Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles from Oxindoles via Indole Intermediates Tirtha Mandal, Gargi Chakraborti, Shilpi Karmakar, and Jyotirmayee Dash* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India

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S Supporting Information *

ABSTRACT: The previously unexplored Grignard addition to oxindoles provides a regiospecific approach to 2- and 2,3disubstituted indole derivatives in high yields via a one-pot aromatization driven dehydration pathway. This method allows a convenient preparation of diallyl indoles that are used as ring-closing metathesis (RCM) precursors for the orthogonal synthesis of pyrido[1,2-a]indoles and carbazoles. The synthetic utility of this method is illustrated by the synthesis of a microtubulin inhibitor and naturally occurring carbazole alkaloids.

I

Scheme 1. Regiospecific Synthesis of Indole Derivatives and Modular Construction of Carbazoles and Pyridoindoles

ndole is a fundamental structural unit in organic chemistry that is present in a myriad of natural products, pharmaceutical agents, and advanced materials.1 In addition to the classical Fischer indole synthesis,2 a large number of methods are known for the synthesis of substituted indoles.3,4 Despite these advances, the development of a modular and regiospecific approach to substituted indoles is of considerable interest. Herein, we disclose a regiospecific synthesis of indole derivatives, which are used as intermediates for the construction of indole-fused saturated and unsaturated pyrido[1,2-a]indoles5,6 and carbazoles (Scheme 1).4a,7−9 Owing to their prevalence in natural products and biologically active molecules,5,7 the development of practical and scalable synthetic approaches for indole-fused heterocyclic scaffolds is desirable. We commenced our studies with the regiospecific synthesis of indole derivatives from oxindoles (Scheme 1). Previously, Lu et al. and Furman et al. reported regiospecific synthesis of 2,3disubstituted indoles utilizing the differential electrophilicity of the two carbonyl groups of isatins.10 These methods are useful only for the synthesis of disubstituted indoles. However, the synthesis of 2,3-diallyl indoles and C3-allyl-containing disubstituted indoles remains a formidable challenge (Scheme 1).11 We envisioned that Grignard addition of oxindole might provide a novel route to 2-substituted as well as 2,3-disubstituted indoles via a one-pot dehydrative aromatization protocol, enabling the synthesis of 2,3-diallyl indoles as well as disubstituted indoles containing a C3 allyl group that could be used as precursors for olefin metathesis (Scheme 1). While much attention has been paid to the functionalization of the C3 carbon of oxindoles,12 the reactivity of the C2 carbonyl group has been far less explored.10,11a,13 Recently, we have used an allyl metal addition to isatins to obtain diallyl oxindoles that are used for the synthesis of carbazoles via ring-closing metathesis14,15 (RCM) and ring rearrangement aromatization © XXXX American Chemical Society

(Scheme 1).16 Considering the structural features of pyriodoindoles 7 and carbazoles 8, we anticipated that the C2, C3, and N1 positions of oxindole could be utilized for the diversity oriented synthesis (DOS)17 of these two classes of tricyclic ring Received: June 12, 2018

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DOI: 10.1021/acs.orglett.8b01827 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters systems in an orthogonal manner by RCM of diallyl indole precursors 3 and 4 followed by aromatization (Scheme 1). In order to examine the feasibility of our proposed approach, a variety of N-allyl 2-oxindoles 1 were prepared from different Nallyl isatin derivatives (see Supporting Information, Schemes S1−S2). We were delighted to observe that the reaction of Nallyl oxindole 1a with allylmagnesium bromide in THF at room temperature led to the formation of 2-allyl indole derivative 3a in 86% yield (Scheme 2). We then explored the scope and

Scheme 3. Regiospecific Synthesis of 2,3-Disubstituted Indolesa,b

Scheme 2. Synthesis of 2-Substituted Indolesa,b

a

The addition of allylmagnesium bromide (3 equiv, 1 M in Et2O) to 1 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at rt for 3 h. b The addition of alkyl or arylmagnesium bromide (5 equiv, 1 M in Et2O) to 1 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at 70 °C for 6 h. a

The addition of allylmagnesium bromide (3 equiv, 1 M in Et2O) to 2 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at rt for 3 h. b The addition of alkyl or arylmagnesium bromide (5 equiv, 1 M in Et2O) to 2 (2.0 mmol, 1 equiv) was carried out in THF (10 mL) at 70 °C for 6 h.

