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Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives
Journal Pre-proofs Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives Masaya Nakajima, Yusuke Kondo, Shun-ichi Nakano, Yusuke Adachi, Dongil Choi, Robert Franzén, Tetsuhiro Nemoto PII: DOI: Reference:
S0040-4039(20)30182-9 https://doi.org/10.1016/j.tetlet.2020.151754 TETL 151754
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
13 November 2019 12 February 2020 17 February 2020
Please cite this article as: Nakajima, M., Kondo, Y., Nakano, S-i., Adachi, Y., Choi, D., Franzén, R., Nemoto, T., Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151754
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.
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Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives
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Masaya Nakajima, Yusuke Kondo, Shun-ichi Nakano, Yusuke Adachi, Dongil Choi, Robert Franzén, and Tetsuhiro Nemoto
1
Tetrahedron Letters journal homepage: www.elsevier.com
Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives Masaya Nakajimaa, Yusuke Kondoa, Shun-ichi Nakanoa, Yusuke Adachia, Dongil Choia, Robert Franzénb, and Tetsuhiro Nemotoa,c, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan School of Chemical Engineering, Department of Chemistry and Materials Science, Aalto University, FI-00076, Aalto, Helsinki, Finland c Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan a b
———
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives was developed. Treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions induced the reaction of the generated vinyl radical intermediates with the internal alkene, producing tricyclic 3alkylidene dihydrobenzofurans in 25%–93% yield. The reaction products could be utilized as the precursors for 3,4-fused tricyclic benzofurans.
Corresponding author (TN). Tel.: +81-43-226-2920; fax: +81-43-226-2920; e-mail: [email protected].
Keywords: Cascade reactions Radical reactions Benzofurans Synthetic Methods
The development of an efficient synthetic method for heterocyclic compounds is an important research aim in organic chemistry because of their potential bioactivities and utility in medicinal chemistry researches. In particular, considerable attention has been focused on the construction of fusedheterocyclic skeletons ubiquitously found in natural products or pharmaceutical compounds. The 3,4-fused tricyclic benzofuran skeleton is one of such structure (Figure 1). Several synthetic methods for this structural motif have been developed and applied to the synthesis of natural products.1 Among them, the synthetic method reported by Jia and co-workers based on a Pdcatalyzed cascade cyclization using alkyne-tethered iodophenol derivatives is the state-of-the-art strategy toward this end.2
2009 Elsevier Ltd. All rights reserved.
Figure 1. Natural Products with a 3,4-Fused Tricyclic Benzofuran Derivative. As part of our ongoing studies aimed at developing a synthetic method for fused-polycyclic heterocycles, we recently reported synthetic methods of 3,4-fused tricyclic indole derivatives3 using a Pd-catalyzed cascade cyclization by Heck insertion of an allene and allylic amination (Scheme 1a)4 and a Pt-catalyzed FriedelCrafts type C–H coupling–allylic amination cascade (Scheme 1b).5 Our strategy was relied on the preparation of 3,4-fused tricyclic 3-alkylidene indolines as synthetic precursors, followed by acid-promoted isomerization to produce the corresponding indole derivatives. As shown in Scheme 1, 3,4-fused tricyclic 3alkylidene indoline was obtained in high yield using compound 1a as a substrate for the Pd catalysis and compound 3a as a substrate for the Pt catalysis. These cascade reactions are potentially applicable for constructing the 3,4-fused tricyclic benzofuran skeleton by replacing the tosylamide unit with a phenol. Thus, we examined the reactions using compounds 1b and 3b as substrates under the same reaction conditions used for the cascade cyclization of 1a and 3a. Pd-catalyzed cascade cyclization of 1b proceeded, but the yield of 2b was significantly decreased compared with that of 2a (Scheme 1a). Furthermore, no product was obtained when compound 3b was used under the Pt catalysis conditions (Scheme 1b). These unsatisfactory results led us to develop a new synthetic method based on a different synthetic strategy.
2
Tetrahedron yield (entries 2 and 3). Although tris(trimethylsilyl)silane was also applicable as a hydride source, the product was obtained in less satisfactory yield (entry 4). The reaction concentration was optimized when toluene was used as the optimum solvent (entries 5–7). When the reaction was performed in refluxed toluene at 0.03 M, the product 10 was obtained in 93% isolated yield. Treatment of 10 with 30 equiv of trifluoroacetic acid (TFA) resulted in the smooth conversion to 3,4-fused tricyclic benzofuran 11 in 92% yield, successfully demonstrating the accessibility to the target skeleton.
