Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 1845−1848
Dearomative Diallylation of N‑Acylindoles Mediated by FeCl3 Ju Wu, Raj Kumar Nandi, Régis Guillot, Cyrille Kouklovsky, and Guillaume Vincent* Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Equipe MSMT, Univ. Paris Sud, CNRS, Université Paris-Saclay, 15, rue Georges Clemenceau, Orsay 91405 Cedex, France S Supporting Information *
ABSTRACT: Three-dimensional indolines possessing two contiguous-stereogenic centers were obtained stereoselectively via the FeCl3-mediated dearomative introduction of two allyl groups to N-acylindoles with allyltrimethylsilane. Synthetic transformations allowed obtention of trans-tetrahydrocarbazoles and an aza[4.4.3]propellane scaffold by RCM. Selective hydration of one of the allyl groups was also achieved. Scheme 1. Reaction of Nucleophiles with Electrophilic N-Acindoles Activated by FeCl3
D
earomatization reactions of achiral heteroarenes,1 and in particular of indoles,2 deliver three-dimensional structures of high interest for the generation of druglike compounds3 or scaffolds of natural products4 through the generation of two contiguous stereogenic centers. Such dearomative processes are therefore the subject of intense synthetic effort, including work by our own group.5 The dearomative difunctionalization of indoles relies on cycloadditions2a,5g,6 or radical-mediated,2a,5c,k,7 electrophile-triggered,2a,5a,8 or palladium-catalyzed reactions9 in which, most of the time, a cyclization event is required to facilitate the dearomatization or to prevent rearomatization. Very few of these methods result in the formation of two C−C bonds from intermolecular reactions of indoles with two external reagents.7h,8b,c Herein, we report a dearomative oxidative difunctionalization of indoles that exploits the intermolecular addition of two nucleophiles10 and which leads to the formation of two C−C bonds at C3 and C2. A few years ago, we reported a regioselective hydroarylation of N-acetylindoles 1 with electron-rich arenes that gave 3arylindolines 2 in the presence of FeCl3 in air (Scheme 1).5b,d−f,h,i We demonstrated, through mechanistic studies,5h that association of the promoter with the carbonyl of the Nacetyl was crucial to generate a C3-electrophilic indole.11 Evidence, including DFT calculations,5h,i suggested that the C2C3 bond was activated by a proton, rather than FeCl3, to form carbocation A, which triggers the Friedel−Crafts reaction with the arene nucleophile. Aromatization of the resulting Wheland intermediate B led to 2. To initiate the reaction and protonate 1, we believe that a catalytic amount of protons are generated by partial hydrolysis of FeCl3 with the humidity of air. Then, during the propagation stage of the reaction, it is the proton released from aromatization of B which can activate the C2C3 bond of 1. At this point, we wondered if we could replace the electron-rich arenes by other nucleophiles to maximize the diversity of the monofunctionalized indolines obtained by this method. After an initial and unsuccessful screening of several oxygen, nitrogen- or phosphoruscontaining nucleophiles, we turned our attention toward © 2018 American Chemical Society
allylsilanes. The formation of an allylated compound such as 3 would be complementary to the monoallylation of indoles 4 at the C2-position,12 leading to 6 through isomerization of the enamine part of the indole into the imine 5 (Scheme 2). While we never observed the monoallylated indoline 3 from allyltrimetylsilane (2.2 equiv) and N-acetylskatole 1a in the presence of FeCl3 (2.4 equiv), we were surprised and thrilled to observe formation of the 2,3-diallylated indoline 7a, albeit in a low 14% yield with a 85:15 diastereoselectivity. We decided to further study this intriguing oxidative diallylation.13 Eventually, increasing the amounts of FeCl3 (7 equiv) and allytrimethylsilane (10 equiv) and running the reaction in a sealed reaction vessel14 improved the yield of 7a to 86% (85:15 dr, Scheme 3). It was possible to perform the synthesis of 7a on a 2 mmol scale in 70% yield (85:15 dr). We then studied the scope of this reaction (Scheme 3). Received: January 31, 2018 Published: March 12, 2018 1845
DOI: 10.1021/acs.orglett.8b00361 Org. Lett. 2018, 20, 1845−1848
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Organic Letters
