HETEROCYCLES

Review | Regular issue | Vol. 78, No. 4, 2009, pp. 843-871
Received, 1st October, 2008, Accepted, 17th November, 2008, Published online, 20th November, 2008.
DOI: 10.3987/REV-08-645

■ Efficient Synthesis of Indoles and Benzo[b]furans via [3,3]-Sigmatropic Rearrangement of N-Trifluoroacetylenehydrazines and Enehydroxylamines

Okiko Miyata,* Norihiko Takeda, and Takeaki Naito*

Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan

Abstract

This review summarizes an efficient synthesis of benzo[b]furans and indoles via [3,3]-sigmatropic rearrangements of N-trifluoroacetyl enehydroxylamines and enehydrazines, which were triggered by acylation of oxime ethers and hydrazines. TFAA and TFAT-DMAP have been proved to be the best reagent to induce [3,3]-sigmatropic rearrangement for the synthesis of benzo[b]furans and indoles. This method was successfully applied to the short synthesis of natural products.

INTRODUCTION
Indole and benzo[b]furan ring systems are the core structural elements in natural and synthetic organic compounds possessing a wide diversity of important biological activities.1 Therefore, their synthesis has received considerable attention and a lot of synthetic methods have been developed up to today. Among known synthetic methods of indoles and benzo[b]furans, the main common synthetic methods based on the construction of pyrrole and furan rings from various arene derivatives can be summarized as shown in Scheme 1.2,3 A survey of the literature shows that these methods can be basically generalized into the two categories. (A) The aniline, phenol and haloarene derivatives bearing a substituent at ortho position on the benzene ring are used as substrates (A-1, A-2, and A-3). (B) In the case of B-1, B-2, and B-3, indoles and benzo[b]furans are prepared from the aniline and phenol derivatives carrying the substituent not on ortho position of benzene ring but on Z group (Scheme 1).

(A-1) Ring closure by formation of the C1-C2 bond.
Substituted benzo[b]furans 2 have been synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes 1 using ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis (RCM).4 Similarly, N-allylanilines 3 were derived into indoles 4 (Scheme 2).5

(A-2) Ring closure by formation of the Z-C1 bond (Larock Heteroannulation)6
The Larock heteroannulation is an extremely attractive method for the formation of complex indoles and benzo[b]furans in a single operation. Heating of o-alkynylphenols 6, which are available from o-halogenophenols 5 and alkynes, with catalysts yields benzo[b]furans 7.7 Both coupling and ring closure can be achieved in one step (8→9).8 o-Amidophenylalkynes 11 are able to cyclize to indoles 12 using palladium-catalyst. The alkynes can be prepared by copper-catalyzed coupling of terminal alkynes with iodoacetanilide 10.9-12 The use of terminal alkynes 11 and N-methanesulfonyl-2-iodoanilines 13 in the presence of both copper and palladium catalysts permits a one-pot synthesis of 2-substituted indoles 14. However, the disadvantage of this reaction is to use toxic transition metals (Scheme 3).

(A-3) Ring closure by formation of the Z-Ar bond
The Copper-catalyzed transformation of readily available ketone derivatives 15 into the corresponding benzo[b]furan 16 were reported.13

The sustainable protocol uses water as the solvent without organic co-solvents. Recently, the first extensions of palladium-catalyzed C-N bond forming reaction to the direct formation of indole rings 18 by intramolecular N-arylation were reported.14 The synthesis of N-aminoindoles 20 via palladium-catalyzed cyclization of o-chloroarylacetaldehyde N,N-dimethylhydrazones 19 were developed.6b,15 A variety of N-arylated and N-alkylated indoles 22 were synthesized by way of PIFA-mediated intramolecular cyclization.16 This novel method allows for the construction of an indole skeleton by joining the N-atom on the side chain to the benzene ring carrying no halogen at the last synthetic step (Scheme 4).

(B-1) Ring closure by formation of Ar-C2 bond
The acid-catalyzed cyclization of α-aryloxymethylcarbonyl and α-arylaminomethylcarbonyl compounds has proved to be of great value for the synthesis of a wide variety of benzo[b]furans and indoles.17,18 Phenols 23 react with α-halogenoketones 24 to give aryloxy compounds 25 which are cyclized in the presence of acid to give benzo[b]furans 26. Acetals 27 of α-aryloxyaldehydes which are easily available from α-halogenoacetals and phenols, are often used as the substrate of benzo[b]furan synthesis. Several groups have explored the use of the diethyl acetal of bromoacetaldehyde as a potential indole precursor. The cyclization of aniline derivatives 29 of aniline occurs under acidic conditions to give indoles 30 (Scheme 5).