Scheme 1. Comparison of the Reactivity. In 1985, Snieckus and co-workers reported a radical cascade reaction for synthesizing 3-alkylidene dihydrobenzofuran derivatives.6 When a propargyl iodophenol derivative was refluxed in benzene in the presence of azobisisobutyronitrile (AIBN) and HSnBu3, the corresponding product was obtained in moderate yield (Scheme 2a). This precedent work led us to hypothesize that treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions would induce the reaction of the generated vinyl radical intermediates with the internal alkene to give the tricyclic 3-alkylidene dihydrobenzofurans, which could then be utilized as the precursors for 3,4-fused tricyclic benzofurans.7
Scheme 3. Synthesis of 3-alkylidene dihydrobenzofuran derivative 10 and its isomerization. (a) propargyl bromide (1.5 equiv), K2CO3 (1.5 equiv), DMF, rt; (b) DABCO (0.65 equiv), methyl acrylate (20 equiv), sonication, rt; (c) acetic anhydride (2 equiv), triethylamine (2 equiv), DMAP (10 mol %), CH2Cl2, 0 °C; (d) DABCO (1 equiv), H2O/THF (1/3), rt, then NaBH4 (2 equiv), rt; (e) trifluoroacetic acid (30 equiv), CH2Cl2, rt. DABCO: 1,4-diazabicyclo[2.2.2]octane; DMAP: N,Ndimethylaminopyridine. Table 1. Optimization of the reaction conditions.
Scheme 2. Plan for this study. We began our investigation by preparing the model substrate (Scheme 3). Propargylation of known compound 5 was carried out to give compound 6 in 83% yield. Morita-Baylis-Hillman reaction of 6 with methyl acrylate in the presence of 0.65 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) proceeded under sonication conditions, providing compound 7 (85% yield), which was followed by acetylation to give compound 8. The acetoxy group was removed under reductive conditions, affording model substrate 9 in 54% yield over two steps. We then evaluated radical cascade cyclization to produce 3,4-fused tricyclic 3alkylidene dihydrobenzofuran 10 (Table 1). When compound 9 was refluxed in benzene (0.05 M) in the presence of 1.1 equiv of HSnBu3 and 10 mol % of AIBN, the desired cascade reaction proceeded smoothly to give compound 10 in 85% yield (entry 1). Solvent screening revealed that toluene slightly improved the
Entry
Solvent (conc.)
Hydride Source
Time
Yielda
1
benzene (0.05M)
HSnBu3
45 min
85%
2
toluene (0.05 M)
HSnBu3
30 min
89%
3
xylene (0.05 M)
HSnBu3
30 min
86%
4
toluene (0.05 M)
HSi(SiMe)3
120 min
70%
5
toluene (0.1 M)
HSnBu3
20 min
86%
6
toluene (0.03 M)
HSnBu3
30 min
93% (93%)b
7
toluene (0.01 M)
HSnBu3
60 min
93%
Determined by 1H-NMR of the crude mixture using CHPh3 as internal standard. a
b
Isolated yield.
3 Compound 12, an N-tosyl variant of 11, was also prepared and reacted under the optimized reaction conditions (Scheme 4). Although the desired radical cascade cyclization proceeded, 3alkylidene indoline adduct 13 was obtained in only 43% yield, indicating that the developed synthetic method is more suitable for 3-alkylidene dihydrobenzofuran synthesis.8
was treated under the optimized conditions, the product with an 8-membered ring 34 was obtained in 50% yield.
Scheme 4. Synthesis of 3-alkylidene indoline derivative 13 via a radical cascade cyclization.
Acknowledgments
Aryl vinyl ketone-type substrate was prepared next according to the synthetic route shown in Scheme 5. After vinylation of the aldehyde in 6 using 1.1 equiv of vinylmagnesium bromide, the obtained allylic alcohol derivative 14 was converted into compound 15 using Dess-Martin reagent (48% yield from 6). Radical cascade cyclization of 15 was then performed under the optimum conditions, and tricyclic product 16 was produced in 61% yield. This product could be isomerized into the corresponding benzofuran derivative 17 in 82% yield by treatment with TFA. Notably, the yield of 18 (18% yield) was significantly decreased when allylic alcohol derivative 14 was used as a substrate. These findings indicated that the electrophilic property of the alkene unit is important for the medium-sized ring formation.
