to only a small range

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of systems that tolerate the peculiarities of a given set of reagents. A selective, inexpensive, and effective catalyst with a broad substrate scope is still missing. The dimerization of aldehydes to form C–C bonds is not limited to b hydroxy carbonyl or the dehydrated a–b unsaturated carbonyl products, the cyclotrimerization of aldehydes to form the well-known 1,3,5-trioxane materials is also known. Trioxanes play an important role in many industrial applications, such as stabilizers in color photography, burning regulators in fumigants, flavoring materials, carriers for scents, repellents, deodorants, and insecticides.19a There are a limited number of reports which describe the synthesis of such materials from moderate to high yields,19b–k and only two reports where a mixture of different products such as, b hydroxy aldehydes, a–b unsaturated aldehydes, b hydroxyesters (Tishchenko’s reaction) and trioxanes have been reported but always as a complex mixture of products.5b,20 To our knowledge there is not a single report of a catalytic system with the ability to selectively induce both the homo-aldol condensation of aldehydes (1) into the a–b unsaturated aldehyde (2) and also the cyclotrimerization of aldehydes to form trioxanes (3). Herein, we report a new synthetic approach which displays dual catalytic activity for both the homo-condensation and cyclotrimerization of aldehydes and uses the inexpensive and commercially available FeCl3, salt as catalyst.

ð1Þ

We have recently disclosed the ability of FeCl3 to effect the dimerization of cycloolefins (Eq. (1)), potentially through the intermediacy of a radical species.21 Spurred by these preliminary findings and a recent report from Han and coworkers,22 we were

interested in exploring the potential of C–C coupling reactions between cycloolefins and aldehydes. Initial experiments found that FeCl3 could indeed catalyze the C–C coupling of aldehydes with 1-methylcyclohexene (MCH) with almost quantitative substrate consumption and selectivity for C–C coupled products of almost 65% (Eq. 2 and Figs. S54–S56 in Supplemental information).

ð2Þ

On the basis of these results, we attempted to extend the utility of this transformation to aldehyde substrates with 1 or 2 a-hydrogens. Unfortunately, these reactions afforded a complex mixture of molecules that did not include the desired C–C coupling products. However, the formation of a–b unsaturated aldehydes (2) and trioxanes (3) was detected by GC–mass spectrometry (Fig. S57). Prompted by the generation of two unexpected, and distinct, reaction products we decided to explore the development of a viable catalytic protocol with product selectivity. Results and discussion Reaction optimization and substrate scope Initially, we choose valeraldehyde (1a) as a model substrate with which to explore the effects of reaction conditions (temperature, catalyst loading, solvent) on product distribution. Shown in Table 1 are our preliminary findings. From these results, we can conclude that the selective cyclotrimerization of valeraldehyde to 1,3,5-trioxane (3a) is favored at lower temperatures (Table 1, entry

Table 1 Optimization of conditions in homo-aldol condensation and cyclotrimerization reactions with valeraldehyde as model substrate

a b c d e f g

Entry

Time (h)

Temp (°C)

Solvent/aldehyde

Aldehyde consumptiona (%)

a,b-Unsaturated aldehydea (%)

1,3,5-Trioxanea (%)

Selectivity (2) (%)

(3) (%)

1b 2b 3b 4b 5b 6c 7c 8d 9d 10e 11e 12f 13f 14g 15g

1 24 2 5 12 0.5 12 0.5 12 4 24 0.5 0.5 4 12

RT RT 30 60 60 30 RT 30 RT RT RT 30 30 30 RT

1:3 1:3 1:3 1:3 1:3 3:1 3:1 3:1 3:1 0:1 0:1 2:1 4:1 2:1 2:1

59 98 94 95 96 91 100 91 93 21 96 28 26 72 75

0 3 10 17 19 0 0 0 0 21 96 18 16 0 0

30 0 9 2 1 51 0 54 0 0 0 5 4 72 75

0 3 10 18 20 0 0 0 0 100 100 18 16 0 0

50 0 9 2 1 56 0 60 0 0 0 5 4 100 100

to 60

to RT to RT

to RT to RT to RT

Calculated from GC–MS. FeCl3 (5 mol %), solvent = MCH. FeCl3 (20 mol %), solvent = MCH. FeCl3 (2 mol %), solvent = MCH. FeCl3 (10 mol %), no solvent. FeCl3 (20 mol %), solvent = benzene. FeCl3 (20 mol %), solvent = benzene/H2O.

