自由基反應在芳香族化合物的合成

行政院國家科學委員會專題研究計畫 成果報告

自由基反應在芳香族化合物的合成

中 華 民 國 95 年 10 月 25 日






  
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Free radical reactions have been become increasingly important in organic synthesis in the last two decades. The carbon-carbon bond formation can be achieved efficiently by the attack of carbon radicals onto the unsaturated bond. These reactions exhibit interesting regio- and stereo- selectivities. Metal ions (Mn+3, Ce+4, Ag+_{, Fe}+3 _{) based oxidative free reactions of 1,3-dicarbonyl compounds have been studied by several groups.}

The carbon radical can also be generated from allylsulfones. The oxidative addition of an electrophilic

carbon-centered radical to alkenes has received considerable attention in organic synthesis for the construction of carbon-carbon bonds. The carbon radical can also be generated from allylsulfones. In this proposal, we wish to study- 1.The free radical reaction of allylsulfones initiated by sulfonyl radical. 2. The oxidative free radical cyclization reactions. 3. The oxidative free radical addition reactions.

Introduction

Free radical reactions have become increasingly important in organic synthesis in the last two decades.The oxidative addition of electrophilic carbon-centered radicals to alkenes mediated by metal salts has received considerable attention in the organic synthesis for the construction of carbon-carbon bonds. Among these, manganese(III) acetate and cerium(IV) ammonium nitrate (CAN) have been used most efficiently. These reactions can be performed intermolecularly and intramolecularly. Recent studies have shown that efficient homolytic substitution of aromatic and hereroaromatic substrates can be accomplished using electrophilic carbon-centered radicals generated by the oxidation of 1,3-dicarbonyl compounds with metal salts. Imine radical can be generated effectively from the oxidation of enamine by metal salts. Free radical reactions mediated by sulfonyl radicals have been noted by several groups. p-Toluenesulfonyl radical can be generated by the oxidation of sodium p-toluenesulfinate with metal salts. The alkyl radicals generated from

p-Toluenesulfonyl radical induced reaction of allylsulfones can undergo free radical cyclization reaction. This

report describes our results on - 1.The free radical reaction of allylsulfones initiated by sulfonyl radical. 2. The oxidative free radical cyclization reactions. 3. The oxidative free radical addition reactions.

Results and discussion

1. The oxidative free radical addition reactions

We first tried the manganese(III) mediated reaction of 2-benzoyl-1,4-naphthoquinones 1 with β-ketoesters 2 (Scheme 1). When 2-benzoyl-1,4-naphthoquinone (1a, R1 = R2 = H) was treated with ethyl butyrylacetate (2a,

R3 = n-PrCO) and manganese(III) acetate in acetic acid at 70 oC, in addition to the expected

naphthacene-5,12-dione 4a (20%), the novel naphtho[2,3-c]furan-4,9-dione 3a was also obtained in 46% yield

(Table 1, entry 1). Although the mechanistic details of this reaction are unclear, 3a and 4a may be formed via

the reaction route presented in Scheme 1. Manganese(III) acetate oxidation of 2a produces radical 5a. This

radical intermediate 5a undergoes intermolecular addition to the quinone ring followed by oxidation to give 6a,

which was then oxidized by manganese(III) acetate to generate 7a. Radical 7a undergoes either a six membered

ring free radical cyclization and subsequent aromatization to give 8a, which undergoes a further retro Claisen

condensation to produce 4a (path a) or oxidation to give 9a (path b). This cation intermediate 9a undergoes a

five membered ring cyclization followed by retro Claisen condensation to generate 3a. Analogous results were

O O R1 R2 O O R1 R2 R3 E E 2 4 O OH O O 3 O R1 R2 E + Mn(OAc)3 E = CO2Et 1 6 3a O O O E R3 O O O E R3 O O O E R3 O O E O R3 O O E R3 1a R3 E 5 4a O +

.