(B-2) Ring closure by two bond formations between Z-C1 and Ar-C2
Zn(OTf)2 catalyzes reaction of propargyl alcohols 32 with PhZH (Z=O, NH) 31 in hot toluene (100 °C) to give indoles 33 and benzo[b]furans 34.18 The transformations proceeded through A and B as reaction intermediates. The 1, 2-nitrogen shift in the formation of indole 33 takes place and its mechanism has been elucidated (Scheme 6).

(B-3) Ring closure by two bond formations between Z-C1 and Ar-C2
The Fischer indole synthesis20 is probably the most versatile method for making indoles; certainly it is the most widely applied. As with the Fischer indole synthesis, an important synthetic advantage is that the initial benzene ring substrate does not need to be ortho-disubstituted. The reaction involves acid-catalyzed conversion of an N-arylhydrazone 35 to an indole 36. The mechanism is thought to involve a [3,3]-sigmatropic rearrangement of an enehydrazine tautomer C to a imine D. Cyclization and aromatization with loss of ammonia provides the indole 36. The N-arylhydrazones 35 are frequently prepared via condensation of an arylhydrazines with ketones. Alternatively, aryldiazonium salts 37 can be converted directly to hydrazones via the Japp-Klingemann reaction. This reaction involves treatment of the aryl diazonium salt 37 with an active methylene or methine compounds 38 under acidic or basic conditions to form an azo derivative which is converted to the hydrazone 39. Highly efficient and metal-catalyzed methods to access arylhydrazone intermediates 40 useful in the Fischer cyclization have emerged over the last 5 years. Furthermore, O-aryloximes 41 give benzo[b]furans 42. 21 This reaction resembles quite closely the Fischer indole synthesis (Scheme 7).
Despite recently developed synthetic methodologies of indoles and benzo[b]furans, such as metal-catalyzed transformations, the venerable Fischer indole synthesis has maintained its prominent role as a route to indoles and benzo[b]furans. However, the synthetic methods of benzo[b]furans and indoles utilizing [3,3]-sigmatropic rearrangement exhibit some disadvantages as follows: (i) acid catalysts such as H2SO4 and HCl, and high temperature are generally required for the successful reaction, (ii) these harsh conditions cannot be applied to acid-sensitive substrates, and (iii) in most cases, the desired benzo[b]furans and indoles were obtained in only moderate yields. From the background described above, we recently found that the [3,3]-sigmatropic rearrangement and subsequent cyclization of N-trifluoroacetyl enehydrazines22 and N-trifluoroacetyl enehydroxylamines 4423 proceed smoothly under mild conditions to give the indoles and benzo[b]furans 45 and 46 (Scheme 8). Furthermore, we have also applied a newly found efficient procedure to short synthesis of natural products.

Herein, we summarize our results on the synthesis of benzo[b]furans and indoles using [3,3]-sigmatropic rearrangement of enehydrazines and enehydroxylamines 44.

BENZO[b]FURAN SYNTHESIS23
[3,3]-Sigmatropic rearrangement of N-trifluoroacetyl enehydroxylamines in situ generated
Sigmatropic rearrangement is eco-friendly attractive organic synthetic reaction because addition of reagent is hardly necessary. Some synthetic methods for benzo[b]furans using [3,3]-sigmatropic rearrangement are known besides Fischer indole synthesis. The Claisen rearrangement of propargylarylethers 47 yields allenes F, which in the presence of base cyclize to give benzo[b]furans 48. 2,24 However, high temperature is required for such rearrangement and cyclization. Recently, J. B. Hendrickson has reported that benzo[b]furans 50 were prepared from phenol and vinylsulfoxide 49 via [3,3]-sigmatropic rearrangement of sulfoxonium intermediate G transiently formed.25 The disadvantage of this method is to prepare vinylsulfoxide 49 and eliminate thiophenol which has foul smell (Scheme 9).