Scheme 5. (a) vinylmagnesium bromide (1.1 equiv), Et2O, rt; (b) Dess-Martin reagent (1.2 equiv), CH2Cl2, rt; (c) HSnBu3 (1.1 equiv), AIBN (10 mol %), toluene, reflux; (d) trifluoroacetic acid (10 equiv), CH2Cl2, rt. This radical cascade process was also applicable to more functionalized substrates (Scheme 6).8 Substrates with a substituent on the alkyne terminal 19–21 and 25–27 were prepared using the synthetic methods shown in Scheme 3 and Scheme 5, respectively, and were reacted under the optimized conditions (See Supplementary Data for details.). The corresponding products with a substituent on the alkylidene unit were obtained in 25%–71% yield. The reaction using a branched ether derivative 31 proceeded to give the product 32 with two substituents on the tricyclic skeleton in 43% yield. Furthermore, when compound 33 with a methylene-unit longer tether than 15
In conclusion, we developed a new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives. When using propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions, the radical cascade process proceeded in the presence of AIBN and HSnBu3, producing 3,4-fused tricyclic 3-alkylidene dihydrobenzofurans in 43%–93% yield. The obtained products could be efficiently transformed into 3,4-fused tricyclic benzofurans by treatment with TFA. Application of the present method to the synthesis of natural products with a 3,4-fused tricyclic benzofuran skeleton is ongoing.
This work was supported by JSPS KAKENHI Grant Number 18H025550, and The Naito Foundation.
Scheme 6. Substrate generality. References and notes 1.
For the synthesis of radermachol, see: (a) Buccini, M.; Piggott, M. J. Org. Lett. 2014, 16, 2490; (b) Samineri, R.; Srihari, P.; Mehta, G. Org. Lett. 2016, 18, 2832. For the synthesis of bussealin E, see: (c) Twigg, D. G.; Baldassarre, L.; Frye, E. C.; Galloway, W. R. J. D.; Spring, D. R. Org. Lett. 2018, 20, 1597. For the synthesis of diptoindonesin G, see: (d) Kim, K.; Kim, I. Org. Lett. 2010, 12, 5314; (e) Liu, J.; Do, T. J.; Simmons, C. J.; Lynch, J. C.; Gu, W.; Ma, Z.-X.; Xu, W.; Tang, W. Org. Biomol. Chem. 2016, 14, 8927; (f) Singh, D. K.; Kim, I. J. Org. Chem. 2018, 83, 1667; (g) Singh, D. K.; Kim, I. Tetrahedron Lett. 2019, 60, 300; (h) Qin, Y.; Zhan, J.-L.; Shan, T; Xu, T. Tetrahedron Lett. 2019, 60, 925. For the
Tetrahedron
4
2. 3.
4.
5.
6. 7. 8.
synthesis of malibatol A, see: (i) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191; (j) Kim, I.; Choi, J. Org. Biomol. Chem. 2009, 7, 2788; (k) Chen, D. Y.-K.; Kang, Q.; Wu, T. R. Molecules 2010, 15, 5909; (l) Jung, Y.; Singh, D. K.; Kim, I. Beilstein J. Org. Chem. 2016, 12, 2689. Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem. Int. Ed. 2015, 54, 6255. For reviews on the synthesis of 3,4-fused tricyclic indoles, see: (a) McCabe, S. R.; Wipf, P. Org. Biomol. Chem. 2016, 14, 5894; (b) Ito, M.; Tahara, Y.; Shibata, T. Chem. Eur. J. 2016, 22, 5468; c) Liu, H.; Jia, Y. Nat. Prod. Rep. 2017, 34, 411; (d) Nemoto, T.; Harada, S.; Nakajima, M. Asian J. Org. Chem. 2018, 7, 1730. (a) Nakano, S.; Inoue, N.; Hamada, Y.; Nemoto, T. Org. Lett. 2015, 17, 2622; (b) Inoue, N.; Nakano, S.; Harada, S.; Hamada, Y.; Nemoto, T. J. Org. Chem. 2017, 82, 2787; (c) Nakano, S.; Hamada, Y.; Nemoto, T. Tetrahedron Lett. 2018, 59, 760. (a) Suzuki, Y.; Tanaka, Y.; Nakano, S.; Dodo, K.; Yoda, N.; Shinohara, K.; Kita, K.; Kaneda, A.; Sodeoka, M.; Hamada, Y.; Nemoto, T. Chem. Eur. J. 2016, 22, 4418; (b) Tanaka, Y.; Suzuki, Y.; Hamada, Y.; Nemoto, T. Heterocycles 2017, 95, 243. Shankaran, K.; Sloan, C. P.; Snieckus, V. Tetrahedron Lett. 1985, 26, 6001. For recent reviews on radical cascade cyclization, see: (a) Xuan, J.; Studer, A. Chem. Soc. Rev. 2017, 46, 4329; (b) Huang, M.-H.; Hao, W.-J.; Jiang, B. Chem. Asian J. 2018, 13, 2958. Formation of highly polar byproducts was observed in thin layer chromatography analysis when the target tricyclic product was obtained in low yield, suggesting that intermolecular radical cascade reactions occurred competitively.
