Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero

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

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Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero)alkoxides Ming-Hui Zhu,†,§ Cheng-Long Yu,†,§ Ya-Lan Feng,† Muhammad Usman,† Dayou Zhong,† Xin Wang,† Nasri Nesnas,‡ and Wen-Bo Liu*,† †

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Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, Sauvage Center for Molecular Sciences, College of Chemistry and Molecular Sciences, Wuhan University, 299 Bayi Road, Wuhan, Hubei 430072, China ‡ Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, Florida 32901, United States S Supporting Information *

ABSTRACT: An efficient strategy for N/O-(deutero)alkylation of indoles and phenols with alkoxides/alcohols as the alkylation reagents is described. The consecutive detosylation/alkylation transformations feature mild reaction conditions, high ipso-selectivity, and good functional group tolerance (>50 examples). A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized. The application of this method is demonstrated by the introduction of isotope-labeled (CD3 and 13CH3) groups using the readily accessible labeled alcohols and the synthesis of pharmaceuticals.

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sotope-labeled chemicals are valuable substances with extensive applications in various fields of chemistry and life sciences.1 Due to the better stability of carbon−deuterium bonds compared with carbon−hydrogen bonds, deuterium incorporation may exhibit the potential to alter the druglike properties of the parent compounds.1,2 Given the prevalence of the NMe and OMe components in small-molecule pharmaceuticals, the synthesis of their trideuterated analogues becomes of particular importance with regard to further enhancing their biological properties, such as pharmacokinetics and pharmacodynamics, alongside their metabolic stability (Figure 1).3 Furthermore, since deuterium is the cheapest and most accessible stable isotope, deuterium-labeled internal standards remain extremely useful in trace quantitative analyses of drugs in complex mixtures.1d The most frequently used method for deuterium introduction is the alkylation of nucleophilic N and O with expensive, highly toxic, and carcinogenic reagents such as CD3I and (CD3)2SO4.4 Recent efforts on trideuteromethyl incorporation were made using the less toxic and cheaper alternatives, CD 3 OD and DMSO-d 6 , as the trideuteromethylating reagents.5−8 Bräse et al. established an acid-mediated dediazonization of triazene resins in CD3OD for the generation of D3CO-substituted arenes (Scheme 1a).5 Beller and © XXXX American Chemical Society

Figure 1. Representative (deutero)methoxy group containing bioactive pharmaceuticals.

Peruncheralathan independently reported palladium-catalyzed C−O coupling reactions of aryl halides and CD3OD for the synthesis of trideuteromethyl aryl ethers (Scheme 1b).6 Recently, an elegant strategy developed by the Chen and Wang group enabled the introduction of CD3 into various nucleophiles using trideuteromethyl sulfoxonium iodide (TDMSOI) (Scheme 1c).7 Notably, TDMSOI was prepared in situ from trimethyl sulfoxonium iodide and DMSO-d6 by Received: July 26, 2019

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DOI: 10.1021/acs.orglett.9b02639 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

(isotopically labeled) alkylation reactions, we decided to develop a practical, highly selective, and general alkylation approach using alkoxides as alkylating reagents. Successful elaboration of this process enabled us to quickly access diverse isotopically labeled functionalities (i.e., CD3 and 13CH3) using the readily available CD3OD and 13CH3OH, respectively. Additionally, a direct and selective alkylation procedure employing the unprotected indole, TsCl and an alkoxide was also demonstrated. In all of the transformations, it is noteworthy that the alkylation occurs only at the ipso-position of the tosyl group. We started our investigation using nonlabeled potassium methoxide, and the methylation was evaluated with Ntosylindole 1a as a model substrate. After careful optimization of the reaction conditions, we found that the expected product 2a was generated in excellent yield in either THF or MeCN (entry 1, Table 1, see Table S1 for details). Notably, the

Scheme 1. Trideuteromethyl Incorporations with Readily Accessible Labeling Reagents

