Hexadecyldimethyl benzyl ammonium bromide: an efficient catalystfor a clean one-pot synthesis of tetrahydrobenzopyran derivatives in water

A clean and efficient method for the synthesis of 2-amino-4-aryl-3-cyano-5-oxo-4 H -5,6,7,8-tetrahydrobenzopyran derivatives using hexadecyldimethylbenzyl ammonium bromide (HDMBAB) as the catalyst is described. This method provides several advantages, such as simple work-up procedure, environmentally benign, neutral conditions and high yields. In addition, water was chosen as a green solvent.


Introduction
In recent years, 4H-benzopyran and its derivatives have attracted strong interest due to their useful biological and pharmacological properties, such as anticoagulant, spasmolytic, diuretic, anticancer, antianaphylactin agents. 1 Some 2-amino-4H-pyrans can be employed as photoactive materials. 2Furthermore, substituted 4H-pyrans also constitute a structural unit of a series of natural products. 3,4The synthesis of 4H-benzopyrans has been reported; 5 the conventional methods are with base as catalyst (piperidine or triethylamine) in an organic solvent such as ethanol, acetic acid or DMF, 6-8 and using ultrasonic irradiation. 9Each of the above methods has its own merit, but some are not entirely satisfactory, owing to such drawbacks as low yields, difficult work-up, problems of corrosiveness and effluent pollution.Consequently, there is a need to develop alternative methods for the synthesis of tetrahydrobenzopyran derivatives under mild and environmentally friendly conditions.
Water has been applied to organic reactions as a solvent, and it has several advantages such as its low cost, safety, non-polluting nature and operational simplicity. 10In 1983, Breslow discovered that the Diels-Alder reaction performed in water was subject to a huge rate acceleration. 11This observation led to increased interest from synthetic organic chemists in organic reactions conducted in water.Soon it was discovered that other organic reactions, like the Claisen rearrangement, 12 the aldol condensation, 13 Diels-Alder reaction, 14 the benzoin condensation, 15 Mannich reaction 16 and Michael reaction 17 exhibit rate enhancements in water.To date, many more organic reactions have been carried out in water. 18n this manuscript, we wish to report a general and highly efficient route for the synthesis of tetrahydrobenzopyrans using an inexpensive, commercially available hexadecyldimethylbenzyl ammonium bromide (HDMBAB) catalyst.This is a one-pot reaction in aqueous media, which is not only operationally simple but also consistently gives the corresponding products in good to excellent yields (Scheme 1).
As shown in Table 1, the three-component cyclocondensation reaction proceeded smoothly at 80-90 °C in water to give the corresponding products 4 in high yields.The electronic nature of the substituents on the aromatic ring did not show a strong effect in terms of yields under these reaction conditions.Both aromatic aldehydes containing electron-withdrawing groups (such as nitro group, halide) or electron-donating groups (such as alkyl group, alkoxy group) gave good to excellent yields of the corresponding 4H-tetrahydrobenzopyrans.
The catalyst plays a crucial role in the success of the reaction in terms of the rate and the yields.Taking the reaction of 4-nitrobenzaldehyde with 1,3-cyclohexanedione 2 and 3 as an example, the reaction could be carried out in the absence of the catalyst when the mixture was heated in water for 6h, but a very poor yield resulted (18%).We have tested some catalysts such as tetrabutyl ammonium bromide, benzyltrimethyl ammonium chloride, sodium dodecyl sulfate and hexadecyldimethylbenzyl ammonium bromide, and the yields using these four catalysts were 78%, 86%, 65% and 96%, respectively.From the yield data, it was found that

ARKAT
We have studied also the effect of the amount of the catalyst on these reactions.With the mixture 1e, 1,3-cyclohexanedione and 3 in the presence of 3mol% HDMBAB, the product 4e was obtained in 77% yield at 80-90 o C in water for 5.5h.Increasing the amount of catalyst to 5mol%, 8mol% and 12mol%, yields of 84%, 88% and 96%, respectively, were obtained.Use of just 12mol% HDMBAB is sufficient to push the reaction forward and higher amounts of the catalyst did not improve the results to any greater extent.Thus, 12mol% HDMBAB was chosen as the amount of catalyst for these reactions.
We propose the possible following mechanism to account for the reaction.First, the aromatic aldehyde 2 is condensed with malononitrile (3) to afford the α-cyanocinnamonitrile derivative 5.The step (2+3→5) can be regarded as a rapid Knoevenagel reaction.Since, in a model reaction, the Knoevenagel reaction of malononitrile and aromatic aldehydes can be carried out in water without any catalyst, we conjecture that the second step requires the presence of HDMBAB.The active methylene of 1 reacts with the electrophilic C=C double bond in 5 giving the intermediate 6, which tautomerizes into 7.The latter is then cyclized by nucleophilic attack of the OH group on the cyano (CN) moiety, giving intermediate 8. Finally, the expected product 4 is afforded by tautomerization (8→4).HDMBAB not only is a phase transfer catalyst, but it serves also as an emulsifier in this reaction process (Scheme 2).In conclusion, we have described a procedure for the preparation of 4H-benzopyran derivatives catalyzed by HDMBAB, using a three-component condensation in heated water.In addition, it is possible to apply the tenets of green chemistry to the generation of biologically interesting products using aqueous media approaches that are less expensive and less toxic than ARKAT those with organic solvents.Moreover, the procedure offers several advantages including high yields, operational simplicity, clean reaction conditions and minimum pollution of the environment, which makes it a useful and attractive process for the synthesis of these compounds.

Experimental Section
General Procedures.IR spectra were recorded on a Bio-Rad FTS-40 spectrometer (KBr). 1 H NMR spectra were measured on a Bruker AVANCE 400 (400 MHz) spectrometer using TMS as internal reference and DMSO-d 6 as solvent.Elemental analyses were determined using Perkin-Elmer 2400 II elemental analyzer.