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8) and varying catalyst concentration does not have any effect at all (Table 1, entry 6). However, when the same mixture is allowed to warm to room temperature the product selectivity and overall product concentration drop rapidly and lead to the formation of numerous unidentified products (Table 1, entries 7 and 9). In this case, we reasoned that the presence of MCH, which can be activated by FeCl3 (Eq. (1)), results in the generation of these undesired by-products (olefin dimers). Thus we replaced MCH with benzene in the hopes this would prove to be a more inert solvent (Table 1, entries 12 and 13), but unfortunately the observed conversion to products was lower and selectivity was poor. Careful examination of prior literature studies of aldol condensation reactions found that water has been shown to play a crucial role in the optimization of many reactions, especially in the presence of a Lewis acid catalyst.23,24 These literature reports implied that water may play an important role in the aldol chemistry but not in the cyclotrimerization reactions. Contrary to

Table 2 Cyclotrimerization of aldehydes containing a-hydrogens Entry

Aldehyde

Time (h)

1,3,5-Trioxane

Yield (%) (CH2)2-CH3

O

1

(CH2)2-CH3

3

O

CH3-(CH2)2

O O

80

(CH2)2-CH3

O O

1

2

O

90

O

O

CH 2-CH3

3

3 CH2-CH3

O

CH3-CH2

O

80

O

CH2-CH3

O

4

(CH2)2-CH3

(CH2)2-CH3

1

O

CH3-(CH2)2

O O

(CH2)2-CH3

O

5

(CH2)5-CH3

(CH2)5-CH3

48

O

CH3-(CH2)5

O O

O

6

80

these statements the presence of water was found to dramatically increase both the overall conversion and selectivity for aldehyde cyclotrimerization products (Table 1, entry 14). Moreover, the presence of water also appears to retard deleterious side reactions previously observed at temperatures above 30 °C allowing the more convenient use of these reactions at room temperature (Table 1, entry 15). Parallel to these findings, we also were interested in finding optimized conditions for the selective homo aldol condensations, an important synthetic approach that still needs to be developed to selectively produce a–b unsaturated aldehydes uncontaminated by the b hydroxy products. From Table 1 (entries 10 and 11), it is clear that homo aldol condensation of valeraldehyde, is favored at room temperature and high conversions of can be achieved in the absence of any solvent. With these conditions in hand, we were able to extend this chemistry to other substrates and demonstrate the generality of the process. Thus, selective homo aldol condensation and cyclotrimerization of aldehydes can be catalyzed by inexpensive and commercially available FeCl3, Tables 2 and 3 respectively. The efficiency of the cyclotrimerization reaction depends on the presence of water. Optimized conditions for this reaction system have concluded that aldehyde, water, and solvent must be present in a 1:1:2 ratio. Deviation from this ratio significantly decreased reaction yields. For example, the yield of trioxane product arising from cyclotrimerization of 2-methylvaleraldehyde (Table 2, entry 4), decreased tremendously in the absence of water from 88% to 4% conversion under the same reactions conditions. However selectivity is unaffected and only the trioxane product was obtained, albeit in low yields (see Fig. S58). We believe that although water is required to obtain high yielding reactions, it is the temperature at which the reactions are carried out that determines the selectivity. It has been believed that the cyclotrimerization reaction is reversible and at higher temperatures the monomeric (aldehyde) form is dominant, a similar phenomenon has been observed in other systems.19d,f,g,i,25 From the examples in Table 2, we observed that the reaction yields increase upon moving from aromatic to aliphatic

90

(CH2)5-CH3

Entry

(CH2)7-CH3

(CH2)7-CH3

24

O

CH3-(CH2)7

O O

Table 3 Homo-aldol condensation of aldehydes

O

O

(CH2)2-CH3

70

O

(CH2)5-CH3 Ph

8

72 Ph

Ph

O

O

70b

O

CH2-Ph

CH3-CH2

O

Ph

Ph

24

(CH2)7-CH3

Ph

O O

O

84c

b

Ph Ph

Reactions conditions: aldehyde/water/toluene (1:1:2) at 30 °C with FeCl3 (10 mol %). b Dichloromethane was used instead of toluene. c Benzene was used instead of toluene.