Supplementary Material Supplementary data associate with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tetlet.
Highlights A new synthetic method for 3,4-fused tricyclic 3alkylidene dihydrobenzofurans was developed. The target skeleton was synthesized using a radical cascade cyclization. The products could be transformed into 3,4-fused tricyclic benzofurans by treatment with acid.
S0040-4039(20)30182-9 https://doi.org/10.1016/j.tetlet.2020.151754 TETL 151754
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
13 November 2019 12 February 2020 17 February 2020
Please cite this article as: Nakajima, M., Kondo, Y., Nakano, S-i., Adachi, Y., Choi, D., Franzén, R., Nemoto, T., Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151754
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.
Graphical Abstract
To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives
Leave this area blank for abstract info.
Masaya Nakajima, Yusuke Kondo, Shun-ichi Nakano, Yusuke Adachi, Dongil Choi, Robert Franzén, and Tetsuhiro Nemoto
1
Tetrahedron Letters journal homepage: www.elsevier.com
Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives Masaya Nakajimaa, Yusuke Kondoa, Shun-ichi Nakanoa, Yusuke Adachia, Dongil Choia, Robert Franzénb, and Tetsuhiro Nemotoa,c, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan School of Chemical Engineering, Department of Chemistry and Materials Science, Aalto University, FI-00076, Aalto, Helsinki, Finland c Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan a b
———
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives was developed. Treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions induced the reaction of the generated vinyl radical intermediates with the internal alkene, producing tricyclic 3alkylidene dihydrobenzofurans in 25%–93% yield. The reaction products could be utilized as the precursors for 3,4-fused tricyclic benzofurans.
Corresponding author (TN). Tel.: +81-43-226-2920; fax: +81-43-226-2920; e-mail: [email protected].
Keywords: Cascade reactions Radical reactions Benzofurans Synthetic Methods
The development of an efficient synthetic method for heterocyclic compounds is an important research aim in organic chemistry because of their potential bioactivities and utility in medicinal chemistry researches. In particular, considerable attention has been focused on the construction of fusedheterocyclic skeletons ubiquitously found in natural products or pharmaceutical compounds. The 3,4-fused tricyclic benzofuran skeleton is one of such structure (Figure 1). Several synthetic methods for this structural motif have been developed and applied to the synthesis of natural products.1 Among them, the synthetic method reported by Jia and co-workers based on a Pdcatalyzed cascade cyclization using alkyne-tethered iodophenol derivatives is the state-of-the-art strategy toward this end.2
2009 Elsevier Ltd. All rights reserved.
Figure 1. Natural Products with a 3,4-Fused Tricyclic Benzofuran Derivative. As part of our ongoing studies aimed at developing a synthetic method for fused-polycyclic heterocycles, we recently reported synthetic methods of 3,4-fused tricyclic indole derivatives3 using a Pd-catalyzed cascade cyclization by Heck insertion of an allene and allylic amination (Scheme 1a)4 and a Pt-catalyzed FriedelCrafts type C–H coupling–allylic amination cascade (Scheme 1b).5 Our strategy was relied on the preparation of 3,4-fused tricyclic 3-alkylidene indolines as synthetic precursors, followed by acid-promoted isomerization to produce the corresponding indole derivatives. As shown in Scheme 1, 3,4-fused tricyclic 3alkylidene indoline was obtained in high yield using compound 1a as a substrate for the Pd catalysis and compound 3a as a substrate for the Pt catalysis. These cascade reactions are potentially applicable for constructing the 3,4-fused tricyclic benzofuran skeleton by replacing the tosylamide unit with a phenol. Thus, we examined the reactions using compounds 1b and 3b as substrates under the same reaction conditions used for the cascade cyclization of 1a and 3a. Pd-catalyzed cascade cyclization of 1b proceeded, but the yield of 2b was significantly decreased compared with that of 2a (Scheme 1a). Furthermore, no product was obtained when compound 3b was used under the Pt catalysis conditions (Scheme 1b). These unsatisfactory results led us to develop a new synthetic method based on a different synthetic strategy.
