Solvent-free synthesis of 4H-benzo[b]pyran derivatives catalyzed by NaOAc and PEG400

Cao Yuqing, Li YaBin, Wu Guoqiang
(College of Pharmacy, Hebei University, Baoding 071002, China)


Abstract4H-benzo[b] pyran derivatives were synthesized by one-pot, three-component reaction of aromatic aldehyde, active methylene compounds, and 1,3- cyclohexanedione in good yields using sodium acetate and PEG400 as catalyst under solvent-free conditions.

4H-benzopyran derivatives have attracted great attention recently in synthetic organic chemistry due to their wide range of biological activity and pharmacological property, such as anti-coagulant, anti-cancer, spasmolytic, diuretic, and anti-ancaphylactin [1]. Literatures reported syntheses of such compounds in organic solvent or ionic liquid [2,3]. These methods have some shortcomings in terms of poor yields, environmental pollution and expensive solvent, not easy work-up. Therefore, the improvements in such synthesis had been sought continuously [4-7]. It also has been reported that these compounds were synthesized by microwave irradiation [8]. Although microwave irradiation in organic reactions is applicable in the laboratory, and it cannot be widely applied in industry.
The demand for increasing clean and efficient chemical synthesis is continuously becoming more urgent from both an economic and an environmental standpoint. Organic synthesis in the absence of solvent has been received much attention because of several advantages in preparative procedures, such as environmental compatibility, easy work-up, enhanced selectivity, reduction of by-products, and much improved reaction rates [9-11]. These would be especially important during industrial production.
Polyethylene glycols (PEGs) can be regarded as the acyclic ether and have been used as PTC in many organic reactions owing to their stability, low cost, poisonlessness, and easy availability [12,13]. PEG400 was more suitable for solid-liquid phase solvent-free reactions. Our laboratory has reportedthe application of PEG400 as phase transfer catalyst in organic reactions [14], herein we report a safe, facile and one-pot synthesis of 5-oxo-5, 6, 7, 8-tetrahydro-4H-benzo [b] pyran derivatives by three-component reaction catalyzed by sodium acetate and PEG400 under solvent-free conditions shown as Scheme.1. The results are summarized in Table 1.


Scheme 1

In order to determine the optimum reaction conditions for the synthesis of 4H-benzopyran derivatives in fast and more efficient way, we have studied the efficiency of different bases. Using NaOAc, NaOH, KF, MgO and CaO as catalyst for the reaction of -nitrobenzaldehyde with 1, 3-cyclohexanedione and malononitrile, the yields of 88%, 74%, 57%, 51%, and 55% respectively, were obtained under the same reaction conditions. The better yields were obtained when sodium acetatewas used as catalyst. Low yield was obtained and long reaction time is needed using KF or MgO as catalyst. In comparison with the case without the participation of NaOAc, the reaction rate was greatly enhanced with the introduction of NaOAc. We have also studied a variety of reaction conditions with -nitrobenzaldehyde using NaOAc as the catalyst. After some experimentation, a set of conditions has been found that generally provides 4H-benzopyran derivatives in good yields. The influence of the amount of the catalyst on the yield was studied and the amount of PEG400 was important to the reaction. An amount of 3-5% mol PEG400 and 10% mol NaOAc is appropriate for the reaction. The reactions using different quantities of reagents were investigated. The best results were obtained with a 1:1.1:1.1 ratio of aldehyde, malononitrile, and 1, 3-cyclohexanedione or 5, 5-dimethyl-1, 3-cyclohexanedione.

Table 1. Preparation of 4H-benzopyran derivatives under solvent-free conditions.