5

CH 3-(CH2)7

87 (CH2)7-CH3

CH2-Ph

36 Ph

Ph

55

O

(CH2)5-CH3

O

Ph

O

O

O

75

12

4

CH2-CH3

Ph

O Ph

O

77 (CH2)2-CH3

O

12

3

Ph

CH2-CH3

72

CH 3-(CH2)5

O

O

a

CH 3-(CH2)2

O

1

2

O

Ph

O

3

1 (CH2)7-CH3

O

Yielda (%)

Product

O

12

7

10

Time (h)

63

O

9

Aldehyde

2

Ph-CH2

80 CH2-Ph

Note: All the reactions were performed in the following ratio aldehyde/solvent (1:2) at 60 °C with FeCl3 (10 mol %). a Isolated yield. b Dichloromethane was used instead of toluene.

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(a)

(b)

(c)

Figure 1. Molecular structures of: (a) 2,4,6-tri(diphenylmethyl)-1,3,5-trioxane, (b) 2,4,6-tri(isopropyl)-1,3,5-trioxane, and (c) 2,4,6-tri(2-phenylethyl)-1,3,5-trioxane. Hydrogen atoms are omitted for clarity.

Scheme 1. Proposed Mechanism for the Selective Homo Aldol Condensation and Cyclotrimerization of Aldehydes Catalyzed by FeCl3.

substituents. In the case of the aliphatic substrates, we can see that branched aliphatic substituents (Table 2, entries 1, 2, 4, and 7), are more reactive than non-branched aliphatic chains (Table 2, entries

3, 5, and 6). At the same time, although the aromatic substrates require longer reaction times the reaction yields remain high (Table 2, entries 8–10). Additionally, most of the trioxane products

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are solids, which make their purification straightforward. Thus, we have been able to isolate for the first time the previously unreported 2,4,6-tri(diphenylmethyl)-1,3,5-trioxane (3j) (Table 2, entry 10). The molecular structure of 3j was determined by X-ray crystallographic analysis and is depicted in Figure 1a. Moreover, it proved possible to obtain similar crystallographic analyses of trioxanes 3a and 3i, Figure 1b and c, respectively. Although these trioxanes have been previously reported, their molecular structures have not been disclosed prior to this work. Catalytic systems capable of promoting the homo condensation of aldehydes selectively are rare and thus are unobserved in many other systems.5,23 Given this context, we considered it important to elaborate upon this chemistry by examining a series of substrates to demonstrate the generality of this new methodology (Table 3). The reaction is limited to aldehydes without substitution at the a-position, which implies that a b-hydroxy adduct is formed but it is unobserved under the catalytic conditions used. It should be noted that in all cases (Table 3), the stereochemistry of the alkene favors the (E) stereoisomer, as evidenced by the presence of an NOE enhancement between the aldehyde proton and the proton of the double bond (b-proton) (see Figs. S59–S63). Only one substrate, phenylacetaldehyde (Table 3, entry 4), did not provide a good yield under homo condensation conditions. The presence of a phenyl group in the b-position should have favored dehydration arising from increased stabilization due to conjugation,5b instead we observed just the opposite. Mechanistic considerations With these results in hand we propose the mechanism shown in Scheme 1 to account for our observations on the role of water and temperature in determining the reaction products obtained: dimerization or cyclotrimerization. Firstly, we will consider the formation of the a,b-unsaturated aldehyde products. Coordination of the aldehyde to the Lewis acidic metal center activates the a-position, which in the presence of water, allows the formation of an enolate species. The metal enolate undergoes a nucleophilic addition to the electrophilic carbon of a second equivalent of aldehyde to form the corresponding (but unobserved) aldol product. The formation of aldol product is accompanied by the concomitant release of water and the metal complex ([Fe] may or not be FeCl3). We have been unable to observe this intermediate aldol species, however under the experimental conditions these aldol products undergo facile dehydration (possibly promoted by the metal complex) to form the a–b unsaturated aldehydes products (2). The unsaturated aldehydes are the species we observe and isolate in very good yields with high selectivity in contrast to earlier reports.5,23 It is tempting to propose that the dehydration process is aided by coordination of the aldol adduct to the metal center followed by the formation of a new metal enolate. Once more, metal coordination activates the aldehyde sufficiently for water to act as a Lewis base and generate the metal enolate. Protonation of the alcohol group followed by loss of water generates the desired a–b unsaturated aldehyde (2). The loss of water to generate the a,b-unsaturated aldehyde product indicates that addition of water to the reaction mixture may inhibit this step and shift the reaction selectivity to favor the cyclotrimerization product. However, it is evident that trace amounts of water must be present to facilitate formation of the key enolate species required to generate aldol products. Using pentanal as a model substrate, we conducted catalytic homo aldol condensations under our optimized conditions and obtained a 98% yield of a,b-unsaturated aldehyde product. In the presence of activated molecular sieves, under otherwise identical conditions, the highest yield of a,b-unsaturated aldehyde product achieved was 54% (see Fig. S65).

