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Furo[3,4-b]indoles and thieno[2,3-c]furans via a Pummerer induced cyclization reaction

C. Oliver Kappe and Albert Padwa*

Department of Chemistry, Emory University, Atlanta, GA 30322, USA


The a-thiocarbocation generated from the Pummerer reaction of an o-heteroaroyl sulfoxide is intercepted by the adjacent keto group to produce an a-thio substituted heteroaromatic isobenzofuran. In the presence of a suitable dienophile, the reactive o-xylylene undergoes a Diels-Alder cycloaddition followed by an acid catalyzed ring-opening and aromatization to give heteroaromatic naphthalene derivatives. This one-pot procedure occurs smoothly with electron deficient dienophiles. In the absence of a dienophile it was possible to isolate 4-ethylthio-6-phenyl-thieno[2,3-c]furan and 1-ethylthio-4-phenylsulfonyl-4H-furoindole. The facility of this tandem Pummerer-Diels-Alder reaction was very dependent on the experimental conditions used to promote the reaction. The best results were achieved by employing a mixture of acetic anhydride and toluene which contained a catalytic amount of p-toluenesulfonic acid.


Isobenzofurans 1 correspond to one of the more interesting members of the o-quinodimethane family of dienes and have been the focus of considerable interest from both the synthetic and theoretical communities [1,2]. As highly reactive heteroaromatic o-xylylenes, they readily participate in inter- and intra-molecular 4+2-cycloaddition reactions [1,2] Further synthetic manipulation of the initially formed oxo-bridged cycloadduct usually provides an easy entry into naphthalene derivatives and related polycyclic aromatic ring systems. In many instances, the reactive isobenzofuran derivative is generated in the presence of a suitable dienophile. By comparison, heteroaromatic isobenzofuran analogues, in particular five-membered heteroaromatic derivatives, have not been extensively studied and only a few examples of synthetically useful Diels-Alder reactions of such species are known [3-10]. Most notable among the heteroaromatic isobenzofurans (2) reported in recent years are the furo[3,4-b]furans [3], thieno[2,3-c]furans [4,5], furo[3,4-d]isoxazoles [6], and furo[3,4-b]indoles [7-10]. These 10pi-systems are isoelectronic with the pentalene dianion and have been of some theoretical interest [3].

Over the years, most of the studies reported in the literature for these systems centre on their use as dienes in inter- and intra-molecular Diels-Alder reactions [3-10]. Such cycloaddition processes allow for a rapid entry into complex polyheterocyclic rings and makes these compounds potentially useful for natural product synthesis.

The vast majority of 2,3-methylene heteroaromatics have been prepared by flash vacuum pyrolysis or by 1,4-elimination from suitable precursors. One limitation of these methods is that the precursors are sometimes not easily available. Recently, we reported on the Pummerer-induced cyclization of keto sulfoxides [11] as a method to prepare thio-substituted isobenzofurans of type 4. The a-thio-carbocation generated from the Pummerer reaction of an o-benzoyl substituted sulfoxide is intercepted by the adjacent keto group to produce isobenzofuran 4 as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with an added dienophile. The resulting cycloadduct 5 can be readily converted to representatives of several types of aryl naphthalene lignans [12]. In a continuation of our studies in this general area, we now report on an extension of the tandem Pummerer Diels-Alder sequence for the synthesis of several thieno[2,3-c]furans and furo[3,4-b]indoles. The results of these studies are described herein.

