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-Trifluoromethyl-(indol-3-yl)methanols as trifluoromethylated C3 1,3dipoles: [3+2] cycloaddition for the synthesis of 1-(trifluoromethyl)cyclopenta[b]indole alkaloids 5

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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x The first formal [3+2] cycloaddition using -trifluoromethyl(indol-3-yl)methanols as the trifluoromethylated C3 1,3dipoles for the construction of the five-membered carbocycle of 1-trifluoromethylated cyclopenta[b]indole alkaloids is described. An unprecedented step-wise dehydrative alkenylation of -trifluoromethyl alcohols was revealed as the crucial transformation.

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Fluorinated organic molecules have enhanced lipophilicity and membrane permeability, elevated electronegativity and oxidation resistance, which are responsible for the increased metabolic stability and bioavailability than their nonfluorinated analogues.1 Consequently, extensive attention has been devoted toward the development of efficient methods for introducing a trifluoromethyl group into organic molecules.2 As part of our studies on ketene dithioacetals as versatile synthons in organic synthesis,3−5 the 1,3-carbothiolation/aromatization reaction of 4(trifluoromethyl)-p-quinols for the synthesis of functionalized (trifluoromethyl)arenes5a and the oxidative -trifluoromethylation reaction5b have been developed based on the nucleophilic character of the-C of ketene dithioacetals.3a,5 The indole framework is a privileged structure motif in a large number of natural products, drugs, and diagnostics.6−10 For example the naturally occurring alkaloids such as scytonemin,6 nostodione A,6a,7 and the antiobesity, antidepressant, and antipsychotic compound, WAY-163909 [(7bR,10aR)1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole]8 have the cyclopenta[b]indole skeleton (Fig. 1). The biosynthesis of cyanobacterial sunscreen scytonemin,6b,c total synthesis of mitotic spindle poison nostodione A,7 and the synthesis of WAY-1639098c have been described. In addition, the construction of cyclopenta[b]indoles through [3+2] cycloadditions of indoles (as two carbon cycloaddition partners) with propargylic alcohols,9a Rh-stabilized vinylcarbenoids,9b 2-alkoxycyclopropanoate esters,9c donoracceptor cyclopropanes,9d alkynyl Fischer carbene complexes,9e and -haloketones9f have been developed. More recently, Guo Department of Chemistry, Northeast Normal University, Changchun 130024, China. E-mail: [email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Experimental details, spectral data and crystallographic data. See DOI: 10.1039/b000000x/

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and co-workers described a multistep one-pot synthesis of enantioenriched polysubstituted cyclopenta[b]indoles via consecutive organo-catalyzed reactions of 3-indolylmethanols with aldehydes and N-protected indoles.10 However, to the best of our knowledge, there have been rare reports on the synthesis of trifluoromethyl cyclopenta[b]indoles, in which a CF3 is attached at the cyclopenta ring.6−10 With consideration of the importance of introducing the trifluoromethyl group into bioactive organic molecules,1,2 we envisioned that the [3+2] cycloaddition of the easily available ketene dithioacetals 2 with -trifluoromethyl 3indolylmethanol silyl ethers 1 (as the trifluoromethylated C3 1,3dipoles)11 would provide an efficient route to 1-(trifluoromethyl)cyclopenta[b]indoles 3 if the step-wise dehydrative alkenylation of 1 with 2 can be achieved. Herein we present the first example of the [3+2] cycloaddition of with ketene dithioacetals as the two-carbon cycloaddition partners,5c which enable the synthesis of 1-(trifluoromethyl)-cyclopenta[b]indoles 3 in a single operation under mild catalytic conditions.

Fig. 1 Natural occuring cyclopenta[b]indole alkaloids.

