Studies and Mechanism of Olefination Reaction in Aryl-Enolates with Paraformaldehyde

A simple, efficient and low-cost methodology for the synthesis of α-aryl-α,βunsaturated esters using paraformaldehyde as a source of carbon was developed. Factors that control reaction yields such as temperature, concentration and reaction time were evaluated. A mechanism is proposed based on experimental structures of the intermediates.

Excellent works about the use of aqueous formaldehyde as methylenation agent via Mannich reaction have been published.For example, in 2006, Erkkilä and Pihko have performed the formation of α-methylenated aldehydes, also Figure 1.Strategies for the synthesis of acrylates.called α-substituted acroleines, using aqueous formaldehyde and secondary amines as a catalyst [12].Several studies employing other aldehydes and different types of alkyl, cyclic, aryl ketones and esters have been developed using diisopropylammonium trifluoroacetate salt [13] or Meldrum's acid as a catalyst.
On the other hand, and in addition to Mannich reaction, one of the most useful strategies for the formation of α,β-unsaturated systems is the aldol condensation [15] [16] due to its efficiency and low cost.In this transformation, the α-carbon of an enolate is bonded with the carbonyl carbon of an aldehyde, and a β-hydroxylated-carbonyl intermediate is obtained.Most of the times, a β-dehydration is observed as part of the process, and an α,β-unsaturated compound is isolated.On the other hand, when a functionalized aldehyde is employed, a trans-β-substituted-α,β-unsaturated compound is obtained [17] [18].Rodriguez et al. [19] reported that when both enolate and aldehyde are functionalized, the corresponding product is an α,β-disubstituted-α,β-unsaturated compound.They also mentioned that with this method, stereochemistry control of this reaction proved to be nontrivial.
Even though the aldol reaction employing formaldehyde is useful in the formation of α-methylenated carbonyl compounds, there are few reports about its use.One of the early reports was that of Laos in 1967 [20] where the α-methylenation of steroidal ketones was carried out with aqueous formaldehyde and potassium acetate as base and methanol or water as solvents.Recently, Liu studied the effect of the acidity of zeolite in the formation of acrylic acid and methyl acrylate from formaldehyde and methyl acetate [21].
A useful and practical source of formaldehyde is paraformaldehyde, a polymer, due to it is a versatile and easily handled reactively.For example, Amri et al. [22] used paraformaldehyde as homologate agent by substituting phosphonate group in the Honer-Wadsworth-Emmons reaction type synthesis of (±)-homosarkomycin with 98% of yield.An aldol type α-methylenation of lactones employing paraformaldehyde, which gives moderate to good yields was performed International Journal of Organic Chemistry by Tanaka and Yamashita [23].Chen et al. [24] also prepared α-nitro ethyl acrylate intermediates using paraformaldehyde, which was then employed as Michael acceptor in the synthesis of tryptophan derivatives.
Traditionally, it is accepted that aqueous formaldehyde and paraformaldehyde are two different sources of the same monomeric reactive and that the only advantage that paraformaldehyde has is that it can be used in water free reactions or solvents.
In the present work, we propose a possible mechanistic pathway of aldol condensation using paraformaldehyde, which is different from that observed in formaldehyde.

Reaction of Methyl Phenylacetate (1a) with Sodium Hydride and Paraformaldehyde (3)
Currently, our research group is interested in the synthesis of β 2 -and β 3 -amino acids via aza-Michael addition to α,β-unsaturated esters [25].One of our method of choice is a facile synthesis of 2-aryl methyl acrylates (4a-d); retrosynthetic approximation is shown in Scheme 1.
In the present study, initially, methyl phenylacetate (1a), paraformaldehyde (3) and NaH were chosen as starting materials.Acrylate 4a synthesis was carried out using toluene as solvent and microwave (MW) heating.The first entry in Table 1 shows the result of the formation of the acrylate 4a using 1.5 equiv. of NaH in toluene and MW heating for 1 h.Compound 5 was isolated as the main product with 55% yield and only traces of 4a (entry 1).An increase of paraformaldehyde from 3 to 9 equiv.and of NaH from 1.5 to 3 equiv., results in a better yield (60%) of acrylate 4a (entry 2).On the other hand, when the reaction is carried out with 16.6 mmol of 1a, acrylate 4a was isolated in higher yield (87% yield, entry 3).When the reaction is carried out at room temperature, 4a was obtained with a smaller yield and 6a, and 7 were also produced in 29% and 5% yields, respectively (entry 4).For this last experiment, it is relevant mentioning that after 1 h, the reaction spontaneously generated an exothermic from 25˚C to 55˚C.
When the reaction was carried out at 55˚C, after 1 h only 4a was obtained with 87% yield (entry 5).The result suggests that temperature can be used to control the production of byproducts 6a and 7a.Finally, in order to explore the solvent effect, the reaction was carried out in THF at the same temperature with a better yield of 4a in only 15 min (entry 6).
Scheme 3 proposes a reaction mechanism for the formation of 4a, 5, 6a, and 7.The enolate of 1a carried out a nucleophilic substitution over paraformaldehyde, and the intermediate 10 was produced.
From there on, the reaction could generate 4a through a β-elimination (E β , Path 1) and subsequently a Michael addition of the enolate of 1a on 4a to form the corresponding compound 5.
Alternatively, two products could be generated via Path 2. 6a is obtained through a nucleophilic substitution by the hydride; and 7 was isolated through the Michael addition of 4a and the enolate 6a.
Recrystallization of 7, afforded a suitable crystal for X-ray diffraction analysis.
The resulting structure is presented in Figure 2.