Results and Discussion

The classical Pummerer reaction can be initiated by a variety of electrophilic reagents (Pummerer promoters) [13]. Acetic anhydride is by far the most commonly used reagent and is often utilized as the solvent at reflux temperature or in combination with other solvents or co-catalysts. In our earlier studies [11,12], we have successfully employed neat acetic anhydride as the Pummerer promoter since we found it to be highly effective for inducing the Pummerer reaction in the isobenzofuran system. However, when thiophene- or indolo-derived sulfoxides (vide infra) were used, the desired cycloadducts were obtained in much lower yield (10-20%), with the major product in most cases being acetoxy sulfides of type 9 [13]. It became evident, therefore, that a modified triggering protocol had to be developed in order to achieve acceptable yields of the desired heterocyclic cycloadducts. After considerable experimentation with a variety of Pummerer promoters and co-catalysts, we found that the highest yield of cycloaddition that could be obtained from the cascade process utilized a mixture of toluene and acetic anhydride which also contained a catalytic quantity of p-toluenesulfonic acid (p-TsOH) [14]. These conditions, whereby the sulfoxide is slowly added to a refluxing mixture of toluene, acetic anhydride (10 equiv.), p-TsOH (catalyst), and the appropriate dienophile (2-3 equiv.) gave consistently the best results (> 80% yields).

The presence of p-TsOH as a co-catalyst dramatically accelerated the rate at which sulfoxides of type 7 undergo the Pummerer transformation (7 -> 8) as compared to reactions carried out without any p-TsOH. The initially formed thionium ion 8 can either be captured internally by the adjacent carbonyl group [15] to give, after proton loss, the isobenzofuran intermediate 10, or it can react in the traditional sense with an external nucleophile (i.e. acetoxy) to furnish the acetoxy sulfide 9. The presence of p-TsOH effectively drives the reaction in the desired direction (8 -> 10) either by preventing the formation of the acetoxy sulfide 9, or by assisting the ejection of the acetoxy group (9 -> 8), should 9 be formed. The presence of p-TsOH also promotes the conversion of the primary cycloadduct 11 into the aromatized product 12, thereby adding another step to this series of cascade reactions.

In order to prepare heterocyclic analogues of our previously described a-thioisobenzofurans we first turned our attention to thiophene analogues. Thiophene-2-carboxylic acid 13 was converted to the Weinreb amide 14 following standard procedures [16]. The ethylthiomethyl functionality was then introduced by NBS bromination and subsequent displacement of bromide with ethanethiol [17]. The resulting sulfide 15 was treated with phenylmagnesium bromide to produce ketone 16, which in turn, was oxidized with sodium periodate [18] to give sulfoxide 17. Treatment of 17 with N-phenyl maleimide or maleic anhydride under the tandem Pummerer Diels-Alder conditions provided benzo[b]thiophene derivatives 22 and 23 in excellent yield. The initially formed primary cycloadducts 19 and 20 could not be isolated or observed. However, when the reaction was carried out in the absence of a dienophile, we were able to isolate thieno[2,3-c]furan 18 in 79% yield. This isobenzofuran analogue proved to be surprisingly stable, and to the best of our knowledge corresponds to the second example of a stable thieno[2,3-c]furan reported in the literature [4]. As expected, 18 cleanly afforded thienoisoindole 22 (80%) when treated with N-phenyl maleimide in toluene in the presence of catalytic amounts of p-TsOH at room temperature. It should be noted that thienofuran 18 also underwent the Diels-Alder reaction when the less reactive methyl acrylate was used as the dienophile. Thus, treatment of 18 with methyl acrylate in the presence of scandium(III)trifluoromethanesulfonate [19] for 2 d gave rise to benzo[b]thiophene 24 in 78% yield.

Since furo[3,4-b]indoles have recently been employed as intermediates in the synthesis of some naturally occurring carbazole derivatives (e.g. ellipticine [7], and murrayaquinone A [8]), we decided to explore the potential of the tandem Pummerer Diels-Alder strategy toward the synthesis of several substituted carbazoles. The required sulfoxide 28 was prepared in the standard manner as outlined below. The readily available N-phenylsulfonyl-indole-2-carbaldehyde 25 [20] was first protected as an imine by treating it with tert-butylamine. The resulting imine was subsequently brominated with NBS to give bromomethyl derivative 26. Nucleophilic displacement of the bromide by ethanethiol followed by acidic hydrolysis of the imine produced aldehyde 27. Oxidation of the sulfide in the usual manner gave sulfoxide 28 in 58% overall yield (five steps).