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The challenge for the step-wise dehydrative alkenylation of trifluoromethyl-alcohols is due to the high activation barrier for the displacement of the hydroxyl group resulted from the strong inductive effect of the CF3 group.2f,12 In the present research, catalyzed by CuBr2,13a the desired [3+2] cycloaddition product, 1(trifluoromethyl)-cyclopenta[b]indole 3aa was obtained in moderate yield by the reaction of 1-methyl-3-(2,2,2-trifluoro-1(trimethylsilyloxy)ethyl)-1H-indole 1a with -benzoyl ketene dithioacetal, 3,3-bis(ethylthio)-1-phenylprop-2-en-1-one 2a in acetonitrile at room temperature for 2 h (Table 1, entry 1). In comparison, the use of a cheap Lewis acid catalyst, BF3·OEt2,5c showed an efficient activity under similar reaction conditions to deliver 3aa along with the hydrolysis product 4a of 1a (Table 1, entry 2). The yield of 3aa was raised to 93% by using 0.3 equiv of BF3·OEt2 (Table 1, entry 4). Catalyzed by BF3·OEt2 with DMF as the solvent, 4a was produced predominantly (Table 1, entry 5). [journal], [year], [vol], 00–00 | 1

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Jinhuan Dong, Ling Pan,* Xianxiu Xu and Qun Liu*

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It was noticed that the reaction of 4a with 2a could also proceed smoothly to give 3aa in excellent yield using lower loadings of BF3·OEt2 (Table 1, entry 7).

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Table 2 BF3·OEt2 catalyzed [3+2] cycloaddition View Article Online

DOI: 10.1039/C4CC05895J

Entry 1 2 3 4 5 6 7c 5

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Catalyst (equiv) CuBr2 (0.2) BF3·OEt2 (0.2) HBr (0.2) BF3·OEt2 (0.3) BF3·OEt2 (0.3) BF3·OEt2 (0.3) BF3·OEt2 (0.2)

Solvent MeCN MeCN MeCN MeCN DMF CH2Cl2 MeCN

Time (h) 2 8 6 4 6 4 1.5

Yieldb (%) 3aa 43% 3aa 54%; 4a 40% 3aa 43% 3aa 93% 4a 90% 3aa 86% 3aa 92%

Reactions were carried out with mol ratio of 1a/2a = 1.0:1.5. b Isolated yield. c Reactions were carried out with 4a and 2a with mol ratio of 4a/2a = 1.0:1.5. a

It is known that the -C of -trifluoromethyl alcohols are inert to nucleophiles because of the energy destabilization by the C–O bond breaking in terms of the strong electron-withdrawing nature of the -trifluoromethyl group.2f,12 It has been demonstrated that when catalyzed by phosphoric acid, the arylation of 2,2,2trifluoro-1-(1H-indole-3-yl)-1-phenylethanol with indole requires longer reaction times (24 h) than its analogue (reaction time, 12 h) with CHF2 in place of CF3 group at 80 °C. Nevertheless, these results show the possibility of the arylation of the tertiary trifluoromethyl alcohols with highly reactive, electron-rich indoles.14 Significantly, the successful preparation of 3aa provides an efficient route to 1-(trifluoromethyl)cyclopenta[b]indoles via a formal [3+2] cycloaddition reaction with the unprecedented step-wise dehydrative alkenylation of secondary -trifluoromethyl-alcohols as the key transformation. Therefore, the scope of the reactions was examined using a series of ketene dithioacetals 2 and -trifluoromethyl 3-indolylmethanol silyl ethers 1 directly under optimal conditions (Table 1, entry 4), and the results are summarized in Table 2. According to the experimental results (Table 2), the above reaction has a broad scope both in terms of -trifluoromethyl 3indolylmethanol silyl ethers 1 and acyclic ketene dithioacetals 2. All the reactions completed within 8 h at room temperature using only catalytic amounts of BF3·OEt2 without the requirement of pre-hydrolysis of silyl ethers 1. Acyclic ketene dithioacetals 2 having phenyl, alkyl, heteroaryl, or N-phenyl as the R4 group can afford the desired 1-(trifluoromethyl)-cyclopenta[b]indoles 3aaai in high to excellent yields. In these reactions the methyl, ethyl, n-butyl, and benzyl as the R3 groups of 2 are tolerated. On the other hand, the reactions of the -trifluoromethyl 3indolylmethanol silyl ethers 1 bearing an N-methyl, N-benzyl or N-allyl group proceeded smoothly to give the desired products in high to excellent yields. In addition, -trifluoromethyl 3indolylmethanol silyl ethers 1 having electron-rich or electrondeficient substituent at the 5-, 6-, or 7-position of the indole ring are also tolerable to the [3+2] cycloadition to give the desired products 3dd-3gd in moderate to high yields.