On the nitrogen, beside the acetyl group, the formyl group was also tolerated and led to 7b in 56% yield (90:10 dr), while 7c bearing an ethyloxy carbonyl group was obtained in 32% yield (90:10 dr). Increasing the steric hindrance at the C3position still allowed diallylated indolines 7d (42%, 85:15 dr) and 7e (34%, 90:10 dr) with n-propyl and n-butyl substituents. The reaction could also be performed in the presence of aryl substituents at C3, delivering 7f (46%, 90:10 dr), 7g (32%, 90:10 dr), and 7h (48%, 90:10 dr). Concerning the electronic effects in the benzene part of the indole, methoxy and methyl electron-donating groups and fluoride at the C5 (7i−k; 39%, 90:10 dr; 71%, 85:15 dr; 44%, 85:15 dr), C6 (7m,n; 78%, 95:5 dr and 51%, 90:10 dr), and C7 positions (7o, 47%, >95:5 dr) afforded the expected diallylated indolines. Less electron-rich groups such as a 5-bromo (7l) did not allow the reaction to proceed. The reaction of these 3-substituted indoles delivered the trans-diallylated indolines 7a−o as the major isomer as demonstrated by X-ray analysis of compound 7g. In contrast, from 2,3-disubstituted indoles, the two allyl groups born by the two contiguous tetrasubstituted stereogenic centers are in a cis relationship.15,16 Indolines 7p (45%, >95:5 dr) and 7q (31%, >95:5 dr) were obtained from 2,3-dimethylindole derivatives, while 7r (39%, >95:5 dr), 7s (38%, >95:5 dr), and 7t (28%, >95:5 dr) emerged from tetrahydrocarbazole derivatives. Surprisingly, alongside the diallylated indoline 7u (18%, > 95:5 dr), cyclopentaindole 1u afforded the cyclobutanecontaining indoline 8u (34%, 2:1 dr), via an intermolecular [2 + 2] annulation between the C2C3 double bond of indole and allylsilane.17 When analyzing the yields it should be taken into account that we have achieved a very rare oxidative coupling between three nucleophiles. From a mechanistic point of view, this transformation is cryptic, and several scenarios can be envisioned. Nevertheless, the formation of cyclobutane 8u could be a clue to rationalize the oxidative diallylation of N-Ac-indoles. It suggests that allylsilane and N-Ac-indole 1 could react together before any oxidation (Scheme 4). During the course of this diallylation reaction and in contrast with our previous hydroarylation (Scheme 1), no protons able to activate the C2C3 bond are generated. Therefore, the activation of the C2C3 bond by FeCl3 could be reasonably envisioned and would lead to β-silyl cation C.18 Subsequently, an intramolecular carbodemetalation would deliver cyclobutane
Scheme 2. Dearomative Allylation of Indoles
Scheme 3. Scope of the Dearomative FeCl3-Mediated Diallylation of N-Ac-indolesa
Scheme 4. Mechanistic Proposal
a Reactions conditions: 1 (0.2 mmol), allyltrimethylsilane (2 mmol), FeCl3 (1.4 mmol) in CH2Cl2 (1 mL) were stirred in a sealed vial at rt for 5 to 16 h; isolated yields of 7 as a mixture of diasteroisomers (dr are the same as the crude mixture).
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DOI: 10.1021/acs.orglett.8b00361 Org. Lett. 2018, 20, 1845−1848
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are formed, leading to three-dimensional indoline structures of high synthetic interest. The stereoselectivity of this transformation is controlled by the substitution of the indole nucleus.
8u. Formation of a terminal olefin via elimination of TMSCl from C could also occur to generate intermediate D. The diallylation reaction involves an oxidation event and FeCl3 is, indeed, an oxidant via a single-electron-transfer (SET) process.19 Allysilane could be oxidized into a radical cation E and then into an electrophilic species F,20 which can be attacked by the carbon−metal bond of D, leading to diallyl indole 7. In order to demonstrate the synthetic potential of this reaction, a few transformations of diallylated indolines 7 were investigated (Scheme 5). Ring-closing metathesis delivered
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00361. Experimental procedures, characterizations, and NMR spectra of all new compounds (PDF)
Scheme 5. Synthetic Transformations of Indolines 7
Accession Codes
CCDC 1589717 and 1811968 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Cyrille Kouklovsky: 0000-0001-5399-9469 Guillaume Vincent: 0000-0003-3162-1320 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS J.W. thanks the China Scholarship Council (CSC) for a Ph.D. fellowship. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/ 2007-2013/under REA Grant Agreement No. 623422 (IIF2013). We also gratefully acknowledge the Université Paris Sud and the CNRS for financial support. We thank the Associate Editor for his suggestions for the mechanistic proposal.