Treatment of 28 with either N-phenyl maleimide or maleic anhydride utilizing the Pummerer Diels-Alder conditions afforded the fused carbazoles 30 and 31 in excellent yield. When the reaction was carried out in the absence of a dienophile, it was possible to isolate furo[3,4-b]indole 29 in 78% yield. Although 29 is not as stable as thienofuran 18, it could be obtained in a high state of purity by rapid work-up and chromatographic purification of the reaction mixture. However, if kept at room temperature, significant decomposition of 18 occurred within days. As expected, a pure sample of furoindole 29 readily reacts with N-phenyl maleimide in the presence of p-TsOH to give pyrrolocarbazole 43.

In conclusion, we have demonstrated that the tandem Pummerer Diels-Alder reaction sequence can be used to efficiently synthesize a variety of polyheterocyclic ring systems. The key intermediates in these cascade processes are a-thio-isobenzofurans, which in some cases can be isolated and independently reacted with an appropriate dienophile to give 4+2 cycloadducts. We found it to be most convenient to carry out these reactions in an all-tandem fashion. Our results clearly indicate that the tandem-cascade process is a powerful method for the construction of complex hetero-aromatic o-quinodimethanes. This area of research is currently being pursued in more detail in our laboratories.


We gratefully acknowledge the National Science Foundation and the National Cancer Institute (CA-26750), DHEW, for generous support of this work. C. O. K. wishes to acknowledge the Austrian Science Foundation (FWF) for an Erwin-Schroedinger-Postdoctoral Fellowship. Use of high-field NMR spectrometer used in these studies was made possible through equipment grants from the NIH and NSF.


1. For a review on isobenzofurans, see: Friedrichsen, W. Adv. Heterocycl. Chem. 1980, 26, 135. Rickborn, B. Adv. Theoret. Interesting Molecules, Thummel, R. P., Ed.; Vol. 1, JAI Press: Greenwich, CT, 1989; p 1. Friedrichsen, W. in Houben-Weyl, Methoden der Organischen Chemie, Kreher, R. Ed.; Vol. E6b, Thieme Verlag: Stuttgart, 1994; p 163-216.

2. Rodrigo, R. Tetrahedron 1988, 44, 2093.

3. Eberbach, W.; Fritz, H.; Laber, N. Angew. Chem., Int. Ed. Engl. 1988, 27, 568. Eberbach, W.; Laber, N.; Bussenius, J.; Fritz, H.; Rihs, G. Chem. Ber. 1993, 126, 975.

4. Schönig, A.; Debaerdemaeker, T.; Zander, M.; Friedrichsen, W. Chem. Ber. 1989, 122, 1119. Schönig, A.; Friedrichsen, W. Liebigs Ann. Chem. 1989, 405. Schönig, A.; Friedrichsen, W.; Tetrahedron Lett. 1988, 29, 1137.

5. Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Nishitani, T.; Kondo, K.; Iwasaki, T. J. Org. Chem. 1994, 59, 7353.

6. Aßmann, L.; Palm, L.; Zander, M.; Friedrichsen, W. Chem. Ber. 1991, 124, 2481. Abszlig;mann, L.; Friedrichsen, W. Heterocycles 1989, 29, 1003. Aßmann, Debaerdemaeker, T.; Friedrichsen, W. Tetrahedron Lett. 1991, 32, 1161.

7. Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M. G.; Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; BelBruno, J. J. J. Org. Chem. 1992, 57, 5878 and references therein.

8. Miki, Y.; Hachiken, H. Synlett 1993, 333.

9. Shiue, J.-S.; Fang, J.-M. J. Chem. Soc., Chem. Commun. 1993, 1277.

10. Nagel, J.; Friedrichsen, W.; Debaerdemaeker, T. Z. Naturforsch. 1993, B48, 213.

11. Cochran, J. E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495.

12. Cochran, J. E.; Padwa, A. J. Org. Chem. 1995, 60, 3938.

13. For a review of the Pummerer reaction and different triggering methods, see: DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions; Paquette, L. A., ed.; John Wiley: 1991, Chap. 3, pp 157-184.

14. Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kumamoto, T. Bull. Chem. Soc. Jpn. 1981, 57, 817.

