08b069ne

http://www.chemistrymag.org/cji/2006/08b069ne.htm	Nov. 1, 2006 Vol.8 No11 P.69 Copyright

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)

Received Sep. 24, 2006.

Abstract 4H-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.
Keywords 4H-benzo[b] pyran, 1,3-cyclohexanedione, PEG400, solvent-free reaction

1. INTRODUCTION
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 solventor 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 reported the 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

2. RESULTS AND DISCUSSION
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 p-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 acetate was 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 p-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	R'	Time (h)	Yield (%)	M.p	M.p ⁽Lit)
4a	4-ClC₆H₄	CN	H	3^a	87	224-227	226-229^[5]
4b	2-ClC₆H₄	CN	H	3^a	92	212-214	213-215^[5]
4c	4-CH₃OC₆H₄	CN	H	6^a	83	194-196	193-195^[5]
4d	4-NO₂C₆H₄	CN	H	2.5^a	88	230-233	234-235^[5]
4e	3-NO₂C₆H₄	CN	H	3^a	89	197-199	198-200^[5]
4f	2,4-Cl₂C₆H₃	CN	H	3^a	90	223-224	225-227^[5]
4g	3,4-OCH₂OC₆H₃	CN	H	4.5^a	85	211-213	211-214^[5]
4h	C₆H₅	CO₂Et	CH₃	2^b	88	161-163	158-160^[2
4i	4-ClC₆H₄	CO₂Et	CH₃	2^b	82	149-150	150-152^[2]
4j	2-ClC₆H₄	CO₂Et	CH₃	2.5^a	85	180-182	181-183^[2]
4k	3-NO₂C₆H₄	CO₂Et	CH₃	2.5^a	85	179-181	180-182^[8
4l	3,4-(CH₃O)₂C₆H₃	CO₂Et	CH₃	3^b	75	153-156	155-157^[8]
4m	4-FC₆H₄	CO₂Et	CH₃	2^b	87	153-154	152-155^[3]
4n	3-BrC₆H₄	CO₂Et	CH₃	2^b	82	133-134	133-135^[3]
4o	4-BrC₆H₃	CO₂Et	CH₃	3^b	85	158-160	160-162^[8]
4p	4-CH₃C₆H₄	CO₂Et	CH₃	2.5^b	80	153-156	156-157^[2]
4q	C₆H₅	CO₂Me	CH₃	2.5^b	83	145-146	146-148^[2]
4r	4-ClC₆H₄	CO₂Me	CH₃	2^b	85	164-166	167-168^[2]
4s	4-CH₃C₆H₄	CO₂Me	CH₃	3^b	70	169-172	172-174^[2]
4t	3,4-(CH₃O)₂C₆H₃	CN	CH₃	3^a	80	173-174	170-173^[2]
4u	4-NO₂C₆H₄	CN	CH₃	2^b	89	127-130	130-132^[2]
4v	4-FC₆H₄	CN	CH₃	2^a	93	182-184	184-186^[3]

^{aThe reactions
temperature were 160^oC

^bThe reactions temperature were
130^oC

^cIsolated 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 -NO₂ 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 -OCH_3. 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 (5) was obtained by aromatic aldehyde reaction with active methyl compounds via Knoevenagel reaction. Secondly, Compound (5) reacted with the electrophilic C=C double bond giving the intermediate (6). Then the intermediate (6) was cyclized by the nucleophilic attack of OH group on the cyano (CN) moiety and gave the intermediate (7). Finally the expected products (4) were obtained by isomerization (7→8→4).

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.

3. EXPERIMENTAL
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 of 4H-benzo[b]pyrans (4)
A mixture of aromatic aldehyde 1 (0.1mol), active methylene compounds 2 (0.11mol), 1,3-cyclohexanedione 3 (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%).

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无溶剂下PEG400和无水醋酸钠一锅法催化合成4H-苯并吡喃衍生物
曹玉庆李亚彬吴国强
（河北大学药学院，071002，保定）
摘要在无溶剂条件下，由PEG400和无水醋酸钠催化的芳香醛，活泼亚甲基化合物，和1,3-环己二酮三种化合物一锅法合成苯并吡喃衍生物取得了较好的收率。
关键词 苯并吡喃，1,3-环己二酮，聚乙二醇400, 无溶剂

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