5

Figure 2. Catalytic seed formed as part of the cyclotrimerization of aldehydes (FeCl3/water/aldehyde).

Thus, it is evident that a delicate balance must be maintained between the need to have water present to act as a base to form enolate and avoiding too much water, which may act to inhibit product formation. Mlynarski26 has also reported on the crucial role water may play in determining reaction pathway. We decided to test our proposed mechanism by using an aldehyde, which does not possess a-hydrogens and thus cannot form an enolate nor would undergo a competing trimerization reaction. Thus, we exposed benzaldehyde to our optimized conditions for formation of a,b-unsaturated products and found this substrate resistant to product formation. However, when we perform the same reaction in the presence of an enolizable aldehyde (pentanal, octanal, decanal, or 3-phenylpropanal) we can generate cross-aldol products arising from reaction of the enolate with non-enolizable benzaldehyde (Figs. S10–S14, and Table S1 in Supplementary material). Under similar catalytic conditions, but at low temperatures (30 °C) and in the presence of water, the system undertakes a different reaction pathway to form the 1,3,5 trioxanes (3) exclusively and in high yields. Shown in Scheme 1 is our proposed mechanism of trioxane formation. Both mechanisms share a common first step, aldehyde coordination to the iron center, however at lower temperatures the metal enolate formation is suppressed. To support this assertion we attempted our model cross-aldol reaction (pentanal with benzaldehyde), which proceeds via generation of the pentanal enolate, and found that at 30 °C no aldol reaction occurred. In the absence of the metal enolate coordination is followed by subsequent nucleophilic attack of second aldehyde to form an anionic species, which reacts with a third aldehyde as shown in Scheme 1. Finally, intramolecular cyclization occurs to yield trioxane product (3). The precise role of water in these reactions is still unknown but it has been proposed by MIynarski and others,27 that metal compounds added to water dissociate and hydration occurs immediately. If an aldehyde is present in the reaction mixture, there is a chance for it to coordinate to the metal cations instead of the water molecules; the aldehyde is then activated. To support this assertion, we wish to report that we have observed that in our reaction vessel water and FeCl3 form an interesting aggregate, but only in the presence of an aldehyde. This aggregate (or seed) remains insoluble throughout the course of the reaction (Fig. 2). To our surprise this ‘seed’ can be isolated by decantation and washed with pentane under ambient conditions and in the absence of any special precautions. Amazingly, the isolated seed is an effective catalyst for cyclotrimerization of pentanal into the corresponding trioxane. The catalyst seed can be recycled up to 6 times with little loss of catalytic activity (see Fig. S66 and Table S2 for further information). Conclusions An efficient and selective homo aldol condensation and cyclotrimerization of aldehydes has been developed, which is

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catalyzed by the inexpensive, nontoxic, and commercially available FeCl3. For the first time it has been shown that the selectivity of the reaction may be tailored to generate a–b unsaturated aldehydes or 1,3,5-trioxanes through use of FeCl3/water at either low or high temperatures. It has also been found also that aldehydes with 1 hydrogen at the a-position can react only in the cyclotrimerization of aldehydes, meanwhile substrates with 2 hydrogens at the a-position can react in both the cyclotrimerization and the homo aldol condensation reactions. Leading us to propose the mechanism shown above (Scheme 1). We have also discovered that a catalytically viable ‘seed’ is generated in the presence of the water/FeCl3/aldehyde mixture.28 This ‘seed’ is readily isolated through simple decanting and is stable to both air and moisture. The seed retains catalytic activity through at least 6 cycles of the cyclotrimerization reaction. We have been unable to ascertain the precise identity of the ‘seed’ and plan further experiments to try to determine the structure. Acknowledgments We are grateful for financial support from the Robert A. Welch Foundation (Grant D1807) and the National Science Foundation (CRIF MU Grant CHE-1048553).

6. 7.

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Please cite this article in press as: Arias-Ugarte, R.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.040