Table 1. Investigation of Protecting Group Effects

entrya

sulfoxonium metathesis. It should be noted that installation of CD3 through carbon−carbon bond formation using DMSO-d6 and CD3OD as the CD3 sources has been realized recently as well.8 Although those methods for O-trideuteromethylation are useful, the present approaches necessitate either elevated temperatures5,7 or transition-metal catalysis6 and are generally not applicable to the N-trideuteromethylation of indoles. While the N1-position of the indole is less nucleophilic as compared to the C3-position, competition between N1- and C3-methylation pathways have been observed.9 To achieve selective N-alkylation, a handful of transition-metal-catalyzed reactions of indoles with alcohols/alkoxides has been explored.10 However, the demand for precious metals, harsh conditions, limited substrate scope, and the necessity of a large excess of deuterium reagents (usually as the solvent) are among the disadvantages of these methods. During our studies of a dehalogenative deuteration of aromatic halides,11 we unexpectedly found that 5-Br-Ntosylindole (1d) was rapidly converted into 5-Br-N-methylindole (2d) upon treatment with potassium methoxide (see Scheme S1 and Scheme 1d). Two consecutive displacement steps are involved in this transformation, namely, addition of methoxide (with R = Me for example) to the sulfonamide to generate an anionic species (I) and methyl 4-methylbenzenesulfonate (II) and a subsequent SN2 substitution reaction between II and I delivering the methylated product 2. Substrate 1 acts as a counterattack reagent12a that serves both as a leaving group in the removal of Ts and as a nucleophile for alkylated substitution. In comparison with traditional stepwise procedures that include two individual reaction preparations and purifications, the one-step counterattack method minimizes laboratory manipulation and process time while increasing yields. However, the utilities of the counterattack strategies in practical syntheses have been scarcely investigated.12b−d Eissenstat,12b Sobolov,12c and Denton12d have reported the deprotection/alkylation of indoles, albeit with limited substrate scope and with the need for harsh reaction conditions, such as temperatures above 100 °C. Based on the prior art and the prominence of

1 2 3 4

R; PG R R R R

= = = =

H; PG = Ts H; PG = PhSO2 H; PG = Tf Br; PG = Ac

2b (%)

deprotectionb (%)

2a, 92 2a, 96 2a, − 2d, −

77 20 (68)c

a

Reactions conducted with 0.2 mmol of 1, 0.4 mmol of KOMe, 0.7 mL of MeCN. bIsolated yield. cRecovered starting material.

reaction occurred at room temperature with exclusive ipsoselectivity. A variety of protecting groups on indole were then studied. Benzenesulfonyl indole was converted to the methylated product 2a smoothly in 96% yield (entry 2). However, only deprotection was observed with trifluoromethanesulfonyl (Tf) and acetyl (Ac) protected indoles (entries 3 and 4). With the optimal conditions established, the generality of this method was then investigated (Scheme 2). A variety of substituted N-tosylindoles (1b−k) were examined first. Electron-deficient (2b−e and 2j) and electron-rich (2f) C5substituted substrates smoothly delivered the corresponding products in 82−94% yields. Indoles with Br and CO2Me substituents at the C4- and C7-positions also efficiently produced the corresponding N-methylindoles (2g, 2h, and 2i) in 65−89% yields. C3- and C2-substituted indoles were found to be suitable substrates and delivered the corresponding products (2k and 2l) in 87% and 51% yields, respectively. In addition, N-methylazaindole (2m) was also synthesized in good yield (85%). Next, we applied this approach to synthesize methyl aryl ethers.13 After a quick optimization in the case of O-tosylphenol (see Table S2), the desired product 2p was isolated in 82% yield in MeCN at slightly increased temperature (45 °C). Substrates with halides, alkyl, aryl, and aryloxy groups were compatible and delivered the desired products (2n−t) in moderate to good yields. The reactions of naphthalenol- and BINOL-derived substrates gave the products 2u and 2v in 70% and 67% yields, respectively. However, Ts-protected aniline (1w) and indoline (1x) failed to give the desired products under the standard conditions probably due to their weaker leaving ability compared with B


Letter

Organic Letters Scheme 2. Substrate Scope for the Methylation.a,b

Scheme 3. Substrate Scope for the Trideuteromethylationa,b

a

Reactions conducted with 0.5 mmol of 1, 1.0 mmol of KOCD3, 2 mL of MeCN. bReactions at rt for indoles and at 45 °C for phenols. c 0.2 mmol scale.

Table S3 for optimizations). A variety of primary aliphatic, benzylic, and allylic alcohols were examined and afforded the corresponding N-alkylated products in moderate to high yields (Scheme 4). 5-Bromo-N-tosylindole reacted with primary aliphatic alcohols bearing a linear chain or a cyclic ring to give Scheme 4. Alkylation of Heteroaromatics and Phenols with Alcoholsa

a

Reactions conducted with 0.2 mmol of 1, 0.4 mmol of KOMe, 0.7 mL (for indoles) or 2 mL (for phenols) of MeCN. bReactions at rt for indoles and at 45 °C for phenols. c0.5 mmol scale. d0.08 mmol scale. e With KOMe (4 equiv).

indole. Treatment of 5-NH2-indole substrate 1y with KOMe delivered the N1-methylation product 2y in 84% yield. Notably, the free amine group (NH2) was untouched during the alkylation reaction, which provided a useful orthogonal selectivity to the alkylation with methyl iodide under basic conditions. Concurrently, in light of our interest in deuterium labeling, we explored the trideuteromethyl incorporation with KOCD3. Gratifyingly, both N- and O-trideuteromethylation reactions were achieved successfully (Scheme 3). Treatment of Ntosylindole 1a delivered the deuterated product 3a in 88% yield. Substrates bearing diverse substituents such as halides, methoxy, and methyl groups on the aromatic rings including the C7-position reacted smoothly with KOCD3 to afford the trideuteromethylated indoles (3b−i) in good to excellent yields. A range of substituted O-tosylphenols were also suitably deuterated (3j, 3k) in 46−68% yields. The good compatibility of this method with halides provided a useful synthetic handle for downstream transformation of the deuterium-containing compounds. Since indoles are quite prevalent in bioactive compounds and natural products, a highly chemoselective N-alkylation reaction enabling the installation of structurally diverse alkyl groups is of eminent significance. Thus, we also explored the alkylation of indoles with in situ formed alkoxides by mixing potassium tert-butoxide with the corresponding alcohol (see