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BF3·OEt2 (50 mol%) was used.

Furthermore, 1-(pentafluoroethyl)-cyclopenta[b]indole 3hd was prepared in high yield from the reaction of pentafluoroethyl 3-indolylmethanol silyl ether 1h with ketene dithioacetal 2d (Table 2).11 However, it was noticed that, under identical reaction conditions, the reaction of 1-tosyl-3-(2,2,2trifluoro-1-(trimethylsilyloxy)ethyl)-1H-indole 1i with 2a afforded, instead of the expected cyclopenta[b]indole product, the hydrolysis product 4i was formed quantitatively [eqn (1)]. Next, the reactions of 1a with selected cyclic ketene dithioacetals 2j-q were investigated. Under optimal reaction conditions (Table 1, entry 4), the step-wise dehydrative alkenylating product, 3-(1,3-dithiolan-2-ylidene)-5,5,5-trifluoro4-(1-methyl-1H-indol-3-yl)pentan-2-one 5aj was produced in high yield. In this case, none of the expected cyclopenta[b]indole product 3aj was obtained from the reaction of 1a with 2j [eqn (2)]. To our delight, the desired [3+2] cycloaddition product, cyclopenta[b]indole 3aj, could be obtained in high yield by using This journal is © The Royal Society of Chemistry [year]

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Table 1 Screening of Reaction Conditions a

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CuBr2 (See Table 1, entry 1)13a as the catalyst at 45 oC in the solvent, acetonitrile. Thus, catalyzed by CuBr2 in place of

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Furthermore, 1-(pentafluoroethyl)-cyclopenta[b]indole 3hj was also prepared in high yield from the reaction of 1h with 2j (Table View Article Online 3). DOI: 10.1039/C4CC05895J In the syntheses of cyclopenta[b]indoles 3ao-aq, anhydrous acetonitrile was required as the solvent to avoid the hydrolysis of the products. For example, 2-benzoyl-4-methyl-1(trifluoromethyl)-1,2-dihydrocyclopenta[b]indol-3(4H)-one 6ao was obtained in 48% yield when commercial acetonitrile was applied as the solvent for the reaction of 1a with 2o [eqn (3)]. Based on the above results and related reports,2-5,13,15 a plausible mechanism for the formation of 1-(trifluoromethyl)cyclopenta[b]indole 3 is proposed in Scheme 1, with the reaction of 1a with 2 as an example. The overall process involves (1) formation of the reactive iminium intermediate B from silyl ethers 1 in the presence of a suitable Lewis acid (for example CuBr2);2c,4i,5a,15 (2) attacking of B by the nucleophilic -C of ketene dithioacetal 23a,5,13 to give intermediate C; and finally, (3) intramolecular cyclization of C followed by deprotonative aromatization to deliver cyclopenta[b]indoles 3, along with the regeneration of catalyst CuBr2 (Scheme 1). It should be noted that, the stable trans-disposition of CF3 and carbonyl groups in products 3 may be controlled by a thermodynamic equilibrium in intermediate C as it has an acidic CH functionality.

Table 3 CuBr2 catalyzed [3+2] cycloaddition

Scheme 1 Proposed reaction mechanism.

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5 a

Anhydrous MeCN was used.