.

naphthacene-5,12-dione 4 was obtained in fair yields. Contrary to the reactions of

2-benzyl-1,4-naphthoquinones with β-ketoesters, 3 is the major product. It indicates that the electron deficiency of benzoyl group disfavours the intramolecular cyclization of electrophilic radical 7 onto the C-C double bond

of benzoyl group (path a). Interesting, reaction of 1 bearing an additional electron-withdrawing halogeno group

gave the corresponding products 3 and 4 in excellent 3/4 ratio. These results can be rationalized by

consideration that the electron deficiency of radical intermediate 7 makes the rate of six membered ring

cyclization to the benzene ring bearing an electron-withdrawing halogeno group much slower (path a) and the competitive oxidation of 7 became the major route (path b).. The formation of naphtho[2,3-c]furan-4,9-diones

is interesting and which are one of the subset of natural products containing a c-fused furan ring. To improve the chemoselectivity, reaction of 2-benzoyl-1,4-naphthoquinone 1a with other β-ketoesters was next

investigated. Reaction of 2-benzoyl-1,4-naphthoquinone 1a with ethyl isobutyrylacetate (2b, R3 ₌ i-_{PrCO) and}

manganese(III) acetate in acetic acid afforded 3a and 4a in 50% and 12% yields, respectively. The 3a/4a ratio

rose to 54/3 when ethyl benzoylacetate (2c, R3 _{= PhCO) was employed. The selectivity of this reaction}

increases as the size of substituents (R3_{) increases. This can be attributed to the steric effect exerted by R}3

group – the cyclization rate of 7 (path a) was retarded by the larger R3 _{group and the oxidation of 7 became the}

major route (path b). On the basis of this finding, by choosing ethyl benzoylacetate (2c) as radical precursor, the

generalities of this reaction were also examined with a variety of 2-benzoyl-1,4-naphthoquinone 1. In all cases,

2-benzoyl-1,4-naphthoquinone 1 was converted to the corresponding 3 in high selectivity.

Next, we investigated this manganese(III) mediated reaction with ethyl hydrogen malonate (2d). Treatment of

2-benzoyl-1,4-naphthoquinone (1a) with 2d and manganese(III) acetate under the above conditions led to the

formation of 3a and 4a in 19% and 38% yields, respectively. These two products 3a and 4a were presumably

generated via the decarboxylation of 8d and 10d, respectively. 8d and 10d were formed via a similar reaction

route for the formation of 8a and 10a (Scheme 1). In contrast to the reaction between

2-benzoyl-1,4-naphthoquinones 1 and β-ketoesters, this reaction is less selective, particularly for

2-benzoyl-1,4-naphthoquinones 1a and 1b (R1 = H, R2 = Me), naphthacene-5,12-diones 4a and 4b are the major

products. It can be rationalized that the radical intermediate 7d bearing a weaker electron withdrawing CO2H

group is less electron deficient and this makes the intramolecular cyclization of 7d (path a) faster than that of 7a.

Similar to the results shown above for ethyl butyrylacetate (2a), the presence of an additional

electron-withdrawing halogeno group on the benzoyl group appears to increase the ratio of 3/4 and

naphtho[2,3-c]furan-4,9-dione 3 was produced as the major product. In particular,

Naphtho[2,3-c]furan-4,9-diones 3g-i were produced in high selectivity from corresponding 1 bearing an ortho

We have continued to study this manganese(III) mediated reaction with 1,3-diketones 11 (Eq. 1). When

2-benzoyl-1,4-naphthoquinone 1a was treated with pentanedione (11a) and manganese(III) acetate, 12a and 13a were obtained in 41% and 8% yields, respectively. Other examples were also examined. In most cases,

2-benzoyl-1,4-naphthoquinone 1 was converted to the corresponding furan product 12 in high selectivity. Again,

the selectivity of this reaction increases as the size of 1,3-diketone increases.

O O R1 R2 O O R1 R2 R3 R3 R3 11 13 O OH O O 12 O R1 R2 R3 + 1 Mn(OAc)3 (eq 1)

In conclusion, 1,4-Naphthquinone 6, generated via the free radical addition of radical intermediate 5 to the C-C

double bond of quinone ring, undergoes efficient manganese(III) mediated cyclization reactions. This reaction provides a method for the synthesis of naphtho[2,3-c]furan-4,9-diones and naphthacene-5,12-diones from readily available 2-benzoyl-1,4-naphthoquinones and 1,3-dicarbonyl compounds. The product distributions are highly dependent on the 1,3-dicarbonyl compounds used and the electronic effect of the substituents on benzoyl groups. With ethyl benzoylacetate and 1,3-diketones, the novel naphtho[2,3-c]furan-4,9-diones were produced effectively in high selectivities.2.