2
Tetrahedron yield (entries 2 and 3). Although tris(trimethylsilyl)silane was also applicable as a hydride source, the product was obtained in less satisfactory yield (entry 4). The reaction concentration was optimized when toluene was used as the optimum solvent (entries 5–7). When the reaction was performed in refluxed toluene at 0.03 M, the product 10 was obtained in 93% isolated yield. Treatment of 10 with 30 equiv of trifluoroacetic acid (TFA) resulted in the smooth conversion to 3,4-fused tricyclic benzofuran 11 in 92% yield, successfully demonstrating the accessibility to the target skeleton.
Scheme 1. Comparison of the Reactivity. In 1985, Snieckus and co-workers reported a radical cascade reaction for synthesizing 3-alkylidene dihydrobenzofuran derivatives.6 When a propargyl iodophenol derivative was refluxed in benzene in the presence of azobisisobutyronitrile (AIBN) and HSnBu3, the corresponding product was obtained in moderate yield (Scheme 2a). This precedent work led us to hypothesize that treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions would induce the reaction of the generated vinyl radical intermediates with the internal alkene to give the tricyclic 3-alkylidene dihydrobenzofurans, which could then be utilized as the precursors for 3,4-fused tricyclic benzofurans.7
Scheme 3. Synthesis of 3-alkylidene dihydrobenzofuran derivative 10 and its isomerization. (a) propargyl bromide (1.5 equiv), K2CO3 (1.5 equiv), DMF, rt; (b) DABCO (0.65 equiv), methyl acrylate (20 equiv), sonication, rt; (c) acetic anhydride (2 equiv), triethylamine (2 equiv), DMAP (10 mol %), CH2Cl2, 0 °C; (d) DABCO (1 equiv), H2O/THF (1/3), rt, then NaBH4 (2 equiv), rt; (e) trifluoroacetic acid (30 equiv), CH2Cl2, rt. DABCO: 1,4-diazabicyclo[2.2.2]octane; DMAP: N,Ndimethylaminopyridine. Table 1. Optimization of the reaction conditions.
Scheme 2. Plan for this study. We began our investigation by preparing the model substrate (Scheme 3). Propargylation of known compound 5 was carried out to give compound 6 in 83% yield. Morita-Baylis-Hillman reaction of 6 with methyl acrylate in the presence of 0.65 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) proceeded under sonication conditions, providing compound 7 (85% yield), which was followed by acetylation to give compound 8. The acetoxy group was removed under reductive conditions, affording model substrate 9 in 54% yield over two steps. We then evaluated radical cascade cyclization to produce 3,4-fused tricyclic 3alkylidene dihydrobenzofuran 10 (Table 1). When compound 9 was refluxed in benzene (0.05 M) in the presence of 1.1 equiv of HSnBu3 and 10 mol % of AIBN, the desired cascade reaction proceeded smoothly to give compound 10 in 85% yield (entry 1). Solvent screening revealed that toluene slightly improved the
Entry
Solvent (conc.)
Hydride Source
Time
Yielda
1
benzene (0.05M)
HSnBu3
45 min
85%
2
toluene (0.05 M)
HSnBu3
30 min
89%
3
xylene (0.05 M)
HSnBu3
30 min
86%
4
toluene (0.05 M)
HSi(SiMe)3
120 min
70%
5
toluene (0.1 M)
HSnBu3
20 min
86%
6
toluene (0.03 M)
HSnBu3
30 min
93% (93%)b
7
toluene (0.01 M)
HSnBu3
60 min
93%
Determined by 1H-NMR of the crude mixture using CHPh3 as internal standard. a
b
Isolated yield.
