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Cite this: Chem. Commun., 2014, 50, 12775 Received 24th June 2014, Accepted 5th September 2014

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Synthesis of nitrogen-containing fused-polycyclic compounds from tyramine derivatives using phenol dearomatization and cascade cyclization† Takuya Yokosaka, Tetsuhiro Nemoto, Hiroki Nakayama, Naoki Shiga and Yasumasa Hamada*

DOI: 10.1039/c4cc04809a www.rsc.org/chemcomm

We developed a novel method of synthesizing nitrogen-containing fused-polycyclic compounds using tyramine derivatives as substrates. The method is based on the dearomatization of phenols via an intramolecular ipso-Friedel–Crafts allenylation and sequential bond-forming–cleavage reactions initiated by the construction of an indole skeleton. Structurally diverse fused-heterocycles were produced in reaction sequences requiring only a few steps.

Spirocyclohexadienones are versatile intermediates in complex molecule synthesis. Various functionalization protocols of the cyclohexadienone unit provide efficient access to polycyclic molecular frameworks.1 The development of an efficient synthetic method for spirocyclohexadienones is therefore in high demand in organic synthesis. Intramolecular dearomatization of phenols is the most straightforward approach to the synthesis of spirocyclohexadienones. Various synthetic methods have been reported to date.2 Tyramine [4-(2-aminoethyl)phenol] and structurally related compounds such as dopamine are representative building blocks in alkaloid biosynthesis. A variety of fused-polycyclic alkaloids are biosynthesized through a Friedel–Crafts type process of such structural motifs.3 As part of our ongoing studies aimed at developing an efficient method of synthesizing fused-polycyclic molecules, we recently reported a novel cascade process producing nitrogen-containing fused-polycyclic compounds with an indole unit, in which the pivotal step is dearomatization of phenols via an acid-promoted intramolecular ipso-Friedel–Crafts alkylation.4 Nitrogen-containing heterocycles are fascinating synthetic targets in medicinal chemistry because of their potential for various bioactivities. This background led us to launch a program on the synthesis of nitrogen-containing fused-polycyclic compounds Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan. E-mail: [email protected]; Fax: +81-43-226-2920; Tel: +81-43-226-2920 † Electronic supplementary information (ESI) available: Experimental procedures, compound characterization, additional experimental data, and NMR charts. CCDC 1007338 and 1008194. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc04809a

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based on the intramolecular dearomatization process using tyramine derivatives as substrates. Our synthetic plan is outlined in Scheme 1. Allenyl spirocyclohexadienones 2 were set as key intermediates for this work. We expected that compounds 2 would be prepared from 2-aminophenyl group-substituted propargyl alcohol derivatives with a tyramine unit 1 through an acid-promoted intramolecular ipso-Friedel– Crafts allenylation of phenols. ortho-Allenyl anilines can be transformed into 2-substituted indoles via the intramolecular C–N bond formation.5 The multi-functional structure of 2 led us to construct an indole skeleton using the ortho-allenyl aniline scaffold, followed by intramolecular modifications of the cyclohexadienone unit, thereby producing fused-polycyclic molecules in only a few steps.6 We first examined an intramolecular ipso-Friedel–Crafts allenylation of tyramine derivative 1a in the presence of an acid promoter (Table 1). The amount of trifluoroacetic acid (TFA) greatly affected the reactivity (entries 1–5). When the reaction was performed in CH2Cl2 (0.02 M) at room temperature using 10 equiv. of TFA, allenyl spiro[5.5]cyclohexadienone derivative 2a was obtained in 97% isolated yield (entry 5).7 Compound 2a was also produced in a synthetically useful yield using 1 equiv. of TsOHH2O (entry 6). Although the reaction was slow, a catalytic amount of TsOHH2O promoted the desired transformation,

Scheme 1

Synthetic plan of this work.

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Table 1

Acid-promoted intramolecular ipso-Friedel–Crafts allenylation

Entry

Acid promoter (equiv.)