15. DeGroot, A.; Jansen, B. J. M. J. Org. Chem. 1984, 49, 2034. Jansen, B. J. M.; Bouwman, C. T.; DeGroot, A. Tetrahedron Lett. 1994, 35, 2977. Jommi, G.; Pagliarin, R.; Sisti, M.; Tavecchia, P. Synth. Comm. 1989, 2467.

16. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. For a review of the chemistry of Weinreb amides, see: Sibi, M., P. Org. Prep. Proced. Int. 1993, 25, 15.

17. Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980, 952.17.

18. Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27, 282.

19. For a review on the use of Sc(OTf)3 as catalyst in Diels Alder reactions, see Kobayashi, S. Synlett 1994, 689.

20. Benzies, D. W. M.; Fresneda, P. M.; Jones, R. A. Synth. Commun. 1986, 16, 1799.


General procedure for the tandem-Pummerer-Diels-Alder reaction sequence.

A mixture of dry toluene (10 mL), acetic anhydride (0.5 mL), and the appropriate dienophile (1 mmol) containing a catalytic amount of p-toluenesulfonic acid (ca. 1 mg) was heated at reflux under argon. To this mixture was added dropwise a solution of the appropriate sulfoxide (0.5 mmol) in dry toluene (5 mL) via syringe over a 20 min period. For the intramolecular cycloadditions, the addition was carried out over a 1 h interval using 25 mL of solvent. After the addition was complete, the solution was heated at reflux for an additional 20 min until no more sulfoxide was detected by TLC. The mixture was evaporated to dryness and the crude residue was purified by flash silica gel chromatography or by recrystallization.

4-Ethylthio-6,8-diphenyl-thieno[2,3-f]isoindole-5,7-dione (22) was prepared from 139 mg (0.5 mmol) sulfoxide 17 and 173 mg (1 mmol) N-phenyl maleimide in 91% yield as pale yellow solid, mp 144-145 deg.C; IR (KBr) 1755, 1710, 1500, 1373, 1118, 759, and 693 cm-1; 1H-NMR (CDCl3) d 1.29 (t, 3H, J = 7.5 Hz), 3.25 (q, 2H, J = 7.5 Hz), 7.34-7.59 (m, 10H), 7.75 (d, 1H, J = 5.0 Hz), and 8.07 (d, 1H, J = 5.0 Hz); 13C-NMR (CDCl3) d 15.2, 30.9, 123.5, 126.0, 126.7, 127.8, 128.3, 128.5, 128.8, 129.0, 130.4, 131.7, 132.3, 134.6, 136.0, 146.3, 147.5, 165.8, and 165.9; Anal. Calcd for C24H17NO2S2: C, 69.37; H, 4.12; N, 3.37. Found: C, 69.25; H, 4.15; N, 3.36.

Methyl 4-ethylthio-7-phenyl-benzo[b]thiophene-6-carboxylate (24). A mixture containing 66 mg (0.25 mmol) of thienofuran 18, 215 mg (2.5 mmol) of methyl acrylate, 12 mg (0.025 mmol) of Sc(OTf)3 and 10 mL of dry THF was stirred under argon at 25 deg.C for 2 d. Evaporation of the solvent under reduced pressure followed by silica gel chromatography gave 64 mg (78%) of cycloadduct 24 as a pale yellow oil; IR (neat) 1718, 1432, 1248, and 1127 cm-1; 1H-NMR (CDCl3) d 1.39 (t, 3H, J = 7.5 Hz), 3.10 (q, 2H, J = 7.5 Hz), 3.63 (s, 3H), 7.39-7.48 (m, 5H), 7.62 (m, 2H), and 7.90 (s, 1H); 13C-NMR (CDCl3) d 14.4, 27.9, 52.0, 123.1, 125.8, 126.2, 128.0, 128.3, 128.4, 130.8, 136.2, 139.6, 141.6, 142.4, and 168.0; m/e 328 (M+ , base), 299, 267, 240, 208, 196, 162, and 112; HRMS (EI) Calcd for C18H16O2S2: 328.0592. Found: 328.0583.