In order to develop new efficient synthesis of benzo[b]furans using [3,3]-sigmatropic rearrangement, we first investigated acetylation of oxime ether 51 (Scheme 10, Table 1). Treatment of oxime ether 51 with trifluoroacetic anhydride (TFAA) (1 eq.) and Et3N (1.5 eq.) in CH2Cl2 at 0 °C gave the rearranged product 54a in 8% yield along with the unreacted starting material 51 (entry 1).
Upon treatment with trifluoroacetic acid (TFA), the phenol 54a could be readily converted to dihydrobenzo[b]furan 53a. This result suggests strongly that 54a could be formed via acylation of oxime ether 51 with TFAA followed by [3,3]-sigmatropic rearrangement of the resulting N-trifluoroacetyl enehydroxylamine 52a. Additionally, TFA was found to be essential for the cyclization reaction of rearranged product 54a as a possible intermediate. Therefore, we expected that reaction of oxime ether 51 with TFAA in the absence of a base would proceed to afford the desired dihydrobenzo[b]furan 53a. In fact, trifluoroacetylation, [3,3]-sigmatropic rearrangement, and cyclization of 51 proceeded smoothly in the presence of TFAA (1 eq.) without a base to afford the corresponding cis-dihydrobenzo[b]furan 53a in excellent yield at even below room temperature (entry 2). In the reaction at room temperature, the desired 53a was formed after being stirred for 1 h (entry 3). This is the first example of the formation of dihydrobenzo[b]furan 53a which was formed only by acylation conditions.
In order to check the possibility that TFA itself might facilitate the [3,3]-sigmatropic rearrangement by protonation at the nitrogen atom, we examined the reaction of oxime ether 51 with only TFA and found that 3a-aminodihydrobenzo[b]furan 53d was isolated in 16% yield (entry 4). Therefore, it is apparent that acylation reaction of 51 for the formation of acyl enehydroxylamine 52 is the main and crucial step for [3,3]-sigmatropic rearrangement.

Next, we investigated systematically the acylation by changing four types of acylating reagents. When trichloroacetic anhydride (TCAA) was used as an acylating reagent, the reaction proceeded in refluxing CH2Cl2 to give dihydrobenzo[b]furan 53b in good yield (entry 5). In contrast to TFAA and TCAA, Ac2O did not give satisfactory results and the starting material 51 was completely recovered (entry 6). The reaction of 51 with trifluoroacetyl triflate (TFAT),26 which is a stronger acylating reagent than TFAA, gave 53a in lower 58% yield (entry 7). Reaction of 51 with TFAT (2 eq.) and Et3N (1 eq.) proceeded smoothly to give the desired dihydrobenzo[b]furan 53a in 80% yield (entry 8). Reaction with a combination of TFAT (2 eq.) and DMAP (1 eq.) gave the desired dihydrobenzo[b]furan 53a in 89% yield (entry 9). Thus, our reaction involving acylation, [3,3]-sigmatropic rearrangement, and cyclization was found to be accelerated when oxime ether was acylated with a stronger reagent bearing an electron-withdrawing group such as the trifluoroacetyl group. We choose TFAA in the formation of dihydrobenzo[b]furan.
In order to establish intermediary N-trifluoroacetyl enehydroxylamine 52a which would be possibly formed by acylating oxime ether 51, we examined acylation of O-benzyl oxime ether 55 (Scheme 11, Table 2). Oxime ether 55 was subjected to acylation with TFAA or TFAT in the presence of DMAP. The product was expected N-trifluoroacetyl enehydroxylamine 56 which was obtained in moderate to good yield (entries 1 and 2). Thus, formation of the intermediate 52a is proposed in our reaction though the isolation was not achieved yet.

We next investigated the reaction of oxime ether 57 derived from cyclohexanone (Scheme 12). When the reaction was carried out in dichloromethane with TFAA at 0 °C, the desired dihydrobenzo[b]furan 58 was obtained as the sole product. On the contrary, treatment of 57 with TFAT and DMAP produced exclusively benzo[b]furan 60 in 92% yield. It is worthy to note that the selective synthesis of either dihydrobenzo[b]furan 58 or benzo[b]furans 60 was achieved only by changing reaction conditions such as the TFAA or TFAT-DMAP system.
The reductive deamination of 58 with sodium cyanoborohydride in TFA proceeded to give the desired 2,3-dihydrobenzo[b]furan 59 in moderate yield.

In order to propose the reaction pathway, we investigated the conversion of dihydrobenzo[b]furan 58 to benzo[b]furan 60 (Scheme 13). Treatment of dihydrobenzo[b]furan 58 with trifluoromethanesulfonic acid (TfOH) gave benzo[b]furan 60 effectively as a result of elimination of the trifluoroacetamido group while reaction with TFA required longer reaction. In the reaction with TFAT, it was clearly indicated that dihydrobenzo[b]furan 58 was converted to benzo[b]furan 60 by action of TfOH which was unavoidably generated as byproduct in the trifluoroacetylation of oxime ether 57.

From the above results, we propose plausible reaction pathways to dihydrobenzo[b]furan 58 and benzo[b]furan 60 as follows (Scheme 14). First, acylation on the nitrogen atom of oxime ether 61 leads to the formation of N-trifluoroacetyl enehydroxylamine 62 and then the [3,3]-sigmatropic rearrangement smoothly follows to form acylimine 63. Formation of dihydrobenzo[b]furan 64 would proceed by intramolecular cyclization of 63. When TFAT was used as an acylating agent, benzo[b]furan 66 was formed through oxonium ion 65 which was generated by elimination of the trifluoroacetamido group in the presence of TfOH. Overall pathway would be very similar to that of Fischer indolization which involves analogues three step key reactions of hydrazones. However, it is generally difficult to isolate dihydrobenzo[b]furans under Fischer indolization conditions. To the best of our knowledge, there has been only one paper21b pertaining to the isolation of dihydrobenzo[b]furans which were synthesized from the oxime ethers bearing α,α´-disubstituted cyclopentane ring.