Conc. (M)

Time (h)

Yielda (%)

1 2 3 4 5 6 7 8 9 10

TFA (1) TFA (2) TFA (5) TFA (10) TFA (10) TsOHH2O (1) TsOHH2O (0.2) B(C6F5)3 (0.2) Sc(OTf)3 (0.2) Yb(OTf)3 (0.2)

0.1 0.1 0.1 0.1 0.02 0.1 0.1 0.1 0.1 0.1

24 24 8 4 7.5 3 11 24 24 24

Trace 41 90 94 97 84 58 Trace Trace Trace

a

Isolated yield.

producing 2a in 58% yield (entry 7). In contrast, the use of other Lewis acid catalysts gave unsatisfactory results (entries 8–10). After the complete consumption of 1a under the reaction conditions shown in entry 5, the reaction media was evaporated under reduced pressure, affording 2a with sufficient purity for the next reaction. A one-pot sequential transformation was then performed using the obtained residue without purification (Table 2). ortho-Allenyl aniline derivatives are converted into the corresponding 2-substituted indole derivatives by treatment with tetrabutylammonium fluoride (TBAF) in THF.5a,b Thus, after Table 2

removing the reaction media, the obtained residue was allowed to react with 2 equiv. of TBAF in THF at 0 1C for 25 min. Formation of an indole skeleton, followed by an intramolecular conjugate addition of the simultaneously formed carbanion to the cyclohexadienone unit, proceeded sequentially to produce penta-substituted cyclopropane derivative 3a in 91% yield in a diastereomerically pure form (entry 1). The structure of 3a was unequivocally determined by X-ray crystal structure analysis (CCDC 1008194). The scope and limitations of different substrates were further examined using 10 or 20 equiv. of TFA (entries 2–7).8 Linear substrates with an electron-donating group and an electronwithdrawing group on the anilinic aromatic ring were applicable to the developed one-pot sequential process, and the corresponding penta-substituted cyclopropane derivatives 3b–g were obtained in 66 to 82% yield.9 A prolonged reaction time of the second step resulted in the decomposition of 3a and fused-pentacyclic product 4a was obtained in 43% yield (Table 1, entry 8. Structure of 4a, see Scheme 2).10 This result led us to optimize the reaction conditions for the synthesis of 4a using 3a as the starting material.11 Solvent effect studies revealed that DMF was optimum for this transformation. Treatment of 3a with 1 equiv. of TBAF in DMF at 0 1C resulted in the formation of compound 4a in 84% yield. Compound 4a was also synthesized from 1a in 56% yield through the one-pot sequential process when DMF was used as a solvent in the second step. A plausible reaction pathway of the cascade cyclization process is shown in Scheme 3. After formation of the indole skeleton by treating 2a with TBAF, conjugate addition of the simultaneously formed carbanion to an enone occurred sequentially

Synthesis of penta-substituted cyclopropane derivatives using a one-pot dearomatization of phenol–cascade cyclization sequence

Entry

Product

Time a/time b

Yielda (%)

1b 2c 3c 4c 5c

3a: R2 = H 3b: R2 = F 3c: R2 = OTs 3d: R2 = Cl 3e: R2 = COOMe

7.5 h/25 min 96 h/20 min 72 h/1.5 h 72 h/20 min 48 h/50 min

91 77 82 66 82

6b 7c 8b

3f: R1 = CH3, R3 = H 3g: R1 = H, R3 = Cl 3a: R2 = H

16 h/30 min 20 h/1 h 7.5 h/24 h

80 76 Trace (4a: 43)

a

Isolated yield.

b

10 equiv. of TFA was used. c 20 equiv. of TFA was used.

12776 | Chem. Commun., 2014, 50, 12775--12778

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Scheme 4

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Scheme 2

Scheme 3

Reaction pathway.

to give compound 3a as a kinetic product. This was probably due to the proximity of both reactive sites in intermediate I. A retro reaction from 3a to intermediate I also proceeded in the presence of TBAF. The retro process proceeded more efficiently when using DMF as the solvent. Compound 4a was formed when the conjugate addition occurred from intermediate II, a resonance structure of intermediate I. Irreversibility between 4a and intermediate II resulted in the conversion from 3a to 4a. cis-Divinyl cyclopropanes and structurally related cis-arylvinyl cyclopropanes are effective substrates for Cope rearrangement,

Table 3

Transition state of the Cope rearrangement.

Synthesis of a fused-indoline derivative.