a

Reactions conducted with 0.5 mmol of 1, 125 mg of 4 Å MS in 5 mL of THF. b0.2 mmol scale. c1.0 mmol scale. d0.4 mmol scale. C


Letter

Organic Letters

8-d was also successfully produced using the present approach with the deuterium labeled alcohol 7-d, which was readily synthesized following An’s procedure.15 In summary, we have described a practical strategy for Nalkylation of indoles and O-alkylation of phenols involving consecutive detosylation and nucleophilic substitution reactions. This environmentally friendly method employs low toxic alkoxides/alcohols as the alkylating reagents and features operationally simple procedures, mild reaction conditions, and a broad substrate scope. Other heteroaromatics, such as carbazole, pyrrole, benzoimidazole, imidazole, and pyrazole, are also compatible substrates. A selective N-alkylation of unprotected indoles with alcohols and TsCl in one pot has also been developed. For indole derivatives, the in situ deprotection/alkylation selectively and exclusively occurs at N1 versus C3 or the free NH2 substituent when present. The significance of this method is further demonstrated by the introduction of isotope labeled (deuterium and 13C) groups using the readily accessible labeled alcohols and the synthesis of (deutero)pramoxine.

products 4a−e in 67−90% yields. When terminal or internal olefinic and halogenated benzyl alcohols were used, the Nalkylated indoles (4f−i) were generated in 65−78% yields. Furthermore, nerol was also well tolerated, and the corresponding product 4j was obtained in 47% yield, which indicates that this strategy can be applied to incorporate indole segments into alcoholic natural products. Significantly, the process can be extended to other Ts-protected heteroaromatic compounds (4k−o). A series of heteroaromatics, including carbazole (4k), pyrrole (4l), benzimidazole (4m), imidazole (4n), and pyrazole (4o) all reacted with hexanol to produce the desired N-alkylated compounds in 41−84% yields. 4Aryloxyphenol was also tested under the alkylation conditions to afford product 4p in moderate yield. Remarkably, the in situ alkoxide formation strategy is applicable to the isotope labeling of indoles (3d and 3f) and phenols (3l and 3m). Previously reported trideuteromethylation methods were commonly conducted with CD3OD as the solvent.5,6 Our chemistry only required 1.1 equiv of CD3OD and resulted in the formation of labeled product in moderate to good yields. In particular, the use of only stoichiometric amounts of labeling reagent is attractive for introducing the costly isotope such as carbon-13 as demonstrated by the synthesis of 13CH3-indole 3d’. Considering that the above procedures require the preinstallation of a tosyl group, we pondered means to simplify the process through a one-pot protocol from unprotected indoles (Scheme 5a). Treatment of 5-bromo-1H-indole

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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.9b02639. Experimental details, characterization and spectra of new compounds (PDF)

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Scheme 5. (a) One-Pot Alkylation of Unprotected Indoles and (b) Synthetic Applications

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Muhammad Usman: 0000-0003-4301-7315 Nasri Nesnas: 0000-0003-3511-940X Wen-Bo Liu: 0000-0003-2687-557X Author Contributions §

M-H.Z. and C.-L.Y. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the NSFC (21772148, 21602160), the Fundamental Research Funds for the Central Universities (2042018kf0017, 2042019kf0208), National Program for 1000 Young Talents of China, and Wuhan University for financial support. Mrs. Hengzhao Li, Xiangdi Zeng, and Prof. Jie An (China Agriculture University) are thanked for the donation of compound 7-d and for helpful discussions.

directly with TsCl, KOtBu, and hexanol led to the reaction exclusively at the nitrogen in 72% yield. The generality of the one-pot procedure was further corroborated by the reactions employing 3-phenylpropanol (4c), cyclopropylmethanol (4e), and (4-bromophenyl)methanol (4g), albeit with slightly diminished yields compared with the alkylation using tosylated indoles, shown in Scheme 4. The importance of this method was further demonstrated by the synthesis of pharmaceuticals (Scheme 5b). The reaction of 3-morpholinopropanol 7 and compound 6 delivered the anesthetic and antipruritic agent 8 in 62% yield. Since ether 6 was readily synthesized from commercially available 4butoxyphenol, and alcohol 7 is also readily accessible, this method provided a straightforward and transition-metal-free synthetic alternative for pramoxine.14 Its deuterated variation

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REFERENCES

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Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero

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