To investigate the scope and limitations of the TFAA or TFAT-DMAP system utilized for benzo[b]furan synthesis, we next tried to use a series of acyclic oxime ethers 67a,b as substrate (Scheme 15). Reaction of oxime ether 67a,b with TFAA gave dihydrobenzo[b]furan 68a,b in good yield. On the contrary, reaction with a combination of TFAT and DMAP gave exclusively benzo[b]furan 69a,b. These results clearly demonstrate the utility of [3,3]-sigmatropic rearrangement as a novel method for the synthesis of complex benzo[b]furans. The remarkable result obtained in the reaction of these oxime ethers prompted us to extend our procedure to the synthesis of various types of 2-arylbenzo[b]furans.

The substituent effect on the benzene ring of the arylimine part; Synthesis of 2-arylbenzo[b]furans
Among benzo[b]furans, 2-arylbenzo[b]furans are inhibitors of cell proliferation and platelet activating factor and some of them show other interesting activities.27 Thus, we started to investigate the substituent effect of our reaction and its application to the synthesis of 2-arylbenzo[b]furans (Scheme 16).

Treatment of unsubstituted oxime ether 70 with TFAT and DMAP gave quantitatively the desired 2-phenylbenzo[b]furan 72. Similarly, reaction of oxime ethers 70 bearing an electron-withdrawing substituent such as a bromo or nitro group at the p-position proceeded smoothly to give 2-arylbenzo[b]furan 72 in good yields. To our delight, when oxime ether 70 bearing a free hydroxy group was reacted with TFAT-DMAP, hydroxybenzo[b]furan 72 was directly obtained after chromatography using silica gel. We succeeded in the isolation of p-trifluoroacetyloxybenzo[b]furan 73 by only recrystallization (not chromatography) of the crude product obtained from oxime ether 70. Unfortunately, reaction of 70 with the p-methoxy group afforded the desired benzo[b]furan 72 (15%) along with 3-trifluoroacetylbenzo[b]furan 74 (21%). Substituents at the m-position had no marked influence on the reaction giving the expected benzo[b]furans 72 in excellent yields.
The next substrate of choice was oxime ethers 70 with an ortho-substituted phenyl group. o-Bromo, o-hydroxy, and o-methoxy-oxime ethers 70 were employed under the same conditions to give the desired benzo[b]furans 72 in good yields. When o-nitro oxime ether 70 was treated with TFAT-DMAP, benzo[b]furan 72 was not obtained but rearranged product 75 was isolated.

The effects of substituents on the phenoxy ring; Synthesis of functionalized 2-phenylbenzo[b]furans
In order to explore wide generality of our benzo[b]furan synthesis, we have newly investigated the substituent effects in [3,3]-sigmatropic rearrangement of O-aryl enehydroxylamines which was generated in situ by acylation of substituted oxime ethers 76 (Scheme 17). Treatment of oxime ethers 76 carrying p-bromo, p-nitro, and p-methyl groups with TFAT-DMAP afforded 5-functionalized 2-phenylbenzo[b]furans 77 in good to excellent yields. A similar trend was observed in the reaction of oxime ethers 76 with the o-substituted group such as bromo, nitro, and methyl groups. o-Bromo and o-methyl oxime ethers 76 gave the corresponding 7-substituted 2-phenylbenzo[b]furans 77 in good yields. Reaction of oxime ether 76 carrying the o-nitro group proceeded to give a separable mixture of 7-substituted 2-phenylbenzo[b]furans 77 and rearranged product 78. Generally, the long reaction time is required for the reaction of oxime ether carrying NO2 group. The m-substituted oxime ethers gave two types of regioisomeric benzo[b]furans with low selectivity in all cases.