generality of this approach with respect to oxindoles and Grignard reagents. Various oxindoles having both electron-rich and -withdrawing groups bearing different N-substituents afforded the corresponding 2-allyl indole derivatives 3a−o in excellent yields. Although the reactions with alkyl or aryl Grignard reagents were slow at room temperature, impressive results were obtained at 70 °C, affording 2-substituted alkyl or aryl indole derivatives 3p−s in good yields (Scheme 2). It is important to mention that there is a lack of general and efficient method(s) for the preparation of 2-allyl indoles, and only recently the synthesis of 2-allyl indoles has been achieved by using protecting group directed transition metal catalyzed18 reactions. In this context, our strategy provides a practical access to 2-substituted indoles, particularly 2-allyl indoles in a one-pot operation. Next we carried out the Grignard reaction with C3substituted 2-oxindoles 2 (Schemes S3−S7). The allyl Grignard reaction proceeded smoothly at room temperature affording the corresponding 2,3-disubstituted indoles 4a−o in excellent yields with broad functional group tolerance (Scheme 3). The disubstituted indole derivatives 4f, 4g, and 4a′ containing a C3 indolyl group, a pyrrolidine ring with a bulky substituent, and a phenylethynyl group, respectively, were synthesized in good yields. As expected, the addition of alkyl or aryl Grignard reagents proceeded at high temperature (70 °C) giving the products 4p−4b′ in good to high yields. The disubstituted indole derivative 4b′ containing a bulky mesityl group at C2 position was obtained in 60% yield. The synthesis of 2,3-disubstituted indoles generally involves annulation of an azacycle to an existing aromatic ring, leading to the formation of regioisomeric mixtures. Recently, Nakamura and co-workers have reported a regioselective method for the synthesis of disubstituted indoles via cyclative formation of 2,3dizincioindoles.11b By using the literature methods,10 it is possible to prepare neither the 2,3-disubstituted dihydroxy

oxindole derivative (I) containing a C3 allyl group nor the C3 allyl iminium ion (II) as C3 allyl migration takes place readily in both cases under the reaction conditions (Scheme 4). We Scheme 4. Proposed Aromatization-Driven Dehydration Pathway with Insight to the Formation of 2,3-Diallyl and C3 Allyl-Containing Disubstituted Indoles

reported that the addition of allyl Grignard reagents to isatins provides the rearranged 2,2-diallyl 3-oxindole derivatives (III) instead of the diallyl dihydroxy oxindole derivatives (I; when R3 = allyl) (Schemes 1 and 4).16 Based on the above results and previous reports, we presume that Grignard reaction of 2oxindoles proceeds with the formation of intermediate A, which upon workup generates the indolinium ion intermediate B. Subsequently, aromatization of the intermediate B by deprotonation provides indole derivatives 3 and 4. The intermediate A upon workup may also directly lead to indoles via dehydrative aromatization (Scheme 4). B

DOI: 10.1021/acs.orglett.8b01827 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters To demonstrate the synthetic potential of this transformation, we synthesized a 2,3-disubstituted indole derivative 11, an inhibitor of microtubulin polymerization.19 The addition of 4methoxyphenylmagnesium bromide to the oxindole 2u (Scheme S12, SI) afforded the required disubstituted indole derivative 9. The deprotection of the N-benzyl group followed by DDQ-mediated C3 methyl oxidation furnished the target compound 11 in 54% overall yield (Scheme 5).

Scheme 7. (a) Synthetic Applications of Dihydro-pyridoindole Derivatives 5 and (b) Natural Products Containing a Tetrahydro-pyrido-indole Ring

Scheme 5. Synthesis of Microtubulin Inhibitor

In order to validate our design strategy (Scheme 1), we used diallyl indoles 3 and 4 for the orthogonal synthesis of fused nitrogen-containing heterocycles using RCM. Various orthogonal approaches have been reported for the efficient construction of heterocyclic ring systems.20 In this approach, the RCM of 1,2-diallyl indolyl derivatives 3a−n and 4a−f with 10 mol % of Grubbs’ first-generation catalyst (G-I)21 in CH2Cl2 at room temperature provided the desired dihydro-pyridoindole derivatives 5 in excellent yields (Scheme 6). The halo

could be successfully achieved to obtain the corresponding products 12a−b, 13, and 14 in excellent yields (Scheme 7). The tetrahydro-pyrido-indole derivatives 12 are important scaffolds in synthetic organic chemistry, and many natural products such as goniomitine,23a tronocarpine,23b vincamine,23c and mitosenes23d contain this motif in their molecular structures. Only a limited number of methods are known for accessing this heterocyclic ring system, and most of the methods involve multisteps and extensive prefunctionalization as well as demand selective hydrogenation of the fully aromatic pyridoindole core.6,24 Our method, which starts from simple precursors, is amenable to variations and should prove valuable for the synthesis of an array of highly functionalized pyridoindole derivatives. On the other hand, the cyclization of 2,3-diallyl indolyl derivatives 4h−o with catalyst G-I (10 mol %) provided dihydrocarbazole derivatives 6a−h in excellent yields (Scheme 8). The dihydrocarbazole derivatives were efficiently aromatized to the corresponding carbazole derivatives 8a−h by oxidation with 100 mol % DDQ at room temperature (Scheme 8). Under similar conditions, 6g afforded 8g via aromatization as well as C5

Scheme 6. Ring-Closing Metathesis of 1,2-Diallyl Indole Derivativesa

Scheme 8. Synthesis of Carbazole Derivatives by RCM and Aromatizationa,b

a

The reactions were performed using of 3 or 4 (0.3 mmol, 1 equiv) and G-I catalyst (10 mol %) in CH2Cl2 (4 mL) at rt for 8 h. bThe reaction was performed using 4f (0.3 mmol, 1 equiv) with G-II catalyst (5 mol %) in CH2Cl2 (4 mL) at rt for 12 h.