2. The oxidative free radical cyclization reactions.

The reaction between 2-benzoylmaleate 1a (R1 = Ph, R2 = OMe, R3 = CO2Me) with preformed

phenacylpyridinium bromide (2a) was first examined (Scheme 1). Treatment of pyridinium salt 2a with

triethylamine followed by 1a in acetonitrile at room temperature for 2 hours gave no desired product 3a, only

resulted in the deterioration of starting 1a. We next studied reaction between 2-benzylidenebenzoylacetate 1b

(R1 = R3 = Ph, R2 = OEt) with preformed phenacylpyridinium bromide (2a). Treatment of pyridinium salt 2a

with triethylamine followed by 1b in acetonitrile at room temperature for 2 hours gave 2,3-dihydrofuran 4b as

the only product in 93% yield and no desired product 3b can be found. The structure of 4b is clearly assigned as

trans compounds by the analysis of the vicinal coupling constant of the two methine protons (J2,3 = 4.3 Hz) and

by the analogy with earlier reported paper. On the basis of this finding, a plausible reaction mechanism is

shown in Scheme 1. Deprotonation of 2a forms ylide 6a, which undergoes congugate addition to enone 1b to

generate enolate 7b. This enolate 7b undergoes a five membered ring O-cyclization to produce 4b (path a). In

this reaction, no cyclopropane 5b derived from a 3-membered ring C-cyclizationof 7b could be found (path b).

Dihydrofurans are the most important heterocycles commonly found in a large variety of naturally occurring substances. The development of new and efficient methods for their synthesis remains an area of current interest, and a whole series of new synthetic methods have appeared in literature. We have continued to study the synthesis of 2,3-dihydrofuran via pyridinium ylide. In attempt to investigate the range of solvents

compatible with this reaction, enone 1b and pyridinium salt 2a were chosen as model compounds and this

reaction was performed in various solvents. The change of solvent to chloroform, DME or ethanol gave similar result. We also used different bases for this reaction. In acetonitrile, replacement of Et3N with other bases

except DBU also led to a similar reaction yield On the basis of these results, by choosing acetonitrile as solvent and potassium carbonate as base, we applied this method to other enones 1c (R1 = R2 = Me, R3 = Ph) and 1d

(R1 = Me, R2 = OEt, R3 = Ph). The reaction worked well and 2,3-dihydrofurans 4c and 4d were formed in 94

and 92% yields, respectively. Pyridinium salts 2b-e bearing other functional groups were also investigated and

2,3-dihydrofuran 4 was produced in good yield. This method proved to be of general applicability on enone 1

and pyridinium salt 2. In all cases, 2,3-dihydrofurans were obtained in good to excellent yield.

The pyridinium salts used in these reactions are readily accessible from pyridines and alkyl halides. In attempt to enhance the efficiency of this reaction we investigated the development of a stoichiometic one-pot process, in which the pyridinium salts and hence the ylides could be generated in situ from corresponding halides (Scheme 2). Addition of pyridine (10a) to phenacyl bromide (9a) in acetonitrile followed by potassium

used phenacyl chloride (9b) as the in situ precursor of pyridinium ylide 6a. After stirred at room temperature

for 16 hours, this one-pot process produced no desired 2,3-dihydrofuran 4c and only resulted in the

deterioration of starting 1c. This is presumably due to the slow reaction rate between chloride 9b and pyridine

(10a). We believe that 2,3-dihydrofuran 3a can be formed effectively from chloride 8b by increasing the

nucleophilicity of 9. Indeed, Reaction of DMAP (10b) with phenacyl chloride (9b), potassium carbonate and 1c

in acetonitrile for 8 hours gave 2,3-dihydrofuran 4c in 85% (entry 3). Analogous results were obtained with

other enone 1 and alkyl halide 8. When pyridinium salts were generated in situ from corresponding bromides,

2,3-dihydrofurans were obtained in a better reaction yield. This modified process offers significant advantages as it precludes the necessity to generate and isolate the pyridinium salt in a separate step.

Py O Ph + 1a 6a R1 R3 R2 O O Py O RX + base 1 2 4 O OEt Ph O PhCO Py 8b OEt Ph O O Ph Ph O 5b path b path a O EtO Ph O 4b H Ph O Ph H O R2 R1 O H R3 O R H H H Ph Ph OEt O O PhCO Py 7b H H Ph R1 R3 R2 O O X O R N + + 1 10 K2CO3 R4 9 O R2 R1 O H R3 O R H 4 R1 R3 R2 O O 3 O R + Scheme 1 (eq 1)

In conclusion, we have developed a new reaction for the synthesis of 2,3-dihydrofurans from readily available starting enones and pyridinium salts. This protocol can provide a novel and effective methodology for the preparation of 2,3-dihydrofurans in a stereoselctive fashion. The reaction is applicable to a range of enones and pyridinium salts with a variety of versatile functional groups. To increase the efficiency of this reaction the one-pot process was also developed, in which the pyridinium salts were generated in situ from corresponding halides.