Effective and short syntheses of stemofuran A, eupomatenoid 6 and coumestan
As mentioned above, our novel synthetic method for benzo[b]furans is efficient and practical because protection of the phenolic hydroxy groups is not required in the synthesis of hydroxylated 2-arylbenzo[b]furans. This finding prompts us to explore a new efficient procedure for the synthesis of biologically active natural benzo[b]furans. Thus, we started to synthesize natural and biologicaliy active benzo[b]furan products such as stemofuran A (82),28 eupomatenoid 6 (87),29 and coumestan (90),30 the latter of which does not have a hydroxy group. Our short synthesis of these products has been accomplished without protection of the phenolic hydroxy groups (Scheme 18).
At first, we examined synthesis of stemofuran A (82), recently isolated from Stemona collinsae.28 The known synthesis of stemofuran A reported by Pasturel et al.31 involved many steps including the protection/deprotection of the hydroxy group. O-Phenylhydroxylamine 80,23c readily prepared from 79, was condensed with 3,5-dihydroxyacetophenone to afford oxime ether 81 in good yield. When oxime ether 81 was treated with TFAT in the presence of DMAP at room temperature, the desired benzo[b]furan was isolated in excellent yield. Thus, short synthesis of stemofuran A (82) was accomplished in four steps with 72% overall yield.

Secondly, we chose eupomatenoid 6 (87)29 as our synthetic target which has shown antifungal, insecticidal, and antioxidant activities. Although Bach’s32 and Stevenson’s33 groups synthesized eupomatenoid 6, the syntheses include many transformations involving protection and deprotection of the hydroxy group. To introduce the (E)-propenyl group of eupomatenoid 6 at the last stage of our synthesis, we constructed the benzo[b]furan part as the first step. Condensation of O-phenylhydroxylamine 84 carrying the p-bromo group with p-hydroxypropiophenone gave oxime ether 85 which was subjected to our reaction conditions to afford 5-bromobenzo[b]furan 86 in 95% yield. Finally, benzo[b]furan 86 was subjected to the Suzuki coupling reaction with (E)-propenyl boronic acid to afford eupomatenoid 6 87 in excellent yield. Thus, we succeeded in total synthesis of eupomatenoid 6 in 52% overall yield from 83 in five steps. Our synthesis is superior to those reported by Bach’s and Stevenson’s groups in both yield and number of step.
The third target of our synthesis is coumestan (90),30 which is a basic pharmacophore containing coumestanes such as coumestrol34 which shows estrogenic activity. Due to its unique structure and biological activities, coumestan (90) had been synthesized by many organic chemists using independent approaches.35 Known synthetic methods involved the preparation of the benzo[b]furan part at the last stage while we constructed the benzo[b]furan part of coumestan as the first step. Condensation of a common O-phenylhydroxylamine 80 with 4-chromanone followed by sequential acylation and rearrangement of the resulting oxime ether 88 furnished the desired tricyclic benzo[b]furan 89 in 73% yield via two steps.
Finally, introduction of the carbonyl group was achieved by treatment of tricyclic benzo[b]furan 89 with PCC to give coumestan (90) in 76% yield. Thus, we succeeded in effective and short total synthesis of stemofuran A (82), eupomatenoid 6 (87), and coumestan (90) without protection of the phenolic hydroxy groups in the former two cases.

Reagent-controlled regioselective [3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehydroxylamine and its synthetic application
The tricyclic benzo[b]furan core with a sterically congested quaternary carbon is an important element in galanthamine-type,36 morphine-type,37 and lunarine-type38 of alkaloids which exhibit remarkable and inherent biological activities. Therefore, synthetic access to such benzo[b]furans has long been a challenge for synthetic chemists. In constructing the universal skeleton, many synthetic methods such as biomimetic phenolic oxidative coupling, photochemical reaction, radical cyclization, intramolecular Heck reaction, semipinacol rearrangement, intermolecular alkylation, and arylation had been reported.36-38 However, to the best of our knowledge, there have been few papers pertaining to the construction of hexahydrodibenzo[b]furans with a quaternary carbon in the ring juncture via [3,3]-sigmatropic rearrangement. Although the oxime ethers prepared from α,α’-disubstituted cyclopentanone gave dihydrobenzo[b]furan bearing a substituent in the ring juncture under acidic conditions,4 unsymmetrically α-mono-substituted oxime ethers are known21b to give the benzo[b]furans as a result of rearrangement at the unsubstituted position.

We have developed a new methodology for the construction of benzo[b]furans carrying a sterically congested quaternary carbon via three sequential reactions involving acylation, regioselective [3,3]-sigmatropic rearrangement, and cyclization of oxime ethers 91a,b (Scheme 19). The treatment of oxime ethers 91a,b carrying an electron-withdrawing group (EWG) with TFAA gave regioselectively dihydrobenzo[b]furans 92 carrying an EWG in the ring juncture while the reaction of 91a,b with TFAT-DMAP afforded dihydrobenzo[b]furans 93a,b and benzo[b]furans 94a,b which are substituted with EWG at the 4-position.
In the absence of a base, a more acidic proton at the root of either ester or nitrile of 91a,b was abstracted to form a more stable intermediate 95A under the thermodynamically controlled conditions. On the other hand, in the presence of a base under the kinetically controlled conditions, the sterically less hindered methylene proton was abstracted by the base to form 95B (Figure 1).