3 Compound 12, an N-tosyl variant of 11, was also prepared and reacted under the optimized reaction conditions (Scheme 4). Although the desired radical cascade cyclization proceeded, 3alkylidene indoline adduct 13 was obtained in only 43% yield, indicating that the developed synthetic method is more suitable for 3-alkylidene dihydrobenzofuran synthesis.8
was treated under the optimized conditions, the product with an 8-membered ring 34 was obtained in 50% yield.
Scheme 4. Synthesis of 3-alkylidene indoline derivative 13 via a radical cascade cyclization.
Acknowledgments
Aryl vinyl ketone-type substrate was prepared next according to the synthetic route shown in Scheme 5. After vinylation of the aldehyde in 6 using 1.1 equiv of vinylmagnesium bromide, the obtained allylic alcohol derivative 14 was converted into compound 15 using Dess-Martin reagent (48% yield from 6). Radical cascade cyclization of 15 was then performed under the optimum conditions, and tricyclic product 16 was produced in 61% yield. This product could be isomerized into the corresponding benzofuran derivative 17 in 82% yield by treatment with TFA. Notably, the yield of 18 (18% yield) was significantly decreased when allylic alcohol derivative 14 was used as a substrate. These findings indicated that the electrophilic property of the alkene unit is important for the medium-sized ring formation.
Scheme 5. (a) vinylmagnesium bromide (1.1 equiv), Et2O, rt; (b) Dess-Martin reagent (1.2 equiv), CH2Cl2, rt; (c) HSnBu3 (1.1 equiv), AIBN (10 mol %), toluene, reflux; (d) trifluoroacetic acid (10 equiv), CH2Cl2, rt. This radical cascade process was also applicable to more functionalized substrates (Scheme 6).8 Substrates with a substituent on the alkyne terminal 19–21 and 25–27 were prepared using the synthetic methods shown in Scheme 3 and Scheme 5, respectively, and were reacted under the optimized conditions (See Supplementary Data for details.). The corresponding products with a substituent on the alkylidene unit were obtained in 25%–71% yield. The reaction using a branched ether derivative 31 proceeded to give the product 32 with two substituents on the tricyclic skeleton in 43% yield. Furthermore, when compound 33 with a methylene-unit longer tether than 15
In conclusion, we developed a new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives. When using propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions, the radical cascade process proceeded in the presence of AIBN and HSnBu3, producing 3,4-fused tricyclic 3-alkylidene dihydrobenzofurans in 43%–93% yield. The obtained products could be efficiently transformed into 3,4-fused tricyclic benzofurans by treatment with TFA. Application of the present method to the synthesis of natural products with a 3,4-fused tricyclic benzofuran skeleton is ongoing.
This work was supported by JSPS KAKENHI Grant Number 18H025550, and The Naito Foundation.
Scheme 6. Substrate generality. References and notes 1.
For the synthesis of radermachol, see: (a) Buccini, M.; Piggott, M. J. Org. Lett. 2014, 16, 2490; (b) Samineri, R.; Srihari, P.; Mehta, G. Org. Lett. 2016, 18, 2832. For the synthesis of bussealin E, see: (c) Twigg, D. G.; Baldassarre, L.; Frye, E. C.; Galloway, W. R. J. D.; Spring, D. R. Org. Lett. 2018, 20, 1597. For the synthesis of diptoindonesin G, see: (d) Kim, K.; Kim, I. Org. Lett. 2010, 12, 5314; (e) Liu, J.; Do, T. J.; Simmons, C. J.; Lynch, J. C.; Gu, W.; Ma, Z.-X.; Xu, W.; Tang, W. Org. Biomol. Chem. 2016, 14, 8927; (f) Singh, D. K.; Kim, I. J. Org. Chem. 2018, 83, 1667; (g) Singh, D. K.; Kim, I. Tetrahedron Lett. 2019, 60, 300; (h) Qin, Y.; Zhan, J.-L.; Shan, T; Xu, T. Tetrahedron Lett. 2019, 60, 925. For the
Tetrahedron
4
2. 3.
4.
5.
6. 7. 8.
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Supplementary Material Supplementary data associate with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tetlet.
Highlights A new synthetic method for 3,4-fused tricyclic 3alkylidene dihydrobenzofurans was developed. The target skeleton was synthesized using a radical cascade cyclization. The products could be transformed into 3,4-fused tricyclic benzofurans by treatment with acid.