tetrahydrocarbazole derivatives 9. The stereochemistry of compounds 9a and 9m was ascertained by X-ray analysis of a crystal of 9a. Interestingly, the synthesis of the related strained trans-5,6-fused bicycles by ring-closing metathesis is uncommon.21,22 Indoline 9p bearing two contiguous quaternary stereogenic centers was obtained from the corresponding cisdiallylated indoline 7p. Hexahydrocarbazole 7r led to the aza[4.4.3]propellane 9r in which the two contiguous stereocenters hold three fused cycles.23 It should be noted that the natural products fruticosine and fruticosamine contain a related skeleton.23a The terminal double bonds of 7a could be hydrogenated into 10, while a double Heck reaction allowed phenyl groups to be introduced at each end of the two olefins to yield 11. Unexpectedly, deacetylation of N-Ac indoline 7a with concentrated chlorhydric acid was accompanied by the selective hydration of the double bond from the allyl group at C2, which delivered alcohol 12. The selective protonation of the allyl group at C2, leading to this pseudodesymmetrization, is obviously directed by the protonated nitrogen of the indoline after deacetylation or by the acetyl before deacetylation. In conclusion, we have devised an intermolecular dearomative 2,3-difunctionalization of N-Ac-indoles with allyltrimethylsilane in the presence of FeCl3. In this process, two carbon−carbon bonds and two contiguous stereogenic centers
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REFERENCES
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(14) Since we observed the formation of a gas, we decided to run the reaction in a sealed reaction vessel in order to perform the reaction under pressure and, therefore, activate the reaction. The nature of the gas which is formed during the reaction is unknown to us. (15) Determined by a NOESY experiment, a connectivity was observed between the two methyls of 7p; see the Supporting Information for details. (16) The exact reason for this switch of diastereoselectivity is not clear. It could be the consequence of the interaction between the C2substituent and the N-acyl group which should influence the conformation of the N(CO) amide bond or it could depend whether the first allylation occurs at the C2- or C3-position of the indole. (17) We have already observed such a [2 + 2] annulation of N-Acindole in the presence of FeCl3 but in the intramolecular mode; see ref 5f. (18) It is likely that the regioselectivity (C2 or C3) of the first allylation depends on the substitution at C2 and C3; for instance, see ref 5h. (19) For a review on oxidative C−C coupling with FeCl3, see: Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009, 38, 2730−2744. (20) For oxidation of allylsilanes into electrophilic allyl species, see: (a) Ochiai, M.; Arimoto, M.; Fujita, E. Tetrahedron Lett. 1981, 22, 4491−4494. (b) Yoshida, J.; Murata, T.; Isoe, S. Tetrahedron Lett. 1986, 27, 3373−3376. (21) Kotha, S.; Gunta, R. Beilstein J. Org. Chem. 2015, 11, 1373− 1378. (22) For synthesis of related trans-hexahydrocarbazoles via photocyclization of N-arylenamines, see: Chapman, O. L.; Eian, G. L.; Bloom, A.; Clardy, J. J. Am. Chem. Soc. 1971, 93, 2918−2928. (23) For the isolation of fruticosine and fruticosamine, see: (a) Torres, E.; Leiva, R.; Gazzarrini, S.; Rey-Carrizo, M.; FrigoléVivas, M.; Moroni, A.; Naesens, L.; Vázquez, S. ACS Med. Chem. Lett. 2014, 5, 831−836. For biologically active azapropellanes, see: (b) Guggisberg, A.; Hesse, M.; Von Philipsborn, W.; Nagarajan, K.; Schmid, H. Helv. Chim. Acta 1966, 49, 2321−2337.
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