We then applied this reagent-controlled methodology to the efficient preparation of key intermediate 102 for synthesis of the macrocyclic spermidine alkaloid, lunarine (103), which was isolated from Lunaria biennis.38a This alkaloid is a competitive, promising target in drug design against tropical parasitic diseases. Lunarine and related compounds had been synthesized and evaluated against TryR in order to determine the features of lunarine that are associated with time-dependent inhibition.38b-f However, some of the reported syntheses involved more steps and gave low yields. 38b-f Our attention is focused on the efficient synthesis of a key intermediate 102 which was already converted to lunarine.38d The appropriately substituted oxime ether 98 was prepared by the condensation of p-bromophenoxyamine 96 with keto-ester 97 and then treated with TFAA. The product was the desired hexahydrodibenzo[b]furan 99. The reductive deamidation of 99 with silylhydride followed by the transformation of the thioacetal in the resulting ester 100 into the corresponding acetal afforded dioxolane 101. Finally, conversion of the ester 101 to aldehyde followed by the Wittig-Horner reaction afforded α,β-unsaturated ester 102 which is a key intermediate for synthesis of lunarine (103) (Scheme 20).

INDOLE SYNTHESIS22
[3,3]-Sigmatropic rearrangement of N-trifluoroacetyl enehydrazines
Prior to our study on benzo[b]furan synthesis, we have established a novel [3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehydrazines 104 for synthesis of indolines and indoles as follows (Scheme 21). In the case of indole synthesis, N-trifluotoacetyl enehydrazines 104 are isolable. At below 100 °C, N-trifluoroacetyl enehydrazine 104 carrying a cyclopentene ring smoothly underwent [3,3]-sigmatropic rearrangement followed by cyclization to give indolines 106 in excellent yield. On the other hand, both cyclohexenyl N-trifluoroacetyl enehydrazine and acyclic N-trifluoroacetyl enehydrazine 104 gave indoles 107 in good yield under the almost same conditions. The N-trifluoromethanesulfonyl enehydrazine 104 was converted into the rearranged product 109 at low temperature. The [3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehydrazines 104 carrying either a methoxy or a methyl group at ortho position on the benzene ring gave dienylimines 108 which correspond to the proposed intermediates of Fischer indolization.20 This reaction provides a new entry to the Fischer indole synthesis.

The substituent effects on the nitrogen atom in [3,3]-sigmatropic rearrangement of enehydrazines bearing a cyclopentene ring
At first, we investigated the substituent effects on the nitrogen atom. Three types of N-acyl　enehydrazines 110a, 110b, and 110c carrying a cyclopentene ring were employed as the substrate (Scheme 22). The hydrazone 111, prepared by condensation of cyclopentanone with N,N-diphenylhydrazine was subjected to acylation with TFAA in the presence of γ-collidine to give the corresponding N-trifluoroacetyl enehydrazines 110a in excellent yield. Similarly, N-trichloroacetyl enehydrazine 110b and N-acetyl enehydrazine 110c were prepared from 111.
Compared with acylation reaction of oxime ether, the acylated enehydrazine 110 could be isolated under the acylating conditions.
When a solution of 110a in THF was heated at 65 °C for 5 h, indoline 112a was obtained in 99% yield (entry 1 in Table 3). Similarly, the reaction of N-trichloroacetyl enehydrazine 110b at the same temperature gave indoline 112b in 56% yield (entry 2). However, in the case of 112c, higher reaction temperature (140 °C) was required for the successful rearrangement and cyclization (entry 3). Surprisingly, the reaction of 110a also proceeded at room temperature but required prolonged reaction time (480 h) (entry 4).

We next examined the rearrangement of the enehydrazine 110d carrying a trifluoromethanesulfonyl group which has higher electron-withdrawing ability (Scheme 23). The sulfonylation of hydrazone 111 with trifluoromethanesulfonic anhydride (Tf2O) was carefully carried out in the presence of γ-collidine at 0 °C. However, the reaction gave not the desired product 110d but the rearranged product 113 in low yield, along with the decomposition of 111.

At lower reaction temperature of –78 °C, 113 was obtained in 25% yield. Replacement of γ-collidine to triethylamine as a base improved the yield to 70%. Thus, this result suggests that the enehydrazine 110a bearing a trifluoroacetyl group is the best substrate for our indole synthesis.
Similarly, N-monophenylenehydrazine 110e, prepared from 114, worked well in toluene at 90 °C to give the indoline 112e along with the unreacted starting material 110e (Scheme 24).