10-Ethylthio-2-phenyl-5-phenylsulfonyl-5H-pyrrolo[3,4-b]carbazole-1,3-dione (30) was obtained from 188 mg (0.5 mmol) sulfoxide 28 and 173 mg (1 mmol) N-phenylmaleimide as colourless solid in 90% yield, mp 249-250 deg.C; IR (KBr) 1760, 1708, 1370, and 1350 cm-1; 1H-NMR (CDCl3) d1.25 (t, 3H J = 7.5 Hz), 3.21 (q, 2H, J = 7.5 Hz), 7.39-7.69 (m, 10H), 7.91 (d, 2H, J = 7.8 Hz), 8.46 (d, 1H, J = 8.4 Hz), 8.92 (s, 1H), and 9.27 (d, 1H, J = 8.1 Hz); 13C-NMR (CDCl3) d 15.0, 31.3, 110.0, 114.6, 124.4, 125.4, 125.7, 126.5, 126.6, 127.2, 128.0, 129.0, 129.3, 129.5, 131.6, 131.7, 131.9, 132.8, 134.5, 137.4, 139.6, 141.1, 165.9, and 166.2; Anal. Cacld for C28H20N2O4S2: C, 65.61; H, 3.93; N, 5.47. Found: C, 65.67; H, 3.96; N, 5.46.

General procedure for the preparation of heterocyclic isobenzofurans 18 and 29.

A mixture containing dry toluene (10 mL), acetic anhydride (0.5 mL) and a catalytic amount of p-toluenesulfonic acid (ca 1 mg) was heated at reflux under argon. A solution of the appropriate sulfoxide (0.5 mmol) in dry toluene (5 mL) was added dropwise via syringe over a 20 min interval. After the addition was complete, the solution was heated at reflux for an additional 10-15 min. The mixture was concentrated in vacuo to ca. 20% of its original volume. The resulting toluene solution was placed on a flash silica gel column and eluted first with hexane, followed by a 6:1 hexane/ethyl acetate mixture. Using this method the following compounds were prepared.

4-Ethylthio-6-phenyl-thieno[2,3-c]furan (18)

Compound 18 was obtained from 139 mg (0.5 mmol) sulfoxide 17 as a colourless oil in 79% yield; IR (neat) 1597, 1481, 1447, 1253, 977, and 760 cm-1; 1H-NMR (CDCl3) d 1.30 (t, 3H, J = 7.5 Hz), 2.84 (q, 2H, J = 7.5 Hz), 6.85 (d, 1H, J = 5.0 Hz), 7.11 (d, 1H, J = 5.0 Hz), 7.24 (dd, 1H, J = 7.6 and 7.6 Hz), 7.43 (dd, 2H, J = 7.6 and 7.6 Hz), and 7.63 (dd, 2H, J = 7.6 and 1.2 Hz); 13C-NMR (CDCl3) d 15.5, 31.3, 115.2, 122.6, 123.6, 126.9, 128.8, 129.8, 132.7, 133.3, 142.2, and 145.1; m/e 260 (M+), 231 (base), 203, 199, and 77; HRMS (EI) Calcd for C14H12OS2: 260.0330. Found: 260.0326.

1-Ethylthio-4-phenylsulfonyl-4H-furo[3,4-b]indole (29)

Compound 24 was obtained from 188 mg (0.5 mmol) sulfoxide 28 as a clear oil in 78% yield; IR (neat) 1448, 1368, 1134, and 956 cm-1; 1H-NMR (CDCl3) d 1.22 (t, 3H, J = 7.5 Hz), 2.84 (q, 2H, J = 7.5 Hz), 7.22-7.51 (m, 5H), 7.75 (d, 1H, J = 7.5 Hz), 7.82 (m, 3H), and 7.96 (d, 1H, J = 8.4 Hz); 13C-NMR (CDCl3) d 15.3, 30.4, 114.8, 121.8, 122.2, 124.4, 125.6, 126.7, 126.9, 127.7, 128.9, 133.6, 133.9, 134.4, 136.5, 144.0; m/e 357 (M+), 328, 216, 188, 141, and 77; HRMS (EI) Calcd for C18H15NO3S2: 357.0493. Found: 357.0492.