BF3·OEt2, cyclopenta[b]indoles 3aj-aq were prepared in high to excellent yields from the reactions of 1a with 2j-q (Table 3).

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The formation of cyclopenta[b]indoles 3 can be taken as a formal [3+2] cycloaddition with ketene dithioacetals 2 as the two carbon push-pull ethylene components5c and -trifluoromethyl 3indolylmethanol silyl ethers 1 as the three carbon 1,3-dipoles.5c,16 In this [3+2] cycloaddition reaction, the step-wise dehydrative alkenylation is the key transformation and the dehydrative alkenylation product 5 can be obtained depending on the reaction conditions and substrate structures [eqn (2)]. It was found that treatment of 3ap with FeCl3 (1.0 equiv) and KI (1.0 equiv) in the presence of methanol at reflux temperature for 6 h led to the formation of cyclopenta[b]indoles 6ap and 6ap’ as a tautomeric keto-enol mixture in 3:1 ratio in 72% yield [eqn (4)]. Furthermore, the reduction of 3aa was performed with Raney Ni and H2 in ethanol at 60 oC for 18 h. As the result, the partial reductive product, thiolether 7aa (80% yield), and the reductive product, tetrahydrocyclopenta[b]indole 8aa (12% yield), were obtained, respectively [eqn (5)]. In conclusion, we have developed a new catalytic [3+2] Journal Name, [year], [vol], 00–00 | 3

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cycloaddition reaction for the efficient synthesis of 1trifluoromethylated cyclopenta[b]indole alkaloids from trifluoromethyl 3-indolylmethanol silyl ethers (as all carbon 1,3dipoles) with ketene dithioacetals (as the two carbon push-pull ethylene components). In this reaction the step-wise dehydrative alkenylation of -trifluoromethyl-(indol-3-yl)methanols is the crucial transformation. The [3+2] cycloaddition reaction can be performed under very mild catalytic conditions and tolerate a wide range of functional groups to give high to excellent yields of products in most cases. Further studies are in progress. Financial support of this research by the National Natural Sciences Foundation of China (21072027, 21172030, 21272034 and 21202015) is greatly acknowledged.