Considering our results obtained above and the related known Fischer indolization,20 we propose a plausible reaction pathway that is shown in Scheme 25. At first, [3,3]-sigmatropic rearrangement of the N-acyl enehydrazines 110a-c followed by isomerization proceeds to form N-acylimines 116a-c which then cyclized intramolecularly to give the indoline 112a-c.

In sulfonylation of hydrazone 111, N-trifluoromethansulfonyl enehydrazine 110d could not be isolated. Probably, the [3,3]-sigmatropic rearrangement of 110d that would be transiently formed from hydrazone 111 would take place easily even at –78 °C because a trifluoromethanesulfonyl group has a very strong electron-withdrawing property. The following cyclization of rearranged intermediate 116d was prevented due to too low temperature (–78 °C). Therefore, 113 was an isolable product in the reaction of 111 with Tf2O.

The substituent effect on the ene part in [3,3]-sigmatropic rearrangement of enehydrazines
We next investigated the substituent effects on the ene part. In the case of cyclohexenehydrazine 110f, the indole 117f was exclusively obtained without formation of the indoline 112f (Scheme 26).

Upon heating at 140 °C, the indoline 112a was converted into the indole 117a in quantitative yield as a result of the elimination of trifluoroacetamide (Scheme 27). Reductive deamination of 112a with sodium cyanoborohydride proceeded smoothly to give the corresponding indoline 118 in 71% yield that is unsubstituted at the 3a-position (Scheme 27).

In general, it is difficult to isolate 2-aminoindolines which is proposed as an intermediate of Fischer indolization. To our knowledge, there has been only a few works39-41 on the isolation of 2-aminoindoline derivatives.
Next, the reaction of enehydrazines 110g and 110h bearing a methyl group on the cyclopentene ring was examined (Scheme 28). The enehydrazines 110g and 110h were prepared by the treatment of hydrazones 119a and 119b with TFAA without formation of the regioisomer 120. The enehydrazine 110g was subjected to the heating at 65 °C to give the indoline 112g in 76% yield while the indoline 112h could not be isolated from 110h under the same conditions probably because of its instability. On the other hand, the reaction of 110h in toluene at 90 °C gave the indole 117h in excellent yield.
The reactions of enehydrazines carrying ester and nitrile group are now in progress.
It is known42 that the classical Fischer indolization of hydrazone prepared from unsymmetrical ketone gives a mixture of substituted indoles with no regioselectivity. Therefore, this regioselective formation of indolines and indoles from unsymmetrical ketones 119a,b would be useful for the synthesis of variously substituted polycyclic indole alkaloids.

We then investigated the reaction of enehydrazine with an acyclic chain on the ene part (Scheme 29). The enehydrazine 110i was prepared by the acylation of hydrazone 121a with TFAA. The acylation of hydrazone 121b with TFAA gave a 3 : 1 mixture of enehydrazines 110j and 110k. The enehydrazine 110i was heated at 65 °C to afford the corresponding indoles 117i as the sole product.

The thermal reaction of 110j at 90 °C gave indole 117j in 77% yield. Similarly, 117k was obtained from 110k. Since the rearrangement and cyclization of 110i-k occurred with no isomerization of the olefin part under mild conditions, the substituted indoles such as 2-mono- and 2,3-disubstituted indoles would be selectively obtained as the sole product.
The substituent effects on benzene ring in [3,3]-sigmatropic rearrangement of enehydrazines bearing cycloalkene ring
To demonstrate the generality of the rearrangement and cyclization of N-trifluoroacetyl enehydrazines, we next investigated the substituent effects on the benzene ring. We chose methoxy, methyl, nitro, and chloro groups as a substituent. At first, the reaction of enehydrazine carrying a substituent at the p-position on the benzene ring was examined (Scheme 30).
The substrate 110l carrying a methoxy group underwent cyclization at lower temperature (65 °C) than the reaction of unsubstituted enehydrazine 110e at 90 °C (see Scheme 24). The indoline 112l was produced in excellent yield. Similarly, the substrate 110m with a methyl group gave the indoline 112m (68%) at 90 °C. On the other hand, in the case of the enehydrazines 110n and 110o carrying an electron-withdrawing group, prolonged reaction time and high reaction temperature were required. These substituent effects are almost in agreement with those obtained in the classical Fischer indolization.20 The existence of an electron-donating group on a benzene ring makes the thermal reaction relatively easy to occur while in the case of an electron-withdrawing group, harsh conditions were required for successful reaction.
The m-substituted enehydrazines gave two types of regioisomeric indoles with low selectivity in all cases.