Entry Ar   R’ Time
M.p M.p Lit
4a 4-ClC CN   3 87 224-227 226-229[5]
4b 2-ClC CN   3 92 212-214 213-215[5]
4c 4-CHOC CN   6 83 194-196 193-195[5]
4d 4-NO CN   2.5 88 230-233 234-235[5]
4e 3-NO CN   3 89 197-199 198-200[5]
4f 2,4-Cl CN   3 90 223-224 225-227[5]
4g 3,4-OCHOC CN   4.5 85 211-213 211-214[5]
4h   COEt CH 2 88 161-163 158-160[2
4i 4-ClC COEt CH 2 82 149-150 150-152[2]
4j 2-ClC COEt CH 2.5 85 180-182 181-183[2]
4k 3-NO COEt CH 2.5 85 179-181 180-182[8
4l 3,4-(CHO) COEt CH 3 75 153-156 155-157[8]
4m 4-FC COEt CH 2 87 153-154 152-155[3]
4n 3-BrC COEt CH 2 82 133-134 133-135[3]
4o 4-BrC COEt CH 3 85 158-160 160-162[8]
4p 4-CH COEt CH 2.5 80 153-156 156-157[2]
4q   COMe CH 2.5 83 145-146 146-148[2]
4r 4-ClC COMe CH 2 85 164-166 167-168[2]
4s 4-CH COMe CH 3 70 169-172 172-174[2]
4t 3,4-(CHO) CN CH 3 80 173-174 170-173[2]
4u 4-NO CN CH 2 89 127-130 130-132[2]
4v 4-FC CN CH 2 93 182-184 184-186[3]

The reactions temperature were 160
The reactions temperature were 130
Isolated and unoptimized yields

From the data in the Table 1, the reaction of aromatic aldehydes with active methylene compounds and 1,3-cyclohexanedione under solvent-free conditions provided the corresponding 4H-benzo[b] pyran derivatives in satisfactory yields. It has been found that the reaction of aldehydes with electron withdrawing groups such as -Cl and -NO in the aromatic ring, with active methylene compounds and 1,3-cyclohexanedione can be carried out in relatively shorter time and high yield than with electron donating group such as -OCH3. The yield of 4H-benzopyran bearing chloro group at para position on the aryl ring is lower than that of the 4H-benzopyran bearing chloro group at ortho position on the aryl ring. The reaction rate would slow down along with increasing amount of the high melting point of products, so a high reaction temperature was needed. However, high temperature will result in low yield especially for the ester bond due to the oxidation and hydrolysis of some reactant and product by water generating in reaction. Higher reaction temperature is necessary for the reactions of the products with the high melting point in order to assue the reaction mixture in liquid state.
We consider the reaction to proceed via aldol condensation, addition, enolisation, cyclodehydration and tautomerisation (Scheme 2.). Firstly, compound () was obtained by aromatic aldehyde reaction with active methyl compounds via Knoevenagel reaction. Secondly, Compound () reacted with the electrophilic C=C double bond giving the intermediate (). Then the intermediate () was cyclized by the nucleophilic attack of OH group on the cyano (CN) moiety and gave the intermediate (). Finally the expected products () were obtained by isomerization (→→).

In summary, we have developed a safe, environment-compatible and easy work-up method for the synthesis of benzopyran derivatives from substituted aromatic aldehydes, active methylene compounds and 1, 3-cyclohexanedione or 5, 5-dimethyl-1, 3-cyclohexanedione in the presence of PEG400 and sodium acetate under solvent-free conditions.

TLC was GF254 thin layer chromatography with petroleum ether/ethyl acetate as eluent. Aromatic aldehydes, active methylene compounds and 1,3-cyclohexanedione were obtained from commercial suppliers and not purified. Melting points were determined on a microscopy apparatus and are uncorrected.
General Procedure for the Synthesis of4H-benzo[b]pyrans (4)
A mixture of aromatic aldehyde (0.1mol), active methylene compounds (0.11mol), 1,3-cyclohexanedione (0.11mol), NaOAc (0.01mol), and PEG400(0.005mol) were taken into a 50ml three-necked, round-bottomed flask equipped with drying tube filled with KOH. The mixture was vigorously stirred and heated at the assigned temperature for a period of time as required to complete the reaction (monitored by TLC). Then the hot mixture was poured into a breaker and cooled to room temperature and washed with water. The solid was obtained by filtration. The crude products were purified by recrystallization from ethanol (95%).