dihydro-pyrido-indoles 5f−i can be applied for cross-coupling reactions. Compound 5o containing a C3-indolyl substituent was prepared by using 5 mol % of Grubbs’ second-generation catalyst (G-II)22 in 74% yield. The presence of the isolated double bond makes these dihydro-pyrido-indole derivatives attractive intermediates for further transformations (Scheme 7). The DDQ-mediated aromatization of compounds 5 provided heteroaromatic pyrido[1,2-a]indole derivatives 7a−h in good yields. Under similar conditions, 5j afforded 7g via aromatization as well as benzylic oxidation. The chemoselective reduction, isomerization, and selective hydroxylation of the double bond

a

The reactions were performed using 4 (0.3 mmol, 1 equiv) and G-I catalyst (10 mol %) in CH2Cl2 (4 mL) at rt for 8 h. bThe reactions were performed using 6 (0.2 mmol, 1 equiv) with DDQ (100 mol %) in EtOAc (3 mL) at rt for 8 h.

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DOI: 10.1021/acs.orglett.8b01827 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

the resulting diallyl indolyl precursor 21 afforded the dihydrocarbazole derivative 22 in 81% yield. DDQ-mediated aromatization followed by debenzylation produced glycozoline27b−d 24 in 56% overall yield. BBr3-mediated demethylation of 24 afforded glycozolinol27a 25 (Scheme 10). Further, our method was used to obtain 2-hydroxy-3methylcarbazole 28, a common intermediate for the synthesis of a library of carbazole alkaloids.28 The allyl Grignard addition to oxindole 2y (Scheme S23, SI) and RCM of the resulting dialkene precursor 26 followed by DDQ-mediated aromatization provided the N- and O-benzyl-protected carbazole derivative 27. The hydrogenolysis of 27 provided 28, which was subsequently used for the synthesis of girinimbine, murrayacine, and euchrestifoline. Knölker and co-workers reported the synthesis of euchrestifoline by cyclization of the free −OH group of the Buchwald adduct followed by one-pot C−C bond formation−Wacker oxidation.29 Subsequently, LiAlH4-mediated dehydration of euchrestifoline provided girinimbine.29 In this work, girinimbine 30 was directly obtained via the cyclization of 28 with prenal 29 using titanium isopropoxide.28a The DDQ-mediated oxidation of girinimbine 30 provided murrayacine28a,30 31, and the Wacker oxidation of girinimbine produced euchrestifoline 32 in excellent yields (Scheme 10). In conclusion, we have developed a dehydrative aromatization protocol for the synthesis of substituted indole derivatives from readily available oxindole derivatives. Importantly, this method provides an efficient access to otherwise inaccessible 2-allyl and 2,3-disubstituted symmetrical or unsymmetrical diallyl indole derivatives. These diallyl indoles have been used as ring-closing metathesis precursors for the synthesis of an array of indolefused heterocycles such as carbazoles, pyrido[1,2-a]indoles, and the challenging dihydro and tetrahydro pyrido[1,2-a]indole derivatives. Moreover, we have applied this chemistry to a concise synthesis of a microtubulin inhibitor and carbazole alkaloids. This work highlights Grignard addition to substituted 2-oxindoles as a tool for generating otherwise difficult nitrogencontaining heterocycles using simple organic transformations.

methyl oxidation. The carbazole derivatives having remote C4Me or Ph substituents (8c and 8d) could be easily prepared using our protocol.25 These results validate our previous hypothesis that carbazole derivatives can be synthesized from isatins by using RCM and aromatization of 2,3-diallyl indolyl precursors.16 The optimized reaction sequence was then employed for the synthesis of dimeric pyridoindole and carbazole derivatives (Scheme 9). The allyl Grignard addition to oxindole precursors Scheme 9. Synthesis of Dimeric Pyridoindole and Carbazole Derivatives

2v and 2w (Schemes S20 and S21, SI) furnished the corresponding dimeric 1,2- and 2,3-diallyl indoles 15 and 18 in excellent yields. RCM of these dimeric dialkenes produced dihydro-pyrido-indole 16 and dihydrocarbazole 19, which underwent smooth aromatization to provide indole-fused dimeric heterocycles 17 and 20 in high yields. The utility of our method was further illustrated by the straightforward synthesis of carbazole natural products such as glycozoline, glycozolinol, girinimbine, murrayacine, and euchrestifoline (Scheme 10). These carbazole alkaloids exhibit a wide range of pharmacological activities.26 The allyl Grignard addition of oxindole 2x (Scheme S22, SI) followed by RCM of

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Scheme 10. Synthesis of Naturally Occuring Carbazole Alkaloids

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01827. Experimental procedures and the copies of 1H NMR and 13

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C NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jyotirmayee Dash: 0000-0003-4130-2841 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS J.D. thanks DST for a SwarnaJayanti fellowship. This work was supported by DST and CSIR-India for funding. T.M., G.C., and S.K. thank CSIR, India, for research fellowships. D

DOI: 10.1021/acs.orglett.8b01827 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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DOI: 10.1021/acs.orglett.8b01827 Org. Lett. XXXX, XXX, XXX−XXX