Iron-Catalyzed Regiospecific Intermolecular Radical Cyclization of

Letter Cite This: Org. Lett. 2018, 20, 1404−1408

pubs.acs.org/OrgLett

Iron-Catalyzed Regiospecific Intermolecular Radical Cyclization of Anilines: Strategy for Assembly of 2,2-Disubstituted Indolines Yang Ni, Qile Yu, Qihao Liu, Honghua Zuo, Huai-Bin Yu, Wen-Jie Wei, Rong-Zhen Liao, and Fangrui Zhong* Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, China S Supporting Information *

ABSTRACT: The first regiospecific catalytic intermolecular assembly of 2,2-disubstituted indolines has been developed. This protocol is based on a ligand and directing group free, iron-catalyzed radical [3 + 2] process, allowing efficient coupling of different N-sulfonylanilines with various αsubstituted styrenes. Preliminary mechanistic studies elucidated the radical mechanism involving a reactive and versatile anilino radical and the importance of iron complex as a Lewis acid, rendering both the reactivity and regiospecificity of this transformation.

I

Scheme 1. Strategies for Assembling Indoline Scaffolds from Anilines

ndole and indolines are privileged structures in many natural alkaloids and biologically active pharmaceuticals. Among them, gem-disubstituted indolines are particularly interesting because of their strong bioactivity profiles, as seen in representative examples such as kopsinine, strempeliopine, and vallesamidine (Figure 1).1 Given the inherent arylamino

Figure 1. Examples of biologically active gem-disubstituted indolines.

functionality and availability of anilines, they have been extensively used in the preparation of indoline alkaloids. Due to significant steric demand, gem-disubstituted indoline skeletons are constructed dominantly via intramolecular cyclization of ortho-functionalized anilines (Scheme 1a).2 Intermolecular [3 + 2] coupling reactions of anilines with alkenes are also well-known.3 However, they are generally realized through directing group-assisted noble metal catalysis (e.g., Pd, Rh, and Ru) and not applicable for preparing gemdisubstituted indolines (Scheme 1b). Therefore, it remains a formidable synthetic task to access such structural motifs via catalytic intermolecular cyclizations. To the best of our knowledge, the only known study in this regard was disclosed by Menéndez on the synthesis of hexahydropyrrolo[3,2b]indoles through an InCl3-catalyzed domino reaction in moderate yield and selectivity.4 © 2018 American Chemical Society

Nitrogen-centered radicals (NCRs) are highly useful intermediates due to their versatile reactivity in constructing C−N bonds and accessing various amines derivatives and nitrogen-containing heterocycles.5 Among different NCRs, Received: January 17, 2018 Published: February 22, 2018 1404

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us to test our proposal of intermolecular annulative radical coupling reactions between anilines and alkenes (Table 1).

anilino radicals are particularly interesting due to interactions of the single electron with the aromatic ring. Early studies using time-resolved resonance Raman spectroscopy revealed that the C−N bond in anilino radicals has considerable double-bond character, which endows them with unique reactivity.6 Despite significant advances on NCRs over the past few decades, synthetic values of anilino radicals species are still poorly appreciated7 due to two major problems: (1) the dearth of convenient routes for their generation under mild conditions and (2) their strong propensity to undergo unselective dimerization8 or oligomerization into so-called “aniline black”.9 In this context, the emergence of visible-light photoredox and electrochemical methods in recent years has boosted the synthetic utility of anilino radicals.10−12 However, these protocols are largely restricted to intramolecular transformations as well as limited substrate scope. As such, the call for new strategies allowing efficient formation of anilino radical species for selective intermolecular reactions is urgent. We envisioned that electrophilic anilino radicals13 could be formed under oxidative conditions14 and render a practical intermolecular [3 + 2] cyclization with nucleophilic α-substituted alkenes to build gem-disubstituted indolines (Scheme 1c). In this design, a two-point functionalization of both N−H and ortho-C−H bonds of anilines is involved, which is potentially associated with an issue of regioselectivity. Inspired by reported studies,10 we speculated that the presence of an electron-withdrawing protecting group at nitrogen atom might be helpful in manipulating reactivity and selectivity of neutral anilino radicals. Although DDQ is known to undergoes a facile hydrogen abstraction from unprotected anilines to yield anilino radical,8d the same process remained mysterious for Nacylanilines. To make a quick examination, different Nacylanilines 1a−e were prepared and treated with DDQ in toluene, followed by EPR spectroscopic analysis (Figure 2). A