Cope rearrangement of 3a–g

which affords cycloheptadiene derivatives.12 Compounds 3a–g possessed an indolylvinyl cyclopropane structural motif, leading us to investigate the construction of fused-polycyclic molecular architectures through a Cope rearrangement of 3 (Table 3). The use of various solvents to heat compound 3a revealed that 1,4-dioxane was the best solvent for this purpose11 and nitrogen-containing fused-polycyclic compound 5a was obtained in 88% yield (entry 1). Cope rearrangement of other substrates 3b–g was performed under the same reaction conditions and the corresponding products 5b–g were obtained in 51 to 83% yield (entries 2–7). The structure of 5a was determined based on 2D-NMR and NOE experiments.11 The Cope rearrangement via the boat transition state well rationalized the observed results including the stereochemistry of the products (Scheme 4). We developed a novel method for synthesizing nitrogencontaining fused-polycyclic compounds based on dearomatization of phenols using tyramine derivatives as substrates. The formation of allenyl spiro[5.5]cyclohexadienones through an intramolecular ipso-Friedel–Crafts allenylation of phenols, followed by multiple bond-forming–cleavage events initiated by the construction of an indole skeleton, provided access to a wide variety of fused-polycyclic molecules with unprecedented chemical architectures in reaction sequences requiring only a few steps. The obtained products are of potential interest as scaffolds for drug discovery. Further studies are in progress to investigate the bioactivities of these molecules. This work was financially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology, Japan, and Chiba University.

Notes and references

Entry

Product

Time (h) Yielda (%)

1 2 3 4 5

5a: R2 = H 5b: R2 = F 5c: R2 = OTs 5d: R2 = Cl 5e: R2 = COOMe

18 9 11 13 15

88 79 65 62 73

6 7

5f: R1 = CH3, R3 = H 20 5g: R1 = H, R3 = Cl 20

83 51

a

Isolated yield.

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1 For reviews, see: (a) S. T. Roche and J. A. Porco Jr., Angew. Chem., Int. Ed., 2011, 50, 4068; (b) C.-X. Zhuo, W. Zhang and S.-L. You, Angew. Chem., Int. Ed., 2011, 51, 12662. 2 For representative examples, see: (a) X. Zhang and R. C. Larock, ´lez-Lo ´pez de Turiso J. Am. Chem. Soc., 2005, 127, 12230; (b) F. Gonza and D. P. Curran, Org. Lett., 2005, 7, 151; (c) T. R. Ibarra-Rivera, ´mez-Montano and L. D. Miranda, Chem. Commun., 2007, 3485; R. Ga (d) Y. Dohi, Y. Minamitsuji, A. Maruyama, S. Hirose and Y. Kita, Org. Lett., 2008, 10, 3559; (e) T. Nemoto, Y. Ishige, M. Yoshida, Y. Kohno, M. Kanematsu and Y. Hamada, Org. Lett., 2010, 12, 5020; ( f ) Q.-F. Wu, W.-B. Liu, C.-X. Zhuo, Z.-Q. Rong, K.-Y. Ye and S.-L. You, Angew. Chem., Int. Ed., 2011, 50, 4455; ( g) T. Nemoto, Z. Zhao, T. Yokosaka, Y. Suzuki, R. Wu and Y. Hamada, Angew. Chem., Int. Ed., 2013, 52, 2217, and references sited therein. 3 M. H. Zenk, M. Rueffer, M. Amann and B. Deus-Neumann, J. Nat. Prod., 1985, 48, 725. 4 (a) T. Yokosaka, T. Nemoto and Y. Hamada, Chem. Commun., 2012, 48, 5431; (b) T. Yokosaka, H. Nakayama, T. Nemoto and Y. Hamada, Org. Lett., 2013, 15, 2978; (c) T. Yokosaka, T. Kanehira, H. Nakayama, T. Nemoto and Y. Hamada, Tetrahedron, 2014, 70, 2151. 5 (a) C. Mukai and Y. Takahashi, Org. Lett., 2005, 7, 5793; (b) N. Kuroda, Y. Takahashi, K. Yoshinaga and C. Mukai, Org. Lett., 2006, 8, 1843; (c) A. Saito, A. Kanno and Y. Hanzawa, Angew. Chem.,