Synthesis of Acrylates Derivatives 4b, 4c, and 4d
We chose to examine the synthesis of other acrylates: 4b, 4c, and 4d under the conditions of entry 6 in Table 1 which are optimized from the reaction time and solvent choice point of view.For this purpose, we first synthesized 2b, 2c, and 2d (see Scheme 4).
Due to the structural diversity presented in methyl esters 2b, 2c, and 2d, a general synthetic route to these compounds was not available.Below, we describe two methodologies, including some developed by our research group.
Compound 1b was first esterified with methanol in the presence of TMSCl.2b and 2d were then synthesized through of the addition of (Boc) 2 O or pivaloyl International Journal of Organic Chemistry Scheme 3. Mechanism approach for the isolation of byproducts 5, 6a and 7. Recrystallization of 2d afforded suitable crystal for X-ray diffraction analysis shown in Figure 3.  Having produced 2b, 2c, and 2d, we then proceed with the syntheses of the acrylates 4b, 4c, and 4d.The results of this series are summarized in Table 2.
As expected from the results shown in Table 1, the desired acrylates derivatives 4b and 4c were obtained in 50% and 62% yield respectively.After purification of 4b by column chromatography, traces of 6b were found (entries 1 and 2, Similar to the case of 2b, here we expect to obtain either 4d or 6d.Instead, we found 8d a product of rearrangement reaction.We hypothesize that this compound formed by the insertion of a -CH 2 O-moiety from paraformaldehyde between the protector group and the indole (Scheme 6).

Conclusion
In summary, although the classical mechanism for this olefination reaction suggests that the paraformaldehyde is dissociated to formaldehyde when it is warmed, and then it reacts with the enolate to get the aldol product and its subsequent dehydration.However, in this study, we demonstrate that the addition of a carbon atom from paraformaldehyde to give rise to the vinyl group occurs through a series of nucleophilic substitutions catalyzed by hydride over acetalic carbons from the polymer.

Experimental Materials and Methods
The course of the reactions was followed by TLC.Silica gel of 70 -230 mesh of Merk (Darmstad, Germany) was used for purification of the products by flash chromatography.Methyl phenyl-acetate (1a), 3-indoleacetic acid and paraformaldehyde (3) were purchased from Aldrich and used without further purification.

Analytical Methods
Spectra data of 1 H NMR and 13  In a flask of 250 mL provided with magnetic stirrer, 5.0 g (28.54 mmol) of 3-indolacetic acid and 50 mL of MeOH were added.The flask was cooled at 0˚C International Journal of Organic Chemistry Scheme 6.A proposed mechanism for the formation of 8d. and then 2.5 mL (4.08 g, 34.27 mmol, 1.2 equiv.) of thionyl chloride.The mixture was stirred during 1 h, and then a saturated K 2 CO 3 solution was added until getting 8 -9 pH.Methanol was evaporated, and the solution was extracted with ethyl acetate (3 × 30 mL).The organic phase was dried over Na 2 SO 4 anhydrous.Concentration in a rotatory evaporator gave the crude product, which was purified by flash chromatography (n-hexane/ethyl acetate, 70:30 -50:50).Red oil, yield 97%. General procedure 1: In a flask provided with magnetic stirrer 1b (or c), 1.1 equiv. of (Boc) 2 O, 0.1 equiv. of 4-DMAP and a 9:1 Toluene: CH 3 CN mixture were added.The reaction mixture was refluxed for 3 h.The mixture of solvents was evaporated, and then H 2 O was added and extracted with ethyl acetate.The organic phase was dried over Na 2 SO 4 anhydrous.Concentration in a rotatory evaporator gave the crude product, which was purified by flash chromatography (n-hexane/ethyl acetate).

General procedure 2:
In a flask provided with a magnetic stirrer and N 2 atmosphere, 1c (or d) and 50 mL of THF anhydrous were added.The flask was cooled at −78˚C and then 1.1 equiv. of NaHMDS and 1.2 equiv. of protective reagent.The mixture was stirred during 2 h, and then a saturated K 2 CO 3 solution was added until getting 8 -9 pH.The solution was extracted with ethyl acetate.The organic phase was dried over Na 2 SO 4 anhydrous.Concentration in a rotatory evaporator gave the crude product, which was purified by flash chromatography (n-hexane/ethyl acetate).

General procedure 3:
In a flask of 100 mL provided with magnetic stirrer 5 equiv. of NaH 60% were added to 50 mL of n-hexane.The mixture was stirred during 15 min, the n-hexane was subtracted, and 50 mL of THF were then added.The flask was cooled at 0˚C and then 2, 9 equiv. of paraformaldehyde were added.The reaction mixture was stirred for 1 h, 20 mL of water were added, and the solution was extracted with diethyl ether (3 × 10 mL).Concentration in a rotatory evaporator gave the crude product, which was purified by flash chromatography International Journal of Organic Chemistry (n-hexane/ethyl acetate).

Table 1 .
Reaction conditions and yields for the aldol condensation of 1a and 3.

Table 2
and Scheme 5).It is worth mentioning that the product 4d could not be obtained under these reaction conditions, but surprisingly one side product (8d) was isolated in 37% yield.International Journal of Organic Chemistry

Table 2 .
Reaction conditions and yields for the aldol condensation of 2b-d with 3.