Table 1. Optimization of Conditions for [3 + 2] Cyclizationa

entry

1

cat.

c

1c 1c 1c 1c 1c 1c 1b 1d 1e 1c 1c 1c 1c 1c 1c 1c 1c 1c

AlCl3 BF3•OEt Zn(OTf)2 Sc(OTf)3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3 FeCl3

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e 16 17 18

oxidant

additive

yieldb (%)

3 Å MS NaHCO3 Na2CO3 K2CO3

NR 22 5 8 trace 69 NR NR trace NR 18 20 21 70 75 76 87 trace

DDQ DDQ DDQ DDQ DDQ DDQ DDQ DDQ DDQ chloranil PIFA BPO DDQ DDQ DDQ DDQ DDQ

a Reactions were performed with 1 (0.2 mmol), 2a (0.6 mmol), catalyst (10 mol %), oxidant (0.24 mmol), additive (0.1 mmol) in toluene (5 mL) at 60 °C for 24 h under N2. bIsolated yield. cAt room temperature or 100 °C. dFeCl3·6H2O was used instead of FeCl3. e10 mg of 3 Å molecular sieves was added.

Nucleophilic α-alkylstyrene 2a was first selected as the reaction partner in order to prepare gem-disubstituted indolines. Unfortunately, the first set of experiments with 1c, 2a, and DDQ afforded only unreacted starting materials (entry 1). Inspired by some reported catalytic radical reactions,13,14 we speculated that a Lewis acid might be helpful to catalyze this process. Accordingly, effects of various Lewis acids, including AlCl3, BF3·OEt, Zn(OTf)2, Sc(OTf)3, and FeCl3, were evaluated (entries 2−6). Pleasingly, a beneficial influence was observed for most of them, and FeCl3 was found to be the best choice. To our surprise, the major product was identified to be 3a, and its regioisomer 3a′ was not detected. This regiospecificity suggested a preference of C-radical over the N-radical for the addition to 2a. Under identical reaction conditions, no reaction took place with either sulfonamide 1b or amide 1d, and poor conversion was recorded with carbamate 1e (entries 7−9). These results agreed well with EPR spectra in Figure 2. A control experiment showed DDQ was indispensable for this process, which was also proven to be superior to other oxidants such as Chloranil, PIFA, and BPO (entries 10−13). Notably, almost the same results were obtained for aniline 1c when hydrated FeCl3 or nonanhydrous toluene was used, while the presence of 3 Å molecular sieves gave an appreciably better result. We thus speculated that the basicity of molecular sieve might be beneficial for this catalytic event rather than its desiccative nature. Such a presumption was proved by examining the effect of different bases, and Na2CO3 turned out to be the best additive (see the Supporting Information).

Figure 2. EPR spectra of different anilines treated with DDQ in toluene.

strong EPR signal was observed for aniline 1a, implying the formation of a radical species. However, N-Ts aniline 1b exhibited an extremely weak signal. The higher bond dissociation energy (BDE) of 1b NH (ca. 93.2 kcal/mol) than 1a (89.7 kcal/mol) might account for such disparity.15 Along this line, p-methoxyaniline sulfonamide 1c with a lower BDE15c was examined, and it indeed displayed a much stronger EPR signal. These results suggest that the reactivity of hydrogen abstraction agrees well with the BDE of their NH bonds, which also explains the inconspicuous signals of amide 1d and carbamate 1e with larger BDE.15c The above EPR studies confirmed that DDQ enables oxidation of aniline 1 into radical species, which encouraged 1405

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limited availability of differently substituted anilines, attempts to make further variations of their aryl moiety were not undertaken. An array of other sulfonyl groups, such as mesyl, nosyl, and naphthylsulfonyl groups, were all well tolerated under the standard reaction conditions, yielding indolines 3w− y in consistently high yields. A gram-scale experiment (3a) showcased the scalability of this cyclization reaction, and the structure of product 3y was further confirmed by X-ray crystallography (see the SI). Mechanistically, EPR studies described above implied that reaction is likely initiated by N−H hydrogen abstraction to generate a N-centered neutral radical A (Scheme 3). On the