We next investigated the reaction of o-substituted enehydrazines (Scheme 31, Table 4). At first, [3,3]-sigmatropic rearrangement of 110p carrying an o-methoxy group was examined. 110p was heated in THF at 65 °C to give a mixture of indoline 112p and two dienylimines 122p in 63 and 36% yields, respectively (entry 1). The dienylimines 122p were obtained as the result of the rearrangement at the root of a methoxy group. Furthermore, 122p was easily separated into two diastereomers, cis-syn-122p and cis-anti-122p, in a 5 : 1 ratio. Interestingly, the polarity of the organic solvent used influences both the product ratio of the indoline and dienylimine and the reaction time. In MeCN, the reaction proceeded smoothly to give a 1 : 1 mixture of 112p and 122p in 99% yield (entry 2). On the other hand, in a less polar solvent, such as toluene and hexane, 112p was obtained as a major product in 69-75% yield, although prolonged reaction time was required for complete consumption of 110p (entries 3 and 4). In methanol, the indole 117p and the dienylimines 122p were obtained with no formation of indoline 112p (entry 5).

Next, we turned our attention to the corresponding o-methyl-N-trifluoroacetyl enehydrazine 110q. The enehydrazine 110q worked well in MeCN at 80 °C to give the indoline 112q, indole 117q,29 cis-syn-122q, and cis-anti-122q (entry 6). When an electron-withdrawing group such as a chlorine or nitro group was present in the o-position, the indolization occurred regioselectively at the unsubstituted position to give 5-substituted products 112 (entries 7 and 8). The reaction of enehydrazine 110t bearing cyclohexene ring gave indole 117t as a major product. On the other hand, cyclobutenylenehydrazine 110v afforded dienylimine 122v in good yield (entries 9-11).
Furthermore, heating the dienylimines, cis-syn-122p and cis-anti-122p, in xylene at 140 °C afforded exclusively indole 117e31 (Scheme 32). This reaction pathway is ambiguous at the moment.
We have succeeded in the isolation and structure determination of the dienylimine intermediate in the thermal reaction of the o-methoxyenehydrazine. Additionally, the cis-syn-isomer was obtained as the major product among dienylimines.

It is well-known20,43-46 that Fischer indolization of (2-methoxyphenyl)hydrazone gives 7-methoxyindole as a minor product and the abnormal 6-substituted indole as a major product without the isolation of dienylimine.

The isolation and determination of the dienylimine intermediates in the Fischer indolization of o-methoxy and o-methyl enehydrazines provides good evidence for the postulated reaction mechanism, including a stereochemical rationalization, particularly for the [3,3]-sigmatropic rearrangement step.
To the best of our knowledge, there has been only one paper47 pertaining to the isolation of a pure dienylimine carrying a methyl group at the 3a-position in which the relative configurations at the 2-, 3- and 3a-position remain to be established. Additionally, Brown48 has reported that attemps to isolate a tricyclic dienylimine carrying a methyl group were unsuccessful. Therefore, our result is the first example of isolation and structure determination of the tricyclic dienylimine with a methyl group.
We next propose the possible reaction pathway for the formation of dienylimines 122 (Scheme 33). The enehydrazines 110 would exist in three different conformations I, J, and K. The indolines 112 were obtained via [3,3]-sigmatropic rearrangement via I. In the case of 112, they were converted into the indoles 117 by the elimination of the trifluoroacetamido group. On the other hand, the rearrangement via J and K followed by the cyclization of the resulting imines L and M gave cis-syn-122 and cis-anti-122, respectively. The conversion of J into cis-syn-122 proceeded more readily than that into cis-anti-122 because conformation K is less stable than conformation J due to the steric hindrance between a methoxy group and methylene on a cyclopentene or cyclohexene ring in K. The rearrangement of 110r,s gave the indolines 112r,s as the sole product. We are unable at this time to offer an explanation of the difference in regioselectivity between enehydrazine carrying an electron-donating group and enehydrazine carrying an electron-withdrawing group.
We next examined the reaction of acyclic enehydrazine 110w carrying the o-methoxy group (Scheme 34). The enehydrazine 110w was heated at 80 °C to give cis-dienylimines 122w and indole 117w in 27% and 68% yields, respectively.

CONCLUSION
We have established a highly efficient and general synthetic method for benzo[b]furans and indoles via the routes involving sequential acylation, rearrangement, and cyclization of oxime ethers under mild conditions. The [3,3]-sigmatropic rearrangement process promoted by the trifluoroacetyl group would represent a general strategy that may be of great use in the synthesis of more complex heterocycles.

ACKNOWLEDGEMENTS
We wish to thank Grants-in Aid for Scientific Research (B) (T. N.) and Scientific Research (C) (O. M.) from Japan Society for the Promotion of Science. Our thanks are also directed to the Science Research Promotion Fund of the Japan Private School Promotion Foundation for a research grant.

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