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Communication Int. Ed., 2007, 46, 3931; (d) A. Saito, S. Oda, H. Fukaya and Y. Hanzawa, J. Org. Chem., 2009, 74, 1517. 6 Recent representative examples of the efficient synthesis of nitrogencontaining fused-polycyclic compounds, see: (a) W. Rao, M. J. Koh, P. Kothandaraman and P. W. H. Chan, J. Am. Chem. Soc., 2012, 134, 10811; (b) S. Zhu and D. W. C. MacMillan, J. Am. Chem. Soc., 2012, 134, 10815; (c) Q. Cai, X.-W. Liang, S.-G. Wang, J.-W. Zhang, X. Zhang and S.-L. You, Org. Lett., 2012, 14, 5022; (d) M. E. Muratore, L. Shi, A. W. Pilling, R. I. Storer and D. J. Dixon, Chem. Commun., 2012, 48, 6351; (e) N. N. B. Kumar, O. A. Mukhina and A. G. Kutateladze, J. Am. Chem. Soc., 2013, 135, 9608; ( f ) T. Piou, A. Bunescu, Q. Wang, L. Neuville and J. Zhu, Angew. Chem., Int. Ed., 2013, 52, 12385; (g) S.-G. Wang, W. Zhang and S.-L. You, Org. Lett., 2013, 15, 1488; (h) I. Aillaud, D. M. Barber, A. L. Thompson and D. J. Dixon, Org. Lett., 2013, 15, 2946; (i) A. W. Gregory, P. Jakubec, P. Turner and D. J. Dixon, Org. Lett., 2013, 15, 4330; ( j) A. Yazici and S. G. Pyne, Org. Lett., 2013, 15, 5878; (k) J. Yang, X. Xie, Z. Wang, R. Mei, H. Zheng, X. Wang, L. Zhang, J. Qi and X. She, J. Org. Chem., 2013, 78, 1230; (l) Z. Li, J. Li, N. Yang, Y. Chen, Y. Zhou, X. Ji, L. Zhang, J. Wang, X. Xie and H. Liu, J. Org. Chem., 2013, 78, 10802; (m) F. D. King, A. E. Aliev, S. Caddick and D. A. Tocher, J. Org. Chem., 2013, 78, 10938; (n) D. Mao, J. Tang, W. Wang, S. Wu, X. Liu, J. Yu and

12778 | Chem. Commun., 2014, 50, 12775--12778

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7

8 9 10 11 12

L. Wang, J. Org. Chem., 2013, 78, 12848; (o) T. Miura, Y. Funakoshi and M. Murakami, J. Am. Chem. Soc., 2014, 136, 2272; (p) A. Iwata, S. Inuki, S. Oishi, N. Fujii and H. Ohno, Chem. Commun., 2014, 50, 298; (q) Z. Shi, M. Boultadakis-Arapinis, D. C. Koester and F. Glorius, Chem. Commun., 2014, 50, 2650. We previously reported a similar reaction using para-hydroxybenzylamine derivatives as substrates. The allenyl spirocyclohexadienones formed in situ were highly reactive under acidic conditions, converting into dihydroquinoline derivatives. T. Yokosaka, N. Shiga, T. Nemoto and Y. Hamada, J. Org. Chem., 2014, 79, 3866. When substrates with an electron-withdrawing group on the anilinic aromatic ring were used, 20 equiv. of TFA was required to promote the smooth reaction. Synthesis of multi-substituted indolyl cyclopropanes via a similar reaction pathway, see: T. Haven, G. Kubik, S. Haubenreisser and M. Niggemann, Angew. Chem., Int. Ed., 2013, 52, 4016. The structure of 4a was determined by X-ray crystal structure analysis (CCDC 1007338). Cycloheptadienone derivative was also isolated in 31% yield. See ESI† for details. See ESI† for details. ´rrez and J. Alfredo Martı´n, Org. Lett., J. Barluenga, F. Aznar, I. Gutie 2002, 4, 2719.

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Synthesis of nitrogen-containing fused-polycyclic compounds from tyramine derivatives using phenol dearomatization and cascade cyclization.

We developed a novel method of synthesizing nitrogen-containing fused-polycyclic compounds using tyramine derivatives as substrates. The method is bas...
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