After further optimization of solvents and temperature (see the SI), the optimal conditions were identified to perform the reaction in toluene at 60 °C, and indoline 3a was isolated in 87% yield (entry 17). Subsequently, the substrate scope for this FeCl3-catalyzed intermolecular radical [3 + 2] cyclization was investigated (Scheme 2). Pleasingly, good to high yields were recorded for a Scheme 2. Scope of FeCl3-Catalyzed Intermolecular [3 + 2] Cyclization of N-Sulfonylaniline 1 with α-Methylstyrenea,b

Scheme 3. Plausible Reaction Mechanism

a

other hand, comparison of the redox potentials (Ep/2 vs SCE in MeCN) of FeCl3 (1.63 V) and 2a (1.85 V) rules out the pathway triggered by single-electron oxidation of 2a to form a radical cation. The electrophilicity of anilino radical A is probably not sufficient to attack styrene 2a,7d whereas activation by iron renders the addition possible. The role of iron as a Lewis acid was also clarified by the positive outcome using BF3·OEt and Zn(OTf)2 (Table 1, entries 3 and 4). As a consequence of coordination, steric hindrance round nitrogen atom makes attack from a carbon radical B to 2a more favored. The subsequent cyclization takes place likely through either a concerted radical cyclization transition state C or a stepwise addition involving a tertiary carbon radical D. To clarify it, a radical clock styrene 2b was used as the substrate, which turned out to produce indoline 3z in 23% yield (eq 1). Meanwhile, a possible N-alkylated olefin side product16 from ring-opening of cyclopropylmethyl moiety was detected. This result suggests that even if a concerted cyclization via C was not operative, an alternative pathway via stepwise addition of radical D to imine nitrogen should be extremely fast. Carbon radical E was consequently generated, wherein the cleavage of ortho-C−H bond might be the rate-determining step as the respective kinetic isotope effect (KIE) was significant (kH/kD = 5.7).17 Product 3a was furnished by the rearomatization of the phenyl ring with concurrent release of FeCl3. Despite an ambiguous cyclization scenario at this stage, it is evident that reaction involves the formation of N-centered radical A and FeCl3 as a Lewis acid catalyst is indispensable for this radical process. Such a presumption was further evidenced by control experiments that TEMPO and BHT as radical scavengers inhibited the reaction to a great extent (see the SI). As HDDQH is

For reactions conditions, see Table 1, entry 17. bIsolated yield.

broad range of α-methylstyrenes with diversely substituted phenyl rings, giving indolines 3a−h in 69−87% yields. Both αunbranched and branched alkylstyrenes possessing simple linear alkyl substituents of different lengths and isobutyl or isopropyl groups proved to be suitable substrates, and indolines 3i−m were accordingly isolated (62−91%). We then moved forward to test the applicability of α-arylstyrenes, as such a special class of substrates would give rise to 2,2-diarylindolines with significant steric demand that are rarely accessible. To our delight, cyclizations proceeded equally well, and isolated yields of products 3n−r were highly independent of the substitution pattern of their phenyl rings (60−70%). Moreover, despite not being the focus, simple styrenes were also found to be good substrates, as demonstrated by the synthesis of indoline 3s (88%). This entry also shows the excellent chemoselectivity of this oxidative catalysis as no overoxidation product (i.e., indole) was detected. Furthermore, when 3-chloro-, 3-methyl-, and 3fluoro-substituted N-tosylanilines were used, indolines 3t−v were also furnished in good yields (64−86%). Due to the 1406

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Organic Letters Accession Codes

accumulated in this process, Na2CO3 probably plays a role to neutralize this adverse acidic side product and improve catalytic efficiency. However, too strong base (e.g., K 2CO3) is deleterious because of the favored deprotonation of NH in competition to hydrogen abstraction by DDQ and consequently interrupts the cyclization (entry 18, Table 1). The removal of tosyl group was accomplished by treating 3a with Red-Al in toluene to afford deprotected indoline rac-4a in 67% yield. 2,2-Disubstituted indolines own significant synthetic value in medicinal chemistry. As an illustration, rac-4a was coupled with sodium 2-(4-morpholino-6-oxo-1,6-dihydropyrimidin-2-yl)acetate 6,18 furnishing compound 7 in 61% yield (Scheme 4a). Such a pyrimidone−indoline amide skeleton has

CCDC 1814106 contains 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 data_ [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

Rong-Zhen Liao: 0000-0002-8989-6928 Fangrui Zhong: 0000-0003-2150-370X

Scheme 4. Synthetic Applications

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21602067) for financial support and are also grateful to the Analytical and Testing Centre of HUST and Testing Centre of School of Chemistry and Chemical Engineering (HUST) as well as 100 Talents Program of the Hubei Provincial Government. Prof. Y. Gong (HUST) is acknowledged for helping with cyclic voltammetry studies.