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(a) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Oxford, U.K., 2009; (b) J. Wang, M. SánchezRoselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432; (c) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; (d) M. C. Walker and M. C. Y. Chang, Chem. Soc. Rev., 2014, 43, 6527. For selected recent reviews, see: (a) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214; (b) L. Chu and F.-L. Qing, Acc. Chem. Res. 2014, 47, 1513; (c) X. Liu, C. Xu, M. Wang and Q. Liu, Chem. Rev. dx.doi.org/10.1021/cr400473a; (d) G. K. S. Prakash and A. K. Yudin, Chem. Rev., 1997, 97, 757; (e) A. D. Dilman and V. V. Levin, Eur. J. Org. Chem., 2011, 831; (f) C. B. Kelly, M. A. Mercadantea and N. E. Leadbeater, Chem. Commun., 2013, 49, 11133. For reviews, see: (a) L. Pan, X. Bi and Q. Liu, Chem. Soc. Rev., 2013, 42, 1251; (b) L. Pan and Q. Liu, Synlett, 2011, 1073; (c) Q. Liu, 1,1-Bis(organosulfanyl)alk-1-enes (Ketene S,S-Acetals), Update 2014/2, in Science of Synthesis, Compounds with Four and Three Carbon-Heteroatom Bonds, ed. M. B. Nielsen, N. Krause, I. Marek, E. Schaumann and T. Wirth, Georg Thieme, Stuttgart, p. 245; (d) H. Junjappa, H. Ila and C. V. Asokan, Tetrahedron, 1990, 46, 5423; (e) R. K. Dieter, Tetrahedron, 1986, 42, 3029. For selected recent reports, see: (a) N. Jung, B. Stanek, S. Gräßle, M. Nieger and S. Bräse, Org. Lett., 2014, 16, 1112; (b) N. Jung, S. Grässle, D. S. Lütjohann and S. Bräse, Org. Lett., 2014, 16, 1036; (c) S. Yugandar, N. C. Misra, G. Parameshwarappa, K. Panda and H. Ila, Org. Lett., 2013, 15, 5250; (d) Y. Dong, B. Liu, P. Chen, Q. Liu and M. Wang, Angew. Chem., Int. Ed., 2014, 53, 3442; (e) T. Wu, L. Pan, X. Xu and Q. Liu, Chem. Commun., 2014, 50, 1797; (f) Y. Liu, B.-D. Barry, H. Yu, J. Liu, P. Liao and X. Bi, Org. Lett., 2013, 15, 2608; (g) G. Fang, J. Li, Y. Wang, M. Gou, Q. Liu, X. Li and X. Bi, Org. Lett., 2013, 15, 4126; (h) H. Yuan, Y. Zheng, Z. Fang, X. Bi and J. Zhang, Green Chem., 2014, 16, 2653; (i) X. Liu, X. Xu, L. Pan, Q. Zhang and Q. Liu, Org. Biomol. Chem., 2013, 11. 6703; (j) X. Liu, L. Zhang, X. Xu, S. Wang, L. Pan, Q. Zhang and Q. Liu, Chem. Commun., 2014, 50, 8764; (k) Y. Zhang, L. Pan, X. Xu, H. Luo and Q. Liu, Chem. Commun., 2014, 50, 11039. (a) X. Liu, L. Pan, J. Dong, X. Xu, Q. Zhang and Q. Liu, Org. Lett., 2013, 15, 6242; (b) C. Xu, J. Liu, W. Ming, Y. Liu, J. Liu, M. Wang and Q. Liu, Chem. Eur. J., 2013, 19, 9104; (c) Z. Fang, J. Liu, Q. Liu and X. Bi, Angew. Chem., Int. Ed., 2014, 53, 5039; (d) Z. Mao, F. Huang, H. Yu, J. Chen, Z. Yu and Z. Xu, Chem. Eur. J., 2014, 20, 3439; (e) Q. Yang, P. Wu, J. Chen and Z. Yu, Chem. Commun., 2014, 50, 6337. (a) P. J. Proteau, W. H. Gerwick, F. Garcia-Pichel and R. Castenholz, Experientia, 1993, 49, 825 (scytonemin structure determination); (b) E. P. Balskus and C. T. Walsh, J. Am. Chem. Soc., 2008, 130, 15260; (c) E. P. Balskus and C. T. Walsh, J. Am. Chem. Soc., 2009, 131, 14648 (biosynthesis of scytonemin). (d) C. P. Miller, P. Bhaket, N. Muthukaman, C. R. Lyttle, M. Shomali, K. Gallacher, C. Slocum and G. Hattersley, Bioorg. Med. Chem. Lett., 2010, 20, 7516.

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Jinhuan Dong, Ling Pan,* Xianxiu Xu and Qun Liu* Department of Chemistry, Northeast Normal University, Changchun 130024, China E-mail: [email protected]; [email protected]

Easily available α-trifluoromethyl 3-indolylmethanol silyl ethers acting as the trifluoromethylated C3 1,3-dipoles in the preparation of 1-trifluoromethyl cyclopenta[b]indole alkaloids.

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α-Trifluoromethyl-(indol-3-yl)methanols as trifluoromethylated C3 1,3-dipoles: [3+2] cycloaddition for the synthesis of 1-(trifluoromethyl)-cyclopenta[b]indole alkaloids

α-Trifluoromethyl-(indol-3-yl)methanols as trifluoromethylated C3 1,3-dipoles: [3+2] cycloaddition for the synthesis of 1-(trifluoromethyl)-cyclopenta[b]indole alkaloids.

The first formal [3+2] cycloaddition using α-trifluoromethyl-(indol-3-yl)methanols as the trifluoromethylated C3 1,3-dipoles for the construction of t...
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