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(1) (a) Bobeck, D. R.; Lee, H. I.; Flick, A. C.; Padwa, A. J. Org. Chem. 2009, 74, 7389. (b) Subramaniam, T. S.; Kam, G.; Yoganathan, K. M.; Sim, K.; Koyano, T.; Toyoshima, M.; Rho, M. C.; Hayashi, M.; Komiyama, K. Bioorg. Med. Chem. Lett. 1998, 8, 2769. (c) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798. (2) For a review, see: (a) Liu, D. Y.; Zhao, G. W.; Xiang, L. Eur. J. Org. Chem. 2010, 2010, 3975. For selected examples, see: (b) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250. (c) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732. (d) Jiang, L.; Xu, R.; Kang, Z.; Feng, Y.; Sun, F.; Hu, W. J. Org. Chem. 2014, 79, 8440. (e) Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C. J. Angew. Chem., Int. Ed. 2014, 53, 5170. (f) Ye, L.; Lo, K.-Y.; Gu, Q.; Yang, D. Org. Lett. 2017, 19, 308. (g) Reddy, A. C. S.; Choutipalli, V. S. K.; Ghorai, J.; Subramanian, V.; Anbarasan, P. ACS Catal. 2017, 7, 6283. (3) For leading references, see: (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. (b) Gao, Y.; Huang, Y.; Wu, W.; Huang, K.; Jiang, H. Chem. Commun. 2014, 50, 8370. (c) Zhao, D.; Vásquez-Cés-pedes, S.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 1657. (d) Manna, M. K.; Hossian, A.; Jana, R. Org. Lett. 2015, 17, 672. (e) Manna, M. K.; Bhunia, S. K.; Jana, R. Chem. Commun. 2017, 53, 6906. (4) (a) Sridharan, V.; Ribelles, P.; Estévez, V.; Villacampa, M.; Ramos, M. T.; Perumal, P. T.; Menéndez, J. C. Chem. - Eur. J. 2012, 18, 5056. For related work using stoichiometric amount of hypervalent iodine reagents, see: (b) Kita, Y.; Tohma, H.; Watanabe, H.; Takizawa, S.; Maegawa, T. Heterocycles 1999, 51, 1785. (5) For selected reviews, see: (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Höfling, S.; Heinrich, M. Synthesis 2011, 2011, 173. (c) Quiclet-Sire, B.; Zard, S. Z. Beilstein J. Org. Chem. 2013, 9, 557. (6) (a) Tripathi, N. R.; Schuler, R. H. Chem. Phys. Lett. 1984, 110, 542. (b) Tripathi, G. N. R.; Schuler, R. H. J. Chem. Phys. 1987, 86, 3795. (7) (a) Forrester, A. R.; Ingram, A. S.; Thomson, R. H. J. Chem. Soc., Perkin Trans. 1 1972, 2847. (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem.

been well investigated as PI3Kβ (a subclass of phospholipid kinases family) inhibitors for the treatment of phosphatase and tensin homologue-deficient cancers.19 In light of the excellent tolerance of sulfonyl groups in the present system, optically pure (+)-10-camphorsulfonylaniline 1f was employed (Scheme 4b), yielding a pair of epimers 8 (55%) and epi-8 (24%). The major one was further deprotected by Red-Al to yield enantiomerically enriched chiral indoline ent-4a (97% ee). In summary, we have developed the first regiospecific catalytic intermolecular assembly of 2,2-disubstitued indolines by coupling in situ formed anilino radical species with αsubstituted styrenes. Mechanistic studies elucidate the radical mechanism and the importance of iron catalyst as a Lewis acid, rendering both the reactivity and regiospecificity of these reactions. The synthetic value of our method has been demonstrated in the synthesis of a PI3Kβ inhibitor analogue and an optically pure indoline. Given the many advantages of iron catalysis,20 we believe our protocol will find broad utility in synthesizing valuable indoline alkaloids. Additional interest in this cyclization stems from the possibility of using a chiral Lewis acid to induce stereoselectivtiy and deserves further in-depth investigation.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00176. Experimental procedures, analytical data for all new compounds, details of mechanistic studies, NMR spectra of the products, crystal data (3y) (PDF) 1407

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